WO2016006630A1 - Médicament pour usage externe type à action générale durable - Google Patents

Médicament pour usage externe type à action générale durable Download PDF

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Publication number
WO2016006630A1
WO2016006630A1 PCT/JP2015/069649 JP2015069649W WO2016006630A1 WO 2016006630 A1 WO2016006630 A1 WO 2016006630A1 JP 2015069649 W JP2015069649 W JP 2015069649W WO 2016006630 A1 WO2016006630 A1 WO 2016006630A1
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Prior art keywords
external preparation
core
acid
drug
shell structure
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PCT/JP2015/069649
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English (en)
Japanese (ja)
Inventor
和志 伊藤
隆之 赤峰
紗織 利根
阿部　佳子
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積水化学工業株式会社
積水メディカル株式会社
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Priority to JP2015545543A priority Critical patent/JPWO2016006630A1/ja
Publication of WO2016006630A1 publication Critical patent/WO2016006630A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the present invention relates to a continuous systemic action external preparation.
  • An external preparation that exhibits a systemic action (systemic action type external preparation) is used by the drug absorbed from the skin moving into the systemic circulation.
  • Patent Document 1 Patent Document 1
  • An object of the present invention is to provide a sustained systemic external preparation having an easily absorbable drug as a main drug.
  • Item 1 A sustained systemic external preparation containing a core-shell structure in which a core part contains an easily absorbable drug and a shell part contains a surfactant.
  • Item 2. In addition, it contains a base phase, The base phase contains the core-shell structure; Item 10.
  • the continuous systemic action external preparation according to Item 1. Item 3.
  • Item 3. Item 3.
  • Item 4. Item 4. The sustained systemic external preparation according to any one of Items 1 to 3, wherein the surfactant contains an alkyl chain.
  • Item 5. The sustained systemic external preparation according to Item 4, wherein the weight ratio of the easily absorbable drug and the alkyl chain is 1: 1 to 1:70.
  • the viscosity of the core-shell structure When the base phase is not included, the viscosity of the core-shell structure, or when the base phase is included, the viscosity of the base phase containing the core-shell structure is Item 7.
  • the sustained systemic external preparation according to any one of Items 2 to 7, wherein the viscosity of the base phase itself is 1000 mPa ⁇ s or more.
  • Item 9. The continuous systemic action external preparation according to any one of Items 1 to 8, which is persistent for 1 day to 1 week.
  • Item 10. The sustained systemic external preparation according to any one of Items 1 to 9, wherein the easily absorbable drug is memantine and / or a salt thereof.
  • the present invention it is possible to provide a systemic action-type external preparation that has an easily absorbable drug as a main drug and has sustained and reduced side effects.
  • the ratio of the maximum blood drug concentration to the minimum blood drug concentration between 24 hours and 48 hours after the start of administration is 2 or less.
  • 6 is a graph showing the results of Examples 1 to 7 and Comparative Examples 1 and 2.
  • 6 is a graph showing the results of Examples 8 to 14 and Comparative Examples 1 and 2.
  • the continuous systemic external preparation of the present invention contains at least the following core-shell structure.
  • the core-shell structure includes an easily absorbable drug in the core portion and a surfactant in the shell portion.
  • the core-shell structure has a core-shell structure in which a core part containing an easily absorbable drug is partially or entirely covered with a surfactant in the shell part.
  • the core part and the shell part only need to be connected to each other to form an aggregate, and the entire surface of the core part need not be covered with the shell part. Due to the core-shell structure having such a configuration, when applied to the skin, the long-acting systemic external preparation of the present invention develops an easily absorbable drug in the core part for a long time and exhibits side effects. Slow release with a release amount that does not occur.
  • the shape and size of the core-shell structure are not particularly limited, but the average size is usually 1 to 10000 nm, and preferably 2 to 5000 nm, more preferably 3 to 700 nm, from the viewpoint of obtaining appropriate transdermal absorbability. More preferably, it is 5 to 300 nm.
  • the average size of the core-shell structure is a number average diameter calculated by a dynamic light scattering method when a solvent (eg, squalane) is dispersed.
  • a solvent eg, squalane
  • the core part easily absorbable drug is not particularly limited as long as it is a drug that is relatively easily absorbed percutaneously, but is typically a drug having the following characteristics:
  • the molecular weight is less than 400 and the octanol water partition coefficient is ⁇ 6 to 6.
  • the molecular weight is preferably 350 or less, more preferably 300 or less, and even more preferably 250 or less. Although the minimum of molecular weight is not specifically limited, Usually, it is 50 or more.
  • the octanol water partition coefficient is preferably ⁇ 2 to 5 or ⁇ 3 to 5, more preferably ⁇ 2 to 4, and still more preferably ⁇ 1 to 4.
  • easily absorbable drugs include, but are not limited to, memantine, nitroglycerin, lidocaine, male hormones, female hormones, nicotine, scopolamine, isosorbide nitrate, clonidine, tulobuterol and oxybutynin hydrochloride.
  • the above-mentioned pharmacologically acceptable salt, neutralized product or hydrate can be used as an easily absorbable drug.
  • the amount of the easily absorbable drug contained in the core-shell structure depends on the kind of the easily-absorbable drug.
  • the raw material charge weight is 0.1 to 30% by weight (total of all raw materials contained in the core-shell structure). Based on weight).
  • the core part may contain two or more easily absorbable drugs as necessary.
  • the sustained systemic external preparation of the present invention can be used as a combination drug.
  • the core part may further contain at least one other component in addition to the easily absorbable drug.
  • at least one other 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, prevents unintended early collapse of the core-shell structure, and ensures the sustained release effect of the easily absorbable 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 can be appropriately set depending on the type of the stabilizer. For example, the weight ratio of the easily absorbable drug and the stabilizer is 1: 0.1 to 1:10. It can also be blended.
  • the percutaneous absorption enhancer is not particularly limited. Specifically, higher alcohol, N-acyl sarcosine and its salt, higher monocarboxylic acid, higher monocarboxylic acid ester, aromatic monoterpene fatty acid ester, carbon number 2 -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 easily absorbable drug and the percutaneous absorption enhancer is 1: 0.01 to 1:50. It can also mix
  • 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.
  • the content ratio of the skin irritation reducing agent in the core portion can be appropriately set depending on the type of the skin irritation reducing agent, but it can also be blended so as to be, for example, 0.1 wt% to 50 wt%.
  • Preservatives are not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and thymol.
  • the content of the preservative in the core portion can be appropriately set depending on the type of the preservative, but for example, it can be blended so as to be 0.01% by weight to 10% by weight.
  • preservative may contain 1 type (s) or 2 or more types.
  • the shell part surfactant is not particularly limited as long as it can form a shell part of a core-shell structure.
  • HLB abbreviation of Hydrophile Lyophile Balance
  • the HLB 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 surfactant is not particularly limited, and can be widely selected from those that can be used as external preparations.
  • the surfactant may be any of a nonionic surfactant, an anionic surfactant, a cationic surfactant and an amphoteric surfactant.
  • nonionic surfactant examples 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. Specific examples include esters of sucrose with fatty acids such as erucic acid, oleic acid, lauric acid, stearic acid and behenic acid.
  • 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.
  • anionic surfactant examples 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.
  • 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 effect of the present invention is exerted.
  • the weight ratio with the easily absorbable drug can be 1: 3 to 1: 100.
  • the sustained systemic external preparation of the present invention has excellent transdermal absorbability.
  • the weight ratio with the easily absorbable drug is preferably 1: 5 to 1: 100, more preferably 1:10 to 1:50 or 1:15 to 1:50.
  • 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 8-30, and is particularly preferably 10-24.
  • the total weight ratio of the easily absorbable drug and the alkyl chain contained in the surfactant is 1: 1 to 1:70, the sustained systemic external preparation of the present invention is excellent in percutaneous absorbability.
  • the same weight ratio is preferably 1: 2 to 1:70 or 1: 2 to 1:50, more preferably 1: 3 to 1:30, and 1: 5 to 1:20. Is even more preferred.
  • the shell portion may further contain at least one other component in addition to the surfactant.
  • at least one other 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.
  • the content ratio of the skin irritation reducing agent in the shell part can be set as appropriate depending on the type of the agent, but for example, it can be blended so as to be 0.1% by weight to 50% by weight.
  • the analgesic is not particularly limited, and specific examples include local anesthetics such as procaine, tetracaine, lidocaine, dibucaine and prilocaine, and salts thereof.
  • An analgesic may contain 1 type (s) or 2 or more types.
  • the content ratio of the analgesic in the shell part can be appropriately set depending on the type of the analgesic, but it can also be blended so as to be, for example, 0.1 wt% to 30 wt%.
  • the percutaneous absorption enhancer is not particularly limited. Specifically, higher alcohol, N-acyl sarcosine and its salt, higher monocarboxylic acid, higher monocarboxylic acid ester, aromatic monoterpene fatty acid ester, carbon number 2 -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 ratio of the percutaneous absorption enhancer in the shell portion can be appropriately set depending on the type of the percutaneous absorption enhancer, but it can also be blended so as to be, for example, 0.1 wt% to 30 wt%.
  • the stabilizer has a function of stabilizing the core-shell structure, prevents unintended early collapse of the core-shell structure, and ensures the sustained release effect of the easily absorbable 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 hydrogen sulfite, L-ascorbic acid, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, tocopherol acetate, dl- ⁇ -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 added so that the weight ratio of the surfactant to the stabilizer is 1: 0.01 to 1:50. You can also
  • Preservatives are not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and thymol.
  • preservative may contain 1 type (s) or 2 or more types.
  • the content of the preservative in the shell part can be set as appropriate depending on the type of the preservative, but for example, it can be blended so as to be 0.01% by weight to 10% by weight.
  • group agent phase persistent generalized acting external preparation of the present invention which further comprises a phase containing a base (base phase), the base phase containing the core-shell structure There may be. At this time, the core-shell structure is dispersed (partially dissolved) in the base phase.
  • the base is not particularly limited, and can be widely selected from those that can be used as external preparations.
  • the base can be appropriately selected from those suitable for dispersing the core-shell structure according to the purpose of use, and is not particularly limited.
  • the base is not particularly limited.
  • vegetable oils, animal oils, neutral lipids, synthetic fats and oils, sterol derivatives, waxes, hydrocarbons, monoalcohol carboxylates, oxyacid esters, polyhydric alcohol fatty acid esters , Silicones, higher (polyhydric) alcohols, higher fatty acids and fluorinated oils are examples of vegetable oils, animal oils, neutral lipids, synthetic fats and oils, sterol derivatives, waxes, hydrocarbons, monoalcohol carboxylates, oxyacid esters, polyhydric alcohol fatty acid esters , 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. .
  • Animal oil is not particularly limited, and examples thereof include mink oil, turtle oil, fish oil, cow oil, horse oil, pig oil, and salmon squalane.
  • the neutral lipid is not particularly limited, and examples thereof include triolein, trilinolein, trimyristin, tristearin, and triarachidonin.
  • Synthetic fats and oils are not particularly limited, and examples thereof include phospholipids and azones.
  • the sterol derivative is not particularly limited, and examples thereof include dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterol, cholic acid, and cholesteryl linoleate.
  • waxes examples 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.
  • hydrocarbons examples include liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, ⁇ -olefin oligomer, polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olive-derived squalane, squalene, petrolatum and solid paraffin. It is done.
  • Monoalcohol carboxylates include octyldodecyl myristate, hexyl decyl myristate, octyl dodecyl isostearate, cetyl palmitate, octyl dodecyl 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, octyldodecy
  • oxyesters examples 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, pentaerythrate
  • Silicones include dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane, decamethylcyclopentasiloxane), phenyltrimethicone, diphenyldimethicone, phenyldimethicone, stearoxypropyl.
  • Polyether modification such as dimethylamine, (aminoethylaminopropylmethicone / dimethicone) copolymer, dimethiconol, dimethiconol crosspolymer, silicone resin, silicone rubber, amino-modified silicone such as aminopropyldimethicone or amodimethicone, cation-modified silicone, 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, cation modified or polyether modified silicone, amino modified or polyether modified silicone, alkyl modified or poly Examples thereof include ether-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, hexyldecanol, 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.
  • Fluorinated oils include perfluorodecane, perfluorooctane and perfluoropolyether.
  • the sustained systemic external preparation of the present invention may contain other additive components depending on the dosage form, purpose of use, and the like.
  • Additive components are not particularly limited, but include excipients, colorants, lubricants, binders, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solvents, solubilizers, suspending agents, A buffer, a pH adjuster, a gelling agent, an adhesive, an antioxidant, a transdermal absorption accelerator, an irritation relaxation agent, an antiseptic, a chelating agent, a dispersing agent and the like can be mentioned.
  • the sustained systemic external preparation of the present invention has a core-shell structure when it does not contain a base phase, or a base phase that contains a core-shell structure when it contains a base phase (hereinafter referred to as “the core-shell structure”). These may be collectively referred to as “core-shell structure-containing basic components”), and may be further dispersed in other components.
  • the sustained systemic external preparation of the present invention is provided by mixing and dispersing or emulsifying the core-shell structure-containing basic component into a component in which the core-shell structure-containing basic component is not completely dissolved.
  • the core-shell structure-containing basic component can be mixed and dispersed or emulsified in the base used for each dosage form.
  • the long-acting systemic external preparation of the present invention is not particularly limited. If the viscosity of the core-shell structure-containing basic component is 500 mPa ⁇ s or more, the blood concentration after administration will be It is preferable in that it can be kept high. In this respect, the viscosity of the core-shell structure-containing basic component is more preferably 1000 mPa ⁇ s or more, and further preferably 2000 mPa ⁇ s or more. The core-shell structure-containing basic component usually has a viscosity of 1000000 mPa ⁇ s or less from the viewpoint of handleability.
  • the viscosity when the viscosity is 1000 mPa ⁇ s or more, it conforms to the standard JIS Z 8803: 2011 “Method for measuring viscosity of liquid” and is 25 ° C. with a cone-plate (cone plate type) rotational viscometer. It means a value measured at 20 rpm, and when it is less than 1000 mPa ⁇ s, it means a value measured at 25 ° C. and 1000 rpm by a ball rotation viscometer.
  • a base phase having a relatively high viscosity can be used.
  • the “viscosity of the base phase itself” refers to the viscosity of the base phase excluding the core-shell structure (in the case where the base phase comprises only the base, the viscosity exhibited by the base).
  • the viscosity of the base phase itself may be 1000 mPa ⁇ s or more, and 2000 mPa ⁇ s or more.
  • the base phase is typically 1000000 mPa ⁇ s or less from the viewpoint of ease of preparation.
  • the base phase having a specific range of viscosity as described above is not particularly limited, but may be obtained by using other components as appropriate in addition to those exemplified above.
  • an additive (gelator) having a gelling action may be further contained so that the viscosity of the sustained systemic external preparation of the present invention can be within a predetermined range.
  • additives include, but are not limited to, hydrocarbons such as resins and silicones, amino acids, cyclic peptides, epoxies, rosins, melamines and polysaccharides, pectins such as surfactants, alginic acid, carrageenan, locust At least one selected from the group consisting of bean gum, guar gum, xanthan gum, dextrin fatty acid ester, inulin fatty acid ester and glycerin fatty acid ester can be used.
  • the resin is not particularly limited, and examples thereof include at least one selected from the group consisting of polyethylene, polypropylene, polyester, polystyrene, and polyurethane.
  • the base containing such a resin is not particularly limited, and for example, a base containing 0.1 to 50%, preferably 1 to 30% of these additives can be used.
  • bases include, but are not limited to, hydrocarbon bases such as liquid paraffin, cyclohexane, n-octane, toluene and xylene; and isopropyl myristate, isononyl isononanoate, isotridecyl isononanoate and triethylhexa
  • An ester base such as noin is preferably used.
  • a base examples include, for example, hydrocarbons such as Plastibase (registered trademark) (Bristol Myers Squibb) containing 95% liquid paraffin and 5% polyethylene resin as a gelling agent.
  • a gel ointment base or the like can be used.
  • the sustained systemic external preparation of the present invention is not particularly limited, and can be produced, for example, as follows.
  • the core-shell structure of the present invention can be manufactured, 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.
  • a solvent such as pure water or phosphate buffer.
  • 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.
  • the core-shell structure of the present invention can be prepared by lyophilization.
  • a continuous systemic external preparation can be produced by a solution coating method.
  • the solution coating method in addition to the core-shell structure and the base of the present invention, hexane, toluene or acetic acid is added so that additional components such as a percutaneous absorption enhancer, a thickener and a gelling agent are added at a predetermined ratio as desired.
  • the solid content concentration in the solution is preferably 10 to 80% by weight, more preferably 20 to 60% by weight.
  • a percutaneously absorbable preparation can be obtained by completing a drug-containing layer and laminating a support on the layer.
  • a release liner may be laminated on the surface of the layer.
  • the core shell structure is added and mixed with additives such as a base, a percutaneous absorption enhancer, a stabilizer, a thickener, and a gelling agent as necessary, depending on the use.
  • additives such as a base, a percutaneous absorption enhancer, a stabilizer, a thickener, and a gelling agent as necessary, depending on the use.
  • Natural fabric members such as gauze or absorbent cotton, synthetic fiber fabric members such as polyester or polyethylene, or a combination of these appropriately processed into a woven fabric or nonwoven fabric, or laminated or impregnated on a permeable membrane or the like It is also possible to use it by covering it with an adhesive cover material or the like.
  • the percutaneous absorption-type 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 phase etc. in the periphery as needed.
  • long-acting systemic external preparation is not particularly limited, but is usually sustained for 1 day to 1 week, and in a preferred embodiment, it is applied once a day to 1 week. Used as is.
  • the target disease varies depending on the type of easily absorbable drug.
  • the long-acting systemic external preparation of the present invention is not particularly limited, but is a tape (reservoir type or matrix type), ointment, lotion, aerosol, plaster, aqueous buccal, cream, gel, It can be used as an aerosol, patch, microneedle and the like.
  • the weight ratio of drug to alkyl chain shown below is an approximate value in view of the fact that the surfactant used in the shell part is a mixture of a plurality of components and it is difficult to completely identify the components.
  • sucrose laurate Mitsubishi Chemical Foods, L-195, main components are diester and triester
  • Example 4 An external preparation was produced in the same manner as in Example 1 except that 0.8 g of the recovered product was immersed in a medical gauze (manufactured by Suzuran Co., Ltd.) cut to 8 cm 2 .
  • liquid paraffin manufactured by Wako Pure Chemical Industries, Ltd., 128-04375
  • Example 14 After adding 25% by weight of dextrin palmitate (manufactured by Chiba Flour Mills Co., Ltd., Leopard KL2) to isopropyl myristate and dissolving at 120 ° C., the gel obtained by standing overnight at room temperature was replaced with isopropyl myristate instead of isopropyl myristate.
  • Comparative Example 1 0.06 g of memantine hydrochloride and 2.79 g of sucrose laurate were added to 11.4 g of isopropyl myristate and dispersed by stirring with a stirrer. A comparative external preparation was produced by immersing 0.4 g of the recovered material in a medical gauze (manufactured by Suzuran Co., Ltd.) cut to 4 cm 2 .
  • Test Example 1 Hairless Rat Transdermal Absorption Test Various external preparations produced in Examples 1 to 14 and Comparative Examples 1 and 2 were applied to the back of hairless rats (HWY / Slc, about 250 g). For Comparative Example 2, the release paper was peeled off and then stuck on the back. Thereafter, the administration site was protected using an adhesive bandage (Silkex, manufactured by ALCAR). Thereafter, approximately 0.7 mL of blood was collected from the tail vein at 3, 6, 24, and 48 hours, and centrifuged to obtain plasma.
  • an adhesive bandage Siliconkex, manufactured by ALCAR

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Abstract

L'invention a pour objet de fournir un médicament pour usage externe type à action générale durable ayant pour principal ingrédient un médicament facilement absorbable. À cet effet, le médicament pour usage externe type à action générale durable comprend une structure cœur/coquille telle qu'une partie cœur et une partie coquille comprennent respectivement le médicament facilement absorbable et un tensio-actif.
PCT/JP2015/069649 2014-07-10 2015-07-08 Médicament pour usage externe type à action générale durable WO2016006630A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018070535A (ja) * 2016-11-01 2018-05-10 積水化学工業株式会社 有効成分含有粒子、製剤、外用薬、化粧品及び注射剤

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006025583A1 (fr) * 2004-08-31 2006-03-09 Aspion Co., Ltd. Preparation externe de type s/o
JP2009013171A (ja) * 2007-06-07 2009-01-22 Hisamitsu Pharmaceut Co Inc メマンチン含有経皮吸収製剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006025583A1 (fr) * 2004-08-31 2006-03-09 Aspion Co., Ltd. Preparation externe de type s/o
JP2009013171A (ja) * 2007-06-07 2009-01-22 Hisamitsu Pharmaceut Co Inc メマンチン含有経皮吸収製剤

Non-Patent Citations (1)

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Title
CHOI ET AL.: "Elastic vesicles as topical/ transdermal drug delivery systems", INTERNATIONAL JOURNAL OF COSMETIC SCIENCE, vol. 27, no. 4, 2005, pages 211 - 221 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018070535A (ja) * 2016-11-01 2018-05-10 積水化学工業株式会社 有効成分含有粒子、製剤、外用薬、化粧品及び注射剤

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