WO2005107716A1

WO2005107716A1 - Controlled release paroxetine-containing tablets based on a core and a coating

Info

Publication number: WO2005107716A1
Application number: PCT/IN2005/000093
Authority: WO
Inventors: Jatin Desai; Keyur Patel; Jogani Pranav; Sandip Tiwari; Raveendra M. Pai
Original assignee: Cadila Healthcare Ltd
Current assignee: Zydus Lifesciences Ltd
Priority date: 2004-03-25
Filing date: 2005-03-28
Publication date: 2005-11-17
Anticipated expiration: 2006-09-25

Abstract

The invention provides a controlled release tablet comprising of: (i) a core consisting of paroxetine or its pharmaceutically acceptable salt, at least one rate controlling hydrophilic polymer, a diluent, a binder and a lubricant; and (ii) a coating consisting of an enteric polymer and a plasticizer.

Description

CONTROLLED RELEASE PAROXETINE-CONTAINING TABLETS BASED ON A CORE AND A COATING

Field of invention

The present invention relates to a controlled release matrix tablets comprising of Paroxetine. The invention uses hydrophilic matrixing agent to get desired drug release. This formulation demonstrates extended in- vitro dissolution profile with substantially simple approach than formulations claimed in prior art.

BACKGROUND OF THE INVENTION AND PRIOR ART

Paroxetine is a selective Serotonin Re-uptake Inhibitor and is used for treatment or prophylaxis of depression. Administration of controlled release or delayed release formulation of paroxetine results into lesser side effects than the conventional immediate release formulation.

Prior Art

U.S. Pat. No.6,548,084 discloses a controlled release formulation containing Paroxetine. The composition uses Calcium Polycarbophill. This patent requires definite geometric form to achieve drug release. The tablets are prepared in two layers, where one layer (Drug core) consists of active and swellable polymer and other layer is the supporting platform applied to deposit core. The supporting platform partially covers the active layer and hence modulates the release from the tablet. The supporting platform also reduces total surface area of the active exposed to the dissolution fluid.

U.S. Pat. No.4,839,177 and 5,422,123 disclose controlled-rate of release of the active substance, consisting of a core of defined geometrical form containing the active substance, polymer substances which swell on contact with aqueous liquids and polymer substances with gelling properties, and a support applied to said core to partly cover its surface, the support consisting of polymer substances which are slowly soluble and/or slowly gellable in aqueous liquids, plasticizing substances, and possibly substances with an adjuvant function.

Our novelty is the formulation of matrix tablet without any specialized technique such as GEOMATRIX, wherein the tablets required to be prepared in bilayer for which a constant geometry is required to be maintained by which constant surface area can be maintained and thus the release rate. The present invention discloses a tablet formulation which is a single layer and consisting of hydrophillic matrixing agent, which is eroding and its surface area changes with exposure to time in dissolution media. Also, the present invention does not use a polymer like calcium polycarbophill and cross-linking agent. Hence, the controlled release tablet prepared by present invention is simple and requires no specialized technique or chemicals.

Objects of the present Invention:

The object of the present invention is to provide a novel controlled release matrix formulation for Paroxetine.

Summary of the invention

The present invention provides an oral pharmaceutical composition comprising of: (i) a core consisting of paroxetine or its pharmaceutically acceptable salt, at least one rate controlling hydrophilic polymer, a diluent, a binder and a lubricant; and (ii) a coating consisting of an enteric polymer and a plasticizer, deposited on the said core with or without barrier coat between the said core and the said enteric coating layer.

Preferably, the hydrophilic polymer is selected from, but not limited to a group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylhydroxy ethylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene oxide, polyethylene glycol, methacrylic acid copolymers, acrylic acid copolymers, maleic anhydride/ methyl vinyl ether copolymers, polymethylmethacrylates, polyhydroxyethyl methacrylate, naturally occuring gums, ionic salts of naturally occuring gums, alginic acid, salts of alginic acid, tragacanth, gelatin, starch, polysaccharides and combinations and mixtures thereof.

Preferably, the amount of hydrophilic polymer is between 1% and 50% by weight in relation to the total weight of the composition. Preferably, amount of hydrophilic polymer is between 5% and 20% by weight in relation to the total weight of the composition.

Preferably, the pharmaceutically acceptable salt of paroxetine is paroxetine hydrochloride.

Preferably, the amount of paroxetine hydrochloride is between 0.5% and 50% by weight in relation to the total weight of the composition.

Preferably, the preferable amount of paroxetine hydrochloride is between 1% and 35% by weight in relation to the total weight of the composition.

Preferably, amount of paroxetine hydrochloride is between 2% and 20% by weight in relation to the total weight of the composition.

Preferably, the barrier coat comprises hydroxypropyl methylcellulose and polyethylene glycol 3350.

Preferably, wherein the enteric polymer is selected from a group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, cellulose acetate trimellitate, carboxymethyl ethylcellulose, shellac and combinations and mixtures thereof.

Preferably, the enteric polymer is Eudragit L 100-55.

Preferably, the amount of enteric polymer is between 0.05% and 10% by weight in relation to the total weight of the composition.

Preferably, the preferable amount of enteric polymer is between 0.1% and 5% by weight in relation to the total weight of the composition.

Preferably, the plasticizer is selected from a group consisting of triacetin, triethyl citrate, acetylated monoglycerides, glycerine triacetate, glyceryl monostearate, polyethylene glycol, citric acid ester,phthalic acid ester, dibutyl succinate, organic amines and combinations and mixtures thereof. Preferably, the plasticizer is triethyl citrate.

Preferably, the amount plasticizer is between 0.01% and 5% by weight in relation to the total weight of the composition.

Preferably, amount plasticizer is between 0.05% and 2% by weight in relation to the total weight of the composition.

Preferably, diluent is selected from a group consisting of lactose, pregelatinized starch, starch, microcrystalline cellulose, sugars, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium phosphate, dextrin, maltodextrin and combinations and mixtures thereof.

Preferably, the diluent is lactose.

Preferably, the amount diluent is between 40% and 90% by weight in relation to the total weight of the composition.

Preferably, the preferable amount diluent is between 60% and 80%) by weight in relation to the total weight of the composition.

Preferably, the binder is selected from a group consisting of cellulose, cellulose derivatives, starch, starch derivatives, povidone, polyvinyl alcohol, gelatin, gum acacia, sugars, sugar derivatives, microcrystalline cellulose and combinations and mixtures thereof.

Preferably, the binder is povidone.

Preferably, the amount binder is between 0.5% and 20% by weight in relation to the total weight of the composition.

Preferably, amount binder is between 1% and 5% by weight in relation to the total weight of the composition.

Preferably, the lubricant is selected from a group consisting of magnesium stearate, zinc stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, talc, waxes, sodium benzoate, sodium lauryl sulfate, magnesium laurayl sulfate, sodium stearyl fumarate, glyceryl behenate and combinations and mixtures thereof.

Preferably, the lubricant is magnesium stearate.

Preferably, the amount lubricant is between 0.1% and 5% by weight in relation to the total weight of the composition.

Preferably, the amount lubricant is between 0.5% and 2% by weight in relation to the total weight of the composition.

The present invention also provides a process for the preparation of the oral pharmaceutical composition: a) dry blending a mixture of Paroxetine or its salts, diluent/s, binder/s and hydrophilic polymer/s to form a uniform mixture of the dry ingredients; b) the blend of step a) is granulated with organic solution or hydroalcoholic solution or aqueous solution selected from the group consists of ethanol, methanol, isopropyl alcohol, acetone, methylene chloride, water and/or combinations thereof, size reduced, and lubricated. c) compressing the blended granules of step b); d) coating the tablets of step c) with or without barrier coat between the said core and the said enteric coating layer.

Detailed description of the invention:

The controlled or sustained release tablets have numbers of advantages over the conventional tablets including reduction in frequency of dose, reduction in side effects and due to these improved patient compliance. Among the various routes and techniques for controlled drug delivery, matrix tablets are simple and more explored due to chances of modulating a drug release profile as well as industrial feasibility in operation. The drug release from the matrix tablets can be modulated by incorporating the active pharmaceutical ingredient in the polymer matrix or by coating the active pharmaceutical ingredient containing core with a polymer. The active pharmaceutical ingredient is release by diffusion or /and erosion.

The pharmaceutically acceptable matrixing agent may be single hydrophilic polymer or mixture of hydrophilic polymers.

Hydrophillic polymers include and are not limited to hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, cellulose derivatives, polyethylene oxide, methacrylic acid copolymers, acrylic acid copolymers, maleic anhydride/ methyl vinyl ether copolymers, polymethylmethacrylate, polyhydroxyethyl methacrylate, naturqally occuring water soluble gum/s., their ionic salts, with and without complexing agent such as saccharides and amines.

Preferably, the polymer selected is a high viscosity hydroxypropyl methylcellulose having viscosity of 2% w/v solution in water in the range of about 100 to about 100,000 Cps. Most preferred grade of hydroxypropyl methylcellulose is with a viscosity of about 4,000-30,000 Cps, commercially available under the Trade name, Methocel, from The Dow Chemical Company. The amount of the polymer in the dosage form generally varies from about 5% to about 50%) by weight of the composition. Preferably, the amount of polymers varies from about 10% to about 25%) by weight of the dosage form. The other preferred polymer is hydroxypropyl cellulose commercially available under the Trade name, Klucel from Aqualon. 2% w/w Hydroxypropyl cellulose in water having viscosity in between 100- 100,000 Cps is more preferred.

The invention as disclosed envisages addition of suitable pharmaceutical excipients for performing various functions. As is known to those skilled in the art, pharmaceutical excipients are routinely incorporated into solid dosage forms. This is done to ease the manufacturing process as well as to improve the performance of the dosage form. Common excipients include diluents or bulking agents, lubricants, binders, etc. The selection of adjuvants is not limited to diluent, binder, disintegrants, lubricant, antiadherent, glidant, flavour, colour, antioxidant, opacifying agent or any coating composition. Preferred diluents include microcrystalline cellulose, dicalcium phosphate, lactose, mannitol, sorbitol, starch, sugar, calcium phosphate, calcium sulfate, kaolin, sodium chloride. Binders include polyvinylpyrrolidone, low viscosity hydroxypropyl methylcellulose, low viscosity hydroxyrporopyl cellulose, guar gum, xanthan gum, cellulose gums such as carboxy methylcellulose, methylcellulose, copolyvidone, polyvinnyl alcohol, ispagula, gelatin, starch, and pregelatinized starch. Examples of suitable lubricants include talc, stearic acid, vegetable oil derivatives, calcium stearate, zinc stearate, magnesium stearate, etc. Glidants are also typically incorporated into the formulation. A glidant improves the flow characteristics of the granulation. Examples of suitable glidant include talc, colloidal silicon dioxide, silica gel and cornstarch.

The barrier coat polymer includes but not limited to film forming polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, an acrylic polymer or a mixture of polymers. The coating solution is generally an aqueous solution or an organic solvent further comprising propylene glycol, sorbitan monoleate, sorbic acid, fillers such as titanium dioxide, talc, plasticizer, a pharmaceutically acceptable colouring agent.

Enteric coating polymers preferred in the present invention includes, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, cellulose acetate trimellitate, carboxymethyl ethylcellulose, shellac and combinations thereof. A preferred tablet composition of the invention will include from about 2 to about 20% by weight pravastatin, from about 5 to about 20% by weight hydrophilic polymer, a diluent, a binder, a lubricant, from about 0.1 to about 5% by weight enteric polymer, with or without barrier coat comprises hydroxypropyl methylcellulose and polyethylene glycol 3350.

More specifically, a Paroxetine tablets of present invention may be prepared by a) dry blending a mixture of Paroxetine, diluent/s, binder/s and hydrophiliic matrixing agent/s to form a uniform mixture of the dry ingredients;

b) the blend of step a) is granulated with a granulating fluid with or without binder/s; c) drying and sizing the wet granules from step b); d) dry blending the granules of step c) with diluent/s or with lubricant/s and/or with pharmaceutical aids; e) compressing the blended granules of step d); f) coating the tablets of step e) with or without barrier coating with an enteric coating polymer.

The following Examples represent preferred embodiments of the present invention.

Example 1 A mixture of Paroxetine, lactose and hydroxypropyl methyl cellulose is blended to form a uniform mixture and the blend is granulated using aqueous/alcoholic/hydroalcoholic solution of polyvinyl pyrrolidone. The wet mass is dried in a fluid bed dryer. Dried granules are passed through mess to get granules. The granules are blended with magnesium stearate. The lubricated granules are compressed into tablets. Example 2

The diluent of example 1, lactose is partially replaced by Dicalcium phosphate and polymer used is Hydroxypropyl cellulose.

Example 3

The hydrophilic polymer is Hydroxypropyl cellulose is used in place of Hydroxypropyl methylcellulose in example 1.

% w/w Composition of Example 1-3

Example 4-5

For purposes of experiments 4 & 5, tablets of example 1, 2 respectively are coated with alcoholic solution of Hydroxypropyl methylcellulose 6 Cps and Polyethylene glycol 3350 to get weight build up of 1% weight composition followed by coating with aqueous dispersion of Eudragit L 100-55, triethyl citrate, and talc to get coating build up of 2% of the core tablet weight. Example 6 Tablets of Example 3 are coated with aqueous dispersion of Eudragit L 100-55 , Triethyl citrate, and Talc to get coating build up of 2% of the core tablet weight. Enteric coating build up can be kept at 5 % of the core tablet weight in any of the above examples.

% w/ Composition of Example 4-5-6

Claims

Claims:

1. An oral pharmaceutical composition comprising of: (i) a core consisting of paroxetine or its pharmaceutically acceptable salt, at least one rate controlling hydrophilic polymer, a diluent, a binder and a lubricant; and (ii) a coating consisting of an enteric polymer and a plasticizer, deposited on the said core with or without barrier coat between the said core and the said enteric coating layer.

2. The pharmaceutical composition as claimed in claim 1, wherein the hydrophilic polymer is selected from, but not limited to a group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylhydroxy ethylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene oxide, polyethylene glycol, methacrylic acid copolymers, acrylic acid copolymers, maleic anhydride/ methyl vinyl ether copolymers, polymethylmethacrylates, polyhydroxyethyl methacrylate, naturally occuring gums, ionic salts of naturally occuring gums, alginic acid, salts of alginic acid, tragacanth, gelatin, starch, polysaccharides and combinations and mixtures thereof.

3. The pharmaceutical composition as claimed in claim 2, wherein the amount of hydrophilic polymer is between 1% and 50% , preferably 5% and 20% by weight in relation to the total weight of the composition.

4. The pharmaceutical composition as claimed in any preceding claim, wherein the pharmaceutically acceptable salt of paroxetine is paroxetine hydrochloride.

5. The pharmaceutical composition according to claim 5, wherein the amount of paroxetine hydrochloride is between 0.5% and 50%, preferably, 1% and 35% by weight of the composition.

6. The composition as claimed in claim 5 wherein the amount of said paroxetine hydrochloride 2% and 20% by weight in relation to the total weight of the composition.

7. The composition as claimed in any preceding claim, wherein the barrier coat comprises hydroxypropyl methylcellulose and polyethylene glycol 3350.

8. The composition as claimed in any preceding claim, wherein the enteric polymer is selected from a group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate^** hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, methacrylic acid copolymers, cellulose acetate trimellitate, carboxymethyl ethylcellulose, shellac and combinations and mixtures thereof.

9. The composition as claimed in claim 8, wherein the amount of enteric polymer is between 0.05% and 10%, preferably, 0.1% and 5% by weight in relation to the total weight of the composition.

10. The composition as claimed in any preceding claim, wherein the plasticizer is selected from a group consisting of triacetin, triethyl citrate, acetylated monoglycerides, glycerine triacetate, glyceryl mono stearate, polyethylene glycol, citric acid ester,phthalic acid ester, dibutyl succinate, organic amines and combinations and mixtures thereof.

11. The composition as claimed in claim 10, wherein the amount plasticizer is between 0.01%) and 5% by weight, preferably, 0.05% and 2% by weight in relation to the total weight of the composition.

12. The composition as claimed in any preceding claim, wherein the diluent is selected from a group consisting of lactose, pregelatinized starch, starch, microcrystalline cellulose, sugars, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium phosphate, dextrin, maltodextrin and combinations and mixtures thereof.

13. The composition as claimed in claim 12, wherein the amount diluent is between 40%) and 90%), preferably, 60% and 80% by weight in relation to the total weight of the composition.

14. The composition as claimed in any preceding claim, wherein the binder is selected from a group consisting of cellulose, cellulose derivatives, starch, starch derivatives, povidone, polyvinyl alcohol, gelatin, gum acacia, sugars, sugar derivatives, microcrystalline cellulose and combinations and mixtures thereof.

15. The composition as claimed in claim 14, wherein the amount binder is between 0.5%) and 20%, preferably, 1% and 5% by weight in relation to the total weight of the composition.

16. The composition as claimed in any preceding claim, wherein the lubricant is selected from a group consisting of magnesium stearate, zinc stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, talc, waxes, sodium benzoate, sodium lauryl sulfate, magnesium laurayl sulfate, sodium stearyl fumarate, glyceryl behenate and combinations and mixtures thereof.

17. The composition as claimed in any preceding claim 16, wherein the amount lubricant is between 0.1% and 5%, preferably, 0.5% and 2% by weight in relation to the total weight of the composition.

18. A process for the preparation of an oral pharmaceutical composition: e) dry blending a mixture of Paroxetine or its salts, diluent/s, binder/s and hydrophilic polymer/s to form a uniform mixture of the dry ingredients; f) the blend of step a) is granulated with organic solution or hydroalcoholic solution or aqueous solution selected from the group consists of ethanol, methanol, isopropyl alcohol, acetone, methylene chloride, water and/or combinations thereof, size reduced, and lubricated. g) compressing the blended granules of step b); h) coating the tablets of step c) with or without barrier coat between the said core and the said enteric coating layer.

19. An oral pharmaceutical composition comprising substantially as hereinbefore described with reference to the foregoing Examples.

20. A process for the preparation of the oral pharmaceutical composition substantially as hereinbefore described with reference to the foregoing Examples.