EP1675574A2 - Pharmaceutical compositions of paroxetine containing microcrystalline cellulose, prepared by wet granulation - Google Patents

Pharmaceutical compositions of paroxetine containing microcrystalline cellulose, prepared by wet granulation

Info

Publication number
EP1675574A2
EP1675574A2 EP04769597A EP04769597A EP1675574A2 EP 1675574 A2 EP1675574 A2 EP 1675574A2 EP 04769597 A EP04769597 A EP 04769597A EP 04769597 A EP04769597 A EP 04769597A EP 1675574 A2 EP1675574 A2 EP 1675574A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
composition according
modified release
paroxetine
granules
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.)
Withdrawn
Application number
EP04769597A
Other languages
German (de)
French (fr)
Inventor
Pratik Kumar
Girish Kumar Jain
Ashok Kumar Rampal
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.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of EP1675574A2 publication Critical patent/EP1675574A2/en
Withdrawn legal-status Critical Current

Links

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • 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

Definitions

  • paroxetine PHARMACEUTICAL COMPOSTIONS OF PAROXETINE Field of the Invention
  • the present invention relates to stable pharmaceutical compositions of paroxetine and processes for their preparation.
  • Background of the Invention The chemical name for paroxetine is (-) - trans-3- [(1, 3 - benzodioxol - 5 - yl oxy) methyl] - 4 - (4 - fluorophenyl) piperidine; (3S, 4R) - 3 - [5 - (1, 3 - dioxaindanyl) oxy methyl] - 4 - (p - fluorophenyl) piperidine, a 5 - hydroxy tryptamine (5 - HT, serotonin).
  • Paroxetine functions as a re-uptake inhibitor and is disclosed in U.S. Patent No. 4,007,196.
  • Paroxetine is indicated for the treatment of psychiatric problems including depression, Parkinson's disease, anxiety disorders, obsessive-compulsive disorders, panic disorders and post-traumatic stress disorder and other symptoms associated with excessive serotonin release. It is marketed in both immediate release and controlled release dosage forms by Glaxo SmithKline under the trade names of Paxil ® and Paxil ® CR respectively.
  • Solid dosage forms of paroxetine often develop certain physical instabilities, depending on the excipients used and the method of their preparation. This is evident by the development of a pink hue, softening of the dosage form or a decrease in the hardness upon storage.
  • paroxetine tablets which (i) are free of hydroxypropyl methylcellulose and (ii) include a filler that is non-hygroscopic or free of hydrochloric acid (HC1).
  • HC1 hydrochloric acid
  • a pharmaceutical composition comprising paroxetine, microcrystalline cellulose, and one or more additional pharmaceutically acceptable inert excipients.
  • the pharmaceutical composition is prepared by a wet granulation technique.
  • Embodiments of the pharmaceutical composition may include one or oreof ht following features.
  • the paroxetine may be free paroxetine base and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • the pharmaceutically acceptable salt may be hydrochloride, maleate, acetate and mesylate.
  • the concentration of microcrystalline cellulose maybe from about 15% to about 45% by weight. More particularly, the concentration of the microcrystalline cellulose may be about 30% by weight.
  • the pharmaceutically acceptable inert excipient may be one or more of fillers, binders, disintegrants, wetting agents, stabilizers, lubricants/glidants, flavoring agents and coloring agents.
  • the wet granulation may be carried out using one or more water miscible solvents, with or without water.
  • the water miscible solvent may be lower alcohols and lower ketones.
  • the lower alcohols may be one or both of ethanol and isopropyl alcohol.
  • the water miscible solvent maybe a mixture of water and isopropyl alcohol.
  • the pharmaceutical composition may be a tablet, capsule, caplet, spheroid, or granule.
  • the pharmaceutical composition may further include a non-functional film- forming polymer coating.
  • a modified release pharmaceutical composition that includes paroxetine, microcrystalline cellulose, at least one modified release polymer, and one or more pharmaceutically acceptable inert excipients.
  • the pharmaceutical composition is prepared by wet granulation technique.
  • Embodiments of the modified release pharmaceutical composition may include one or more of the following features.
  • the modified release polymer may be one or more of cellulose derivatives, alginic acid derivatives, methacrylic acid derivatives, polysaccharides, and alkylene oxides.
  • the modified release polymer may be hydroxypropyl methylcellulose of one or more of the low, medium and high viscosity grades of hydroxypropyl methylcellulose and mixtures thereof.
  • the concentration of the hydroxypropyl methylcellulose may be from about 10% to about 30% by weight of the total composition weight.
  • the paroxetine may be free paroxetine base and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • the concentration of microcrystalline cellulose maybe from about 15% to about 45%> by weight.
  • the one or more pharmaceutically acceptable inert excipients may be one or more of fillers, binders, disintegrants, wetting agents, stabilizers, lubricants/glidants, flavoring agents and coloring agents.
  • the wet granulation may be carried out using a water miscible solvent, with or without water.
  • the water miscible solvent may be lower alcohols and lower ketones.
  • the water miscible solvent may be a mixture of water and isopropyl alcohol.
  • the pharmaceutical composition may be a solid dosage form.
  • the solid dosage form may be tablets, capsules, caplets, spheroids, and granules.
  • the pharmaceutical composition may further include an enteric polymer coating.
  • the enteric polymer may be one or more of cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and one or more methacrylic acid copolymers.
  • the enteric polymer coating may be about 1% to about 10% w/w of the total weight of the uncoated composition.
  • the pharmaceutical composition may further include a non functional film coating.
  • a process for the preparation of a pharmaceutical composition of paroxetine there is provided.
  • the process includes (a) blending paroxetine, microcrystalline cellulose, and one or more pharmaceutically acceptable excipients to form a blend; (b) wet granulating the blend to form granules; (c) drying and sizing the granules; and (d) lubricating and processing the granules into a solid dosage form.
  • Embodiments of the process may include one or more of the features described above.
  • a process for the preparation of a modified release pharmaceutical composition of paroxetine is provided.
  • the process includes (a) blending paroxetine with microcrystalline cellulose, hydroxypropyl methylcellulose, and one or more of fillers, binders and disintegrants to form a blend; (b) wet granulating the blend to form granules; (c) drying and sizing the granules; and (d) lubricating the granules and compressing into tablets.
  • Embodiments of the process may include one or more of the following features or those described above.
  • the process may further include (e) coating the tablet with enteric polymers up to a weight gain of about 10% w/w; and (f) film coating up to a weight gain of about 3% w/w.
  • a pharmaceutical composition including granules.
  • the granules include paroxetine and microcrystalline cellulose.
  • the granules are prepared by a wet granulation technique.
  • Embodiments of the pharmaceutical composition may include one or more of the features described above.
  • a method of treating depression in a subject in need thereof includes administering a pharmaceutical composition that includes paroxetine, microcrystalline cellulose, and one or more pharmaceutically acceptable inert excipients.
  • the pharmaceutical composition is prepared by wet granulation technique.
  • Embodiments of the process may include one or more of the following features or those described above.
  • compositions of paroxetine of the present invention may be prepared by the wet granulation technique using microcrystalline cellulose (MCC) as a filler, and hydroxypropyl methylcellulose (HPMC) as a modified release polymer without the development of either the pink hue or decrease in hardness upon storage.
  • MCC microcrystalline cellulose
  • HPMC hydroxypropyl methylcellulose
  • the preparation of the granulation for tableting by the wet granulation process is amongst the oldest and most widely used techniques.
  • MCC being a porous material, promotes easy wetting and rapid drying of wet granulation, and the granules exhibit good flow properties with a low lubricant demand.
  • 'stable' as used herein refers to mechanical stability of pharmaceutical composition of paroxetine wherein the composition does not lose its hardness or develop pink discoloration on storage at a temperature of 40°C and 75% relative humidity for 5 days.
  • paroxetine' as used herein includes paroxetine and pharmaceutically acceptable salts thereof, such as, hydrochloride, maleate, acetate, mesylate and hydrates and solvates thereof.
  • paroxetine hydrochloride hemihydrate may be used.
  • pharmaceutical composition' as used herein refers to solid dosage forms for oral administration such as tablet, capsule, pill, spheroid, granule and the like. For example, tablets may be used.
  • modified release dosage form as used herein includes dosage forms intended for slow release, such as controlled release, prolonged release, delayed release, timed release, etc. that are capable of modifying the release of the drug up to a period of about 12 hours.
  • a delayed release dosage form may be used.
  • the term 'wet granulation' as used herein refers to granulation using water miscible solvent(s) with or without water.
  • Suitable water miscible solvents include one or more of lower alcohols, such as ethanol and isopropyl alcohol (IP A), and lower ketones, such as acetone.
  • IP A isopropyl alcohol
  • MCC is purified partially de-polymerized alpha-cellulose. The de-polymerization is catalyzed by hydrochloric acid.
  • MCC is a white, odorless, tasteless free flowing powder, which is insoluble in water, soluble in acids and most organic solvents and is practically insoluble in sodium hydroxide solution.
  • the concentration of MCC may range from about 15% to about 45% by weight. In particular MCC at a concentration of about 30% may be used. It is commercially available under the trade name of Avicel ® (manufactured by FMC Corporation) in various grades such as PH 103, PH 105, PH 101, PH 113 and PH 301. hi particular, Avicel ® PH 101 may be used.
  • Suitable modified release polymers include one or more of cellulose derivatives, alginic acid derivatives, methacrylic acid derivatives, polysaccharides, alkylene oxides and the like. Specific examples of cellulose derivatives include HPMC, hydroxypropyl cellulose (HPC), methylcellulose, carboxymethyl cellulose, and hydroxyethyl cellulose.
  • Alginic acid derivative as used herein include alginic acid and its physiologically acceptable salts such as those of sodium, potassium, calcium, and the like.
  • methacrylic acid derivatives include the various grades available under the trade name of Eudragit®.
  • polysaccharides include chitosan, gellan, xanthan gum and the like.
  • alkylene oxide include polyethylene oxide.
  • HPMC is cellulose ether, derived from alkali treated cellulose that is reacted with methyl chloride and propylene oxide. It has several names including 2-hydroxy propyl ether of methyl cellulose, propylene glycol ether of methyl cellulose, 2-hydroxy propyl methyl ether, hypromellose, etc.
  • HPMC modified release polymer, binder, and in coating compositions. It is widely used as a modified release polymer, binder, and in coating compositions. It is commercially available as Methocel® (manufactured by Dow Chemicals) in various viscosity grades.
  • concentration of HPMC may range from about 10% to about 30% by weight. In particular, HPMC at a concentration of about 14% may be used.
  • HPMC of low viscosity grades include Methocel E-5, Methocel E-15 LV, Methocel E-50 LV, Methocel K-100 LV and Methocel F-50 LV, whose 2% w/v aqueous solutions have viscosities of 5 cPs, 15 cPs, 100 cPs and 50 cPs, respectively.
  • HPMC of medium viscosity grade examples include Methocel E4M and Methocel K4MCR, whose 2% w/v aqueous solutions have a viscosity of 4000 cPs.
  • HPMC of high viscosity grade examples include Methocel Kl 5M and Methocel K 100M whose 2% w/v aqueous solutions have viscosities of 15,000 and 10,000 cPs, respectively.
  • Methocel K4MCR and Methocel E-15 LV may be used.
  • Suitable pharmaceutically acceptable inert excipients include one or more of wetting agents, fillers, binders, disintegrants, coloring agents, flavoring agents, stabilizers, lubricants/glidants and plasticizers.
  • Suitable wetting agents used in the present embodiment include both ionic and non-ionic wetting agents.
  • polyethylene glycols include one or more of polyethylene glycols; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer”; polyglycerin fatty acid ester, such as decaglyceryl monolaurate and decaglyceryl monomyristate, polyoxyethylene sorbitan fatty acid ester, such as polyoxyethylene sorbitan monooleate, polyethylene glycol fatty acid ester, such as polyoxyethylene monosterate, polyoxyethylene alkyl ether, such as poluoxyethylene lauryl ether; polyoxyethylene castor oil and hardened castor oil, such as polyoxyethylene hardened castor oil; sucrose ester of fatty acid, such as sucrose state ester and sucrose palmitate ester and alkyl sulfate salt, such as sodium lauryl sulfate and magnesium lauryl sulfate; sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene
  • poloxamer available under the trade name of Lutrol
  • Suitable fillers include one or more of calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and other suitable fillers.
  • Suitable binders include one or more of polyvinyl pyrrolidone, methylcellulose, hydroxypropyl cellulose, HPMC, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and other suitable binders.
  • Suitable disintegrants include one or more of microcrystalline cellulose, croscarmellose sodium, crospovidone, carboxymethyl starch sodium, sodium starch glycollate, and other suitable disintegrants.
  • Suitable lubricants and glidants include one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
  • plasticizers include one or more of polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl sebacate, and other suitable plasticizers.
  • stabilizers include one or more of antioxidants, buffers, acids, and other suitable stabilizers.
  • coloring agents include any FDA approved colors for oral use.
  • the pharmaceutical composition of paroxetine may be prepared by a process which includes the steps of: blending paroxetine with microcrystalline cellulose, an additional filler, binder, and disintegrant; wet granulating the blend to form granules; drying the granules; lubricating the granules; and compressing the granules into tablets.
  • the modified release pharmaceutical composition of paroxetine may be prepared by a process which includes the steps of: blending paroxetine with microcrystalline cellulose, at least one modified release polymer, another filler, binder, and disintegrant; wet granulating the blend to form granules; drying the granules; lubricating the granules; and compressing the granules into tablets.
  • the modified release pharmaceutical composition of paroxetine may be prepared by a process that includes the steps of: blending paroxetine with microcrystalline cellulose, hydroxypropyl methylcellulose, another filler, binder, and disintegrant; wet granulating the blend to form granules; drying the granules; lubricating the granules; and compressing the granules into tablets.
  • the tablets prepared in any of the above embodiments may further be coated with one or more conventional film-forming polymers and / or modified release polymer.
  • the tablets may be coated with an enteric polymer to provide a delayed release of paroxetine.
  • Suitable film-forming polymers include one or more of ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose; waxes, such as polyethylene glycol; methacrylic acid polymers, such as Eudragit ® RL and RS; and the like.
  • the coating may be performed using commercially available, ready-to-coat preparations, such as, various grades of Opadry ® .
  • Suitable enteric polymer include one or more of cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate; methacrylic acid copolymers, such as Eudragit ® L 100-55, Eudragit ® L 30, Eudragit ® D55, Eudragit ® L 100, Eudragit ® S 100; and the like.
  • the enteric coating may be continued up to a weight gain of about 1% to about 50% by weight of the uncoated tablet.
  • the enteric coating may be continued up to a weight gain of about 1% to about 10% by weight of uncoated tablet and more particularly, up to a weight gain of about 5% to 10% of the uncoated tablet.
  • a modified release pharmaceutical composition of paroxetine may be prepared by a process which includes the steps of: blending paroxetine with microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, and polyvinyl pyrrolidone; wet granulating the blend to form granules, drying the granules, lubricating the granules; compressing into tablets; coating the tablets with enteric polymers up to a weight gain of 8-10% w/w, and coating with Opadry ® up to a weight gain of 2-3%o w/w.
  • the invention is further illustrated by the following examples, which is for illustrative purpose and should not be construed as limiting the scope of the invention in any way. Examples 1 and 2
  • Example 1 and 2 were tested for in vitro release of paroxetine hydrochloride hemihydrate in USP type II dissolution apparatus with #10 sinker at 100 rpm and temperature of 37 ⁇ 0.5°C, in 500 ml of 0.1N hydrochloric acid for 2 hours and then transferred to 900 ml of pH 6.8 buffer for the remaining period. 10 ml samples were withdrawn at pre-determined intervals and replaced with an equal volume of the appropriate pre-warmed dissolution medium. The withdrawn samples were analyzed for paroxetine hydrochloride hemihydrate content after appropriate dilution. The results of the study are shown in Table 2. Table 2. In vitro release profile of paroxetine hydrochloride hemihydrate from the prepared tablets

Abstract

The present invention relates to stable pharmaceutical compositions of paroxetine and process for preparation thereof. The pharmaceutical composition includes paroxetine, microcrystalline cellulose, and one or more additional pharmaceutically acceptable inert excipients. The pharmaceutical composition is prepared by a wet granulation technique.

Description

PHARMACEUTICAL COMPOSTIONS OF PAROXETINE Field of the Invention The present invention relates to stable pharmaceutical compositions of paroxetine and processes for their preparation. Background of the Invention The chemical name for paroxetine is (-) - trans-3- [(1, 3 - benzodioxol - 5 - yl oxy) methyl] - 4 - (4 - fluorophenyl) piperidine; (3S, 4R) - 3 - [5 - (1, 3 - dioxaindanyl) oxy methyl] - 4 - (p - fluorophenyl) piperidine, a 5 - hydroxy tryptamine (5 - HT, serotonin). Paroxetine functions as a re-uptake inhibitor and is disclosed in U.S. Patent No. 4,007,196. Paroxetine is indicated for the treatment of psychiatric problems including depression, Parkinson's disease, anxiety disorders, obsessive-compulsive disorders, panic disorders and post-traumatic stress disorder and other symptoms associated with excessive serotonin release. It is marketed in both immediate release and controlled release dosage forms by Glaxo SmithKline under the trade names of Paxil® and Paxil®CR respectively. Solid dosage forms of paroxetine often develop certain physical instabilities, depending on the excipients used and the method of their preparation. This is evident by the development of a pink hue, softening of the dosage form or a decrease in the hardness upon storage. Skillful selection of pharmaceutically inert excipients and controlled manufacturing processes is necessary to obtain paroxetine dosage forms having the desired properties. Few methods have been proposed or used to overcome these problems. For example, U.S. Patent No. 6,113,944 attributes the development of an undesirable pink hue on paroxetine tablets to water used during processing. The patent proposes overcoming this discoloration by preparing tablets using processes such as dry granulation and direct compression. These processes generally do not involve the use of water. WO 03/057150 discloses that paroxetine tablets using hydroxypropyl methylcellulose (HPMC) and microcrystalline cellulose (MCC), two of the most widely accepted and used pharmaceutical excipients, lose their mechanical strength on storage. It is suggested that this problem of increased friability can be overcome by making paroxetine tablets which (i) are free of hydroxypropyl methylcellulose and (ii) include a filler that is non-hygroscopic or free of hydrochloric acid (HC1). In particular, it excludes the use of the widely accepted conventional filler, microcrystalline cellulose, and binder hydroxypropyl methylcellulose. Hydroxypropyl methylcellulose is also used in dosage forms as a modified release polymer. Thus there exists a need for the development of stable paroxetine dosage forms using conventional excipients without the discoloration and friability problems disclosed by the prior art. To that end, we have now developed an easy and simple process employing the wet granulation processing technique for preparing stable paroxetine compositions using conventional excipients. Summary of the Invention In one general aspect there is provided a pharmaceutical composition comprising paroxetine, microcrystalline cellulose, and one or more additional pharmaceutically acceptable inert excipients. The pharmaceutical composition is prepared by a wet granulation technique. Embodiments of the pharmaceutical composition may include one or oreof ht following features. For example, the paroxetine may be free paroxetine base and pharmaceutically acceptable salts, hydrates and solvates thereof. The pharmaceutically acceptable salt may be hydrochloride, maleate, acetate and mesylate. The concentration of microcrystalline cellulose maybe from about 15% to about 45% by weight. More particularly, the concentration of the microcrystalline cellulose may be about 30% by weight. The pharmaceutically acceptable inert excipient may be one or more of fillers, binders, disintegrants, wetting agents, stabilizers, lubricants/glidants, flavoring agents and coloring agents. The wet granulation may be carried out using one or more water miscible solvents, with or without water. The water miscible solvent may be lower alcohols and lower ketones. The lower alcohols may be one or both of ethanol and isopropyl alcohol. The water miscible solvent maybe a mixture of water and isopropyl alcohol. The pharmaceutical composition may be a tablet, capsule, caplet, spheroid, or granule. The pharmaceutical composition may further include a non-functional film- forming polymer coating. In another general aspect there is provided a modified release pharmaceutical composition that includes paroxetine, microcrystalline cellulose, at least one modified release polymer, and one or more pharmaceutically acceptable inert excipients. The pharmaceutical composition is prepared by wet granulation technique. Embodiments of the modified release pharmaceutical composition may include one or more of the following features. For example, the modified release polymer may be one or more of cellulose derivatives, alginic acid derivatives, methacrylic acid derivatives, polysaccharides, and alkylene oxides. The modified release polymer may be hydroxypropyl methylcellulose of one or more of the low, medium and high viscosity grades of hydroxypropyl methylcellulose and mixtures thereof. The concentration of the hydroxypropyl methylcellulose may be from about 10% to about 30% by weight of the total composition weight. The paroxetine may be free paroxetine base and pharmaceutically acceptable salts, hydrates and solvates thereof. The concentration of microcrystalline cellulose maybe from about 15% to about 45%> by weight. The one or more pharmaceutically acceptable inert excipients may be one or more of fillers, binders, disintegrants, wetting agents, stabilizers, lubricants/glidants, flavoring agents and coloring agents. The wet granulation may be carried out using a water miscible solvent, with or without water. The water miscible solvent may be lower alcohols and lower ketones. The water miscible solvent may be a mixture of water and isopropyl alcohol. The pharmaceutical composition may be a solid dosage form. The solid dosage form may be tablets, capsules, caplets, spheroids, and granules. The pharmaceutical composition may further include an enteric polymer coating. The enteric polymer may be one or more of cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and one or more methacrylic acid copolymers. The enteric polymer coating may be about 1% to about 10% w/w of the total weight of the uncoated composition. The pharmaceutical composition may further include a non functional film coating. In another general aspect there is provided a process for the preparation of a pharmaceutical composition of paroxetine. The process includes (a) blending paroxetine, microcrystalline cellulose, and one or more pharmaceutically acceptable excipients to form a blend; (b) wet granulating the blend to form granules; (c) drying and sizing the granules; and (d) lubricating and processing the granules into a solid dosage form. Embodiments of the process may include one or more of the features described above. In another general aspect there is provided a process for the preparation of a modified release pharmaceutical composition of paroxetine. The process includes (a) blending paroxetine with microcrystalline cellulose, hydroxypropyl methylcellulose, and one or more of fillers, binders and disintegrants to form a blend; (b) wet granulating the blend to form granules; (c) drying and sizing the granules; and (d) lubricating the granules and compressing into tablets. Embodiments of the process may include one or more of the following features or those described above. For example, the process may further include (e) coating the tablet with enteric polymers up to a weight gain of about 10% w/w; and (f) film coating up to a weight gain of about 3% w/w. In another general aspect there is provided a pharmaceutical composition including granules. The granules include paroxetine and microcrystalline cellulose. The granules are prepared by a wet granulation technique. Embodiments of the pharmaceutical composition may include one or more of the features described above. hi another general aspect there is provided a method of treating depression in a subject in need thereof. The method includes administering a pharmaceutical composition that includes paroxetine, microcrystalline cellulose, and one or more pharmaceutically acceptable inert excipients. The pharmaceutical composition is prepared by wet granulation technique. Embodiments of the process may include one or more of the following features or those described above. For example, at least one of the pharmaceutically acceptable inert excipients may be hydroxypropyl methylcellulose and the pharmaceutical composition may be a modified release pharmaceutical composition. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims Detailed Description of the Invention Pharmaceutical compositions of paroxetine of the present invention may be prepared by the wet granulation technique using microcrystalline cellulose (MCC) as a filler, and hydroxypropyl methylcellulose (HPMC) as a modified release polymer without the development of either the pink hue or decrease in hardness upon storage.
Advantageously, the preparation of the granulation for tableting by the wet granulation process is amongst the oldest and most widely used techniques. Further, MCC, being a porous material, promotes easy wetting and rapid drying of wet granulation, and the granules exhibit good flow properties with a low lubricant demand. The term 'stable' as used herein refers to mechanical stability of pharmaceutical composition of paroxetine wherein the composition does not lose its hardness or develop pink discoloration on storage at a temperature of 40°C and 75% relative humidity for 5 days. The term 'paroxetine' as used herein includes paroxetine and pharmaceutically acceptable salts thereof, such as, hydrochloride, maleate, acetate, mesylate and hydrates and solvates thereof. In particular, paroxetine hydrochloride hemihydrate may be used. The term 'pharmaceutical composition' as used herein refers to solid dosage forms for oral administration such as tablet, capsule, pill, spheroid, granule and the like. For example, tablets may be used. The term "modified release dosage form" as used herein includes dosage forms intended for slow release, such as controlled release, prolonged release, delayed release, timed release, etc. that are capable of modifying the release of the drug up to a period of about 12 hours. For example, a delayed release dosage form may be used. The term 'wet granulation' as used herein refers to granulation using water miscible solvent(s) with or without water. Suitable water miscible solvents include one or more of lower alcohols, such as ethanol and isopropyl alcohol (IP A), and lower ketones, such as acetone. For example, a mixture of water and IP A may be used. MCC is purified partially de-polymerized alpha-cellulose. The de-polymerization is catalyzed by hydrochloric acid. MCC is a white, odorless, tasteless free flowing powder, which is insoluble in water, soluble in acids and most organic solvents and is practically insoluble in sodium hydroxide solution. The concentration of MCC may range from about 15% to about 45% by weight. In particular MCC at a concentration of about 30% may be used. It is commercially available under the trade name of Avicel® (manufactured by FMC Corporation) in various grades such as PH 103, PH 105, PH 101, PH 113 and PH 301. hi particular, Avicel® PH 101 may be used. Suitable modified release polymers include one or more of cellulose derivatives, alginic acid derivatives, methacrylic acid derivatives, polysaccharides, alkylene oxides and the like. Specific examples of cellulose derivatives include HPMC, hydroxypropyl cellulose (HPC), methylcellulose, carboxymethyl cellulose, and hydroxyethyl cellulose. Alginic acid derivative as used herein include alginic acid and its physiologically acceptable salts such as those of sodium, potassium, calcium, and the like. Examples of methacrylic acid derivatives include the various grades available under the trade name of Eudragit®. Examples of polysaccharides include chitosan, gellan, xanthan gum and the like. Examples of alkylene oxide include polyethylene oxide. HPMC is cellulose ether, derived from alkali treated cellulose that is reacted with methyl chloride and propylene oxide. It has several names including 2-hydroxy propyl ether of methyl cellulose, propylene glycol ether of methyl cellulose, 2-hydroxy propyl methyl ether, hypromellose, etc. It is widely used as a modified release polymer, binder, and in coating compositions. It is commercially available as Methocel® (manufactured by Dow Chemicals) in various viscosity grades. The concentration of HPMC may range from about 10% to about 30% by weight. In particular, HPMC at a concentration of about 14% may be used. Examples of HPMC of low viscosity grades include Methocel E-5, Methocel E-15 LV, Methocel E-50 LV, Methocel K-100 LV and Methocel F-50 LV, whose 2% w/v aqueous solutions have viscosities of 5 cPs, 15 cPs, 100 cPs and 50 cPs, respectively. Examples of HPMC of medium viscosity grade include Methocel E4M and Methocel K4MCR, whose 2% w/v aqueous solutions have a viscosity of 4000 cPs. Examples of HPMC of high viscosity grade include Methocel Kl 5M and Methocel K 100M whose 2% w/v aqueous solutions have viscosities of 15,000 and 10,000 cPs, respectively. For example, Methocel K4MCR and Methocel E-15 LV may be used. Suitable pharmaceutically acceptable inert excipients include one or more of wetting agents, fillers, binders, disintegrants, coloring agents, flavoring agents, stabilizers, lubricants/glidants and plasticizers. Suitable wetting agents used in the present embodiment include both ionic and non-ionic wetting agents. These include one or more of polyethylene glycols; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; polyglycerin fatty acid ester, such as decaglyceryl monolaurate and decaglyceryl monomyristate, polyoxyethylene sorbitan fatty acid ester, such as polyoxyethylene sorbitan monooleate, polyethylene glycol fatty acid ester, such as polyoxyethylene monosterate, polyoxyethylene alkyl ether, such as poluoxyethylene lauryl ether; polyoxyethylene castor oil and hardened castor oil, such as polyoxyethylene hardened castor oil; sucrose ester of fatty acid, such as sucrose state ester and sucrose palmitate ester and alkyl sulfate salt, such as sodium lauryl sulfate and magnesium lauryl sulfate; sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and other suitable wetting agents. For example, poloxamer (available under the trade name of Lutrol) may be used. Suitable fillers include one or more of calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and other suitable fillers. Suitable binders include one or more of polyvinyl pyrrolidone, methylcellulose, hydroxypropyl cellulose, HPMC, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and other suitable binders. Suitable disintegrants include one or more of microcrystalline cellulose, croscarmellose sodium, crospovidone, carboxymethyl starch sodium, sodium starch glycollate, and other suitable disintegrants. Suitable lubricants and glidants include one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like. Examples of plasticizers include one or more of polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl sebacate, and other suitable plasticizers. Examples of stabilizers include one or more of antioxidants, buffers, acids, and other suitable stabilizers. Examples of coloring agents include any FDA approved colors for oral use. In one process, the pharmaceutical composition of paroxetine may be prepared by a process which includes the steps of: blending paroxetine with microcrystalline cellulose, an additional filler, binder, and disintegrant; wet granulating the blend to form granules; drying the granules; lubricating the granules; and compressing the granules into tablets. In another process, the modified release pharmaceutical composition of paroxetine may be prepared by a process which includes the steps of: blending paroxetine with microcrystalline cellulose, at least one modified release polymer, another filler, binder, and disintegrant; wet granulating the blend to form granules; drying the granules; lubricating the granules; and compressing the granules into tablets. In yet another process, the modified release pharmaceutical composition of paroxetine may be prepared by a process that includes the steps of: blending paroxetine with microcrystalline cellulose, hydroxypropyl methylcellulose, another filler, binder, and disintegrant; wet granulating the blend to form granules; drying the granules; lubricating the granules; and compressing the granules into tablets. The tablets prepared in any of the above embodiments may further be coated with one or more conventional film-forming polymers and / or modified release polymer. For example, the tablets may be coated with an enteric polymer to provide a delayed release of paroxetine. Suitable film-forming polymers include one or more of ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose; waxes, such as polyethylene glycol; methacrylic acid polymers, such as Eudragit® RL and RS; and the like. The coating may be performed using commercially available, ready-to-coat preparations, such as, various grades of Opadry®. Suitable enteric polymer include one or more of cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate; methacrylic acid copolymers, such as Eudragit® L 100-55, Eudragit® L 30, Eudragit® D55, Eudragit® L 100, Eudragit® S 100; and the like. The enteric coating may be continued up to a weight gain of about 1% to about 50% by weight of the uncoated tablet. In particular, the enteric coating may be continued up to a weight gain of about 1% to about 10% by weight of uncoated tablet and more particularly, up to a weight gain of about 5% to 10% of the uncoated tablet. In one particular process, a modified release pharmaceutical composition of paroxetine may be prepared by a process which includes the steps of: blending paroxetine with microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, and polyvinyl pyrrolidone; wet granulating the blend to form granules, drying the granules, lubricating the granules; compressing into tablets; coating the tablets with enteric polymers up to a weight gain of 8-10% w/w, and coating with Opadry® up to a weight gain of 2-3%o w/w. The invention is further illustrated by the following examples, which is for illustrative purpose and should not be construed as limiting the scope of the invention in any way. Examples 1 and 2
Procedure: For the preparation of tablets of paroxetine hydrochloride hemihydrate as per Examples 1 and 2, the drug was blended with other solid ingredients (except for the magnesium stearate and talc), granulated with a mixture of water and isopropyl alcohol (4:96 v/v), and dried. The dried granules were blended with magnesium stearate and talc and compressed into tablets. The compressed tablets were further enteric coated using an Eudragit® L-100-55 dispersion up to a weight gain of 8-10 % w/w and the enteric coated tablets then were further coated with Opadry up to a weight gain of 2-3% w/w. The hardness and friability of the prepared tablets were tested immediately and after 15 days of storage at 40°C and 75% relative humidity using a Monsatto hardness tester and Roche's friabilator. The data is shown in Table 1. Table 1. Hardness of Paroxetine hydrochloride hemihydrate tablets
The tablets of Examples 1 and 2 were tested for in vitro release of paroxetine hydrochloride hemihydrate in USP type II dissolution apparatus with #10 sinker at 100 rpm and temperature of 37±0.5°C, in 500 ml of 0.1N hydrochloric acid for 2 hours and then transferred to 900 ml of pH 6.8 buffer for the remaining period. 10 ml samples were withdrawn at pre-determined intervals and replaced with an equal volume of the appropriate pre-warmed dissolution medium. The withdrawn samples were analyzed for paroxetine hydrochloride hemihydrate content after appropriate dilution. The results of the study are shown in Table 2. Table 2. In vitro release profile of paroxetine hydrochloride hemihydrate from the prepared tablets
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

We Claim:1. A pharmaceutical composition comprising paroxetine, microcrystalline cellulose, and one or more additional pharmaceutically acceptable inert excipients, wherein the pharmaceutical composition is prepared by a wet granulation technique.
2. The pharmaceutical composition according to claim 1, wherein the paroxetine comprises free paroxetine base and pharmaceutically acceptable salts, hydrates and solvates thereof.
3. The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable salt comprises hydrochloride, maleate, acetate and mesylate.
4. The pharmaceutical composition according to claim 1, wherein the concentration of microcrystalline cellulose comprises from about 15% to about 45% by weight.
5. The pharmaceutical composition according to claim 4, wherein the concentration of the microcrystalline cellulose comprises about 30% by weight.
6. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable inert excipient comprises one or more of fillers, binders, disintegrants, wetting agents, stabilizers, lubricants / glidants, flavoring agents and coloring agents.
7. The pharmaceutical composition according to claim 1, wherein the wet granulation is carried out using one or more water miscible solvents, with or without water.
8. The pharmaceutical composition according to claim 7, wherein the water miscible solvent comprises lower alcohols and lower ketones.
9. The pharmaceutical composition according to claim 8, wherein the lower alcohols comprise one or both of ethanol and isopropyl alcohol.
10. The pharmaceutical composition according to claim 8, wherein the water miscible solvent comprises a mixture of water and isopropyl alcohol.
11. The pharmaceutical composition according to claim 1 , wherein the composition comprises a tablet, capsule, caplet, spheroid, or granule.
12. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises a non-functional film-forming polymer coating.
13. A modified release pharmaceutical composition comprising paroxetine, microcrystalline cellulose, at least one modified release polymer, and one or more pharmaceutically acceptable inert excipients, wherein the pharmaceutical composition is prepared by wet granulation technique.
14. The modified release pharmaceutical composition according to claim 13, wherein the modified release polymer comprises one or more of cellulose derivatives, alginic acid derivatives, methacrylic acid derivatives, polysaccharides, and alkylene oxides.
15. The modified release pharmaceutical composition according to claims 13, wherein the paroxetine comprises free paroxetine base and pharmaceutically acceptable salts, hydrates and solvates thereof.
16. The modified release pharmaceutical composition according to claim 13, wherein the concentration of microcrystalline cellulose comprises from about 15% to about 45% by weight.
17. The modified release pharmaceutical composition according to claim 13, wherein the modified release polymer comprises hydroxypropyl methylcellulose of one or more of the low, medium and high viscosity grades of hydroxypropyl methylcellulose and mixtures thereof.
18. The modified release pharmaceutical composition according to claim 17, wherein the concentration of the hydroxypropyl methylcellulose comprises from about 10% to about 30% by weight of the total composition weight.
19. The modified release pharmaceutical composition according to claim 13, wherein the one or more pharmaceutically acceptable inert excipient comprises one or more of fillers, binders, disintegrants, wetting agents, stabilizers, lubricants / glidants, flavoring agents and coloring agents.
20. The modified release pharmaceutical composition according to claim 13, wherein the wet granulation is carried out using a water miscible solvent, with or without water.
21. The modified release pharmaceutical composition according to claim 20, wherein the water miscible solvent comprises lower alcohols and lower ketones.
22. The modified release pharmaceutical composition according to claims 29, wherein the water miscible solvent comprises a mixture of water and isopropyl alcohol.
23. The modified release pharmaceutical composition according to claims 16, wherein the pharmaceutical composition comprises a solid dosage form.
24. The modified release pharmaceutical composition according to claim 23, wherein the solid dosage form comprises tablets, capsules, caplets, spheroids, and granules.
25. The modified release pharmaceutical composition according to claims 13, wherein the pharmaceutical composition further comprises an enteric polymer coating.
26. The modified release pharmaceutical composition according to claim 25, wherein the enteric polymer comprises one or more of cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and one or more methacrylic acid copolymers.
27. The modified release pharmaceutical composition according to claim 25, wherein the enteric polymer coating comprises about 1% to about 10% w/w of the total weight of the uncoated composition.
28. The modified release pharmaceutical composition according to claim 13, wherein the pharmaceutical composition further comprises a non functional film coating.
29. A process for the preparation of a pharmaceutical composition of paroxetine, the process comprising (a) blending paroxetine, microcrystalline cellulose, and one or more pharmaceutically acceptable excipients to form a blend; (b) wet granulating the blend to form granules; (c) drying and sizing the granules; and, (d) lubricating and processing the granules into a solid dosage form.
30. A process for the preparation of a modified release pharmaceutical composition of paroxetine, the process comprising: (a) blending paroxetine with microcrystalline cellulose, hydroxypropyl methylcellulose, and one or more of fillers, binders and disintegrants to form a blend; (b) wet granulating the blend to form granules; (c) drying and sizing the granules; and (d) lubricating the granules and compressing into tablets.
31. The process of claim 30, further comprising: (e) coating the tablet with one or more enteric polymers up to a weight gain of about 10% w/w; and, (f) film coating up to a weight gain of about 3% w/w.
32. A pharmaceutical composition including granules, the granules comprising paroxetine and microcrystalline cellulose, wherein the granules are prepared by a wet granulation technique.
33. A method of treating depression in a subj ect in need thereof, the method comprising administering a pharmaceutical composition comprising paroxetine, microcrystalline cellulose, and one or more pharmaceutically acceptable inert excipients, wherein the pharmaceutical composition is prepared by wet granulation technique.
34. The method of claim 33, wherein at least one of the pharmaceutically acceptable inert excipients comprises hydroxypropyl methylcellulose and the pharmaceutical composition comprises a modified release pharmaceutical composition.
EP04769597A 2003-10-08 2004-10-08 Pharmaceutical compositions of paroxetine containing microcrystalline cellulose, prepared by wet granulation Withdrawn EP1675574A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1247DE2003 2003-10-08
PCT/IB2004/003295 WO2005034954A2 (en) 2003-10-08 2004-10-08 Pharmaceutical compositions of paroxetine containing microcrystalline cellulose, prepared by wet granulation

Publications (1)

Publication Number Publication Date
EP1675574A2 true EP1675574A2 (en) 2006-07-05

Family

ID=34430679

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04769597A Withdrawn EP1675574A2 (en) 2003-10-08 2004-10-08 Pharmaceutical compositions of paroxetine containing microcrystalline cellulose, prepared by wet granulation

Country Status (2)

Country Link
EP (1) EP1675574A2 (en)
WO (1) WO2005034954A2 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007012968A2 (en) * 2005-07-29 2007-02-01 Aurobindo Pharma Ltd Stable dosage form of an antidepressant
MX2008002512A (en) * 2005-08-26 2008-04-03 Bpsi Holdings Inc Drug compositions containing controlled release hypromellose matrices.
WO2007132344A2 (en) * 2006-05-09 2007-11-22 Aurobindo Pharma Limited Controlled release compositions of an antidepressant agent
CN102525966B (en) * 2010-12-13 2016-06-29 江苏万全特创医药生物技术有限公司 A kind of tablet containing paroxetine and preparation method thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE20100529U1 (en) * 2001-01-11 2001-05-10 Synthon Bv Pharmaceutical tablet comprising paroxetine mesylate
DK200100341A (en) * 2001-03-02 2002-09-03 Gea Farmaceutisk Fabrik As Process for the preparation of pharmaceutical tablets containing paroxetine hydrochloride anhydrate
WO2003057151A2 (en) * 2001-12-28 2003-07-17 Teva Pharmaceutical Industries Ltd. A stable pharmaceutical formulation of paroxetine hydrochloride anhydrous and a process for preparation thereof
CA2415154C (en) * 2002-12-24 2009-06-16 Biovail Laboratories Inc. Modified release formulations of selective serotonin re-uptake inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005034954A3 *

Also Published As

Publication number Publication date
WO2005034954A2 (en) 2005-04-21
WO2005034954A3 (en) 2005-06-02

Similar Documents

Publication Publication Date Title
US20210113582A1 (en) Pharmaceutical solid preparation comprising benzazepines and production method thereof
JP2005320354A (en) Matrix control release device
JP2002097132A (en) Dry coated tablet of cilostazol
WO2008027600A2 (en) Imatinib compositions
US7163696B2 (en) Pharmaceutical formulations
JP2010519200A (en) Controlled release formulation containing cilostazol and method for producing the same
WO2012018056A1 (en) Compressed composition
BG107372A (en) Sustained-release preparations of quinolone antibiotics and method for preparation thereof
AU2014225449B2 (en) Stabilization of moisture-sensitive drugs
US20140010883A1 (en) Controlled release pharmaceutical compositions of selective serotonin reuptake inhibitor
AU2006274565B2 (en) Novel controlled release compositions of selective serotonin reuptake inhibitors
US20100305179A1 (en) Oral sustained-release tablet
WO2005034954A2 (en) Pharmaceutical compositions of paroxetine containing microcrystalline cellulose, prepared by wet granulation
WO2012014052A2 (en) Novel coated extended release pharmaceutical compositions containing paliperidone
JP4999297B2 (en) High content terbinafine hydrochloride small tablets
CA2893480C (en) Pharmaceutical formulation of n-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl]benzamide
US20080260785A1 (en) Paroxetine compositions
US20080081069A1 (en) Novel controlled release formulations of divalproex sodium
EP1434570B1 (en) Pharmaceutical formulations for the controlled release of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline
KR101428018B1 (en) Orally disintegrating tablet containing aripiprazole and manufacturing method thereof
EP4091604B1 (en) Granules containing posaconazole
US20090130206A1 (en) Controlled Release Compositions of an Antidepressant Agent
WO2020249500A1 (en) Stable tablet formulation of nifurtimox and process for producing the same
AU2002341260A1 (en) Pharmaceutical formulations for the controlled release of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20060508

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20070501