FIELD OF INVENTION

The invention relates to the pharmaceutical field. More specifically, it relates to multi-particulate pharmaceutical compositions comprising orlistat, sugar alcohol(s) and one or more pharmaceutically acceptable excipients. Further, the invention also relates to extrusion-spheronization processes for preparing the multi-particulate pharmaceutical compositions comprising orlistat, sugar alcohol(s) and one or more pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS
Orlistat, also known as tetrahydrolipstatin, is an inhibitor of pancreatic lipases and indicated for obesity management including weight loss and weight maintenance, when used in conjunction with a reduced-calorie diet. Orlistat is described chemically as (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-

[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl]-dodecyl ester. Its empirical formula is C29H53NO5, and its molecular weight is 495.7. Orlistat is a white to off-white crystalline powder, practically insoluble in water, freely soluble in chloroform, and very soluble in methanol and ethanol.

Orlistat was introduced into the U.S. under the brand name of Xenical® (orlistat 120 mg) which is available for oral administration. Each capsule contains a pellet formulation consisting 120 mg of orlistat and microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone, and talc as inactive ingredients.

PCT Application No. WO2002/098413 discloses use of fatty acid and/or fatty acid salts for in-situ transformation of orlistat into liquid droplets to improve its dissolution inside gastrointestinal tract. Said application in Example 11 discloses orlistat tablet consisting of orlistat, sodium laurate, mannitol and HPMC,

wherein said tablet is prepared by employing wet granulation process using ethanol/water (50:50% m/m) solution as granulating liquid.

U.S. Patent No. 6,004,996 discloses multi-particulate formulations comprising plurality of pellets comprising orlistat and one or more pharmaceutically acceptable excipients. The multi-particulate formulations preferably contained povidone and/or lactose as stabilizers, microcrystalline cellulose as a mandatory diluent, and one or more other pharmaceutically acceptable excipients.

The use of microcrystalline cellulose for the preparation of said pellets utilizing the process of extrusion-spheronization was mandatory and unavoidable according to said patent. The patent further discloses that microcrystalline cellulose in an amount ranging between 10% to about 60% by weight was required to provide pellets containing orlistat that do not feature the sticking and picking phenomena encountered during tablet compression or encapsulation and which exhibited superior orlistat stability.

Thus, from above prior art, it seems that the use of microcrystalline cellulose is apparently critical for the preparation of pellets comprising orlistat, through the use of the extrusion-spheronization process and which do not feature the sticking and picking phenomena and further which exhibits superior orlistat stability.

Surprisingly, the present inventors have found that the pellets comprising orlistat and one or more pharmaceutically acceptable excipient(s) can be prepared using the extrusion-spheronization process, without the use of microcrystalline cellulose in said composition.

More particularly, the inventors found that pellets comprising orlistat, sugar alcohol(s) and one or more pharmaceutical acceptable excipient(s) can be successfully prepared by the use of extrusion-spheronization process, which are similar in appearance and which also do not exhibit sticking and picking phenomena and further which exhibits improved stability, when compared with the marketed Xenical® which contains microcrystalline cellulose.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to multi-particulate pharmaceutical compositions comprising orlistat, sugar alcohol(s) and one or more pharmaceutically acceptable excipients, wherein said compositions are devoid of microcrystalline cellulose. Further, the invention also relates to extrusion-spheronization processes for preparing the multi-particulate pharmaceutical compositions comprising orlistat.

An objective of the invention, is to prepare multi-particulate pharmaceutical composition comprising orlistat, sugar alcohol(s) and one or more pharmaceutically acceptable excipients, wherein the composition is devoid of microcrystalline cellulose.
Another objective of the invention, is to prepare multi-particulate pharmaceutical composition in the form of pellets or beads comprising orlistat, sugar alcohol(s) and one or more pharmaceutically acceptable excipients, wherein the pellets or beads are devoid of microcrystalline cellulose.

Another objective of the invention, is to prepare a capsule formulation comprising plurality of pellets or beads containing orlistat, sugar alcohol(s) and one or more pharmaceutically acceptable excipients wherein the pellets or beads are devoid of microcrystalline cellulose.

Another objective of the invention, relates to the process of preparing pellets or beads comprising orlistat, sugar alcohol(s) and one or more pharmaceutically acceptable excipients by employing extrusion-spheronization process, wherein said pellets or beads are devoid of microcrystalline cellulose.

Another objective of the invention, is to prepare pellets or beads comprising orlistat and one or more pharmaceutically acceptable excipients, wherein said pellets or beads essentially comprises mannitol and povidone.

Yet another objective of the invention, is to prepare capsule formulation comprising plurality of pellets or beads comprising orlistat, sugar alcohol(s) and one or more pharmaceutically acceptable excipients, having comparable in-vitro dissolution profile with that of the marketed Xenical® capsules and wherein said pellets or beads are devoid of microcrystalline cellulose.

BRIEF DESCRIPTION OF THE DRAWINGS OR FIGURES:

Figure 1: Comparative view of orlistat pellets or beads in marketed Xenical® capsule, comprising microcrystalline cellulose and in orlistat capsule prepared according to Example 4, comprising mannitol.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention particularly relates to multi-particulate pharmaceutical compositions comprising orlistat, sugar alcohol(s) and one or more pharmaceutically acceptable excipients prepared by employing extrusion-spheronization process.

As discussed in the background of the invention, the selection of excipients, especially diluent(s) and stabilizer(s) are very critical for the preparation of multi-particulate pharmaceutical composition comprising orlistat. Thus, per the prior art, the use of microcrystalline cellulose is critical for the preparation of pellets comprising orlistat, through the use of the extrusion-spheronization process and which do not feature the sticking and picking phenomena and further which exhibits superior orlistat stability.

Microcrystalline cellulose is primarily used as a base excipient in pellet or bead formulations and is reported to aid the extrusion-spheronization process by holding or absorbing large quantity of water, thus improving plasticity and enhancing rheological properties of wet mass. Microcrystalline cellulose is required for producing pellets or beads with a smooth surface, low friability and low density.

As discussed above, and per the teachings of prior art, U.S. Patent No. 6,004,996, the use of microcrystalline cellulose is therefore mandatory and unavoidable for preparing orlistat pellet or bead formulation.

On the contrary, the present inventors have invented that the pellets or beads comprising orlistat can be prepared by using sugar alcohol(s) and one or more pharmaceutical acceptable excipients by employing extrusion-spheronization process, without incorporating microcrystalline cellulose.

Surprisingly, the present inventors have found that the pellets or beads comprising orlistat and one or more pharmaceutical acceptable excipient(s) can be prepared using the extrusion-spheronization process, without the use of microcrystalline cellulose in said composition.

More particularly, the inventors found that pellets or beads comprising orlistat, sugar alcohol(s) and one or more pharmaceutically acceptable excipient(s) can be successfully prepared by the use of extrusion-spheronization process, which are similar in appearance, which also do not exhibit sticking and picking phenomena and further which exhibits improved stability, when compared with the marketed Xenical® which contains microcrystalline cellulose.

In context of the invention, terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for orlistat or its pharmaceutically acceptable salts or esters or derivatives thereof.

According to the invention, orlistat may be present in an amorphous or crystalline form. As used herein, the term "orlistat" is intended to include the active agent itself, as well as its pharmaceutically acceptable salts or polymorphs or derivatives thereof.

As used herein, the term "multi-particulate" when used in connection with the term "pharmaceutical composition" refers to plurality of pellets or beads or granules comprising orlistat and one or more pharmaceutically acceptable excipients.

As used herein, the term "pellet or bead or granule" relates to a small, solid or densely packed rounded and/or cylindrical compacted mass of orlistat and one or more pharmaceutically acceptable excipient(s) obtained by extrusion-spheronization process. Said pellets or beads could be compressed into tablet or filled in a capsule shell.

As used herein, the term "stabilizer" refers to an agent having a rate of moisture uptake greater than the rate of moisture uptake for orlistat to retard hydrolytic degradation of orlistat.

Extrusion-spheronization is a multiple-step process capable of making uniformly sized spherical or cylindrical particles commonly referred to as beads or pellets. Extrusion-spheronization process essentially comprises the steps of:

a) dry mixing of ingredient to achieve homogenous powder blend;

b) controlled wet massing of the powder blend to produce a wet mass;

c) extrusion of the wet mass to form rod shaped particles of uniform diameter and

length;

d) spheronization to round off these rod shaped particles into spherical/cylindrical particles with narrow size distribution;

e) drying to achieve desired final moisture content; and

f) screening to obtain desired size of beads/pellets.

According to an embodiment of the invention, aqueous or non-aqueous or hydro-alcoholic solvent can used for wet massing of powder blend to get wet mass with suitable consistency for extrusion-spheronization process.

Primarily, water or aqueous based solvent are preferred for the extrusion-spheronization process. However, according to an embodiment of the invention, non-aqueous solvents for use in wet massing of powder blend could also be used which include, but are not limited to methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, ethyl acetate, dimethylsulfoxide or their combinations thereof.

According to an embodiment of the invention, hydro-alcoholic solvents are mixtures of one or more alcohols and water, in various volume ratios. Sugar alcohol(s) are used in solid oral pharmaceutical formulations because of their high solubility, abundant availability, low hygroscopicity and chemical compatibility.

However, its use in the preparation of the multi¬particulate pharmaceutical formulation comprising orlistat has not been taught or disclosed in the prior art. According to an embodiment of the invention, the term "sugar alcohol" as used herein, relates to polyol or polyhydric alcohol or polyalcohol. A sugar alcohol according to the invention includes, but is not limited to mannitol, erythritol, xylitol, maltitol, or mixture thereof. Preferred, sugar alcohol is mannitol.

According to an embodiment of the invention, preferably granular or spray-dried mannitol having average particle size less than 300 microns, preferably less than 200 microns is used for preparing orlistat pellet formulation by employing extruder spheronization process.

According to an embodiment of the invention, sugar alcohol(s) is used in an amount form about 20 to about 70% w/w of final composition, preferably from about 30 to about 60% w/w of final composition.

According to an embodiment of the invention, the capsule formulation comprising orlistat relates to the pellets or beads obtained through the process of extrusion-spheronization, which pellets or beads or granules preferably comprises sugar alcohol as a diluent.

According to an embodiment of the invention, following extruder and spheronizer were used for development (lab scale) and scale up (production scale) of orlistat multi-particulate formulation:

For development (Lab scale): Extruder:

• Manufacturer: Fuji Paudal Co. Ltd

• Model: MG 55 (Single screw, Table top model) Spheronizer:

• Manufacturer: Fuji Paudal Co. Ltd

• Model: QJ- 230T -1

• Capacity: lltr

For scale up (Production scale): Extruder:

• Manufacturer: Fuji Paudal Co. Ltd

• Model: EXD (C)(R)S(J) 60G (Twin screw) Spheronizer:

• Manufacturer: Fuji Paudal Co. Ltd

• Model: QS- 400TG

• Capacity: 40 to 120kg/hr

According to an embodiment of the invention, the capsule formulation comprising plurality of orlistat pellets may further contain one or more other pharmaceutically acceptable excipient(s) selected from a group comprising stabilizer(s), disintegrant(s), surfactant(s), glidant(s), and/or lubricant(s), etc.

Suitable stabilizer(s) according to the invention include, but are not limited to povidone, copovidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, lactose or combinations thereof. Preferably, povidone or copovidone is used as a stabilizer.

Suitable disintegrant(s) according to the invention include, but are not limited to carboxymethylcellulose calcium, carboxymethylcellulose sodium, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC) and pregelatinized starch or combinations thereof.

Preferably, crospovidone or sodium starch glycolate or their combinations are used as disintegrants. Suitable surfactant(s) according to the invention include, but are not limited to, anionic surfactants such as potassium laurate, triethanolamine stearate, sodium lauryl sulfate, cationic surfactants include quaternary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide; nonionic surfactants include glycerol monostearate, cetyl alcohol, cetostearyl alcohol, and. polyoxyethylene glycol sorbitan alkyl esters (polysorbate), sorbitan alkyl esters (span), poloxamer or combinations thereof. Preferably, sodium lauryl sulfate is used as a surfactant.

Suitable glidant(s) and/or lubricant(s) according to the invention include, but are not limited to, colloidal silicon dioxide, talc, magnesium stearate, sodium stearyl fumarate, calcium stearate or combinations thereof.

According to preferred embodiment of the invention, pellets or beads or granules comprising orlistat essentially comprises mannitol or spray dried mannitol as a diluent and povidone as a stabilizer.

Preferably, according to an embodiment of the invention, the process for preparing capsule formulation comprising plurality of pellets comprising orlistat and one or more pharmaceutically acceptable excipients includes the following steps:

a) Dissolving surfactant and stabilizer in purified water to get a clear granulating solution;

b) Sifting together orlistat, diluent and disintegrant(s) through size #30 mesh;

c) Loading of sifted material of step (b) into rapid mixer granulator and mixing;

d) Granulating the material obtained in step (c) with the granulating solution obtained in step (a) to get wet mass;

e) Extruding the wet mass of step (d) through extruder followed by spheronization to get pellets or beads;

f) Drying the pellets or beads of step (e) using suitable drying method at a temperature of 35±5°C;

g) Filling dried pellets of step (f) in to empty hard gelatin capsule shells. Suitable drying methods according to the invention include, but not limited to tray drying, fluid-bed drying, and vacuum drying. More preferably, fluid bed drying is employed. The embodiments of the invention are described in the following examples, but the examples are illustrative and do not limit the scope of this invention.

EXAMPLE 1;

Unit Composition:

Brief manufacturing process:

a) Dissolve sodium lauryl sulfate and povidone in purified water to get clear granulating solution;

b) Sift together orlistat, mannitol, crospovidone and sodium starch glycolate through size #30 mesh;

c) Load sifted material of step (b) into rapid mixer granulator and mix it for 10 minutes;

d) Granulate the blend obtained in step (c) with the granulating solution obtained in step (a) to get wet mass;

e) Extrude the wet mass of step (d) through extruder followed by spheronization, to get pellets or beads;

f) Dry the pellets or beads of step (e) at a temperature of 35±5°C in a fluid bed dryer;

g) Fill dried pellets or beads of step (f) in to empty hard gelatin
capsule shells.

Brief manufacturing process:

a) Dissolve sodium lauryl sulfate and povidone in purified water to get clear granulating solution;

b) Sift together orlistat, mannitol, and sodium starch glycolate through size #30 mesh;

c) Load sifted material of step (b) into rapid mixer granulator and mix it for 10 minutes;

d) Granulate the blend obtained in step (c) with the granulating solution obtained in step (a) to get wet mass;

e) Extrude the wet mass of step (d) through extruder followed by spheronization, to get pellets or beads;

f) Dry the pellets or beads of step (e) at a temperature of 35±5°C in a fluid bed dryer;

g) Fill dried pellets or beads of step (f) in to empty hard gelatin capsule shells.

Brief manufacturing process:

a) Dissolve sodium lauryl sulfate and povidone in purified water to get clear granulating solution;

b) Sift together orlistat, mannitol, crospovidone and sodium starch glycolate through size #30 mesh;

c) Load sifted material of step (b) into rapid mixer granulator and mix it for 10 minutes;

d) Granulate the blend obtained in step (c) with the granulating solution obtained in step (a) to get wet mass;

e) Extrude the wet mass of step (d) through extruder followed by spheronization, to get pellets or beads;

f) Dry the pellets or beads of step (e) at a temperature of 35±5°C in a fluid bed dryer;

g) Sift talc through size #60 mesh and lubricate the pellets or beads obtained in step

(f) with sifted talc;

h) Fill lubricated pellets or beads of step (g) in to empty hard gelatin capsule shells.

Brief manufacturing process:

a) Dissolve sodium lauryl sulfate and povidone in purified water to get clear granulating solution;

b) Sift together orlistat, mannitol, crospovidone and sodium starch glycolate through size #30 mesh;

c) Load sifted material of step (b) into rapid mixer granulator and mix it for 10 minutes;

d) Granulate the blend obtained in step (c) with the granulating solution obtained in step (a) to get wet mass;

e) Extrude the wet mass of step (d) through extruder followed by spheronization, to get pellets or beads;

f) Dry the pellets or beads of step (e) at a temperature of 35±5°C in a fluid bed dryer;

g) Sift talc through size #60 mesh and lubricate the pellets or beads obtained in step

(f) with sifted talc;

h) Fill lubricated pellets or beads of step (g) in to empty hard gelatin capsule shells.
Orlistat pellets or beads prepared according to the above Examples 1 to 4, showed no signs of sticking or picking phenomenon during encapsulation (capsule filling) process.

A comparative Example (Example 5) below, (which is not a part of this invention), was prepared in order to bring out/ highlight the inventive aspects of the embodiments of the invention.

COMPARATIVE EXAMPLE 5;

Brief manufacturing process:

a) Dissolve sodium lauryl sulfate and povidone in purified water to get clear granulating solution;

b) Sift together orlistat, microcrystalline cellulose, and sodium starch glycolate through size #30 mesh;

c) Load sifted material of step (b) into rapid mixer granulator and mix it for 10 minutes;

d) Granulate the blend obtained in step (c) with the granulating solution obtained in step (a) to get wet mass;

e) Extrude the wet mass of step (d) through extruder followed by spheronization, to get pellets or beads;

f) Dry the pellets or beads of step (e) at a temperature of 35±5°C on fluid bed dryer;

g) Fill dried pellets or beads of step (f) in to empty hard gelatin
capsule shells.

Stability Studies:

The stability studies of the above five formulations (Example 1 to 4 according to invention and Example 5 for comparison) of orlistat 120 mg capsule and the marketed Xenical® 120mg capsules were conducted. The capsules along with their respective placebos were packed and stored under stability conditions recommended by ICH as per the following protocol.

The samples were analyzed for impurities after 24 weeks and compared with the initial results as provided below:

Above stability data shows that the orlistat 120 mg capsules prepared according to Example 1 to 4 were better in terms of chemical stability, when compared to the capsules prepared according to Comparative Example 5 and marketed Xenical® 120 mg capsules containing microcrystalline cellulose.

Dissolution Studies

The in-vitro drug release profiles of orlistat 120 mg capsules prepared according Example 1 to 4 and Comparative Example 5 were conducted in 900 mL of 0.5% Sodium Chloride solution having 3% of sodium lauryl sulphate (pH = 6.0±0.2) using the USP Dissolution Apparatus II (Paddle) set at 75 rpm.

The samples were withdrawn at the requisite time points and were analyzed for the dissolution profile at each time point and which was compared with that of the Xenical® dissolution profile.

The comparative cumulative drug release as per the dissolution profile of orlistat capsules as per the invention (Example 1 to 4), comparative Example 5 and that of the marketed Xenical® is provided below:

Above in-vitro dissolution data also shows that the orlistat 120 mg capsules prepared according to Example 1 to 4 has comparative similar in-vitro dissolution profile as that of marketed Xenical® 120 mg capsule.

WE CLAIM:

1. A multiparticulate pharmaceutical composition comprising orlistat, wherein said composition comprises sugar alcohol(s) and optionally one or more pharmaceutically acceptable excipients.

2. A multiparticulate pharmaceutical composition comprising orlistat, prepared by extrusion-spheronization process, wherein said composition comprises sugar alcohol(s) and optionally one or more pharmaceutically acceptable excipients.

3. The pharmaceutical composition according to claim 1 and 2 wherein the sugar alcohol(s) is selected from a group consisting of mannitol, erythritol, xylitol, maltitol, or their combination thereof.

4. The pharmaceutical composition according to claim 1 and 2 wherein the sugar alcohol(s) is used in an amount from about 20 to about 70% w/w of the final composition.

5. A multiparticulate pharmaceutical composition containing plurality of pellets or beads comprising orlisat, mannitol and optionally other pharmaceutically acceptable excipients, wherein said pellets or beads are prepared by extrusion-spheronization process.

6. The pharmaceutical composition according to claim 5, wherein the mannitol has an average particle size less than 300 micron.

7. A multiparticulate pharmaceutical composition containing plurality of pellets or beads comprising orlistat, having the following unit composition:

Ingredients mg/capsule

Orlistat 120.000

Mannitol 154.750

Crospovidone 35.000

Sodium starch glycolate 10.500

Sodium lauryl sulfate 10.500

Povidone 17.500

Talc 1.750

Purified water q.s

"Capsule Fill Weight | 350.000

8. A process to prepare the multiparticulate pharmaceutical composition according to claim 7, wherein said process involves the following steps:

a) Dissolve sodium lauryl sulfate and povidone in purified water to get clear granulating solution;

b) Sift together orlistat, mannitol, crospovidone and sodium starch glycolate through size #30 mesh;

c) Load sifted material of step (b) into rapid mixer granulator and mix;

d) Granulate the blend obtained in step (c) with the granulating solution obtained in step (a) to get wet mass;

e) Extrude the wet mass of step (d) through extruder followed by spheronization, to get pellets or beads;

f) Dry the pellets or beads of step (e) at a temperature of 35±5°C in a fluid bed dryer;

g) Sift talc through size #60 mesh and lubricate the pellets or beads obtained in step

(f) with sifted talc;

h) Optionally fill lubricated pellets or beads of step (g) in to empty hard gelatin capsule shells.

9. A multiparticulate pharmaceutical composition comprising orlistat, sugar alcohol(s) and optionally one or more pharmaceutically acceptable excipients, prepared by extrusion-spheronization process, wherein said composition is devoid of microcrystalline cellulose.

10. A multiparticulate pharmaceutical composition containing plurality of pellets or beads comprising orlistat, mannitol and optionally one or more pharmaceutical acceptable excipients as herein described and exemplified.