Technical Field of the Invention
The present invention relates to a bioequivalent orlistat formulation and the process of preparation thereof, wherein the said formulation is bioequivalent to the commercially available formulation of orlistat.
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 exerts its pharmacological activity in the lumen of the stomach and intestine by forming covalent bond with the active serine residue of the gastric and pancreatic lipases and consequently renders the enzymes unavailable to hydrolyze dietary triglyceride fat into absorbable free fatty acids and monoglycerides. This results in calorific deficit which may have a positive effect on weight control. 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.
The systemic absorption of orlistat is minimal (approximately 2% of the administered dose is absorbed) even after repeated dosing. Owing to the negligible bioavailability of orlistat and the fact that it binds to gastric and pancreatic lipases in the lumen of the stomach and small intestine, pharmacokinetic parameters have not proved to be effective to demonstrate the efficacy and pharmacological activity of orlistat. Consequently, designing a method to evaluate the therapeutic equivalence for orlistat formulations has proved to be challenging to those skilled in the art. Our prior published document IPCOM000146877D, titled "Method of determination of therapeutic equivalence of orlistat formulations" addresses this problem and identifies a method that can be used to determine the therapeutic equivalence between a commercially available orlistat formulation and its generic version using the pharmacodynamic end

point of mean fecal fat excretion at steady state over a 24-hour interval (FFE24). However, none of the documents in the art disclose an orlistat formulation that would be bioequivalent when compared to the existing marketed orlistat formulation, such as XENICAL® or ALLI® capsules.
The present invention relates to a pharmaceutical formulation comprising a therapeutically effective amount of orlistat and one or more pharmaceutically acceptable excipients, wherein the said formulation is bioequivalent to the commercially available XENICAL® or ALLI® formulation. It also relates to the process of preparation of said formulation.
Summary of the Invention
In one general aspect, it relates to a bioequivalent orlistat formulation comprising a therapeutically effective amount of orlistat, and one or more pharmaceutically acceptable excipients, wherein the said formulation is bioequivalent when compared with the commercially available XENICAL® or ALLI® capsules.
In one general aspect, it relates to a bioequivalent orlistat formulation comprising a therapeutically effective amount of orlistat, and one or more of pharmaceutically acceptable excipients selected from the group comprising of microcrystalline cellulose, N-vinyl-2-pyrrolidone/vinyl acetate copolymer, gelatin, hydroxypropyl cellulose-L, sodium starch glycolate and sodium lauryl sulphate, wherein the said formulation is bioequivalent when compared with the commercially available XENICAL® or ALLI® capsules.
In one general aspect, it relates to a bioequivalent orlistat formulation comprising a therapeutically effective amount of orlistat, and one or more pharmaceutically acceptable excipients, wherein the said formulation is bioequivalent when compared with the commercially available XENICAL® or ALLI® capsules, and wherein the

bioequivalence is determined using a pharmacodynamic end point of mean fecal fat excretion at steady state over a 24-hour interval (FFE24).
In another general aspect, it relates to a bioequivalent orlistat formulation comprising a therapeutically effective amount of orlistat, and one or more of pharmaceutically acceptable excipients selected from the group comprising of microcrystalline cellulose, N-vinyl-2-pyrrolidone/vinyl acetate copolymer, gelatin, hydroxypropylcellulose-L, sodium starch glycolate and sodium lauryl sulphate, wherein the said formulation is bioequivalent when compared with the commercially available XENICAL® or ALLI® capsules, and wherein the bioequivalence is determined using a pharmacodynamic end point of mean fecal fat excretion at steady state over a 24-hour interval (FFE24).
In another general aspect, it relates to a process of preparation of a bioequivalent formulation of orlistat, wherein the process comprises of the following steps:
a) Orlistat is blended with microcrystalline cellulose, sodium starch glycolate and
sodium lauryl sulphate in a suitable mixer.
b) The blend of step (a) is kneaded using a cooled aqueous N-vinyl-2-
pyrrolidone/vinyl acetate copolymer solution.
c) The wet mass obtained in step (b) is extruded in an Extruder with a suitable
screen.
d) The extrudate of step (c) is charged to a spheronizer to obtain pellets.
e) The pellets obtained in step (d) is dried and sized.
f) The sized pellets of step (e) are mixed with a glidant, such as talc.
g) The blend of step (f) is optionally filled into capsules using appropriate tooling,
wherein the said formulation is bioequivalent when compared with the commercially
available XENICAL® or ALLI® capsules.
In another general aspect, it relates to a process of preparation of a bioequivalent formulation of orlistat, wherein the process comprises of the following steps:
a) Orlistat is blended with microcrystalline cellulose, sodium starch glycolate and sodium lauryl sulphate in a suitable mixer.

b) The blend of step (a) is kneaded using an aqueous gelatin solution.
c) The wet mass obtained in step (b) is extruded in an Extruder with a suitable
screen.
d) The extrudate of step (c) is charged to a spheronizer to obtain pellets.
e) The pellets obtained in step (d) is dried and sized.
f) The sized pellets of step (e) are mixed with a glidant, such as talc.
g) The blend of step (f) is optionally filled into capsules using appropriate tooling,
wherein the said formulation is bioequivalent when compared with the commercially
available XENICAL® or ALLI® capsules.
In another general aspect, it relates to a process of preparation of a bioequivalent formulation of orlistat, wherein the process comprises of the following steps:
a) Orlistat is blended with microcrystalline cellulose, sodium starch glycolate and
sodium lauryl sulphate in a suitable mixer.
b) The blend of step (a) is kneaded using a cooled aqueous
hydroxypropylcellulose-L solution.
c) The wet mass obtained in step (b) is extruded in an Extruder with a suitable
screen.
d) The extrudate of step (c) is charged to a spheronizer to obtain pellets.
e) The pellets obtained in step (d) is dried and sized.
f) The sized pellets of step (e) are mixed with a glidant, such as talc.
g) The blend of step (f) is optionally filled into capsules using appropriate tooling,
wherein the said formulation is bioequivalent when compared with the commercially
available XENICAL® or ALLI® capsules.
In another general aspect, it relates to a process of preparation of a bioequivalent formulation of orlistat, wherein the process comprises of the following steps:
a) Orlistat is blended with microcrystalline cellulose, sodium starch glycolate,
and sodium lauryl sulphate in a suitable mixer.
b) The blend of step (a) is granulated using an aqueous cooled N-vinyl-2-
pyrrolidone/vinyl acetate copolymer solution

c) The wet mass of step (b) are dried and sized.
d) The sized granules of step (c) are mixed with a glidant, such as talc.
e) The blend of step (d) is optionally filled into capsules using appropriate
tooling,
wherein the said formulation is bioequivalent when compared with the commercially available XENICAL® capsules.
In one embodiment of the above aspects, the dosage strength is equal to XENICAL® or ALLI® capsules.
Detailed Description of the Invention
The term "bioequivalent" commonly refers to as a product that is a pharmaceutical equivalent to a reference product, wherein the rate and extent of absorption in case of both products are not statistically different when administered to patients or subjects at the same molar dose under similar experimental conditions, i.e. they contain the same active ingredient(s), are of the same dosage form, route of administration and are identical in strength or concentration but may differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients (including colours, flavors, preservatives), expiration time, and, within certain limits, labeling. The intention is to provide therapeutic effect equivalent to the reference product.
The systemic absorption of orlistat is minimal (approximately 2% of the administered dose is absorbed) even after repeated dosing. This has been proved in therapeutic studies involving monitoring of plasma samples, following oral administration of orlistat, when detection of intact orlistat in plasma was found to be sporadic and concentrations were extremely low (<10 ng/mL or 0.02 uM) without evidence of accumulation. The metabolism of orlistat occurs mainly within the gastrointestinal wall, when it primarily forms two metabolites M1 (4-member lactone ring hydrolyzed) and M3 (M1 with N-formyl leucine moiety cleaved). These metabolites have extremely weak lipase inhibitory activity and low plasma levels at the therapeutic dose and hence are

considered pharmacologically inconsequential. Orlistat is found to be eliminated unchanged from the body by the fecal route. The time to reach complete excretion (fecal plus urinary) is 3 to 5 days.
For the determination of therapeutic equivalence, the pharmacokinetic parameters of the drug product to be measured (as appropriate) are usually Cmax, tmax, mean absorption time, mean residence time, Cmax normalized to AUC, ti/2, and cumulative urinary excretion. However, in case of orlistat due to poor plasma and urine concentrations, it is difficult for a person skilled in the art to design a study for the determination of therapeutic equivalence of the drug comprising conventional pharmacokinetic parameters. Therefore, a pharmacodynamic end point of mean fecal fat excretion at steady state over a 24-hour interval (FFE24) is used for the determination of bioequivalence between the orlistat formulation of the present invention and the commercially available orlistat formulations. In one embodiment, the study design and method of assay followed for determination of bioequivalence is as per the disclosure in our prior published document IPCOM000146877D.
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 60 to about 720mg of orlistat that may be administered in an amount from about 180 to about 360mg of orlistat, administered preferably 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 bioequivalent formulations of orlistat 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 bioequivalent formulations of orlistat are prepared by a process, comprising the following steps:
a) Orlistat is blended with microcrystalline cellulose, sodium starch glycolate,
and sodium lauryl sulphate in a suitable mixer.
b) The blend of step (a) is kneaded using an aqueous cooled N-vinyl-2-
pyrrolidone/vinyl acetate copolymer solution.
c) The wet mass obtained in step (b) is extruded in an Extruder with a suitable
screen.
d) The extrudate of step (c) is charged to a spheronizer to obtain pellets.
e) The pellets of step (d) are dried and sized.
f) The sized pellets of step (e) are mixed with a glidant, such as talc.
g) The blend of step (f) is optionally filled into size '1' capsules using appropriate
tooling.
In one embodiment, the bioequivalent formulations of orlistat are prepared by a process, comprising the following steps:
a) Orlistat is blended with microcrystalline cellulose, sodium starch glycolate,
and sodium lauryl sulphate in a suitable mixer.
b) The blend of step (a) is kneaded using an aqueous cooled gelatin solution.
c) The wet mass obtained in step (b) is extruded in an Extruder with a suitable
screen.
d) The extrudate of step (c) is charged to a spheronizer to obtain pellets.
e) The pellets of step (d) are dried and sized.
f) The sized pellets of step (e) are mixed with a glidant, such as talc.

g) The blend of step (f) is optionally filled into size 1 capsules using appropriate tooling.
In one embodiment, the bioequivalent formulations of orlistat are prepared by a process, comprising the following steps:
a) Orlistat is blended with microcrystalline cellulose, sodium starch glycolate,
and sodium lauryl sulphate in a suitable mixer.
b) The blend of step (a) is kneaded using an aqueous cooled
hydroxypropylcellulose-L solution.
c) The wet mass obtained in step (b) is extruded in an Extruder with a suitable
screen.
d) The extrudate of step (c) is charged to a spheronizer to obtain pellets.
e) The pellets of step (d) are dried and sized.
f) The sized pellets of step (e) are mixed with a glidant, such as talc.

g) The blend of step (f) is optionally filled into size T capsules using appropriate
tooling.
In one embodiment, the bioequivalent formulations of orlistat are prepared by a process, comprising the following steps:
a) Orlistat is blended with microcrystalline cellulose, sodium starch glycolate,
and sodium lauryl sulphate in a suitable mixer.
b) The blend of step (a) is granulated using an aqueous cooled N-vinyl-2-
pyrrolidone/vinyl acetate copolymer solution
c) The wet mass of step (b) are dried and sized.
d) The sized granules of step (c) are mixed with a glidant, such as talc.
e) The blend of step (d) is optionally filled into size T capsules using
appropriate tooling.
In one embodiment, the bioequivalent formulations of orlistat are prepared by a process, comprising the following steps:

a) Orlistat is blended with microcrystalline cellulose, sodium starch glycolate,
and sodium lauryl sulphate in a suitable mixer.
b) The blend of step (a) is granulated using an aqueous cooled N-vinyl-2-
pyrrolidone/vinyl acetate copolymer solution
c) The wet mass of step (b) are dried and sized.
d) The sized granules of step (c) are mixed with a glidant, such as talc.
e) The blend of step (d) is optionally filled into size '3' capsules using
appropriate tooling.
In one embodiment, the bioequivalent formulations of orlistat are prepared by a process, comprising the following steps:

a) Orlistat is blended with microcrystalline cellulose, sodium starch glycolate,
and sodium lauryl sulphate in a suitable mixer.
b) The blend of step (a) is kneaded using an aqueous cooled N-vinyl-2-
pyrrolidone/vinyl acetate copolymer solution.
c) The wet mass obtained in step (b) is extruded in an Extruder with a suitable
screen.
d) The extrudate of step (c) is charged to a spheronizer to obtain pellets.
e) The pellets of step (d) are dried and sized.
f) The sized pellets of step (e) are mixed with a glidant, such as talc.
g) The blend of step (f) is optionally filled into size '3' capsules using appropriate
tooling.
Bioequivalent orlistat formulations 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 - 4:
(Table Removed)

Procedure: Example 1
Orlistat 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.
Example 2
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.
Example 3
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.
Example 4
Orlistat 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.
Capsules prepared as per the composition of the invention and commercially available 120mg strength XENICAL® capsules (Lot No. U1347) were subjected to dissolution studies in a USP II Apparatus in 0.5% sodium chloride+3%Sodium lauryl sulfate in pHG.O 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 composition of the invention and commercially available XENICAL® 120mg capsules (Lot No. U1347) in (JSP II apparatus in 0.5% sodium chloride+3%Sodium lauryl sulfate in pH6.0 buffer (900ml_), at 75 rpm
(Table Removed)

Example 5
An open label randomized, steady state, two-way crossover pharmacodynamic study under fed conditions was designed to assess the therapeutic equivalence of XENICAL 120 mg orlistat capsules [Lot No. U1437] and Orlistat 120 mg capsules prepared as per the composition of the invention designated as Reference Product B and Test product A respectively. A run-in period of 5 days was followed by two dosing periods, namely First Dosing Period and Second Dosing Period of ten days each. Throughout the dosing period, Reference Product B and Test product A were administered thrice daily 10 minutes after the first bite of each meal. Fecal fat were collected for each volunteer during the last two days of the run-in period and over the last 5 days of each of the dosing periods. Furthermore, each patient was used as his/her own control in a crossover design, and treatment sequences were randomized, with a washout period between treatments. The study population consisted of 18 healthy adult volunteers (12 males and 6 females), with a mean age 28 years (range of 19-39 years), mean height of 167 cm (range of 152-181 cm), mean weight of 64.3 kg (range of 54.7-78.0 kg) and a mean BMI of 23.0 kg/m2 (range: 19.4-26.7 kg/m2). The study design was optimized to control for external factors that can potentially affect the amount of fat ingested and excreted and to allow a precise collection of feces. Mean values of fat ingested (g/day), excreted (g/day) and FFE24 (%) for the run-in period and after repeated oral administrations of orlistat capsules prepared as per the composition of the invention and

the commercially available XENICAL 120mg capsules (Lot No. U1347) were assayed and the result is presented in Table 2.
Table 2: Mean (CV%) values of fat ingested, excreted and FFE24 during the run-in period and after repeated oral administrations of 120mg orlistat capsules three time daily in healthy subjects.

(Table Removed)
A: Orlistat capsule formulation prepared as per the composition of the invention, B: XENICAL® 120mg capsules (Lot No. U1347)
The ratios of LSM and 90% confidence intervals of untransformed FFE24 values derived from the ANOVA were within 80.0 to 125.0%, suggesting that the orlistat capsule formulation prepared as per the composition of the invention was bioequivalent to the commercially available XENICAL® 120mg capsule formulations under fed conditions in healthy subjects.

WE CLAIM:
1. A bioequivalent orlistat formulation comprising a therapeutically effective amount of
orlistat, and one or more pharmaceutically acceptable excipients, wherein the said
formulation is bioequivalent when compared with the commercially available
XENICAL® or ALLI® capsules.
2. The bioequivalent orlistat formulation according to claim 1, wherein the
pharmaceutically acceptable excipients is selected from a group comprising of
microcrystalline cellulose, N-vinyl-2-pyrrolidone/vinyl acetate copolymer, gelatin,
hydroxypropyl cellulose-L, sodium starch glycolate and sodium lauryl sulphate ,
wherein the said formulation is bioequivalent when compared with the
commercially available XENICAL® or ALLI® capsules.
3. The bioequivalent orlistat formulation according to claim 1, wherein the
bioequivalence is determined using the pharmacodynamic end point of mean fecal
fat excretion at steady state over a 24-hour interval (FFE24).
4. The bioequivalent orlistat formulation according to claim 1, wherein orlistat is
present in an amount of 60mg or 120mg.
5. A process of preparation of a bioequivalent orlistat formulation according to claim
1, wherein the process comprises of:

a) Orlistat is blended with microcrystalline cellulose, sodium starch glycolate,
and sodium lauryl sulphate in a suitable mixer;
b) The blend of step (a) is kneaded using an aqueous cooled solution
comprising of N-vinyl-2-pyrrolidone/vinyl acetate copolymer, gelatin or
hydroxypropylcellulose-L to obtain a wet mass; and
c) Processing the wet mass of step (b) into a dosage form.

6. The process of preparation of bioequivalent orlistat formulation according to claim
5, wherein the process further comprises of the wet mass of (b) being extruded and
spheronized to obtain pellets.
7. The process of preparation of bioequivalent orlistat formulation according to claim
5, wherein the process further comprises of drying and sizing the wet mass of (b) to
obtain granules.
8. The process of preparation of bioequivalent orlistat formulation according to claims
6 or 7 wherein the process further comprises of blending the resulting granules or
pellets with a glidant to obtain a final blend.
9. The process of preparation of bioequivalent orlistat formulation according to claim
8, wherein the process further comprises of filling the final blend in capsules of size
'1' or size '3' using appropriate tooling.
10. The bioequivalent orlistat formulation and process for the preparation thereof
substantially as described and illustrated by examples herein.