FIELD OF INVENTION

The present invention relates to a controlled release pharmaceutical composition in the form of mini-tablets.

More particularly, the present invention relates to a controlled release pharmaceutical composition in the form of mini-tablets comprising an effective amount of acetazolamide and one or more pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION

A controlled release profile from a drug dosage form is desirable in clinical use to reduce side effects and improve patient compliance.

The present invention provides a controlled release pharmaceutical composition in the form of mini-tablets comprising an effective amount of acetazolamide and one or more pharmaceutically acceptable excipients.

The chemical name for acetazolamide is N-(5-Sulfamoyl-l, 3, 4-thiadiazol-2-yl) acetamide and it has the following chemical structure:

Acetazolamide is an inhibitor of carbonic anhydrase and is used mainly in the management of glaucoma. It is also used in the treatment of various forms of epilepsy, to prevent or ameliorate the symptoms of acute high altitude sickness and in the promotion of diuresis in instances of abnormal fluid retention, for example, cardiac edema.

It is available as a controlled release capsule dosage form and marketed in the U.S. as Diamox™. It has been formulated as sustained-release capsules filled with non-spherical granules of acetazolamide in a wax matrix (PDR 43rd Ed.).

Controlled release formulations of acetazolamide have been described in the prior art. For example, US 5,776,489 disclose capsules containing acetazolamide pellets comprising active spherical granules made by conventional extrusion/spheronization procedures. EP 0 540 813 Bl discloses a sustained release formulation of acetazolamide, comprising substantially spherical and essentially binder-free pellets being coated with a release-controlling membrane. The pellets are prepared by extrusion-spheronization technique.

Therefore, the need for a controlled release pharmaceutical composition of acetazolamide, which is produced by a process that can be more efficient, more consistent and more economical, is apparent.

SUMMARY AND OBJECTIVES OF THE INVENTION

The present invention relates to a controlled release pharmaceutical composition in the form of mini-tablets.

More particularly, the present invention relates to a controlled release pharmaceutical composition in the form of mini-tablets comprising an effective amount of acetazolamide and one or more pharmaceutically acceptable excipients.

It is an objective of the present invention to provide a controlled release pharmaceutical composition in the form of mini-tablets comprising an effective amount of acetazolamide and one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a process for preparing a controlled release pharmaceutical composition in the form of mini-tablets comprising an effective amount of acetazolamide and one or more pharmaceutically acceptable excipient.

Another objective of the present invention is to provide a controlled release pharmaceutical composition in the form of mini-tablets comprising an effective amount of acetazolamide and one or more pharmaceutically acceptable excipient, having a comparable drug release profile as that of commercially available Diamox™.

Yet another object of the present invention is to provide a controlled release pharmaceutical composition in the form of mini-tablets comprising an effective amount of acetazolamide and one or more pharmaceutically acceptable excipient, which is bioequivalent to the commercially available DiamoxTM .

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the comparative mean plasma concentration of equivalent doses of controlled release composition comprising acetazolamide and Diamox™ under fed condition in healthy human volunteers.

DETAILED DESCRIPTION OF THE INVENTION

The term "controlled release" for the purpose of this invention refers to the release of active pharmaceutical agent over a prolonged period of time, such as for example over a period of at least 8 hours. The term controlled release encompasses the terms prolonged release, slow release, extended release and the like.

The term "drug release profile" for the purpose of this invention refers to a dissolution profile exhibited by a composition in a suitable dissolution medium wherein the percentage of drug released from the composition is measured as a function of time.

The term "acetazolamide" for the purpose of this invention, embraces pharmaceutically acceptable racemates, enantiomers, polymorphs, hydrates, salts, solvates and derivatives thereof.
The term "effective amount" for the purpose of this invention, encompasses that amount of active agent, which halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition.

The term "mini-tablet" for the purpose of this invention, refers to a tablet having a diameter in the range between 2 to 5 mm.

In an embodiment the present invention provides a controlled release pharmaceutical composition in the form of mini-tablets comprising an effective amount of acetazolamide and one or more of pharmaceutically acceptable excipient.

Said one or more of pharmaceutically acceptable excipient comprises among others, one or more drug release rate controlling agents.

The drug release rate controlling agents are selected from water soluble polymers which include, but are not limited to, hydrxpropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, hydroxyethylcellulose, methylcellulose, xanthum gum, carboxypolymethylene and polyethylene oxide. In a preferred embodiment, the drug release rate controlling agent is hydrxpropyl methylcellulose in an amount from about 2% to about 8% by weight.

According to the present invention, acetazolamide is present in the mini-tablet in an amount from about 70% to about 80% by weight.

The mini-tablets of the present embodiment can optionally contain other pharmaceutically acceptable excipients, well known to one skilled in the art. Such excipients include without limitation diluents, binders, disintegrants, surfactants, glidants, lubricants and the like.

Suitable diluents include but are not limited to calcium salts such as calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate and the like; cellulose derivatives such as microcrystalline cellulose, silicified microcrystalline cellulose and the like and saccharides such as lactose, starch, mannitol and the like. In a preferred embodiment, the diluent used is microcrystalline cellulose in an amount from about 15% to about 25% by weight.

Suitable binders are selected from the group comprising polyvinylpyrrolidone, cellulose derivatives such as hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, carboxy methyl cellulose sodium, starch and the like.

Suitable disintegrants include sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, starch, calcium carboxymethlycellulose, croscarmellose sodium and the like.

Suitable surfactants include, but are not limited to poloxamers, sodium lauryl sulphate, polysorbates and the like. In a preferred embodiment, sodium lauryl sulphate is included as a surfactant in an amount from about 0.5% to about 1.5% by weight.

Suitable lubricants include stearic acid and stearates, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil, mineral oil, polyethylene glycols, sodium stearyl fumarate, talc and the like. In a preferred embodiment, lubricant used is, magnesium stearate in an amount from about 0.5% to about 1.5% by weight.
Suitable glidants include colloidal silicon dioxide, magnesium trisilicate, talc and the like. In a preferred embodiment, talc is included as a glidant in an amount from about 0.5% to about 1.5% by weight.

It should be appreciated that there is considerable overlap between the above-listed additives in common usage, since a given additive is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in compositions of the present invention.

The mini-tablets may optionally be coated with one or more film coating layers. Film coating layer comprises film-forming polymers and optionally one or more other coating additives, if desired. The mini-tablets can be coated by using any of the conventional coating techniques and utilizing conventional equipments well known in the art. The non-functional coating layers comprise of one or more excipients selected from the group consisting of film forming agents, adhesion promoting agents, plasticizers, opacifiers, colouring agents, antitacking agents and the like. In a preferred embodiment, the commercially available coating composition Opadry™ is used as a coating agent.

In one embodiment, the present invention provides a process for preparation of a controlled release pharmaceutical composition in the form of mini-tablets comprising an effective amount of acetazolamide as hereinabove
described comprising the steps of:

i) sifting the weighed quantities of active agent, one or more rate controlling agents and optionally one or more pharmaceutically acceptable excipient through a suitable sieve followed by blending;

ii) granulating the mix of step (i) with an aqueous solution of a surfactant;

iii) extruding the wet granules of step (ii) at suitable speed through an extruder (Fuji, Pandal Co., Ltd., Japan) with the required screen size;

iv) drying the extrudes at suitable temperature and sifting through a suitable sieve;

v) pre-lubricating the sifted blend of step (iv) with sifted extra-granular excipients followed by lubrication with sifted lubricant(s) and

vi) compressing the lubricated blend of step (v) into mini-tablets which are optionally coated.

The mini-tablets thus obtained can further be filled into a capsule shell.

The following are few representative examples of the invention and in no way construed as being limited to the invention.

EXAMPLES 1-2

Unit Composition:

Brief manufacturing process:

Sifted Acetazolamide and microcrystalline cellulose were granulated with sodium lauryl sulfate solution until desired consistency of wet mass was achieved. The wet mass of step no. 1 was extruded through an extruder (with 0.8 mm screen at 60 rpm), dried at around 60° C and milled to get suitable granules. The obtained granules were lubricated with talc and magnesium stearate in a blender. The lubricated blend was compressed to mini-tablets using suitable punches. Mini-tablets thus obtained were further coated with Opadry™. The required numbers of mini-tablets were filled in suitable size capsules.

Dissolution Study:

The drug release profile of the above controlled release mini-tablets of the invention, were tested in 900 ml of dissolution media at 37° C and in 40-mesh basket (USP Type 1) rotated at 100 rpm with the dissolution media being pH 4.5 acetate buffer. The drug release profile obtained [given in Table below] is compared with the commercially available Diamox™, which was also studied for drug release under the same dissolution condition.

Bio-equivalence Study:

A randomized, two treatment, two period, two sequence, single dose, crossover bioavailability study in 13 healthy, adult, male, human subjects was conducted under fed conditions and the pharmacokinetic parameters of Acetazolamide 500 mg extended release capsule (Example 2), was compared with the commercially available Diamox™ (manufactured by Duramed Pharmaceuticals, USA). The mean drug plasma levels are shown in FIG. 1 and the pharmacokinetic parameters are shown in Table below:

While the invention has been described in detail with respect to specific embodiments thereof, it will be apparent that numerous modifications and variations are possible without departing from the scope of the invention as defined by the following claims.

WE CLAIM

1. A controlled release pharmaceutical composition in the form of mini-tablets comprising an effective amount of acetazolamide, wherein said mini-tablet comprises at least one rate controlling agent.

2. The controlled release pharmaceutical composition according to claim 1, wherein said rate controlling agent is a water soluble polymer.

3. The controlled release pharmaceutical composition according to claim 2, wherein said water soluble polymer is selected from hydrxpropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, hydroxyethylcellulose, methylcellulose,xanthum gum, carboxypolymethylene and polyethylene oxide.

4. The controlled release pharmaceutical composition according to claim 1, further comprises one or more pharmaceutically acceptable additives selected from the group comprising diluents, binders, disintegrants, surfactants, lubricants and glidants.

5. A process for preparing a controlled release pharmaceutical composition in the form of mini-tablets comprising an effective amount of acetazolamide, wherein said process comprises the step of:

i) sifting acetazolamide, one or more rate controlling agents and optionally one or more pharmaceutically acceptable additives through a suitable sieve followed by blending;

ii) granulating the blend of step (i) with an aqueous solution of a surfactant to get a wet mass;

iii) extruding said wet mass of step (ii) through extruder to get extrudates;

iv) drying said extrudates and pre-lubricating said extrudates with extra-granular excipients;

v) final lubrication of step (iv) materials with lubricants to get lubricated blend;

vi) compressing said lubricated blend of step (v) into mini-tablets which are optionally coated.

6. The controlled release pharmaceutical composition according to claim 3, wherein said rate controlling agent is hydroxpropyl methylcellulose.

7. The controlled release pharmaceutical composition according to claim 1, wherein said mini-tablets are filled in hard gelatin capsule shell.

8. A controlled release pharmaceutical composition in the form of mini-tablets comprising an effective amount of acetazolamide, at least one rate controlling agent, and optionally other pharmaceutically acceptable excipient, said mini-tablets being bioequivalent to Diamox™.

9. A mini-tablet composition comprising acetazolamide as herein described and exemplified.