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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • 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
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to injectable or orally administered formulations of azetidine derivatives.
• azetidine derivatives used in the pharmaceutical compositions according to the invention may be designated by the following general formula (Ia) or (Ib):
• Ar is an aromatic or heteroaromatic group optionally substituted by one or more (Cl-C4) alkyl, halogen, NO 2, CN, (Cl- C4) alkoxy or OH.
• aromatic group is understood to mean in particular a phenyl, naphthyl group, heteroaromatic group, a pyridyl, furyl, thienyl, thiazolyl, imidazolyl or oxazolyl group, and by halogen, fluorine, chlorine, bromine or iodine.
• azetidine derivatives of general formula (Ia) or (Ib) have been described as well as their applications.
• these azetidine derivatives are particularly interesting for their strong affinity for cannabinoid receptors and particularly CB1 type receptors.
• compositions comprising a digestible oil, a lipophilic surfactant and a hydrophilic surfactant for the formulation of hydrophobic active ingredients and the improvement of their bioavailability.
• azetidine derivatives above have been shown to be too bioavailable in this type of formulation.
• the formulation of such azetidine derivatives in a Miglyol® / Capryol® / Cremophor® system has also been insufficient in vivo from the pharmacokinetic point of view.
• the present invention relates to formulations consisting of either a binary system or a ternary injectable or orally administrable system for humans.
• the present invention relates to a binary system composed of the active ingredient of formula (Ia) or (Ib) and the excipient polysorbate 80 (POE (polyethylene oxide) monooleate) or solutol HS 15 (PEG (polyethylene glycol) hydroxystearate ).
• POE polyethylene oxide
• solutol HS 15 PEG (polyethylene glycol) hydroxystearate
• the present invention relates to a binary system composed of the active ingredient N- ⁇ 1- [bis- (4-chlorophenyl) memyl] azetidin-3-yl ⁇ -N- (3,5-difluorophenyl) methylsulfonamide and the excipient polysorbate 80 (POE monooleate) or solutol HS 15 (PEG hydroxystearate).
• the excipient polysorbate 80 POE monooleate
• solutol HS 15 PEG hydroxystearate
• the present invention also relates to a ternary system composed of the active ingredient of formula (Ia) or (Ib), the surfactant polysorbate 80 (POE monooleate) or solutol HS 15 (PEG hydroxystearate) and co-solvent ethanol, the PEG 400 or propylene glycol.
• the active ingredient of formula (Ia) or (Ib) the surfactant polysorbate 80 (POE monooleate) or solutol HS 15 (PEG hydroxystearate) and co-solvent ethanol, the PEG 400 or propylene glycol.
• the present invention relates to a ternary system composed of the active ingredient N- ⁇ 1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl ⁇ -N- (3,5-difluorophenyl) methylsulfonamide, surfactant polysorbate 80 (POE monooleate) or solutol HS 15 (PEG hydroxystearate) and co-solvent ethanol, PEG 400 or propylene glycol.
• surfactant polysorbate 80 POE monooleate
• solutol HS 15 PEG hydroxystearate
• co-solvent ethanol PEG 400 or propylene glycol.
• the active ingredient of general formula (Ia) or (Ib) represents from 0.01 to 60% by weight of the total composition. Preferably, it represents from 0.1 to 20% by weight and more particularly from 0.1% to 5% by weight of the total composition.
• said active ingredient represents maximally 5% of the total composition.
• the active ingredient may be in the dispersed state, and may represent up to 60% by weight of the total composition.
• said co-solvent represents from 1 to 70% relative to the total weight of the pharmaceutical composition. Preferably, it represents from 10 to 50% by weight, and even more particularly, from 20 to 40% by weight of the total composition.
• the dosage may vary depending on the degree or nature of the condition to be treated.
• the amount of active product in a composition according to the invention will be determined in such a way that a suitable dosage can be prescribed.
• the amount of azetidine derivative of general formula (Ia) or (Ib) varies according to its solubility in the mixture and also according to the appropriate dosage for the treatment of patients.
• the daily doses administered orally are generally between 0.1 and 100 mg of azetidine derivative of general formula (Ia) or (Ib).
• compositions are prepared in such a way that a unit dose contains from 0.1 to 100 mg of active product.
• the active principle of formula (Ia) or (Ib) is dispersed in the surfactant or in a surfactant / co-solvent mixture.
• the excipient will be melted beforehand at 40-50 ° C., and subsequently mixed with a co-solvent or directly with the active principle. The whole is kept under mechanical stirring until complete homogenization.
• Different dosages can be prepared, depending on the initial ratio active principle / excipient (s). For injectable use, the dosage of active ingredient can not be greater than the solubility value of the active ingredient in the excipient or in the excipient / co-solvent mixture.
• Example 1 illustrate compositions according to the present invention.
• Binary system with Solutol HS 15 the active ingredient (20 mg / g excipient) is dispersed in Solutol HS 15, then kept under mechanical stirring until complete dissolution.
• Solutol HS 15 solid at room temperature
• the final formulation (concentrate) is solid at room temperature, and must be melted before dilution with isotonic medium and iv administration.
• the solid formulation (concentrate) is chemically stable for at least 6 months at 5 ° C.
• the diluted formulation (ready-to-use) is chemically and physically stable at least 6 hours after dilution with isotonic medium (glucose 5%).
• Binary system with Polysorbate 80 the active principle (10 mg / g excipient) is dispersed in Polysorbate 80, then kept under mechanical stirring until complete dissolution.
• the Polysorbate was preheated to 40 ° C to reduce its viscosity.
• the final formulation (concentrate) is liquid but viscous at room temperature.
• the diluted (ready-to-use) formulation is physically stable for at least 6 hours after dilution with isotonic media (5% glucose).
• Example 3 Ternary system with Solutol HS15 / ethanol 20%: the active ingredient (10 mg / g excipient) is dispersed in the mixture Solutol HS15 / ethanol 80:20 (w / w), then maintained under mechanical stirring until dissolution complete.
• Solutol HS 15 solid at room temperature
• the final formulation (concentrate) is liquid at room temperature, and chemically stable for at least 8 months at 5 ° C.
• the diluted (ready-to-use) formulation is chemically and physically stable at least 24 hours after dilution with isotonic media (5% glucose).

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Molecular Biology (AREA)
• Biochemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Dermatology (AREA)
• Diabetes (AREA)
• Hematology (AREA)
• Obesity (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Plural Heterocyclic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

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• 2004
  • 2004-12-27 FR FR0413937A patent/FR2879932B1/fr not_active Expired - Fee Related
• 2005
  • 2005-12-14 PE PE2005001449A patent/PE20060743A1/es not_active Application Discontinuation
  • 2005-12-22 SV SV2005002355A patent/SV2006002355A/es unknown
  • 2005-12-22 GT GT200500387A patent/GT200500387A/es unknown
  • 2005-12-22 PA PA20058658201A patent/PA8658201A1/es unknown
  • 2005-12-22 AR ARP050105502A patent/AR052181A1/es not_active Application Discontinuation
  • 2005-12-23 JP JP2007547578A patent/JP2008525390A/ja active Pending
  • 2005-12-23 BR BRPI0519271-4A patent/BRPI0519271A2/pt not_active Application Discontinuation
  • 2005-12-23 RU RU2007128812/15A patent/RU2007128812A/ru not_active Application Discontinuation
  • 2005-12-23 CA CA002586895A patent/CA2586895A1/fr not_active Abandoned
  • 2005-12-23 MX MX2007006926A patent/MX2007006926A/es unknown
  • 2005-12-23 WO PCT/FR2005/003263 patent/WO2006070129A1/fr active Application Filing
  • 2005-12-23 EP EP05850602A patent/EP1835906A1/de not_active Withdrawn
  • 2005-12-23 KR KR1020077014546A patent/KR20070092970A/ko not_active Application Discontinuation
  • 2005-12-23 CN CNA2005800450089A patent/CN101090719A/zh active Pending
  • 2005-12-23 AU AU2005321112A patent/AU2005321112A1/en not_active Abandoned
  • 2005-12-26 TW TW094146437A patent/TW200635581A/zh unknown
  • 2005-12-27 UY UY29318A patent/UY29318A1/es unknown
• 2007
  • 2007-05-28 IL IL183483A patent/IL183483A0/en unknown
  • 2007-05-29 US US11/754,569 patent/US20070244085A1/en not_active Abandoned
• 2009
  • 2009-10-05 US US12/573,465 patent/US20100022501A1/en not_active Abandoned

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