FIELD OF THE INVENTION;

The present invention relates to a pharmaceutical composition comprising Orlistat including its salts, solvates, polymorphs, racemic mixtures, enantiomers, and mixtures thereof and a process for preparing the formulation and their methods of use.

BACKGROUND OF THE INVENTION:

Tetrahydrolipstatin (THL) is an inhibitor of pancreatic lipase and is known under the officially adopted name Orlistat. Orlistat has a chemical name (S)-l-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]-dodecyl ester, which is represented by a structural formula I

Formula -1

Orlistat is a white to off-white crystalline powder. Orlistat is practically insoluble in water, freely soluble in chloroform, and very soluble in methanol and ethanol. Orlistat has no pKa within the physiological pH range.

Orlistat mainly acts by reducing the absorption of amount of fats taken up by the patient, which leads to excretion of the unabsorbed fats in the feaces. Reduction in the absorption of the fats leads to reduction in body weight.

Orlistat is available in hard gelatin capsules in the two strengths of 60 mg and 120 mg, respectively marketed as XENICAL® and ALLI®.

XENICAL and ALLI products are used in the treatment of obesity management, including weight loss and weight maintenance, when used in conjunction with a reduced-calorie diet. The products are also indicated to reduce the risk for weight regain after prior weight loss.

Orlistat was first disclosed in US 4,598,089 and a process for the preparation thereof. Further the pharmaceutical composition comprising the Orlistat and its use as medicament, particularly as anti-obesity agent is described in this patent.

US 6,004,996, discloses that due to the low melting point of Orlistat, which is about 44°C, it undergoes both thermal and hydrolytic degradation, particularly when stored in a humid atmosphere or above 35°C in a dry atmosphere. Furthermore, conventional dosage forms such as described in US 4,598,089, for example, tablets or hard gelatin capsules, cannot easily be formulated from powder mix or by conventional wet granulation procedure due to picking and sticking phenomena during tablet compression or encapsulation. And thus this patent explains the need for developing Orlistat containing products and dosage forms, which would be stable against moisture and heat during production and storage. This patent particularly discloses that when Orlistat particles are in the form of pellets, it is critical to employ microcrystalline cellulose.

The present inventors have succeeded in preparing a formulation without using microcrystalline cellulose, where the formulation exhibits better dissolution and stability. The current invention provides the manufacturing of Orlistat composition with ease i.e., without any picking and sticking nature and better stability.

US 6,730,319 US 2008-0021092, WO 1993/4787, WO 2000/09122, WO 2000/09123, WO 2000/013667 WO 2002/00201, WO 2003/090742, WO 2006/035296, WO 2006/11080, WO 2007/021073, WO 2008/034533, WO 2008/000420, WO 2007/123338, and 2271808, 2239428, 2248218, and 2241462, disclose various pharmaceutical formulations of Orlistat.

OBJECTIVE OF THE INVENTION:

The main object of the present invention is to provide a pharmaceutical composition comprising Orlistat including its salts, solvates, polymorphs, racemic mixtures, enantiomers, and mixtures thereof.

According to another object of the present invention is to provide a process for the preparation of the pharmaceutical compositions comprising Orlistat including its salts, solvates, polymorphs, racemic mixtures, enantiomers, and mixtures thereof.

SUMMARY OF THE INVENTION:

The main aspect of the present invention is to provide a pharmaceutical composition comprising Orlistat or its pharmaceutically acceptable salts with at least one pharmaceutically acceptable excipient, which is devoid of microcrystalline cellulose.

Further aspect of the present invention is to provide Orlistat pellet, which is devoid of microcrystalline cellulose.

The other aspect of the present invention is to provide a pharmaceutical composition comprising (i) Orlistat or its pharmaceutically acceptable salts (ii) at least one pharmaceutically acceptable excipient selected from the group of Dibasic calcium phosphate, Corn starch, Crospovidone, Cellulosic derivatives preferably L-Hydroxypropyl cellulose or mixtures thereof.

According to another object of the present invention is to provide a process for the preparation of the pharmaceutical composition comprising (i) Orlistat or its pharmaceutically acceptable salts (ii) at least one pharmaceutically acceptable excipient selected from the group of Dibasic calcium phosphate, Corn starch, Crospovidone, Cellulosic derivatives like L-Hydroxypropyl cellulose or mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to a pharmaceutical composition comprising Orlistat or its pharmaceutically acceptable salts with at least one pharmaceutically acceptable excipient, which is devoid of microcrystalline cellulose.

Further, the present invention relates to the pharmaceutical composition comprising (i) Orlistat or its pharmaceutically acceptable salts (ii) at least one pharmaceutically acceptable excipient selected from the group of Dibasic calcium phosphate, Corn starch, Crospovidone, Cellulosic derivative preferably L-Hydroxypropyl cellulose or mixtures thereof.

According to the first embodiment, pharmaceutically acceptable excipient includes binders, diluents, dispersing agents, glidants, lubricants, surfactants, disintegrants, plasticizers coating agents and coloring agents. As understood by a person skilled in the art, these excipients are conventional excipients which are well known in the pharmaceutical art.

The term "Pharmaceutical composition" means pharmaceutical dosage form comprising Orlistat or a salt thereof. The pharmaceutical formulations of the present invention can be prepared as solid oral dosage forms. Solid oral dosage forms include, for example, tablets, caplets, capsules (hard or soft gelatin capsules), orally disintegrating dosage forms, chewable dosage forms, pills, granules, sachets, and the like.

The present invention also relates to the process for preparing the pharmaceutical compositions of Orlistat comprising the following steps:

a) blending Orlistat or its pharmaceutically acceptable salts with desired excipients

b) preparing the binder solution,

c) mixing the blend with the binder solution to prepare a wet mass which is subjected to extrusion and optionally,

d) converting the extrudes to related dosage forms such as tablets, mups, capsules, sachets.

In one embodiment, the dry mixing can be carried out using high shear mixer, rapid mixer granulator and planetary mixers preferably using rapid mixer granulator. The granules can be prepared using high shear mixer, rapid mixer granulator, fluid bed granulator or extrusion- spheronization, preferably by rapid mixer granulator.

The present invention provides a better dissolution rate of the Orlistat pellets, which may be determined by the following method.

Table -1

In the appended table, the above described dissolution test was used to determine the release rates of the particular dosage forms.

Table - II:

Comparative Dissolution profile of Orlistat capsules 120 mg with Xenical (Orlistat) 120 mg


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.

The present invention can be illustrated in one of its embodiment by the following non- limiting examples.

EXAMPLES:

Example 1: Preparation of Orlistat pellets containing 50% drug load

The process for the preparation of example 1 is as follows:

Orlistat, Dibasic calcium phosphate anhydrous, Sodium Lauryl Sulfate (SLS), Crospovidone, Sodium Starch Glycolate and Talc were sieved through #30 sieve and collected separately. Hydroxypropylmethyl cellulose, Sodium Lauryl sulfate & Polysorbate 80 were dissolved in purified water under continuous stirring till clear slightly viscous solution was obtained. The sifted dry blend was shifted to Rapid Mixer Granulator and the binder solution was slowly added into the dry mix blend in the Rapid Mixer Granulator, the wet mass was discharged into the IPC lined with double polyethylene bag opening the discharge port. The wet mixed material was fed to the hopper of the extruder and the extrudes were collected in to container and dried.

Example 2: Preparation of Orlistat pellets containing 50% drug load:

The process for the preparation of example 2 is as follows:

Orlistat, L- Hydroxypropylcellulose, Crospovidone, and Talc were sieved through #30 sieve and collected separately. Polyvinyl pyrrolidone was dissolved in purified water under continuous stirring till clear slightly viscous solution was obtained. The sifted dry blend was shifted to Rapid Mixer Granulator and the binder solution was slowly added into the dry mix blend in the Rapid Mixer Granulator, the wet mass was discharged into the IPC lined with double polyethylene bag opening the discharge port. The wet mixed material was fed to the hopper of the extruder and the extrudes were collected in to container and dried.

Example 3: Preparation of Orlistat pellets containing 50% drug load:



The process for the preparation of example 3 is as follows:

Orlistat, Polyplasdone, Corn starch, and Talc were sieved through #30 sieve and collected separately. Polyvinyl pyrrolidone and Sodium lauryl sulphate were dissolved in purified water under continuous stirring till clear slightly viscous solution was obtained. The sifted dry blend was shifted to Rapid Mixer Granulator and the binder solution was slowly added into the dry mix blend in the Rapid Mixer Granulator, the wet mass was discharged into the IPC lined with double polyethylene bag opening the discharge port. The wet mixed material was fed to the hopper of the extruder and extrudes were collected in to container and dried.

Example 4: Preparation of Orlistat pellets containing 50% drug load:

The process for the preparation of example 4 is as follows:

Orlistat, Polyplasdone and Talc were sieved through #30 sieve and collected separately. Polyvinyl pyrrolidone and Sodium lauryl sulphate were dissolved in purified water under continuous stirring till clear slightly viscous solution was obtained. The sifted dry blend was shifted to Rapid Mixer Granulator and the binder solution was slowly added into the dry mix blend in the Rapid Mixer Granulator, the wet mass was discharged into the IPC lined with double polyethylene bag opening the discharge port. The wet mixed material was fed to the hopper of the extruder and the extrudes were collected in to container and dried.

We Claim;

1) A pharmaceutical composition comprising Orlistat or its pharmaceutically acceptable salts with at least one pharmaceutically acceptable excipient, which is devoid of microcrystalline cellulose.

2) A pharmaceutical composition comprising (i) Orlistat or its pharmaceutically acceptable salts (ii) at least one pharmaceutically acceptable excipient selected from the group of Dibasic calcium phosphate, Corn starch, Crospovidone, Cellulosic derivative preferably L-hydroxypropyl cellulose or mixtures thereof.

3) A pharmaceutical composition according to claim 1 is a pellet, which is devoid of microcrystalline cellulose.

4) A process for the preparation of pharmaceutical composition of Orlistat or its pharmaceutically acceptable salts comprising the steps of:

a. blending Orlistat with atleast one pharmaceutically acceptable excipient selected from the group of Dibasic calcium phosphate, Corn starch, Crospovidone, Cellulosic derivative or mixtures thereof; and other pharmaceutically acceptable excipients

b. preparing the binder solution,

c. mixing the blend with the binder solution to prepare a wet mass which is subjected to extrusion and optionally,

d. converting the extrudes to related dosage forms.

5) The pharmaceutical composition according to claim 1, 2 and 4 pharmaceutically acceptable excipients are selected from the group of glidants, lubricants, fillers, binders, disintegrants, diluents, surfactants, and solutions.

6) The pharmaceutical composition according to claim 2, wherein the related dosage forms are selected from the group of capsules, tablets, mups and sachets.