JP2016179962A - Formulation containing core-shell structure - Google Patents

Abstract

Disclosed is a preparation containing a core-shell structure, which has both transdermal absorbability and sustainability, and is excellent in storage stability. A pharmaceutical preparation containing a drug-containing phase containing a core-shell structure in which a core part contains a drug and a shell part contains a surfactant, and the ratio of the core-shell structure to the whole drug-containing phase Is 30% by weight or more. [Selection figure] None

Description

  The present invention relates to a preparation containing a core-shell structure, in particular, a transdermally absorbable preparation.

  An external preparation (percutaneous absorbable preparation) in which a drug absorbed from the skin acts in the body is used. As such a transdermally absorbable preparation, a preparation containing a core-shell structure in which a core part contains a drug and a shell part contains a surfactant has been proposed (Patent Document 1).

  For transdermally absorbable preparations, those having both transdermal absorbability and sustainability are required. In addition, as a general characteristic, storage stability is also required for transdermally absorbable preparations.

International Publication No. 2006/025583

  In many cases, the present inventors have found that a preparation containing a core-shell structure has a problem in that percutaneous absorption and storage stability are contradictory.

  Then, this invention makes it a subject to provide the formulation containing a core-shell structure, Comprising: The balance of transdermal absorbability, sustainability, and storage stability is improved.

The inventors of the present invention have made extensive studies to solve the above-mentioned problems, and the phase in the preparation in which the core-shell structure containing the drug exists (depending on the form of the preparation, only the core-shell structure exists alone. In some cases, the core-shell structure is dispersed in a phase containing a dispersant as a basic component, and such a phase is referred to as a “drug-containing phase” in the present invention. It has been found that it is important to keep the ratio of the core-shell structure in a certain level or more. That is, it has been found that the above problem can be solved if the ratio of the core-shell structure in the drug-containing phase is 30% by weight or more. The present invention has been completed through further trial and error based on this finding, and includes the following aspects.
Item 1.
A preparation comprising a drug-containing phase containing a core-shell structure in which a core part contains a drug and a shell part contains a surfactant, respectively,
The ratio of the core-shell structure to the whole drug-containing phase is 30% by weight or more.
Item 2.
Item 2. The preparation according to Item 1, which is a transdermally absorbable preparation.
Item 3.
Item 3. The preparation according to Item 1 or 2, wherein the surfactant has an HLB value of 10 or less.
Item 4.
Item 4. The preparation according to any one of Items 1 to 3, wherein the surfactant has a melting point of 50 ° C or lower.
Item 5.
Item 5. The preparation according to any one of Items 1 to 4, wherein the surfactant has an alkyl chain.
Item 6.
Item 6. The preparation according to any one of Items 1 to 5, wherein the drug is a hydrophilic drug.
Item 7.
Item 7. The preparation according to any one of Items 1 to 6, wherein the drug is memantine and / or a salt thereof.

  ADVANTAGE OF THE INVENTION According to this invention, the external preparation which has sustainability and transdermal absorbability, and is excellent also in storage stability can be provided.

2 is a schematic diagram of a drug skin permeation test cell used in Test Example 1. FIG. It is a graph which shows the result of Examples 1-9 and Comparative Example 1.

1. Composition of Formulation The formulation of the present invention has a drug-containing phase, and the drug-containing phase contains at least the following core-shell structure.

1.1 Core-shell structure The core-shell structure contains a drug in the core part and a surfactant in the shell part.

  The core-shell structure has a core-shell structure in which a core part containing a drug is partially or entirely covered with a surfactant in the shell part. Since the core-shell structure has such a configuration, when applied to the skin, the preparation of the present invention can continuously absorb the drug in the core part.

  The preparation of the present invention is characterized in that the core-shell structure is contained so that the ratio of the core-shell structure to the whole drug-containing phase is 30% by weight or more. Due to this feature, the preparation of the present invention has both durability and transdermal absorbability and excellent storage stability.

  From the viewpoint of percutaneous absorption and storage stability, the preparation of the present invention preferably contains the core-shell structure so that the proportion of the whole of the drug-containing phase is 50% by weight or more, and also 70% by weight or more. More preferably, it is even more preferably 90% by weight or more.

  The core-shell structure contained in the preparation of the present invention is not particularly limited, but usually the number average particle size can be 1 nm to 50000 nm. In terms of sustainability, transdermal absorbability, and storage stability, the number average particle size of the core-shell structure contained in the preparation of the present invention is preferably 5 nm to 10,000 nm, and more preferably 10 nm to 5000 nm.

  However, in the above, the number average particle diameter is calculated by a dynamic light scattering method during solvent dispersion.

  The core-shell structure contained in the preparation of the present invention is not particularly limited, but the ratio of the core part to the shell part (core part: shell part) is 1: 3 to 1 in terms of weight ratio in terms of the effects of the present invention. : 100, preferably 1: 5 to 1:70, more preferably 1:10 to 1:50.

1.1.1 The core drug is not particularly limited, but is preferably a hydrophilic drug.

The drug is not particularly limited when it is a hydrophilic drug, but typically has the following properties:
The molecular weight is 10,000 or less, and the octanol water partition coefficient is -8 to 6.

  In the above, the molecular weight is preferably 1000 or less, and more preferably 500 or less. Although the minimum of molecular weight is not specifically limited, Usually, it is 50 or more.

  In the above, the octanol water partition coefficient is preferably -6 to 5, and more preferably -5 to 4.

  In the present invention, the octanol water partition coefficient is calculated by the following formula from the drug concentration of each phase after adding the drug into a flask containing octanol and an aqueous buffer solution of pH 7 and then shaking. .

Octanol water partition coefficient = Log ₁₀ (concentration in octanol phase / concentration in water phase)
Although it does not specifically limit as a medicine, The thing for which a systemic action and a local effect | action are calculated | required is used suitably.

  Specific examples of the drug include, but are not limited to, memantine, nitroglycerin, lidocaine, fentanyl, male hormones, female hormones, nicotine, memantine hydrochloride, donepezil hydrochloride, clomipramine hydrochloride, diphenhydramine hydrochloride, nalfrafin hydrochloride, Metoprolol tartrate, fesoterodine fumarate, vardenafil hydrochloride hydrate, nalfrafin hydrochloride, tandospirone citrate, beraprost sodium, tartrelin, lurasidone hydrochloride, nefazodone hydrochloride, rifaximin, benidipine hydrochloride, doxazosin mesylate, Examples include nicardipine hydrochloride, formoterol fumarate, romeridine hydrochloride, amlodipine besylate, risedronate sodium and gabapentin. In addition, the above-mentioned pharmacologically acceptable salt can also be used as a drug.

  Although the amount of the drug contained in the core-shell structure depends on the kind of the drug, it can be set to, for example, 0.1 to 30% by weight with respect to the entire core-shell structure.

  The core part may contain two or more kinds of drugs as necessary. In this case, the preparation of the present invention can be used as a compounding agent.

  The core part may further contain at least one other component in addition to the drug. Although it does not specifically limit as another component, For example, a stabilizer, a transdermal absorption promoter, a skin irritation reducing agent, a preservative, etc. are mentioned.

  The stabilizer has a function of stabilizing the core-shell structure, has a role of preventing an unintended early collapse of the core-shell structure, and ensuring a sustained release effect of the drug.

  The stabilizer is not particularly limited, and specific examples include polysaccharides, proteins, and hydrophilic polymer materials. A stabilizer may contain 1 type, or 2 or more types. The content of the stabilizer in the core part can be appropriately set depending on the type of the stabilizer. For example, the stabilizer can be blended so that the weight ratio of the drug to the stabilizer is 100: 1 to 1:10. .

  Although it does not specifically limit as a percutaneous absorption enhancer, Specifically, higher alcohol, N-acyl sarcosine and its salt, higher monocarboxylic acid, higher monocarboxylic acid ester, aromatic monoterpene fatty acid ester, carbon number 2 To 10 divalent carboxylic acids and salts thereof, polyoxyethylene alkyl ether phosphates and salts thereof, lactic acid, lactic acid esters, and citric acid. The percutaneous absorption enhancer may contain one kind or two or more kinds. The content of the percutaneous absorption enhancer in the core part can be appropriately set depending on the type of the percutaneous absorption enhancer. For example, the weight ratio of the drug to the percutaneous absorption enhancer is 100: 1 to 1:50. You can also

  The skin irritation reducing agent is not particularly limited. Specifically, hydroquinone glycoside, pantethine, tranexamic acid, lecithin, titanium oxide, aluminum hydroxide, sodium nitrite, sodium hydrogen nitrite, soybean lecithin, methionine, Examples include glycyrrhetinic acid, BHT, BHA, vitamin E and derivatives thereof, vitamin C and derivatives thereof, benzotriazole, propyl gallate, and mercaptobenzimidazole. The skin irritation reducing agent may contain one kind or two or more kinds. Although the content rate in the core part of a skin irritation reducing agent can be suitably set according to the kind, it can also mix | blend, for example so that it may be 0.1%-50%.

  The preservative is not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and thymol. Although the content rate in the core part of an antiseptic | preservative can be set suitably also with the kind, For example, it can also mix | blend so that it may become 0.01%-10%. An antiseptic | preservative may contain 1 type (s) or 2 or more types.

1.1.2 The shell part surfactant is not particularly limited as long as it can form a shell part of a core-shell structure.

  A plurality of types of surfactants may be used in combination.

  As the surfactant, one having an HLB value of 10 or less, preferably 5 or less can be used.

  The surfactant is preferably one having a melting point of 50 ° C. or lower and more preferably 40 ° C. or lower in terms of skin permeability.

  As the surfactant, those having an HLB value of 10 or less and a melting point of 50 ° C. or less can be preferably used, and more preferably those having an HLB value of 5 or less and a melting point of 50 ° C. or less. More preferably, those having an HLB value of 5 or less and a melting point of 40 ° C. or less can be used.

  The HLB (abbreviation of Hydrophile Lyophile Balance) value in the present invention is an index for knowing whether an emulsifier is hydrophilic or lipophilic, and takes a value of 0 to 20. It shows that lipophilicity is so strong that an HLB value is small. In the present invention, it is calculated from the following Griffin equation.

HLB value = 20 × {(molecular weight of hydrophilic portion) / (total molecular weight)}
The melting point in the present invention is determined from an endothermic peak in differential scanning calorimeter (DSC) measurement.

  Surfactant is not specifically limited, For example, it can select widely from what can be used as an external preparation.

  The surfactant may be any of a nonionic surfactant, an anionic surfactant, a cationic surfactant, and an amphoteric surfactant.

  Nonionic surfactants include, but are not limited to, fatty acid esters, fatty alcohol ethoxylates, polyoxyethylene alkylphenyl ethers, alkyl glycosides and fatty acid alkanolamides.

  The fatty acid ester is not particularly limited, but a sugar fatty acid ester is preferable. In particular, sucrose fatty acid ester is preferable. Specific examples include esters of sucrose with fatty acids such as erucic acid, oleic acid, lauric acid, stearic acid and behenic acid.

  Other fatty acid esters are not particularly limited, and examples include esters of fatty acids with at least one of glycerin, polyglycerin, polyoxyethylene glycerin, sorbitan, and polyoxyethylene sorbit. In particular, polyglycerol fatty acid ester is preferable.

  Examples of the anionic surfactant include alkyl sulfate ester salts, polyoxyethylene alkyl ether sulfate ester salts, alkylbenzene sulfonate salts, fatty acid salts, and phosphate ester salts.

  Examples of the cationic surfactant include alkyl trimethyl ammonium salts, dialkyl dimethyl ammonium salts, alkyl dimethyl benzyl ammonium salts, and amine salts.

  Examples of amphoteric surfactants include alkylamino fatty acid salts, alkylbetaines, and alkylamine oxides.

  The blending amount of the surfactant can be appropriately set within the range in which the effects of the present invention can be achieved. For example, the weight ratio with the drug can be 1: 3 to 1: 100. At this time, the preparation of the present invention has excellent transdermal absorbability. In this respect, the weight ratio with the drug is preferably 1: 5 to 1:70.

  The surfactant is not particularly limited, but may have an alkyl chain. The alkyl chain length is not particularly limited, but can be selected from a wide range of 8 to 30, and preferably 10 to 24.

  When only a surfactant having an alkyl chain is used, or when a surfactant having an alkyl chain is used in combination with another surfactant, the total weight ratio of the drug and the alkyl chain contained in the surfactant is 1 : 1-1: 70, the preparation of the present invention has excellent transdermal absorbability. In this respect, the same weight ratio is preferably set to 1: 2 to 1:50.

  The shell portion may further contain at least one other component in addition to the surfactant. Although it does not specifically limit as another component, For example, a skin irritation reducing agent, an analgesic, a percutaneous absorption promoter, a stabilizer, an antiseptic, etc. are mentioned.

  The skin irritation reducing agent is not particularly limited. Specifically, hydroquinone glycoside, pantethine, tranexamic acid, lecithin, titanium oxide, aluminum hydroxide, sodium nitrite, sodium hydrogen nitrite, soybean lecithin, methionine, Examples include glycyrrhetinic acid, BHT, BHA, vitamin E and derivatives thereof, vitamin C and derivatives thereof, benzotriazole, propyl gallate, and mercaptobenzimidazole. The skin irritation reducing agent may contain one kind or two or more kinds. Although the content rate in the shell part of a skin irritation reducing agent can be suitably set according to the kind, it can also mix | blend, for example so that it may be 0.1%-50%.

  Although it does not specifically limit as an analgesic, Specifically, local anesthetics, such as procaine, tetracaine, lidocaine, dibucaine, and prilocaine, its salt, etc. are mentioned. An analgesic may contain 1 type (s) or 2 or more types. Although the content rate in the shell part of an analgesic can be suitably set according to the kind, it can also mix | blend so that it may be 0.1%-30%, for example.

  Although it does not specifically limit as a percutaneous absorption enhancer, Specifically, higher alcohol, N-acyl sarcosine and its salt, higher monocarboxylic acid, higher monocarboxylic acid ester, aromatic monoterpene fatty acid ester, carbon number 2 To 10 divalent carboxylic acids and salts thereof, polyoxyethylene alkyl ether phosphates and salts thereof, lactic acid, lactic acid esters, and citric acid. The percutaneous absorption enhancer may contain one kind or two or more kinds. Although the content rate in the shell part of a percutaneous absorption enhancer can be suitably set according to the kind, it can also mix | blend so that it may be set to 0.1%-30%, for example.

  The stabilizer has a function of stabilizing the core-shell structure, has a role of preventing an unintended early collapse of the core-shell structure, and ensuring a sustained release effect of the drug.

  The stabilizer is not particularly limited, and specifically, fatty acids and salts thereof, parahydroxybenzoates such as methylparaben and propylparapen, alcohols such as chlorobutanol, pendyl alcohol, and phenylethyl alcohol, thimerosal , Acetic anhydride, sorbic acid, sodium bisulfite, L-ascorbic acid, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, tocopherol acetate, dl-α-tocopherol, protein and polysaccharides. A stabilizer may contain 1 type, or 2 or more types. The content of the stabilizer in the shell part can be appropriately set depending on the type of the stabilizer. For example, the stabilizer is mixed so that the weight ratio of the surfactant to the stabilizer is 1: 0.01 to 1:50. You can also

  The preservative is not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and thymol. An antiseptic | preservative may contain 1 type (s) or 2 or more types. Although the content rate in the shell part of an antiseptic | preservative can be suitably set according to the kind, it can also mix | blend, for example so that it may become 0.01%-10%.

1.1.3 preparation of drug-containing phase present invention contains a drug-containing phase. The drug-containing phase contains at least a core-shell structure. The drug-containing phase may further contain a dispersant as required. In this case, the core-shell structure is dispersed in the dispersant.

  The dispersant is not particularly limited, and can be selected from a wide range of agents that can be used as external preparations.

  The dispersant can be appropriately selected from those suitable for dispersing the core-shell structure according to the purpose of use, and is not particularly limited.

  A plurality of types of dispersants may be used in combination.

  Although it does not specifically limit as a dispersing agent, For example, vegetable oil, animal oil, neutral lipid, synthetic fat, sterol derivative, waxes, hydrocarbons, monoalcohol carboxylic acid esters, oxyacid esters, polyhydric alcohol fatty acid ester , Silicones, higher (polyhydric) alcohols, higher fatty acids and fluorinated oils.

  The vegetable oil is not particularly limited, and examples thereof include soybean oil, sesame oil, olive oil, palm oil, balm oil, rice bran oil, cottonseed oil, sunflower oil, rice bran oil, cacao butter, corn oil, bean flower oil and rapeseed oil. .

  Although it does not specifically limit as animal oil, For example, mink oil, turtle oil, fish oil, cow oil, horse oil, pig oil, shark squalane, etc. are mentioned.

  The neutral lipid is not particularly limited, and examples thereof include triolein, trilinolein, trimyristin, tristearin, and triarachidonin.

  Although it does not specifically limit as synthetic fats and oils, For example, a phospholipid, an azone, etc. are mentioned.

  The sterol derivative is not particularly limited, and examples thereof include dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterol, cholic acid, and cholesteryl linoleate.

  Examples of waxes include candelilla wax, carnauba wax, rice wax, beeswax, beeswax, montan wax, ozokerite, ceresin, paraffin wax, microcrystalline wax, petrolatum, Fischer-Tropsch wax, polyethylene wax, and ethylene / propylene copolymer. Can be mentioned.

  Examples of hydrocarbons include liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, α-olefin oligomer, polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olive-derived squalane, squalene, petrolatum and solid paraffin. It is done.

  Examples of monoalcohol carboxylic acid esters include octyldodecyl myristate, hexyldecyl myristate, octyldodecyl isostearate, cetyl palmitate, octyldodecyl palmitate, cetyl octoate, hexyldecyl octoate, isotridecyl isononanoate, isononanoyl isononanoate, Octyl isononanoate, isotridecyl isononanoate, isodecyl neopentanoate, isotridecyl neopentanoate, isostearyl neopentanoate, octyldodecyl neodecanoate, oleyl oleate, octyl dodecyl oleate, octyldodecyl ricinoleate, octyldodecyl lanolinate, hexyldecyl dimethyloctanoate , Octyldodecyl erucate, isostearic acid hydrogenated castor oil, ethyl oleate Avocado oil fatty acid ethyl, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl isostearate, isopropyl lanolin fatty acid, diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, diisopropyl adipate, dibutyloctyl sebacate, diisobutyl adipate, Examples include dioctyl succinate and triethyl citrate.

  Examples of oxyesters include cetyl lactate, diisostearyl malate, and hydrogenated castor oil monoisostearate.

  Polyhydric alcohol fatty acid esters include glyceryl trioctanoate, glyceryl trioleate, glyceryl triisostearate, glyceryl diisostearate, glyceryl tri (caprylic acid / capric acid), tri (caprylic acid / capric acid / myristic acid / stearic acid) ) Glyceryl, hydrogenated rosin triglyceride (hydrogenated ester gum), rosin triglyceride (ester gum), glyceryl behenate, trimethylolpropane trioctanoate, trimethylolpropane triisostearate, neopentylglycol dioctanoate, neopentyl glycol dicaprate Pentyl glycol, 2-butyl-2-ethyl-1,3-propanediol dioctanoate, propylene glycol dioleate, pentaerythrtetraoctanoate Chill, hydrogenated rosin pentaerythrityl, triethylhexanoic acid ditrimethylolpropane, (isostearic acid / sebacic acid) ditrimethylolpropane, triethylhexanoic acid pentaerythrityl, (hydroxystearic acid / stearic acid / rosinic acid) dipentaerythrityl, diisostearic acid di Glyceryl, polyglyceryl tetraisostearate, polyglyceryl-10 nonaisostearate, deca (erucic acid / isostearic acid / ricinoleic acid) polyglyceryl-8, (hexyldecanoic acid / sebacic acid) diglyceryl oligoester, glycol distearate (ethylene glycol distearate) Dineopentanoic acid 3-methyl-1,5-pentanediol and dineopentanoic acid 2,4-diethyl-1,5-penta Diol, and the like.

  Silicones include dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane, decamethylcyclopentasiloxane), phenyltrimethicone, diphenyldimethicone, phenyldimethicone, stearoxypropyl. Dimethylamine, (aminoethylaminopropylmethicone / dimethicone) copolymer, dimethiconol, dimethiconol crosspolymer, silicone resin, silicone rubber, amino-modified silicone such as aminopropyldimethicone or amodimethicone, cation-modified silicone, polyether modified such as dimethicone copolyol Silicone, polyglycerin modified silicone, sugar modified silicone, carboxylic acid modified silicone, phosphoric acid modified silicone Sulfuric acid modified silicone, alkyl modified silicone, fatty acid modified silicone, alkyl ether modified silicone, amino acid modified silicone, peptide modified silicone, fluorine modified silicone, cationic modified or polyether modified silicone, amino modified or polyether modified silicone, alkyl modified or polyether Examples thereof include modified silicones and polysiloxane / oxyalkylene copolymers.

  Higher (polyhydric) alcohols include cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearyl alcohol, stearyl alcohol, aralkyl alcohol, behenyl alcohol, jojoba alcohol, chimyl alcohol, seraalkyl alcohol, batyl alcohol, hexyl decanol, Examples include isostearyl alcohol, 2-octyldodecanol, and dimer diol.

  Higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, undecylenic acid, 12-hydroxystearic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, erucic acid, docosahexaenoic acid Eicosapentaenoic acid, isohexadecanoic acid, anteisohenicosanoic acid, long-chain branched fatty acid, dimer acid and hydrogenated dimer acid.

  Examples of the fluorinated oils include perfluorodecane, perfluorooctane and perfluoropolyether.

  Other dispersants are not particularly limited, and examples include dispersants used in ointments, creams, aerosols, tapes, patches, poultices, gels, microneedles, and the like.

  The proportion of the dispersing agent in the whole drug-containing phase is usually 70% by weight or less, preferably 50% by weight or less, more preferably 30% by weight or less in terms of transdermal absorbability and storage stability. And even more preferably 10% by weight or less.

  The above-mentioned drug-containing phase may further comprise an excipient, a colorant, a lubricant, a binder, an emulsifier, a thickener, a wetting agent, a stabilizer, a storage, depending on the dosage form and purpose of use of the preparation of the present invention. Additives such as agents, solvents, solubilizers, suspending agents, buffering agents, pH adjusters, gelling agents, adhesives, antioxidants, percutaneous absorption enhancers, irritation relaxation agents, preservatives, and chelating agents May be contained.

2. Method for Producing Formulation The formulation of the present invention is not particularly limited, but can be produced, for example, as follows.

  First, although not particularly limited, the core-shell structure of the present invention can be produced, for example, as follows. The drug and optionally additional components such as a stabilizer, a transdermal absorption enhancer, and a skin irritation reducing agent are dissolved in a solvent such as pure water or phosphate buffer. To this, a solution in which an additional component such as a surfactant and optionally a skin irritation reducing agent, an analgesic agent, a transdermal absorption accelerator and a stabilizer is dissolved in a solvent such as cyclohexane, hexane or toluene is added, and the mixture is stirred by a homogenizer. . Thereafter, the core-shell structure of the present invention can be prepared by lyophilization.

  The core-shell structure thus obtained may be used as it is (or almost as it is) as a preparation, or may be used after being dispersed in the dispersant. In any of these cases, additional components such as a percutaneous absorption enhancer, a stabilizer, a thickener, and a gelling agent can be added as necessary. The preparation thus obtained may be used as it is, or depending on the use, a natural fabric member such as gauze or absorbent cotton, a synthetic fiber fabric member such as polyester or polyethylene, or a woven fabric or a combination thereof as appropriate. It can be used after being processed into a nonwoven fabric or the like, or in a state of being laminated and impregnated on a permeable membrane or the like, and further covered with an adhesive cover material or the like as necessary.

  Another method for producing a transdermal absorption preparation is, for example, a solution coating method. For example, first, the core-shell structure or the combination of the core-shell structure and the dispersant used in the present invention may be added with a predetermined proportion of additional components such as the percutaneous absorption enhancer, thickener, and gelling agent as desired. Add to a solvent such as hexane, toluene or ethyl acetate and stir to prepare a homogeneous solution. The solid content concentration in the solution is preferably 10 to 80% by weight, more preferably 20 to 60% by weight. Next, the above solution containing each component is uniformly applied on a release liner (silicone-treated polyester film, etc.) using a coating machine such as a knife coater, comma coater, or reverse coater, and dried. A percutaneously absorbable preparation can be obtained by completing a drug-containing layer and laminating a support on the layer. Depending on the type of the support, after the layer is formed on the support, a release liner may be laminated on the surface of the layer.

  The percutaneously absorbable preparation thus obtained is appropriately cut into an oval shape, a circular shape, a square shape, a rectangular shape or the like according to the intended use. Moreover, you may provide an adhesive layer etc. in the periphery as needed.

3. Use of the preparation The preparation of the present invention is not particularly limited, but can be used as a continuous transdermally absorbable preparation. In this case, it is usually sustained for 1 day to 1 week, and in a preferred embodiment, it is used so as to be applied once a day to 1 week.

  The target disease varies depending on the type of drug.

  The sustained-type transdermally absorbable preparation of the present invention is not particularly limited, but is a tape (reservoir type, matrix type, etc.), ointment, lotion, aerosol, plaster, aqueous buccal, cream, gel, It can be used as an aerosol, patch, microneedle and the like.

  Hereinafter, the present invention will be described in detail by way of examples and test examples, but the present invention is not limited to these examples.

Example 1
A solution in which 0.1 g of memantine hydrochloride is dissolved in 40 g of pure water and 3 g of sucrose erucic acid ester (manufactured by Mitsubishi Chemical Foods, ER-290; HLB value 2, melting point of about 4 ° C.) is dissolved in 80 g of cyclohexane. And stirred with a homogenizer (10,000 rpm). This was followed by lyophilization for 2 days to prepare a core-shell structure type preparation.
(Core shell structure content 100% by weight)

Example 2
An external preparation was used in the same manner as in Example 1, except that sucrose laurate (L-195; HLB value 1, melting point of about 24 ° C.) was used instead of sucrose erucate. Manufactured. (Core shell structure content 100% by weight)

Example 3
External preparation in the same manner as in Example 1 except that polyglycerin oleate (manufactured by Mitsubishi Chemical Foods, O-50D; HLB value 7, melting point: about 45 ° C.) was used instead of sucrose erucic acid ester. Manufactured. (Core shell structure content 100% by weight)

Example 4
An external preparation was produced in the same manner as in Example 1 except that the amount of sucrose erucic acid ester was changed to 5 g. (Core shell structure content 100% by weight)

Example 5
An external preparation was produced in the same manner as in Example 1 except that the amount of sucrose erucic acid ester was changed to 1 g. (Core shell structure content 100 wt%)

Example 6
An external preparation was produced in the same manner as in Example 1 except that the amount of sucrose erucic acid ester was changed to 0.5 g. (Core shell structure content 100% by weight)

Example 7
1 g of liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd., 128-04375) was added to 3 g of the core-shell structure of Example 1, and the mixture was mixed and dispersed to prepare a preparation. (Core shell structure content 75 wt%)

Example 8
3 g of liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd., 128-04375) was added to 3 g of the core-shell structure of Example 1, and the mixture was mixed and dispersed to produce a preparation. (Core shell structure content 50% by weight)

Example 9
6 g of liquid paraffin was added to 3 g of the core-shell structure of Example 1, and the mixture was mixed and dispersed to produce a preparation. (Core shell structure content 33% by weight)

Comparative Example 1
8 g of liquid paraffin was added to 3 g of the core-shell structure of Example 1 and mixed and dispersed in a mortar to produce a preparation. (Core shell structure content 27% by weight)

Comparative Example 2
3 g of sucrose erucic acid ester was added to 0.1 g of memantine hydrochloride and mixed in a mortar, but due to poor dispersibility, it was not used in the test described below.

Test Example 1 Hairless Rat Skin Permeability Test Hairless rat skin (extracted from Japan SLC, HWY / Slc, 8 weeks old) was set in a drug skin permeation test cell (FIG. 1). 0.5 g (about 3 cm ² ) of various external preparations produced in Examples 1 to 9 and Comparative Example 1 was applied to the upper part of this apparatus, and 5 × 10 5 NaH ₂ PO ₄ was added to distilled water in the lower receptor layer. ^over ₄ M, Na ₂ HPO 4 to 2 × ¹⁰ -4 M, NaCl to 1.5 × ^{10 -4} M, gentamicin sulfate (manufactured by Wako Pure Chemical Industries, Ltd., G1658) with NaOH the solution was contained 10ppm of pH7.2 The adjusted buffer solution was added, and the apparatus was installed in a thermostatic bath maintained at 32 ° C. from the start of the test. After starting the test, 1 ml of the liquid in the tank was collected from the lower receptor layer after a predetermined time, and immediately after that, 1 ml of the liquid having the same composition was replenished. Methanol was added to each of the collected receptor solution samples, and the eluted lipids were extracted and centrifuged. Then, the concentration of memantine hydrochloride in the supernatant was determined using GC (column used: JEOL ZB1 30 m long, inner diameter 0.32 mm). ).

  The results are shown in FIG. It was found that the external preparation of the example had a large amount of drug permeation continuously compared to the external preparation of Comparative Example 1.

Test example 2 Shape stability test
The stability of the manufactured evaluation sample was confirmed using the shape of the preparation using an optical microscope (manufactured by Nikon Corporation, Eclipse ME600 model number) (200 times magnification) as an index.
The external preparations of Examples 1 to 9 and Comparative Example 1 were stored at room temperature of 25 ° C., and after 3 days were compared with the shape in the initial state, and the following evaluation items were used as indicators.

(Shape evaluation item)
○: No change △: Partial change ×: Change

  Table 1 shows the results of studying the stability of various evaluation samples. In Comparative Example 1, the change in shape was remarkably observed, whereas in the external preparation of the example, the change was slight.

  From these results, it was confirmed that the external preparation of the example had a large amount of skin permeation and a shape stability.

1 Parafilm 2 Skin 3 Formulation 4 Receptor solution (pH = 7.2 phosphate buffer)
5 Stir bar

Claims (7)

A preparation comprising a drug-containing phase containing a core-shell structure in which a core part contains a drug and a shell part contains a surfactant, respectively,
The ratio of the core-shell structure to the whole drug-containing phase is 30% by weight or more. The preparation according to claim 1, which is a transdermally absorbable preparation. The preparation according to claim 1 or 2, wherein the surfactant has an HLB value of 10 or less. The formulation as described in any one of Claims 1-3 whose melting | fusing point of the said surfactant is 50 degrees C or less. The preparation according to any one of claims 1 to 4, wherein the surfactant has an alkyl chain. The preparation according to any one of claims 1 to 5, wherein the drug is a hydrophilic drug. The preparation according to any one of claims 1 to 6, wherein the drug is memantine and / or a salt thereof.