[go: up one dir, main page]

WO2009044380A2 - Formulations containing orlistat particles having controlled particle size - Google Patents

Formulations containing orlistat particles having controlled particle size Download PDF

Info

Publication number
WO2009044380A2
WO2009044380A2 PCT/IB2008/054068 IB2008054068W WO2009044380A2 WO 2009044380 A2 WO2009044380 A2 WO 2009044380A2 IB 2008054068 W IB2008054068 W IB 2008054068W WO 2009044380 A2 WO2009044380 A2 WO 2009044380A2
Authority
WO
WIPO (PCT)
Prior art keywords
orlistat
particle size
particles
pharmaceutical formulation
controlled particle
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2008/054068
Other languages
French (fr)
Other versions
WO2009044380A3 (en
Inventor
Shanmugam Kumar
Girish Karanth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2009044380A2 publication Critical patent/WO2009044380A2/en
Publication of WO2009044380A3 publication Critical patent/WO2009044380A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones

Definitions

  • the present invention relates to pharmaceutical formulations comprising a therapeutically effective amount of orlistat particles having a controlled particle size, wherein the formulations exhibit enhanced absorption and dissolution characteristics.
  • Orlistat tetrahydrolipstatin is a reversible lipase inhibitor which is chemically described as (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo- 2-oxetanyl] methylj-dodecyl ester. Orlistat is disclosed specifically in U.S. Patent No.
  • 4,598,089 which also describes a 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/m 2 or > 27 kg/m 2 in the presence of other risk factors (e.g., hypertension, diabetes, and dyslipidemia).
  • BMI body mass index
  • orlistat is commercially available as XENICAL ® conventional hard gelatin capsules in strengths of 120 mg from Hoffman La-Roche, Basel, Switzerland.
  • the recommended dose of orlistat is one 120 mg capsule three times a day with each meal containing fat (during or up to 1 hour after the meal).
  • Glaxo SmithKline has launched 60 mg strength capsules of orlistat in the USA for over-the-counter use under the proprietary name ALLI ® .
  • U.S. Patent No. 6,004,996 discloses a pharmaceutical composition of orlistat which comprises a plurality of particles having an average diameter of from 0.25mm to 2mm, wherein each particle contains tetrahydrolipstatin, polyvinylpyrrolidone, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulphate and talc.
  • U.S. Patent No. 6,004,996 discloses a pharmaceutical composition of orlistat which comprises a plurality of particles having an average diameter of from 0.25mm to 2mm, wherein each particle contains tetrahydrolipstatin, polyvinylpyrrolidone, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulphate and talc.
  • 6,358,522 discloses 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 emulsif ⁇ ers, 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.
  • Indian patent application 62/D EL/2006 describes a stable pharmaceutical composition comprising crystalline Form I of orlistat, wherein Form I does not convert into Form II over normal storage temperature over a period of time.
  • a therapeutically effective amount of orlistat particles having a controlled particle size has been formulated into suitable pharmaceutical dosage forms, such that the dosage forms exhibit improved dissolution properties.
  • compositions comprising a therapeutically effective amount of orlistat particles having a controlled particle size and a pharmaceutically acceptable carrier are provided herein.
  • compositions comprising a therapeutically effective amount of orlistat particles having a controlled particle size and a pharmaceutically acceptable carrier, wherein the orlistat particles have a D50 value not more than 120 micron and D90 value not more than 225 micron are provided herein.
  • processes for the preparation of pharmaceutical formulations comprising orlistat particles having a controlled particle size wherein the orlistat particles have a D50 value of not more than about 120 micron and D90 value not more than about 225 micron are provided herein.
  • processes for the preparation of pharmaceutical formulations comprising orlistat particles having a controlled particle size wherein the process comprises extrusion and spheronization are provided herein.
  • processes for the preparation of pharmaceutical formulations comprising orlistat particles having a controlled particle size, wherein the process comprises wet granulation are provided herein.
  • terapéuticaally effective amount is understood to mean an effective dose of orlistat which stops or reduces the progress of a condition to be treated or which otherwise completely or partly cures or acts palliatively on such a condition.
  • the dose may range from about 60 mg to about 720 mg of orlistat.
  • orlistat may be administered in an amount from about 180 to about 360 mg of orlistat, administered in divided doses two or three times per day.
  • the recommended dose of XENIC AL ® which is 120 mg or ALLI ® which is 60 mg 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, suspensions or emulsions.
  • orlistat particles having a controlled particle size as used herein include orlistat particles which have been subjected 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 include, for example, comminution, spray drying, recrystallization of poorly soluble materials using liquid solvents and antisolvents, and the like.
  • Comminution techniques like milling rely upon mechanical stress to reduce particle size which may be done in conventionally known mills, including, for example, ball mills, colloid mills, grinding mills, air jet mills, roller mills, impact mills, and the like.
  • Another method for reducing the particle size and having a controlled size range distribution is, for example, 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.
  • orlistat particles having controlled particle size have been obtained by sieving.
  • orlistat particles having a D50 particle size of not more than about 120 micron, and a D90 particle size of not more than about 225 micron results in improved bioavailability of orlistat pharmaceutical compositions as compared to pharmaceutical compositions that contain orlistat with larger particle sizes.
  • Orlistat particles having a D50 particle size of not more than about 120 micron, and a D90 particle size of not more than about 225 micron as referred to herein as "orlistat particles having a controlled particle size”.
  • the D 50 and D 90 represent the median or the 50 th percentile and the 90 th percentile of the particle size distribution, respectively, as measured by volume.
  • D50 is defined as the size in microns below which 50 percent of the particles reside on a volume basis
  • D90 is defined as the size in microns below which 90 percent of the particles reside, on a volume basis.
  • Particle size can be determined, for example, by laser light scattering using a particle size analyser, such as the proprietary MastersizerTM apparatus available from Malvern Instruments Ltd.
  • Orlistat particles having a controlled particle size may be formulated into suitable pharmaceutical formulations using pharmaceutically acceptable carriers.
  • the pharmaceutically acceptable carriers may be selected from, for example, diluents, binders, disintegrants, wetting agents, stabilizers and lubricants, glidants and combinations thereof.
  • the diluent may be selected from one or more of, for example, 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, for example, one or more of polyvinylpyrrolidone, N-vinyl-2-pyrrolidone/vinyl acetate copolymer, gelatin, hydroxypropylcellulose and hydroxypropyl methylcellulose.
  • the disintegrant may be selected from, for example, 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 can be, for example,, sodium lauryl sulphate.
  • the lubricant or glidant may be selected from one or more of, for example, 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 conventional techniques known in the art, for example, aqueous or non-aqueous wet granulation, dry granulation, or direct compression.
  • a 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.
  • step (b) blending the orlistat particles having controlled particle size of step (a) with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in a suitable mixer; (c) kneading the blend of step (b) using an aqueous cooled N-vinyl-2- pyrrolidone/vinyl acetate copolymer solution;
  • step (d) extruding the wet mass obtained in step (c) in an Extruder with a suitable screen
  • step (e) charging the extrudate of step (d) to a spheronizer to obtain pellets; (f) drying and sizing the pellets of step (e);
  • step (g) mixing the sized pellets of step (f) with a glidant
  • step (h) optionally filling the blend of step (g) into capsules using appropriate tooling.
  • step (b) blending the orlistat particles having controlled particle size of step (a) with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in a suitable mixer; (c) granulating the blend of step (b) using an aqueous cooled N-vinyl-2- pyrrolidone/vinyl acetate copolymer solution; (d) drying and sizing the wet mass of step (c); (e) mixing the sized granules of step (d) with a glidant; and
  • step (f) optionally filling the blend of step (e) into capsules using appropriate tooling.
  • step (b) blending the orlistat particles having controlled particle size of step (a) with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in a suitable mixer; (c) kneading the blend of step (b) using an aqueous cooled N-vinyl-2- pyrrolidone/vinyl acetate copolymer solution;
  • step (d) extruding the wet mass obtained in step (c) in an Extruder with a suitable screen
  • step (e) charging the extrudate of step (d) to a spheronizer to obtain pellets; (f) drying and sizing the pellets of step (e);
  • step (g) mixing the sized pellets of step (f) with a glidant
  • step (h) optionally filling the blend of step (g) into capsules using appropriate tooling.
  • step (b) blending the orlistat particles having controlled particle size of step (a) with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in a suitable mixer; (c) granulating the blend of step (b) using an aqueous cooled N-vinyl-2- pyrrolidone/vinyl acetate copolymer solution;
  • step (d) drying and sizing the wet mass of step (c);
  • step (e) mixing the sized granules of step (d) with a glidant
  • step (f) optionally filling the blend of step (e) into capsules using appropriate tooling.
  • the pharmaceutical formulations of orlistat particles having controlled particle size can be prepared by a process comprising: (a) the reduction of particle size of orlistat particles;
  • step (b) blending the orlistat particles having controlled particle size of step (a) with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in a suitable mixer; (c) kneading the blend of step (b) using an aqueous cooled gelatin solution;
  • step (d) extruding the wet mass obtained in step (c) in an Extruder with a suitable screen
  • step (e) charging the extrudate of step (d) to a spheronizer to obtain pellets;
  • step (f) drying and sizing the pellets of step (e); (g) mixing the sized pellets of step (f) with a glidant;
  • step (h) optionally filling the blend of step (g) into capsules using appropriate tooling.
  • the pharmaceutical formulations of orlistat particles having controlled particle size can be prepared by a process comprising: (a) the reduction of particle size of orlistat particles;
  • step (b) blending the orlistat particles having controlled particle size of step (a) with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in a suitable mixer;
  • step (c) kneading the blend of step (b) using an aqueous cooled hydroxypropyl cellulose- L solution;
  • step (d) extruding the wet mass obtained in step (c) in an Extruder with a suitable screen
  • step (e) charging the extrudate of step (d) to a spheronizer to obtain pellets;
  • step (f) drying and sizing the pellets of step (e); (g) mixing the sized pellets of step (f) with a glidant;
  • step (h) optionally filling the blend of step (g) into capsules using appropriate tooling.
  • Orlistat having controlled particle size (D 50 of 72.0 microns, D 90 of 168.1 microns) and unprocessed orlistat for Example 1 and 2, respectively, were 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.
  • Orlistat having controlled particle size (see specification of Example 1) 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.
  • Orlistat having controlled particle size (see specifications of Example 1) 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.
  • Example 5 Orlistat having controlled particle size (see specifications of Example 1) 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.
  • Orlistat (see specifications of Example 1) 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 7 Orlistat (see specifications of Example 1) 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 II Apparatus in 0.5% sodium chloride+3%Sodium lauryl sulfate in pH 6.0 buffer, (90OmL) at 75 rpm. 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 (90OmL), at 75 rpm

Landscapes

  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to pharmaceutical formulations comprising a therapeutically effective amount of orlistat particles having a controlled particle size and a pharmaceutically acceptable carrier, wherein the formulations exhibit enhanced absorption and dissolution characteristics, and wherein the orlistat particles have a D50 value of not more than about 120 micron and D90 value of not more than about 225 micron.

Description

FORMULATIONS CONTAINING ORLISTAT PARTICLES HAVING CONTROLLED PARTICLE SIZE
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 formulations exhibit enhanced absorption and dissolution characteristics.
Background of the Invention
Orlistat (tetrahydrolipstatin) is a reversible lipase inhibitor which is chemically described as (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo- 2-oxetanyl] methylj-dodecyl ester. Orlistat is disclosed specifically in U.S. Patent No.
4,598,089 which also describes a 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 120 mg from Hoffman La-Roche, Basel, Switzerland. The recommended dose of orlistat is one 120 mg capsule three times a day with each meal containing fat (during or up to 1 hour after the meal). Recently Glaxo SmithKline has launched 60 mg strength capsules of orlistat in the USA for over-the-counter use under the proprietary name ALLI®.
Several references relate to formulations comprising orlistat. U.S. Patent No. 6,004,996 discloses a pharmaceutical composition of orlistat which comprises a plurality of particles having an average diameter of from 0.25mm to 2mm, wherein each particle contains tetrahydrolipstatin, polyvinylpyrrolidone, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulphate and talc. U.S. Patent No. 6,358,522 discloses 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 emulsifϊers, 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. Indian patent application 62/D EL/2006 describes a stable pharmaceutical composition comprising crystalline Form I of orlistat, wherein Form I does not convert into Form II over normal storage temperature over a period of time. Orlistat being practically insoluble in aqueous media, exhibits a generally poor dissolution profile and consequently poor bioavailability. Hence, there exists a need to design a formulation comprising orlistat which would exhibit acceptable absorption and dissolution and at the same time would be manufactured by a simple, cost-effective and industrially viable process. Summary of the Invention
A therapeutically effective amount of orlistat particles having a controlled particle size has been formulated into suitable pharmaceutical dosage forms, such that the dosage forms exhibit improved dissolution properties.
In one general aspect, pharmaceutical formulations comprising a therapeutically effective amount of orlistat particles having a controlled particle size and a pharmaceutically acceptable carrier are provided herein.
In another general aspect, pharmaceutical formulations comprising a therapeutically effective amount of orlistat particles having a controlled particle size and a pharmaceutically acceptable carrier, wherein the orlistat particles have a D50 value not more than 120 micron and D90 value not more than 225 micron are provided herein.
In another general aspect, processes for the preparation of pharmaceutical formulations comprising orlistat particles having a controlled particle size, wherein the orlistat particles have a D50 value of not more than about 120 micron and D90 value not more than about 225 micron are provided herein. In another general aspect, processes for the preparation of pharmaceutical formulations comprising orlistat particles having a controlled particle size, wherein the process comprises extrusion and spheronization are provided herein.
In another general aspect, processes for the preparation of pharmaceutical formulations comprising orlistat particles having a controlled particle size, wherein the process comprises wet granulation are provided herein.
Detailed Description of the Invention
The term "therapeutically effective amount", as used herein, is understood to mean an effective dose of orlistat which stops or reduces the progress of a condition to be treated or which otherwise completely or partly cures or acts palliatively on such a condition. The dose may range from about 60 mg to about 720 mg of orlistat. For example, orlistat may be administered in an amount from about 180 to about 360 mg of orlistat, administered in divided doses two or three times per day. The recommended dose of XENIC AL® which is 120 mg or ALLI® which is 60 mg 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, suspensions or emulsions.
The term "reduction of particle size" as described herein means a 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 subjected 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 include, for example, comminution, spray drying, recrystallization of poorly soluble materials using liquid solvents and antisolvents, and the like. Comminution techniques like milling rely upon mechanical stress to reduce particle size which may be done in conventionally known mills, including, for example, ball mills, colloid mills, grinding mills, air jet mills, roller mills, impact mills, and the like. Another method for reducing the particle size and having a controlled size range distribution is, for example, 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 have been obtained by sieving.
The reduction of the particle size of orlistat particles to a D50 particle size of not more than about 120 micron, and a D90 particle size of not more than about 225 micron, results in improved bioavailability of orlistat pharmaceutical compositions as compared to pharmaceutical compositions that contain orlistat with larger particle sizes. Orlistat particles having a D50 particle size of not more than about 120 micron, and a D90 particle size of not more than about 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. Particle size can be determined, for example, by laser light scattering using a particle size analyser, such as the proprietary Mastersizer™ apparatus available from Malvern Instruments Ltd.
Orlistat particles having a controlled particle size may be formulated into suitable pharmaceutical formulations using pharmaceutically acceptable carriers. The pharmaceutically acceptable carriers may be selected from, for example, diluents, binders, disintegrants, wetting agents, stabilizers and lubricants, glidants and combinations thereof.
The diluent may be selected from one or more of, for example, 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, for example, one or more of polyvinylpyrrolidone, N-vinyl-2-pyrrolidone/vinyl acetate copolymer, gelatin, hydroxypropylcellulose and hydroxypropyl methylcellulose. The disintegrant may be selected from, for example, 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 can be, for example,, sodium lauryl sulphate. The lubricant or glidant may be selected from one or more of, for example, 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 conventional techniques known in the art, for example, aqueous or non-aqueous wet granulation, dry granulation, or direct compression. A 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 can be prepared by a process comprising:
(a) the reduction of particle size of orlistat particles;
(b) blending the orlistat particles having controlled particle size of step (a) with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in a suitable mixer; (c) kneading the blend of step (b) using an aqueous cooled N-vinyl-2- pyrrolidone/vinyl acetate copolymer solution;
(d) extruding the wet mass obtained in step (c) in an Extruder with a suitable screen;
(e) charging the extrudate of step (d) to a spheronizer to obtain pellets; (f) drying and sizing the pellets of step (e);
(g) mixing the sized pellets of step (f) with a glidant; and
(h) optionally filling the blend of step (g) into capsules using appropriate tooling.
In another embodiment the pharmaceutical formulations of orlistat particles having controlled particle size can be prepared by a process comprising:
(a) the reduction of particle size of orlistat particles;
(b) blending the orlistat particles having controlled particle size of step (a) with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in a suitable mixer; (c) granulating the blend of step (b) using an aqueous cooled N-vinyl-2- pyrrolidone/vinyl acetate copolymer solution; (d) drying and sizing the wet mass of step (c); (e) mixing the sized granules of step (d) with a glidant; and
(f) optionally filling the blend of step (e) into capsules using appropriate tooling.
In one embodiment the pharmaceutical formulations of orlistat particles having controlled particle size can be prepared by a process comprising:
(a) the reduction of particle size of orlistat particles;
(b) blending the orlistat particles having controlled particle size of step (a) with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in a suitable mixer; (c) kneading the blend of step (b) using an aqueous cooled N-vinyl-2- pyrrolidone/vinyl acetate copolymer solution;
(d) extruding the wet mass obtained in step (c) in an Extruder with a suitable screen;
(e) charging the extrudate of step (d) to a spheronizer to obtain pellets; (f) drying and sizing the pellets of step (e);
(g) mixing the sized pellets of step (f) with a glidant; and
(h) optionally filling the blend of step (g) into capsules using appropriate tooling.
In another embodiment the pharmaceutical formulations of orlistat particles having controlled particle size can be prepared by a process comprising:
(a) the reduction of particle size of orlistat particles;
(b) blending the orlistat particles having controlled particle size of step (a) with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in a suitable mixer; (c) granulating the blend of step (b) using an aqueous cooled N-vinyl-2- pyrrolidone/vinyl acetate copolymer solution;
(d) drying and sizing the wet mass of step (c);
(e) mixing the sized granules of step (d) with a glidant; and
(f) optionally filling the blend of step (e) into capsules using appropriate tooling.
In another embodiment the pharmaceutical formulations of orlistat particles having controlled particle size can be prepared by a process comprising: (a) the reduction of particle size of orlistat particles;
(b) blending the orlistat particles having controlled particle size of step (a) with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in a suitable mixer; (c) kneading the blend of step (b) using an aqueous cooled gelatin solution;
(d) extruding the wet mass obtained in step (c) in an Extruder with a suitable screen;
(e) charging the extrudate of step (d) to a spheronizer to obtain pellets;
(f) drying and sizing the pellets of step (e); (g) mixing the sized pellets of step (f) with a glidant; and
(h) optionally filling the blend of step (g) into capsules using appropriate tooling.
In another embodiment the pharmaceutical formulations of orlistat particles having controlled particle size can be prepared by a process comprising: (a) the reduction of particle size of orlistat particles;
(b) blending the orlistat particles having controlled particle size of step (a) with microcrystalline cellulose, sodium starch glycolate, and sodium lauryl sulphate in a suitable mixer;
(c) kneading the blend of step (b) using an aqueous cooled hydroxypropyl cellulose- L solution;
(d) extruding the wet mass obtained in step (c) in an Extruder with a suitable screen;
(e) charging the extrudate of step (d) to a spheronizer to obtain pellets;
(f) drying and sizing the pellets of step (e); (g) mixing the sized pellets of step (f) with a glidant; and
(h) optionally filling the blend of step (g) into capsules using appropriate tooling.
Formulations containing orlistat particles having a controlled particle size and processes for the preparation thereof described herein are further illustrated by the following examples but these do not limit the scope of invention. Examples 1 - 7:
Figure imgf000009_0001
Procedure for Examples 1 and 2:
Orlistat having controlled particle size (D50 of 72.0 microns, D90 of 168.1 microns) and unprocessed orlistat for Example 1 and 2, respectively, were 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:
Orlistat having controlled particle size (see specification of Example 1) 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:
Orlistat having controlled particle size (see specifications of Example 1) 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: Orlistat having controlled particle size (see specifications of Example 1) 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 (see specifications of Example 1) 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 (see specifications of Example 1) 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 II Apparatus in 0.5% sodium chloride+3%Sodium lauryl sulfate in pH 6.0 buffer, (90OmL) at 75 rpm. 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 (90OmL), at 75 rpm
Figure imgf000011_0001

Claims

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 orlistat particles have a D50 value of not more than about 120 micron and D90 value of not more than about 225 micron.
2. The pharmaceutical formulation of claim 1 , wherein orlistat particles are present in an amount of from about 60 mg to about 720 mg.
3. The pharmaceutical formulation according to claim 1, wherein the pharmaceutically acceptable carrier is selected from diluents, binders, wetting agents, disintegrants, lubricants, glidants and combinations thereof.
4. The pharmaceutical formulation according to claim 3, wherein the diluent is 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.
5. The pharmaceutical formulation according to claim 3, wherein the binder is selected from one or more of polyvinylpyrrolidone, N-vinyl-2-pyrrolidone/vinyl acetate copolymer, gelatin, hydroxypropylcellulose and hydroxypropyl methylcellulose.
6. The pharmaceutical formulation according to claim 3, wherein the wetting agent is sodium lauryl sulphate.
7. The pharmaceutical formulation according to claim 3, wherein the disintegrants are selected from one or more of cross-linked carboxymethylcellulose and its sodium salt, crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxypropyl cellulose and sodium alginate.
8. The pharmaceutical formulation according to claim 3, wherein the lubricant or glidant is selected from one or more of talc, magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate, stearic acid, talc and colloidal silicon dioxide.
9. A process for the preparation of a pharmaceutical formulation comprising of orlistat having a controlled particle size, wherein the process comprises extrusion and spheronization.
10. A process for the preparation of a pharmaceutical formulation comprising of orlistat having a controlled particle size, wherein the process comprises wet granulation.
PCT/IB2008/054068 2007-10-05 2008-10-03 Formulations containing orlistat particles having controlled particle size Ceased WO2009044380A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2091/DEL/2007 2007-10-05
IN2091DE2007 2007-10-05

Publications (2)

Publication Number Publication Date
WO2009044380A2 true WO2009044380A2 (en) 2009-04-09
WO2009044380A3 WO2009044380A3 (en) 2010-01-14

Family

ID=40451344

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2008/054068 Ceased WO2009044380A2 (en) 2007-10-05 2008-10-03 Formulations containing orlistat particles having controlled particle size

Country Status (1)

Country Link
WO (1) WO2009044380A2 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009116880A3 (en) * 2008-03-20 2009-12-10 Zaklady Farmaceutyczne Polpharma Sa Process for obtaining powder compositions of orlistat to be filled into a capsule
WO2011091816A1 (en) * 2010-02-01 2011-08-04 Laboratorios Bagó S.A. Pharmaceutical composition with anti-obesity activity comprising a premixture of pure orlistat and preparation process
KR101833250B1 (en) 2010-10-25 2018-03-02 한미사이언스 주식회사 Spherical extruded granule comprising an active ingredient having a low melting point, tablet for oral administration comprising the same, and method for the preparation thereof
US10835495B2 (en) 2012-11-14 2020-11-17 W. R. Grace & Co.-Conn. Compositions containing a biologically active material and a non-ordered inorganic oxide material and methods of making and using the same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4598089A (en) 1983-06-22 1986-07-01 Hoffmann-La Roche Inc. Leucine derivatives
US6004996A (en) 1997-02-05 1999-12-21 Hoffman-La Roche Inc. Tetrahydrolipstatin containing compositions
US6358522B1 (en) 1998-08-14 2002-03-19 Hoffmann-La Roche Inc. Pharmaceutical compositions containing lipase inhibitor
WO2007021073A1 (en) 2005-08-17 2007-02-22 Boram Pharm.Co., Ltd. Pharmaceutical formulation with high stability and dissolution and manufacturing process

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006110809A2 (en) * 2005-04-12 2006-10-19 Elan Pharma International, Limited Nanoparticulate lipase inhibitor formulations
WO2009039157A2 (en) * 2007-09-17 2009-03-26 Dr. Reddy's Laboratories Ltd. Orlistat pharmaceutical formulations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4598089A (en) 1983-06-22 1986-07-01 Hoffmann-La Roche Inc. Leucine derivatives
US6004996A (en) 1997-02-05 1999-12-21 Hoffman-La Roche Inc. Tetrahydrolipstatin containing compositions
US6358522B1 (en) 1998-08-14 2002-03-19 Hoffmann-La Roche Inc. Pharmaceutical compositions containing lipase inhibitor
WO2007021073A1 (en) 2005-08-17 2007-02-22 Boram Pharm.Co., Ltd. Pharmaceutical formulation with high stability and dissolution and manufacturing process

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009116880A3 (en) * 2008-03-20 2009-12-10 Zaklady Farmaceutyczne Polpharma Sa Process for obtaining powder compositions of orlistat to be filled into a capsule
EP2268266A2 (en) 2008-03-20 2011-01-05 Zaklady Farmaceutyczne "Polpharma" S.A. Process for obtaining powder compositions of orlistat to be filled into a capsule
EP3682869A1 (en) * 2008-03-20 2020-07-22 Zaklady Farmaceutyczne Polpharma S.A. Process for obtaining powder compositions of orlistat
WO2011091816A1 (en) * 2010-02-01 2011-08-04 Laboratorios Bagó S.A. Pharmaceutical composition with anti-obesity activity comprising a premixture of pure orlistat and preparation process
US20120294941A1 (en) * 2010-02-01 2012-11-22 Eastbrand Holding Gmbh Pharmaceutical composition with anti-obesity activity comprising a premixture of pure orlistat and preparation process
US8685449B2 (en) 2010-02-01 2014-04-01 Laboratorios Bago S.A. Pharmaceutical composition with anti-obesity activity comprising a premixture of pure orlistat and preparation process
KR101833250B1 (en) 2010-10-25 2018-03-02 한미사이언스 주식회사 Spherical extruded granule comprising an active ingredient having a low melting point, tablet for oral administration comprising the same, and method for the preparation thereof
US10835495B2 (en) 2012-11-14 2020-11-17 W. R. Grace & Co.-Conn. Compositions containing a biologically active material and a non-ordered inorganic oxide material and methods of making and using the same

Also Published As

Publication number Publication date
WO2009044380A3 (en) 2010-01-14

Similar Documents

Publication Publication Date Title
KR100876302B1 (en) Method for preparing telmisartan, which is in fact amorphous form
CN1642526A (en) Formulations of atorvastatin stabilized with alkali metal additions
WO2010035282A1 (en) Pharmaceutical compositions comprising deferasirox
WO2015189386A1 (en) Composition with a high drug load of sofosbuvir
ZA200309289B (en) Oxcarbazepine dosage forms.
WO2015124995A1 (en) Solid dosage forms of rivaroxaban
EA028950B1 (en) Process for preparing pharmaceutical compositions comprising fingolimod
CN1214791C (en) Quinoline keto derivatives medicinal composition and its preparing method
CN101351192A (en) Pharmaceutical composition of wet granulation of aripiprazole
EP1814593A1 (en) An oral preparation having improved bioavailability
AU757547B2 (en) Novel compositions of eprosartan
WO2009044380A2 (en) Formulations containing orlistat particles having controlled particle size
JP2004525887A (en) New fenofibrate tablets
EP2701689B1 (en) Pharmaceutical compositions of raltegravir, methods of preparation and use thereof
CN115957183A (en) Canagliflozin composition and preparation method thereof
JP2015536969A (en) Co-micronized products containing selective progesterone receptor modulators
EP3784218A1 (en) Tablet compositions comprising abiraterone acetate
US20250000839A1 (en) Pharmaceutical composition comprising enavogliflozin
CN109925293B (en) Eplerenone oral solid preparation and preparation method thereof
EP2846778B1 (en) Oral solid dosage formulation of 1,1-dimethylethyl [(1s)-1-{[(2s,4r)-4-(7-chloro-4methoxyisoquinolin-1-yloxy)-2-({(1r,2s)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}carbamoyl)pyrrolidin-1-yl]carbonyl}-2,2-dimethylpropyl]carbamate
KR20230048032A (en) Oral solid preparation containing carbamate compound and preparation method thereof
JP2025526729A (en) Amorphous solid dispersions containing napolafenib
JP2011513328A (en) Valsartan solid oral dosage form and method for producing such a formulation
EP4321154A1 (en) A tablet of tolvaptan and at least one binder processed with spray granulation
WO2026019402A1 (en) A pharmaceutical composition comprising nanosuspension of canagliflozin

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08807882

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08807882

Country of ref document: EP

Kind code of ref document: A2