Technical Field of the Invention
The present invention relates to pharmaceutical formulations comprising a therapeutically effective amount of orlistat particles having a controlled particle size, wherein the said formulations exhibit enhanced absorption and dissolution characteristics.
Background of the Invention
Orlistat or tetrahydrolipstatin is a reversible lipase inhibitor which is chemically known as (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl]-dodecyl ester. Orlistat is disclosed specifically in US Patent No. 4,598,089 which also describes the process of preparation of orlistat. Further, it also relates to a method of preventing and/or treating diseases like obesity or hyperlipidemia in a mammal by administering orlistat. Orlistat is indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet, as well as, to reduce the risk for weight regain after prior weight loss. It is indicated for obese patients with an initial body mass index (BMI) ≥ 30 kg/m2 or ≥ 27 kg/m2 in the presence of other risk factors (e.g., hypertension, diabetes, and dyslipidemia).
Currently, orlistat is commercially available as XENICAL® conventional hard gelatin capsules in strengths of 120mg from Hoffman La-Roche, Basel, Switzerland. The recommended dose of orlistat is one 120mg capsule three times a day with each meal containing fat (during or up to 1 hour after the meal). Recently GlaxoSmithKline has launched 60mg strength capsules of orlistat in USA for over-the-counter use under the proprietary name ALLI®.
Several references have been documented in the art that relates to formulations comprising orlistat. US Pat. No. 6,004,996 discloses a pharmaceutical composition of orlistat which comprise of a plurality of particles having an average diameter of form 0.25mm to 2mm, wherein each particle contains tetrahydrolipstatin, polyvinylpyrrolidone, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulphate and talc. US Patent No. 6,358,522 discusses pharmaceutical compositions containing an inhibitor of gastrointestinal lipase, like orlistat, one (or more) additive(s) of the group consisting of substantially non-digestible, substantially non-fermentable, hydrophilic and/or hydrocolloidal food grade thickeners and emulsifiers, and auxiliary

excipients and also provides methods preventing and treating anal leakage of oil in a patient by administering such compositions. The PCT application WO/2007/021073 discloses a pharmaceutical formulation comprising 1 part by weight of orlistat, 0.01 to 20 parts by weight of a solvent, 0.01 to 20 parts by weight of a solubilizer, 0.01 to 10 parts by weight of a surfactant, 0.01 to 2 parts by weight of an antioxidant, and 0.1 to 20 parts by weight of an adsorbent or dispersant, wherein such a formulation exhibits high stability and dissolution. Our co-pending Indian patent application 62/DEL/2006 describes a stable pharmaceutical composition comprising the crystalline Form I of orlistat, wherein the said Form I does not convert into Form II over normal storage temperature over a period of time.
Orlistat being practically insoluble in aqueous media, have an insufficient dissolution profile and consequently poor bioavailability. Hence, there still exists a need to design a formulation comprising orlistat which would exhibit acceptable absorption, dissolution and at the same time would be manufactured by a simple, cost-effective and industrially viable process. It is known in the art that the bioavailability of low solubility drugs is often intrinsically related to drug particle size. By reducing the particle size, the increased surface area is available for dissolution and consequently, enhanced dissolution properties. In the present invention, a therapeutically effective amount of orlistat particles having a controlled particle size have been formulated into suitable pharmaceutical dosage forms incorporating this theory, such that the said dosage forms exhibit improved dissolution properties.
Summary of the Invention
In one general aspect, it relates to a pharmaceutical formulation comprising a therapeutically effective amount of orlistat particles having a controlled particle size and a pharmaceutically acceptable carrier.
In another general aspect, it relates to a pharmaceutical formulation comprising a therapeutically effective amount of orlistat particles having a controlled particle size and a pharmaceutically acceptable carrier, wherein the said orlistat particles have a D50 value not more than 120 micron and D90 value not more than 225 micron.
In another general aspect, it relates to a process for the preparation a pharmaceutical formulation comprising of orlistat particles having a controlled particle size, wherein the

said orlistat particles have a D50 value not more than 120 micron and D90 value not more than 225 micron.
In another general aspect, it relates to a process for the preparation a pharmaceutical formulation comprising of orlistat particles having a controlled particle size, wherein the process is extrusion and spheronization.
In another general aspect, it relates to a process for the preparation a pharmaceutical formulation comprising of orlistat particles having a controlled particle size, wherein the process is wet granulation.
Detailed Description of the Invention
The term "therapeutically effective amount", as used herein, is understood to mean the effective dose of orlistat which stops or reduces the progress of the condition to be treated or which otherwise completely or partly cures or acts palliatively on the condition. The dose may range from about 60mg to about 720mg of orlistat. Preferably, orlistat may be administered in an amount from about 180 to about 360mg of orlistat, administered in divided doses two or three times per day. The recommended dose of XENICAL® which is 120mg or ALLI® which is 60mg may be considered as a standard dose. The subject is preferably an obese or overweight human, i.e. a human with a body mass index of 25 or greater.
The pharmaceutical formulation as referred to herein may be in the form of granules, tablets, capsules, pellets, powders, suspension or emulsion.
The term "reduction of particle size" as described herein means any process or method by which the size of the particles has been controlled and/or reduced. Accordingly, "orlistat particles having a controlled particle size" as used herein include orlistat particles which have been subject to "reduction of particle size".
The "reduction of particle size" of orlistat particles may be carried out using techniques well known in the art. The conventional methods of reduction of particle size are comminution, spray drying, recrystallization of poorly soluble materials using liquid solvents and antisolvents, etc. Comminution techniques like milling rely upon mechanical stress to reduce particle size which may be done in conventionally known mills, namely ball mill, colloid mill, grinding mill, air jet mill, roller mill, impact mill, etc.

Another method for reducing the particle size and having a controlled size range distribution is by passing the material through sieves of a desired mesh size. This process have particular advantages of being simple, cost-effective, energy saving and may be used for products that are susceptible to degradation when subjected to mechanical stress or high temperature. In one embodiment, orlistat particles having controlled particle size has been obtained by sieving.
The reduction of the particle size of orlistat particles to a D50 particle size of not more than 120 micron, and a D90 particle size of not more than 225 micron, results in improved bioavailability of orlistat pharmaceutical compositions as compared to pharmaceutical compositions that contain orlistat with larger particle size. Orlistat particles having a D50 particle size of not more than 120 micron, and a D90 particle size of not more than 225 micron, as referred to herein as "orlistat particles having a controlled particle size". As used herein, the D50 and D90 represent the median or the 50th percentile and the 90th percentile of the particle size distribution, respectively, as measured by volume. This means, the term "D50" is defined as the size in microns below which 50 percent of the particles reside on a volume basis and similarly, the term "D90" is defined as the size in microns below which 90 percent of the particles reside, on a volume basis.
The particle size is determined by laser light scattering using a particle size analyser, such as the proprietary Mastersizer™ apparatus available from Malvern Instruments Ltd. Particle sizes are determined by measuring the angular distribution of laser light scattered by a homogeneous suspension of particles. The size distribution is determined from the light scattering data using the theory of light scattering as postulated by Gustav Mie.
Orlistat particles having a controlled particle size may be formulated into suitable pharmaceutical formulations using a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be selected from the group comprising of diluents, binders, disintegrants, wetting agents, stabilizers and lubricants, glidants and combinations thereof.
The diluent may be selected from one or more of mannitol, sorbitol, xylitol, lactose, microcrystalline cellulose, magnesium carbonate, calcium carbonate, dicalcium

phosphate, tribasic calcium phosphate, calcium sulphate and magnesium trisilicate. The binder may be selected from one or more of polyvinylpyrrolidone, N-vinyl-2-pyrrolidone/vinyl acetate copolymer, gelatin, hydroxypropylcellulose and hydroxypropyl methylcellulose. The disintegrant may be selected from cross-linked carboxymethylcellulose and its sodium salt, crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxypropyl cellulose and sodium alginate. A suitable wetting agent for e.g. sodium lauryl sulphate may be used in the formulation. The lubricant or glidant may be selected from one or more of talc, magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate, stearic acid, talc and colloidal silicon dioxide.
The pharmaceutical formulations of orlistat particles having a controlled particle size as described herein may be manufactured using any conventional techniques known in the art, namely aqueous or non-aqueous wet granulation, dry granulation, or direct compression. Pelletization technique may also be employed for the preparation of orlistat pellets by extrusion and spheronization, or by granulation in a fluidized bed apparatus or by agglomeration granulation in high shear mixers.
In one embodiment the pharmaceutical formulations of orlistat particles having controlled particle size are prepared by a process, comprising the following steps:
(a) The reduction of particle size of orlistat particles.
(b) The orlistat particles having controlled particle size of step (a) is blended with
microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in
a suitable mixer.
(c) The blend of step (b) is kneaded using an aqueous cooled N-vinyl-2-
pyrrolidone/vinyl acetate copolymer solution.
(d) The wet mass obtained in step (c) is extruded in an Extruder with a suitable
screen.
(e) The extrudate of step (d) is charged to a spheronizer to obtain pellets.
(f) The pellets of step (e) are dried and sized.
(g) The sized pellets of step (f) are mixed with a glidant, such as talc.
(h) The blend of step (g) is optionally filled into size '1' capsules using appropriate tooling.

In another embodiment the pharmaceutical formulations of orlistat particles having controlled particle size are prepared by a process, comprising the following steps:
(a) The reduction of particle size of orlistat particles.
(b) The orlistat particles having controlled particle size of step (a) is blended with
microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in
a suitable mixer.
(c) The blend of step (b) is granulated using an aqueous cooled N-vinyl-2-
pyrrolidone/vinyl acetate copolymer solution.
(d) The wet mass of step (c) is dried and sized.
(e) The sized granules of step (d) are mixed with a glidant, such as talc.
(f) The blend of step (e) is optionally filled into size T capsules using appropriate
tooling.
In one embodiment the pharmaceutical formulations of orlistat particles having controlled particle size are prepared by a process, comprising the following steps:
(a) The reduction of particle size of orlistat particles.
(b) The orlistat particles having controlled particle size of step (a) is blended with
microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in
a suitable mixer.
(c) The blend of step (b) is kneaded using an aqueous cooled N-vinyl-2-
pyrrolidone/vinyl acetate copolymer solution.
(d) The wet mass obtained in step (c) is extruded in an Extruder with a suitable
screen.
(e) The extrudate of step (d) is charged to a spheronizer to obtain pellets.
(f) The pellets of step (e) are dried and sized.
(g) The sized pellets of step (f) are mixed with a glidant, such as talc.
(h) The blend of step (g) is optionally filled into size '3' capsules using appropriate tooling.
In another embodiment the pharmaceutical formulations of orlistat particles having controlled particle size are prepared by a process, comprising the following steps:
(a) The reduction of particle size of orlistat particles.
(b) The orlistat particles having controlled particle size of step (a) is blended with
microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in
a suitable mixer.

(c) The blend of step (b) is granulated using an aqueous cooled N-vinyl-2-
pyrrolidone/vinyl acetate copolymer solution.
(d) The wet mass of step (c) is dried and sized.
(e) The sized granules of step (d) are mixed with a glidant, such as talc.
(f) The blend of step (e) is optionally filled into size '3' capsules using appropriate
tooling.
In another embodiment the pharmaceutical formulations of orlistat particles having controlled particle size are prepared by a process, comprising the following steps:
(a) The reduction of particle size of orlistat particles.
(b) The orlistat particles having controlled particle size of step (a) is blended with
microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in
a suitable mixer.
(c) The blend of step (b) is kneaded using an aqueous cooled gelatin solution.
(d) The wet mass obtained in step (c) is extruded in an Extruder with a suitable
screen.
(e) The extrudate of step (d) is charged to a spheronizer to obtain pellets.
(f) The pellets of step (e) are dried and sized.
(g) The sized pellets of step (f) are mixed with a glidant, such as talc.
(h) The blend of step (g) is optionally filled into size '1' capsules using appropriate tooling.
In another embodiment the pharmaceutical formulations of orlistat particles having controlled particle size are prepared by a process, comprising the following steps:
(a) The reduction of particle size of orlistat particles.
(b) The orlistat particles having controlled particle size of step (a) is blended with
microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in
a suitable mixer.
(c) The blend of step (b) is kneaded using an aqueous cooled Hydroxypropyl
cellulose- L solution.
(d) The wet mass obtained in step (c) is extruded in an Extruder with a suitable
screen.
(e) The extrudate of step (d) is charged to a spheronizer to obtain pellets.
(f) The pellets of step (e) are dried and sized.
(g) The sized pellets of step (f) are mixed with a glidant, such as talc.

(h) The blend of step (g) is optionally filled into size '1' capsules using appropriate tooling.
Formulations containing orlistat particles having a controlled particle size and process for the preparation thereof described herein is further illustrated by the following examples but these should not be construed as limiting the scope of invention.
Examples 1 - 7:
(Examples Removed)
Procedure for Examples 1 and 2:
The active ingredient (orlistat having controlled particle size and unprocessed orlistat for Example 1 and 2 respectively) was mixed with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate and kneaded using a cooled aqueous solution of N-vinyl-2-pyrrolidone/vinyl acetate copolymer. The wet mass so obtained was extruded in an extruder with suitable screen. The extrudate was then charged into a spheronizer to obtain pellets. The pellets so obtained were dried in a Fluidized Bed Dryer, suitably sized, and then blended with talc in a non-shear blender. The final blend was filled into size "1" capsules using appropriate tooling.
Procedure for Example 3:
The active ingredient (orlistat having controlled particle size) was mixed with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate and
granulated using a cooled aqueous solution of N-vinyl-2-pyrrolidone/vinyl acetate copolymer. The wet mass so obtained was dried in a Fluidized Bed Dryer, suitably sized, and then blended with talc in a non-shear blender. The final blend was filled into size "1" capsules using appropriate tooling.
Procedure for Example 4:
The active ingredient (orlistat having controlled particle size) was mixed with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate and kneaded using a cooled aqueous solution of N-vinyl-2-pyrrolidone/vinyl acetate copolymer. The wet mass so obtained was extruded in an extruder with suitable screen. The extrudate was then charged into a spheronizer to obtain pellets. The pellets so obtained were dried in a Fluidized Bed Dryer, suitably sized, and then blended with talc in a non-shear blender. The final blend was filled into size "3" capsules using appropriate tooling.
Procedure for Example 5:
The active ingredient (orlistat having controlled particle size) was mixed with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate and granulated using a cooled aqueous solution of N-vinyl-2-pyrrolidone/vinyl acetate copolymer. The wet mass so obtained was dried in a Fluidized Bed Dryer, suitably sized, and then blended with talc in a non-shear blender. The final blend was filled into size "3" capsules using appropriate tooling.
Procedure for Example 6:
Orlistat was mixed with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate and kneaded using a cooled aqueous solution of gelatin. The wet mass so obtained was extruded in an extruder with suitable screen. The extrudate was then charged into a spheronizer to obtain pellets. The pellets so obtained were dried in a Fluidized Bed Dryer, suitably sized, and then blended with talc in a non-shear blender. The final blend was filled into size "1" capsules using appropriate tooling.

Procedure for Example 7:
Orlistat was mixed with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate and kneaded using a cooled aqueous solution of Hydroxypropyl
cellulose- L. The wet mass so obtained was extruded in an extruder with suitable

screen. The extrudate was then charged into a spheronizer to obtain pellets. The pellets so obtained were dried in a Fluidized Bed Dryer, suitably sized, and then blended with talc in a non-shear blender. The final blend was filled into size "1" capsules using appropriate tooling.
Capsules prepared as per the composition of Examples 1 and 2 were subjected to dissolution studies in a USP || Apparatus in 0.5% sodium chloride+3%Sodium lauryl sulfate in pH 6.0 buffer, (900mL) at 75rpm. Dissolution profiles of these capsules are given in Table 1.
Table 1: In-vitro release pattern of orlistat capsules prepared as per the formulations of Examples 1 and 2 in USP II apparatus in 0.5% sodium chloride+3%Sodium lauryl sulfate in pH6.0 buffer (900mL), at 75 rpm
(Table Removed)

WE CLAIM:
1. A pharmaceutical formulation comprising a therapeutically effective amount of
orlistat particles having a controlled particle size; and at least one
pharmaceutically acceptable carrier, wherein the said orlistat particles have a D50
value not more than 120 micron and D90 value not more than 225 micron.
2. The pharmaceutical formulation of claim 1, wherein orlistat particles are present
in an amount from about 60mg to about 720mg.
3. The pharmaceutical formulation according to claim 1, wherein the
pharmaceutically acceptable carrier is selected from the group comprising of
diluents, binders, wetting agents, disintegrants, lubricants, glidants and
combinations thereof.
4. A process for the preparation a pharmaceutical formulation comprising of orlistat
having a controlled particle size according to claim 1, wherein the process is
extrusion and spheronization.
5. A process for the preparation a pharmaceutical formulation comprising of orlistat
having a controlled particle size according to claim 1, wherein the process is wet
granulation.
6. A pharmaceutical formulation comprising a therapeutically effective amount of
orlistat particles having a controlled particle size and a pharmaceutically
acceptable carrier and the process for the preparation thereof, wherein the said
orlistat particles have a D50 value not more than 120 micron and D90 value not
more than 225 micron, substantially as described and illustrated by examples
herein.