WO2012029456A1 - Oil-in-water emulsion composition containing poorly-soluble drug, and method for manufacturing same - Google Patents
Oil-in-water emulsion composition containing poorly-soluble drug, and method for manufacturing same Download PDFInfo
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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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- 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
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- 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
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- 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
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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
- A61K9/0012—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
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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
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- 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.
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Abstract
An oil-in-water emulsion composition containing a poorly-soluble drug: has a solubility in water of less than 1 mg/mL; contains a poorly soluble drug with a molecular weight of at least 500, an oil constituent in an amount of more than 6 mass % but not more than 25 mass % with respect to the mass of the entire composition, and containing medium-chain triglycerides in an amount of more than 80 mass % but not more than 100 mass %, and a surfactant constituent containing phospholipids in an amount of not less than 50 mass % and not more than 100 mass %; and which has emulsified particles with an average particle diameter of less than 500 nm.
Description
本発明は、難溶性薬物含有水中油型乳化組成物及びその製造方法に関する。
The present invention relates to a poorly soluble drug-containing oil-in-water emulsion composition and a method for producing the same.
近年、医薬品分野において創製される薬物については、分子量が大きくなり、化学構造も複雑化する傾向がある。このような、水にも油にもほとんど溶解しない薬物、いわゆる難溶性薬物を非経口投与可能な製剤とすることは、極めて重要な課題となっている。
In recent years, 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.
このような難溶性薬物としては、たとえば癌化学療法において広範に使用されているタキサン系薬物が挙げられる。タキサン系薬物は溶液を注射または点滴により投与する場合、ポリソルベートやポリオキシエチル化ひまし油のような非イオン系界面活性剤、およびエタノールを用いて薬物を可溶化している。しかしながら、これらの可溶化剤の使用には、過敏症などの副作用が懸念されている。
このため、タキサン系薬物、ならびにその他の難溶性薬物を、可溶化剤を使用することなく、安全に非経口投与するため、多くの技術が提案されている。特に、費用効率が高く、且つ、投与が容易な乳化製剤が、難水溶性薬物を非経口投与可能とする製剤形態として注目されている。 Examples of such poorly soluble drugs include taxane drugs widely used in cancer chemotherapy. 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. However, the use of these 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. In particular, 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.
このため、タキサン系薬物、ならびにその他の難溶性薬物を、可溶化剤を使用することなく、安全に非経口投与するため、多くの技術が提案されている。特に、費用効率が高く、且つ、投与が容易な乳化製剤が、難水溶性薬物を非経口投与可能とする製剤形態として注目されている。 Examples of such poorly soluble drugs include taxane drugs widely used in cancer chemotherapy. 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. However, the use of these 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. In particular, 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.
一般に、医薬用、特に注射用乳化製剤に用いる油としてはトリグリセリド類に由来する鹸化可能な油、例えば、ダイズ油、ゴマ油、綿実油、ベニバナ油などがよく利用される。しかしながら、これらの油が利用される注射用乳化製剤は、主として、脂溶性が高い薬物であるか、あるいは低分子量の薬物に適用されており、近年増加している水にも油にもほとんど溶解しない薬物、いわゆる難溶性薬物には適用できていないのが実情である。
Generally, saponifiable 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. However, 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.
上記問題点の解決のため、特表平10-502921号公報では、パクリタキセルの溶解油として大豆油を使用せず、サフラワー油を使用し、界面活性剤として卵黄レシチンとコレステロールを用いた乳化製剤が開示されている。
In order to solve the above problems, 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.
特表平11-509545号公報では、少なくとも5種の成分:治療薬と、ビタミンEと、薬剤およびビタミンEが溶解される油と、安定剤(リン脂質、レシチンまたはポリオキシエチレン-ポリオキシプロピレン共重合体であるポロキサマーのいずれか)と、水とを含む脂質薬剤送達組成物を開示している。ビタミンEがパクリタキセルに対して良好な溶解性を持つことを利用し、ダイズ油とビタミンEとを等量併用し、さらに界面活性剤としてプルロニックP105を使用した例が開示されている。
In 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. Using vitamin E having good solubility in paclitaxel, an example is disclosed in which soybean oil and vitamin E are used in equal amounts, and pluronic P105 is used as a surfactant.
特表2003-501376号公報では、パクリタキセルの溶解油としてトリブチリンを使用し、界面活性剤としてジパルミトイルフォスファチジルグリセロール、ジオレ油ホスファチジルコリン、およびコレステロールを使用した油コア組成物が例示されている。また、この油コア組成物の粒子サイズは16.3μmと記載されている。
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 μm.
特表2008-514720号公報では、パクリタキセルの溶解油として中鎖脂肪酸トリグリセリドと大豆油を併用し、界面活性剤として卵黄レシチンを使用した乳化製剤が開示されている。しかしながら、乳化製剤中における油成分の割合が10質量%を上回るとクリーム状となると記載されており、このため、タキサン系薬物を内包する油成分の濃度は、最大でも6質量%以下に限定されている。
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. However, it is described that when the proportion of the oil component in the emulsified preparation exceeds 10% by mass, it becomes creamy. For this reason, the concentration of the oil component containing the taxane drug is limited to 6% by mass or less at the maximum. ing.
このように種々の乳化製剤が提案されているが、パクリタキセルのような難溶性薬物を溶解するために、サフラワー油では溶解性が充分とは言えず、トリブチリンは注射用添加剤として適しているとは言えない。また、難溶性薬物を溶解するためにビタミンEを多量に使用することは、乳化組成物の安定性が損なわれることがある。
また、注射剤として使用するには、薬剤を高濃度に含有させると共に乳化粒子の粒子径が充分に小さいことが必要であり、一方で、クリーム状では注射剤として使用できない。 Various emulsified preparations have been proposed in this way, but in order to dissolve poorly soluble drugs such as paclitaxel, it cannot be said that the solubility of safflower oil is sufficient, and tributyrin is suitable as an additive for injection. It can not be said. In addition, using a large amount of vitamin E to dissolve a poorly soluble drug may impair the stability of the emulsion composition.
In addition, in order to use as an injection, it is necessary to contain the drug at a high concentration and the particle size of the emulsified particles must be sufficiently small. On the other hand, creams cannot be used as an injection.
また、注射剤として使用するには、薬剤を高濃度に含有させると共に乳化粒子の粒子径が充分に小さいことが必要であり、一方で、クリーム状では注射剤として使用できない。 Various emulsified preparations have been proposed in this way, but in order to dissolve poorly soluble drugs such as paclitaxel, it cannot be said that the solubility of safflower oil is sufficient, and tributyrin is suitable as an additive for injection. It can not be said. In addition, using a large amount of vitamin E to dissolve a poorly soluble drug may impair the stability of the emulsion composition.
In addition, in order to use as an injection, it is necessary to contain the drug at a high concentration and the particle size of the emulsified particles must be sufficiently small. On the other hand, creams cannot be used as an injection.
従って、本発明は、難溶性薬物を高濃度に含有すると共に、良好な安定性で且つ注射剤として好適な水中油型乳化組成物及びその製造方法を提供することを目的とする。
Therefore, 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.
本発明は以下のとおりである。
[1] 水への溶解度が1mg/mL未満であり、かつ分子量が500以上の難溶性薬物と、80質量%を超え100質量%以下の量で中鎖脂肪酸トリグリセリドを含有し、且つ組成物の全質量に対して6質量%を超え25質量%以下の量の油成分と、50質量%以上100質量%の量でリン脂質を含有する界面活性剤成分と、を含み、乳化粒子の平均粒子径が500nm未満である難溶性薬物含有水中油型乳化組成物。
[2] 前記中鎖脂肪酸トリグリセリドにおける構成脂肪酸の平均炭素数が9.9以下である[1]に記載の難溶性薬物含有水中油型乳化組成物。
[3] 前記油成分の全質量に対する界面活性剤成分の割合が80質量%以下である[1]又は[2]に記載の難溶性薬物含有水中油型乳化組成物。
[4] 前記難溶性薬物が、タキサン系抗ガン剤から選択される[1]~[3]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[5] 前記難溶性薬物が、パクリタキセル、ドセタキセルおよびそれらの類縁体から選択される薬物である[4]記載の難溶性薬物含有水中油型乳化組成物。
[6] 前記難溶性薬物がタクロリムス、シクロスポリンおよびそれらの類縁体から選択される薬物である[1]~[3]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[7] 前記リン脂質がレシチンである[1]~[6]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[8] 前記乳化粒子の平均粒子径が1nm以上200nm以下である[1]~[7]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[9] 前記中鎖脂肪酸トリグリセリドにおける構成脂肪酸の平均炭素数が8.8以下である[1]~[8]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[10] 前記中鎖脂肪酸トリグリセリドにおける構成脂肪酸の平均炭素数が8.5以下である[1]~[8]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[11] 前記中鎖脂肪酸トリグリセリドにおける構成脂肪酸の平均炭素数が8.2以下である[1]~[8]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[12] 前記難溶性薬物、前記油成分及び前記リン脂質を含有する界面活性剤成分を少なくとも含む油相成分を、これらを共通して溶解可能な有機溶媒に溶解して油相を調製すること、前記油相と水相とを混合して水中油型乳化物を調製すること、前記水中油型乳化物を調製する前又は後の油相を、前記有機溶媒を前記油相の質量に対して10質量%未満まで脱溶媒すること、ことを含む[1]~[11]のいずれかに記載の難溶性薬物含有水中油型乳化組成物の製造方法。
[13] 前記混合が、脱溶媒後の油相と水相とを混合するものである[12]に記載の難溶性薬物含有水中油型乳化組成物の製造方法。
[14] 前記有機溶媒が、水溶性有機溶媒である[12]又は[13]に記載の難溶性薬物含有水中油型乳化組成物の製造方法。 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.
[2] The hardly soluble drug-containing oil-in-water emulsion composition according to [1], wherein the average carbon number of the constituent fatty acid in the medium-chain fatty acid triglyceride is 9.9 or less.
[3] The hardly soluble drug-containing oil-in-water emulsion composition according to [1] or [2], wherein the ratio of the surfactant component to the total mass of the oil component is 80% by mass or less.
[4] The hardly soluble drug-containing oil-in-water emulsion composition according to any one of [1] to [3], wherein the hardly soluble drug is selected from taxane anticancer agents.
[5] The poorly soluble drug-containing oil-in-water emulsion composition according to [4], wherein the poorly soluble drug is a drug selected from paclitaxel, docetaxel and analogs thereof.
[6] The poorly soluble drug-containing oil-in-water emulsion composition according to any one of [1] to [3], wherein the poorly soluble drug is a drug selected from tacrolimus, cyclosporine, and analogs thereof.
[7] The oil-in-water emulsion composition containing a poorly soluble drug according to any one of [1] to [6], wherein the phospholipid is lecithin.
[8] The hardly soluble drug-containing oil-in-water emulsion composition according to any one of [1] to [7], wherein an average particle size of the emulsified particles is 1 nm to 200 nm.
[9] 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 8.8 or less.
[10] 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 8.5 or less.
[11] 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.
[12] 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 method for producing a poorly soluble drug-containing oil-in-water emulsion composition according to any one of [1] to [11], comprising removing the solvent to less than 10% by mass.
[13] The process for producing a poorly soluble drug-containing oil-in-water emulsion composition according to [12], wherein the mixing is to mix the oil phase after desolvation and the aqueous phase.
[14] The method for producing a poorly soluble drug-containing oil-in-water emulsion composition according to [12] or [13], wherein the organic solvent is a water-soluble organic solvent.
[1] 水への溶解度が1mg/mL未満であり、かつ分子量が500以上の難溶性薬物と、80質量%を超え100質量%以下の量で中鎖脂肪酸トリグリセリドを含有し、且つ組成物の全質量に対して6質量%を超え25質量%以下の量の油成分と、50質量%以上100質量%の量でリン脂質を含有する界面活性剤成分と、を含み、乳化粒子の平均粒子径が500nm未満である難溶性薬物含有水中油型乳化組成物。
[2] 前記中鎖脂肪酸トリグリセリドにおける構成脂肪酸の平均炭素数が9.9以下である[1]に記載の難溶性薬物含有水中油型乳化組成物。
[3] 前記油成分の全質量に対する界面活性剤成分の割合が80質量%以下である[1]又は[2]に記載の難溶性薬物含有水中油型乳化組成物。
[4] 前記難溶性薬物が、タキサン系抗ガン剤から選択される[1]~[3]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[5] 前記難溶性薬物が、パクリタキセル、ドセタキセルおよびそれらの類縁体から選択される薬物である[4]記載の難溶性薬物含有水中油型乳化組成物。
[6] 前記難溶性薬物がタクロリムス、シクロスポリンおよびそれらの類縁体から選択される薬物である[1]~[3]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[7] 前記リン脂質がレシチンである[1]~[6]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[8] 前記乳化粒子の平均粒子径が1nm以上200nm以下である[1]~[7]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[9] 前記中鎖脂肪酸トリグリセリドにおける構成脂肪酸の平均炭素数が8.8以下である[1]~[8]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[10] 前記中鎖脂肪酸トリグリセリドにおける構成脂肪酸の平均炭素数が8.5以下である[1]~[8]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[11] 前記中鎖脂肪酸トリグリセリドにおける構成脂肪酸の平均炭素数が8.2以下である[1]~[8]のいずれかに記載の難溶性薬物含有水中油型乳化組成物。
[12] 前記難溶性薬物、前記油成分及び前記リン脂質を含有する界面活性剤成分を少なくとも含む油相成分を、これらを共通して溶解可能な有機溶媒に溶解して油相を調製すること、前記油相と水相とを混合して水中油型乳化物を調製すること、前記水中油型乳化物を調製する前又は後の油相を、前記有機溶媒を前記油相の質量に対して10質量%未満まで脱溶媒すること、ことを含む[1]~[11]のいずれかに記載の難溶性薬物含有水中油型乳化組成物の製造方法。
[13] 前記混合が、脱溶媒後の油相と水相とを混合するものである[12]に記載の難溶性薬物含有水中油型乳化組成物の製造方法。
[14] 前記有機溶媒が、水溶性有機溶媒である[12]又は[13]に記載の難溶性薬物含有水中油型乳化組成物の製造方法。 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.
[2] The hardly soluble drug-containing oil-in-water emulsion composition according to [1], wherein the average carbon number of the constituent fatty acid in the medium-chain fatty acid triglyceride is 9.9 or less.
[3] The hardly soluble drug-containing oil-in-water emulsion composition according to [1] or [2], wherein the ratio of the surfactant component to the total mass of the oil component is 80% by mass or less.
[4] The hardly soluble drug-containing oil-in-water emulsion composition according to any one of [1] to [3], wherein the hardly soluble drug is selected from taxane anticancer agents.
[5] The poorly soluble drug-containing oil-in-water emulsion composition according to [4], wherein the poorly soluble drug is a drug selected from paclitaxel, docetaxel and analogs thereof.
[6] The poorly soluble drug-containing oil-in-water emulsion composition according to any one of [1] to [3], wherein the poorly soluble drug is a drug selected from tacrolimus, cyclosporine, and analogs thereof.
[7] The oil-in-water emulsion composition containing a poorly soluble drug according to any one of [1] to [6], wherein the phospholipid is lecithin.
[8] The hardly soluble drug-containing oil-in-water emulsion composition according to any one of [1] to [7], wherein an average particle size of the emulsified particles is 1 nm to 200 nm.
[9] 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 8.8 or less.
[10] 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 8.5 or less.
[11] 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.
[12] 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 method for producing a poorly soluble drug-containing oil-in-water emulsion composition according to any one of [1] to [11], comprising removing the solvent to less than 10% by mass.
[13] The process for producing a poorly soluble drug-containing oil-in-water emulsion composition according to [12], wherein the mixing is to mix the oil phase after desolvation and the aqueous phase.
[14] The method for producing a poorly soluble drug-containing oil-in-water emulsion composition according to [12] or [13], wherein the organic solvent is a water-soluble organic solvent.
本発明の難溶性薬物含有水中油型乳化組成物は、水への溶解度が1mg/mL未満であり、かつ分子量が500以上の難溶性薬物と、80質量%を超え100質量%以下の量で中鎖脂肪酸トリグリセリドを含有し、且つ組成物の全質量に対して6質量%を超え25質量%以下の量の油成分と、50質量%以上100質量%の量でリン脂質を含有する界面活性剤成分と、を含み、乳化粒子の平均粒子径が500nm未満である難溶性薬物含有水中油型乳化組成物である。
本発明によれば、油成分として中鎖脂肪酸トリグリセリドを80質量%超100質量%以下で含む油成分を用いることによって、難溶性薬物を油成分に高濃度で溶解させて油成分中に内包させ、また、このような油成分を6質量%を超える量で含み、界面活性剤成分の50質量%以上100質量%以下をリン脂質とし、乳化粒子の平均粒子径が500nm未満の水中油型乳化組成物とすることによって、高濃度の薬物を含有すると共に注射剤に適した粘度且つ良好な安定性を維持することができる。この結果、難溶性薬物を高濃度に含有すると共に、良好な安定性で且つ注射剤として好適な剤型の難溶性薬物含有水中油型乳化組成物とすることができる。
なお、本明細書において難溶性薬物含有水中油型乳化組成物を単に「乳化組成物」又は「組成物」ということがある。 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 surfactant containing medium-chain fatty acid triglycerides and containing an oil component in an amount of more than 6% by weight and not more than 25% by weight with respect to the total weight of the composition, and a phospholipid in an amount of 50% by weight to 100% by weight. A poorly soluble drug-containing oil-in-water emulsion composition having an average particle size of the emulsified particles of less than 500 nm.
According to the present invention, by using 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. In addition, oil-in-water emulsification in which such an oil component is contained in an amount exceeding 6% by mass, 50% by mass to 100% by mass of the surfactant component is phospholipid, and the average particle size of the emulsified particles is less than 500 nm. By setting it as a composition, it is possible to maintain a viscosity and good stability suitable for an injection while containing a high concentration of drug. As a result, it is possible to obtain 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.
In the present specification, the slightly soluble drug-containing oil-in-water emulsion composition is sometimes simply referred to as “emulsion composition” or “composition”.
本発明によれば、油成分として中鎖脂肪酸トリグリセリドを80質量%超100質量%以下で含む油成分を用いることによって、難溶性薬物を油成分に高濃度で溶解させて油成分中に内包させ、また、このような油成分を6質量%を超える量で含み、界面活性剤成分の50質量%以上100質量%以下をリン脂質とし、乳化粒子の平均粒子径が500nm未満の水中油型乳化組成物とすることによって、高濃度の薬物を含有すると共に注射剤に適した粘度且つ良好な安定性を維持することができる。この結果、難溶性薬物を高濃度に含有すると共に、良好な安定性で且つ注射剤として好適な剤型の難溶性薬物含有水中油型乳化組成物とすることができる。
なお、本明細書において難溶性薬物含有水中油型乳化組成物を単に「乳化組成物」又は「組成物」ということがある。 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 surfactant containing medium-chain fatty acid triglycerides and containing an oil component in an amount of more than 6% by weight and not more than 25% by weight with respect to the total weight of the composition, and a phospholipid in an amount of 50% by weight to 100% by weight. A poorly soluble drug-containing oil-in-water emulsion composition having an average particle size of the emulsified particles of less than 500 nm.
According to the present invention, by using 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. In addition, oil-in-water emulsification in which such an oil component is contained in an amount exceeding 6% by mass, 50% by mass to 100% by mass of the surfactant component is phospholipid, and the average particle size of the emulsified particles is less than 500 nm. By setting it as a composition, it is possible to maintain a viscosity and good stability suitable for an injection while containing a high concentration of drug. As a result, it is possible to obtain 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.
In the present specification, the slightly soluble drug-containing oil-in-water emulsion composition is sometimes simply referred to as “emulsion composition” or “composition”.
本明細書において「工程」との語は、独立した工程だけでなく、他の工程と明確に区別できない場合であっても本工程の所期の作用が達成されれば、本用語に含まれる。
また、本明細書において「~」を用いて示された数値範囲は、「~」の前後に記載される数値をそれぞれ最小値及び最大値として含む範囲を示す。
また、本発明において、組成物中の各成分の量について言及する場合、組成物中に各成分に該当する物質が複数存在する場合には、特に断らない限り、組成物中に存在する当該複数の物質の合計量を意味する。
以下、本発明について説明する。 In this specification, 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. .
In the present specification, 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.
Further, in the present invention, when referring to 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.
また、本明細書において「~」を用いて示された数値範囲は、「~」の前後に記載される数値をそれぞれ最小値及び最大値として含む範囲を示す。
また、本発明において、組成物中の各成分の量について言及する場合、組成物中に各成分に該当する物質が複数存在する場合には、特に断らない限り、組成物中に存在する当該複数の物質の合計量を意味する。
以下、本発明について説明する。 In this specification, 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. .
In the present specification, 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.
Further, in the present invention, when referring to 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.
[難溶性薬物]
本発明における難溶性薬物とは、水への溶解度が1mg/mL未満であり、かつ分子量が500以上の難溶性薬物である。水への溶解度が1mg/mL未満であって、後述するように所定の有機溶媒に溶解する薬物であればよい。好ましくは、水にも油にも溶解しない難溶性薬物である。「油にも溶解しない」との表現は、例えば、大豆油に対する25℃での溶解度が15mg/mL未満の薬物を意味する。また、難溶性薬物の分子量は、分子量が500以上であればよく、より好ましくは分子量が800以上である。
また、本発明における油成分中での安定性の観点より、難溶性薬物の水/オクタノール分配係数(以下LogPと略す)は、8.0以下であることが好ましく、更に好ましくは2.0以上6未満である。LogPが8.0以下であれば、本発明の効果を充分に発揮することができる。また、LogPが2.0以上であれば、油相中での安定性を充分に維持することができる。
このような難溶性薬物としては、特にタキサン系抗ガン剤及び、タクロリムス又はシクロスポリンなどを挙げることができる。 [Slightly soluble drug]
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. In addition, the molecular weight of the poorly soluble drug may be 500 or more, more preferably 800 or more.
Further, from the viewpoint of stability in the oil component in the present invention, 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.
本発明における難溶性薬物とは、水への溶解度が1mg/mL未満であり、かつ分子量が500以上の難溶性薬物である。水への溶解度が1mg/mL未満であって、後述するように所定の有機溶媒に溶解する薬物であればよい。好ましくは、水にも油にも溶解しない難溶性薬物である。「油にも溶解しない」との表現は、例えば、大豆油に対する25℃での溶解度が15mg/mL未満の薬物を意味する。また、難溶性薬物の分子量は、分子量が500以上であればよく、より好ましくは分子量が800以上である。
また、本発明における油成分中での安定性の観点より、難溶性薬物の水/オクタノール分配係数(以下LogPと略す)は、8.0以下であることが好ましく、更に好ましくは2.0以上6未満である。LogPが8.0以下であれば、本発明の効果を充分に発揮することができる。また、LogPが2.0以上であれば、油相中での安定性を充分に維持することができる。
このような難溶性薬物としては、特にタキサン系抗ガン剤及び、タクロリムス又はシクロスポリンなどを挙げることができる。 [Slightly soluble drug]
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. In addition, the molecular weight of the poorly soluble drug may be 500 or more, more preferably 800 or more.
Further, from the viewpoint of stability in the oil component in the present invention, 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.
タキサン系抗ガン剤としてはタキサン類を挙げることができる。タキサン類としては、パクリタキセル(paclitaxel);ドセタキセル(docetaxel);スピカチン(spicatin);アセトンとのタキサン-2,13-ジオン,5β,9β,10β-トリヒドロキシ-環式-9,10-アセタール又はアセテート;アセトンとのタキサン-2,13-ジオン-5β,9β,10β-トリヒドロキシ-環式-9,10-アセタール;アセトンとのタキサン-2β,5β,9β,10β-テトロール-環式-9,10-アセタール;タキサン;セファロマンニン-7-キシロシド(cephalomannine-7-xyloside);7-エピ-10-デアセチルセファロマンニン(7-epi-10-deacetylcephalomannine);10-デアセチルセファロマンニン;セファロマンニン(cephalomannine);タキソールB(taxol B);13-(2’,3’-ジヒドロキシ-3’-フェニルプロピオニル)バカチンIII;ユナンキソール(yunnanxol);7-(4-アジドベンゾイル)バカチンIII;N-デベンゾイルタキソールA(N-debenzoyltaxol A);O-アセチルバカチンIV(O-acetylbaccatin IV);7-(トリエチルシリル)バカチンIII;7,10-ジ-O-〔(2,2,2-トリクロロエトキシ)カルボニル〕バカチンIII;バカチンIII 13-O-アセテート;バカチンジアセテート;バカチン(baccatin);バカチンVII;バカチンVI;バカチンIV;7-エピ-バカチンIII;バカチンV;バカチンI;バカチンIII;バカチンA;10-デアセチル-7-エピタキソール;エピタキソール(epitaxol);10-デアセチルタキソールC;7-キシロシル-10-デアセチルタキソール;10-デアセチルタキソール-7-キシロシド(10-deacetyltaxol-7-xyloside);7-エピ-10-デアセチルタキソール;10-デアセチルタキソール;および10-デアセチルタキソールBが包含される。なかでも、パクリタキセル、ドセタキセル及び上述したようなこれらの類縁体であることが好ましい。
またタクロリムスおよびタクロリムス類縁体としては、Tanaka et al.,(J.Am.Chem.Soc.,109:5031,1987)、米国特許第4,894,366号、第4,929,611号、第4,956,352号、および特表2002-519378号などに記載されたものを挙げることができ、特にタクロリムス、タクロリムス水和物、アスコマイシン、33-エピ-クロロ-33-デスオキシアスコマイシンなどのハロゲン化誘導体等のアスコマイシン誘導体を挙げることができる。
シクロスポリンおよびシクロスポリン類縁体としては、シクロスポリンA、ジヒドロシクロスポリンC、シクロスポリンDおよびジヒドロシクロスポリンDなどを挙げることができる。
これらの薬剤は、通常単独で用いられるが、2種以上を混合して用いることを排除するものではない。 Examples of taxane anticancer agents include taxanes. Taxanes include: paclitaxel; docetaxel; spicatin; taxane-2,13-dione, 5β, 9β, 10β-trihydroxy-cyclic-9,10-acetal or acetate with acetone Taxane-2,13-dione-5β, 9β, 10β-trihydroxy-cyclic-9,10-acetal with acetone; taxane-2β, 5β, 9β, 10β-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; N-debenzoyltaxol A; O-acetylbaccatin IV; 7- (triethyl) Silyl) baccatin III; 7,10-di-O-[(2,2,2-trichloroethoxy) carbonyl] baccatin III; baccatin III 13-O-acetate; baccatin diacetate; baccatin; baccatin VII; Vaccine IV; 7-epi-baccatin III; baccatin V; baccatin I; baccatin III; baccatin A; 10-deacetyl-7-epitaxol; epitaxol; 10-deacetyltaxol C; 7-xylosyl- 10-deacetyltaxol; 10-deacetyltaxol -7-xyloside; 7-epi-10-deacetyltaxol; 10-deacetyltaxol; and 10-deacetyltaxol B are included. Of these, paclitaxel, docetaxel and the analogs thereof as described above are preferable.
Examples of 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.
またタクロリムスおよびタクロリムス類縁体としては、Tanaka et al.,(J.Am.Chem.Soc.,109:5031,1987)、米国特許第4,894,366号、第4,929,611号、第4,956,352号、および特表2002-519378号などに記載されたものを挙げることができ、特にタクロリムス、タクロリムス水和物、アスコマイシン、33-エピ-クロロ-33-デスオキシアスコマイシンなどのハロゲン化誘導体等のアスコマイシン誘導体を挙げることができる。
シクロスポリンおよびシクロスポリン類縁体としては、シクロスポリンA、ジヒドロシクロスポリンC、シクロスポリンDおよびジヒドロシクロスポリンDなどを挙げることができる。
これらの薬剤は、通常単独で用いられるが、2種以上を混合して用いることを排除するものではない。 Examples of taxane anticancer agents include taxanes. Taxanes include: paclitaxel; docetaxel; spicatin; taxane-2,13-dione, 5β, 9β, 10β-trihydroxy-cyclic-9,10-acetal or acetate with acetone Taxane-2,13-dione-5β, 9β, 10β-trihydroxy-cyclic-9,10-acetal with acetone; taxane-2β, 5β, 9β, 10β-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; N-debenzoyltaxol A; O-acetylbaccatin IV; 7- (triethyl) Silyl) baccatin III; 7,10-di-O-[(2,2,2-trichloroethoxy) carbonyl] baccatin III; baccatin III 13-O-acetate; baccatin diacetate; baccatin; baccatin VII; Vaccine IV; 7-epi-baccatin III; baccatin V; baccatin I; baccatin III; baccatin A; 10-deacetyl-7-epitaxol; epitaxol; 10-deacetyltaxol C; 7-xylosyl- 10-deacetyltaxol; 10-deacetyltaxol -7-xyloside; 7-epi-10-deacetyltaxol; 10-deacetyltaxol; and 10-deacetyltaxol B are included. Of these, paclitaxel, docetaxel and the analogs thereof as described above are preferable.
Examples of 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.
本発明の乳化組成物において難溶性薬物は、一般には、組成物の全質量に対して1μg/mL~50mg/mL(組成物の全質量に対して0.0001質量%~5.0質量%)の量で存在し得る。
In the emulsified composition of the present invention, the poorly soluble drug is generally 1 μg / 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). ).
[油成分]
本発明における油成分は、80質量%を超え100質量%以下の量で中鎖脂肪酸トリグリセリドを含有する。80質量%を超える量で中鎖脂肪酸トリグリセリドを含有することによって、難溶性薬物を高含有量で溶解し油成分中に安定して内包することができる。また、中鎖脂肪酸トリグリセリドの油成分中の含有量は、乳化組成物中の油成分濃度を更に高め、かつ微細化を促進し、安定性を向上させるため、90質量%以上100質量%以下とすることがより好ましい。 [Oil component]
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. By containing the medium chain fatty acid triglyceride in an amount exceeding 80% by mass, the poorly soluble drug can be dissolved at a high content and stably encapsulated in the oil component. In addition, 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.
本発明における油成分は、80質量%を超え100質量%以下の量で中鎖脂肪酸トリグリセリドを含有する。80質量%を超える量で中鎖脂肪酸トリグリセリドを含有することによって、難溶性薬物を高含有量で溶解し油成分中に安定して内包することができる。また、中鎖脂肪酸トリグリセリドの油成分中の含有量は、乳化組成物中の油成分濃度を更に高め、かつ微細化を促進し、安定性を向上させるため、90質量%以上100質量%以下とすることがより好ましい。 [Oil component]
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. By containing the medium chain fatty acid triglyceride in an amount exceeding 80% by mass, the poorly soluble drug can be dissolved at a high content and stably encapsulated in the oil component. In addition, 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.
本明細書において「油成分」は、約37℃で液体であり、および注射可能な製剤中で薬理学的に許容できる、炭化水素、炭水化物、または同様の有機化合物を示す。このような油成分の例としては、各種植物油、動物性脂肪、中鎖脂肪酸トリグリセリドなどのトリグリセリド類やコレステロールなどの非グリセリド類が挙げられる。
As used herein, “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. Examples of such oil components include various vegetable oils, animal fats, triglycerides such as medium chain fatty acid triglycerides, and non-glycerides such as cholesterol.
本発明において、中鎖脂肪酸トリグリセリドとは、含有するトリグリセリドを構成する脂肪酸鎖の平均炭素数が8以上12以下の油脂を意味する。中鎖脂肪酸トリグリセリドにおける脂肪酸の平均炭素数とは、中鎖脂肪酸トリグリセリドに含まれるトリグリセリドを構成する脂肪酸鎖(本明細書中では「構成脂肪酸」ということがある)の炭素数(例えば、カプリル酸であれば8、カプリン酸であれば10)を構成脂肪酸の組成比によって加重平均したものである。薬物をより高濃度に内包でき、乳化組成物の安定性、粘度及びの観点より、構成脂肪酸の平均脂肪鎖長は、9.9以下であり、より好ましくは8.8以下であり、更に好ましくは8.5以下であり、最も好ましくは8.2以下である。
In the present invention, 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.
本発明に使用する中鎖脂肪酸トリグリセリドは、構成脂肪酸鎖の平均炭素数が上述した範囲内であれば、構成脂肪酸に特に制限はなく、例えば炭素数が6以上12以下の脂肪酸を挙げることができ、これらの脂肪酸は飽和又は不飽和であってもよい。好ましくは、主として炭素数6以上12以下の飽和脂肪酸のトリグリセリドで構成されたものである。また、天然植物油由来のものであってもよく、合成脂肪酸のトリグリセリドであってもよい。これらを単独で又は2種以上を組み合わせて使用してよい。また、中鎖脂肪酸トリグリセリドは、構成脂肪酸鎖の平均炭素数が上述した範囲内であれば、1種単独で用いられてもよく、構成脂肪酸鎖の平均炭素数が異なる2種以上の中鎖脂肪酸トリグリセリドの混合物であってもよい。2種以上の中鎖脂肪酸トリグリセリドを混合する場合には、中鎖脂肪酸トリグリセリドの混合物の全体として、構成脂肪酸の平均炭素数が上述した範囲内になればよい。
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. Further, 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.
本発明では、SASOL GmbH(独国)のミグリオール812、ミグリオール810、花王のココナードMT、ココナードRKなどが中鎖脂肪酸トリグリセリドとして好適に用いられる。またこの他の低融点中鎖脂肪酸トリグリセリドも、本発明において使用することができる。
In the present invention, 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.
中鎖脂肪酸トリグリセリド以外と併用可能な油成分としては、とく限定されないが、植物油が好ましい。植物油とは、植物の種子または堅果由来の油分(長鎖脂肪酸トリグリセリド)を意味し、例えば、アーモンド油、ルリヂサ油、クロフサスグリ種子油、ヒマシ油、トウモロコシ油、ベニバナ油、ダイズ油、ゴマ油、綿実油、ピーナッツ油、オリーブ油、ナタネ油、ココナツ油、ヤシ油、およびカノーラ油などを含むが、これらに限定されるものではない。
また、動物性脂肪も、本発明の効果に影響しない範囲で用いることができる。動物性脂肪とは、動物給源由来の油分を意味する。これは、トリグリセリドも含むが、3種の脂肪酸鎖の長さおよび不飽和結合は、植物油と比べて変動する。室温で固形である給源由来の動物性脂肪(獣脂、ラードなど)を使用する場合には、それらを液体とするよう処理した上で、使用することが好ましい。 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. This also includes triglycerides, but the lengths and unsaturated bonds of the three fatty acid chains vary compared to vegetable oils. When using animal-derived animal fats (tallow fat, lard, etc.) that are solid at room temperature, it is preferable to use them after treating them to be liquid.
また、動物性脂肪も、本発明の効果に影響しない範囲で用いることができる。動物性脂肪とは、動物給源由来の油分を意味する。これは、トリグリセリドも含むが、3種の脂肪酸鎖の長さおよび不飽和結合は、植物油と比べて変動する。室温で固形である給源由来の動物性脂肪(獣脂、ラードなど)を使用する場合には、それらを液体とするよう処理した上で、使用することが好ましい。 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. This also includes triglycerides, but the lengths and unsaturated bonds of the three fatty acid chains vary compared to vegetable oils. When using animal-derived animal fats (tallow fat, lard, etc.) that are solid at room temperature, it is preferable to use them after treating them to be liquid.
本発明の乳化組成物は、少なくとも6質量%を上回る量で且つ25質量%以下の油成分を含有する。これにより、難溶性薬物を高含有量で含む乳化組成物とすることができる。
難溶性薬物を多量に含有し、かつ乳化組成物の安定性および粘度を両立させるという観点から、好適な油成分濃度としては、乳化組成物全質量の7質量%~25質量%であり、更に好ましい範囲としては、8質量%~15質量%である。乳化組成物中に占める油成分の割合を高くすることで、比例して乳化組成物中の薬物濃度を高めることができるため、点滴時間を短くすることができるなどの利点がある。 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.
From the viewpoint of containing a large amount of a poorly soluble drug and achieving both stability and viscosity of the emulsion composition, 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. By increasing the ratio of the oil component in the emulsified composition, the drug concentration in the emulsified composition can be increased proportionally, and thus there is an advantage that the infusion time can be shortened.
難溶性薬物を多量に含有し、かつ乳化組成物の安定性および粘度を両立させるという観点から、好適な油成分濃度としては、乳化組成物全質量の7質量%~25質量%であり、更に好ましい範囲としては、8質量%~15質量%である。乳化組成物中に占める油成分の割合を高くすることで、比例して乳化組成物中の薬物濃度を高めることができるため、点滴時間を短くすることができるなどの利点がある。 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.
From the viewpoint of containing a large amount of a poorly soluble drug and achieving both stability and viscosity of the emulsion composition, 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. By increasing the ratio of the oil component in the emulsified composition, the drug concentration in the emulsified composition can be increased proportionally, and thus there is an advantage that the infusion time can be shortened.
[界面活性剤成分]
本発明おける界面活性剤成分は、50質量%以上100質量%以下の量でリン脂質を含有する。界面活性剤成分中のリン脂質の割合が50質量%未満では、安定性及び安全性が充分とは言えない。乳化組成物の粘度、安定性及び安全性の観点から、界面活性剤成分中のリン脂質の含有量は、80質量%以上100質量%以下であることが好ましく、90質量%以上100質量%以下であることが更に好ましく、100質量%、即ち界面活性剤としてリン脂質のみを用いることが最も好ましい。 [Surfactant component]
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. From the viewpoint of the viscosity, stability and safety of the emulsion composition, 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.
本発明おける界面活性剤成分は、50質量%以上100質量%以下の量でリン脂質を含有する。界面活性剤成分中のリン脂質の割合が50質量%未満では、安定性及び安全性が充分とは言えない。乳化組成物の粘度、安定性及び安全性の観点から、界面活性剤成分中のリン脂質の含有量は、80質量%以上100質量%以下であることが好ましく、90質量%以上100質量%以下であることが更に好ましく、100質量%、即ち界面活性剤としてリン脂質のみを用いることが最も好ましい。 [Surfactant component]
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. From the viewpoint of the viscosity, stability and safety of the emulsion composition, 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.
本発明におけるリン脂質には、純粋なリン脂質、または2種もしくはそれ以上のリン脂質の混合物を含む。「リン脂質」の用語は、2個の脂肪酸および1個のリン酸イオンを伴うグリセロールのトリエステルを意味する。本発明において有用なリン脂質の例は、ホスファチジルコリン、レシチン(コリンエステルのリン酸化されたジアシルグリセリドとの混合)、ホスファチジルエタノールアミン、ホスファチジルグリセロール、約4~約22個の炭素原子、より一般には約10~約18個の炭素原子を有しおよび飽和度が変動するホスファチジン酸を含むが、これらに限定されるものではない。また、上記リン脂質に対しポリエチレングリコール(PEG)が結合した、PEG-リン脂質を含んでもよい。
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.
本発明においては、合成のレシチンを使用することもできるが、天然起源のリン脂質が好ましい。天然のリン脂質は、ダイズレシチン、卵レシチン、水素化されたダイズレシチン、水素化された卵レシチン、スフィンゴシン、ガングリオシド、およびフィトスフィンゴシンならびにそれらの組合せを含み、安全性及び組成物の安定性の観点から、レシチンが好ましく、特に卵レシチンが好ましい。
In the present invention, 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.
天然のレシチンは、一般にホスファチジルコリンと称されるリン酸のコリンエステルへ連結された、ステアリン酸、パルミチン酸およびオレイン酸のジグリセリドの混合物であり、ならびに卵およびダイズ豆のような様々な供給源から得ることができる。ダイズレシチンおよび卵レシチン(これらの化合物の水素化された形を含む)は、安全性に関する長い歴史を有し、乳化および可溶化の組合せられた特性を有し、ならびにほとんどの合成界面活性剤よりもより迅速に無害物質へ代謝される傾向がある。市販されているダイズリン脂質は、Central Soyaから市場に出され販売されているCentrophaseおよびCentrolex製品、Phospholipid GmbH(独国)からのPhospholipon、Lipoid GmbH(独国)によるLipoid、およびDegussaによるEPIKURONがある。また市販されている卵黄レシチンには、キューピーPL-100M、PC-98Nなどがある。
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. Commercially available 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.
水素化されたレシチンとは、レシチンを構成する脂肪鎖中の不飽和二重結合の一部、または全部が水素添加された製品である。これも本発明において使用することができる。
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.
本発明における界面活性剤成分として使用可能なその他の界面活性剤としては、プロピレングリコールモノ-およびジ-脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレン-ポリオキシプロピレンコポリマーおよびブロックコポリマー、脂肪族アルコール硫酸塩、ソルビタン脂肪酸エステル、ポリエチレン-グリコールグリセロールエーテルのエステル、油およびワックスベースの界面活性剤、グリセロールモノステアレート、グリセリンソルビタン脂肪酸エステルを含むが、これらに限定されるものではない。
Other surfactants that can be used as the surfactant component in the present invention include propylene glycol mono- and di-fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene-polyoxypropylene copolymers And block copolymers, fatty alcohol sulfates, sorbitan fatty acid esters, esters of polyethylene-glycol glycerol ether, oil and wax-based surfactants, glycerol monostearate, glycerin sorbitan fatty acid esters is not.
本発明の乳化組成物における界面活性剤成分は、乳化組成物の粘度を注射剤として適切な範囲にすると共に、安定性を保持し、かつ十分な油成分量を達成するために、油成分の全質量に対する界面活性剤成分の割合として80質量%以下であることが好ましく、1質量%~80質量%であることがより好ましく、また更に好ましくは、5質量%~50質量%であり、更により好ましくは10質量%~25質量%である。
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.
本発明の乳化組成物は、場合によって、酸化剤、アルカリ剤、緩衝剤、キレート剤、複合体形成剤および可溶化剤、酸化防止剤、および抗酸化剤、抗微生物保存剤、懸濁化剤および/または粘度調節剤、等張化剤などの添加剤、ならびに他の生体適合性物質または治療的物質を含んでもよい。このような物質は一般に、乳化組成物の水相中に存在する。このような添加剤は、乳化組成物または乳化組成物中の薬物の安定性を強化し、また本発明の乳化組成物がより生体親和的になることを補助する。
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.
[水相成分]
本発明の乳化組成物における水相を構成する水相成分が含まれる。水相成分としては、上述した添加剤のいずれも含むことができる。上述した添加剤は、添加剤の種類等に基づいて水相成分又は油相成分とすることができる。
水相は一般に、約300mOsmの浸透圧を有し、塩化カリウムまたは塩化ナトリウム、トレハロース、ショ糖、ソルビトール、グリセロール、マンニトール、ポリエチレングリコール、プロピレングリコール、アルブミン、アミノ酸およびそれらの混合物を含有することができる。少なくとも250mOsmの張度が、ソルビトールまたはショ糖などの、粘度を増大する物質により実現される。本発明の乳化組成物の浸透圧を変更するために有用な化合物は、一般に「等張化剤」または「浸透圧改善剤」と称される。 [Water phase component]
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. 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”.
本発明の乳化組成物における水相を構成する水相成分が含まれる。水相成分としては、上述した添加剤のいずれも含むことができる。上述した添加剤は、添加剤の種類等に基づいて水相成分又は油相成分とすることができる。
水相は一般に、約300mOsmの浸透圧を有し、塩化カリウムまたは塩化ナトリウム、トレハロース、ショ糖、ソルビトール、グリセロール、マンニトール、ポリエチレングリコール、プロピレングリコール、アルブミン、アミノ酸およびそれらの混合物を含有することができる。少なくとも250mOsmの張度が、ソルビトールまたはショ糖などの、粘度を増大する物質により実現される。本発明の乳化組成物の浸透圧を変更するために有用な化合物は、一般に「等張化剤」または「浸透圧改善剤」と称される。 [Water phase component]
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. 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”.
本発明において使用される「抗酸化剤」は主に、注射可能な製品内で使用する際に安全な金属イオンキレート剤および/または還元剤が好ましい。金属イオンキレート剤は、金属イオンと結合し、これにより、薬物、油分またはリン脂質成分の酸化反応に対する金属イオンの触媒作用を低下することにより、抗酸化剤として機能する。本発明において有用な金属キレート剤は、EDTA、グリシンおよびクエン酸またはそれらの塩を含むが、これらに限定されるものではない。
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.
本発明の乳化組成物中の乳化粒子の平均粒径は、500nm未満である。500nm以上では、注射剤として用いるのには不向きである。組成物の安定性及び粘度、又は注射剤として取扱いの観点から、好ましくは1nm~200nmであり、より好ましくは5nm~200nmであり、更により好ましくは10nm~180nmであり、もっとも好ましくは15nm~150nmである。
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.
本発明における粒径範囲および測定の容易さから、本発明における乳化粒子の粒径測定では動的光散乱法が好ましい。動的光散乱を用いた市販の測定装置としては、ナノトラックUPA(日機装(株))、動的光散乱式粒径分布測定装置LB-550((株)堀場製作所)、濃厚系粒径アナライザーFPAR-1000(大塚電子(株))等が挙げられるが、本発明における粒径は、粒ナノトラックUPA(日機装(株))を用いて25℃で測定した値を採用する。
即ち、粒径の測定方法は、水中油型乳化組成物の場合には純水で10倍に希釈し、粉末組成物の場合には固形分濃度が1質量%となるように純水で希釈を行い、ナノトラックUPA(日機装(株))を用いて求める。 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 (Otsuka Electronics Co., Ltd.) and the like can be mentioned. As the particle size in the present invention, a value measured at 25 ° C. using a grain nanotrack UPA (Nikkiso Co., Ltd.) is adopted.
That is, 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.).
即ち、粒径の測定方法は、水中油型乳化組成物の場合には純水で10倍に希釈し、粉末組成物の場合には固形分濃度が1質量%となるように純水で希釈を行い、ナノトラックUPA(日機装(株))を用いて求める。 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 (Otsuka Electronics Co., Ltd.) and the like can be mentioned. As the particle size in the present invention, a value measured at 25 ° C. using a grain nanotrack UPA (Nikkiso Co., Ltd.) is adopted.
That is, 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.).
本発明の水中油型乳化組成物は、凍結乾燥された製剤から再構成されたものも含む。したがって、本発明の乳化組成物は、1種もしくは複数の凍結保護剤含んでもかまわない。
「凍結-乾燥助剤」または「凍結-乾燥バルク剤」としても公知である「凍結保護剤」は、凍結-乾燥プロセス時および、固形物中油型分散システムを形成するために、液滴を固形マトリックスとするための乳化組成物の水分の除去時に、乳化組成物の離散したサブミクロンの液滴を維持するために添加される構成成分を意味する。凍結保護剤の例は、ポリオール、単糖、二糖、多糖、アミノ酸、ペプチド、タンパク質、および親水性ポリマー、ならびにそれらの混合物を含む。乳化組成物の油滴を安定化するのに十分な凍結保護剤の濃度は、典型的には約5質量%~20質量%の範囲であるが、この範囲に限定されない。 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. Examples of cryoprotectants include polyols, monosaccharides, disaccharides, polysaccharides, amino acids, peptides, proteins, and hydrophilic polymers, and mixtures thereof. The 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.
「凍結-乾燥助剤」または「凍結-乾燥バルク剤」としても公知である「凍結保護剤」は、凍結-乾燥プロセス時および、固形物中油型分散システムを形成するために、液滴を固形マトリックスとするための乳化組成物の水分の除去時に、乳化組成物の離散したサブミクロンの液滴を維持するために添加される構成成分を意味する。凍結保護剤の例は、ポリオール、単糖、二糖、多糖、アミノ酸、ペプチド、タンパク質、および親水性ポリマー、ならびにそれらの混合物を含む。乳化組成物の油滴を安定化するのに十分な凍結保護剤の濃度は、典型的には約5質量%~20質量%の範囲であるが、この範囲に限定されない。 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. Examples of cryoprotectants include polyols, monosaccharides, disaccharides, polysaccharides, amino acids, peptides, proteins, and hydrophilic polymers, and mixtures thereof. The 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.
本発明の乳化組成物は、非経口投与することができ、たとえば静脈内、動脈内、髄腔内、腹腔内、眼内、関節内、筋肉内または皮下注射することができる。
本発明の乳化組成物は、このような注射剤として使用するために適切な粘度を有する。注射剤として使用するために適切な粘度とは、25℃での振動型粘度計による測定で、1mPa・s~200mPa・sの範囲を意味し、安全性の観点から好ましくは100mPa・s以下であり、更に好ましくは10mPa・s以下である。 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.
本発明の乳化組成物は、このような注射剤として使用するために適切な粘度を有する。注射剤として使用するために適切な粘度とは、25℃での振動型粘度計による測定で、1mPa・s~200mPa・sの範囲を意味し、安全性の観点から好ましくは100mPa・s以下であり、更に好ましくは10mPa・s以下である。 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.
[製造方法]
本発明の乳化組成物は、前記難溶性薬物、前記油成分及び前記リン脂質を含有する界面活性剤を少なくとも含む油相成分を、これらを共通して溶解可能な有機溶媒に溶解して油相を調製すること(以下、油相調製工程という)、前記油相と水相とを混合して水中油型乳化物を調製すること(以下、乳化工程という)、前記水中油型乳化物を調製する前又は後の油相を、前記有機溶媒を前記油相の質量に対して10質量%未満まで脱溶媒すること(以下、脱溶媒工程という)、を含む製造方法で得ることができる。 [Production method]
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. (Hereinafter referred to as 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).
本発明の乳化組成物は、前記難溶性薬物、前記油成分及び前記リン脂質を含有する界面活性剤を少なくとも含む油相成分を、これらを共通して溶解可能な有機溶媒に溶解して油相を調製すること(以下、油相調製工程という)、前記油相と水相とを混合して水中油型乳化物を調製すること(以下、乳化工程という)、前記水中油型乳化物を調製する前又は後の油相を、前記有機溶媒を前記油相の質量に対して10質量%未満まで脱溶媒すること(以下、脱溶媒工程という)、を含む製造方法で得ることができる。 [Production method]
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. (Hereinafter referred to as 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).
油相調製工程では、(i)難溶性薬物、(ii)油成分(例えば中鎖脂肪酸トリグリセリド)、及び(iii)リン脂質、を少なくとも含む油相成分をそれぞれ適量含有する混合物(油相)を、これらを共通して溶解可能な有機溶媒に溶解する。
ここで用いられる有機溶媒としては、(i)~(iii)の各油相成分が、25℃において、0.1質量%以上溶解する有機溶媒であれば、いかなる物質でも構わない。このような有機溶媒としては、水溶性有機溶媒であることが好ましい。 In the 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.
ここで用いられる有機溶媒としては、(i)~(iii)の各油相成分が、25℃において、0.1質量%以上溶解する有機溶媒であれば、いかなる物質でも構わない。このような有機溶媒としては、水溶性有機溶媒であることが好ましい。 In the 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.
本発明において水溶性有機溶媒は、水に対する25℃での溶解度が10質量%以上の有機溶媒を指す。水に対する溶解度はできあがった乳化物の安定性の観点から30質量%以上が好ましく、50質量%以上が更に好ましい。
水溶性有機溶媒は、単独で用いてもよく、複数の水溶性有機溶媒の混合溶媒でもよい。また、水との混合物として用いてもよい。水との混合物を用いる場合には、上記水溶性有機溶媒は、混合物の容量に対して少なくとも50容量%以上含まれていることが好ましく、70容量%以上であることがより好ましい。 In the present invention, 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. When a mixture with water is used, 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.
水溶性有機溶媒は、単独で用いてもよく、複数の水溶性有機溶媒の混合溶媒でもよい。また、水との混合物として用いてもよい。水との混合物を用いる場合には、上記水溶性有機溶媒は、混合物の容量に対して少なくとも50容量%以上含まれていることが好ましく、70容量%以上であることがより好ましい。 In the present invention, 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. When a mixture with water is used, 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.
このような水溶性有機溶媒の例としては、メタノール、エタノール、1-プロパノール、2-プロパノール、2-ブタノール等のアルコール;、エチレングリコール、1,3ブタンジオール、1,4ブタンジオール、プロピレングリコール、ジエチレングリコール、トリエチレングリコール等の多価アルコール;アセトン、テトラヒドロフラン、アセトニトリル、メチルエチルケトン、ジプロピレングリコールモノメチルエーテル、酢酸メチル、アセト酢酸メチル、N-メチルピロリドン、ジメチルスルフォキシド等、並びにそれらの2以上の混合物を挙げられる。これらの中でも、食品への用途に限定した場合、エタノール等のアルコール、プロピレングリコール、又はアセトンが好ましく、エタノール、又はエタノールと水との混合液が特に好ましい。
Examples of such water-soluble organic solvents 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. Among these, when it limits to the use to a foodstuff, alcohol, such as ethanol, propylene glycol, or acetone is preferable and ethanol or the liquid mixture of ethanol and water is especially preferable.
脱溶媒工程では、油相中の有機溶媒を油相の質量に対して10質量%未満、乳化組成物の安定性の観点から好ましくは5質量%未満まで脱溶媒する。10質量%以上では、安全性の観点から注射剤としての適用に不向きである。脱溶媒、即ち、溶媒を除去する方法としては、ロータリーエバポレーター、フラッシュエバポレーター、超音波アトマイザー等を用いた蒸発法、限外濾過膜、逆浸透膜等の膜分離法が知られているが、いずれであってもよい。これらは公知の装置をそのまま適用すればよい。
In the solvent removal step, 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.
乳化工程では、油相と水相とを混合(乳化)して水中油型乳化物を調製する。乳化方法としては、一般に用いられるいずれの方法であってもよい。
汎用的に用いられる乳化法として、機械力を用いた方法、すなわち外部から強い剪断力を与えることで油滴を分裂させる方法が適用されている。機械力として最も一般的なものは、高速、高剪断攪拌機である。このような攪拌機としては、ホモミキサー、ディスパーミキサーおよびウルトラミキサーと呼ばれるものが市販されている。
また、微細化に有用な別な機械的な乳化装置として高圧ホモジナイザーがあり、種々の装置が市販されている。高圧ホモジナイザーは、攪拌方式と比べて大きな剪断力を与えることができるために、乳化剤の量を比較的少なくても微細化が可能である。 In the emulsification step, an oil phase and an aqueous phase are mixed (emulsified) to prepare an oil-in-water emulsion. As an emulsification method, any method generally used may be used.
As 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. As such a stirrer, what is called a homomixer, a disper mixer and an ultramixer are commercially available.
Moreover, 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.
汎用的に用いられる乳化法として、機械力を用いた方法、すなわち外部から強い剪断力を与えることで油滴を分裂させる方法が適用されている。機械力として最も一般的なものは、高速、高剪断攪拌機である。このような攪拌機としては、ホモミキサー、ディスパーミキサーおよびウルトラミキサーと呼ばれるものが市販されている。
また、微細化に有用な別な機械的な乳化装置として高圧ホモジナイザーがあり、種々の装置が市販されている。高圧ホモジナイザーは、攪拌方式と比べて大きな剪断力を与えることができるために、乳化剤の量を比較的少なくても微細化が可能である。 In the emulsification step, an oil phase and an aqueous phase are mixed (emulsified) to prepare an oil-in-water emulsion. As an emulsification method, any method generally used may be used.
As 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. As such a stirrer, what is called a homomixer, a disper mixer and an ultramixer are commercially available.
Moreover, 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.
前記高圧ホモジナイザーとしては、処理液の流路が固定されたチャンバーを有するチャンバー型高圧ホモジナイザー及び均質バルブを有する均質バルブ型高圧ホモジナイザーが挙げられる。これらの中でも、均質バルブ型高圧ホモジナイザーは、処理液の流路の幅を容易に調節でき、操作時の圧力及び流量を任意に設定できるため、その操作範囲が広く、特に本発明にかかるエマルション組成物の製造方法にとって好ましい。
また、操作の自由度は低いが、圧力を高める機構が作りやすいため、超高圧を必要とする場合、チャンバー型高圧ホモジナイザーも好適に用いることができる。 Examples of the high-pressure homogenizer 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. Among these, 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.
In addition, although 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.
また、操作の自由度は低いが、圧力を高める機構が作りやすいため、超高圧を必要とする場合、チャンバー型高圧ホモジナイザーも好適に用いることができる。 Examples of the high-pressure homogenizer 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. Among these, 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.
In addition, although 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.
前記チャンバー型高圧ホモジナイザーとしては、マイクロフルイダイザー(マイクロフルイディクス社製)、ナノマイザー(吉田機械興業(株)製)、アルティマイザー((株)スギノマシン製)等が挙げられる。
前記均質バルブ型高圧ホモジナイザーとしては、ゴーリンタイプホモジナイザー(APV社製)、ラニエタイプホモジナイザー(ラニエ社製)、高圧ホモジナイザー(ニロ・ソアビ社製)、ホモゲナイザー(三和機械(株)製)、高圧ホモゲナイザー(イズミフードマシナリ(株)製)、超高圧ホモジナイザー(イカ社製)等が挙げられる。 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.
前記均質バルブ型高圧ホモジナイザーとしては、ゴーリンタイプホモジナイザー(APV社製)、ラニエタイプホモジナイザー(ラニエ社製)、高圧ホモジナイザー(ニロ・ソアビ社製)、ホモゲナイザー(三和機械(株)製)、高圧ホモゲナイザー(イズミフードマシナリ(株)製)、超高圧ホモジナイザー(イカ社製)等が挙げられる。 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.
本発明において、前記高圧ホモジナイザーの圧力は、乳化粒子の微細化及び組成物の安定性の観点から、好ましくは50MPa以上、より好ましくは50~250MPa、更に好ましくは100~250MPaで処理することが好ましい。
また、乳化分散された組成物である乳化液はチャンバー通過直後30秒以内、好ましくは3秒以内に何らかの冷却器を通して冷却することが、乳化粒子の粒子径保持の観点から好ましい。 In the present invention, 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. .
Moreover, it is preferable from the viewpoint of maintaining the particle diameter of the emulsified particles that 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.
また、乳化分散された組成物である乳化液はチャンバー通過直後30秒以内、好ましくは3秒以内に何らかの冷却器を通して冷却することが、乳化粒子の粒子径保持の観点から好ましい。 In the present invention, 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. .
Moreover, it is preferable from the viewpoint of maintaining the particle diameter of the emulsified particles that 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.
本発明の乳化組成物を製造する際に、脱溶媒工程と乳化工程とはいずれを先に行ってもよいが、乳化組成物の安定性の観点から、脱溶媒工程を先に行うことが好ましい。この場合の水相と油相との混合、即ち乳化工程では、脱溶媒後の油相と、水相とを混合する。
When producing the emulsified composition of the present invention, 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. . In this case, in the mixing of the water phase and the oil phase, that is, in the emulsification step, the oil phase after the solvent removal and the water phase are mixed.
本製造方法では、上述した油相調製工程、脱溶媒工程及び乳化工程の他に、(A)乳化組成物のpHを望ましい範囲に調節する工程、(B)乳化組成物を0.2μmフィルターを用い濾過する、または加熱殺菌することにより滅菌する工程;の一つまたは複数を含んでもよい。
In this production method, in addition to the above-described oil phase preparation step, solvent removal step and emulsification step, (A) a step of adjusting the pH of the emulsion composition to a desired range, and (B) a 0.2 μm filter of the emulsion composition. One or more of using, filtering or sterilizing by heat sterilization.
本発明における難溶性薬物含有水中油型乳化組成物は、安定性が良好で高濃度に難溶性薬物を含有し、注射剤として好適であるため、このような難溶性薬物含有水中油型乳化組成物を使用する方法も、本発明は提供する。
例えば、本発明は、本明細書に説明された難溶性薬物含有乳化組成物を、それが必要な患者へ投与することで、難溶性薬物の用途に応じた治療方法を提供する。即ち、難溶性薬物としてタキサン系抗ガン剤を用いた乳化組成物の場合には、ガンの治療方法であり、また難溶性薬物として免疫抑制剤(たとえば、シクロスポリンまたはタクロリムス)を含有する乳化組成物の倍には、臓器移植等にともなう拒絶反応を抑制したり、またあるいはリュウマチ等の免疫性疾患を治療する方法を提供する。投与は、静脈内、筋肉内、動脈内、髄腔内、眼内、皮下、関節内および腹腔内であってよい。 Since 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.
For example, 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. That is, in the case of 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. In this case, a method of suppressing rejection associated with organ transplantation or treating an immune disease such as rheumatism is provided. Administration can be intravenous, intramuscular, intraarterial, intrathecal, intraocular, subcutaneous, intraarticular and intraperitoneal.
例えば、本発明は、本明細書に説明された難溶性薬物含有乳化組成物を、それが必要な患者へ投与することで、難溶性薬物の用途に応じた治療方法を提供する。即ち、難溶性薬物としてタキサン系抗ガン剤を用いた乳化組成物の場合には、ガンの治療方法であり、また難溶性薬物として免疫抑制剤(たとえば、シクロスポリンまたはタクロリムス)を含有する乳化組成物の倍には、臓器移植等にともなう拒絶反応を抑制したり、またあるいはリュウマチ等の免疫性疾患を治療する方法を提供する。投与は、静脈内、筋肉内、動脈内、髄腔内、眼内、皮下、関節内および腹腔内であってよい。 Since 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.
For example, 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. That is, in the case of 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. In this case, a method of suppressing rejection associated with organ transplantation or treating an immune disease such as rheumatism is provided. Administration can be intravenous, intramuscular, intraarterial, intrathecal, intraocular, subcutaneous, intraarticular and intraperitoneal.
以下、本発明を実施例にて詳細に説明する。しかしながら、本発明はそれらに何ら限定されるものではない。
Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to them.
[試験例]
(脂肪酸組成の測定)
中鎖脂肪酸トリグリセリドであるココナードRK、ココナードML(以上、花王社)、ミグリオール810(Sasol社)につき、下記の方法で脂肪酸組成を測定した。
試料を0.030g採取し、0.5mol/Lの水酸化ナトリウムのメタノール溶液1.5mLを添加し、100℃で9分間加熱してけん化を行った。三ふっ化ホウ素メタノール錯体メタノール溶液2.0mLを添加して100℃で7分間加熱し、メチルエステル化を行った。 [Test example]
(Measurement of fatty acid composition)
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.
(脂肪酸組成の測定)
中鎖脂肪酸トリグリセリドであるココナードRK、ココナードML(以上、花王社)、ミグリオール810(Sasol社)につき、下記の方法で脂肪酸組成を測定した。
試料を0.030g採取し、0.5mol/Lの水酸化ナトリウムのメタノール溶液1.5mLを添加し、100℃で9分間加熱してけん化を行った。三ふっ化ホウ素メタノール錯体メタノール溶液2.0mLを添加して100℃で7分間加熱し、メチルエステル化を行った。 [Test example]
(Measurement of fatty acid composition)
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.
ヘキサン3mLおよび飽和食塩水5mLを添加し、ヘキサン層を採取し、ガスクロマトグラフ法[機種:GC-1700(島津製作所社、検出器:FID、カラム:DB-23(J&W SCIENTIFIC社)φ0.25mm×30mm、膜厚0.25μm、温度:試料注入口 250℃、検出器 250℃、カラム 50℃(1分保持)→10℃/分昇温→170℃→1.2℃/分昇温→210℃、試料導入系:スプリットレス、ガス流量:ヘリウム(キャリヤーガス)1.5mL/分、ヘリウム(メイクアップガス)80kPa、ガス圧力:水素60kPa、空気50kPa)にて測定を行った。得られた結果を表1に示す。表1中、脂肪酸組成の数値は質量%を表す。
3 mL of hexane and 5 mL of saturated saline were added, and the hexane layer was collected, followed by gas chromatography [model: GC-1700 (Shimadzu Corporation, detector: FID, column: DB-23 (J & W SCIENTIFIC)) φ0.25 mm × 30 mm, film thickness 0.25 μm, temperature: sample inlet 250 ° C., detector 250 ° C., column 50 ° C. (1 minute hold) → 10 ° C./minute temperature rise → 170 ° C. → 1.2 ° C./minute temperature rise → 210 The measurement was performed at 0 ° C., sample introduction system: splitless, gas flow rate: helium (carrier gas) 1.5 mL / min, helium (makeup gas) 80 kPa, gas pressure: hydrogen 60 kPa, air 50 kPa. The obtained results are shown in Table 1. In Table 1, the numerical value of the fatty acid composition represents mass%.
(パクリタキセルの溶解度の測定)
油成分中の中鎖脂肪酸トリグリセリドの含有量とパクリタキセル(PTX)、ドセタキセル(DTX)の溶解性との関係を明らかにするために、中鎖脂肪酸トリグリセリド(花王ココナードRK)と長鎖脂肪酸トリグリセリドとして知られている大豆油を様々な比率で混合し、その油成分に対する各薬剤の溶解度を測定した。
各薬剤と該油成分とを十分量のエタノールに添加しかつ攪拌混合することで、各薬剤を溶解させた。これを、遠心エバポレータ(genevac社 EZ-2)を用いて、減圧下でエタノール含量が油成分中2質量%以下となるまで脱溶媒し、4℃で放置し、不溶物の析出の有無により溶解度(mg/mL)を判定した。結果を表2に示す。表2中、ココナードRKの含有量は組成物の質量に対する質量%を表す。
表2に示されるように、油成分中の中鎖脂肪酸トリグリセリド含有量が高いほど各薬剤の溶解度は高く、特に中鎖脂肪酸トリグリセリド含有量を80質量%以上とすることにより溶解度が著しく上昇した。
これにより、油成分中の中鎖脂肪酸トリグリセリドの含有量を高くすることによって、難溶性薬物を高濃度に油成分に内包できることがわかった。 (Measurement of solubility of paclitaxel)
Known as medium-chain fatty acid triglycerides (Kao Coconut RK) and long-chain fatty acid triglycerides to clarify the relationship between the content of medium-chain fatty acid triglycerides in oil components and the solubility of paclitaxel (PTX) and docetaxel (DTX) Soybean oil was mixed at various ratios, and the solubility of each drug in the oil component was measured.
Each drug and the oil component were added to a sufficient amount of ethanol and mixed by stirring to dissolve each drug. Using a centrifugal evaporator (genevac EZ-2), 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. In Table 2, the content of coconard RK represents mass% with respect to the mass of the composition.
As shown in Table 2, the higher the medium chain fatty acid triglyceride content in the oil component, the higher the solubility of each drug. In particular, the solubility was significantly increased by setting the medium chain fatty acid triglyceride content to 80% by mass or more.
Thus, it was found that 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.
油成分中の中鎖脂肪酸トリグリセリドの含有量とパクリタキセル(PTX)、ドセタキセル(DTX)の溶解性との関係を明らかにするために、中鎖脂肪酸トリグリセリド(花王ココナードRK)と長鎖脂肪酸トリグリセリドとして知られている大豆油を様々な比率で混合し、その油成分に対する各薬剤の溶解度を測定した。
各薬剤と該油成分とを十分量のエタノールに添加しかつ攪拌混合することで、各薬剤を溶解させた。これを、遠心エバポレータ(genevac社 EZ-2)を用いて、減圧下でエタノール含量が油成分中2質量%以下となるまで脱溶媒し、4℃で放置し、不溶物の析出の有無により溶解度(mg/mL)を判定した。結果を表2に示す。表2中、ココナードRKの含有量は組成物の質量に対する質量%を表す。
表2に示されるように、油成分中の中鎖脂肪酸トリグリセリド含有量が高いほど各薬剤の溶解度は高く、特に中鎖脂肪酸トリグリセリド含有量を80質量%以上とすることにより溶解度が著しく上昇した。
これにより、油成分中の中鎖脂肪酸トリグリセリドの含有量を高くすることによって、難溶性薬物を高濃度に油成分に内包できることがわかった。 (Measurement of solubility of paclitaxel)
Known as medium-chain fatty acid triglycerides (Kao Coconut RK) and long-chain fatty acid triglycerides to clarify the relationship between the content of medium-chain fatty acid triglycerides in oil components and the solubility of paclitaxel (PTX) and docetaxel (DTX) Soybean oil was mixed at various ratios, and the solubility of each drug in the oil component was measured.
Each drug and the oil component were added to a sufficient amount of ethanol and mixed by stirring to dissolve each drug. Using a centrifugal evaporator (genevac EZ-2), 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. In Table 2, the content of coconard RK represents mass% with respect to the mass of the composition.
As shown in Table 2, the higher the medium chain fatty acid triglyceride content in the oil component, the higher the solubility of each drug. In particular, the solubility was significantly increased by setting the medium chain fatty acid triglyceride content to 80% by mass or more.
Thus, it was found that 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.
平均炭素数の高い中鎖脂肪酸トリグリセリドと比べて優れた溶解性を明らかにするために、平均炭素数の異なる中鎖脂肪酸トリグリセリドを用い、その油成分に対するパクリタキセルの溶解度を、上記のパクリタキセルの溶解度の測定と同様に測定した。結果を表3に示す。
構成脂肪酸の平均炭素数が低い中鎖脂肪酸トリグリセリドほど高いパクリタキセル溶解性を示した。評価した油脂の中で最も平均炭素数の小さいココナードRKに対するパクリタキセルの溶解度は60mg/mLであった。
これにより、中鎖脂肪酸トリグリセリド中の平均炭素数が低い程、パクリタキセルを高濃度に内包できることがわかった。 In order to clarify the superior solubility compared with medium chain fatty acid triglycerides having a high average carbon number, 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.
構成脂肪酸の平均炭素数が低い中鎖脂肪酸トリグリセリドほど高いパクリタキセル溶解性を示した。評価した油脂の中で最も平均炭素数の小さいココナードRKに対するパクリタキセルの溶解度は60mg/mLであった。
これにより、中鎖脂肪酸トリグリセリド中の平均炭素数が低い程、パクリタキセルを高濃度に内包できることがわかった。 In order to clarify the superior solubility compared with medium chain fatty acid triglycerides having a high average carbon number, 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.
[実施例1]
(パクリタキセル含有水中油型乳化組成物の作製)
表4に示される最終濃度となるように、パクリタキセル、ココナードRK及び精製卵黄レシチンを、十分量のエタノール中に添加しかつ混合することにより、透明な黄色溶液を調製した。この溶液を、遠心エバポレータ(genevac社 EZ-2)を用い、減圧下で乾燥し、粘稠な黄色液体を得た。この液体は、油成分の質量に対する残留エタノール含量が2質量%であった。
表4に示される最終濃度となるように、適量のグリセリンを秤量し、適量の水で溶解し、水相を調製した。水相を油相へ添加し、小型超音波ホモジナイザー(US-150T、日本精機製作所社)で48秒、さらに大型超音波ホモジナイザー(US-600T、日本精機製作所社)で1分間超音波照射し、粗乳化液を得た。これを高圧乳化機(スターバースト ミニラボ機、スギノマシン社)を用いて245MPaの条件で通過させ、水中油型乳化組成物を作製した。表4以下、表中の各成分の含有量は組成物の質量に対する質量%(w/w%)を表す。 [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. Add the aqueous phase to the oil phase and irradiate with a small ultrasonic homogenizer (US-150T, Nippon Seiki Seisakusho) for 48 seconds, and with a large ultrasonic homogenizer (US-600T, Nippon Seiki Seisakusho) for 1 minute, A crude emulsion was obtained. This was passed under the condition of 245 MPa using a high-pressure emulsifier (Starburst Minilab Machine, Sugino Machine Co., Ltd.) to prepare an oil-in-water emulsion composition. In Table 4 and below, the content of each component in the table represents mass% (w / w%) relative to the mass of the composition.
(パクリタキセル含有水中油型乳化組成物の作製)
表4に示される最終濃度となるように、パクリタキセル、ココナードRK及び精製卵黄レシチンを、十分量のエタノール中に添加しかつ混合することにより、透明な黄色溶液を調製した。この溶液を、遠心エバポレータ(genevac社 EZ-2)を用い、減圧下で乾燥し、粘稠な黄色液体を得た。この液体は、油成分の質量に対する残留エタノール含量が2質量%であった。
表4に示される最終濃度となるように、適量のグリセリンを秤量し、適量の水で溶解し、水相を調製した。水相を油相へ添加し、小型超音波ホモジナイザー(US-150T、日本精機製作所社)で48秒、さらに大型超音波ホモジナイザー(US-600T、日本精機製作所社)で1分間超音波照射し、粗乳化液を得た。これを高圧乳化機(スターバースト ミニラボ機、スギノマシン社)を用いて245MPaの条件で通過させ、水中油型乳化組成物を作製した。表4以下、表中の各成分の含有量は組成物の質量に対する質量%(w/w%)を表す。 [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. Add the aqueous phase to the oil phase and irradiate with a small ultrasonic homogenizer (US-150T, Nippon Seiki Seisakusho) for 48 seconds, and with a large ultrasonic homogenizer (US-600T, Nippon Seiki Seisakusho) for 1 minute, A crude emulsion was obtained. This was passed under the condition of 245 MPa using a high-pressure emulsifier (Starburst Minilab Machine, Sugino Machine Co., Ltd.) to prepare an oil-in-water emulsion composition. In Table 4 and below, the content of each component in the table represents mass% (w / w%) relative to the mass of the composition.
作製した乳化組成物は、乳化粒子(油滴粒子)の平均粒子径140nmの水中油型乳化組成物であり、4℃2ヶ月間は乳化物の凝集・析出が観察されず安定であった。なお、油滴粒子径は動的光散乱式 粒子径・粒度分布測定装置(UPA UT-151、日機装社)を用いて計測した。
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.).
[実施例2、比較例1及び比較例2]
表5に示される最終濃度となるように、実施例2、比較例1及び比較例2の各乳化組成物を、実施例1と同様にして調製した。 [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.
表5に示される最終濃度となるように、実施例2、比較例1及び比較例2の各乳化組成物を、実施例1と同様にして調製した。 [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.
実施例2の処方で作製した乳化組成物は、2週間は乳化物の凝集・析出が観察されず安定であった。一方で比較例1および2の処方で作製した乳化組成物は、翌日には析出が発生する不安定な乳化組成物であった。
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. On the other hand, 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.
[実施例3]
(ドセタキセル含有乳化組成物の作製)
ドセタキセル含有乳化組成物(表6)を、実施例1に説明されたものと同様の調製法を用いて調製した。作製した乳化組成物は、乳化粒子(油滴粒子)の平均粒子径が110nmで、4℃、2ヶ月間は乳化物の凝集や析出が観察されず、安定であった。 [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.
(ドセタキセル含有乳化組成物の作製)
ドセタキセル含有乳化組成物(表6)を、実施例1に説明されたものと同様の調製法を用いて調製した。作製した乳化組成物は、乳化粒子(油滴粒子)の平均粒子径が110nmで、4℃、2ヶ月間は乳化物の凝集や析出が観察されず、安定であった。 [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.
[実施例4]
(タクロリムス含有乳化組成物の作製)
ドセタキセル含有乳化組成物(表7)を、実施例1に説明されたものと同様の調製法を用いて調製した。作製した乳化組成物は、乳化粒子(油滴粒子)の平均粒子径が140nmで、4℃、2ヶ月間は乳化物の凝集や析出が観察されず、安定であった。 [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.
(タクロリムス含有乳化組成物の作製)
ドセタキセル含有乳化組成物(表7)を、実施例1に説明されたものと同様の調製法を用いて調製した。作製した乳化組成物は、乳化粒子(油滴粒子)の平均粒子径が140nmで、4℃、2ヶ月間は乳化物の凝集や析出が観察されず、安定であった。 [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.
[実施例5]
表8に示される最終濃度となるように、実施例5の乳化組成物を実施例1と同様にして調製した。 [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.
表8に示される最終濃度となるように、実施例5の乳化組成物を実施例1と同様にして調製した。 [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.
実施例5の処方で作製した乳化物の粘度は14.7[mPa・s]であった。この粘度は、注射剤として使用可能な範囲の粘度であった。
一方で実施例1の処方で作製した乳化物についても、同様に粘度を測定した結果、実施例1の乳化物の粘度は3.86[mPa・s]であった。これらの結果は、実施例1の乳化物が、実施例5の処方と比較して粘度が低く、注射剤としては実施例1がより好ましいことを示している。 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.
On the other hand, 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]. These results show that the emulsion of Example 1 has a lower viscosity than the formulation of Example 5, and that Example 1 is more preferable as an injection.
一方で実施例1の処方で作製した乳化物についても、同様に粘度を測定した結果、実施例1の乳化物の粘度は3.86[mPa・s]であった。これらの結果は、実施例1の乳化物が、実施例5の処方と比較して粘度が低く、注射剤としては実施例1がより好ましいことを示している。 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.
On the other hand, 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]. These results show that the emulsion of Example 1 has a lower viscosity than the formulation of Example 5, and that Example 1 is more preferable as an injection.
このように、本発明によれば、高濃度に難溶性薬物を含有すると共に、安定性が良好で注射剤として好適な難溶性薬物含有水中油型乳化組成物を提供できることがわかる。
Thus, it can be seen that according to the present invention, 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.
2010年8月31日に出願された日本国特許出願第2010-194296号の開示は、その全体が参照により本明細書に取り込まれる。
本明細書に記載された全ての文献、特許出願、および技術規格は、個々の文献、特許出願、および技術規格が参照により取り込まれることが具体的かつ個々に記された場合と同程度に、本明細書中に援用されて取り込まれる。 The disclosure of Japanese Patent Application No. 2010-194296 filed on August 31, 2010 is incorporated herein by reference in its entirety.
All documents, patent applications, and technical standards mentioned in this specification are to the same extent as if each individual document, patent application, and technical standard were specifically and individually described to be incorporated by reference, Incorporated herein by reference.
本明細書に記載された全ての文献、特許出願、および技術規格は、個々の文献、特許出願、および技術規格が参照により取り込まれることが具体的かつ個々に記された場合と同程度に、本明細書中に援用されて取り込まれる。 The disclosure of Japanese Patent Application No. 2010-194296 filed on August 31, 2010 is incorporated herein by reference in its entirety.
All documents, patent applications, and technical standards mentioned in this specification are to the same extent as if each individual document, patent application, and technical standard were specifically and individually described to be incorporated by reference, Incorporated herein by reference.
Claims (14)
- 水への溶解度が1mg/mL未満であり、かつ分子量が500以上の難溶性薬物と、
80質量%を超え100質量%以下の量で中鎖脂肪酸トリグリセリドを含有し、且つ組成物の全質量に対して6質量%を超え25質量%以下の量の油成分と、
50質量%以上100質量%の量でリン脂質を含有する界面活性剤成分と、
を含み、乳化粒子の平均粒子径が500nm未満である難溶性薬物含有水中油型乳化組成物。 A poorly soluble drug having a solubility in water of less than 1 mg / mL and a molecular weight of 500 or more;
Containing medium chain fatty acid triglycerides in an amount of more than 80% by weight and less than 100% by weight, and an oil component in an amount of more than 6% by weight and less than 25% by weight with respect to the total weight of the composition;
A surfactant component containing a phospholipid in an amount of 50% by mass or more and 100% by mass;
And a sparingly soluble drug-containing oil-in-water emulsion composition in which the average particle size of the emulsified particles is less than 500 nm. - 前記中鎖脂肪酸トリグリセリドにおける構成脂肪酸の平均炭素数が9.9以下である請求項1に記載の難溶性薬物含有水中油型乳化組成物。 The hardly soluble drug-containing oil-in-water emulsion composition according to claim 1, wherein the average carbon number of the constituent fatty acid in the medium-chain fatty acid triglyceride is 9.9 or less.
- 前記油成分の全質量に対する界面活性剤成分の割合が80質量%以下である請求項1又は請求項2に記載の難溶性薬物含有水中油型乳化組成物。 The hardly soluble drug-containing oil-in-water emulsion composition according to claim 1 or 2, wherein the ratio of the surfactant component to the total mass of the oil component is 80% by mass or less.
- 前記難溶性薬物が、タキサン系抗ガン剤から選択される請求項1から請求項3のいずれか1項に記載の難溶性薬物含有水中油型乳化組成物。 The hardly soluble drug-containing oil-in-water emulsion composition according to any one of claims 1 to 3, wherein the hardly soluble drug is selected from taxane anticancer agents.
- 前記難溶性薬物が、パクリタキセル、ドセタキセルおよびそれらの類縁体から選択される薬物である請求項4に記載の難溶性薬物含有水中油型乳化組成物。 The poorly soluble drug-containing oil-in-water emulsion composition according to claim 4, wherein the poorly soluble drug is a drug selected from paclitaxel, docetaxel and analogs thereof.
- 前記難溶性薬物がタクロリムス、シクロスポリンおよびそれらの類縁体から選択される薬物である請求項1から請求項3のいずれか1項に記載の難溶性薬物含有水中油型乳化組成物。 The poorly soluble drug-containing oil-in-water emulsion composition according to any one of claims 1 to 3, wherein the poorly soluble drug is a drug selected from tacrolimus, cyclosporine, and analogs thereof.
- 前記リン脂質がレシチンである請求項1から請求項6のいずれか1項に記載の難溶性薬物含有水中油型乳化組成物。 The poorly soluble drug-containing oil-in-water emulsion composition according to any one of claims 1 to 6, wherein the phospholipid is lecithin.
- 前記乳化粒子の平均粒子径が1nm以上200nm以下である請求項1から請求項7のいずれか1項に記載の難溶性薬物含有水中油型乳化組成物。 The poorly soluble drug-containing oil-in-water emulsion composition according to any one of claims 1 to 7, wherein an average particle size of the emulsified particles is 1 nm to 200 nm.
- 前記中鎖脂肪酸トリグリセリドにおける構成脂肪酸の平均炭素数が8.8以下である請求項1から請求項8のいずれか1項に記載の難溶性薬物含有水中油型乳化組成物。 The hardly soluble drug-containing oil-in-water emulsion composition according to any one of claims 1 to 8, wherein an average carbon number of the constituent fatty acid in the medium-chain fatty acid triglyceride is 8.8 or less.
- 前記中鎖脂肪酸トリグリセリドにおける構成脂肪酸の平均炭素数が8.5以下である請求項1から請求項8のいずれか1項に記載の難溶性薬物含有水中油型乳化組成物。 The hardly soluble drug-containing oil-in-water emulsion composition according to any one of claims 1 to 8, wherein the average carbon number of the constituent fatty acid in the medium-chain fatty acid triglyceride is 8.5 or less.
- 前記中鎖脂肪酸トリグリセリドにおける構成脂肪酸の平均炭素数が8.2以下である請求項1から請求項8のいずれか1項に記載の難溶性薬物含有水中油型乳化組成物。 The hardly soluble drug-containing oil-in-water emulsion composition according to any one of claims 1 to 8, wherein the average carbon number of the constituent fatty acid in the medium-chain fatty acid triglyceride is 8.2 or less.
- 前記難溶性薬物、前記油成分及び前記リン脂質を含有する界面活性剤成分を少なくとも含む油相成分を、これらを共通して溶解可能な有機溶媒に溶解して油相を調製すること、
前記油相と水相とを混合して水中油型乳化物を調製すること、
前記水中油型乳化物を調製する前又は後の油相を、前記有機溶媒を前記油相の質量に対して10質量%未満まで脱溶媒すること、
を含む、請求項1から請求項11のいずれかに記載の難溶性薬物含有水中油型乳化組成物の製造方法。 Preparing an oil phase by dissolving an oil phase component including 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;
Mixing the oil phase and the aqueous phase to prepare an oil-in-water emulsion,
Desolvating the organic phase before or after preparing the oil-in-water emulsion to less than 10% by mass of the organic solvent based on the mass of the oil phase;
The manufacturing method of the sparingly soluble medicine containing oil-in-water emulsion composition in any one of Claims 1-11 containing this. - 前記混合が、脱溶媒後の油相と水相とを混合するものである請求項12記載の難溶性薬物含有水中油型乳化組成物の製造方法。 The method for producing a poorly soluble drug-containing oil-in-water emulsion composition according to claim 12, wherein the mixing comprises mixing the oil phase after desolvation and the aqueous phase.
- 前記有機溶媒が、水溶性有機溶媒である請求項12又は請求項13記載の難溶性薬物含有水中油型乳化組成物の製造方法。 The method for producing a poorly soluble drug-containing oil-in-water emulsion composition according to claim 12 or 13, wherein the organic solvent is a water-soluble organic solvent.
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JP2000509021A (en) * | 1996-04-03 | 2000-07-18 | リサーチ・トライアングル・ファーマシューティカルズ | Cyclosporine emulsion |
JP2008514720A (en) * | 2004-09-28 | 2008-05-08 | エスディー ファーマシューティカルズ インコーポレイティッド | Low oil emulsion composition for delivering taxoids and other insoluble drugs |
JP2010513363A (en) * | 2006-12-22 | 2010-04-30 | バイオフロンテラ バイオサイエンス ゲゼルシャフト ミット ベシュレンクテル ハフツング | Nanoemulsion |
WO2009083664A1 (en) * | 2007-10-10 | 2009-07-09 | Aventis Pharma S.A. | Novel taxoid-based compositions |
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WO2013157664A1 (en) * | 2012-04-20 | 2013-10-24 | Sucampo Ag | Tricyclo compound-polymer conjugate |
WO2014013903A1 (en) * | 2012-07-19 | 2014-01-23 | 富士フイルム株式会社 | Liquid composition containing taxane-based active ingredient, process for producing same, and liquid medicinal preparation |
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