WO2012082083A1 - Pharmaceutical formulation containing tetrahydrolipstatin as an active ingredient - Google Patents

Pharmaceutical formulation containing tetrahydrolipstatin as an active ingredient Download PDF

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Publication number
WO2012082083A1
WO2012082083A1 PCT/TN2011/000006 TN2011000006W WO2012082083A1 WO 2012082083 A1 WO2012082083 A1 WO 2012082083A1 TN 2011000006 W TN2011000006 W TN 2011000006W WO 2012082083 A1 WO2012082083 A1 WO 2012082083A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
tetrahydrolipstatin
silica
thl
polyvinyl pyrrolidone
Prior art date
Application number
PCT/TN2011/000006
Other languages
French (fr)
Inventor
Lassaâd BOUJBEL
Mohamed Amine Boujbel
Original Assignee
Les Laboratoires Medis Sa
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 Les Laboratoires Medis Sa filed Critical Les Laboratoires Medis Sa
Publication of WO2012082083A1 publication Critical patent/WO2012082083A1/en

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds

Definitions

  • the invention relates to pharmaceutical composition containing tetrahydrolipstatin as an active ingredient. More particularly, the present invention relates to powder mix of tetrahydrolipstatin, polyvinylpyrrolidone-coated silica and pharmaceutically acceptable ingredients like a suitable filler and lubricant.
  • the composition of present invention prevents picking and sticking providing good technological parameters for formulation of oral dosage forms, for example tablets or hard gelatin capsules.
  • Tetrahydrolipstatin also known by its generic name orlistat, is an inhibitor of pancreatic lipase used as anti-obesity agent. Because of its physico-chemical parameters THL requires special handling conditions. First, with melting point of 44 C, THL is sensitive to thermal degradation, which starts at about 35 C when THL is kept in dry atmosphere, when stored in humid environment, THL undergoes even faster degradation. Second, because of its picking and sticking behavior, tablets or hard gelatin capsules can not be easily formulated either from powder mix or by wet granulation. Hence, there was a need for THL containing formulations which are stable against moisture and heat degradation during production and storage and in which the picking and sticking phenomena is minimized providing good condition for development of conventional oral dosage forms like tablets or hard gelatin capsules.
  • pellets with diameter of 0.25 to 2.0 mm, containing THL are prepared by pelletisation comprising wetting and kneading of both THL and excipients, where particles are prepared in extruder followed by spheronisation and drying.
  • This invention provides pellets which can be simply formulated in any conventional oral formulation.
  • the process is using aqueous solution and requires drying, which means that THL is potentially exposed to both stress factors, i.e. humidity and temperature, during the production process.
  • the present invention offers a possibility to formulate THL containing pharmaceutical preparations by using of powder mix, providing a composition suitable for conventional oral formulation by eliminating wetting and drying of THL during the whole production process. Summary of invention
  • the present invention relates to a product containing powder mix of THL, as active ingredient, polyvinyl pyrrolidone -silica coated particles and pharmaceutically acceptable ingredients like manitol and magnesium stearate.
  • THL containing polyvinyl pyrrolidone-silica coated particles prevent the sticking and picking of the formulation and exhibit good long term THL stability.
  • the subject of invention provides powder mix of THL, polyvinyl pyrrolidone- coated silica particles and pharmaceutical acceptable excipients like suitable filler and lubricant.
  • suitable filler and lubricant like suitable filler and lubricant.
  • the use of mix in hard gelatin capsules is preferred.
  • polyvinyl pyrrolidone-coated particles when mixed with THL provide and excellent protection against humidity.
  • PVP-coated silica particles also minimize picking and sticking phenomenom encountered during THL formulation manipulation, e.g. tablet compression or encapsulation, providing easier manipulation and finalization of THL containing formulations.
  • Composition of the present invention can be prepared by first coating of silica by PVP, drying, and mixing with THL, filler and lubricant.
  • Preferred composition typically contained from 15 to 60% by weight THL, 5 to 25% by weight of PVP coated silica and 20 to 60% of filler, preferably manitol, and lubricant. More preferably, the composition contains 25 to 45% by weight THL, from 10 to 20% by weight PVP coated silica, from 30 to 50% by weight manitol, and about 0.1% magnesium stearate. Preferred ratio silica:PVP ranges from 0.5: 1 to 2:0.5.
  • Such mixtures are chemically stable and can be filled in hard gelatin capsules without sticking and picking.
  • Substantial advantage of the preferred embodiment of this invention is that the THL is not exposed to increased humidity or higher temperature during the whole process which prevents fast degradation.
  • a further advantage of the final direct mixed powder provides reduced picking and sticking making the mixture optimal for formulation in tablets or hard gelatin capsules.
  • Example 1 is illustrative but in no way limit the invention.

Abstract

The present invention relates to pharmaceutical formulation containing tetrahydrolipstatin as an active ingrédient. Composition of present pharmaceutical formulation includes powder mix of tetrahydrolipstatin, polyvinyl pyrrolidone-coated silica, and pharmaceutically acceptable ingrédients like a suitable filler and lubricant. The composition of present invention provides an easy way to oral formulations, for example tablets or hard gelatin capsules.

Description

PHARMACEUTICAL FORMULATION CONTAINING TETRAHYDROLIPSTATIN AS
AN ACTIVE INGREDIENT.
Field of invention
The invention relates to pharmaceutical composition containing tetrahydrolipstatin as an active ingredient. More particularly, the present invention relates to powder mix of tetrahydrolipstatin, polyvinylpyrrolidone-coated silica and pharmaceutically acceptable ingredients like a suitable filler and lubricant. The composition of present invention prevents picking and sticking providing good technological parameters for formulation of oral dosage forms, for example tablets or hard gelatin capsules.
Background of invention
Tetrahydrolipstatin (THL), also known by its generic name orlistat, is an inhibitor of pancreatic lipase used as anti-obesity agent. Because of its physico-chemical parameters THL requires special handling conditions. First, with melting point of 44 C, THL is sensitive to thermal degradation, which starts at about 35 C when THL is kept in dry atmosphere, when stored in humid environment, THL undergoes even faster degradation. Second, because of its picking and sticking behavior, tablets or hard gelatin capsules can not be easily formulated either from powder mix or by wet granulation. Hence, there was a need for THL containing formulations which are stable against moisture and heat degradation during production and storage and in which the picking and sticking phenomena is minimized providing good condition for development of conventional oral dosage forms like tablets or hard gelatin capsules.
As mentioned above, the original approach based on formulation of conventional oral dosage forms, described in U.S. Pat. No. 4,598,089 met technological difficulties because of picking and sticking THL phenomena. The approach based on pellets containing THL prepared by extrusion and spheronisation has been described by U.S. Pat. No. 6,004,996. According to this invention, pellets with diameter of 0.25 to 2.0 mm, containing THL, are prepared by pelletisation comprising wetting and kneading of both THL and excipients, where particles are prepared in extruder followed by spheronisation and drying. This invention provides pellets which can be simply formulated in any conventional oral formulation. However, the process is using aqueous solution and requires drying, which means that THL is potentially exposed to both stress factors, i.e. humidity and temperature, during the production process.
The present invention offers a possibility to formulate THL containing pharmaceutical preparations by using of powder mix, providing a composition suitable for conventional oral formulation by eliminating wetting and drying of THL during the whole production process. Summary of invention
The present invention relates to a product containing powder mix of THL, as active ingredient, polyvinyl pyrrolidone -silica coated particles and pharmaceutically acceptable ingredients like manitol and magnesium stearate.
Surprisingly, it was found that THL containing polyvinyl pyrrolidone-silica coated particles prevent the sticking and picking of the formulation and exhibit good long term THL stability.
Detailed description of the invention
The subject of invention will be described now in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention, however are not to be construed as limitating.
The subject of invention provides powder mix of THL, polyvinyl pyrrolidone- coated silica particles and pharmaceutical acceptable excipients like suitable filler and lubricant. The use of mix in hard gelatin capsules is preferred.
Surprisingly, it was found that polyvinyl pyrrolidone-coated particles when mixed with THL provide and excellent protection against humidity. In addition, besides stabilizing the formulation, PVP-coated silica particles also minimize picking and sticking phenomenom encountered during THL formulation manipulation, e.g. tablet compression or encapsulation, providing easier manipulation and finalization of THL containing formulations.
Composition of the present invention can be prepared by first coating of silica by PVP, drying, and mixing with THL, filler and lubricant.
Preferred composition typically contained from 15 to 60% by weight THL, 5 to 25% by weight of PVP coated silica and 20 to 60% of filler, preferably manitol, and lubricant. More preferably, the composition contains 25 to 45% by weight THL, from 10 to 20% by weight PVP coated silica, from 30 to 50% by weight manitol, and about 0.1% magnesium stearate. Preferred ratio silica:PVP ranges from 0.5: 1 to 2:0.5.
Such mixtures are chemically stable and can be filled in hard gelatin capsules without sticking and picking.
Substantial advantage of the preferred embodiment of this invention is that the THL is not exposed to increased humidity or higher temperature during the whole process which prevents fast degradation. A further advantage of the final direct mixed powder provides reduced picking and sticking making the mixture optimal for formulation in tablets or hard gelatin capsules.
The following examples are illustrative but in no way limit the invention. Example 1
Figure imgf000004_0001
* evaporates during the process
Process:
1) Solubilize PVP in ethanol.
2) Add to the fluid bed colloidal silicon dioxide (in side) and granulate with PVP ethanol solution.
3) Dry the granulate until 0,5% to 2% of moisture.
4) Add to the blender orlistat, crospovidone, dry granulate, lactose, colloidal silicon dioxide (out side), sodium laurilsulfate and talc. Mixture.
5) Encapsulate in hard capsules
Example 2
Figure imgf000004_0002
* evaporates during the process
Process:
1) Solubilize PVP in ethanol.
2) Add to the fluid bed colloidal silicon dioxide (in side) and granulate with PVP ethanol solution.
3) Dry the granulate until 0.5% to 2% of moisture.
4) Add to the blender orlistat, crospovidone, dry granulate, lactose, colloidal silicon dioxide (out side) and magnesium stearate. Mixture.
5) Encapsulate in hard capsules.

Claims

Example 3 Process: 1) Solubilize PVP in ethanol. 2) Add to the fluid bed colloidal silicon dioxide (in side) and granulate with PVP ethanol solution. 3) Dry the granulate until 0.5% to 2% of moisture. 4) Add to the blender orlistat, crospovidone, dry granulate, mannitol, sodium laurilsulfate, colloidal silicon dioxide (out side) and magnesium stearate. Mixture. 5) Encapsulate in hard capsules. Claims What is claimed is:
1. Pharmaceutical composition comprising a powder mixture of tetrahydrolipstatin, silica, and pharmaceutically acceptable excipients like a suitable filler and lubricant
2. Composition of claim 1 , wherein silica is coated by polyvinyl pyrrolidone, dried and mixed directly with tetrahydrolipstatin
3. Composition of claim 2, wherein the ratio silica and polyvinyl pyrrolidone varies between 0.5:1 to 2:05 %.
4. Composition of claim 1 , wherein polyvinyl pyrrolidone coated silica acts as a stabilizer.
5. Composition of claim 1, wherein manitol is used as a filler
6. Composition of claim 1 , wherein magnesium stearate is used as a lubricant
7. Composition of claim 1 , which comprises about 15 to 60% tetrahydrolipstatin, about 2 to 25% polyvinylpyrrolidone coated silica, about 20 to 60% manitol,
8. Composition of claim 1 which is in unit dosage form
9. Composition of claim 4 which is in unit dosage form
10. Composition of claim 1 which comprises about 120 mg of tetrahydrolipstatin.
11. Compositon of claim 1 which comprises about 60 mg of THL.
12. Composition of claim 9 which is in unit dosage form.
PCT/TN2011/000006 2010-12-15 2011-12-14 Pharmaceutical formulation containing tetrahydrolipstatin as an active ingredient WO2012082083A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TNTN2010/0581 2010-12-15
TN10581 2010-12-15

Publications (1)

Publication Number Publication Date
WO2012082083A1 true WO2012082083A1 (en) 2012-06-21

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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 (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040126424A1 (en) * 2002-12-17 2004-07-01 Jandacek Ronald James Compositions, methods, and kits useful for the alleviation of gastrointestinal effects
US20080200536A1 (en) * 2005-08-17 2008-08-21 Boram Pharm.Co., Ltd Pharmaceutical Formulation with High Stability and Dissolution and Manufacturing Process
WO2009039157A2 (en) * 2007-09-17 2009-03-26 Dr. Reddy's Laboratories Ltd. Orlistat pharmaceutical formulations
WO2009050720A1 (en) * 2007-10-15 2009-04-23 Inventis Dds Pvt Limited Pharmaceutical composition of orlistat
WO2009116880A2 (en) * 2008-03-20 2009-09-24 Zaklady Farmaceutyczne Polpharma Sa Process for obtaining powder compositions of orlistat

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040126424A1 (en) * 2002-12-17 2004-07-01 Jandacek Ronald James Compositions, methods, and kits useful for the alleviation of gastrointestinal effects
US20080200536A1 (en) * 2005-08-17 2008-08-21 Boram Pharm.Co., Ltd Pharmaceutical Formulation with High Stability and Dissolution and Manufacturing Process
WO2009039157A2 (en) * 2007-09-17 2009-03-26 Dr. Reddy's Laboratories Ltd. Orlistat pharmaceutical formulations
WO2009050720A1 (en) * 2007-10-15 2009-04-23 Inventis Dds Pvt Limited Pharmaceutical composition of orlistat
WO2009116880A2 (en) * 2008-03-20 2009-09-24 Zaklady Farmaceutyczne Polpharma Sa Process for obtaining powder compositions of orlistat

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

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