FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITIONS OF BENZOQUINOLIZINE-2-CARBOXYLIC ACID OR PHARMACEUTICALLY ACCEPTABLE SALTS, ESTERS OR PRODUCTS THEREOF
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 pharmaceutical composition, wherein the composition comprises of more than 40% of 8-{4-[2(S)-Amino-propionyloxy] piperidine-1-yl}-9-fluoro-5 (S)-methyl-6, 7-dihydro-1-oxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid or pharmaceutically acceptable salts, esters or products thereof in a unit dosage form along with other pharmaceutically acceptable excipients.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. Description
The present invention provides a pharmaceutical composition, wherein the
composition comprises of more than 40% of 8-{4-[2(S)-Amino-propionyloxy]
piperidine-1-yl}-9-fluoro-5 (S)-methyl-6, 7-dihydro-1-oxo-1H, 5H-
benzo[I;j]quinolizine-2-carboxylic acid (hereafter referred as Compound of
formula I) or pharmaceutically acceptable salts, esters or products thereof in a unit dosage form along with other pharmaceutically acceptable excipients.
The compound of formula I can be used to treat bacterial Gram-positive, Gram-negative and anaerobic infections; especially infections caused by resistant Gram-positive organism and Gram-negative organism, mycobacterial infections and emerging nosocomial pathogen infections. Its structural formula is:

Formula I
US 6,514,986 describes the substantially amorphous and substantially crystalline form of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1 -yl)-5-methyl-1 -oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt.
US 6,664,267, describes a crystalline monohydrate form of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1 H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt.
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One of the aspects of the present invention provides a pharmaceutical composition, wherein the composition comprises of more than 40% of compound of formula I or pharmaceutically acceptable salts, esters or products thereof in a unit dosage form along with other pharmaceutically acceptable excipients.
Pharmaceutically acceptable salts refer to inorganic acid addition salts and organic acid addition salts.
Further inorganic and organic acid addition salts include but not limited to hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, lactate, mesylate, besylate, succinate, oxalate, maleate.

A pharmaceutical composition, wherein composition comprises of more than
40% of compound of formula I or pharmaceutically acceptable salts, esters or products thereof wherein compound of formula I is present as mesylate salt.
A pharmaceutical composition, wherein composition comprises of more than 40% of compound of formula I or pharmaceutically acceptable salts, esters or products thereof wherein compound of formula I is present as hydrochloride salt.
By providing high loading of the compound of formula I, the overall size of the finished dosage form can be reduced.
Compound of formula 1 or pharmaceutically acceptable salts, esters or products thereof can be present from 200-1500 mg.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include binders, fillers, lubricants, disintegrants, and glidants.
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Suitable binder may be selected from a group comprising one or more of, povidone, starch, stearic acid, gums, celluloses and the like.
Suitable filler may be selected from a group comprising one or more of, microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable lubricants may be selected from a group comprising one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate and the like.
Suitable glidants may be one or more of colloidal silicon dioxide, talc or cornstarch and the like.
Suitable disintegrant may be one or more of starch, croscarmellose sodium, crosspovidone, sodium starch glycolate and the like.
In another aspect of the invention, there is provided a process for preparing pharmaceutical composition wherein process comprises of granulating compound of formula I or pharmaceutically acceptable salts, esters or products thereof along with lactose, croscarmellose sodium using povidone solution, drying the granules, mixing the dried granules with other ingredients and compressing the final blend.
In yet another aspect of the invention, there is provided a solid oral dosage formulation comprising compound of formula I or pharmaceutically acceptable salts, esters or products thereof, and a pharmaceutically acceptable excipient; and wherein the formulation exhibits a dissolution profile such that within 30 minutes, more than 80% of the compound of formula I or a pharmaceutically acceptable salts, esters or products thereof is released, wherein the release rate
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is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 900 ml of 0.1NHCI at 37 degree C.
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 compound of formula I tablets (200, 400 and 600mg).

S.No Ingredients Quantity/tablet (%w/w)
INTRAGRANULAR
1. Compound of formula I or pharmaceutical^ acceptable salts, esters or products thereof 40-95
2. Lactose 0-30
3. Croscarmellose sodium 5-10
4. Povidone 1-5
EXTRAGRANULAR
5. Talc 1-5
6. Croscarmellose sodium 5-10
7. Microcrystalline cellulose 0-30
8. Sodium stearyl fumarate 0-5
9. Opadry coating 1-5
Procedure: Compound of formula I or pharmaceutically acceptable salts, esters or products thereof, lactose and croscarmellose sodium are sifted and
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dry mixed in rapid mixer granulator. Above mass is granulated by spraying aqueous solution of povidone. Granules are dried in fluidized bed drier, sifted and oversize granules are milled in Quadro mill. Resultant granules are mixed with talc, croscarmellose sodium, microcrystalline cellulose and sodium stearyl fumarate in double cone blender. Lubricated granules are compressed into tablets using suitable tooling. Tablets are coated with aqueous dispersion of opadry.
Table 2 -Dissolution data of the tablets prepared as per the present invention

Time (min) % drug dissolved
Example 1 Tablets (200mg) Example 1 Tablets (400mg) Example 1 Tablets (600mg)
5 39 34 20
10 79 75 58
15 92 92 90
20 95 95 96
30 97 96 99
45 97 97 100
60 97 97 100
Table 2 provides the dissolution data for the compound of formula I or pharmaceutically acceptable salts, esters or products thereof tablets prepared as per the formula given in Table 1. For determination of drug release rate, USP Type 2 Apparatus (rpm 50) was used wherein 0.1N hydrochloric acid (900 ml) was used as a medium.
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WE CLAIM:
1. A pharmaceutical composition, wherein the composition comprises of more than 40% of Compound of formula I or pharmaceutically acceptable salts, esters or products thereof in a unit dosage form along with other pharmaceutically acceptable excipients.
2. A pharmaceutical composition according to claim 1, wherein compound of formula I is present as mesylate salt.
3. A pharmaceutical composition according to claim 1, wherein compound of formula I is present as hydrochloride salt.
4. A pharmaceutical composition according to claim 1, wherein compound of formula I is present from 200-1500 mg.
5. A pharmaceutical composition according to claim 1, wherein pharmaceutically acceptable excipients are binders, fillers, lubricants, disintegrants, glidants.
6. A process for preparing pharmaceutical composition wherein process comprises of granulating compound of formula I or pharmaceutically acceptable salts, esters or products thereof along with lactose, croscarmellose sodium using povidone solution, drying the granules, mixing the dried granules with other ingredients and compressing the final blend.
7. A solid oral dosage formulation comprising compound of formula I or pharmaceutically acceptable salts, esters or products thereof, and a pharmaceutically acceptable excipient; and wherein the formulation exhibits a dissolution profile such that within 30 minutes, more than 80% of the compound of formula I or a pharmaceutically acceptable salts, esters or products thereof is released, wherein the release rate is
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measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 900 ml of 0.1NHCIat37degreeC.

Dated this 30th day of October, 2006 For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory
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