WO2002072064A2 - Composition granulaire - Google Patents

Composition granulaire Download PDF

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Publication number
WO2002072064A2
WO2002072064A2 PCT/US2002/000264 US0200264W WO02072064A2 WO 2002072064 A2 WO2002072064 A2 WO 2002072064A2 US 0200264 W US0200264 W US 0200264W WO 02072064 A2 WO02072064 A2 WO 02072064A2
Authority
WO
WIPO (PCT)
Prior art keywords
dry
granulated composition
cellulose ether
composition
granulated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2002/000264
Other languages
English (en)
Other versions
WO2002072064A3 (fr
Inventor
Shawn A. Mitchell
Tina P. Dasbach
Thomas D. Reynolds
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dow Global Technologies LLC
Original Assignee
Dow Global Technologies LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dow Global Technologies LLC filed Critical Dow Global Technologies LLC
Priority to AU2002234219A priority Critical patent/AU2002234219A1/en
Publication of WO2002072064A2 publication Critical patent/WO2002072064A2/fr
Publication of WO2002072064A3 publication Critical patent/WO2002072064A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • This invention relates to a novel granular composition which comprises a therapeutically active compound and a cellulose ether as well as to the use of the novel granular composition in a pharmaceutical composition for oral administration.
  • achieving the desired bioavailability of the therapeutically active compound is important for efficacy and safety reasons.
  • the aqueous solubility of the therapeutically active compound and permeation of the dissolved compound across the walls of the gastrointestinal tract and into the blood stream are known to be important factors influencing the bioavailability of therapeutically active compounds.
  • a poorly water-soluble therapeutically active compound it is generally acknowledged that the rate of dissolution can be the rate-determining step of absorption.
  • U.S. Patent No. 5,093,372 discloses a pharmaceutical composition comprising a physical mixture of exifone and a water-soluble hydroxypropyl methyl cellulose ether, a hydroxypropyl cellulose ether or a methyl cellulose ether.
  • the U.S. Patent discloses that by coexistence of exifone and the mentioned water-soluble polymer the drawback that exifone is sparingly soluble in water is improved and high bioavailability can be attained upon oral administration.
  • an organic solvent such as ethanol
  • the nanoparticulate formulations are said to have an increased rate of dissolution in vitro and an increased rate of absorption in vivo.
  • the nanoparticulate HIV protease inhibitors have a cellulosic surface stabilizer absorbed thereon in an amount sufficient to maintain an effective average particle size of less than about 1000 nm.
  • the nanoparticulate HIV protease inhibitor particles are prepared by wet milling of an HIV protease inhibitor.
  • the HIN protease inhibitor can be milled in the presence of the cellulosic surface stabilizer or the drug particles can be contacted with the cellulosic surface stabilizer following the milling process.
  • this wet- milling procedure may require several days to complete, requires a large amount of grinding media, such as zirconium oxide or polymeric beads, and poses significant difficulties when scaling up from laboratory-scale to a production-scale.
  • U.S. Patent No. 5,861,172 discloses compacted granulates of a mixture of 99.9-90 weight percent, most preferably 98.75-96.5 weight percent of an antibiotic and 0.1 to 10 weight percent, most preferably 1.25-3.5 weight percent of an intragranular disintegrant selected from starches, such as maize starch, rice starch, cross-linked N-vinyl-2-pyrrolidone, sodium starch glycollate, croscarmellose sodium and formaldehyde-casein.
  • starches such as maize starch, rice starch, cross-linked N-vinyl-2-pyrrolidone, sodium starch glycollate, croscarmellose sodium and formaldehyde-casein.
  • the U.S. patent teaches that the intimate contact between the antibiotic and the intragranular disintegrant in the granulate appears to assist in improved disintegration and dispersion of the granulate in contact with water to release antibiotic particles and to provide finely dispersed suspensions.
  • the compacted granules can be used in encapsulated formulations or can be compacted together into a tablet form together with a wide variety of extra-granular disintegrants and optionally also an extra-granular lubricant.
  • the granulate amounts to 70 percent or more, most preferably 95 percent or more of the total tablet weight.
  • the U.S patent does not teach how to increase the dissolution rate of sparingly water-soluble drugs.
  • U.S. Patent No. 5,340,591 discloses a method of producing a solid dispersion of the sparingly water-soluble drug nilvadipine in a water-soluble polymer, such as hydroxypropyl methyl cellulose or methyl cellulose, wherein the drug and the water-soluble polymer are mixed and heated below the melting points of the two components.
  • a water-soluble polymer such as hydroxypropyl methyl cellulose or methyl cellulose
  • One aspect of the present invention is a method of increasing the dissolution rate of a therapeutically active compound in an aqueous liquid which comprises the steps of i) preparing an essentially dry mixture consisting essentially of a) a therapeutically active compound and b) a cellulose ether, ii) compacting the resulting mixture under pressure and iii) comminuting the compacted mixture.
  • the dissolution rate of poorly water-soluble therapeutically active compounds can be substantially more increased by the method of the present invention than by preparing a corresponding dry-blended, non-compressed physical mixture of the therapeutically active compound a) and the cellulose ether b).
  • Another aspect of the present invention is a dry-granulated composition which consists essentially of a) a therapeutically active compound and b) a cellulose ether, wherein the dry-granulated composition comprises agglomerates of the compound a) and the cellulose ether b) and at least 10 weight percent of the dry-granulated composition has a particle size of greater than 425 micrometers.
  • Yet another aspect of the present invention is the use of an above-mentioned dry- granulated composition for preparing a pharmaceutical composition for oral administration.
  • Yet another aspect of the present invention is a method of preparing a pharmaceutical composition for oral administration wherein an above-mentioned dry- granulated composition is blended with a liquid or solid excipient and compounded to produce the pharmaceutical composition.
  • Yet another aspect of the present invention is a pharmaceutical composition for oral administration which comprises the above-mentioned dry-granulated composition.
  • the dry-granulated composition of the present invention consists essentially of the therapeutically active compound a) and the cellulose ether b).
  • the term "consists essentially of means that the combined weights of a) and b) are at least 80 weight percent, preferably at least 90 weight percent, more preferably at least 95 weight percent, most preferably at least 98 weight percent, based on the total weight of the dry-granulated composition.
  • the present invention is particularly suitable for poorly water-soluble drugs, that means drugs with a low solubility in water resulting in a poor bioavailability after oral administration.
  • low solubility is meant to encompass all drugs in which the aqueous solubility of the drug hinders its oral administration.
  • Poorly water-soluble drugs generally have an aqueous solubility of less than 33 mg/mL, typically less than 10 mg/mL, more typically less than 1 mg/mL.
  • poorly water-soluble is used herein synonymously to other terms known in the art, such as “sparingly water-soluble", “water- insoluble” or “practically water-insoluble”.
  • the dry-granulated composition of the present invention comprises a cellulose ether b).
  • the cellulose ether is preferably water-soluble at a temperature of up to 40°C.
  • suitable cellulose ethers are alkyl cellulose ethers, preferably methyl cellulose ethers; or alkyl hydroxyalkyl cellulose ethers, preferably C !
  • -C 3 -alkyl hydroxy- .s- alkyl cellulose ethers more preferably hydroxypropyl methyl cellulose ethers; or hydroxyalkyl cellulose ethers, preferably hydroxy- .s-alkyl cellulose ethers, more preferably hydroxypropyl cellulose ethers; or mixed hydroxyalkyl cellulose ethers, preferably mixed hydroxy- -Cs-alkyl cellulose ethers.
  • Methyl cellulose ethers and hydroxypropyl methyl cellulose ethers are particularly preferred.
  • the most preferred cellulose ethers are methyl cellulose ethers with a methoxyl substitution of from 21 to 42 percent, more preferably from 26 to 33 percent, and methyl hydroxypropyl cellulose ethers with a methoxyl substitution of from 16 to 33 percent, more preferably from 19 to 30 percent, and a hydroxypropoxyl substitution of from 1 to 32 percent, preferably from 3 to 12 percent.
  • Methylcellulose ethers generally will have a non-methoxyl substitution content of about 5% or less, more preferably about 1 percent or less, if they contain any measurable non-methoxyl substitution.
  • the viscosity of the cellulose ether preferably is up to 4000 mPa's, more preferably up to 100 mPas, most preferably up to 10 mPa s, measured as a 2 weight percent aqueous solution at 20 °C using an Ubbelohde viscosimeter.
  • the viscosity of the cellulose ether is generally 0.1 mPa ' s or more, typically 3 mPa's or more, measured as indicated above.
  • the dry-granulated composition generally comprises a) from 9 to 91 weight percent, preferably from 16 to 84 weight percent, more preferably from 25 to 75 weight percent, most preferably from 40 to 60 weight percent of the therapeutically active compound, b) from 9 to 91 weight percent, preferably from 16 to 84 weight percent, more preferably from 25 to 75 weight percent, most preferably from 40 to 60 weight percent of the cellulose ether, and c) from 0 to 20 weight percent, preferably from 0 to 10 weight percent, more preferably from 0 to 5 weight percent, most preferably from 0 to 2 weight percent of an excipient other than the cellulose ether b), the amounts of a), b) and c) being based on the total weight of the dry-granulated composition.
  • the total amount of a) and b) is at least 80 weight percent, preferably at least 90 weight percent, more preferably at least 95 weight percent, most preferably at least 98 weight percent, based on the total weight of the dry- granulated composition.
  • Excipients other than cellulose ethers which can be incorporated in the dry- granulated composition of the present invention as component c) are generally solid at room temperature and pharmaceutically inert. Their amount should be low enough that the excipient does not substantially decrease the effect of the cellulose ether b) on the dissolution rate of the therapeutically active compound a). Suitable amounts of the excipient, if present, are indicated above.
  • diluents such as crystalline cellulose, starch, D-mannitol or lactose
  • surfactants such as sodium laurel sulfate, polyethylene glycols, or polysorbates
  • binders such as lubricants such as magnesium stearate
  • desintegrants such as hydroxypropyl starch or starch-glycolate.
  • the dry-granulated composition of the present invention comprises more than one type of therapeutically active compounds a) or cellulose ethers b) or excipients c), the weight amounts of the total of compounds a), the total of cellulose ethers b) and the total of excipients c) is generally within the ranges indicated above.
  • At least 10 weight percent, preferably at least 20 weight percent, more preferably at least 30 weight percent of the dry-granulated composition has a particle size of greater than 425 micrometers.
  • at least 20 weight percent, preferably at least 30 weight percent, more preferably at least 40 weight percent of the dry-granulated composition has a particle size of greater than 250 micrometers.
  • Preferably less than 30 weight percent, more preferably less than 25 weight percent of the dry-granulated composition has a particle size of less than 75 micrometers.
  • particle size is meant the size of the sieve mesh on which the particles are excluded.
  • the average particle size of the dry-granulated composition of the present invention is preferably at least 5 micrometers, more preferably at least 10 micrometers.
  • composition of the present invention is dry-granulated.
  • dry-granulated is meant that not more than about 10 percent, preferably not more than about 5 percent, more preferably not more than about 2 percent of a liquid has been added prior to or during granulation, based on the total weight of the composition, if any liquid has been added at all.
  • Some liquid can be added to the composition to be granulated, for example to reduce dust, however the presence of liquid is not required and its amount should be within the limits indicated above.
  • the dry-granulated composition of the present invention is free from solvent residues. By visual comparison of the composition under the microscope, it is discernible whether the composition is dry- granulated or whether it has been produced by a conventional wet granulation method requiring the presence of a liquid, such as water or an organic solvent.
  • an essentially dry mixture of components a) and b) and optionally c) may be mixed in a known mixing device, such as a N-blender.
  • An "essentially dry mixture” means that not more than about 10 percent, preferably not more than about 5 percent, more preferably not more than about 2 percent of a liquid, based on the total weight of the mixture, has been added to the mixture if any liquid has been at all.
  • Preferred therapeutically active compounds a), preferred cellulose ethers b), optional excipients c) and preferred weight ranges of the components a) and b) and the optional excipient c) are indicated above.
  • the mixing is preferably carried out at room temperature.
  • step ii) of the method of the present invention the resulting mixture is compacted under pressure.
  • the pressure generally is at least 1,000 psi (6.9 MPa), preferably at least 5,000 psi (34.5 MPa), more preferably at least 10,000 psi (69 MPa).
  • Any conventional methods and devices for compacting the mixture known in the art can be used.
  • a preferred method is by slugging on a tablet press, such as a rotary tablet press.
  • the most preferred method is by roller compaction.
  • the compacted mixture typically has a coherent structure, such as a ribbon or a slug.
  • step iii) of the method of the present invention the compacted mixture is comminuted to a granular composition.
  • At least 10 weight percent, preferably at least 20 weight percent, most preferably at least 30 weight percent of the granular composition has a particle size of greater than 425 micrometers and/or generally at least 20 weight percent, preferably at least 30 weight percent, more preferably at least 40 weight percent has a particle size of greater than 250 micrometers and/or preferably less than 30 weight percent, more preferably less than 25 weight percent of the granular composition has a particle size of less than 75 micrometers.
  • Any conventional comminution method and device may be used, including bill mills, co-mills, or other communition devices known in the art.
  • liquid can be added to the essentially dry mixture obtained in step i) prior to or during the compacting and comminuting steps ii) and iii), for example to reduce dust, however the presence of liquid is not required and its total amount should be within the limits indicated further above.
  • no substantial amount of heat is added to the essentially dry mixture obtained in step i) prior to or during the compacting and comminuting steps ii) and iii).
  • no substantial amount is meant that the mixture is not subjected to an external heat source with the purpose to raise the temperature of the mixture.
  • steps i), ii) and iii) of the method of the present invention are carried out without addition of a liquid and without use of an external heat source.
  • the dry-granulated composition prepared as described above has a drug dissolution rate which is considerably higher than I) the drug dissolution rate of the same, but non- diluted therapeutically active compound a) and II) the drug dissolution rate of a corresponding dry-blended, non-compressed physical mixture of the therapeutically active compound a) and the cellulose ether b) and an optional excipient c).
  • the difference in dissolution rate depends on various factors, such as the characteristics of the therapeutically active compound a) and the type and viscosity of the cellulose ether b).
  • the dry-granulated composition prepared as described above is useful for preparing a pharmaceutical composition for oral admimstration.
  • the dry-granulated composition can be blended with a liquid or solid excipient and compounded to a pharmaceutical composition in a known manner.
  • the dry-granulated composition can be combined with known excipients, such as those listed further above, and compounded to tablets.
  • the dry-granulated composition is particularly useful in the preparation of capsules which are filled with the dry-granulated composition of the present invention.
  • hydroxypropyl methyl cellulose ether 200 g of the drug naproxen and 200 g of a hydroxypropyl methyl cellulose ether, commercially available from The Dow Chemical Company under the Trademark METHOCEL K3PLN cellulose ether are dry blended in a N-blender for 20 minutes.
  • the hydroxypropyl methyl cellulose ether has a methoxyl substitution of 19-24 percent, a hydroxypropoxyl substitution of 7-12 percent and a viscosity of 3 mPa's.
  • the resulting physical mixture is roller compacted using smooth rolls on a Freund roller compactor, Model mini, commercially available from Vector Co ⁇ oration, Marion, Iowa under the following conditions: Screw Motor: 8.0 RPM, 0.6 amps Roll Motor: 2.0 RPM, 1.3 amps Roll Force: 3 tons (29.4 k ⁇ ).
  • the resulting ribbons are milled with a CoMil, Model 197S from Quadro Engineering, Waterloo, Ontario, Canada at 1000 RPM.
  • Example 1 is repeated except that nifedipine is used as a drug instead of naproxen.
  • Example 1 150 g of carbamazepine and 150 g of METHOCEL K3PLN cellulose ether are dry blended as described in Example 1. The resulting physical mixture is roller compacted and milled as described in Example 1 except that the Freund roller compactor is run under the following conditions.
  • Screw Motor 4.0 RPM, 0.3 amps Roll Motor: 2.0 RPM, 1.3 amps Roll Force: 3 tons (29.4 k ⁇ )
  • EXAMPLE 4 25.0 g of naproxen and 25.0 g of METHOCEL K3PLN cellulose ether are dry blended in a glass jar for 10 minutes. Slugs are compressed from the resulting physical mixture on a commercially available Carver Press (Model C) using the following conditions: Punch and Die: 0.8755 in (22.2 mm) diameter, round, flat faced
  • the resulting slugs are milled as described in Example 1 except that the mill is run at 1450
  • Example 4 is repeated except that nifedipine is used as a drug instead of naproxen.
  • Example 4 is repeated except that carbamazepine is used as a drag instead of naproxen.
  • Comparative Examples A to C 10 g METHOCEL K3PLN cellulose ether is dry blended with 10 g of the drag naproxen (Comparative Example A) or with 10 g of the drug nifedipine (Comparative Example B) or with 10 g of the drag carbamazepine (Comparative Example C) in a glass jar for 20 minutes.
  • Example 4 is repeated, except that 20.0 g of the drag naproxen from a different lot than in Example 4 is dry blended with 20.0 g of a hydroxypropyl methyl cellulose ether, commercially available from The Dow Chemical Company under the Trademark METHOCEL E3PLN cellulose ether.
  • the hydroxypropyl methyl cellulose ether has a methoxyl substitution of 28-30 percent, a hydroxypropoxyl substitution of 7-12 percent and a viscosity of 3 mPa's.
  • Comparative Example E Comparative Example A is repeated except that the drag naproxen from the same lot as in Example 7 and the same hydroxypropyl methyl cellulose ether as in Example 7 are used.
  • Example 7 is repeated, except that a hydroxypropyl methyl cellulose ether, commercially available from The Dow Chemical Company under the Trademark METHOCEL E5PLN cellulose ether is used.
  • the hydroxypropyl methyl cellulose ether has a methoxyl substitution of 28-30 percent, a hydroxypropoxyl substitution of 7-12 percent and a viscosity of 5 mPas.
  • Comparative Example F Comparative Example E is repeated except that the same methyl cellulose ether as in Example 8 is used.
  • Example 4 is repeated, except that a methyl cellulose ether, commercially available from The Dow Chemical Company under the Trademark METHOCEL A4M cellulose ether is used.
  • the methyl cellulose ether has a methoxyl substitution of 27.5-31.5 percent and a viscosity of 4,000 mPa's.
  • the methyl cellulose ether is subjected to a molecular weight reduction with anhydrous hydrochloric acid whereby the viscosity is reduced from 4,000 mPa.s to 5.5 mPa.s. 30.0 g of the thus treated cellulose ether material is blended with 30.0 g of naproxen, originating from the same lot as in Example 4, and the process of Example 4 is performed.
  • Comparative Example D Comparative Example A is repeated except that the same methyl cellulose ether as in Example 9 with a viscosity of 5.5 mPa.s is used.
  • the measuring device is only capable of measuring a carbamazepine concentration of up to 40 mg/L. The listed concentration is higher.
  • Tables II and 'III illustrate that a dry-granulated composition prepared according to the present invention has a drag dissolution rate which is considerably higher than i) the drag dissolution rate of the same, but non-diluted therapeutically active compound and ii) the drag dissolution rate of a corresponding dry-blended, non-compressed physical mixture of the therapeutically active compound a) and a cellulose ether b).
  • Example 2 2.0 g of the dry-granulated composition produced according to Example 2, 0.4 g of microcrystalline cellulose, 0.2 g of cross-linked sodium carboxymethycellulose (trademark Ac-Di-Sol), and 1.4 g of Fast-Flo lactose (#316) are blended in a glass jar for 10 minutes. 10 mg of magnesium stearate is added and the formulation is blended for an additional 1 minute. Tablets are compressed from the resulting mixture exactly as described in Example 10.
  • Example 11 is repeated, except that the dry-granulated composition produced according to Example 3 is used instead of the dry-granulated composition produced according to Example 2.
  • Example 10 is repeated, except that 5.0 g of the dry-granulated composition produced according to Example 9 is used instead of the dry-granulated composition produced according to Example 1.
  • Controlled release tablets are prepared as follows: 4.0 g of the dry-granulated composition produced according to Example 1, 2.0 g of a hydroxypropyl methyl cellulose ether, commercially available from The Dow Chemical Company under the Trademark METHOCEL K4MP CR cellulose ether, and 2.0 g of Fast-Flo lactose (#316) are blended in a glass jar for 10 minutes.
  • the hydroxypropyl methyl cellulose ether has a methoxyl substitution of 19-24 percent, a hydroxypropoxyl substitution of 7-12 percent and a viscosity of 4,000 mPas. 25 mg of magnesium stearate is added and the formulation is blended for an additional 1 minute. Tablets are compressed from the resulting mixture exactly as described in Example 10.
  • Controlled release tablets are prepared as follows: 0.4 g of the dry-granulated composition produced according to Example 1, 1.2 g of METHOCEL K4MP CR cellulose ether, and 2.4 g of Fast-Flo lactose (#316) are blended in a glass jar for 10 minutes. 10 mg of magnesium stearate is added and the formulation is blended for an additional 1 minute. Tablets are compressed from the resulting mixture exactly as described in Example 10.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne la vitesse de dissolution d'un composé thérapeutiquement actif dans un liquide aqueux, que l'on augmente i) en préparant un mélange sensiblement sec composé sensiblement a) d'un composé thérapeutiquement actif et b) d'un éther de cellulose; ii) en tassant sous pression le mélange résultant et iii) en broyant le mélange tassé.
PCT/US2002/000264 2001-03-09 2002-01-03 Composition granulaire Ceased WO2002072064A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002234219A AU2002234219A1 (en) 2001-03-09 2002-01-03 Granular composition comprising an active compound and a cellulose ether and the use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US27470801P 2001-03-09 2001-03-09
US60/274,708 2001-03-09

Publications (2)

Publication Number Publication Date
WO2002072064A2 true WO2002072064A2 (fr) 2002-09-19
WO2002072064A3 WO2002072064A3 (fr) 2003-03-06

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PCT/US2002/000264 Ceased WO2002072064A2 (fr) 2001-03-09 2002-01-03 Composition granulaire

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AU (1) AU2002234219A1 (fr)
WO (1) WO2002072064A2 (fr)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4590062A (en) * 1984-04-16 1986-05-20 Tech Trade Corp. Dry direct compression compositions for controlled release dosage forms
GB8722306D0 (en) * 1987-09-22 1987-10-28 Aps Research Ltd Sustained-release formulation
US4973470A (en) * 1989-06-26 1990-11-27 Warner-Lambert Company Sustained release pharmaceutical compositions
US5965161A (en) * 1994-11-04 1999-10-12 Euro-Celtique, S.A. Extruded multi-particulates
US6045829A (en) * 1997-02-13 2000-04-04 Elan Pharma International Limited Nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers
DE10029201A1 (de) * 2000-06-19 2001-12-20 Basf Ag Verfahren zur Herstellung fester oraler Darreichungsformen mit retardierender Wirkstoffreisetzung

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AU2002234219A1 (en) 2002-09-24
WO2002072064A3 (fr) 2003-03-06

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