FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
CONTROLLED RELEASE ANTIBIOTIC COMPOSITION
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a controlled release pharmaceutical composition comprising an erythromycin derivative or salt thereof, greater than 50 weight percent based on total weight of composition a combination of two or more hydrophilic polymers, wherein at least one polymer is having viscosity in the range of about 2 cps to about 40 cps and at least one polymer is having viscosity in the range of about 50 cps to about 150 cps.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. Description
The present invention provides a controlled release pharmaceutical composition comprising an erythromycin derivative or salt thereof, greater than 50 weight percent based on total weight of composition a combination of two or more hydrophilic polymers, wherein at least one polymer is having viscosity in the range of about 2 cps to about 40 cps and at least one polymer is having viscosity in the range of about 50 cps to about 150 cps.
Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6-0-methylerythromycin. The molecular formula is C38H69NO13, and the molecular weight is 747.96. Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone, slightly soluble in methanol, ethanol, and acetonitrile, and practically insoluble in water. Its structural formula is:

Clarithromycin indicated for the treatment of adults with mild to moderate infection such as acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis and community-acquired pneumonia caused by susceptible strains microorganisms.
US Patent No. 6,010,718 discloses a pharmaceutical composition for extended release of an erythromycin derivative and from about 5 to about 50% by weight of a pharmaceutically acceptable polymer.

US Patent No. 6,673,369 discloses a controlled release formulation, comprising a pharmaceutical^ effective amount of at least one drug and from about 0.1% to about 4.5% w/w of one or more rate controlling high viscosity cellulosic ether polymers wherein the high viscosity polymer comprises a polymer having a viscosity of at least about 4,000 cps or more.
US Patent No. 4,808,411 discloses a composition comprising from about 25% to about 95% of erythromycin or a derivative thereof and from about 5% to about 75% of a carbomer.
US Patent No. 5,705,190 discloses a controlled release, solid pharmaceutical composition adapted for oral administration comprising a therapeutically effective amount of at least one basic drug, a water-soluble alginate salt; a complex salt of alginic acid.
US Patent No. 5,919,489 discloses a process for preparing granules of a macrolide antibiotic comprising the steps of: (a) mixing a macrolide antibiotic and a carbomer in a weight ratio of between about 1:10 and about 5:2.
US Patent No. 6,565,877 discloses a taste masked composition comprising a bitter tasting drug and a combination of two enteric polymers comprising, a methacrylic acid copolymer and a phthalate polymer.
US Patent No. 7,037,523 discloses a pharmaceutical composition for controlled release of an active agent, a pharmaceutically acceptable water insoluble polymer and an optimizing agent.
US Patent No. 7,063,862 discloses a pharmaceutical composition, comprising: a therapeutically active agent; from about 0.1% to about 4.9% by weight of a swellable and water-soluble pharmaceutically acceptable polymer; and from about 0.1% to about 30% by weight of a pharmaceutically acceptable acid.

US Application No. 20050064034 discloses a controlled release dosage form comprising at least one drug which is sparingly soluble to insoluble, at least one polymer having viscosity less than 50 cps, and at least one polymer having viscosity greater than 200 cps.
US Application No. 20050136107 discloses an extended release antibiotic composition comprising at least one antibiotic and greater than 50 weight percent, based on the total weight of the composition, of a polymer component, wherein said polymer component comprises at least one pharmaceutically acceptable hydrophilic polymer, and said polymer component has a viscosity of less than about 50 cps.
US Application No. 2006193908 discloses an extended release composition containing macrolide antibiotic, one or more surfactants and one or more non-lipophilic, non-polymeric excipients.
The present inventors while working on the clarithromycin formulation have surprisingly found that the controlled release formulation based on the combination of two or more hydrophilic polymers greater than 50 weight percent based on total weight of composition, wherein at least one polymer is having viscosity in the range of about 2 cps to about 40 cps and at least one polymer is having viscosity in the range of about 50 cps to about 150 cps, results in better control of drug release.
One of the aspects of the present invention provides a controlled release pharmaceutical composition comprising
a) an erythromycin derivative or salt thereof,
b) greater than 50 weight percent based on total weight of composition a combination of two or more hydrophilic polymers,

wherein at least one polymer is having viscosity in the range of about 2 cps to about 40 cps and at least one polymer is having viscosity in the range of about 50 cps to about 150 cps.
The controlled release pharmaceutical composition of the present invention includes an erythromycin derivative known to skilled artisan and may include one or more of erythromycin, roxithromycin, azithromycin, clarithromycin and pharmaceutical^ acceptable salts thereof.
In one of the embodiments of the present invention, the controlled release pharmaceutical composition consists of clarithromycin or pharmaceutically acceptable salt thereof as an active ingredient and is present in the form of clarithromycin base.
The controlled release pharmaceutical composition of the present invention,
comprises combination of two or more hydrophilic polymers selected from the
group comprising of polyvinylpyrrolidone, hydroxypropylmethylcellulose,
hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose,
methylcellulose, sodium carboxymethylcelluloses, carboxyethylcellulose, polyvinyl alcohol, sodium alginate, methacrylic acid copolymers and the like.
In one of the embodiments of the present invention, the total content of hydrophilic polymers is greater than 50 weight percent of the total weight of the composition.
The combination of hydrophilic polymers in the present invention comprises of at least one polymer having viscosity in the range of about 2 cps to about 40 cps and at least one polymer having viscosity in the range of about 50 cps to about 150 cps.

In one of the embodiments of the present invention, at least one hydrophilic polymer is having viscosity in range of about 2 cps to about 20 cps and at least one hydrophilic polymer is having viscosity in range of about 90 cps to about 110 cps.
The controlled release pharmaceutical formulation of the present invention can be prepared by wet granulation or dry granulation.
In one of the embodiments of the present invention, the controlled pharmaceutical composition is prepared by wet granulation that involves the step of granulating the erythromycin derivative, hypromellose of different viscosity grades and lactose with aqueous solution of polyvinylpyrrolidone. The dried granules are mixed with talc, colloidal silicon dioxide, followed by lubricating the blend with magnesium stearate. The lubricated granules are compressed to form tablet using suitable tooling.
The compressed tablets of the present invention may be coated with nonfunctional coat that rapidly disintegrates or dissolves in water or in the environment of use. The coat may be a conventional sugar or polymeric film coating, which is applied in a coating pan or by conventional spraying techniques. Preferred materials for the coat are commercially available under the OPADRY trade name. Generally, the coat surrounding the core will comprise from about 1 to 5%.
The controlled release pharmaceutical composition of the present invention may also comprise pharmaceutical^ acceptable excipients selected from the group comprising of diluent, binder, glidants, lubricant and the like.
The suitable diluents may be one or more of microcrystalline cellulose, dicalcium phosphate, mannitol, starch, lactose monohydrate and the like.

The suitable binder may be one or more of sugars, gums, low molecular weight hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, povidone K-30, potato starch, wheat starch and corn starch, gum tragacanth, acacia gum and gelatin, purified water and the like.
The suitable glidants include, but are not limited to silicon dioxide, powdered cellulose, starch, talc.
The suitable lubricants may be selected from a group comprising one or more of magnesium stearate, mineral oils, vegetable oils and glyceryl esters of fatty acids wherein mineral oils, vegetable oils and glyceryl esters of fatty acids comprises hydrogenated vegetable oil, hydrogenated castor oil, light mineral oil, glycerol monostearate, glycerol monobehenate, glyceryl behenate, glyceryl palmitostearate and the like.
The controlled release pharmaceutical composition of the present invention can be present in the form of tablet, capsule, beads, caplet, disc, pills, spheroids, minitablets, granules in capsule, beads in capsule, minitablets in capsule or any other dosage form suitable for oral administration.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1 Table 1: Composition of clarithromycin controlled release tablets (500 mg)

S.N. Ingredients Weight %
1 Clarithromycin 35-40
2 Hypromellose [Methocel K 100 LVCR] 3-6
3 Hypromellose [Methocel E 6 Premium LV EP1 30-45
4 Hypromellose [Methocel E 15 Premium 8-16

LVEP]
5 Lactose monohydrate 2-4
6 Talc 0.5-1.5
7 Povidone K-30 0.5-2
8 Colloidal Silicon Dioxide [Aerosil 200] 0.2-0.6
9 Mg stearate 0.2-1
10 Coating polymer 2-3
Procedure: The controlled release pharmaceutical compositions mentioned in examples 1 is prepared by mixing geometrically clarithromycin, Methocel K 100 LVCR, Methocel E 6 Premium LV EP and Methocel E 15 Premium LV EP followed by granulating the it with aqueous solution of polyvinylpyrrolidone. The obtained granules are mixed with talc, colloidal silicon dioxide and then lubricated with magnesium stearate. The lubricated granules are compressed to form a tablet using suitable tooling. The obtained tablets are coated with dispersion of Opadry.

WE CLAIM:
1. A controlled release pharmaceutical composition comprising
a) an erythromycin derivative or salt thereof,
b) greater than 50 weight percent based on total weight of composition a combination of two or more hydrophilic polymers,
wherein at least one polymer is having viscosity in the range of about 2 cps to about 40 cps and at least one polymer is having viscosity in the range of about 50 cps to about 150 cps.
2. The controlled release pharmaceutical composition of claim 1, wherein the erythromycin derivative is clarithromycin.
3. The controlled release pharmaceutical composition of claim 1, wherein the hydrophilic polymers are selected from the group comprising of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxymethylcelluloses, carboxyethylcellulose, polyvinyl alcohol, sodium alginate, methacrylic acid copolymers and the like.
4. The controlled release pharmaceutical composition of claim 3, wherein the hydrophilic polymers are hydroxypropylmethylcellulose and polyvinylpyrrolidone.
5. The controlled release pharmaceutical composition of claim 1 may additionally comprises of pharmaceutically acceptable excipients selected from the group comprising of diluent, binder, glidants, lubricant and the like.
6. The controlled release pharmaceutical composition of claim 5, wherein diluents comprise one or more of microcrystalline cellulose, dicalcium phosphate, mannitol, starch, lactose monohydrate.

7. The controlled release pharmaceutical composition of claim 5, wherein binders comprise one or more of sugars, gums, low molecular weight hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, povidone K-30, potato starch, wheat starch and corn starch, gum tragacanth, acacia gum and gelatin, purified water.
8. The controlled release pharmaceutical composition of claim 5, wherein lubricants comprise one or more of magnesium stearate, mineral oils, vegetable oils and glyceryl esters of fatty acids wherein mineral oils, vegetable oils and glyceryl esters of fatty acids comprises hydrogenated vegetable oil, hydrogenated castor oil, light mineral oil, glycerol monostearate, glycerol monobehenate, glyceryl behenate, glyceryl palmitostearate.
9. The controlled release pharmaceutical composition of claim 5, wherein glidants include, but are not limited to silicon dioxide, powdered cellulose, starch, talc.
10. The controlled release pharmaceutical composition of claim 1 may be present in the form of tablet, capsule, beads, caplet, disc, pills, spheroids, minitablets, granules in capsule, beads in capsule, minitablets in capsule or any other dosage form suitable for oral administration.
Dated this 26TH day of May, 2007
For Wockhardt Limited

Abstract
The present invention provides a controlled release pharmaceutical composition comprising an erythromycin derivative or salts thereof, a combination of one or more hydrophilic polymers.