WO2009059989A1 - Émulsions aqueuses contenant un principe actif hydrophobe - Google Patents

Émulsions aqueuses contenant un principe actif hydrophobe Download PDF

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Publication number
WO2009059989A1
WO2009059989A1 PCT/EP2008/064979 EP2008064979W WO2009059989A1 WO 2009059989 A1 WO2009059989 A1 WO 2009059989A1 EP 2008064979 W EP2008064979 W EP 2008064979W WO 2009059989 A1 WO2009059989 A1 WO 2009059989A1
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WIPO (PCT)
Prior art keywords
mol
emulsion
peo
pla
emulsion according
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PCT/EP2008/064979
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German (de)
English (en)
Inventor
Sonja Dick
Andreas Greiner
Joachim H. Wendorff
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B. Braun Melsungen Ag
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Priority to DE112008002914T priority Critical patent/DE112008002914A5/de
Publication of WO2009059989A1 publication Critical patent/WO2009059989A1/fr

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    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics

Definitions

  • the invention relates to a hydrophobic drug-containing aqueous emulsions, processes for their preparation, pharmaceutical compositions such as therapeutics, diagnostics and / or prophylactics, in particular anesthetics comprising the aqueous emulsion, the use of aqueous emulsions for the production of medicaments and methods for therapeutic and / or prophylactic treatment of the human or animal body and / or for diagnosis by administration of the aqueous emulsion according to the invention.
  • a parenteral administration can not be done because either no suitable particle size can be achieved by the preparation of suspensions or the required solvent volume precipitates too large.
  • oil-in-water emulsions have been shown to be the drug carrier for the parenteral dosage form of poorly water-soluble but fat-soluble pharmaceutical agents.
  • the oil core of the emulsions is used as an active ingredient vehicle.
  • pharmaceutical active ingredients which are sparingly soluble in aqueous media can be incorporated in sufficient amounts in O / W emulsions with sufficient fat solubility. Due to the problem of solubility in the common oils, only a few products have so far been approved. Examples are intravenous therapy with Disoprivan ®, diazepam Lipuro ®, ® and Lipotalon Etomidat- Lipuro ®.
  • US-A-2004/0225022 describes aqueous pharmaceutical preparations in which propofol is emulsified.
  • surfactants inter alia, lecithin or ethoxylated ethers or esters
  • a solvent (vehicle) for propofol for example, soybean oil is used.
  • Preferred weight ratios of propofol to soybean oil are 1: 3 to 6 and 2: 3 to 6.
  • the oil-in-water emulsions used typically have a fat content of 10 to 20%, mainly consisting of long-chain and medium-chain triglycerides, 1 to 3% emulsifier (usually lecithin), 2 to 3% glycerol for isotonization and water as the outer phase for injections.
  • a high caloric energy supply and substitution of essential fatty acids can be achieved.
  • long and medium chain triglycerides are used as a readily available source of energy. This can lead to an increase in liver weight, especially with long-term dosing.
  • parenteral administration of large amounts of lipid emulsions and / or the administration of lipid emulsions over a long period of time can lead to hyperlipidemia.
  • lipids are good breeding grounds for bacterial growth, which is particularly problematic in the production and storage of the drug can lead.
  • Preservatives bacteriostats
  • substances that can inhibit the growth of germs in fat emulsions can simultaneously lead to intolerances.
  • a preservative which is slightly water-soluble, for example, benzyl alcohol is mentioned.
  • some preservatives such as sodium disulfite, cause reactions similar to an allergy in humans. Such reactions may be characterized by anaphylactic reactions and life-threatening or asthmatic flare-ups in humans susceptible to sulfites. It has also been demonstrated that sodium disulfite catalyzes the degradation of some drugs, such as propofol.
  • the chelating property of preservatives results in an increased excretion of trace elements, such as zinc, copper and iron.
  • trace elements such as zinc, copper and iron.
  • sterile filtration of the O / W emulsions with a commercially available sterile filter is not effective because the emulsions are thermodynamically too unstable and tend to break under the necessary shear force.
  • O / W emulsions are only partially stable to dilution or the addition of salts, glucose or other common excipients.
  • lecithins are used.
  • the concentration of lecithin used in the 10 and 20% fat emulsions is usually about 1.2%.
  • egg lecithin used as an emulsifier or soybean oil used as a solubilizer may induce anaphylactic or anaphylactoid reactions in humans allergic to egg lecithin and / or soybean oil.
  • Cremophor ® EL a mixture of the reaction products of castor oil with ethylene oxide (molar ratio 1: 35), able to solubilize hydrophobic drugs in an aqueous environment.
  • the critical Micelle concentration (CMC) of Cremophor ® EL is 0.009 wt .-%.
  • the size of the micelles from the main component of the Cremophor ® EL, Polyoxyethylenglycerolricinoleat formed is below 100 nm. Investigations of paclitaxel, which was formulated with Cremophor ® EL, have shown that the drug release through the micelle, however, slowed down. Furthermore, it turned out that Cremophor ® EL can trigger allergic reactions, which is why it has lost much of its importance as a drug carrier.
  • poloxamers i. H. Copolymers consisting of poly (ethylene oxide) and poly (propylene oxide) blocks and varying in their molecular weight, in the ratio of the polymer blocks and their surfactant properties, form micelles in aqueous solution in which the poly (ethylene oxide) blocks form the outer hydrophilic shell and the poly (propylene oxide) blocks form the hydrophobic core of the micelle.
  • hydrophobic drugs can be incorporated.
  • Such poloxamer micelles have a small diameter in the range between 20 and 80 nm.
  • WO-A-2005/72343 describes aqueous pharmaceutical compositions containing a hydrophobic pharmaceutical agent and a poloxamer, preferably P188, as well as poly (ethylene glycol).
  • a hydrophobic pharmaceutical agent preferably P188
  • poly (ethylene glycol) preferably poly(ethylene glycol)
  • the preferred weight ratio of active ingredient to poloxamer is given in the examples as 1: 6 to 1: 9, the preferred weight ratio of active ingredient to emulsifier in the aqueous pharmaceutical composition is 1:10 to 1:12.
  • WO-A-2004/10941 describes transparent aqueous compositions containing propofol and at least one excipient.
  • auxiliaries poloxamers and / or PEG are preferably used.
  • weight ratios of propofol to polymer of 1: 12, 1: 11 and 1:10 are called.
  • EP-A-0 552 802 describes particles consisting of chemically fixed (cross-linked) copolymer micelles and a hydrophobic component.
  • EP-A-0 520 888 describes nanoparticles in the form of micelles consisting of poly (lactide) / poly (ethylene glycol) copolymers and optionally a water-insoluble active ingredient.
  • the number ratio of solubilized molecules to surfactant molecules is low and rarely greater than 2, i. the inside of the micelles does not represent an independent oil phase that has the properties of the bulks, as opposed to emulsions. This is detectable by electron microscopy.
  • An electron micrograph shows nanoparticles, such as micelles,
  • Emulsion drops and liposome distinguishable.
  • micelles For the construction of micelles and the incorporation of hydrophobic drugs in it is a relatively large
  • solubilizers eg. B. soybean oil or
  • Cremophor ® EL as well as a large polymer (solubilizer): drug ratio and, as a result, a high risk of side effects.
  • the object of the invention was to provide an aqueous preparation containing at least one hydrophobic active ingredient which is free of lipids and has an improved active ingredient / polymer ratio compared with the prior art.
  • the invention relates to the aqueous emulsion according to claim 1, the method according to claim 32 and claim 40, the pharmaceutical composition according to claim 37, the anesthetic according to claim 38 and the use of the emulsion according to the invention according to claim 39.
  • the emulsion of the invention comprises water as the continuous phase, a hydrophobic pharmaceutical agent as a dispersed (discontinuous) phase, and at least one block copolymer wherein the hydrophobic pharmaceutical agent has a melting point of 25 ° C or less, the block copolymer is a poly (ethylene oxide).
  • Block hereinafter abbreviated to PEO
  • at least one poly (lactide) block abbreviated to PLA hereinafter
  • the weight ratio of the hydrophobic drug to the block copolymer is 1: 1 to 10: 1.
  • the hydrophobic pharmaceutical active substance used in the invention has a melting point of 25 ° C or less, such as 22 ° C or less, of 20 0 C or less, or of 18 ° C or less, or a melting range up to 25 ° C to 22 ° C, up to 20 0 C or up to 18 ° C.
  • hydrophobic in the context of the pharmaceutical agent means that at 20 ° C., the solubility of the drug in water is 700 ⁇ g substance per ml water or less, such as 500 ⁇ g / ml or less or 350 ⁇ g / ml or less.
  • the hydrophobic active ingredient at 20 0 C a water solubility in the range of 20 ug / ml to 200 ug / ml.
  • the hydrophobic pharmaceutical active substance can be used in the field of human and / or veterinary medicine for therapy and / or prophylaxis.
  • Active ingredient according to this invention is a substance that produces a biological effect in a living organism.
  • a biological effect is the totality of changes in a biological system caused by an active substance.
  • the biological effect is such that the active ingredient can be used for the prevention, alleviation, healing and / or detection of diseases.
  • the active ingredient may be used as a pharmaceutically active ingredient in the manufacture of medicaments or, when used in the manufacture of medicaments, may become a pharmaceutically active ingredient of the medicaments.
  • the hydrophobic drug is selected from the group consisting of propofol and its pharmaceutically acceptable salts or derivatives, propanidide, isoflurane, enflurane, sevoflurane, vitamin Ki (phytonadione, phylloquinone), clofibrate, ethyl ester of poppy seed iodinated fatty acids (e.g. available under the trade name Ethiodol ®, Lipiodol ®).
  • Propofol (2,6-diisopropylphenol) is a highly effective lipophilic narcotic which is dissolved in the commercial preparations in a lipid emulsion.
  • Propofol acts as a hypnotic, but has no analgesic (ie analgesic) effect. It is used to induce and maintain general anesthesia and to sedate ventilated patients as part of intensive care treatment and for sedation, such as gastric (gastroscopy) or colonoscopy (colonoscopy) alone or with an analgesic.
  • gastric gastroscopy
  • colonoscopy colonoscopy
  • Propofol is a colorless to slightly yellowish oily liquid at room temperature with a melting point of 18 ° C.
  • the only ionizable functionality is the
  • Hydroxyl group which has a pK a value of about 11.
  • the remaining essential parts of the molecule consisting of a benzene ring and isopropyl
  • Solubility in water (about 150 ⁇ g / ml at 25 ° C) and good solubility in organic solvents.
  • the block copolymer used according to the invention comprises at least one poly (ethylene oxide) block and at least one poly (lactide) block.
  • Poly (lactide) and its copolymers are the biodegradable polymers most extensively studied for the manufacture of depot dosage forms. They are also used as absorbable surgical sutures and provide the matrix of on the market drug-containing implants (z. B. Zoladex ®) and microparticles (z. B. Enantone Depot ®) represents.
  • Polyesters of L-lactic acid, racemate D, L-lactic acid and copolymers of L-lactide with D-lactide or with D, L-lactide are degraded by the body.
  • Suitable PLA are composed of monomers of D-lactic acid or L-lactic acid or of D-lactic acid and L-lactic acid monomers.
  • copolymers of D, L-lactic acid with glycolic acid are used for the block copolymer used according to the invention.
  • PEO Poly (ethylene oxide)
  • the block copolymer is a diblock copolymer PEO-PLA, a triblock copolymer PEO-PLA-PEO, a triblock copolymer Copolymer PLA-PEO-PLA or a tetrablock copolymer PEO-PLA-PEO-PLA, preferably a diblock copolymer PEO-PLA or a triblock copolymer PEO-PLA-PEO.
  • Particularly preferred is the use of diblock copolymer PEO-PLA.
  • the block copolymer according to the invention can be prepared in a manner known to the person skilled in the art.
  • polyethylene oxide may be reacted with an appropriate amount of lactide (for example D, L-lactide, L-lactide or D-lactide) in the presence of a suitable catalyst, for example a catalytic tin compound such as stannous oxide or tin ( II) octoate, be reacted at a temperature in the range of 120 0 C to 180 0 C.
  • a suitable catalyst for example a catalytic tin compound such as stannous oxide or tin ( II) octoate
  • poly (ethylene glycol) methyl ester can be reacted under the same conditions with an appropriate amount of lactide (for example, D, L-lactide, L-lactide, or D-lactide).
  • the poly (ethylene oxide) block in the abovementioned block copolymers has an average molecular weight (Mw) of from 1000 g / mol to 7000 g / mol, preferably from 2500 g / mol to 6000 g / mol preferably from 4500 g / mol to 5500 g / mol.
  • the poly (lactide) block in the abovementioned block copolymers has an average molecular weight (Mw) of from 800 g / mol to 8000 g / mol, preferably from 2000 g / mol to 7000 g / mol or 4000 g / mol to 7000 g / mol, more preferably from 5500 g / mol to 6500 g / mol.
  • Mw average molecular weight
  • the block copolymer has an average molecular weight (Mw) of from 3000 g / mol to 20 000 g / mol, preferably from 4000 g / mol to 15000 g / mol, more preferably from 5500 g / mol to 10000 g / mol on.
  • Mw average molecular weight
  • a molecular weight of 1000 corresponds to a mass of 1 kDa.
  • the diblock copolymer has a PEO: PLA molar ratio ranging from 1: 0.05 to 1: 1.3, alternatively from 1: 0.1 to 1: 1.2, preferably from 1: 0 , 2 to 1: 1.0 or from 1: 0.25 to 1: 0.75 and also preferably from 1: 0.35 to 1: 0.65 or from 1: 0.45 to 1: 0.55 ,
  • the diblock copolymer has a molar ratio PEO: PLA in the range of 1: 0.01 to 1: 0.30 and / or in the range of 1: 0.50 to 1: 1.3.
  • the triblock copolymer has a PEO: PLA molar ratio in the range of from 3: 1 to 25: 1, preferably from 4: 1 to 20: 1, preferably from 5: 1 to 15: 1, more preferably from 7 : 1 to 10: 1 up.
  • a block copolymer to be used according to the invention may be prepared by any suitable method known to those skilled in the art.
  • US-B-6322805 in its Preparation Examples 1 to 4 describes the preparation of triblock copolymers having a PEO: PLA molar ratio of 1: 0.31, 1: 0.37, 1: 0.49 and 1: 0.61 and in its Preparation Examples 5 to 8, the preparation of diblock copolymers having a molar ratio PEO: PLA of 1: 0.15, 1: 0.31, 1: 0.46 and 1: 0.55.
  • 6,322,205 starts from a commercially available bifunctional polyethylene oxide for the preparation of the triblock copolymers or from a commercially available monofunctional polyethylene oxide for the preparation of the diblock copolymers, in which, until the desired molecular weight of the polylactide chain is obtained in the presence of a catalyst , Stannous octoate, lactide units are grafted.
  • Emulsions are disperse systems consisting of two immiscible liquid or liquid crystalline phases.
  • One liquid forms the inner, ie the dispersed (discontinuous) phase, the other the outer, that is the continuous phase.
  • the dispersion medium ie the outer phase
  • water forms the continuous phase
  • the hydrophobic active ingredient forms the disperse phase in which water in turn can be dispersed.
  • the weight ratio of the hydrophobic drug to the block copolymer in the emulsion of the present invention is 1: 1 to 10: 1. In a preferred embodiment of the invention, the weight ratio of the drug to the block copolymer is 1.5: 1 to 5: 1.
  • the molar ratio of active ingredient: block copolymer is preferably in the range from 400: 1 to 50: 1, more preferably in the range from 300: 1 to 70: 1.
  • the content of the block copolymer in the emulsion is from 0.1 to 1.0% by weight, preferably from 0.2 to 0.85% by weight, preferably from 0.3 to 0, 7 wt .-%, also preferably from 0.4 to 0.55 wt .-%, based on the total weight of the emulsion.
  • the content of active ingredient is one of the emulsion from 0.5 to 10.0 wt .-%, preferably from 1.0 to 8.0 wt .-%, preferably from 1.5 to 6.5 wt %, also preferably from 2.0 to 4.0% by weight, based on the total weight of the emulsion.
  • the emulsion according to the invention preferably has a narrow particle size distribution.
  • fat-like particles with a particle diameter of greater than 7.5 microns can adapt to the shape of the capillaries and pass through the pulmonary vessels without difficulty. From this point of view, individual particles with a particle diameter of greater than 5 microns are tolerable, especially when it comes to moldable particles such. B. drug drops is.
  • the USP XXII United States Pharmacopeia
  • particle sizes of less than 2 ⁇ m, in some cases significantly less than 1 ⁇ m are required in many cases.
  • the average droplet size (average diameter of the droplets) of the dispersed phase is 2 ⁇ m or less, for example, the average droplet size is 1 ⁇ m or less and is preferably in the range of 75 nm to 500 nm, more preferably in the range of 75
  • the mean droplet size is measured by photon correlation spectroscopy (PCS, USP 30, General Chapter 729), also called dynamic light scattering.
  • the emulsion according to the invention is preferably stable.
  • stable in connection with the emulsion according to the invention means that when stored at 25 ° C. for at least one year, preferably at least two years, no coalescence of the dispersed drops of the active substance occurs, which leads to drops having an average drop size of more than 1 micron leads.
  • the mean droplet number of the dispersed phase of the emulsion according to the invention in the range of 1.5 1 IO 11 to 6.0 1 IO 12 per ml of emulsion, preferably in the range of 5 1 IO 11 to 1.2 1 IO 12 per ml of emulsion.
  • the mean number of drops per ml of emulsion can be calculated by means of the density of the active substance and the mean drop volume.
  • the emulsion has an osmolality in the range from 250 to 400 mOsmol / kg, preferably in the range from 280 to 350 mOsmol / kg.
  • the emulsion of the invention preferably has a pH in the physiologically acceptable range, in particular a pH in the range of 6.5 to 8, preferably in the range of 7.0 to 7.5.
  • the emulsion may further comprise adjuvants and / or adjuvants selected from the group consisting of glycerol, at least one pharmaceutically acceptable salt and preservative.
  • the concentration of glycerol in the emulsion according to the invention is preferably from 1 to 5% by weight, more preferably about 2.5% by weight, based on the total weight of the emulsion.
  • the emulsion according to the invention contains as pharmaceutically acceptable salt sodium chloride, preferably in a concentration of about 0.9% by weight, based on the total weight of the emulsion (physiological saline).
  • the emulsion according to the invention if necessary, contains as the pharmaceutically acceptable salt sodium hydroxide for adjusting (raising) the pH of the emulsion.
  • the emulsion of the invention may further contain a preservative.
  • the preservative is preferably selected from the group consisting of EDTA, disodium edetate, sodium disulfite, cysteine and its salts, benzyl alcohol and mixtures thereof. Most preferably, the emulsion according to the invention contains no preservative.
  • the emulsions according to the invention are preferably parenterally administrable, preferably injectable or infusible or both, particularly preferably intravenous, intramuscular and / or subcutaneously injectable or infusible or both.
  • parenterally administrable preferably injectable or infusible or both, particularly preferably intravenous, intramuscular and / or subcutaneously injectable or infusible or both.
  • the emulsion according to the invention comprises a narcotic selected from the group consisting of propofol, propanidide, isoflurane, enflurane and sevoflurane.
  • the emulsion according to the invention comprises propofol.
  • the emulsion according to the invention comprises propanidide.
  • the emulsion according to the invention comprises isoflurane.
  • the emulsion according to the invention comprises enflurane.
  • the emulsion according to the invention comprises sevoflurane.
  • emulsion of the invention containing a narcotic as described above is as defined above. In the following, preferred embodiments are described.
  • the content of propofol is preferably from 0.5 to 2.0% by weight, preferably from 1.0 to 2.0% by weight, based on the total weight of the emulsion.
  • the content of propanidide is preferably from 0.5 to 10.0% by weight, preferably from 4.0 to 6.0% by weight, for example 5.0% by weight. %, based on the total weight of the emulsion.
  • the content of the narcotic is preferably from 0.5 to 10.0% by weight, preferably from 1.0 to 8.0% by weight. %, preferably from 1.5 to 6.5 wt .-%, also preferably from 2.0 to 4.0 wt .-%, based on the total weight of the emulsion.
  • the emulsion according to the invention containing a narcotic as hydrophobic active ingredient may further contain at least one block copolymer in the ratio propofol to block copolymer of 1: 1 to 10: 1, wherein the block copolymer is a diblock copolymer PEO-PLA or a triblock Copolymer PEO-PLA-PEO.
  • the poly (ethylene oxide) block preferably has an average molecular weight (Mw) of 1000 g / mol to 7000 g / mol, preferably 2500 g / mol to 6000 g / mol, particularly preferably from 4500 g / mol to 5500 g / mol ,
  • the poly (lactide) block preferably has an average molecular weight (Mw) of from 800 g / mol to 8000 g / mol, preferably from 2000 g / mol to 4200 g / mol.
  • the block copolymer preferably has an average molecular weight (Mw) of from 3,000 g / mol to 20,000 g / mol, preferably from 4,000 g / mol to 15,000 g / mol, more preferably from 5,500 g / mol to 10,000 g / mol.
  • Mw average molecular weight
  • the diblock copolymer preferably has a molar ratio PEO: PLA in the range from 1: 0.05 to 1: 1.3, alternatively up to 1: 0.62 or 1: 0.49, preferably from 1: 0.08 to 1: 1.0 alternatively to 1: 0.31 or to 1: 0.23.
  • the triblock copolymer preferably has a PEO: PLA molar ratio ranging from 3: 1 to 25: 1, preferably from 4: 1 to 20: 1, preferably from 5: 1 to 15: 1, more preferably from 7: 1 to 10: 1 on.
  • the content of the block copolymer in the narcotic-containing emulsion is preferably from 0.1 to 1.0% by weight, preferably from 0.2 to 0.85% by weight. preferably from 0.3 to 0.7 wt .-%, also preferably from 0.4 to 0.55 wt .-%, based on the total weight of the emulsion.
  • the content of the block copolymer in the narcotic-containing emulsion is in the range of 0.4 to 1.2 wt .-%, based on the total weight of the emulsion.
  • the content of the block copolymer is preferably from 0.1 to 0.6% by weight, for example, 0.2 to 0.45% by weight .-%, based on the total weight of the emulsion.
  • the content of the block copolymer is preferably from 0.2 to 0.4 Wt .-%, based on the total weight of the emulsion.
  • the content of the block copolymer is preferably from 0.05 to 0.5 Wt .-%, for example 0.1 to 0.3 wt .-% or 0.15 to 0.25 wt .-%, based on the total weight of the emulsion.
  • the mean droplet size of the dispersed phase is preferably 2 ⁇ m or less, for example 1 ⁇ m or less, preferably measured by photon correlation spectroscopy, and is preferably in the range of 75 nm to 500 nm, most preferably in the range of 75 nm to 300 nm.
  • the mean droplet number of the dispersed phase per ml of the emulsion of the invention is in the range of 1.5 1 IO 11 to 6.0 1 IO 12 per ml of emulsion, preferably in the range of 5 1 IO 11 to 1.2 1 IO 12 per ml of emulsion ,
  • the mean number of drops per ml of emulsion can be calculated from the density of the narcotic and the mean drop volume.
  • the emulsion preferably has an osmolality in the range from 250 to 400 mOsmol / kg, preferably in the range from 280 to 350 mOsmol / kg.
  • the emulsion of the invention has a pH in the physiologically acceptable range, in particular in the range of 6.5 to 8, preferably in the range of 7.0 to 7.5.
  • the emulsion may further contain the above-mentioned additives and / or auxiliaries.
  • the emulsion according to the invention can in principle be prepared by any method known in the art.
  • An exemplary process for preparing the emulsion according to the invention comprises homogenizing a mixture which comprises water, the hydrophobic active substance, the at least one block copolymer and optionally additives and / or auxiliaries.
  • the method according to the invention comprises the following steps:
  • the homogenization is carried out by means of a homogenizer, preferably at a pressure in the range of 300 bar to 1000 bar, such as piston-gap high-pressure homogenizer, or by means of a microfluidizer, preferably at a pressure in the range of 300 bar to 1000 bar , in particular 400 bar to 600 bar, for example about 500 bar.
  • a homogenizer preferably at a pressure in the range of 300 bar to 1000 bar, such as piston-gap high-pressure homogenizer, or by means of a microfluidizer, preferably at a pressure in the range of 300 bar to 1000 bar , in particular 400 bar to 600 bar, for example about 500 bar.
  • Suitable homogenizers are, for example, the Lab 2000 and the APV Micron LAB 40 (available from APV Systems, D-Unna).
  • a suitable microfluidizer is, for example, Model 110-Y from Microfluidics.
  • the mixture is homogenized for a period of 2 to 10 minutes, preferably 4 to 7 minutes, at a rate in the range of 15,000 rpm to 30,000 rpm, preferably from 19,000 rpm to 24,000 Stirred rpm, preferably by means of Ultra Turrax (available from IKA ® -Werke GmbH & CO. KG, Staufen, Germany).
  • the inventive method as a further step comprises the step of sterilization of the emulsion, preferably by heating the emulsion to a temperature in the range of 90 0 C to 140 0 C, preferably from 115 ° C to 130 0 C, preferably for a Duration in the range of 7 minutes to 25 minutes, preferably from 12 minutes to 18 minutes.
  • Another object of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the emulsion according to the invention.
  • the pharmaceutical composition is preferably selected from the group consisting of a therapeutic, a diagnostic and a prophylactic.
  • a particular object of the present invention relates to an anesthetic comprising the above-described emulsion according to the invention, for example containing an active substance of the group consisting of propofol, propanidide, isoflurane, enflurane, sevoflurane or mixtures thereof, and preferably containing propofol.
  • Another object of the present invention relates to a diagnostic agent (contrast agent) comprising the above-described inventive emulsion, for example containing ethyl esters of iodinated fatty acids from poppy seed oil.
  • Another object of the present invention relates to a lipid-lowering medicament comprising the above-described inventive emulsion, for example containing clofibrate.
  • Another object of the present invention relates to a vitamin preparation comprising the above-described inventive emulsion, for example containing vitamin Ki.
  • the emulsion according to the invention can be used for the preparation of a medicament for human or veterinary medicine.
  • the emulsion of the invention containing one selected from the group consisting of propofol, propanidide, isoflurane, enflurane, sevoflurane or mixtures thereof, and preferably propofol, may be used to prepare an anesthetic.
  • the ethyl ester of the iodinated fatty acids of poppy oil-containing emulsion of the present invention may be used for the preparation of a diagnostic agent (contrast agent).
  • the vitamin Ki-containing emulsion according to the invention can be used for the preparation of a vitamin preparation.
  • the clofibrate-containing emulsion of the present invention can be used for the preparation of a lipid-lowering drug.
  • the emulsion according to the invention can furthermore be used for the prophylaxis and / or therapy and / or diagnosis in human or veterinary medicine, in particular as anesthetic, diagnostic agent, lipid-lowering medicament and vitamin preparation.
  • Another object of the present invention relates to a method for therapeutic and / or prophylactic and / or diagnostic treatment of the human or animal body by administering the emulsion of the invention defined above, containing the hydrophobic drug, preferably by parenteral administration, preferably by injection or infusion, especially preferably by intravenous, intramuscular and / or subcutaneous injection or infusion.
  • the quality of the propofol and glycerol used corresponds to the quality according to known monographs.
  • DL-lactide and poly (ethylene glycol) methyl ester (PEGME) were mixed in a 50 ml nitrogen flask with tin (II) octoate as a catalyst under an argon atmosphere. With constant stirring, the mixture was heated at 130 0 C for 4 h. The resulting block copolymer was taken up in 30 ml of chloroform and precipitated in 500 ml of diethyl ether. After 12 h, the precipitate was filtered off and dried at 40 0 C at 15 mbar.
  • PEGME poly (ethylene glycol) methyl ester
  • the resulting block copolymer was dissolved in 200 ml of tetrahydrofuran (THF) and separated from the tin precipitate by centrifugation followed by filtration. After filtration, the THF solution was concentrated to about 60 ml.
  • the block copolymer was again precipitated in 600 ml of diethyl ether and dried at 15 mbar for 12 h at 40 0 C.
  • Mw molecular weights

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Anesthesiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des émulsions aqueuses contenant un principe actif hydrophobe, des procédés pour leur production, des compositions pharmaceutiques, telles que des agents thérapeutiques, diagnostiques et/ou prophylactiques, en particulier des agents anesthésiques, comprenant l'émulsion aqueuse, l'utilisation de ces émulsions aqueuses pour produire des médicaments, ainsi que des procédés pour le traitement thérapeutique et/ou prophylactique du corps humain ou animal et/ou pour le diagnostic par administration de l'émulsion aqueuse.
PCT/EP2008/064979 2007-11-06 2008-11-05 Émulsions aqueuses contenant un principe actif hydrophobe WO2009059989A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE112008002914T DE112008002914A5 (de) 2007-11-06 2008-11-05 Einen hydrophoben Wirkstoff enthaltende wässrige Emulsionen

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP07120052.1 2007-11-06
EP07120052 2007-11-06

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WO2009059989A1 true WO2009059989A1 (fr) 2009-05-14

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DE (1) DE112008002914A5 (fr)
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6322805B1 (en) * 1995-09-21 2001-11-27 Samyang Corporation Biodegradable polymeric micelle-type drug composition and method for the preparation thereof
WO2004019041A1 (fr) * 2002-08-20 2004-03-04 Proteome Systems Intellectual Property Pty Ltd Nouveaux marqueurs pronostiques et diagnostiques d'une exacerbation aigue de la maladie pulmonaire et retablissement
WO2004032858A2 (fr) * 2002-10-11 2004-04-22 Baxter International, Inc. Methode de cardioprotection et de neuroprotection par administration intraveineuse d'anesthesiques volatiles halogenes
WO2005079758A1 (fr) * 2004-02-13 2005-09-01 Bioavailability, Inc. Preparation de micro-emulsion a forte teneur en propofol a des fins anesthesiques
WO2006127953A2 (fr) * 2005-05-23 2006-11-30 University Of Utah Research Foundation Microbulles et microemulsions echogenes utilisees pour apporter des agents charges sur des nanoparticules, l'apport etant renforce par des ultrasons

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6322805B1 (en) * 1995-09-21 2001-11-27 Samyang Corporation Biodegradable polymeric micelle-type drug composition and method for the preparation thereof
WO2004019041A1 (fr) * 2002-08-20 2004-03-04 Proteome Systems Intellectual Property Pty Ltd Nouveaux marqueurs pronostiques et diagnostiques d'une exacerbation aigue de la maladie pulmonaire et retablissement
WO2004032858A2 (fr) * 2002-10-11 2004-04-22 Baxter International, Inc. Methode de cardioprotection et de neuroprotection par administration intraveineuse d'anesthesiques volatiles halogenes
WO2005079758A1 (fr) * 2004-02-13 2005-09-01 Bioavailability, Inc. Preparation de micro-emulsion a forte teneur en propofol a des fins anesthesiques
WO2006127953A2 (fr) * 2005-05-23 2006-11-30 University Of Utah Research Foundation Microbulles et microemulsions echogenes utilisees pour apporter des agents charges sur des nanoparticules, l'apport etant renforce par des ultrasons

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BABAK ET AL: "The effect of hydrophile-lipophile balance of water-soluble poly(ethylene glycol)-poly(lactic acid) diblock copolymers on the stability of microscopic emulsion films and nanoemulsions", MENDELEEV COMMUNICATIONS, INSTITUTE OF PHYSICS PUBLISHING, BRISTOL, GB, vol. 8, no. 3, 1 January 1998 (1998-01-01), pages 105 - 107, XP022529613, ISSN: 0959-9436 *
HAGAN: "PLA-PEG copolymers - a novel biodegradable drug delivery system", 19000101, 1 January 1900 (1900-01-01), XP009099653 *

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