FIELD OF THE INVENTION
The present invention describes novel extended release pharmaceutical compositions comprising a core, wherein the core comprises a water soluble active agent which is venlafaxine or alfuzosin or pramipexole or rivastigmine, or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof; at least one water insoluble non-swellable polymer(s), at least one hydration inhibitor(s), and optionally one or more pharmaceutically acceptable excipient(s); and at least one coat; wherein the said composition provides therapeutic concentrations of active agent for extended periods of time. Preferably the coating composition comprises at least one pH independent water insoluble non-porous polymer(s) and at least one channel former(s), and optionally one or more pharmaceutically acceptable excipient(s). Preferably the compositions are in the form of mini-tablets filled into capsules or layered tablets. Further, this invention relates to process of preparation of such novel compositions and methods of using them.
BACKGROUND OF THE INVENTION
Controlled release formulations have been described in the prior art and many methods have been used to provide controlled-release pharmaceutical dosage forms in order to maintain therapeutic serum levels of medicaments and to minimize the effects of missed doses of drugs caused by a lack of patient compliance. Extended Release (ER) delivery systems provide a uniform concentration/amount of the drug at the absorption site and thus, after absorption, allow maintenance of plasma concentrations within a therapeutic range over an extended period of time, which can minimize side effects and also reduces the frequency of administration. ER dosage forms release the drug slowly, so that plasma concentrations are maintained at a therapeutic level for a prolonged period of time. Typically, these products provide numerous benefits compared to immediate release compositions, including greater effectiveness in the treatment of chronic conditions, reduced side effects, greater convenience, and higher degree of patient compliance due to simplified dosing schedule.
Alfuzosin acts as a selective and competitive antagonist of alpha-1 adrenoceptor mediated contraction of prostatic capsule, bladder base and proximal urethral structures and used in the treatment of moderate to severe symptoms of benign prostatic hyperplasia. Alfuzosin is conventionally administered three times per day as 2.5 mg immediate release tablet dosage form. Pramipexole is a nonergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3
than to D2 or D4 receptor subtypes. The precise mechanism of action of pramipexole as a treatment for parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. Venlafaxine, chemically designated as (R/S)-l-[2-(dimethylamino)-l-(4methoxyphenyl) ethyl]cyclohexanol, is a bicyclic compound with antidepressant properties affecting chemical messengers within the brain. Rivastigmine is a reversible cholinesterase inhibitor approved for treatment of mild to moderate dementia of the Alzheimer's type and for mild to moderate dementia related to Parkinson's disease.
The US Patent nos. 6274171, 6403120, and 6419958 disclose encapsulated extended release formulations of venlafaxine hydrochloride. The encapsulated dosage form is taught to comprise spheroids of venlafaxine hydrochloride, microcrystalline cellulose, and hydroxypropyl methylcellulose (HPMC). These spheroids are coated with a mixture of ethyl cellulose and HPMC. By providing an appropriate amount of the coating, the desired blood plasma profile can be obtained. Further, as found by the inventors of the present invention by experimentation and as disclosed in the PCT Publication no. WO200574895, the core composition as disclosed in the US Patent, nos. 6274171, 6403120, and 6419958 when extruded, spheronized and dried to prepare uncoated spheroids, the cylindrical extrudes of the composition were very sticky and fragile with variable length of the extruded cylinders which resulted in the formation of non-uniform spheroids during spheronization and the process of spheronization was also difficult. The formed spheroids were irregular shaped and excessively sticky in nature which resulted in the formation of aggregates. During coating, the fragile nature of the spheroids results in formation of too many fines, which leads to bridging of the formation of few aggregates during coating process. This leads to several drawbacks like difficulty in manufacturing and reproducibility in the dosage form compositions.
US Publication no. 20030190354 describes an extended release composition comprising as active agent venlafaxine hydrochloride in a matrix tablet dosage form, in which venlafaxine is mixed with a combination of hydrophilic, e.g. HPMC, and hydrophobic, e.g. Ethyl cellulose, matrix forming components and Kollidon®SR, either in its dry form or as suspension that may be used as a binder. PCT Publication no. WO200355475 teaches the controlled release formulation of venlafaxine that comprises for example a core consisting of an active drug which may be advantageously in amorphous form, polyvinylpyrrolidone, a combination of two hydrophilic polymers having different viscosity and optionally other commonly used ingredients for solid dosage forms. The core is coated with a polymeric coating comprising a combination of two
polymers having different water permeability. US Publication no. 20050048118 relates to a modified release tablet that can provide modified release of venlafaxine hydrochloride wherein the tablet composition comprises a core, which comprises a lipophilic matrix and an effective amount of venlafaxine hydrochloride; and a water insoluble, permeable coating over said core. The lipophilic matrix is preferably a fatty acid wax and the water insoluble, permeable coating is preferably comprised of an acrylic polymer such as a methacrylate copolymer. US Patent no. 6703044 relates to a formulation comprising a compressed core coated with a relatively rigid water insoluble, hydrophobic polymer, in which particles of water insoluble but hydrophilic material are embedded. PCT Publication no. WO200469228 relates to 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, glyceryl behenate and glyceryl palmitostearate; and a lubricant optionally in combination with a filling material and/or other excipients. PCT Publication no. WO200412699 and related US Publication no. 20040096501 teach the use of dual retard technique to effectively control the release rate of modified release active ingredient by using small quantity of release controlling agents. The dosage form comprises of micro matrix particles containing high solubility active ingredient and one or more hydrophobic release controlling agent, and coating of micro matrix particles with one or more hydrophobic release controlling agents.
The compositions disclosed in the prior art have several drawbacks pertaining to ease-of-manufacture, consistency and predictability in drug release and patient compliance. The water soluble active agents exhibit a potential problem of dose dumping and burst release from an extended release matrix and hence matrix delivery system is not suitable for consistent and prolonged delivery of such active agents to the desired site of action. It is therefore essential to develop dosage form compositions to ensure consistent delivery and prolonged plasma levels with insignificant contribution to the initial release in case of a failure of the system, thereby avoiding dose dumping, and any associated toxicity issues. Several attempts to provide dosage forms for delivery of active agent for extended periods of time have been described previously. However, there still exists a need to develop effective improved extended release dosage form compositions having reduced side effects, which can provide extended delivery of active agent, that are easier to manufacture, involves a low formulation cost and possess enhanced patient compliance. The present invention provides such novel extended release compositions.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide novel extended release pharmaceutical compositions comprising a core, wherein the core comprises a water soluble active agent which is venlafaxine or alfuzosin or pramipexole or rivastigmine, or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof from about 0.05% w/w to about 98% w/w, at least one water insoluble non-swellable polymer(s) from about 5% w/w to about 80% w/w, at least one hydration inhibitor(s) from about 10% w/w to about 50% w/w, at least one lubricant(s) upto about 30% w/w and optionally one or more pharmaceutically acceptable excipient(s) from 0% w/w to about 10% w/w of the core composition, wherein the ratio of water insoluble non-swellable polymer(s) and hydration inhibitor(s) is from about 1:50 to about 50:1; and at least one coat; wherein the ratio by weight of the core composition to the coat composition is between about 1:10 to about 10:1, and wherein the composition provides therapeutic concentrations of active agent for extended time periods.
It is an objective of the present invention to provide novel extended release pharmaceutical compositions comprising a core and a coat, wherein the core is formulated as a hydrophilic, non-swellable. erodible matrix system, and the coat provided on the core predominantly acts as a release controlling system.
It is also an objective of the present invention to provide novel extended release pharmaceutical composition comprising a core and a coat, wherein the core comprises a water soluble active agent which is venlafaxine or alfuzosin or pramipexole or rivastigmine, or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, at least one water insoluble non-swellable polymer(s), at least one hydration inhibitor(s), at least one lubricant(s) and optionally one or more pharmaceutically acceptable excipient(s); wherein the coat comprises at least one pH independent water insoluble non-porous polymer(s) and at least one channel former(s), optionally one or more pharmaceutically acceptable excipient(s); and wherein the composition provides therapeutic concentrations of active agent for extended periods of time.
It is a further objective of the present invention to provide compositions with a core and a coat, wherein the coating composition is formulated such that the coat is substantially uniform and firm and remains substantially intact throughout the release of the active agent. The release of the active agent from the core matrix takes place predominantly by diffusion through the channels in
the coat gradually in the desired manner for an extended period of time into the desired environment irrespective of the pH of the environment.
It is yet another objective of the present invention to provide novel extended release pharmaceutical compositions comprising a core, wherein the core comprises a water soluble active agent which is venlafaxine or alfuzosin or pramipexole or rivastigmine, or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, at least one water insoluble non-swellable polymer(s), at least one hydration inhibitor(s), optionally one or more pharmaceutically acceptable excipient(s); and one or more lubricants, wherein the lubricant(s) aid in making the core composition amenable to high speed production.
It is another objective of the present invention to provide novel extended release pharmaceutical compositions comprising a core and a first coat surrounding the said core wherein the core comprises a water soluble active agent which is venlafaxine or alfuzosin or pramipexole or rivastigmine, or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, at least one water insoluble non-swellable polymer(s), at least one hydration inhibitor(s); at least one lubricant(s); and optionally one or more pharmaceutically acceptable excipient(s); wherein the said first coat comprises at least one pH independent water insoluble non-porous polymer(s) and at least one channel former(s), optionally one or more pharmaceutically acceptable excipient(s); and wherein at least one additional coating layer is present on the said first coat.
It is another objective of the present invention to provide process for preparation of such compositions.
It is a further objective of the present invention to provide process for preparation of such
composition, which comprises of the following steps:
i) mixing the water soluble active agent with water insoluble non-swellable polymer(s),
hydration inhibitor(s), lubricant(s) and optionally one or more pharmaceutically acceptable
excipient(s),
ii) formulating the mixture of step (i) into a suitable core composition, iii) coating the core composition of step (ii) with a coating composition comprising at least one pH
independent water insoluble non-porous polymer(s) and at least one channel former(s), optionally
one or more pharmaceutically acceptable excipient(s) to obtain the coated composition,
iv) optionally providing a second coating layer on the first coat, and
v) optionally formulating the coated composition of step (iii) or (iv) into a suitable dosage form.
It is still further objective of the present invention to provide a process for preparation of such
composition, which comprises of the following steps:
i) mixing the water soluble active agent with water insoluble non-swellable polymer(s),
hydration inhibitor(s), and optionally one or more pharmaceutically acceptable excipient(s), ii) mixing the material of step (i) alongwith a portion of a lubricant(s) to obtain a
homogeneous blend, iii) compacting the blend of step (ii) followed by crushing of the compacts obtained and sifting
the material through suitable sieve to obtain granules, iv) optionally mixing the sifted material of step (iii) with other pharmaceutically acceptable
excipient(s),
v) adding the remaining portion of lubricant(s) to the material of step (iv) and mixing, vi) compressing the material of step (v) into minitablets to form the core composition, vii) coating the core composition with a coating composition comprising at least one pH
independent water insoluble non-porous polymer(s), at least one channel former(s) and
plasticizer(s), optionally one or more pharmaceutically acceptable excipient(s) to obtain the
coated composition, and viii) formulating the coated minitablets into a suitable dosage form.
It is yet another objective of present invention to provide a method of using such composition which comprises administering to a subject in need thereof an effective amount of composition.
The novel extended release dosage form of the present invention may be in the form of coated tablets or mini-tablets, layered tablets, capsules, granules and other dosage forms suitable for oral administration and may be preferably administered twice daily or once daily.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel extended release pharmaceutical compositions comprising a core, wherein the core comprises a water soluble active agent which is venlafaxine or alfuzosin or pramipexole or rivastigmine, or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof from about 0.05% w/w to about 98% w/w, at least one water insoluble non-swellable polymer(s) from about 5% w/w to about 80% w/w, at least one hydration inhibitor(s) from about 10% w/w
to about 50% w/w and optionally one or more pharmaceutically acceptable excipient(s) from 0% w/w to about 10% w/w of the core composition; and at least one coat; wherein the ratio by weight of the core composition to the coat composition is between about 1:10 to about 10:1, and wherein the composition provides therapeutic concentrations of active agent for extended periods of time. In an embodiment of the present invention, it might be appreciated that the at least one water insoluble non-swellable polymer(s) is substantially water insoluble; however if the water insoluble non-swellable polymer(s) component is a mixture of two or more compounds, then one or more of the compound of such mixture may be a water soluble component, but when taken together the mixture behaves as a water insoluble non-swellable system.
Preferably the core is formulated as a hydrophilic, non-swellable, credible matrix system. In an embodiment, the hydrophilicity of the core is primarily due to the presence of a substantially high concentration of the water soluble component(s). In an embodiment wherein the composition comprises a low amount of the water soluble active agent defined herein preferably present in an amount of about 0.1-50% by weight of the core composition, at least one additional water soluble or hydrophilic component(s) preferably acting as a filler or a diluent is present in the core in order to make the core predominantly hydrophilic. In a preferred embodiment, the water soluble active agent itself acts as a channel forming agent in the core and thus facilitates its own release from the core matrix. However, in order to have a gradual extended release of the active agent from the dosage form, the inventors of the present invention by their intellectual efforts and extensive experimentation have devised and optimized the core composition so as to contain non-hydrophilic components also such as at least one water insoluble non-swellable polymer(s) and at least one hydration inhibitor(s), which alone or together serve to allow the desired hydration of the core gradually, thus controlling drug release from the hydrophilic core.
In an embodiment of the present invention is provided a novel extended release pharmaceutical composition comprising a core and a coat, wherein the core comprises a water soluble active agent which is venlafaxine or alfuzosin or pramipexole or rivastigmine, or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, at least one water insoluble non-swellable polymer(s), at least one hydration inhibitor(s) and optionally one or more pharmaceutically acceptable excipient(s); wherein the coat comprises at least one pH independent water insoluble non-porous polymer(s) and at least one channel former(s), optionally one or more pharmaceutically acceptable excipient(s); and wherein the composition provides therapeutic concentrations of the active agent for extended periods of time.
Preferably the core composition of the present invention does not substantially swell upon contact with the aqueous fluids in vitro and/or in vivo and thus does not substantially disturb the intactness of the coat, such that the composition is substantially devoid of burst release of the active agent, and instead provides a gradual extended drug release throughout the desired period. In another embodiment of the present invention is provided a novel extended release pharmaceutical composition comprising a core, wherein the core comprises a water soluble active agent which is venlafaxine or alfuzosin or pramipexole or rivastigmine, or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, at least one water insoluble non-swellable polymer(s), at least one hydration inhibitor(s), optionally one or more pharmaceutically acceptable excipient(s), and one or more lubricant(s), wherein the lubricant(s) aid in making the core composition amenable to high speed production. In a further embodiment of the present invention, at least one, preferably two, more preferably at least three lubricants are present in the core composition.
In another embodiment of the present invention is provided a novel extended release pharmaceutical composition comprising a core wherein the core comprises a water soluble active agent which is venlafaxine or alfuzosin or pramipexole or rivastigmine, or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, at least one water insoluble non-swellable polymer(s), at least one hydration inhibitor(s), at least one lubricant(s), at least one water insoluble filler(s) in the core; a release controlling system for coating the core comprising at least one pH independent water insoluble non-porous polymer(s) and at least one channel former(s), at least one plasticizer(s); and optionally one or more pharmaceutically acceptable excipient(s); wherein the composition provides therapeutic concentrations of active agent for extended time period.
In another embodiment of the present invention, the core composition comprises at least one binder selected from but not limited to a group comprising water insoluble or water soluble polymer such as cellulosic polymer e.g. hydroxypropyl cellulose, polyvinylacetate, and polyvinylpyrrolidone, and the like, or suitable mixtures thereof.
In another embodiment of the present invention, the water insoluble non-swellable polymer is selected from but not limited to a group comprising methacrylate copolymers such as Eudragit®RLPO, Eudragit®RSPO or their mixture; polyvinylacetate/polyvinylpyrrolidone mixtures; polyvinylacetate; ethyl cellulose; or suitable combinations thereof. In a preferred
embodiment, the water insoluble non-swellable polymer used in the core is a mixture of polyvinylacetate and polyvinylpyrrolidone (povidone) preferably in the ratio 8:2 such as for example, Kollidon®SR, and the like.
The term "hydration inhibitor" as used herein refers to a substance that controls the hydration of the core. In a further embodiment of the present invention, the hydration inhibitor is used preferably in the core composition to provide a controlled entry of aqueous fluids into the system, which in turn leads to a controlled and gradual hydration of the core and a gradual formation of channels that aids in providing a gradual extended release and prevents the burst effect of the drug release. The said hydration inhibitor is selected from but not limited to a group comprising glyceryl behenate such as Compritol®888 ATO, Compritol®HD5 ATO, and the like or mixtures thereof; hydrogenated vegetable oil such as hydrogenated castor oil e.g. Lubritab®; glyceryl palmitostearate such as Precirol®ATO5; glyceryl monostearate; stearic acid; stearates such as magnesium stearate, calcium stearate, zinc stearate and the like, or mixtures thereof.
In an embodiment of the present invention, the ratio of water insoluble non-swellable polymer(s) and hydration inhibitor(s) is about 1:10 to about 10:1.
In another embodiment of the present invention, the coating composition is formulated as a release controlling system that aids in providing extended release of the active agent. In another embodiment of the present invention, the release controlling system for coating the core comprises at least one pH independent water insoluble non-porous polymer(s), at least one channel former(s) and a plasticizer. The term "non-porous" as stated herein refers to the absence of pores in the compound which makes the compound substantially impermeable to any matter. The water insoluble non-porous polymer(s) is selected from but not limited to a group comprising vinyl acetate polymers and copolymers such as Kollicoat®SR 30D which is polyvinyl acetate (-27% w/w) stabilized with polyvinylpyrrolidone (-2-5% w/w) and sodium lauryl sulfate (-0.3% w/w); low viscosity ethyl cellulose; and the like or mixtures thereof.
In another embodiment, the coat additionally comprises one or more methacrylate copolymers and/or aminoalkyl methacrylate copolymers such as ethyl acrylate/methyl methacrylate copolymer and an ethyl acrylate/methyl methacrylate/trimethylammonioethyl methacrylate copolymer e.g. Eudragit®RLPO or Eudragit®RSPO; Kollicoat®EMM30D which is a copolymerisate based on ethyl acrylate and methyl methacrylate in a 2:1 ratio available as a 30 % aqueous dispersion; and the like or mixtures thereof.
A "channel former" according to the present invention is a substance which is present in the matrix composition and which dissolves in aqueous fluids leading to the formation of pores/channels thus allowing the passage of fluids into the matrix system. In a further embodiment, the channel former(s) useful in the coating composition is selected from but not limited to a group comprising alkyl celluloses such as methyl cellulose; hydroxyalkyl alkylcelluloses such as hydroxypropyl methylcellulose (HPMC, Methocel®E5 or El5); hydroxyalkyl celluloses such as hydroxypropyl cellulose (HPC, Klucel®EXF) and hydroxyethyl cellulose (HEC, Natrosol®250 HX); polyethylene glycols (PEG 6000, PEG 10000); copolymers of ethylene oxide with propylene oxide (Poloxamer 407, Poloxamer 188 or the like); gelatin; polyvinylpyrrolidones (PVP, Kollidon®12 PF, Kollidon®17 PF, Kollidon®K15, Kollidon®K30, Kollidon®K90); vinylpyrrolidones; polyvinylimidazoles; polyvinylpyridine N-oxides; copolymer of polyvinyl alcohol-polyethylene glycol (Kollicoat®IR); Kollicoat®Protect which is a solid solution of KoIlicoat®IR and polyvinyl alcohol; copolymers of vinylpyrrolidone with long-chained alpha-olefins; poly(vinylpyrrolidone/dimethylaminoethyl methacrylates); copolymers of vinylpyrrolidone/dimethylaminopropyl methacrylamides; copolymers of vinylpyrrolidone/ dimethylaminopropyl acrylamides; quaternised copolymers of vinylpyrrolidones and dimethylaminoethyl methacrylates; terpolymers of vinylcaprolactam/vinylpyrrolidone/ dimethylaminoethyl methacrylates; copolymers of vinylpyrrolidone and methacrylamidopropyl-trimethylammonium chloride; terpolymers of caprolactam/vinylpyrrolidone/dimethylaminoethyl methacrylates; copolymers of styrene and acrylic acid; polycarboxylic acids; polyacrylamides; polyvinyl alcohols (PVA) such as Mowiol®40-88; hydrolysed polyvinyl acetate; sugars such as mannitol, lactose, dextrose, sucrose, maltitol, sorbitol; and the like, or mixtures thereof. In an embodiment, the water soluble active agent might itself act as a channel former.
In an embodiment, the plasticizer(s) useful in the present invention is selected from but not limited to a group comprising KoIlicoat®lR, triethyl citrate, polyethylene glycol, propylene glycol and the like, or mixtures thereof. In another embodiment, an anti-foaming agent is additionally used in the coating composition selected from but not limited to a group comprising simethicone, polydimethylsiloxane, and the like or mixtures thereof.
In another preferred embodiment of the present invention, the ratio of pH independent water insoluble non-porous polymer(s) to the channel former(s) in the coat ranges from about 20:1 to about 1:20. The coat expressed as a proportion of the total weight of the dosage form, may also vary according to the release characteristics of the active agent required. Preferably, the coat constitutes about 1% w/w to
about 50% w/w of the pharmaceutical dosage form, more preferably about 5% w/w to about 30% w/w of the pharmaceutical dosage form. The ratio of the water soluble material to inert or insoluble material in the coat will also be determined by the release profile desired. A higher proportion of soluble material will, in general, result in faster release of the active agent from the composition.
In a preferred embodiment of the present invention, the water soluble active agent comprises from about 0.1% w/w to about 90% w/w of the dosage form, preferably about 10% w/w to about 75% w/w of the dosage form. In a further embodiment of the present invention, the core comprises from about 0.05% w/w to about 98% w/w of the water soluble active agent, from about 5% w/w to about 80% w/w of the water insoluble non-swellable polymer(s), from about 10% w/w to about 50% w/w of the hydration inhibitor(s) and from 0% w/w to about 10% w/w of excipient(s) such as diluents, binders, glidants or lubricants or any combinations thereof, wherein the % w/w of the ingredients is with reference to the core composition.
It has been surprisingly found by the inventors of the present invention that a specific proportion of lubricant in the core such as upto about 30% w/w of the core composition would result in high speed production of mini-tablets and would overcome the stickiness due to poor flow property of the active agent during the formulation of the composition such as during the compression of the mini-tablets. In a preferred embodiment, the lubricants are selected from but not limited to a group comprising talc, colloidal silicon dioxide, magnesium stearate, calcium stearate, zinc stearate, stearic acid, sodium stearyl fumarate, mineral oil, glyceryl behenate, hydrogenated vegetable oil, and the like, or mixtures thereof. In an embodiment, at least three lubricants are present in the core preferably in a ratio of 1:1:1. Preferably the three lubricants useful according to the present invention are colloidal silicon dioxide, talc and magnesium stearate.
In an embodiment of the present invention, the core may additionally comprise alkalizing agent(s) selected from but not limited to a group comprising disodium hydrogen phosphate; organic amines such as diethylamine or triethylamine; metal oxides such as magnesium oxide; carbonates and bicarbonates of metals such as calcium carbonate, magnesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, and the like; or mixtures thereof. In another embodiment of the present invention, the core may additionally comprise acidifying agent(s) selected from but not limited to a group comprising citric acid, tartaric acid, and other organic acids, or mixtures thereof. Preferably the core comprises an alkaline agent when the active agent is basic and comprises an acidifying agent when the active agent is acidic in nature.
Pharmaceutically acceptable excipients according to the present invention are selected from excipients generally used by persons skilled in the art, e.g. diluents or fillers, disintegrants, binders, stabilizers, lubricants, anti-adherents or glidants, antioxidants, vehicles, buffers, preservatives, complexing agents, colorants, flavorants, pH modifiers, channel formers, surfactants, viscosifiers, gelling agents, tonicity modifiers, lipid components, emulsifiers, coating agents, plasticizers, organic solvents, stabilizers, chelating agents, and the like, or mixtures thereof. The diluents or fillers useful in the present invention are selected from but not limited to a group comprising lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, dibasic calcium phosphate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate, calcium lactate, dextrose, dextran, dextrates, inositol, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, cellulose powder, pregelatinized starch such as Starch® 1500, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, glycine, or bentonites, and the like or mixtures thereof. The disintegrants useful in the present invention are selected from but not limited to a group comprising croscarmellose sodium (e.g. Primellose®, Vivasol®, Ac-di-sol®), sodium starch glycollate, starches, pregelatinized starch, celluloses, cross-linked carboxymethylcellulose, crospovidone, clays, alginates, gums and the like, or mixtures thereof. The anti-adherents or glidants useful in the present invention are selected from but not limited to a group comprising talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, colloidal silicon dioxide, and the like, or mixtures thereof. It might however be emphasized that an excipient disclosed in present invention can be employed to serve one or more than one purpose.
The controlled release dosage form may be in the form of tablets, mini-tablets, capsules, granules, mini-tablets/tablets filled in capsule, and other dosage forms suitable for oral administration. In a preferred embodiment, the composition of the present invention is in the form of tablets. The tablets can be prepared by either direct compression, dry compression (slugging) or by granulation. In a preferred embodiment of the present invention, the oral composition is prepared by direct compression/compaction or slugging. The composition may also be prepared by wet granulation technique, which might be either aqueous or non-aqueous. The non-aqueous solvent used is selected from a group comprising ethanol, isopropyl alcohol, methylene chloride or acetone. In an embodiment, the compositions of the present invention are in the form of compacted tablets/mini-tablets, compressed tablets/mini-tablets, or moulded tablets/mini-tablets, and the like. In another embodiment, the coated tablets/mini-tablets may optionally comprise a part or whole of the active agent in the coating composition. The tablets may be formulated as layered tablets comprising at least two layers wherein the same active agent is present in all the layers exhibiting different

release profiles or one or more additional active agent(s) is present in the layers exhibiting different release profiles. The tablet/mini-tablets may be optionally filled into capsules.
In another embodiment, the composition of the present invention is formulated as a coated layered tablet comprising at least one immediate release (IR) layer intended to provide fast release of the active agent and one sustained release (SR) layer intended to provide a sustained release of the active agent. In such composition, the core matrix as well the coating composition together contributes in providing the release of the active agent for extended period of time.
In an embodiment of the present invention, the active agent(s) is released mainly by diffusion mechanism irrespective of the gastro-intestinal pH. The dosage form remains almost intact even after the complete release of the active agent, which leads to a more reliable drug delivery system providing a pH independent, predictable and reproducible release profile of active agent(s), particularly as evidenced by the in vitro dissolution study. The extended release compositions of the present invention release the active agent(s) in a consistent and uniform manner and are devoid of substantial variations in the release of the active agent(s) between individual unit dosage forms.
Further, the core composition of the present invention is preferably formulated as a hydrophilic, non-swellable, erodible system. Different compositions of core particularly comprising varied amounts of water soluble active agent, water insoluble non-swellable polymer(s) and hydration inhibitor(s) were studied for in vitro % drug release using USP Dissolution Apparatus-II (paddles) at 50 RPM with 900 ml DM water as dissolution media. The results of study showed that all the compositions provide an immediate release of the active agent; wherein at least about 75% of the active agent is released in 1 hour. In the said study, it was observed that the erosion of the core depends on the amount of the hydrophilic component(s) and hydrophobic or water insoluble component(s). In order to obtain desired hydration of the core matrix and the release characteristics of the active agent, the amount of hydration inhibitor(s) and water insoluble non-swellable polymer(s) is adjusted such as for example, if the active agent is highly water soluble then the amount of hydration inhibitor(s) is increased and if the active agent(s) is moderately water soluble, then the amount of water insoluble non-swellable polymer(s) is increased.
In an essential embodiment, the core does not swell upon contact with the aqueous fluids, as a result of which the rate limiting coat shall not be disturbed and hence, the system provides sustained drug release of the active agent till the desired period without any burst effect of the drug release. The core comprises of water insoluble polymer(s) capable of forming pores upon
contact with aqueous fluids, and hydration inhibitor(s) that provides controlled entry of aqueous fluids into the system. In a preferred embodiment, the ratio of water insoluble polymer(s) and hydration inhibitor(s) is from about 1:50 to about 50:1, which provides suitable intactness of the composition as well as desired drug release profile upon contact with the dissolution media.
It has been surprisingly found by the inventors of the present invention that irrespective of the pH of the media used, the composition releases the desired active agent over a period of about 8-24 hours in a controlled manner, which is necessary to maintain the desired therapeutic plasma levels of the active agent. The composition of the present invention is capable of releasing the active agent along gastrointestinal tract and independent of pH conditions of gastrointestinal tract to achieve and maintain effective concentrations of active agent for extended time period.
The exact dose of active agent and the particular formulation to be administered depends on individual factors, e.g. the condition to be treated, the desired duration of the treatment and the rate of release of the active agent. For example, in a preferred embodiment, the solid dosage form however, is described to contain from about 0.1-500 mg of the active agent used either as the free base or as its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, or mixtures thereof.
In yet another embodiment, the compositions of the present invention are subjected to 'curing' at a temperature of about 35-60°C alone or a temperature of 35-60°C alongwith RH (relative humidity) of about 40-90%. The said 'curing' process involves exposing the composition directly to the said condition of temperature or temperature/RH for a particular period of time and is done primarily to ensure stability of the product during storage, and to alleviate/minimize the chances of variation in the drug release.
In another embodiment of the present invention, the compositions of the present invention may additionally comprise another coating layer. The said second coating layer preferably is a film coating and comprises one or more excipients selected from but not limited to a group comprising Kollicoat®IR Protect, Opadry®AMB, or mixtures thereof as the film former; plasticizers such as propylene glycol or triethyl citrate; lubricants such as talc; and any other excipient(s) known to the art. The second coating preferably acts as a seal coat which prevents or minimizes the transfer of moisture to or from the composition thus alleviating/minimizing the chances of variation in desired release profile of active agent(s) during shelf life of the product. In another embodiment, the present invention provides a process for preparation of such novel
composition. In a further embodiment the process comprises of the following steps:
i) mixing the water soluble active agent with water insoluble non-swellable polymer(s), hydration inhibitor(s), lubricant(s), and optionally one or more pharmaceutically acceptable excipient(s),
ii) formulating the mixture of step (i) into a suitable core composition,
iii) coating the core composition of step (ii) with a coating composition comprising at least one pH independent water insoluble non-porous polymer(s) and at least one channel former(s), optionally one or more pharmaceutically acceptable excipient(s) to obtain the coated composition,
iv) optionally providing a second coating layer on the first coat, and
v) optionally formulating the coated composition of step (iii) or (iv) into a suitable dosage form.
It is still further objective of the present invention to provide a process for preparation of such
composition, which comprises of the following steps:
i) mixing the water soluble active agent with water insoluble non-swellable polymer(s),
hydration inhibitor(s), and optionally one or more pharmaceutically acceptable excipient(s), ii) mixing the material of step (i) alongwith a portion of a lubricant(s) to obtain a
homogeneous blend, iii) compacting the blend of step (ii) followed by crushing of the compacts obtained and sifting
the material through suitable sieve to obtain granules, iv) optionally mixing the sifted material of step (iii) with other pharmaceutically acceptable
excipient(s),
v) adding the remaining portion of lubricant(s) to the material of step (iv) and mixing, vi) compressing the material of step (v) into minitablets to form the core composition, vii) coating the core composition with a coating composition comprising at least one pH independent
water insoluble non-porous polymer(s), at least one channel formers) and plasticizer(s), optionally
one or more pharmaceutically acceptable excipient(s) to obtain the coated composition, and viii) formulating the coated minitablets into a suitable dosage form.
In yet another embodiment of the present invention is provided method of using such composition, which comprises administering to a patient in need thereof an effective amount of the composition comprising the active agent. The compositions are useful for prophylaxis, amelioration and/or treatment of disease conditions in a subject. For example, the composition comprising venlafaxine as the active agent is useful in the treatment of major depressive disorder. The composition comprising alfuzosin as the active agent is useful in the treatment of moderate to severe symptoms of benign prostatic hyperplasia. The composition comprising
pramipexole as active agent is useful particularly for treatment of signs and symptoms of idiopathic Parkinson's disease. The composition comprising rivastigmine is useful for the treatment of mild to moderate dementia related to Parkinson's disease.
The extended release oral dosage form may be administered once daily or twice daily depending on the nature of the active agent. The examples given below serve to illustrate embodiments of the present invention. However they do not intend to limit the scope of the present invention.
EXAMPLES
Exam pie-1:
S. No. Ingredient mg/capsule
Core composition
1. Venlafaxine hydrochloride 179.57
2. Partially pregelatinized starch (Starch 1500) 5.93
3. Glyceryl behenate 66.50
4. Polyvinylacetate and povidone copolymer 66.50
5. Hydroxypropyl cellulose 10.50
6. Colloidal silicon dioxide 7.00
7. Talc 7.00
8. Magnesium stearate 7.00
Coating composition
9. Polyvinyl acetate dispersion (Kollicoat®SR 30D) 36.75
10. Polyvinylalcohol polyethylene glycol graft copolymer (Kollicoat®IR) 7.35
11. Talc 4.06
12. Polyethylene glycol 1.58
13. Simethicone emulsion 0.26
14. Purified water q.s. (lost during processing)
Procedure:
i) Venlafaxine hydrochloride, Partially pregelatinized starch, Glyceryl behenate, Hydroxypropyl cellulose, and Polyvinylacetate and povidone copolymer were weighed together and mixed well and passed through #40 sieve.
ii) The powder blend of step (i) was lubricated with a portion of #60 sieve passed Magnesium stearate, Talc and Colloidal silicon dioxide and roller compacted to obtain compacts.
iii) The compacts in step (ii) were passed through sieve #30 and retained on sieve #60 to get
granules, iv) The granules of step (iii) were lubricated with remaining portion of #60 sieve passed
Magnesium stearate, Colloidal silicon dioxide and Talc. v) The granules of step (iv) were compressed to obtain mini-tablets, vi) Polyvinylalcohol polyethylene glycol graft copolymer was weighed and dissolved in
Purified water, vii) Polyvinyl acetate dispersion was added to the material in step (vi) followed by addition of
Simethicone emulsion, Polyethylene glycol and Talc and stirred well, viii) The coating dispersion of step (vii) was filtered through #100 sieve and the filtered material
was coated onto the mini-tablets of step (v). ix) The coated mini-tablets of step (viii) were dried and filled into capsules.
Example-2:
S. No. Ingredient mg/capsule
Core composition
1. Venlafaxine hydrochloride 179.57
2. Pregelatinized starch 5.93
3. Glyceryl behenate 60.00
4. Polyvinylacetate and povidone copolymer 73.00
5. Hydroxypropyl cellulose 10.50
6. Colloidal silicon dioxide 14.00
7. Magnesium stearate 7.00
Coating composition
8. Polyvinyl acetate dispersion (Kollicoat®SR 30D) 36.75
9. Polyvinylalcohol polyethylene glycol graft copolymer (Kollicoat®IR) 6.56
10. Polyvinylpyrrolidone (PVP K-30) 2.63
11. Talc 4.22
12. Triacetin 1.58
13. Simethicone emulsion 0.26
14. Purified water q.s. (lost during processing)
Procedure:
i) Venlafaxine hydrochloride, Pregelatinized starch, Glyceryl behenate, Hydroxypropyl
cellulose, and Polyvinylacetate and povidone copolymer were weighed together and mixed
well and passed through #40 sieve.
ii) The powder blend of step (i) was lubricated with a portion of #60 sieve passed Magnesium
stearate and Colloidal silicon dioxide and roller compacted to obtain compacts, iii) The compacts in step (ii) were passed through sieve #30 and retained on sieve #60 to get granules. iv) The granules of step (iii) were lubricated with remaining portion of #60 sieve passed
Magnesium stearate and Colloidal silicon dioxide, v) The granules of step (iv) were compressed to obtain mini-tablets, vi) Polyvinyl alcohol polyethylene glycol graft copolymer and polyvinyl pyrrolidone were
weighed and dissolved in Purified water, vii) Polyvinyl acetate dispersion was added to the material in step (vi) followed by addition of
Simethicone emulsion, Triacetin and Talc, and stirred well, viii) The coating dispersion of step (vii) was filtered through #100 sieve and the filtered material
was coated onto the mini-tablets of step (v). ix) The coated mini-tablets of step (viii) were filled into capsules.
Example-3:
S. No. Ingredient nig/capsule
Core composition
1. Venlafaxine hydrochloride 179.57
2. Mannitol 16.43
3. Glyceryl behenate 66.50
4. Ammonio methacrylate copolymer type-B (Eudragit®RSPO) 66.50
5. Colloidal silicon dioxide 6.00
6. Talc 9.00
7. Magnesium stearate 12.00
Coating composition
8. Polyvinyl acetate dispersion (Kollicoat®SR 30D) 36.75
9. Polyvinylalcohol polyethylene glycol graft copolymer (Kollicoat®IR) 7.35
10. Talc 4.06
11. Polyethylene glycol (PEG 400) 1.58
12. Polydimethylsiloxane 0.26
13. Purified water q.s. (lost during processing)
Procedure:
i) Venlafaxine hydrochloride, Mannitol, Glyceryl behenate, and Ammonio methacrylate
copolymer type-B were weighed together and mixed well and passed through #40 sieve.
ii) The powder blend of step (i) was lubricated with a portion of #60 sieve passed Magnesium
stearate, Talc and Colloidal silicon dioxide and roller compacted to obtain compacts. iii) The compacts in step (ii) were passed through sieve #30 and retained on sieve #60 to get granules, iv) The granules of step (iii) were lubricated with remaining portion of #60 sieve passed
Magnesium stearate, Colloidal silicon dioxide and Talc, v) The granules of step (iv) were compressed to obtain mini-tablets. vi) Polyvinylalcohol polyethylene glycol graft copolymer was weighed and dissolved in
Purified water, vii) Polyvinyl acetate dispersion was added to the material in step (vi) followed by addition of
Polyethylene glycol, Talc and Polydimethylsiloxane and stirred well, viii) The coating dispersion of step (vii) was filtered through #100 sieve and the filtered material
was coated onto the mini-tablets of step (v). ix) The coated mini-tablets of step (viii) were filled into capsules.
Example 4:
S. No. Ingredient mg/capsule
Core composition
1. Venlafaxine hydrochloride 179.57
2. Dextrose 5.93
3. Hydrogenated vegetable oil (Lubritab®) 66.50
4. Ethyl cellulose 66.50
5. Hydroxypropyl cellulose (KlucefEXF) 10.50
6. Colloidal silicon dioxide 8.00
7. Talc 7.00
8. Calcium stearate 6.00
First Coating composition
9. Polyvinyl acetate dispersion (Kollicoat®SR 30D) 36.75
10. Polyvinylalcohol polyethylene glycol graft copolymer (Kollicoat®IR) 7.35
11. Talc 4.06
12. Polyethylene glycol (PEG 400) 1.58
13. Simethicone emulsion 0.26
14. Purified water q.s. (lost during processing)
Second Coating composition
15. Opadry®AMB 10.00
16. Purified water q.s. (lost in processing)
Procedure:
i) Venlafaxine hydrochloride, Dextrose, Hydrogenated vegetable oil, Hydroxypropyl cellulose,
and Ethyl cellulose were weighed together and mixed well and passed through #40 sieve, ii) The powder blend of step (i) was lubricated with a portion of #60 sieve passed Calcium
stearate, Talc and Colloidal silicon dioxide and roller compacted to obtain compacts. iii) The compacts in step (ii) were passed through sieve #30 and retained on sieve #60 to get
granules, iv) The granules of step (iii) were lubricated with remaining portion of #60 sieve passed
Calcium stearate, Colloidal silicon dioxide and Talc, v) The granules of step (iv) were compressed to obtain mini-tablets, vi) Polyvinylalcohol polyethylene glycol graft copolymer was weighed and dissolved in
Purified water, vii) Polyvinyl acetate dispersion was added to the material in step (vi) followed by addition of
Simethicone emulsion, Polyethylene glycol and Talc, and stirred well, viii) The coating dispersion of step (vii) was filtered through #100 sieve and the filtered material
was coated onto the mini-tablets of step (v).
ix) Opadry®AMB was dispersed in Purified water to obtain a homogeneous dispersion. x) Coated mini-tablets of step (viii) were coated with second coating material of step (ix). xi) The coated mini-tablets of step (x) were dried and filled into capsules.
Example 5:
S. No. Ingredient rag/capsule
Core composition
1. Pramipexole dihydrochloride monohydrate 4.80
2. Lactose 80.00
3. Glyceryl palmitostearate (Precirol®ATO 5) 40.00
4. Polyvinylacetate and povidone copolymer 42.00
5. Hydroxypropyl cellulose 10.00
6. Colloidal silicon dioxide 6.00
7. Calcium stearate 4.00
Coating composition
8. Polyvinyl acetate dispersion (KollicoatSR 30D) 31.79
9. Polyvinyl alcohol polyethylene glycol graft copolymer (Kollicoat®IR) 7.56
10. Talc 2.91
11. Polyethylene glycol (PEG 400) 0.87
12. Simethicone emulsion 0.07
13. Purified water q.s. (lost during processing)
Procedure:
i) Pramipexole dihydrocholride monohydrate and Lactose were mixed well.
ii) Glyceryl palmitostearate, Hydroxypropyl cellulose, Polyvinylacetate and povidone
copolymer were weighed together and mixed well.
iii) Step (ii) powder blend was mixed with step (i) blend and passed through #40 sieve. iv) The powder blend of step (iii) was lubricated with a portion of #60 sieve passed Calcium
stearate and Colloidal silicon dioxide and roller compacted to obtain compacts. v) The compacts in step (iv) were passed through sieve #30 and retained on sieve #60 to get
granules, vi) The granules of step (v) were lubricated with remaining portion of #60 sieve passed
Calcium stearate and Colloidal silicon dioxide, vii) The granules of step (vi) were compressed to obtain mini-tablets, viii) Polyvinylalcohol polyethylene glycol graft copolymer was weighed and dissolved in
Purified water, ix) Polyvinyl acetate dispersion was added to the material in step (viii) followed by addition of
Simethicone emulsion, Polyethylene glycol and Talc, and mixed well, x) The coating dispersion of step (ix) was filtered through #100 sieve and the filtered material
was coated onto the mini-tablets of step (vii). xi) The coated mini-tablets of step (x) were dried and filled into capsules.
Example 6:
S. No. Ingredient mg/capsule
Core composition
1. Alfuzosin hydrochloride 10.00
2. Dibasic calcium phosphate 28.00
3. Glyceryl behenate 85.00
4. Polyvinylacetate and povidone copolymer 65.00
5. Colloidal silicon dioxide 4.00
6. Talc 4.00
7. Calcium stearate 4.00
Coating composition
8. Polyvinyl acetate dispersion (Kollicoat®SR SOD) 21.79
9. Polyvinyl alcohol polyethylene glycol graft copolymer (Kollicoat®IR) 4.36
10. Talc 2.91
11. Polyethylene glycol (PEG 400) 0.87
12. Simethicone emulsion 0.07
13. Purified water q.s. (lost during processing)
Procedure:
i) Alfuzosin hydrochloride was weighed and mixed with Dibasic calcium phosphate.
ii) Glyceryl behenate, Polyvinylacetate and povidone copolymer were weighed and mixed
together well.
iii) Step (ii) powder blend was mixed with step (i) blend and passed through #40 sieve, iv) The powder blend of step (iii) was lubricated with a portion of #60 sieve passed Calcium
stearate, Talc and Colloidal silicon dioxide, and roller compacted to obtain compacts. v) The compacts in step (iv) were passed through sieve #30 and retained on sieve #60 to get
granules. vi) The granules of step (v) were lubricated with remaining portion of #60 sieve passed
Calcium stearate, Colloidal silicon dioxide and Talc, vii) The granules of step (vi) were compressed to obtain mini-tablets, viii) Polyvinylalcohol polyethylene glycol graft copolymer was weighed and dissolved in
Purified water, ix) Polyvinyl acetate dispersion was added to the material in step (viii) followed by addition of
Simethicone emulsion. Polyethylene glycol and Talc, and mixed well. x) The coating dispersion of step (ix) was filtered through #100 sieve and the filtered material
was coated onto the mini-tablets of step (vii). xi) The coated mini-tablets of step (x) were dried and filled into capsules.
Example 7:
S. No. Ingredient ing/capsule
Core composition
1. Rivastigmine tartrate 12.00
2. Lactose 86.00
3. Glyceryl behenate 35.00
4. Ethyl cellulose 45.00
5. Hydroxypropyl cellulose 10.00
6. Colloidal silicon dioxide 4.00
7. Talc 4.00
8. Magnesium stearate 4.00
Coating composition
9. Polyvinyl acetate dispersion (Kollicoat®SR 30D) 21.79
10. Polyvinyl alcohol polyethylene glycol graft copolymer (Kollicoat®IR) 4.36
11. Talc 2.91
12. Polyethylene glycol (PEG 400) 0.87
13. Simethicone emulsion 0.07
14. Purified water q.s. (lost during processing)
Procedure:
i) Rivastigmine tartrate was weighed and mixed with Lactose.
ii) Glyceryl behenate, Hydroxypropyl cellulose and Ethyl cellulose were weighed together and
mixed well.
iii) Step (ii) powder blend was mixed with step (i) blend and passed through #40 sieve, iv) The powder blend of step (iii) was lubricated with a portion of #60 sieve passed
Magnesium stearate, Talc and Colloidal silicon dioxide, and roller compacted to obtain
compacts. v) The compacts in step (iv) were passed through sieve #30 and retained on sieve #60 to get
granules, vi) The granules of step (v) were lubricated with remaining portion of #60 sieve passed
Magnesium stearate, Colloidal silicon dioxide and Talc, vii) The granules of step (vi) were compressed to obtain mini-tablets, viii) Polyvinylalcohol polyethylene glycol graft copolymer was weighed and dissolved in
Purified water. ix) Polyvinyl acetate dispersion was added to the material in step (viii) followed by addition of
Simethicone emulsion, Polyethylene glycol and Talc and mixed well, x) The coating dispersion of step (ix) was filtered through #100 sieve and the filtered material
was coated onto the mini-tablets of step (vii). xi) The coated mini-tablets of step (x) were dried and filled into capsules.

We claim:
1. A novel extended release pharmaceutical composition comprising a core, wherein the core
comprises a water soluble active agent which is venlafaxine or alfuzosin or pramipexole or
rivastigmine, or its pharmaceutically acceptable salts, derivatives, isomers, polymorphs, solvates,
hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof from about 0.05% w/w to
about 98% w/w, at least one water insoluble non-swellable polymer(s) from about 5% w/w to
about 80% w/w, at least one hydration inhibitor(s) from about 10% w/w to about 50% w/w, at
least one lubricant(s) upto about 30% w/w and optionally one or more pharmaceutically
acceptable excipient(s) from 0% w/w to about 10% w/w of the core composition, wherein the
ratio of water insoluble non-swellable polymer(s) and hydration inhibitor(s) is from about 1:50 to
about 50:1; and at least one coat; wherein the ratio by weight of the core composition to the coat
composition is between about 1:10 to about 10:1, and wherein the composition provides
therapeutic concentrations of active agent for extended time periods.
2. A composition according to claim 1, wherein the water insoluble non-swellable polymer is
selected from a group comprising methacrylate copolymers, polyvinylacetate,
polyvinylacetate/polyvinylpyrrolidone mixtures, ethyl cellulose, and the like, or suitable
mixtures thereof.
3. A composition according to claim 1, wherein the hydration inhibitor is selected from a
group comprising glyceryl behenate, hydrogenated vegetable oil, glyceryl palmitostearate,
glyceryl monostearate, stearic acid, stearates, and the like, or mixtures thereof.
4. A composition according to claim 1, wherein the lubricant is selected from a group
comprising talc, colloidal silicon dioxide, magnesium stearate, calcium stearate, zinc
stearate, stearic acid, sodium stearyl fumarate, mineral oil, glyceryl behenate, hydrogenated
vegetable oil, and the like, or mixtures thereof.
5. A composition according to claim 4, wherein the core comprises the lubricants colloidal
silicon dioxide, talc and magnesium stearate in a ratio of 1:1:1.
6. A composition according to claim 1, wherein the coat comprises at least one pH
independent water insoluble non-porous polymer(s) and at least one channel former(s),
optionally one or more pharmaceutically acceptable excipient(s), and wherein the ratio of
pH independent water insoluble non-porous polymer(s) to the channel former(s) in the coat
ranges from about 20:1 to about 1:20.
7. A composition according to claim 6, wherein the pH independent water insoluble non-
porous polymer used in the coat is selected from a group comprising vinyl acetate polymers and copolymers, low viscosity ethyl cellulose, or mixtures thereof.
8. A composition according to claim 6, wherein the channel former is selected from a group
comprising alkyl celluloses; hydroxyalkyl alkylcelluloses; polyethylene glycols;
copolymers of ethylene oxide with propylene oxide; gelatin; polyvinylpyrrolidones;
vinylpyrrolidones; polyvinylimidazoles; polyvinylpyridine N-oxides; copolymer of
polyvinyl alcohol-polyethylene glycol; solid solution of copolymer of polyvinyl alcohol-
polyethylene glycol and polyvinyl alcohol; copolymers of vinylpyrrolidone with long-
chained alpha-olefms; poly(vinylpyrrolidone/dimethylaminoethyl methacrylates);
copolymers of vinylpyrrolidone/dimethylaminopropyl methacrylamides; copolymers of
vinylpyrrolidone/ dimethylaminopropyl acrylamides; quaternised copolymers of
vinylpyrrolidones and dimethylaminoethyl methacrylates; terpolymers of
vinylcaprolactam/vinylpyrrolidone/ dimethylaminoethyl methacrylates; copolymers of
vinylpyrrolidone and methacrylamidopropyl-trimethylammonium chloride; terpolymers of
caprolactam/vinylpyrrolidone/dimethylaminoethyl methacrylates; copolymers of styrene
and acrylic acid; polycarboxylic acids; polyacrylamides; polyvinyl alcohols; hydrolysed
polyvinyl acetate; sugars; and the like, or mixtures thereof
9. A composition according to claim 1, wherein the coat additionally comprises one or more
methacrylate copolymers and/or aminoalkyl methacrylate copolymers such as ethyl
acrylate/methyl methacrylate copolymer and an ethyl acrylate/methyl
methacrylate/trimethylammonioethyl methacrylate copolymer; a copolymerisate based on
ethyl acrylate and methyl methacrylate; and the like, or mixtures thereof.
10. A composition according to claim 1, wherein the core additionally comprises alkalizing
agent selected from a group comprising disodium hydrogen phosphate, organic amines,
metal oxides, carbonates and bicarbonates of metals or mixtures thereof, and/or an
acidifying agent selected from a group comprising citric acid, tartaric acid, and other
organic acids, or mixtures thereof.
11. A composition according to claim 1, wherein the pharmaceutically acceptable excipients
are selected from a group comprising diluents, disintegrants, binders, fillers, bulking
agents, anti-adherents, anti-oxidants, buffering agents, colorants, flavoring agents, coating
agents, plasticizers, organic solvents, stabilizers, preservatives, lubricants, glidants,
chelating agents, surfactants, used either alone or in combination thereof.
12. A process for the preparation novel controlled release pharmaceutical composition
according to claim 1, which comprises of the following steps:
i) mixing the water soluble active agent with water insoluble non-swellable polymer(s), hydration inhibitor(s), lubricant(s) and optionally one or more pharmaceutically acceptable excipient(s),
ii) formulating the mixture of step (i) into a suitable core composition,
iii) coating the core composition of step (ii) with a coating composition comprising at least one pH independent water insoluble non-porous polymer(s) and at least one channel former(s), optionally one or more pharmaceutically acceptable excipient(s) to obtain the coated composition,
iv) optionally providing a second coating layer on the first coat, and
v) optionally formulating the coated composition of step (iii) or (iv) into a suitable dosage form.
13. A process for the preparation novel controlled release pharmaceutical composition
according to claim 1, which comprises of the following steps:
i) mixing the water soluble active agent with water insoluble non-swellable polymer(s), hydration inhibitor(s), and optionally one or more pharmaceutically acceptable excipient(s),
ii) mixing the material of step (i) alongwith a portion of a lubricant(s) to obtain a homogeneous blend,
iii) compacting the blend of step (ii) followed by crushing of the compacts obtained and sifting the material through suitable sieve to obtain granules,
iv) optionally mixing the sifted material of step (iii) with other pharmaceutically acceptable excipient(s),
v) adding the remaining portion of lubricant(s) to the material of step (iv) and mixing, vi) compressing the material of step (v) into minitablets to form the core composition,
vii) coating the core composition with a coating composition comprising at least one pH independent water insoluble non-porous polymer(s), at least one channel former(s) and plasticizer(s), optionally one or more pharmaceutically acceptable excipient(s) to
obtain the coated composition, and
viii) formulating the coated minitablets into a suitable dosage form.
14. The pharmaceutical composition and process for the preparation of a pharmaceutical composition substantially as herein described and illustrated by the examples.