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 GATIFLOXACIN
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 immediate release formulations comprising an intra-granular and an extra-granular phase wherein the intra-granular phase comprises of gatifloxacin or salt, solvate or hydrate thereof without any pharmaceutically acceptable excipient.
The following specification particularly describes the invention and the manner
in which it is to be performed.
4. DESCRIPTION
The present invention provides immediate release formulations comprising an intra-granular and an extra-granular phase wherein the intra-granular phase comprises of gatifloxacin or salt, solvate or hydrate thereof without any pharmaceutically acceptable excipient.
Gatifloxacin is a synthetic broad-spectrum 8-methoxyfluoroquinolone antibacterial agent for oral or intravenous administration. Chemically, gatifloxacin is (±)-1 -cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1 -piperazinyl)-4-oxo-3-quinolinecarboxylic acid of Formula 1. Gatifloxacin is indicated for the
1

treatment of infections due to susceptible strains of the designated microorganisms listed below:
Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Staphylococcus aureus, Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Neisseria gonorrhoeae.
0 F^ ^^ JK /COOH

CH3
FORMULA I
US Patent No 4,980,470 (the '470 Patent) provide process for preparation of gatifloxacin and pharmaceutical compositions thereof.
US Patent No 5,880,283 (the 283 Patent) provides a process for preparation and pharmaceutical compositions of gatifloxacin sesquihydrate.
US Patent No 6,413,969 provides method of preparation of crystalline gatifloxacin pentahydrate and a pharmaceutical composition in the form of powder for oral administration.
US Patent application 2005-0031683 provides a direct compression process for making tablets of 8-alkoxyquinolonecarboxylic acid wherein the drug is mixed with polyethylene glycol; the blend is compressed in to a tablet dosage form after mixing with suitable excipients such as at least one of a diluent, a disintegrant, a glidant, or a lubricant.
2

US Patent No. 6,291,462 provide multiphase tablets that has the inner phase (Intra-granular phase) comprising gatifloxacin or pharmaceutically acceptable salts or hydrates thereof and auxiliary substances from the group of binders, fillers, disintegration aids, and at least one outer phase (Extra-granular phase) containing at least one disintegrating agent and at least one lubricant.
PCT Patent Application WO 2005/021000 provides solid oral dosage forms of gatifloxacin having an intra-granular phase that includes gatifloxacin and one or more of a filler, a binder, a wicking agent, and a disintegration aid and an extra-granular phase which is free of any disintegration aid.
The present inventors noticed that the Gatifloxacin compositions, when prepared by using aqueous granulation, are not stable and during course of time tend to get converted into other higher hydrated forms of gatifloxacin, which results in varying release profile and disintegration pattern of the composition.
For preparation of solid oral dosage form such as tablet dosage forms, direct compression method is the easiest method, but many active ingredients do not possess all of the properties such as compressibility and flow characteristics, which are required for direct compression. Moreover, many active ingredients show problems such as adhering to punches and/or dies during tableting. The tableting of certain active ingredients therefore becomes difficult due to their inherent properties or characteristics. It is therefore desired to develop formulations by using granulation method comprising excipients, which will eliminate the problems like sticking, picking, poor flow and compressibility, making tableting possible.
While working on the development of oral dosage form of gatifloxacin or salt thereof present inventors have embarked upon a simple technique, which eliminates the need of addition of any excipient other than a drug substance to
3

the intra-granular phase. This was achieved by granulating gatifloxacin or salt thereof with non-aqueous solvent to make intra-granular phase. To this was added, extra-granularly, suitable pharmaceutically acceptable excipients to provide the final composition, which can be suitably compressed to make tablets or filled in to the empty capsule shells or sachets. The developed process is simpler and industrially applicable as it reduces the number of unit operations and provides a product having desirable pharmacokinetic properties while retaining the same hydrated form of gatifloxacin or salt thereof.
In one of the aspects of the present invention there is provided a pharmaceutical composition comprising an intra-granular and an extra-granular phase wherein the intra-granular phase comprises of gatifloxacin or salt, solvate or hydrate thereof without any pharmaceutically acceptable excipient and the extra-granular phase comprises of at least one pharmaceutically acceptable ingredient selected from diluent, filler, disintegrant, lubricant or binder.
In another aspects of the present invention there is provided a pharmaceutical composition which comprises intra-granular phase and extra-granular phase, wherein the intra-granular phase comprises of granules of gatifloxacin or salt thereof prepared by non-aqueous granulation and extra-granular phase comprising of at least one pharmaceutically acceptable excipient.
In yet another aspect of the present invention there is provided an immediate release formulation which comprises intragranular phase, containing gatifloxacin or salt, solvate or hydrate thereof, which is granulated by using non aqueous solvent without addition of any pharmaceutically acceptable excipient and extra-granular phase comprising of at least one pharmaceutically acceptable excipients.
The pharmaceutical composition of the present invention can be a solid oral dosage form such as tablets, capsules or pellets.
4

Gatifloxacin or salt, hydrate thereof is first granulated using non-aqueous solvent. The so obtained granules are mixed with at least one of extra-granular filler, diluent, lubricant, disintegrant or colorant. The so obtained blend can be compressed using suitable tooling to make tablet dosage form. Additionally, the blend obtained can be sized to desired particle range and filled in to the empty capsule shells.
The non- aqueous solvents can be selected from the group comprising of chlorinated hydrocarbon such as chloroform, methylene chloride; acetone or alcohol such as methanol, ethanol or isopropanol.
Pharmaceutically acceptable excipients can be diluent, filler, disintegrant, lubricant, coloring or flavoring or film forming agents and the like. The disintegrant may be one or more of crosscarmellose sodium, sodium starch glycollate, and crosspovidone. The lubricants may be one or more of talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate. Suitable coloring or flavoring agents include those approved for use by the United States Food and Drug Administration (FDA) and are well known to those skilled in the art. The film forming agents can be selected from the group of suitable cellulose ethers include one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers.
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.
5

Examples
The composition of the batches is provided in Table 1 and drug release profile of the tablets prepared as per the present invention in comparison to the Tequin® tablets in 0.1 N HCI is provided in Table 2.
Table 1:

Ingredient Example 1 Example 2
Mg/tab Mg/tab
Gatifloxacin 200.00 400.00
Isopropyl alcohol q.s q.s.
Microcrystalline cellulose 48.00 96.00
Mannitol 21.00 42.00
Crosscarmellose sodium 10.00 20.00
Magnesium Stearate 1.50 3.00
Total weight 292.50 585.0
OpadryY-1-7000 q.s. q.s.
Total Weight 300.00 mg 600.00 mg
Table 2: Drug Release Profile

Time [min] % Drug released Example 1 % Drug released Example 2 % Drug released Tequin® Tablets
0 0 0 0
5 82 87 96
10 97 97 100
20 98 102 101
30 99 103 102
6

Gatifloxacin was sifted and granulated with required quantity of non-aqueous solvent; the wet granules were passed through suitable mesh and dried. The dry granules were passed through ASTM # 20 mesh to form an intra-granular phase. Microcrystalline cellulose, mannitol, along with crosscarmellose sodium were sifted through ASTM # 40 mesh and mixed with intragranular phase. The resulting blend was lubricated with pre sifted (through ASTM # 60 mesh) magnesium stearate. The lubricated blend was subjected either for filling in empty capsule shell or for compression as tablets using suitable tooling. The tablet was then coated with aqueous dispersion of Opadry Y-1-7000.
7

WE CLAIM:
1. A pharmaceutical composition comprising an intra-granular and an extra-granular phase wherein the intra-granular phase comprises of gatifloxacin or salt, solvate or hydrate thereof without any pharmaceutically acceptable excipient and the extra-granular phase comprises of at least one pharmaceutically acceptable excipient.
2. A pharmaceutical composition which comprises intra-granular phase and extra-granular phase, wherein the intra-granular phase comprises of granules of gatifloxacin or salt thereof prepared by non-aqueous granulation and extra-granular phase comprising of at least one pharmaceutically acceptable excipient.
3. An immediate release formulation which comprises intra-granular phase, comprising gatifloxacin or salt, solvate or hydrate thereof, which is granulated by using non aqueous solvent without addition of any other pharmaceutically acceptable excipient and extra-granular phase comprising of at least one pharmaceutically acceptable excipient.
4. A pharmaceutical composition of claims 1 to 3 wherein the pharmaceutically acceptable excipient is selected from group comprising diluent, filler, disintegrant, lubricant, colorant, flavorant or binder.

5. A pharmaceutical composition of claims 1 to 4 wherein the intra-granular phase comprises of gatifloxacin hemihydrate.
6. A pharmaceutical composition of claims 1 to 4 wherein the intra-granular phase comprises of gatifloxacin pentahydrate.
8

7. A pharmaceutical composition of claim 2 and 3 wherein the non-aqueous granulation solvent is selected from chlorinated hydrocarbons, acetone or alcohol.
8. A pharmaceutical composition of claim 7 wherein the non-aqueous solvent is isopropanol.
9. A pharmaceutical composition of claims 1 to 8 in form of tablet or capsule or pellet.
10. A pharmaceutical composition of claim 9 wherein the tablet can be coated or non-coated.
Dated this 17TH day of January 2006.
For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
9