FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
PROVISIONAL SPECIFICATION
(SECTION 10)
"CONTROLLED RELEASE SOLID DOSAGE FORMS"
Glenrnark Generics Limited


an Indian Company, registered under the Indian company's Act 1957
and having its registered office at
B/2, Mahalaxmi Chambers, 22 Bhulabhai Desai Road,
Mumbai - 400 026

THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

31JUL 2008

FIELD OF THE INVENTION
The present invention relates to a controlled release pharmaceutical composition of acetazolamide, and to a process for preparing such composition.
DESCRIPTION OF THE RELATED ART
Acetazolamide is an inhibitor of the enzyme carbonic anhydrase. Acetazolamide, an effective ocular hypotensive drug was disclosed in US Pat No. 2,554,816. It is available in the market under trade name Diamox, in the form of injection and extended release capsule.
DiamoxRTM (acetazolamide--Lederle Laboratories—Wayne, N.J.) has been formulated as sustained-release capsules filled with non-spherical granules of acetazolamide in a wax matrix (PDR 43rd Ed.). This product is discontinued.
DIAMOX® SEQUELS® is currently available extended release capsule of acetazolamide (500mg). It is indicated for the adjunctive treatment of: chronic simple (open-angle) glaucoma, secondary glaucoma, and preoperatively in acute angle-closure glaucoma where delay of surgery is desired in order to lower intraocular pressure. DIAMOX is also indicated for the prevention or amelioration of symptoms associated with acute mountain sickness despite gradual ascent.
US Pat. No. 4132753; discloses a process of preparing controlled release granules of acetazolamide. The disclosed process includes, continuous agitation of a mixture of powdered medicament and finely divided wax-like material while subjecting the mixture to radiation heating.
US Pat. No. 5,776,489; discloses a controlled release pharmaceutical composition in the form of active spherical granules filled into capsules, comprising an effective amount of at least one carbonic anhydrase inhibitor, a pharmaceutically acceptable solid diluent adapted to form a diffusable matrix for the carbonic anhydrase inhibitor and an optional pharmaceutically acceptable excipients. Method for the preparation and administration of invented composition was also provided.

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EP 0540813 provides sustained release formulation of acetazolamide. The formulation comprises substantially spherical binder-free pellets having not more than 0.1% by weight of a binder or being totally binder free, said pellets being coated with a release-controlling membrane.
SUMMARY OF THE INVENTION
The present invention provides controlled release pharmaceutical composition comprising acetazolamide or pharmaceutically acceptable.. salt thereof and at least one or more release controlling ingredient.
According to one embodiment of present invention, the release of acetazolamide or pharmaceutically acceptable salt thereof is controlled by using polymeric matrix.
In another embodiment of present invention the release of acetazolamide or pharmaceutically acceptable salt thereof is controlled by using swelling and/ or gelling polymeric matrix, which optionally includes one or more water insoluble polymer.
Further, the controlled release matrix of present invention may be coated with water soluble/ insoluble release retarding polymeric coat.
In another embodiment of present invention, the controlled release pharmaceutical compositions of acetazolamide or pharmaceutically acceptable salt thereof having coarser particles size are provided.
In another embodiment this invention provides a process for preparing controlled release pharmaceutical formulations of acetazolamide or pharmaceutically acceptable salt thereof.
According to present invention the controlled release composition of acetazolamide or pharmaceutically acceptable salt thereof is provided in solid dosage forms like tablet, minitablets, granules, multiparticulates, capsules.
In accordance with another embodiment of present invention, the composition of present invention provides a unit dosage form permitting once-a-day dosing of acetazolamide or pharmaceutically acceptable salt thereof.
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DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present provides controlled release pharmaceutical composition comprising acetazolamide or pharmaceutically acceptable salt thereof. The invented composition provides controlled release of acetazolamide for the duration of at least 10 hrs. This invention further provides a method for preparing a controlled release formulation of acetazolamide.
The present invention provides oral controlled release pharmaceutical composition of acetazolamide or pharmaceutically acceptable salt thereof, which includes matrix and/ or reservoir forming polymers.
The controlled release pharmaceutical composition of acetazolamide or pharmaceutically acceptable salt thereof, is in the form of a matrix, optionally reservoir in combination of matrix may be useful.
In accordance with another embodiment of this invention, controlled release pharmaceutical composition comprising acetazolamide of present invention can be in the form of tablets, minitablets, pellets, and or granules.
The acetazolamide-containing tablets, minitablets, pellets, and or granules of the present invention can be filled into hard gelatin capsules or otherwise presented in a unit dosage form for administration to a patient.
In another embodiment the composition of present invention provides a unit dosage form permitting once-a-day dosing of acetazolamide.
Acetazolamide or pharmaceutically acceptable salt thereof construct 60-95% w/w of controlled release dosage form, more preferably 75-85% w/w of controlled release dosage form.
The amount of control release polymer in the invented composition varies from 5% w/w to 25% w/w, more preferably 10 % to 20%.
In order to achieve desired controlled release profile, the acetazolamide or pharmaceutically acceptable salt thereof, can be mixed and or coated with one or more release-controlling pharmaceutical excipients selected from cellulosic polymers, wax, resins, alginates, gums such as
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guar and xanthan gums, polyacrylic acid derivatives such as carbomers, carageenan, povidone, polyethylene oxides, and polyvinyl alcohol.
The preferred release controlling polymers are cellulosic derivatives. The preferred cellulose derivatives include ethylcellulose, hydroxypropyl methylcellulose, hydroxylpropyl cellulose, hydroxyethylcellulose, methylcellulose, powdered cellulose, cellulose acetate, sodium carboxymethylcellulose, calcium salt of carboxymethylcellulose, or mixtures thereof. More preferred cellulosic polymers are various grades of HPMC and ethylcellulose.
In the present invention, carriers or diluents are selected from starch, saccharides, microcrystalline cellulose, other cellulose derivatives, calcium phosphate, NaCaPO4 sugar alcohols, lactose and mixtures thereof.
Binders are agents used to impart cohesive properties to the pellets or granules. It includes water soluble and insoluble binder, more preferable water soluble binder. The preferred binders are cellulose derivatives, sugars, gums, gelatin, povidone, pregelatinized starch, sugar solution, and polyvinyl alcohol. Most preferred water soluble binder is hydroxypropyl methylcellulose (HPMC) of different viscosity grades.
Disintegrating agents are the substances or mixtures of substances added to the formulation to facilitate its breakup or disintegration after administration. The typical examples of disintegtants are modified or unmodified starches, clays, cross-linked PVP, modified or unmodified celluloses.
Preferably the composition of present invention included one or more lubricants, which may be added to assure proper processing. Non-limiting examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, stearic acid, polyethylene glycol, leucine, glyceryl behenate, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated vegetable oils, and other waxes. The lubricant, when present, is typically in an amount of from about 0.1 wt. % to about 15 wt. % of the composition, preferably from about 1 to about 10 wt. %, and more preferably about 0.3 to about 5.0 wt. %.
The choice of excipients is not limited to the example disclosed herewith; it may include any suitable excipients mentioned in hand book of pharmaceutical excipients (51 ed.).
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The composition of present invention is preferably formulated into a granules, minitablets or tablets, using methods known in the art including a wet granulation method, dry granulation (compaction) and a direct compression method. The dosage form of present invention can be prepared by tablet press, roller compactor, extruder or any other machine or machine aid used to prepare solid dosage forms, known in the art. See, for example, Remington's Pharmaceutical Sciences, 18.sup.th Edition, A. Gennaro, Ed., Mack Pub. Co. (Easton, Pa. 1990), Chapters 88-91, the entirety of which is hereby incorporated by reference.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The invention is described below in particularity with the following illustrative example; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiment below.
EXPERIMENTAL:
Table 1: Acetazolamide ER compositions and process;

Example No. Example 1 Example 2 Example 3 Example 4
Process Granulation Glatt
Granulation Compaction Mini Tablet
Ingredients mg/cap mg/cap mg/cap mg/cap
Acetazolamide 500 500 500 500
HPMC K4M CR ' 23 23 18 0
HPMC K100M CR 30 30 25 0
Ethyl cellulose 4 cPs 25 25 25 0
Avicel pH 102 0 0 0 90
*Methylene chloride Approx. 1000 mg Approx.5000 - 0
*Isopropyl Alcohol Approx. 1000 mg - 0
Talc 1 4 6 5
Magnesium stearate 1 4 6 5
Total (mg) 580 586 580 600
* wall no remain in the final product.
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Process: Example 1:
The uniform blend of acetazoalmide, methocel K4M CR, methocel 100 CR was granulated with binder solution of Ethyl cellulose 4 cps in methylene chloride. The granules were dried and sized. Sized granules were lubricated with talc and magnesium stearate and filled into capsule.
Example 2:
Granulate the sifted acetazoalmide with binder solution/ dispersion of Methocel K4M CR, Methocel K100M CR and Ethyl cellulose 4 cps in Isopropyl alcohol and then add methylene chloride. The binder solution was sprayed onto the acetazolamide under controlled condition of temperature (inlet temperature 40-55 "C and product temperature 28-37oC), and granules were dried after spraying complete binder solution. Dried granules were shifted and lubricated with talc and magnesium stearate; lubricate granules were filled into capsules. Example 3:
Uniformly mix the acetazoalmide, methocel K4M CR, methocel K100 M CR and ethocel 4 cps in a double cone blender; and lubricate this mixture with talc and magnesium stearate. Compact the lubricated mixture with roller compactor and screen through 20 mesh. Screen this 20 mesh material through 60 mesh and again lubricate with talc & magnesium stearate. Filled these lubricated granules into capsules of suitable size. Example 3:
Lubricate the uniform mixture of acetazoalmide and Avicel pH 102 by using talc and Magnesium stearate; and compress into minitablets. These minitablets were filled into capsules of suitable size.
DISSOLUTION STUDIES:
The dissolution studies were carried out in USP dissolution apparatus II, using 900 ml acetate buffer of pH 4.5 having 2.2 % tween 20, as dissolution media. The results of dissolution studies are given in table no. 2. Dissolution studies reveal that the release profiles of invented compositions are equivalent with marketed product of acetazolamide.
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Table 2: Results of dissolution studies

Time Percent dissolution

Innovator Example 1
1hr 25 30
2 hr 43 43
3 hr 57 54
4 hr 68 62
5 hr 75. 72
6 hr 81 75
8 hr 93 88
10 hr 101 98
12 hr 105 105
Dated this

VIJAY NASARE
(Sr. Manager-IPM)
Glenmark Generics Limited
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