CA2038672C - Dosage form for delivering drug to the intestine - Google Patents
Dosage form for delivering drug to the intestine Download PDFInfo
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- CA2038672C CA2038672C CA002038672A CA2038672A CA2038672C CA 2038672 C CA2038672 C CA 2038672C CA 002038672 A CA002038672 A CA 002038672A CA 2038672 A CA2038672 A CA 2038672A CA 2038672 C CA2038672 C CA 2038672C
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- drug
- wall
- fluid
- composition
- coat
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- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
-
- 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
Abstract
A drug delivery device (10) is disclosed for delivering a drug (17) to the intestine and the colon. The device (10) comprises external means (13) for delaying the delivery of drug (17) in the stomach, and hydrophobic means for preventing the passage of fluid through the delay external means (13).
Description
~~~~~°~i~
DOSAGE FORM FOR DELIVERING
DRUG TO THE INTESTINE
DISCLOSURE OF TECHNICAL FIELD
s The present invention pertains to a novel delivery system for administering a therapeutic drug to a preselected region of the gastrointestinal tract, specifically the intestine. The invention concerns also a method for administering orally a drug to the intestine of a warm-blooded animal.
io DISCLOSURE OF THE BACKGROUND ART
As is known in the medical and the pharmaceutical arts, the desiderata of an enteric coat is to protect an orally administered i5 drug from the environment of the stomach. The enteric coat provides protection from the environment of the stomach including its fluids, its acidity, its enzymes and peristaltic agitation in the stomach.
It is desirable also for the enteric coat to maintain its integrity during the time needed for the drug to pass through the stomach and zo enter the intestine.
Heretobefore, enteric coats were used to safeguard a drug in the stomach, but frequently they were not satisfactory. One reason they were not satisfactory is they allowed water transport through zs the enteric coat causing the drug to be released prematurely. For some dosage forms, such as an osmotic device, the passage of water through the enteric coat hydrates the device and this causes the drug to be released too rapidly and early once the device enters the intestine and the enteric coat disintegrates. Consequently, as a so result of this action, the drug may be absorbed or metabolized at the start of the intestine and it is not delivered at a controlled rate throughout the intestine for its intended effect. One effort to overcome this consists in applying thicker enteric coats, however, this too lets fluid flux therethrough and the thicker coats often 3s rupture under the influence of agitation in the stomach.
~o~s~~~
In view of the above presentation, it is immediately self-evident that a need exists for a dosage form comprising an enteric coat that comprises means for substantially preventing the passage of water through its enteric coat. The need exists for a dosage form s comprising an enteric coat that is hydrophobic for preventing the flux of water through the enteric coat particularly during the time the dosage form is in the stomach.
DISCLOSURE OF OBJECTS OF THE INDENTION
io It is an immediate object of this invention to provide a novel dosage form comprising an enteric coat that overcomes the aforesaid disadvantages associated with the prior art dosage forms.
is It is another object of this invention to provide a dosage form manufactured as an osmotic device comprising an enteric coat that substantially prevents the passage of water therethrough.
It is another object of this invention to provide an osmotic zo device for the controlled delivery of a beneficial drug to the intestine, which delivery device represents an advancement in intestine-specific therapy.
It is another object of this invention to provide a dosage form 2s that provides intestine and colon specific therapies.
It is another object of this invention to provide an osmotic device that delays the onset of drug release from the osmotic device for a period of time required for the osmotic device to pass through ao the stomach and enter the small intestine.
It is another object of this invention to provide an osmotic device comprising an enteric coat that comprises hydrophobic means for preventing the passage of biological fluid including water 35 through the enteric coat.
It is yet another object of this invention to provide an osmotic device comprising an exterior enteric coat comprising a hydrophobic composition that impedes fluid transport into the osmotic system until the interior semipermeable wall of the device is exposed to fluid.
It is another object of this invention to provide an osmotic device comprising a semipermeable wall carrying on its outer surface means for delaying the delivery of a drug during the time required for the osmotic device to pass through the stomach.
It is another object of this invention to provide an osmotic device that delivers a drug to a preselected area of the gastrointestinal tract, comprising the intestine and the colon.
It is yet another object of this invention to provide an osmotic device comprising a wall carrying an exterior enteric composition comprising at least two components for restricting the passage of a biological fluid through the intact composition.
It is another object of this invention to provide an osmotic device comprising means for denying fluid access to the device and for concomitantly denying fluid imbibition into the device.
Other objects, features, aspects and advantages of this invention will be more apparent to those versed in the dispensing art from the following detailed specification taken in conjunction with the drawing figures and the accompanying claims.
3a According to one aspect of the present invention, there is provided an improvement in a device for delivering a drug to the intestine and colon fluid environment, wherein the device comprises: (a) a wall that comprises a surface that faces the environment, said wall comprising at least in part a composition permeable to the passage of fluid and substantially impermeable to the passage of drug, which wall surrounds; (b) a compartment; (c) a drug in the compartment; (d) push means in the compartment for pushing the drug from the device; (e) exit means in the wall for delivering the drug from the device; (f) coat means in contact with the surface of the wall that faces the environment for delaying the delivery of drug from the device, and wherein the improvement comprises; (g) a hydrophobic compound in the coat means in excess of its solubility in the coat means for substantially preventing the passage of fluid present in the environment through the coat means.
According to another aspect of the present invention, there is provided an improvement in a device for delivering a drug to an intestine and colon fluid environment to use, wherein the device comprises: (a) a wall comprising at least in part a composition permeable to the passage of fluid, which wall surrounds; (b) a compartment; (c) a first composition in the compartment, which composition comprises a drug and forms a dispensable formulation in the presence of fluid that enters the device; (d) a second composition in the compartment comprising means for pushing the first composition from the device; (e) at least one exit passageway in the wall for delivering a drug from the device; (f) a coat on the wall facing the environment of use for delaying the delivery of drug from the device, and wherein the improvement comprises; (g) a hydrophobic compound in the coat in excess of its solubility in 3b the coat for substantially preventing the passage of fluid present in the environment through the coat.
BRIEF DISCLOSURE OF THE DRAWINGS
In the drawing figures, which are not drawn to scale, but are set forth to illustrate various embodiments of the invention, the drawing figures are as follows:
~~38~~2 Figure I, is a view of a dosage form designed for administering orally a therapeutic drug to the gastrointestinal tract regions comprising the intestine and colon regions;
s Figure 2, is a view of the dosage form of Figure 1, wherein Figure 2 depicts an exterior coat for substantially preventing fluid passage into the dosage form;
Figure 3, is an opened view of the dosage form of Figure 1 and io Figure 2, wherein Figure 3 depicts the structure of the dosage form;
Figure 4, is a view of the dosage form provided by this invention manufactured as a different embodiment for administering a therapeutic drug to the preselected intestine and colon areas of the is gastrointestinal tract; and, Figure 5 is a graph that depicts the release rate from a delivery device first in artificial gastric fluid, and then in artificial intestinal fluid.
In the drawing figures and in the specification, like parts in related drawing figures are identified by like numbers. The terms appearing earlier in the specification and in the description of the drawing figures, as well as embodiments thereof, are further detailed 2s elsewhere in the specification.
DETAILED DISCLOSURE OF THE
DRAWING FIGURES
3o Turning now to the drawing figures in detail, which drawings are examples of the delivery systems provided by the invention and are preferably manufactured as osmotic devices, and which examples are not to be construed as limiting, one example of an osmotic device as seen in Figure 1, identified by the numeral 10. In Figure 1, the ss osmotic device 10 is sized, shaped and adapted for use as an orally administrable osmotic dosage form. The osmotic device 10 comprises a 20~~6~~
body 11 and a passageway 12, for connecting the exterior with the interior of osmotic device 10, not seen in Figure 1.
Drawing figure 2 depicts osmotic device 10 comprising an s exterior coat 13. Exterior coat 13 is an enteric coat designed for simultaneously (a) preventing osmotic device 10 from delivering a drug in the stomach, and (b) preventing fluids such as biological fluids and water from entering osmotic device 10.
io Drawing figure 3 depicts osmotic device 10 in opened view for illustrating the structural members of osmotic device 10. In Figure 3, device 10 comprises body 11 and wall 14. Wall 14 comprises at least one passageway 12 that extends through wall 14 for connecting the exterior of device 10 with an interior compartment 15. Wall 14 is comprises in total, or at least in part a semipermeable composition that is permeable to the passage of an external fluid present in the environment of use, such as biological fluids, aqueous and aqueous-like fluids. Wall 14 is essentially impermeable to the passage of drug. Wall 14 is substantially inert, and it keeps its physical and ~o chemical integrity during the dispensing-life of a drug. Wall 14 comprises a composition that is non-toxic to animals, including humans.
In drawing figure 3, dosage form 10 comprises an exterior coat z5 13 for (a) essentially delaying the delivery of a drug from dosage form 10 during the passage of dosage form 10 through the stomach; for (b) essentially preventing the passage of biological and aqueous fluid through coat 13; and, for (c) essentially preventing exterior biological and aqueous fluids from contacting the exterior surface 16 so of wall 14. The exterior surface 16 of wall 14 faces the environment of use, that is, the gastrointestinal tract.
Exterior coat 13 comprises a composition that maintains its physical and chemical integrity in an acid environment such as the ss stomach, and it maintains its physical and chemical integrity in the presence of agitation in the stomach. The phrase, maintains its ~~~8~~2 physical and chemical integrity, as used for the purpose of this invention means coat 13 does not dissolve, disintegrate, or break-up in the stomach. Coat 13 consequently as carried on wall 14 delays the release of drug from dosage from 10 during coat 13 tenure on the s exterior surface 16 of wall 14. The word hydrophobic as used herein denotes substantially a lack of affinity for water and substantially impermeable to the passage of water, biological fluids, and lipophilic fluids.
io Compartment 15, in one preferred embodiment, comprises a therapeutic drug 17, represented by dots. Drug 17 can be soluble to very soluble in an external fluid imbibed into compartment 15, and it exhibits an osmotic pressure gradient across wall 14. Compartment 15, in another embodiment, comprises drug 17 that is insoluble to is poorly soluble in the external fluid, and in this instance drug 17 exhibits a limited osmotic pressure gradient across wall 14. In this latter embodiment, drug 17 optionally is mixed with an osmagent 18, indicated by wavy lines, that is soluble in the external fluid and it exhibits an osmotic pressure gradient across wail 14 against an 2o external fluid.
Drawing Figure 4 illustrates another embodiment of dosage form 10. In drawing Figure 4, dosage form 10 comprises internal wall 14 that surrounds internal compartment 15. Passageway means 12 zs through internal wall 14 connects the exterior of dosage form 10 with compartment 15. An exterior coat 13 prevents dosage form 10 from delivering a drug in the stomach and it concomitantly prevents fluid from passing through wall 14. Coat 13, in its initial embodiment seals passageway 12 until coat 13 is released from dosage form 10.
so In drawing Figure 4, internal compartment 14 comprises a first composition 19 and a second composition 20. First composition 19 comprises a therapeutically active drug 17 that can be from insoluble to very soluble in fluid imbibed into the compartment. Drug 17 optionally is mixed with an osmagent 21, represented by dashes, that as is soluble in fluid imbibed into compartment 14 and exhibits an osmotic pressure gradient across semipermeable wail 14 against an external fluid. First composition 19 in another preferred embodiment, comprises an osmopolymer 22, represented by half-circles, that imbibes fluid into the first composition 19 to form a dispensable drug formulation. First composition 19 optionally s comprises other therapeutic composition forming ingredients 23, represented by triangles, such as lubricants, binders, and the like.
First composition 19 is non-toxic and it comprises pharmaceutically acceptable ingredients.
io Second composition 20 is in contacting relation with first composition 19. Second composition 20 is an osmotic driving force that expands and pushes dispensable first composition 19 fram device 10. The second composition in operation imbibes fluid into the second composition, absorbs the imbibed fluid into the second is composition, and expands in compartment 15. The continuous uptake of incoming fluid by composition 20 causes it to continuously expand and push first composition 19 through passageway 12 into the preselected area of the gastrointestinal tract. In one presently preferred embodiment, secand composition 22 comprises an osmopolymer 24, also Zo known as a hydrophilic hydrogel, that exhibits an osmotic pressure gradient across wall 14 against an external fluid present in the gastrointestinal tract. In another presently preferred embodiment, second composition 20 comprises an osmopolymer 24 and an osmagent 25, depicted by slant dashes. Osmagents are known also as osmotically zs effective compounds, and as osmotic solutes, and they exhibit an osmotic pressure gradient across a semipermeable wall 14 against a fluid present in the animal environment of use. The osmopolymer in cooperation with the osmagent imbibe fluid into second composition 20 for optimizing the maximum expansion of second composition 20 to an so enlarged state for pushing dispensable composition 19 through drug releasing exit means 12 from device 10.
Delivery system 10, as seen in Figures 1 to 4 can be made into many embodiments for oral use for administering a locally or a ss systemically acting therapeutically acting drug in the intestine, or in the intestine and colon of the gastrointestinal tract. In one w~~~~~~
presently preferred embodiment, the delivery device for oral use can have various conventional shapes and sizes such as round, egg-shape, kidney-bean shape, and the like. The oral delivery system can comprise a small to a large diameter, such a 5/16 inches to 9/16 s inches, and the like. The oral dosage systems in another manufacture are optionally sized and shaped as small tiny osmotic pills having a diameter of about 2 mm to 10 mm. The small dosage systems can be administered individually or as a plurality of tiny pills in a single piece or a two piece capsules. The capsule can house 1,5 or a io plurality of small dosage pills from 1 to 100, or the like.
DETAILED DISCLOSURE OF THE INDENTION
In accordance with the practice of this invention, wall 14 is comprises a composition that is permeable to the passage of fluid, and is substantially impermeable to the passage of drugs, osmotic solutes, binders, suspending agents and the like. The semipermeable composition does not adversely affect the active drug, nor an animal host. The selectively permeable materials comprising wall 14 are 2o semipermeable materials that are insoluble in body fluids and they are non-erodible. Representative selective materials for forming wall 14 comprise semipermeable polymer, homopolymer, copolymers and the like. The polymeric compositions presently preferred for manufacturing wall 14 comprise a member selected from the group zs consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose ester, cellulose ether, and cellulose ester-ether. Exemplary semipermeable polymers comprise cellulose acetate, cellulose diacetate, cellulose triacetate, dimethylcellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, and the so like. Semipermeable polymers are known in U.S. Pat. Nos. 3,173,876;
3,276,586; 3,541,005; 3,541,006; 3,546,142; 3,845,770; 3,916,899;
4,036,228; and 4,111,202.
Exterior, enteric coat 13 that substantially prevents delivery ss device 10 from releasing a drug in the stomach and simultaneously substantially prevents passage of fluid through coat 13, comprises a ~~3~6~2 composition that does not dissolve, disintegrate, or change its structural nature in the stomach and during the period of time delivery device 10 needs to pass through the stomach. The exterior coat 13 provided by this invention comprises at least one compounds, s that forms the exterior, enteric coat, and at least one hydrophobic compound that substantially prevents fluid flux therethrough.
Representative composition that keep their integrity in the stomach comprise a member selected from the group consisting of (a) keratin, keratin sandarac-tolu, salol, salol beta-naphyl benzoate and io acetotannin, salol with balsam of Peru, salol with tolu, salol with gum mastic, salol and stearic acid, and salol and shellac; (b) a member selected from the group consisting of formalized protein, formalized gelatin, and formalized cross-linked gelatin and exchange resins; (c) a member selected from the group consisting of myristic is acid-hydrogenated castor oil-cholesterol, stearic acid-mutton tallow, stearic acid-balsam of tolu, and stearic acid-castor oil; (d) a member selected from the group consisting of shellac, ammoniated shellac, ammoniated shellac-salol, shellac-wool fat, shellac-acetyl alcohol, shellac-stearic acid-balsam of tolu, and shellac n-butyl zo stearate; (e) a member selected from the group consisting of abietic acid, methyl abietate, benzoin, balsam of tolu, sandarac, mastic with tolu, and mastic with tolu, and mastic with acetyl alcohol; (f) acrylic resins represented by anionic polymers synthesized from methacrylic acid and methacrylic acid methyl ester, copolymeric zs acrylic resins of methacrylic and methacrylic acid and methacrylic acid alkyl esters, copolymers of alkacrylic acid and alkacrylic acid alkyl esters, acrylic resins such as dimethyl-aminoethylmethacrylate-butylmethacrylate-methylmethacrylate copolymer of 150,000 molecular weight, methacrylic acid-methylmethacrylate 50:50 copolymer of so 135,000 molecular weight, methacrylic acid-methylmethacrylate-30:70-copolymer of 135,000 mol. wt., trimethylammoniumethyl-methacrylatechloride-methylmethacrylate-ethyiacrylate-10:60:30 copolymers of 135,000 mol. wt., trimethylammoniumethyl-methacrylate-chloride-methylmethacryiate-ethylacrylate-5:65:30-copolymer of ss 150,000 mol. wt., ethylacrylate-methylmethacrylate-70:30-copolymer of 800,000 mol. wt., methacrylic acid-ethylacrylate-50:50-copolymer of zo~s6~z 250,000 mol. wt., methacryiic acid-dimethylaminoethyl-methacrylate-ethylacrylate of 750,000 mol. wt., methacrylic acid-methylmethacrylate-ethylacrylate of 1,000,000 mol. wt., and ethylacrylate-methylmethacrylate-ethylacrylate of 550,000 mol. wt;
s and, (g) an enteric composition comprising a member selected from the group consisting of cellulose acetyl phthalate, cellulose diacetyl phthalate, cellulose triacetyl phthalate, cellulose acetate phthalate, hydroxypropyl methylcelluiose phthalate, sodium cellulose acetate phthalate, cellulose ester phthalate, cellulose ether io phthalate, methylcellulose phthalate, cellulose ester-ether phthalate, hydroxypropyl cellulose phthalate, alkali salts of cellulose acetate phthalate, alkaline earth salts of cellulose acetate phthalate, calcium salt of cellulose acetate phthalate, ammonium salt of hydroxypropyl methylceilulose phthalate, cellulose is acetate hexahydrophthalate, hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate diethyl phthalate, dibutyl phthalate, dialkyl phthalate wherein the alkyl comprises from 1 to 7 straight and branched alkyl groups, aryl phthalates, and the like.
The hydrophobic compound homogenously blended with the enteric coat exemplified by groups (a) through (g) comprises a homogenous compound from the same group or a hydrophobic compound from a different group. The hydrophobic compound homogenously blended with z5 an enteric coat represented by groups (a) through (g) in a presently preferred embodiment comprises a member selected from the group consisting of cellulose acetyl phthalate, cellulose diacetyl phthalate, cellulose triacetyl phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, sodium cellulose so acetate phthalate, cellulose ester phthalate, cellulose ether phthalate, methylcellulose phthalate, cellulose ester-ether phthalate, hydroxypropyl cellulose phthalate, alkali salts of cellulose acetate phthalate, alkaline earth salts of cellulose acetate phthalate, calcium salt of cellulose acetate phthalate, as ammonium salt of hydroxypropyl methylcellulose phthalate, cellulose acetate hexahydrophthaiate, hydroxypropyl methylcellulose 2U3~6~~
hexahydrophthalate, polyvinyl acetate phthalate diethyl phthalate, dibutyl phthalate, dialkyl phthalate wherein the alkyl comprises from 1 to 7 straight and branched alkyl groups, aryl phthalates, and the like.
In a presently preferred embodiment the hydrophobic compound is blended into the enteric coat in excess of solubility in the enteric coat. The hydrophobic compound in the enteric coat migrates to the surfaces of the enteric coat wherein it impedes fluid transport into io delivery system 10. In this manufacture, the invention provides an improvement over standard enteric coats which while not disintegrating let fluid pass at pH of the stomach. This invention provides a hydrophobic compound in the enteric coat for substantially preventing fluid transport through the enteric coat. The hydrophobic is compounds, in one presently preferred embodiment, are mixed initially with the entire coat in a pharmaceutically acceptable form selected from the group consisting of crystalline, particle, pellet, granule, powder, dry and lyophilized forms. In this embodiment the added hydrophobic compounds can homogeneously or heterogeneously blend with 2o the entire coat and they are presently available for migrating to the surface of the entire coat. The amount of hydrophobic compound in the exterior, enteric coat about I weight percent to 50 weight percent, and in a presently more preferred amount by 10 weight percent to 50 weight percent. The enteric percent to 50 weight 2s percent. The enteric compounds are known in Remin ton's Pharmaceutical Sciences, 13th Ed., pages 604-605, (1965), published by Mack Publishing Co., Eaton, PA; Eudragit~ Coatings Rohm Pharma., (1985); and U.S. Pat. No. 4,627,851.
so The term, drug 17, as used for the purpose of this invention embraces drug that are administered in the lower gastrointestinal to produce a therapeutic effect. The drugs include the drugs conventionally used in the treatment of colitis, ulcerative colitis, Crohn's disease, idiopathic prototis and other diseases of the lower 35 gastrointestinal tract. Representative drugs include salicyiazosulfapyridine, also known as sulphasalazine, and salazopyrin; adrenocorticosteroids such as hydrocortisone, prednisolone, prednisolone phosphate, prednisolone sulfate, prednisone, prednisolone, prednisolone metasulpho-benzoate sodium, prednisolone sodium phosphate and the like; corticosteroids such as s beclomethasone, beclomethasone acetate, beclomethasone valerate, beclomethasone propionate, beclomethasone dipropionate, and the like;
cyclosporin; and the like. In another aspect, drug 17 also includes drugs for treatment of irritable bowel syndrome, or drug 17 alters bowl motility and fluid absorption, such drugs are represented by io calcium channel blocking drugs, opiads, anticholinergics and benzodiazepides. The amount of drug in a delivery device 10 can be from 10 ng to 1.5 g, and the amount of drug in the tiny dosage forms is from 10 ng, to 25 mg, and the like.
is The osmotically effective compounds that can be used for the purpose of this invention for mixing with a drug, or for mixing with an osmopolymer comprise inorganic and organic compounds that exhibit an osmotic pressure gradient across a semipermeable against an external fluid. The osmotically effective compounds imbibe fluid zo into the device thereby making available in situ fluid for imbibition by an osmopolymer to enhance its expansion, or for forming a solution or suspension comprising a drug for its delivery through a passageway from the delivery system. 0smotically effective compounds are known also as osmotically effective solutes or osmagents and they are zs exemplified by magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium chloride, potassium acid phosphate, mannitol, glucose, urea, inositol, magnesium succinate, potassium chloride, tartaric acid, carbohydrates such as raffinose, succrose, alpha-d-lactose monohydrate, and mixtures so thereof. The amount of osmagent mixed with a drug generally is from 0.01 to 30~, or higher, and the amount of osmagent when mixed with an osmopolymer is from 0.01% to 40%, or higher. Osmagents are known in U.S. Pat. No. 4,765,989.
35 The first composition 19, as seen in Figure 4, comprises a non-toxic polymer that forms a drug disposable formulation comprising for 203~6~2 example a hydrophilic polymer that exhibits the ability to absorb or imbibe fluid and retain the fluid to form a viscous solution, or the like. In a presently preferred embodiment, the hydrophilic polymer is a drug carrier means, usually a noncross-linked hydrogel and it is s preferably a different hydrogel than the expandable hydrogel comprising second composition 20. Generally, the hydrogel for carrying the drug will have a viscosity of about 100 centipoise at a 5% concentration to a solution viscosity of 1000 centipoise at a similar concentration. The solution viscosity of a polymer can be io measured using a Brookfield viscometer. Methods for measuring viscosity are disclosed in Pharmaceutical Sciences, by Remington, 14th Ed., pp 361-371, (1970), published by Mack Publishing Co., Easton, PA. Methods for measuring viscosity are disclosed in Encyclopedia of Chemists, by Clark, 2nd Ed., pp 663-667, (1966), is published by Uan Nostrand Reinhold Co., New York; and in Handbook of Common Polymers, by Scot, Sect. 52, pp 487-493, (1971), published by Chemical Rubber Co., Cleveland, 0H.' In Figure 4, first composition 19, in one presently preferred 2o embodiment comprises a water soluble, nonionic hydrophilic polymer, such as from 75 weight percent to 95 weight percent of a polyethylene oxide selected from the group consisting of a polyethylene oxide having a 100,000 molecular weight, a polyethylene oxide having a 200,000 molecular weight, a polyethylene oxide having a 300,000 2s molecular weight, and the like; from 0 weight percent to 20 weight percent of a hydroxypropylmethylcellulose having a 9,000 to 20,000 number average molecular weight. The first composition optionally comprises from zero weight percent to 3 weight percent of lubricant such as stearic acid, or magnesium stearate, and from 0 weight 3o percent to 10 weight percent of a binder such as polyvinyl pyrrolidone, with the total weight percent of all ingredients equal to 100 weight percent.
Second composition 20, in Figure 4, comprises means far ss interacting with aqueous and biological fluid, for swelling or expanding for pushing the first composition 19 from the delivery ~~~~6'~2 device. The second composition 20 comprises means for retaining a significant portion of imbibed and absorbed fluid within its molecular structure. Representative compositions comprise osmopolymers that are noncross-linked or lightly cross-linked by s covalent or ionic bonds. The osmopolymers can be of natural or of synthetic origin. The osmopolymers are hydrophilic polymers.
Representative polymers for forming second composition 17 include poly(hydroxyalkylmethacrylate) having a molecular weight of from 30,000 to 5,000,000; poly(vinylpyrrolidone) having a molecular weight io of from 10,000 to 360,000; anionic and cationic hydrogels;
polyelectrolyte complexes; polyvinyl alcohol) cross-linked with glyoxal, formaldehyde or glutaraldehyde and a degree of polymerization from 20,000 to 30,000; a mixture of cross-linked agar, methyl cellulose and carboxymethyl cellulose; a water insoluble, is water swellable copolymer reduced by forming a dispersion of finely divided copolymer of malefic anhydride with styrene, ethylene, propylene, butylene or isobutylene cross-linked with from 0.001 to about 0.5 moles of polyunsaturated cross-linking agent per mole of malefic anhydride in the copolymer; water swellable polymers of 2o N-vinyl lactams; and the like.
In another presently preferred embodiment, second composition 20 comprises a member selected from the group consisting of acidic carboxy polymers having a molecular weight of 450,000 to 4,000,000;
zs polyacrylamides; cross-linked water swellable indene-malefic anhydride polymers; polyaerylic acid having a molecular weight of 80,000 to 200,000; polyalkylene oxide polymers having a molecular weight of 100,000 to 8,000,000; starch graft copolymers; acrylate polymers;
diester cross-linked polygiucan; and the like. Representative 3o polymers that form hydrogels are known to the prior art in U.S. Pat.
No. 3,865,108 issued to Hartop; U.S. Pat. No. 4,002,173 issued to Manning; U.S. Pat. No. 4,207,893 issued to Michaels, and in Handbook of Common Polymers, by Scott and Roff, published by Chemical Rubber Company, Cleveland, OH.
DOSAGE FORM FOR DELIVERING
DRUG TO THE INTESTINE
DISCLOSURE OF TECHNICAL FIELD
s The present invention pertains to a novel delivery system for administering a therapeutic drug to a preselected region of the gastrointestinal tract, specifically the intestine. The invention concerns also a method for administering orally a drug to the intestine of a warm-blooded animal.
io DISCLOSURE OF THE BACKGROUND ART
As is known in the medical and the pharmaceutical arts, the desiderata of an enteric coat is to protect an orally administered i5 drug from the environment of the stomach. The enteric coat provides protection from the environment of the stomach including its fluids, its acidity, its enzymes and peristaltic agitation in the stomach.
It is desirable also for the enteric coat to maintain its integrity during the time needed for the drug to pass through the stomach and zo enter the intestine.
Heretobefore, enteric coats were used to safeguard a drug in the stomach, but frequently they were not satisfactory. One reason they were not satisfactory is they allowed water transport through zs the enteric coat causing the drug to be released prematurely. For some dosage forms, such as an osmotic device, the passage of water through the enteric coat hydrates the device and this causes the drug to be released too rapidly and early once the device enters the intestine and the enteric coat disintegrates. Consequently, as a so result of this action, the drug may be absorbed or metabolized at the start of the intestine and it is not delivered at a controlled rate throughout the intestine for its intended effect. One effort to overcome this consists in applying thicker enteric coats, however, this too lets fluid flux therethrough and the thicker coats often 3s rupture under the influence of agitation in the stomach.
~o~s~~~
In view of the above presentation, it is immediately self-evident that a need exists for a dosage form comprising an enteric coat that comprises means for substantially preventing the passage of water through its enteric coat. The need exists for a dosage form s comprising an enteric coat that is hydrophobic for preventing the flux of water through the enteric coat particularly during the time the dosage form is in the stomach.
DISCLOSURE OF OBJECTS OF THE INDENTION
io It is an immediate object of this invention to provide a novel dosage form comprising an enteric coat that overcomes the aforesaid disadvantages associated with the prior art dosage forms.
is It is another object of this invention to provide a dosage form manufactured as an osmotic device comprising an enteric coat that substantially prevents the passage of water therethrough.
It is another object of this invention to provide an osmotic zo device for the controlled delivery of a beneficial drug to the intestine, which delivery device represents an advancement in intestine-specific therapy.
It is another object of this invention to provide a dosage form 2s that provides intestine and colon specific therapies.
It is another object of this invention to provide an osmotic device that delays the onset of drug release from the osmotic device for a period of time required for the osmotic device to pass through ao the stomach and enter the small intestine.
It is another object of this invention to provide an osmotic device comprising an enteric coat that comprises hydrophobic means for preventing the passage of biological fluid including water 35 through the enteric coat.
It is yet another object of this invention to provide an osmotic device comprising an exterior enteric coat comprising a hydrophobic composition that impedes fluid transport into the osmotic system until the interior semipermeable wall of the device is exposed to fluid.
It is another object of this invention to provide an osmotic device comprising a semipermeable wall carrying on its outer surface means for delaying the delivery of a drug during the time required for the osmotic device to pass through the stomach.
It is another object of this invention to provide an osmotic device that delivers a drug to a preselected area of the gastrointestinal tract, comprising the intestine and the colon.
It is yet another object of this invention to provide an osmotic device comprising a wall carrying an exterior enteric composition comprising at least two components for restricting the passage of a biological fluid through the intact composition.
It is another object of this invention to provide an osmotic device comprising means for denying fluid access to the device and for concomitantly denying fluid imbibition into the device.
Other objects, features, aspects and advantages of this invention will be more apparent to those versed in the dispensing art from the following detailed specification taken in conjunction with the drawing figures and the accompanying claims.
3a According to one aspect of the present invention, there is provided an improvement in a device for delivering a drug to the intestine and colon fluid environment, wherein the device comprises: (a) a wall that comprises a surface that faces the environment, said wall comprising at least in part a composition permeable to the passage of fluid and substantially impermeable to the passage of drug, which wall surrounds; (b) a compartment; (c) a drug in the compartment; (d) push means in the compartment for pushing the drug from the device; (e) exit means in the wall for delivering the drug from the device; (f) coat means in contact with the surface of the wall that faces the environment for delaying the delivery of drug from the device, and wherein the improvement comprises; (g) a hydrophobic compound in the coat means in excess of its solubility in the coat means for substantially preventing the passage of fluid present in the environment through the coat means.
According to another aspect of the present invention, there is provided an improvement in a device for delivering a drug to an intestine and colon fluid environment to use, wherein the device comprises: (a) a wall comprising at least in part a composition permeable to the passage of fluid, which wall surrounds; (b) a compartment; (c) a first composition in the compartment, which composition comprises a drug and forms a dispensable formulation in the presence of fluid that enters the device; (d) a second composition in the compartment comprising means for pushing the first composition from the device; (e) at least one exit passageway in the wall for delivering a drug from the device; (f) a coat on the wall facing the environment of use for delaying the delivery of drug from the device, and wherein the improvement comprises; (g) a hydrophobic compound in the coat in excess of its solubility in 3b the coat for substantially preventing the passage of fluid present in the environment through the coat.
BRIEF DISCLOSURE OF THE DRAWINGS
In the drawing figures, which are not drawn to scale, but are set forth to illustrate various embodiments of the invention, the drawing figures are as follows:
~~38~~2 Figure I, is a view of a dosage form designed for administering orally a therapeutic drug to the gastrointestinal tract regions comprising the intestine and colon regions;
s Figure 2, is a view of the dosage form of Figure 1, wherein Figure 2 depicts an exterior coat for substantially preventing fluid passage into the dosage form;
Figure 3, is an opened view of the dosage form of Figure 1 and io Figure 2, wherein Figure 3 depicts the structure of the dosage form;
Figure 4, is a view of the dosage form provided by this invention manufactured as a different embodiment for administering a therapeutic drug to the preselected intestine and colon areas of the is gastrointestinal tract; and, Figure 5 is a graph that depicts the release rate from a delivery device first in artificial gastric fluid, and then in artificial intestinal fluid.
In the drawing figures and in the specification, like parts in related drawing figures are identified by like numbers. The terms appearing earlier in the specification and in the description of the drawing figures, as well as embodiments thereof, are further detailed 2s elsewhere in the specification.
DETAILED DISCLOSURE OF THE
DRAWING FIGURES
3o Turning now to the drawing figures in detail, which drawings are examples of the delivery systems provided by the invention and are preferably manufactured as osmotic devices, and which examples are not to be construed as limiting, one example of an osmotic device as seen in Figure 1, identified by the numeral 10. In Figure 1, the ss osmotic device 10 is sized, shaped and adapted for use as an orally administrable osmotic dosage form. The osmotic device 10 comprises a 20~~6~~
body 11 and a passageway 12, for connecting the exterior with the interior of osmotic device 10, not seen in Figure 1.
Drawing figure 2 depicts osmotic device 10 comprising an s exterior coat 13. Exterior coat 13 is an enteric coat designed for simultaneously (a) preventing osmotic device 10 from delivering a drug in the stomach, and (b) preventing fluids such as biological fluids and water from entering osmotic device 10.
io Drawing figure 3 depicts osmotic device 10 in opened view for illustrating the structural members of osmotic device 10. In Figure 3, device 10 comprises body 11 and wall 14. Wall 14 comprises at least one passageway 12 that extends through wall 14 for connecting the exterior of device 10 with an interior compartment 15. Wall 14 is comprises in total, or at least in part a semipermeable composition that is permeable to the passage of an external fluid present in the environment of use, such as biological fluids, aqueous and aqueous-like fluids. Wall 14 is essentially impermeable to the passage of drug. Wall 14 is substantially inert, and it keeps its physical and ~o chemical integrity during the dispensing-life of a drug. Wall 14 comprises a composition that is non-toxic to animals, including humans.
In drawing figure 3, dosage form 10 comprises an exterior coat z5 13 for (a) essentially delaying the delivery of a drug from dosage form 10 during the passage of dosage form 10 through the stomach; for (b) essentially preventing the passage of biological and aqueous fluid through coat 13; and, for (c) essentially preventing exterior biological and aqueous fluids from contacting the exterior surface 16 so of wall 14. The exterior surface 16 of wall 14 faces the environment of use, that is, the gastrointestinal tract.
Exterior coat 13 comprises a composition that maintains its physical and chemical integrity in an acid environment such as the ss stomach, and it maintains its physical and chemical integrity in the presence of agitation in the stomach. The phrase, maintains its ~~~8~~2 physical and chemical integrity, as used for the purpose of this invention means coat 13 does not dissolve, disintegrate, or break-up in the stomach. Coat 13 consequently as carried on wall 14 delays the release of drug from dosage from 10 during coat 13 tenure on the s exterior surface 16 of wall 14. The word hydrophobic as used herein denotes substantially a lack of affinity for water and substantially impermeable to the passage of water, biological fluids, and lipophilic fluids.
io Compartment 15, in one preferred embodiment, comprises a therapeutic drug 17, represented by dots. Drug 17 can be soluble to very soluble in an external fluid imbibed into compartment 15, and it exhibits an osmotic pressure gradient across wall 14. Compartment 15, in another embodiment, comprises drug 17 that is insoluble to is poorly soluble in the external fluid, and in this instance drug 17 exhibits a limited osmotic pressure gradient across wall 14. In this latter embodiment, drug 17 optionally is mixed with an osmagent 18, indicated by wavy lines, that is soluble in the external fluid and it exhibits an osmotic pressure gradient across wail 14 against an 2o external fluid.
Drawing Figure 4 illustrates another embodiment of dosage form 10. In drawing Figure 4, dosage form 10 comprises internal wall 14 that surrounds internal compartment 15. Passageway means 12 zs through internal wall 14 connects the exterior of dosage form 10 with compartment 15. An exterior coat 13 prevents dosage form 10 from delivering a drug in the stomach and it concomitantly prevents fluid from passing through wall 14. Coat 13, in its initial embodiment seals passageway 12 until coat 13 is released from dosage form 10.
so In drawing Figure 4, internal compartment 14 comprises a first composition 19 and a second composition 20. First composition 19 comprises a therapeutically active drug 17 that can be from insoluble to very soluble in fluid imbibed into the compartment. Drug 17 optionally is mixed with an osmagent 21, represented by dashes, that as is soluble in fluid imbibed into compartment 14 and exhibits an osmotic pressure gradient across semipermeable wail 14 against an external fluid. First composition 19 in another preferred embodiment, comprises an osmopolymer 22, represented by half-circles, that imbibes fluid into the first composition 19 to form a dispensable drug formulation. First composition 19 optionally s comprises other therapeutic composition forming ingredients 23, represented by triangles, such as lubricants, binders, and the like.
First composition 19 is non-toxic and it comprises pharmaceutically acceptable ingredients.
io Second composition 20 is in contacting relation with first composition 19. Second composition 20 is an osmotic driving force that expands and pushes dispensable first composition 19 fram device 10. The second composition in operation imbibes fluid into the second composition, absorbs the imbibed fluid into the second is composition, and expands in compartment 15. The continuous uptake of incoming fluid by composition 20 causes it to continuously expand and push first composition 19 through passageway 12 into the preselected area of the gastrointestinal tract. In one presently preferred embodiment, secand composition 22 comprises an osmopolymer 24, also Zo known as a hydrophilic hydrogel, that exhibits an osmotic pressure gradient across wall 14 against an external fluid present in the gastrointestinal tract. In another presently preferred embodiment, second composition 20 comprises an osmopolymer 24 and an osmagent 25, depicted by slant dashes. Osmagents are known also as osmotically zs effective compounds, and as osmotic solutes, and they exhibit an osmotic pressure gradient across a semipermeable wall 14 against a fluid present in the animal environment of use. The osmopolymer in cooperation with the osmagent imbibe fluid into second composition 20 for optimizing the maximum expansion of second composition 20 to an so enlarged state for pushing dispensable composition 19 through drug releasing exit means 12 from device 10.
Delivery system 10, as seen in Figures 1 to 4 can be made into many embodiments for oral use for administering a locally or a ss systemically acting therapeutically acting drug in the intestine, or in the intestine and colon of the gastrointestinal tract. In one w~~~~~~
presently preferred embodiment, the delivery device for oral use can have various conventional shapes and sizes such as round, egg-shape, kidney-bean shape, and the like. The oral delivery system can comprise a small to a large diameter, such a 5/16 inches to 9/16 s inches, and the like. The oral dosage systems in another manufacture are optionally sized and shaped as small tiny osmotic pills having a diameter of about 2 mm to 10 mm. The small dosage systems can be administered individually or as a plurality of tiny pills in a single piece or a two piece capsules. The capsule can house 1,5 or a io plurality of small dosage pills from 1 to 100, or the like.
DETAILED DISCLOSURE OF THE INDENTION
In accordance with the practice of this invention, wall 14 is comprises a composition that is permeable to the passage of fluid, and is substantially impermeable to the passage of drugs, osmotic solutes, binders, suspending agents and the like. The semipermeable composition does not adversely affect the active drug, nor an animal host. The selectively permeable materials comprising wall 14 are 2o semipermeable materials that are insoluble in body fluids and they are non-erodible. Representative selective materials for forming wall 14 comprise semipermeable polymer, homopolymer, copolymers and the like. The polymeric compositions presently preferred for manufacturing wall 14 comprise a member selected from the group zs consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose ester, cellulose ether, and cellulose ester-ether. Exemplary semipermeable polymers comprise cellulose acetate, cellulose diacetate, cellulose triacetate, dimethylcellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, and the so like. Semipermeable polymers are known in U.S. Pat. Nos. 3,173,876;
3,276,586; 3,541,005; 3,541,006; 3,546,142; 3,845,770; 3,916,899;
4,036,228; and 4,111,202.
Exterior, enteric coat 13 that substantially prevents delivery ss device 10 from releasing a drug in the stomach and simultaneously substantially prevents passage of fluid through coat 13, comprises a ~~3~6~2 composition that does not dissolve, disintegrate, or change its structural nature in the stomach and during the period of time delivery device 10 needs to pass through the stomach. The exterior coat 13 provided by this invention comprises at least one compounds, s that forms the exterior, enteric coat, and at least one hydrophobic compound that substantially prevents fluid flux therethrough.
Representative composition that keep their integrity in the stomach comprise a member selected from the group consisting of (a) keratin, keratin sandarac-tolu, salol, salol beta-naphyl benzoate and io acetotannin, salol with balsam of Peru, salol with tolu, salol with gum mastic, salol and stearic acid, and salol and shellac; (b) a member selected from the group consisting of formalized protein, formalized gelatin, and formalized cross-linked gelatin and exchange resins; (c) a member selected from the group consisting of myristic is acid-hydrogenated castor oil-cholesterol, stearic acid-mutton tallow, stearic acid-balsam of tolu, and stearic acid-castor oil; (d) a member selected from the group consisting of shellac, ammoniated shellac, ammoniated shellac-salol, shellac-wool fat, shellac-acetyl alcohol, shellac-stearic acid-balsam of tolu, and shellac n-butyl zo stearate; (e) a member selected from the group consisting of abietic acid, methyl abietate, benzoin, balsam of tolu, sandarac, mastic with tolu, and mastic with tolu, and mastic with acetyl alcohol; (f) acrylic resins represented by anionic polymers synthesized from methacrylic acid and methacrylic acid methyl ester, copolymeric zs acrylic resins of methacrylic and methacrylic acid and methacrylic acid alkyl esters, copolymers of alkacrylic acid and alkacrylic acid alkyl esters, acrylic resins such as dimethyl-aminoethylmethacrylate-butylmethacrylate-methylmethacrylate copolymer of 150,000 molecular weight, methacrylic acid-methylmethacrylate 50:50 copolymer of so 135,000 molecular weight, methacrylic acid-methylmethacrylate-30:70-copolymer of 135,000 mol. wt., trimethylammoniumethyl-methacrylatechloride-methylmethacrylate-ethyiacrylate-10:60:30 copolymers of 135,000 mol. wt., trimethylammoniumethyl-methacrylate-chloride-methylmethacryiate-ethylacrylate-5:65:30-copolymer of ss 150,000 mol. wt., ethylacrylate-methylmethacrylate-70:30-copolymer of 800,000 mol. wt., methacrylic acid-ethylacrylate-50:50-copolymer of zo~s6~z 250,000 mol. wt., methacryiic acid-dimethylaminoethyl-methacrylate-ethylacrylate of 750,000 mol. wt., methacrylic acid-methylmethacrylate-ethylacrylate of 1,000,000 mol. wt., and ethylacrylate-methylmethacrylate-ethylacrylate of 550,000 mol. wt;
s and, (g) an enteric composition comprising a member selected from the group consisting of cellulose acetyl phthalate, cellulose diacetyl phthalate, cellulose triacetyl phthalate, cellulose acetate phthalate, hydroxypropyl methylcelluiose phthalate, sodium cellulose acetate phthalate, cellulose ester phthalate, cellulose ether io phthalate, methylcellulose phthalate, cellulose ester-ether phthalate, hydroxypropyl cellulose phthalate, alkali salts of cellulose acetate phthalate, alkaline earth salts of cellulose acetate phthalate, calcium salt of cellulose acetate phthalate, ammonium salt of hydroxypropyl methylceilulose phthalate, cellulose is acetate hexahydrophthalate, hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate diethyl phthalate, dibutyl phthalate, dialkyl phthalate wherein the alkyl comprises from 1 to 7 straight and branched alkyl groups, aryl phthalates, and the like.
The hydrophobic compound homogenously blended with the enteric coat exemplified by groups (a) through (g) comprises a homogenous compound from the same group or a hydrophobic compound from a different group. The hydrophobic compound homogenously blended with z5 an enteric coat represented by groups (a) through (g) in a presently preferred embodiment comprises a member selected from the group consisting of cellulose acetyl phthalate, cellulose diacetyl phthalate, cellulose triacetyl phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, sodium cellulose so acetate phthalate, cellulose ester phthalate, cellulose ether phthalate, methylcellulose phthalate, cellulose ester-ether phthalate, hydroxypropyl cellulose phthalate, alkali salts of cellulose acetate phthalate, alkaline earth salts of cellulose acetate phthalate, calcium salt of cellulose acetate phthalate, as ammonium salt of hydroxypropyl methylcellulose phthalate, cellulose acetate hexahydrophthaiate, hydroxypropyl methylcellulose 2U3~6~~
hexahydrophthalate, polyvinyl acetate phthalate diethyl phthalate, dibutyl phthalate, dialkyl phthalate wherein the alkyl comprises from 1 to 7 straight and branched alkyl groups, aryl phthalates, and the like.
In a presently preferred embodiment the hydrophobic compound is blended into the enteric coat in excess of solubility in the enteric coat. The hydrophobic compound in the enteric coat migrates to the surfaces of the enteric coat wherein it impedes fluid transport into io delivery system 10. In this manufacture, the invention provides an improvement over standard enteric coats which while not disintegrating let fluid pass at pH of the stomach. This invention provides a hydrophobic compound in the enteric coat for substantially preventing fluid transport through the enteric coat. The hydrophobic is compounds, in one presently preferred embodiment, are mixed initially with the entire coat in a pharmaceutically acceptable form selected from the group consisting of crystalline, particle, pellet, granule, powder, dry and lyophilized forms. In this embodiment the added hydrophobic compounds can homogeneously or heterogeneously blend with 2o the entire coat and they are presently available for migrating to the surface of the entire coat. The amount of hydrophobic compound in the exterior, enteric coat about I weight percent to 50 weight percent, and in a presently more preferred amount by 10 weight percent to 50 weight percent. The enteric percent to 50 weight 2s percent. The enteric compounds are known in Remin ton's Pharmaceutical Sciences, 13th Ed., pages 604-605, (1965), published by Mack Publishing Co., Eaton, PA; Eudragit~ Coatings Rohm Pharma., (1985); and U.S. Pat. No. 4,627,851.
so The term, drug 17, as used for the purpose of this invention embraces drug that are administered in the lower gastrointestinal to produce a therapeutic effect. The drugs include the drugs conventionally used in the treatment of colitis, ulcerative colitis, Crohn's disease, idiopathic prototis and other diseases of the lower 35 gastrointestinal tract. Representative drugs include salicyiazosulfapyridine, also known as sulphasalazine, and salazopyrin; adrenocorticosteroids such as hydrocortisone, prednisolone, prednisolone phosphate, prednisolone sulfate, prednisone, prednisolone, prednisolone metasulpho-benzoate sodium, prednisolone sodium phosphate and the like; corticosteroids such as s beclomethasone, beclomethasone acetate, beclomethasone valerate, beclomethasone propionate, beclomethasone dipropionate, and the like;
cyclosporin; and the like. In another aspect, drug 17 also includes drugs for treatment of irritable bowel syndrome, or drug 17 alters bowl motility and fluid absorption, such drugs are represented by io calcium channel blocking drugs, opiads, anticholinergics and benzodiazepides. The amount of drug in a delivery device 10 can be from 10 ng to 1.5 g, and the amount of drug in the tiny dosage forms is from 10 ng, to 25 mg, and the like.
is The osmotically effective compounds that can be used for the purpose of this invention for mixing with a drug, or for mixing with an osmopolymer comprise inorganic and organic compounds that exhibit an osmotic pressure gradient across a semipermeable against an external fluid. The osmotically effective compounds imbibe fluid zo into the device thereby making available in situ fluid for imbibition by an osmopolymer to enhance its expansion, or for forming a solution or suspension comprising a drug for its delivery through a passageway from the delivery system. 0smotically effective compounds are known also as osmotically effective solutes or osmagents and they are zs exemplified by magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium chloride, potassium acid phosphate, mannitol, glucose, urea, inositol, magnesium succinate, potassium chloride, tartaric acid, carbohydrates such as raffinose, succrose, alpha-d-lactose monohydrate, and mixtures so thereof. The amount of osmagent mixed with a drug generally is from 0.01 to 30~, or higher, and the amount of osmagent when mixed with an osmopolymer is from 0.01% to 40%, or higher. Osmagents are known in U.S. Pat. No. 4,765,989.
35 The first composition 19, as seen in Figure 4, comprises a non-toxic polymer that forms a drug disposable formulation comprising for 203~6~2 example a hydrophilic polymer that exhibits the ability to absorb or imbibe fluid and retain the fluid to form a viscous solution, or the like. In a presently preferred embodiment, the hydrophilic polymer is a drug carrier means, usually a noncross-linked hydrogel and it is s preferably a different hydrogel than the expandable hydrogel comprising second composition 20. Generally, the hydrogel for carrying the drug will have a viscosity of about 100 centipoise at a 5% concentration to a solution viscosity of 1000 centipoise at a similar concentration. The solution viscosity of a polymer can be io measured using a Brookfield viscometer. Methods for measuring viscosity are disclosed in Pharmaceutical Sciences, by Remington, 14th Ed., pp 361-371, (1970), published by Mack Publishing Co., Easton, PA. Methods for measuring viscosity are disclosed in Encyclopedia of Chemists, by Clark, 2nd Ed., pp 663-667, (1966), is published by Uan Nostrand Reinhold Co., New York; and in Handbook of Common Polymers, by Scot, Sect. 52, pp 487-493, (1971), published by Chemical Rubber Co., Cleveland, 0H.' In Figure 4, first composition 19, in one presently preferred 2o embodiment comprises a water soluble, nonionic hydrophilic polymer, such as from 75 weight percent to 95 weight percent of a polyethylene oxide selected from the group consisting of a polyethylene oxide having a 100,000 molecular weight, a polyethylene oxide having a 200,000 molecular weight, a polyethylene oxide having a 300,000 2s molecular weight, and the like; from 0 weight percent to 20 weight percent of a hydroxypropylmethylcellulose having a 9,000 to 20,000 number average molecular weight. The first composition optionally comprises from zero weight percent to 3 weight percent of lubricant such as stearic acid, or magnesium stearate, and from 0 weight 3o percent to 10 weight percent of a binder such as polyvinyl pyrrolidone, with the total weight percent of all ingredients equal to 100 weight percent.
Second composition 20, in Figure 4, comprises means far ss interacting with aqueous and biological fluid, for swelling or expanding for pushing the first composition 19 from the delivery ~~~~6'~2 device. The second composition 20 comprises means for retaining a significant portion of imbibed and absorbed fluid within its molecular structure. Representative compositions comprise osmopolymers that are noncross-linked or lightly cross-linked by s covalent or ionic bonds. The osmopolymers can be of natural or of synthetic origin. The osmopolymers are hydrophilic polymers.
Representative polymers for forming second composition 17 include poly(hydroxyalkylmethacrylate) having a molecular weight of from 30,000 to 5,000,000; poly(vinylpyrrolidone) having a molecular weight io of from 10,000 to 360,000; anionic and cationic hydrogels;
polyelectrolyte complexes; polyvinyl alcohol) cross-linked with glyoxal, formaldehyde or glutaraldehyde and a degree of polymerization from 20,000 to 30,000; a mixture of cross-linked agar, methyl cellulose and carboxymethyl cellulose; a water insoluble, is water swellable copolymer reduced by forming a dispersion of finely divided copolymer of malefic anhydride with styrene, ethylene, propylene, butylene or isobutylene cross-linked with from 0.001 to about 0.5 moles of polyunsaturated cross-linking agent per mole of malefic anhydride in the copolymer; water swellable polymers of 2o N-vinyl lactams; and the like.
In another presently preferred embodiment, second composition 20 comprises a member selected from the group consisting of acidic carboxy polymers having a molecular weight of 450,000 to 4,000,000;
zs polyacrylamides; cross-linked water swellable indene-malefic anhydride polymers; polyaerylic acid having a molecular weight of 80,000 to 200,000; polyalkylene oxide polymers having a molecular weight of 100,000 to 8,000,000; starch graft copolymers; acrylate polymers;
diester cross-linked polygiucan; and the like. Representative 3o polymers that form hydrogels are known to the prior art in U.S. Pat.
No. 3,865,108 issued to Hartop; U.S. Pat. No. 4,002,173 issued to Manning; U.S. Pat. No. 4,207,893 issued to Michaels, and in Handbook of Common Polymers, by Scott and Roff, published by Chemical Rubber Company, Cleveland, OH.
2~~~~~~
The expression, exit means, as used herein, comprises means and methods suitable for the metered release of beneficial drug of dosage from the internal compartment of dosage form 10. The exit means include at least one passageway, orifice or the like, through wall s for communicating with compartment. The expression, at least one passageway, includes aperture, orifice, bore, pore, porous element through which the drug can migrate, hollow fiber, capillary tube, porous overlay, porous insert, and the like. The expression also includes a material that erodes or is leached from wall in the fluid io environment of use to produce at least one passageway in dosage form 10. Representative materials suitable for forming at least one passageway, or a multiplicity of passageways, include an erodible poly(glycolic) acid or erodible poly(lactic) acid member in the wall;
a gelatinous filament; polyvinyl alcohol); leachabie materials such is as fluid removable pore forming polysaccharides; salts, oxides, and the like. A passageway or a plurality of passageways can be formed by leaching a material such as sorbitol, lactose, or the like, from the wall. The passageway can have any shape such as round, triangular, square, elliptical, and the like, for assisting in the 2o metered release of drug from dosage form. Dosage form can be constructed with one or more passageways in spaced apart relations, or more than one passageway on a single surface of dosage form.
Passageways and equipment for forming passageways are disclosed in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,063,064; and 4,088,864.
2s Passageways for releasing a drug formed by leaching or controlled pore forming are disclosed in U.S. Pat. No. 4,200,098 and 4,285,987.
The wall of a dosage form, and the exterior coat can be formed in separate steps using the air suspension procedure. This procedure so consists in suspending and in tumbling the drug forming compartment in a current of air and then coating with a wall forming composition, or followed by the exterior coat composition until, in either operation the wall or the exterior coat is applied to the layered drug forming compartment. The air suspension procedure is 3s well-suited far independently forming the wall on the enteric coat.
The air suspension procedure is described in U.S. Pat. No. 2,799,241;
2~~86~2 in J. Am. Pharm. Assoc. Vol. 48, pp 451-59, (1959); and ibid., Vol.
49, pp 82-4, (1960). Dosage-forming devices can also be coated with the wall forming composition or with the enteric forming composition, with a Wurster~ air suspension coater using various solvents such as s methylene dichloride-methanol cosolvent 80/20 (w/w), using 2.5 to 4%
solids. The Aeromatic~ air suspension coater using a methylene dichloride/methanol cosolvent 87/13 (w/w) also can be used for applying the wall, or the enteric coat. Other wall and delayed coating techniques such as pan coating can be used for providing the io delivery device. In the pan coating system, wall forming, or enteric coating compositions are deposited by successive spraying of the compositions of the compartment forming cores, accompanied by tumbling in a rotating pan. A pan coater also is used to produce a thicker wall or a thicker enteric coat. A larger volume of solvent is can be used in a cosolvent to produce a thinner wall or an enteric coat. Finally, the wall with the exterior coated compartment are dried in a forced air oven at 50°C for a week to free the dosage form of solvent. Generally, the wall formed by these techniques will have a thickness of 2 to 20 mils with a presently preferred thickness of 4 zo to 10 mils. The exterior coat generally will have a thickness of 0.5 to 15 mils, usually 0.5 to 7.5 mils.
Exemplary solvents suitable for manufacturing the wall or the exterior coat include inorganic and organic solvents that do not z5 adversely harm the wall, the outer coat nor the final delivery system. The solvents broadly include a member selected from the group consisting of alcohol, ketone, ester, ether, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic solvents, aromatic, heterocyclic, aqueous solvents, and mixtures thereof.
The dosage form as seen in Figure 3 can be made by a dry granulation process of manufacture. The dry process comprises first mixing all the composition forming ingredients, except for the lubricant, passing the mixed ingredients through a grinding mill to a small mesh size, and then transferring the sized powder to a dry compactor. The compactor densifies the powder and is extruded as a 1~ ARC 1699 sheet or ribbon which is then passed through a sizing mill to regrind the composition. The composition is ground to a small size, typically 20 mesh or smaller. Finally, a dry lubricant is added and the ingredients blended to produce the final composition. Then, the s respective composition is fed to a bi-layer tablet press and each composition is intimately bonded into contacting layers comprising dosage form 10.
In another manufacturing, the dosage form is manufactured by io the wet granulation technique. In the wet granulation technique, the drug and the ingredients are blended using an organic solvent.
First, the ingredients are individually passed dry through a mesh screen and then thoroughly blended in a mixer. Next, other ingredients are dissolved in a portion of the granulation fluid and i5 this latter prepared granulating solution is added slowly to the drug blend with continual mixing in the blender. The granulating fluid is added until a wet blend is produced, which wet mass then is forced through a 20 mesh screen onto oven trays. The blend is dried for 18 to 24 hours at 50°C. The dry granules are then sized using a 20 mesh zo screen. Next, a lubricant is passed through a screen and added to the dry granule blend. The granulation is placed into a blender and mixed for 5 to 10 minutes. The composition is then compressed into drug cores and coated with the inside semipermeable membrane wall and the exterior coat.
First composition 19 and second composition 20 are manufactured from well mixed individual composition forming members. Far example a first composition is made as follows: first, each of the ingredients comprising a dosage form is independently screened and so then blended together, except for a lubricant. Then, the homogeneous blend is wet granulated by adding a solvent such as anhydrous ethanol, and the wet ingredients mixed until a uniform blend is obtained by said process. Next, the wet blend is passed through a screen and dried to evaporate the solvent. The resulting granules ss are passed again through a sieve. Next, a small amount of a finely divided lubricant is added to the dry granules and the lubricant and ~~~~6~~
granules blended to provide a uniform blend. Then, the first composition is fed to a hopper of a bilayer tablet press, and the first composition pressed into the first layered composition. The process is repeated for the second composition. Typically about one-fourth to two tons of pressure are applied to yield the dosage form, which is coated with the internal semipermeable membrane wall and then the exterior coat.
The following examples are merely illustrative of the present io invention, and it should not be considered as limiting the scope of the invention in any way, as this example and other equivalents thereof will become apparent to those versed in the drug delivery art in light of the present disclosure and the accompanying claims.
t5 DISCLOSURE OF EXAMPLES FOR
PROVIDING THE INVENTION
zo A delivery device for administering a therapeutic drug to the intestine and colon of a warm-blooded animal is made as follows:
first, in a standard blender, 1,000 g of hydroxypropyimethylcellulose having a 9,600 molecular weight is blended with 18,114 g of polyethylene oxide having a 300,000 molecular weight, to yield a z5 uniform mass. Next, 800 g of polyvinylpyrrolidone is dissolved in 6 liters of anhydrous, ethyl alcohol with stirring, and when all the polyvinylpyrroiidone is in solution, 86 g beclomethasone dipropionate is added to solution, with constant stirring to yield a granulation solution. Then, the granulation solution is added slowly to the ao hydroxypropylmethylcellulose, polyethylene oxide blend and the alcohol content raised to 10 liters. Then, the wet mass is mixed far minutes in a blender. Next, the wet mass is passed through an 8 mesh screen to form wet granules. The wet granules are dried in a forced air circulating oven overnight at 25°C. Finally, the oven 35 temperature is raised to 50°C and drying continued for 2 hours to remove the last traces of ethyl alcohol. Finally, the dry granules are passed through a 20 mesh stainless steel screen and stored in a closed container.
Next, a second composition is prepared as follows: first, s 9,705 g of polyethylene oxide having a 5,000,000 molecular weight, 4,395 g of sodium chloride, 750 g of hydroxypropylmethylcellulose and 150 g of red ferric oxide are blended to produce a homogenous blend, and the blend passed through a 40 mesh stainless steel screen. The screened particles are next blended with granulating fluid comprising io anhydrous ethanol to produce a wet blend. The total volume of granulating fluid used is about 8 liters. The wet mass is passed through a 15 mesh sizing screen to form wet granules. The wet granules are transferred to drying sheets and dried in a forced air circulating oven at 25°C over 16 to 24 hours to remove the is granulating fluid, ethyl alcohol. The dry granules are stored in a closed containers until needed for further formulation of the delivery device.
Next, the first composition and the second composition are 2o pressed into a first layer and a second layer in a tabletting machine. The first composition is laminated against the second composition to provide a drug-push core. The first composition comprises 0.4348 wt % of beclomethasone dipropionate, 5.0 wt % of hydroxypropylmethylcellulose, 90.57 wt % of polyethylene oxide and zs 4.0 wt % of polyvinyipyrrolidone. The second composition comprises 64.70 g wt % of polyethylene oxide, 29.30 wt % of sodium chloride, 5.0 wt % of hydroxypropylmethylcellulose and 1.0 wt % red ferric oxide.
so Next, a semipermeable wall is applied around the contacting laminated compositions. The wall forming composition comprises 97 wt % cellulose triacetate having an acetyl content of 43.5% and 3 wt polyethylene glycol 3350. The wall forming solvent comprises 80 parts of methylene chloride and 20 parts of methanol, wt/wt. The 3s wall forming composition comprises 3% solids. The wall forming ingredients are dissolved in the solvents and stirred until a clear ~o~~o~~
solution is obtained. The wall is formed in an Accela-Cota~ pan coater to an approximate thickness of 0.076 mm (3 mils). After drying, and removing the cosolvent, a 0.25 mil orifice is laser drilled in the semipermeable wall to communicate with the first, drug s layer. The drilled systems are placed on opened trays in a humidity oven set at 50% relative humidity at 50°C for 24 hours to remove the remaining solvent.
Next, an exterior coat is prepared in a blender containing 95 io part ethyl alcohol and 5 parts of distilled water, wt/wt, to which is added slowly and with constant stirring 90 g of copolymeric methacrylic acid-methylmethacrylate, to produce a clear solution.
Then, 10 g of hydrophobic dibutyl phthalate is added to the blender and stirring continued for 30 minutes. The final concentration of is the exterior coat comprises 90% copolymer and 10% hydrophobic compound to give a 3% solids exterior coat.
Next, the semipermeable wall coated delivery systems are placed into an air suspension coater and the exterior coating composition is 2o added to the coater, and the delivery systems uniformly coated with an exterior coat. The exterior coated delivery systems are removed from the coater, placed on trays, and dried in a forced air circulating oven at 50°C for 24 hours to yield the final delivery system.
The procedure of Example 1 is repeated with all the steps as set forth, except that in this example the exterior coat comprises 75 so wt % methacrylic acid-methylmethacrylate copolymer and 25 wt hydrophobic dibutyl phthalate. The release rate per hour for this delivery system is seen in Figure 5 wherein AGF is artificial gastric fluid and AIF is artificial intestinal fluid, and the amount of beclomethasone dipropionate is measured over 30 hours. Artificial ss gastric and artificial fluids are known in The United States Pharmacopoeia, Twentieth Revision, p 1105, published 1980.
~U~86~2 A delivery device for delivering a therapeutic drug is made as follows: first, 22,642.85 grams of polyethylene oxide, having a s molecular weight of about 300,000, and 1,250 grams of hydroxypropylmethylcellulose, having a molecular weight of 9,500, are dry screened through a Fitzmill~ comminuter using a 35 mesh stainless steel screen, and then transferred to a Hobart~ blender. Next, 107.15 grams of beclomethasone dipropionate is dissolved in anhydrous io ethanol along with 1000 grams of polyvinylpyrrolidone. This granulating fluid is slowly added to the blender to produce a homogeneous blend. Next, the wet blend is passed through the comminuter using an 8 mesh stainless steel screen. The wet granules resulting from the screening process are dried in a forced air oven is for about 18 hours at 30°C. Finally, the dry granules are passed through the comminuter using a 16 mesh stainless steel screen to yield the first composition comprising the drug beclomethasone dipropionate.
zo Next, the second composition is prepared as follows: 12,940 gram of polyethylene oxide, having a 5,000,000 molecular weight, 5,860 grams of sodium chloride, 1000 grams of hydroxypropylmethylcellulose, having a 11,300 molecular weight, and 200 grams of ferric oxide, are added to and passed through the zs comminuter using a 35 mesh stainless steel screen. The screened particles next are transferred to the blender and blend to produce a well mixed blend, and to the blending ingredients anhydrous ethanol is added as a granulating fluid. Next, the wet blend is transferred to the Fitzmill comminuter using a 7 mesh stainless steel screen.
3o Then, the wet granules are transferred to drying sheets and dried in a forced air oven at 30°C for about 18 hours. The dried granules are passed through the comminuter using a I6 mesh stainless steel screen to yield the second composition comprising means for pushing the first composition from the delivery device.
2~386~~
Next, the first composition and the second composition are pressed into a first layer and into a second layer in a tableting machine using a 3/16 inch punch and die. The first composition weighed 23 mg and it comprises 0.1000 mg of beclomethasone s dipropionate, 1.1666 mg of hydroxypropylmethylcellulose, 21.1321 mg of the polyethylene oxide, and 0.9333 mg of the polyvinylpyrrolidone;
the second composition comprises 10.784 mg of the polyethylene oxide coagulant, 4.8837 mg of sodium chloride, 0.8384 mg of hydroxypropylmethylcellulose and 0.1667 mg of ferric oxide.
io Next, a semipermeable wall is applied around the compressed laminated compositions The wall forming composition comprises 97 wt of cellulose triacetate having an acetyl content of 43.5%, and 3 wt %
of polyethylene glycol 3350. The wall forming ingredients are is dissolved in a cosolvent comprising 80:20 wt/wt methylene chloride-methanol comprising 5% solids. The wall is formed in an Accela-Cota pan costar to an approximate thickness of 3 mils (0.076 mm) to provide a coating weight of 5 mg. After drying, and removing the cosolvent, a 25 mil orifice is laser drilled in the semipermeable 2o wall to the first composition.
Next, an outside exterior wall, comprising means for delaying the release of drug from the device during the devices' passage through an acidic environment, and for simultaneously preventing an zs exterior fluid from entering the device is coated onto the outside surface of the semipermeable, wall. The outside wall forming composition comprises 85 wt % of a copolymer of (methacrylic acid and methacrylic acid methyl ester, also known as Eudragit~ S-100) and 15 wt % of hydrophobic cellulose acetyl phthalate for saturating the so coat in 95% ethanol to provide 3% solids. The outside wall is applied in a 24 inch Accela-Cota~ pan costar to apply a 3 mil (0.076 mm) wall.
The delivery devices made by the above procedure are dried in a 3s humidity oven for 48 hrs at 50% relative humidity. Then, the delivery devices are dried an additional 24 hrs at 50°C in a forced air oven.
In another presently preferred embodiment, 5 delivery devices s are encapsulated in a number 2 gelatin capsule. Each delivery device contains 0.100 mg (100 fig) of beclomethasone dipropionate and total delivery system delivers 500 ~g of beclomethasone dipropionate to the intestine and colon.
io EXAMPLE 4 The procedure described in Example 2 is followed with all conditions as set forth, except that in these examples the drug steroid is a member selected from the group consisting of i5 beclomethasone, beclomethasone 17-propionate, beclomethasone 21-acetate, beclomethasone butyrate, and beclomethasone di propionate monohydrate.
Delivery device are made comprising salicylazosulphapyridine for treating Crohn's disease, and with an outer coat comprising a membrane selected from the group consisting of dimethylaminoethylmethacrylate-butylmethacrylate-methylmethacrylate is copolymer of 150,000 molecular weight blended with a membrane selected from the group consisting of cellulose acetyl phthalate, cellulose diacetyl phthalate, dialkyl phthalate, cellulose triacetyl phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, sodium cellulose acetate phthalate, cellulose ether 3o phthalate, cellulose ester phthalate, and methylcellulose phthalate.
Delivery devices for delivering a drug are made according to 35 the present examples wherein the drug is a member selected from the group consisting of hydrocortisone, prednisolone, prednisolone ~o~~s~~
phosphate and prednisone, and wherein the exterior coat for delaying drug release in an acidic environment and for preventing water passage through the coat is a member selected from the group consisting of polymers of methacrylic acid and methacrylic acid s methyl esters, methacryiic acid-ethylacrylate copolymer, and trimethylammonium ethylmethacrylatechloride-methylacrylate-ethylacrylate copolymer, blended with a hydrophobic member selected from the group consisting of cellulose acetyl phthalate, cellulose diacetyl phthalate, cellulose triacetyl phthalate, cellulose acetate io phthalate, hydroxypropylmethylcellulose phthalate, sodium cellulose acetate phthalate, cellulose ether phthalate, cellulose ester phthalate, and methylcellulose phthalate:
is The procedure of Example 1 is followed with the manufacturing procedures as previously set forth, except that the outside coat forming composition comprises 75 wt % of a copolymer of trimethyl ammonium ethylmethacrylate chloride-methylmethacrylate-ethylacrylate zo in the ratio of 5:65:3, 20 wt % dibutyl phthalate, and 5 wt acetyltriethylcitrate, in 95% ethanol, to provide 3% solids, and the drug is 5-aminosalicylic acid.
DESCRIPTION OF METHOD OF
zs PERFORMING THE INDENTION
A presently preferred embodiment of the invention pertains to a method for delivering a drug to the intestinal tract of a human at a controlled rate and continuously, which method comprise the steps of:
so (A) admitting orally into the humans gastrointestinal tract a dispensing device comprising: (1) a wall comprising an inside surface that surrounds and forms an internal compartment, said wall comprising a composition permeable to the passage of a biological fluid; (2) coating means on the outside surface of the wall for ss substantially preventing fluid access to the wall and, consequently, preventing the passage of fluid through the wall during the period of 2~3~~~~
time the dispensing device passes through the stomach; (3) a drug means in the compartment for delivering drug to the intestine (4) means in the compartment for pushing the drug means from the device;
(5) exit means in the device for delivering the drug from the device;
s (B) releasing the exterior coat means from the wall, (C) imbibing fluid through the wall into the compartment for converting the drug means into a dispensable formulation; (D) imbibing fluid into the compartment at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall, thereby causing the io means for pushing to expand and push the drug dispensable formulation from the device; and (E) delivering the beneficial drug formulation from the compartment by the expandable means continuously expanding thereby causing the drug to be dispensed through the exit means at a therapeutically,effective amount at a controlled rate over a period is of time to the intestinal tract of a human.
Inasmuch as the foregoing specification comprises preferred embodiments of the invention it is understood that variations and modifications may be made herein, in accordance with the inventive 2o principles disclosed, without departing from the scope of the invention.
The expression, exit means, as used herein, comprises means and methods suitable for the metered release of beneficial drug of dosage from the internal compartment of dosage form 10. The exit means include at least one passageway, orifice or the like, through wall s for communicating with compartment. The expression, at least one passageway, includes aperture, orifice, bore, pore, porous element through which the drug can migrate, hollow fiber, capillary tube, porous overlay, porous insert, and the like. The expression also includes a material that erodes or is leached from wall in the fluid io environment of use to produce at least one passageway in dosage form 10. Representative materials suitable for forming at least one passageway, or a multiplicity of passageways, include an erodible poly(glycolic) acid or erodible poly(lactic) acid member in the wall;
a gelatinous filament; polyvinyl alcohol); leachabie materials such is as fluid removable pore forming polysaccharides; salts, oxides, and the like. A passageway or a plurality of passageways can be formed by leaching a material such as sorbitol, lactose, or the like, from the wall. The passageway can have any shape such as round, triangular, square, elliptical, and the like, for assisting in the 2o metered release of drug from dosage form. Dosage form can be constructed with one or more passageways in spaced apart relations, or more than one passageway on a single surface of dosage form.
Passageways and equipment for forming passageways are disclosed in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,063,064; and 4,088,864.
2s Passageways for releasing a drug formed by leaching or controlled pore forming are disclosed in U.S. Pat. No. 4,200,098 and 4,285,987.
The wall of a dosage form, and the exterior coat can be formed in separate steps using the air suspension procedure. This procedure so consists in suspending and in tumbling the drug forming compartment in a current of air and then coating with a wall forming composition, or followed by the exterior coat composition until, in either operation the wall or the exterior coat is applied to the layered drug forming compartment. The air suspension procedure is 3s well-suited far independently forming the wall on the enteric coat.
The air suspension procedure is described in U.S. Pat. No. 2,799,241;
2~~86~2 in J. Am. Pharm. Assoc. Vol. 48, pp 451-59, (1959); and ibid., Vol.
49, pp 82-4, (1960). Dosage-forming devices can also be coated with the wall forming composition or with the enteric forming composition, with a Wurster~ air suspension coater using various solvents such as s methylene dichloride-methanol cosolvent 80/20 (w/w), using 2.5 to 4%
solids. The Aeromatic~ air suspension coater using a methylene dichloride/methanol cosolvent 87/13 (w/w) also can be used for applying the wall, or the enteric coat. Other wall and delayed coating techniques such as pan coating can be used for providing the io delivery device. In the pan coating system, wall forming, or enteric coating compositions are deposited by successive spraying of the compositions of the compartment forming cores, accompanied by tumbling in a rotating pan. A pan coater also is used to produce a thicker wall or a thicker enteric coat. A larger volume of solvent is can be used in a cosolvent to produce a thinner wall or an enteric coat. Finally, the wall with the exterior coated compartment are dried in a forced air oven at 50°C for a week to free the dosage form of solvent. Generally, the wall formed by these techniques will have a thickness of 2 to 20 mils with a presently preferred thickness of 4 zo to 10 mils. The exterior coat generally will have a thickness of 0.5 to 15 mils, usually 0.5 to 7.5 mils.
Exemplary solvents suitable for manufacturing the wall or the exterior coat include inorganic and organic solvents that do not z5 adversely harm the wall, the outer coat nor the final delivery system. The solvents broadly include a member selected from the group consisting of alcohol, ketone, ester, ether, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic solvents, aromatic, heterocyclic, aqueous solvents, and mixtures thereof.
The dosage form as seen in Figure 3 can be made by a dry granulation process of manufacture. The dry process comprises first mixing all the composition forming ingredients, except for the lubricant, passing the mixed ingredients through a grinding mill to a small mesh size, and then transferring the sized powder to a dry compactor. The compactor densifies the powder and is extruded as a 1~ ARC 1699 sheet or ribbon which is then passed through a sizing mill to regrind the composition. The composition is ground to a small size, typically 20 mesh or smaller. Finally, a dry lubricant is added and the ingredients blended to produce the final composition. Then, the s respective composition is fed to a bi-layer tablet press and each composition is intimately bonded into contacting layers comprising dosage form 10.
In another manufacturing, the dosage form is manufactured by io the wet granulation technique. In the wet granulation technique, the drug and the ingredients are blended using an organic solvent.
First, the ingredients are individually passed dry through a mesh screen and then thoroughly blended in a mixer. Next, other ingredients are dissolved in a portion of the granulation fluid and i5 this latter prepared granulating solution is added slowly to the drug blend with continual mixing in the blender. The granulating fluid is added until a wet blend is produced, which wet mass then is forced through a 20 mesh screen onto oven trays. The blend is dried for 18 to 24 hours at 50°C. The dry granules are then sized using a 20 mesh zo screen. Next, a lubricant is passed through a screen and added to the dry granule blend. The granulation is placed into a blender and mixed for 5 to 10 minutes. The composition is then compressed into drug cores and coated with the inside semipermeable membrane wall and the exterior coat.
First composition 19 and second composition 20 are manufactured from well mixed individual composition forming members. Far example a first composition is made as follows: first, each of the ingredients comprising a dosage form is independently screened and so then blended together, except for a lubricant. Then, the homogeneous blend is wet granulated by adding a solvent such as anhydrous ethanol, and the wet ingredients mixed until a uniform blend is obtained by said process. Next, the wet blend is passed through a screen and dried to evaporate the solvent. The resulting granules ss are passed again through a sieve. Next, a small amount of a finely divided lubricant is added to the dry granules and the lubricant and ~~~~6~~
granules blended to provide a uniform blend. Then, the first composition is fed to a hopper of a bilayer tablet press, and the first composition pressed into the first layered composition. The process is repeated for the second composition. Typically about one-fourth to two tons of pressure are applied to yield the dosage form, which is coated with the internal semipermeable membrane wall and then the exterior coat.
The following examples are merely illustrative of the present io invention, and it should not be considered as limiting the scope of the invention in any way, as this example and other equivalents thereof will become apparent to those versed in the drug delivery art in light of the present disclosure and the accompanying claims.
t5 DISCLOSURE OF EXAMPLES FOR
PROVIDING THE INVENTION
zo A delivery device for administering a therapeutic drug to the intestine and colon of a warm-blooded animal is made as follows:
first, in a standard blender, 1,000 g of hydroxypropyimethylcellulose having a 9,600 molecular weight is blended with 18,114 g of polyethylene oxide having a 300,000 molecular weight, to yield a z5 uniform mass. Next, 800 g of polyvinylpyrrolidone is dissolved in 6 liters of anhydrous, ethyl alcohol with stirring, and when all the polyvinylpyrroiidone is in solution, 86 g beclomethasone dipropionate is added to solution, with constant stirring to yield a granulation solution. Then, the granulation solution is added slowly to the ao hydroxypropylmethylcellulose, polyethylene oxide blend and the alcohol content raised to 10 liters. Then, the wet mass is mixed far minutes in a blender. Next, the wet mass is passed through an 8 mesh screen to form wet granules. The wet granules are dried in a forced air circulating oven overnight at 25°C. Finally, the oven 35 temperature is raised to 50°C and drying continued for 2 hours to remove the last traces of ethyl alcohol. Finally, the dry granules are passed through a 20 mesh stainless steel screen and stored in a closed container.
Next, a second composition is prepared as follows: first, s 9,705 g of polyethylene oxide having a 5,000,000 molecular weight, 4,395 g of sodium chloride, 750 g of hydroxypropylmethylcellulose and 150 g of red ferric oxide are blended to produce a homogenous blend, and the blend passed through a 40 mesh stainless steel screen. The screened particles are next blended with granulating fluid comprising io anhydrous ethanol to produce a wet blend. The total volume of granulating fluid used is about 8 liters. The wet mass is passed through a 15 mesh sizing screen to form wet granules. The wet granules are transferred to drying sheets and dried in a forced air circulating oven at 25°C over 16 to 24 hours to remove the is granulating fluid, ethyl alcohol. The dry granules are stored in a closed containers until needed for further formulation of the delivery device.
Next, the first composition and the second composition are 2o pressed into a first layer and a second layer in a tabletting machine. The first composition is laminated against the second composition to provide a drug-push core. The first composition comprises 0.4348 wt % of beclomethasone dipropionate, 5.0 wt % of hydroxypropylmethylcellulose, 90.57 wt % of polyethylene oxide and zs 4.0 wt % of polyvinyipyrrolidone. The second composition comprises 64.70 g wt % of polyethylene oxide, 29.30 wt % of sodium chloride, 5.0 wt % of hydroxypropylmethylcellulose and 1.0 wt % red ferric oxide.
so Next, a semipermeable wall is applied around the contacting laminated compositions. The wall forming composition comprises 97 wt % cellulose triacetate having an acetyl content of 43.5% and 3 wt polyethylene glycol 3350. The wall forming solvent comprises 80 parts of methylene chloride and 20 parts of methanol, wt/wt. The 3s wall forming composition comprises 3% solids. The wall forming ingredients are dissolved in the solvents and stirred until a clear ~o~~o~~
solution is obtained. The wall is formed in an Accela-Cota~ pan coater to an approximate thickness of 0.076 mm (3 mils). After drying, and removing the cosolvent, a 0.25 mil orifice is laser drilled in the semipermeable wall to communicate with the first, drug s layer. The drilled systems are placed on opened trays in a humidity oven set at 50% relative humidity at 50°C for 24 hours to remove the remaining solvent.
Next, an exterior coat is prepared in a blender containing 95 io part ethyl alcohol and 5 parts of distilled water, wt/wt, to which is added slowly and with constant stirring 90 g of copolymeric methacrylic acid-methylmethacrylate, to produce a clear solution.
Then, 10 g of hydrophobic dibutyl phthalate is added to the blender and stirring continued for 30 minutes. The final concentration of is the exterior coat comprises 90% copolymer and 10% hydrophobic compound to give a 3% solids exterior coat.
Next, the semipermeable wall coated delivery systems are placed into an air suspension coater and the exterior coating composition is 2o added to the coater, and the delivery systems uniformly coated with an exterior coat. The exterior coated delivery systems are removed from the coater, placed on trays, and dried in a forced air circulating oven at 50°C for 24 hours to yield the final delivery system.
The procedure of Example 1 is repeated with all the steps as set forth, except that in this example the exterior coat comprises 75 so wt % methacrylic acid-methylmethacrylate copolymer and 25 wt hydrophobic dibutyl phthalate. The release rate per hour for this delivery system is seen in Figure 5 wherein AGF is artificial gastric fluid and AIF is artificial intestinal fluid, and the amount of beclomethasone dipropionate is measured over 30 hours. Artificial ss gastric and artificial fluids are known in The United States Pharmacopoeia, Twentieth Revision, p 1105, published 1980.
~U~86~2 A delivery device for delivering a therapeutic drug is made as follows: first, 22,642.85 grams of polyethylene oxide, having a s molecular weight of about 300,000, and 1,250 grams of hydroxypropylmethylcellulose, having a molecular weight of 9,500, are dry screened through a Fitzmill~ comminuter using a 35 mesh stainless steel screen, and then transferred to a Hobart~ blender. Next, 107.15 grams of beclomethasone dipropionate is dissolved in anhydrous io ethanol along with 1000 grams of polyvinylpyrrolidone. This granulating fluid is slowly added to the blender to produce a homogeneous blend. Next, the wet blend is passed through the comminuter using an 8 mesh stainless steel screen. The wet granules resulting from the screening process are dried in a forced air oven is for about 18 hours at 30°C. Finally, the dry granules are passed through the comminuter using a 16 mesh stainless steel screen to yield the first composition comprising the drug beclomethasone dipropionate.
zo Next, the second composition is prepared as follows: 12,940 gram of polyethylene oxide, having a 5,000,000 molecular weight, 5,860 grams of sodium chloride, 1000 grams of hydroxypropylmethylcellulose, having a 11,300 molecular weight, and 200 grams of ferric oxide, are added to and passed through the zs comminuter using a 35 mesh stainless steel screen. The screened particles next are transferred to the blender and blend to produce a well mixed blend, and to the blending ingredients anhydrous ethanol is added as a granulating fluid. Next, the wet blend is transferred to the Fitzmill comminuter using a 7 mesh stainless steel screen.
3o Then, the wet granules are transferred to drying sheets and dried in a forced air oven at 30°C for about 18 hours. The dried granules are passed through the comminuter using a I6 mesh stainless steel screen to yield the second composition comprising means for pushing the first composition from the delivery device.
2~386~~
Next, the first composition and the second composition are pressed into a first layer and into a second layer in a tableting machine using a 3/16 inch punch and die. The first composition weighed 23 mg and it comprises 0.1000 mg of beclomethasone s dipropionate, 1.1666 mg of hydroxypropylmethylcellulose, 21.1321 mg of the polyethylene oxide, and 0.9333 mg of the polyvinylpyrrolidone;
the second composition comprises 10.784 mg of the polyethylene oxide coagulant, 4.8837 mg of sodium chloride, 0.8384 mg of hydroxypropylmethylcellulose and 0.1667 mg of ferric oxide.
io Next, a semipermeable wall is applied around the compressed laminated compositions The wall forming composition comprises 97 wt of cellulose triacetate having an acetyl content of 43.5%, and 3 wt %
of polyethylene glycol 3350. The wall forming ingredients are is dissolved in a cosolvent comprising 80:20 wt/wt methylene chloride-methanol comprising 5% solids. The wall is formed in an Accela-Cota pan costar to an approximate thickness of 3 mils (0.076 mm) to provide a coating weight of 5 mg. After drying, and removing the cosolvent, a 25 mil orifice is laser drilled in the semipermeable 2o wall to the first composition.
Next, an outside exterior wall, comprising means for delaying the release of drug from the device during the devices' passage through an acidic environment, and for simultaneously preventing an zs exterior fluid from entering the device is coated onto the outside surface of the semipermeable, wall. The outside wall forming composition comprises 85 wt % of a copolymer of (methacrylic acid and methacrylic acid methyl ester, also known as Eudragit~ S-100) and 15 wt % of hydrophobic cellulose acetyl phthalate for saturating the so coat in 95% ethanol to provide 3% solids. The outside wall is applied in a 24 inch Accela-Cota~ pan costar to apply a 3 mil (0.076 mm) wall.
The delivery devices made by the above procedure are dried in a 3s humidity oven for 48 hrs at 50% relative humidity. Then, the delivery devices are dried an additional 24 hrs at 50°C in a forced air oven.
In another presently preferred embodiment, 5 delivery devices s are encapsulated in a number 2 gelatin capsule. Each delivery device contains 0.100 mg (100 fig) of beclomethasone dipropionate and total delivery system delivers 500 ~g of beclomethasone dipropionate to the intestine and colon.
io EXAMPLE 4 The procedure described in Example 2 is followed with all conditions as set forth, except that in these examples the drug steroid is a member selected from the group consisting of i5 beclomethasone, beclomethasone 17-propionate, beclomethasone 21-acetate, beclomethasone butyrate, and beclomethasone di propionate monohydrate.
Delivery device are made comprising salicylazosulphapyridine for treating Crohn's disease, and with an outer coat comprising a membrane selected from the group consisting of dimethylaminoethylmethacrylate-butylmethacrylate-methylmethacrylate is copolymer of 150,000 molecular weight blended with a membrane selected from the group consisting of cellulose acetyl phthalate, cellulose diacetyl phthalate, dialkyl phthalate, cellulose triacetyl phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, sodium cellulose acetate phthalate, cellulose ether 3o phthalate, cellulose ester phthalate, and methylcellulose phthalate.
Delivery devices for delivering a drug are made according to 35 the present examples wherein the drug is a member selected from the group consisting of hydrocortisone, prednisolone, prednisolone ~o~~s~~
phosphate and prednisone, and wherein the exterior coat for delaying drug release in an acidic environment and for preventing water passage through the coat is a member selected from the group consisting of polymers of methacrylic acid and methacrylic acid s methyl esters, methacryiic acid-ethylacrylate copolymer, and trimethylammonium ethylmethacrylatechloride-methylacrylate-ethylacrylate copolymer, blended with a hydrophobic member selected from the group consisting of cellulose acetyl phthalate, cellulose diacetyl phthalate, cellulose triacetyl phthalate, cellulose acetate io phthalate, hydroxypropylmethylcellulose phthalate, sodium cellulose acetate phthalate, cellulose ether phthalate, cellulose ester phthalate, and methylcellulose phthalate:
is The procedure of Example 1 is followed with the manufacturing procedures as previously set forth, except that the outside coat forming composition comprises 75 wt % of a copolymer of trimethyl ammonium ethylmethacrylate chloride-methylmethacrylate-ethylacrylate zo in the ratio of 5:65:3, 20 wt % dibutyl phthalate, and 5 wt acetyltriethylcitrate, in 95% ethanol, to provide 3% solids, and the drug is 5-aminosalicylic acid.
DESCRIPTION OF METHOD OF
zs PERFORMING THE INDENTION
A presently preferred embodiment of the invention pertains to a method for delivering a drug to the intestinal tract of a human at a controlled rate and continuously, which method comprise the steps of:
so (A) admitting orally into the humans gastrointestinal tract a dispensing device comprising: (1) a wall comprising an inside surface that surrounds and forms an internal compartment, said wall comprising a composition permeable to the passage of a biological fluid; (2) coating means on the outside surface of the wall for ss substantially preventing fluid access to the wall and, consequently, preventing the passage of fluid through the wall during the period of 2~3~~~~
time the dispensing device passes through the stomach; (3) a drug means in the compartment for delivering drug to the intestine (4) means in the compartment for pushing the drug means from the device;
(5) exit means in the device for delivering the drug from the device;
s (B) releasing the exterior coat means from the wall, (C) imbibing fluid through the wall into the compartment for converting the drug means into a dispensable formulation; (D) imbibing fluid into the compartment at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall, thereby causing the io means for pushing to expand and push the drug dispensable formulation from the device; and (E) delivering the beneficial drug formulation from the compartment by the expandable means continuously expanding thereby causing the drug to be dispensed through the exit means at a therapeutically,effective amount at a controlled rate over a period is of time to the intestinal tract of a human.
Inasmuch as the foregoing specification comprises preferred embodiments of the invention it is understood that variations and modifications may be made herein, in accordance with the inventive 2o principles disclosed, without departing from the scope of the invention.
Claims (6)
1. ~An improvement in a device for delivering a drug to the intestine and colon fluid environment, wherein the device comprises:
(a) a wall that comprises a surface that faces the environment, said wall comprising at least in part a composition permeable to the passage of fluid and substantially impermeable to the passage of drug, which wall surrounds;
(b) a compartment;
(c) a drug in the compartment;
(d) push means in the compartment for pushing the drug from the device;
(e) exit means in the wall for delivering the drug from the device;
(f) coat means in contact with the surface of the wall that faces the environment for delaying the delivery of drug from the device, and wherein the improvement comprises;
(g) a hydrophobic compound in the coat means in excess of its solubility in the coat means for substantially preventing the passage of fluid present in the environment through the coat means.
(a) a wall that comprises a surface that faces the environment, said wall comprising at least in part a composition permeable to the passage of fluid and substantially impermeable to the passage of drug, which wall surrounds;
(b) a compartment;
(c) a drug in the compartment;
(d) push means in the compartment for pushing the drug from the device;
(e) exit means in the wall for delivering the drug from the device;
(f) coat means in contact with the surface of the wall that faces the environment for delaying the delivery of drug from the device, and wherein the improvement comprises;
(g) a hydrophobic compound in the coat means in excess of its solubility in the coat means for substantially preventing the passage of fluid present in the environment through the coat means.
2. The improvement in a device for delivering the drug to the fluid environment according to claim 1, wherein the fluid environment is acidic.
3. The improvement in a device for delivering the drug to the fluid environment according to claim 1, wherein the drug is a member selected from the group consisting of beclomethasone, beclomethasone monoester, beclomethasone diester, beclomethasone acetate, beclomethasone butyrate, beclomethasone valerate, beclomethasone propionate, beclomethasone dipropionate and beclomethasone divalerianate.
4. The improvement in a device for delivering the drug to the fluid environment according to claim 1, wherein the drug is a steroid selected from the group consisting of hydrocortisone, prednisolone, prednisolone phosphate, prednisone, prednisolone metasulphobenzoate and prednisolone sodium phosphate.
5. The improvement in a device for delivering a drug to the fluid environment according to claim 1, wherein the drug is salicylazosulphapyridine.
6. An improvement in a device for delivering a drug to an intestine and colon fluid environment to use, wherein the device comprises:
(a) a wall comprising at least in part a composition permeable to the passage of fluid, which wall surrounds;
(b) a compartment;
(c) a first composition in the compartment, which composition comprises a drug and forms a dispensable formulation in the presence of fluid that enters the device;
(d) a second composition in the compartment comprising means for pushing the first composition from the device;
(e) at least one exit passageway in the wall for delivering a drug from the device;
(f) a coat on the wall facing the environment of use for delaying the delivery of drug from the device, and wherein the improvement comprises;
(g) a hydrophobic compound in the coat in excess of its solubility in the coat for substantially preventing the passage of fluid present in the environment through the coat.
(a) a wall comprising at least in part a composition permeable to the passage of fluid, which wall surrounds;
(b) a compartment;
(c) a first composition in the compartment, which composition comprises a drug and forms a dispensable formulation in the presence of fluid that enters the device;
(d) a second composition in the compartment comprising means for pushing the first composition from the device;
(e) at least one exit passageway in the wall for delivering a drug from the device;
(f) a coat on the wall facing the environment of use for delaying the delivery of drug from the device, and wherein the improvement comprises;
(g) a hydrophobic compound in the coat in excess of its solubility in the coat for substantially preventing the passage of fluid present in the environment through the coat.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US498,121 | 1990-03-23 | ||
US07/498,121 US5178866A (en) | 1990-03-23 | 1990-03-23 | Dosage form for delivering drug to the intestine |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2038672A1 CA2038672A1 (en) | 1991-09-24 |
CA2038672C true CA2038672C (en) | 2002-01-15 |
Family
ID=23979678
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002038672A Expired - Fee Related CA2038672C (en) | 1990-03-23 | 1991-03-20 | Dosage form for delivering drug to the intestine |
Country Status (18)
Country | Link |
---|---|
US (2) | US5178866A (en) |
EP (1) | EP0521074B1 (en) |
JP (1) | JP2963766B2 (en) |
KR (1) | KR0169145B1 (en) |
AT (1) | ATE102029T1 (en) |
AU (1) | AU644645B2 (en) |
CA (1) | CA2038672C (en) |
DE (1) | DE69101314T2 (en) |
DK (1) | DK0521074T3 (en) |
ES (1) | ES2062779T3 (en) |
FI (1) | FI924247A (en) |
IE (1) | IE62393B1 (en) |
MX (1) | MX173300B (en) |
NO (1) | NO923590L (en) |
NZ (1) | NZ237516A (en) |
PT (1) | PT97086B (en) |
WO (1) | WO1991014426A1 (en) |
ZA (1) | ZA912069B (en) |
Families Citing this family (81)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5681585A (en) * | 1991-12-24 | 1997-10-28 | Euro-Celtique, S.A. | Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer |
US5472712A (en) * | 1991-12-24 | 1995-12-05 | Euroceltique, S.A. | Controlled-release formulations coated with aqueous dispersions of ethylcellulose |
US5580578A (en) * | 1992-01-27 | 1996-12-03 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
US5968551A (en) * | 1991-12-24 | 1999-10-19 | Purdue Pharma L.P. | Orally administrable opioid formulations having extended duration of effect |
US5223265A (en) * | 1992-01-10 | 1993-06-29 | Alza Corporation | Osmotic device with delayed activation of drug delivery |
US7070806B2 (en) * | 1992-01-27 | 2006-07-04 | Purdue Pharma Lp | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
US5248310A (en) * | 1992-03-27 | 1993-09-28 | Alza Corporation | Oral osmotic device with hydrogel driving member |
US5512299A (en) * | 1992-03-30 | 1996-04-30 | Alza Corporation | Method of treating oral inflammatory disease |
CA2144077C (en) * | 1992-09-18 | 2005-05-24 | Kazuhiro Sako | Hydrogel-type sustained-release preparation |
US5358502A (en) * | 1993-02-25 | 1994-10-25 | Pfizer Inc | PH-triggered osmotic bursting delivery devices |
US6440457B1 (en) * | 1993-05-27 | 2002-08-27 | Alza Corporation | Method of administering antidepressant dosage form |
US7740881B1 (en) | 1993-07-01 | 2010-06-22 | Purdue Pharma Lp | Method of treating humans with opioid formulations having extended controlled release |
US5514663A (en) * | 1993-10-19 | 1996-05-07 | The Procter & Gamble Company | Senna dosage form |
HU213407B (en) * | 1993-12-09 | 1997-06-30 | Egyt Gyogyszervegyeszeti Gyar | Process for producing tablet with diffusive-osmotic release |
US5849327A (en) * | 1994-07-29 | 1998-12-15 | Advanced Polymer Systems, Inc. | Delivery of drugs to the lower gastrointestinal tract |
FR2723536A1 (en) * | 1994-08-11 | 1996-02-16 | Seth Pawan | COMPOSITION FOR SELECTIVE RELEASE OF AN ACTIVE INGREDIENT |
GB2292079B (en) * | 1994-08-12 | 1998-07-15 | Flexpharm Ltd | Coated prednisolone preparation for the treatment of inflamatory bowel disease |
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 |
US6361796B1 (en) * | 1996-10-25 | 2002-03-26 | Shire Laboratories, Inc. | Soluble form osmotic dose delivery system |
WO1998018452A1 (en) * | 1996-10-25 | 1998-05-07 | Shire Laboratories, Inc. | Soluble form osmotic dose delivery system |
US6919373B1 (en) | 1996-11-12 | 2005-07-19 | Alza Corporation | Methods and devices for providing prolonged drug therapy |
WO1999001111A1 (en) | 1997-07-02 | 1999-01-14 | Euro-Celtique, S.A. | Stabilized sustained release tramadol formulations |
DE19732903A1 (en) * | 1997-07-30 | 1999-02-04 | Falk Pharma Gmbh | Pellet formulation for the treatment of the intestinal tract |
US6099859A (en) | 1998-03-20 | 2000-08-08 | Andrx Pharmaceuticals, Inc. | Controlled release oral tablet having a unitary core |
US6099862A (en) * | 1998-08-31 | 2000-08-08 | Andrx Corporation | Oral dosage form for the controlled release of a biguanide and sulfonylurea |
NZ512599A (en) | 1998-12-30 | 2003-10-31 | Dexcel Ltd | Formulation for cyclosporin administration featuring a hydrophilic solvent and a surfactant with a HLB of less than 5 |
US6217895B1 (en) * | 1999-03-22 | 2001-04-17 | Control Delivery Systems | Method for treating and/or preventing retinal diseases with sustained release corticosteroids |
US20040121014A1 (en) * | 1999-03-22 | 2004-06-24 | Control Delivery Systems, Inc. | Method for treating and/or preventing retinal diseases with sustained release corticosteroids |
US6562375B1 (en) * | 1999-08-04 | 2003-05-13 | Yamanouchi Pharmaceuticals, Co., Ltd. | Stable pharmaceutical composition for oral use |
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 |
US7732404B2 (en) | 1999-12-30 | 2010-06-08 | Dexcel Ltd | Pro-nanodispersion for the delivery of cyclosporin |
AR026148A1 (en) * | 2000-01-21 | 2003-01-29 | Osmotica Argentina S A | OSMOTIC DEVICE WITH PREFORMED PASSAGE THAT INCREASES SIZE |
US6669954B2 (en) | 2000-01-25 | 2003-12-30 | John R. Crison | Controlled release of drugs |
US6375972B1 (en) | 2000-04-26 | 2002-04-23 | Control Delivery Systems, Inc. | Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof |
US6866866B1 (en) * | 2000-11-03 | 2005-03-15 | Andrx Labs, Llc | Controlled release metformin compositions |
US20060034922A1 (en) * | 2000-11-03 | 2006-02-16 | Andrx Labs, Llc | Controlled release metformin compositions |
US6790459B1 (en) | 2000-11-03 | 2004-09-14 | Andrx Labs, Llc | Methods for treating diabetes via administration of controlled release metformin |
JP2004531463A (en) | 2000-11-03 | 2004-10-14 | アンドルクス ラブス,エルエルシー | Sustained release metformin composition |
US7491407B2 (en) * | 2001-10-31 | 2009-02-17 | North Carolina State University | Fiber-based nano drug delivery systems (NDDS) |
WO2003053400A1 (en) * | 2001-12-19 | 2003-07-03 | Alza Corporation | Formulation & dosage form for the controlled delivery of therapeutic agents |
US8871241B2 (en) | 2002-05-07 | 2014-10-28 | Psivida Us, Inc. | Injectable sustained release delivery devices |
US20050208132A1 (en) * | 2002-07-29 | 2005-09-22 | Gayatri Sathyan | Methods and dosage forms for reducing side effects of benzisozazole derivatives |
US20050232995A1 (en) * | 2002-07-29 | 2005-10-20 | Yam Nyomi V | Methods and dosage forms for controlled delivery of paliperidone and risperidone |
ES2529180T3 (en) | 2002-09-20 | 2015-02-17 | Andrx Labs Llc | Multi-stage formulation containing a biguanide and a thiazolidinedione derivative |
US20050051922A1 (en) * | 2002-09-20 | 2005-03-10 | Avinash Nangia | Pharmaceutical composition with sodium lauryl sulfate as an extra-granular absorption/compression enhancer and the process to make the same |
EP1572217B1 (en) * | 2002-12-12 | 2008-08-20 | Nycomed GmbH | Combination medicament of r,r-formoterol and ciclesonide |
CA2538929A1 (en) * | 2003-09-11 | 2005-03-24 | Glykon Technologies Group, Llc | Enteric delivery of (-)-hydroxycitric acid |
CA2538202C (en) * | 2003-09-15 | 2013-01-15 | Altana Pharma Ag | Use of ciclesonide for the treatment of inflammatory bowel diseases |
PL1670482T5 (en) * | 2003-09-16 | 2022-10-03 | Covis Pharma Gmbh | Use of ciclesonide for the treatment of respiratory diseases |
US20050181050A1 (en) * | 2004-01-28 | 2005-08-18 | Collegium Pharmaceutical, Inc. | Dosage forms using drug-loaded ion exchange resins |
JP2007533706A (en) * | 2004-04-20 | 2007-11-22 | ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング | Use of ciclesonide for the treatment of respiratory diseases in smoking patients |
WO2005117591A2 (en) * | 2004-05-28 | 2005-12-15 | Andrx Labs Llc | Novel pharmaceutical formulation containing a biguanide and an angiotensin antagonist |
US20050287185A1 (en) * | 2004-06-23 | 2005-12-29 | David Wong | Extended release oxybutynin formulation |
US9011831B2 (en) * | 2004-09-30 | 2015-04-21 | Advanced Cardiovascular Systems, Inc. | Methacrylate copolymers for medical devices |
US7500679B2 (en) * | 2004-10-08 | 2009-03-10 | Wade James T | Board for supporting front of snow vehicle |
WO2006081518A2 (en) * | 2005-01-28 | 2006-08-03 | Collegium Pharmaceutical, Inc. | Non-ionic non-aqueous vehicles for topical and oral administration of carrier-complexed active agents |
WO2007011972A2 (en) * | 2005-07-19 | 2007-01-25 | Inverseon, Inc. | Improved pharmacokinetic profile of beta-adrenergic inverse agonists for the treatment of pulmonary airway diseases |
US20070082028A1 (en) * | 2005-10-07 | 2007-04-12 | Aimutis William R Jr | Compositions and methods for inducing satiety and reducing caloric intake |
US20070082085A1 (en) * | 2005-10-07 | 2007-04-12 | Catani Steven J | Compositions and methods for reducing food intake and controlling weight |
US20070082026A1 (en) * | 2005-10-07 | 2007-04-12 | Aimutis William R Jr | Compositions and methods for reducing food intake and controlling weight |
US20070082108A1 (en) * | 2005-10-07 | 2007-04-12 | Aimutis William R Jr | Methods for reducing calorie intake |
US20070082030A1 (en) * | 2005-10-07 | 2007-04-12 | Aimutis William R | Fiber satiety compositions |
US20070082114A1 (en) * | 2005-10-07 | 2007-04-12 | Catani Steven J | Methods for reducing weight |
US20070082029A1 (en) * | 2005-10-07 | 2007-04-12 | Aimutis William R | Fiber satiety compositions |
US20070082115A1 (en) * | 2005-10-07 | 2007-04-12 | Aimutis William Ronald Jr | Methods for inducing satiety, reducing food intake and reducing weight |
US20070082084A1 (en) * | 2005-10-07 | 2007-04-12 | Catani Steven J | Methods for weight management |
US20070082025A1 (en) * | 2005-10-07 | 2007-04-12 | Catani Steven J | Methods for achieving and maintaining weight loss |
US20080085354A1 (en) * | 2006-10-06 | 2008-04-10 | Teresa Marie Paeschke | Controlled hydration of hydrocolloids |
US20090036414A1 (en) * | 2007-08-02 | 2009-02-05 | Mutual Pharmaceutical Company, Inc. | Mesalamine Formulations |
US20090087484A1 (en) * | 2007-09-28 | 2009-04-02 | Alza Corporation | Formulation and dosage form for increasing oral bioavailability of hydrophilic macromolecules |
EP2334178A4 (en) * | 2008-10-03 | 2012-04-11 | Falk Pharma Gmbh | Compositions and methods for the treatment of bowel diseases with granulated mesalamine |
CA2785468A1 (en) * | 2009-12-23 | 2011-06-30 | Psivida Us, Inc. | Sustained release delivery devices |
WO2012088306A2 (en) * | 2010-12-22 | 2012-06-28 | Psivida Us, Inc. | Two-piece injectable drug delivery device with heat-cured seal |
CA3107450A1 (en) | 2012-03-29 | 2013-10-03 | Therabiome, Llc | Gastrointestinal site-specific oral vaccination formulations active on the ileum and appendix |
US9907755B2 (en) | 2013-03-14 | 2018-03-06 | Therabiome, Llc | Targeted gastrointestinal tract delivery of probiotic organisms and/or therapeutic agents |
CA3018328A1 (en) | 2014-10-31 | 2016-04-30 | Purdue Pharma | Methods and compositions particularly for treatment of attention deficit disorder |
US20160256611A1 (en) * | 2015-03-04 | 2016-09-08 | Microvention, Inc. | Drug Delivery Device |
US20180185378A1 (en) * | 2017-01-05 | 2018-07-05 | Cormedix Inc. | Antimicrobial delivery system for the prevention and treatment of infections in the colon |
US9707217B1 (en) | 2017-02-03 | 2017-07-18 | Osmotica Kereskedelmi Es Szolgaltato Kft | Dose-dumping resistant controlled release dosage form |
US10722473B2 (en) | 2018-11-19 | 2020-07-28 | Purdue Pharma L.P. | Methods and compositions particularly for treatment of attention deficit disorder |
CA3201057A1 (en) | 2020-12-08 | 2022-06-16 | Mark Christopher LAY | Improvements to devices and methods for delivery of substances to animals |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3845770A (en) * | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US4036227A (en) * | 1973-04-25 | 1977-07-19 | Alza Corporation | Osmotic releasing device having a plurality of release rate patterns |
US4503030A (en) * | 1983-06-06 | 1985-03-05 | Alza Corporation | Device for delivering drug to certain pH environments |
US4717566A (en) * | 1984-03-19 | 1988-01-05 | Alza Corporation | Dosage system and method of using same |
US4627851A (en) * | 1984-10-26 | 1986-12-09 | Alza Corporation | Colonic-therapeutic delivery system |
US4904473A (en) * | 1986-06-23 | 1990-02-27 | International Minerals & Chemical Corp. | Ruminant feed antacid containing potassium, sodium and chlorine |
US4816262A (en) * | 1986-08-28 | 1989-03-28 | Universite De Montreal | Controlled release tablet |
US4810502A (en) * | 1987-02-27 | 1989-03-07 | Alza Corporation | Pseudoephedrine brompheniramine therapy |
US4904474A (en) * | 1988-01-25 | 1990-02-27 | Alza Corporation | Delivery of drug to colon by oral disage form |
US4855141A (en) * | 1988-03-25 | 1989-08-08 | Alza Corporation | Device comprising means for protecting and dispensing fluid sensitive medicament |
GB8820353D0 (en) * | 1988-08-26 | 1988-09-28 | Staniforth J N | Controlled release tablet |
-
1990
- 1990-03-23 US US07/498,121 patent/US5178866A/en not_active Expired - Lifetime
-
1991
- 1991-02-20 KR KR1019920702288A patent/KR0169145B1/en not_active IP Right Cessation
- 1991-03-20 DK DK91906850.2T patent/DK0521074T3/en active
- 1991-03-20 IE IE91991A patent/IE62393B1/en not_active IP Right Cessation
- 1991-03-20 AT AT91906850T patent/ATE102029T1/en not_active IP Right Cessation
- 1991-03-20 JP JP3507281A patent/JP2963766B2/en not_active Expired - Fee Related
- 1991-03-20 EP EP91906850A patent/EP0521074B1/en not_active Expired - Lifetime
- 1991-03-20 ZA ZA912069A patent/ZA912069B/en unknown
- 1991-03-20 AU AU75813/91A patent/AU644645B2/en not_active Ceased
- 1991-03-20 MX MX025007A patent/MX173300B/en unknown
- 1991-03-20 CA CA002038672A patent/CA2038672C/en not_active Expired - Fee Related
- 1991-03-20 NZ NZ237516A patent/NZ237516A/en unknown
- 1991-03-20 DE DE69101314T patent/DE69101314T2/en not_active Expired - Fee Related
- 1991-03-20 PT PT97086A patent/PT97086B/en not_active IP Right Cessation
- 1991-03-20 ES ES91906850T patent/ES2062779T3/en not_active Expired - Lifetime
- 1991-03-20 WO PCT/US1991/001850 patent/WO1991014426A1/en active IP Right Grant
- 1991-05-06 US US07/696,473 patent/US5650170A/en not_active Expired - Lifetime
-
1992
- 1992-09-16 NO NO92923590A patent/NO923590L/en unknown
- 1992-09-22 FI FI924247A patent/FI924247A/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
MX173300B (en) | 1994-02-14 |
PT97086B (en) | 1998-08-31 |
WO1991014426A1 (en) | 1991-10-03 |
AU7581391A (en) | 1991-10-21 |
NO923590L (en) | 1992-11-23 |
FI924247A0 (en) | 1992-09-22 |
AU644645B2 (en) | 1993-12-16 |
DK0521074T3 (en) | 1994-05-09 |
ZA912069B (en) | 1991-12-24 |
KR0169145B1 (en) | 1999-01-15 |
EP0521074B1 (en) | 1994-03-02 |
NZ237516A (en) | 1993-04-28 |
NO923590D0 (en) | 1992-09-16 |
CA2038672A1 (en) | 1991-09-24 |
ATE102029T1 (en) | 1994-03-15 |
JPH05506022A (en) | 1993-09-02 |
US5178866A (en) | 1993-01-12 |
US5650170A (en) | 1997-07-22 |
PT97086A (en) | 1991-10-31 |
ES2062779T3 (en) | 1994-12-16 |
KR930700074A (en) | 1993-03-13 |
DE69101314D1 (en) | 1994-04-07 |
FI924247A (en) | 1992-09-22 |
DE69101314T2 (en) | 1994-06-09 |
IE62393B1 (en) | 1995-01-25 |
JP2963766B2 (en) | 1999-10-18 |
EP0521074A1 (en) | 1993-01-07 |
IE910919A1 (en) | 1991-09-25 |
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EEER | Examination request | ||
MKLA | Lapsed |