WO2016006630A1 - Sustained systemically acting external preparation - Google Patents

Abstract

To address the problem of providing a sustained systemically acting external preparation having an easily absorbable drug as the principal agent thereof, the present invention provides, as a means of solving the problem, a sustained systemically acting external preparation containing a core-shell structure in which the core section thereof contains an easily absorbable drug, and the shell section thereof contains a surfactant.

Description

Long-acting systemic external preparation

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.

In the percutaneous absorption process of drugs, it is affected by skin barrier function and metabolism. These effects vary from drug to drug.

When a drug that is relatively easily absorbed through the skin (easily absorbable drug) is formulated and used, a high medicinal effect can be obtained soon after the start of administration, but as a result of early absorption, the main drug in the preparation is depleted and the medicinal effect is There is a problem of not persisting. In addition, there is a problem that the blood concentration exceeds the level at which the drug effect is expressed and reaches the level at which the side effect occurs.

For this reason, there has been a demand for the development of a long-acting systemic external preparation containing an easily absorbable drug as a main drug. However, such conventional systemic external preparations had a point to be improved in terms of effects and the like (Patent Document 1).

US Patent Application Publication No. 2006/0142398

An object of the present invention is to provide a sustained systemic external preparation having an easily absorbable drug as a main drug.

The inventors of the present invention have made extensive studies to solve the above problems, and solved the above problems by using a core-shell structure in which the core part contains an easily absorbable drug and the shell part contains a surfactant. I found out that I can do it. The present invention has been completed through further trial and error based on this finding, and includes the following aspects.
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. The sustained systemic external preparation according to Item 1 or 2, wherein the weight ratio of the easily absorbable drug and the surfactant is 1: 3 to 1: 100.
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.
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.
Item 6.
Item 6. The continuous systemic action external preparation according to any one of Items 1 to 5, wherein the easily absorbable drug is a drug having the following characteristics:
The molecular weight is less than 400 and the octanol water partition coefficient is -6 to 6.
Item 7.
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 1 to 6, which is 500 mPa · s or more.
Item 8.
Item 8. 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.
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.
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.

According to 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. In a particularly preferred embodiment, 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.

1. Constitution of persistent systemic external preparation The continuous systemic external preparation of the present invention contains at least the following core-shell structure.
1.1 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.

In the present invention, 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.

1.1.1 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.

In the above, 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.

In the above, 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.

In the present invention, the octanol water partition coefficient is expressed by the formula: octanol water partition coefficient = Log ₁₀ from the drug concentration of each phase after adding the drug to a flask containing octanol and pH 7 aqueous buffer solution. Calculated by (concentration in octanol phase / concentration in aqueous phase).

As the easily absorbable drug, those requiring systemic action are used.

Specific examples of 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. In addition, as an easily absorbable drug, the above-mentioned pharmacologically acceptable salt, neutralized product or hydrate can be used.

The amount of the easily absorbable drug contained in the core-shell structure depends on the kind of the easily-absorbable drug. For example, 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. In this case, 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. 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, 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 | blend so that it may become.

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. 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.

Moreover, multiple types of surfactants may be used in combination.

As the surfactant, one having an HLB value of 7 or less, preferably 5 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 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.

Examples of the nonionic surfactant 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.

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.

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 effect of the present invention is exerted. For example, the weight ratio with the easily absorbable drug can be 1: 3 to 1: 100. . At this time, the sustained systemic external preparation of the present invention has excellent transdermal absorbability. In this respect, 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.

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 easily absorbable drug and the alkyl chain contained in the surfactant However, if it is 1: 1 to 1:70, the sustained systemic external preparation of the present invention is excellent in percutaneous absorbability. In this respect, 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. 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. 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-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 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. An antiseptic | 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.

1.1.3 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.

Also, multiple types of bases may be used in combination.

The base is not particularly limited. For example, 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.

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.

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, octyldodecyl ricinoleate, octyldodecyl lanolinate, hexyldecyl dimethyloctanoate , Octyldodecyl erucate, isostearic acid hydrogenated castor oil, ethyl oleate , Ethyl avocado oil, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl isostearate, lanolin fatty acid isopropyl, diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, diisopropyl adipate, dibutyloctyl sebacate, diisobutyl adipate , Dioctyl succinate, triethyl citrate and the like.

Examples of the 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, pentaerythrate tetraoctanoate Lithyl, 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-pentene Njioru, and the like.

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.

1.1.4 Other Additive Components 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.

Further, 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. In this case, 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. Although it can select suitably by dosage form and it is not specifically limited, For example, as an ointment, a cream agent, an aerosol agent, a tape agent (reservoir type or a matrix type etc.), a patch agent, a poultice agent, a gel agent, or a microneedle etc. In order to provide it, the core-shell structure-containing basic component can be mixed and dispersed or emulsified in the base used for each dosage form.

2. Characteristics of long- acting systemic external preparation 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.

In the present invention, 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.

Although not particularly limited, in order to impart a relatively high viscosity to the sustained systemic external preparation as described above, a base phase having a relatively high viscosity can be used. In the present invention, 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). In order to impart a relatively high viscosity to the sustained systemic external preparation so that the effects of the present invention can be obtained, the viscosity of the base phase itself may be 1000 mPa · s or more, and 2000 mPa · s or more. Preferably, it is preferably 5000 mPa · s or more. There is no particular upper limit as long as it can be used as an external preparation, but the viscosity of 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. In particular, 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.

Examples of such 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. Examples of such 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. Although not particularly limited, specific examples of such a base 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.

3. Method for Producing Long-acting Systemic External Agent The sustained systemic external preparation of the present invention is not particularly limited, and can be produced, for example, as follows.

First, although not particularly limited, 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. 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.

Using the core-shell structure, for example, a continuous systemic external preparation can be produced by a solution coating method. In 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. Add to a solvent such as ethyl 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.

In addition, as another method, for example, 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. 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.

4). Use of long-acting systemic external preparation The long-acting systemic external preparation of the present invention 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.

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.

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.

Example 1
A solution prepared by dissolving 0.1 g of memantine hydrochloride in 40 g of pure water and dissolving 5 g of sucrose laurate (Mitsubishi Chemical Foods, L-195, main components are diester and triester) in 80 g of cyclohexane. In addition, the homogenizer was stirred (10,000 rpm). This was followed by lyophilization for 2 days to prepare a core-shell structure (drug: alkyl chain weight ratio = 1: 25). 2.85 g of the product was added to 11.4 g of isopropyl myristate and dispersed by stirring with a stirrer. An 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 .

Example 2
An external preparation was used in the same manner as in Example 1 except that sucrose erucic acid ester (manufactured by Mitsubishi Chemical Foods, ER-290, main components were diester and triester) was used instead of sucrose laurate. Prepared (drug: alkyl chain weight ratio = 1: 30).

Example 3
An external preparation was produced in the same manner as in Example 2 except that the amount of sucrose erucic acid ester was changed to 3 g (drug: alkyl chain weight ratio = 1: 20).

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 .

Example 5
An external preparation was prepared in the same manner as in Example 3 except that liquid paraffin (manufactured by Wako Pure Chemical Industries, Ltd., 128-04375) was used instead of isopropyl myristate (drug: alkyl chain weight ratio = 1: 20).

Example 6
Instead of isopropyl myristate, a mixture of liquid paraffin and plastic base (Taisho Pharmaceutical Co., Ltd., Japanese Pharmacopoeia) in a weight ratio of 2: 8 was used, and instead of medical gauze, a polyethylene terephthalate film ( An external preparation was produced in the same manner as in Example 3 except that 3M) was used (drug: alkyl chain weight ratio = 1: 20).

Example 7
An external preparation was produced in the same manner as in Example 3 except that plastibase was used instead of isopropyl myristate and a polyethylene terephthalate film (manufactured by 3M) was used instead of medical gauze (drug: alkyl) Chain weight ratio = 1: 20).

Example 8
An external preparation was produced in the same manner as in Example 7 except that the amount of sucrose erucic acid ester was changed to 1 g (drug: alkyl chain weight ratio = 1: 6).

Example 9
An external preparation was produced in the same manner as in Example 7 except that the amount of sucrose erucic acid ester was changed to 0.5 g (drug: alkyl chain weight ratio = 1: 3).

Example 10
An external preparation was prepared in the same manner as in Example 7 except that sucrose laurate was used instead of sucrose erucate (drug: alkyl chain weight ratio = 1: 15).

Example 11
An external preparation was produced in the same manner as in Example 10 except that the amount of sucrose laurate was changed to 1 g (drug: alkyl chain weight ratio = 1: 5).

Example 12
Example 3 except that white petrolatum (manufactured by Kenei Pharmaceutical Co., Japan Pharmacopoeia) was used instead of isopropyl myristate, and polyethylene terephthalate film (manufactured by 3M) was used instead of medical gauze. Similarly, an external preparation was prepared (drug: alkyl chain weight ratio = 1: 20).

Example 13
An external preparation was produced in the same manner as in Example 3 except that olive oil (manufactured by Wako Pure Chemical Industries, Ltd.) was used instead of isopropyl myristate (drug: alkyl chain weight ratio = 1: 20).

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. An external preparation was produced in the same manner as in Example 3 except that a polyethylene terephthalate film (manufactured by 3M) was used instead of the medical gauze (drug: alkyl chain weight ratio = 1: 20).

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 .

Comparative Example 2
Ethyl acetate was added to 8.3 parts of memantine and 91.7 parts of acrylic adhesive (Duro-Tak 87-2510) so that the non-volatile content was 30%, and mixed until uniform to prepare a plaster solution. The obtained plaster liquid was uniformly developed on a release paper, dried at 80 ° C., a support made of a polyethylene terephthalate film was laminated, and punched out to 3 cm ² to obtain a comparative external preparation.

(Viscosity measurement)
Using a cone rotor viscometer (TV-22 type, manufactured by Toki Sangyo Co., Ltd.), the external preparations obtained in Examples 7 to 12 and Example 14 and Examples 6 to 12 under the conditions of 20 ° C. and 20 rpm The viscosity of the base used in Example 14 was measured. Further, the external preparations obtained in Examples 1 to 6 and 13 and Comparative Example 1 and Examples 1 to 5 under the conditions of 25 ° C. and 1000 rpm using a ball rotation viscometer (manufactured by Kyoto Electronics Co., Ltd., EMS-1000) 13 and the viscosity of the base used in Comparative Example 1 were measured.
Table 1 shows the results.

 

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 internal standard substance was added to this plasma, and solid phase extraction was performed with Oasis MCX (manufactured by Waters), followed by LC-MS / MS (column used: Phenomenex Kinetex PFP 2.6 μm, 3.0 × 50 mm). Plasma concentration was quantified.

The results are shown in Figs. In Comparative Example 1 where only the materials were mixed, it was shown that the transdermal absorbability was remarkably lower than that of the Examples. In Comparative Example 2, a transient rapid increase in blood concentration occurred.

On the other hand, it was found that the external preparations of the examples can maintain the blood concentration continuously without causing a transient rapid increase in blood concentration.

Claims (10)

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.
2. In addition, it contains a base phase,
   The base phase contains the core-shell structure;
   The continuous systemic action-type external preparation of Claim 1.
3. 3. The sustained systemic external preparation according to claim 1 or 2, wherein the weight ratio of the easily absorbable drug and the surfactant is 1: 3 to 1: 100.
4. The sustained systemic external preparation according to any one of claims 1 to 3, wherein the surfactant contains an alkyl chain.
5. 5. The sustained systemic external preparation according to claim 4, wherein a weight ratio of the easily absorbable drug and the alkyl chain is 1: 1 to 1:70.
6. The sustained systemic external preparation according to any one of claims 1 to 5, wherein the easily absorbable drug is a drug having the following characteristics:
   The molecular weight is less than 400 and the octanol water partition coefficient is −6 to 6.
7. 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
   The continuous systemic action external preparation according to any one of claims 1 to 6, which is 500 mPa · s or more.
8. The continuous systemic external preparation according to any one of claims 2 to 7, wherein the viscosity of the base phase itself is 1000 mPa · s or more.
9. The continuous systemic action-type external preparation according to any one of claims 1 to 8, which is continuous for 1 day to 1 week.
10. The long-acting systemic external preparation according to any one of claims 1 to 9, wherein the easily absorbable drug is memantine and / or a salt thereof.
    
    

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