FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. -
SUSTAINED RELEASE PHARMACEUTICAL COMPOSITION OF FAROPENEM AND PROCESS FOR PREPARATION THEREOF

2. Applicant(s)
(a) NAME:
(b) NATIONALITY:
(c) ADDRESS:

CAD1LA HEALTHCARE LIMITED
INDIAN
SARKHEJ-BAVLA N. H. No. 8A, MORAIYA, Tal. SANAND, Dist.: AHMEDABAD-382 210, GUJARAT. INDIA

The following specification describes the invention:


FIELD OF THE INVENTION
The present invention relates to a sustained release pharmaceutical composition of faropenem and to a process for preparation thereof and to its medical use. In particular, the invention relates to sustained release tablets of faropenem.
BACKGROUND OF THE INVENTION
Penem compounds are non-natural beta-lactam compounds that are designed based on the concept of combining the structures of penicillin and cephalosporin (e.g. see Woodward, R.B., In Recent Advances in the Chemistry of beta-lactam Antibiotics; Elks, J., Ed: The Chemical Society; London, 1977; Spec. No. 28, pp. 167-180, Japanese Patent Public Disclosure (Kokai) Nos. 207387/86, 162694/88, 222486/85 and 119486/79), with the aim of creating a new range of antibiotics which have the broad antibacterial spectrum and high safety of penicillin antibiotics and cephem antibiotics belonging to beta-lactam antibiotics combined with the potent antibacterial activity and high stability to beta-lactamase of carbapenem antibiotics.
The penem compounds are reported to show potent antibacterial activity not only on methicillin-sensitive Staphylococcus aureus (MSSA), Streptococcus pyrogenes and Streptococcus pneumoniae but also on gram-positive bacteria less susceptible to conventional beta-lactam agents such as penicillin-resistant Streptococcus pneumoniae (PRSP), stomatic Streptococcus sp. and Enterococcus sp. by virtue of the novel skeleton called penem ring.
A well-known carbapenem (5R, 6S)-6-[(l R)-1 -hydroxyethyI]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-l-azabicyclo[3.2.0] hept-2-ene-2-carboxylic acid, is also known as faropenem. having following formula:


Faropenem is chemically labile to hydrolysis, oxidation, photoisomerization, etc. The drug is orally available. Faropenem has a half-life of 1 hour. It is poorly bioavailable from GIT. The sodium salt of faropenem is available under the trade name Farom® in the Japan market. The frequency of dosing of this product is thrice daily.
The PCT application WO 99/36048, assigned to Block Drug Co., discloses topical composition of faropenem. It discloses the composition which comprises a non-aqueous base blended with faropenem or a pharmaceutically acceptable salt thereof.
The U.S. patent no. 5,354,748, assigned to Suntory Ltd., discloses oral antibacterial compositions of penem or carbapenem antibiotics with improved gastrointestinal absorption and also to a method for the improvement of gastrointestinal absorption of penems. More specifically, it discloses compositions and method of making use of a substance such as an inhibitor for the dipeptidase localized on/in epithelial cells of the small intestine.
The European application EP 1561459 Al, assigned to Daiichi Suntory Pharma Co Ltd, discloses a hard capsule stably comprising faropenem deloxate.
Highly fluctuating blood concentrations of drug such as faropenem may produce unwanted side effects in the patient if the drug level is too high, or may fail to exert the proper therapeutic effect if the drug level is too low. Sustained release drug products offer several important advantages over immediate-release dosage forms of the same drug. Sustained release allows for sustained therapeutic blood

levels of the drug; sustained blood levels provide for a prolonged and consistent clinical response in the patient. Moreover, if the drug input rate is constant the blood levels should not fluctuate between a maximum and minimum, as in a multiple-dose regimen with an immediate-release drug product. Another advantage of sustained release is patient convenience, which leads to better patient compliance. The present invention provides a sustained release pharmaceutical composition comprising faropenem.
SUMMARY OF THE INVENTION
In one aspect, the invention provides an oral sustained release composition
comprising:
(i) faropenem,
(ii) a sustained release polymer; and
(iii) one or more pharmaceutically acceptable excipients.
In another aspect, the invention provides a process for preparing an oral sustained release pharmaceutical composition, wherein the process comprises the steps of:
(i) mixing faropenem, a sustained release polymer and one or more pharmaceutically acceptable excipients;
(ii) granulating the mixture to form granules;
(iii) drying the granules;
(iv) lubricating the granules; and
(v) compressing the lubricated granules into a tablet.
DETAILED DESCRIPTION OF THE INVENTION
The term "sustained release" as used herein means release, which is not immediate release and is taken to encompass release of drug from the dosage form for about 12 hours.
The term "faropenem" as used herein means faropenem drug can be present in the form of a free acid or in the form of pharmaceutically acceptable salts. Further, it

may be present either in the form of one substantially optically pure enantiomer or as a mixture of enantiomers or polymorphs thereof Faropenem may be used in an amount of 10-70% by weight of the total composition.
The term "sustained release polymer" as used herein includes hydrophilic polymer, hydrophobic polymer or mixtures thereof. The hydrophilic polymer may be selected from methyl cellulose, polyethylene oxide, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxy methylcellulose, sodium carboxym ethyl cellulose or a hydrophilic methacrylic acid derivative. The hydrophobic polymer may be selected from ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, a hydrophobic polyacrylamide derivative or a hydrophobic methacrylic acid derivative. The polymer may be used either alone or in combination with other polymers. The preferred polymer used in the invention is hydroxypropyl methylcellulose. The sustained release polymer may be used in an amount of 10-70%, preferably 10-40%, most preferably 10-25% by weight of the total composition.
The pharmaceutical compositions as described herein may comprise of one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, binder, stabilizer, lubricant, glidant, plasticizer. anti-tacking agent, opacifying agent, and the like.
Diluent may be selected from microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol or erythritol; and mixtures thereof. Diluent may be added to increase the bulk volume of the powder to facilitate granulation or compression.

Disintegrant may be selected from croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and mixtures thereof. The disintegrant may be present in an amount ranging from 1 % to 10 % by weight of the composition.
Binder may be selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methyl cellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the like. The binder may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
Stabilizer may be used in the composition to obtain stable final product and also to increase gastrointestinal absorption. a,o>diamineacetate compounds are linear hydrocarbons having an aminoacetate group at each end, which may be used as a stabilizer in the present invention. Examples of a,co-diamineacetate compounds include polyaminocarboxylic acid chelating agents such as ethylenediamjnetetraacetic acid, hydr oxy ethyl ethyl en edi am in etri acetic acid, dihydroxyethylethylenediaminediacetic acid, 1,3-propanediaminetetraacetic acid, diethylenetriaminepentaacetic acid, triethylenetetraminehexaacetic acid and salts thereof. Especially, ethylenediaminetetraacetic acid and salts thereof may be preferably used in respect of safety, specifically calcium ethylenediaminetetraacetate, disodium calcium ethylenedi amine tetraacetate, sodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate tetrahydrate. Preferably, disodium ethylenediaminetetraacetate (Disodium EDTA) may be used as a stabilizer in an amount of 0.01-5 %, preferably 1-3% by weight of the total composition.

Lubricant, glidant or anti-tacking agent may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid,.hydrogenated vegetable oil, glyceryl paimitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, kaolin; and mixtures thereof. It would be appreciated that a person skilled in the art is cognizant of the fact that lubricant, glidant or anti-tacking agent may be used interchangeably. The lubricant, glidant or anti-tacking agent may be present in an amount ranging from 0.1 % to 20 % by weight of the composition.
The pharmaceutical compositions as described herein may be prepared by processes known to the person having ordinary skill in the art of pharmaceutical technology such as direct compression, wet granulation, dry granulation or melt granulation. For example, the sustained release tablets may be prepared by mixing faropenem, a sustained release polymer and one or more pharmaceutically acceptable excipients; lubricating the mixture and compressing the lubricated mixture into tablets. Similarly, the sustained release tablets may also be prepared by mixing faropenem, a sustained release polymer and one or more pharmaceutically acceptable excipients; wetting with water or organic solvent and mixing in a high shear granulator to form a homogeneous wet mass; drying and lubricating the granules; and compressing the granules into tablets. Similarly, the sustained release tablets may also be prepared by mixing faropenem, a sustained release polymer and one or more pharmaceutically acceptable excipients; compressing into large slugs or roller compacted into ribbon like strands; milling to produce free flowing powder; and compressing into tablets. In any of the granulation techniques, faropenem may be added intragranularly or extragranularly or both. Moreover, the pharmaceutical composition as described herein may be in the form of bilayer tablet having at least one layer containing faropenem formulated for immediate release and at least one layer containing faropenem formulated for sustained release. Both layers may be prepared by any

technique known to the person having ordinary skill in the art of pharmaceutical technology.
The pharmaceutical composition may be coated using suitable coating techniques
known in the art which do not affect the dissolution properties of the final
formulation. The film coat may comprise film-forming polymer such as
hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium
carboxym ethyl cellulose, polyvinyl pyrrolidone, and the like; a plasticizer such as glyceryltriacetate, dibutyl sebacate, diethylphthalate, polyethylene glycol, propylene glycol, glycerol, castor oil, copolymers of propylene oxide and ethylene oxide, and the like; an opacifying agent such as titanium dioxide, iron oxides, and the like.
The dosage form according to the present invention may be in the form of a tablet, a capsule, granules, powder or a sachet. The tablet may be a monolayer or bilayer tablet.
In one embodiment of the present invention, a sustained release tablet may be prepared by mixing faropenem, microcrystalline cellulose, hydroxypropyl methylcellulose and disodium EDTA; granulating with a binder solution containing hydroxypropyl cellulose; lubricating the dried granules with colloidal silicon dioxide and magnesium stearate; and compressing into tablets.
In another embodiment, a sustained release tablet may be prepared by mixing faropenem, a sustained release polymer and one or more pharmaceutically acceptable excipients; lubricating the mixture and compressing the lubricated mixture into tablets.
In another embodiment, a sustained release tablet may be prepared by mixing faropenem, microcrystalline cellulose, hydroxypropyl methylcellulose and disodium EDTA; compressing into large slugs or roller compacted into ribbon

like strands; milling the slugs to produce free flowing powder; and compressing into tablets.
In yet another embodiment, a sustained release tablet comprises faropenem in an amount of30-60% by weight of composition; disodium EDTA in an amount of 1-3% by weight of composition; microcrystalline cellulose in an amount of 20-40% by weight of composition and hydroxypropyl methylcellulose in an amount of 10-25% by weight of composition.
In yet another embodiment, the tablets prepared in accordance with example 1 were subjected to a dissolution test in 900 ml of purified water, USP type II apparatus (Paddle), 50 rpm (Table 1).
The pharmaceutical compositions as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:

EXAMPLE 1

Sr.
No. Ingredients Quantity
(mg/tab)
I Faropenem sodium eq. to Faropenem 320.95
2 Disodium EDTA 14.00
3 Microcrystalline cellulose 216.05
4 Hydroxypropyl methylcellulose (HPMCK100M) 100.00
5 Hydroxypropylcellulose 14.00
6 Isopropyl alcohol q.s.
7 Low-substituted Hydroxypropylcellulose 10.50
8 Colloidal silicon dioxide 14.00
9 Magnesium stearate 10.50
Process:
1. Faropenem, microcrystalline cellulose, disodium EDTA and hydroxypropyl methylcellulose were sifted using suitable sieve.
2. The material of step no. 1 was blended in suitable mixer.
3. Hydroxypropyl cellulose was dissolved in isopropyl alcohol to make a binder solution.
4. Blended material of step no. 2 was granulated with solution of step no. 3 in suitable granulator.
5. Granulated wet mass of step no. 4 was then dried.
6. Low-substituted hydroxypropylcellulose, colloidal silicon dioxide and magnesium stearate were added to the dried granules.
7. The lubricated mass was compressed into tablets by using proper tooling apparatus.
8. The tablets were optionally film-coated.

Table 1: Dissolution profile of tablets of Example 1

Time (hr) % drug dissolved
0 0.0
1 28.9
2 44.4
4 66.5
6 79.8
8 90.7
12 98.1
fPissolution parameters: Medium: Purified water; Volume: 900 mL; Apparatus: USP type II dissolution apparatus (paddle); RPM: 50]
EXAMPLE 2

Sr.
No. Ingredients Quantity
(mg/tab)
1 Faropenem sodium eq. to Faropenem 320.92
2 Disodium EDTA 123.08
3 Microcrystalline cellulose 16.00
4 Hydroxypropyl methylcellulose (HPMCK 100 M) 320.00
5 Colloidal silicon dioxide 8.00
6 Magnesium stearate 12.00
Process:
1. Faropenem, microcrystalline cellulose. disodium EDTA and hydroxypropyl methylcellulose were sifted using suitable sieves and mixed together.

2. The mixture was lubricated with colloidal silicon dioxide and magnesium stearate.
3. The lubricated mixture was compressed into tablets by using proper tooling apparatus.


Process:
Sustained Release Layer
1. Faropenem, microcrystalline cellulose, disodium EDTA and hydroxypropyl methylcellulose were mixed.
2. The mixture of step 1 was granulated by using binder solution having ethylcellulose and polyvinylpyrrolidone in a solvent mixture of isopropyl alcohol and dichloromethane.
3. The granules of step 2 were dried and lubricated with colloidal silicon dioxide and magnesium stearate.
Immediate Release Layer
1. Faropenem, microcrystalline cellulose and disodium EDTA were sifted using suitable sieves and mixed together.
2. A cited quantity of low-substituted hydroxypropylcellulose was added .to the mixture of step 1.
3. The mixture of step 2 was lubricated with magnesium stearate.
Compression of Tablets
1. The material for sustained release layer and immediate release layer were compressed to obtain bilayered tablets.


Dated this 1st day of June 2009.
To
The Controller of Patents
The Patent Office
At Mumbai.