WO2013057569A2

WO2013057569A2 - Extended release pharmaceutical composition containing amoxicillin and clavulanic acid

Info

Publication number: WO2013057569A2
Application number: PCT/IB2012/002092
Authority: WO
Inventors: Rajesh Kshirsagar; Ganesh Shinde; Rashmi Ranjan PANDA; Dharmaraj Balasaheb MORE
Original assignee: Micro Labs Limited
Priority date: 2011-10-19
Filing date: 2012-10-19
Publication date: 2013-04-25
Also published as: WO2013057569A3

Abstract

An extended release pharmaceutical composition comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof and a process for preparing thereof. The present invention particularly relates to composition containing various coatings in order to retard the release of the drug from tablet.

Description

EXTENDED RELEASE PHARMACEUTICAL COMPOSITION CONTAINING AMOXICILLIN AND CLAVULANIC ACID FIELD OF INVENTION:

The present invention relates to an extended release pharmaceutical composition comprising amoxicillin and clavulanic acid, or pharmaceutically acceptable salts thereof and a process for preparing thereof.

BACKGROUND OF INVENTION:

Amoxicillin is chemically designated as (2S, 5R, 6R) - 6-{[(2R)-2-amino- 2-(4- hydroxyphenyl) - acetyl] amino} - 3, 3-dimethyl- 7-oxo- 4-thia- 1-azabicyclo [3.2.0] heptane- 2-carboxylic acid. It is a β-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice because it is better absorbed, following oral administration, than other β-lactam antibiotics. Clavulanic acid is chemically designated as (2R, 5R, Z) - 3-(2- hydroxyethylidene)- 7-oxo- 4-oxa- 1-aza- bicyclo [3.2.0] heptane- 2-carboxylic acid. It is a competitive beta-lactamase inhibitor and is used to overcome resistance in bacteria that secrete beta-lactamase, which otherwise inactivates most penicillins. Combination of amoxicillin and Clavulanic acid are particularly effective for treatment of community-acquired infections, in particular upper respiratory tract infections in adults and otitis media in children.

Combination comprising amoxicillin and potassium clavulanate are available as AUGMENTIN XR extended release tablets in strength of 1 ,000 mg of amoxicillin and clavulanate potassium equivalent to 62.5 mg of clavulanic acid. Various tablet formulations of amoxicillin and potassium clavulanate have been approved for marketing, comprising various different weights and ratios of amoxicillin and potassium clavulanate.

The pharmaceutical formulation comprising amoxicillin and clavulanic acid in weight ratio between 10: 1 and 20: 1 is disclosed in WO 97/09042.

US pat no. 6,783,773 discloses a modified release pharmaceutical formulation comprising amoxicillin and potassium clavulanate in which all of the potassium clavulanate and a first part of amoxicillin are formulated with pharmaceutically acceptable excipients which allow for immediate release of the potassium clavulanate and the first part of amoxicillin to form a immediate release phase, and further comprising a second part of amoxicillin formulated with pharmaceutically acceptable excipients which allow for slow release of the second part of amoxicillin, to form a slow release phase. '773 discloses amount of amoxicillin in the formulation is within the range of 1900 and 2600 mg and amount clavulanic is such that the weight ratio of amoxicillin to clavulanate is from 2: 1 to 20: 1.

US 6,756,057 discloses a pharmaceutical formulation to provide a unit dosage of amoxicillin and potassium clavulanate which comprises from 100 to 150 mg of potassium clavulanate and from 1700 to 2500 mg of amoxicillin; which formulation is a modified release formulation comprising an immediate and a slow release phase and in which all of the potassium clavulanate and from 0 to 50% of the amoxicillin is in an immediate release phase and from 50 to 100 % of the amoxicillin is in a slow release phase.

Thus there is still exists need to develop a stable, extended release composition of amoxicillin and clavulanic acid.

SUMMARY OF THE INVENTION:

In one aspect, the present invention provides an extended release pharmaceutical composition comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof and one or more pharmaceutical excipients.

In yet another aspect, the present invention provides an extended release pharmaceutical composition comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof and one or more pharmaceutical excipients wherein the core comprises amoxicillin sodium and a compression coat on the core comprises amoxicillin trihydrate and clavulanic acid.

In yet another aspect of present invention provides an extended release pharmaceutical composition comprising:

(a) first layer comprising amoxicillin or its pharmaceutical acceptable salt thereof, coated with a hydrophilic polymer and hydrophobic polymer;

(b) second layer comprising amoxicillin or its pharmaceutical acceptable salt thereof, clavulanic acid or its pharmaceutical acceptable salt thereof and one or more pharmaceutically acceptable excipients; (c) wherein first and second layer compressed into a tablet and the said tablet is coated with hydrophilic polymer and hydrophobic polymer such that drug is released from tablet in the gastro intestinal tract (GIT) over an extended period of time.

In yet another aspect, present invention further provides a process of preparation of an extended release pharmaceutical composition comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof and one or more pharmaceutical excipients.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an extended release pharmaceutical composition comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof and one or more pharmaceutical excipients. The present invention further provides a process of preparation of an extended release pharmaceutical composition comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof and one or more pharmaceutical excipients.

The term "pharmaceutical composition" herein refers to the combination of one or more drug substances and one or more excipients, "Drug product," "pharmaceutical dosage form," "dosage form," "final dosage form" and the like, refer to a pharmaceutical composition that is administered to a subject in need of treatment and generally may be in the form of tablets, capsules, bilayer tablet, tablet in tablet, tablets filled in capsule, mini tablets filled in capsule, sachets containing powder or granules, pellets, liquid solutions or suspensions, patches, and the like.

The term "extended release formulation " herein refers to any formulation or dosage form that comprises an active drug and which is formulated to provide a longer duration of pharmacological response after administration of the dosage form than is ordinarily experienced after administration of a corresponding immediate release formulation comprising the same drug in the same amount. Controlled release formulations include, inter alia, those formulations described elsewhere as "controlled release", "delayed release", "sustained release", "prolonged release", "programmed release", "time release" and/or "rate controlled" formulations or dosage forms. By "pharmaceutically acceptable" is meant a carrier comprised of a material that is not biologically or otherwise undesirable.

The term "Amoxicillin" as used in the invention is meant to cover amoxicillin in the form of freebase or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof. The term also includes all polymorphic forms, whether crystalline or amorphous.

The term "Clavulanic acid" as used in the invention is meant to cover clavulanic acid in the form of freebase or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof. The term also includes all polymorphic forms, whether crystalline or amorphous.

The pharmaceutical compositions of the present invention can be any solid dosage form for example, but not limited to tablet, capsule, pellets, granules, tablet in tablet, and tablet in capsule. The core dosage forms can be prepared by any means using excipients well known to the person skilled in the art.

The formulation according to present invention will, in general comprise of one or more excipients. Examples of pharmaceutical excipients include, but are not limited to binders, fillers or diluents, lubricants, glidants, disintegrants. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.

Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as products known under the registered trade marks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinylpyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations thereof and other materials known to one of ordinary skill in the art and mixtures thereof.

Fillers or diluents, which include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.

Lubricants includes, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.

Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art.

The formulation according to present invention may also comprise a disintegrant which may be included in all or part of the oral dosage form to ensure rapid disintegration of the dosage form or part of the dosage form (for example, one of the layers in a bilayer tablet) after administration.

Disintegrants include, but are not limited to: alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate and starches and other materials known to one of ordinary skill in the art and combinations thereof.

The formulations of the present invention can optionally have one or more coatings such as film coating, sugar coating, extended release coating, enteric coating, bioadhesive coating and other coatings known in the art. These coatings help formulations to release the drug at and for the required time. The most preferable coating is extended release coating. The amount of coating may vary within the ranges conventional in the art.

These coating comprises one or more excipients selected from the group comprising coating agents, opacifiers, fillers, polishing agents, coloring agents, anti-tacking agents and the like.

Coating agent is selected from hydrophilic polymer and hydrophobic polymer. Hydrophilic polymers include but are not limited to cellulose derivatives such as hydroxypropylmethylcellulose (hypromellose), hydroxypropylcellulose, methylcellulose hydroxymethylcellulose, hydroxyethylcellulose, sodium carboxy methylcellulose, hydroxyethylmethylcellulose and like. Hydrophobic polymers includes but are not limited to cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, hydroxy propyl methyl cellulose phthalate, polyvinylacetatephthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, methyl methacrylate and diethylaminoethyl methacrylate copolymer. The enteric coating may also include insoluble substances which are neither decomposed nor solubilized in living bodies, such as alkyl cellulose derivatives such as ethyl cellulose, crosslinked polymers such as styrene- divinylbenzene copolymer, polysaccharides having hydroxyl groups such as dextran, cellulose derivatives which are treated with bifunctional crosslinking agents such as epichlorohydrin, dichlorohydrin, 1, 2-, 3, 4-diepoxybutane and combination thereof.

The enteric coating may also include starch and/or dextrin. These agents may be applied from aqueous or non-aqueous systems or combinations of aqueous and non-aqueous systems as appropriate. Additives can be included along with the film formers to obtain satisfactory films. These additives can include plasticizers such as dibutyl phthalate, triethylcitrate, polyethylene glycol (PEG) and the like, antitacking agents such as talc, stearic acid, magnesium stearate and colloidal silicon dioxide and the like, fillers such as talc, precipitated calcium carbonate, polishing agents such as beeswax, carnauba wax, synthetic chlorinated wax and opacifying agents such as titanium dioxide and the like. All these excipients can be used at levels well known to the persons skilled in the art.

The polymer composition used in the invention may be stabilized by one or more surfactant or emulsifier including but are not limited to macrogol cetostearyl ether, sodium lauryl sulfates, sorbitan esters, polysorbates, and poloxamers.

The various embodiments of the present invention can be assembled in several different ways. In the preferred embodiment, the present invention provides an extended release pharmaceutical composition comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof and one or more excipients.

In yet another embodiment of present invention provides an extended release pharmaceutical composition comprising:

(b) second layer comprising amoxicillin or its pharmaceutical acceptable salt thereof, clavulanic acid or its pharmaceutical acceptable salt thereof and one or more pharmaceutically acceptable excipients;

(c) wherein first and second layer compressed into a tablet and the said tablet is coated with hydrophilic polymer and hydrophobic polymer such that drug is released from tablet in the gastro intestinal tract (GIT) over an extended period of time.

In yet another embodiment, the present invention provides an extended release composition comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof, containing core tablet of amoxicillin or pharmaceutically acceptable salts thereof, wherein the core tablet is coated with a enteric coating composition.

In yet another embodiment, the present invention provides an extended release composition comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof, wherein the enteric coated tablet of amoxicillin or pharmaceutically acceptable salts thereof, is compression coated with the other composition comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof.

In yet another embodiment, the present invention provides a process of preparing an extended release pharmaceutical composition comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof and one or more excipients.

In yet another embodiment, the present invention provides process of preparing an extended release pharmaceutical composition, comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof and one or more excipients, the process, which comprises various steps such as:

i) preparation of an enteric coated tablet comprising amoxicillin or pharmaceutically acceptable salts thereof and one or more excipients, ii) compression coating of the enteric coated tablet with the blend comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof and one or more excipients,

iii) seal coating of the tablet in tablet composition and

iv) coating with release retarding polymer.

In yet another embodiment, the present invention provides a process of preparing an extended release pharmaceutical composition comprising amoxicillin and clavulanic acid or pharmaceutically acceptable salts thereof are prepared by process well known by those of skill in the art. For example, core tablets can be prepared by wet granulation (aqueous/non-aqueous or combination), dry granulation, melt granulation, direct compression and the like. In the preferred embodiment, the tablets are prepared by roller compaction.

In yet another embodiment, the extended release composition comprises amoxicillin or pharmaceutically acceptable salt thereof in the concentration range from about 600mg to about 1400mg.

In yet another embodiment, the extended release composition comprises clavulanic acid or pharmaceutically acceptable salt thereof in the concentration range from about 40 mg to about 120mg.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope of the spirit of the invention: Example 1

A) Formula for Enteric Coated Amoxicillin Sodium

* Available from Colorcon and contains hypromellose, triacetin and talc B) Formula for compression coat of Amoxicillin Trihydrate, Amoxicillin Sodium and Potassium Clavulanate

Outer Compression Coat - Amoxicillin Trihydrate eq. to amoxicillin base 562.5 mg + Amoxicillin Sodium eq. to amoxicillin base 262.5 mg + Potassium Clavulanate eq. to clavulanic acid 62.5mg

Ingredients mg/ Tablet

Amoxicillin Trihydrate (Equivalent to Amoxicillin 562.5 mg) 645.60

Amoxicillin Sodium (Equivalent to Amoxicillin 262.5 mg) 279.06

Diluted Potassium Clavulanate (Potassium Clavulanate + MCC 148.9 Avicel PH 102 (1 : 1))

Macrocrystalline Cellulose (Avicel PH 102) 318.44

Colloidal Silicon Dioxide 3.0

Magnesium Stearate 10.0

Pre lubrication

Microcrystalline Cellulose (Avicel PH 102) 4.0

Sodium Starch Glycolate 29.0

Colloidal Silicon Dioxide 7.0

Lubrication

Magnesium Stearate 5.0

Total weight of compression coat 1450.0

C) Compression Coating

* Solid content

# Available from BASF and contains methyl methacrylate and diethylaminoethyl methacrylate copolymer stabilized with 0.6% macrogol cetostearyl ether and 0.8% sodium lauryl sulfate.

Manufacturing process

Step A- Enteric coated amoxicillin sodium tablets

Amoxicillin sodium, microcrystalline cellulose (Avicel PH 102) and sodium starch glycolate was sifted through suitable sieve and mixed. This blend was mixed with part pf sifted magnesium stearate and the blend was passed through roller compactor to form compacts. The compacts were passed through suitable sieve and the granules were mixed with colloidal silicon dioxide and remaining quantity of magnesium stearate and compressed into tablets. The tablets are first coated with aqueous solution of Opadry clear 03K 19229 and then coated with enteric coating solution of HPMC phthalate, Triethyl citrate, talc and titanium dioxide in mixture of acetone and water in conventional coating equipment.

Step B- Compression coat of Amoxicillin Trihydrate, Amoxicillin Sodium and Potassium Clavulanate

Amoxicillin trihydrate, Amoxicillin sodium, microcrystalline cellulose (Avicel PH 102), Diluted potassium clavulanate and Colloidal silicon dioxide was sifted through suitable sieve and mixed. This blend was mixed with half quantity of sifted magnesium stearate and passed through roller compactor to form a compact. The compacts was passed through suitable sieve and mixed with sifted microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and lubricated with remaining quantity of sifted magnesium stearate.

Step C- Tablet in Tablet (Compression coating)

The blend of step B was tabletted together with the enteric-coated tablet core prepared in step A to form a tablet in tablet.

Step D- Coating with opadry clear 03K19229

The compression coated tablet of step C are coated with coating solution of Opadry clear 03K19229 prepared in mixture of isopropyl alcohol and methylene chloride using conventional coating equipment.

Step E- Coating with Methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersion

The coated tablets of step D are coated with aqueous dispersion of Methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersion, Triethyl citrate and talc using conventional coating equipment.

The dissolution tests of enteric coated tablets of Amoxicillin sodium of step A were performed in 900 ml of 0.1N HC1 followed by pH 6.8 phosphate buffer, at 37°C, apparatus USP Type II (Paddle apparatus), 75 rpm. This demonstrates that enteric coating allows the release of Amoxicillin sodium at alkaline pH. The results are shown in table 1. The dissolution test of compression coated tablets of step C (Tablet in Tablet) coated with opadry clear 03K19229 (Tablet of step D) and coated with aqueous dispersion of Methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersion, triethyl citrate and talc (tablets of step E) were performed in different media i.e. in 900 ml of Deionised Water, pH 4.5 Acetate buffer, pH 5.5 Acetate buffer and pH 6.8 Phosphate buffer, at 37°C, apparatus USP Type II (Paddle apparatus), 75 rpm. The results demonstrated that tablet of step D release the Amoxicillin and clavulanic acid in water whereas tablets of step E coated with Kollicoat smart seal 30D do not show the release in water and buffer with pH 5.8 to pH 7.2 and release the Amoxicillin and clavulanic acid in acetate buffer pH 4.5, acetate buffer pH 5.5. The results are shown in table 2.

The formulation of Example no. 1 was subjected to in-vitro dissolution studies and the results obtained are subjected in following tables:

Table 1: Release of Amoxicillin from enteric coated tablets of Amoxicillin sodium in 0.1N HC1 (0 to 2 hours) followed by pH 6.8 Phosphate buffer.

Dissolution media Time Cumulative % Amoxicillin Released

0.1 N HCL 1 hr 0

2 hr 0

Phosphate buffer pH 6.8 15 min 59

30 min 97

45 min 98

5 Table 2: Release of Amoxicillin and Clavulanic acid tablets of step D in Deionised Water and tablet of step E in Deionised Water, Acetate buffer pH 4.5, Acetate buffer pH 5.5 and Phosphate buffer pH 6.8

10

Example 2

A. Formula for Enteric Coated Amoxicillin Sodium

* Available from Colorcon and contains hypromellose, triacetin and talc B. Formula for compression coat of Amoxicillin Trihydrate, Amoxicillin Sodium and Potassium Clavulanate

Outer Compression Coat : Amoxicillin Trihydrate eq. to amoxicillin base 562.5 mg + Amoxicillin Sodium eq. to amoxicillin base 262.5 mg + Potassium Clavulanate eq.

to clavulanic acid 62.5mg

Ingredients mg/ Tablet

Dry mix

Amoxicillin Trihydrate (Equivalent to Amoxicillin 562.5

mg) 647.49

Amoxicillin Sodium (Equivalent to Amoxicillin 262.5

mg) 279.06

Macrocrystalline Cellulose (Avicel PH 1 12) 316.55

Colloidal Silicon Dioxide (Aerosil 200M) 3.0

Magnesium Stearate 10.0

Pre lubrication

Microcrystalline Cellulose (Avicel PH 1 12) 4.0

Sodium Starch Glycolate (Type A) 29.0

Diluted Potassium Clavulanate (Potassium Clavulanate 148.9

eq. to clavulanic acid 62.5 mg + MCC Avicel PH 102

(1 : 1)

Colloidal Silicon Dioxide (Aerosil 200M) 7.0

Lubrication

Magnesium Stearate 5.0

Total weight of compression coat 1450.0 C. Compression Coating

Ingredients mg/ Tablet

Enteric coated tablet of Amoxicillin Sodium 249.75

Blend of Compression coat 1450.0

Total weight of compression coated tablet 1699.75

D. Seal Coating

Seal Coating

Opadry clear 03 K 19229* 51.00

Isopropyl alcohol q.s.

Methylene Chloride q.s.

Total weight 1750.75

E. Coating with Kollicoat Smart seal 30D

Coating

Kollicoat smart seal 30D " 26.42*

Triethyl citrate 3.44

Talc 21.14

Purified Water q.s.

Total weight 1801.75

* Solid content # Available from BASF and contains methyl methacrylate and diethylaminoethyl methacrylate copolymer stabilized with 0.6% macrogol cetostearyl ether and 0.8% sodium lauryl sulfate.

Manufacturing process

Step A- Enteric coated amoxicillin sodium tablets

Amoxicillin sodium, microcrystalline cellulose (Avicel PH 112) and sodium starch glycolate was sifted through suitable sieve and mixed. This blend was mixed with part of sifted magnesium stearate and the blend was passed through roller compactor to form compacts. The compacts were passed through suitable sieve and the granules were mixed with colloidal silicon dioxide and remaining quantity of magnesium stearate and compressed into tablets.

The tablets are first coated with solution of Opadry clear 03K19229 prepared in mixture of Isopropyl alcohol and Methylene chloride and then coated with enteric coating solution of Eudragit L 100-55, Triethyl citrate, talc and titanium dioxide in mixture of acetone and Isopropyl alcohol in conventional coating equipment.

Amoxicillin trihydrate, Amoxicillin sodium, microcrystalline cellulose (Avicel PH 1 12), and Colloidal silicon dioxide was sifted through suitable sieve and mixed. This blend was mixed with half quantity of sifted magnesium stearate and passed through roller compactor to form compacts. The compacts was passed through suitable sieve and mixed with sifted microcrystalline cellulose, Diluted potassium clavulanate, sodium starch glycolate, and colloidal silicon dioxide and lubricated with remaining quantity of sifted magnesium stearate.

Step C- Tablet in Tablet (Compression coating)

Step D- Seal Coating with Opadry clear 03K19229

Step E- Coating with Kollicoat Smart seal 30D

The dissolution tests of enteric coated tablets of Amoxicillin sodium of step A were performed in 900 ml of 0.1N HC1 followed by pH 6.8 phosphate buffer, at 37°C, apparatus USP Type II (Paddle apparatus), 75 rpm. This demonstrated that enteric coating allowed the release of Amoxicillin sodium at alkaline pH. The results are shown in table 3. The dissolution test of compression coated tablets of step C (Tablet in Tablet) coated with opadry clear 03K19229 (Tablet of step D) and coated with aqueous dispersion of Methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersion, triethyl citrate and talc (tablets of step E) were performed in different media i.e. in 900 ml of Deionised Water, pH 4.5 Acetate Buffer, pH 5.5 Acetate buffer and pH 6.8 phosphate buffer, 37°C, USP Type II (Paddle apparatus) at 75 rpm. The results demonstrated that tablets of step D release Amoxicillin and clavulanic acid in water (Table 4) whereas tablets of step E coated with Kollicoat smart seal 30 D do not show the release in water (Table 4), phosphate buffer pH 5.8 to phosphate buffer pH 7.2 (Results now shown). Drug release of Amoxicillin and clavulanic acid in acetate buffers i.e. pH 4.5 and pH 5.5 and in phosphate buffer i.e. pH 6.8 are shown in Table 4. Release of amoxicillin from tablet of step E in 0.1N HC1 (0 - 2hrs) followed by 6.8 phosphate buffer (2 hrs) is shown in table 5.

The formulation of Example no. 2 was subjected to in-vitro dissolution studies and the results obtained are subjected in following tables:

Table 3: Release of Amoxicillin from enteric coated tablets of Amoxicillin sodium in 0.1N HC1 (0 to 2 hours) followed by pH 6.8 Phosphate buffer.

Dissolution media Time Cumulative % Amoxicillin Released

0.1 N HCL 1 hr 0

2 hr 0

Phosphate buffer pH 6.8 15 min 9

30 min 48

45 min 75

60 min 81

90 min 80 Table 4: Release of Amoxicillin and Clavulanic acid tablets of step D in Deionised Water and tablet of step E in Deionised Water, Acetate buffer pH 4.5, Acetate buffer pH 5.5 and Phosphate buffer pH 6.8

5

10

15 Table 5: Release of Amoxicillin from tablets of step E coated tablets in 0.1HC1 (0-2 Hrs) followed by phosphate buffer pH 6.8 (2 Hrs)

Tablets of Step E

Time (Minutes) Cumulative Amoxicillin Released (%)

0 0

15 41

30 69

45 78

60 76

90 73

120 70

135 76

150 82

165 84

180 85

210 85

240 85

Claims

We claim:

1. An extended release pharmaceutical composition comprising :

(c) wherein first and second layer compressed into a tablet and the said tablet is coated with hydrophilic polymer and hydrophobic polymer such a that drug is released from tablet in the gastro intestinal tract (GIT) over an extended period of time.

2. The composition of claim 1, wherein the hydrophilic polymer for coating of first layer is selected from cellulose derivatives such as hydroxypropylmethylcellulose (hypromellose),hydroxypropylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, sodium carboxy methylcellulose, Hydroxyethylmethylcellulose and like.

3. The composition of claim 1, wherein the hydrophobic polymer for coating of first layer is selected from group consisting of cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, hydroxy propyl methyl cellulose phthalate, polyvinylacetatephthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate- methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, methyl methacrylate, diethylaminoethyl methacrylate copolymer,alkyl cellulose derivatives such as ethyl cellulose, crosslinked polymers such as styrene-divinylbenzene copolymer, polysaccharides having hydroxyl groups such as dextran, cellulose derivatives which are treated with bifunctional crosslinking agents such as epichlorohydrin, dichlorohydrin, 1, 2-, 3, 4-diepoxybutane, starch , dextrin and combination thereof.

4. The composition of claim 1, wherein the hydrophilic polymer for coating of tablet is selected from cellulose derivatives such as hydroxypropylmethylcellulose (hypromellose),hydroxypropylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, sodium carboxy methylcellulose, Hydroxyethylmethylcellulose and like.

The composition of claim 1, wherein the hydrophobic polymer for coating of tablet is selected form group consisting of cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, hydroxy propyl methyl cellulose phthalate, poiyvinylacetatephthalate, polyvinylbutyrate acetate,, vinyl acetate-maleic anhydride copolymer, styrene- maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, methyl methacrylate, diethylaminoethyl methacrylate copolymer, alky 1 cellulose derivatives such as ethyl cellulose, crosslinked polymers such as styrene-divinylbenzene copolymer, polysaccharides having hydroxyl groups such as dextran, cellulose derivatives which are treated with bifunctional crosslinking agents such as epichlorohydrin, dichlorohydrin, 1, 2-, 3, 4-diepoxybutane, starch, dextrin and combination thereof.

The composition of claim 1, wherein the composition is in the form of compression coated tablet or bilayer tablet.

A composition of claim 1, wherein composition is prepared by process comprising a step of:

(a) preparing first layer comprising amoxicillin or its pharmaceutical acceptable salt thereof and coating said layer with hydrophilic polymer and hydrophobic polymer;

(b) preparing second layer comprising amoxicillin or its pharmaceutical acceptable salt thereof, clavulanic acid or its pharmaceutical acceptable salt thereof and one or more pharmaceutically acceptable excipients;

(c) compressing first and second layer into a tablet and coating said tablet with hydrophilic polymer and hydrophobic polymer.

A composition of claim 1, wherein the said composition exhibits an in vitro dissolution profile when measured using USP Type II (Paddle apparatus),at 75 rpm in 900 ml , 0.1 N HCL for first two hour followed by media with pH 6.8 buffer at 37°C; whereby said in vitro dissolution profile is characterized by a release of amoxicillin is from about 50 to about 75 % within 30 minutes, from about 65 to about 85 % within 1 hour and not less than 80% of amoxicillin is released after 4 hours.