Field of the invention
The present invention relates to an extended release formulations of macrolide antibiotic. More particularly, the present invention relates to an extended release formulation of erythromycin derivatives.
The present invention also relates to a process for the preparation of extended release formulation containing erythromycin derivatives.
Background of the invention
Erythromycin derivatives exhibits broad spectrum of antibacterial activity against gram-positive and gram-negative microorganisms. These erythromycin derivatives include azithromycin, clarithromycin and roxithromycin.
Various erythromycin derivatives available in the market for the treatment of bacterial infections include azithromycin marketed under the trade name Zithromax, clarithromycin marketed under the trade name Biaxin®.
Chemically, clarithromycin is 6-0-methylerythromycin, which is commercially available as granules for oral suspension, film coated tablets and extended release tablets.
Chemically, azithromycin is N-methyl-11 -aza-10-deoxo-10-dihydro-erythromycin A which is commercially available as tablets, suspension, extended release suspension and injection.
In general erythromycin derivatives possess bitter taste, particularly clarithromycin has bitter metallic taste, thereby resulting in poor patient compliance, when administered as twice or thrice daily immediate release tablets. To improve the patient compliance, extended release formulations have been developed which results in reduced frequency of dosing, improved patient compliance and reduced frequency of side effects.

Commercially available clarithromycin extended release tablets contain 500 mg of clarithromycin as active ingredient and excipients such as cellulosic polymers, lactose monohydrate, magnesium stearate, propylene glycol, sorbic acid, sorbitan monooleate, talc, titanium dioxide, D&C Yellow No. 10 and vanillin.
Given below are the patents/patent publications, which disclose extended release erythromycin derivative compositions:
U.S. 5,705,190 discloses controlled release compositions comprising poorly soluble basic drug, a water-soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid to facilitate dissolution of the basic drug.
U.S. 6,010,718 discloses extended release pharmaceutical composition comprising an erythromycin derivative and from about 5 to about 50% by weight of a pharmaceutically acceptable polymer, wherein the polymer is selected from the group consisting of polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, vinylacetate/crotonicacid copolymers, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures.
U.S. 6,068,859 discloses a controlled release dosage form comprising azithromycin and a pharmaceutically acceptable carrier wherein azithromycin is embedded in a matrix which releases azithromycin by eroding.
U.S. 6,642,276 discloses controlled release formulation comprising, a macrolide citrate salt; at least one hydrophilic polymer; a binder, a filler; and a lubricant. The preferred range of hydrophilic polymer is from about 5-15% by weight.

U.S. 6,673,369 discloses controlled release formulation, suitable for once daily administration, comprising a pharmaceutically effective amount of at least one drug having a water solubility of less than one part per 30 parts water, and from about 0.1% to about 4.5% w/w of one or more rate controlling high viscosity cellulosic ether polymers.
U.S. 7,037,523 discloses controlled release composition comprising a mixture of a macrolide antibacterial agent, a pharmaceutically acceptable water insoluble polymer and an optimizing agent wherein the insoluble polymer is selected from water insoluble cellulosic derivatives, polyvinyl chloride, amino alkyl methacrylates and the like. The preferred range of water insoluble polymer is from about 10 to about 40% in addition to other excipients.
This patent further discloses that the preferable optimizing agent is a combination comprising a polymer of methacrylic acid and methyl methacrylate and a compound selected from the group consisting of lactose, dicalcium phosphate and tricalcium phosphate or a mixture thereof present in the range of 10 to about 90%.
U.S. 7,063,862 discloses composition comprising clarithromycin, 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. This patent further discloses that the pharmaceutically acceptable acid in the pharmaceutical composition enhances the gelling process of the pharmaceutically acceptable polymer to achieve the zero-order drug release profile.
U.S. 2004/0043073 discloses controlled release oral dosage form comprising a matrix comprising a drug having a pH dependent solubility; at least one wax material in an effective amount to provide a controlled release of

said drug for at least 12 hours in an environment of use; and at least one pH modifying agent.
U.S. 2005/0136107 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 pharaiaceutically acceptable hydrophilic polymer, and said polymer component has a viscosity of less than about 50 cps.
U.S. 2006/0193908 discloses extended release composition comprising a macrolide antibiotic; one or more surfactants and one or more non-lipophilic, non-polymeric excipients.
U.S. 2007/0015719 discloses stable nanoparticulate composition comprising particles of clarithromycin, having an effective average particle size of less than about 2000 nm and at least one surface stabilizer.
EP 1 757 277 Al discloses an oral preparation comprising a complex obtained by dissolving clarithromycin and gastric high-molecular compound in a low melting point substance and then coating the said complex with insoluble high-molecular compound and a disintegrator.
The above prior art references discloses various controlled release formulations of erythromycin derivatives that permits once-a-day dosing. Still, there exists a need to develop extended release formulations of erythromycin derivatives that effectively control the release of the drug from the dosage form over an extended period of time using minimal amounts of polymer.
Objective of the invention
Accordingly, the main objective of the present invention is to provide extended release formulations of erythromycin derivative.

Yet another objective of the present invention is to provide an extended release formulation of erythromycin derivative in such a way that it will comply with the reference product in terms of in vivo parameters like Cmax tmaxAUC and in vitro parameters like dissolution etc.
Yet another objective of the present invention is to provide process for the preparation of an extended release formulation of erythromycin derivative.
Summary of the invention
Accordingly, the main embodiment of the present invention is to provide an extended release formulation comprising erythromycin derivative and release rate controlling polymer selected from 0.1 to 10% by weight of water insoluble methacrylic acid copolymer and/or methacrylate ester copolymers, 0.1 to 5% by weight of hydrophilic polymer and mixtures thereof, wherein the hydrophilic polymer is not cellulose ether.
Detailed description of the invention
In another embodiment of the present invention, erythromycin derivative include azithromycin, clarithromycin and roxithromycin.
In another embodiment of the present invention, the extended release formulation further comprises one or more excipients selected from diluents, glidants and lubricants.
In one embodiment of the present invention, the extended release formulation comprises at least 50% by weight of erythromycin derivative and a combination of 0.1 to 5% by weight of water insoluble methacrylic acid copolymer and/or methacrylate ester copolymer and hydrophilic polymer wherein the ratio of water insoluble methacrylic acid copolymer and hydrophilic polymer is about 1:3 to about 3:1 by weight.

In another embodiment of the present invention, water insoluble methacrylic acid copolymer and/or methacrylate ester copolymer include Eudragit RS PO, Eudragit RS 100, Eudragit RS 12.5, Eudragit NE 30 D and Eudragit RS 30D which is a copolymer of Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride). The amount of water insoluble methacrylic acid copolymer and/or methacrylate ester copolymer may range from about 0.1 to about 10% w/w, preferably about 0.1 to about 6% w/w.
In another embodiment of the present invention, hydrophilic polymer includes polyethylene oxide, carbomer, vinyl acetate copolymers and the like.
The extended release formulation of the present invention is essentially free of organic acid, which enhances the gelling process of the polymer to achieve the zero-order drug release profile.
Suitable diluents of the present invention includes sucrose, calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, starch, pregelatinised starch, sorbitol and the like or combination thereof. The amount of diluent may range from about 10% to 40% by weight.
The extended release formulation of the present invention may
optionally contain binder such as polyvinylpyrrolidone, xanthan gum,
carboxymethylcellulose, hydroxypropylmethylcellulose,
hydroxypropylcellulose, methylcellulose, ethylcellulose, gelatin, starch, pregelatinized starch and the like.
Suitable glidants of the present invention include calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, talc, silicon dioxide, starch and the like.

Suitable lubricants of the present invention include sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc, carnauba wax and the like.
In another embodiment, the preferable extended release formulation according to present invention comprise at least 50% by weight of clarithromycin, 0.1 to 10% by weight of water insoluble methacrylic acid copolymer and/or methacrylate ester copolymer selected from Eudragit RS PO, Eudragit NE 30 D and Eudragit RS 30D; 10% to 40% by weight of diluent selected from lactose monohydrate and microcrystalline cellulose and binder selected from povidone and pregelatinised starch.
In another embodiment, the preferable extended release formulation according to present invention comprise at least 50% by weight of clarithromycin, 0.1 to 5% of hydrophilic polymer selected from polyethylene oxide, carbomer; 10% to 40% by weight of diluent selected from lactose monohydrate or microcrystalline cellulose and binder selected from povidone and pregelatinised starch.
In another embodiment, the preferable extended release formulation according to present invention comprise at least 50% by weight of clarithromycin, 0.1 to 10% by weight of water insoluble methacrylic acid copolymer and/or methacrylate ester copolymer selected from Eudragit RS PO, Eudragit NE 30 D and Eudragit RS 30D; 0.1 to 5% of hydrophilic polymer selected from polyethylene oxide, carbomer; 10% to 40% by weight of diluent selected from lactose monohydrate or microcrystalline cellulose and binder selected from povidone and pregelatinised starch.

In another embodiment of the present invention, the extended release formulations are prepared either by granulation technique such as dry or wet granulation or direct compression.
In another embodiment of the present invention, the dosage forms of the extended release formulations include tablets or capsules. The tablets may be uncoated or optionally coated. The film coating composition comprises a solution / suspension of film coating polymers and one or more excipients such as lactose, titanium dioxide, solubilizing agent and antisticking agent.
Suitable film coating polymers used according to the present invention
are selected from ethylcellulose, hydroxypropylcellulose,
hydroxypropylmethyl cellulose and the like or mixtures thereof.
The solubilizing agent of the present invention may be selected from anionic or non-ionic surfactants such as sodium lauryl sulphate, polyethylene-propylene glycol copolymer (poloxamer), polyoxyethylene stearates (Macrogol-stearate), poly sorbates, propylene glycol, and the like or mixtures thereof.
Suitable anti-sticking agents used according to the present invention are selected from talc, magnesium stearate and the like or a mixture thereof.
A preferable process for the preparation of extended release formulation comprising erythromycin derivative and release rate controlling polymer selected from 0.1 to 10% by weight of water insoluble methacrylic acid copolymer and/or methacrylate ester copolymers, 0.1 to 5% by weight of hydrophilic polymer and mixtures thereof, wherein the hydrophilic polymer is not cellulose ether comprises the following steps: i) blending erythromycin derivative with intra granular excipients, ii) granulating the blend of step (i).

iii) drying the granules obtained in step (ii),
iv) blending the dried granules of step (iii) with extra granular excipients,
v) lubricating the blend of step (iv),
v) compressing the blend of step (v) into tablets or filled into capsules and
vi) finally coating the tablets of step (vi) with film forming materials.
The solvents used for granulation according to the present invention are selected from water, isopropyl alcohol, ethanol, acetone, methylene chloride and the like or mixture thereof.
In yet another embodiment, the present invention also provides a method of treating acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis and/or community-acquired pneumonia by administering extended release formulation prepared according to present invention.
The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.



The processing steps involved are:
i) clarithromycin and microcrystalline cellulose were blended,
ii) a solution of eudragit in isopropyl alcohol and water was prepared,
iii) granulated the blended material of step (i) with a solution of step (ii)
and dried the granulated mass,
iv) granules of step (iii) were blended with microcrystalline cellulose,
v) lubricated the of granules of step (iv),
vi) compressed the blend of step (v) into tablets and
vii) tablets of step (vi) were then coated with a solution / suspension of
opadry in water.


i) clarithromycin, lactose monohydrate and microcrystalline cellulose
were blended,
ii) granulated the blended material of step (i) with eudragit dispersion and
the granulated mass was dried,
iii) granules of step (ii) were blended with colloidal silicon dioxide,
iv) compressed the blend of step (iii) into tablets and
v) tablets of step (iv) were then coated with a solution / suspension of opadry in water.
The compositions given in examples 4 to 6 were prepared using similar procedure described in example 3.

i) clarithromycin, lactose monohydrate, microcrystalline cellulose and
Polyethylene oxide were blended,
ii) a solution of eudragit was prepared,
iii) granulated the blended material of step (i) with a solution of step (ii)
and dried the granulated mass,
iv) granules of step (iii) were blended with colloidal silicon dioxide,
v) compressed the blend of step (iv) into tablets and
vi) tablets of step (v) were then coated with a solution / suspension of opadry in water.
The compositions given in examples 8 to 12 were prepared using similar procedure described in example 7.

We claim:
1. An extended release formulation comprising erythromycin derivative and release rate controlling polymer selected from 0.1 to 10% by weight of water insoluble methacrylic acid copolymer and/or methacrylate ester copolymers, 0.1 to 5% by weight of hydrophilic polymer and mixtures thereof, wherein the hydrophilic polymer is not cellulose ether.
2. The extended release formulation as claimed in claim 1, wherein the erythromycin derivative is selected from azithromycin, clarithromycin and roxithromycin.
3. The extended release formulation as claimed in claim 1, wherein the water insoluble methacrylic acid copolymer and/or methacrylate ester copolymer is selected from Eudragit RS PO, Eudragit RS 100, Eudragit RS 12.5, Eudragit NE 30 D and Eudragit RS 30D or combination thereof.
4. The extended release formulation as claimed in claim 1, wherein hydrophilic polymer is selected from polyethylene oxide, carbomer, vinyl acetate copolymers or combination thereof
5. The extended release formulation as claimed in claim 1, further comprises one or more excipients selected from diluent, binder, glidant and lubricant.
6. The extended release formulation as claimed in claim 5, wherein the diluent is selected from calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, starch, pregelatinised starch, sorbitol or combination thereof.
7. An extended release formulation comprising at least 50% by weight of clarithromycin, 0.1 to 10% by weight of water insoluble methacrylic acid copolymer and/or methacrylate ester copolymer selected from Eudragit RS PO,

Eudragit NE 30 D and Eudragit RS SOD; 10% to 40% by weight of diluent selected from lactose monohydrate and microcrystalline cellulose and binder selected from povidone and pregelatinised starch.
8. An extended release formulation comprising at least 50% by weight of clarithromycin, 0.1 to 10% by weight of water insoluble methacrylic acid copolymer and/or methacrylate ester copolymer selected from Eudragit RS PO, Eudragit NE 30 D and Eudragit RS 30D, 0.1 to 5% of hydrophilic polymer selected from polyethylene oxide, carbomer, 10% to 40% by weight of diluent selected from lactose monohydrate or microcrystalline cellulose and binder selected from povidone and pregelatinised starch.
9. An extended release formulation comprising at least 50% by weight of clarithromycin, 0.1 to 5% of hydrophilic polymer selected from polyethylene oxide (Polyox, carbomer; 10% to 40% by weight of diluent selected from lactose monohydrate or microcrystalline cellulose and binder selected from povidone and pregelatinised starch.
10. A process for the preparation of extended release formulation comprising erythromycin derivative and release rate controlling polymer selected from 0.1 to 10% by weight of water insoluble methacrylic acid copolymer and/or methacrylate ester copolymers, 0.1 to 5% by weight of hydrophilic polymer and mixtures thereof, wherein the hydrophilic polymer is not cellulose ether comprises the following steps:
i) blending erythromycin derivative with intra granular excipients,
ii) granulating the blend of step (i),
iii) drying the granules obtained in step (ii),
iv) blending the dried granules of step (iii) with extra granular excipients,
v) lubricating the blend of step (iv),

v) compressing the blend of step (v) into tablets or filled into capsules and vi) finally coating the tablets of step (vi) with film forming materials.