WO2012029456A1 - Composition d'émulsion huile dans l'eau contenant un médicament médiocrement soluble et son procédé de fabrication - Google Patents

Composition d'émulsion huile dans l'eau contenant un médicament médiocrement soluble et son procédé de fabrication Download PDF

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WO2012029456A1
WO2012029456A1 PCT/JP2011/067146 JP2011067146W WO2012029456A1 WO 2012029456 A1 WO2012029456 A1 WO 2012029456A1 JP 2011067146 W JP2011067146 W JP 2011067146W WO 2012029456 A1 WO2012029456 A1 WO 2012029456A1
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oil
soluble drug
emulsion composition
water emulsion
mass
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PCT/JP2011/067146
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English (en)
Japanese (ja)
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史朗 園家
泰之 泉
永田　幸三
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富士フイルム株式会社
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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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a poorly soluble drug-containing oil-in-water emulsion composition and a method for producing the same.
  • drugs created in the pharmaceutical field tend to have a large molecular weight and a complicated chemical structure. It is an extremely important issue to prepare such a drug that hardly dissolves in water or oil, that is, a so-called poorly soluble drug, that can be administered parenterally.
  • Examples of such poorly soluble drugs include taxane drugs widely used in cancer chemotherapy.
  • a taxane drug When a taxane drug is administered by injection or infusion, the drug is solubilized using a nonionic surfactant such as polysorbate or polyoxyethylated castor oil, and ethanol.
  • a nonionic surfactant such as polysorbate or polyoxyethylated castor oil, and ethanol.
  • solubilizers is concerned about side effects such as hypersensitivity. Therefore, many techniques have been proposed to safely administer taxane drugs and other poorly soluble drugs parenterally without using solubilizers.
  • emulsified preparations that are cost-effective and easy to administer are drawing attention as preparation forms that allow parenteral administration of poorly water-soluble drugs.
  • oils derived from triglycerides such as soybean oil, sesame oil, cottonseed oil, safflower oil and the like are often used as oils used in pharmaceutical preparations, particularly injection emulsions.
  • injectable emulsion preparations using these oils are mainly drugs with high fat solubility or low molecular weight drugs, and are almost soluble in water and oil, which have been increasing in recent years. In fact, it cannot be applied to drugs that do not work, so-called poorly soluble drugs.
  • JP-T-10-502921 discloses an emulsified preparation that uses safflower oil instead of soy oil as dissolved oil of paclitaxel, and uses egg yolk lecithin and cholesterol as surfactants. Is disclosed.
  • JP-A-11-509545 at least five components: therapeutic agent, vitamin E, oil in which drug and vitamin E are dissolved, and stabilizer (phospholipid, lecithin or polyoxyethylene-polyoxypropylene)
  • a lipid drug delivery composition comprising any of the copolymers poloxamer) and water is disclosed.
  • vitamin E having good solubility in paclitaxel
  • soybean oil and vitamin E are used in equal amounts
  • pluronic P105 is used as a surfactant.
  • JP 2003-501376 exemplifies an oil core composition using tributyrin as a dissolved oil of paclitaxel and using dipalmitoylphosphatidylglycerol, dioleoylphosphatidylcholine, and cholesterol as surfactants.
  • the particle size of the oil core composition is described as 16.3 ⁇ m.
  • JP-T-2008-514720 discloses an emulsified preparation in which medium chain triglyceride and soybean oil are used in combination as dissolved oil of paclitaxel and egg yolk lecithin is used as a surfactant.
  • medium chain triglyceride and soybean oil are used in combination as dissolved oil of paclitaxel and egg yolk lecithin is used as a surfactant.
  • concentration of the oil component containing the taxane drug is limited to 6% by mass or less at the maximum. ing.
  • an object of the present invention is to provide an oil-in-water emulsified composition containing a poorly soluble drug at a high concentration, having good stability and suitable as an injection, and a method for producing the same.
  • the present invention is as follows. [1] A water-soluble drug having a solubility in water of less than 1 mg / mL and a molecular weight of 500 or more, medium chain fatty acid triglyceride in an amount of more than 80% by mass and 100% by mass or less, and An average particle size of emulsified particles comprising an oil component in an amount of more than 6% by mass and not more than 25% by mass with respect to the total mass, and a surfactant component containing phospholipid in an amount of 50% by mass to 100% by mass
  • a poorly soluble drug-containing oil-in-water emulsion composition having a diameter of less than 500 nm.
  • the hardly soluble drug-containing oil-in-water emulsion composition according to any one of [1] to [8], wherein an average carbon number of the constituent fatty acid in the medium chain fatty acid triglyceride is 8.2 or less.
  • To prepare an oil phase by dissolving an oil phase component containing at least the hardly soluble drug, the oil component and a surfactant component containing the phospholipid in an organic solvent that can be commonly dissolved.
  • the oil phase and the aqueous phase are mixed to prepare an oil-in-water emulsion, the oil phase before or after the oil-in-water emulsion is prepared, and the organic solvent relative to the mass of the oil phase.
  • the poorly soluble drug-containing oil-in-water emulsion composition of the present invention has a solubility in water of less than 1 mg / mL and a poorly soluble drug having a molecular weight of 500 or more and an amount of more than 80% by mass and less than 100% by mass.
  • a poorly soluble drug-containing oil-in-water emulsion composition having an average particle size of the emulsified particles of less than 500 nm.
  • an oil component containing medium-chain fatty acid triglyceride in an oil component at a concentration of more than 80% by mass and 100% by mass or less as the oil component a poorly soluble drug is dissolved in the oil component at a high concentration and included in the oil component.
  • a poorly soluble drug-containing oil-in-water emulsion composition of a dosage form containing a poorly soluble drug at a high concentration and having a good stability and suitable as an injection is sometimes simply referred to as “emulsion composition” or “composition”.
  • the term “process” is not limited to an independent process, and is included in this term if the intended action of this process is achieved even when it cannot be clearly distinguished from other processes. .
  • a numerical range indicated by using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
  • the amount of each component in the composition when there are a plurality of substances corresponding to each component in the composition, the plurality present in the composition unless otherwise specified. Means the total amount of substances. The present invention will be described below.
  • the poorly soluble drug in the present invention is a poorly soluble drug having a solubility in water of less than 1 mg / mL and a molecular weight of 500 or more. Any drug may be used as long as it has a solubility in water of less than 1 mg / mL and dissolves in a predetermined organic solvent as described later. Preferably, it is a poorly soluble drug that does not dissolve in water or oil.
  • the expression “not soluble in oil” means, for example, a drug having a solubility in soybean oil at 25 ° C. of less than 15 mg / mL.
  • the molecular weight of the poorly soluble drug may be 500 or more, more preferably 800 or more.
  • the water / octanol partition coefficient (hereinafter abbreviated as LogP) of the poorly soluble drug is preferably 8.0 or less, and more preferably 2.0 or more. Is less than 6. If LogP is 8.0 or less, the effect of the present invention can be sufficiently exerted. Moreover, if LogP is 2.0 or more, the stability in an oil phase can fully be maintained. Examples of such poorly soluble drugs include taxane anticancer agents and tacrolimus or cyclosporine.
  • taxane anticancer agents include taxanes.
  • Taxanes include: paclitaxel; docetaxel; spicatin; taxane-2,13-dione, 5 ⁇ , 9 ⁇ , 10 ⁇ -trihydroxy-cyclic-9,10-acetal or acetate with acetone Taxane-2,13-dione-5 ⁇ , 9 ⁇ , 10 ⁇ -trihydroxy-cyclic-9,10-acetal with acetone; taxane-2 ⁇ , 5 ⁇ , 9 ⁇ , 10 ⁇ -tetrol-cyclic-9 with acetone; 10-acetal; taxane; cephalomannin-7-xyloside; 7-epi-10-deacetylcephalomannine; 10-deacetylcephalomannine; Cephalomannine; taxol B; 13- (2 ′, 3′-dihydroxy-3′-phenylpropi Nyl) baccatin III; yunnanxol; 7- (4-azidobenzoyl) baccatin III;
  • tacrolimus and tacrolimus analogs include Tanaka et al., (J. Am. Chem. Soc., 109: 5031, 1987), US Pat. Nos. 4,894,366, 4,929,611, No. 4,956,352, and Japanese translations of PCT publication No. 2002-519378. Tacrolimus, tacrolimus hydrate, ascomycin, 33-epi-chloro-33-desoxyascomycin, etc.
  • Ascomycin derivatives such as halogenated derivatives of Examples of cyclosporine and cyclosporine analogs include cyclosporin A, dihydrocyclosporin C, cyclosporin D, and dihydrocyclosporin D. These drugs are usually used alone, but it does not exclude the use of a mixture of two or more.
  • the poorly soluble drug is generally 1 ⁇ g / mL to 50 mg / mL with respect to the total mass of the composition (0.0001% by mass to 5.0% by mass with respect to the total mass of the composition). ).
  • the oil component in the present invention contains medium-chain fatty acid triglyceride in an amount of more than 80% by mass and 100% by mass or less.
  • the poorly soluble drug can be dissolved at a high content and stably encapsulated in the oil component.
  • the content of the medium chain fatty acid triglyceride in the oil component is 90% by mass or more and 100% by mass or less in order to further increase the oil component concentration in the emulsion composition and to promote refinement and improve stability. More preferably.
  • oil component refers to a hydrocarbon, carbohydrate, or similar organic compound that is liquid at about 37 ° C. and is pharmacologically acceptable in an injectable formulation.
  • oil components include various vegetable oils, animal fats, triglycerides such as medium chain fatty acid triglycerides, and non-glycerides such as cholesterol.
  • the medium-chain fatty acid triglyceride means an oil or fat having an average carbon number of 8 to 12 in the fatty acid chain constituting the triglyceride contained.
  • the average carbon number of the fatty acid in the medium-chain fatty acid triglyceride is the number of carbon atoms (for example, caprylic acid in the fatty acid chain constituting the triglyceride contained in the medium-chain fatty acid triglyceride). 8 if present, and 10) if capric acid, the weighted average by the composition ratio of the constituent fatty acids.
  • the drug can be encapsulated at a higher concentration, and from the viewpoints of stability and viscosity of the emulsion composition, the average fatty chain length of the constituent fatty acid is 9.9 or less, more preferably 8.8 or less, and still more preferably Is 8.5 or less, most preferably 8.2 or less.
  • the medium-chain fatty acid triglyceride used in the present invention is not particularly limited as long as the average carbon number of the constituent fatty acid chain is within the above-described range, and examples thereof include fatty acids having 6 to 12 carbon atoms. These fatty acids may be saturated or unsaturated. Preferably, it is composed mainly of triglycerides of saturated fatty acids having 6 to 12 carbon atoms. Moreover, the thing derived from natural vegetable oil may be sufficient and the triglyceride of a synthetic fatty acid may be sufficient. You may use these individually or in combination of 2 or more types.
  • the medium chain fatty acid triglyceride may be used alone if the average carbon number of the constituent fatty acid chain is within the above-mentioned range, and two or more kinds of medium chain fatty acids having different average carbon numbers of the constituent fatty acid chain may be used. It may be a mixture of triglycerides. When two or more kinds of medium chain fatty acid triglycerides are mixed, the average number of carbon atoms of the constituent fatty acids may be within the above-described range as a whole mixture of medium chain fatty acid triglycerides.
  • SASOL GmbH Germany
  • Miglyol 812 Miglyol 810, Kao's coconut MT, coconut RK, etc. are suitably used as the medium chain fatty acid triglycerides.
  • Other low melting point medium chain fatty acid triglycerides can also be used in the present invention.
  • the oil component that can be used in combination with other than medium chain fatty acid triglycerides is not particularly limited, but vegetable oil is preferred.
  • the vegetable oil means oils derived from plant seeds or nuts (long-chain fatty acid triglycerides), such as almond oil, borage oil, black currant seed oil, castor oil, corn oil, safflower oil, soybean oil, sesame oil, cottonseed oil, Examples include, but are not limited to, peanut oil, olive oil, rapeseed oil, coconut oil, coconut oil, and canola oil.
  • Animal fats can also be used as long as they do not affect the effects of the present invention.
  • Animal fat means oil derived from animal sources.
  • animal-derived animal fats tallow fat, lard, etc.
  • the emulsified composition of the present invention contains an oil component in an amount of at least over 6% by mass and 25% by mass or less. Thereby, it can be set as the emulsion composition which contains a poorly soluble drug with high content.
  • the preferred oil component concentration is 7% by mass to 25% by mass of the total mass of the emulsion composition.
  • a preferable range is 8 to 15% by mass.
  • the surfactant component in the present invention contains phospholipid in an amount of 50% by mass or more and 100% by mass or less. If the ratio of the phospholipid in the surfactant component is less than 50% by mass, the stability and safety cannot be said to be sufficient.
  • the content of the phospholipid in the surfactant component is preferably 80% by mass or more and 100% by mass or less, and 90% by mass or more and 100% by mass or less. More preferably, it is 100% by mass, that is, it is most preferable to use only phospholipid as a surfactant.
  • the phospholipid in the present invention includes a pure phospholipid or a mixture of two or more phospholipids.
  • the term “phospholipid” means a triester of glycerol with two fatty acids and one phosphate ion.
  • Examples of phospholipids useful in the present invention include phosphatidylcholine, lecithin (mixture of choline ester with phosphorylated diacylglyceride), phosphatidylethanolamine, phosphatidylglycerol, about 4 to about 22 carbon atoms, more generally about This includes, but is not limited to, phosphatidic acids having 10 to about 18 carbon atoms and varying degrees of saturation. It may also contain PEG-phospholipid in which polyethylene glycol (PEG) is bound to the phospholipid.
  • PEG polyethylene glycol
  • synthetic lecithin can be used, but naturally occurring phospholipids are preferred.
  • Natural phospholipids include soy lecithin, egg lecithin, hydrogenated soy lecithin, hydrogenated egg lecithin, sphingosine, ganglioside, and phytosphingosine and combinations thereof, in terms of safety and stability of the composition Therefore, lecithin is preferable, and egg lecithin is particularly preferable.
  • Natural lecithin is a mixture of diglycerides of stearic acid, palmitic acid and oleic acid linked to a choline ester of phosphate, commonly referred to as phosphatidylcholine, and obtained from various sources such as eggs and soybeans be able to.
  • Soy lecithin and egg lecithin (including hydrogenated forms of these compounds) have a long history of safety, have combined properties of emulsification and solubilization, and more than most synthetic surfactants Tend to be metabolized more quickly to harmless substances.
  • soybean phospholipids are Centrophase and Centrolex products marketed and sold by Central Soya, Phospholipon from Phospholipid GmbH (Germany), Lipoid from Lipoid GmbH (Germany), and EPIKURON from Degussa.
  • Commercially available egg yolk lecithin includes Kewpy PL-100M and PC-98N.
  • Hydrogenated lecithin is a product in which part or all of unsaturated double bonds in the fatty chain constituting lecithin are hydrogenated. This can also be used in the present invention.
  • the surfactant component in the emulsified composition of the present invention has an oil component in order to bring the viscosity of the emulsified composition to an appropriate range as an injection, maintain stability, and achieve a sufficient amount of oil component.
  • the ratio of the surfactant component to the total mass is preferably 80% by mass or less, more preferably 1% by mass to 80% by mass, and still more preferably 5% by mass to 50% by mass. More preferably, the content is 10% by mass to 25% by mass.
  • the emulsified composition of the present invention may optionally contain an oxidizing agent, an alkaline agent, a buffering agent, a chelating agent, a complexing agent and a solubilizing agent, an antioxidant, and an antioxidant, an antimicrobial preservative, and a suspending agent. And / or additives such as viscosity modifiers, tonicity agents, and other biocompatible or therapeutic substances. Such materials are generally present in the aqueous phase of the emulsion composition. Such additives enhance the stability of the emulsified composition or drug in the emulsified composition, and assist in making the emulsified composition of the present invention more biocompatible.
  • the water phase component which comprises the water phase in the emulsion composition of this invention is contained. Any of the above-described additives can be included as the aqueous phase component.
  • the additive mentioned above can be made into an aqueous phase component or an oil phase component based on the kind of additive.
  • the aqueous phase generally has an osmotic pressure of about 300 mOsm and can contain potassium chloride or sodium chloride, trehalose, sucrose, sorbitol, glycerol, mannitol, polyethylene glycol, propylene glycol, albumin, amino acids and mixtures thereof. .
  • a tonicity of at least 250 mOsm is achieved with substances that increase viscosity, such as sorbitol or sucrose.
  • substances that increase viscosity such as sorbitol or sucrose.
  • Compounds useful for altering the osmotic pressure of the emulsion composition of the present invention are commonly referred to as “isotonic agents” or “osmotic pressure improvers”.
  • the “antioxidant” used in the present invention is preferably a metal ion chelating agent and / or a reducing agent that is safe when used in an injectable product.
  • a metal ion chelator functions as an antioxidant by binding to metal ions, thereby reducing the catalytic action of the metal ions on the oxidation reaction of the drug, oil or phospholipid component.
  • Metal chelators useful in the present invention include, but are not limited to, EDTA, glycine and citric acid or salts thereof.
  • the average particle size of the emulsified particles in the emulsified composition of the present invention is less than 500 nm. Above 500 nm, it is unsuitable for use as an injection. From the viewpoint of stability and viscosity of the composition or handling as an injection, it is preferably 1 nm to 200 nm, more preferably 5 nm to 200 nm, still more preferably 10 nm to 180 nm, and most preferably 15 nm to 150 nm. It is.
  • the dynamic light scattering method is preferred for measuring the particle size of the emulsified particles in the present invention because of the particle size range in the present invention and ease of measurement.
  • Commercially available measuring devices using dynamic light scattering include Nanotrac UPA (Nikkiso Co., Ltd.), dynamic light scattering type particle size distribution measuring device LB-550 (Horiba, Ltd.), and a concentrated particle size analyzer.
  • FPAR-1000 Oleuka Electronics Co., Ltd.
  • As the particle size in the present invention a value measured at 25 ° C. using a grain nanotrack UPA (Nikkiso Co., Ltd.) is adopted.
  • the particle size is measured by diluting 10 times with pure water in the case of an oil-in-water emulsion composition, and diluted with pure water so that the solid content concentration is 1% by mass in the case of a powder composition. And using Nano Track UPA (Nikkiso Co., Ltd.).
  • the oil-in-water emulsion composition of the present invention includes those reconstituted from a freeze-dried preparation. Therefore, the emulsion composition of the present invention may contain one or more cryoprotectants.
  • cryoprotectants also known as “freeze-drying aids” or “freeze-dry bulk agents”, solidify droplets during freeze-drying processes and to form oil-in-solid dispersion systems in solids. It refers to a component added to maintain discrete sub-micron droplets of the emulsified composition upon removal of moisture from the emulsified composition to form a matrix.
  • cryoprotectants include polyols, monosaccharides, disaccharides, polysaccharides, amino acids, peptides, proteins, and hydrophilic polymers, and mixtures thereof.
  • concentration of cryoprotectant sufficient to stabilize the oil droplets of the emulsified composition is typically in the range of about 5% to 20% by weight, but is not limited to this range.
  • the emulsified composition of the present invention can be administered parenterally, for example, it can be injected intravenously, intraarterially, intrathecally, intraperitoneally, intraocularly, intraarticularly, intramuscularly or subcutaneously.
  • the emulsified composition of the present invention has an appropriate viscosity for use as such an injection.
  • Viscosity suitable for use as an injection means a range of 1 mPa ⁇ s to 200 mPa ⁇ s as measured by a vibration viscometer at 25 ° C., and preferably 100 mPa ⁇ s or less from the viewpoint of safety. More preferably, it is 10 mPa ⁇ s or less.
  • the emulsion composition of the present invention comprises an oil phase component obtained by dissolving an oil phase component containing at least the hardly soluble drug, the oil component and a surfactant containing the phospholipid in an organic solvent that can be dissolved in common.
  • oil phase preparation step to prepare an oil-in-water emulsion by mixing the oil phase and the aqueous phase (hereinafter referred to as emulsification step), and to prepare the oil-in-water emulsion
  • the oil phase before or after the removal can be obtained by a production method including desolvating the organic solvent to less than 10% by mass with respect to the mass of the oil phase (hereinafter referred to as a desolvation step).
  • oil phase preparation step a mixture (oil phase) containing an appropriate amount of an oil phase component containing at least (i) a poorly soluble drug, (ii) an oil component (for example, a medium chain fatty acid triglyceride), and (iii) a phospholipid. These are dissolved in a commonly soluble organic solvent.
  • the organic solvent used here may be any substance as long as each of the oil phase components (i) to (iii) is dissolved in an amount of 0.1% by mass or more at 25 ° C.
  • Such an organic solvent is preferably a water-soluble organic solvent.
  • the water-soluble organic solvent refers to an organic solvent having a solubility in water at 25 ° C. of 10% by mass or more.
  • the solubility in water is preferably 30% by mass or more, more preferably 50% by mass or more from the viewpoint of the stability of the finished emulsion.
  • the water-soluble organic solvent may be used alone or a mixed solvent of a plurality of water-soluble organic solvents. Moreover, you may use as a mixture with water.
  • the water-soluble organic solvent is preferably contained in an amount of at least 50% by volume, more preferably 70% by volume or more based on the volume of the mixture.
  • water-soluble organic solvents examples include methanol, ethanol, 1-propanol, 2-propanol, 2-butanol and other alcohols; ethylene glycol, 1,3 butanediol, 1,4 butanediol, propylene glycol, Polyhydric alcohols such as diethylene glycol and triethylene glycol; acetone, tetrahydrofuran, acetonitrile, methyl ethyl ketone, dipropylene glycol monomethyl ether, methyl acetate, methyl acetoacetate, N-methylpyrrolidone, dimethyl sulfoxide, etc., and mixtures of two or more thereof Can be mentioned.
  • alcohol such as ethanol, propylene glycol, or acetone is preferable and ethanol or the liquid mixture of ethanol and water is especially preferable.
  • the organic solvent in the oil phase is desolvated to less than 10% by mass relative to the mass of the oil phase, and preferably from less than 5% by mass from the viewpoint of the stability of the emulsion composition. If it is 10 mass% or more, it is unsuitable for application as an injection from the viewpoint of safety.
  • Solvent removal that is, methods for removing the solvent, are known evaporation methods using a rotary evaporator, flash evaporator, ultrasonic atomizer, membrane separation methods such as ultrafiltration membranes and reverse osmosis membranes. It may be. A known apparatus may be applied as it is.
  • an oil phase and an aqueous phase are mixed (emulsified) to prepare an oil-in-water emulsion.
  • an emulsification method any method generally used may be used.
  • a general-purpose emulsification method a method using mechanical force, that is, a method of breaking oil droplets by applying a strong shearing force from the outside is applied.
  • the most common mechanical force is a high speed, high shear stirrer.
  • a stirrer what is called a homomixer, a disper mixer and an ultramixer are commercially available.
  • there is a high-pressure homogenizer as another mechanical emulsification apparatus useful for miniaturization, and various apparatuses are commercially available. Since the high-pressure homogenizer can give a larger shearing force than the stirring method, it can be made fine even if the amount of the emulsifier is relatively small.
  • the high-pressure homogenizer examples include a chamber-type high-pressure homogenizer having a chamber in which a flow path for processing liquid is fixed, and a homogeneous valve-type high-pressure homogenizer having a homogeneous valve.
  • the homogeneous valve type high-pressure homogenizer can easily adjust the width of the flow path of the processing liquid and can arbitrarily set the pressure and flow rate during the operation, so that the operation range is wide, especially the emulsion composition according to the present invention. It is preferable for the manufacturing method of a thing.
  • the degree of freedom of operation is low, a mechanism for increasing the pressure is easy to make. Therefore, when an ultra-high pressure is required, a chamber-type high-pressure homogenizer can be suitably used.
  • Examples of the chamber-type high-pressure homogenizer include a microfluidizer (manufactured by Microfluidics), a nanomizer (manufactured by Yoshida Kikai Kogyo Co., Ltd.), and an optimizer (manufactured by Sugino Machine Co., Ltd.).
  • Examples of the homogeneous valve type high pressure homogenizer include Gorin type homogenizer (manufactured by APV), Lanier type homogenizer (manufactured by Lanier), high pressure homogenizer (manufactured by Niro Soavi), homogenizer (manufactured by Sanwa Machinery Co., Ltd.), and high pressure homogenizer. (Made by Izumi Food Machinery Co., Ltd.), ultrahigh pressure homogenizer (made by Ika Co., Ltd.) and the like.
  • the pressure of the high-pressure homogenizer is preferably 50 MPa or more, more preferably 50 to 250 MPa, and still more preferably 100 to 250 MPa, from the viewpoints of finer emulsion particles and stability of the composition. .
  • the emulsified liquid which is an emulsified and dispersed composition, is cooled through some cooler within 30 seconds, preferably within 3 seconds immediately after passing through the chamber.
  • either the solvent removal step or the emulsification step may be performed first, but from the viewpoint of the stability of the emulsion composition, the solvent removal step is preferably performed first. .
  • the solvent removal step is preferably performed first.
  • the oil phase after the solvent removal and the water phase are mixed.
  • the poorly soluble drug-containing oil-in-water emulsion composition in the present invention has good stability and contains a poorly soluble drug at a high concentration and is suitable as an injection, such a poorly soluble drug-containing oil-in-water emulsion composition
  • the present invention also provides a method of using an object.
  • the present invention provides a therapeutic method according to the use of a poorly soluble drug by administering the poorly soluble drug-containing emulsion composition described herein to a patient in need thereof.
  • an emulsion composition using a taxane anticancer agent as a poorly soluble drug it is a method for treating cancer, and an emulsion composition containing an immunosuppressant (eg, cyclosporine or tacrolimus) as a poorly soluble drug.
  • an immunosuppressant eg, cyclosporine or tacrolimus
  • Administration can be intravenous, intramuscular, intraarterial, intrathecal, intraocular, subcutaneous, intraarticular and intraperitoneal.
  • the fatty acid composition was measured by the following method for Coconut RK, Coconut ML (above, Kao) and Miglyol 810 (Sasol), which are medium chain fatty acid triglycerides. 0.030 g of a sample was collected, 1.5 mL of a 0.5 mol / L sodium hydroxide methanol solution was added, and saponification was performed by heating at 100 ° C. for 9 minutes. Methyl esterification was performed by adding 2.0 mL of boron trifluoride methanol complex methanol solution and heating at 100 ° C. for 7 minutes.
  • the solvent was removed under reduced pressure until the ethanol content was 2% by mass or less in the oil component, and the mixture was left at 4 ° C. (Mg / mL) was determined.
  • the results are shown in Table 2.
  • the content of coconard RK represents mass% with respect to the mass of the composition.
  • the higher the medium chain fatty acid triglyceride content in the oil component the higher the solubility of each drug.
  • the solubility was significantly increased by setting the medium chain fatty acid triglyceride content to 80% by mass or more.
  • the poorly soluble drug can be included in the oil component at a high concentration by increasing the content of the medium chain fatty acid triglyceride in the oil component.
  • the solubility of paclitaxel in the oil component of the medium chain fatty acid triglyceride having a different average carbon number was compared with the solubility of the above-mentioned paclitaxel. It measured similarly to the measurement. The results are shown in Table 3. Medium chain fatty acid triglycerides with lower average carbon number of constituent fatty acids showed higher paclitaxel solubility. The solubility of paclitaxel in coconut RK having the smallest average carbon number among the evaluated fats and oils was 60 mg / mL. Thus, it was found that the lower the average carbon number in the medium chain fatty acid triglyceride, the higher the concentration of paclitaxel.
  • Example 1 Preparation of paclitaxel-containing oil-in-water emulsion composition
  • a clear yellow solution was prepared by adding and mixing paclitaxel, coconard RK and purified egg yolk lecithin in a sufficient amount of ethanol to achieve the final concentrations shown in Table 4.
  • This solution was dried under reduced pressure using a centrifugal evaporator (genevac EZ-2) to obtain a viscous yellow liquid.
  • This liquid had a residual ethanol content of 2% by mass relative to the mass of the oil component.
  • An appropriate amount of glycerin was weighed so as to have the final concentration shown in Table 4, and dissolved in an appropriate amount of water to prepare an aqueous phase.
  • the prepared emulsion composition was an oil-in-water emulsion composition having an average particle diameter of 140 nm of emulsion particles (oil droplet particles), and was stable without aggregation or precipitation of the emulsion observed at 4 ° C. for 2 months.
  • the oil droplet particle size was measured using a dynamic light scattering soot particle size / particle size distribution measuring device (UPA UT-151, Nikkiso Co., Ltd.).
  • Example 2 Comparative Example 1 and Comparative Example 2
  • Each emulsified composition of Example 2, Comparative Example 1 and Comparative Example 2 was prepared in the same manner as in Example 1 so that the final concentrations shown in Table 5 were obtained.
  • the emulsion composition prepared according to the formulation of Example 2 was stable for 2 weeks with no aggregation or precipitation of the emulsion observed.
  • the emulsion composition prepared by the formulations of Comparative Examples 1 and 2 was an unstable emulsion composition in which precipitation occurred on the next day.
  • Example 3 (Preparation of docetaxel-containing emulsion composition)
  • a docetaxel-containing emulsion composition (Table 6) was prepared using the same preparation method as described in Example 1. The prepared emulsified composition was stable because the average particle diameter of the emulsified particles (oil droplet particles) was 110 nm, and no aggregation or precipitation of the emulsion was observed at 4 ° C. for 2 months.
  • Example 4 (Preparation of tacrolimus-containing emulsion composition) A docetaxel-containing emulsion composition (Table 7) was prepared using a preparation similar to that described in Example 1. The prepared emulsified composition was stable because the average particle diameter of the emulsified particles (oil droplet particles) was 140 nm, and no aggregation or precipitation of the emulsion was observed at 4 ° C. for 2 months.
  • Example 5 The emulsified composition of Example 5 was prepared in the same manner as Example 1 so that the final concentrations shown in Table 8 were obtained.
  • the viscosity of the emulsion prepared by the formulation of Example 5 was 14.7 [mPa ⁇ s]. This viscosity was in a range usable as an injection.
  • the viscosity of the emulsion prepared in Example 1 was measured in the same manner. As a result, the viscosity of the emulsion in Example 1 was 3.86 [mPa ⁇ s].
  • a poorly soluble drug-containing oil-in-water emulsion composition containing a poorly soluble drug at a high concentration and having good stability and suitable as an injection can be provided.

Abstract

La présente invention concerne une composition d'émulsion huile dans l'eau contenant un médicament médiocrement soluble qui : présente une solubilité dans l'eau inférieure à 1 mg/ml ; contient un médicament médiocrement soluble d'une masse moléculaire d'au moins 500, un constituant huileux dans une quantité supérieure à 6 % en masse mais pas supérieure à 25 % en masse par rapport à la masse de la composition entière, et contenant des triglycérides à chaîne moyenne dans une quantité supérieure à 80 % en masse mais pas supérieure à 100 % en masse, et un constituant tensioactif contenant des phospholipides dans une quantité qui n'est pas inférieure à 50 % en masse et pas supérieure à 100 % en masse ; et qui comprend des particules émulsifiées présentant un diamètre moyen de particule qui n'est pas inférieur à 500 nm.
PCT/JP2011/067146 2010-08-31 2011-07-27 Composition d'émulsion huile dans l'eau contenant un médicament médiocrement soluble et son procédé de fabrication WO2012029456A1 (fr)

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WO2013157664A1 (fr) * 2012-04-20 2013-10-24 Sucampo Ag Conjugué composé tricyclo - polymère
WO2014013903A1 (fr) * 2012-07-19 2014-01-23 富士フイルム株式会社 Composition liquide contenant un principe actif à base de taxane, son procédé de fabrication et préparation médicinale liquide

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CN101926757B (zh) * 2010-09-01 2013-01-02 北京大学 一种难溶性药物的液体组合物及其制备方法
JP6071291B2 (ja) * 2012-07-12 2017-02-01 キッコーマン株式会社 食用油脂含有可溶化醤油及びその製造法
US10722466B2 (en) * 2016-10-28 2020-07-28 Les Laboratoires Servier Liposomal formulation for use in the treatment of cancer

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