Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• • 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
  • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
  • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the invention relates to a novel formulation of (-) - (1R, 2 "S) -2- (2" -benzyloxy) propyl 4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan (BIII 890) or one of its pharmacologically acceptable salts, especially its hydrochloride, containing a complex of the active ingredient and a cyclodextrin, in particular hydroxypropyl- ⁇ -cyclodextrin, optionally in the presence of a hydroxy acid, for parenteral, in particular for intravenous administration, their preparation and use ,
• BHI 890 and "active ingredient” is always the compound known from WO 99/14199 (-) - (1 R, 2 "S) -2- (2" -benzyloxy) propyl-4'-hydroxy 5,9,9-trimethyl-6,7-benzomorphan of the formula
• BIII 890 is crobenetins and [2? - [2,3 (S *), 6]] - 1,2 J 3,4,5,6-hexahydro-6 > 11, 11-trimethyl-3- [ 2- (phenylmethoxy) propyl] -2,6-methano-3-benzazocin-10-ol.
• BIII 890 is a sodium channel blocker with neuroprotective properties; the main indications are thromboembolic stroke, brain injury and pain.
• the object of the invention is to provide a new formulation for the active ingredient BIII 890, irisbesondere for its hydrochloride.
• the invention relates to pharmaceutical compositions comprising the active ingredient BIII 890 or one of its pharmaceutically acceptable salts, in particular its hydrochloride, and a cyclodextrin derivative, in particular gamma-cyclodextrin ( ⁇ -CD), hydroxypropyl-gamma-cyclodextrin (HP- ⁇ -CD) , Hydroxypropyl-beta-cycodextrin (HP- ⁇ -CD) or sulfobutyl ether-beta-cyclodextrin (SBE- ⁇ -CD).
• ⁇ -CD gamma-cyclodextrin
• HP- ⁇ -CD Hydroxypropyl-beta-cycodextrin
• SBE- ⁇ -CD sulfobutyl ether-beta-cyclodextrin
• the preferred cyclodextrin derivative is hydroxypropyl- ⁇ -cyclodextrin.
• Hydroxypropyl- ⁇ -cyclodextrin having a molar degree of substitution of 0.5 to 0.7 is commercially available, for example, from Wacker-Chemie GmbH, D-Burghausen, under the name "CAVASOL® W8 HP Pharma.”
• CAVASOL® W8 HP Pharma is particularly preferred for the pharmaceutical composition of the invention.
• BIII 890 is therefore conveniently administered parenterally.
• the pharmaceutical compositions according to the invention intended for parenteral administration may contain hydroxy acids such as, for example, malic acid, lactic acid, tartaric acid or citric acid.
• they also contain conventional excipients and carriers such as the isotonic agents glucose, mannitol or sodium chloride or sodium acetate or sodium acetate trihydrate as a buffer in conjunction with acetic acid or a citric acid / phosphate buffer consisting e.g. from citric acid and disodium hydrogen phosphate or disodium hydrogen phosphate dihydrate.
• the solvent is usually water for injections.
• Suitable cyclodextrins include, for example, substituted ⁇ -cyclodextrin (consisting of 7 glucopyranose units), hydroxypropyl ⁇ -cyclodextrin (HP ⁇ CD), sulfobutyl ether ⁇ -cyclodextrin (SBE ⁇ CD), ⁇ -cyclodextrin (consisting of 8 glucopyranose units) and hydroxypropyl- ⁇ Cyclodextrin (HP ⁇ CD).
• Another embodiment of the invention relates to the complexing of the active ingredient or one of its salts with cyclodextrins and hydroxy acids.
• the required amount of cyclodextrin can be reduced by the formation of a ternary complex consisting of BIII 890, the respective cyclodextrin and a hydroxy acid.
• Suitable cyclodextrins include, for example, hydroxypropyl ⁇ -cyclodextrin (HP ⁇ CD), sulfobutyl ether ⁇ -cyclodextrin (SBE ⁇ CD), ⁇ -cyclodextrin and hydroxypropyl ⁇ -cyclodextrin (HP ⁇ CD).
• HP ⁇ CD hydroxypropyl ⁇ -cyclodextrin
• SBE ⁇ CD sulfobutyl ether ⁇ -cyclodextrin
• HP ⁇ CD hydroxypropyl ⁇ -cyclodextrin
• hydroxy acids are, for example, malic acid, lactic acid, tartaric acid and citric acid in question.
• An embodiment according to the invention of a parenteral preparation of BIM 890 or one of its physiologically tolerated salts, e.g. the hydrochloride, contains the active ingredient in dosages of 1 mg / kg body weight to 30 mg / kg body weight daily, preferably in the range 3-15 mg / kg body weight.
• the application is preferably via continuous infusion over 24 hours, or optionally over several days, to maintain a steady state plasma level.
• the molar ratio of active ingredient to cyclodextrin according to the invention is between 1: 1 and 1: 5. A molar ratio of 1: 2.5 to 1: 3.5 is preferred. In the presence of hydroxy acid, the molar ratio of active ingredient to cyclodextrin according to the invention is between 1: 0.5 and 1: 3; a molar ratio of 1: 0.5 to 1: 1, 5 is preferred.
• Example 3 Infusion / injection solution containing a hydroxypropyl- ⁇ -cyclodextrin complex
• Example 4 Infusion / injection solution containing a sulfobutyl ether- ⁇ -cyclodextrin complex
• Example 5 Infusion / injection solution containing a hydroxypropyl- ⁇ -cyclodextrin complex in the presence of hydroxy acids
• the administered amount of the active ingredient can be controlled.
• the daily application of 100 ml of a solution according to Example 1 corresponds to a dose of 280 mg BIII 890 daily.

Landscapes

• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Chemical & Material Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Nanotechnology (AREA)
• Medical Informatics (AREA)
• Vascular Medicine (AREA)
• Biotechnology (AREA)
• General Engineering & Computer Science (AREA)
• Urology & Nephrology (AREA)
• Molecular Biology (AREA)
• Crystallography & Structural Chemistry (AREA)
• Biophysics (AREA)
• Epidemiology (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Polysaccharides And Polysaccharide Derivatives (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Other In-Based Heterocyclic Compounds (AREA)

Priority Applications (5)

Applications Claiming Priority (2)

Publications (1)

Family

ID=29432393

Family Applications (1)

Country Status (12)

Citations (2)

Family Cites Families (4)

• 2002
  • 2002-05-29 DE DE10223783A patent/DE10223783A1/de not_active Withdrawn
• 2003
  • 2003-05-23 AT AT03735445T patent/ATE373492T1/de not_active IP Right Cessation
  • 2003-05-23 AU AU2003237664A patent/AU2003237664A1/en not_active Abandoned
  • 2003-05-23 CA CA002487150A patent/CA2487150A1/en not_active Abandoned
  • 2003-05-23 JP JP2004506859A patent/JP2005527615A/ja active Pending
  • 2003-05-23 ES ES03735445T patent/ES2294295T3/es not_active Expired - Lifetime
  • 2003-05-23 WO PCT/EP2003/005399 patent/WO2003099336A1/de not_active Ceased
  • 2003-05-23 EP EP03735445A patent/EP1511517B1/de not_active Expired - Lifetime
  • 2003-05-23 DE DE50308227T patent/DE50308227D1/de not_active Expired - Fee Related
  • 2003-05-27 PE PE2003000511A patent/PE20040066A1/es not_active Application Discontinuation
  • 2003-05-27 UY UY27823A patent/UY27823A1/es not_active Application Discontinuation
  • 2003-05-28 TW TW092114414A patent/TW200400029A/zh unknown
  • 2003-05-28 AR ARP030101863A patent/AR040134A1/es not_active Application Discontinuation

Patent Citations (2)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events