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
  • A61P23/00—Anaesthetics

Definitions

• This invention relates to a pharmaceutical composition containing an inclusion complex of propofol and a water soluble cyclodextrin, in freeze dried form.
• Propofol (2,6 di-isopropylphenol) is widely used as an induction agent for anaesthesia.
• the high lipophilicity of the agent facilitates rapid penetration of the drug into the central nervous system thus providing rapid onset of action.
• the commercial intravenous preparation is formulated as a lipid emulsion in soya bean oil, egg phospholipids and glycerol. Formation of the emulsion demands sophisticated industrial processes to ensure nanoparticulate dimensions of the lipid phase to enable sterilization by filtration and maintain stability.
• Cyclodextrins are cyclic oligosaccharides with a cone-like shape.
• the interior of the cone behaves as a hydrophobic cavity whilst the exterior of the cone is hydrophilic.
• the former property enables cyclodextrins to form inclusion complexes with a wide variety of lipophilic molecules which "fit" into the cavity while the latter property facilitates aqueous solubility.
• Cyclodextrin derivatives such as 2-hydroxypropylated beta-cyclodextrins have been extensively studied for use as parenteral drug carriers owing to their high water solubility and low toxicity [Cyclodextrins in Pharmacy. Fr ⁇ mming, K-H. & Szejtli, J.
• Solid inclusion complexes of propofol/2-hydroxypropyl-beta-cyclodextrin were prepared by dissolving the propofol in ethanol to obtain concentrations between 10 and 20 %. One part of the drug solution was added to up to three parts of 2-hydroxypropyl-beta-cyclodextrin and kneaded in a mortar until the solvent evaporated. The resulting powder was dried under vacuum to constant weight. Proof of inclusion complexation in the solid state was provided by infrared spectroscopic analysis and differential scanning calorimetry.
• propofol was prepared as a 0,1M aqueous solution in 40% w/v 2-hydroxypropyl-beta-cyclodextrin (corresponding to 17,83mg/ml propofol in 400mg/ml 2-hydroxypropyl-beta- cyclodextrin or a mass ratio of 1:22,4 or a molar ratio of 1:2,8 mol/mol propofol to 2-hydroxypropyl-beta-cyclodextrin) and as the commercial lipid emulsion [Pedersen, CM., Thirstup, S.
• Propofol showed three times higher muscle relaxant activity when solubilized with 2-hydroxypropyl-beta-cyclodextrin compared with the lipid emulsion.
• HPBCD 2-hydroxypropyl- ⁇ -cyclodextrin
• ketoprofen does in fact form an inclusion complex with a variety of cyclodextrins, including beta-cyclodextrin, in solution with a high stability (Pharm Dev Technol 1998 Aug;3(3):307-13). It is therefore apparent that mere freeze-drying of a solution of drug and cyclodextrin may not result in a complex isolated in the solid state.
• a pharmaceutical composition in freeze dried form comprising an inclusion complex of propofol and a water soluble cyclodextrin, wherein the molar ratio of propofol to cyclodextrin is 1 : greater than 1.
• the water soluble cyclodextrin is preferably hydroxypropyl-beta- cyclodextrin, in which case the molar ratio of propofol to cyclodextrin is preferably 1 :1.5 to 1 :2.
• a pharmaceutical composition in freeze dried form comprising an inclusion complex of propofol and a water soluble cyclodextrin, and a lyoprotectant.
• the lyoprotectant may be for example glycerol, polyethyleneglycol or ethanol.
• a pharmaceutical composition in unit dose form comprising an inclusion complex of propofol and a water soluble cyclodextrin, the unit dose containing from 50 mg to 400 mg inclusive of propofol.
• compositions of the invention have the advantages that the inclusion complex of propofol and the water soluble cyclodextrin is present in amorphous solid form which means that the compositions are stable. Further, the pharmaceutical compositions of the invention may easily be reconstituted by dissolution in water to provide a solution for injection.
• a pharmaceutical composition in freeze dried form comprising an inclusion complex of propofol and a water soluble cyclodextrin, including the steps of:
• step (b) subjecting the solution of step (a) to a rapid freezing cycle and subsequently freeze drying to complete dryness to give the freeze dried pharmaceutical composition.
• Step (b) of the method of the invention preferably includes the steps of: (i) filling the solution of step (a) into a vial;
• the crux of the invention is a pharmaceutical composition in freeze dried form comprising an inclusion complex of propofol and a water soluble cyclodextrin.
• the molar ratio of propofol to cyclodextrin in the inclusion complex is 1 : greater than 1.
• the pharmaceutical composition includes a lyoprotectant in an amount which ensures optimal consistency of the freeze dried composition and rapid and complete dissolution of the freeze dried composition.
• the pharmaceutical composition is provided in unit dose form, each unit dose containing from 50 mg to 400 mg inclusive of propofol.
• a concentrated aqueous solution of HPBCD (79.1 % m/v) is prepared at 30°C.
• the required amount of propofol is gradually added with vigorous stirring. Stirring is continued for 1 hour and the heat is removed. The clear solution is stirred until room temperature is reached.
• the preferred molar stoichiometry of propofol to HPBCD is 1:1.5 to 1:2.
• the average degree of substitution of the 2-hydroxypropyl-beta-cyclodextrin is preferably between 2,5 and 9,0 and more preferably between 4.6 and 5,1 2- hydroxypropyl groups per beta-cyclodextrin molecule.
• 2-hydroxypropyl-beta- cyclodextrin with an average degree of substitution of 4,6 has a corresponding average molecular mass of around 1400 grams per mole as determined by nuclear magnetic resonance spectrometry.
• the mass ratio of propofol to 2-hydroxypropyl-beta-cyclodextrin may be between 1:11,78 to 1:15.7 when the average degree of substitution is 4,6 2-hydroxypropyl groups per cyclodextrin molecule.
• the solution may contain other physiologically compatible compounds such as an anti-oxidant, for example acetylcysteine and/or EDTA, or sodium metabisulphite or potassium nitrate, or monothioglycerol and/or a preservative, for example benzalkonium chloride or bronopol or chlorhexidine gluconate or chlorobutanol, or a pharmaceutically acceptable lyoprotectant such as a glycerol, polyethylene glycol or ethanol.
• an anti-oxidant for example acetylcysteine and/or EDTA, or sodium metabisulphite or potassium nitrate
• monothioglycerol and/or a preservative for example benzalkonium chloride or bronopol or chlorhexidine gluconate or chlorobutanol
• a pharmaceutically acceptable lyoprotectant such as a glycerol, polyethylene glycol or ethanol.
• the solution may contain a buffer such as TRIS or similar organic amine buffer to maintain the pH of the solution between 7 and 7.4.
• a buffer such as TRIS or similar organic amine buffer to maintain the pH of the solution between 7 and 7.4.
• the solution is brought to final volume and is degassed with nitrogen.
• the solution is sterilized by filtration and aseptically transferred into vials under a nitrogen atmosphere.
• the solution is subjected to a rapid freezing cycle with chamber at less than -20°C, preferably less than -30°C and most preferably at -35°C.
• the product temperature drops below -30°C, the product is evacuated at 0.2mbar and the shelf temperature increased to 10°C.
• equilibration i.e. product temperature reaches 10°C
• the shelf temperature is increased to 30°C and drying continued to complete dryness. The vacuum is broken with dried dinitrogen and the vials sealed.
• the composition of the invention preferably has a concentration of propofol of 5 mg per millilitre, more preferably about 10 or 20 mg per milliter up to 30 mg per millilitre.
• composition may be formulated in unit dose form, each unit dose containing from 50 to 400 mg inclusive of propofol.
• the preferred unit dose contains 200 mg propofol.
• compositions of the invention may be used for the induction and maintenance of anaesthesia by intravenous injection.
• compositions are suitable for further dilution if required in conventional intravenous diluents such as water for injection or dextrose solution.
• compositions are suitable for Y-site administration in suitable solutions such as dextrose solution.
• compositions are also suitable for use as a retention enema, particularly for pre-operative paediatric sedation.
• the aqueous nature of the compositions has advantages over the conventional emulsion-based formula, as aqueous formulations are generally better retained than oily formulations.
• freeze-drying time is calculated on the basis of 5.1 h per ml water.
• compositions according to the invention therefore present advantages in respect of reduced drying time and consequently are significantly more economical than those taught in the prior art.
• compositions according to the invention also have important clinical benefits over the currently available commercial fat emulsion based preparations, namely:
• the solution is passed through 0,22 micron filter into presterilized glass vials such that each vial contains the equivalent of 200mg propofol.
• the vials are subjected to a rapid freezing cycle with the chamber at -35°C. Once product temperature is less than -30°C, the vials are evacuated at 0.2mbar and the shelf temperature increased to 10°C. Once product temperature reaches -10°C, the shelf temperature is increased to 30°C and drying continued to complete dryness. The vacuum is broken with dried dinitrogen and the vials sealed under nitrogen. The product is a white powder plug. Reconstitution with 18.2 ml water for injection produces a clear solution in under 60 seconds. Propofol content is verified by HPLC analysis to be 10,0 ⁇ 0,1 mg propofol per ml.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nanotechnology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Biotechnology (AREA)
• Medical Informatics (AREA)
• Molecular Biology (AREA)
• Epidemiology (AREA)
• Crystallography & Structural Chemistry (AREA)
• Biophysics (AREA)
• General Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Anesthesiology (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (10)

Applications Claiming Priority (4)

Publications (2)

Family

ID=27669352

Family Applications (1)

Country Status (12)

Cited By (9)

Families Citing this family (8)

Family Cites Families (9)

• 2003
  • 2003-01-29 DE DE60305438T patent/DE60305438T2/de not_active Expired - Lifetime
  • 2003-01-29 MX MXPA04007328A patent/MXPA04007328A/es unknown
  • 2003-01-29 CA CA002474710A patent/CA2474710A1/en not_active Abandoned
  • 2003-01-29 BR BR0307518-4A patent/BR0307518A/pt not_active IP Right Cessation
  • 2003-01-29 EP EP03702813A patent/EP1469886B8/en not_active Expired - Lifetime
  • 2003-01-29 JP JP2003563518A patent/JP2005522422A/ja active Pending
  • 2003-01-29 NZ NZ534598A patent/NZ534598A/en not_active IP Right Cessation
  • 2003-01-29 CN CNA038031442A patent/CN1625414A/zh active Pending
  • 2003-01-29 AT AT03702813T patent/ATE326985T1/de not_active IP Right Cessation
  • 2003-01-29 AU AU2003205930A patent/AU2003205930B2/en not_active Ceased
  • 2003-01-29 US US10/503,067 patent/US20050239746A1/en not_active Abandoned
  • 2003-01-29 WO PCT/IB2003/000266 patent/WO2003063824A2/en not_active Ceased

Also Published As

Similar Documents

Legal Events