WO2005102289A1

WO2005102289A1 - Clarithromycin extended release formulation

Info

Publication number: WO2005102289A1
Application number: PCT/IN2005/000085
Authority: WO
Inventors: Suryakumar Jayanthi; Vineeth Raghavan; Nilesh Bhandari; Himadri Sen
Original assignee: Lupin Limited
Priority date: 2004-03-24
Filing date: 2005-03-17
Publication date: 2005-11-03
Also published as: EP1732518A1; AU2005235237A1; BRPI0508743A; MXPA06010805A

Abstract

A pharmaceutical composition for extended release of erythromycin or a derivative thereof. the composition comprises comprising a pharmaceutically effective amount of the drug and about 50% to about 65% by weight of one or more pharmaceutically acceptable polymer(s). The pharmaceutically acceptable polymer(s) are selected from the group comprising polyvinyl pyrrolidine, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, ethyl cellulose, polyvinyl pyrrolidone/polyvinyl acetate copolymers, polyethylene oxide polymers, acrylic acid polymers, methacrylic acid copolymers, natural gums, and derivatives and mixtures thereof.

Description

CLARITHROMYCIN EXTENDED RELEASE FORMULATION

FIELD OF INVENTION

The present invention relates to extended release pharmaceutical compositions of erythromycin or derivatives thereof for once daily administration.

BACKGROUND OF THE INVENTION

The advantages of extended release dosage forms are well known i.e. reduced daily dosage, patient convenience and improved patient compliance. Erythromycin and derivatives are known for their anti-bacterial activity against a number of micro-organisms and are typically administered as immediate release (IR) compositions, two or three times a day, for a regimen of 10 to 14 days.

In particular the 6-O-methylerythromycin A (Clarithromycin), which has been disclosed in US patent No. 4,331,803. It is currently marketed by Abbott as an immediate release formulation, for at least twice daily administration. Abbott is also marketing controlled release composition of Clarithromycin 500 mg under the brand "Biaxin XL".

Literature discloses various approaches for therapeutic dosage forms, which are designed to deliver the drug at an extended rate to the gastrointestinal tract.

U.S. Patent 4,842,866 discloses the development of a controlled release formulation of erythromycin derivatives using an alginate matrix comprising a water-soluble alginate and a complex salt of alginic acid, having one cation that yields a soluble alginate salt and another cation that alone yields an insoluble alginate salt.

U.S. Patent 5,705,190, claims formulations using soluble alginate, a complex salt of alginic acid and an organic carboxylic acid. The said patent discloses compositions containing equimolar quantities of citric acid and clarithromycin.

US patents 6,010,718, and 6,551,616 disclose formulations of extended release clarithromycin containing 5 to 50% w/w of pharmaceutically acceptable polymer. The specification and examples of this patent disclose preferred formulations containing 10%-

30% by weight of hydroxypropyl methylcellulose, the rate-controlling polymer, in the formulation in addition to other excipients. This patent covers Clarithromycin extended release formulation currently marketed under the trade name Biaxin XL™.

US patent application 2003/0175341 discloses controlled release formulations containing about 0.1% to about 4.5% of one or more cellulosic ether rate controlling polymers.

PCT application WO 03/082241 discloses clarithromycin formulations having improved bioavailability, using micronized drug. The patent exemplifies formulations of extended release clarithromycin containing the drug of particle size less than 35 microns. Improved dissolution relative to un-micronized drug is documented in the said patent. However, the formulation as disclosed in the patent application does not show significant improvement in bioavailability.

U.S. Pat. No. 4,389,393 describes sustained release therapeutic composition using less than about one third of the weight of the solid unit dosage form, of hydroxypropyl methylcellulose or a mixture of hydroxypropyl methylcellulose with certain other rate controlling polymers. In the specification of this patent, the inventors disclose that they have been able to achieve sustained release from solid dosage forms containing as little as about 5 to about 30 weight percent of these hydroxypropyl methylcelluloses. All the examples disclose compositions containing 9% or more of the rate-controlling polymer.

It has been surprisingly found that compositions prepared using polymers in the range of about 50% to about 65% showed pharmacokinetic profile similar to the innovator, which has lower polymer content.

OBJECT OF THE INVENTION

The object of the present invention is to provide a pharmaceutical composition for extended release of erythromycin or its derivatives for once daily administration comprising about 50% to about 65% by weight of pharmaceutically acceptable polymers.

Another object of the invention is to provide a process for preparing extended release composition of erythromycin or its derivatives comprising mixing the drug with about 50% to about 65% by weight of one or more than one of pharmaceutically acceptable polymers, granulating the blend by wet or dry means, followed by either filling the granules into capsules, sachets or compressing them into tablets.

Yet another object of the present invention is to provide a pharmaceutical composition for extended release of Clarithromycin comprising from about 50% to about 65% of pharmaceutically acceptable polymers, wherein the T/R ratio of the geometric mean of Cmax and AUC are within acceptable limit (80-125%) with respect to the currently marketed extended release Clarithromycin formulation marketed under the trade name Biaxin XL.

SUMMARY OF THE INVENTION

According to a basic aspect of the present invention there is provided an extended release formulation of erythromycin or its derivatives suitable for once daily oral administration, comprising about 50% to about 65% by weight of pharmaceutically acceptable polymers or combinations thereof.

According to a preferred aspect the invention provides for an extended release formulation of erythromycin or derivatives thereof, comprising erythromycin or derivatives thereof, pharmaceutically acceptable polymers in the range of about 50% to about 65% by weight, in addition to other pharmaceutically acceptable excipients

The extended release formulation of the invention is prepared by following the processes of wet or dry granulation, filling the granules into capsules, sachets or compressing into tablets.

DETAILED DESCRIPTION OF THE INVENTION

Erythromycin or derivatives used according to the present invention comprise about 10% to about 40% of the total weight of the formulation. The pharmaceutically acceptable polymers are present in the range of about 50% to about 65% by weight.

The pharmaceutically acceptable polymers according to the present invention may be selected from group of polyvinyl pyrrolidine, celluloses, polyvinyl pyrrolidone/polyvinyl acetate copolymers, polyethylene oxide polymers, acrylic acid polymers, methacrylic acid copolymers, natural gums, and derivatives and mixtures thereof.

Celluloses used in accordance with the present invention include hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, methylcellulose and the like. The viscosity of the polymers may be in the range of 5 to 200 cps.

Polyvinyl pyrrolidone/polyvinyl acetate copolymers according to the present invention may be such as available under the brand name Kollidon SR (BASF).

Polyethylene oxide polymers are sold by Union Carbide.

Natural gums according to the present invention include Xanthan gum, Locust bean gum, guar gum, gum karaya, alginates and the like.

Acrylic acid polymers according to the present invention may be such as available under the brand name carbopol (B.F. Goodrich, USA).

In addition to the pharmaceutically acceptable polymers the composition may contain pharmaceutically acceptable excipients such as buffering agents, binders, lubricants and fillers.

Buffering agents may be selected from the groups comprising alkali and alkaline earth metal phosphates, citrates, succinates, and the like.

Fillers according to the present invention may be selected from amongst those conventionally used in the art such as lactose, starches, glucose, sucrose, mannitol, silicic acid and mixtures thereof.

The composition according to the present invention may also contain pharmaceutically acceptable lubricants such as those selected from amongst talc, calcium stearate, magnesium stearate, polyethylene glycol, silicon dioxide, sodium stearyl fumarate and the like.

The release profile of the product is evaluated using USP apparatus Type 1 (basket), at 100 rpm in 900 ml. Medium for 0 to 2h, pH 3.5 acetate buffer. The medium was then changed to pH 6.8 phosphate buffer, for the next 12 hours.

EXAMPLES

The following examples illustrate the invention, without limiting it.

Example 1 i) Clarithromycin 38.46 % ii) Hydroxypropyl Methylcellulose lOOcps 7.00 % iii) Hydroxypropyl Methylcellulose 5cps 48.00 % iv) Lactose 4.23 % v) Talc 1.54 % vi) Magnesium Stearate 0.77 % vii) Water qs

Procedure: The drug and excipients were blended and granulated with water. The granules were dried, sized, lubricated and compressed into tablets of suitable size and hardness.

Example 2 i) Clarithromycin 38.46 % ii) Hydroxypropyl Methylcellulose 5cps 50.00 % iii) Kollidone SR 5.00 % iv) Lactose 4,23 % v) Talc 1.54 % vi) Magnesium Stearate 0.77 % vii) Water qs Procedure : The drug and excipients were blended and granulated with water. The granules were dried, sized, lubricated and compressed into tablets of suitable size and hardness.

Example 3 i) Clarithromycin 38.46 % ii)Hydroxypropyl Methylcellulose 5cps 46.50 % iii) Hydroxypropyl Methylcellulose lOOcps 7.00 % iv) Sodium alginate (Keltone LVCR) 1.50 % v) Lactose 4.23 % vi) Talc 1.54 % vii) Magnesium Stearate 0.77 % viii) Water qs

Example 4 i) Clarithromycin 38.46 % ii) Hydroxypropyl Methylcellulose lOOcps 10.00 % iii) Hydroxypropyl Methylcellulose 5cps 45.00 % iv) Lactose 4.23 % v) Talc 1.54 % vi) Magnesium Stearate 0.77 % vii) Water qs

Procedure: The drug and excipients were blended, and granulated with water. The granules were dried, sized, lubricated and compressed into tablets of suitable size and hardness. ample 5 i) Clarithromycin 35.89 % ii)Hydroxypropyl Methylcellulose 5cps 48.00 % iii) Hydroxypropyl Methylcellulose lOOcps 7.00 % (Methocel KlOO LN) iv) Sodium alginate (Keltone LNCR) 3.00 % v) Lactose 3.95 % vi) Talc 1.44 % vii) Magnesium Stearate 0.72 % viii) Water qs

Example 6 i) Clarithromycin 35.89 % ii)Hydroxypropyl Methylcellulose 5cps 48.50 % iii) Hydroxypropyl Methylcellulose lOOcps 7.00 % ( Methocel KlOO LN) iv) Sodium alginate (Keltone LNCR) 1.50 % v) Xanthan Gum 1.00 % vi) Lactose 3.95 % vii) Talc 1.44 % viii) Magnesium Stearate 0.72 % ix) Water qs

Procedure: The drug and excipients were blended and granulated with water. The granules were dried, sized, lubricated and compressed into tablets of suitable size and hardness. Dissolution profiles of the above examples are summarized below in Table I:

Formulation prepared according to one of the preceeding examples was subjected to a bioequivalence study against the extended release formulation of Clarithromycin marketed under the name Biaxin XL TM in the US. The T/R ratio of geometric mean of Cmax and AUC was within acceptable limits (80%-125%) as shown in Table II.

It was surprisingly found that our formulation comprising from about 50% to about 65% of pharmaceutically acceptable polymers was bio-equivalent to Biaxin XL.

Claims

1. A pharmaceutical composition for extended release of erythromycin or a derivative thereof, comprising a pharmaceutically effective amount of the drug and about 50% to about 65% by weight of one or more pharmaceutically acceptable polymer(s).

2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable polymer(s) are selected from the group comprising polyvinyl pyrrolidine, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, ethyl cellulose, polyvinyl pyrrolidone/polyvinyl acetate copolymers, polyethylene oxide polymers, acrylic acid polymers, methacrylic acid copolymers, natural gums, and derivatives and mixtures thereof.

3. The extended release pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable polymer(s) is hydroxypropylmethyl cellulose or combinations thereof.

4. The extended release pharmaceutical composition according to claim 3, wherein the hydroxypropylmethyl cellulose with viscosity ranging from about 5 to about 200 cps.

5. The extended release pharmaceutical composition according to claim 1, wherein the composition comprises from about 30% to about 45% by weight of the erythromycin or a derivative.

6. The extended release pharmaceutical composition according to claim 1 , wherein the erythromycin derivative is clarithromycin.

7. A pharmaceutical composition prepared according to claim 1, wherein the extended release composition further comprises pharmaceutical aids such as buffering agents, fillers, binders and lubricants.

8. A pharmaceutical composition according to claim 7, wherein the buffering agents may be selected from the groups comprising alkali and alkaline earth metal phosphates, citrates, succinates, and the like.

9. A pharmaceutical composition according to claim 7, wherein the fillers may be selected from lactose, starch, glucose, sucrose, mannitol, silicic acid and mixtures thereof.

10. A pharmaceutical composition according to claim 7, wherein the binder is selected from starch, polyvinyl pyrrolidone, gelatin, gums and the like.

11. A pharmaceutical composition according to claim 7 wherein the lubricants are selected from talc, stearates, polyethylene glycol, silicon dioxide, sodium stearyl fumarate and the like.

12. A method of using an extended release composition comprising erythromycin or its derivatives and about 50% to about 65% by weight of pharmaceutically acceptable polymer(s), for the treatment of bacterial infections in a mammal.

13. A process for preparing extended release composition of erythromycin or its derivatives, comprising mixing the drug with about 50% to about 65% by weight of one or more than one of pharmaceutically acceptable polymers, granulating the blend by wet or dry means, followed by either filling the granules into capsules or sachets or compressing them into tablets.

14. A pharmaceutical composition for extended release according to claim 1, wherein the T/R ratio of geometric means of C max and AUC are within the acceptable limits(80% - 125%) in comparison with Clarithromycin controlled release formulation as shown in Table II.