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WO1996032135A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique Download PDF

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Publication number
WO1996032135A1
WO1996032135A1 PCT/GB1996/000737 GB9600737W WO9632135A1 WO 1996032135 A1 WO1996032135 A1 WO 1996032135A1 GB 9600737 W GB9600737 W GB 9600737W WO 9632135 A1 WO9632135 A1 WO 9632135A1
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WO
WIPO (PCT)
Prior art keywords
beta
cyclodextrin
hydroxypropyl
propofol
mol
Prior art date
Application number
PCT/GB1996/000737
Other languages
English (en)
Inventor
Lawrence John Penkler
Darryl Vanstone Whittaker
Original Assignee
Farmarc Nederland Bv Of Citco Trust International Management (T.I.M.) B.V.
Dyer, Alison, Margaret
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 Farmarc Nederland Bv Of Citco Trust International Management (T.I.M.) B.V., Dyer, Alison, Margaret filed Critical Farmarc Nederland Bv Of Citco Trust International Management (T.I.M.) B.V.
Priority to AU51550/96A priority Critical patent/AU5155096A/en
Publication of WO1996032135A1 publication Critical patent/WO1996032135A1/fr

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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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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

Definitions

  • compositions according to the invention are stable non-colloidal aqueous solutions containing up to 30 mg/ml propofol convenient and suitable for direct intravenous administration, or use as a retention enema.
  • 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.
  • 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. From phase solubility studies in phosphate buffer the stability constant of the propofol/ 2-hydroxypropyl-beta-cyclodextrin complex with 1 : 1 mol/mol stoichiometry was estimated to be 2940 M " '. The solid complexes were dissolved in artificial plasma, leading to a colloidal solution which was suitable for intravenous administration. Compared with commercial propofol injection no differences were observed between the two dosage forms in the onset, duration and maximal effect.
  • 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.
  • a method of preparing a pharmaceutical composition for administration as an injection or as a retention enema comprising an inclusion complex of propofol and 2- hydroxypropyl-beta-cyclodextrin with approximately a 1:2 mol/mol stoichiometry, which method includes the steps of: (a) dissolving in water an amount of 2-hydroxypropyl-beta-cyclodextrin and then adding, with mixing, an amount of propofol to provide an approximate molar ratio of propofol to 2-hydroxypropyl-beta- cyclodextrin of 1 :2 to 1 :2,5, to produce a clear colourless solution; and (b) if necessary adjusting the osmolality of the solution by adding a pharmaceutically acceptable osmolality adjustment agent.
  • the solution contains the inclusion complex of propofol and 2- hydroxypropyl-beta-cyclodextrin with approximately a 1 :2 mol/mol stoichometry and is suitable for use as an injection or as a retention enema, to induce sedation or anaesthesia.
  • the excess of 2-hydroxypropyl-beta- cyclodextrin present in the solution acts to stabilize the complex.
  • a pharmaceutical composition for administration as an injection or as a retention enema comprising an inclusion complex of propofol and 2- hydroxypropyl-beta-cyclodextrin with a stoichiometry of approximately 1 :2 mol/mol, which method includes the steps of:
  • the solution contains the inclusion complex of propofol and 2- hydroxypropyl-beta-cyclodextrin with approximately a 1:2 mol mol stoichiometry and is suitable for use as an injection or as a retention enema, to induce sedation or anaesthesia.
  • the excess of propofol present which is not complexed is solubilized by the co-solvent, to give a clear colourless solution.
  • a pharmaceutical composition produced by either of the two methods described above.
  • the two methods of the invention may include the additional steps of:
  • a pharmaceutically acceptable anti-oxidant such as acetylcysteine and/or EDTA, or sodium metabisulphite, or potassium nitrate and/or a preservative such as benzalkonium chloride or bronopol or chlorhexidine gluconate or chlorobutanol;
  • the molar ratio of propofol to 2- hydroxypropyl-beta-cyclodextrin used is approximately 1 :2 to 1 :2,5 mol/mol, such that the bolus dose of a composition containing 200 mg propofol contains about 3,1 to 4,3g 2-hydroxypropyl-beta-cyclodextrin.
  • a pharmaceutically acceptable co-solvent so that the molar ratio of propofol to 2-hydroxypropyl- beta-cyclodextrin may be reduced to between 1:1,5 and 1 : ⁇ 2 such that the bolus dose of a composition containing 200 mg propofol may contain below 3,0g 2-hydroxypropyl-beta-cyclodextrin.
  • the temperature at which dissolution takes place may be between ambient temperature and an elevated temperature up to about 50°C.
  • step (a) of the first method and in step (1) of the second method of the invention the propofol is preferably introduced in a controlled manner over a period of time with vigorous mixing, to the solution containing the calculated amount of 2-hydroxypropyl-beta-cyclodextrin.
  • the average degree of substitution of the 2-hydroxypropyl-beta-cyclodextrin used is preferably between 2,5 and 9,0, and more preferably between 3,9 and 5,1 2-hydroxypropyl groups per beta-cyclodextrin molecule.
  • the pharmaceutically acceptable osmolality adjustment agent may be selected from glycerol, dextrose, mannitol and sorbitol. In this step, there may also be a final volume adjustment.
  • the pharmaceutically acceptable co-solvent may be selected from glycerol, a glycol such as propylene glycol or preferably polyethylene glycol with an average molecular mass of 300, a macrogol, or a water soluble polymeric organic compound such as polyvinyl pyrrolidone or a hydroxyalkylated starch derivative such as hydroxyethylated starch with an average molecular mass of 200 000.
  • the pharmaceutical composition of the invention preferably has a concentration of propofol of 5 mg per millilitre or more preferably about 10 or 20 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.
  • the unit dose may be further diluted if required with suitable diluents such as water for injection or dextrose.
  • Figure 1 shows the structures and proton notations for propofol and 2- hydroxypropyl-beta-cyclodextrin.
  • the propofol structure (top) shows equivalent protons with prime notation.
  • the 2-hydroxypropyl-beta- cyclodextrin structure (bottom) is composed of seven glucopyranose units shown with the 2-hydroxypropyl (CH 3 CH(OH)CH 2 -) groups omitted which may be substituted on the 2', 3' or 6' hydroxyl oxygens;
  • Figure 2 shows the assigned 500 MHz proton magnetic resonance spectrum of a solution containing propofoL/2-hydroxypropyl-beta-cyclodextrin in a 1:2 mol/mol stoichiometry in deuterated water recorded on a Bruker AMX-500 nuclear magnetic resonance spectrometer;
  • Figure 3 shows the assigned two-dimensional nuclear Overhauser enhancement spectrum of the propofol 2-hydroxypropyl-beta-cyclodextrin 1 :2 mol/mol complex in deuterated water recorded in the rotating frame on a Bruker AMX-500 nuclear magnetic resonance spectrometer;
  • Figure 4a shows a proton magnetic resonance based molecular model of the aqueous inclusion complex formed between propofol and 2-hydroxypropyl- beta-cyclodextrin, with a perspective view being shown and with the propofol being shown in bold and the 2-hydroxypropyl groups omitted;
  • Figure 4b shows a space filling model of the complex obtained in Figure 4a indicating the complete molecular encapsulation of propofol by two cyclodextrin molecules
  • Figure 4c shows the model obtained in Figure 4b with the Z-axis being partially cut away to reveal the interaction between the isopropyl groups of propofol and the hydrophobic cyclodextrin cavity according to the NMR results shown in Figure 3.
  • compositions according to the invention are stable non- colloidal aqueous solutions containing up to 30 mg/ml propofol convenient and suitable for direct intravenous administration.
  • the first method of the invention is preferred.
  • the major step of both methods of the invention is gradually to add the propofol to a concentrated solution of a calculated amount of 2- hydroxypropyl-beta-cyclodextrin in purified water with vigourous mixing at a temperature from ambient temperature but preferably between 30 and 50 °C.
  • the solution is allowed to cool to room temperature with continued stirring.
  • the propofol and the 2-hydroxypropyl-beta-cyclodextrin are used in an approximate molar ratio of 1 :2 to 1 :2,5 to produce a complex with approximately a 1:2 mol/mol stoichiometry.
  • the propofol and the 2-hydroxypropyl-beta-cyclodextrin are used in an approximate molar ratio of 1 :1,5 to 1 : ⁇ 2 to again produce a complex with a stoichiometry of approximately 1:2 mol/mol.
  • Beta-cyclodextrin consists of 7 glucose units in a ring structure, also referred to as cyclohepta-amylose. Each glucose unit contains 3 hydroxyl groups which may be etherified by 2-hydroxypropylation to give 2-hydroxypropyl- beta-cyclodextrin (HPB). HPB is produced by reacting beta-cyclodextrin with propylene oxide under controlled conditions so that the average molar substitution (mole propylene oxide per glucose unit) is between 0,25 and 1. This implies that only between 1,75 and 7 hydroxypropyl groups are introduced per beta-cyclodextrin molecule, out of a theoretically possible 21.
  • the average degree of substitution (D.S.) per beta-cyclodextrin molecule may be calculated from the 'H-NMR integrals corresponding to the anomeric and methyl signals between 4,95-5,3 and 0,9-1,2 ppm respectively from the NMR spectrum of HPB in D 2 O.
  • the approximate molecular mass may in turn be calculated from the value of D.S.
  • a is the integral of anomeric protons and b is the integral of methyl protons.
  • the average degree of substitution of the 2-hydroxypropyl-beta-cyclodextrin is preferably between 2,5 and 9,0 and more preferably between 3,9 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 :11,0 to 1 :20,0 or more preferably between 1 :15,72 to 1 :19,65, when the average degree of substitution is 4,6 2-hydroxypropyl groups per cyclodextrin molecule.
  • a pharmaceutically acceptable co- solvent or mixture of co-solvents is added to the solution.
  • the co-solvents may be selected from the group consisting of glycerol, glycols, macrogols or suitable water soluble polymeric organic compounds such as polyvinyl pyrrolidone or hydroxyalkylated starch derivatives.
  • Glycerol may be used in the concentration range of 3 to 10 % m/v (mass volume) of the final solution volume.
  • the glycol is preferably propylene glycol or more preferably polyethylene glycol with an average molecular mass of 300 used in the concentration range of 1 to 10 % m/v of the final solution volume.
  • the hydroxyalkylated starch is preferably hydroxyethylated starch with an average molecular mass of 200 000.
  • osmolality adjustment agents such as glycerol, dextrose, mannitol or sorbitol.
  • 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, and/or a preservative, for example benzalkonium chloride or bronopol or chlorhexidine gluconate or chlorobutanol.
  • an anti-oxidant for example acetylcysteine and/or EDTA
  • sodium metabisulphite or potassium nitrate sodium metabisulphite or potassium nitrate
  • a preservative for example benzalkonium chloride or bronopol or chlorhexidine gluconate or chlorobutanol.
  • the solution is brought to final volume and is degassed with nitrogen.
  • the solution is sterilized by filtration and aseptically transferred into vials or ampoules optionally under a nitrogen atmosphere.
  • 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.
  • composition produced by the methods of the invention may be used for the induction and short term maintenance of anaesthesia by intravenous injection.
  • composition is suitable for further dilution if required in conventional intravenous diluents such as water for injection or dextrose solution.
  • composition is suitable for Y-site administration in suitable solutions such as dextrose solution.
  • composition is also suitable for use as a retention enema, particularly for pre-operative paediatric sedation.
  • the aqueous nature of the composition has advantages over the conventional emulsion-based formula, as aqueous formulations are generally better retained than oily formulations.
  • the optimum hydroxypropyl-beta- cyclodextrin concentration to provide a stable aqueous solution containing propofol in a clinically useful concentration of 10 mg/ml, which may be infused to maintain anaesthesia for at least one hour, without undue hydroxypropyl-beta-cyclodextrin toxicological hazard is a maximum of about 215 mg hydroxypropyl-beta-cyclodextrin per ml of solution, corresponding to a propofol/hydroxypropyl-beta-cyclodextrin mol/mol stoichiometry of 1 :2,5. when the average degree of substitution of 2- hydroxypropyl-beta-cyclodextrin is 4,6.
  • the following examples relate to the preparation of inclusion complexes between propofol and 2-hydroxypropyl-beta-cyclodextrin. their characterization and pharmaceutical compositions containing them.
  • the solution is filtered through a 0,22 micron filter and 1,0 ml is transferred to a 5 mm nuclear magnetic resonance (NMR) tube.
  • the remainder of the solution is analyzed by high performance liquid chromatography (HPLC) for propofol content.
  • HPLC high performance liquid chromatography
  • the amount of propofol is found to be 10,0 ⁇ 0,1 mg per millilitre.
  • the NMR sample is placed in the probe of a Bruker AMX-500 NMR spectrometer operating at 500 MHz with probe temperature at 303 K.
  • a one dimensional proton spectrum of the sample is recorded with 128 scans.
  • the spectral assignments were made on the basis of reported values for cyclodextrins and substituted phenols and on the basis of chemical shift, signal intensity, multiplicity of signals and proton correlations obtained from the two-dimensional spectra.
  • the assigned proton spectrum is shown in Figure 2 with the proton notations shown in Figure 1.
  • ROESY Rotating frame Overhauser Enhancement spectroscopy
  • the structure shown in figure 4a was obtained by initial molecular mechanics energy minimisation of the X-ray crystallographic based structure of beta-cyclodextrin and a computer generated structure of propofol in energy optimised confirmation whereby the 2-cyclodextrin molecules were allowed to complex with each isopropyl moiety respectively in a trimolecular energy minimisation routine.
  • the commercial molecular modelling software HyperChemTM was used for the calculations and drawings.
  • the solution When ambient temperature is attained the solution is gradually brought to volume (100 ml) by the addition of aliquots of water for injection with vigorous stirring. Prior to final volume adjustment glycerol is added with stirring to adjust osmolality to 280 - 320 mOsm/kg. The solution is stirred for 10 minutes and bubbled with sterile nitrogen for 20 minutes. The solution is passed through 0,22 micron filter into presterilized glass ampoules. The ampoules are optionally sealed under nitrogen. Propofol content is verified by HPLC analysis to be 10,0 ⁇ 0,1 mg propofol per ml. The clarity of solution is determined by transmittance spectrophotometry at a wavelength of 800 nanometres and found to be 99,9 %. The solution is stable for at least one month.
  • the solution When ambient temperature is attained the solution is gradually brought to volume (100 ml) by the addition of aliquots of water for injection with vigorous stirring. The solution is stirred for 10 minutes and the osmolality of the solution is measured (380 ⁇ 20 mOsm/kg). The solution is stirred for 10 minutes and bubbled with sterile nitrogen for 20 minutes. The solution is passed through 0,22 micron filter into presterilized glass ampoules. The ampoules are optionally sealed under nitrogen. Propofol content is verified by HPLC analysis to be 20,0 ⁇ 0,2 mg propofol per ml. The clarity of solution is determined by transmittance spectrophotometry at a wavelength of 800 nanometres and found to be 99,9 %. The solution is stable for at least one month.
  • the solution is gradually brought to volume (100 ml) by the addition of aliquots of water for injection with vigorous stirring.
  • the solution is stirred for 10 minutes and bubbled with sterile nitrogen for 20 minutes.
  • the solution is passed through 0,22 micron filter into presterilized glass ampoules.
  • the ampoules are optionally sealed under nitrogen.
  • Propofol content is verified by HPLC analysis to be 10,0 ⁇ 0,1 mg propofol per ml.
  • the clarity of solution is determined by Transmittance spectrophotometry at a wavelength of 800 nanometres and found to be 99,9 %.
  • the solution is stable for at least two weeks.
  • the solution is gradually brought to volume (100 ml) by the addition of aliquots of water for injection with vigorous stirring.
  • the solution is stirred for 10 minutes and bubbled with sterile nitrogen for 20 minutes.
  • the solution is passed through 0,22 micron filter into presterilized glass ampoules.
  • the ampoules are optionally sealed under nitrogen.
  • Propofol content is verified by HPLC analysis to be 10,0 ⁇ 0,1 mg propofol per ml.
  • the clarity of solution is determined by transmittance spectrophotometry at a wavelength of 800 nanometres and found to be 99,9 %.
  • the solution is stable for at least two weeks.
  • the solution When ambient temperature is attained the solution is gradually brought to volume (5000 ml) by the addition of aliquots of water for injection with vigorous stirring. The solution is stirred for 20 minutes. The solution is stirred and bubbled with sterile nitrogen until the oxygen concentration is below 0,5 mg/1. The solution is passed through 0,22 micron filter into presterilized glass ampoules. The ampoules are optionally sealed under nitrogen. Propofol content is verified by HPLC analysis to be 10,0 ⁇ 0,5 mg propofol per ml.
  • compositions of Examples 2 to 6 may be used either as compositions for injection or as compositions for use as retention enemas, as described above.

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Abstract

Une composition pharmaceutique administrable sous forme d'injection ou de lavement à garder contient un complexe d'inclusion de propofol et de 2-hydroxypropyl-bêta-cyclodextrine, selon une st÷chiométrie de 1:2 mol/mol, cette composition comprenant, si nécessaire, un cosolvant. Pour préparer ladite composition pharmaceutique on dissout dans de l'eau une quantité de 2-hydroxypropyl-bêta-cyclodextrine puis on ajoute une quantité de propofol qu'on mélange afin d'obtenir le rapport molaire désiré, et, si nécessaire, on ajoute le cosolvant pharmaceutiquement acceptable.
PCT/GB1996/000737 1995-04-10 1996-03-27 Composition pharmaceutique WO1996032135A1 (fr)

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AU51550/96A AU5155096A (en) 1995-04-10 1996-03-27 Pharmaceutical composition

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ZA95/2938 1995-04-10
ZA952938 1995-04-10

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WO1996032135A1 true WO1996032135A1 (fr) 1996-10-17

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6326406B1 (en) 1997-05-26 2001-12-04 Westy Ag Clear, injectable formulation of an anesthetic compound
WO2001097796A1 (fr) * 2000-06-21 2001-12-27 Bharat Serums & Vaccines Ltd. Composition anesthesique aqueuse claire
US6551584B2 (en) 2000-10-10 2003-04-22 Pharmacia & Upjohn Company Topical antibiotic composition for treatment of eye infection
WO2003063824A3 (fr) * 2002-02-01 2004-06-17 Shimoda Biotech Pty Ltd Composition pharmaceutique
EP1383445A4 (fr) * 2001-03-20 2005-04-13 Cydex Inc Preparation contenant du propofol et de la cyclodextrine d'ether sulfoalkylique
US6887866B2 (en) 2002-01-25 2005-05-03 Theravance, Inc. Short-acting sedative hypnotic agents for anesthesia and sedation
WO2005067905A1 (fr) * 2004-01-14 2005-07-28 Otsuka Pharmaceutical Factory, Inc. Preparation d'une emulsion grasse contenant du propofol
US6989381B2 (en) 2000-08-22 2006-01-24 Pharmacia Corporation Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading
US7034013B2 (en) 2001-03-20 2006-04-25 Cydex, Inc. Formulations containing propofol and a sulfoalkyl ether cyclodextrin
US7041705B2 (en) 1998-08-19 2006-05-09 Jagotec Ag Injectable aqueous dispersions of propofol
WO2007052295A3 (fr) * 2005-08-12 2007-07-26 Bharat Serums & Vaccines Ltd Compositions aqueuses anesthesiques comprenant du propofol
US7790766B2 (en) 2003-07-23 2010-09-07 Theravance, Inc. Pharmaceutical compositions of short-acting sedative hypnotic agent
EP2484350A1 (fr) * 2011-02-04 2012-08-08 Roewer, Norbert, Univ.-Prof. Dr. med. Préparation pharmaceutique comprenant un complexe d'un sel de propofol et d'une cyclodextrine
WO2013078500A1 (fr) 2011-11-29 2013-06-06 Jurox Pty Ltd Procédés de conservation de compositions pharmaceutiques injectables comprenant une cyclodextrine et un médicament hydrophobe
US9925274B2 (en) 2012-11-15 2018-03-27 Sapiotec Gmbh Delphinidin complex as an antiphlogistic or immunosuppressive active ingredient
US9949947B2 (en) 2012-12-11 2018-04-24 Sapiotec Gmbh Delphinidin for combating melanoma cells

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993017711A1 (fr) * 1992-03-11 1993-09-16 Australian Commercial Research & Development Limited Nouvelles cyclodestrines et medicaments de formule nouvelle

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993017711A1 (fr) * 1992-03-11 1993-09-16 Australian Commercial Research & Development Limited Nouvelles cyclodestrines et medicaments de formule nouvelle

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
207TH NATIONAL MEETING OF THE AMERIC. CHEM. SOC,, 13 March 1994 (1994-03-13) - 17 March 1994 (1994-03-17), SAN DIEGO, CALIFORNIA, USA, pages 207 *
BREWSTER, MARCUS E. ET AL: "Solubilization and electrochemical stabilization of substituted phenols through the use of 2 - hydroxypropyl -.beta.- cyclodextrin", SUPRAMOL. CHEM. (1994), 4(1), 69-76 CODEN: SCHEER;ISSN: 1061-0278, 1994, XP002009543 *
CHEMICAL ABSTRACTS, vol. 114, no. 10, 11 March 1991, Columbus, Ohio, US; abstract no. 88481, FRIJLINK, H. W. ET AL: "The effects of cyclodextrins on drug absorption. II. In vivo observations" XP002009540 *
DATABASE BIOSIS BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; XP002009542 *
E. PROP. ET AL.: "BRAIN TARGETORS OF 2,6-DIISOPROPYLPHENOL (PROPOFOL)", PHARM. RES., vol. 8, no. 10, October 1991 (1991-10-01), pages S-157, XP002009538 *
H. VIERSTEIN ET AL.: "PREPARATION AND CENTRAL ACTION OF PROPOFOL /HYDROXYPROPYL-BETA-CYCLODEXTRIN COMPLEXES IN RABBITS.", ARZNEIMITTEL FORSCHUNG DRUG RESEARCH., vol. 43, no. 8, 1993, AULENDORF DE, pages 818 - 821, XP002009536 *
INT. J. PHARM. (1990), 64(2-3), 195-205 CODEN: IJPHDE;ISSN: 0378-5173, 1990 *
PEDERSEN, CHARLES M. ET AL: "Smooth muscle relaxant effects of propofol and ketamine in isolated guinea pig trachea", EUR. J. PHARMACOL. (1993), 238(1), 75-80 CODEN: EJPHAZ;ISSN: 0014-2999, 1993, XP002009537 *
S. J. BIELEN ET AL.: "THE EFFECT OF A CYCLODEXTRIN VEHICLE ON THE CARDIOVASCULAR PROFILE OF PROPOFOL IN RATS.", ANESTH. ANALG., vol. 82, 1996, pages 920 - 924, XP002009539 *

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6326406B1 (en) 1997-05-26 2001-12-04 Westy Ag Clear, injectable formulation of an anesthetic compound
US7097849B2 (en) 1998-08-19 2006-08-29 Jagotec Ag Injectable aqueous dispersions of propofol
US7041705B2 (en) 1998-08-19 2006-05-09 Jagotec Ag Injectable aqueous dispersions of propofol
WO2001097796A1 (fr) * 2000-06-21 2001-12-27 Bharat Serums & Vaccines Ltd. Composition anesthesique aqueuse claire
JP2003535893A (ja) * 2000-06-21 2003-12-02 ブハラット セルムズ アンド ヴァクシンズ リミテッド 透明水性麻酔剤組成物
US7138387B2 (en) * 2000-06-21 2006-11-21 Bharat Serums And Vaccines Limited Clear aqueous composition comprising propofol and hydroxypropyl-beta-cyclodextrin
US6989381B2 (en) 2000-08-22 2006-01-24 Pharmacia Corporation Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading
US6551584B2 (en) 2000-10-10 2003-04-22 Pharmacia & Upjohn Company Topical antibiotic composition for treatment of eye infection
EP1383445A4 (fr) * 2001-03-20 2005-04-13 Cydex Inc Preparation contenant du propofol et de la cyclodextrine d'ether sulfoalkylique
US7034013B2 (en) 2001-03-20 2006-04-25 Cydex, Inc. Formulations containing propofol and a sulfoalkyl ether cyclodextrin
US7939689B2 (en) 2002-01-25 2011-05-10 Theravance, Inc. Short-acting sedative hypnotic agents for anesthesia and sedation
US6887866B2 (en) 2002-01-25 2005-05-03 Theravance, Inc. Short-acting sedative hypnotic agents for anesthesia and sedation
US7514425B2 (en) 2002-01-25 2009-04-07 Theravance, Inc. Short-acting sedative hypnotic agents for anesthesia and sedation
WO2003063824A3 (fr) * 2002-02-01 2004-06-17 Shimoda Biotech Pty Ltd Composition pharmaceutique
JP2005522422A (ja) * 2002-02-01 2005-07-28 シモダ、バイオテック（プロプライエタリー）リミテッド 医薬組成物
AU2003205930B2 (en) * 2002-02-01 2007-08-16 Shimoda Biotech (Pty) Ltd Pharmaceutical composition
US7790766B2 (en) 2003-07-23 2010-09-07 Theravance, Inc. Pharmaceutical compositions of short-acting sedative hypnotic agent
US7981931B2 (en) 2003-07-23 2011-07-19 Theravance, Inc. Pharmaceutical compositions of short-acting sedative hypnotic agent
JPWO2005067905A1 (ja) * 2004-01-14 2007-12-27 株式会社大塚製薬工場 プロポフォール含有脂肪乳剤
WO2005067905A1 (fr) * 2004-01-14 2005-07-28 Otsuka Pharmaceutical Factory, Inc. Preparation d'une emulsion grasse contenant du propofol
WO2007052295A3 (fr) * 2005-08-12 2007-07-26 Bharat Serums & Vaccines Ltd Compositions aqueuses anesthesiques comprenant du propofol
EA014673B1 (ru) * 2005-08-12 2010-12-30 Бхарат Сирумс Энд Вэксинс Лтд. Водные анестезирующие композиции, содержащие пропофол
EP2484350A1 (fr) * 2011-02-04 2012-08-08 Roewer, Norbert, Univ.-Prof. Dr. med. Préparation pharmaceutique comprenant un complexe d'un sel de propofol et d'une cyclodextrine
WO2012104730A1 (fr) * 2011-02-04 2012-08-09 Norbert Roewer Préparation pharmaceutique
US9006215B2 (en) 2011-02-04 2015-04-14 Norbert Roewer Pharmaceutical preparation comprising propofol salt and cyclodextrin
JP2014507430A (ja) * 2011-02-04 2014-03-27 ノルベルト・レーヴァー 医薬製剤
JP2014533703A (ja) * 2011-11-29 2014-12-15 ジュロックス プロプライエタリー リミテッド 薬学的組成物
CN103998046A (zh) * 2011-11-29 2014-08-20 优奥斯私人有限公司 包含环糊精和疏水性药物的可注射药物组合物的防腐方法
WO2013078500A1 (fr) 2011-11-29 2013-06-06 Jurox Pty Ltd Procédés de conservation de compositions pharmaceutiques injectables comprenant une cyclodextrine et un médicament hydrophobe
EP2785352A4 (fr) * 2011-11-29 2015-07-29 Jurox Pty Ltd Procédés de conservation de compositions pharmaceutiques injectables comprenant une cyclodextrine et un médicament hydrophobe
US9492552B2 (en) 2011-11-29 2016-11-15 Jurox Pty Ltd Injectable aqueous pharmaceutical compositions comprising a cyclodextrin, a hydrophobic drug, a co-solvent, and a preservative
CN107261152A (zh) * 2011-11-29 2017-10-20 优奥斯私人有限公司 包含环糊精和疏水性药物的可注射药物组合物的防腐方法
US10188664B2 (en) 2011-11-29 2019-01-29 Jurox Pty Ltd Injectable pharmaceutical compositions comprising a cyclodextrin a hydrophobic drug, a co-solvent, and a preservative
EP3446692A1 (fr) * 2011-11-29 2019-02-27 Jurox Pty. Ltd. Procédés de conservation de compositions pharmaceutiques injectables comprenant une cyclodextrine et un médicament hydrophobe
CN103998046B (zh) * 2011-11-29 2021-04-06 优奥斯私人有限公司 包含环糊精和疏水性药物的可注射药物组合物的防腐方法
CN107261152B (zh) * 2011-11-29 2022-03-04 优奥斯私人有限公司 包含环糊精和疏水性药物的可注射药物组合物的防腐方法
US12303519B2 (en) 2011-11-29 2025-05-20 Zoetis Services Llc Injectable pharmaceutical compositions comprising a cyclodextrin a hydrophobic drug, a co-solvent, and a preservative
US9925274B2 (en) 2012-11-15 2018-03-27 Sapiotec Gmbh Delphinidin complex as an antiphlogistic or immunosuppressive active ingredient
US9949947B2 (en) 2012-12-11 2018-04-24 Sapiotec Gmbh Delphinidin for combating melanoma cells

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