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 :
PHARMACEUTICAL COMPOSITION OF S-(-)-9-FLUORO-6,7-DIHYDRO-8-(4-HYDROXYPIPERIDIN-l-YL)-5-METHYL-l-OXO-lH,5H-BENZO[i,j]QUINOLIZINE -2-CARBOXYLIC ACID ARGININE SALT
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D-4, MIDC, Chikalthana,
Aurangabad (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The invention relates to pharmaceutical compositions as a solid dosage form comprising 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 arginine salt or hydrates polymorphs thereof, as a therapeutically active ingredient, and to a method for manufacturing thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The invention relates to pharmaceutical compositions as a solid dosage form comprising 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 arginine salt (hereafter referred as Compound of Formula I) or hydrates polymorphs thereof, as a therapeutically active ingredient, and to a method for manufacturing thereof.
O

US patent 7,247,642 discloses compound of Formula I for the treatment of 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.
US 6,514,986 describes the substantially amorphous and substantially crystalline form of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,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.
US 7,164,023, describes crystalline tetrahydrate polymorph of S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1 -yl)-5-methyl-1 -oxo-1 H,5H-benzo[i j ]quinolizine-2-carb oxylic acid L-arginine salt.

The invention relates to pharmaceutical compositions as a solid dosage form comprising Compound of Formula I or hydrates polymorphs thereof, as a therapeutically active ingredient, and to a method for manufacturing thereof.
O O

One of the aspects of the invention provides a pharmaceutical composition, wherein the composition comprises of more than 50% of compound of Formula I or hydrates polymorphs thereof in a unit dosage form along with other pharmaceutically acceptable excipients.
By providing high loading of the compound of Formula I, the overall size of the finished dosage form can be reduced. The pharmaceutical composition of the invention may comprise compound of Formula 1 or hydrates polymorphs 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.
Suitable binder may be selected from a group comprising one or more of, povidone, starch, stearic acid, sodium lauryl sulphate, L-arginine, 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, 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, silicified microcrystalline cellulose, 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 process for the preparation of pharmaceutical composition wherein the process comprises of;
i) mixing compound of Formula I or hydrates polymorphs thereof, and an excipient,
diluent or carrier, or mixture thereof, optionally in the presence of a wetting agent;
ii) subjecting the resulting mixture to formation of a granulate, optionally in the
presence of a wetting agent, suitable for compression into said solid dosage form;
iii) optionally, performing said mixing and/or formation of a granulate in the presence
of at least one additive selected from a disintegrating agent, lubricant, binder and a
mixture thereof;
iv) optionally, drying said granulate;
v) compressing said granulate into said solid dosage form, wherein said solid dosage
form is a tablet;
vi) optionally, coating the compresses tablets with aqueous dispersion of opadry.
The invention relates to a process for the preparation of pharmaceutical composition wherein process comprises of mixing compound of Formula I or hydrates polymorphs thereof along with microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, talc and blending it with magnesium stearate and compressing the final blend.
The invention further relates to a process for the preparation of a pharmaceutical composition comprising of granulating compound of Formula I or hydrates polymorphs thereof along with pre-gelatinized maize starch, croscarmellose sodium using aqueous alcoholic solution of sodium lauryl sulphate, drying the granules, mixing the dried

granules with croscarmellose sodium, silicified microcrystalline cellulose, colloidal silicon dioxide, talc and magnesium stearate and compressing the final blend.
Furthermore the invention relates to a process for the preparation of pharmaceutical composition wherein the process comprises of granulating compound of Formula I or hydrates polymorphs thereof along with pre-gelatinized maize starch, croscarmellose sodium using aqueous solution of L-arginine, drying the granules, mixing the dried granules with croscarmellose sodium, silicified microcrystalline cellulose, colloidal silicon dioxide, talc and magnesium stearate and compressing the final blend. The compresses tablets are coated with 10-15 % aqueous dispersion of opadry. The pharmaceutical composition of the invention comprises opadry used for coating in the range of 1 to 5 percent by weight of the pharmaceutical composition.
In yet another aspect of the invention, there is provided a solid oral dosage Formulation comprising Compound of Formula I or hydrates polymorphs thereof, and a pharmaceutically acceptable excipient; and wherein the Formulation exhibits a dissolution profile such that within 45 minutes, more than 70% of the compound of Formula I or hydrates polymorphs thereof is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 900 ml of 0.1 N HC1 at 37 °C.
The pharmaceutical composition of solid oral dosage Formulation is adapted for administration by a route selected from the group consisting of oromucosal, buccal and sublingual administration.
The pharmaceutical composition of invention can be used for the treatment and/or prevention of systemic or topical bacterial infection, comprising administering an pharmaceutical composition of the invention in a human or non-human animal.

While the 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 invention.
EXAMPLES
The following examples are provided for the purpose of illustrating the invention but are
not to be construed as limiting.
EXAMPLE 1
Table 1: Composition of the tablets.

SN Ingredients Quantity/Tablet (mg)
1 Compound of Formula I or hydrates or polymorphs thereof 667.33
2 Microcrystalline cellulose 100.0
3 Sodium starch glycolate 42.0
4 Colloidal silicon dioxide 3.0
5 Talc 8.0
6 Magnesium stearate 5.0
Procedure: Compound of Formula I or hydrates polymorphs thereof, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and talc are sifted and dry mixed in rapid mixer granulator. Above blend is mixed magnesium stearate in double cone blender and the final blend is compressed into tablets using suitable tooling.
Table 2: Dissolution of tablet of Example 1

Time [min] % Dissolved
15 44
30 52

45 72
60 87
Table 2 provides the dissolution data for the compound of Formula I or hydrates or polymorphs 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.
EXAMPLE 2
Table 3: Composition of the tablets.

SN Ingredients Quantity/Tablet (mg)
Intragranular
1 Compound of Formula I or hydrates polymorphs thereof 667.34
2 Croscarmellose sodium 30.0
3 Pre-gelatinized maize starch 20.0
4 Sodium Lauryl Sulphate 10.0
5 Purified Water q.s.
6 Isopropyl alcohol q.s.
Extragranular
7 Croscarmellose sodium 60.0
8 Silicified microcrystalline cellulose 52.0
9 Colloidal silicon dioxide 10.0
10 Talc 9.0
11 Magnesium stearate 5.0
Procedure: Compound of Formula I or hydrates polymorphs thereof, croscarmellose sodium and pre-gelatinized maize starch (Starch 1500) are sifted and dry mixed in rapid mixer granulator. Above mass is granulated by spraying aqueous alcoholic solution of sodium lauryl sulphate. Granules are dried in fluidized bed drier, sifted and oversize

granules are milled in Quadro mill. Resultant granules are mixed with croscarmellose sodium, silicified microcrystalline cellulose, colloidal silicon dioxide, talc and magnesium stearate in double cone blender. Lubricated granules are compressed into tablets using suitable tooling.
EXAMPLE 3
Table 4: Composition of the tablets.

SN Ingredients Quantity/Tablet (mg)
Intragranular
1 Compound of Formula I or hydrates polymorphs thereof 666.53
2 Croscarmellose sodium 30.0
3 Pre-gelatinized maize starch 15.0
4 L-Arginine 55.0
5 Purified Water q.s.
Extragranular
6 Croscarmellose sodium 50.0
7 Silicified microcrystalline cellulose 53.5
8 Colloidal silicon dioxide 5.0
9 Talc 15.0
10 Magnesium stearate 10.0
11 Opadry coating 20.0
Procedure: Compound of Formula I or hydrates polymorphs thereof, croscarmellose sodium and pre-gelatinized maize starch (Starch 1500) are sifted and dry mixed in rapid mixer granulator. Above mass is granulated by spraying aqueous solution of L- Arginine. Granules are dried in fluidized bed drier, sifted and oversize granules are milled in Quadro mill. Resultant granules are mixed with croscarmellose sodium, silicified microcrystalline cellulose, colloidal silicon dioxide, talc and magnesium stearate in

double cone blender. Lubricated granules are compressed into tablets using suitable tooling. Tablets are coated with aqueous dispersion of opadry.
Table 5: Dissolution of Compound of Formula I Tablets

Time [min) % Dissolved
15 53
30 83
45 95
60 100
Table 5 provides the dissolution data for the compound of Formula I or hydrates polymorphs thereof, tablets prepared as per the Formula given in Table 4. 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.

We Claim
1. A pharmaceutical composition, wherein the composition comprises of more than 50% of Compound of Formula I or hydrates or polymorphs thereof in a unit dosage form along with other pharmaceutically acceptable excipients, diluent or carrier, or mixture thereof.
2. A pharmaceutical composition according to claim 1, comprising of mixing compound of Formula I or hydrates polymorphs thereof along with microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, talc and blending it with magnesium stearate and compressing the final blend.

3. A pharmaceutical composition according to claim 1, comprising of granulating compound of Formula I or hydrates polymorphs thereof along with pre-gelatinized maize starch, croscarmellose sodium using aqueous alcoholic solution of sodium lauryl sulphate, drying the granules, mixing the dried granules with croscarmellose sodium, silicified microcrystalline cellulose, colloidal silicon dioxide, talc and magnesium stearate and compressing the final blend.
4. A pharmaceutical composition according to claim 1, comprising of granulating compound of Formula I or hydrates polymorphs thereof along with pre-gelatinized maize starch, croscarmellose sodium using aqueous solution of L-arginine, drying the granules, mixing the dried granules with croscarmellose sodium, silicified microcrystalline cellulose, colloidal silicon dioxide, talc and magnesium stearate, compressing the final blend into tablets and coating the tablets with aqueous dispersion of opadry.

5. The pharmaceutical composition according to claim 1, wherein the total combined amount of said excipient, diluent and carrier is from 10 to 50 percent by weight of the pharmaceutical composition.
6. A process for the preparation of a pharmaceutical composition according to claim 1, comprising of:

i) mixing compound of Formula I or hydrates polymorphs thereof, and an excipient,
diluent or carrier, or mixture thereof, optionally in the presence of a wetting agent;
ii) subjecting the resulting mixture to formation of a granulate, optionally in the
presence of a wetting agent, suitable for compression into said solid dosage form;
iii) optionally performing said mixing and/or formation of a granulate in the presence
of at least one additive selected from a disintegrating agent, lubricant, binder and a
mixture thereof;
iv) optionally drying said granulate;
v) compressing said granulate into said solid dosage form, wherein said solid dosage
form is a tablet.
vi) optionally coating the tablet using aqueous dispersion of opadry.
7. The pharmaceutical composition according to claim 6, wherein said wetting agent is selected from water and a mixture of water and an alcohol.
8. A solid oral dosage Formulation comprising compound of Formula I or hydrates polymorphs thereof, and a pharmaceutically acceptable excipient; and wherein the Formulation exhibits a dissolution profile such that within 45 minutes, more than 70% of the compound of Formula I or hydrates polymorphs thereof is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 900 ml of 0.1N HCl at 37 °C.
9. The pharmaceutical composition according to claim 1, wherein said solid oral dosage Formulation is adapted for administration by a route selected from the group consisting of oromucosal, buccal and sublingual administration.
10. The use of a pharmaceutical composition of claim 1 for the treatment and/or
prevention of systemic or topical bacterial infection; comprising administering
pharmaceutical composition according to claim 1, in a human or non-human animal


Abstract
The invention relates to pharmaceutical compositions as a solid dosage form comprising 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 arginine salt or hydrates polymorphs thereof, as a therapeutically active ingredient together with a pharmaceutically acceptable excipient, diluent or carrier, or mixture, and to a method for manufacturing thereof.