MXPA06010805A

MXPA06010805A - Clarithromycin extended release formulation.

Info

Publication number: MXPA06010805A
Application number: MXPA06010805A
Authority: MX
Inventors: Himadrisen; Suryakumar Jayanthi; Vineeth Raghavan; Nilesh Bhandari
Original assignee: Lupin Ltd
Priority date: 2004-03-24
Filing date: 2005-03-17
Publication date: 2006-12-19
Also published as: AU2005235237A1; BRPI0508743A; WO2005102289A1; EP1732518A1

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

trade name "Biaxin XL". The literature sets out several approaches for therapeutic dosage forms that are designed to deliver the drug at a rate that allows it to reach the gastrointestinal tract. U.S. Patent No. 4,842,866 discloses the development of a controlled release formulation of erythromycin derivatives, wherein an alginate matrix comprising a water-soluble alginate and a complex salt of the alginic acid having a cation is used. which forms a soluble alginate salt and another cation which only forms an insoluble alginate salt. U.S. Patent No. 5,705,190, claims formulations in which a soluble alginate, a complex salt of alginic acid and an organic carboxylic acid are used. The patent discloses compositions containing equimolar amounts of citric acid and clarithromycin. U.S. Patents Nos. 6,010,718 and 6,551,616 disclose sustained release clarithromycin formulations containing 5 to 50% w / w of a pharmaceutically acceptable polymer. The specification and examples of this patent disclose preferred formulations containing 10% to 30% by weight of hydroxypropyl methylcellulose, a polymer for controlling speed, in addition to other excipients. This patent covers the prolonged release formulation of clarithromycin that is currently marketed under the trade name Biaxin XLm. The United States patent application 2003/0175341 discloses controlled release formulations containing about 0.1% to 4.5% of one or more cellulosic ether polymers that control the rate of release. PCT application WO 03/082241 discloses clarithromycin formulations that have better bioavailability when using the micronized active principle. The patent exemplifies clarithromycin prolonged release formulations in which the active ingredient has a particle size of less than 35 microns. The patent documents the improved relative dissolution with respect to the drug without micronising. However, the formulation as set forth in the patent does not show a significant improvement in bioavailability. U.S. Patent No. 4,389,393 discloses a sustained release composition that uses approximately less than one third of the weight of the solid unit dose of hydroxypropylmethylcellulose or a mixture of hydroxypropylmethylcellulose with some other rate-controlling polymers. In the specification of this patent, the inventors state that they have been able to achieve prolonged release from solid dosage forms containing approximately 5 to 30 weight percent of these hydroxypropylmethylcelluloses. All examples describe compositions containing 9% or more of the speed controlling polymer. Unexpectedly it has been found that compositions made with polymers that are used in a ratio ranging from about 50% to 65%, showed a pharmacokinetic profile similar to the innovative composition, which has lower polymer content.

OBJECTIVE OF THE INVENTION The object of the present invention is to provide a pharmaceutical composition for the prolonged release of erythromycin or its derivatives, which is administered once a day, this composition comprises approximately 50% to 65% by weight of pharmaceutically acceptable polymers. Another object of the invention is to provide a process for preparing a sustained release composition of erythromycin or its derivatives, which consists of mixing the active principle with about 50% to 65% by weight of one or more pharmaceutically acceptable polymers, granulating the mixture wet or dry and then deposit the granules in capsules or sachets or compress them to form tablets. Yet another objective of the present invention is to provide a pharmaceutical composition for the prolonged release of clarithromycin, comprising approximately 50% to 65% of pharmaceutically acceptable polymers, wherein the ratio T / R (time / rate or time / speed) of the geometric mean of Cmax and the ABC (area under the curve) are within an acceptable limit (80-125%) with respect to the current formulation of clarithromycin extended release marketed under the trade name Biaxin XL.

SUMMARY OF THE INVENTION In a basic aspect of the present invention, there is set forth a sustained release formulation of erythromycin or its own derivatives to be administered orally once a day, comprising approximately 50% to 65% by weight of pharmaceutically available polymers. acceptable or combinations thereof. In a preferred aspect of the invention there is disclosed a sustained release formulation of erythromycin or its derivatives, comprising erythromycin or its derivatives, pharmaceutically acceptable polymers in a proportion of about 50% to 65% by weight, in addition to other pharmaceutically acceptable excipients. The prolonged release formulation of the invention is prepared according to the wet or dry granulation processes and then depositing the granules in capsules or sachets or compressing them to form tablets.

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, erythromycin or its derivatives constitute approximately 10% to 40% of the total weight of the formulation. The pharmaceutically acceptable polymers are present in a proportion ranging from 50% to 65% by weight. The pharmaceutically acceptable polymers according to the present invention may be selected from the group consisting of polyvinyl pyrrolidine, celluloses, polyvinyl pyrrolidone / polyvinyl acetate copolymers, poly (ethylene oxide) polymers, acrylic acid polymers, methacrylic acid copolymers, natural gums , and derivatives and mixtures thereof. The celluloses used according to the present invention include hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, methylcellulose and the like. The viscosity of the polymers can be in the range of 5 to 200 cps. The polyvinyl pyrrolidone / polyvinyl acetate copolymers according to the present invention can be like those commercially available under the tradename Kollidon SR (BASF). The poly (ethylene oxide) polymers are marketed by Union Carbide. Natural gums according to the present invention include xanthan gum, locust bean gum, guar gum, karaya gum, alginates and the like. The acrylic acid polymers according to the present invention can be like those found on the market under the trade name Carbopol (B.F. Goodrich, USA). In addition to pharmaceutically acceptable polymers, the composition may contain pharmaceutically acceptable excipients such as buffers, binders, lubricants and fillers. The buffers can be selected from the groups consisting of alkali and alkaline earth metal phosphates, citrates, succinates, and the like. According to the present invention, the fillers may be selected from 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 selected from talc, calcium stearate, magnesium stearate, polyethylene glycol, silicon dioxide, sodium stearyl fumarate, and the like. The release profile of the product is evaluated using the USP type 1 device (basket), at 100 rpm in 900 ml. During 0 to 2h, the medium is acetate buffer, pH 3.5. Then, during the next 12 hours, the medium is exchanged for phosphate buffer, pH 6.8.

EXAMPLES The following examples illustrate the invention, without limiting it.

Example 1 i) Clarithromycin 38.46% ii) Hydroxypropylmethylcellulose lOOcps 7.00% iii) Hydroxypropylmethylcellulose 5cps 48.00% iv) Lactose 4.23% v) Talcum 1.54% vi) Magnesium stearate 0.77% vii) Water c .b .p.

Procedure: The active principle and the excipients were mixed and granulated with water. The granules were dried, left at a certain size, lubricated and compressed to form tablets of suitable size and hardness.

Example 2 i) Clarithromycin 38.46% ii) Hydroxypropylmethylcellulose 5cps 50.00% iii) Ollidone SR 5.00% iv) Lactose 4.23% v) Talcum 1.54% vi) Magnesium stearate 0.77% vii) Water c.b.p.

Example 3 i) Clarithromycin 38.46% ii) Hydroxypropylmethylcellulose 5cps 46.50% iii) Hydroxypropylmethylcellulose lOOcps 7.00% iv) Sodium alginate (Keltone LVCR) 1.50% v) Lactose 4.23% vi) Talcum 1.54% vii) Magnesium stearate 0.77% viii) Water c .b .p.

Example 4 i) Clarithromycin 38.46% ii) Hydroxypropylmethylcellulose lOOcps 10.00% iii) Hydroxypropylmethylcellulose 5cps 45.00% iv) Lactose 4.23% v) Talcum 1.54% vi) Magnesium stearate 0.77% vii) Water c .b .p.

Example 5 i) Clarithromycin 35.89 ii) Hydroxypropylmethylcellulose 5cps 48.00 iii) Hydroxypropylmethylcellulose lOOcps 7. 00% (Methocel K100 LV) iv) Sodium alginate (Keltone LVCR) 3. 00% v) Lactose 3. 95% vi) Talc 1. 44% vii) Magnesium stearate 0.72% viii) Water c .b .p.

Example 6 i) Clarithromycin 35.89% ii) Hydroxypropylmethylcellulose 5cps 48.50% iii) Hydroxypropylmethylcellulose lOOcps 7.00% (Methocel K100 LV) iv) Sodium alginate (Keltone LVCR) 1.50% v) Xanthana gum 1.00% vi) Lactose 3.95% vii) Talc 1.44 % viii) Magnesium stearate 0.72% ix) Water cbp Procedure: The active principle and the excipients were mixed and granulated with water. The granules were dried, left at a certain size, lubricated and compressed to form tablets of suitable size and hardness. The dissolution profiles of the previous examples are summarized in Table I: TABLE I A formulation prepared according to previous examples was subjected to a bioequivalence study with respect to the clarithromycin extended release formulation marketed in the United States as Biaxin XLMR. The T / R ratio of the geometric mean of Cmax and ABC was within acceptable limits (80% -125%) as shown in Table II.

TABLE II Surprisingly it was found that our formulation comprising approximately 50% to 65% pharmaceutically acceptable polymers was bioequivalent with respect to Biaxin XL.

Claims

CLAIMS 1. A pharmaceutical composition for the prolonged release of erythromycin or a derivative thereof, comprising a pharmaceutically effective amount of the active ingredient and about 50% to 65% by weight of one or more pharmaceutically acceptable polymers. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable polymers are selected from the group consisting of polyvinyl pyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl pyrrolidone / polyvinyl acetate copolymers, poly (ethylene oxide) polymers, acrylic acid polymers, methacrylic acid copolymers, natural gums, and derivatives and mixtures thereof. 3. The prolonged release pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable polymer is hydroxypropylmethylcellulose or combinations thereof. . The prolonged release pharmaceutical composition according to claim 3, wherein the hydroxypropylmethylcellulose has a viscosity ranging from about 5 to 200 cps. The prolonged release pharmaceutical composition according to claim 1, wherein the composition contains about 30% to 45% by weight of erythromycin or a derivative. 6. The prolonged 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 also contains pharmaceutical auxiliaries such as buffers, fillers, lubricating binders. 8. A pharmaceutical composition according to claim 7, wherein the buffers can be selected from the groups formed by alkali or alkaline earth metal phosphates, citrates, succinates, and the like. 9. A pharmaceutical composition according to claim 7, wherein the fillers can 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 for using a sustained release composition comprising erythromycin or its derivatives and about 50% to 65% by weight of pharmaceutically acceptable polymers, for the treatment of bacterial infections in a mammal. 13. A process for preparing a sustained release composition of erythromycin or its derivatives, which consists of mixing the active pharmaceutical ingredient with about 50% to 65% by weight of one or more of the pharmaceutically acceptable polymers, granulating the mixture wet or Dry and then deposit the granules in capsules or sachets or compress them to form tablets. 14. A prolonged release pharmaceutical composition according to claim 1, wherein the ratio T / R of geometric means of Cmax and ABC is within acceptable limits (80% - 125%) compared to the controlled release formulation of clarithromycin, as shown in Table II.