JP2012051823A - Oil-in-water emulsion composition containing poorly-soluble drug, and method for manufacturing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an oil-in-water type emulsified composition for in a high density containing a sparingly soluble medicament, for being excellent, and suitable for being suitable as the stability and an injection, and the production method.SOLUTION: An oil-in-water emulsion composition containing a poorly-soluble drug having emulsified particles with an average particle diameter of less than 500 nm contains a poorly-soluble drug having a solubility in water of less than 1 mg/mL with a molecular weight of equal to or more than 500, an oil constituent containing medium chain fatty acid triglycerides in an amount of more than 80 mass% and an amount of more than 6 mass% with respect to the mass of the entire composition, and a surfactant constituent containing phospholipids in an amount of equal to or more than 50 mass%.

Description

  The present invention relates to a poorly soluble drug-containing oil-in-water emulsion composition and a method for producing the same.

  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.

Examples of such poorly soluble drugs include taxane drugs widely used in cancer chemotherapy. Taxane drugs are solubilized using nonionic surfactants such as polysorbate and polyoxyethylated castor oil, and ethanol when the solution is administered by injection or infusion. 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.

  In general, 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.

  In order to solve the above problems, Patent Document 1 discloses an emulsified preparation using soy oil as a dissolved oil of paclitaxel, using safflower oil, and using egg yolk lecithin and cholesterol as surfactants. .

  In Patent Document 2, at least five kinds of ingredients: therapeutic drug, vitamin E, drug and oil in which vitamin E is dissolved, stabilizer (phospholipid, lecithin or poloxamer which is a polyoxyethylene-polyoxypropylene copolymer) And a lipid drug delivery composition comprising water. Using vitamin E having good solubility in paclitaxel, an example in which an equivalent amount of soybean oil and vitamin E is used together and Pluronic P105 is used as a surfactant is disclosed.

  Patent Document 3 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.

  Patent Document 4 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.

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.

Japanese National Patent Publication No. 10-502921 Japanese National Patent Publication No. 11-509545 Japanese translation of PCT publication No. 2003-501376 Special table 2008-514720 gazette

  Accordingly, an object of the present invention is to provide an oil-in-water emulsion composition that contains a poorly soluble drug at a high concentration, has good stability, and is suitable as an injection, and a method for producing the same.

The present invention is as follows.
[1] A sparingly 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 triglycerides in an amount exceeding 80% by mass, and based on the total mass of the composition A poorly soluble drug-containing oil-in-water type comprising an oil component in an amount exceeding 6% by mass and a surfactant component containing a phospholipid in an amount of 50% by mass or more, wherein the average particle size of the emulsified particles is less than 500 nm Emulsified composition.
[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 hardly soluble drug-containing oil-in-water emulsion composition 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] A surfactant component containing the poorly soluble drug, the oil component, and the phospholipid is dissolved in an organic solvent that can be commonly dissolved, and an oil phase is prepared. The hardly water-soluble drug-containing oil-in-water type according to any one of [1] to [8], comprising desolvating to less than 10% by mass with respect to the mass of the oil phase, and mixing the oil phase and the aqueous phase. A method for producing an emulsified composition.
[10] The method for producing a sparingly soluble drug-containing oil-in-water emulsion composition according to [9], wherein the mixing comprises mixing the oil phase after the solvent removal and the aqueous phase.
[11] The method for producing a poorly soluble drug-containing oil-in-water emulsion composition according to [9] or [10], wherein the organic solvent is a water-soluble organic solvent.

  According to the present invention, it is possible to provide an oil-in-water emulsion 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 poorly soluble drug-containing oil-in-water emulsion composition of the present invention comprises a sparingly soluble drug having a solubility in water of less than 1 mg / mL and a molecular weight of 500 or more, and a medium-chain fatty acid triglyceride in an amount exceeding 80% by mass. And an oil component in an amount exceeding 6% by mass with respect to the total mass of the composition, and a surfactant component containing a phospholipid in an amount of 50% by mass or more, and an average particle size of the emulsified particles Is a poorly soluble drug-containing oil-in-water emulsion composition having a diameter of less than 500 nm.
According to the present invention, by using an oil component containing medium-chain fatty acid triglyceride at more than 80% by mass as an oil component, a poorly soluble drug is dissolved in the oil component at a high concentration and encapsulated. In an oil-in-water emulsion composition in which the average particle size of the emulsified particles is less than 500 nm. Containing and maintaining a viscosity suitable for injections and good stability. As a result, it is possible to obtain an oil-in-water emulsion composition containing a poorly soluble drug at a high concentration and having a good stability and a suitable dosage form as an injectable preparation.
In the present specification, the slightly soluble drug-containing oil-in-water emulsion composition is sometimes simply referred to as “emulsion composition” or “composition”.

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. .
Moreover, the numerical value range shown using "to" in this specification shows the range which includes the numerical value described before and behind "to" as a minimum value and a 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.

[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 term “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.

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; cephalomannine-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-vacatin 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 JP-T-2002-519378 can be mentioned, in particular 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.

  In the emulsified composition of the present invention, the poorly soluble drug may generally be present in an amount of 1 μg / mL to 50 mg / mL with respect to the total mass of the composition.

[Oil component]
The oil component in the present invention contains medium-chain fatty acid triglycerides in an amount exceeding 80% by mass. 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 more preferably 90% by mass or more in order to further increase the oil component concentration in the emulsion composition, promote the refinement, and improve the stability. preferable.

  As used herein, “oil component” refers to a hydrocarbon, carbohydrate, or similar organic compound that is liquid at about 37 ° C. and is pharmaceutically 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.

  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 to be 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 number of carbon atoms 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 mainly composed 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 of the mixture of medium chain fatty acid triglycerides.

  In the present invention, SASOL GmbH (Germany) Miglyol 812, Miglyol 810, Kao's Coconut MT, Coconard RK and the like 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. 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, or 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.

The emulsified composition of the present invention contains an oil component in an amount exceeding at least 6% by mass. 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 to 25% by mass of the total mass of the emulsion composition, and a more preferable range. As, it is 8-15 mass%. By increasing the proportion of the oil component in the emulsified composition, the drug concentration in the emulsified composition can be increased proportionally, so that there is an advantage that the infusion time can be shortened.

[Surfactant component]
The surfactant component in the present invention contains phospholipid in an amount of 50% by mass or more. If the phospholipid content 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, more preferably 90% by mass or more, and 100 Most preferably, only phospholipids are used as mass%, ie surfactant.

  The phospholipid in the present invention includes a pure phospholipid or a mixture of two or more phospholipids. “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. Moreover, you may include the PEG-phospholipid which polyethyleneglycol (PEG) couple | bonded with the said phospholipid.

  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.

  Natural lecithin is a mixture of stearic, palmitic and oleic diglycerides linked to a choline ester of phosphate, commonly referred to as phosphatidylcholine, and is 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 the 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 is hydrogenated. This can also be used in the present invention.

  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.

  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, it is 10 mass%-25 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 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”.

  The “antioxidant” used in the present invention is mainly preferably a metal ion chelating agent and / or a reducing agent that is safe for use 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. As a commercially available measuring device using dynamic light scattering, Nanotrac UPA (Nikkiso Co., Ltd.), dynamic light scattering type particle size distribution measuring device LB-550 (Horiba, Ltd.), 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.).

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 the freeze-dry process and to form an oil-in-solid dispersion system 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, or 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.

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. Yes, more preferably 10 mPa · S or less.

[Production method]
In the emulsified composition of the present invention, an oil phase is prepared by dissolving the poorly soluble drug, the oil component and the surfactant containing the phospholipid in an organic solvent that can be dissolved in common (hereinafter referred to as “oil phase”). , Referred to as oil phase preparation step), removing the organic solvent to less than 10% by mass relative to the mass of the oil phase (hereinafter referred to as desolvation step), mixing the oil phase and the aqueous phase ( Hereinafter, it can be obtained by a production method including an emulsification step).

In the oil phase preparation step, (i) a poorly soluble drug, (ii) an oil component (for example, medium chain fatty acid triglyceride), and (iii) a mixture (oil phase) containing an appropriate amount of phospholipid can be dissolved in common. Dissolve in any 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.

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 at least 50% by volume, more preferably 70% by volume or more.

  Examples of such water-soluble organic solvents include methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, acetone, tetrahydrofuran, acetonitrile, methyl ethyl ketone, dipropylene glycol monomethyl ether, methyl acetate, methyl acetoacetate, N -Methylpyrrolidone, dimethyl sulfoxide, ethylene glycol, 1,3 butanediol, 1,4 butanediol, propylene glycol, diethylene glycol, triethylene glycol and the like and mixtures thereof. Among these, when limited to food applications, ethanol, propylene glycol, or acetone is preferable, and ethanol or a mixed solution of ethanol and water is particularly preferable.

  In the solvent removal step, the organic solvent in the oil phase is desolvated to less than 10% by mass with respect to the mass of the oil phase, and preferably from less than 5% by mass from the viewpoint of 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.

In the emulsification step, the oil phase and the aqueous phase are mixed (emulsified). 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.

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.

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.

In the present invention, the pressure of the high-pressure homogenizer is preferably 50 MPa or more, more preferably 50 to 250 MPa, 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.

  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.

  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.

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.

  Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to them.

[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.

  Hexane 3mL and saturated saline 5mL were added, the hexane layer was collected, and gas chromatograph method [model: GC-1700 (Shimadzu Corporation, detector: FID, column: DB-23 (J & W SCIENTIFIC)) φ0.25mm × 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.

(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.
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.

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.

[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.

  The prepared emulsified composition was an oil-in-water emulsified composition having an average particle diameter of 140 nm of emulsified particles (oil droplet particles), and was stable with no aggregation or precipitation of the emulsion observed at 4 ° C. for 2 months. The oil droplet particle diameter was measured using a dynamic light scattering particle diameter / particle size distribution measuring apparatus (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 emulsified composition prepared with 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.

[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.
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.

  Thus, according to the present invention, it can be seen that 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.

Claims (11)

A poorly soluble drug having a solubility in water of less than 1 mg / mL and a molecular weight of 500 or more;
An oil component containing medium chain fatty acid triglycerides in an amount exceeding 80% by weight and exceeding 6% by weight relative to the total weight of the composition;
A surfactant component containing phospholipids in an amount of 50% by weight or more;
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.   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.   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.   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.   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.   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 a drug selected from tacrolimus, cyclosporine, and analogs thereof.   The poorly soluble drug-containing oil-in-water emulsion composition according to any one of claims 1 to 6, wherein the phospholipid is lecithin.   The poorly soluble drug-containing oil-in-water emulsion composition according to any one of claims 1 to 7, wherein an average particle diameter of the emulsified particles is 1 nm or more and 200 nm or less. Preparing an oil phase by dissolving the poorly soluble drug, the oil component and the surfactant component containing the phospholipid in an organic solvent that can be commonly dissolved;
Desolvating the organic solvent to less than 10% by mass relative to the mass of the oil phase;
Mixing the oil phase and the aqueous phase;
The manufacturing method of the hardly soluble medicine containing oil-in-water type emulsion composition in any one of Claim 1 to 8 containing this.   The method for producing a poorly soluble drug-containing oil-in-water emulsion composition according to claim 9, wherein the mixing comprises mixing the oil phase after desolvation and the aqueous phase.   The method for producing a poorly soluble drug-containing oil-in-water emulsion composition according to claim 9 or 10, wherein the organic solvent is a water-soluble organic solvent.