WO2008038106A1 - Venlafaxine extended release formulations - Google Patents
Venlafaxine extended release formulations Download PDFInfo
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- WO2008038106A1 WO2008038106A1 PCT/IB2007/002795 IB2007002795W WO2008038106A1 WO 2008038106 A1 WO2008038106 A1 WO 2008038106A1 IB 2007002795 W IB2007002795 W IB 2007002795W WO 2008038106 A1 WO2008038106 A1 WO 2008038106A1
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- extended release
- release formulation
- formulation according
- tablet
- venlafaxine
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- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- 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
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
Definitions
- the present invention relates to extended release formulations of venlafaxine hydrochloride, process for its preparation and to the use of the extended release formulations in treating various diseases or conditions.
- Venlafaxine is chemically (R/S)-l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl]-cyclohexanol, having structural formula
- venlafaxine hydrochloride is marketed in united states as conventional immediate release tablets or as 24 hours extended release multiparticulate capsules under proprietary name EFFEXOR ® and EFFEXOR ® respectively.
- U.S. patent No. 4,535,186 discloses venlafaxine hydrochloride as being useful antidepressant.
- Venlafaxine hydrochloride is very soluble in water. It is known that it is very difficult to develop a pharmaceutical dosage form with extended release of a freely soluble drug like venlafaxine hydrochloride.
- Several formulations for the extended release of venlafaxine are known in prior art.
- U.S. Patent No. 6,274,171 and related European publication EP 0 797 991 disclose extended release capsule formulations of venlafaxine hydrochloride. Wherein capsules formulations is taught to comprise spheroids of venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropylmethylcellulose (HPMC). These spheroids are coated with a mixture of ethyl cellulose and HPMC. By providing appropriate amount of coating the desired blood plasma profile can be obtained.
- U.S. Patent No. 6,274,171 and related European publication EP 0 797 991 also state that due to high water solubility of venlafaxine hydrochloride, numerous attempts to produce extended release tablets by hydrogel technology proved to be fruitless because the compressed tablets were either physically unstable (poor compressibility or capping problems) or dissolved too rapidly in dissolution studies. See U.S. Pat. No. 6,274,171 column 4, lines 60-65 and EP 0 797 991 at page 3 lines 35-37.
- WO 99/22724 discloses extended release encapsulated dosage forms of venlafaxine hydrochloride, wherein the spheroids is substantially free of HPMC as compared to those described in U.S. Patent No. 6,274,171 and related European publication EP 0797991.
- WO 94/27589 and WO 01/37815 disclose osmotic drug delivery systems containing venlafaxine hydrochloride.
- United states publication US 2003/0190351 relates to surprising discovery that sodium carboxymethyl cellulose can provide superior controlled release of venlafaxine, this patent publication is specific only to use of sodium carboxymethyl cellulose as extended release agent.
- US 2003/0190354 discloses a matrix tablet dosage form in which venlafaxine is mixed with a combination of hydrophilic and hydrophobic matrix forming components.
- US 2005/0042290 discloses a solid controlled release pharmaceutical formulation particularly in the form of tablet for once daily administration comprising a core comprising venlafaxine, polyvinylpyrrolidone, a low viscosity hydrophilic polymer, a high viscosity hydrophilic polymer and a polymeric coating comprising a water high permeable polymer and a water low permeable polymer.
- US 2005/0048118 relates to modified release venlafaxine hydrochloride tablet of venlafaxine hydrochloride formed by a core containing a lipophilic matrix and water insoluble permeable coating.
- US 2005/0118264 discloses an extended release composition of venlafaxine wherein venlafaxine hydrochloride is coated on a non pareil inert core, which coated core is then coated with a polymeric layer, which enables the controlled release of venlafaxine hydrochloride.
- US 2005/0136109 describes an oral extended release composition in compressed tablet form comprising venlafaxine hydrochloride and a carboxyvinyl polymer.
- US 2005/0169985 relates to an extended release once daily formulation of venlafaxine hydrochloride in the form of mini tablets filled in capsules, wherein the mini tablets comprise a core comprising venlafaxine hydrochloride, diluent, water soluble component and an outer coating comprising water insoluble polymer and water soluble polymer.
- US 2005/0226923 discloses a pharmaceutical composition comprising microtablets comprising 0.1 to 99.9 % by weight of venlafaxine, about 0.1- 20% by weight of a lubricant, wherein microtablets have a tablet weight of 1 to 50 mg.
- EP 1473030 discloses an extended release formulation for oral administration in an oral tablet dosage form comprising a core containing venlafaxine, a filler, a water soluble cellulosic polymer, water insoluble cellulosic polymer and coating comprising a mixture of water soluble and water insoluble* cellulosic polymers.
- WO 2004/069228 describes a sustained release tablet formulation comprising venlafaxine, a sustained release agent selected from povidone, a mixture of povidone and polyvinyl acetate, hydrogenated vegetable oil, polyethylene glycol, glyceril behenate and glyceril palmitostearate.
- a sustained release agent selected from povidone, a mixture of povidone and polyvinyl acetate, hydrogenated vegetable oil, polyethylene glycol, glyceril behenate and glyceril palmitostearate.
- Kollidone SR a mixture of povidone and polyvinyl acetate
- the tablet formulation is further coated with polymethacrylates to control the initial release of venlafaxine, it is also disclosed that conventional hydroxypropylmethylcellulose based coatings do not affect the dissolution rate of sustained release tablets.
- WO 2005/009414 describes an extended release formulation of venlafaxine HCl comprising hard gelatin capsule comprising effective number of mini tablets comprising functional core comprising 40-80% of a gelling agent, 30-60% of a non swelling agent, 2-
- matrix based extended release compositions of venlafaxine are known, all those formulations invariably use a hydrophobic polymer either in the core and/or in the coating alone and/or in combination with hydrophilic polymer.
- hydrophobic polymer either in the core and/or in the coating alone and/or in combination with hydrophilic polymer.
- the formulations of the art use different ratios of hydrophilic-hydrophobic polymer, as well as channeling agents and surfactants.
- all those formulations are described to be particularly suited to one dosage form either as a tablet or as a capsule formulation which containing mini or micro tablets.
- compositions of the present invention presents a distinct advantage that the compositions can be conveniently formulated in to different oral solid dosage forms.
- the present invention describes a simple matrix formulation solely based on hydrophilic matrix materials, which adequately control the release venlafaxine hydrochloride.
- Hydrogel technology compositions based on hydrophilic matrix materials have been found to extend the release of very water soluble venlafaxine hydrochloride.
- the pharmaceutical compositions of the present invention contain a core comprising venlafaxine hydrochloride, hydrophilic matrix material and acceptable excipients, wherein the core if required is coated with a coating composition comprising hydrophilic film forming polymers.
- a hydrophilic matrix material as used in the core is one, which is water soluble, and that swells or gels upon contact with water to thereby slow the diffusion release of the active ingredient.
- the hydrophilic matrix material is selected from celluloses such as methylcelluloses (i.e. having a viscosity of 400 cP to 4000 cP), hydroxy ethylcellulose, Hydroxy propyl methylcelluloses (HPMC) with varying degrees of substitution and/or varying molecular weights corresponding to varying viscosity levels (i.e.
- polysaccharides such as galactomannans, potassium alginates, sodium alginates, agar-agar, carrageen, Arabic gum and sterculia gum and other water soluble polymers such as polyvinylpyrollidone, polyethylene oxide and combinations thereof.
- Hydroxy propyl methylcellulose is preferred.
- the hydrophilic film forming polymers as used in coating is selected from the groups of cellulose derivatives such as soluble alkyl- or hydroxyalkylcellulose derivatives such as methylcellulose, hydroxy methylcellulose, hydroxy ethylcellulose, hydroxy propylcellulose, hydroxy propyl methylcellulose, dextrins, soluble starches and starch derivatives, natural gums such as gum arabic, xanthans, alginates; and other water soluble film forming polymers such as polyvinylpyrollidone, polyethylene oxide and the like.
- hydroxy propyl methylcellulose with varying degrees of substitution and/or varying molecular weights corresponding to varying viscosity levels of the aqueous solutions may be used as suitable film-forming agents.
- the venlafaxine hydrochloride used in the present invention can be based on the racemate or mixture of enantiomers of venlafaxine, or, on the pure or substantially pure (+) or (-) enantiomer of venlafaxine and can be made by synthetic techniques known in the art.
- compositions of the present invention generally contain by weight about 10 % to about 50% of venlafaxine hydrochloride and about 10% to about 75% more typically about 30% to about 50% of hydrophilic matrix material.
- the ratio of hydrophilic matrix material to venlafaxine hydrochloride ranges from about 0.5 parts to about 3 parts by weight of hydrophilic matrix material to about lpart by weight of venlafaxine hydrochloride.
- the film coating represents from about 1% to about 30% by weight of the core.
- compositions of the present invention can conveniently be formulated in to different solid oral dosage forms.
- the core comprising venlafaxine hydrochloride, hydrophilic matrix material and acceptable excipients can be compressed into a single monolithic tablet and if required followed by film coating with coating composition comprising hydrophilic film forming polymer and used as such or can be ' filled in to hard gelatin capsule to represent a unit dosage form.
- the core can be compressed in to multiple mini tablets, which if required are then film coated with coating composition comprising hydrophilic film forming polymer and required number of mini tablets are filled in hard gelatin capsule to represent a unit dosage form.
- excipients as used in the core are well known in the art and include without limitation, diluents, fillers, binders, surfactants, lubricants, disintegrants, glidants, colorants, plasticizers etc.
- the excipients are selected based in part on the dosage form, the intended mode of administration, the intended release rate and manufacturing reliability.
- the core further comprises fillers and lubricants in order to assure good properties of the composition.
- Suitable fillers are e.g. calcium hydrogenphosphate, microcrystalline cellulose and lactose; suitable lubricants are magnesium stearate or talc.
- the coating composition in addition to hydrophilic film forming polymers may also contain classical excipients such as plasticizers selected from but not limited to polyethylene glycol, triethyl citrate, glycerol, 1,2 propylene glycol; colorants, opacifiers (usually titanium oxide), adhesive agents (such as low viscous HPMC, hydroxypropyl cellulose and polyvinylpyrrolidone). Ethanol, acetone, water-isopropyl alcohol, methylene chloride, chloroform or any other suitable solvents may be used as well as mixtures of the solvents as long as they can dissolve or uniformly disperse the constituents of the coating mixture. Alternatively the aqueous coating dispersions may also be used.
- plasticizers selected from but not limited to polyethylene glycol, triethyl citrate, glycerol, 1,2 propylene glycol; colorants, opacifiers (usually titanium oxide), adhesive agents (such as low viscous HPMC, hydroxypropyl cellulose
- the extended release formulations of the present invention in a dissolution test using USP apparatus 1 (basket type) at 100 rpm in purified water at 37° C, less than 80% of the venlafaxine hydrochloride is dissolved during the first two hours, more typically less than 50% of venlafaxine hydrochloride is dissolved during the first two hours.
- the extended release formulations of the present invention may be produced by any standard technique, e.g. by wet granulation, dry granulation or direct compression. In general dry processes are preferred.
- dry granulation procedures comprise mixing the excipients of the core (except lubricants) compacting the mixture in a compactor (e.g. roller compactor) or double compression, milling the compacted mass, screening the milled granules, mixing the lubricant with the granules and the lubricated granules are compressed into a single monolithic tablet, the tablet is coated by spraying the coating solution or suspension using a coating pan or a perforated turbine or a fludized bed apparatus.
- the coated monolithic tablet may be used as such or filled into hard gelatin capsule.
- the lubricated granules are compressed into multiple mini tablets, the mini tablets are than coated by spraying the coating solution or suspension using a coating pan or a perforated turbine or a fludized bed apparatus. Then required number of mini tablets is filled into a hard gelatin capsule.
- a unit dose, (i.e. one tablet or capsule) of the pharmaceutical composition of the present invention generally contains from 2 mg to 300 mg of venlafaxine hydrochloride.
- Contemplated doses include 37.5 mg, 75 mg, 100 mg, 150 mg, 200 mg, and 300 mg strengths. All amounts of venlafaxine hydrochloride are expressed in terms of the weight of the free base contained in the hydrochloride salt, as is convention in the art.
- compositions of the present invention can be used to treat without limitation depressions, panic disorder, generalized anxiety disorder, obesity, posttraumatic stress disorder, late luteal phase dysphoric disorder, attention deficit disorders, (refer to US 2001/0012855 for a description of uses of venlafaxine and salts thereof).
- the extended release formulations of the present invention are administered orally via one or two unit dosage forms (tablet or capsule) per day, one unit dosage form per day is preferred.
- the intragranular portion comprising Venlafaxine Hydrochloride and other ingredients are mixed using a blender and if required sifted through a suitable mesh.
- the sifted mass is then roll compacted to from granules, the granules if required are sifted through a suitable mesh to produce granules for compaction,
- the sifted mass is granulated with a solution of polyvinyl pyrrolidone and the granulated mass is dried and the dried granules if required are passed through a suitable mesh to produce granules for compaction.
- the resulting granules are lubricated with extragranular portion and can be processed as follows
- the lubricated granules are compressed either into a single monolithic tablet, if required the tablet is coated which is used as such or single monolithic tablet is filled in hard gelatin capsule.
- compositions were tested for dissolution of venlafaxine hydrochloride in 900 ml of water as dissolution media at 37° C using USP Type 1 dissolution apparatus rotated at 100 rpm.
- the dissolution data presented is the mean of at least 3 tablets or capsules.
- Example 1 Composition:
- Copovidone (copolymer of N- 110.7 vinyl-2-pyrrolidone and vinyl acetate)
- Copovidone (copolymer of N- 110.7 vinyl-2-pyrrolidone and vinyl acetate)
- the intragranular ingredients are mixed and compacted; the compact is passed through #20 mesh. To this extragranular ingredients were added for lubrication and compressed into tablet. The tablet was coated using hydroxy propyl cellulose and filled into hard gelatin capsule.
- Example 8 Composition:
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Abstract
The present invention relates to extended release formulations of venlafaxine hydrochloride, process for its preparation and to the use of the extended release formulations in treating various diseases or conditions.
Description
VENLAFAXINE EXTENDED RELEASE FORMULATIONS
FIELD OF INVENTION:
The present invention relates to extended release formulations of venlafaxine hydrochloride, process for its preparation and to the use of the extended release formulations in treating various diseases or conditions.
BACKGROUND OF INVENTION: Venlafaxine is chemically (R/S)-l-[2-(dimethylamino)-l-(4-methoxyphenyl) ethyl]-cyclohexanol, having structural formula
presently venlafaxine hydrochloride is marketed in united states as conventional immediate release tablets or as 24 hours extended release multiparticulate capsules under proprietary name EFFEXOR® and EFFEXOR® respectively.
U.S. patent No. 4,535,186 discloses venlafaxine hydrochloride as being useful antidepressant. Venlafaxine hydrochloride is very soluble in water. It is known that it is very difficult to develop a pharmaceutical dosage form with extended release of a freely soluble drug like venlafaxine hydrochloride. Several formulations for the extended release of venlafaxine are known in prior art.
U.S. Patent No. 6,274,171 and related European publication EP 0 797 991 disclose extended release capsule formulations of venlafaxine hydrochloride. Wherein capsules formulations is taught to comprise spheroids of venlafaxine hydrochloride, microcrystalline cellulose and hydroxypropylmethylcellulose (HPMC). These spheroids
are coated with a mixture of ethyl cellulose and HPMC. By providing appropriate amount of coating the desired blood plasma profile can be obtained.
U.S. Patent No. 6,274,171 and related European publication EP 0 797 991 also state that due to high water solubility of venlafaxine hydrochloride, numerous attempts to produce extended release tablets by hydrogel technology proved to be fruitless because the compressed tablets were either physically unstable (poor compressibility or capping problems) or dissolved too rapidly in dissolution studies. See U.S. Pat. No. 6,274,171 column 4, lines 60-65 and EP 0 797 991 at page 3 lines 35-37.
WO 99/22724 discloses extended release encapsulated dosage forms of venlafaxine hydrochloride, wherein the spheroids is substantially free of HPMC as compared to those described in U.S. Patent No. 6,274,171 and related European publication EP 0797991. WO 94/27589 and WO 01/37815 disclose osmotic drug delivery systems containing venlafaxine hydrochloride.
United states publication US 2003/0190351 relates to surprising discovery that sodium carboxymethyl cellulose can provide superior controlled release of venlafaxine, this patent publication is specific only to use of sodium carboxymethyl cellulose as extended release agent.
US 2003/0190354 discloses a matrix tablet dosage form in which venlafaxine is mixed with a combination of hydrophilic and hydrophobic matrix forming components. US 2005/0042290 discloses a solid controlled release pharmaceutical formulation particularly in the form of tablet for once daily administration comprising a core comprising venlafaxine, polyvinylpyrrolidone, a low viscosity hydrophilic polymer, a high viscosity hydrophilic polymer and a polymeric coating comprising a water high permeable polymer and a water low permeable polymer.
US 2005/0048118 relates to modified release venlafaxine hydrochloride tablet of venlafaxine hydrochloride formed by a core containing a lipophilic matrix and water insoluble permeable coating. US 2005/0118264 discloses an extended release composition of venlafaxine wherein venlafaxine hydrochloride is coated on a non pareil inert core, which coated core is then coated with a polymeric layer, which enables the controlled release of venlafaxine hydrochloride. US 2005/0136109 describes an oral extended release
composition in compressed tablet form comprising venlafaxine hydrochloride and a carboxyvinyl polymer. US 2005/0169985 relates to an extended release once daily formulation of venlafaxine hydrochloride in the form of mini tablets filled in capsules, wherein the mini tablets comprise a core comprising venlafaxine hydrochloride, diluent, water soluble component and an outer coating comprising water insoluble polymer and water soluble polymer. US 2005/0226923 discloses a pharmaceutical composition comprising microtablets comprising 0.1 to 99.9 % by weight of venlafaxine, about 0.1- 20% by weight of a lubricant, wherein microtablets have a tablet weight of 1 to 50 mg.
EP 1473030 discloses an extended release formulation for oral administration in an oral tablet dosage form comprising a core containing venlafaxine, a filler, a water soluble cellulosic polymer, water insoluble cellulosic polymer and coating comprising a mixture of water soluble and water insoluble* cellulosic polymers.
WO 2004/069228 describes a sustained release tablet formulation comprising venlafaxine, a sustained release agent selected from povidone, a mixture of povidone and polyvinyl acetate, hydrogenated vegetable oil, polyethylene glycol, glyceril behenate and glyceril palmitostearate. In particular Kollidone SR (a mixture of povidone and polyvinyl acetate) is used as sustained release agent. The tablet formulation is further coated with polymethacrylates to control the initial release of venlafaxine, it is also disclosed that conventional hydroxypropylmethylcellulose based coatings do not affect the dissolution rate of sustained release tablets.
WO 2005/009414 describes an extended release formulation of venlafaxine HCl comprising hard gelatin capsule comprising effective number of mini tablets comprising functional core comprising 40-80% of a gelling agent, 30-60% of a non swelling agent, 2-
12% of a conjugation agent and/or a functional coating comprising a polymer and a water soluble compound. It is also described that linearity between the different strengths of drug product and total weight of dosage form cannot be achieved matrix tablet dosage form.
Although matrix based extended release compositions of venlafaxine are known, all those formulations invariably use a hydrophobic polymer either in the core and/or in the coating alone and/or in combination with hydrophilic polymer. In order to modify the wettability of the described matrix the formulations of the art use different ratios of
hydrophilic-hydrophobic polymer, as well as channeling agents and surfactants. Also all those formulations are described to be particularly suited to one dosage form either as a tablet or as a capsule formulation which containing mini or micro tablets.
Thus there is a need to provide a less complicated dosage form that nonetheless provides extended release of venlafaxine, wherein the matrix (i.e. core) and/or the coating is solely based on hydrophilic matrix materials. In addition the compositions of the present invention presents a distinct advantage that the compositions can be conveniently formulated in to different oral solid dosage forms.
DESCRIPTION OF THE INVENTION:
The present invention describes a simple matrix formulation solely based on hydrophilic matrix materials, which adequately control the release venlafaxine hydrochloride. Hydrogel technology compositions based on hydrophilic matrix materials have been found to extend the release of very water soluble venlafaxine hydrochloride. The pharmaceutical compositions of the present invention contain a core comprising venlafaxine hydrochloride, hydrophilic matrix material and acceptable excipients, wherein the core if required is coated with a coating composition comprising hydrophilic film forming polymers.
A hydrophilic matrix material as used in the core is one, which is water soluble, and that swells or gels upon contact with water to thereby slow the diffusion release of the active ingredient. The hydrophilic matrix material is selected from celluloses such as methylcelluloses (i.e. having a viscosity of 400 cP to 4000 cP), hydroxy ethylcellulose, Hydroxy propyl methylcelluloses (HPMC) with varying degrees of substitution and/or varying molecular weights corresponding to varying viscosity levels (i.e. having a viscosity of 4000 to 100000 cP), polysaccharides such as galactomannans, potassium alginates, sodium alginates, agar-agar, carrageen, Arabic gum and sterculia gum and other water soluble polymers such as polyvinylpyrollidone, polyethylene oxide and combinations thereof. Generally Hydroxy propyl methylcellulose is preferred.
The hydrophilic film forming polymers as used in coating is selected from the groups of cellulose derivatives such as soluble alkyl- or hydroxyalkylcellulose derivatives such as methylcellulose, hydroxy methylcellulose, hydroxy ethylcellulose, hydroxy
propylcellulose, hydroxy propyl methylcellulose, dextrins, soluble starches and starch derivatives, natural gums such as gum arabic, xanthans, alginates; and other water soluble film forming polymers such as polyvinylpyrollidone, polyethylene oxide and the like. Preferably hydroxy propyl methylcellulose with varying degrees of substitution and/or varying molecular weights corresponding to varying viscosity levels of the aqueous solutions may be used as suitable film-forming agents.
The venlafaxine hydrochloride used in the present invention can be based on the racemate or mixture of enantiomers of venlafaxine, or, on the pure or substantially pure (+) or (-) enantiomer of venlafaxine and can be made by synthetic techniques known in the art.
The pharmaceutical compositions of the present invention generally contain by weight about 10 % to about 50% of venlafaxine hydrochloride and about 10% to about 75% more typically about 30% to about 50% of hydrophilic matrix material. The ratio of hydrophilic matrix material to venlafaxine hydrochloride ranges from about 0.5 parts to about 3 parts by weight of hydrophilic matrix material to about lpart by weight of venlafaxine hydrochloride. The film coating represents from about 1% to about 30% by weight of the core.
The pharmaceutical compositions of the present invention can conveniently be formulated in to different solid oral dosage forms. The core comprising venlafaxine hydrochloride, hydrophilic matrix material and acceptable excipients can be compressed into a single monolithic tablet and if required followed by film coating with coating composition comprising hydrophilic film forming polymer and used as such or can be ' filled in to hard gelatin capsule to represent a unit dosage form. Alternatively the core can be compressed in to multiple mini tablets, which if required are then film coated with coating composition comprising hydrophilic film forming polymer and required number of mini tablets are filled in hard gelatin capsule to represent a unit dosage form.
Additional pharmaceutically acceptable excipients as used in the core are well known in the art and include without limitation, diluents, fillers, binders, surfactants, lubricants, disintegrants, glidants, colorants, plasticizers etc. The excipients are selected based in part on the dosage form, the intended mode of administration, the intended
release rate and manufacturing reliability. Typically the core further comprises fillers and lubricants in order to assure good properties of the composition. Suitable fillers are e.g. calcium hydrogenphosphate, microcrystalline cellulose and lactose; suitable lubricants are magnesium stearate or talc.
The coating composition in addition to hydrophilic film forming polymers may also contain classical excipients such as plasticizers selected from but not limited to polyethylene glycol, triethyl citrate, glycerol, 1,2 propylene glycol; colorants, opacifiers (usually titanium oxide), adhesive agents (such as low viscous HPMC, hydroxypropyl cellulose and polyvinylpyrrolidone). Ethanol, acetone, water-isopropyl alcohol, methylene chloride, chloroform or any other suitable solvents may be used as well as mixtures of the solvents as long as they can dissolve or uniformly disperse the constituents of the coating mixture. Alternatively the aqueous coating dispersions may also be used.
The extended release formulations of the present invention in a dissolution test using USP apparatus 1 (basket type) at 100 rpm in purified water at 37° C, less than 80% of the venlafaxine hydrochloride is dissolved during the first two hours, more typically less than 50% of venlafaxine hydrochloride is dissolved during the first two hours.
The extended release formulations of the present invention may be produced by any standard technique, e.g. by wet granulation, dry granulation or direct compression. In general dry processes are preferred.
In general dry granulation procedures comprise mixing the excipients of the core (except lubricants) compacting the mixture in a compactor (e.g. roller compactor) or double compression, milling the compacted mass, screening the milled granules, mixing the lubricant with the granules and the lubricated granules are compressed into a single monolithic tablet, the tablet is coated by spraying the coating solution or suspension using a coating pan or a perforated turbine or a fludized bed apparatus. The coated monolithic tablet may be used as such or filled into hard gelatin capsule. Alternatively the lubricated granules are compressed into multiple mini tablets, the mini tablets are than coated by spraying the coating solution or suspension using a coating pan or a perforated turbine or a fludized bed apparatus. Then required number of mini tablets is filled into a hard gelatin capsule.
A unit dose, (i.e. one tablet or capsule) of the pharmaceutical composition of the present invention generally contains from 2 mg to 300 mg of venlafaxine hydrochloride.
Contemplated doses include 37.5 mg, 75 mg, 100 mg, 150 mg, 200 mg, and 300 mg strengths. All amounts of venlafaxine hydrochloride are expressed in terms of the weight of the free base contained in the hydrochloride salt, as is convention in the art.
The pharmaceutical compositions of the present invention can be used to treat without limitation depressions, panic disorder, generalized anxiety disorder, obesity, posttraumatic stress disorder, late luteal phase dysphoric disorder, attention deficit disorders, (refer to US 2001/0012855 for a description of uses of venlafaxine and salts thereof). The extended release formulations of the present invention are administered orally via one or two unit dosage forms (tablet or capsule) per day, one unit dosage form per day is preferred.
The following non limiting examples illustrate the following invention
General Procedure for the Preparation of Extended Release Formulations:
The intragranular portion comprising Venlafaxine Hydrochloride and other ingredients are mixed using a blender and if required sifted through a suitable mesh. (i) The sifted mass is then roll compacted to from granules, the granules if required are sifted through a suitable mesh to produce granules for compaction, (ii) Alternatively the sifted mass is granulated with a solution of polyvinyl pyrrolidone and the granulated mass is dried and the dried granules if required are passed through a suitable mesh to produce granules for compaction.
The resulting granules are lubricated with extragranular portion and can be processed as follows
(i) The lubricated granules are compressed either into a single monolithic tablet, if required the tablet is coated which is used as such or single monolithic tablet is filled in hard gelatin capsule.
(ii) Alternatively the lubricated granules are compressed into multiple mini tablets, if required the mini tablets are coated and required number of mini tablets is filled in hard gelatin capsule.
Dissolution Method:
For all examples, the compositions were tested for dissolution of venlafaxine hydrochloride in 900 ml of water as dissolution media at 37° C using USP Type 1 dissolution apparatus rotated at 100 rpm. The dissolution data presented is the mean of at least 3 tablets or capsules.
Example 1 Composition:
Ingredient Qty in mg
I. Core
Intragranular Portion
Venlafaxine Hydrochloride 169.3
Hydroxypropyl methylcellulose 170.0
Microcrystalline cellulose 366.2
Poloxamer 80.0
Hydroxy Propylcellulose 80.0
Polyvinyl Pyrrolidone 75.0
Colloidal silicon dioxide 16.5
Talc 12.0
Extragranular Portion
Colloidal silicon dioxide 5.5
Magnesium stearate 5.5
II. Coating
Opadry white (Y- 1-7000) 50.0
Purified water q.s.
Total weight 1030.0
* Does not appear in the final product except in traces.
Manufacturing Procedure:
The intragranular ingredients are mixed and compacted; the compact is passed through #20 mesh. To this extragranular ingredients were added for lubrication and compressed into tablet. The tablet was coated using Opadry white.
Dissolution Profile:
Time (hour) Percent Venlafaxine HCl released
2 28
4 43
8 64
12 79
24 100
Example 2
Composition:
Ingredient Qty in mg
I. Core
Intragranular Portion
Venlafaxine Hydrochloride 169.3
Hydroxypropyl methylcellulose 170.0
Microcrystalline cellulose 366.7
Hydroxy Propylcellulose 80.0
Polyvinyl Pyrrolidone 75.0
Colloidal silicon dioxide 13.0
Talc 8.0
Extragranular Portion
Colloidal silicon dioxide 4.0
Magnesium stearate 4.0
II. Coating
Opadry white (Y- 1-7000) 50.0
Purified water * q.s.
Total weight 940.0
* Does not appear in the final product except in traces.
Manufacturing Procedure:
The intragranular ingredients are mixed and compacted; the compact is passed through #20 mesh. To this extragranular ingredients were added for lubrication and compressed into tablet. The tablet was coated using Opadry white.
Dissolution Profile:
Time (hour) Percent Venlafaxine HCl released
2 31
4 48
8 70
12 84
24 95
Example 3
Composition:
Ingredient Qty in mg
I. Core
Intragranular Portion
Venlafaxine Hydrochloride 169.3
Hydroxypropyl methylcellulose 170.0
Microcrystalline cellulose 366.2
Sodium chloride 80.0
Hydroxy Propylcellulose 80.0
Polyvinyl Pyrrolidone 75.0
Colloidal silicon dioxide 14.7
Talc 9.8
Extragranular Portion
Colloidal silicon dioxide 5.0
Magnesium stearate 10.0
II. Coating
Opadry white (Y- 1-7000) 50.0
Purified water * q.s.
Total weight 1030.0
* Does not appear in the final product except in traces.
Manufacturing Procedure:
The intragranular ingredients are mixed and compacted; the compact is passed through #20 mesh. To this extragranular ingredients were added for lubrication and compressed into tablet. The tablet was coated using Opadry white.
Dissolution Profile:
Time (hour) Percent Venlafaxine HCl released
2 34
4 53
8 79
12 96
24 107
Example 4 Composition:
Ingredient Qty in mg
I. Core
Intragranular Portion
Venlafaxine Hydrochloride 169.3
Hydroxyprόpyl methylcellulose 170.0
Microcrystalline cellulose 601.7
Colloidal silicon dioxide 16.0
Talc 12.0
Extragranular portion
Colloidal silicon dioxide 5.5
Magnesium stearate 10.5
H.Coating
Opadry white (Y- 1-7000) 50.0
Purified water * q.s.
Total weight 1035.0
* Does not appear in the final product except in traces.
Manufacturing Procedure: The intragranular ingredients are mixed and compacted; the compact is passed through #20 mesh. To this extragranular ingredients were added for lubrication and compressed into tablet. The tablet was coated using Opadry white.
Dissolution Profile:
Time (hour) Percent Venlafaxine HCl released
2 35
4 52
8 72
12 84
24 95
Example 5
Composition:
Ingredient Qty in mg
I. Core
Intragranular Portion
Venlafaxine Hydrochloride 169.3
Hydroxypropyl methylcellulose 250.0
Copovidone (copolymer of N- 110.7 vinyl-2-pyrrolidone and vinyl acetate)
Colloidal silicon dioxide 8.0
Talc 5.0
Extragranular portion
Colloidal silicon dioxide 2.0
Magnesium stearate 5.0
Il.Coating
Opadry Clear 82.5
Isopropyl alcohol * q.s.
Methylene chloride* q.s
Total weight 632.5
* Does not appear in the final product except in traces.
Manufacturing Procedure:
The intragranular ingredients are mixed and compacted; the compact is passed through #20 mesh. To this extragranular ingredients were added for lubrication and compressed into tablet. The tablet was coated using Opadry clear and filled into hard gelatin capsule.
Dissolution Profile:
Time (hour) Percent Venlafaxine HCl released
2 23
4 44
8 70
12 87
24 99
Example 6
Composition:
Ingredient Qty in mg
I. Core
Intragranular Portion
Venlafaxine Hydrochloride 169.3
Hydroxypropyl methylcellulose 250.0
Copovidone (copolymer of N- 110.7 vinyl-2-pyrrolidone and vinyl acetate)
Colloidal silicon dioxide 8.0
Talc 5.0
Extragranular portion
Colloidal silicon dioxide 2.0
Magnesium stearate 5.0
Il.Coating
Hydroxy propyl cellulose 82.5
Isopropyl alcohol * q.s.
Methylene chloride* q.s
Total weight 632.5
Does not appear in the final product except in traces.
Manufacturing Procedure:
The intragranular ingredients are mixed and compacted; the compact is passed through #20 mesh. To this extragranular ingredients were added for lubrication and compressed into tablet. The tablet was coated using hydroxy propyl cellulose and filled into hard gelatin capsule.
Dissolution Profile:
Time (hour) Percent Venlafaxine HCl released
2 24
4 44
8 71
12 87
24 100
Example 7 Composition:
Ingredient Qty in mg
I. Core
Intragranular Portion
Venlafaxine Hydrochloride 169.3
Hydroxypropyl methylcellulose 150.0
Xanthan gum 100.7
Colloidal silicon dioxide 4.0
Talc 4.0
Extragranular portion
Magnesium stearate 2.0
Total weight 430.0
* Does not appear in the final product except in traces.
Manufacturing Procedure: The intragranular ingredients are mixed and compacted; the compact is passed through #20 mesh. To this extragranular ingredients were added for lubrication and compressed into tablet. The uncoated tablet was filled into hard gelatin capsule.
Dissolution Profile:
Time (hour) Percent Venlafaxine HCl released
2 35
4 52
8 71
12 80
24 92
Example 8 Composition:
Ingredient Qty in mg
I. Core
Venlafaxine Hydrochloride 169.3
Polyethylene oxide 250.0
Microcrystalline cellulose 50.7
Colloidal silicon dioxide 6.0
Magnesium stearate 4.0
Total weight 480.0
* Does not appear in the final product except in traces.
Manufacturing Procedure: The ingredients are mixed and directly compressed into tablet. The uncoated tablet was filled into hard gelatin capsule.
Dissolution Profile:
Time (hour) Percent Venlafaxine HCl released 2 30 4 47 8 69 12 85 24 96
Claims
1. An extended release formulation comprising a core containing venlafaxine hydrochloride, hydrophilic matrix material and optionally other pharmaceutically acceptable excipients.
2. The extended release formulation according to claim 1, wherein less than 50% of venlafaxine hydrochloride is dissolved during first two hours when tested for dissolution using USP type I apparatus at 100 rpm in purified water at 37° C.
3. The extended release formulation according to claim 1, wherein said hydrophilic matrix material is selected from cellulose polymers, polyvinylpyrrolidone, polyethylene oxide, polysaccharide and combinations thereof.
4. The extended release formulation according to claim 3, wherein said cellulose polymer is selected from methylcellulose, hydroxy ethylcellulose, hydroxy propyl cellulose, hydroxy propyl methylcellulose and combinations thereof.
5. The extended release formulation according to claim 3, wherein said polysaccharide is selected from galactomannans, alginates, agar-agar, carrageen, arabic gum and sterculia gum and combinations thereof.
6. The extended release formulation according to claim 1, wherein said core contains from about 10% to about 50% by weight of venlafaxine hydrochloride and from about 10% to about 75% by weight of hydrophilic matrix material.
7. The extended release formulation according to claim 6, wherein the core contains from about 30% to about 50% by weight of hydrophilic matrix material.
8. The extended release formulation according to claim 1, wherein said core is further coated with coating composition comprising hydrophilic film forming polymers.
9. The extended release formulation according to claim 8, wherein said hydrophilic film forming polymer is selected from cellulose derivatives such as methylcellulose, hydroxy methylcellulose, hydroxy ethylcellulose, hydroxy propyl cellulose, hydroxy propyl methylcellulose, dextrins, soluble starches and starch derivatives, natural gums such as gum arabic, xanthans, alginates, polyvinyl pyrollidone, polyethylene oxide and combinations thereof.
10. The extended release formulation according to claim 8, wherein said coating composition further comprises plasticizers, colorants, opacifiers, adhesive agents and combinations thereof.
11. The extended release formulation according to claim 1, wherein said pharmaceutical acceptable excipients is selected from diluents, binders, surfactants, lubricants, disintegrants, glidants, colorants, plasticizers and combinations thereof.
12. The extended release formulation according to claim 1 is tablet formulation, pellet formulation or capsule formulation filled with tablet or mini tablets or pellets.
13. A process for preparing the extended release formulation comprising steps: a) Forming mixture of venlafaxine hydrochloride, hydrophilic matrix material and optionally other pharmaceutically acceptable excipients b) Processing the mixture in to desired dosage form.
14. The process according to claim 13, wherein said mixture is formed by wet granulation, dry granulation or direct compression.
15. The process according to claim 13, wherein the said dosage form is tablet, pellet or capsule filled with tablet, mini tablets or pellets.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1777/CHE/2006 | 2006-09-27 | ||
| IN1777CH2006 | 2006-09-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2008038106A1 true WO2008038106A1 (en) | 2008-04-03 |
Family
ID=39229774
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2007/002795 WO2008038106A1 (en) | 2006-09-27 | 2007-09-26 | Venlafaxine extended release formulations |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2008038106A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112716916A (en) * | 2019-10-14 | 2021-04-30 | 蒋海松 | Sustained-release micro-tablet capsule of 5-hydroxytryptamine, norepinephrine and dopamine reuptake inhibitor and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003055475A1 (en) * | 2002-01-03 | 2003-07-10 | Lek Pharmaceutical And Chemical Company D.D. | Controlled release pharmaceutical formulation containing venlafaxine |
| US20040147510A1 (en) * | 2003-01-13 | 2004-07-29 | Dynogen Pharmaceuticals, Inc. | Method of treating nausea, vomiting, retching or any combination thereof |
| US20050250838A1 (en) * | 2004-05-04 | 2005-11-10 | Challapalli Prasad V | Formulation for sustained delivery |
-
2007
- 2007-09-26 WO PCT/IB2007/002795 patent/WO2008038106A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003055475A1 (en) * | 2002-01-03 | 2003-07-10 | Lek Pharmaceutical And Chemical Company D.D. | Controlled release pharmaceutical formulation containing venlafaxine |
| US20040147510A1 (en) * | 2003-01-13 | 2004-07-29 | Dynogen Pharmaceuticals, Inc. | Method of treating nausea, vomiting, retching or any combination thereof |
| US20050250838A1 (en) * | 2004-05-04 | 2005-11-10 | Challapalli Prasad V | Formulation for sustained delivery |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112716916A (en) * | 2019-10-14 | 2021-04-30 | 蒋海松 | Sustained-release micro-tablet capsule of 5-hydroxytryptamine, norepinephrine and dopamine reuptake inhibitor and preparation method thereof |
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