CA2183881C - Pharmaceutical excipient having improved compressibility - Google Patents

Pharmaceutical excipient having improved compressibility Download PDF

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Publication number
CA2183881C
CA2183881C CA002183881A CA2183881A CA2183881C CA 2183881 C CA2183881 C CA 2183881C CA 002183881 A CA002183881 A CA 002183881A CA 2183881 A CA2183881 A CA 2183881A CA 2183881 C CA2183881 C CA 2183881C
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Prior art keywords
silicon dioxide
solid dosage
dosage form
composition
microcrystalline cellulose
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CA002183881A
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French (fr)
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CA2183881A1 (en
Inventor
Bob E. Sherwood
John N. Staniforth
Edward A. Hunter
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Mendell Edward Co Inc
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Mendell Edward Co Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2009Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • A61K9/2018Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/2036Silicones; Polysiloxanes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00Nanotechnology
    • Y10S977/70Nanostructure
    • Y10S977/724Devices having flexible or movable element
    • Y10S977/727Devices having flexible or movable element formed from biological material
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00Nanotechnology
    • Y10S977/70Nanostructure
    • Y10S977/773Nanoparticle, i.e. structure having three dimensions of 100 nm or less
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00Nanotechnology
    • Y10S977/70Nanostructure
    • Y10S977/773Nanoparticle, i.e. structure having three dimensions of 100 nm or less
    • Y10S977/775Nanosized powder or flake, e.g. nanosized catalyst
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00Nanotechnology
    • Y10S977/70Nanostructure
    • Y10S977/788Of specified organic or carbon-based composition
    • Y10S977/797Lipid particle
    • Y10S977/798Lipid particle having internalized material
    • Y10S977/799Containing biological material
    • Y10S977/801Drug
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00Nanotechnology
    • Y10S977/84Manufacture, treatment, or detection of nanostructure
    • Y10S977/89Deposition of materials, e.g. coating, cvd, or ald
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
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    • Y10S977/00Nanotechnology
    • Y10S977/84Manufacture, treatment, or detection of nanostructure
    • Y10S977/895Manufacture, treatment, or detection of nanostructure having step or means utilizing chemical property
    • Y10S977/896Chemical synthesis, e.g. chemical bonding or breaking
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00Nanotechnology
    • Y10S977/902Specified use of nanostructure
    • Y10S977/904Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00Nanotechnology
    • Y10S977/902Specified use of nanostructure
    • Y10S977/904Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/906Drug delivery
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00Nanotechnology
    • Y10S977/902Specified use of nanostructure
    • Y10S977/904Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/915Therapeutic or pharmaceutical composition
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]

Abstract

A microcrystalline cellulose-based excipient having improved compressibility, whether utilized in direct compression, dry granulation or wet granulation formulations, is disclosed. The excipient is an agglomerate of microcrystalline cellulose particles and from about 0.1 % to about 20 % silicon dioxide particles, by weight of the microcrystalline cellulose, wherein the microcrystalline cellulose and silicon dioxide are in intimate association with each other. The silicon dioxide utilized in the novel excipient has a particle size from about 1 nanomoter to about 100 microns. Most preferably, the silicon dioxide is a grade of colloidal silicon dioxide.

Description

WO 96/21429 PCTlUS96/00660 O
The present invention relates to a novel excipient for use in the manufacture of pharmaceuticals, and in particular, solid dosage forms such as tablets which include one or-more active ingredients.

In order to prepare a so).id dosage form containing one or more active ingredients (such as drugs), it is necessary that the material to be compressed into the dosage form possess certain physical -characteristics which lend themselves to processing in such a manner.

Among other things, the material to be compressed must be free-flowing, must be lubricated, and, importantly, must possess sufficient cohesiveness to insure that the solid dosage form remains intact after compression.

In the case of tablets, the tablet is formed by pressure being applied to the material to be tabletted on a tablet press. A tablet press includes a lower punch which fits into a die from the bottom and a upper punch having a corresponding shape and dimension which enters the die cavity from the top after the tabletting material fills the die cavity. The tablet is formed by pressure applied on the lower and upper punches. The ability of the material to flow freely into the die is important in order to insure that there is a uniform filling of the die and a continuous movement of the material from the source of the material, e.g. a feeder hopper. The lubricity of the material is crucial in the preparation ' of. the solid dosage forms since the compressed material must be readily ejected from the punch faces.

' Sincemost drugs have none or only some of these properties; methods of tablet formulation have been de-~~~3~$I
veloped in order to impart these desirable character-istics to the materials) which is to be compressed into a solid dosage form. Typically, the material to be compressed into a solid dosage form includes one or more , excipients which impart the free-flowing, lubrication, and cohesive properties to the drugs) which is being formulated into a dosage form.

Lubricants are typically added to avoid the mater-ia l s) being tabletted from sticking to the punches.
Commonly used lubricants include magnesium stearate and calcium stearate. Such lubricants are-commonly included in the final tabletted product in amounts of less than 1%

by weight:
In addition to lubricants, solid dosage forms often contain diluents. Diluents are frequently added in order to increase the bulk weight of the material to be tabletted in order to make the tablet a practical size for compression. This is often necessary where the dose of the drug is relatively small.
Another commonly used.class of excipients in solid dosage forms are binders. Binders are agents which impart cohesive qualities to the powdered material(s).

Commonly used binders include starch, and sugars such as sucrose, glucose, dextrose, and lactose.

Disintegrants are often included in order to ensure that the ultimately prepared compressed solid dosage form has an acceptable disintegration rate in an environment of use (such as the gastrointestinal tract). Typical disintegrants include stare derivatives and salts of carboxymethylcellulose.
There are three general methods of preparation of the materials to be included in the solid dosage form prior to compression: (1) dry granulation; (2) direct , compression; and (3) wet granulation.
WO 96121429 r - - t y , . .- . ., PCT/US96/00660 Dry granulation procedures may be utilized where one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tabletted. The , method includes mixing the ingredients, slugging the ingredients, dry screening, lubricating and finally compressing the ingredients.
In direct-compression, the powdered materials) to be included in the solid dosage form is compressed directly without modifying the physical nature of the material itself.
The wet granulation procedure includes mixing the powders to be incorporated into the dosage form in, e.g., a twin shell blender or double-cone blender and thereafter adding solutions of a binding agent to the mixed powders to obtain a granulation. Thereafter, the damp mass is screened, e.g., in a 6- or 8-mesh screen and then dried, e.g., via tray drying, the use of a fluid-bed dryer, spray-dryer, radio-frequency dryer, microwave, vacuum, or infra-red dryer.-The use of direct compression is limited to those situations where the drug or active ingredient has a requisite crystalline structure and physical character-istics required for formation of a pharmaceutically ac-ceptable tablet: On the other hand, it is well known in the art to include one or more excipients which make the direct compression method applicable to drugs or active ingredients which do not possess the requisite physical properties. For solid-dosage-forms wherein the drug itself is to be administered in a relatively high dose (e.g., the drug itself comprises a substantial portion of ' the total tablet weight), it is necessary that the drugs) itself have sufficient physical characteristics " (e. g., cohesiveness) far-the ingredients to be directly compressed.
W096121429 ~ PCT1US96100660 .. i Typically, however, excipients are added to the formulation which impart good flow and compression characteristics to the material as a whole which is to be compressed. Such properties are typically imparted to these excipients via a pre-processing step such as wet granulation, slugging, spray drying, spheronization, or crystallization. Useful direct compression excipients include processed forms of ~ cellulose, sugars, and dicalcium phosphate dihydrate, among others.
A processed cellulose, microcrystalline cellulose, has been utilized extensively in the pharmaceutical industry as a direct compression vehicle-for solid dosage forms. Microcrystalline cellulose is commercially avail-able under the tradename EMCOCEL~~ from Edward Mendell Co., Inc. and as Avicel~ from FMC Corp. Compared to other directly compressible excipients, microcrystalline cellulose is generally considered to exhibit superior compressibility and disintegration properties.
Another limitation of direct compression as a method of tablet manufacture is the size of the tablet. If the amount of active ingredient is high, a pharmaceutical formulator may choose to wet granulate the active with other excipients to attain an acceptably sized tablet with the desired compact strength. Usually the amount of filler/binder or excipients needed in wet granulation is less than that required for direct compression since the process of wet granulation contributes .to some extent toward the desired physical properties of a tablet.
Thus, despite the advantages of direct compression (such as reduced processing times and costs), wet granulation is widely used in the industry in the preparation of solid dosage forms. Many of those skilled in the art prefer wet granulation as compared to direct compression because this method has a greater probability of over-WO 96/21429 pCT/US96/00660 -coming any problems associated with the physical charac-teristics of the various ingredients in the formulation, thereby providing a material which has the requisite flow and cohesive characteristics necessary to obtain an acceptable solid dosage form.

The popularity of the wet granulation process as compared to the direct compression process is based on at least three advantages. First, wet granulation provides the material to be compressed with better wetting proper-ties, particularly in the case of hydrophobic drug sub-stances. The addition of a hydrophilic excipient makes the surface of a hydrophobic drug more hydrophilic, easing disintegration and dissolution. Second, the content uniformity of the solid dosage forms is generally improved. Via the wet granulation method, allof the granules thereby obtained should contain approximately the same amount of drug. Thus, segregation of the different ingredients of the material to be compressed (due to different physical characteristics such as density) is avoided. Segregation is a potential problem with the direct compression method. Finally, the particle size and shape of the particles comprising the granulate to be compressed are optimized via the wet granulation process. This is dueto the fact that when a dry solid is-wet granulated, the binder "glues" par-ticles together, so that they agglomerate -in the granules which are more or less spherical.

Due to the popularity of microcrystalline cellulose, pharmaceutical formulators have deemed it desirable to include this excipient in a formulation which is wet granulated prior to tabletting. Unfortunately, currently-available microcrystalline cellulose does not hold to the typical principle that the amount of filler/binder needed in wet granulation is less than that in direct compression. It is known that the exposure of the microcrystalline cellulose to moisture in the wet granulation process severely reduces the compressibility of this excipient. The loss of compressibility of micro-s crystalline cellulose is particularly problematic -where the formulation dictates that the final product will be relatively large in the environment of use. For example, if a pharmaceutical formulator desires to prepare a solid oral dosage form of-a high dose- drug, and the use of the wet granulation technique is deemed necessary, the loss of compressibility of the microcrpstalline cellulose dictates that a larger amount of this material may be needed to obtain an acceptably compressed final product.

The additional amount of microcrystalline cellulose needed adds cost to the preparation, but more import-antly adds bulk, making the product more difficult to swallow.

The loss of compressibility of microcrystalline cellulose when exposed to wet granulation has long been considered a problem in the art for which there has been 2p no satisfactory solution.
Attempts have been made to-provide an excipient having high compressibility, a small bulk (high apparent density), and good flowability, while being capable of providing satisfactory disintegration of the solid dosage form, which is applicable to wet granulation as well as to dry granulation and direct compression methods for preparation of solid dosage forms.

For example, U.S. Patent No. 4,159,345 (Taken, et al.) describes an excipient which consists essentially of a microcrystalline cellulose having an average degree of polymerization of 60 to 375 and obtained through acid , hydrolysis or alkaline oxidative degradation of a cellu-losicsubstance selected. from linters,- pulps and regen-erated fibers. The microcrystalline cellulose is said to be a white cellulosic powder having an apparent specific _ . volume of 1.6-3.1 cc/g, a repose angle of 35 to 42, a 200-mesh sieve residue of 2 to 80% by weight and a . tapping apparent specific volume of at lest 1.4 cc/g.

In U.S. Patent No. 4,744,987 (Mehra, et al.), a par-ticulate ro-processed microcrystalline cellulose and calcium carbonate composition is described wherein the respective components are present in a weight ratio of 75:25 to 35:65. The co-processed composition is said to be prepared by forming a well-dispersed aqueous slurry of microcrystalline cellulose and calcium carbonate and then drying the slurry to yield a particulate product: The combination of these two ingredients is said to provide a lower cost excipient which has tabletting characteristics similar to those of- microcrystalline cellulose and which would satisfy a need for an economical excipient with good performance that is desired by the vitamin market.

European Patent Application EP 0609976A1 (assigned to Asahi Kasei Kabushiki Kaisha) describes an excipient comprising white powdery microcrystalline cellulose having an average degree of polymerization of from 100 to 375, preferably from 190 to 210, and an acetic acid holding capacity of 280% or more, preferably from 290 to 370%. The excipient is said to exhibit high compactability and a high rate of disintegration and is said to be obtained by heat-treating an aqueous dispersion of purified cellulose particles, which has a solids content of 40% or less by weight, at 100C or more, followed by drying, or by subjecting an aqueous ' dispersion of purified cellulose particles having a solids content of 23% or less by weight to thin film-forming treatment and drying the resultant thin film.

The excipient is said to possess a high compressibility, WO 96!21429 PCTIUS961006G0 and a good balance of compactability and rate of disintegration. , There still remains a need in the industry for a pharmaceutical excipient which possesses excellent compressibility whether utilized in a direct compression or wet granulation procedure.

~ AND SLID'MARY OE THE INVENTION

It is an object of the present invention to provide an exc=pient which is useful in a variety of applications, and which may be utiliz-ed in direct compression or wet granulation methods.

It is a further object- of the present invention to -provide an excipient useful in direct compression methods which has improved compressibility relative to microcrys-, talline cellulose.

ther object of the present invention to f i ur s a It provide an excipient useful in wet granulation methods which has improved compressibility relative to microcrys-talline cellulose.

It is a further object of the present invention to provide a free-flowing -excipient which has excellent compressibility properties when utilized in direct com-pression or wet granulation methods, and which furthermore possesses pharmaceutically acceptable disintegration properties.

It is a further object of the-present invention to provide an improved microcrystalline cellulose excipient crystalline cellulose has not been micr h th i o e c in wh chemically altered, and which has improved compressibility relative to "off-the-shelf" commercially a available microcrystalline-cellulose.

It is a further object of the present invention to provide a solid dosage form which includes one or more ,.
active ingredients and the improved microcrystalline cellulose excipient of the present invention.

It is a further object-of the present invention to . provide an oral solid dosage form for one or more drugs which is economical to manufacture, which maintains its integrity during storage, and which possesses excellent disintegration and dissolution properties when exposed, e.g., to gastrointestinal fluid.

In accordance with the above objects and others which will be obvious to those skilled in the art, the present invention is directed to an excipient comprising a particulate agglomerateof coprocessed microcrystalline cellulose and from about 0.1% to about 20o silicon dioxide, by weight of the microcrystalline cellulose, the microcrystalline cellulose and silicon dioxide being in intimate association with each other, and the silicon di-oxide portion of the agglomerate being derived from a silicon dioxide having a particle size from about 1 nanometer (nm) to about 100 -microns (um), based on average primary particle size.

In preferred embodiments, the silicon dioxide comprises from-about 0.5% to about 10s of the excipient, and most preferably from about 1.250 to about 5% by weight relative to the microcrystalline cellulose.

In additional preferred embodiments of the invention, the silicon dioxide has a particle size from about 5 nm to about 40 ~,m, and most preferably from about 5 nm to about 50 ~.m.

In preferred embodiments of the present invention, the silicon dioxide is further characterized by a ' surface area from about 10 m'g to about 500 m'/r, preferably from about 50 m~/g to about 500 m-/g, and more preferably from about 175 m~/g to about 350 m'/g.
The present invention is further directed to an aqueous slurry useful in the preparation of a , compressible excipient useful in dry and wet granulation formulation methods, comprising a mixture of , microcrystalline cellulose and from about 0.1% to about 20% silicon dioxide, by weight relative to the micro-crystalline cellulose, the- silicon dioxide having a particle size from about 1 nm to about 100 um. The solids content of the aqueous slurry is from about 0.5%

to about 25%, by weight, preferably from about 15% to about 20% by weight, and most preferably from about 17%

to about 19% by weight.
The present invention is further directed to a mixture of an active ingredients) and an excipient comprising a particulate agglomerate of coprocessed microcrystalline cellulose and from about 0.1% to about 20% silicon dioxide, by weight of the microcrystalline cellulose, the microcrystalline cellulose and silicon dioxide being in intimate association with each other, and the silicon dioxide having a particle size from about 1 nm to about 100 wm. The ratio of active ingredient to excipient is from about 1:99 to about 99:1, by weight.

The present invention is further directed to a granulate of an active, ingredient(s.) and the -novel excipient described herein, wherein the active ingredients) and excipient-have been subjected to a wet granulation procedure.
The present invention is further directed to a compressed solid dosage form comprising an active ingredients) and the novel excipient described herein, wherein the active ingredients) and excipient have been directly compressed into the solid dosage form or have been subjected to a wet granulation procedure and thereafter compressed into the solid dosage ford. The compressed solid dosage form provides a suitable immediate -release dissolution profile of the active ingredients) when exposed to aqueous solutions during . in-vitro dissolution testing, and provides a release of drug in an environment of use which is considered bioavailable. In further embodiments of the invention, the dissolution profile of the solid dosage form is modified to provide a controlled or sustained release dissolution profile.

The present invention is further directed to a method of maintaining and/or enhancing the compressibility of microcrystalline cellulose. The method includes forming an aqueous slurry containing a mixture of microcrystalline cellulose and silicon dioxide having a particle size from about 1 nm to about 100 ~,m, and drying the slurry to obtain microcrystalline cellu-lose-based excipient particles in which the silicon di-oxide particles have been integrated with the microcrystalline cellulose particles. Within this aspect of the invention, the slurry contains from about 0.5$ to about 25% by weight microcrystalline cellulose, with amounts of from about 15% to about 20% being preferred.

Furthermore, the slurry contains from about 0.25% to about 5% by weight silicon dioxide.

The novel excipient described herein is free-flowing, possesses excellent disintegration properties, and importantly, in certain embodiments possesses improved compressibility relative to normal "off-the-shelf" commercially available microcrystalline cellulose when directly compressed. The advantages of the novel excipient described lier-_in are especially realized in pharmaceutical formulations prepared using wet - granulation techniques. When utilized in wet granulation techniques, the novel excipient surprisingly provides a PC1'IUS96100660 compressibility which is substantially improved in preferred embodiments in comparison to the compress-ibility of normal "off-the-shelf" commercially available microcrystalline cellulose used in wet granulation and is even comparable to "off-the-shelf" microcrystalline cellulose used in direct compression techniques. In other embodiments, the novel excipient surprisingly provides a compressibility which is substantially superior to the compressibility of normal "off-the-shelf"
commercially available microcrystalline cellulose used in direct compression techniques.
The term "environmental fluid" is meant for purposes of the invention to encompass, e.g., an aqueous solution, or gastrointestinal fluid.
By "sustained release" it is meant for purposes of the invention that the therapeutically active medicament .s released from the formulation at a controlled rate such that therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time, e.g., providing a 12 hour or a 24 hour dosage form.
By "bioavailable" itis meant for purposes of the invention that the therapeutically active medicament is absorbed from the sustained release formulation and becomes available in the body at the intended site of drug action.

By "primary particle size" it is meant for purposes of the invention that the particles are not agglomerated.
Agglomeration is common with respect to silicon dioxide particles, resulting in a comparatively average large agglomerated particle size.

prepared by partially depolymerizing cellulose obtained as a pulp from fibrous plant material with dilute mineral acid solutions. Following hydrolysis, the hydrocellulose thereby obtained is purified via filtration and the aqueous slurry is spray dried to form dry, white odorless, tasteless crystalline powder of porous particles of a broad size distribution. Another method of preparing microcrystalline cellulose is disclosed in U.S. Patent No. 3,141,875. This reference discloses subjecting cellulose to the hydrolytic action of hydrochloric acid at boiling temperatures so that amorphous ce11u1osic material can be removed and aggre-gates of crystalline cellulose are formed. The aggregates are collected by filtration, washed with water and aqueous ammonia and disintegrated into small fragments, often called cellulose crystallites by vigorous mechanical means such as a blender.

Microcrystalline cellulose is commercially available in several grades which range in average particle size from 20 to 200 microns.

Microcrystalline cellulose is water-insoluble, but the material has the ability to draw fluid into a tablet by capillary action. The tablets then swell on contact and the microcrystalline cellulose thus acts as a disintegrating agent. The material has sufficient self-lubricating qualities so as to allow a lower level of lubricant as compared to other excipients.

Typically, microcrystalline cellulose has an apparent density of about 0.28 g/cm' and a tap density of about 0.43-g/cm~. handbook of Pharmaceutscai Fxcigs n ~

, pages 53=55. -When utilized in pharmaceutical applications, micro-crystalline cellulose is typically used as a tablet binder/diluent-in wet granulation and direct compression liR r ~ I?FECRTPmTON OF THE DR_AWINGs The following drawings are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims.
Figure 1 graphically shows a comparison of the tensile strength of tablets prepared in accordance with the invention and prior art tablets.
Figure 2 graphically shows a comparison of the tensile strength of APAP containing tablets prepared in accordance with the invention and prior. artAPAP

containing tablets.
Figure 3 graphically shows a comparison of the tensile strength of tablets prepared in accordance with the invention to contain MCC coprocessed with diatomaceous earth, tablets containing MCC coprocessed with 2% w/w Sio, and prior art tablets prepared to contain only unmodified MCC.
Figure 4 graphically illustrates a comparison of the tensile strength of tablets prepared using MCC

coprocessed with silica gel, tablets prepared with the novel coprocessed MCC and tablets prepared with MCC

alone.
Figure 5 graphically illustrates a comparison of the tensile strength of tablets prepared using MCC

coprocessed with HS 5 grade S3.o_., tablets prepared using coprocessed MCC-Si0_ and prior art tablets prepared to contain only unmodified MCC.

pgTAII,gDDF~RTPTTOh OF mHE TNVENTION
Microcrystalline cellulose is a well-known tablet diluent and disintegrant. Its chief advantage over other excipients is that it can be directly compressed into self-binding tablets which disintegrate rapidly when placed into water. This widely-used ingredient is formulations in amounts of 5-30~ of the formulation, or more. However, it is known to use more or less microcrystalline cellulose in pharmaceutical products, depending upon the requirements ofthe formulation.

Silicon dioxide is obtained by insolubilizing dis-solved silica in sodium silicate solution. When obtained by the addition of sodium silicate to a mineral acid, the product is termed silica gel. 'When obtained by the de-stabilization of a solution of sodium silicate in such a l0 manner as to yield very fine particles, the product is termed precipitated silica. Silicon dioxide isinsoluble in water. Prior to the present invention, silicon dioxide, and in particular colloidal silicon dioxide, was used mainly as a glidant-and anti-adherent in tabletting processes and encapsulation, promoting the flowability of the granulation. The amount of silicon dioxide included in such tablets for those applications is very limited, 0.1-0.5~ by weight. Handbook of Pharmac-~ 5-a1-Hxc,~gj.ents, m1986 American -Pharmaceutical Association, page 255.- This is due in part to the fact that increasing the amount of silicon dioxide in the mixture to be tabletted causes the mixture to flow too well, causing a phenomena known to those skilled in the tabletting art-as "flooding". If the mixture flows too well, a varying tablet weight with uneven content uniformity can result.

Those skilled in the art will appreciate that the name and/or method of preparation of the silicon dioxide uti?.ized in the present invention is not determinative of the usefulness of the product. Rather, as previously mentioned, it has been surprisingly discovered that it is the physical characteristics of the silicon dioxide which are critical_ Sn particular, it has been discovered that silicon dioxide having a relatively large particle size IS

(and correspondingly small surface areaj, such as silica is not useful in the preparation of the improved el g , microcrystalline cellulose products of the invention.

The appended claims are deemed to encompass all forms of silicon dioxide having an average primary particle size from about 1 nm to about 100 Vim, and/or a surface area from about 10 m'/g to about 500 m2/g.

The silicon dioxide utilized in the invention is of the very fine particle size variety. In the most the invention, the silicon of preferred embodiments .
, dioxide utilized is a -colloidal silicon dioxide.

Colloidal silicon dioxide is a submicron fumed silica prepared by the vapor-phase hydrolysis (e.g., at 1110 C) f a silicon compound, such as silicon tetrachloride.

o 5 The product itself is a submicron, fluffy, light, loose, 1 bluish-white, odorless and tasteless amorphous powder which is commercially available from a number of sources, including Cabot Corporation (under the tradename-Cab-O-Sil): Degussa, Inc. (under the tradename Aerosil): E.I.

DuPOnt & Co. ; and W.R. Grace & Co. Colloidal silicon xide is also known as colloidal silica, fumed silica, di o light anhydrous silicic acid, silicic anhydride, and silicon dioxide fumed, among others. A variety of commercial- grades of colloidal silicon dioxide are produced by varying the manufacturing process. These modifications do not affect the silica content,- specific gravity, refractive index, color or amorphous form. How-these modifications are known to change the ever, particlesize, surface areas, and bulk densities of the colloidal silicon dioxide products.

The surface area of -the preferred class of silicon dioxides utilized in the invention ranges from about 50 m'/gm to about 50o m /gm._ The average primary particle diameter of the preferred class of silicon dioxides utilized in the invention ranges from about 5 nm to about 50 nm. However, in commercial colloidal silicon dioxide products, these particles are agglomerated or aggregated to varying extents. The bulk density of the preferred class of silicon dioxides utilized in the invention ranges from about 20 g/1 to about 100 g/1.

Commercially available colloidal silicon dioxide products have, for example, a BET surface area ranging from about 50 15 m2/gm (Aerosil OX50) to about 400 20 (Cab-O-Sil S-17) or 390 40 m'/gm (Cab-O-Sil EH-5).

Commercially available particle sizes range from a nominal particle diameter of 7 nm (e.g., Cab-O-Sil S-17 or Cab-O-Sil EH-5) to an average primary particle size of -40 nm (Aerosil OX50). The density of these products range from 72.0 8 g/1 (Cab-O-Sil S-17) to 36.8 g/1 (e.g., Cab-O-Sil M-5). The pH of the these products at 4$ aqueous dispersion ranges from pH 3.5-4.5. These commercially available products are described for exemplification purposes of acceptable properties of the preferred class of silicon dioxides only, and this description is not meant to limit the scope of the invention in any manner whatsoever.

When the novel excipient of the invention utilizes a colloidal silicon dioxide, it has been found that the resultant excipient product surprisingly provides a com-pressibility which is substantially improved in preferred embodiments even in comparison to the compressibility of normal "off-the-shelf" commercially available microcrystalline cellulose used in direct compression techniques.

In other-embodiments of the present invention, it has been discovered that the compressibility of microcrystalline cellulose which is wet granulated is significantly improved by a wider range of silicon dioxide products: Thus, in embodiments of- the present invention where an improvement in overall compressibility of the microcrystalline cellulose (whether. utilized in wet granulation or dry granulation) is not important, and the microcrystalline cellulose product is to be subjected to wet granulation, it has been discovered that the surface area of the silicon dioxide can be as low as about 50 m'/gm and the average primary particle diameter can be as large as about 100 Vim. Such silicon dioxide products are also deemed to be encompassed within the scope of the invention.
Both microcrystalline cellulose and silicon dioxide are substantially water insoluble. Therefore, the particle size of these -ingredients as present in the well-dispersed aqueous slurry is directly related to the particle size of these two ingredients as they were introduced into the aqueous solution. There is no appreciable dissolution of either ingredient in the aqueous slurry.
After a uniform mixture of the ingredients is obtained in the suspension, the suspension is dried to provide a plurality of microcrystalline cellulose-based excipient particles having enhanced compressibility.
In the spray-drying process, the aqueous dispersion of microcrystalline cellulose and silicon dioxide is brought together with a sufficient volume-of hot air to produce evaporation and drying of the liquid droplets.
The highly dispersed slurry of microcrystalline cellulose and silicon dioxide is pumpable and capable of being atomized. It is sprayed into a current of warm filtered air, which supplies the heat for evaporation and conveys a dried product to a collecting device. The air is then exhausted with the removed moisture. The resultant spray-dried powder particles are approximately spherical WO 96!21429 PCT/US96/00660 in shape and are relatively uniform in size, thereby possessing excellent flowability. The coprocessed product consists of microcrystalline cellulose and silicon dioxide in intimate association with each other.

Magnifications of the resultant particles indicate that the silicon dioxide is integrated with, or partially coats, the surfaces of the microcrystalline cellulose particles. When the amount of silicon dioxide including in the excipient is greater than about 20~ by weight relative to the microcrystalline cellulose, the silicon dioxide appears to substantially coat the surfaces of the microcrystalline cellulose particles. The exact relationship of the two ingredients of the excipients after coprocessing is not presently understood; however, far purposes of description the coprocessed particles are described herein as including an agglomerate of microcrystalline cellulose and silicon dioxide in intimate association with each other. By "intimate association", it is meant that the silicon dioxide has in some manner been integrated with the microcrystalline cellulose-particles, e.g., via a partial coating of the microcrystalline particles, as opposed to a chemical interaction of the two ingredients. The term "intimate association" is therefore deemed for purposes of the present description as being synonymous with "integrated"

or "united". The coprocessed particles are not necessarily uniform or homogeneous. Rather, under magni-fication, e.g., scanning electron microscope at 500x, the silicon dioxide at the preferred percent inclusion appears to be an "edge-coating".

It is most preferred in the present invention that the microcrystalline cellulose and silicon dioxide are coprocessed, resulting in an intimate association of these ingredients, rather than being combined, e.g., as ~~~~~8 a dry mixture: In preferred embodiments of the present invention, the aqueous slurry of the microcrystalline cellulose and silicon dioxide are introduced into the spray dryer as a single aqueous medium. However, it is possible to separately introduce each ingredient into separate aqueous medium which are then combined. Other procedures for combining the microcrystalline cellulose and silicon dioxide known to those skilled in the art are deemed to be equivalent to the spray-drying technique described above, and are further deemed to be encompassed by the appended claims.
In certain preferred embodiments of the present in-vention, the coprocessing of the microcrystalline cellulose and silicon dioxide is accomplished by forming a well-dispersed aqueous -slurry of . microcrystalline cellulose and silicon dioxide, and thereafter drying the slurry and forming a plurality of microcrystalline cellulose-based excipient particles. Typically, microcrystalline cellulose is first added to an aqueous solution so that a slurry or suspension containing from about 0.5$ to about 25% microcrystalline cellulose in the form of solids is obtained. Preferably, the slurry or suspension contains fr:m about 15% to 20% microcrys-talline cellulose and most preferably from about 17% to about 19% microcrystalline cellulose. At this stage, it is often desirable toadjust the pH of the slurry to about neutral with ammonium hydroxide, sodium hydroxide, and mixtures thereof or-the like. The suspension is kept under constant agitation for a sufficient time to assure a uniform distribution of the solids prior to being combined with the silicon dioxide.

At this point, the silicon dioxide is addedto the suspension or slurry in amounts ranging from 0.1% to about 20% by weight, based on the amount of WO 96121429 PCTlUS96/00660 microcrystalline cellulose, amounts from about 0.5% to about 10% are preferred while amounts of from about 1.25%

to about 5% by weight are especially preferred. The silicon dio:tide is preferably in colloidal form prior to addition to the MCC slurry. The microcrystalline cellulose and colloidal silicon dioxide are well-dispersed in the slurry or suspension prior drying and forming the novel particles.

It is preferred that the suspension be dried using spray-drying techniques, as they are known in the art.

Otherdrying techniques, however, such as flash drying, ring drying, micron drying, tray drying, vacuum drying, radio-frequency drying, and possibly microwave drying, can also be used. The exact manner in which the suspension is dried is not believed to be critical for the microcrystalline cellulose/silicon dioxide particles to demonstrate enhanced compressibility after wet granulating.

Depending upon the amount and type of drying, the concentration of the microcrystalline cellulose and silicon dioxide in the suspension, the novel compressible particles will have different particle sizes, densities, pH, moisture content, etc.

The particulate coprocessed product of the present invention possesses desirable performance attributes that are not present when the combination of microcrystalline cellulose and silicon dioxide are combined as a dry mix-ture. It is believed that the beneficial result obtained by the combination of these two materials is-due to the fact that the two materials are intimately associated with each other.

The average particle size of the integrated excipient of the present invention ranges from about 10 microns to about 1000 microns. Particle sizes of about 10-500 microns are preferred, particle sizes of about 30-250 microns are more preferred and particle sizes of about 40-200 microns are most preferred. It will be appreciated by those of ordinary skill in the art that the drying of the microcrystalline cellulose-silicon dioxide suspension results in a random size distribution of the novel excipient particles being produced. For example if spray drying techniques are used, droplet size, temperatures, agitation, dispersion, air flow, atomizer wheel speed, etc. will effect final particle size. Furthermore, it is within the scope of the invention to sort or mechanically alter the _driec:
particles according to ranges of particle sizes depending upon end uses. The particle size of the integrated excipient is not narrowly critical, the important parameter being that the average size of the particle must-permit the formation of a directly- compressible excipient which forms pharmaceutically acceptable tablets.
The novel excipienthasa bulk (loose) density ranging from about 0.2 g/ml to about 0.6 g/ml, and most preferably from about 0.35 g/ml to about 0.55 g/ml. The novel excipient has a tapped density ranging from about 0.2 g/ml to .-about 0.6 g/ml, and most preferably from about 0.35 g/ml to about 0.55 g/ml. The pH of the particles is most- preferably about neutral, although granulates having a pH of from about 3.0 to about 8.5 are possible. The moisture content of the excipient particles will broadly range from about 0.5% to about 15%, preferably °_rom about 2.5% to about 6%, and most preferably from about 3.0% to about 5% by weight.
The angle of -repose is a measurement used to determine the flow characteristics of a powder. The angle of repose is subject to experiment and WO 96/21429 r PGT/US96100660 experimenter, but in a comparative test, the novel excipient is superior.

The novel excipient of the invention is free-flowing and directly compressible. Accordingly, the excipient may be mixed in the desired proportion with an active agent and optional lubricant (dry granulation), and then directly compressed into solid dosage forms. In preferred embodiments of the present invention wherein the silicon dioxide is colloidal silicon dioxide, the novel excipient comprising the coprocessed microcrys-talline cellulose and colloidal silicon dioxide integrated together represents an augmented microcrystalline cellulose having improved compressibility as compared to standard commercially available grad a of microcrystalline cellulose.

Alternatively, alI or part of the excipient may be subjected to a wet granulation with the active ingredient. A representative wet granulation includes loading the novel excipient particles into a suitable granulator, such as those available from Baker-Perlcins , and granulating the particles together with the active ingredient, preferably using an aqueous granulating liquid. The granulating liquid is added to the mixture with stirring until the powdery mass has the consistency of damp snow and then wet screened through a desired mesh screen, for example, having a mesh from about 12 to about 16. The screened granulate is then dried, using standard drying apparatus such as a convection oven before undergoing a final screening. Additional dry screening of this material is possible, such as by using screens of from about 40 to about 200 mesh. Those materials flowing through 40 and 60 mesh screens may be further ground prior to ultimate tablet formulation. The thus obtained wet granulate containing novel excipient is now capable of undergoing tabletting or otherwise placed into a unit dosage form.
In certain preferred embodiments, a portion of the total amount of the novel excipient is wet granulated with the active ingredient, and thereafter the additional portion of the novel excipient is added to the granulate.
In yet other embodiments, the additional portion of the novel excipient to be added to the excipient/active ingredient granulate may be substituted with conventional microcrystalline cellulose, or other excipients commonly used by those skilled in the art, depending of course upon the requirements of the particular formulation.
gy virtue of the novel excipient of the present in vention, the amount of the novel excipient compared to the amount of microcrystalline cellulose which must be used in a wet granulation technique to obtain an acceptable solid dosage form is substantially reduced.
In other embodiments of the invention, a further material is added to the slurry of microcrystalline cellulose and silicon dioxide. Such additional materials include non-silicon metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, cellulose ethers, celluloses esters and mixtures thereof. These additives may be included in desired amounts which will be apparent to those skilled in the art.
In addition to one or more active ingredients, addi-tional pharmaceutically acceptable excipients (in the case of pharmaceuticals) or other additives known to those skilled in the art (for non-pharmaceutical applications) can be added to the novel excipient prior to preparation of the final product. For example, if desired, any generally -accepted soluble or insoluble inert pharmaceutical filler (diluent) material- can be included in the final product (e. g., a solid dosage WO 96121429 PCTltIS96/00660 form). Preferably, the inert pharmaceutical filler comprises a monosaccharide, a disaccharide, a polyhydric alcohol, inorganic phosphates, sulfates or carbonates, and/or mixtures thereof. Examples of suitable inert pharmaceutical fillers include sucrose, dextrose, lactose, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, calcium carbonate, ~~off-the-shelf~~
microcrystalline cellulose, mixtures thereof, and the like.
An effective amount of any generally accepted pharmaceutical lubricant, including the calcium or magnesium soaps may optionally be added to the novel excipient at the time the medicament is added, or in any event prior to-compression into a solid dosage form. The lubricant may comprise, for example, magnesium stearate in any amount of about 0.5-3~ by weight of the solid dosage form.
The complete mixture, in an amount sufficient to make a uniform batch of tablets; may then subjected to tabletting in a conventional production scale tabletting machine at normal compression pressures for that machine, e.g., about 1500-10,000 lbs/sq in. The mixture should not be compressed to such a degree that there is subsequent difficulty in its hydration when exposed to gastric fluid.
The average tablet size for round tablets is prefer-ably about 50 mg to 500 mg and for capsule-shaped tablets about 20o mg to 2000 mg. However, other formulations prepared in accordance with the present invention may be suitably shaped for other uses or locations, such as other body cavities, e.g:, periodontal pockets, surgical wounds, vaginally. It is contemplated that for certain uses, e.g., antacid tablets, vaginal tablets and possibly implants, that the tablet will be larger.

pCTIUS96/00660 In certain embodiments of the invention, the tablet is coated with a sufficient amount of a hydrophobic polymer to render he formulation capably of providing a release of the medicament such that a 12 or 24-hour formulation is obtained. The hydrophobic polymer which included in the tablet coating may be the same or different material as compared to the hydrophobic polymeric material which is optionally granulated with the sustained release excipient. In other embodiments of the present invention, the tablet coating may comprise an enteric coating material in addition to or instead or the hydrophobic polymer coating. Examples of suitable enteric polymers include cellulose, acetate phthalate, hydroxypropylmethy1ce11ulosE phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trimellitate, and mixtures of any of the foregoing. An -example of a suitable commercially available enteric material is available under the trade name EudragitT"" L

100-555.
In further embodiments, the dosage form may be coated with a hydrophilic coating in addition to or instead of the above-mentioned coatings. An example of a suitable material which may be used for such a hydrophilic coating is ; hydroxypropylmethylcellulose ~e,g,, Opadry~, commercially available from Colorcon, West Point, Pennsylvania).
The coatings may be applied in any pharmaceutically acceptable manner known to those skilled in the art. For example, in one embodiment, the coating is applied via a fluidized bed or in a coating pan. For- example, the , coated tablets may be dried,- e.g., at about 60-70 C for about 3-4 hours in a coating pan. The solvent for the hydrophobic polymer or enteric coating may be organic, aqueous, or a mixture of an organic and an aqueous solvent. The organic solvents may be, e.g., isopropyl alcohol, ethanol, and the like, with or without water.
The coatings which may be optionally applied to the compressed solid dosage form of the invention may comprise from about 0.5% to about 30% by weight of the final solid dosage form.
In additional embodiments of the present invention, a support platform is applied to the tablets manufactured in accordance with the present invention. Suitable support platforms are well known to those skilled in the art. An example of suitable support platforms is set forth, e.g., in U.S.
Patent No. 4,839,177. In that patent, the support platform partially coats the tablet, and consists of a polymeric material insoluble in aqueous liquids. The support platform may, for example, be designed to maintain its impermeability characteristics during the transfer of the therapeutically active medicament. The support platform may be applied to the tablets, e.g., via compression coating onto part of the tablet surface, by spray coating the polymeric materials comprising the support platform onto all or part of the tablet surface, or by immersing the tablets in a solution of the polymeric materials.
The support platform may have a thickness of, e.g., about 2 mm if applied by compression, and about 10 ~.m if applied via spray-coating or immersion-coating. Generally, in embodiments of the invention wherein a hydrophobic polymer or enteric coating is applied to the tablets, the tablets are coated to a weight gain from about 1% to about 20%, and in certain embodiments preferably from about 5% to about 10%.

PCTIUS96l00660 Materials useful in the hydrophobic coatings and support platforms of the present invention include derivatives of acrylic acid (such as esters of acrylic acid, methacrylic acid, and copolymers thereof) celluloses and derivatives thereof (such as ethylcellulose), polyvinylalcohols, and the like.
In certain embodiments of the present invention, the tablet core includes an additional dose of the medicament included in either the hydrophobic or enteric coating, or in an additional overcoating coated on the outer surface of the tablet core (without the hydrophobic or enteric coating) or as a second coating layer coated on the surface of the base coating comprising the hydrophobic or enteric coating material. This may be desired when, for example, a loading dose of a therapeutically active agent is needed to provide therapeutically effective blood levels of the active agent when the formulation is first exposed to gastric fluid. The loading dose of medicament included in the coating layer may be, e.g., from about 10~ to about 400 of the total amount of medicament included in the formulation.
The active agents) which may be incorporated with the novel excipient described herein into solid dosage forms invention include systemically active therapeutic agents, locally active therapeutic agents, disinfecting agents, chemical impregnants, cleansing agents, deodorants, fragrances, dyes, animal repellents, insect repellents, a fertilizing agents, pesticides, herbicides, fungicides, and plant growth stimulants, and the like.
A wide variety of therapeutically active agents can be used in conjunction with the present invention. The therapeutically active agents (e. g. pharmaceutical agents) which may be used in the compositions of the present invention include both water soluble and water insoluble drugs.
Examples of such therapeutically active agents include antihistamines (e.g., dimenhydrinate, diphemhydramine, chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g., ASPIRIN~, codeine, morphine, dihydromorphone, oxycodone, etc.), non-steroidal anti-inflammatory agents (e.g., naproxyn, diclofenac, indomethacin, ibuprofen, sulindac), anti-emetics (e.g., metoclopramide), anti-epileptics (e.g., phenytoin meprobamate and nitrezepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine), anti-tussive agents and expectorants (e.g., codeine phosphate), anti-asthmatics (e.g., theophylline), antacids, anti-spasmodics (e.g., atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid, bendrotluazide), anti-nypotenslves ~e.g., propranolol, clonidine), antihypertensives (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, psycho-tropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine).
The above list is not meant to be exclusive.
A wide variety of locally active agents can be used in conjunction with the novel excipient described herein, and include both water soluble and water insoluble agents. The locally active agents) which may be included in the controlled release formulation of the present invention is intended to exert its effect in the environment of use, e.g., the oral cavity, although in some instances the active agent may also have systemic activity via absorption into the blood via the r surrounding mucosa.
The locally active agents) include antifungal agents (e. g., amphotericin B, clotrimazole, nystatin, ketoconazole, miconazol, etc.), antibiotic agents (penicillins, cephalosporins, erythromycin, tetracycline, aminoglycosides, etc.), antiviral agents (e. g, acyclovir, idoxuridine, etc.), breath fresheners (e. g. chlorophyll), antitussive agents (e. g., dextromethorphan hydro-chloride), anti-cariogenic compounds (e. g., metallic salts of fluoride, sodium monofluorophosphate, stannous fluoride, amine fluorides), analgesic agents (e. g., methylsalicylate, salicylic acid, etc.), local anesthetics (e. g., benzocaine), oral antiseptics (e. g., chlorhexidine and salts-- thereof, hexylresorcinol, dequalinium chloride, cetylpyridinium chloride), anti-flammatory agents (e. g., dexamethasone, betamethasone, prednisone, prednisolone, triamcinolone, hydrocortisone, etc.), hormonal agents (oestriol), antiplaque agents (e~g, chlorhexidine and salts thereof, octenidine, and mixtures of thymol, menthol, methysalicylate, eucalyptol), acidity reducing agents (e. g., buffering agents such as potassium phosphate dibasic, calcium carbonate, sodium bicarbonate, sodium and potassium hydroxide, etc.), and tooth desensitizers (e~g~~
potassium nitrate). This list is not meant to be-exclu-sive. The solid formulations of the invention may also include other locally active agents, such as flavorants and sweeteners. Generally any flavoring or-food additive such as those described in '~ i rTaed in Food P cc~c~ Pub 1274 by the National Academy of Sciences, pages 63-25F3 may be used.- Generally, the final, product may include from about -0.1% to about 5% by weight flavorant.

The tablets of the present invention may also contain effective amounts of coloring agents, (e.g., titanium dioxide, F.D. & C. and D. & C.
dyes;
see the Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 5, pp. 857-884), stabilizers, binders, odor controlling agents, and preservatives.
Alternatively, the novel excipient can be utilized in other applications wherein it is not compressed. For example, the granulate can be admixed with an active ingredient and the mixture then filled into capsules. The granulate can further be molded into shapes other than those typically associated with tablets. For example, the granulate together with active ingredient can be molded to "fit" into a particular area in an environment of use (e.g., an implant). All such uses would be contemplated by those skilled in the art and are deemed to be encompassed within the scope of the appended claims.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.
The examples set forth the preparation of various microcrystalline cellulose/silicon dioxide compositions. Tablets were prepared using each of compositions and each of tablet preparations was tested for tensile strength.

vvarfyT~F.$ 1-3- _. . _ PREPARATION OF COPRO~FSSED MCC-$i0 COD'PO$rTTON~ AND
~ANL1LATTONS THEhrOF
_FXAMPLE 1 rndnct- 59d w/w SiO., MCC i$ O P

A. rorcnrT PARTTCLE$
In this example, about 6.2 kilograms of microcrystalline cellulose (MCC), (Mendell--Co., Inc.
Patterson, NY) in the form of a wet cake was combined with 5.2 kilograms of water in a mix tank to form a slurry containing about 15o solids. The pH was adjusted to about neutral with about 3 ml of ammonium hydroxide.
The slurry was allowed to mix for about 15 minutes before being combined with 5~ w/w silicon dioxide (Si02) , 200 m=/g (CaboSil, PTG grade,- available from Cabot Corp., Tuscola, IL.) After allowing the materials to_become intimately combined, the slurry was spray dried using a Niro Production Minor (Niro, Columbia, MD),- inlet temperature-215C, outlet temperature-125C, atomizer wheel speed 22,300 rpm, to provide MCC-Sio: having an average particle size of 40-60 microns.

B. RaNtItATTON OF EXCTPTFNT PARTICLES
The MCC-Si0= particles obtained as a result of step 1 A. were wet granulated in a Baker-Perkins 10 liter high-sheer granulator for 3 minutes using water as the granulating fluid. The resultant product was wet screened through a 12 mesh screen, tray dried in a convection oven for about 2-3 hours until a moisture content of less than 5% was obtained, dry screened and sieved to obtain an average particle size of from about 55 to about 70 microns.

W O 96121429 PCTlUS96/00660 i RX
MCC-Si0 produ~'+- 20% w/w Rin The processes of Example 1A and B were repeated except that 20% w/w silicon dioxide was used to form the product.
EXAMPLE z MCC-si,0 rod ct- 2"- w/w Si0 In this example, the processes of Example 1A and B
l0 were repeated except that 2% w/w silicon dioxide was used to form the product.

D__r~~lelld mix of Hrrn ~.nd Ei0 (s~ ~i omna a+, As a control, EMCOCEL~ grade 50 M microcrystalline cellulose (Mendell Co., Inc.) and 5% w/w silicon dioxide, 200 m2/g (CaboSil, PTG grade) were dry blended. No spray drying or other treatment of the mixture was undertaken.
The method of Example 1B, however, was repeated.

Proces$ d MCC without sin As a second control, the process described in Example 1B was repeated except that no Sio. was added.

2~.83~8~
FxaMPLE 6 In this example, batches of compressed tablets were prepared using each of the-products obtained as a result of Examples 1-5. The tablets were prepared using a Korsch tablet press having a punch size of 3/8" and an aim weight of about 245 mg. The granulations were included in five separate tabletting runs using compression forces of 6, 12, 18, 24 and 30 kN
respectively. Ten tablets from each run were weighed, measured for diameter and tested for thickness and hardness on the Erweka TBH 30 tablet hardness tester to determine the compressibility of the microcrystalline cellulose as measured by tensile strength. The results of the analysis are graphically illustrated in Figure 1 as a comparison of tensile strength versus compression force.
As can be seen from the graph, substantial benefits are obtained by coprocessing MCC with Si0_. The tablets prepared using the products of comparative examples 4 and 5 demonstrated poor tensile strength. The novel excipient is superior and demonstrates approximately the same relative improvement across the entire range of compression forces. Furthermore, the graph also illustrates that tablets prepared with a mere dry admixture of P1CC and SiO, (example 4 formulation) failed to demonstrate acceptable tensile strengths. Thus, the WO 96!21429 PCT/US96/D0660 coprocessed MCC-Si0_ described herein provides significant retention of MCC compressibility.

In these examples, compressed tablet products con-taming 70% by weight MCC and 30~ acetaminophen (APAP
herein) were prepared. The products of examples 7-9 were controls and prepared without the coprocessed MCC-SiO~ of the present invention. The products of examples l0-12, on the other hand, included 70% by weight of the novel coprocessed MCC-Si0_ and 30$ APAP. Details concerning the preparation of-each granulation product is set forth below. A graphical comparison of the tensile strength versus compression force for each tabletted product is provided in Figure 2.

':

Tn aaranula as anu~at~on of APAP with MCC
In this example, tablets were prepared using off-the-shelf MCC (EMCOCEL~ 50 M) according to the following formula:
INGREDIENTS WEIGHT (GRAMS) APAP 114.8 Deionized water 165.8 One half of the MCC was added to a Baker-Perkins 10 liter blender and combined with all of the APAP. The blender impeller was adjusted to 200 rpm and the chopper was set at 1000 rpm. After one minute, the water was added over 90 seconds using a rinse bottle. Thereafter, mixing was continued for an additional 90 seconds. The granulation was removed from the blender, wet screened through a 12 screen mesh and dried in a convection oven for 2-3 hours at 60° C. until a moisture content of less than 5~ was obtained. The granulation was then dry screened through a 16 mesh screen before being blended for l0 minutes with the remaining portion of the MCC in a 2 quart V-blender. The granulation was removed from the blenderand tabletted in accordance with the method described below.

W O 96121429 ' . : , PCTlUS96/00660 TABLET STRENGTH TESTING
In order to prepare tablets for the formulations of examples 7, 8, 10 and 11, the following procedure was used:
the wet granulation products were weighed and mixed in a 2 quart -V-blender for 5 minutes with 0.2g PruvTM
(sodium stearyl fumarate, available from Mendell Co., Inc.).
Five separate tabletting runs were undertaken with compression forces of 5, 10, 15, 20 and 25 kN
respectively using a Korsch tablet press having a punch size of 3/8~~ and an aim weight of about 245 mg. Ten tablets from each compression force were selected and used in the experiment set forth in Example 13.
-EX1~MPT~E 8 Wet Qran~l ats on o APAP ki yh r.C~
In this example, only wet granulation or the intra granulation step as described above was undertaken. The formulation was prepared according to the following formula using off-the-shelf EMCOCEL~ 50 M MCC:
INGREDIENTS WEIGHT (GRAMS
MCC 178.6 APAP 76.5 Deionized water 170.1 The MCC was added to a Haker-Perkins 10 liter blender and combined with the APAP. The blender impeller was adjusted to 200 rpm and the chopper was set at 1000 rpm. After one minute, the water was added over 90 seconds using a rinse bottle. Thereafter, mixing was continued for an additional 90 seconds. The granulation was removed from the blender, wet screened through a 12 screen mesh and then dried in a convection oven at 60° C.
for 2-3 hours, until a moisture content of less than 5%
was achieved. The granulation was then dry screened through a 16 mesh screen and tabletted in accordance with the method described in example 7.
ovarwTE 9 ~on formu~at~o11 of APAP ~~~h MCC
A direct compression formulation for tablets was prepared to contain 70% off-the-shelf EMCOCEL~ 50 M MCC
and 30% APAP by weight. The tablets were prepared according to the following formula:
" INGREDIENTS WEIGHT (GRAMS
175.0 MCC
74.5 APAP
0.5 PRUV
The MCC and APAP were combined in a V-blender and mixed for 15 minutes. Thereafter, the Pruv was added and WO 96/21429 PCTlUS96/0066D
mixing was continued for another 5 minutes. The granula-~ tion was removed and five separate tabletting runs were undertaken using compression forces of 5, 10, 15, 20 and 25 kN respectively on a Korsch tablet press. The tablet press had a punch size of 3/8~~ and an aim weight of about 245 mg. Ten tablets from each compression force were used in the experiment set forth in Example 13.
E7~EMPLE 10 lU Wet granulation 9f APAP with coproaesaa$ MCC SAO
(5%w/w) In this example, tablets were prepared by wet granu lation with the coprocessed MCC (5% w/w Si0_) of Example lA. The tablet granulation was prepared according to the 15 following formula:
INGREDIENTS WEIGHT (GRAMS) MCC-SiO.. 178.6 APAP
76.5 Deionized water 170.1 The MCC-Si0_ was added to a Baker-Perkins 10 liter blender and combined with the APAP. The blender impeller was adjusted to 200 rpm and-the chopper was set at 1000 rpm. After one-minute, the water was added over 90 25 seconds using a rinse bottle. Thereafter, mixing was continued for an additional 90 seconds. The granulation was removed from the blender, wet screened through a 12 screen mesh and then dried in a convection oven for 2-3 hours at 60°C. until a moisture cpntent of less than 5~
was achieved. The granulation was then dry screened through a 16 mesh screen and tabletted according to the method set forth in Example 7.
tra 'and Extraaranulation of APAP with MCC-SiO, l5%w/w1 A granulation for compressed tablets was prepared according to the follD~ingformula:
INGREDIENTS WEIGHT (GRAMS) MCC-Si0> 267.9 APAP 114.8 Deionized water 165.8 One half of the coprocessed MCC-SiO~ (prepared as in Example 1A) was added to a Baker-Perkins 10 liter blender and combi~.::d with all of the APAP. The blender impeller was adjusted to 200 rpm and the chopper was set at 1000 rpm. After one minute, the water was added over 90 seconds using a rinse bottle. Thereafter, mixing was continued for an additional 90 seconds. The granulation was removed from the blender, wet screened through a 12 screen mesh and then dried in a convection oven for 2-3 hours at 60°C. until a moisture content of less than 5%

WO 9G/2i429 PCTlUS96l00660 was achieved. The granulation was then dry screened through a 16 mesh screen before being blended for 10 minutes with the remaining portion of the coprocessed MCC-Si02 in a 2 quart V-blender, removed from the blender, and tabletted according to the method of Example 7.
FXAt.rvr.F ~ p D~.rect agmpressicn formu~a+~~T of APAP with M 8 m f 5~w/w1 _ _ A direct compression formulation similar to that set forth in example 9 was undertaken except that the tablets were prepared to contain the coprocessed MCC-SiO, of Example lA. The tablet granulation was prepared according to the following formula:
INGREDIENTS WEIGHT (GRAM&) MCC-510, 175.0 APAP 74.5 PRUV - 0.5 As was the case in example 9, five separate tabletting runs were undertaken using compression forces of 5, 10, 15, 20 and 25 kN respectively on a Korsch tablet press, (punch size: 3/8" and aim weight - about 245 mg). Ten tablets from each compression force were used to carry out the experiment set forth in Example 13.

RX~MpT~F ~ 3 ~Fm STRENCmH TF TTNG
Ten tablets from each compression force run for each formulation prepared in Examples 7-12 were weighed, meas ured for diameter and tested for thickness and hardness on the Erweka TBH 30 tablet hardness tester to determine the compressibility of the microcrystalline cellulose.
The results are graphically illustrated in Figure 2 as a comparison of tensile strength versus compression force.
Referring now to Figure 2, it can be seen that com-pressed tablets made with the inventive coprocessed MCC-Sio, have relatively high tensile strengths when compared to those made with off-the-shelf MCC. The advantages of the coprocessed MCC-si0~ are clearly seen in both direct compression and wet granulation formulations and especially in wet granulation products.
F,o~wunrt~e 7 d-1 (, pTATOMACEONS EARTH
2p In these examples, the coprocessing method described in Example 1A was repeated except that diatomaceous earth of about 40 micron particle size (J. T. Baker, Phillipsburg, N.J was used as the source of Si0_).

Exam le Diatomaoeous Earth (wt %) 14 2.0 15 1.0 16 0.5 The resultant granulates prepared according to Example '1B
were tabletted according to the same method described in Example 6 and evaluated for tensile strength.
The products of inventive Example 3 (MCC-Sio 7.0 2%w/w) and Example 5 (MCC alone) were included in Figure 3 for comparison purposes.

Referring now to Figure 3, it can be seen that al-though the retention of compressibility afforded by co-processing diatomaceous earth is not as great as that provided by colloidal Sio_ having surface areas of about 200 m'/g, the coprocessed MCC-diatomaceous earth nonetheless demonstrates improved compressibility in wet granulation formulations.

In these examples, the coprocessing method described in Example lA was repeated using silica gel 200 micron particle size (VWR Corp., Piscataway, NJ as the source of SiO~) .

Example Silica Gel (wt %) The resultant granulates prepared according to Example 1B were tabletted according to the same method described in Example 6 and evaluated for tensile strength. The products of inventive Example 3 (MCC-SiO
l0 2~w/w) and Example 5 (MCC alone) were included in Figure 4 for comparison purposes.
Referring now to Figure 4, it can be seen that the retention of compressibility afforded by coprocessing with silica gel is well-below that provided by colloidal SiOhaving surface areas of about 200 m'/g. In fact, MCC
coprocessed with silica gel demonstrates compressibility properties about the same as off-the-shelf MCC in wet granulation formulations.
~ 5 crrade S~~-aon n~oxiae In these examples, the coprocessing method described in example 1 was repeated using FIS-5 grade Si0_ surface area -_325 m'/g (Cabot Corp., Tuscola, IL.).

W0 96121429 PCT/fJS96/00660 Example Silica Gel (wt %) 22 0.5 The resultant granulates prepared according to Example 1B were tabletted according to the same method described in Example 6 and evaluated for tensile strength. The products of inventive Example 3 (MCC-Si0=
2$w/w) and Example 5 (off-the-shelf MCC) were included in Figure 5 for comparison purposes.
Referring now to Figure 5, the retention of compressibility afforded-by coprocessing with HS-5 is comparable to that obtained using SiOi having surface areas of about 200 mv/g.
While there have been described what are presently believed-to -be the preferred embodiments of the invention, those skilled in the art will realize that changes and modifications may be made thereto without departing from the spirit ofthe invention. It is intended to claim all such changes and modifications that fall within the true scope of the invention.
4.S

Claims (42)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An excipient composition comprising a particulate agglomerate of microcrystalline cellulose coprocessed with from about 0.1% to about 20% by weight silicon dioxide, the microcrystalline cellulose and silicon dioxide being in intimate association with each other and said silicon dioxide being integrated with or partially coating said microcrystalline cellulose, said silicon dioxide portion of said agglomerate being derived from a silicon dioxide having an average primary particle size from about 1 nm to about 100 µm.
2. An excipient composition, comprising from about 1% to about 99% of an excipient comprising a particulate agglomerate of microcrystalline cellulose coprocessed with from about 0.1% to about 20% silicon dioxide by weight of said microcrystalline cellulose, the microcrystalline cellulose and silicon dioxide being in intimate association with each other and said silicon dioxide being integrated with or partially coating said microcrystalline cellulose, and the silicon dioxide portion of said agglomerate being derived from a silicon dioxide having an average primary particle size from about 1 nm to about 100 µm, and from about 99% to about 1% of an active ingredient.
3. An excipient composition, comprising a particulate excipient of microcrystalline cellulose integrated with from about 0.1% to about 20%
silicon dioxide by weight of said microcrystalline cellulose, said silicon dioxide coprocessed with and partially coating said microcrystalline cellulose and silicon dioxide portion of said excipient being derived from silicon dioxide having a surface area from about 10 m2/g to about 500 m2/g.
4. A solid dosage form composition of a compressed mixture of from about 1% to about 99% of an excipient comprising a particulate agglomerate of coprocessed microcrystalline cellulose and from about 0.1% to about 20% by weight silicon dioxide, the microcrystalline cellulose and silicon dioxide being in intimate association with each other, said silicon dioxide portion of said agglomerate being derived from a silicon dioxide having an average primary particle size from about 1 nm to about 100 µm, and from about 99% to about 1% of a therapeutically active ingredient.
5. The composition of claims 1, 2, and 4 wherein said silicon dioxide portion of said agglomerate is derived from a silicon dioxide having an average primary particle size from about 5 nm to about 40 µm.
6. The composition of claims 1 - 4, wherein said silicon dioxide portion of said composition is derived from colloidal silicon dioxide.
7. The composition of claims 1 - 4, wherein said silicon dioxide is from about 0.5% to about 10% by weight, based on the weight of said microcrystalline cellulose.
8. The composition of claims 1 - 4, wherein said silicon dioxide is included in an amount of from about 1.25% to about 5%, based on the weight of said microcrystalline cellulose.
9. The composition of claims 1 and 4, wherein said composition is comprised of particles having an average particle size of from about 10 µm to about 1,000 µm.
10. The composition of claims 1 and 4, wherein said composition is comprised of particles having an average particle size of from about 10 µm to about 500 µm.
11. The composition of claims 1 and 4, wherein said composition is comprised of particles having an average particle size from about 30 µm to about 250 µm.
12. The composition of claims 1 and 4, wherein said composition is comprised of particles having a moisture content from about 0.5% to about 15%.
13. The composition of claims 1 - 4, wherein said composition further comprises a member selected from the group consisting of non-silicon metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, celluloses, cellulose ethers, cellulose esters and mixtures thereof.
14. The composition of claims 1, 2 and 4, wherein said silicon dioxide portion of said agglomerate is derived from a silicon dioxide having a surface area from about 10 m2/g to about 500 m2/g.
15. The composition of claims 1 - 4, wherein said silicon dioxide portion of said agglomerate is derived from a silicon dioxide having a surface area from about 175 m2/g to about 350 m2/g.
16. The composition of claims 1 - 4, wherein said composition has a bulk density from about 0.2 g/ml to about 0.6 g/ml.
17. The composition of claim 6, wherein said composition has a bulk density from about 0.35 g/ml to about 0.55 g/ml.
18. The composition of claims 1, 2, 6 and 12, which has been wet granulated.
19. The solid dosage form of claim 4, which has been wet granulated prior to compression.
20. The composition of claims 1 and 2 which has been incorporated into a solid form.
21. The composition of claims 1 and 3, which has been wet granulated with an active agent.
22. The solid dosage form of claim 4 wherein the silicon dioxide portion of said agglomerate is derived from a silicon dioxide having an average primary particle size from about 5 µm to about 50 µm.
23. The solid dosage form of claim 4, wherein said excipient has a bulk density from about 0.35 g/ml to about 0.55 g/ml.
24. The solid dosage form of claim 4, prepared by a process comprising the steps of (a) forming an aqueous slurry containing a mixture of microcrystalline cellulose in the form of a wet cake and silicon dioxide;
(b) drying said slurry to obtain an excipient comprising a plurality of agglomerated particles of said microcrystalline cellulose in intimate association with said silicon dioxide, said silicon dioxide having a particle size from about 1 nm to about 100 µm, the amount of silicon dioxide being from about 0.1% to about 20% relative to the amount of microcrystalline cellulose;
(c) mixing an active ingredient with said excipient in a ratio from about 1:99 to about 99:1, by weight; and (d) incorporating said mixture obtained in step (c) into a plurality of solid dosage forms.
25. The solid dosage form of claim 4, wherein a dissolution profile of the solid dosage form provides a controlled release dissolution profile.
26. The solid dosage form of claim 4, wherein a dissolution profile of the solid dosage form provides a sustained release dissolution profile.
27. The solid dosage form of claim 4, wherein a dissolution profile of the solid dosage form provides an immediate release dissolution profile.
28. The solid dosage form of claim 4, further comprising a coating of a hydrophobic polymer.
29. The solid dosage form of claim 28, wherein the solid dosage form includes a sufficient amount of the hydrophobic polymer coating to provide a sustained release of the therapeutically active ingredient over a predetermined period.
30. The solid dosage form of claim 28, wherein the coating further includes an enteric coating material.
31. The solid dosage form of claim 4, further comprising a coating of an enteric coating material.
32. The solid dosage form of claim 31, wherein the enteric coating material is selected from a group consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trimellitate, and mixtures thereof.
33. The solid dosage form of claim 28, wherein the coating further includes a hydrophilic material.
34. The solid dosage form of claim 4, further comprising a coating of a hydrophilic material.
35. The solid dosage form of claims 31 and 34 wherein the solid dosage form includes a sufficient amount of the coating to provide a sustained release of the therapeutically active ingredient over a predetermined period.
36. The solid dosage form of claims 29 and 35, wherein the predetermined period is 12 hours.
37. The solid dosage form of claims 29 and 35, wherein the predetermined period is 24 hours.
38. The solid dosage form of claim 34, wherein the hydrophilic material is hydroxypropylmethylcellulose.
39. The solid dosage form of claims 25 - 27, wherein said excipient further comprises a member selected from the group consisting of non-silicon metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, celluloses, cellulose ethers, cellulose esters and mixtures thereof.
40. The solid dosage form of claims 4, 25 - 27, further comprising a coating of an additional amount of the therapeutically active agent.
41. The solid dosage form of claims 28 and 31, wherein the coating further includes an additional amount of the therapeutically active agent.
42. The solid dosage form of claims 4, 26 - 27 further comprising at least a partial coating of a support platform.
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