WO2003026629A2 - Modified release dosage forms - Google Patents

Modified release dosage forms Download PDF

Info

Publication number
WO2003026629A2
WO2003026629A2 PCT/US2002/031117 US0231117W WO03026629A2 WO 2003026629 A2 WO2003026629 A2 WO 2003026629A2 US 0231117 W US0231117 W US 0231117W WO 03026629 A2 WO03026629 A2 WO 03026629A2
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
core
shell
active ingredient
coating
Prior art date
Application number
PCT/US2002/031117
Other languages
French (fr)
Other versions
WO2003026629A3 (en
Inventor
Der-Yang Lee
Shun-Por Li
Harry S. Sowden
Martin Thomas
David Wynn
Original Assignee
Mcneil-Ppc, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/966,497 external-priority patent/US7122143B2/en
Priority claimed from US09/966,450 external-priority patent/US6982094B2/en
Priority claimed from US09/967,414 external-priority patent/US6742646B2/en
Priority claimed from US09/966,939 external-priority patent/US6837696B2/en
Priority claimed from US09/966,509 external-priority patent/US6767200B2/en
Priority to JP2003530266A priority Critical patent/JP2005535558A/en
Priority to US10/476,530 priority patent/US8545887B2/en
Priority to EP02799689A priority patent/EP1438030A2/en
Priority to BR0213588-4A priority patent/BR0213588A/en
Priority to MXPA04002979A priority patent/MXPA04002979A/en
Priority to CA002461684A priority patent/CA2461684A1/en
Priority to KR10-2004-7004656A priority patent/KR20040045030A/en
Application filed by Mcneil-Ppc, Inc. filed Critical Mcneil-Ppc, Inc.
Priority to JP2004539769A priority patent/JP2006517182A/en
Priority to KR1020057005195A priority patent/KR100995486B1/en
Priority to EP03714356A priority patent/EP1551374B1/en
Priority to CN03823065.8A priority patent/CN1684671A/en
Priority to EP03716788A priority patent/EP1545452A1/en
Priority to AU2003225945A priority patent/AU2003225945B2/en
Priority to ES03798655T priority patent/ES2355233T3/en
Priority to CA002499955A priority patent/CA2499955A1/en
Priority to MXPA05003281A priority patent/MXPA05003281A/en
Priority to AU2003220472A priority patent/AU2003220472A1/en
Priority to AT03798655T priority patent/ATE490764T1/en
Priority to PCT/US2003/008847 priority patent/WO2004028511A1/en
Priority to AT03714356T priority patent/ATE444739T1/en
Priority to NZ538842A priority patent/NZ538842A/en
Priority to US10/393,610 priority patent/US20030219484A1/en
Priority to AU2003225944A priority patent/AU2003225944A1/en
Priority to CA2500313A priority patent/CA2500313C/en
Priority to JP2004539767A priority patent/JP2006517514A/en
Priority to US10/393,764 priority patent/US20030229158A1/en
Priority to BR0314547-6A priority patent/BR0314547A/en
Priority to AU2003220479A priority patent/AU2003220479A1/en
Priority to RU2005108608/15A priority patent/RU2005108608A/en
Priority to CA002500312A priority patent/CA2500312A1/en
Priority to JP2004539770A priority patent/JP2006517183A/en
Priority to US10/393,638 priority patent/US20030232082A1/en
Priority to US10/393,756 priority patent/US20030228368A1/en
Priority to CA2499882A priority patent/CA2499882C/en
Priority to US10/393,871 priority patent/US7416738B2/en
Priority to BR0314804-1A priority patent/BR0314804A/en
Priority to EP10177295A priority patent/EP2255795A1/en
Priority to MXPA05003280A priority patent/MXPA05003280A/en
Priority to PCT/US2003/008960 priority patent/WO2004028514A1/en
Priority to RU2005108576/15A priority patent/RU2005108576A/en
Priority to EP03798656A priority patent/EP1542662A1/en
Priority to EP03716781.4A priority patent/EP1542661B1/en
Priority to AU2003220468A priority patent/AU2003220468A1/en
Priority to KR1020057005346A priority patent/KR20050084605A/en
Priority to DE60329614T priority patent/DE60329614D1/en
Priority to MXPA05003283A priority patent/MXPA05003283A/en
Priority to CA002500311A priority patent/CA2500311A1/en
Priority to KR1020057005272A priority patent/KR20050071517A/en
Priority to BR0314787-8A priority patent/BR0314787A/en
Priority to PCT/US2003/008891 priority patent/WO2004028504A1/en
Priority to PCT/US2003/008845 priority patent/WO2004028510A1/en
Priority to PCT/US2003/008897 priority patent/WO2004028513A1/en
Priority to RU2005108609/15A priority patent/RU2005108609A/en
Priority to MXPA05003282A priority patent/MXPA05003282A/en
Priority to EP03798655A priority patent/EP1545472B1/en
Priority to AU2003218359A priority patent/AU2003218359A1/en
Priority to RU2005108577/15A priority patent/RU2005108577A/en
Priority to CA2499979A priority patent/CA2499979C/en
Priority to PCT/US2003/008859 priority patent/WO2004028512A1/en
Priority to PCT/US2003/008894 priority patent/WO2004028508A1/en
Priority to US10/393,765 priority patent/US20040018327A1/en
Priority to DE60335270T priority patent/DE60335270D1/en
Priority to US10/393,752 priority patent/US7635490B2/en
Priority to CA002499977A priority patent/CA2499977A1/en
Priority to BR0314777-0A priority patent/BR0314777A/en
Priority to MXPA05003279A priority patent/MXPA05003279A/en
Priority to BR0314781-9A priority patent/BR0314781A/en
Priority to RU2005108611/15A priority patent/RU2005108611A/en
Priority to AU2003220466A priority patent/AU2003220466A1/en
Publication of WO2003026629A2 publication Critical patent/WO2003026629A2/en
Priority to US10/695,347 priority patent/US7838026B2/en
Publication of WO2003026629A3 publication Critical patent/WO2003026629A3/en
Priority to US10/860,972 priority patent/US20040253312A1/en
Priority to NO20051979A priority patent/NO20051979L/en
Priority to NO20052037A priority patent/NO20052037L/en
Priority to NO20052036A priority patent/NO20052036L/en
Priority to US12/049,628 priority patent/US20080305150A1/en

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    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/13—Hollow or container type article [e.g., tube, vase, etc.]
    • Y10T428/1352—Polymer or resin containing [i.e., natural or synthetic]

Definitions

  • This invention relates to modified release dosage forms such as modified release pharmaceutical compositions. More particularly, this invention relates to modified release dosage forms having partial coatings, for example dosage forms partially coated by first material for controlling the surface area through which dissolution of at least one active ingredient contained within the dosage form takes place upon contacting of the dosage form with a liquid medium.
  • Modified release pharmaceutical dosage forms have long been used to optimize drug delivery and enhance patient compliance, especially by reducing the number of doses of medicine the patient must take in a day.
  • the rate at which an orally delivered pharmaceutical active ingredient reaches its site of action in the body depends on a number of factors, including the rate and extent of drug abso ⁇ tion through the g.i. mucosa.
  • the drug To be absorbed into the circulatory system (blood), the drug must first be dissolved in the g.i. fluids.
  • diffusion across the g.i. membranes is relatively rapid compared to dissolution.
  • the dissolution of the active ingredient is the rate limiting step in drug abso ⁇ tion, and controlling the rate of dissolution allows the formulator to control the rate of drug abso ⁇ tion into the circulatory system of a patient.
  • the dissolution rate of a drug in the g.i. fluids depends, among other things, on the drug's solubility and the effective surface area of contact between dissolving drug particles and the dissolution medium.
  • the Nernst-Brunner equation describes the dissolution rate of a dmg:
  • dC/dt (D K 2 S) (1/vh) (C s - C t )
  • D the diffusion coefficient for the drug
  • K is a dissolution constant
  • h the effective thickness of the diffusion layer
  • S is the surface area of contact between the drug and the dissolution medium
  • C s is the solubility of the drug in the medium (i.e. the concentration of a saturated solution at the surface of the dissolving particle)
  • C t is the concentration of drug in the bulk solution at a time t.
  • the abso ⁇ tion process constantly removes drug from the g.i. tract, usually at a rate faster than that of drug dissolution. This creates what is known as a "sink" condition, where , the concentration of drug in the bulk solution, is much less than C s , the concentration of dmg in the saturated region at the surface of the dissolving particle.
  • the primary non-constant terms in this model are S, the surface area of contact between the dmg and the dissolution medium, and h, the effective thickness of the diffusion layer.
  • S the surface area of contact between the dmg and the dissolution medium
  • h the effective thickness of the diffusion layer.
  • U.S. Patent No. 4,803,076 discloses a tablet press for use in the manufacture of a tablet in the approximate shape of a tmncated cone, as well as an apparatus for removal of a portion of the coated dosage form in order to expose an area for dissolution of the dmg.
  • the dosage form disclosed therein suffers from the limitation of possessing a flat cylinder or disc shaped central portion, defined by the straight die walls, and a "land" area defined by the perimeter of the upper and lower punches in the compression machine.
  • non-conventionally shaped dosage forms that provide constant controlled release rates by virtue of their shape with a shell of a more regular shape to facilitate swallowing, or reduce friability (susceptibility to breakage).
  • dosage forms comprising a core in the shape of a torus or truncated cone containing an active ingredient therein, protected by a spheroid or elypsoid shaped shell.
  • Such dosage forms would be easy to swallow, maintain their stractural integrity during handling and shipping, and yet provide the functional benefits confened by the shape of the core.
  • the apparatus and methods of copending U.S. Patent Application Serial Nos. 09/966,497, pages 27-51 and 09/966,450, pages 57-63 advantageously enable the production of such dosage forms according to this invention.
  • the dosage form of this invention comprises: (a) at least one active ingredient; (b) a core having a first surface portion upon which resides an first coating and a second surface portion which is substantially free of the first coating; and (c) a shell which resides upon at least the second surface portion, wherein the shell comprises a different material from the first coating.
  • the core comprises a cavity therein such that at least part of the second surface portion of the core is located within the cavity, and the shell resides upon at least a part of the second surface portion of the core which is located within the cavity.
  • the cavity is an aperture which extends entirely through the core such that the aperture provides the second surface portion of the core.
  • the shell resides upon at least part of both the first coating and the second surface portion of the core.
  • the shell resides over all the first coating and the second surface of the core.
  • the shell comprises a material selected from water soluble or water swellable thermoplastic film formers, water soluble or water swellable thickeners, crystallizable and non-crystallizable carbohydrates.
  • the core is in the shape of a tmncated cone.
  • the dosage form of this invention comprises: (a) at least one active ingredient; (b) a core comprising (i) a center portion having an exterior surface and (ii) an annular portion having an exterior surface and an interior surface, wherein the annular portion interior surface is in contact with at least portion of the center portion exterior surface, and an first coating resides on at least a portion of the annular portion exterior surface; and (c) a shell which resides upon at least a portion of the exterior surface of the center portion, wherein the shell comprises a different material from the first coating.
  • the core comprises at least one active ingredient.
  • the center portion of the core comprises at least one active ingredient.
  • the annular portion of the core comprises at least one active ingredient.
  • the center portion of the core comprises a first active ingredient and the annular portion of the core comprises a second active ingredient.
  • the shell comprises at least one active ingredient.
  • both the shell and the core each comprise at least one active ingredient.
  • the first coating resides upon the entire annular portion exterior surface.
  • the shell resides upon the entire first coating and the center portion surface.
  • the shell comprises a material selected from water soluble or water swellable thermoplastic film formers, water soluble or water swellable thickeners, crystallizable and non-crystallizable carbohydrates.
  • the core annular portion has the shape of a torus.
  • the dosage form of this invention comprises: (a) at least one active ingredient; (b) a core having an outer surface and a cavity which extends at least partially through the core such that the core outer surface has at least a first opening therein; (c) a first coating which resides on at least a portion of the core outer surface, wherein the first shell portion comprises a different material from the first coating; and (d) a first shell portion which is adjacent to the first opening and covers at least the first opening.
  • the cavity extends entirely through the core such that the core has first and second openings therein, the first shell portion is adjacent to and covers at least the first opening, and the dosage form additionally comprises a second shell portion which is adjacent to and covers at least the second opening, wherein the first and second shell portions each comprise a material different from the first coating.
  • the core has the shape of a torus.
  • the first shell portion comprises at least one water soluble material.
  • the second shell portion comprises at least one water soluble material.
  • first and second shell portions each comprise at least one water soluble material.
  • the first shell portion or the core or a combination thereof comprises at least one active ingredient.
  • the first shell portion, second shell portion or the core or a combination thereof comprises at least one active ingredient.
  • the first shell portion resides upon at least a portion of the first coating.
  • the shell resides upon the entire outer surface of the first coating.
  • At least a portion of the active ingredient is released in a sustained manner.
  • the dosage form releases at least a portion of the active ingredient at a substantially constant rate.
  • the release of at least one active ingredient from the center portion of the core meets USP specifications for immediate release tablets containing the particular active ingredient employed.
  • the center portion of the core provides a time delay to the release of active ingredient from the annular portion of the core.
  • the core functions as an eroding matrix.
  • the core functions as a diffusional matrix.
  • the core comprises a release-modifying excipient selected from the group consisting of swellable erodible hydrophillic materials, insoluble edible materials, pH-dependent polymers, and mixtures thereof.
  • the first coating comprises at least about 30 weight percent of a thermal reversible carrier, based on the weight of the first coating.
  • the first coating comprises at lease about 10 weight percent of a film former selected from the group consisting of film-forming water soluble polymers, film- forming proteins, film- forming water insoluble polymers, and film-forming pH-dependent polymers.
  • a film former selected from the group consisting of film-forming water soluble polymers, film- forming proteins, film- forming water insoluble polymers, and film-forming pH-dependent polymers.
  • the film-former for making the core or shell or portion thereof by molding may be selected from cellulose acetate, ammonio methacrylate copolymer type B, shellac, hydroxypropylmethylcellulose, and polyethylene oxide, and combinations thereof.
  • the shell or shell portion comprises thermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides, and combinations thereof.
  • the shell portion is breached or dissolved within 30 minutes in 900 ml water or 0.1 N HCl, or phosphate buffer solution at 37°C with stirring by a USP type 2 (Paddle method) at 50 or 100 ⁇ m.
  • the release of at least one active ingredient follows a double pulse profile.
  • the release of at least one active ingredient follows a delayed then sustained release profile.
  • release of a first portion of active ingredient from the dosage form meets USP specifications for immediate release tablets containing the particular active ingredient employed, and release of a second portion of active ingredient from the dosage form follows a sustained, prolonged, extended, or retarded release profile.
  • the immediately released first portion of active ingredient is contained in the shell, and the sustained release second portion of active ingredient is contained in the core.
  • the release of one or more active ingredients follows a zero-order, first-order, or square root of time profile.
  • the shell is substantially free of pores in the diameter range of 0.5 to 5.0 microns.
  • this invention provides a method of applying a partial coating to a core in a dosage form by thermal cycle molding.
  • this invention provides a method of applying a partial coating to a core in a dosage form by thermal setting molding.
  • the first coating comprises up to about 55 weight percent of a release-modifying excipient selected from water-insoluble polymers and low- melting hydrophobic materials and combinations thereof.
  • the release-modifying excipeint is a polycaprolactone.
  • Figs. 1 A and IB depict overhead and side views of one embodiment of the dosage form of this invention.
  • Figs. 2 A and 2B depict overhead and side views of another embodiment of the dosage form of this invention.
  • Figs. 3 A and 3B depict overhead and side views of another embodiment of the dosage form of this invention.
  • Figs. 4 A and 4B depict overhead and side views of another embodiment of the dosage form of this invention.
  • Figs. 5 A and 5B depict overhead and side views of another embodiment of the dosage form of this invention.
  • Fig. 6 depicts the % release of active ingredient vs. hours measured for the dosage form of Example 1.
  • Figs. 7A and 7B depict another embodiment of a dosage form according to the invention.
  • dosage form applies to any solid object, semi-solid, or liquid composition designed to contain a specific pre-determined amount (i.e. dose) of a certain ingredient, for example an active ingredient as defined below.
  • Suitable dosage forms may be pharmaceutical drag delivery systems, including those for oral administration, buccal administration, rectal administration, topical or mucosal delivery, or subcutaneous implants, or other implanted drug delivery systems; or compositions for delivering minerals, vitamins and other nutraceuticals, oral care agents, flavorants, and the like.
  • the dosage forms of the present invention are considered to be solid, however they may contain liquid or semi-solid components.
  • the dosage form is an orally administered system for delivering a pharmaceutical active ingredient to the gastro-intestinal tract of a human.
  • the dosage forms of the present invention contain one or more active ingredients which are released therefrom upon contact of the dosage form with a liquid medium, for example a dissolution medium.
  • a liquid medium for example a dissolution medium.
  • suitable dissolution media for the dosage form of the invention include gastrointestinal fluids for embodiments in which the dosage form is orally ingested, mucosal fluids for embodiments in which the dosage form is for buccal delivery, intracellular fluids for embodiments in which the dosage form is an implant, moisture in the soil for embodiments in which the dosage form delivers a fertilizer or plant nutrient, and synthetic dissolution media, e.g. water or aqueous buffer solutions, for testing the performance of the dosage form in vitro.
  • Water soluble as used herein in connection with non-polymeric materials, shall mean from sparingly soluble to very soluble, i.e., not more than 100 parts water required to dissolve 1 part of the non-polymeric, water soluble solute. See Remington, The Science and Practice of Pharmacy, pp 208 - 209 (2000).
  • Water soluble as used herein in connection with polymeric materials, shall mean that the polymer swells in water and can be dispersed at the molecular level to form a homogeneous dispersion or colloidal "solution.”
  • the dosage forms of the invention exhibit modified release of one or more active ingredients contained therein.
  • One or more active ingredients may be found in any portion of the dosage form, for example one or more active ingredients may be found within the core, the center portion, the shell portion, or coated or uncoated particles distributed therethrough.
  • the term "modified release” shall apply to dosage forms, matrices, particles, coatings, portions thereof, or compositions that alter the release of an active ingredient in any manner.
  • Types of modified release include controlled, prolonged, sustained, extended, delayed, pulsatile, repeat action, and the like. Suitable mechanisms for achieving these types of modified release include diffusion, erosion, surface area control via geometry and/or impermeable barriers, or other mechanisms known in the art.
  • the modified release properties of the dosage form may be achieved through design of the core or a portion thereof, or the first coating, or the shell portion, or a combination of two or more of these parts of the dosage form.
  • the dosage form releases one or more active ingredients contained therein in a controlled manner, e.g. in a sustained, extended, prolonged, or retarded manner, more preferably at a substantially constant rate upon contacting of the dosage form with a liquid medium.
  • the core or center portion or shell or a portion thereof may function as a diffusional matrix or an eroding matrix.
  • the dosage form of the invention comprises a first coating which resides upon a first surface portion of the core.
  • the first coating may function as a barrier to prevent release therethrough of an active ingredient contained in the underlying core portion.
  • active ingredient is typically released from a portion of the core which is not covered by the barrier coating portion.
  • Such embodiments advantageously allow for control of the surface area for release of the active ingredient.
  • the surface area for release of active ingredient can be maintained substantially constant over time.
  • the surface area for release of active ingredient can increase over time during the dissolution period of the dosage form.
  • the surface area for release of active ingredient may be controlled by a combination of the size of the uncoated area on the core surface, and the overall shape of the core.
  • the barrier coating preferably comprises a water insoluble material such as for example a water insoluble polymer. Since surface area is one factor in the dissolution equation, controlling surface area for drag release advantageously enables a further degree of control over the release rate of the drag from the dosage form. In a particularly prefened embodiment, the release of at least one active ingredient follows substantially zero-order kinetics.
  • the dosage form also comprises a shell or shell portion that resides on (i.e., directly contacts) or covers (i.e., shields or screens but does not necessarily directly contact) at least a portion of the exterior surface of the core where no first coating is present.
  • the shell may reside on or cover the entire portion of the core free of first coating. Alternately the shell may reside on only a portion of the uncoated core surface. Additionally, the shell may cover all, none, or a portion of the first coating as well. In a particularly prefened embodiment the shell resides upon only the portion of the core free of first coating, and does not contact the first coating.
  • the shell covers the entire portion of the core free of first coating, and connects with the first coating at an interface, but does not substantially cover the first coating. In yet another embodiment, the shell covers both the entire portion of the core free of first coating and the entire first coating.
  • the shell comprises a material that is different from the first coating.
  • the shell comprises the overall outer surface of the dosage form
  • the shell is preferably of a smooth overall shape, e.g. a spheroid, ellypsoid, or other easily swallowable shape such as those having rounded edges. Accordingly, the dosage form resists damage during transport and handling and is easy to swallow, despite the shape of the core inside.
  • FIG. 1 A depicts an overhead view
  • Fig. IB depicts a side view of a dosage form 2 which comprises a core 4 having a first surface portion 6 and second surface portions 8.
  • a first coating 10 resides upon the first surface portion 6 of core 4.
  • the second surface portion 8 of core 4 is substantially free of first coating 10.
  • a shell 12 resides upon the second surface portion 8 of core 4.
  • core 4 of the dosage form depicted in Figures 1 A and IB may contain a cavity as shown in Figures 2A and 2B, which respectively depict overhead and side views of a dosage form 202 which comprises a core 204 having a first surface portion 206, a cavity 205 and a second surface portion 208.
  • a first coating 210 resides upon the first surface portion 206 of core 204.
  • the second surface portion 208 of core 204 is defined at least in part by cavity 205 and the second surface portion 208 is substantially free of first coating 210.
  • a shell 212 resides upon the second surface portion 208 of core 204.
  • FIGs. 3 A and 3B depict a further variation of the dosage form of Figures 1 A and IB.
  • Figures 3 A and 3B depict overhead and side views of a dosage form 302 which comprises a core 304 having a first surface portion 306, an aperture 305 which extends completely through core 304 and a second surface portion 308.
  • the second surface portion 308 of core 304 is defined by aperture 305.
  • a first coating 310 resides upon the first surface portion 306 of core 304.
  • the second surface portion 308 is substantially free of first coating 310.
  • a shell 312 resides upon the second surface portion 308 of core 304.
  • FIGs. 4A and 4B depict overhead and side views of dosage form 402, which comprises a core 404 made up of a center portion 405 sunounded by an annular portion 409.
  • the center portion 405 has a surface 407, while the annular portion 409 has an exterior surface 411 and an interior surface 413.
  • the annular portion interior surface 413 is in contact with a portion of the center portion surface 407.
  • the annular portion exterior surface 410 is covered by a first coating 410.
  • a shell, divided into first and second shell portions 415 reside upon a portion of the center portion surface 407
  • FIGs. 5 A and 5B depict overhead and side views of dosage form 502 which comprises a core 504 having an outer surface 506 and an inner surface 508 that is defined by an aperture 505 extending completely through the core 504.
  • a first coating 510 resides upon the outer surface 506 of core 504.
  • the inner surface 508 is substantially free of first coating 510.
  • a first shell portion 513 covers one end of the aperture 505, and a second shell portion 515 covers the opposite end of the aperture 505. Accordingly, a void is created inside the dosage form.
  • Figure 7 A depicts another embodiment of the invention, hi this embodiment, the dosage form 702 comprises a core 704 having the shape of a torus. This shape has been found to be especially conducive to controlled release of an active ingredient.
  • the core 704 has an outer surface 706 and an inner surface 708 that is defined by an aperture 705.
  • a first coating 710 resides on the outer surface 706 of the core 704, as shown in Fig. 7B.
  • the inner surface 708 is substantially free of first coating 710.
  • a shell 715 encloses the entire core 704 and first coating 710.
  • the shell 715 has a generally elliptical shape.
  • Suitable active ingredients for use in this invention include for example pharmaceuticals, minerals, vitamins and other nutraceuticals, oral care agents, flavorants and mixtures thereof.
  • suitable pharmaceuticals include analgesics, anti-inflammatory agents, antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, decongestants, contraceptives, diuretics, expectorants, gastrointestinal agents, migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tract agents and mixtures thereof.
  • Suitable oral care agents include breath fresheners, tooth whiteners, antimicrobial agents, tooth mineralizers, tooth decay inhibitors, topical anesthetics, mucoprotectants, and the like.
  • Suitable flavorants include menthol, peppermint, mint flavors, fruit flavors, chocolate, vanilla, bubblegum flavors, coffee flavors, liqueur flavors and combinations and the like.
  • Suitable gastrointestinal agents include antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum sodium carbonate; stimulant laxatives, such as bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures thereof; H2 receptor antagonists, such as famotadine, ranitidine, cimetadine, nizatidine; proton pump inhibitors such as omeprazole or lansoprazole; gastrointestinal cytoprotectives, such as sucraflate and misoprostol; gastrointestinal prokinetics, such as prucalopride, antibiotics for H.
  • antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum
  • pylori such as clarithromycin, amoxicillin, tetracycline, and metronidazole
  • antidianheals such as diphenoxylate and loperamide
  • glycopynolate such as glycopynolate
  • antiemetics such as ondansetron
  • analgesics such as mesalamine
  • the active agent may be selected from bisacodyl, famotadine, ranitidine, cimetidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • the active agent is selected from analgesics, anti- inflammatories, and antipyretics, e.g. non-steroidal anti-inflammatory drugs (NSAIDs), including propionic acid derivatives, e.g. ibuprofen, naproxen, ketoprofen and the like; acetic acid derivatives, e.g. indomethacin, diclofenac, sulindac, tohnetin, and the like; fenamic acid derivatives, e.g. mefanamic acid, meclofenamic acid, flufenamic acid, and the like; biphenylcarbodylic acid derivatives, e.g.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • the active agent is selected from propionic acid derivative NSAIDs, e.g. ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pi ⁇ rofen, ca ⁇ rofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof.
  • NSAIDs e.g. ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pi ⁇ rofen, ca ⁇ rofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof.
  • the active agent may be selected from acetaminophen, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • the active agent may be selected from pseudoephedrine, phenylpropanolamine, chlo ⁇ heniramine, dextrometho ⁇ han, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine, desloratidine, doxilamine, norastemizole, cetirizine, mixtures thereof and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • Suitable polydimethylsiloxanes which include, but are not limited to dimethicone and simethicone, are those disclosed in United States Patent Nos. 4,906,478, 5,275,822, and 6,103,260.
  • simethicone refers to the broader class of polydimethylsiloxanes, including but not limited to simethicone and dimethicone.
  • the active ingredient or ingredients are present in the dosage form in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining such amounts, the particular active ingredient being administered, the bioavailability characteristics of the active ingredient, the dose regime, the age and weight of the patient, and other factors must be considered, as known in the art.
  • the dosage form comprises at least about 85 weight percent of the active ingredient.
  • the core comprises at least about 85 weight percent of the active ingredient.
  • the active ingredient or ingredients may be present in the dosage form in any form.
  • the active ingredient may be dispersed at the molecular level, e.g. melted or dissolved, within the dosage form, or may be in the form of particles, which in turn may be coated or uncoated.
  • the particles typically have an average particle size of about 1-2000 microns.
  • such particles are crystals having an average particle size of about 1-300 microns.
  • the particles are granules or pellets having an average particle size of about 50-2000 microns, preferably about 50-1000 microns, most preferably about 100-800 microns.
  • an active ingredient may be optionally coated with a release-modifying coating, as known in the art.
  • a release-modifying coating as known in the art.
  • the particles may be as described herein, and the particles may be coated using conventional coating technology which is well known to those skilled in the art including microencapsulation techniques such as coacervation, spray-drying, and fluidized bed coating including tangential spray rotor coating and bottom spray wurster coating. Examples of suitable particle coating methods and materials can be found in United States Patent Nos. 5,286,497; 4,863,742; 4,173,626; 4,980,170; 4,984,240; 5,912,013; 6,270,805; and 6,322,819.
  • the active ingredient or ingredients are preferably capable of dissolution upon contact with a fluid such as water, gastric fluid, intestinal fluid or the like.
  • a fluid such as water, gastric fluid, intestinal fluid or the like.
  • the dissolution characteristics of at least one active ingredient meets USP specifications for immediate release tablets containing the active ingredient.
  • USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2 (paddles) at 50 ⁇ m, at least 80% of the acetaminophen contained in the dosage form is released therefrom within 30 minutes after dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer, using USP apparatus 2 (paddles) at 50 ⁇ m, at least 80% of the ibuprofen contained in the dosage form is released therefrom within 60 minutes after dosing. See USP 24, 2000 Version, 19 - 20 and 856 (1999).
  • the immediately released active ingredient is preferably contained in the shell or on the surface of the shell, e.g. in a further coating sunounding at least a portion of the shell.
  • the dissolution characteristics of one or more active ingredients are modified: e.g. controlled, sustained, extended, retarded, prolonged, delayed and the like.
  • the modified release active or actives are preferably contained in the core.
  • the core of the present invention may be prepared by any suitable method, including for example compression and molding, and depending on the method by which it is made, typically comprises, in addition to the active ingredient, a variety of excipients (inactive ingredients which may be useful for conferring desired physical properties to the dosage form).
  • suitable method including for example compression and molding, and depending on the method by which it is made, typically comprises, in addition to the active ingredient, a variety of excipients (inactive ingredients which may be useful for conferring desired physical properties to the dosage form).
  • the core is prepared by the compression methods and apparatus described in copending U.S. Patent Application Serial No. 09/966,509, pages 16- 27, the disclosure of which is inco ⁇ orated herein by reference.
  • the core is made using a rotary compression module comprising a fill zone, insertion zone, compression zone, ejection zone, and purge zone in a single apparatus having a double row die construction as shown in Figure 6 of U.S. Patent Application Serial No. 09/966,509.
  • the dies of the compression module are preferably filled using the assistance of a vacuum, with filters located in or near each die.
  • the purge zone of the compression module includes an optional powder recovery system to recover excess powder from the filters and return excess powder to the dies.
  • suitable excipients include fillers, binders, disintegrants, lubricants, glidants, and the like, as known in the art.
  • the core may further comprise a release-modifying compressible excipient.
  • Suitable fillers for use in making the core, or a portion thereof, by compression include water-soluble compressible carbohydrates such as sugars, which include dextrose, sucrose, maltose, and lactose, sugar-alcohols, which include mannitol, sorbitol, maltitol, xylitol, starch hydrolysates, which include dextrins, and maltodextrins, and the like, water insoluble plastically deforming materials such as microcrystalline cellulose or other cellulosic derivatives, water-insoluble brittle fracture materials such as dicalcium phosphate, tricalcium phosphate and the like and mixtures thereof.
  • water-soluble compressible carbohydrates such as sugars, which include dextrose, sucrose, maltose, and lactose
  • sugar-alcohols which include mannitol, sorbitol, maltitol, xylitol
  • starch hydrolysates which include dextrins, and
  • Suitable binders for making the core, or a portion thereof, by compression include dry binders such as polyvinyl pynolidone, hydroxypropylmethylcellulose, and the like; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, canageenan, carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, , inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pynolidone, cellulosics, sucrose, starches, and the like; and derivatives and mixtures thereof.
  • dry binders such as polyviny
  • Suitable disintegrants for making the core, or a portion thereof, by compression include sodium starch glycolate, cross-linked polyvinylpynolidone, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose, and the like.
  • Suitable lubricants for making the core, or a portion thereof, by compression include long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides and waxes.
  • Suitable glidants for making the core, or a portion thereof, by compression include colloidal silicon dioxide, and the like.
  • Suitable release-modifying compressible excipients for making the core, or a portion thereof, by compression include swellable erodible hydrophillic materials, insoluble edible materials, pH-dependent polymers, and mixtures thereof.
  • Suitable swellable erodible hydrophilic materials for use as release-modifying excipients for making the core, or a portion thereof, by compression include: water swellable cellulose derivatives, polyalkalene glycols, thermoplastic polyalkalene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, and swelling cross-linked polymers, and derivitives, copolymers, and combinations thereof.
  • suitable water swellable cellulose derivatives include sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose,hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylethylcellulose.
  • suitable polyalkalene glyclols include polyethylene glycol.
  • suitable thermoplastic polyalkalene oxides include poly (ethylene oxide).
  • acrylic polymers include potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL (high-molecular weight cross-linked acrylic acid homopolymers and copolymers), and the like.
  • suitable hydrocolloids include alginates, agar, guar gum, locust bean gum, kappa canageenan, iota canageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan.
  • Suitable clays include smectites such as bentonite, kaolin, and laponite; magnesium trisilicate, magnesium aluminum silicate, and the like, and derivatives and mixtures thereof.
  • suitable gelling starches include acid hydrolyzed starches, swelling starches such as sodium starch glycolate, and derivatives thereof.
  • suitable swelling cross-linked polymers include cross-linked polyvinyl pynolidone, cross-linked agar, and cross-linked carboxymethylcellose sodium.
  • Suitable insoluble edible materials for use as release-modifying excipients for making the core, or a portion thereof, by compression include water-insoluble polymers, and low-melting hydrophobic materials.
  • suitable water-insoluble polymers include ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof.
  • Suitable low-melting hydrophobic materials include fats, fatty acid esters, phospholipids, and waxes.
  • suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts.
  • suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides.
  • Suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid.
  • suitable waxes include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate; and the like.
  • Suitable pH-dependent polymers for use as release-modifying excipients for making the core, or a portion thereof, by compression include enteric cellulose derivatives, for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1 :2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L; and the like, and derivatives, salts, copolymers, and combinations thereof.
  • Suitable pharmaceutically acceptable adjuvants for making the core, or a portion thereof, by compression include, preservatives; high intensity sweeteners such as aspartame, acesulfame potassium, sucralose, and saccharin; flavorants; colorants; antioxidants; surfactants; wetting agents; and the like and mixtures thereof.
  • the core or a portion thereof may also be formed by molding, using either a solvent free, or solvent based method.
  • the core is prepared by thermal setting molding using the method and apparatus described in copending U.S. patent application Serial No. 09/966,450, pages 57-63, the disclosure of which is inco ⁇ orated herein by reference.
  • the core is formed by injecting a starting material in flowable form into a molding chamber.
  • the starting material preferably comprises an active ingredient and a thermal setting material at a temperature above the melting point of the thermal setting material but below the decomposition temperature of the active ingredient.
  • the starting material is cooled and solidifies in the molding chamber into a shaped form (i.e., having the shape of the mold).
  • the core is prepared by thermal cycle molding using the method and apparatus described in copending U.S. patent application Serial No.
  • the core is formed by injecting a starting material in flowable form into a heated molding chamber.
  • the starting material preferably comprises an active ingredient and a thermoplastic material at a temperature above the set temperature of the thermoplastic material but below the decomposition temperature of the active ingredient.
  • the starting material is cooled and solidifies in the molding chamber into a shaped form (i.e., having the shape of the mold).
  • the first coating may be applied to the core by known methods, such as dipping, or spraying. In a prefened embodiment, however, the first coating is applied to the core by molding.
  • the first coating may be molded using a solvent free or solvent based method, preferably using either the thermal cycling molding module, or thermal setting molding module, as described herein.
  • This invention advantageously achieves a cost effective process for applying a partial coating to selected portions of a core without the need for costly and complex subsequent steps of previously known methods, such as application of a complete coating to a core, followed by removal of a portion of the core and coating to permit selective application of another coating to a portion of the core.
  • the first coating may function as a barrier to the passage of water or active ingredient therethrough.
  • the first coating may function as a semi-permeable membrane, allowing water or solvent to pass into the core, but being impermeable to dissolved active ingredient, thereby preventing the passage of active ingredient therethrough.
  • the first coating may function as a diffusional membrane, allowing the passage of active ingredient therethrough at a rate controlled by the thickness, porosity and tortuosity of the first coating.
  • the first coating may function as an erosional coating to provide a time delay to the release of one or more portions of active ingredient in the core.
  • the first coating may comprise one or more active ingredients.
  • the first coating may comprise a water soluble active ingredient intended for immediate release from the dosage form, which dissolves promptly upon contact of the dosage form with a liquid medium, thereby creating pores in the first coating for the diffusion of a second dose of active ingredient contained in the core or a portion thereof.
  • the first coating preferably comprises from about 10 to about 100 weight percent of a film former.
  • the film former is preferably a water insoluble material such as for example a water insoluble polymer.
  • the film former is preferably selected from water insoluble polymers, pH-dependent polymers, water soluble polymers, and combinations thereof.
  • the film former is preferably selected from water insoluble polymers, pH-dependent polymers, and combinations thereof; and the first coating preferably further comprises a pore former.
  • first coating preferably further comprises a swellable erodible hydrophilic material.
  • the shell comprises a material that is compositionally different from the first coating.
  • compositionally different means having features that are readily distinguishable by qualitative or quantitative chemical analysis, physical testing, or visual observation.
  • the first coating and shell materials may contain different ingredients, or different levels of the same ingredients, or the first and second materials may have different physical or chemical properties, different functional properties, or be visually distinct. Examples of physical or chemical properties that may be different include hydrophylicity, hydrophobicity, hygroscopicity, elasticity, plasticity, tensile strength, crystallinity, and density.
  • Examples of functional properties which may be different include rate and/or extent of dissolution of the material itself or of an active ingredient therefrom, rate of disintegration of the material, permeability to active ingredients, permeability to water or aqueous media, and the like.
  • Examples of visual distinctions include size, shape, topography, or other geometric features, color, hue, opacity, and gloss.
  • the first coating and shell may comprise different types or levels of colorants, opacifiers, film-formers, etc.
  • the first coating and shell may have different thickness.
  • the first coating and shell may have different functionalities.
  • the first coating and shell may confer different release properties to an active ingredient contained in either the subject coating or shell, or in a conesponding underlying core portion.
  • the first coating may function as a barrier to the passage therethrough of one or more active ingredients contained in the underlying core portion; and the shell may function as an eroding matrix from which active ingredient dispersed in the shell or shell portion is liberated by the dissolution of successive layers of the shell portion surface.
  • the core, or the first coating, or the shell, or a portion thereof is prepared by molding.
  • the core, or the shell, or a portion thereof comprises a flowable material.
  • the flowable material may be any edible material that is flowable at a temperature between about 37°C and 250°C, and that is solid, semi-solid, or can form a gel at a temperature between about -10°C and about 35°C.
  • the flowable material may comprise a dissolved or molten component, and optionally a solvent such as for example water or organic solvents, or combinations thereof. The solvent may be partially or substantially removed by drying.
  • Suitable flowable materials for making the core, or the first coating or the shell, or a portion thereof by molding include those comprising thermoplastic materials; film formers; thickeners such as gelling polymers or hydrocolloids; low melting hydrophobic materials such as fats and waxes; non-crystallizable carbohydrates; and the like.
  • Suitable molten components of the flowable material include thermoplastic materials, low melting hydrophobic materials, and the like.
  • Suitable dissolved components for the flowable material include film formers, thickeners such as gelling polymers or hydrocolloids, non-crystallizable carbohydrates, and the like.
  • Suitable thermoplastic materials can be molded and shaped when heated, and include both water soluble and water insoluble polymers that are generally linear, not crosslinked, nor strongly hydrogen bonded to adjacent polymer chains.
  • suitable thermoplastic materials include: thermoplastic water swellable cellulose derivatives, thermoplastic water insoluble cellulose derivatives, thermoplastic vinyl polymers, thermoplastic starches, thermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides, and amo ⁇ hous sugar-glass, and the like, and derivatives, copolymers, and combinations thereof.
  • suitable thermoplastic water swellable cellulose derivatives include hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC).
  • thermoplastic water insoluble cellulose derivatives examples include cellulose acetate (CA), ethyl cellulose (EC), cellulose acetate butyrate (CAB), cellulose propionate.
  • suitable thermoplastic vinyl polymers include polyvinyl alcohol (PVA) and polyvinyl pynolidone (PVP).
  • suitable thermoplastic starches include those disclosed in U.S. Patent No. 5,427,614, which is inco ⁇ orated herein by reference.
  • suitable thermoplastic polyalkalene glycols include polyethylene glycol;
  • suitable thermoplastic polyalkalene oxides include polyethylene oxide having a molecular weight from about 100,000 to about 900,000 Daltons.
  • Other suitable thermoplastic materials include sugar in the form on an amo ⁇ hous glass such as that used to make hard candy forms.
  • any film former known in the art is suitable for use in the flowable material of the present invention.
  • suitable film formers include, but are not limited to, film- forming water soluble polymers, film-forming proteins, film-forming water insoluble polymers, and film-forming pH-dependent polymers.
  • the film-former for making the core or shell or portion thereof by molding may be selected from cellulose acetate, ammonio methacrylate copolymer type B, shellac, hydroxypropylmethylcellulose, and polyethylene oxide, and combinations thereof.
  • Suitable film-forming water soluble polymers include water soluble vinyl polymers such as polyvinylalcohol (PVA); water soluble polycarbohydrates such as hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethyl starch, carboxymethyl starch, pre- gelatinized starches, and film-forming modified starches; water swellable cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), hydroxyethylmethylcellulose (HEMC), hydroxybutylmethylcellulose (HBMC), hydroxyethylethylcellulose (HEEC), and hydroxyethylhydroxypropylmethyl cellulose (HEMPMC); water soluble copolymers such as methacrylic acid and methacrylate ester copolymers, polyvinyl alcohol and polyethylene glycol copolymers, polyethylene oxide and polyvinylpynolidone copolymers; and
  • Suitable film- forming proteins may be natural or chemically modified, and include gelatin, whey protein, myofibrillar proteins, coaggulatable proteins such as albumin, casein, caseinates and casein isolates, soy protein and soy protein isolates, zein; and polymers, derivatives and mixtures thereof.
  • Suitable film-forming water insoluble polymers include for example ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof.
  • Suitable film-forming pH-dependent polymers include enteric cellulose derivatives, such as for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins, such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1 :2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L; and the like, and derivatives, salts, copolymers, and combinations thereof.
  • enteric cellulose derivatives such as for example hydroxypropyl methylcellulose
  • HPMC 2910 is a cellulose ether having a degree of substitution of about 1.9 and a hydroxypropyl molar substitution of 0.23, and containing, based upon the total weight of the compound, from about 29% to about 30% methoxyl groups and from about 7% to about 12% hydroxylpropyl groups.
  • HPMC 2910 is commercially available from the Dow Chemical Company under the tradename METHOCEL E.
  • METHOCEL E5 which is one grade of HPMC-2910 suitable for use in the present invention, has a viscosity of about 4 to 6 cps (4 to 6 millipascal-seconds) at 20°C in a 2% aqueous solution as determined by a Ubbelohde viscometer.
  • METHOCEL E6 which is another grade of HPMC-2910 suitable for use in the present invention, has a viscosity of about 5 to 7 cps ( 5 to 7 millipascal-seconds) at 20°C in a 2% aqueous solution as determined by a Ubbelohde viscometer.
  • METHOCEL El 5 which is another grade of HPMC-2910 suitable for use in the present invention, has a viscosity of about 15000 cps (15 millipascal-seconds) at 20°C in a 2% aqueous solution as determined by a Ubbelohde viscometer.
  • degree of substitution shall mean the average number of substituent groups attached to a anhydroglucose ring
  • hydroxypropyl molar substitution shall mean the number of moles of hydroxypropyl per mole anhydroglucose.
  • polyvinyl alcohol and polyethylene glycol copolymer are commercially available from BASF Co ⁇ oration under the tradename KOLLICOAT IR.
  • modified starches include starches that have been modified by crosslinking, chemically modified for improved stability or optimized performance, or physically modified for improved solubility properties or optimized performance.
  • chemically-modified starches are well known in the art and typically include those starches that have been chemically treated to cause replacement of some of its hydroxyl groups with either ester or ether groups.
  • Crosslinking as used herein, may occur in modified starches when two hydroxyl groups on neighboring starch molecules are chemically linked.
  • pre-gelatinized starches or “instantized starches” refers to modified starches that have been pre-wetted, then dried to enhance their cold-water solubility.
  • Suitable modified starches are commercially available from several suppliers such as, for example, A.E. Staley Manufacturing Company, and National Starch & Chemical Company.
  • One suitable film forming modified starch includes the pre-gelatinized waxy maize derivative starches that are commercially available from National Starch & Chemical Company under the tradenames PURITY GUM and FILMSET, and derivatives, copolymers, and mixtures thereof.
  • Such waxy maize starches typically contain, based upon the total weight of the starch, from about 0 percent to about 18 percent of amylose and from about 100% to about 88% of amylopectin.
  • Another suitable film forming modified starch includes the hydroxypropylated starches, in which some of the hydroxyl groups of the starch have been etherified with hydroxypropyl groups, usually via treatment with propylene oxide.
  • hydroxypropyl starch that possesses film-forming properties is available from Grain Processing Company under the tradename, PURE-COTE B790.
  • Suitable tapioca dextrins for use as film formers include those available from National Starch & Chemical Company under the tradenames CRYSTAL GUM or K-4484, and derivatives thereof such as modified food starch derived from tapioca, which is available from National Starch and Chemical under the tradename PURITY GUM 40, and copolymers and mixtures thereof.
  • Any thickener known in the art is suitable for use in the flowable material of the present invention. Examples of such thickeners include but are not limited to hydrocolloids (also refened to herein as gelling polymers), clays, gelling starches, and crystallizable carbohydrates, and derivatives, copolymers and mixtures thereof.
  • hydrocolloids also refened to herein as gelling polymers
  • suitable hydrocolloids such as alginates, agar, guar gum, locust bean, canageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan.
  • Suitable clays include smectites such as bentonite, kaolin, and laponite; magnesium trisilicate, magnesium aluminum silicate, and the like, and derivatives and mixtures thereof.
  • suitable gelling starches include acid hydrolyzed starches, and derivatives and mixtures thereof.
  • Additional suitable thickening hydrocolloids include low-moisture polymer solutions such as mixtures of gelatin and other hydrocolloids at water contents up to about 30%, such as for example those used to make "gummi" confection forms.
  • Suitable thickeners include crystallizable carbohydrates, and the like, and derivatives and combinations thereof.
  • Suitable crystallizable carbohydrates include the monosaccharides and the oligosaccharides.
  • the aldohexoses e.g., the D and L isomers of allose, alfrose, glucose, mannose, gulose, idose, galactose, talose
  • the ketohexoses e.g., the D and L isomers of fructose and sorbose along with their hydrogenated analogs: e.g., glucitol (sorbitol), and mannitol are prefened.
  • the 1,2-disaccharides sucrose and frehalose, the 1,4-disaccharides maltose, lactose, and cellobiose, and the 1,6-disaccharides gentiobiose and melibiose, as well as the trisaccharide raffinose are prefened along with the isomerized form of sucrose known as isomaltulose and its hydrogenated analog isomalt.
  • Other hydrogenated forms of reducing disaccharides such as maltose and lactose
  • maltitol and lactitol are also prefened.
  • the hydrogenated forms of the aldopentoses e.g., D and L ribose, arabinose, xylose, and lyxose and the hydrogenated forms of the aldotetroses: e.g., D and L erythrose and threose are prefened and are exemplified by xylitol and erythritol, respectively.
  • the flowable material comprises gelatin as a gelling polymer.
  • Gelatin is a natural, thermogelling polymer. It is a tasteless and colorless mixture of derived proteins of the albuminous class wliich is ordinarily soluble in warm water.
  • Two types of gelatin - Type A and Type B - are commonly used.
  • Type A gelatin is a derivative of acid-treated raw materials.
  • Type B gelatin is a derivative of alkali-treated raw materials.
  • the moisture content of gelatin, as well as its Bloom strength, composition and original gelatin processing conditions, determine its transition temperature between liquid and solid. Bloom is a standard measure of the strength of a gelatin gel, and is roughly conelated with molecular weight.
  • Bloom is defined as the weight in grams required to move a half-inch diameter plastic plunger 4 mm into a 6.67% gelatin gel that has been held at 10°C for 17 hours.
  • the flowable material is an aqueous solution comprising 20% 275 Bloom pork skin gelatin, 20% 250 Bloom Bone Gelatin, and approximately 60% water.
  • Suitable xanthan gums include those available from CP. Kelco Company under the tradenames KELTROL 1000, XANTROL 180, or K9B310.
  • Suitable clays include smectites such as bentonite, kaolin, and laponite; magnesium trisilicate, magnesium aluminum silicate, and the like, and derivatives and mixtures thereof.
  • Acid-hydrolyzed starch is one type of modified starch that results from treating a starch suspension with dilute acid at a temperature below the gelatinization point of the starch. During the acid hydrolysis, the granular form of the starch is maintained in the starch suspension, and the hydrolysis reaction is ended by neutralization, filtration and drying once the desired degree of hydrolysis is reached. As a result, the average molecular size of the starch polymers is reduced. Acid-hydrolyzed starches (also known as “thin boiling starches”) tend to have a much lower hot viscosity than the same native starch as well as a strong tendency to gel when cooled.
  • Gelling starches include those starches that, when combined with water and heated to a temperature sufficient to form a solution, thereafter form a gel upon cooling to a temperature below the gelation point of the starch.
  • gelling starches include, but are not limited to, acid hydrolyzed starches such as that available from Grain Processing Co ⁇ oration under the tradename PURE-SET B950; hydroxypropyl distarch phosphate such as that available from Grain Processing Co ⁇ oration under the tradename, PURE-GEL B990, and mixtures thereof.
  • Suitable low-melting hydrophobic materials include fats, fatty acid esters, phospholipids, and waxes.
  • suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts.
  • Suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides.
  • suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid.
  • suitable waxes include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate; and the like.
  • Suitable non-crystallizable carbohydrates include non-crystallizable sugars such as polydextrose, and starch hydrolysates, e.g. glucose syrup, com syrup, and high fructose com syrup; and non-crystallizable sugar-alcohols such as maltitol syrup.
  • Suitable solvents for optional use as components of the flowable material include water; polar organic solvents such as methanol, ethanol, isopropanol, acetone, and the like; and non-polar organic solvents such as methylene chloride, cyclohexane, and the like; and mixtures thereof.
  • the flowable material may optionally comprise adjuvants or excipients, which may comprise up to about 30% by weight of the flowable material.
  • suitable adjuvants or excipients include plasticizers, detackifiers, humectants, surfactants, anti- foaming agents, colorants, flavorants, sweeteners, opacifiers, and the like.
  • Suitable plasticizers for making the core, the shell, or a portion thereof, by molding include, but not be limited to polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl citrate; tribuyl citrate; dibutyl sebecate; vegetable oils such as castor oil, rape oil, olive oil, and sesame oil; surfactants such as polysorbates, sodium lauryl sulfates, and dioctyl-sodium sulfosuccinates; mono acetate of glycerol; diacetate of glycerol; triacetate of glycerol; natural gums; triacetin; acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate; diethylmalonate; dioctylphthalate; dibutylsuccinate; glyceroltributyrate; hydrogenated castor oil; fatty acids
  • the plasticizer is triethyl citrate.
  • the shell is substantially free of plasticizers, i.e. contains less than about 1%, say less than about 0.01% of plasticizers.
  • the flowable material comprises less than 5% humectants, or alternately is substantially free of humectants, such as glycerin, sorbitol, maltitol, xylitol, or propylene glycol. Humectants have traditionally been included in preformed films employed in enrobing processes, such as that disclosed in U.S. Patent Nos. 5,146,730 and 5,459,983, to ensure adequate flexibility or plasticity and bondability of the film during processing.
  • Humectants function by binding water and retaining it in the film. Pre-formed films used in enrobing processes can typically comprise up to 45% water. Disadvantageously, the presence of humectant prolongs the drying process, and can adversely affect the stability of the finished dosage form.
  • the core, or the first coating, or the shell, or portions thereof may be molded using a solvent- free process.
  • the core, or the first coating, or the shell, or portions thereof may comprise active ingredient contained within a molded excipient matrix.
  • the core, or the first coating, or the shell, or portions thereof may comprise a molded excipient matrix substantially free of active ingredient.
  • the molded matrix typically comprises at least about 30 weight percent of a thermal-reversible carrier.
  • the molded matrix may optionally further comprise up to about 55 weight percent of one or more release- modifying moldable excipients as described below, and optionally up to about 30 weight percent of various adjuvants such as for example plasticizers, gelling agents, colorants, stabilizers, preservatives, and the like as known in the art.
  • various adjuvants such as for example plasticizers, gelling agents, colorants, stabilizers, preservatives, and the like as known in the art.
  • the core or the first coating or the shell or a portion or portions thereof are prepared using a solvent-based molding process
  • the molded core or coating or shell or portion will typically comprise at least about 10 weight percent, e.g. at least about 12 weight percent or at least about 15 weight percent or at least about 20 weight percent or at least about 25 weight percent of a film- former.
  • the solvent-molded shell portion or portions may optionally further comprise up to about 55 weight percent of a release-modifying excipient.
  • the solvent-molded shell portion or portions may again also optionally further comprise up to about 30 weight percent total of various plasticizers, adjuvants, and excipients.
  • the core, or a portion thereof may function as a diffusional matrix.
  • the core or core portion preferably comprises active ingredient, distributed throughout an insoluble porous matrix, which contains pores or channels through which fluids can enter the core or core portion, and the active ingredient must diffuse in order to be released from the dosage form.
  • the rate of active ingredient release from the core portion will depend upon the area (A) of the matrix, the diffusion coefficient (D), the porosity (E) and tortuosity (T) of the matrix, the drag solubility (Cs) in the dissolution medium, and the drug concentration (Cp) in the dosage form.
  • the release of the active ingredient from the core or core portion may be described as controlled, prolonged, sustained, or extended.
  • the contribution to active ingredient dissolution from the subject core portion may follow zero-order, first-order, or preferably square-root of time kinetics.
  • the core may be made by compression or molding.
  • the core or core portion preferably comprises a release-modifying excipient selected from combinations of insoluble edible materials and pore formers.
  • the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated.
  • the core or portion thereof may function as an eroding matrix from which active ingredient dispersed in the core or core portion is liberated by the dissolution of successive layers of the core or core portion surface.
  • the rate of active ingredient release will depend on the dissolution rate of the matrix material in the core or core portion.
  • Particularly useful matrix materials for providing surface erosion include those that first absorb liquid, then swell and/or gel prior to dissolving.
  • the core or core portion thereof functions as an eroding matrix from which dispersed active ingredient is liberated in a sustained, extended, prolonged, or retarded manner
  • the core or core portion may be made by compression or by molding, and the core or core portion preferably comprises a release-modifying excipient selected from swellable erodible hydrophilic materials, pH-dependent polymers, insoluble edible materials, and combinations thereof.
  • the eroding matrix core or core portion preferably comprises a swellable erodible hydrophilic material.
  • one or more shell portions contain active ingredient which is released essentially immediately upon ingestion of the dosage form.
  • the shell portion preferably comprises materials which exhibit rapid dissolution in gastro-intestinal fluids.
  • one or more shell portions function as a diffusional membrane which contains pores through which fluids can enter the dosage form, and dissolved active ingredient can be released.
  • the rate of release of active ingredient from an underlying core portion will depend upon the total pore area in the shell portion, the pathlength of the pores, and the solubility and diffusivity of the active ingredient (in addition to its rate of release from the core portion itself).
  • the release of the active ingredient from the dosage form may be described as controlled, prolonged, sustained or extended.
  • the contribution to active ingredient dissolution from the subject shell portion may follow zero-order, first-order, or square-root of time kinetics.
  • the diffusional membrane shell portion preferably comprises a pore former and an insoluble material such as for example a film forming water insoluble polymer.
  • one or more shell portions function as an eroding matrix from which active ingredient dispersed in the shell portion is liberated by the dissolution of successive layers of the shell portion surface.
  • the rate of active ingredient release will depend on the dissolution rate of the matrix material in the shell portion.
  • Particularly useful matrix materials for providing surface erosion include those which first absorb liquid, then swell and/or gel prior to dissolving.
  • the eroding matrix shell portion preferably comprises a swellable erodible hydrophilic material.
  • one or more shell portions function as a barrier to prevent release therethrough of an active ingredient contained in the underlying core or first coating.
  • active ingredient is typically released from a portion of the dosage form which is not covered by the barrier shell portion.
  • the barrier shell portion preferably comprises a water insoluble material such as for example a water insoluble polymer.
  • one or more shell portions function as a delayed release coating to delay release of an active ingredient which is contained in the core or a portion thereof.
  • the lag-time for onset of active ingredient release may be governed by erosion of the coating or diffusion through the coating or a combination thereof.
  • the eroding matrix shell portion preferably comprises a swellable erodible hydrophilic material.
  • the thickness of the coating or shell portion is critical to the release properties of the dosage form.
  • the dosage forms of the invention can be made with precise control over coating and shell thickness.
  • the first coating or shell portions function to modify the release of an active ingredient which is contained in the core or the subject coating or shell portion
  • the first coating or shell portion or portions are made by the thermal cycle or thermal setting molding methods described herein.
  • Suitable thermal-reversible carriers for making the core, or the first coating, or the shell, or a portion thereof, by molding are thermoplastic materials typically having a melting
  • suitable thermal-reversible carriers for solvent-free molding include thermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides, low melting hydrophobic materials, thermoplastic polymers, thermoplastic starches, and the like.
  • Prefened thermal-reversible carriers include polyethylene glycol and polyethylene oxide.
  • Suitable thermoplastic polyalkylene glycols for use as thermal-reversible carriers include polyethylene glycol having molecular weight from about 100 to about 20,000, e.g. from about 1000 to about 8,000 Daltons.
  • Suitable thermoplastic polyalkalene oxides include polyethylene oxide having a molecular weight from about 100,000 to about 900,000 Daltons.
  • Suitable low-melting hydrophobic materials for use as thermal-reversible carriers include fats, fatty acid esters, phospholipids, and waxes which are solid at room temperature, fat-containing mixtures such as chocolate; and the like.
  • suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts.
  • Suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides.
  • suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid.
  • suitable waxes which are solid at room temperature include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax.
  • suitable thermoplastic polymers for use as thermal-reversible carriers include thermoplastic water swellable cellulose derivatives, thermoplastic water insoluble polymers, thermoplastic vinyl polymers, thermoplastic starches, and thermoplastic resins, and combinations thereof.
  • Suitable thermoplastic water swellable cellulose derivatives include include hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), carboxymethylcellulose (CMC), cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxybutylcellulose (HBC), hydroxyethylcellulose (HEC), hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylethylcellulose, and salts, derivatives, copolymers, and combinations thereof.
  • HPMC hydroxypropylmethyl cellulose
  • MC methyl cellulose
  • CMC carboxymethylcellulose
  • HPC hydroxypropyl cellulose
  • HBC hydroxybutylcellulose
  • HEC hydroxyethylcellulose
  • thermoplastic water insoluble polymers include ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers, and the like and derivatives, copolymers, and combinations thereof.
  • Suitable thermoplastic vinyl polymers include polyvinylacetate, polyvinyl alcohol, and polyvinyl pynolidone (PVP).
  • suitable thermoplastic starches for use as thermal-reversible carriers include those disclosed in U.S. Patent No. 5,427,614, which is inco ⁇ orated herein by reference.
  • thermoplastic resins for use as thermal-reversible carriers include dammars, mastic, rosin, shellac, sandarac, and glycerol ester of rosin.
  • the thermal-reversible carrier for making the core, or a portion thereof, by molding is selected from polyalkylene glycols, polyalkaline oxides, and combinations thereof.
  • Suitable release-modifying excipients for making the core, or the shell, or a portion thereof, by solvent free or solvent based molding include but are not limited to swellable erodible hydrophilic materials, pH-dependent polymers, pore formers, and insoluble edible materials.
  • suitable release-modifying excipients for making the core, or the shell, or a portion thereof, by molding include hydroxypropylmethylcellulose, polyethylene oxide, ammonio methacrylate copolymer type B, and shellac, and combinations thereof.
  • Suitable swellable erodible hydrophilic materials for use as release-modifying excipients for making the core, or the shell, or a portion thereof by a solvent-free molding process include water swellable cellulose derivatives, polyalkalene glycols, thermoplastic polyalkalene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, and swelling cross-linked polymers, and derivitives, copolymers, and combinations thereof.
  • suitable water swellable cellulose derivatives include sodium carboxymethylcellulose, cross- linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose,hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylethylcellulose.
  • suitable polyalkalene glyclols include polyethylene glycol.
  • suitable thermoplastic polyalkalene oxides include poly (ethylene oxide).
  • acrylic polymers include potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL (high- molceular weight cross-linked acrylic acid homopolymers and copolymers), and the like.
  • suitable hydrocolloids include alginates, agar, guar gum, locust bean gum, kappa canageenan, iota canageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan.
  • Suitable clays include smectites such as bentonite, kaolin, and laponite; magnesium trisilicate, magnesium aluminum silicate, and the like, and derivatives and mixtures thereof.
  • suitable gelling starches include acid hydrolyzed starches, swelling starches such as sodium starch glycolate, and derivatives thereof.
  • suitable swelling cross-linked polymers include cross-linked polyvinyl pynolidone, cross-linked agar, and cross-linked carboxymethylcellose sodium.
  • Suitable pH-dependent polymers for use as release-modifying moldable excipients for making the molded matrix or molded core or molded shell or a portion thereof by molding include enteric cellulose derivatives, for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1 :2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1 :1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L; and the like, and derivatives,
  • Suitable insoluble edible materials for use as release-modifying excipients making the core, or the shell, or a portion thereof by molding include water-insoluble polymers, and low-melting hydrophobic materials.
  • suitable water-insoluble polymers include ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof.
  • Suitable low-melting hydrophobic materials include fats, fatty acid esters, phospholipids, and waxes.
  • suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts.
  • suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides.
  • Suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid.
  • suitable waxes include camauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate; and the like.
  • Suitable pore formers for use as release-modifying excipients for making the molded matrix, the core, the shell, or a portion thereof by molding include water-soluble organic and inorganic materials. In one embodiment the pore former is hydroxypropylmethylcellulose.
  • suitable water-soluble organic materials include water soluble polymers including water soluble cellulose derivatives such as hydroxypropylmethylcellulose, and hydroxypropylcellulose; water soluble carbohydrates such as sugars, and starches; water soluble polymers such as polyvinylpynolidone and polyethylene glycol, and insoluble swelling polymers such as microcrystalline cellulose.
  • suitable water soluble inorganic materials include salts such as sodium chloride and potassium chloride and the like and/or mixtures thereof.
  • the core may be in a variety of different shapes.
  • the core may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, truncated cone, cylinder, sphere, torus, or the like.
  • the core may have the shape of a torus, cylinder, or tmncated cone.
  • the core has one or more major faces.
  • the core surface typically has two opposing major faces formed by contact with the upper and lower punch faces in the compression machine.
  • the core surface typically further comprises a "belly-band" located between the two major faces, and formed by contact with the die walls in the compression machine.
  • exemplary core shapes which may be employed include tablet shapes formed from compression tooling shapes described by "The Elizabeth Companies Tablet Design Training Manual” (Elizabeth Carbide Die Co., Inc., p. 7 (McKeesport, Pa.) (inco ⁇ orated herein by reference) as follows (the tablet shape conesponds inversely to the shape of the compression tooling): 1. Shallow Concave.
  • the core comprises multiple portions, for example a first portion and a second portion.
  • the portions may be prepared by the same or different methods and mated using various techniques, such as the thermal cycle molding and thermal setting molding methods described herein.
  • the first and second portions may both be made by compression, or both may be made by molding.
  • one portion may be made by compression and the other by molding.
  • the compression module of copending U.S. patent application Serial No. 09/966,509, pp. 16-27, the disclosure of which is inco ⁇ orated herein by reference, may be employed to make the compressed portion.
  • the molded portion may be made using the thermal cycle molding module described in U.S. patent application Serial No. 09/966,497, pp.
  • the shell typically has a thickness of about 500 to about 4000 microns. In embodiments wherein the shell or a portion thereof is prepared by a solvent-based molding process, the shell typically has a thickness of less than about 800 microns, e.g. about 100 to about 600 microns, e.g. about 150 to about 400 microns.
  • the shell or a portion thereof is prepared by molding using a solvent based process.
  • the solvent-molded shell typically comprises at least about 10 weight percent of a film- former.
  • the solvent-molded shell may optionally further comprise up to about 55 weight percent of a release-modifying agent.
  • the solvent-molded shell may again also optionally further comprise up to about 30 weight percent total of various plasticizers, adjuvants and excipients.
  • the shell In embodiments in which the shell is prepared by molding, either by a solvent-free process or by a solvent-based process, the shell typically is substantially free of pores in the diameter range of 0.5 to 5.0 microns, i.e. has a pore volume in the pore diameter range of 0.5 to 5.0 microns of less than about 0.02 cc/g, preferably less than about 0.01 cc/g, more preferably less than about 0.005 cc/g. Typical compressed materials have pore volumes in this diameter range of more than about 0.02 cc/g.
  • Pore volume, pore diameter and density may be determined using a Quantachrome Instruments PoreMaster 60 mercury intrusion porosimeter and associated computer software program known as "Porowin.” The procedure is documented in the Quantachrome Instruments PoreMaster Operation Manual.
  • the PoreMaster determines both pore volume and pore diameter of a solid or powder by forced intrusion of a non-wetting liquid (mercury), which involves evacuation of the sample in a sample cell (penetrometer), filling the cell with mercury to sunound the sample with mercury, applying pressure to the sample cell by: (i) compressed air (up to 50 psi maximum); and (ii) a hydraulic (oil) pressure generator (up to 60000 psi maximum).
  • Intraded volume is measured by a change in the capacitance as mercury moves from outside the sample into its pores under applied pressure.
  • High pressure fluid (Dila AX, available from Shell Chemical Co.).
  • the samples remain in sealed packages or as received in the dessicator until analysis.
  • the vacuum pump is switched on, the mercury vapor cold trap is filled with liquid nitrogen, the compressed gas supply is regulated at 55 psi., and the instrument is turned on and allowed a warm up time of at least 30 minutes.
  • the empty penetrometer cell is assembled as described in the instrument manual and its weight is recorded. The cell is installed in the low pressure station and "evacuation and fill only" is selected from the analysis menu, and the following settings are employed:
  • Fine Evacuation time 1 min.
  • Fine Evacuation rate 10 Coarse Evacuation time: 5 min.
  • the cell (filled with mercury) is then removed and weighed.
  • the cell is then emptied into the mercury reservoir, and two tablets from each sample are placed in the cell and the cell is reassembled.
  • the weight of the cell and sample are then recorded.
  • the cell is then installed in the low-pressure station, the low-pressure option is selected from the menu, and the following parameters are set:
  • the shell or a portion thereof comprises an active ingredient intended to have immediate release from the dosage form
  • the shell or that portion thereof is preferably prepared via the solvent-free molding method described above.
  • the thermal-reversible carrier is preferably selected from polyethylene glycol with weight average molecular weight from about 1450 to about 20000, polyethylene oxide with weight average molecular weight from about 100,000 to about 900,000, and the like.
  • the release-modifying agent in the shell preferably comprises a swellable erodible hydrophilic material, and may optionally comprise a secondary gelling agent such as for example cross-linked carboxymethylcellulose, cross- linked polyvinylpynolidone, or sodium starch glycolate.
  • At least one active ingredient contained within the dosage form exhibits a delayed and sustained release profile.
  • delayed then sustained release profile it is meant that the release of that particular active ingredient from the dosage form is delayed for a pre-determined time after ingestion by the patient, and the delay period ("lag time") is followed by sustained (prolonged, extended, or retarded) release of that active ingredient.
  • the shell or shell portion provides for the delay period, and is preferably substantially free of the active ingredient to be released in a delayed then sustained manner.
  • the delayed then sustained release active ingredient is preferably contained within the conesponding underlying core portion, or optionally dispersed throughout the entire core.
  • the core or core portion may function for example as an eroding matrix or a diffusional matrix, or an osmotic pump.
  • the core portion functions as a diffusional matrix through which active ingredient is liberated in a sustained, extended, prolonged, or retarded manner
  • the core portion preferably comprises a release-modifying excipient selected from combinations of insoluble edible materials and pore-formers.
  • the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated.
  • the core portion functions as an eroding matrix from which dispersed active ingredient is liberated in a sustained, extended, prolonged, or retarded manner
  • the core portion preferably comprises a release-modifying compressible or moldable excipient selected from swellable erodible hydrophilic materials, pH-dependent polymers, and combinations thereof.
  • At least one active ingredient contained within the dosage form exhibits a double pulse release profile.
  • double pulse it is meant that a first portion of active ingredient is released essentially immediately upon contacting of the dosage form with a liquid medium, followed by a delay period, followed by immediate release of a second portion of active ingredient.
  • the shell portion preferably comprises materials which exhibit rapid dissolution in gastro-intestinal fluids.
  • the immediate release shell portion or portions may comprise readily soluble materials selected from water soluble or water swellable thermoplastic film formers, water soluble or water swellable thickeners, crystallizable and non-crystallizable carbohydrates.
  • suitable water soluble or water swellable thermoplastic film formers may be selected from water swellable cellulose derivatives, thermoplastic starches, polyalkalene glycols, polyalkalene oxides, and amo ⁇ hous sugar glass, and combinations thereof.
  • suitable film formers may be selected from film forming water soluble polymers such as for example water soluble vinyl polymers, water soluble polycarbohydrates, water swellable cellulose derivatives, and water soluble copolymers; film-forming proteins, and combinations thereof.
  • suitable thickeners may be selected from gelling polymers or hydrocolloids; gelling starches, and crystallizable carbohydrates.
  • suitable non-crystallizable carbohydrates may be selected from polydextrose, starch hydrolysates, and non-crystallizable sugar alcohols.
  • the immediate release shell portion will preferably be breached or dissolved within 30 minutes in 900 ml water or 0.1 N HCl, or phosphate buffer
  • Example 1 Dosage forms according to the invention were made as follows. First, cores were prepared using the following ingredients:
  • the pseudoephedrine HCl crystal, hydroxypropyl methylcellulose, polyethylene oxide and FD&C Blue #1 were mixed in a plastic bag for 1-2 minutes.
  • This powder mixture was added to the (5 qt) bowl of a planetary mixer (Hobart Co ⁇ ., Dayton, OH).
  • the alcohol was added to the powder mixture while mixing at low speed.
  • the ingredients were mixed for 10 minutes.
  • the resulting granulation was removed from the bowl and was dried at room temperature for 12 to 16 hours to remove all residual solvent.
  • the granulation was screened through a 20-mesh screen and put into a plastic bag. Magnesium stearate was added to the dry granules, followed by mixing for 3 minutes.
  • Cores were then prepared by pressing the granulation using a Manesty Beta-press (Thomas Engineering, Inc., Hoffman Estates, IL). A round, concave punch and die unit having 0.4455" diameter was used for compression. Granulation was fed into the cavity of the press and compressed into solid cores.
  • a first coating material was next prepared from the following ingredients:
  • polycaprolactones were first added to a beaker.
  • the isopropanol was added thereto and the combination was mixed with a spatula until a uniform dispersion was obtained.
  • thermal cycle molding module as described in copending U.S. Application Serial No. 09/966,497 at pages 27-51, the disclosure of which is inco ⁇ orated herein by reference, was used to apply the first coating material onto the cores.
  • the thermal cycle molding module was a laboratory scale unit and comprised a single mold made from an upper mold assembly and a lower mold assembly. The lower mold assembly was first cycled to a cold
  • a beaker was submersed in a 70°C water bath (Ret digi-visc; Antal-Direct, Wayne,
  • the polyethylene glycol (PEG) was added to the beaker and was mixed with a spatula until melted.
  • the molten PEG was then introduced into a rubber capsule-shape mold (20.5 mm x 12.6 mm x 10.7 mm).
  • Additional molten PEG was added to fill the mold.
  • the mold was then allowed to cool for five minutes, hardening the PEG into a shell.
  • the resulting dosage form comprising a PEG shell was removed from the mold.
  • Example 2 Dosage forms of the invention are made in a continuous process using an apparatus comprising three thermal cycle molding modules linked in series via two transfer devices as described at pages 14-16 of copending U.S. Application Serial No. 09/966,939, the disclosure of which is inco ⁇ orated herein by reference.
  • the dosage forms have the structure shown in
  • Figure 7 each comprise a core having a toroidal shape (i.e., donut-shaped) coated first with an first coating on its entire exterior surface except for the surface inside the hole of the donut.
  • the dosage forms further comprise a shell completely overlying the core and the first coating, thereby forming the outermost layer of the dosage form.
  • the core is made of a core flowable material comprising the following ingredients:
  • the first coating is made from an first coating flowable material comprising the following ingredients:
  • the polycaprolactones are first mixed with the isopropanol until a uniform dispersion is obtained.
  • the shell is made from a shell flowable material comprising the following ingredient:
  • the thermal cycle molding modules have the general configuration shown in Figure 3 of copending U.S. Application Serial No. 09/966,939, which depicts a thermal cycle molding module 200 comprising a rotor 202 around which a plurality of mold units 204 are disposed.
  • Each thermal cycle molding module includes its own reservoir 206 (see Figure 4 of copending U.S. Application Serial No. 09/966,939) for holding the core flowable material, the first coating flowable material, and the shell flowable material, respectively.
  • each thermal cycle molding module is provided with a temperature control system for rapidly heating and cooling the mold units.
  • Figures 55 and 56 of copending U.S. Application Serial No. 09/966,939 depict the temperature control system 600.
  • the cores are made in a first thermal cycle molding module, which is linked via a first transfer device to a second thermal cycle molding module, which is in turn linked via a second transfer device to a third thermal cycle molding module.
  • the first thermal cycle molding module has the specific configuration shown in Figure 26A of copending U.S. Application Serial No. 09/966,939.
  • the first thermal cycle molding module comprises center mold assemblies 212 and upper mold assemblies 214 as shown in Figure 26C, which mate to form mold cavities having the shape of a donut. As rotor 202 rotates, the opposing center and upper mold assemblies close. Core flowable material, which is heated to a flowable state in reservoir 206, is injected into the resulting mold cavities.
  • Both the first and second transfer devices have the structure shown as 300 in Figure 3 of copending U.S. Application Serial No. 09/966,939.
  • Each comprises a plurality of transfer units 304 attached in cantilever fashion to a belt 312 as shown in Figures 68 and 69 of copending U.S. Application Serial No. 09/966,939.
  • the transfer devices rotate and operate in sync with the thermal cycle molding modules to which they are coupled.
  • Transfer units 304 comprise retainers 330 for holding the partially made dosage forms as they travel around each transfer device.
  • the first transfer device transfers the donut-shaped cores to the second thermal cycle molding module, which applies the first coating to the cores.
  • the second thermal cycle molding module is of the type shown in Figure 28 A of copending U.S. Application Serial No. 09/966,939.
  • the mold units 204 of the second thermal cycle molding module comprise upper mold assemblies 214, rotatable center mold assemblies 212 and lower mold assemblies 210 as shown in Figure 28C.
  • Donut-shaped cores are continuously transfened to the mold assemblies, which then close over the cores.
  • First coating flowable material which is heated to a flowable state in reservoir 206, is injected into the mold cavities created by the closed mold assemblies. The temperature of the first coating flowable material is then decreased, hardening it.
  • the mold assemblies open and eject the partially coated cores, which are received by the second transfer device. Coating is performed in two steps, each half of the cores being coated separately as shown in the flow diagram of Figure 28B of copending U.S. Application Serial No. 09/966,939 via rotation of the center mold assembly.
  • the construction of the mold assemblies in the second thermal cycle molding module is such that the portion of the donut-shaped cores inside the hole is masked by the mold assemblies during application of the first coating.
  • the inside surface of the mold assembly has a masking protrasion to cover the hole of the donut-shaped cores. Accordingly, the surface of the cores inside the hole remains uncoated upon exiting the second thermal cycle molding module.
  • the second transfer device carries the partially coated cores to the third thermal cycle molding module, which applies the shell.
  • the third thermal cycle molding module is also of the type shown in Figures 28A-C of copending U.S. Application Serial No. 09/966,939 comprising rotatable center mold assemblies 212, lower mold assemblies 210 and upper mold assemblies 214. Cores bearing the first coating are continuously transfened to the mold assemblies of the third thermal cycle molding module.
  • Shell flowable material which is heated to a flowable state in reservoir 206, is injected into the mold cavities created by the closed mold assemblies holding the cores. The temperature of the shell flowable material is then decreased, hardening it.
  • the mold assemblies open and eject the finished dosage forms.
  • Shell coating is performed in two steps, each half of the dosage forms being coated separately as shown in the flow diagram of Figure 28B of copending U.S. Application Serial No. 09/966,939 via rotation of the center mold assembly.

Abstract

A dosage form comprises: (a) at least one active ingredient: (b) a core having a first surface portion upon which resides a first coating and a second surface portion which is substantially free of the first coating; and (c) a shell which resides upon at least a portion of the second surface portion, wherein the shell comprises a different material from the first coating. In another embodiment, the dosage form comprises: (a) at least one active ingredient; (b)a core comprising a center portion having an exterior surface and an annular portion having an exterior surface and an interior surface, wherein the annular portion interior surface is in contact with at least a portion of the center portion exterior surface, and a coating resides on at least a portion of the annular portion exterior surface; and (c) a shell which resides upon at least a portion of the exterior surface of the center portion, wherein the shell comprises a different material than the impermeable coating. In another embodiment, the dosage form comprises: (a) at least one active ingredient; (b) a core having an outer surface and a cavity which extends at least partially through the core such that the core outer surface has at least a first opening therein; (c) a first coating which resides on at least a portion of the core outer surface, wherein the first shell portion comprises a different material from the first coating; and (d) a first shell portion which is adjacent to the first opening and covers at least the first opening.

Description

MODIFIED RELEASE DOSAGE FORMS
BACKGROUND OF THE INVENTION
1. Field of the Invention
[0001] This invention relates to modified release dosage forms such as modified release pharmaceutical compositions. More particularly, this invention relates to modified release dosage forms having partial coatings, for example dosage forms partially coated by first material for controlling the surface area through which dissolution of at least one active ingredient contained within the dosage form takes place upon contacting of the dosage form with a liquid medium.
2. Background Information
[0002] Modified release pharmaceutical dosage forms have long been used to optimize drug delivery and enhance patient compliance, especially by reducing the number of doses of medicine the patient must take in a day. For this purpose, it is often desirable to modify the rate of release of drug (one prefened type of active ingredient) from a dosage form into the gastrointestinal (g.i.) fluids of a patient, especially to slow the release to provide prolonged action of the drug in the body. In many cases, it is particularly desirable to provide a constant (i.e. zero-order) release rate of the drug. For patients taking a particular medication on a chronic basis, matching the rate of drug absorption into the circulatory system with its rate of metabolism and excretion from the body could enable achievement of a steady state in which a relatively constant level of drug is maintained in the blood. This can have the advantageous effect of minimizing undesirable side effects which may occur at high blood levels, while maintaining a therapeutic level of the active ingredient (e.g. drug) in the body.
[0003] The rate at which an orally delivered pharmaceutical active ingredient reaches its site of action in the body depends on a number of factors, including the rate and extent of drug absoφtion through the g.i. mucosa. To be absorbed into the circulatory system (blood), the drug must first be dissolved in the g.i. fluids. For many drugs, diffusion across the g.i. membranes is relatively rapid compared to dissolution. In these cases, the dissolution of the active ingredient is the rate limiting step in drug absoφtion, and controlling the rate of dissolution allows the formulator to control the rate of drug absoφtion into the circulatory system of a patient.
[0004] The dissolution rate of a drug in the g.i. fluids depends, among other things, on the drug's solubility and the effective surface area of contact between dissolving drug particles and the dissolution medium. The Nernst-Brunner equation describes the dissolution rate of a dmg:
dC/dt = (D K2 S) (1/vh) (Cs - Ct) where dC/dt is the drug dissolution rate, D is the diffusion coefficient for the drug, K is a dissolution constant, h is the effective thickness of the diffusion layer, S is the surface area of contact between the drug and the dissolution medium, Cs is the solubility of the drug in the medium (i.e. the concentration of a saturated solution at the surface of the dissolving particle), and Ct is the concentration of drug in the bulk solution at a time t. In the body, the absoφtion process constantly removes drug from the g.i. tract, usually at a rate faster than that of drug dissolution. This creates what is known as a "sink" condition, where , the concentration of drug in the bulk solution, is much less than Cs, the concentration of dmg in the saturated region at the surface of the dissolving particle.
[0005] The primary non-constant terms in this model are S, the surface area of contact between the dmg and the dissolution medium, and h, the effective thickness of the diffusion layer. In a typical sustained release matrix tablet, the surface area of contact between the dmg and dissolution medium decreases over time, while in a diffusional matrix system, the path-length for diffusion increases over time, as the dissolution "front" recedes from the surface towards the center of the dosage form. The combination of these effects results in a decrease in dissolution rate of the dmg over time.
[0006] Various dosage forms have been proposed to approach a constant dissolution rate by employing dosage form shapes in which the surface area of contact between the dmg and dissolution medium increase at the same rate as the path-length for diffusion. Most involve coating a portion of the dosage form with an impermeable layer to control the surface area available for dissolution of the dmg. See for example, U.S. Patent Nos. 3,146,169; 3,851,638; 4,663,147; 4,816,262; and 6,110,500. One shape of particular interest has been that of a torus. Another has been that of a truncated cone. The primary limitation of such designs has been laborious manufacturing processes which typically include making a core, coating the core with impermeable material, then removing a portion of the core and coating to create the area for drug dissolution. These types of processes have not been shown to be suitable for commercial scale manufacture.
[0007] U.S. Patent No. 4,803,076 discloses a tablet press for use in the manufacture of a tablet in the approximate shape of a tmncated cone, as well as an apparatus for removal of a portion of the coated dosage form in order to expose an area for dissolution of the dmg. However, the dosage form disclosed therein suffers from the limitation of possessing a flat cylinder or disc shaped central portion, defined by the straight die walls, and a "land" area defined by the perimeter of the upper and lower punches in the compression machine.
[0008] There remains an unmet need for a commercially efficient method of producing a partial coating on a dosage form. Such partial coatings would be useful for controlling the surface area through which dmg is released from the dosage form, including providing a surface area for drag release from the dosage form that remains constant during the drag release period; and providing a surface area for drug release from the dosage form that increases during the dmg release period. The apparatus and methods described in copending U.S. Patent Application Serial Nos. 09/966,497, pages 27-51 and 09/966,450, pages 57-63, the disclosures of which are incoφorated herein by reference, advantageously enable manufacture of partially coated dosage forms without the need for a partial coating removal step.
[0009] It would additionally be desirable to have a method for making such partially coated dosage forms with a further shell portion, residing upon at least a portion of the uncoated core surface, for example to deliver an immediate release loading dose of one or more active ingredients; or to confer a unique elegant appearance. It would be particularly desirable for the shell portion to reside upon and cover only the uncoated portion of the core surface, and not the first coating material. In would further be desirable to make the shell portion optionally removable by the consumer or healthcare professional prior to ingestion of the dosage form in order to customize dosing. Another beneficial use for such partially coated dosage forms include as containers for holding liquid or solid materials, which may be removed from the dosage form for example by removing the shell portion, and pouring through the uncoated portion prior to use. It would additionally be desirable to have a modified release dosage form comprising an inactive core having a specialized shape or structure, and comprising for example swelling or gelling excipients, which effect the release of active ingredient from one or more shell compartments.
[0010] It would also be desirable to coat non-conventionally shaped dosage forms that provide constant controlled release rates by virtue of their shape with a shell of a more regular shape to facilitate swallowing, or reduce friability (susceptibility to breakage). For example it would be useful to have dosage forms comprising a core in the shape of a torus or truncated cone containing an active ingredient therein, protected by a spheroid or elypsoid shaped shell. Such dosage forms would be easy to swallow, maintain their stractural integrity during handling and shipping, and yet provide the functional benefits confened by the shape of the core. The apparatus and methods of copending U.S. Patent Application Serial Nos. 09/966,497, pages 27-51 and 09/966,450, pages 57-63 advantageously enable the production of such dosage forms according to this invention.
[0011] It is one object of this invention to provide a dosage form in which at least one active ingredient contained therein exhibits a modified release profile upon contacting of the dosage form with a liquid medium. It is another object of this invention to provide a dosage form in which the surface area for dissolution of at least one active ingredient contained therein is controlled by a partial coating. Other objects features and advantages of the invention will be apparent to those skilled in the art from the detailed description set forth below.
SUMMARY OF THE INVENTION [0012] In one embodiment, the dosage form of this invention comprises: (a) at least one active ingredient; (b) a core having a first surface portion upon which resides an first coating and a second surface portion which is substantially free of the first coating; and (c) a shell which resides upon at least the second surface portion, wherein the shell comprises a different material from the first coating.
[0013] In another embodiment, the core comprises a cavity therein such that at least part of the second surface portion of the core is located within the cavity, and the shell resides upon at least a part of the second surface portion of the core which is located within the cavity. [0014] In another embodiment, the cavity is an aperture which extends entirely through the core such that the aperture provides the second surface portion of the core.
[0015] In another embodiment, the shell resides upon at least part of both the first coating and the second surface portion of the core.
[0016] In another embodiment, the shell resides over all the first coating and the second surface of the core.
[0017] In another embodiment, the shell comprises a material selected from water soluble or water swellable thermoplastic film formers, water soluble or water swellable thickeners, crystallizable and non-crystallizable carbohydrates.
[0018] In another embodiment, the core is in the shape of a tmncated cone.
[0019] In another embodiment, the dosage form of this invention comprises: (a) at least one active ingredient; (b) a core comprising (i) a center portion having an exterior surface and (ii) an annular portion having an exterior surface and an interior surface, wherein the annular portion interior surface is in contact with at least portion of the center portion exterior surface, and an first coating resides on at least a portion of the annular portion exterior surface; and (c) a shell which resides upon at least a portion of the exterior surface of the center portion, wherein the shell comprises a different material from the first coating.
[0020] In another embodiment, the core comprises at least one active ingredient.
[0021] In another embodiment, the center portion of the core comprises at least one active ingredient.
[0022] In another embodiment, the annular portion of the core comprises at least one active ingredient. [0023] In another embodiment, the center portion of the core comprises a first active ingredient and the annular portion of the core comprises a second active ingredient.
[0024] In another embodiment, the shell comprises at least one active ingredient.
[0025] In another embodiment, both the shell and the core each comprise at least one active ingredient.
[0026] In another embodiment, the first coating resides upon the entire annular portion exterior surface.
[0027] In another embodiment, the shell resides upon the entire first coating and the center portion surface.
[0028] In another embodiment, the shell comprises a material selected from water soluble or water swellable thermoplastic film formers, water soluble or water swellable thickeners, crystallizable and non-crystallizable carbohydrates.
[0029] In another embodiment, the core annular portion has the shape of a torus.
[0030] In yet another embodiment, the dosage form of this invention comprises: (a) at least one active ingredient; (b) a core having an outer surface and a cavity which extends at least partially through the core such that the core outer surface has at least a first opening therein; (c) a first coating which resides on at least a portion of the core outer surface, wherein the first shell portion comprises a different material from the first coating; and (d) a first shell portion which is adjacent to the first opening and covers at least the first opening.
[0031] In another embodiment, the cavity extends entirely through the core such that the core has first and second openings therein, the first shell portion is adjacent to and covers at least the first opening, and the dosage form additionally comprises a second shell portion which is adjacent to and covers at least the second opening, wherein the first and second shell portions each comprise a material different from the first coating.
[0032] In another embodiment, the core has the shape of a torus.
[0033] In another embodiment, the first shell portion comprises at least one water soluble material.
[0034] In another embodiment, the second shell portion comprises at least one water soluble material.
[0035] In another embodiment, the first and second shell portions each comprise at least one water soluble material.
[0036] In another embodiment, the first shell portion or the core or a combination thereof comprises at least one active ingredient.
[0037] In another embodiment, the first shell portion, second shell portion or the core or a combination thereof comprises at least one active ingredient.
[0038] In another embodiment, the first shell portion resides upon at least a portion of the first coating.
[0039] In another embodiment, the shell resides upon the entire outer surface of the first coating.
[0040] In another embodiment, at least a portion of the active ingredient is released in a sustained manner.
[0041] In another embodiment, the dosage form releases at least a portion of the active ingredient at a substantially constant rate. [0042] In another embodiment, the release of at least one active ingredient from the center portion of the core meets USP specifications for immediate release tablets containing the particular active ingredient employed.
[0043] In another embodiment, the center portion of the core provides a time delay to the release of active ingredient from the annular portion of the core.
[0044] In another embodiment, the core functions as an eroding matrix.
[0045] In another embodiment, the core functions as a diffusional matrix.
[0046] In another embodiment, the core comprises a release-modifying excipient selected from the group consisting of swellable erodible hydrophillic materials, insoluble edible materials, pH-dependent polymers, and mixtures thereof.
[0047] In another embodiment, the first coating comprises at least about 30 weight percent of a thermal reversible carrier, based on the weight of the first coating.
[0048] In another embodiment, the first coating comprises at lease about 10 weight percent of a film former selected from the group consisting of film-forming water soluble polymers, film- forming proteins, film- forming water insoluble polymers, and film-forming pH-dependent polymers.
[0049] In another embodiment, the film-former for making the core or shell or portion thereof by molding may be selected from cellulose acetate, ammonio methacrylate copolymer type B, shellac, hydroxypropylmethylcellulose, and polyethylene oxide, and combinations thereof.
[0050] In another embodiment, the shell or shell portion comprises thermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides, and combinations thereof. [0051] In another embodiment, the shell portion is breached or dissolved within 30 minutes in 900 ml water or 0.1 N HCl, or phosphate buffer solution at 37°C with stirring by a USP type 2 (Paddle method) at 50 or 100 φm.
[0052] In another embodiment, the release of at least one active ingredient follows a double pulse profile.
[0053] In another embodiment, the release of at least one active ingredient follows a delayed then sustained release profile.
[0054] In another embodiment, release of a first portion of active ingredient from the dosage form meets USP specifications for immediate release tablets containing the particular active ingredient employed, and release of a second portion of active ingredient from the dosage form follows a sustained, prolonged, extended, or retarded release profile.
[0055] In another embodiment, the immediately released first portion of active ingredient is contained in the shell, and the sustained release second portion of active ingredient is contained in the core.
[0056] In another embodiment, the release of one or more active ingredients follows a zero-order, first-order, or square root of time profile.
[0057] In another embodiment, the shell is substantially free of pores in the diameter range of 0.5 to 5.0 microns.
[0058] In yet another embodiment, this invention provides a method of applying a partial coating to a core in a dosage form by thermal cycle molding.
[0059] In yet another embodiment, this invention provides a method of applying a partial coating to a core in a dosage form by thermal setting molding. [0060] In yet another embodiment, the first coating comprises up to about 55 weight percent of a release-modifying excipient selected from water-insoluble polymers and low- melting hydrophobic materials and combinations thereof.
[0061] In yet another embodiment, the release-modifying excipeint is a polycaprolactone.
BRIEF DESCRIPTION OF THE DRAWINGS [0062] Figs. 1 A and IB depict overhead and side views of one embodiment of the dosage form of this invention.
[0063] Figs. 2 A and 2B depict overhead and side views of another embodiment of the dosage form of this invention.
[0064] Figs. 3 A and 3B depict overhead and side views of another embodiment of the dosage form of this invention.
[0065] Figs. 4 A and 4B depict overhead and side views of another embodiment of the dosage form of this invention.
[0066] Figs. 5 A and 5B depict overhead and side views of another embodiment of the dosage form of this invention.
[0067] Fig. 6 depicts the % release of active ingredient vs. hours measured for the dosage form of Example 1.
[0068] Figs. 7A and 7B depict another embodiment of a dosage form according to the invention. DETAILED DESCRIPTION OF THE P VENTION [0069] As used herein, the term "dosage form" applies to any solid object, semi-solid, or liquid composition designed to contain a specific pre-determined amount (i.e. dose) of a certain ingredient, for example an active ingredient as defined below. Suitable dosage forms may be pharmaceutical drag delivery systems, including those for oral administration, buccal administration, rectal administration, topical or mucosal delivery, or subcutaneous implants, or other implanted drug delivery systems; or compositions for delivering minerals, vitamins and other nutraceuticals, oral care agents, flavorants, and the like. Preferably the dosage forms of the present invention are considered to be solid, however they may contain liquid or semi-solid components. In a particularly prefened embodiment, the dosage form is an orally administered system for delivering a pharmaceutical active ingredient to the gastro-intestinal tract of a human.
[0070] The dosage forms of the present invention contain one or more active ingredients which are released therefrom upon contact of the dosage form with a liquid medium, for example a dissolution medium. Examples of suitable dissolution media for the dosage form of the invention include gastrointestinal fluids for embodiments in which the dosage form is orally ingested, mucosal fluids for embodiments in which the dosage form is for buccal delivery, intracellular fluids for embodiments in which the dosage form is an implant, moisture in the soil for embodiments in which the dosage form delivers a fertilizer or plant nutrient, and synthetic dissolution media, e.g. water or aqueous buffer solutions, for testing the performance of the dosage form in vitro.
[0071] "Water soluble," as used herein in connection with non-polymeric materials, shall mean from sparingly soluble to very soluble, i.e., not more than 100 parts water required to dissolve 1 part of the non-polymeric, water soluble solute. See Remington, The Science and Practice of Pharmacy, pp 208 - 209 (2000). "Water soluble," as used herein in connection with polymeric materials, shall mean that the polymer swells in water and can be dispersed at the molecular level to form a homogeneous dispersion or colloidal "solution."
[0072] The dosage forms of the invention exhibit modified release of one or more active ingredients contained therein. One or more active ingredients may be found in any portion of the dosage form, for example one or more active ingredients may be found within the core, the center portion, the shell portion, or coated or uncoated particles distributed therethrough. As used herein, the term "modified release" shall apply to dosage forms, matrices, particles, coatings, portions thereof, or compositions that alter the release of an active ingredient in any manner. Types of modified release include controlled, prolonged, sustained, extended, delayed, pulsatile, repeat action, and the like. Suitable mechanisms for achieving these types of modified release include diffusion, erosion, surface area control via geometry and/or impermeable barriers, or other mechanisms known in the art. Moreover, the modified release properties of the dosage form may be achieved through design of the core or a portion thereof, or the first coating, or the shell portion, or a combination of two or more of these parts of the dosage form.
[0073] In certain particularly prefened embodiments of this invention, the dosage form releases one or more active ingredients contained therein in a controlled manner, e.g. in a sustained, extended, prolonged, or retarded manner, more preferably at a substantially constant rate upon contacting of the dosage form with a liquid medium. In such embodiments, the core or center portion or shell or a portion thereof may function as a diffusional matrix or an eroding matrix.
[0074] The dosage form of the invention comprises a first coating which resides upon a first surface portion of the core. In certain embodiments, the first coating may function as a barrier to prevent release therethrough of an active ingredient contained in the underlying core portion. In such embodiments, active ingredient is typically released from a portion of the core which is not covered by the barrier coating portion. Such embodiments advantageously allow for control of the surface area for release of the active ingredient. In certain particular embodiments, for example, the surface area for release of active ingredient can be maintained substantially constant over time. In certain other particular embodiments, for example, the surface area for release of active ingredient can increase over time during the dissolution period of the dosage form. The surface area for release of active ingredient may be controlled by a combination of the size of the uncoated area on the core surface, and the overall shape of the core. In certain such embodiments, the barrier coating preferably comprises a water insoluble material such as for example a water insoluble polymer. Since surface area is one factor in the dissolution equation, controlling surface area for drag release advantageously enables a further degree of control over the release rate of the drag from the dosage form. In a particularly prefened embodiment, the release of at least one active ingredient follows substantially zero-order kinetics.
[0075] The dosage form also comprises a shell or shell portion that resides on (i.e., directly contacts) or covers (i.e., shields or screens but does not necessarily directly contact) at least a portion of the exterior surface of the core where no first coating is present. The shell may reside on or cover the entire portion of the core free of first coating. Alternately the shell may reside on only a portion of the uncoated core surface. Additionally, the shell may cover all, none, or a portion of the first coating as well. In a particularly prefened embodiment the shell resides upon only the portion of the core free of first coating, and does not contact the first coating. In another embodiment, the shell covers the entire portion of the core free of first coating, and connects with the first coating at an interface, but does not substantially cover the first coating. In yet another embodiment, the shell covers both the entire portion of the core free of first coating and the entire first coating. The shell comprises a material that is different from the first coating.
[0076] In certain embodiments in which the shell comprises the overall outer surface of the dosage form, the shell is preferably of a smooth overall shape, e.g. a spheroid, ellypsoid, or other easily swallowable shape such as those having rounded edges. Accordingly, the dosage form resists damage during transport and handling and is easy to swallow, despite the shape of the core inside.
[0077] A first embodiment of this invention is depicted in Figs. 1 A and IB. Figure 1 A depicts an overhead view and Fig. IB depicts a side view of a dosage form 2 which comprises a core 4 having a first surface portion 6 and second surface portions 8. A first coating 10 resides upon the first surface portion 6 of core 4. However, the second surface portion 8 of core 4 is substantially free of first coating 10. A shell 12 resides upon the second surface portion 8 of core 4.
[0078] Optionally, core 4 of the dosage form depicted in Figures 1 A and IB may contain a cavity as shown in Figures 2A and 2B, which respectively depict overhead and side views of a dosage form 202 which comprises a core 204 having a first surface portion 206, a cavity 205 and a second surface portion 208. A first coating 210 resides upon the first surface portion 206 of core 204. The second surface portion 208 of core 204 is defined at least in part by cavity 205 and the second surface portion 208 is substantially free of first coating 210. A shell 212 resides upon the second surface portion 208 of core 204.
[0079] Another embodiment of this invention is depicted in Figs. 3 A and 3B, which depict a further variation of the dosage form of Figures 1 A and IB. Figures 3 A and 3B depict overhead and side views of a dosage form 302 which comprises a core 304 having a first surface portion 306, an aperture 305 which extends completely through core 304 and a second surface portion 308. The second surface portion 308 of core 304 is defined by aperture 305. A first coating 310 resides upon the first surface portion 306 of core 304. Again, the second surface portion 308 is substantially free of first coating 310. A shell 312 resides upon the second surface portion 308 of core 304.
[0080] Another embodiment of this invention is depicted in Figs. 4A and 4B, which depict overhead and side views of dosage form 402, which comprises a core 404 made up of a center portion 405 sunounded by an annular portion 409. The center portion 405 has a surface 407, while the annular portion 409 has an exterior surface 411 and an interior surface 413. The annular portion interior surface 413 is in contact with a portion of the center portion surface 407. The annular portion exterior surface 410 is covered by a first coating 410. A shell, divided into first and second shell portions 415 reside upon a portion of the center portion surface 407
[0081] Another embodiment of this invention is depicted in Figs. 5 A and 5B, which depict overhead and side views of dosage form 502 which comprises a core 504 having an outer surface 506 and an inner surface 508 that is defined by an aperture 505 extending completely through the core 504. A first coating 510 resides upon the outer surface 506 of core 504. The inner surface 508 is substantially free of first coating 510. A first shell portion 513 covers one end of the aperture 505, and a second shell portion 515 covers the opposite end of the aperture 505. Accordingly, a void is created inside the dosage form.
[0082] Figure 7 A depicts another embodiment of the invention, hi this embodiment, the dosage form 702 comprises a core 704 having the shape of a torus. This shape has been found to be especially conducive to controlled release of an active ingredient. The core 704 has an outer surface 706 and an inner surface 708 that is defined by an aperture 705. A first coating 710 resides on the outer surface 706 of the core 704, as shown in Fig. 7B. The inner surface 708 is substantially free of first coating 710. A shell 715 encloses the entire core 704 and first coating 710. The shell 715 has a generally elliptical shape.
[0083] Suitable active ingredients for use in this invention include for example pharmaceuticals, minerals, vitamins and other nutraceuticals, oral care agents, flavorants and mixtures thereof. Suitable pharmaceuticals include analgesics, anti-inflammatory agents, antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, decongestants, contraceptives, diuretics, expectorants, gastrointestinal agents, migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tract agents and mixtures thereof.
[0084] Suitable oral care agents include breath fresheners, tooth whiteners, antimicrobial agents, tooth mineralizers, tooth decay inhibitors, topical anesthetics, mucoprotectants, and the like.
[0085] Suitable flavorants include menthol, peppermint, mint flavors, fruit flavors, chocolate, vanilla, bubblegum flavors, coffee flavors, liqueur flavors and combinations and the like.
[0086] Examples of suitable gastrointestinal agents include antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum sodium carbonate; stimulant laxatives, such as bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures thereof; H2 receptor antagonists, such as famotadine, ranitidine, cimetadine, nizatidine; proton pump inhibitors such as omeprazole or lansoprazole; gastrointestinal cytoprotectives, such as sucraflate and misoprostol; gastrointestinal prokinetics, such as prucalopride, antibiotics for H. pylori, such as clarithromycin, amoxicillin, tetracycline, and metronidazole; antidianheals, such as diphenoxylate and loperamide; glycopynolate; antiemetics, such as ondansetron, analgesics, such as mesalamine.
[0087] In one embodiment of the invention, the active agent may be selected from bisacodyl, famotadine, ranitidine, cimetidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
[0088] In another embodiment, the active agent is selected from analgesics, anti- inflammatories, and antipyretics, e.g. non-steroidal anti-inflammatory drugs (NSAIDs), including propionic acid derivatives, e.g. ibuprofen, naproxen, ketoprofen and the like; acetic acid derivatives, e.g. indomethacin, diclofenac, sulindac, tohnetin, and the like; fenamic acid derivatives, e.g. mefanamic acid, meclofenamic acid, flufenamic acid, and the like; biphenylcarbodylic acid derivatives, e.g. diflunisal, flufenisal, and the like; and oxicams, e.g. piroxicam, sudoxicam, isoxicam, meloxicam, and the like. In a particularly prefened embodiment, the active agent is selected from propionic acid derivative NSAIDs, e.g. ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, piφrofen, caφrofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof. In a particular embodiment of the invention, the active agent may be selected from acetaminophen, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof. [0089] In another embodiment of the invention, the active agent may be selected from pseudoephedrine, phenylpropanolamine, chloφheniramine, dextromethoφhan, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine, desloratidine, doxilamine, norastemizole, cetirizine, mixtures thereof and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
[0090] Examples of suitable polydimethylsiloxanes, which include, but are not limited to dimethicone and simethicone, are those disclosed in United States Patent Nos. 4,906,478, 5,275,822, and 6,103,260. As used herein, the term "simethicone" refers to the broader class of polydimethylsiloxanes, including but not limited to simethicone and dimethicone.
[0091] The active ingredient or ingredients are present in the dosage form in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining such amounts, the particular active ingredient being administered, the bioavailability characteristics of the active ingredient, the dose regime, the age and weight of the patient, and other factors must be considered, as known in the art. Preferably, the dosage form comprises at least about 85 weight percent of the active ingredient. In one prefened embodiment, the core comprises at least about 85 weight percent of the active ingredient.
[0092] The active ingredient or ingredients may be present in the dosage form in any form. For example, the active ingredient may be dispersed at the molecular level, e.g. melted or dissolved, within the dosage form, or may be in the form of particles, which in turn may be coated or uncoated. If the active ingredient is in form of particles, the particles (whether coated or uncoated) typically have an average particle size of about 1-2000 microns. In one prefened embodiment, such particles are crystals having an average particle size of about 1-300 microns. In another prefened embodiment, the particles are granules or pellets having an average particle size of about 50-2000 microns, preferably about 50-1000 microns, most preferably about 100-800 microns.
[0093] In embodiments where an active ingredient is contained within the core, at least a portion of the active ingredient may be optionally coated with a release-modifying coating, as known in the art. This advantageously provides an additional tool for modifying the release profile of the dosage form. In particular embodiments of this invention in which coated particles are employed, the particles may be as described herein, and the particles may be coated using conventional coating technology which is well known to those skilled in the art including microencapsulation techniques such as coacervation, spray-drying, and fluidized bed coating including tangential spray rotor coating and bottom spray wurster coating. Examples of suitable particle coating methods and materials can be found in United States Patent Nos. 5,286,497; 4,863,742; 4,173,626; 4,980,170; 4,984,240; 5,912,013; 6,270,805; and 6,322,819.
[0094] In embodiments in which it is desired for the active ingredient to be absorbed into the systemic circulation of an animal, the active ingredient or ingredients are preferably capable of dissolution upon contact with a fluid such as water, gastric fluid, intestinal fluid or the like. In one embodiment, the dissolution characteristics of at least one active ingredient meets USP specifications for immediate release tablets containing the active ingredient. For example, for acetaminophen tablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2 (paddles) at 50 φm, at least 80% of the acetaminophen contained in the dosage form is released therefrom within 30 minutes after dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer, using USP apparatus 2 (paddles) at 50 φm, at least 80% of the ibuprofen contained in the dosage form is released therefrom within 60 minutes after dosing. See USP 24, 2000 Version, 19 - 20 and 856 (1999). In embodiments in which at least one active ingredient is released immediately, the immediately released active ingredient is preferably contained in the shell or on the surface of the shell, e.g. in a further coating sunounding at least a portion of the shell. In another embodiment, the dissolution characteristics of one or more active ingredients are modified: e.g. controlled, sustained, extended, retarded, prolonged, delayed and the like. In a prefened embodiment in which one or more active ingredients are released in a modified manner, the modified release active or actives are preferably contained in the core.
[0095] The core of the present invention may be prepared by any suitable method, including for example compression and molding, and depending on the method by which it is made, typically comprises, in addition to the active ingredient, a variety of excipients (inactive ingredients which may be useful for conferring desired physical properties to the dosage form).
[0096] In a prefened embodiment, the core is prepared by the compression methods and apparatus described in copending U.S. Patent Application Serial No. 09/966,509, pages 16- 27, the disclosure of which is incoφorated herein by reference. Specifically, the core is made using a rotary compression module comprising a fill zone, insertion zone, compression zone, ejection zone, and purge zone in a single apparatus having a double row die construction as shown in Figure 6 of U.S. Patent Application Serial No. 09/966,509. The dies of the compression module are preferably filled using the assistance of a vacuum, with filters located in or near each die. The purge zone of the compression module includes an optional powder recovery system to recover excess powder from the filters and return excess powder to the dies.
[0097] In embodiments in which the core, or a portion thereof, is made by compression, suitable excipients include fillers, binders, disintegrants, lubricants, glidants, and the like, as known in the art. In embodiments in which the core is made by compression, the core may further comprise a release-modifying compressible excipient.
[0098] Suitable fillers for use in making the core, or a portion thereof, by compression include water-soluble compressible carbohydrates such as sugars, which include dextrose, sucrose, maltose, and lactose, sugar-alcohols, which include mannitol, sorbitol, maltitol, xylitol, starch hydrolysates, which include dextrins, and maltodextrins, and the like, water insoluble plastically deforming materials such as microcrystalline cellulose or other cellulosic derivatives, water-insoluble brittle fracture materials such as dicalcium phosphate, tricalcium phosphate and the like and mixtures thereof.
[0099] Suitable binders for making the core, or a portion thereof, by compression include dry binders such as polyvinyl pynolidone, hydroxypropylmethylcellulose, and the like; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, canageenan, carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, , inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pynolidone, cellulosics, sucrose, starches, and the like; and derivatives and mixtures thereof.
[00100] Suitable disintegrants for making the core, or a portion thereof, by compression, include sodium starch glycolate, cross-linked polyvinylpynolidone, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose, and the like.
[00101] Suitable lubricants for making the core, or a portion thereof, by compression include long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides and waxes. [0100] Suitable glidants for making the core, or a portion thereof, by compression, include colloidal silicon dioxide, and the like.
[0101] Suitable release-modifying compressible excipients for making the core, or a portion thereof, by compression include swellable erodible hydrophillic materials, insoluble edible materials, pH-dependent polymers, and mixtures thereof.
[0102] Suitable swellable erodible hydrophilic materials for use as release-modifying excipients for making the core, or a portion thereof, by compression include: water swellable cellulose derivatives, polyalkalene glycols, thermoplastic polyalkalene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, and swelling cross-linked polymers, and derivitives, copolymers, and combinations thereof. Examples of suitable water swellable cellulose derivatives include sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose,hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples of suitable polyalkalene glyclols include polyethylene glycol. Examples of suitable thermoplastic polyalkalene oxides include poly (ethylene oxide). Examples of suitable acrylic polymers include potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL (high-molecular weight cross-linked acrylic acid homopolymers and copolymers), and the like. Examples of suitable hydrocolloids include alginates, agar, guar gum, locust bean gum, kappa canageenan, iota canageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan. Examples of suitable clays include smectites such as bentonite, kaolin, and laponite; magnesium trisilicate, magnesium aluminum silicate, and the like, and derivatives and mixtures thereof. Examples of suitable gelling starches include acid hydrolyzed starches, swelling starches such as sodium starch glycolate, and derivatives thereof. Examples of suitable swelling cross-linked polymers include cross-linked polyvinyl pynolidone, cross-linked agar, and cross-linked carboxymethylcellose sodium.
[0103] Suitable insoluble edible materials for use as release-modifying excipients for making the core, or a portion thereof, by compression include water-insoluble polymers, and low-melting hydrophobic materials. Examples of suitable water-insoluble polymers include ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof. Suitable low-melting hydrophobic materials include fats, fatty acid esters, phospholipids, and waxes. Examples of suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts. Examples of suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid. Examples of suitable waxes include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate; and the like.
[0104] Suitable pH-dependent polymers for use as release-modifying excipients for making the core, or a portion thereof, by compression include enteric cellulose derivatives, for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1 :2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L; and the like, and derivatives, salts, copolymers, and combinations thereof.
[0105] Suitable pharmaceutically acceptable adjuvants for making the core, or a portion thereof, by compression include, preservatives; high intensity sweeteners such as aspartame, acesulfame potassium, sucralose, and saccharin; flavorants; colorants; antioxidants; surfactants; wetting agents; and the like and mixtures thereof.
[0106] The core or a portion thereof may also be formed by molding, using either a solvent free, or solvent based method.
[0107] In another embodiment, the core is prepared by thermal setting molding using the method and apparatus described in copending U.S. patent application Serial No. 09/966,450, pages 57-63, the disclosure of which is incoφorated herein by reference. In this embodiment, the core is formed by injecting a starting material in flowable form into a molding chamber. The starting material preferably comprises an active ingredient and a thermal setting material at a temperature above the melting point of the thermal setting material but below the decomposition temperature of the active ingredient. The starting material is cooled and solidifies in the molding chamber into a shaped form (i.e., having the shape of the mold). [0108] In another embodiment, the core is prepared by thermal cycle molding using the method and apparatus described in copending U.S. patent application Serial No. 09/966,497, pages 27-51, the disclosure of which is incoφorated herein by reference. In this embodiment, the core is formed by injecting a starting material in flowable form into a heated molding chamber. The starting material preferably comprises an active ingredient and a thermoplastic material at a temperature above the set temperature of the thermoplastic material but below the decomposition temperature of the active ingredient. The starting material is cooled and solidifies in the molding chamber into a shaped form (i.e., having the shape of the mold).
[0109] The first coating may be applied to the core by known methods, such as dipping, or spraying. In a prefened embodiment, however, the first coating is applied to the core by molding. The first coating may be molded using a solvent free or solvent based method, preferably using either the thermal cycling molding module, or thermal setting molding module, as described herein. This invention advantageously achieves a cost effective process for applying a partial coating to selected portions of a core without the need for costly and complex subsequent steps of previously known methods, such as application of a complete coating to a core, followed by removal of a portion of the core and coating to permit selective application of another coating to a portion of the core.
[0110] In certain embodiments of the invention, the first coating may function as a barrier to the passage of water or active ingredient therethrough. In certain other embodiments, the first coating may function as a semi-permeable membrane, allowing water or solvent to pass into the core, but being impermeable to dissolved active ingredient, thereby preventing the passage of active ingredient therethrough. In certain other embodiments, the first coating may function as a diffusional membrane, allowing the passage of active ingredient therethrough at a rate controlled by the thickness, porosity and tortuosity of the first coating. In certain other embodiments, the first coating may function as an erosional coating to provide a time delay to the release of one or more portions of active ingredient in the core. In certain other embodiments, the first coating may comprise one or more active ingredients. In one embodiment in which the first coating comprises active ingredient, the first coating may comprise a water soluble active ingredient intended for immediate release from the dosage form, which dissolves promptly upon contact of the dosage form with a liquid medium, thereby creating pores in the first coating for the diffusion of a second dose of active ingredient contained in the core or a portion thereof.
[0111] The first coating preferably comprises from about 10 to about 100 weight percent of a film former. In embodiments in which the first coating functions as a barrier, the film former is preferably a water insoluble material such as for example a water insoluble polymer. In embodiments in which the first coating functions as a semipermeable membrane, allowing water or solvent to pass into the core, but being impermeable to dissolved active ingredient, thereby preventing the passage of active ingredient therethrough, the film former is preferably selected from water insoluble polymers, pH-dependent polymers, water soluble polymers, and combinations thereof. In embodiments in which the first coating may function as a diffusional membrane, allowing the passage of active ingredient therethrough at a rate controlled by the thickness, porosity and tortuosity of the first coating, the film former is preferably selected from water insoluble polymers, pH-dependent polymers, and combinations thereof; and the first coating preferably further comprises a pore former. In embodiments in which the first coating functions as a delayed release coating to delay release of a portion of active ingredient which is contained in the core or a portion thereof, first coating preferably further comprises a swellable erodible hydrophilic material. [0112] The shell or shell portion of the present invention is preferably applied by molding, such as thermal cycle or thermal setting molding, as described herein, using either a solvent free or solvent based method. The method of the invention advantageously enables a partial shell to be applied to or deposited upon a selected area of the core and optionally the first coating.
[0113] The shell comprises a material that is compositionally different from the first coating. As used herein, the term "compositionally different" means having features that are readily distinguishable by qualitative or quantitative chemical analysis, physical testing, or visual observation. For example, the first coating and shell materials may contain different ingredients, or different levels of the same ingredients, or the first and second materials may have different physical or chemical properties, different functional properties, or be visually distinct. Examples of physical or chemical properties that may be different include hydrophylicity, hydrophobicity, hygroscopicity, elasticity, plasticity, tensile strength, crystallinity, and density. Examples of functional properties which may be different include rate and/or extent of dissolution of the material itself or of an active ingredient therefrom, rate of disintegration of the material, permeability to active ingredients, permeability to water or aqueous media, and the like. Examples of visual distinctions include size, shape, topography, or other geometric features, color, hue, opacity, and gloss.
[0114] For example the first coating and shell may comprise different types or levels of colorants, opacifiers, film-formers, etc. Alternatively, the first coating and shell may have different thickness. The first coating and shell may have different functionalities. For example, the first coating and shell may confer different release properties to an active ingredient contained in either the subject coating or shell, or in a conesponding underlying core portion. In one particular embodiment, the first coating may function as a barrier to the passage therethrough of one or more active ingredients contained in the underlying core portion; and the shell may function as an eroding matrix from which active ingredient dispersed in the shell or shell portion is liberated by the dissolution of successive layers of the shell portion surface.
[0115] In certain prefened embodiments of the invention, the core, or the first coating, or the shell, or a portion thereof, is prepared by molding. In such embodiments, the core, or the shell, or a portion thereof, comprises a flowable material. The flowable material may be any edible material that is flowable at a temperature between about 37°C and 250°C, and that is solid, semi-solid, or can form a gel at a temperature between about -10°C and about 35°C. When it is in the fluid or flowable state, the flowable material may comprise a dissolved or molten component, and optionally a solvent such as for example water or organic solvents, or combinations thereof. The solvent may be partially or substantially removed by drying.
[0116] Suitable flowable materials for making the core, or the first coating or the shell, or a portion thereof by molding include those comprising thermoplastic materials; film formers; thickeners such as gelling polymers or hydrocolloids; low melting hydrophobic materials such as fats and waxes; non-crystallizable carbohydrates; and the like. Suitable molten components of the flowable material include thermoplastic materials, low melting hydrophobic materials, and the like. Suitable dissolved components for the flowable material include film formers, thickeners such as gelling polymers or hydrocolloids, non-crystallizable carbohydrates, and the like.
[0117] Suitable thermoplastic materials can be molded and shaped when heated, and include both water soluble and water insoluble polymers that are generally linear, not crosslinked, nor strongly hydrogen bonded to adjacent polymer chains. Examples of suitable thermoplastic materials include: thermoplastic water swellable cellulose derivatives, thermoplastic water insoluble cellulose derivatives, thermoplastic vinyl polymers, thermoplastic starches, thermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides, and amoφhous sugar-glass, and the like, and derivatives, copolymers, and combinations thereof. Examples of suitable thermoplastic water swellable cellulose derivatives include hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC). Examples of suitable thermoplastic water insoluble cellulose derivatives include cellulose acetate (CA), ethyl cellulose (EC), cellulose acetate butyrate (CAB), cellulose propionate. Examples of suitable thermoplastic vinyl polymers include polyvinyl alcohol (PVA) and polyvinyl pynolidone (PVP). Examples of suitable thermoplastic starches include those disclosed in U.S. Patent No. 5,427,614, which is incoφorated herein by reference. Examples of suitable thermoplastic polyalkalene glycols include polyethylene glycol; Examples of suitable thermoplastic polyalkalene oxides include polyethylene oxide having a molecular weight from about 100,000 to about 900,000 Daltons. Other suitable thermoplastic materials include sugar in the form on an amoφhous glass such as that used to make hard candy forms.
[0118] Any film former known in the art is suitable for use in the flowable material of the present invention. Examples of suitable film formers include, but are not limited to, film- forming water soluble polymers, film-forming proteins, film-forming water insoluble polymers, and film-forming pH-dependent polymers. In one embodiment, the film-former for making the core or shell or portion thereof by molding may be selected from cellulose acetate, ammonio methacrylate copolymer type B, shellac, hydroxypropylmethylcellulose, and polyethylene oxide, and combinations thereof.
[0119] Suitable film-forming water soluble polymers include water soluble vinyl polymers such as polyvinylalcohol (PVA); water soluble polycarbohydrates such as hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethyl starch, carboxymethyl starch, pre- gelatinized starches, and film-forming modified starches; water swellable cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), hydroxyethylmethylcellulose (HEMC), hydroxybutylmethylcellulose (HBMC), hydroxyethylethylcellulose (HEEC), and hydroxyethylhydroxypropylmethyl cellulose (HEMPMC); water soluble copolymers such as methacrylic acid and methacrylate ester copolymers, polyvinyl alcohol and polyethylene glycol copolymers, polyethylene oxide and polyvinylpynolidone copolymers; and derivatives and combinations thereof.
[0120] Suitable film- forming proteins may be natural or chemically modified, and include gelatin, whey protein, myofibrillar proteins, coaggulatable proteins such as albumin, casein, caseinates and casein isolates, soy protein and soy protein isolates, zein;; and polymers, derivatives and mixtures thereof.
[0121] Suitable film-forming water insoluble polymers, include for example ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof.
[0122] Suitable film-forming pH-dependent polymers include enteric cellulose derivatives, such as for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins, such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1 :2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L; and the like, and derivatives, salts, copolymers, and combinations thereof.
[0123] One suitable hydroxypropylmethylcellulose compound for use as a thermoplastic film- forming water soluble polymer is HPMC 2910, which is a cellulose ether having a degree of substitution of about 1.9 and a hydroxypropyl molar substitution of 0.23, and containing, based upon the total weight of the compound, from about 29% to about 30% methoxyl groups and from about 7% to about 12% hydroxylpropyl groups. HPMC 2910 is commercially available from the Dow Chemical Company under the tradename METHOCEL E. METHOCEL E5, which is one grade of HPMC-2910 suitable for use in the present invention, has a viscosity of about 4 to 6 cps (4 to 6 millipascal-seconds) at 20°C in a 2% aqueous solution as determined by a Ubbelohde viscometer. Similarly, METHOCEL E6 , which is another grade of HPMC-2910 suitable for use in the present invention, has a viscosity of about 5 to 7 cps ( 5 to 7 millipascal-seconds) at 20°C in a 2% aqueous solution as determined by a Ubbelohde viscometer. METHOCEL El 5, which is another grade of HPMC-2910 suitable for use in the present invention, has a viscosity of about 15000 cps (15 millipascal-seconds) at 20°C in a 2% aqueous solution as determined by a Ubbelohde viscometer. As used herein, "degree of substitution" shall mean the average number of substituent groups attached to a anhydroglucose ring, and "hydroxypropyl molar substitution" shall mean the number of moles of hydroxypropyl per mole anhydroglucose.
[0124] One suitable polyvinyl alcohol and polyethylene glycol copolymer is commercially available from BASF Coφoration under the tradename KOLLICOAT IR.
[0125] As used herein, "modified starches" include starches that have been modified by crosslinking, chemically modified for improved stability or optimized performance, or physically modified for improved solubility properties or optimized performance. Examples of chemically-modified starches are well known in the art and typically include those starches that have been chemically treated to cause replacement of some of its hydroxyl groups with either ester or ether groups. Crosslinking, as used herein, may occur in modified starches when two hydroxyl groups on neighboring starch molecules are chemically linked. As used herein, "pre-gelatinized starches" or "instantized starches" refers to modified starches that have been pre-wetted, then dried to enhance their cold-water solubility. Suitable modified starches are commercially available from several suppliers such as, for example, A.E. Staley Manufacturing Company, and National Starch & Chemical Company. One suitable film forming modified starch includes the pre-gelatinized waxy maize derivative starches that are commercially available from National Starch & Chemical Company under the tradenames PURITY GUM and FILMSET, and derivatives, copolymers, and mixtures thereof. Such waxy maize starches typically contain, based upon the total weight of the starch, from about 0 percent to about 18 percent of amylose and from about 100% to about 88% of amylopectin.
[0126] Another suitable film forming modified starch includes the hydroxypropylated starches, in which some of the hydroxyl groups of the starch have been etherified with hydroxypropyl groups, usually via treatment with propylene oxide. One example of a suitable hydroxypropyl starch that possesses film-forming properties is available from Grain Processing Company under the tradename, PURE-COTE B790.
[0127] Suitable tapioca dextrins for use as film formers include those available from National Starch & Chemical Company under the tradenames CRYSTAL GUM or K-4484, and derivatives thereof such as modified food starch derived from tapioca, which is available from National Starch and Chemical under the tradename PURITY GUM 40, and copolymers and mixtures thereof. [0128] Any thickener known in the art is suitable for use in the flowable material of the present invention. Examples of such thickeners include but are not limited to hydrocolloids (also refened to herein as gelling polymers), clays, gelling starches, and crystallizable carbohydrates, and derivatives, copolymers and mixtures thereof.
[0129] Examples of suitable hydrocolloids (also refened to herein as gelling polymers) such as alginates, agar, guar gum, locust bean, canageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan. Examples of suitable clays include smectites such as bentonite, kaolin, and laponite; magnesium trisilicate, magnesium aluminum silicate, and the like, and derivatives and mixtures thereof. Examples of suitable gelling starches include acid hydrolyzed starches, and derivatives and mixtures thereof. Additional suitable thickening hydrocolloids include low-moisture polymer solutions such as mixtures of gelatin and other hydrocolloids at water contents up to about 30%, such as for example those used to make "gummi" confection forms.
[0130] Additional suitable thickeners include crystallizable carbohydrates, and the like, and derivatives and combinations thereof. Suitable crystallizable carbohydrates include the monosaccharides and the oligosaccharides. Of the monosaccharides, the aldohexoses e.g., the D and L isomers of allose, alfrose, glucose, mannose, gulose, idose, galactose, talose, and the ketohexoses e.g., the D and L isomers of fructose and sorbose along with their hydrogenated analogs: e.g., glucitol (sorbitol), and mannitol are prefened. Of the oligosaccharides, the 1,2-disaccharides sucrose and frehalose, the 1,4-disaccharides maltose, lactose, and cellobiose, and the 1,6-disaccharides gentiobiose and melibiose, as well as the trisaccharide raffinose are prefened along with the isomerized form of sucrose known as isomaltulose and its hydrogenated analog isomalt. Other hydrogenated forms of reducing disaccharides (such as maltose and lactose), for example, maltitol and lactitol are also prefened. Additionally, the hydrogenated forms of the aldopentoses: e.g., D and L ribose, arabinose, xylose, and lyxose and the hydrogenated forms of the aldotetroses: e.g., D and L erythrose and threose are prefened and are exemplified by xylitol and erythritol, respectively.
[0131] In one embodiment of the invention, the flowable material comprises gelatin as a gelling polymer. Gelatin is a natural, thermogelling polymer. It is a tasteless and colorless mixture of derived proteins of the albuminous class wliich is ordinarily soluble in warm water. Two types of gelatin - Type A and Type B - are commonly used. Type A gelatin is a derivative of acid-treated raw materials. Type B gelatin is a derivative of alkali-treated raw materials. The moisture content of gelatin, as well as its Bloom strength, composition and original gelatin processing conditions, determine its transition temperature between liquid and solid. Bloom is a standard measure of the strength of a gelatin gel, and is roughly conelated with molecular weight. Bloom is defined as the weight in grams required to move a half-inch diameter plastic plunger 4 mm into a 6.67% gelatin gel that has been held at 10°C for 17 hours. In a prefened embodiment, the flowable material is an aqueous solution comprising 20% 275 Bloom pork skin gelatin, 20% 250 Bloom Bone Gelatin, and approximately 60% water.
[0132] Suitable xanthan gums include those available from CP. Kelco Company under the tradenames KELTROL 1000, XANTROL 180, or K9B310.
[0133] Suitable clays include smectites such as bentonite, kaolin, and laponite; magnesium trisilicate, magnesium aluminum silicate, and the like, and derivatives and mixtures thereof.
[0134] "Acid-hydrolyzed starch," as used herein, is one type of modified starch that results from treating a starch suspension with dilute acid at a temperature below the gelatinization point of the starch. During the acid hydrolysis, the granular form of the starch is maintained in the starch suspension, and the hydrolysis reaction is ended by neutralization, filtration and drying once the desired degree of hydrolysis is reached. As a result, the average molecular size of the starch polymers is reduced. Acid-hydrolyzed starches (also known as "thin boiling starches") tend to have a much lower hot viscosity than the same native starch as well as a strong tendency to gel when cooled.
[0135] "Gelling starches," as used herein, include those starches that, when combined with water and heated to a temperature sufficient to form a solution, thereafter form a gel upon cooling to a temperature below the gelation point of the starch. Examples of gelling starches include, but are not limited to, acid hydrolyzed starches such as that available from Grain Processing Coφoration under the tradename PURE-SET B950; hydroxypropyl distarch phosphate such as that available from Grain Processing Coφoration under the tradename, PURE-GEL B990, and mixtures thereof.
[0136] Suitable low-melting hydrophobic materials include fats, fatty acid esters, phospholipids, and waxes. Examples of suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts. Examples of suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid. Examples of suitable waxes include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate; and the like.
[0137] Suitable non-crystallizable carbohydrates include non-crystallizable sugars such as polydextrose, and starch hydrolysates, e.g. glucose syrup, com syrup, and high fructose com syrup; and non-crystallizable sugar-alcohols such as maltitol syrup.
[0138] Suitable solvents for optional use as components of the flowable material include water; polar organic solvents such as methanol, ethanol, isopropanol, acetone, and the like; and non-polar organic solvents such as methylene chloride, cyclohexane, and the like; and mixtures thereof.
[0139] The flowable material may optionally comprise adjuvants or excipients, which may comprise up to about 30% by weight of the flowable material. Examples of suitable adjuvants or excipients include plasticizers, detackifiers, humectants, surfactants, anti- foaming agents, colorants, flavorants, sweeteners, opacifiers, and the like. Suitable plasticizers for making the core, the shell, or a portion thereof, by molding include, but not be limited to polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl citrate; tribuyl citrate; dibutyl sebecate; vegetable oils such as castor oil, rape oil, olive oil, and sesame oil; surfactants such as polysorbates, sodium lauryl sulfates, and dioctyl-sodium sulfosuccinates; mono acetate of glycerol; diacetate of glycerol; triacetate of glycerol; natural gums; triacetin; acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate; diethylmalonate; dioctylphthalate; dibutylsuccinate; glyceroltributyrate; hydrogenated castor oil; fatty acids; substituted triglycerides and glycerides; and the like and/or mixtures thereof. In one embodiment, the plasticizer is triethyl citrate. In certain embodiments, the shell is substantially free of plasticizers, i.e. contains less than about 1%, say less than about 0.01% of plasticizers. [0140] In one prefened embodiment, the flowable material comprises less than 5% humectants, or alternately is substantially free of humectants, such as glycerin, sorbitol, maltitol, xylitol, or propylene glycol. Humectants have traditionally been included in preformed films employed in enrobing processes, such as that disclosed in U.S. Patent Nos. 5,146,730 and 5,459,983, to ensure adequate flexibility or plasticity and bondability of the film during processing. Humectants function by binding water and retaining it in the film. Pre-formed films used in enrobing processes can typically comprise up to 45% water. Disadvantageously, the presence of humectant prolongs the drying process, and can adversely affect the stability of the finished dosage form.
[0141] In certain particularly prefened embodiments of the invention, the core, or the first coating, or the shell, or portions thereof may be molded using a solvent- free process. In certain such embodiments, the core, or the first coating, or the shell, or portions thereof may comprise active ingredient contained within a molded excipient matrix. In other such embodiments, the core, or the first coating, or the shell, or portions thereof may comprise a molded excipient matrix substantially free of active ingredient. The molded matrix typically comprises at least about 30 weight percent of a thermal-reversible carrier. The molded matrix may optionally further comprise up to about 55 weight percent of one or more release- modifying moldable excipients as described below, and optionally up to about 30 weight percent of various adjuvants such as for example plasticizers, gelling agents, colorants, stabilizers, preservatives, and the like as known in the art.
[0142] In certain other particularly prefened embodiments of the invention, the core or the first coating or the shell or a portion or portions thereof are prepared using a solvent-based molding process, the molded core or coating or shell or portion will typically comprise at least about 10 weight percent, e.g. at least about 12 weight percent or at least about 15 weight percent or at least about 20 weight percent or at least about 25 weight percent of a film- former. Here, the solvent-molded shell portion or portions may optionally further comprise up to about 55 weight percent of a release-modifying excipient. The solvent-molded shell portion or portions may again also optionally further comprise up to about 30 weight percent total of various plasticizers, adjuvants, and excipients.
[0143] In certain embodiments in which one or more active ingredients contained in the core are released from the dosage form in a controlled manner, the core, or a portion thereof may function as a diffusional matrix. In these embodiments, the core or core portion preferably comprises active ingredient, distributed throughout an insoluble porous matrix, which contains pores or channels through which fluids can enter the core or core portion, and the active ingredient must diffuse in order to be released from the dosage form. In these embodiments, the rate of active ingredient release from the core portion will depend upon the area (A) of the matrix, the diffusion coefficient (D), the porosity (E) and tortuosity (T) of the matrix, the drag solubility (Cs) in the dissolution medium, and the drug concentration (Cp) in the dosage form. In prefened embodiments in which a core portion functions as a diffusional matrix, the release of the active ingredient from the core or core portion may be described as controlled, prolonged, sustained, or extended. In these embodiments, the contribution to active ingredient dissolution from the subject core portion may follow zero-order, first-order, or preferably square-root of time kinetics. In these embodiments, the core may be made by compression or molding. In embodiments in which the core or portion thereof functions as a diffusional matrix through which active ingredient contained therein is liberated in a sustained, extended, prolonged, or retarded manner, the core or core portion preferably comprises a release-modifying excipient selected from combinations of insoluble edible materials and pore formers. Alternately, in such embodiments in which the core or core portion is prepared by solvent- free molding, the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated.
[0144] In certain other embodiments in which one or more active ingredients contained in the core are released from the dosage form in a controlled manner, the core or portion thereof may function as an eroding matrix from which active ingredient dispersed in the core or core portion is liberated by the dissolution of successive layers of the core or core portion surface. In these embodiments, the rate of active ingredient release will depend on the dissolution rate of the matrix material in the core or core portion. Particularly useful matrix materials for providing surface erosion include those that first absorb liquid, then swell and/or gel prior to dissolving. In embodiments in which the core or portion thereof functions as an eroding matrix from which dispersed active ingredient is liberated in a sustained, extended, prolonged, or retarded manner, the core or core portion may be made by compression or by molding, and the core or core portion preferably comprises a release-modifying excipient selected from swellable erodible hydrophilic materials, pH-dependent polymers, insoluble edible materials, and combinations thereof. In certain particular such embodiments, the eroding matrix core or core portion preferably comprises a swellable erodible hydrophilic material.
[0145] In certain prefened embodiments of the invention, one or more shell portions contain active ingredient which is released essentially immediately upon ingestion of the dosage form. In these embodiments, the shell portion preferably comprises materials which exhibit rapid dissolution in gastro-intestinal fluids.
[0146] In certain other embodiments, one or more shell portions function as a diffusional membrane which contains pores through which fluids can enter the dosage form, and dissolved active ingredient can be released. In these embodiments, the rate of release of active ingredient from an underlying core portion will depend upon the total pore area in the shell portion, the pathlength of the pores, and the solubility and diffusivity of the active ingredient (in addition to its rate of release from the core portion itself). In prefened embodiments in which a shell portion functions as a diffusional membrane, the release of the active ingredient from the dosage form may be described as controlled, prolonged, sustained or extended. In these embodiments, the contribution to active ingredient dissolution from the subject shell portion may follow zero-order, first-order, or square-root of time kinetics. In certain such embodiments, the diffusional membrane shell portion preferably comprises a pore former and an insoluble material such as for example a film forming water insoluble polymer.
[0147] In certain other embodiments, one or more shell portions function as an eroding matrix from which active ingredient dispersed in the shell portion is liberated by the dissolution of successive layers of the shell portion surface. In these embodiments, the rate of active ingredient release will depend on the dissolution rate of the matrix material in the shell portion. Particularly useful matrix materials for providing surface erosion include those which first absorb liquid, then swell and/or gel prior to dissolving. In certain such embodiments, the eroding matrix shell portion preferably comprises a swellable erodible hydrophilic material.
[0148] In certain other embodiments, one or more shell portions function as a barrier to prevent release therethrough of an active ingredient contained in the underlying core or first coating. In such embodiments, active ingredient is typically released from a portion of the dosage form which is not covered by the barrier shell portion. Such embodiments advantageously allow for further control of the surface area for release of the active ingredient. In certain such embodiments, the barrier shell portion preferably comprises a water insoluble material such as for example a water insoluble polymer.
[0149] In certain other embodiments, one or more shell portions function as a delayed release coating to delay release of an active ingredient which is contained in the core or a portion thereof. In these embodiments, the lag-time for onset of active ingredient release may be governed by erosion of the coating or diffusion through the coating or a combination thereof. In certain such embodiments, the eroding matrix shell portion preferably comprises a swellable erodible hydrophilic material.
[0150] In embodiments in which the first coating, the shell, or a portion thereof function to modify the release of an active ingredient which is contained in the core or the subject coating or shell portion, the thickness of the coating or shell portion is critical to the release properties of the dosage form. Advantageously the dosage forms of the invention can be made with precise control over coating and shell thickness. In a prefened embodiment in which the first coating or shell portions function to modify the release of an active ingredient which is contained in the core or the subject coating or shell portion, the first coating or shell portion or portions are made by the thermal cycle or thermal setting molding methods described herein.
[0151] Suitable thermal-reversible carriers for making the core, or the first coating, or the shell, or a portion thereof, by molding are thermoplastic materials typically having a melting
point below about 110°C, more preferably between about 20 and about 100°C. Examples of
suitable thermal-reversible carriers for solvent-free molding include thermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides, low melting hydrophobic materials, thermoplastic polymers, thermoplastic starches, and the like. Prefened thermal-reversible carriers include polyethylene glycol and polyethylene oxide. Suitable thermoplastic polyalkylene glycols for use as thermal-reversible carriers include polyethylene glycol having molecular weight from about 100 to about 20,000, e.g. from about 1000 to about 8,000 Daltons. Suitable thermoplastic polyalkalene oxides include polyethylene oxide having a molecular weight from about 100,000 to about 900,000 Daltons. Suitable low-melting hydrophobic materials for use as thermal-reversible carriers include fats, fatty acid esters, phospholipids, and waxes which are solid at room temperature, fat-containing mixtures such as chocolate; and the like. Examples of suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts. Examples of suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid. Examples of suitable waxes which are solid at room temperature include carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax. Suitable thermoplastic polymers for use as thermal-reversible carriers include thermoplastic water swellable cellulose derivatives, thermoplastic water insoluble polymers, thermoplastic vinyl polymers, thermoplastic starches, and thermoplastic resins, and combinations thereof. Suitable thermoplastic water swellable cellulose derivatives include include hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), carboxymethylcellulose (CMC), cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxybutylcellulose (HBC), hydroxyethylcellulose (HEC), hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylethylcellulose, and salts, derivatives, copolymers, and combinations thereof. Suitable thermoplastic water insoluble polymers include ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers, and the like and derivatives, copolymers, and combinations thereof. Suitable thermoplastic vinyl polymers include polyvinylacetate, polyvinyl alcohol, and polyvinyl pynolidone (PVP). Examples of suitable thermoplastic starches for use as thermal-reversible carriers include those disclosed in U.S. Patent No. 5,427,614, which is incoφorated herein by reference. Examples of suitable thermoplastic resins for use as thermal-reversible carriers include dammars, mastic, rosin, shellac, sandarac, and glycerol ester of rosin. In one embodiment, the thermal-reversible carrier for making the core, or a portion thereof, by molding is selected from polyalkylene glycols, polyalkaline oxides, and combinations thereof.
[0152] Suitable release-modifying excipients for making the core, or the shell, or a portion thereof, by solvent free or solvent based molding include but are not limited to swellable erodible hydrophilic materials, pH-dependent polymers, pore formers, and insoluble edible materials. In one embodiment, suitable release-modifying excipients for making the core, or the shell, or a portion thereof, by molding include hydroxypropylmethylcellulose, polyethylene oxide, ammonio methacrylate copolymer type B, and shellac, and combinations thereof.
[0153] Suitable swellable erodible hydrophilic materials for use as release-modifying excipients for making the core, or the shell, or a portion thereof by a solvent-free molding process include water swellable cellulose derivatives, polyalkalene glycols, thermoplastic polyalkalene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, and swelling cross-linked polymers, and derivitives, copolymers, and combinations thereof. Examples of suitable water swellable cellulose derivatives include sodium carboxymethylcellulose, cross- linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose,hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples of suitable polyalkalene glyclols include polyethylene glycol. Examples of suitable thermoplastic polyalkalene oxides include poly (ethylene oxide). Examples of suitable acrylic polymers include potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL (high- molceular weight cross-linked acrylic acid homopolymers and copolymers), and the like. Examples of suitable hydrocolloids include alginates, agar, guar gum, locust bean gum, kappa canageenan, iota canageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan. Examples of suitable clays include smectites such as bentonite, kaolin, and laponite; magnesium trisilicate, magnesium aluminum silicate, and the like, and derivatives and mixtures thereof. Examples of suitable gelling starches include acid hydrolyzed starches, swelling starches such as sodium starch glycolate, and derivatives thereof. Examples of suitable swelling cross-linked polymers include cross-linked polyvinyl pynolidone, cross-linked agar, and cross-linked carboxymethylcellose sodium.
[0154] Suitable pH-dependent polymers for use as release-modifying moldable excipients for making the molded matrix or molded core or molded shell or a portion thereof by molding include enteric cellulose derivatives, for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1 :2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1 :1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L; and the like, and derivatives, salts, copolymers, and combinations thereof.
[0155] Suitable insoluble edible materials for use as release-modifying excipients making the core, or the shell, or a portion thereof by molding, include water-insoluble polymers, and low-melting hydrophobic materials. Examples of suitable water-insoluble polymers include ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof. Suitable low-melting hydrophobic materials include fats, fatty acid esters, phospholipids, and waxes. Examples of suitable fats include hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts. Examples of suitable fatty acid esters include sucrose fatty acid esters, mono, di, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid. Examples of suitable waxes include camauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate; and the like. [0156] Suitable pore formers for use as release-modifying excipients for making the molded matrix, the core, the shell, or a portion thereof by molding include water-soluble organic and inorganic materials. In one embodiment the pore former is hydroxypropylmethylcellulose. Examples of suitable water-soluble organic materials include water soluble polymers including water soluble cellulose derivatives such as hydroxypropylmethylcellulose, and hydroxypropylcellulose; water soluble carbohydrates such as sugars, and starches; water soluble polymers such as polyvinylpynolidone and polyethylene glycol, and insoluble swelling polymers such as microcrystalline cellulose. Examples of suitable water soluble inorganic materials include salts such as sodium chloride and potassium chloride and the like and/or mixtures thereof.
[0157] The core may be in a variety of different shapes. For example, the core may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, truncated cone, cylinder, sphere, torus, or the like. In certain embodiments the core may have the shape of a torus, cylinder, or tmncated cone. In certain embodiments, the core has one or more major faces. For example in embodiments wherein the core is a compressed tablet, the core surface typically has two opposing major faces formed by contact with the upper and lower punch faces in the compression machine. In such embodiments the core surface typically further comprises a "belly-band" located between the two major faces, and formed by contact with the die walls in the compression machine. Exemplary core shapes which may be employed include tablet shapes formed from compression tooling shapes described by "The Elizabeth Companies Tablet Design Training Manual" (Elizabeth Carbide Die Co., Inc., p. 7 (McKeesport, Pa.) (incoφorated herein by reference) as follows (the tablet shape conesponds inversely to the shape of the compression tooling): 1. Shallow Concave.
2. Standard Concave.
3. Deep Concave.
4. Extra Deep Concave.
5. Modified Ball Concave.
6. Standard Concave Bisect.
7. Standard Concave Double Bisect.
8. Standard Concave European Bisect.
9. Standard Concave Partial Bisect.
10. Double Radius.
11. Bevel & Concave.
12. Flat Plain.
13. Flat-Faced-Beveled Edge (F.F.B.E.).
14. F.F.B.E. Bisect.
15. F.F.B.E. Double Bisect.
16. Ring.
17. Dimple.
18. Ellipse.
19. Oval.
20. Capsule.
21. Rectangle.
22. Square.
23. Triangle.
24. Hexagon.
25. Pentagon.
26. Octagon.
27. Diamond.
28. Anowhead.
29. Bullet.
30. Shallow Concave.
31. Standard Concave.
32. Deep Concave.
33. Extra Deep Concave.
34. Modified Ball Concave.
35. Standard Concave Bisect.
36. Standard Concave Double Bisect.
37. Standard Concave European Bisect.
38. Standard Concave Partial Bisect.
39. Double Radius.
40. Bevel & Concave.
41. Flat Plain.
42. Flat-Faced-Beveled Edge (F.F.B.E.).
43. F.F.B.E. Bisect.
44. F.F.B.E. Double Bisect.
45. Ring.
46. Dimple.
47. Ellipse.
48. Oval.
49. Capsule.
50. Rectangle. 51. Square.
52. Triangle.
53. Hexagon.
54. Pentagon.
55. Octagon.
56. Diamond.
57. Anowhead.
58. Bullet.
59. Banel.
60. Half Moon.
61. Shield.
62. Heart.
63. Almond.
64. House/Home Plate.
65. Parallelogram.
66. Trapezoid.
67. Figure 8/Bar Bell.
68. Bow Tie.
69. Uneven Triangle.
[0158] In one embodiment of the invention, the core comprises multiple portions, for example a first portion and a second portion. The portions may be prepared by the same or different methods and mated using various techniques, such as the thermal cycle molding and thermal setting molding methods described herein. For example, the first and second portions may both be made by compression, or both may be made by molding. Or one portion may be made by compression and the other by molding. The compression module of copending U.S. patent application Serial No. 09/966,509, pp. 16-27, the disclosure of which is incoφorated herein by reference, may be employed to make the compressed portion. The molded portion may be made using the thermal cycle molding module described in U.S. patent application Serial No. 09/966,497, pp. 27-51 or the thermal setting molding module described in U.S. patent application Serial No. 09/966,450, pp. 57-63, the disclosures of which are incoφorated herein by reference. A transfer device as described in U.S. patent application Serial No. 09/966,414, pp. 51-57, the disclosure of which is incoφorated herein by reference, may be used to transfer the compressed portion of the molding module. [0159] The same or different active ingredient may be present in the first and second portions of the core. Alternately, one or more core portions may be substantially free of active ingredients.
[0160] In embodiments wherein the shell is prepared by a solvent- free molding process, the shell typically has a thickness of about 500 to about 4000 microns. In embodiments wherein the shell or a portion thereof is prepared by a solvent-based molding process, the shell typically has a thickness of less than about 800 microns, e.g. about 100 to about 600 microns, e.g. about 150 to about 400 microns.
[0161] In certain other embodiments, the shell or a portion thereof is prepared by molding using a solvent based process. In such embodiments the solvent-molded shell typically comprises at least about 10 weight percent of a film- former. Here, the solvent-molded shell may optionally further comprise up to about 55 weight percent of a release-modifying agent. The solvent-molded shell may again also optionally further comprise up to about 30 weight percent total of various plasticizers, adjuvants and excipients.
[0162] In embodiments in which the shell is prepared by molding, either by a solvent-free process or by a solvent-based process, the shell typically is substantially free of pores in the diameter range of 0.5 to 5.0 microns, i.e. has a pore volume in the pore diameter range of 0.5 to 5.0 microns of less than about 0.02 cc/g, preferably less than about 0.01 cc/g, more preferably less than about 0.005 cc/g. Typical compressed materials have pore volumes in this diameter range of more than about 0.02 cc/g. Pore volume, pore diameter and density may be determined using a Quantachrome Instruments PoreMaster 60 mercury intrusion porosimeter and associated computer software program known as "Porowin." The procedure is documented in the Quantachrome Instruments PoreMaster Operation Manual. The PoreMaster determines both pore volume and pore diameter of a solid or powder by forced intrusion of a non-wetting liquid (mercury), which involves evacuation of the sample in a sample cell (penetrometer), filling the cell with mercury to sunound the sample with mercury, applying pressure to the sample cell by: (i) compressed air (up to 50 psi maximum); and (ii) a hydraulic (oil) pressure generator (up to 60000 psi maximum). Intraded volume is measured by a change in the capacitance as mercury moves from outside the sample into its pores under applied pressure. The conesponding pore size diameter (d) at which the intrusion takes place is calculated directly from the so-called "Washburn Equation": d= -
(4γ(cosθ)/P) where γ is the surface tension of liquid mercury, θ is the contact angle between
mercury and the sample surface and P is the applied pressure.
[0163] Equipment used for pore volume measurements:
1. Quantachrome Instruments PoreMaster 60.
2. Analytical Balance capable of weighing to O.OOOlg.
3. Desiccator.
[0164] Reagents used for measurements:
1. High purity nitrogen.
2. Triply distilled mercury.
3. High pressure fluid (Dila AX, available from Shell Chemical Co.).
4. Liquid nitrogen (for Hg vapor cold trap).
5. Isopropanol or methanol for cleaning sample cells.
6. Liquid detergent for cell cleaning.
[0165] Procedure:
The samples remain in sealed packages or as received in the dessicator until analysis. The vacuum pump is switched on, the mercury vapor cold trap is filled with liquid nitrogen, the compressed gas supply is regulated at 55 psi., and the instrument is turned on and allowed a warm up time of at least 30 minutes. The empty penetrometer cell is assembled as described in the instrument manual and its weight is recorded. The cell is installed in the low pressure station and "evacuation and fill only" is selected from the analysis menu, and the following settings are employed:
Fine Evacuation time: 1 min. Fine Evacuation rate: 10 Coarse Evacuation time: 5 min.
[0166] The cell (filled with mercury) is then removed and weighed. The cell is then emptied into the mercury reservoir, and two tablets from each sample are placed in the cell and the cell is reassembled. The weight of the cell and sample are then recorded. The cell is then installed in the low-pressure station, the low-pressure option is selected from the menu, and the following parameters are set:
Mode: Low pressure
Fine evacuation rate: 10
Fine evacuation until: 200μ Hg
Coarse evacuation time: 10 min.
Fill pressure: Contact +0.1
Maximum pressure: 50
Direction: Intrusion And Extrusion
Repeat: 0
Mercury contact angle: 140
Mercury surface tension: 480
[0167] Data acquisition is then begun. The pressure vs. cumulative volume-intruded plot is displayed on the screen. After low-pressure analysis is complete, the cell is removed from the low-pressure station and reweighed. The space above the mercury is filled with hydraulic oil, and the cell is assembled and installed in the high-pressure cavity. The following settings are used:
Mode: Fixed rate
Motor speed: 5
Start pressure: 20
End pressure: 60,000
Direction: Intrusion and extrusion
Repeat: 0
Oil fill length: 5
Mercury contact angle: 140
Mercury surface tension: 480 [0168] Data acquisition is then begun and graphic plot pressure vs. intraded volume is displayed on the screen. After the high pressure run is complete, the low-and high-pressure data files of the same sample are merged.
[0169] In embodiments in which the shell or a portion thereof comprises an active ingredient intended to have immediate release from the dosage form, the shell or that portion thereof is preferably prepared via the solvent-free molding method described above. In such embodiments the thermal-reversible carrier is preferably selected from polyethylene glycol with weight average molecular weight from about 1450 to about 20000, polyethylene oxide with weight average molecular weight from about 100,000 to about 900,000, and the like.
[0170] In embodiments in which the shell confers sustained, extended, or retarded release of an active ingredient contained in the shell, the release-modifying agent in the shell preferably comprises a swellable erodible hydrophilic material, and may optionally comprise a secondary gelling agent such as for example cross-linked carboxymethylcellulose, cross- linked polyvinylpynolidone, or sodium starch glycolate.
[0171] In a particular embodiment of this invention at least one active ingredient contained within the dosage form exhibits a delayed and sustained release profile. By "delayed then sustained release profile" it is meant that the release of that particular active ingredient from the dosage form is delayed for a pre-determined time after ingestion by the patient, and the delay period ("lag time") is followed by sustained (prolonged, extended, or retarded) release of that active ingredient. In this embodiment, the shell or shell portion provides for the delay period, and is preferably substantially free of the active ingredient to be released in a delayed then sustained manner. In such embodiments, the delayed then sustained release active ingredient is preferably contained within the conesponding underlying core portion, or optionally dispersed throughout the entire core. In such embodiments the core or core portion may function for example as an eroding matrix or a diffusional matrix, or an osmotic pump. In embodiments in which the core portion functions as a diffusional matrix through which active ingredient is liberated in a sustained, extended, prolonged, or retarded manner, the core portion preferably comprises a release-modifying excipient selected from combinations of insoluble edible materials and pore-formers. Alternately, in such embodiments in which the core portion is prepared by molding, the thermal-reversible carrier may function by dissolving and forming pores or channels through which the active ingredient may be liberated. In embodiments in which the core portion functions as an eroding matrix from which dispersed active ingredient is liberated in a sustained, extended, prolonged, or retarded manner, the core portion preferably comprises a release-modifying compressible or moldable excipient selected from swellable erodible hydrophilic materials, pH-dependent polymers, and combinations thereof.
[0172] In another particular embodiment of this invention at least one active ingredient contained within the dosage form exhibits a double pulse release profile. By "double pulse" it is meant that a first portion of active ingredient is released essentially immediately upon contacting of the dosage form with a liquid medium, followed by a delay period, followed by immediate release of a second portion of active ingredient. In such embodiments in which one or more shell portions contain active ingredient which is released essentially immediately upon ingestion of the dosage form, the shell portion preferably comprises materials which exhibit rapid dissolution in gastro-intestinal fluids. For example the immediate release shell portion or portions may comprise readily soluble materials selected from water soluble or water swellable thermoplastic film formers, water soluble or water swellable thickeners, crystallizable and non-crystallizable carbohydrates. In certain such embodiments, suitable water soluble or water swellable thermoplastic film formers may be selected from water swellable cellulose derivatives, thermoplastic starches, polyalkalene glycols, polyalkalene oxides, and amoφhous sugar glass, and combinations thereof. In certain other such embodiments, suitable film formers may be selected from film forming water soluble polymers such as for example water soluble vinyl polymers, water soluble polycarbohydrates, water swellable cellulose derivatives, and water soluble copolymers; film-forming proteins, and combinations thereof. In certain other such embodiments, suitable thickeners may be selected from gelling polymers or hydrocolloids; gelling starches, and crystallizable carbohydrates. In certain other such embodiments, suitable non-crystallizable carbohydrates may be selected from polydextrose, starch hydrolysates, and non-crystallizable sugar alcohols. In such embodiments, the immediate release shell portion will preferably be breached or dissolved within 30 minutes in 900 ml water or 0.1 N HCl, or phosphate buffer
solution at 37°C with stirring by a USP type 2 (Paddle method) at 50 or 100 φm.
[0173] This invention will be illustrated by the following examples, which are not meant to limit the invention in any way.
Example 1 [0174] Dosage forms according to the invention were made as follows. First, cores were prepared using the following ingredients:
Figure imgf000058_0001
[0175] The pseudoephedrine HCl crystal, hydroxypropyl methylcellulose, polyethylene oxide and FD&C Blue #1 were mixed in a plastic bag for 1-2 minutes. This powder mixture was added to the (5 qt) bowl of a planetary mixer (Hobart Coφ., Dayton, OH). The alcohol was added to the powder mixture while mixing at low speed. The ingredients were mixed for 10 minutes. The resulting granulation was removed from the bowl and was dried at room temperature for 12 to 16 hours to remove all residual solvent. The granulation was screened through a 20-mesh screen and put into a plastic bag. Magnesium stearate was added to the dry granules, followed by mixing for 3 minutes.
[0176] Cores were then prepared by pressing the granulation using a Manesty Beta-press (Thomas Engineering, Inc., Hoffman Estates, IL). A round, concave punch and die unit having 0.4455" diameter was used for compression. Granulation was fed into the cavity of the press and compressed into solid cores.
[0177] A first coating material was next prepared from the following ingredients:
Figure imgf000058_0002
Figure imgf000059_0001
[0178] The polycaprolactones were first added to a beaker. The isopropanol was added thereto and the combination was mixed with a spatula until a uniform dispersion was obtained.
[0179] A thermal cycle molding module as described in copending U.S. Application Serial No. 09/966,497 at pages 27-51, the disclosure of which is incoφorated herein by reference, was used to apply the first coating material onto the cores. The thermal cycle molding module was a laboratory scale unit and comprised a single mold made from an upper mold assembly and a lower mold assembly. The lower mold assembly was first cycled to a cold
stage at 25°C for 30 seconds. First coating material was then introduced into a cavity in the
lower mold assembly. A core as prepared above was then inserted into the same cavity. The
upper mold assembly was then cycled to a cold stage at 25°C for 30 seconds. First coating
material was added to a cavity in the upper mold assembly. The lower and upper mold
assemblies were mated and cycled to a hot stage at 85°C for 1 minute, followed by cycling to
a cold stage at 10°C for 1 minute to harden the first coating. The upper and lower mold
assemblies were separated and the core coated with the first coating was ejected.
[0180] The "weight gains" of the cores due to the presence of the first coating were recorded. The coated cores were dried at room temperature for 24 hours to remove all residual solvent.
[0181] Next, holes were drilled through the centers of the coated cores. 0.277 cm holes were drilled through in one set of coated cores using a 3/8" drill (model 315.10491, Sears, Roebuck and Co.) equipped with a 7/64" drill bit. 0.397-cm holes were drilled in a second set of coated cores using a 3/8" drill equipped with a 5/32" drill bit.
[0182] Finally, a shell material was prepared using the following ingredient:
Figure imgf000060_0001
[0183] A beaker was submersed in a 70°C water bath (Ret digi-visc; Antal-Direct, Wayne,
PA). The polyethylene glycol (PEG) was added to the beaker and was mixed with a spatula until melted. The molten PEG was then introduced into a rubber capsule-shape mold (20.5 mm x 12.6 mm x 10.7 mm). A coated core containing a hole, prepared as described above, was inserted into the mold. Additional molten PEG was added to fill the mold. The mold was then allowed to cool for five minutes, hardening the PEG into a shell. The resulting dosage form comprising a PEG shell was removed from the mold.
[0184] The release profiles versus time for two dosage forms of the invention were compared with the release profile of an uncoated solid core material. The release profile (i.e. % released vs. time) for each is shown in Figure 6. In Figure 6, curve "c" is the release profile of the uncoated solid core, curve "b" is the release profile of the dosage form having a 0.397 cm hole, and curve "a" is the release profile of the dosage form having a 0.280 cm hole.
Example 2 [0185] Dosage forms of the invention are made in a continuous process using an apparatus comprising three thermal cycle molding modules linked in series via two transfer devices as described at pages 14-16 of copending U.S. Application Serial No. 09/966,939, the disclosure of which is incoφorated herein by reference. The dosage forms have the structure shown in
Figure 7 and each comprise a core having a toroidal shape (i.e., donut-shaped) coated first with an first coating on its entire exterior surface except for the surface inside the hole of the donut. The dosage forms further comprise a shell completely overlying the core and the first coating, thereby forming the outermost layer of the dosage form.
[0186] The core is made of a core flowable material comprising the following ingredients:
Figure imgf000061_0001
[0187] The ingredients are processed as set forth in Example 1.
[0188] The first coating is made from an first coating flowable material comprising the following ingredients:
Figure imgf000061_0002
[0189] The polycaprolactones are first mixed with the isopropanol until a uniform dispersion is obtained.
[0190] The shell is made from a shell flowable material comprising the following ingredient:
Figure imgf000062_0001
[0191] The thermal cycle molding modules have the general configuration shown in Figure 3 of copending U.S. Application Serial No. 09/966,939, which depicts a thermal cycle molding module 200 comprising a rotor 202 around which a plurality of mold units 204 are disposed. Each thermal cycle molding module includes its own reservoir 206 (see Figure 4 of copending U.S. Application Serial No. 09/966,939) for holding the core flowable material, the first coating flowable material, and the shell flowable material, respectively. In addition, each thermal cycle molding module is provided with a temperature control system for rapidly heating and cooling the mold units. Figures 55 and 56 of copending U.S. Application Serial No. 09/966,939 depict the temperature control system 600.
[0192] The cores are made in a first thermal cycle molding module, which is linked via a first transfer device to a second thermal cycle molding module, which is in turn linked via a second transfer device to a third thermal cycle molding module. The first thermal cycle molding module has the specific configuration shown in Figure 26A of copending U.S. Application Serial No. 09/966,939. The first thermal cycle molding module comprises center mold assemblies 212 and upper mold assemblies 214 as shown in Figure 26C, which mate to form mold cavities having the shape of a donut. As rotor 202 rotates, the opposing center and upper mold assemblies close. Core flowable material, which is heated to a flowable state in reservoir 206, is injected into the resulting mold cavities. The temperature of the core flowable material is then decreased, hardening the core flowable material into donut-shaped cores. The mold assemblies open and eject the cores, which are received by the first transfer device. [0193] Both the first and second transfer devices have the structure shown as 300 in Figure 3 of copending U.S. Application Serial No. 09/966,939. Each comprises a plurality of transfer units 304 attached in cantilever fashion to a belt 312 as shown in Figures 68 and 69 of copending U.S. Application Serial No. 09/966,939. The transfer devices rotate and operate in sync with the thermal cycle molding modules to which they are coupled. Transfer units 304 comprise retainers 330 for holding the partially made dosage forms as they travel around each transfer device.
[0194] The first transfer device transfers the donut-shaped cores to the second thermal cycle molding module, which applies the first coating to the cores. The second thermal cycle molding module is of the type shown in Figure 28 A of copending U.S. Application Serial No. 09/966,939. The mold units 204 of the second thermal cycle molding module comprise upper mold assemblies 214, rotatable center mold assemblies 212 and lower mold assemblies 210 as shown in Figure 28C. Donut-shaped cores are continuously transfened to the mold assemblies, which then close over the cores. First coating flowable material, which is heated to a flowable state in reservoir 206, is injected into the mold cavities created by the closed mold assemblies. The temperature of the first coating flowable material is then decreased, hardening it. The mold assemblies open and eject the partially coated cores, which are received by the second transfer device. Coating is performed in two steps, each half of the cores being coated separately as shown in the flow diagram of Figure 28B of copending U.S. Application Serial No. 09/966,939 via rotation of the center mold assembly.
[0195] The construction of the mold assemblies in the second thermal cycle molding module is such that the portion of the donut-shaped cores inside the hole is masked by the mold assemblies during application of the first coating. [0196] The inside surface of the mold assembly has a masking protrasion to cover the hole of the donut-shaped cores. Accordingly, the surface of the cores inside the hole remains uncoated upon exiting the second thermal cycle molding module.
[0197] The second transfer device carries the partially coated cores to the third thermal cycle molding module, which applies the shell. The third thermal cycle molding module is also of the type shown in Figures 28A-C of copending U.S. Application Serial No. 09/966,939 comprising rotatable center mold assemblies 212, lower mold assemblies 210 and upper mold assemblies 214. Cores bearing the first coating are continuously transfened to the mold assemblies of the third thermal cycle molding module. Shell flowable material, which is heated to a flowable state in reservoir 206, is injected into the mold cavities created by the closed mold assemblies holding the cores. The temperature of the shell flowable material is then decreased, hardening it. The mold assemblies open and eject the finished dosage forms. Shell coating is performed in two steps, each half of the dosage forms being coated separately as shown in the flow diagram of Figure 28B of copending U.S. Application Serial No. 09/966,939 via rotation of the center mold assembly.
[0198] Although this invention has been illustrated by reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made which clearly fall within the scope of this invention.

Claims

The invention claimed is:
1. A dosage form comprising: (a) at least one active ingredient: (b) a core having a first surface portion upon which resides a first coating and a second surface portion which is substantially free of the first coating; and (c) a shell which resides upon at least a portion of the second surface portion, wherein the shell comprises a different material from the first coating.
2. The dosage form of Claim 1 , in which the core comprises a cavity therein such that at least part of the second surface portion of the core is located within the cavity, and the shell resides upon at least a part of the second surface portion of the core which is located within the cavity.
3. The dosage form of Claim 2, in which the cavity is an aperture which extends entirely through the core such that the aperture provides the second surface portion of the core.
4. The dosage form of either Claim 2 or Claim 3, in which the shell resides upon at least part of both the first coating and the second surface portion of the core.
5. The dosage form of Claim 1, in which the shell resides over all the first coating and the second surface of the core.
6. The dosage form of Claim 1, in which the shell comprises a material selected from water soluble or water swellable thermoplastic film formers, water soluble or water swellable thickeners, crystallizable and non-crystallizable carbohydrates.
7. The dosage form of Claim 1, in which the shell comprises a thermal-reversible carrier selected from the group consisting of thermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides, and combinations thereof.
8. A dosage form comprising: (a) at least one active ingredient; (b) a core comprising a center portion having an exterior surface and an annular portion having an exterior surface and an interior surface, wherein the annular portion interior surface is in contact with at least a portion of the center portion exterior surface, and a coating resides on at least a portion of the annular portion exterior surface; and (c) a shell which resides upon at least a portion of the exterior surface of the center portion, wherein the shell comprises a different material than the impermeable coating.
9. The dosage form of Claim 1 or Claim 8, in which the core comprises at least one active ingredient.
10. The dosage form of Claim 8, in which the center portion of the core comprises at least one active ingredient.
11. The dosage form of Claim 8, in which the annular portion of the core comprises at least one active ingredient.
12. The dosage form of Claim 8, in which the center portion of the core comprises a first active ingredient and the annular portion of the core comprises a second active ingredient.
13. The dosage form of Claim 1 of Claim 8, in which the shell comprises at least one active ingredient.
14. The dosage form of Claim 1 or Claim 8, in which both the shell and the core each comprise at least one active ingredient.
15. The dosage form of Claim 8, in which the first coating resides upon the entire annular portion exterior surface.
16. The dosage form of Claim 15, in which the shell resides upon the entire first coating and the center portion surface.
17. The dosage form of Claim 8, in which the shell comprises a material selected from water soluble or water swellable thermoplastic film formers, water soluble or water swellable thickeners, crystallizable and non-crystallizable carbohydrates.
18. The dosage form of Claim 8, in which the core annular portion has the shape of a toms.
19. The dosage form of Claim 8, in which the shell comprises a thermal-reversible carrier selected from the group consisting of thermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides, and combinations thereof.
20. A dosage form comprising: (a) at least one active ingredient; (b) a core having an outer surface and a cavity which extends at least partially through the core such that the core outer surface has at least a first opening therein; (c) a first coating which resides on at least a portion of the core outer surface, wherein the first shell portion comprises a different material from the first coating; and (d) a first shell portion which is adjacent to the first opening and covers at least the first opening.
21. The dosage form of Claim 20, in which the cavity extends entirely through the core such that the core has first and second openings therein, the first shell portion is adjacent to and covers at least the first opening, and the dosage form additionally comprises a second shell portion which is adjacent to and covers at least the second opening, wherein the first and second shell portions each comprise a material different from the first coating.
22. The dosage form of Claim 20, in which the core has the shape of a torus.
23. The dosage form of Claim 20, in which the first shell portion comprises at least one water soluble material.
24. The dosage form of Claim 20, in which the second shell portion comprises at least one water soluble material.
25. The dosage form of Claim 20, in which the first and second shell portions each comprise at least one water soluble material.
26. The dosage form of Claim 20, in which the first shell portion or the core or a combination thereof comprises at least one active ingredient.
27. The dosage form of Claim 20, in which the first shell portion, second shell portion or the core or a combination thereof comprises at least one active ingredient.
28. The dosage form of Claim 20 or Claim 21 , in which the first shell portion resides upon at least a portion of the first coating.
29. The dosage form of Claim 27, in which the shell resides upon the entire outer surface of the first coating.
30. The dosage form of Claim 1, Claim 8 or Claim 20, in which at least a portion of the active ingredient is released in a sustained manner.
31. The dosage form of Claim 29, in which the dosage form releases at least a portion of the active ingredient at a substantially constant rate.
32. The dosage form of Claim 9, in which the release of at least one active ingredient from the center portion of the core meets USP specifications for immediate release tablets containing the particular active ingredient employed.
33. The dosage form of Claim 8, in which the center portion of the core provides a time delay to the release of active ingredient from the annular portion of the core.
34. The dosage form of Claim 1, Claim 8 or Claim 20, in which the core functions as an eroding matrix.
35. The dosage form of Claim 1, Claim 8 or Claim 20, in which the core functions as a diffusional matrix.
36. The dosage form of Claim 1, Claim 8 or Claim 20, in which the core comprises a release-modifying excipient selected from the group consisting of swellable erodible hydrophillic materials, insoluble edible materials, pH-dependent polymers, and mixtures thereof.
37. The dosage form of Claim 1, Claim 8 or Claim 20, in which the first coating comprises at least about 30 weight percent of a thermal reversible carrier, based on the weight of the first coating.
38. The dosage form of Claim 1, Claim 8 or Claim 20, in which the first coating comprises at lease about 10 weight percent of a film former selected from the group consisting of film-forming water soluble polymers, film-forming proteins, film- forming water insoluble polymers, and film-forming pH-dependent polymers, and combinations thereof.
39. The dosage form of Claim 1, Claim 8 or Claim 20, in which the shell or shell portion comprises thermoplastic polyalkalene glycols, thermoplastic polyalkalene oxides, and combinations thereof.
40. The dosage form of Claim 1, Claim 8 or Claim 20, in which the shell portion is breached or dissolved within 30 minutes in 900 ml water or 0.1 N HCl, or phosphate buffer
solution at 37°C with stirring by a USP type 2 (Paddle method) at 50 or 100 φm.
41. The dosage form of Claim 1, Claim 8 or Claim 20, in which the release of at least one active ingredient follows a double pulse profile.
42. The dosage form of Claim 1, Claim 8 or Claim 20, in which the release of at least one active ingredient follows a delayed then sustained release profile.
43. The dosage form of Claim 1, Claim 8 or Claim 20, in which release of a first portion of active ingredient from the dosage form meets USP specifications for immediate release tablets containing the particular active ingredient employed, and release of a second portion of active ingredient from the dosage form follows a sustained, prolonged, extended, or retarded release profile.
44. The dosage form of Claim 43, in which the immediately released first portion of active ingredient is contained in the shell, and the sustained release second portion of active ingredient is contained in the core.
45. The dosage form of Claim 1, Claim 8, or Claim 20, in which the release of one or more active ingredients follows a zero-order, first-order, or square root of time profile.
46. The dosage form of Claim 1, Claim 8, or Claim 20, in which the shell is substantially free of pores in the diameter range of 0.5 to 5.0 microns.
47. The dosage form of Claim 1, Claim 8, or Claim 20, in which the first coating comprises up to about 55 weight percent of a release-modifying excipient selected from water-insoluble polymers and low-melting hydrophobic materials and combinations thereof.
48. The dosage form of Claim 47, in which the release-modifying excipeint is a polycaprolactone.
PCT/US2002/031117 2001-09-28 2002-09-28 Modified release dosage forms WO2003026629A2 (en)

Priority Applications (75)

Application Number Priority Date Filing Date Title
KR10-2004-7004656A KR20040045030A (en) 2001-09-28 2002-09-28 Modified release dosage forms
US10/476,530 US8545887B2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
JP2003530266A JP2005535558A (en) 2001-09-28 2002-09-28 Modified release dosage form
EP02799689A EP1438030A2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
BR0213588-4A BR0213588A (en) 2001-09-28 2002-09-28 Modified Release Dosage Forms
MXPA04002979A MXPA04002979A (en) 2001-09-28 2002-09-28 Modified release dosage forms.
CA002461684A CA2461684A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
RU2005108611/15A RU2005108611A (en) 2002-09-28 2003-03-21 TWO-Kernel Modified Release Dosage Forms
AU2003220466A AU2003220466A1 (en) 2002-09-28 2003-03-21 Delayed release dosage forms
US10/393,871 US7416738B2 (en) 2001-09-28 2003-03-21 Modified release dosage form
AU2003220468A AU2003220468A1 (en) 2002-09-28 2003-03-21 Solid dosage form comprising ketoprofen
EP03714356A EP1551374B1 (en) 2002-09-28 2003-03-21 Polymer composition and dosage forms comprising the same
CN03823065.8A CN1684671A (en) 2002-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein
EP03716788A EP1545452A1 (en) 2002-09-28 2003-03-21 Modified release dosage forms
AU2003225945A AU2003225945B2 (en) 2002-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein
ES03798655T ES2355233T3 (en) 2002-09-28 2003-03-21 DOSED FORMS OF MODIFIED RELEASE WITH TWO CORES AND ONE OPENING.
CA002499955A CA2499955A1 (en) 2002-09-28 2003-03-21 Delayed release dosage forms
MXPA05003281A MXPA05003281A (en) 2002-09-28 2003-03-21 Modified release dosage forms with two cores and an opening.
AU2003220472A AU2003220472A1 (en) 2002-09-28 2003-03-21 Modified release dosage form with two cores
AT03798655T ATE490764T1 (en) 2002-09-28 2003-03-21 SUSTAINED RELEASE PHARMACEUTICAL FORMS HAVING TWO CORE AND ONE OPENING
PCT/US2003/008847 WO2004028511A1 (en) 2002-09-28 2003-03-21 Solid dosage form comprising ketoprofen
AT03714356T ATE444739T1 (en) 2002-09-28 2003-03-21 POLYMER COMPOSITION AND DOSAGE FORMS CONTAINING SAME
NZ538842A NZ538842A (en) 2002-09-28 2003-03-21 Immediate release dosage form comprising a solid core of density 0.9 g/ml surrounded by a shell that is readily soluble to gastrointestinal fluids
US10/393,610 US20030219484A1 (en) 2001-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein
AU2003225944A AU2003225944A1 (en) 2002-09-28 2003-03-21 Modified release dosage forms with two cores and an opening
CA2500313A CA2500313C (en) 2002-09-28 2003-03-21 Polymer composition and dosage forms comprising the same
JP2004539767A JP2006517514A (en) 2002-09-28 2003-03-21 Adjustable release dosage form with two cores
US10/393,764 US20030229158A1 (en) 2001-09-28 2003-03-21 Polymer composition and dosage forms comprising the same
BR0314547-6A BR0314547A (en) 2002-09-28 2003-03-21 Immediate release dosage form comprising a shell having openings therein
AU2003220479A AU2003220479A1 (en) 2002-09-28 2003-03-21 Modified release dosage forms
RU2005108608/15A RU2005108608A (en) 2002-09-28 2003-03-21 DOSED IMMEDIATE RELEASE FORM CONTAINING HOLE HOUSING
CA002500312A CA2500312A1 (en) 2002-09-28 2003-03-21 Modified release dosage form
JP2004539770A JP2006517183A (en) 2002-09-28 2003-03-21 Immediate release dosage form having a shell with an opening
US10/393,638 US20030232082A1 (en) 2001-09-28 2003-03-21 Modified release dosage forms
US10/393,756 US20030228368A1 (en) 2001-09-28 2003-03-21 Edible solid composition and dosage form
CA2499882A CA2499882C (en) 2002-09-28 2003-03-21 Modified release dosage form with two cores
JP2004539769A JP2006517182A (en) 2002-09-28 2003-03-21 Adjustable release dosage form with two cores and openings
BR0314804-1A BR0314804A (en) 2002-09-28 2003-03-21 Modified Release Dosage Form
EP10177295A EP2255795A1 (en) 2002-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein
MXPA05003280A MXPA05003280A (en) 2002-09-28 2003-03-21 Modified release dosage forms.
PCT/US2003/008960 WO2004028514A1 (en) 2002-09-28 2003-03-21 Polymer composition and dosage forms comprising the same
RU2005108576/15A RU2005108576A (en) 2002-09-28 2003-03-21 POLYMERIC COMPOSITION AND CONTAINING ITS MEDICINAL FORMS
EP03798656A EP1542662A1 (en) 2002-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein
EP03716781.4A EP1542661B1 (en) 2002-09-28 2003-03-21 Modified release dosage form with two cores
KR1020057005195A KR100995486B1 (en) 2002-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein
KR1020057005346A KR20050084605A (en) 2002-09-28 2003-03-21 Modified release dosage forms with two cores and an opening
DE60329614T DE60329614D1 (en) 2002-09-28 2003-03-21 POLYMERIC COMPOSITION AND PHARMACEUTICAL FORMS CONTAINING THEREOF
MXPA05003283A MXPA05003283A (en) 2002-09-28 2003-03-21 Polymer composition and dosage forms comprising the same.
CA002500311A CA2500311A1 (en) 2002-09-28 2003-03-21 Modified release dosage forms
KR1020057005272A KR20050071517A (en) 2002-09-28 2003-03-21 Modified release dosage form with two cores
BR0314787-8A BR0314787A (en) 2002-09-28 2003-03-21 Modified Release Dosage Form
PCT/US2003/008891 WO2004028504A1 (en) 2002-09-28 2003-03-21 Modified release dosage forms
PCT/US2003/008845 WO2004028510A1 (en) 2002-09-28 2003-03-21 Delayed release dosage forms
PCT/US2003/008897 WO2004028513A1 (en) 2002-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein
RU2005108609/15A RU2005108609A (en) 2002-09-28 2003-03-21 MEDICINAL FORMS WITH MODIFIED RELEASE, WITH TWO CORES AND HOLE
MXPA05003282A MXPA05003282A (en) 2002-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein.
EP03798655A EP1545472B1 (en) 2002-09-28 2003-03-21 Modified release dosage forms with two cores and an opening
AU2003218359A AU2003218359A1 (en) 2002-09-28 2003-03-21 Polymer composition and dosage forms comprising the same
RU2005108577/15A RU2005108577A (en) 2002-09-28 2003-03-21 DOSED FORMS WITH MODIFIED RELEASE
CA2499979A CA2499979C (en) 2002-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein
PCT/US2003/008859 WO2004028512A1 (en) 2002-09-28 2003-03-21 Modified release dosage form with two cores
PCT/US2003/008894 WO2004028508A1 (en) 2002-09-28 2003-03-21 Modified release dosage forms with two cores and an opening
US10/393,765 US20040018327A1 (en) 2001-09-28 2003-03-21 Delayed release dosage forms
DE60335270T DE60335270D1 (en) 2002-09-28 2003-03-21 PHARMACEUTICAL FORMS FOR DELAYED RELEASE WITH TWO NUCLEARS AND ONE OPENING
US10/393,752 US7635490B2 (en) 2001-09-28 2003-03-21 Modified release dosage form
CA002499977A CA2499977A1 (en) 2002-09-28 2003-03-21 Edible solid composition and dosage form
BR0314777-0A BR0314777A (en) 2002-09-28 2003-03-21 Modified Release Dosage Forms
MXPA05003279A MXPA05003279A (en) 2002-09-28 2003-03-21 Modified release dosage form with two cores.
BR0314781-9A BR0314781A (en) 2002-09-28 2003-03-21 Polymer composition and dosage forms comprising the same
US10/695,347 US7838026B2 (en) 2001-09-28 2003-10-28 Burst-release polymer composition and dosage forms comprising the same
US10/860,972 US20040253312A1 (en) 2001-09-28 2004-06-04 Immediate release dosage form comprising shell having openings therein
NO20051979A NO20051979L (en) 2002-09-28 2005-04-22 Dosage form for immediate release comprising shell with openings.
NO20052037A NO20052037L (en) 2002-09-28 2005-04-26 Dosage forms with two cores and a modified release aperture
NO20052036A NO20052036L (en) 2002-09-28 2005-04-26 Dosage form with two cores with modified release
US12/049,628 US20080305150A1 (en) 2001-09-28 2008-03-17 Polymer Composition And Dosage Forms Comprising The Same

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US09/966,497 2001-09-28
US09/967,414 2001-09-28
US09/966,509 2001-09-28
US09/966,497 US7122143B2 (en) 2001-09-28 2001-09-28 Methods for manufacturing dosage forms
US09/966,450 US6982094B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/967,414 US6742646B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/966,939 2001-09-28
US09/966,939 US6837696B2 (en) 2001-09-28 2001-09-28 Apparatus for manufacturing dosage forms
US09/966,450 2001-09-28
US09/966,509 US6767200B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms

Related Parent Applications (6)

Application Number Title Priority Date Filing Date
US09/967,414 Continuation-In-Part US6742646B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/966,450 Continuation-In-Part US6982094B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/966,509 Continuation-In-Part US6767200B2 (en) 2001-09-28 2001-09-28 Systems, methods and apparatuses for manufacturing dosage forms
US09/966,497 Continuation-In-Part US7122143B2 (en) 2001-09-28 2001-09-28 Methods for manufacturing dosage forms
US09/966,939 Continuation-In-Part US6837696B2 (en) 2001-09-28 2001-09-28 Apparatus for manufacturing dosage forms
PCT/US2002/031062 Continuation-In-Part WO2003026626A2 (en) 2001-09-28 2002-09-28 Modified release dosage forms

Related Child Applications (8)

Application Number Title Priority Date Filing Date
PCT/US2002/031129 Continuation-In-Part WO2003026630A1 (en) 2001-09-28 2002-09-28 Dosage forms having an inner core and outer shell with different shapes
US10/393,764 Continuation-In-Part US20030229158A1 (en) 2001-09-28 2003-03-21 Polymer composition and dosage forms comprising the same
US10/393,871 Continuation-In-Part US7416738B2 (en) 2001-09-28 2003-03-21 Modified release dosage form
US10/393,638 Continuation-In-Part US20030232082A1 (en) 2001-09-28 2003-03-21 Modified release dosage forms
US10/393,765 Continuation-In-Part US20040018327A1 (en) 2001-09-28 2003-03-21 Delayed release dosage forms
US10/393,756 Continuation-In-Part US20030228368A1 (en) 2001-09-28 2003-03-21 Edible solid composition and dosage form
US10/393,610 Continuation-In-Part US20030219484A1 (en) 2001-09-28 2003-03-21 Immediate release dosage form comprising shell having openings therein
US10/393,752 Continuation-In-Part US7635490B2 (en) 2001-09-28 2003-03-21 Modified release dosage form

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WO2003026629A3 WO2003026629A3 (en) 2004-03-04

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PCT/US2002/031024 WO2003026625A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
PCT/US2002/031116 WO2003026615A2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
PCT/US2002/031022 WO2003026624A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
PCT/US2002/031066 WO2003026612A2 (en) 2001-09-28 2002-09-28 Dosage forms having an inner core and outer shell
PCT/US2002/031115 WO2003026614A1 (en) 2001-09-28 2002-09-28 Dosage form containing a confectionery composition
PCT/US2002/031063 WO2003026628A2 (en) 2001-09-28 2002-09-28 Composite dosage forms having an inlaid portion
PCT/US2002/031163 WO2003026627A1 (en) 2001-09-28 2002-09-28 Composite dosage forms
PCT/US2002/031129 WO2003026630A1 (en) 2001-09-28 2002-09-28 Dosage forms having an inner core and outer shell with different shapes
PCT/US2002/031117 WO2003026629A2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
PCT/US2002/031062 WO2003026626A2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
PCT/US2002/031067 WO2003026613A1 (en) 2001-09-28 2002-09-28 Fondant-based pharmaceutical composition
PCT/US2002/031164 WO2003026616A1 (en) 2001-09-28 2002-09-28 Edible composition and dosage form comprising an edible shell

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PCT/US2002/031024 WO2003026625A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
PCT/US2002/031116 WO2003026615A2 (en) 2001-09-28 2002-09-28 Modified release dosage forms
PCT/US2002/031022 WO2003026624A1 (en) 2001-09-28 2002-09-28 Modified release dosage forms
PCT/US2002/031066 WO2003026612A2 (en) 2001-09-28 2002-09-28 Dosage forms having an inner core and outer shell
PCT/US2002/031115 WO2003026614A1 (en) 2001-09-28 2002-09-28 Dosage form containing a confectionery composition
PCT/US2002/031063 WO2003026628A2 (en) 2001-09-28 2002-09-28 Composite dosage forms having an inlaid portion
PCT/US2002/031163 WO2003026627A1 (en) 2001-09-28 2002-09-28 Composite dosage forms
PCT/US2002/031129 WO2003026630A1 (en) 2001-09-28 2002-09-28 Dosage forms having an inner core and outer shell with different shapes

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PCT/US2002/031067 WO2003026613A1 (en) 2001-09-28 2002-09-28 Fondant-based pharmaceutical composition
PCT/US2002/031164 WO2003026616A1 (en) 2001-09-28 2002-09-28 Edible composition and dosage form comprising an edible shell

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KR (11) KR20040045030A (en)
CN (10) CN1638740A (en)
AT (4) ATE476957T1 (en)
AU (1) AU2002330164A1 (en)
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ES (3) ES2444549T3 (en)
HK (1) HK1072902A1 (en)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006528636A (en) * 2003-07-24 2006-12-21 スミスクライン・ビーチャム・コーポレイション Orally soluble film
WO2009154810A2 (en) * 2008-02-25 2009-12-23 Dr. Reddy's Laboratories Ltd. Delivery systems for multiple active agents
JP2012001542A (en) * 2004-06-09 2012-01-05 Glaxosmithkline Llc Apparatus and method for producing pharmaceutical product

Families Citing this family (311)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8071128B2 (en) 1996-06-14 2011-12-06 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US6607751B1 (en) * 1997-10-10 2003-08-19 Intellipharamaceutics Corp. Controlled release delivery device for pharmaceutical agents incorporating microbial polysaccharide gum
CA2327685C (en) * 1998-04-03 2008-11-18 Bm Research A/S Controlled release composition
US20090149479A1 (en) * 1998-11-02 2009-06-11 Elan Pharma International Limited Dosing regimen
DE10026698A1 (en) 2000-05-30 2001-12-06 Basf Ag Self-emulsifying active ingredient formulation and use of this formulation
US20040234602A1 (en) 2001-09-21 2004-11-25 Gina Fischer Polymer release system
US20040253310A1 (en) 2001-09-21 2004-12-16 Gina Fischer Morphine polymer release system
JP2005508325A (en) 2001-09-28 2005-03-31 マクニール−ピーピーシー・インコーポレイテッド Dosage form having an inner core and an outer shell
US9358214B2 (en) 2001-10-04 2016-06-07 Adare Pharmaceuticals, Inc. Timed, sustained release systems for propranolol
GB0203296D0 (en) 2002-02-12 2002-03-27 Glaxo Group Ltd Novel composition
DK1476138T3 (en) * 2002-02-21 2012-02-20 Valeant Internat Barbados Srl Modified release formulations of at least one form of tramadol
US8323692B2 (en) 2002-02-21 2012-12-04 Valeant International Bermuda Controlled release dosage forms
US7169450B2 (en) 2002-05-15 2007-01-30 Mcneil-Ppc, Inc. Enrobed core
US20060083791A1 (en) * 2002-05-24 2006-04-20 Moerck Rudi E Rare earth metal compounds methods of making, and methods of using the same
US20040161474A1 (en) * 2002-05-24 2004-08-19 Moerck Rudi E. Rare earth metal compounds methods of making, and methods of using the same
US7776314B2 (en) 2002-06-17 2010-08-17 Grunenthal Gmbh Abuse-proofed dosage system
US8637512B2 (en) 2002-07-29 2014-01-28 Glaxo Group Limited Formulations and method of treatment
US20060159758A1 (en) * 2002-12-11 2006-07-20 Rajesh Gandhi Coating composition for taste masking coating and methods for their application and use
GB0229258D0 (en) * 2002-12-16 2003-01-22 Boots Healthcare Int Ltd Medicinal compositions
US8367111B2 (en) 2002-12-31 2013-02-05 Aptalis Pharmatech, Inc. Extended release dosage forms of propranolol hydrochloride
US20050220870A1 (en) * 2003-02-20 2005-10-06 Bonnie Hepburn Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid
ATE495732T1 (en) 2003-03-26 2011-02-15 Egalet As CONTROLLED RELEASE MORPHINE SYSTEM
CA2520312C (en) * 2003-03-26 2013-06-18 Egalet A/S Matrix compositions for controlled delivery of drug substances
PT1631251E (en) 2003-04-24 2011-09-19 Jagotec Ag Delayed release tablet with defined core geometry
JP4908200B2 (en) * 2003-04-24 2012-04-04 ヤゴテック アーゲー Tablet with colored core
CA2527133A1 (en) * 2003-05-29 2004-12-09 Glykon Technologies Group, Llc Method and composition for stable and controlled delivery of (-)-hydroxycitric acid
CA2529984C (en) 2003-06-26 2012-09-25 Isa Odidi Oral multi-functional pharmaceutical capsule preparations of proton pump inhibitors
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
DE102004032051A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Process for the preparation of a secured against misuse, solid dosage form
DE10361596A1 (en) 2003-12-24 2005-09-29 Grünenthal GmbH Process for producing an anti-abuse dosage form
US20070048228A1 (en) 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
DE102005005446A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Break-resistant dosage forms with sustained release
DE10336400A1 (en) 2003-08-06 2005-03-24 Grünenthal GmbH Anti-abuse dosage form
WO2005016278A2 (en) * 2003-08-12 2005-02-24 Advancis Pharmaceuticals Corporation Antibiotic product, use and formulation thereof
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8025899B2 (en) 2003-08-28 2011-09-27 Abbott Laboratories Solid pharmaceutical dosage form
JP2005075826A (en) * 2003-08-29 2005-03-24 Boehringer Ingelheim Internatl Gmbh Controlled release preparation comprising porous silica support
GB0320854D0 (en) 2003-09-05 2003-10-08 Arrow No 7 Ltd Buccal drug delivery
WO2005046363A2 (en) 2003-11-07 2005-05-26 U.S. Smokeless Tobacco Company Tobacco compositions
US8627828B2 (en) 2003-11-07 2014-01-14 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US7879354B2 (en) 2004-01-13 2011-02-01 Mcneil-Ppc, Inc. Rapidly disintegrating gelatinous coated tablets
US8067029B2 (en) 2004-01-13 2011-11-29 Mcneil-Ppc, Inc. Rapidly disintegrating gelatinous coated tablets
US20050196448A1 (en) * 2004-03-05 2005-09-08 Hai Yong Huang Polymeric compositions and dosage forms comprising the same
US20050196442A1 (en) * 2004-03-05 2005-09-08 Huang Hai Y. Polymeric compositions and dosage forms comprising the same
US20050196446A1 (en) * 2004-03-05 2005-09-08 Huang Hai Y. Polymeric compositions and dosage forms comprising the same
US20050196447A1 (en) * 2004-03-05 2005-09-08 Huang Hai Y. Polymeric compositions and dosage forms comprising the same
CN1929838B (en) * 2004-03-10 2012-05-09 大正制药株式会社 Solid pharmaceutical preparation containing sparingly water-soluble drug
US8545881B2 (en) 2004-04-19 2013-10-01 Eurand Pharmaceuticals, Ltd. Orally disintegrating tablets and methods of manufacture
CA2566793C (en) 2004-05-11 2013-07-16 Egalet A/S A novel dosage form
US7622137B2 (en) * 2004-05-21 2009-11-24 Accu-Break Technologies, Inc. Dosage forms contained within a capsule or sachet
US8815916B2 (en) 2004-05-25 2014-08-26 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20060002986A1 (en) * 2004-06-09 2006-01-05 Smithkline Beecham Corporation Pharmaceutical product
US20050281876A1 (en) * 2004-06-18 2005-12-22 Shun-Por Li Solid dosage form for acid-labile active ingredient
DE102004032049A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Anti-abuse, oral dosage form
US8394409B2 (en) 2004-07-01 2013-03-12 Intellipharmaceutics Corp. Controlled extended drug release technology
US8609198B2 (en) * 2004-07-21 2013-12-17 Hewlett-Packard Development Company, L.P. Pharmaceutical dose form with a patterned coating and method of making the same
BRPI0513598A (en) * 2004-07-26 2008-05-13 Teva Pharma enteric release coated tablet dosage forms
US20060024361A1 (en) * 2004-07-28 2006-02-02 Isa Odidi Disintegrant assisted controlled release technology
US7621734B2 (en) 2004-07-28 2009-11-24 Mars, Incorporated Apparatus and process for preparing confectionery having an inclusion therein using forming rolls and a forming pin
US20060024368A1 (en) * 2004-07-30 2006-02-02 Reza Fassihi Compressed composite delivery system for release-rate modulation of bioactives
EP1639899A1 (en) * 2004-08-23 2006-03-29 Friesland Brands B.V. Powdered, cold-water soluble/dispersible, foamable composition
US10624858B2 (en) * 2004-08-23 2020-04-21 Intellipharmaceutics Corp Controlled release composition using transition coating, and method of preparing same
EP1944004A3 (en) * 2004-09-24 2008-07-23 BioProgress Technology Limited Additional improvements in powder compaction and enrobing
KR20070057977A (en) * 2004-09-24 2007-06-07 바이오프로그레스 테크놀로지 리미티드 Additional improvement in powder compaction and enrobing
EP2335921A1 (en) * 2004-09-30 2011-06-22 MonoSolRX, LLC Multi-layer films
US9884014B2 (en) 2004-10-12 2018-02-06 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
CA2583548A1 (en) * 2004-10-15 2006-04-27 Altairnano, Inc. Phosphate binder with reduced pill burden
EP2417969A1 (en) 2004-10-21 2012-02-15 Aptalis Pharmatech, Inc. Taste-masked pharmaceutical compositions with gastrosoluble pore-formers
US20060088593A1 (en) * 2004-10-27 2006-04-27 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US20070281022A1 (en) * 2004-10-27 2007-12-06 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US20060088586A1 (en) * 2004-10-27 2006-04-27 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US20070190133A1 (en) * 2004-10-27 2007-08-16 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US20060087051A1 (en) * 2004-10-27 2006-04-27 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
US8383159B2 (en) 2004-10-27 2013-02-26 Mcneil-Ppc, Inc. Dosage forms having a microreliefed surface and methods and apparatus for their production
US20060088587A1 (en) * 2004-10-27 2006-04-27 Bunick Frank J Dosage forms having a microreliefed surface and methods and apparatus for their production
GB0423964D0 (en) * 2004-10-28 2004-12-01 Jagotec Ag Dosage form
US20060093560A1 (en) * 2004-10-29 2006-05-04 Jen-Chi Chen Immediate release film coating
AR051654A1 (en) * 2004-11-04 2007-01-31 Astrazeneca Ab NEW FORMULATIONS OF MODIFIED RELEASE PELLETS FOR PROTON PUMP INHIBITORS
AR052225A1 (en) * 2004-11-04 2007-03-07 Astrazeneca Ab FORMULATIONS OF MODIFIED RELEASE TABLETS FOR INHIBITORS OF THE PUMP OF PROTONS
PT1836665E (en) 2004-11-19 2013-04-11 Glaxosmithkline Llc Method for customized dispensing of variable dose drug combination products for individualizing of therapies
US7404708B2 (en) * 2004-12-07 2008-07-29 Mcneil-Ppc, Inc. System and process for providing at least one opening in dosage forms
US7530804B2 (en) * 2004-12-07 2009-05-12 Mcneil-Ppc, Inc. System and process for providing at least one opening in dosage forms
US8481565B2 (en) 2004-12-27 2013-07-09 Eisai R&D Management Co., Ltd. Method for stabilizing anti-dementia drug
US20070129402A1 (en) * 2004-12-27 2007-06-07 Eisai Research Institute Sustained release formulations
JP5227591B2 (en) * 2005-01-07 2013-07-03 サンド・アクチエンゲゼルシヤフト Method for preparing granules containing amoxicillin
DE102005005449A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Process for producing an anti-abuse dosage form
US20080187581A1 (en) * 2005-03-16 2008-08-07 Subhash Pandurang Gore Delivery System For Mulitple Drugs
EP1874274A2 (en) * 2005-04-06 2008-01-09 Mallinckrodt Inc. Matrix-based pulse release pharmaceutical formulation
AU2006235483B2 (en) * 2005-04-12 2010-11-25 Elan Pharma International Limited Controlled release compositions comprising a cephalosporin for the treatment of a bacterial infection
US20060233882A1 (en) * 2005-04-15 2006-10-19 Sowden Harry S Osmotic dosage form
US8673352B2 (en) * 2005-04-15 2014-03-18 Mcneil-Ppc, Inc. Modified release dosage form
WO2006116718A2 (en) 2005-04-28 2006-11-02 Proteus Biomedical, Inc. Pharma-informatics system
WO2006118265A1 (en) * 2005-04-28 2006-11-09 Eisai R & D Management Co., Ltd. Composition containing antidementia agent
US8802183B2 (en) 2005-04-28 2014-08-12 Proteus Digital Health, Inc. Communication system with enhanced partial power source and method of manufacturing same
US9161918B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
JP2008539779A (en) * 2005-05-18 2008-11-20 ラボラトワール ゴエマル New food materials and products containing them
AU2006254554B2 (en) * 2005-06-03 2011-11-24 Egalet Ltd A solid pharmaceutical composition with a first fraction of a dispersion medium and a second fraction of a matrix, the latter being at least partially first exposed to gastrointestinal fluids
NZ561375A (en) * 2005-06-27 2011-06-30 Biovail Lab Int Srl Bupropion hydrobromide, and crystalline forms, compositions, and uses of this compound
US20070009573A1 (en) * 2005-07-07 2007-01-11 L N K International Method of forming immediate release dosage form
DE102005034043B4 (en) * 2005-07-18 2019-12-12 Südzucker Aktiengesellschaft Mannheim/Ochsenfurt Mixture containing L-carnitine and trehalulose and product containing the mixture
US20070015834A1 (en) * 2005-07-18 2007-01-18 Moshe Flashner-Barak Formulations of fenofibrate containing PEG/Poloxamer
US20080058250A1 (en) * 2005-08-17 2008-03-06 Allison Wren Treatment of chronic renal failure and other conditions in domestic animals: compositions and methods
TWI274889B (en) * 2005-10-06 2007-03-01 Elan Microelectronics Corp Resistive touch screen measurement system
EA200801080A1 (en) * 2005-10-14 2009-02-27 Х. Лундбекк А/С STABLE PHARMACEUTICAL MEDICINE FORMS CONTAINING ESCITALOPRAM AND BUPROPION
US8778924B2 (en) 2006-12-04 2014-07-15 Shionogi Inc. Modified release amoxicillin products
US8357394B2 (en) 2005-12-08 2013-01-22 Shionogi Inc. Compositions and methods for improved efficacy of penicillin-type antibiotics
US10064828B1 (en) 2005-12-23 2018-09-04 Intellipharmaceutics Corp. Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems
WO2007086846A1 (en) * 2006-01-24 2007-08-02 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
JP2007224012A (en) * 2006-01-30 2007-09-06 Fujifilm Corp Enzymatically crosslinked protein nanoparticle
US20070184111A1 (en) * 2006-02-03 2007-08-09 Pharmavite Llc Hybrid tablet
US20070190131A1 (en) * 2006-02-10 2007-08-16 Perry Ronald L Press-fit rapid release medicament and method and apparatus of manufacturing
US20070224258A1 (en) * 2006-03-22 2007-09-27 Bunick Frank J Dosage forms having a randomized coating
US20070231389A1 (en) * 2006-03-28 2007-10-04 Bunick Frank J Non-homogenous dosage form coatings
US9561188B2 (en) 2006-04-03 2017-02-07 Intellipharmaceutics Corporation Controlled release delivery device comprising an organosol coat
EP2010162A4 (en) * 2006-04-03 2013-01-09 Isa Odidi Drug delivery composition
US10960077B2 (en) 2006-05-12 2021-03-30 Intellipharmaceutics Corp. Abuse and alcohol resistant drug composition
EP2037895A4 (en) * 2006-05-23 2009-12-02 Orahealth Corp Xylitol troches and methods of use
US20070293587A1 (en) * 2006-05-23 2007-12-20 Haley Jeffrey T Combating sinus, throat, and blood infections with xylitol delivered in the mouth
WO2007149860A1 (en) * 2006-06-19 2007-12-27 Accu-Break Technologies, Inc. Segmented pharmaceutical dosage forms
ES2400446T5 (en) 2006-08-03 2017-03-13 Horizon Pharma Ag Treatment with delayed-release glucocorticoids of a rheumatic disease
SA07280459B1 (en) 2006-08-25 2011-07-20 بيورديو فارما إل. بي. Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic
US8399230B2 (en) * 2006-10-12 2013-03-19 Kemin Industries, Inc. Heat-stable enzyme compositions
EP1916006A1 (en) * 2006-10-19 2008-04-30 Albert Schömig Implant coated with a wax or a resin
JP5389656B2 (en) 2006-10-20 2014-01-15 マクニール−ピーピーシー・インコーポレーテツド Acetaminophen / ibuprofen combinations and methods for their use
MX2009004439A (en) * 2006-10-25 2009-05-11 Mcneil Ppc Inc Ibuprofen composition.
EP2104493A2 (en) * 2007-01-16 2009-09-30 Egalet A/S Use of i) a polyglycol and n) an active drug substance for the preparation of a pharmaceutical composition for i) mitigating the risk of alcohol induced dose dumping and/or ii) reducing the risk of drug abuse
US7767248B2 (en) 2007-02-02 2010-08-03 Overly Iii Harry J Soft chew confectionary with high fiber and sugar content and method for making same
GB0702974D0 (en) * 2007-02-15 2007-03-28 Jagotec Ag Method and apparatus for producing a tablet
JP5224790B2 (en) * 2007-03-02 2013-07-03 株式会社明治 Solid food and method for producing the same
MX2009006114A (en) * 2007-03-02 2009-11-10 Meda Pharmaceuticals Inc Compositions comprising carisoprodol and methods of use thereof.
DE102007011485A1 (en) 2007-03-07 2008-09-11 Grünenthal GmbH Dosage form with more difficult abuse
US20080292692A1 (en) * 2007-05-21 2008-11-27 Shira Pilch Impermeable Capsules
US20080300322A1 (en) * 2007-06-01 2008-12-04 Atlantic Pharmaceuticals, Inc. Delivery vehicles containing rosin resins
EP2155167A2 (en) 2007-06-04 2010-02-24 Egalet A/S Controlled release pharmaceutical compositions for prolonged effect
CA2687560C (en) * 2007-06-11 2013-05-14 The Procter & Gamble Company Benefit agent containing delivery particle
US20080317677A1 (en) * 2007-06-22 2008-12-25 Szymczak Christopher E Laser Marked Dosage Forms
US20080317678A1 (en) * 2007-06-22 2008-12-25 Szymczak Christopher E Laser Marked Dosage Forms
US20090004248A1 (en) * 2007-06-29 2009-01-01 Frank Bunick Dual portion dosage lozenge form
CN101801350A (en) * 2007-08-13 2010-08-11 阿巴斯迪特宁医药有限公司 Abuse resistant drugs, using method and preparation method
US20090060983A1 (en) * 2007-08-30 2009-03-05 Bunick Frank J Method And Composition For Making An Orally Disintegrating Dosage Form
EP2197448A4 (en) * 2007-09-12 2010-11-17 Elan Pharma Int Ltd Dosing regimen
AR066166A1 (en) * 2007-09-21 2009-07-29 Organon Nv DRUG SUPPLY SYSTEM
FR2921835B1 (en) * 2007-10-05 2012-05-04 Soc Dexploitation De Produits Pour Les Industries Chimiques Seppic COATING COMPOSITION COMPRISING POLYDEXTROSE, PROCESS FOR PREPARING THE SAME, AND USE FOR COATING INFRINGABLE SOLID FORMS
US8707964B2 (en) * 2007-10-31 2014-04-29 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US8303573B2 (en) 2007-10-17 2012-11-06 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US8789536B2 (en) 2007-10-17 2014-07-29 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US20090105561A1 (en) * 2007-10-17 2009-04-23 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Medical or veterinary digestive tract utilization systems and methods
AU2008313032B2 (en) † 2007-10-19 2013-05-02 Otsuka Pharmaceutical Co., Ltd. Matrix-type pharmaceutical solid preparation
US8808276B2 (en) * 2007-10-23 2014-08-19 The Invention Science Fund I, Llc Adaptive dispensation in a digestive tract
US8109920B2 (en) * 2007-10-31 2012-02-07 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
CN101842085B (en) * 2007-10-31 2013-01-30 麦克内尔-Ppc股份有限公司 Orally disintegrated dosage form
US8333754B2 (en) * 2007-10-31 2012-12-18 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US20090163894A1 (en) * 2007-10-31 2009-06-25 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Medical or veterinary digestive tract utilization systems and methods
US8808271B2 (en) * 2007-10-31 2014-08-19 The Invention Science Fund I, Llc Medical or veterinary digestive tract utilization systems and methods
US20090137866A1 (en) * 2007-11-28 2009-05-28 Searete Llc, A Limited Liability Corporation Of The State Delaware Medical or veterinary digestive tract utilization systems and methods
AU2009204360B2 (en) 2008-01-04 2014-12-18 Src, Inc. The use of analgesic potentiating compounds to potentiate the analgesic properties of an analgesic compound and single dose compositions thereof
US8383152B2 (en) 2008-01-25 2013-02-26 Gruenenthal Gmbh Pharmaceutical dosage form
EP2262484B1 (en) 2008-03-11 2013-01-23 Depomed, Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
US8372432B2 (en) 2008-03-11 2013-02-12 Depomed, Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
WO2009137648A1 (en) * 2008-05-09 2009-11-12 Aptapharma, Inc. Multilayer proton pump inhibitor tablets
HUE030803T2 (en) 2008-05-09 2017-06-28 Gruenenthal Gmbh Process for the preparation of an intermediate powder formulation and a final solid dosage form under usage of a spray congealing step
US20110165290A1 (en) * 2008-05-14 2011-07-07 Cadbury Adams Usa Llc Confectionery with enzymatically manipulated texture
WO2009146537A1 (en) * 2008-06-02 2009-12-10 Pharmascience Inc. Multilayer control-release drug delivery system
KR200452140Y1 (en) * 2008-06-20 2011-02-08 주식회사 부성시스템 Control device for nonwoven open/closed device of vinyl house
JP5681626B2 (en) 2008-07-14 2015-03-11 ポリーペイド リミテッドＰｏｌｙｐｉｄ Ｌｔｄ． Sustained release drug carrier composition
KR200450450Y1 (en) * 2008-07-16 2010-10-04 이봉석 The case of position limit switch
US20110136921A1 (en) * 2008-08-07 2011-06-09 Nilesh Tanhaji Dumbre Sustained release composition
US8038424B2 (en) 2008-09-22 2011-10-18 Xerox Corporation System and method for manufacturing sold ink sticks with an injection molding process
FR2936952A1 (en) * 2008-10-09 2010-04-16 Monique Bellec Product, useful as nutritional supplements, comprises a composition in powder/anhydrous liquid form, having active ingredient and gelling agent e.g. lecithin and alginic acid, where composition is enclosed in edible water-soluble envelope
IT1394597B1 (en) * 2008-11-05 2012-07-05 Politi DRY GRANULATION IN GAS FLOW.
WO2010067478A1 (en) * 2008-12-12 2010-06-17 株式会社ミツヤコーポレーション Food and method for processing the same
EP2391369A1 (en) * 2009-01-26 2011-12-07 Nitec Pharma AG Delayed-release glucocorticoid treatment of asthma
WO2010088911A1 (en) * 2009-02-06 2010-08-12 Egalet A/S Pharmaceutical compositions resistant to abuse
NZ594207A (en) 2009-02-06 2013-03-28 Egalet Ltd Immediate release composition resistant to abuse by intake of alcohol
BRPI1007945C8 (en) * 2009-02-13 2021-05-25 Romark Laboratories Lc pharmaceutical formulation of controlled release of nitazoxanide, tizoxanide or a combination thereof, and bilayer tablet for oral administration
MX2011011506A (en) 2009-04-28 2012-05-08 Proteus Biomedical Inc Highly reliable ingestible event markers and methods for using the same.
US8388983B2 (en) * 2009-05-12 2013-03-05 Bpsi Holdings, Llc Film coatings containing fine particle size detackifiers and substrates coated therewith
WO2010133961A1 (en) 2009-05-22 2010-11-25 Inventia Healthcare Private Limited Extended release compositions of cyclobenzaprine
NZ603579A (en) 2009-06-24 2014-02-28 Egalet Ltd Controlled release formulations
US8992979B2 (en) 2009-07-14 2015-03-31 Polypid Ltd. Sustained-release drug carrier composition
KR101738369B1 (en) 2009-07-22 2017-05-22 그뤼넨탈 게엠베하 Hot-melt extruded controlled release dosage form
RU2555531C2 (en) 2009-07-22 2015-07-10 Грюненталь Гмбх Misuse protected dosage form for oxidation sensitive opioids
CA2766775C (en) * 2009-07-24 2015-02-03 Nihon Kraft Foods Limited Multiple-region candy and manufacturing method therefor
WO2011017389A1 (en) 2009-08-05 2011-02-10 Idenix Pharmaceuticals, Inc. Macrocyclic serine protease inhibitors useful against viral infections, particularly hcv
WO2011025673A1 (en) * 2009-08-26 2011-03-03 Aptapharma, Inc. Multilayer minitablets
WO2011026125A2 (en) * 2009-08-31 2011-03-03 Depomed, Inc. Gastric retentive pharmaceutical compositions for immediate and extended release of acetaminophen
CN102575016B (en) * 2009-09-01 2015-06-10 罗地亚管理公司 Polymer compositions
US8313768B2 (en) * 2009-09-24 2012-11-20 Mcneil-Ppc, Inc. Manufacture of tablet having immediate release region and sustained release region
US9610224B2 (en) * 2009-09-24 2017-04-04 Johnson & Johnson Consumer Inc. Manufacture of tablet in a die utilizing powder blend containing water-containing material
US20110070286A1 (en) * 2009-09-24 2011-03-24 Andreas Hugerth Process for the manufacture of nicotine-comprising chewing gum and nicotine-comprising chewing gum manufactured according to said process
US8858210B2 (en) 2009-09-24 2014-10-14 Mcneil-Ppc, Inc. Manufacture of variable density dosage forms utilizing radiofrequency energy
EP2316432A1 (en) * 2009-10-30 2011-05-04 ratiopharm GmbH Compound containing fesoterodine and roughage
WO2011056764A1 (en) 2009-11-05 2011-05-12 Ambit Biosciences Corp. Isotopically enriched or fluorinated imidazo[2,1-b][1,3]benzothiazoles
CA2782285A1 (en) 2009-12-02 2011-06-09 Luigi Mapelli Fexofenadine microcapsules and compositions containing them
UA109424C2 (en) * 2009-12-02 2015-08-25 PHARMACEUTICAL PRODUCT, PHARMACEUTICAL TABLE WITH ELECTRONIC MARKER AND METHOD OF MANUFACTURING PHARMACEUTICAL TABLETS
CN102639122A (en) * 2009-12-07 2012-08-15 麦克内尔-Ppc股份有限公司 Partial dip coating of dosage forms for modified release
MX2012006877A (en) 2009-12-18 2012-08-31 Idenix Pharmaceuticals Inc 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors.
US10485770B2 (en) 2009-12-21 2019-11-26 Aptapharma, Inc. Functionally-coated multilayer tablets
JP5860409B2 (en) 2010-01-19 2016-02-16 ポリピッド リミテッド Sustained release nucleic acid matrix composition
WO2011094890A1 (en) 2010-02-02 2011-08-11 Argusina Inc. Phenylalanine derivatives and their use as non-peptide glp-1 receptor modulators
US9579285B2 (en) 2010-02-03 2017-02-28 Gruenenthal Gmbh Preparation of a powdery pharmaceutical composition by means of an extruder
US9138309B2 (en) 2010-02-05 2015-09-22 Allergan, Inc. Porous materials, methods of making and uses
US9205577B2 (en) * 2010-02-05 2015-12-08 Allergan, Inc. Porogen compositions, methods of making and uses
GB201003766D0 (en) 2010-03-05 2010-04-21 Univ Strathclyde Pulsatile drug release
GB201003734D0 (en) * 2010-03-05 2010-04-21 Univ Strathclyde Delayed prolonged drug delivery
GB201003731D0 (en) * 2010-03-05 2010-04-21 Univ Strathclyde Immediate/delayed drug delivery
CA2792232C (en) * 2010-03-11 2014-07-15 Wockhardt Limited A device for the manufacture of a dosage form with a hole and method of manufacture
WO2011112689A2 (en) 2010-03-11 2011-09-15 Ambit Biosciences Corp. Saltz of an indazolylpyrrolotriazine
US8486013B2 (en) * 2010-03-18 2013-07-16 Biotronik Ag Balloon catheter having coating
US9743688B2 (en) * 2010-03-26 2017-08-29 Philip Morris Usa Inc. Emulsion/colloid mediated flavor encapsulation and delivery with tobacco-derived lipids
BR112012025650A2 (en) 2010-04-07 2020-08-18 Proteus Digital Health, Inc. miniature ingestible device
US11202853B2 (en) * 2010-05-11 2021-12-21 Allergan, Inc. Porogen compositions, methods of making and uses
US8961917B2 (en) 2010-05-12 2015-02-24 Spectrum Pharmaceuticals, Inc. Lanthanum carbonate hydroxide, lanthanum oxycarbonate and methods of their manufacture and use
US20110280936A1 (en) * 2010-05-17 2011-11-17 Aptapharma, Inc. Self Breaking Tablets
WO2011161666A2 (en) * 2010-06-21 2011-12-29 White Innovation Ltd. Enclosed liquid capsules
CA2809994A1 (en) 2010-09-01 2012-03-08 Ambit Biosciences Corporation An optically active pyrazolylaminoquinazoline, and pharmaceutical compositions and methods of use thereof
EP2611792B1 (en) 2010-09-01 2017-02-01 Ambit Biosciences Corporation Hydrobromide salts of a pyrazolylaminoquinazoline
AR082862A1 (en) 2010-09-02 2013-01-16 Gruenenthal Gmbh ALTERATION RESISTANT DOSAGE FORM INCLUDING AN ANIONIC POLYMER
EP2611426B1 (en) 2010-09-02 2014-06-25 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
EP2642983A4 (en) 2010-11-22 2014-03-12 Proteus Digital Health Inc Ingestible device with pharmaceutical product
AU2011338530B2 (en) 2010-12-06 2017-06-15 Follica, Inc. Methods for treating baldness and promoting hair growth
US10821085B2 (en) * 2010-12-07 2020-11-03 Kimberly-Clark Worldwide, Inc. Wipe coated with a botanical composition having antimicrobial properties
AU2011342893A1 (en) 2010-12-13 2013-05-02 Purdue Pharma L.P. Controlled release dosage forms
WO2012080050A1 (en) 2010-12-14 2012-06-21 F. Hoffmann-La Roche Ag Solid forms of a phenoxybenzenesulfonyl compound
CA2825152A1 (en) 2011-01-31 2012-08-09 Celgene Corporation Pharmaceutical compositions of cytidine analogs and methods of use thereof
US9353100B2 (en) 2011-02-10 2016-05-31 Idenix Pharmaceuticals Llc Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating HCV infections
US20120252721A1 (en) 2011-03-31 2012-10-04 Idenix Pharmaceuticals, Inc. Methods for treating drug-resistant hepatitis c virus infection with a 5,5-fused arylene or heteroarylene hepatitis c virus inhibitor
US9937335B2 (en) * 2011-06-06 2018-04-10 Oak Crest Institute Of Science Drug delivery device employing wicking release window
USD723766S1 (en) 2011-06-30 2015-03-10 Intercontinental Great Brands Llc Confectionary article
WO2015112603A1 (en) 2014-01-21 2015-07-30 Proteus Digital Health, Inc. Masticable ingestible product and communication system therefor
US9756874B2 (en) 2011-07-11 2017-09-12 Proteus Digital Health, Inc. Masticable ingestible product and communication system therefor
EA201400172A1 (en) 2011-07-29 2014-06-30 Грюненталь Гмбх SUSTAINABLE TO DESTRUCTION TABLET THAT PROVIDES IMMEDIATE RELEASE OF MEDICINES
AR087359A1 (en) 2011-07-29 2014-03-19 Gruenenthal Gmbh TEST ALTERATION TABLET PROVIDING IMMEDIATE RELEASE OF THE PHARMACO
US20130078307A1 (en) 2011-09-22 2013-03-28 Niconovum Usa, Inc. Nicotine-containing pharmaceutical composition
US9629392B2 (en) 2011-09-22 2017-04-25 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
US9084439B2 (en) 2011-09-22 2015-07-21 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
US9474303B2 (en) 2011-09-22 2016-10-25 R.J. Reynolds Tobacco Company Translucent smokeless tobacco product
AU2011378770B2 (en) 2011-10-14 2015-01-29 Hill's Pet Nutrition, Inc. Process for preparing a food composition
KR101384055B1 (en) * 2012-02-02 2014-04-14 한국원자력연구원 Burst type lagged-release controlled composition and preparation method thereof
EP2819656A1 (en) 2012-02-28 2015-01-07 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
WO2013138613A1 (en) 2012-03-16 2013-09-19 Axikin Pharmaceuticals, Inc. 3,5-diaminopyrazole kinase inhibitors
US20130261372A1 (en) * 2012-03-30 2013-10-03 Elwha LLC, a limited liability company of the State of Delaware Device, System, and Method for Delivery of Sugar Glass Stabilized Compositions
MX362357B (en) 2012-04-18 2019-01-14 Gruenenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form.
US9985320B2 (en) * 2012-04-30 2018-05-29 Carnegie Mellon University Water-activated, ingestible battery
US9445971B2 (en) * 2012-05-01 2016-09-20 Johnson & Johnson Consumer Inc. Method of manufacturing solid dosage form
US9511028B2 (en) 2012-05-01 2016-12-06 Johnson & Johnson Consumer Inc. Orally disintegrating tablet
US9233491B2 (en) 2012-05-01 2016-01-12 Johnson & Johnson Consumer Inc. Machine for production of solid dosage forms
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
EP2857006A4 (en) * 2012-06-05 2015-12-30 Takeda Pharmaceutical Dry-coated tablet
CA2877183A1 (en) 2012-07-06 2014-01-09 Egalet Ltd. Abuse deterrent pharmaceutical compositions for controlled release
CN102824640A (en) * 2012-08-06 2012-12-19 济南圣泉唐和唐生物科技有限公司 Capsule shell and preparation method thereof
US20140193546A1 (en) * 2013-01-09 2014-07-10 Alexander Vigneri Coated chocolate confection with improved dye acceptance
US11149123B2 (en) 2013-01-29 2021-10-19 Otsuka Pharmaceutical Co., Ltd. Highly-swellable polymeric films and compositions comprising the same
DE102013004263A1 (en) 2013-03-13 2014-09-18 Martin Lipsdorf Fast-dissolving oral dosage form and method of making the same
WO2014146093A2 (en) 2013-03-15 2014-09-18 Inspirion Delivery Technologies, Llc Abuse deterrent compositions and methods of use
US10130760B2 (en) * 2013-03-15 2018-11-20 Incube Labs, Llc Multi-stage biodegradable drug delivery platform
JP5941240B2 (en) 2013-03-15 2016-06-29 プロテウス デジタル ヘルス， インコーポレイテッド Metal detector device, system and method
US9470489B2 (en) * 2013-05-14 2016-10-18 Kerry Thaddeus Bowden Airsoft marking round
JP6445537B2 (en) 2013-05-29 2018-12-26 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Tamper-resistant dosage forms containing one or more particles
AR096439A1 (en) 2013-05-29 2015-12-30 Gruenenthal Gmbh DOSAGE METHOD RESISTING TO INDEED USE CONTAINING ONE OR MORE PARTICLES
EA032465B1 (en) 2013-07-12 2019-05-31 Грюненталь Гмбх Tamper-resistant oral pharmaceutical dosage form containing ethylene-vinyl acetate polymer and process for the production thereof
US9796576B2 (en) 2013-08-30 2017-10-24 Proteus Digital Health, Inc. Container with electronically controlled interlock
NZ631142A (en) 2013-09-18 2016-03-31 Axikin Pharmaceuticals Inc Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors
EP3046924A1 (en) 2013-09-20 2016-07-27 IDENIX Pharmaceuticals, Inc. Hepatitis c virus inhibitors
US10084880B2 (en) 2013-11-04 2018-09-25 Proteus Digital Health, Inc. Social media networking based on physiologic information
AU2014356581C1 (en) 2013-11-26 2020-05-28 Grunenthal Gmbh Preparation of a powdery pharmaceutical composition by means of cryo-milling
US10413504B2 (en) 2013-12-11 2019-09-17 Merck Sharp & Dohme Corp. Intravaginal ring drug delivery system
US10596103B2 (en) 2013-12-11 2020-03-24 Merek Sharp & Dohme B.V. Drug delivery system for delivery of anti-virals
WO2015095230A1 (en) * 2013-12-16 2015-06-25 Massachusetts Institute Of Technology Micromolded or 3-d printed pulsatile release vaccine formulations
US10137092B2 (en) * 2013-12-23 2018-11-27 Xiaoguang WEN Double-layer tablet and preparation method thereof
AU2015204763A1 (en) 2014-01-10 2016-07-21 Johnson & Johnson Consumer Inc. Process for making tablet using radiofrequency and lossy coated particles
US9375033B2 (en) 2014-02-14 2016-06-28 R.J. Reynolds Tobacco Company Tobacco-containing gel composition
US20170066779A1 (en) 2014-03-05 2017-03-09 Idenix Pharmaceuticals Llc Solid forms of a flaviviridae virus inhibitor compound and salts thereof
MX2016012097A (en) 2014-03-20 2017-04-27 Capella Therapeutics Inc Benzimidazole derivatives as erbb tyrosine kinase inhibitors for the treatment of cancer.
KR102409739B1 (en) 2014-03-20 2022-06-17 카펠라 테라퓨틱스, 인크. Benzimidazole derivatives as erbb tyrosine kinase inhibitors for the treatment of cancer
AU2015261060A1 (en) 2014-05-12 2016-11-03 Grunenthal Gmbh Tamper resistant immediate release capsule formulation comprising Tapentadol
CA2949422A1 (en) 2014-05-26 2015-12-03 Grunenthal Gmbh Multiparticles safeguarded against ethanolic dose-dumping
US10729685B2 (en) 2014-09-15 2020-08-04 Ohemo Life Sciences Inc. Orally administrable compositions and methods of deterring abuse by intranasal administration
TWI703133B (en) 2014-12-23 2020-09-01 美商艾克斯基製藥公司 3,5-diaminopyrazole kinase inhibitors
WO2016116619A1 (en) * 2015-01-22 2016-07-28 Pfeifer & Langen GmbH & Co. KG Cellobiose-containing sugar mass
US10174275B2 (en) * 2015-01-30 2019-01-08 Follmann Gmbh & Co. Kg Thermally opening stable core/shell microcapsules
USD765828S1 (en) 2015-02-19 2016-09-06 Crossford International, Llc Chemical tablet
US9839212B2 (en) 2015-04-16 2017-12-12 Bio-Lab, Inc. Multicomponent and multilayer compacted tablets
EP3285745A1 (en) 2015-04-24 2018-02-28 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US11051543B2 (en) 2015-07-21 2021-07-06 Otsuka Pharmaceutical Co. Ltd. Alginate on adhesive bilayer laminate film
JP2018526414A (en) 2015-09-10 2018-09-13 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Protection against oral overdose with abuse-inhibiting immediate release formulations
EP3389628A4 (en) 2015-12-19 2019-08-07 Dixit, Manesh A. Soft-chew tablet pharmaceutical formulations
US20190022013A1 (en) 2015-12-19 2019-01-24 First Time Us Generics Llc Soft-chew tablet pharmaceutical formulations
JP2017158534A (en) * 2016-03-07 2017-09-14 焼津水産化学工業株式会社 Manufacturing method of chip-like foods and chip-like foods
WO2017159653A1 (en) * 2016-03-15 2017-09-21 アステラス製薬株式会社 Tablet
TWI728155B (en) 2016-07-22 2021-05-21 日商大塚製藥股份有限公司 Electromagnetic sensing and detection of ingestible event markers
US11229577B2 (en) * 2016-09-09 2022-01-25 Merck Patent Gmbh Process for the manufacture of a solid pharmaceutical administration form
RU2019109695A (en) 2016-09-26 2020-10-26 Дзе Проктер Энд Гэмбл Компани DOSAGE FOR LONGER SYMPTOMS REDUCTION
AU2017348094B2 (en) 2016-10-26 2022-10-13 Otsuka Pharmaceutical Co., Ltd. Methods for manufacturing capsules with ingestible event markers
CN106945323B (en) * 2017-03-14 2018-11-02 常熟市双月机械有限公司 A kind of efficient metal powder hydraulic press
US10493026B2 (en) 2017-03-20 2019-12-03 Johnson & Johnson Consumer Inc. Process for making tablet using radiofrequency and lossy coated particles
US10604632B2 (en) * 2017-04-07 2020-03-31 The Procter & Gamble Company Water-soluble films
DE102017107845A1 (en) 2017-04-11 2018-10-11 Gelita Ag Gelatin product with a core component and process for its preparation
WO2018237212A1 (en) 2017-06-22 2018-12-27 The Procter & Gamble Company Films including a water-soluble layer and a vapor-deposited organic coating
WO2018237213A1 (en) 2017-06-22 2018-12-27 The Procter & Gamble Company Films including a water-soluble layer and a vapor-deposited inorganic coating
US10537585B2 (en) 2017-12-18 2020-01-21 Dexcel Pharma Technologies Ltd. Compositions comprising dexamethasone
US11000471B2 (en) * 2018-03-05 2021-05-11 Kashiv Specialty Pharmaceuticals, Llc Programmable pharmaceutical compositions for chrono drug release
EP3587467A1 (en) * 2018-06-25 2020-01-01 Rudolf GmbH Functional multi-walled core-shell particle
US20210259275A1 (en) * 2018-06-28 2021-08-26 Mars, Incorporated Improved edible ink formulations including calcium carbonate
KR102151342B1 (en) * 2019-03-18 2020-09-02 박문수 Oral capsule and manufacturing method of the same
CN110006918B (en) * 2019-04-17 2021-04-30 湖北三环锻造有限公司 Penetrant flaw detection agent for penetrant flaw detection process
BR112022004419A2 (en) * 2019-09-12 2022-05-31 Nulixir Inc Controlled release core-shell particles and suspensions including the same
CA3124579A1 (en) 2020-07-15 2022-01-15 Schabar Research Associates Llc Unit oral dose compositions composed of naproxen sodium and famotidine for the treatment of acute pain and the reduction of the severity of heartburn and/or the risk of heartburn
WO2022015784A1 (en) 2020-07-15 2022-01-20 Schabar Research Associates Llc Unit oral dose compositions composed of ibuprofen and famotidine for the treatment of acute pain and the reduction of the severity and/or risk of heartburn

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3146169A (en) * 1960-01-21 1964-08-25 Burroughs Wellcome Co Pharmaceutical formulations and their manufacture
GB1372040A (en) * 1970-12-23 1974-10-30 Boehringer Sohn Ingelheim Tablets
US5681584A (en) * 1993-04-23 1997-10-28 Ciba-Geigy Corporation Controlled release drug delivery device
EP0861659A1 (en) * 1991-02-21 1998-09-02 University Of Kentucky Research Foundation Sustained release drug delivery devices

Family Cites Families (435)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US599865A (en) * 1898-03-01 Emanuel l
US231129A (en) * 1880-08-10 wiesebrook
US231024A (en) * 1880-08-10 Machine for lining sheets of straw-board
US231163A (en) * 1880-08-17 hamlin
US542614A (en) * 1895-07-09 Office
US3371136A (en) * 1968-02-27 United States Borax Chem Detergent tablet forming machine
US231062A (en) * 1880-08-10 Felt hat
US231117A (en) * 1880-08-10 Folding boat
US582438A (en) 1897-05-11 John scheidler
US966450A (en) * 1909-06-18 1910-08-09 John W S Jones Couch or bed.
US966509A (en) * 1909-06-25 1910-08-09 Charles A Wulf Flushing-valve.
US967414A (en) * 1910-02-11 1910-08-16 William W Hallam Railway-rail.
US966939A (en) * 1910-05-02 1910-08-09 James V Mitchell Sash-lock.
US996497A (en) * 1911-03-30 1911-06-27 Kokomo Sanitary Mfg Co Tank-cover fastener.
US1036647A (en) 1911-06-19 1912-08-27 St Louis Briquette Machine Company Briquet-machine.
US1437816A (en) 1922-07-26 1922-12-05 Howard S Paine Process for preparing fondant or chocolate soft cream centers
US1505827A (en) * 1923-04-25 1924-08-19 Villasenor Eduardo Tablet-making machine
US1900012A (en) * 1925-09-04 1933-03-07 Western Cartridge Co Process of and apparatus for making wads
US2307371A (en) 1941-08-13 1943-01-05 Ray O Vac Co Molding process
US2415997A (en) * 1946-01-12 1947-02-18 John W Eldred Article handling apparatus
US2823789A (en) * 1952-05-06 1958-02-18 Gilman Engineering & Mfg Corp Parts feeder ribbon
US2996431A (en) * 1953-12-16 1961-08-15 Barry Richard Henry Friable tablet and process for manufacturing same
US2849965A (en) 1954-04-15 1958-09-02 John Holroyd & Company Ltd Machines for use in the production of coated tablets and the like
GB759081A (en) 1954-04-15 1956-10-10 John Holroyd And Company Ltd Improvements relating to machines for the production of coated tablets and the like
US2966431A (en) 1956-03-24 1960-12-27 Basf Ag Separation of filter material from carbon black
US2946298A (en) 1957-11-13 1960-07-26 Arthur Colton Company Compression coating tablet press
US2931276A (en) * 1958-02-10 1960-04-05 Jagenberg Werke Ag Methods of and means for producing, processing, and for treating articles
GB866681A (en) 1958-05-22 1961-04-26 May & Baker Ltd N-substituted piperidines
GB888038A (en) 1959-12-16 1962-01-24 William Warren Triggs C B E Medicinal tablet
GB936386A (en) 1959-01-16 1963-09-11 Wellcome Found Pellets for supplying biologically active substances to ruminants
US2963993A (en) 1959-01-20 1960-12-13 John Holroyd & Company Ltd Machines for making coated tablets by compression
US3096248A (en) 1959-04-06 1963-07-02 Rexall Drug & Chemical Company Method of making an encapsulated tablet
US3029752A (en) * 1959-07-20 1962-04-17 Stokes F J Corp Tablet making machine
GB990784A (en) * 1960-05-23 1965-05-05 Dunlop Rubber Co Improvements in or relating to balls
US3173876A (en) * 1960-05-27 1965-03-16 John C Zobrist Cleaning methods and compositions
GB994742A (en) 1960-09-09 1965-06-10 Wellcome Found Pharmaceutical tablets containing anthelmintics, and the manufacture thereof
US3108046A (en) 1960-11-25 1963-10-22 Smith Kline French Lab Method of preparing high dosage sustained release tablet and product of this method
NL271831A (en) * 1960-11-29
NL272604A (en) * 1960-12-28
US3430535A (en) * 1961-08-25 1969-03-04 Independent Lock Co Key cutter
NL297357A (en) * 1962-08-31
US3185626A (en) * 1963-03-06 1965-05-25 Sterling Drug Inc Tablet coating method
US3279995A (en) 1963-05-31 1966-10-18 Allen F Reid Shaped pellets
US3276586A (en) * 1963-08-30 1966-10-04 Rosaen Filter Co Indicating means for fluid filters
US3300063A (en) * 1965-01-25 1967-01-24 Mayer & Co Inc O Vacuum gripping apparatus
FR1603314A (en) * 1965-02-23 1971-04-05 Pharmaceutical tablets - having a core and a matrix material
US3328840A (en) * 1965-04-23 1967-07-04 Pentronix Inc Powder compacting press
US3279360A (en) 1965-09-13 1966-10-18 Miehle Goss Dexter Inc Machine for printing on cylindrical articles
US3330400A (en) 1966-03-08 1967-07-11 Miehle Goss Dexter Inc Mechanism for transferring cylindrical articles
GB1212535A (en) * 1966-10-12 1970-11-18 Shionogi & Co Method and apparatus for producing molded article
US3458968A (en) 1966-11-16 1969-08-05 Lester Gregory Jr Dispensing and feed mechanism
GB1144915A (en) * 1966-11-24 1969-03-12 Armour Pharma Improvements in or relating to pastille formulations
US3546142A (en) * 1967-01-19 1970-12-08 Amicon Corp Polyelectrolyte structures
US3656518A (en) * 1967-03-27 1972-04-18 Perry Ind Inc Method and apparatus for measuring and dispensing predetermined equal amounts of powdered material
US3563170A (en) * 1968-04-16 1971-02-16 Reynolds Metals Co Machine for marking the exterior cylindrical surfaces of cans in a continous nonidexing manner
US3605479A (en) 1968-05-08 1971-09-20 Textron Inc Forming press
US3584114A (en) 1968-05-22 1971-06-08 Hoffmann La Roche Free-flowing powders
SE335202B (en) 1968-06-19 1971-05-17 Aco Laekemedel Ab
US3541006A (en) * 1968-07-03 1970-11-17 Amicon Corp Ultrafiltration process
FR1581088A (en) 1968-07-17 1969-09-12
US3567043A (en) * 1968-08-05 1971-03-02 Sun Chemical Corp Transfer assembly for use with container printing machines
US3627583A (en) * 1969-04-29 1971-12-14 Sucrest Corp Direct compression vehicles
US3604417A (en) * 1970-03-31 1971-09-14 Wayne Henry Linkenheimer Osmotic fluid reservoir for osmotically activated long-term continuous injector device
US3640654A (en) * 1970-06-25 1972-02-08 Wolverine Pentronix Die and punch assembly for compacting powder and method of assembly
US3832252A (en) * 1970-09-29 1974-08-27 T Higuchi Method of making a drug-delivery device
US3811552A (en) * 1971-01-11 1974-05-21 Lilly Co Eli Capsule inspection apparatus and method
US3995631A (en) * 1971-01-13 1976-12-07 Alza Corporation Osmotic dispenser with means for dispensing active agent responsive to osmotic gradient
US3760804A (en) * 1971-01-13 1973-09-25 Alza Corp Improved osmotic dispenser employing magnesium sulphate and magnesium chloride
US3726622A (en) 1971-08-20 1973-04-10 Wolverine Pentronix Compacting apparatus
DE2157465C3 (en) * 1971-11-19 1975-04-24 Werner & Pfleiderer, 7000 Stuttgart Filling device for a hydraulic block press
GB1371244A (en) * 1971-12-09 1974-10-23 Howorth Air Conditioning Ltd Machines acting on continuously running textile yarns
BE794951A (en) * 1972-02-03 1973-05-29 Parke Davis & Co WATER SOLUBLE PACKAGING
US3975888A (en) 1972-04-26 1976-08-24 R. A. Jones & Company, Inc. Method and apparatus for forming, filling and sealing packages
US3851751A (en) 1972-04-26 1974-12-03 Jones & Co Inc R A Method and apparatus for forming, filling and sealing packages
US3845770A (en) * 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3912441A (en) 1972-12-13 1975-10-14 Yasuo Shimada Compressing roll in rotary power compression molding machine
US3851638A (en) 1973-02-02 1974-12-03 Kam Act Enterprises Inc Force multiplying type archery bow
DE2309202A1 (en) 1973-02-21 1974-08-29 Schering Ag MEDICINAL FORMS WITH MICRO-ENCAPSULATED MEDICINAL ACTIVE
US3832525A (en) * 1973-03-26 1974-08-27 Raymond Lee Organization Inc Automatic heating device to prevent freezing of water supply lines
US3916899A (en) * 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US3884143A (en) * 1973-09-04 1975-05-20 Hartnett Co R W Conveyor link for tablet printing apparatus
DE2401419A1 (en) 1974-01-12 1975-07-17 Bosch Gmbh Robert VEHICLE WITH A HYDROSTATIC AND MECHANICAL DRIVE
US3891375A (en) 1974-01-21 1975-06-24 Vector Corp Tablet press
GB1497044A (en) 1974-03-07 1978-01-05 Prodotti Antibiotici Spa Salts of phenyl-alkanoic acids
US3988403A (en) * 1974-07-09 1976-10-26 Union Carbide Corporation Process for producing molded structural foam article having a surface that reproducibly and faithfully replicates the surface of the mold
US4139589A (en) 1975-02-26 1979-02-13 Monique Beringer Process for the manufacture of a multi-zone tablet and tablet manufactured by this process
US4230693A (en) * 1975-04-21 1980-10-28 Armour-Dial, Inc. Antacid tablets and processes for their preparation
FR2312247A1 (en) * 1975-05-30 1976-12-24 Parcor THIENO-PYRIDINE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS
US4097606A (en) * 1975-10-08 1978-06-27 Bristol-Myers Company APAP Tablet containing an alkali metal carboxymethylated starch and processes for manufacturing same
US4077407A (en) * 1975-11-24 1978-03-07 Alza Corporation Osmotic devices having composite walls
SE414386B (en) 1976-03-10 1980-07-28 Aco Laekemedel Ab VIEW TO PREPARE AND AT THE SAME PACKAGE PHARMACEUTICAL DOSAGE UNITS
GB1548022A (en) * 1976-10-06 1979-07-04 Wyeth John & Brother Ltd Pharmaceutial dosage forms
US4111202A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system for the controlled and delivery of agent over time
US4218433A (en) 1977-03-03 1980-08-19 Nippon Kayaku Kabushiki Kaisha Constant-rate eluting tablet and method of producing same
US4139627A (en) * 1977-10-06 1979-02-13 Beecham Inc. Anesthetic lozenges
DE2752971C2 (en) * 1977-11-28 1982-08-19 Lev Nikolaevič Moskva Koškin Injection molding machine for the production of injection molded parts from thermoplastic materials
GB2030042A (en) * 1978-09-21 1980-04-02 Beecham Group Ltd Antacid fondant
DE2849494A1 (en) 1978-11-15 1980-05-29 Voss Gunter M METHOD FOR THE PRODUCTION OF MEDICINAL FORMS
US4173626A (en) 1978-12-11 1979-11-06 Merck & Co., Inc. Sustained release indomethacin
US4198390A (en) * 1979-01-31 1980-04-15 Rider Joseph A Simethicone antacid tablet
US4304232A (en) * 1979-03-14 1981-12-08 Alza Corporation Unit system having multiplicity of means for dispensing useful agent
US4286497A (en) * 1979-06-18 1981-09-01 Shamah Alfred A Ratchet-securable toggle retainer
US4271142A (en) * 1979-06-18 1981-06-02 Life Savers, Inc. Portable liquid antacids
JPS5827162B2 (en) 1979-08-24 1983-06-08 株式会社ヤクルト本社 Constant speed transport mechanism
NL7906689A (en) * 1979-09-06 1981-03-10 Dawsonville Corp Nv TATTOO.
DE2936040C2 (en) * 1979-09-06 1982-05-19 Meggle Milchindustrie Gmbh & Co Kg, 8094 Reitmehring Coating process and means for carrying out the process, consisting essentially of sucrose, at least one other sugar and water
US4273793A (en) * 1979-10-26 1981-06-16 General Foods Corporation Apparatus and process for the preparation of gasified confectionaries by pressurized injection molding
US4271206A (en) * 1979-10-26 1981-06-02 General Foods Corporation Gasified candy having a predetermined shape
US4543370A (en) 1979-11-29 1985-09-24 Colorcon, Inc. Dry edible film coating composition, method and coating form
US4318746A (en) * 1980-01-08 1982-03-09 Ipco Corporation Highly stable gel, its use and manufacture
US4473526A (en) 1980-01-23 1984-09-25 Eugen Buhler Method of manufacturing dry-pressed molded articles
US4292017A (en) 1980-07-09 1981-09-29 Doepel Wallace A Apparatus for compressing tablets
US4362757A (en) * 1980-10-22 1982-12-07 Amstar Corporation Crystallized, readily water dispersible sugar product containing heat sensitive, acidic or high invert sugar substances
FR2492661A1 (en) * 1980-10-28 1982-04-30 Laruelle Claude NOVEL GALENIC FORM OF ADMINISTRATION OF METOCLOPRAMIDE, ITS PREPARATION METHOD AND MEDICINAL PRODUCT COMPRISING THIS NOVEL FORM
US4683256A (en) 1980-11-06 1987-07-28 Colorcon, Inc. Dry edible film coating composition, method and coating form
US4327076A (en) * 1980-11-17 1982-04-27 Life Savers, Inc. Compressed chewable antacid tablet and method for forming same
US4327725A (en) * 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
US4340054A (en) * 1980-12-29 1982-07-20 Alza Corporation Dispenser for delivering fluids and solids
US5002970A (en) * 1981-07-31 1991-03-26 Eby Iii George A Flavor masked ionizable zinc compositions for oral absorption
IE53102B1 (en) * 1981-05-12 1988-06-22 Ici Plc Pharmaceutical spiro-succinimide derivatives
US4372942A (en) * 1981-08-13 1983-02-08 Beecham Inc. Candy base and liquid center hard candy made therefrom
DE3144678A1 (en) * 1981-11-10 1983-05-19 Eugen Dipl.-Ing. 8871 Burtenbach Bühler METHOD AND DEVICE FOR THE PRODUCTION OF MOLDINGS FROM A GIANT CAPABILITY
JPS58152813A (en) 1982-03-08 1983-09-10 Sumitomo Chem Co Ltd Tablet having clear carved seal and its preparation
US4449983A (en) 1982-03-22 1984-05-22 Alza Corporation Simultaneous delivery of two drugs from unit delivery device
DK151608C (en) * 1982-08-13 1988-06-20 Benzon As Alfred PROCEDURE FOR PREPARING A PHARMACEUTICAL PERORAL POLYDEPOT PREPARATION WITH CONTROLLED RELEASE
US4517205A (en) * 1983-01-03 1985-05-14 Nabisco Brands, Inc. Co-deposited two-component hard candy
US4576604A (en) * 1983-03-04 1986-03-18 Alza Corporation Osmotic system with instant drug availability
US4882167A (en) 1983-05-31 1989-11-21 Jang Choong Gook Dry direct compression compositions for controlled release dosage forms
US4533345A (en) * 1983-06-14 1985-08-06 Fertility & Genetics Associates Uterine catheter
FR2548675B1 (en) * 1983-07-06 1987-01-09 Seppic Sa FILM-FORMING COMPOSITIONS FOR COATING SOLID FORMS OF PHARMACEUTICAL OR FOOD PRODUCTS AND PRODUCTS OBTAINED COATED WITH SUCH COMPOSITIONS
US4749575A (en) * 1983-10-03 1988-06-07 Bio-Dar Ltd. Microencapsulated medicament in sweet matrix
AU591171B2 (en) 1983-11-02 1989-11-30 Alza Corporation Dispenser for delivering thermo-responsive composition
NL194820C (en) 1983-11-02 2003-04-03 Alza Corp Preparation for the release of a heat-reacting composition.
US4781714A (en) * 1983-11-02 1988-11-01 Alza Corporation Dispenser for delivering thermo-responsive composition
DE3404108A1 (en) * 1984-02-07 1985-08-14 Kilian & Co GmbH, 5000 Köln TABLET PRESS
US4518335A (en) * 1984-03-14 1985-05-21 Allied Corporation Dilatant mold and dilatant molding apparatus
US4564525A (en) 1984-03-30 1986-01-14 Mitchell Cheryl R Confection products
JPS60217106A (en) 1984-04-12 1985-10-30 高橋　信之 Inorganic-powder freezing molding method
US4661521A (en) 1984-04-30 1987-04-28 Mallinckrodt, Inc. Direct tableting acetaminophen compositions
US4528335A (en) * 1984-05-18 1985-07-09 Phillips Petroleum Company Polymer blends
US4666212A (en) * 1984-06-15 1987-05-19 Crucible S.A. Metal value recovery
US4610884A (en) * 1984-06-29 1986-09-09 The Procter & Gamble Company Confectionery cremes
US4643894A (en) * 1984-07-24 1987-02-17 Colorcon, Inc. Maltodextrin coating
US4828841A (en) 1984-07-24 1989-05-09 Colorcon, Inc. Maltodextrin coating
US4894234A (en) * 1984-10-05 1990-01-16 Sharma Shri C Novel drug delivery system for antiarrhythmics
JPS61100519A (en) * 1984-10-23 1986-05-19 Shin Etsu Chem Co Ltd Hard capsule for drug
US4684534A (en) * 1985-02-19 1987-08-04 Dynagram Corporation Of America Quick-liquifying, chewable tablet
US4874614A (en) * 1985-03-25 1989-10-17 Abbott Laboratories Pharmaceutical tableting method
US4627971A (en) * 1985-04-22 1986-12-09 Alza Corporation Osmotic device with self-sealing passageway
CA1234717A (en) * 1985-06-28 1988-04-05 Leslie F. Knebl Moist chewing gum composition
GB8517073D0 (en) 1985-07-05 1985-08-14 Hepworth Iron Co Ltd Pipe pipe couplings &c
GB8518301D0 (en) * 1985-07-19 1985-08-29 Fujisawa Pharmaceutical Co Hydrodynamically explosive systems
DK8603837A (en) * 1985-08-13 1987-02-14
US4665116A (en) 1985-08-28 1987-05-12 Turtle Wax, Inc. Clear cleaner/polish composition
US4663147A (en) * 1985-09-03 1987-05-05 International Minerals & Chemical Corp. Disc-like sustained release formulation
US5188840A (en) * 1985-09-26 1993-02-23 Chugai Seiyaku Kabushiki Kaisha Slow-release pharmaceutical agent
US4898733A (en) * 1985-11-04 1990-02-06 International Minerals & Chemical Corp. Layered, compression molded device for the sustained release of a beneficial agent
US4853249A (en) 1985-11-15 1989-08-01 Taisho Pharmaceutical Co., Ltd. Method of preparing sustained-release pharmaceutical/preparation
US5229164A (en) * 1985-12-19 1993-07-20 Capsoid Pharma Gmbh Process for producing individually dosed administration forms
DE3601516A1 (en) * 1986-01-20 1987-07-23 Agie Ag Ind Elektronik PHOTOELECTRIC BARRIER
JPS62230600A (en) 1986-03-31 1987-10-09 東洋ゴム工業株式会社 Forklift with expansible fork
DE3610878A1 (en) 1986-04-01 1987-10-08 Boehringer Ingelheim Kg PELLET SHAPES
US4873231A (en) 1986-04-08 1989-10-10 Smith Walton J Decreasing the toxicity of an ibuprofen salt
SE8601624D0 (en) * 1986-04-11 1986-04-11 Haessle Ab NEW PHARMACEUTICAL PREPARATIONS
US4857330A (en) * 1986-04-17 1989-08-15 Alza Corporation Chlorpheniramine therapy
GB2189699A (en) 1986-04-30 1987-11-04 Haessle Ab Coated acid-labile medicaments
GB2189698A (en) 1986-04-30 1987-11-04 Haessle Ab Coated omeprazole tablets
US4960416A (en) * 1986-04-30 1990-10-02 Alza Corporation Dosage form with improved delivery capability
US5200196A (en) * 1986-05-09 1993-04-06 Alza Corporation Improvement in pulsed drug therapy
US4802924A (en) 1986-06-19 1989-02-07 Colorcon, Inc. Coatings based on polydextrose for aqueous film coating of pharmaceutical food and confectionary products
IE58401B1 (en) 1986-06-20 1993-09-08 Elan Corp Plc Controlled absorption pharmaceutical composition
US4757090A (en) 1986-07-14 1988-07-12 Mallinckrodt, Inc. Direct tableting acetaminophen compositions
US4762719A (en) 1986-08-07 1988-08-09 Mark Forester Powder filled cough product
US4816262A (en) 1986-08-28 1989-03-28 Universite De Montreal Controlled release tablet
DE3629994A1 (en) 1986-09-03 1988-03-17 Weissenbacher Ernst Rainer Pro Device for administration of medicaments in body cavities or on body surfaces
US4803076A (en) 1986-09-04 1989-02-07 Pfizer Inc. Controlled release device for an active substance
CA1290526C (en) * 1986-11-07 1991-10-15 Marianne Wieser Mold and die operation
DE3640574A1 (en) 1986-11-27 1988-06-09 Katjes Fassin Gmbh & Co Kg METHOD FOR PRODUCING AN EDIBLE PRALINE-SHAPED PRODUCT AND DEVICE FOR IMPLEMENTING THE METHOD
US4828845A (en) * 1986-12-16 1989-05-09 Warner-Lambert Company Xylitol coated comestible and method of preparation
IT1201136B (en) 1987-01-13 1989-01-27 Resa Farma TABLET FOR PHARMACEUTICAL USE SUITABLE FOR THE RELEASE OF SUBSTANCES OF ACTIVE SUBSTANCES
US4801461A (en) 1987-01-28 1989-01-31 Alza Corporation Pseudoephedrine dosage form
US4820524A (en) * 1987-02-20 1989-04-11 Mcneilab, Inc. Gelatin coated caplets and process for making same
US5200193A (en) 1987-04-22 1993-04-06 Mcneilab, Inc. Pharmaceutical sustained release matrix and process
US4808413A (en) * 1987-04-28 1989-02-28 E. R. Squibb & Sons, Inc. Pharmaceutical compositions in the form of beadlets and method
US4792448A (en) * 1987-06-11 1988-12-20 Pfizer Inc. Generic zero order controlled drug delivery system
US4813818A (en) 1987-08-25 1989-03-21 Michael Sanzone Apparatus and method for feeding powdered materials
US4978483A (en) 1987-09-28 1990-12-18 Redding Bruce K Apparatus and method for making microcapsules
US4996061A (en) * 1987-10-07 1991-02-26 Merrell Dow Pharmaceuticals Inc. Pharmaceutical composition for piperidinoalkanol-decongestant combination
US4851226A (en) * 1987-11-16 1989-07-25 Mcneil Consumer Products Company Chewable medicament tablet containing means for taste masking
US4894236A (en) 1988-01-12 1990-01-16 Choong-Gook Jang Direct compression tablet binders for acetaminophen
CA1330886C (en) 1988-01-22 1994-07-26 Bend Research Inc. Osmotic system for delivery of dilute solutions
CH676470A5 (en) * 1988-02-03 1991-01-31 Nestle Sa
US4929446A (en) * 1988-04-19 1990-05-29 American Cyanamid Company Unit dosage form
US5279660A (en) * 1988-05-24 1994-01-18 Berol Nobel Stenungsund Ab Use of viscosity-adjusting agent to counteract viscosity decrease upon temperature increase of a water-based system
US4999226A (en) 1988-06-01 1991-03-12 Merrell Dow Pharmaceuticals Inc. Pharmaceutical compositions for piperidinoalkanol-ibuprofen combination
DE3822095A1 (en) 1988-06-30 1990-01-04 Klinge Co Chem Pharm Fab NEW MEDICAMENT FORMULATION AND METHOD FOR THE PRODUCTION THEREOF
GB8820353D0 (en) 1988-08-26 1988-09-28 Staniforth J N Controlled release tablet
WO1990002546A1 (en) * 1988-09-09 1990-03-22 The Ronald T. Dodge Company Pharmaceuticals microencapsulated by vapor deposited polymers and method
US5194464A (en) * 1988-09-27 1993-03-16 Takeda Chemical Industries, Ltd. Enteric film and preparatoin thereof
JPH0816051B2 (en) 1988-12-07 1996-02-21 エスエス製薬株式会社 Sustained release suppositories
US4906478A (en) * 1988-12-12 1990-03-06 Valentine Enterprises, Inc. Simethicone/calcium silicate composition
US4984240A (en) * 1988-12-22 1991-01-08 Codex Corporation Distributed switching architecture for communication module redundancy
US5610214A (en) * 1988-12-29 1997-03-11 Deknatel Technology Corporation, Inc. Method for increasing the rate of absorption of polycaprolactone
IL92966A (en) * 1989-01-12 1995-07-31 Pfizer Dispensing devices powered by hydrogel
US5030452A (en) * 1989-01-12 1991-07-09 Pfizer Inc. Dispensing devices powered by lyotropic liquid crystals
US5032406A (en) * 1989-02-21 1991-07-16 Norwich Eaton Pharmaceuticals, Inc. Dual-action tablet
US5006297A (en) * 1989-02-22 1991-04-09 Acushnet Company Method of molding polyurethane covered golf balls
US4956182A (en) 1989-03-16 1990-09-11 Bristol-Myers Company Direct compression cholestyramine tablet and solvent-free coating therefor
US4931286A (en) * 1989-04-19 1990-06-05 Aqualon Company High gloss cellulose tablet coating
NZ233403A (en) 1989-04-28 1992-09-25 Mcneil Ppc Inc Simulated capsule-like medicament
US4990535A (en) * 1989-05-03 1991-02-05 Schering Corporation Pharmaceutical composition comprising loratadine, ibuprofen and pseudoephedrine
US4960169A (en) * 1989-06-20 1990-10-02 Modien Manufacturing Co. Baffle for tubular heat exchanger header
US4992277A (en) * 1989-08-25 1991-02-12 Schering Corporation Immediate release diltiazem formulation
EP0419410A3 (en) 1989-09-19 1991-08-14 Ciba-Geigy Ag Alkanophenones
US5146730A (en) * 1989-09-20 1992-09-15 Banner Gelatin Products Corp. Film-enrobed unitary-core medicament and the like
DK469989D0 (en) 1989-09-22 1989-09-22 Bukh Meditec PHARMACEUTICAL PREPARATION
US5178878A (en) * 1989-10-02 1993-01-12 Cima Labs, Inc. Effervescent dosage form with microparticles
US5223264A (en) * 1989-10-02 1993-06-29 Cima Labs, Inc. Pediatric effervescent dosage form
US5275822A (en) * 1989-10-19 1994-01-04 Valentine Enterprises, Inc. Defoaming composition
JPH03139496A (en) * 1989-10-25 1991-06-13 Sanshin Ind Co Ltd Ship propulsion machinery
US5169645A (en) 1989-10-31 1992-12-08 Duquesne University Of The Holy Ghost Directly compressible granules having improved flow properties
FR2655266B1 (en) * 1989-12-05 1992-04-03 Smith Kline French Lab CIMETIDINE PHARMACEUTICAL COMPOSITIONS.
US5223266A (en) 1990-01-24 1993-06-29 Alza Corporation Long-term delivery device with early startup
US5100676A (en) * 1990-02-02 1992-03-31 Biosurface Technology, Inc. Cool storage of cultured epithelial sheets
US5158777A (en) * 1990-02-16 1992-10-27 E. R. Squibb & Sons, Inc. Captopril formulation providing increased duration of activity
US4983394A (en) 1990-05-03 1991-01-08 Warner-Lambert Company Flavor enhancing and medicinal taste masking agent
US4980169A (en) 1990-05-03 1990-12-25 Warner-Lambert Company Flavor enhancing and increasing efficacy of cough drops
US5213738A (en) 1990-05-15 1993-05-25 L. Perrigo Company Method for making a capsule-shaped tablet
US5089270A (en) 1990-05-15 1992-02-18 L. Perrigo Company Capsule-shaped tablet
US5075114A (en) * 1990-05-23 1991-12-24 Mcneil-Ppc, Inc. Taste masking and sustained release coatings for pharmaceuticals
US5464631A (en) 1990-06-27 1995-11-07 Warner-Lambert Company Encapsulated dosage forms
US5133892A (en) 1990-10-17 1992-07-28 Lever Brothers Company, Division Of Conopco, Inc. Machine dishwashing detergent tablets
US5436026A (en) * 1990-11-05 1995-07-25 Mcneil-Ppc, Inc. Discharge and transfer system for apparatus for gelatin coating tablets
US5538125A (en) * 1990-11-05 1996-07-23 Mcneil-Ppc, Inc. Indexing and feeding systems for apparatus for gelatin coating tablets
US5503673A (en) 1990-11-05 1996-04-02 Mcneil-Ppc, Inc Apparatus for dip coating product
US5228916A (en) * 1990-11-05 1993-07-20 Mcneil-Ppc, Inc. Apparatus for creating a gelatin coating
US5683719A (en) 1990-11-22 1997-11-04 British Technology Group Limited Controlled release compositions
US5098715A (en) * 1990-12-20 1992-03-24 Burroughs Wellcome Co. Flavored film-coated tablet
US5232706A (en) 1990-12-31 1993-08-03 Esteve Quimica, S.A. Oral pharmaceutical preparation containing omeprazol
DE4101873C2 (en) * 1991-01-23 1993-12-09 Isis Pharma Gmbh Orally administrable drug form for the treatment of central dopamine deficiency states
NZ241613A (en) 1991-02-27 1993-06-25 Janssen Pharmaceutica Nv Highlighting intagliations in tablets
CA2061520C (en) 1991-03-27 2003-04-22 Lawrence J. Daher Delivery system for enhanced onset and increased potency
US5286497A (en) * 1991-05-20 1994-02-15 Carderm Capital L.P. Diltiazem formulation
CA2068402C (en) * 1991-06-14 1998-09-22 Michael R. Hoy Taste mask coatings for preparation of chewable pharmaceutical tablets
YU48263B (en) 1991-06-17 1997-09-30 Byk Gulden Lomberg Chemische Fabrik Gmbh. PROCEDURE FOR OBTAINING PANTOPRAZOLE PHARMACEUTICAL PRODUCT
US5252338A (en) * 1991-06-27 1993-10-12 Alza Corporation Therapy delayed
US5314696A (en) * 1991-06-27 1994-05-24 Paulos Manley A Methods for making and administering a blinded oral dosage form and blinded oral dosage form therefor
US5190927A (en) * 1991-07-09 1993-03-02 Merck & Co., Inc. High-glyceryl, low-acetyl gellan gum for non-brittle gels
US5326570A (en) 1991-07-23 1994-07-05 Pharmavene, Inc. Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine
US5200191A (en) * 1991-09-11 1993-04-06 Banner Gelatin Products Corp. Softgel manufacturing process
US5405617A (en) * 1991-11-07 1995-04-11 Mcneil-Ppc, Inc. Aliphatic or fatty acid esters as a solventless carrier for pharmaceuticals
US5407686A (en) * 1991-11-27 1995-04-18 Sidmak Laboratories, Inc. Sustained release composition for oral administration of active ingredient
US5200195A (en) 1991-12-06 1993-04-06 Alza Corporation Process for improving dosage form delivery kinetics
DK171536B1 (en) 1991-12-06 1996-12-23 Rasmussen Kann Ind As Window with frame of extruded profile items
US5200194A (en) * 1991-12-18 1993-04-06 Alza Corporation Oral osmotic device
GB2284760B (en) 1993-11-23 1998-06-24 Euro Celtique Sa A method of preparing pharmaceutical compositions by melt pelletisation
KR940703886A (en) 1992-01-17 1994-12-12 토머스 디. 뵈닝 Film Coatings and Film Coating Compositions Based on Cellulosic Polymers and Lactose
US5427614A (en) * 1992-02-14 1995-06-27 Warner-Lambert Company Starch based formulations
US5209746A (en) * 1992-02-18 1993-05-11 Alza Corporation Osmotically driven delivery devices with pulsatile effect
US5221278A (en) * 1992-03-12 1993-06-22 Alza Corporation Osmotically driven delivery device with expandable orifice for pulsatile delivery effect
US5656296A (en) * 1992-04-29 1997-08-12 Warner-Lambert Company Dual control sustained release drug delivery systems and methods for preparing same
US5260068A (en) * 1992-05-04 1993-11-09 Anda Sr Pharmaceuticals Inc. Multiparticulate pulsatile drug delivery system
GR1002332B (en) 1992-05-21 1996-05-16 Mcneil-Ppc Inc. Novel simethicone containing pharmaceutical compositions.
EP0572731A1 (en) 1992-06-01 1993-12-08 The Procter & Gamble Company Chewable preparation containing a decongestant
US5317849A (en) 1992-08-07 1994-06-07 Sauter Manufacturing Corporation Encapsulation equipment and method
IT1255522B (en) * 1992-09-24 1995-11-09 Ubaldo Conte COMPRESSED FOR THERAPEUTIC USE SUITABLE FOR SELLING ONE OR MORE ACTIVE SUBSTANCES WITH DIFFERENT SPEEDS
JPH07507564A (en) 1992-09-30 1995-08-24 ファイザー・インク． Articles containing a core and a coating of variable thickness
KR950703935A (en) * 1992-11-30 1995-11-17 밋첼 아이, 커시너 Pharmaceutical compositions that block taste
US5375963A (en) 1993-01-19 1994-12-27 Wohlwend; Clayton E. Multipurpose lifting apparatus
TW272942B (en) 1993-02-10 1996-03-21 Takeda Pharm Industry Co Ltd
US5391378A (en) 1993-02-22 1995-02-21 Elizabeth-Hata International, Inc. Two-part medicinal tablet and method of manufacture
JP2524955B2 (en) 1993-04-22 1996-08-14 トーワ株式会社 Method and apparatus for resin sealing molding of electronic parts
IL119660A (en) 1993-05-10 2002-09-12 Euro Celtique Sa Controlled release formulation comprising tramadol
US5415868A (en) 1993-06-09 1995-05-16 L. Perrigo Company Caplets with gelatin cover and process for making same
JP3054989B2 (en) * 1993-06-19 2000-06-19 八幡 貞男 Insulated expression container
IT1264855B1 (en) * 1993-06-21 1996-10-17 Zambon Spa PHARMACEUTICAL COMPOSITIONS CONTAINING S (+) - 2- (4-ISOBUTYLPHENYL) PROPIONIC ACID SALTS WITH BASIC AMINO ACIDS
ZA944949B (en) 1993-07-12 1995-04-05 Smithkline Beecham Corp Matrix-entrapped beadlet preparation
AU680019B2 (en) 1993-08-30 1997-07-17 Warner-Lambert Company Llc Tablet coating based on a melt-spun mixture of a saccharide and apolymer
US5518551A (en) 1993-09-10 1996-05-21 Fuisz Technologies Ltd. Spheroidal crystal sugar and method of making
US5622719A (en) * 1993-09-10 1997-04-22 Fuisz Technologies Ltd. Process and apparatus for making rapidly dissolving dosage units and product therefrom
US5397574A (en) * 1993-10-04 1995-03-14 Andrx Pharmaceuticals, Inc. Controlled release potassium dosage form
US5433951A (en) 1993-10-13 1995-07-18 Bristol-Myers Squibb Company Sustained release formulation containing captopril and method
US5500227A (en) * 1993-11-23 1996-03-19 Euro-Celtique, S.A. Immediate release tablet cores of insoluble drugs having sustained-release coating
DE4341442C2 (en) 1993-12-04 1998-11-05 Lohmann Therapie Syst Lts Device for the controlled release of active substances and their use
US5458887A (en) * 1994-03-02 1995-10-17 Andrx Pharmaceuticals, Inc. Controlled release tablet formulation
US6060639A (en) * 1994-03-04 2000-05-09 Mentor Corporation Testicular prosthesis and method of manufacturing and filling
US5453920A (en) * 1994-03-08 1995-09-26 Eubanks; William W. Trouble light having a shroud with see-through opening
US5559110A (en) 1994-03-09 1996-09-24 The Dupont Merck Pharmaceutical Company Pharmaceutical formulations of cyclic urea type compounds
JPH07281423A (en) * 1994-04-07 1995-10-27 Konica Corp Plate making method of printing plate
US5464633A (en) 1994-05-24 1995-11-07 Jagotec Ag Pharmaceutical tablets releasing the active substance after a definite period of time
US6020002A (en) * 1994-06-14 2000-02-01 Fuisz Technologies Ltd. Delivery of controlled-release system(s)
SE9402431D0 (en) * 1994-07-08 1994-07-08 Astra Ab New tablet formulation
MX9600857A (en) 1994-07-08 1997-06-28 Astra Ab Multiple unit tableted dosage form i.
US5788979A (en) * 1994-07-22 1998-08-04 Inflow Dynamics Inc. Biodegradable coating with inhibitory properties for application to biocompatible materials
IT1274034B (en) 1994-07-26 1997-07-14 Applied Pharma Res PHARMACEUTICAL COMPOSITIONS BASED ON RUBBER TO BE CHEWED AND PROCEDURE FOR THEIR PREPARATION
US5849327A (en) 1994-07-29 1998-12-15 Advanced Polymer Systems, Inc. Delivery of drugs to the lower gastrointestinal tract
EP0773866B1 (en) * 1994-08-03 1998-04-08 Gunter Meinhardt Voss Method or producing coated tablets
DE9414065U1 (en) * 1994-08-31 1994-11-03 Roehm Gmbh Thermoplastic plastic for pharmaceutical casings soluble in intestinal juice
DE4431653C2 (en) 1994-09-06 2000-01-20 Lohmann Therapie Syst Lts Coated tablet for the controlled release of active substances, a process for their preparation and their use
US5733575A (en) * 1994-10-07 1998-03-31 Bpsi Holdings, Inc. Enteric film coating compositions, method of coating therewith, and coated forms
US5614578A (en) 1994-10-28 1997-03-25 Alza Corporation Injection-molded dosage form
US5738875A (en) * 1994-10-28 1998-04-14 R.P. Scherer Corporation Process for preparing solid pharmaceutical dosage forms
US5593696A (en) 1994-11-21 1997-01-14 Mcneil-Ppc, Inc. Stabilized composition of famotidine and sucralfate for treatment of gastrointestinal disorders
US5756123A (en) * 1994-12-01 1998-05-26 Japan Elanco Co., Ltd. Capsule shell
US5626896A (en) * 1994-12-09 1997-05-06 A.E. Staley Manufacturing Co. Method for making liquid-centered jelly candies
US5582838A (en) * 1994-12-22 1996-12-10 Merck & Co., Inc. Controlled release drug suspension delivery device
DE4446468A1 (en) * 1994-12-23 1996-06-27 Basf Ag Process for the production of coated tablets
US6471994B1 (en) * 1995-01-09 2002-10-29 Edward Mendell Co., Inc. Pharmaceutical excipient having improved compressibility
ES2094694B1 (en) * 1995-02-01 1997-12-16 Esteve Quimica Sa NEW PHARMACEUTICALLY STABLE FORMULATION OF A COMPOUND OF BENZMIDAZOLE AND ITS PROCESS OF OBTAINING.
ES2124956T3 (en) * 1995-02-07 1999-02-16 Hermann Kronseder TRANSPORTATION STAR FOR CONTAINERS.
SE9500478D0 (en) * 1995-02-09 1995-02-09 Astra Ab New pharmaceutical formulation and process
US5558879A (en) 1995-04-28 1996-09-24 Andrx Pharmaceuticals, Inc. Controlled release formulation for water soluble drugs in which a passageway is formed in situ
US5736159A (en) * 1995-04-28 1998-04-07 Andrx Pharmaceuticals, Inc. Controlled release formulation for water insoluble drugs in which a passageway is formed in situ
US5827874A (en) 1995-05-05 1998-10-27 Meyer; Hans Methods of treating pain and inflammation with proline
AU5655296A (en) 1995-05-09 1996-11-29 Colorcon Limited Electrostatic coating
DE59601245D1 (en) * 1995-05-13 1999-03-18 Hermann Kronseder Transport star for vessels
US5627971A (en) * 1995-06-01 1997-05-06 Northern Telecom Limited Machine method for determining the eligibility of links in a network
US5578336A (en) * 1995-06-07 1996-11-26 Monte; Woodrow C. Confection carrier for vitamins, enzymes, phytochemicals and ailmentary vegetable compositions and method of making
US5654005A (en) 1995-06-07 1997-08-05 Andrx Pharmaceuticals, Inc. Controlled release formulation having a preformed passageway
DE69618956T2 (en) 1995-06-09 2002-08-22 Scherer Technologies Inc R P SOFT GELATINE CAPSULE WITH PARTICLE MATERIAL
US5614207A (en) * 1995-06-30 1997-03-25 Mcneil-Ppc, Inc. Dry mouth lozenge
GB9517031D0 (en) * 1995-08-19 1995-10-25 Procter & Gamble Confection compositions
DE69628444T2 (en) 1995-09-21 2004-05-06 Pharma Pass Ii Llc, Irvine ACID CONTAINING PHARMACEUTICAL COMPOSITION CONTAINING ACID, AND METHOD FOR THE PRODUCTION THEREOF
AUPN605795A0 (en) * 1995-10-19 1995-11-09 F.H. Faulding & Co. Limited Analgesic pharmaceutical composition
DE19539361A1 (en) 1995-10-23 1997-04-24 Basf Ag Process for the preparation of multilayer, solid pharmaceutical forms for oral or rectal administration
IT1279673B1 (en) * 1995-11-07 1997-12-16 Acma Spa EQUIPMENT AND METHOD FOR THE FORMATION OF ORDERED GROUPS OF PRODUCTS TO BE FOOD BY STEP.
US5733578A (en) * 1995-11-15 1998-03-31 Edward Mendell Co., Inc. Directly compressible high load acetaminophen formulations
US5807579A (en) * 1995-11-16 1998-09-15 F.H. Faulding & Co. Limited Pseudoephedrine combination pharmaceutical compositions
JP3220373B2 (en) * 1995-11-28 2001-10-22 バイエル薬品株式会社 Long-acting nifedipine preparation
US6489346B1 (en) 1996-01-04 2002-12-03 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
SE9600071D0 (en) * 1996-01-08 1996-01-08 Astra Ab New oral formulation of two active ingredients I
SE9600070D0 (en) 1996-01-08 1996-01-08 Astra Ab New oral pharmaceutical dosage forms
US5879728A (en) * 1996-01-29 1999-03-09 Warner-Lambert Company Chewable confectionary composition and method of preparing same
IT1282576B1 (en) * 1996-02-06 1998-03-31 Jagotec Ag PHARMACEUTICAL TABLET SUITABLE TO GIVE THE ACTIVE SUBSTANCE IN SUBSEQUENT AND PREDETERMINABLE TIMES
US6245351B1 (en) * 1996-03-07 2001-06-12 Takeda Chemical Industries, Ltd. Controlled-release composition
US5711691A (en) * 1996-05-13 1998-01-27 Air Packaging Technologies, Inc. Self-closing and self-sealing valve device for use with inflatable structures
US5827535A (en) 1996-06-21 1998-10-27 Banner Pharmacaps, Inc. Graphically impressed softgel and method for making same
US5797898A (en) 1996-07-02 1998-08-25 Massachusetts Institute Of Technology Microchip drug delivery devices
US5824338A (en) * 1996-08-19 1998-10-20 L. Perrigo Company Caplet and gelatin covering therefor
US5916881A (en) * 1996-10-07 1999-06-29 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo High trehalose content syrup
US5807580A (en) 1996-10-30 1998-09-15 Mcneil-Ppc, Inc. Film coated tablet compositions having enhanced disintegration characteristics
US6077539A (en) * 1996-11-12 2000-06-20 Pozen, Inc. Treatment of migraine headache
GB9624110D0 (en) * 1996-11-20 1997-01-08 Molins Plc Transferring rod like articles
US5830801A (en) * 1997-01-02 1998-11-03 Motorola, Inc. Resistless methods of gate formation in MOS devices
DE19710213A1 (en) 1997-03-12 1998-09-17 Basf Ag Process for the manufacture of solid combination dosage forms
US6210710B1 (en) * 1997-04-28 2001-04-03 Hercules Incorporated Sustained release polymer blend for pharmaceutical applications
US5837301A (en) 1997-04-28 1998-11-17 Husky Injection Molding Systems Ltd. Injection molding machine having a high speed turret
KR20010012402A (en) 1997-05-09 2001-02-15 세이지 파마슈티칼스, 인크. Stable oral pharmaceutical dosage forms
US6149939A (en) * 1997-05-09 2000-11-21 Strumor; Mathew A. Healthful dissolvable oral tablets, and mini-bars
AU7755398A (en) * 1997-06-25 1999-01-19 Ipr-Institute For Pharmaceutical Research Ag Method for reducing body weight
ID23503A (en) * 1997-07-01 2000-04-27 Pfizer SERTRALINA SALES AND DETAILED FORMS OF SERTRALINA
WO1999002136A1 (en) 1997-07-09 1999-01-21 Peter Greither Method and device for producing a multi-layer, physiologically tolerated presentation form
US6103260A (en) * 1997-07-17 2000-08-15 Mcneil-Ppc, Inc. Simethicone/anhydrous calcium phosphate compositions
US5942034A (en) * 1997-07-24 1999-08-24 Bayer Corporation Apparatus for the gelatin coating of medicaments
US6110499A (en) 1997-07-24 2000-08-29 Alza Corporation Phenytoin therapy
DE19733505A1 (en) * 1997-08-01 1999-02-04 Knoll Ag Fast acting analgesic
US6602522B1 (en) 1997-11-14 2003-08-05 Andrx Pharmaceuticals L.L.C. Pharmaceutical formulation for acid-labile compounds
US6174548B1 (en) 1998-08-28 2001-01-16 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6096340A (en) 1997-11-14 2000-08-01 Andrx Pharmaceuticals, Inc. Omeprazole formulation
ATE216220T1 (en) * 1997-12-05 2002-05-15 Alza Corp OSMOTIC DOSAGE FORM WITH TWO LAYERS
US6485748B1 (en) * 1997-12-12 2002-11-26 Andrx Pharmaceuticals, Inc. Once daily pharmaceutical tablet having a unitary core
US6022554A (en) * 1997-12-15 2000-02-08 American Home Products Corporation Polymeric microporous film coated subcutaneous implant
CN100379407C (en) 1997-12-19 2008-04-09 史密丝克莱恩比彻姆公司 Process for manufacturing bite-dispersion tablets
US6432442B1 (en) 1998-02-23 2002-08-13 Mcneil-Ppc, Inc. Chewable product
US6110500A (en) 1998-03-25 2000-08-29 Temple University Coated tablet with long term parabolic and zero-order release kinetics
US6365185B1 (en) * 1998-03-26 2002-04-02 University Of Cincinnati Self-destructing, controlled release peroral drug delivery system
US6372254B1 (en) * 1998-04-02 2002-04-16 Impax Pharmaceuticals Inc. Press coated, pulsatile drug delivery system suitable for oral administration
US6394094B1 (en) 1998-05-01 2002-05-28 Enhance Pharmaceuticals, Inc. Method for injection molding manufacture of controlled release devices
US6365183B1 (en) 1998-05-07 2002-04-02 Alza Corporation Method of fabricating a banded prolonged release active agent dosage form
AU748359B2 (en) 1998-05-15 2002-06-06 Chugai Seiyaku Kabushiki Kaisha Controlled-release formulations
UA69413C2 (en) 1998-05-22 2004-09-15 Брістол-Майерс Сквібб Компані Enteric coated pharmaceutical composition, pharmaceutical composition in form of spheroid beads, method for manufacturing pharmaceutical composition
EP1449524A1 (en) 1998-06-03 2004-08-25 ALZA Corporation Methods and devices for providing prolonged drug therapy
US6106267A (en) * 1998-06-05 2000-08-22 Aylward; John T. Apparatus for forming a compression-molded product
US6099865A (en) * 1998-07-08 2000-08-08 Fmc Corporation Croscarmellose taste masking
US6103257A (en) 1998-07-17 2000-08-15 Num-Pop, Inc. System for delivering pharmaceuticals to the buccal mucosa
UA73092C2 (en) * 1998-07-17 2005-06-15 Брістол-Майерс Сквібб Компані Tablets with enteric coating and method for their manufacture
FR2781152B1 (en) * 1998-07-20 2001-07-06 Permatec Tech Ag USE OF ACRYLIC-TYPE POLYMER AS A DISAGGREGING AGENT
DE19834180A1 (en) * 1998-07-29 2000-02-03 Benckiser Nv Composition for use in a dishwasher
US6200590B1 (en) * 1998-08-10 2001-03-13 Naphcare, Inc. Controlled, phased-release suppository and its method of production
DE19840256A1 (en) * 1998-09-03 2000-03-09 Basf Ag Widely applicable, continuous method for preparing coated solid dosage forms, comprises extruding mixture of drug and thermoplastic binder then applying coating composition in liquid or vapor form
US5997905A (en) 1998-09-04 1999-12-07 Mcneil-Ppc Preparation of pharmaceutically active particles
US6174547B1 (en) 1999-07-14 2001-01-16 Alza Corporation Dosage form comprising liquid formulation
US6602521B1 (en) 1998-09-29 2003-08-05 Impax Pharmaceuticals, Inc. Multiplex drug delivery system suitable for oral administration
US6322819B1 (en) 1998-10-21 2001-11-27 Shire Laboratories, Inc. Oral pulsed dose drug delivery system
JP3449253B2 (en) * 1998-10-29 2003-09-22 シオノギクオリカプス株式会社 Manufacturing method of hard capsule
US6165512A (en) 1998-10-30 2000-12-26 Fuisz Technologies Ltd. Dosage forms containing taste masked active agents
SE9803772D0 (en) 1998-11-05 1998-11-05 Astra Ab Pharmaceutical formulation
US6270805B1 (en) * 1998-11-06 2001-08-07 Andrx Pharmaceuticals, Inc. Two pellet controlled release formulation for water soluble drugs which contains an alkaline metal stearate
US6183681B1 (en) * 1998-12-07 2001-02-06 Centurion International, Inc. Multi-stage insert molding method
EP1029892B1 (en) * 1999-02-10 2002-06-05 Dr. Suwelack Skin & Health Care AG Freeze-dried product containing beta-1,3-glucan from Euglena, its preparation and use
US6274162B1 (en) 2000-01-14 2001-08-14 Bpsi Holdings, Inc. Elegant film coating system
US6248361B1 (en) 1999-02-26 2001-06-19 Integ, Ltd. Water-soluble folic acid compositions
DE19913692A1 (en) * 1999-03-25 2000-09-28 Basf Ag Mechanically stable pharmaceutical dosage forms containing liquid or semi-solid surface-active substances
US6090401A (en) * 1999-03-31 2000-07-18 Mcneil-Ppc, Inc. Stable foam composition
JP3716901B2 (en) * 1999-04-14 2005-11-16 シオノギクオリカプス株式会社 Cellulose ether film
US6248760B1 (en) * 1999-04-14 2001-06-19 Paul C Wilhelmsen Tablet giving rapid release of nicotine for transmucosal administration
DE19925710C2 (en) 1999-06-07 2002-10-10 Byk Gulden Lomberg Chem Fab New preparation and dosage form containing an acid labile proton pump inhibitor
US6375963B1 (en) 1999-06-16 2002-04-23 Michael A. Repka Bioadhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery and process for preparation thereof
US6555139B2 (en) 1999-06-28 2003-04-29 Wockhardt Europe Limited Preparation of micron-size pharmaceutical particles by microfluidization
US20020102309A1 (en) * 1999-09-14 2002-08-01 Jane C. I. Hirsh Controlled release formulation for administration of an anti-inflammatory naphthalene derivative
DE19954420A1 (en) 1999-11-12 2001-05-31 Lohmann Therapie Syst Lts Preparation consisting of a film, foil or wafer-like dosage form with a two-layer structure and integrated labeling
DE19960494A1 (en) * 1999-12-15 2001-06-21 Knoll Ag Device and method for producing solid active substance-containing forms
JP2003518487A (en) * 1999-12-23 2003-06-10 ファイザー・プロダクツ・インク Hydrogel-driven laminated drug formulation
DE19963569B4 (en) * 1999-12-29 2006-11-16 Reckitt Benckiser N.V. Composition for use in a dishwasher
US6599532B2 (en) 2000-01-13 2003-07-29 Osmotica Corp. Osmotic device containing alprazolam and an antipsychotic agent
US6627223B2 (en) 2000-02-11 2003-09-30 Eurand Pharmaceuticals Ltd. Timed pulsatile drug delivery systems
FR2807034B1 (en) 2000-03-29 2002-06-14 Roquette Freres MANNITOL POWDER AND PROCESS FOR PRODUCING THE SAME
US20020028240A1 (en) 2000-04-17 2002-03-07 Toyohiro Sawada Timed-release compression-coated solid composition for oral administration
US6372252B1 (en) * 2000-04-28 2002-04-16 Adams Laboratories, Inc. Guaifenesin sustained release formulation and tablets
GB2362350A (en) 2000-05-11 2001-11-21 Reckitt Benekiser N V Process and press for the production of tablets
US20030086972A1 (en) 2000-08-09 2003-05-08 Appel Leah E. Hydrogel-driven drug dosage form
US6727200B2 (en) * 2000-08-31 2004-04-27 Mra Laboratories, Inc. High dielectric constant very low fired X7R ceramic capacitor, and powder for making
WO2002019833A2 (en) 2000-09-07 2002-03-14 Akpharma Inc. Edible candy compositions and methods of using the same
GB0027471D0 (en) * 2000-11-08 2000-12-27 Smithkline Beecham Plc Processes
US6649187B2 (en) 2001-02-16 2003-11-18 Bristol-Myers Squibb Pharma Company Use of polyalkylamine polymers in controlled release devices
US20030070584A1 (en) * 2001-05-15 2003-04-17 Cynthia Gulian Dip coating compositions containing cellulose ethers
AR034757A1 (en) 2001-07-16 2004-03-17 Astrazeneca Ab PHARMACEUTICAL FORMULATION INCLUDING A PROTON AND ANTI-PUMP PUMP INHIBITOR
US6558722B2 (en) * 2001-07-18 2003-05-06 Wm. Wrigley Jr. Company Use of powdered gum in making a coating for a confection
GB0120835D0 (en) 2001-08-28 2001-10-17 Smithkline Beecham Plc Process
US20030059466A1 (en) 2001-09-14 2003-03-27 Pawan Seth Delayed release tablet of venlafaxin
US7122143B2 (en) * 2001-09-28 2006-10-17 Mcneil-Ppc, Inc. Methods for manufacturing dosage forms
US7323192B2 (en) 2001-09-28 2008-01-29 Mcneil-Ppc, Inc. Immediate release tablet
JP2005508325A (en) 2001-09-28 2005-03-31 マクニール−ピーピーシー・インコーポレイテッド Dosage form having an inner core and an outer shell
US6982094B2 (en) * 2001-09-28 2006-01-03 Mcneil-Ppc, Inc. Systems, methods and apparatuses for manufacturing dosage forms
US6742646B2 (en) * 2001-09-28 2004-06-01 Mcneil-Ppc, Inc. Systems, methods and apparatuses for manufacturing dosage forms
US20030066068A1 (en) 2001-09-28 2003-04-03 Koninklijke Philips Electronics N.V. Individual recommender database using profiles of others
US6767200B2 (en) * 2001-09-28 2004-07-27 Mcneil-Ppc, Inc. Systems, methods and apparatuses for manufacturing dosage forms
US6837696B2 (en) * 2001-09-28 2005-01-04 Mcneil-Ppc, Inc. Apparatus for manufacturing dosage forms
US20040006111A1 (en) 2002-01-25 2004-01-08 Kenneth Widder Transmucosal delivery of proton pump inhibitors
US7790215B2 (en) 2002-03-26 2010-09-07 Purdue Pharma Lp Sustained-release gel coated compositions
EP1764655A3 (en) * 2002-06-11 2007-09-19 ASML Netherlands B.V. Lithographic apparatus and device manufacturing method
TW578439B (en) * 2002-10-25 2004-03-01 Ritdisplay Corp Organic light emitting diode and material applied in the organic light emitting diode
US20050008695A1 (en) * 2003-05-21 2005-01-13 Control Delivery Systems, Inc. Compositions and methods for delivering a biologically active agent
US20050074514A1 (en) 2003-10-02 2005-04-07 Anderson Oliver B. Zero cycle molding systems, methods and apparatuses for manufacturing dosage forms
EP2417969A1 (en) 2004-10-21 2012-02-15 Aptalis Pharmatech, Inc. Taste-masked pharmaceutical compositions with gastrosoluble pore-formers

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3146169A (en) * 1960-01-21 1964-08-25 Burroughs Wellcome Co Pharmaceutical formulations and their manufacture
GB1372040A (en) * 1970-12-23 1974-10-30 Boehringer Sohn Ingelheim Tablets
EP0861659A1 (en) * 1991-02-21 1998-09-02 University Of Kentucky Research Foundation Sustained release drug delivery devices
US5681584A (en) * 1993-04-23 1997-10-28 Ciba-Geigy Corporation Controlled release drug delivery device

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006528636A (en) * 2003-07-24 2006-12-21 スミスクライン・ビーチャム・コーポレイション Orally soluble film
US9675548B2 (en) 2003-07-24 2017-06-13 GlaxoSmithKline, LLC Orally dissolving films
JP2012001542A (en) * 2004-06-09 2012-01-05 Glaxosmithkline Llc Apparatus and method for producing pharmaceutical product
WO2009154810A2 (en) * 2008-02-25 2009-12-23 Dr. Reddy's Laboratories Ltd. Delivery systems for multiple active agents
WO2009154810A3 (en) * 2008-02-25 2010-03-11 Dr. Reddy's Laboratories Ltd. Delivery systems for multiple active agents

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