Title of Invention

A PROCESS FOR PREPARING ORAL COMPOSITION OF ONDANSETRON

Abstract

the invention Controlled release tablets with pH - independent release of Ondansetron is disclosed. The tablets comprise of combination of a water swellable polymer with pH-independent swelling ability, an organic acid and a water-soluble carbohydrate. The tablets control the release of organic acid from its core, which in turn provides a constant acidic microenvironment in the swollen tablet core of sufficient strength for prolonged period of time and helps in the release of Ondansetron from the tablets in a controlled and pH-independent manner. To,

Full Text

THE PATENT ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (Section 10) 1. A PROCESS FOR PREARING ORAL COMPOSITION OF ONDANCETRON 2. (a) Nagarsenker Man gal Shailesh (b) Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Santacrur (East), Mumbai - 400 098, Maharashtra, India. (c) Indian. (a) Rane Manish Subhashchandra (b) Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Santacruz (East), Mumbai - 400 098, Maharashtra, India. (c) Indian. The following specification (particularly) describes the nature of the invention and the manner in which it is to be performed. 2 3. DESCRIPTION OF THE INVENTION FIELD OF THE INVENTION This invention relates to a process for preparing controlled release formulations of Ondansetron. Ondansetron is a weakly basic drug showing pH-dependent solubility, that is, it exhibits good solubility in acidic pH and its solubility drastically reduces in alkaline pH. More specifically, this invention relates to a process for preparing tablets, which retard release of Ondansetron in gastric acid, and improve release of Ondansetron in intestinal fluids, which have alkaline pH, in a manner so as to give controlled release of Ondansetron in a pH-independent manner. 3 OBJECTS OF THE INVENTION Accordingly, in view of the above presentation, it is an immediate object of this invention to provide a process for preparing novel and useful dosage form(s) of Ondansetron or its acid addition salt(s) that represents an unexpected improvement in the dispensing art and substantially overcomes the limitations of the prior art. Another object of the present invention is to provide a process for preparing a dosage form that can release Ondansetron or its acid addition salt(s) in a pH-independent and controlled release manner. Another object of the present invention is to provide a process for preparing a dosage form that can reduce the dosing frequency upto twice or once daily. Another object of the present invention is to provide a process for preparing a dosage form comprising of a dosage of Ondansetron or its acid addition salt(s) in a single dosage form so that Ondansetron is released by the dosage form in almost linear fashion and in a pH-independent manner till the duration of therapy after administration of the dosage form to the drug recipient. Another object of this invention is to provide a process for preparing dosage form comprising of (a) at least one pharmacologically acceptable water swellable and non-ionic polymer, (b) at least one pharmacologically acceptable organic acid and (c) at least one pharmacologically acceptable water soluble carbohydrate, in an intimate combination SUMMARY OF THE INVENTION This invention provides, in one aspect, a process for preparing a pH-independent and controlled release tablets of Ondansetron or its acid addition salt(s), a weak base exhibiting pH-dependent solubility characteristics, which can reduce the dosing frequency to twice or once daily. Another aspect of the invention is an art of formulating the dosage form by a critical and a unique proportion of non-ionic-water soluble polymer(s), organic acid(s) and water soluble carbohydrate(s) capable of releasing Ondansetron in a pH-independent and a controlled manner for prolonged period of time. A further aspect of the invention is to control the release of the organic acid from the tablets in such a way, so as to provide a constant acidic microenvironment within the tablet throughout the release of Ondansetron. The invention is pharmaceutical^ useful. The present invention relates to a process for preparing a pharmaceutical composition for the controlled and pH-independent release of Ondansetron which comprises of (a) mixing at least one pharmacologically acceptable release rate controlling polymer with pH-independent aqueous swelling ability in a concentration of 20% to 80% w/w with at least one pharmacologically acceptable organic acid or organic acid substance in a concentration of 5% to 60% w/w, (b) adding at least one pharmacologically acceptable water-soluble carbohydrate in a concentration of 5% to 60% w/w, such that it is homogeneously distributed, (c) mixing Ondansetron or Ondansetron Hydrochloride or Ondansetron Hydrochloride Dihydrate or other acid addition salts thereof at a dose of 2mg to 120mg equivalent to Ondansetron free base to the aforesaid such that it is uniformly distributed. DETAILED DESCRIPTION OF THE INVENTION Applicants have developed a process for preparing Ondansetron or its acid addition salt(s) controlled release dosage form with pH-independent release, which overcomes the natural physicochemical properties of Ondansetron or its acid addition salt(s) of having pH-dependent solubility. This development has been achieved by a novel combination of different principles and skills involved in the pharmaceutical formulations. The following principles were applied. 1. Ondansetron or it acid addition salt(s) being weakly basic in nature, show good solubility at acidic pH of stomach whereas, its solubility drastically reduces at alkaline pH of the intestinal tract. This difference in its solubility is compensated by providing a constant acidic microenvironment by means of addition of organic acid of sufficient acidic strength to provide constant dissolution of Ondansetron or its acid addition salt(s) within the dosage form and its subsequent release in the intestinal lumen. 2. The release of Ondansetron or its acid addition salt(s) was controlled by using non-ionic water swellable polymer in the form of matrix tablets. The non-ionic water soluble polymer, swells uniformly in the aqueous environment of gastrointestinal pH and allows for dissolution of organic acid, thus creating an acidic microenvironment necessary for the dissolution of Ondansetron or its acid addition salt(s) at alkaline pH of the intestine. 3. The hydration of non-ionic water swellable polymer was assisted by incorporation of a water-soluble carbohydrate, which acts as a channeling or pore-forming agent. This agent dissolves in aqueous medium and escape from the matrix of the tablets, thus forming pores or channels or voids within the hydrating polymer matrix, which We claim: 1. A process for preparing a pharmaceutical composition for the controlled and pH-independent release of Ondansetron which comprises of (a) mixing at least one pharmacologically acceptable release rate controlling polymer with pH-independent aqueous swelling ability in a concentration of 20% to 80% w/w with at least one pharmacologically acceptable organic acid or organic acid substance in a concentration of 5% to 60% w/w, (b) adding at least one pharmacologically acceptable water-soluble carbohydrate in a concentration of 5% to 60% w/w, such that it is homogeneously distributed, (c) mixing Ondansetron or Ondansetron Hydrochloride or Ondansetron Hydrochloride Dihydrate or other acid addition salts thereof at a dose of 2mg to 120mg equivalent to Ondansetron free base to the aforesaid such that it is uniformly distributed. 2. The process as claimed in claim 1, wherein said composition is compressed into a tablet with suitable tooling. 3. The process as claimed in claim 1, wherein the polymer comprises of hydroxypropylmethylceilulose having viscosity in the range of 2,000-1,20,000 centipoise. 4. The process as claimed in claim 1, wherein the polymer is hydroxypropylcellulose having viscosity in the range of 2,000-1,20,000 centipoise. 5. The process as claimed in claim 1, wherein the polymer is hydroxyethylcellulose having viscosity in the range of 2,000-1,20,000 centipoise. 6. The process as claimed in claim 1, wherein the polymer is methyl cellulose having viscosity in the range of 2,000-1,20,000 centipoise. 7. The process as claimed in claim 1, wherein the release rate controlling polymer is a mixture of, but not restricted to, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and methylcellulose. 8. The process as claimed in claim 1, wherein the organic acid is succinic acid or its salt, in a concentration of 5% to 60% w/w. 9. The process as claimed in claim 1, wherein the organic acid is citric acid or its salt, in a concentration of 5% to 60% w/w. 10. The process as claimed in claim I, wherein the organic acid is tartaric acid or its salt, in a concentration of 5% to 60% w/w. 11. The process as claimed in claim 1, wherein the organic acid is adipic acid or its salt, in a concentration of 5% to 60% w/w. 12. The process as claimed in claim 1, wherein the organic acid is fumaric acid or its salt, in a concentration of 5% to 60% w/w. 13. The process as claimed in claim 1, wherein the organic acid is malic acid or its salt, in a concentration of 5% to 60% w/w. 14. The process as claimed in claim 1, wherein the organic acid is maleic acid or its salt, in a concentration of 5% to 60% w/w. 15. The process as claimed in claim 1, wherein the organic acid is ascorbic acid or its salt, in a concentration of 5% to 60% w/w. 16. The process as claimed in claim 1, wherein the organic acid is sorbic acid or its salt in a concentration of 5% to 60% w/w. 17. The process as claimed in claim J, wherein the organic acid is a mixture of, but not restricted to, succinic acid, citric actd, tartaric acid, adipic acid, fumaric acid, ascorbic acid, malic acid, maleic acid, sorbic acid, or their salts. 18. The process as claimed in claim 1, wherein the water-soluble carbohydrate is a monosaccharide or a disaccharide. 19. The process as claimed in claim 18, wherein the carbohydrate is lactose, in a concentration of 5% to 60% w/w. 20. The process as claimed in claim 18, wherein the carbohydrate is sucrose, in a concentration of 5% to 60% w/w. 21. The process as claimed in claim 18, wherein the carbohydrate is maltose, in a concentration of 5% to 60% w/w. 22. The process as claimed in claim 18, wherein the carbohydrate is galactose, in a concentration of 5% to 60% w/w. 23. The process as claimed in claim 18, wherein the carbohydrate is mannose, in a concentration of 5% to 60% w/w. 24. The process as claimed in claim 18, wherein the carbohydrate is glucose, in a concentration of 5% to 60% w/w. 25. The process as claimed in claim 18, wherein the carbohydrate is fructose, in a concentration of 5% to 60% w/w. 26. The process as claimed in claim 18, wherein the carbohydrate is sorbose, in a concentration of 5% to 60% w/w. 27. The process as claimed in claim 1, wherein the lubricant is magnesium stearate in a concentration of 0.1% to 3.0% w/w. 28. The process as claimed in claim 1, wherein the tablets are prepared by direct compression of the mixture of ingredients along with Ondansetron. 29. The process as claimed in claim I, wherein the tablets are prepared by slugging the mixture of ingredients along with Ondansetron, sieving to give free flowing granules, followed by compression. 30. The process as claimed in claim 1, wherein the tablets are prepared by first granulating the mixture of ingredients along with Ondansetron using non¬aqueous solvent(s) containing a binder, drying to an acceptable residual solvent level, sieving to give free flowing granules, followed by compression. 31. The process as claimed in claim 1, wherein the tablets are prepared by first granulating the mixture of ingredients along with Ondansetron using aqueous solvent containing a binder, drying to an acceptable moisture content, sieving to give free flowing granules, followed by compression. 32. The process as claimed in claim 30, wherein the composition of binder comprises of hydroxypropylmethylcellulose, methylcellulose, polyvinly pyrolidone or mixture thereof, at a concentration of 0.1% to 10 % w/w of the total tablet weight, in organic, pharmaceutical acceptable and volatile solvent. 33. The process as claimed in claim 32, wherein the composition of volatile organic solvent comprises of isopropylalcohol, ethanol, dichloromethane, acetone or mixture thereof.

Documents:

1060-mum-2003-abstract.doc

1060-mum-2003-abstract.pdf

1060-mum-2003-claims.doc

1060-mum-2003-claims.pdf

1060-mum-2003-correspondence(ipo).pdf

1060-mum-2003-correspondence.pdf

1060-mum-2003-description(granted).doc

1060-mum-2003-description(granted).pdf

1060-mum-2003-drawing.pdf

1060-mum-2003-esp document.pdf

1060-mum-2003-form 1(super seded)-10-oct-2003.pdf

1060-mum-2003-form 13.pdf

1060-mum-2003-form 19.pdf

1060-mum-2003-form 2(granted).doc

1060-mum-2003-form 2(granted).pdf

1060-mum-2003-form 2(title page).pdf

1060-mum-2003-form 3.pdf

1060-mum-2003-form 5.pdf

1060-mum-2003-others.pdf

1060-mum-2003-power of attorney.pdf

1060-mum-2003-us patent.pdf

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