WO2016052617A1 - Nalfurafine-containing preparation for topical application - Google Patents

Nalfurafine-containing preparation for topical application Download PDF

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Publication number
WO2016052617A1
WO2016052617A1 PCT/JP2015/077741 JP2015077741W WO2016052617A1 WO 2016052617 A1 WO2016052617 A1 WO 2016052617A1 JP 2015077741 W JP2015077741 W JP 2015077741W WO 2016052617 A1 WO2016052617 A1 WO 2016052617A1
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Prior art keywords
preparation
nalfurafine
polyoxyethylene
topical preparation
topical
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PCT/JP2015/077741
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French (fr)
Japanese (ja)
Inventor
博 長瀬
健 佐伯
潤 下山
麻希子 多田
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国立大学法人筑波大学
三笠製薬株式会社
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Priority to JP2016552116A priority Critical patent/JPWO2016052617A1/en
Publication of WO2016052617A1 publication Critical patent/WO2016052617A1/en

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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
    • A61K9/08—Solutions
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the present invention relates to a topical preparation containing nalflavine, which has both high drug stability during preparation and high drug migration from the preparation to the living body. More specifically, it contains a free form of nalfurafine, preferably using a specific topical preparation base, and containing the free form of nalfurafine in the base, thereby improving drug stability and preparation in the preparation.
  • the present invention relates to a preparation for topical application containing nalflavine, which has a high drug transfer from a living body to a living body.
  • Pruritus is a sensation peculiar to the epidermis (skin, mucous membrane and cornea) and is a symptom that we feel in daily life, and is the symptom most frequently felt as pain in skin diseases accompanied by inflammation.
  • Diseases associated with itching include visceral diseases such as renal diseases (chronic renal failure), liver diseases, diabetes, and malignant tumors in addition to those caused by skin diseases such as urticaria and atopic dermatitis. If the itch becomes severe, scratching behavior and irritability will increase and you will not be able to stay still. As a result, daily life will be disturbed, sleep disturbance will be caused, etc., and the patient's QOL (Quality of Life) will be remarkably increased. It will decrease.
  • QOL Quality of Life
  • Antihistamines and antiallergic drugs are common treatments for such itching, but these are effective for some itching such as urticaria and are associated with atopic dermatitis and visceral diseases
  • Antihistamines and antiallergic drugs are common treatments for such itching, but these are effective for some itching such as urticaria and are associated with atopic dermatitis and visceral diseases
  • For severe pruritus there were patients who did not respond to various existing treatments at all, ranging from taking antihistamines and antiallergic drugs, from external use of steroids to folk remedies. .
  • nalfraphine is attracting attention as a drug that exhibits an excellent therapeutic effect even for patients with such intractable itch.
  • Nalfurafine is an opioid ⁇ (kappa) receptor agonist that is essential for central itching involving the opioid system, which is clinically refractory, apart from conventional peripheral itching. Shows an antipruritic action. It is known that this essential antipruritic action of nalflavine is also effective against intractable itching where antihistamines and antiallergic drugs are not effective (Patent Documents 1, 2 and 3). Therefore, Remitch capsules 2.5 ⁇ g (Torii Pharmaceutical Co., Ltd.), which is a pruritus-improving agent containing narfrafin hydrochloride, has been developed as an oral administration agent.
  • Orally administered drugs are the most common dosage form for drug treatment and are usually used as the first choice.
  • a topical preparation is used to reduce the risk of systemic side effects. Is recommended as a first-line drug.
  • nalfurafine hydrochloride is recognized to have insomnia, constipation, drowsiness and the like as systemic side effects, there is an increasing need for preparations for topical application.
  • Patent Document 4 a technique for improving drug stability in a preparation by using several kinds of antioxidants has been developed. In order to find the optimum kind and concentration from among these antioxidants, It can take a lot of time.
  • Patent Document 5 by mixing morphine with a monoglyceride of a saturated or unsaturated fatty acid having 6 to 12 carbon atoms and a monoglyceride of saturated fatty acid having 12 to 18 carbon atoms, A technique for improving drug transfer from a preparation to a living body has been developed, but nalfrafin and its salts (such as nalfurafine hydrochloride) have not been studied.
  • nalflaphine-containing topical preparation having high drug stability in the preparation and high drug transfer from the preparation to the living body.
  • the object of the present invention has been made in view of the above-described circumstances, and is to provide a topical preparation containing nalflaphine which has both high drug stability during preparation and high drug migration from the preparation to the living body.
  • the inventors of the present invention contain a free form of nalfurafine, preferably using a specific topical preparation base, and free of nalfurafine in the base. It has been found that a nalfrafin-containing topical preparation with high drug stability in the preparation and drug transfer from the preparation to the living body can be obtained by containing the body, and based on this finding, the present invention has been completed. It was. That is, the present invention is as shown in the following (1) to (5). (1) A topical preparation containing a free form of nalflavine.
  • the cumulative permeation amount of nalfurafine per unit area 20 hours after application of the preparation in the rat skin permeation test is 100 ng / Nalflafine-containing topical preparation according to (4) above, which is at least / cm 2 .
  • the present invention can provide a nalflaphine-containing topical preparation having high drug stability during preparation and high drug migration from the preparation to the living body.
  • drug stability in formulation means the residual ratio of nalflaphine in the formulation when the formulation is stored at 60 ° C. for 2 weeks. That is, the case where the residual ratio of nalfurafine in the preparation after storage at 60 ° C. for 2 weeks is 90 to 100% is regarded as “high drug stability in preparation”, and the content of nalfrafin in the preparation after storage for 2 weeks is below the detection limit. Alternatively, the case where the residual ratio of nalflaphine in the preparation was less than 90% was regarded as “low drug stability in preparation”. “Drug stability in formulation” can be evaluated, for example, according to Test Example 1 (stability test) described later.
  • drug transferability from the preparation to the living body means the cumulative permeation amount of nalfraphine per unit area when the preparation is applied to the skin extracted from the hairless rat. That is, a case where the cumulative permeation amount of nalflaphine per unit area at 20 hours after application of the preparation is 100 ng / cm 2 or more is defined as “high drug transfer from the preparation to the living body”, and a case where it is less than 100 ng / cm 2 Drug transfer from the body to the body is low. " The “drug transferability from the preparation to the living body” can be evaluated, for example, according to Test Example 2 (rat skin permeation test) described later.
  • containing a free form of nalfurafine means that a free form of nalfurafine is present in the preparation. That is, even when a salt of nalfurafine is used as a raw material, if the salt is present in the preparation after the preparation process or after the preparation, Included in the concept of “to do”.
  • “containing a free form of nalfurafine” of the present invention means that nalfurafine is blended in the form of a free form in a preparation, or is blended with an additive having a base as a salt form, and the salt Is converted into a free form and present in the preparation.
  • the additive having such a base examples include diisopropanolamine, monoethanolamine, diethanolamine, triethanolamine, sodium phosphate, sodium hydroxide, potassium hydroxide, calcium hydroxide, and the like. It can be used in combination of more than one species.
  • the salt of nalfurafine used in the present invention is generally a salt of nalfurafine and an acid capable of forming a salt, and is not particularly limited as long as it is a medically or pharmaceutically acceptable salt.
  • the content of the free form of nalfurafine in the nalflavine-containing topical preparation of the present invention is not particularly limited as long as it can be formulated, but is 0.0001 to 10% by weight based on the total weight of the topical preparation. More preferably, it is 0.001 to 5% by weight, and particularly preferably 0.001 to 1% by weight. If the amount is less than 0.0001% by weight relative to the total preparation for topical application, sufficient medicinal effects cannot be obtained, and if it exceeds 10% by weight, the risk of developing side effects increases, which is not preferable.
  • an oily base comprising an emulsion base and a hydrocarbon oil is preferable.
  • examples of the emulsion base include a W / O emulsion base and an O / W emulsion base.
  • an oil, a surfactant, and the like can be used, and further, water and the like can be used as necessary.
  • the oil used in the emulsion base is not particularly limited as long as it is an oil-soluble substance usually used in the fields of pharmaceuticals, cosmetics, etc.
  • dimethylpolysiloxane, dimethylcyclopolysiloxane, methylphenylpolysiloxane dimethylpolysiloxane, dimethylcyclopolysiloxane, methylphenylpolysiloxane.
  • Silicone oils such as siloxane, methyl hydrogen polysiloxane, higher fatty acid-modified organopolysiloxane, higher alcohol-modified organopolysiloxane, trimethylsiloxysilicate, hydrocarbons such as liquid paraffin, squalane, petrolatum, polyethylene, polyisobutylene, and microcrystalline wax , Esters such as isopropyl myristate, myristyl octyldodecanol, di- (2-ethylhexyl) succinate, neopentyl glycol diisooctanoate, monostearate Glyceryl phosphate, isostearic acid triglyceride, palm oil fatty acid triglycerides, glycerides such as castor oil, lower alcohols such as ethanol, octyldodecanol, hexadecyl alcohol, cetyl alcohol, oleyl alcohol, ste
  • Vaseline is particularly preferable from the viewpoints of properties and usability.
  • the amount of oil is not particularly limited as long as it exhibits the effects of the present invention, but is 10.0 to 95.0 with respect to the weight of the emulsion base from the viewpoint of moisture retention and feeling of use. % By weight is preferred.
  • surfactant used in the emulsion base examples include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant. Although it can be used in combination, a nonionic surfactant is particularly preferable.
  • Examples of the cationic surfactant include alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, and behenyltrimethylammonium bromide. Or it can be used in combination of two or more.
  • anionic surfactant examples include lignin sulfonate, alkylbenzene sulfonate, alkyl sulfonate, polyoxyethylene alkyl sulfonate, polyoxyethylene alkyl phenyl ether sulfonate, polyoxyethylene alkyl phenyl ether.
  • amphoteric surfactants include alkyl carboxymethyl hydroxyethyl imidazolinium betaine, alkyl dimethyl ammonium propyl sulfonate, acylaminoethyl hydroxyethyl glycine salt, acylaminoethyl hydroxyethyl propionate, and the like. Two or more types can be used in combination.
  • Nonionic surfactants include, for example, polyvalent polyols such as propylene glycol monofatty acid ester, ethylene glycol monofatty acid ester, glycerin monofatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, and methylglucoside fatty acid ester.
  • polyvalent polyols such as propylene glycol monofatty acid ester, ethylene glycol monofatty acid ester, glycerin monofatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, and methylglucoside fatty acid ester.
  • Alcohol fatty acid ester polyhydric alcohol alkyl ether such as alkyl polyglucoside, polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene cholesterol, polyoxyethylene cholestanol, Polyoxyethylene ether such as polyoxyethylene polyoxypropylene alkyl ether, poly Xylethylene mono fatty acid ester, polyethylene glycol difatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene methyl glucoside fatty acid ester, polyoxyethylene castor oil, polyoxyethylene Hardened castor oil, polyoxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid ester, ether ester such as polyoxyethylene polyoxypropylene glycol, and the like can be used, and can be used alone or in combination of two or more, preferably sorb
  • the blending amount of the surfactant is not particularly limited as long as the blending amount exerts the effects of the present invention, but is preferably 0.1 to 10% by weight with respect to the total weight of the emulsion base, More preferably, it is 1 to 5% by weight.
  • the water used for the emulsion base examples include purified water, sterilized water, natural water, normal water, and injection water. These can be used alone or in combination of two or more, but preferably purified water. It is.
  • the amount of water forming the internal phase or the external phase varies depending on the dosage form. In general, in the case of an O / W type emulsion base, it is preferably 5.0 to 80.0% by weight based on the total weight of the O / W type emulsion base.
  • a W / O type emulsion base it may not contain water, so that it is 0.0 to 70.0% by weight based on the total weight of the W / O type emulsion base.
  • the emulsion base used in the present invention include hydrophilic petrolatum (W / O emulsion base, for example, hydrophilic petrolatum prescribed in the 16th revision Japanese Pharmacopoeia), hydrophilic ointment (O / W type).
  • Emulsion bases for example, hydrophilic ointments prescribed in the 16th revision Japanese Pharmacopoeia).
  • the oily base is preferably composed of a hydrocarbon oil.
  • the oleaginous base composed of a hydrocarbon oil include petrolatum (for example, white petrolatum (for example, white petrolatum prescribed in the 16th revised Japanese Pharmacopoeia)), gelled hydrocarbon (for example, plastic base (for example, Solid paraffin in which polyethylene having an average molecular weight of 21,000 is gelled to 5% in heavy liquid paraffin (registered trademark)), liquid paraffin, ⁇ -olefin oligomer, microcrystalline wax, paraffin, isoparaffin, isohexadecane, squalane , Squalene, polybutene, polyethylene and the like, and can be used alone or in combination of two or more.
  • petrolatum for example, white petrolatum (for example, white petrolatum prescribed in the 16th revised Japanese Pharmacopoeia)
  • gelled hydrocarbon for example, plastic base (for example, Solid paraffin in which polyethylene having an average molecular weight of 21,000 is
  • the nalflaphine-containing topical preparation of the present invention has various components that are acceptable in the production of pharmaceuticals within the range that does not impair the effects of the present invention, that is, a wetting agent, a surfactant, a chelating agent, a fragrance, A refreshing agent, an antioxidant, an antiseptic, a pH adjuster, an absorption accelerator and the like can be appropriately blended.
  • wetting agent examples include propylene glycol, 1,3-butylene glycol, dipropylene glycol, glycerin, xylitol, sorbitol, maltitol, trehalose, erythritol, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, polyethylene glycol, dl -Pyrrolidone carboxylate, fish collagen, phytosteryl-12-hydroxystearate and the like can be mentioned, and these can be used alone or in combination of two or more.
  • the blending amount of the wetting agent is preferably 10% by weight or less with respect to the total weight of the nalflavine-containing topical preparation. When the amount of the wetting agent is more than 10% by weight, the skin irritation may become strong, which is not preferable.
  • surfactant examples include cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants, which can be used alone or in combination of two or more.
  • cationic surfactant examples include alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, and behenyltrimethylammonium bromide. Or it can be used in combination of two or more.
  • anionic surfactant examples include lignin sulfonate, alkylbenzene sulfonate, alkyl sulfonate, polyoxyethylene alkyl sulfonate, polyoxyethylene alkyl phenyl ether sulfonate, polyoxyethylene alkyl phenyl ether.
  • amphoteric surfactants include alkyl carboxymethyl hydroxyethyl imidazolinium betaine, alkyl dimethyl ammonium propyl sulfonate, acylaminoethyl hydroxyethyl glycine salt, acylaminoethyl hydroxyethyl propionate, and the like. Two or more types can be used in combination.
  • Nonionic surfactants include, for example, polyvalent polyols such as propylene glycol monofatty acid ester, ethylene glycol monofatty acid ester, glycerin monofatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, and methylglucoside fatty acid ester.
  • polyvalent polyols such as propylene glycol monofatty acid ester, ethylene glycol monofatty acid ester, glycerin monofatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, and methylglucoside fatty acid ester.
  • Alcohol fatty acid ester polyhydric alcohol alkyl ether such as alkyl polyglucoside, polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene cholesterol, polyoxyethylene cholestanol, Polyoxyethylene ethers such as polyoxyethylene polyoxypropylene alkyl ether, Siethylene mono fatty acid ester, polyethylene glycol difatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene methyl glucoside fatty acid ester, polyoxyethylene castor oil, polyoxyethylene Hardened castor oil, polyoxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid ester, ether ester such as polyoxyethylene polyoxypropylene glycol, and the like can be used, and can be used alone or in combination of two or more, preferably sorbitan F
  • chelating agent examples include edetic acid, oxalic acid, citric acid, pyrophosphoric acid, hexametaphosphoric acid, gluconic acid, and salts thereof, and can be used alone or in combination of two or more.
  • fragrances and refreshing agents include mint oil, mint oil, cinnamon oil, clove oil, fennel oil, castor oil, turpentine oil, eucalyptus oil, orange oil, lavender oil, lemon oil, rose oil, lemongrass oil, Fragrances such as Daiwichi Oil, Chimian Oil, Henopoi Oil, Yamadine Oil, Touka Oil, Bergamot Oil, Citronella Oil, Camphor Oil, Rosemary, Sage, 1-Menthol, Camphor, Thymol, N-ethyl-p-menthane-carboxyl
  • the cooling agent include amide, p-menthane-3,8-diol, 1-isopulegol, and 1-menthyl glyceryl ether, and these can be used alone or in combination of two or more.
  • antioxidants examples include ascorbic acid, sodium thiosulfate, propyl gallate, butylhydroxyanisole, dibutylhydroxytoluene, nordihydroguaiaretic acid, tocopherol, tocopherol acetate and the like alone or in combination of two or more. Can be used.
  • preservatives examples include thymol, isopropylmethylphenol, benzoic acid and its salts, methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, benzyl alcohol, benzalkonium chloride, and benzethonium chloride. Can be used alone or in combination of two or more.
  • pH adjusters include acetic acid, formic acid, lactic acid, tartaric acid, oxalic acid, glycolic acid, malic acid, citric acid, succinic acid, fumaric acid, phosphoric acid, hydrochloric acid, nitric acid, sulfuric acid and their salts, sodium hydroxide , Potassium hydroxide, calcium hydroxide, arginine, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine, tripropylamine, monomethanolamine, monoethanolamine, monopropanolamine, dimethanol Amine, diethanolamine, dipropanolamine, trimethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, tripropanolamine, aqueous ammonia, guanidine carbonate, bicarbonate Potassium, and ammonium carbonate and the like, may be used alone or in combination of two
  • Absorption enhancers include, for example, olive oil, squalane, propylene glycol, lauryl alcohol, triacetin, isostearic acid, propylene glycol monocaprylate, N-methyl-2-pyrrolidone, isopropyl myristate, isopropyl palmitate, diisopropyl adipate, mono Examples include sorbitan oleate, propylene carbonate, oleyl alcohol, crotamiton, and l-menthol, and these can be used alone or in combination of two or more.
  • the symptom to be treated by the topical preparation containing nalflaphine of the present invention is not particularly limited as long as it exhibits an effect on opioid ⁇ (kappa) receptor and a therapeutic effect can be obtained.
  • the topical preparation containing nalflavine of the present invention can be safely used for humans and mammals (eg, mouse, hamster, guinea pig, rat, rabbit, dog, cat, goat, sheep, cow, pig, monkey, etc.). it can.
  • the preparation of the present invention is advantageous in that systemic side effects in oral administration are reduced by applying it locally to the epidermis (skin, mucous membrane and cornea).
  • the application method of the topical preparation containing nalflavine according to the present invention is not particularly limited, and may be applied directly to the patient's epidermis or the like, for example, or may be laminated on a support or the like and applied locally to the patient's epidermis or the like as a patch. You may apply.
  • the dosage of the nalflaphine-containing topical preparation of the present invention varies depending on the target disease, the severity of the disease, etc., and can be appropriately selected.
  • the method for producing the nalflavine-containing topical preparation of the present invention is not particularly limited, and can be produced by referring to a conventionally known method or a newly provided method according to the dosage form.
  • an oleaginous base as a base for a topical preparation, for example, by heating and dissolving the hydrocarbon oil and other optional ingredients, cooling, and mixing with narfrafin and other optional ingredients
  • it can be produced by simultaneously heating and dissolving a hydrocarbon-based oil component, narfrafin and other optional components, and then cooling.
  • nalfrafin is added to an oily component or an aqueous component, and the component, oily or aqueous component, surfactant And other optional components may be mixed and emulsified, or oily components, aqueous components, surfactants and other optional components may be mixed and emulsified before mixing with nalfurafine. .
  • a method of stirring using a homomixer or the like can be mentioned, but if necessary, the obtained emulsion is further refined using a homogenizer or the like. You can also
  • Example 1 Based on the formulation shown in Table 1, it was prepared by the method of Preparation Method 1 described later to obtain a nalflaphine-containing topical preparation 1 of the present invention. As a result of conducting a stability test according to Test Example 1 using the obtained nalflavine-containing topical preparation 1 obtained, the residual ratio of nalfurafine after storage at 60 ° C. for 2 weeks was 96%, and the drug stability in the preparation was high. It was.
  • Test Example 1 Stability test Using the above-mentioned topical preparation containing nalfurafine of Example 1, the topical preparation containing nalfurafine containing Examples 2 to 4 and the topical application preparations of Comparative Examples 1 to 6 described later, the stability test was carried out by the following method. Went. Each topical formulation was placed in a sealed container and stored at 60 ° C. At the start of storage and 2 weeks after the start of storage, the content of nalflavin in each topical preparation was quantified by high performance liquid chromatography.
  • nalfurafin residual rate The nalfuraffin content at 2 weeks after the start of storage relative to the nalfurafin content at the start of storage was calculated as a percentage, and was defined as the nalfurafin residual rate (%). In addition, for the case where the nalfurafin residual ratio exceeded 100% due to measurement error, the nalfurafin residual ratio was set to 100%.
  • Test Example 2 Rat skin permeation test Using the above-described topical preparation containing nalfurafine of Example 1, the topical preparation containing nalflaphine of Examples 2 to 4 and the topical preparation of Comparative Examples 1 to 6, which will be described later, rat skin was tested in the following manner. A permeation test was performed. Abdominal skin of a HWY hairless rat (male, 8 weeks old, body weight about 250 g) was removed and the subcutaneous tissue was removed was used as test skin. The previous test skin was attached to a Franz diffusion cell, and 0.1 g of each topical preparation was uniformly spread and applied to the test skin in a circular shape having a diameter of 2 cm.
  • the receiver side of the Franz diffusion cell was filled with phosphate buffered saline (pH 7.4) (hereinafter referred to as “receiver solution”), and stirring was continued until the end of the test.
  • the jacket temperature of the Franz diffusion cell was kept at about 38 ° C., and the receiver solution was sampled 20 hours after application of each topical formulation.
  • the amount of nalfurafine in the sampled receiver solution was measured by LC / MS / MS (Liquid Chromatography-Tandem Mass Spectrometry) to obtain the amount of nalfurafine that permeated the skin.
  • the amount of nalflaphine permeated through the skin was divided by the application area of the preparation to calculate the cumulative amount of nalflaphine per unit area.
  • Example 2 In Example 1, except for using hydrophilic ointment instead of hydrophilic petrolatum, exactly the same preparation method as Example 1 was repeated to obtain a nalflaphine-containing topical preparation 2. As a result of conducting a stability test according to Test Example 1 using the obtained nalflavine-containing topical preparation 2 obtained, the residual ratio of nalfurafine after storage at 60 ° C. for 2 weeks was 92%, and the drug stability in the preparation was high. It was.
  • Example 3 In Example 1, the same preparation method as Example 1 was repeated except that white petrolatum was used in place of hydrophilic petrolatum to obtain a nalfrafin-containing topical preparation 3. As a result of conducting a stability test according to Test Example 1 using the obtained nalfurafine-containing topical preparation 3 obtained, the residual ratio of nalfurafin after storage at 60 ° C. for 2 weeks was 98%, and the drug stability in the preparation was high. It was.
  • Example 4 In Example 1, the same preparation method as Example 1 was repeated except that Plastibase (registered trademark) was used in place of hydrophilic petrolatum to obtain a nalflaphine-containing topical preparation 4. As a result of conducting a stability test according to Test Example 1 using the obtained nalflavine-containing topical preparation 4 obtained, the residual ratio of nalfrafin after storage at 60 ° C. for 2 weeks was 100%, and the drug stability in the preparation was high. It was.
  • Plastibase registered trademark
  • Example 1 the preparation for topical application 1 was obtained by repeating exactly the same preparation method as in Example 1 except that nalfurafine hydrochloride was used instead of the free form of nalfurafine. In addition, the blending amount of nalfurafine hydrochloride was adjusted so that the content of nalfurafine in the preparation was 0.1% by weight as a free form of nalfurafine. As a result of carrying out a stability test according to Test Example 1 using the obtained topical preparation 1, the residual ratio of nalfrafin after storage at 60 ° C. for 2 weeks was 85%, and the drug stability in the preparation was low.
  • Example 2 a preparation for topical application 2 was obtained by repeating exactly the same preparation method as in Example 2 except that nalfurafine hydrochloride was used instead of the free form of nalfurafine. In addition, the blending amount of nalfurafine hydrochloride was adjusted so that the content of nalfurafine in the preparation was 0.1% by weight as a free form of nalfurafine. As a result of conducting a stability test according to Test Example 1 using the obtained topical preparation 2, the nalfurafin residual ratio after storage at 60 ° C. for 2 weeks was 92%, and the stability of nalfurafine in the preparation was high.
  • Example 3 a preparation for topical application 3 was obtained by repeating exactly the same preparation method as in Example 3 except that nalfurafine hydrochloride was used instead of the free form of nalfurafine. In addition, the blending amount of nalfurafine hydrochloride was adjusted so that the content of nalfurafine in the preparation was 0.1% by weight as a free form of nalfurafine. As a result of conducting a stability test according to Test Example 1 using the obtained topical preparation 3, the residual ratio of nalfurafin after storage at 60 ° C. for 2 weeks was 78%, and the drug stability in the preparation was low.
  • Example 4 topical application formulation 4 was obtained by repeating exactly the same preparation method as in Example 4 except that nalfurafine hydrochloride was used in place of the free form of nalflafine. In addition, the blending amount of nalfurafine hydrochloride was adjusted so that the content of nalfurafine in the preparation was 0.1% by weight as a free form of nalfurafine. As a result of conducting a stability test according to Test Example 1 using the obtained topical preparation 4, the residual ratio of nalfurafin after storage at 60 ° C. for 2 weeks was 88%, and the drug stability in the preparation was low.
  • Example 5 In Example 1, the same preparation method as Example 1 was repeated except that Macrogol ointment was used instead of hydrophilic petrolatum, thereby obtaining a topical preparation 5. As a result of carrying out a stability test using the obtained topical preparation 5 according to Test Example 1, the drug stability in the preparation was low because the content of nalflaphine after storage at 60 ° C. for 2 weeks was below the detection limit. It was. Next, as a result of conducting a rat skin permeation test in accordance with Test Example 2, the cumulative permeation amount of narfrafin per unit area for 20 hours after application of the formulation was 1.8 ng / cm 2 , indicating that the drug transferability from the formulation to the living body was high. It was low. The results are shown in Table 1.
  • Comparative Example 6 a preparation for topical application 6 was obtained by repeating exactly the same preparation method as in Comparative Example 5 except that nalfurafine hydrochloride was used instead of the free form of nalfurafine. In addition, the blending amount of nalfurafine hydrochloride was adjusted so that the content of nalfurafine in the preparation was 0.1% by weight as a free form of nalfurafine. As a result of carrying out a stability test according to Test Example 1 using the obtained topical preparation 6, the drug stability in the preparation was low because the content of nalfrafin after storage at 60 ° C. for 2 weeks was below the detection limit. It was.
  • the present invention relates to a nalflaphine-containing topical preparation having both high drug stability in the preparation and drug transfer from the preparation to the living body, and can be sufficiently used industrially.

Abstract

The present invention addresses the problem of providing a nalfurafine-containing preparation for topical application that has high drug stability in the preparation and excellent drug transfer properties from the preparation to a living body. The nalfurafine-containing preparation for topical application, which contains nalfurafine as a free compound and which contains an oily base comprising an emulsion base or a hydrocarbon-base oil and thus shows a residual ratio of nalfurafine of 90-100% after storing for 2 weeks at 60°C and a cumulative permeation amount of nalfurafine per unit area of 100 ng/cm2 or greater 20 hours after the application of the preparation in a rat skin permeation test, has high drug stability in the preparation and excellent drug transfer properties from the preparation to a living body.

Description

ナルフラフィン含有局所適用製剤Nalfurafine-containing topical preparation
　本発明は、製剤中薬物安定性と製剤から生体への薬物移行性のいずれも高いナルフラフィン含有局所適用製剤に関する。さらに詳しくは、ナルフラフィンのフリー体を含有すること、好ましくは、特定の局所適用製剤用基剤を用いて、当該基剤中にナルフラフィンのフリー体を含有することで、製剤中薬物安定性と製剤から生体への薬物移行性のいずれも高いナルフラフィン含有局所適用製剤に関するものである。 The present invention relates to a topical preparation containing nalflavine, which has both high drug stability during preparation and high drug migration from the preparation to the living body. More specifically, it contains a free form of nalfurafine, preferably using a specific topical preparation base, and containing the free form of nalfurafine in the base, thereby improving drug stability and preparation in the preparation. The present invention relates to a preparation for topical application containing nalflavine, which has a high drug transfer from a living body to a living body.
　そう痒（痒み）は、表皮（皮膚、粘膜および角膜）特有の感覚で、我々が日常でも感じる症状であり、炎症を伴う皮膚疾患においては最も高頻度に苦痛として感じられる症状である。痒みを伴う疾患には、蕁麻疹、アトピー性皮膚炎などの皮膚疾患によるものに加え、腎疾患（慢性腎不全）、肝疾患、糖尿病、悪性腫瘍などの内臓疾患がある。痒みが重度になると、引っ掻き行動やイライラ感が増大してじっとしては居られず、ひいては日常生活に支障が出たり、睡眠障害を引き起こしたりするなど、患者のＱＯＬ（Ｑｕａｌｉｔｙ　ｏｆ　Ｌｉｆｅ）を著しく低下させてしまう。そのような痒みに対する治療薬としては、抗ヒスタミン薬や抗アレルギー薬が一般的であるが、これらが奏効するのは蕁麻疹などの一部の痒みであり、アトピー性皮膚炎や内臓疾患に伴う重度の痒みには、抗ヒスタミン薬や抗アレルギー薬の服用、ステロイド薬の外用から民間療法に至るまで種々の既存治療法が全く奏効しない患者が存在することが医療上の大きな問題となっていた。現在、そのような難治性の痒みを有する患者に対しても優れた治療効果を示す薬物として、ナルフラフィンが注目されている。 Pruritus (itching) is a sensation peculiar to the epidermis (skin, mucous membrane and cornea) and is a symptom that we feel in daily life, and is the symptom most frequently felt as pain in skin diseases accompanied by inflammation. Diseases associated with itching include visceral diseases such as renal diseases (chronic renal failure), liver diseases, diabetes, and malignant tumors in addition to those caused by skin diseases such as urticaria and atopic dermatitis. If the itch becomes severe, scratching behavior and irritability will increase and you will not be able to stay still. As a result, daily life will be disturbed, sleep disturbance will be caused, etc., and the patient's QOL (Quality of Life) will be remarkably increased. It will decrease. Antihistamines and antiallergic drugs are common treatments for such itching, but these are effective for some itching such as urticaria and are associated with atopic dermatitis and visceral diseases For severe pruritus, there were patients who did not respond to various existing treatments at all, ranging from taking antihistamines and antiallergic drugs, from external use of steroids to folk remedies. . At present, nalfraphine is attracting attention as a drug that exhibits an excellent therapeutic effect even for patients with such intractable itch.
　ナルフラフィンは、オピオイドκ（カッパー）受容体作動薬として、従来の末梢性の痒みとは別の、臨床的には難治性といわれてきたオピオイドシステムが関与する中枢性の痒みに対して、本質的に止痒作用を示す。このナルフラフィンの本質的な止痒作用は、抗ヒスタミン薬および抗アレルギー薬が有効ではない難治性の痒みに対しても有効であることが知られている（特許文献１、２および３）。そのため、ナルフラフィン塩酸塩を含有したそう痒症改善剤であるレミッチカプセル２．５μｇ（鳥居薬品（株））が、経口投与剤として開発されている。 Nalfurafine is an opioid κ (kappa) receptor agonist that is essential for central itching involving the opioid system, which is clinically refractory, apart from conventional peripheral itching. Shows an antipruritic action. It is known that this essential antipruritic action of nalflavine is also effective against intractable itching where antihistamines and antiallergic drugs are not effective (Patent Documents 1, 2 and 3). Therefore, Remitch capsules 2.5 μg (Torii Pharmaceutical Co., Ltd.), which is a pruritus-improving agent containing narfrafin hydrochloride, has been developed as an oral administration agent.
　経口投与剤は薬物治療において最も一般的な剤形で、第一選択として用いられるのが通常であるが、そう痒治療の分野においては、全身性の副作用リスクを軽減するために、局所適用製剤を第一選択薬として用いることが推奨されている。実際に、ナルフラフィン塩酸塩は、全身性の副作用として不眠、便秘および眠気などが認められているため、局所適用製剤化のニーズが高まっている。 Orally administered drugs are the most common dosage form for drug treatment and are usually used as the first choice. However, in the field of pruritus treatment, a topical preparation is used to reduce the risk of systemic side effects. Is recommended as a first-line drug. In fact, since nalfurafine hydrochloride is recognized to have insomnia, constipation, drowsiness and the like as systemic side effects, there is an increasing need for preparations for topical application.
　しかしながら、ナルフラフィンやその塩（ナルフラフィン塩酸塩等）を局所適用製剤に含有した場合、製剤中薬物安定性および製剤から生体への薬物移行性が低いことが課題となっていた。特許文献４では、数種類の抗酸化剤を用いることで製剤中の薬物安定性を改善させる技術が開発されているが、これらの抗酸化剤の中から最適な種類や濃度を見出すためには、多くの時間を要する場合がある。また、特許文献５では、モルフィン類に、炭素数６～１２の飽和または不飽和脂肪酸のモノグリセリドと、炭素数１２～１８の飽和脂肪酸のモノ、ジおよびトリグリセリドからなる混合物とを混合することによって、製剤から生体への薬物移行性を向上させる技術が開発されているが、ナルフラフィンやその塩（ナルフラフィン塩酸塩等）に関しては検討されていない。 However, when nalflavine or a salt thereof (such as nalfrafin hydrochloride) is contained in a topical preparation, the problem is that the drug stability in the preparation and the drug transfer from the preparation to the living body are low. In Patent Document 4, a technique for improving drug stability in a preparation by using several kinds of antioxidants has been developed. In order to find the optimum kind and concentration from among these antioxidants, It can take a lot of time. Further, in Patent Document 5, by mixing morphine with a monoglyceride of a saturated or unsaturated fatty acid having 6 to 12 carbon atoms and a monoglyceride of saturated fatty acid having 12 to 18 carbon atoms, A technique for improving drug transfer from a preparation to a living body has been developed, but nalfrafin and its salts (such as nalfurafine hydrochloride) have not been studied.
　そこで、製剤中薬物安定性と製剤から生体への薬物移行性のいずれも高いナルフラフィン含有局所適用製剤の開発が望まれていた。 Therefore, it has been desired to develop a nalflaphine-containing topical preparation having high drug stability in the preparation and high drug transfer from the preparation to the living body.
特許第３５３１１７０号公報Japanese Patent No. 3531170 特許第３６１７０５５号公報Japanese Patent No. 3617055 特許第３７４３４４９号公報Japanese Patent No. 3743449 特許第４３１１３６９号公報Japanese Patent No. 431369 特許第３５１４４８０号公報Japanese Patent No. 3514480
　本発明の目的は、上述の状況を鑑みてなされたもので、製剤中薬物安定性と製剤から生体への薬物移行性のいずれも高いナルフラフィン含有局所適用製剤を提供することである。 The object of the present invention has been made in view of the above-described circumstances, and is to provide a topical preparation containing nalflaphine which has both high drug stability during preparation and high drug migration from the preparation to the living body.
　本発明者らは、上述の課題を解決すべく鋭意検討した結果、ナルフラフィンのフリー体を含有すること、好ましくは、特定の局所適用製剤用基剤を用いて、当該基剤中にナルフラフィンのフリー体を含有することで、製剤中薬物安定性と製剤から生体への薬物移行性のいずれも高いナルフラフィン含有局所適用製剤を得ることができることを見出し、この知見に基づき、本発明を完成するに至った。
　すなわち、本発明は、以下の（１）～（５）に示すものである。
（１）ナルフラフィンのフリー体を含有する局所適用製剤。
（２）ナルフラフィンのフリー体の含有量が、局所適用製剤の全重量に対して０．００１～１重量％であることを特徴とする上記（１）に記載のナルフラフィン含有局所適用製剤。
（３）局所適用製剤の基剤が乳剤性基剤または炭化水素油分からなる油脂性基剤であることを特徴とする上記（２）に記載のナルフラフィン含有局所適用製剤。
（４）炭化水素油分からなる油脂性基剤がワセリンおよびゲル化炭化水素からなる群より選ばれた少なくとも１種を含むことを特徴とする上記（３）に記載のナルフラフィン含有局所適用製剤。
（５）安定性試験における６０℃で２週間保存後のナルフラフィン残存率が９０～１００％であり、および、ラット皮膚透過試験における製剤適用後２０時間の単位面積当たりのナルフラフィンの累積透過量が１００ｎｇ／ｃｍ２以上であることを特徴とする上記（４）に記載のナルフラフィン含有局所適用製剤。 As a result of intensive investigations to solve the above-mentioned problems, the inventors of the present invention contain a free form of nalfurafine, preferably using a specific topical preparation base, and free of nalfurafine in the base. It has been found that a nalfrafin-containing topical preparation with high drug stability in the preparation and drug transfer from the preparation to the living body can be obtained by containing the body, and based on this finding, the present invention has been completed. It was.
That is, the present invention is as shown in the following (1) to (5).
(1) A topical preparation containing a free form of nalflavine.
(2) The nalfurafine-containing topical preparation described in (1) above, wherein the content of the free form of nalflavine is 0.001 to 1% by weight based on the total weight of the topical preparation.
(3) The topical preparation containing nalflavine as described in (2) above, wherein the base of the topical preparation is an oily base comprising an emulsion base or a hydrocarbon oil.
(4) The nalfrafine-containing topical preparation described in (3) above, wherein the oily base comprising a hydrocarbon oil contains at least one selected from the group consisting of petrolatum and gelled hydrocarbon.
(5) The residual ratio of nalflaphine after storage at 60 ° C. for 2 weeks in the stability test is 90 to 100%, and the cumulative permeation amount of nalfurafine per unit area 20 hours after application of the preparation in the rat skin permeation test is 100 ng / Nalflafine-containing topical preparation according to (4) above, which is at least / cm 2 .
　以上述べたように、本発明は、製剤中薬物安定性と製剤から生体への薬物移行性のいずれも高いナルフラフィン含有局所適用製剤を提供することができる。 As described above, the present invention can provide a nalflaphine-containing topical preparation having high drug stability during preparation and high drug migration from the preparation to the living body.
　以下、本発明のナルフラフィン含有局所適用製剤を詳細に説明する。なお、本明細書に記載の例示は、本発明を特に限定するものではない。
　本明細書において、「製剤中薬物安定性」とは、製剤を６０℃の条件下で２週間保存した際の、製剤中のナルフラフィン残存率を意味する。すなわち、６０℃で２週間保存後における製剤中のナルフラフィン残存率が９０～１００％の場合を「製剤中薬物安定性が高い」とし、２週間保存後における製剤中のナルフラフィン含有量が検出限界以下または製剤中のナルフラフィン残存率が９０％未満の場合を「製剤中薬物安定性が低い」とした。
　「製剤中薬物安定性」は、例えば、後述の試験例１（安定性試験）に従って評価することができる。 Hereinafter, the nalflaphine-containing topical preparation of the present invention will be described in detail. Note that the examples described in the present specification do not particularly limit the present invention.
In the present specification, “drug stability in formulation” means the residual ratio of nalflaphine in the formulation when the formulation is stored at 60 ° C. for 2 weeks. That is, the case where the residual ratio of nalfurafine in the preparation after storage at 60 ° C. for 2 weeks is 90 to 100% is regarded as “high drug stability in preparation”, and the content of nalfrafin in the preparation after storage for 2 weeks is below the detection limit. Alternatively, the case where the residual ratio of nalflaphine in the preparation was less than 90% was regarded as “low drug stability in preparation”.
“Drug stability in formulation” can be evaluated, for example, according to Test Example 1 (stability test) described later.
　本明細書において、「製剤から生体への薬物移行性」とは、ヘアレスラットから摘出した皮膚に製剤を適用した際の、単位面積当たりのナルフラフィンの累積透過量を意味する。すなわち、製剤適用後２０時間における単位面積当たりのナルフラフィンの累積透過量が１００ｎｇ／ｃｍ２以上の場合を「製剤から生体への薬物移行性が高い」とし、１００ｎｇ／ｃｍ２未満の場合を「製剤から生体への薬物移行性が低い」とした。
　「製剤から生体への薬物移行性」は、例えば、後述の試験例２（ラット皮膚透過試験）に従って評価することができる。 In the present specification, “drug transferability from the preparation to the living body” means the cumulative permeation amount of nalfraphine per unit area when the preparation is applied to the skin extracted from the hairless rat. That is, a case where the cumulative permeation amount of nalflaphine per unit area at 20 hours after application of the preparation is 100 ng / cm 2 or more is defined as “high drug transfer from the preparation to the living body”, and a case where it is less than 100 ng / cm 2 Drug transfer from the body to the body is low. "
The “drug transferability from the preparation to the living body” can be evaluated, for example, according to Test Example 2 (rat skin permeation test) described later.
　本発明において、「ナルフラフィンのフリー体を含有する」とは、製剤中にナルフラフィンのフリー体が存在することを意味する。すなわち、原料としてナルフラフィンの塩を用いた場合であっても、製剤の製造過程又は製造後に該塩がフリー体に変換されて製剤中に存在する場合は、本発明の「ナルフラフィンのフリー体を含有する」の概念に含まれる。
　具体的には、本発明の「ナルフラフィンのフリー体を含有する」とは、製剤中にナルフラフィンをフリー体の形態で配合するか、または塩の形態として塩基を有する添加剤とともに配合し、該塩がフリー体に変換されて製剤中に存在することである。このような塩基を有する添加剤としては、たとえば、ジイソプロパノールアミン、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン、リン酸ナトリウム、水酸化ナトリウム、水酸化カリウム、水酸化カルシウムなどが挙げられ、単独または２種以上組み合わせて使用することができる。
　本発明において用いられるナルフラフィンの塩は、一般にナルフラフィンと塩を形成可能な酸との塩であり、医学的または薬学的に許容される塩であれば特に限定はないが、たとえば、ナルフラフィン塩酸塩、ナルフラフィン硫酸塩、ナルフラフィンリン酸塩、ナルフラフィン硝酸塩、ナルフラフィンホウ酸塩、ナルフラフィンスルホン酸塩、ナルフラフィン炭酸塩に代表される無機酸塩、ナルフラフィン乳酸塩、ナルフラフィンギ酸塩、ナルフラフィン酢酸塩、ナルフラフィン酒石酸塩、ナルフラフィンリンゴ酸塩、ナルフラフィンクエン酸塩に代表される有機酸塩などが挙げられ、より好ましくは、ナルフラフィン塩酸塩である。 In the present invention, “containing a free form of nalfurafine” means that a free form of nalfurafine is present in the preparation. That is, even when a salt of nalfurafine is used as a raw material, if the salt is present in the preparation after the preparation process or after the preparation, Included in the concept of “to do”.
Specifically, “containing a free form of nalfurafine” of the present invention means that nalfurafine is blended in the form of a free form in a preparation, or is blended with an additive having a base as a salt form, and the salt Is converted into a free form and present in the preparation. Examples of the additive having such a base include diisopropanolamine, monoethanolamine, diethanolamine, triethanolamine, sodium phosphate, sodium hydroxide, potassium hydroxide, calcium hydroxide, and the like. It can be used in combination of more than one species.
The salt of nalfurafine used in the present invention is generally a salt of nalfurafine and an acid capable of forming a salt, and is not particularly limited as long as it is a medically or pharmaceutically acceptable salt. Nalfurafine sulfate, Nalfurafine phosphate, Nalfurafine nitrate, Nalfurafine borate, Nalfurafine sulfonate, Inorganic acid salt typified by nalfurafine carbonate, Nalfurafine lactate, Nalfurafine formate, Nalfurafine acetate, Nalfurafine Examples thereof include organic acid salts such as tartrate, nalflavine malate, and nalflafine citrate, and nalfrafine hydrochloride is more preferable.
　本発明のナルフラフィン含有局所適用製剤中のナルフラフィンのフリー体の含有量は、製剤化が可能である限り特に限定はないが、局所適用製剤の全重量に対して０．０００１～１０重量％であることが好ましく、より好ましくは０．００１～５重量％であり、特に好ましくは０．００１～１重量％である。局所適用製剤全体に対して０．０００１重量％未満であると十分な薬効が得られず、また、１０重量％を超えると副作用を発現するリスクが高くなるため、好ましくない。 The content of the free form of nalfurafine in the nalflavine-containing topical preparation of the present invention is not particularly limited as long as it can be formulated, but is 0.0001 to 10% by weight based on the total weight of the topical preparation. More preferably, it is 0.001 to 5% by weight, and particularly preferably 0.001 to 1% by weight. If the amount is less than 0.0001% by weight relative to the total preparation for topical application, sufficient medicinal effects cannot be obtained, and if it exceeds 10% by weight, the risk of developing side effects increases, which is not preferable.
　本発明のナルフラフィン含有局所適用製剤における基剤としては、乳剤性基剤、炭化水素油分からなる油脂性基剤が好ましい。
　本発明において、乳剤性基剤としては、たとえば、Ｗ／Ｏ型乳剤性基剤、Ｏ／Ｗ型乳剤性基剤などが挙げられる。
　乳剤性基剤の成分としては、油分、界面活性剤などが使用でき、さらには、必要に応じて水などが使用できる。 As the base in the nalflavine-containing topical preparation of the present invention, an oily base comprising an emulsion base and a hydrocarbon oil is preferable.
In the present invention, examples of the emulsion base include a W / O emulsion base and an O / W emulsion base.
As components of the emulsion base, an oil, a surfactant, and the like can be used, and further, water and the like can be used as necessary.
　乳剤性基剤に使用する油分としては、医薬品、化粧品などの分野において通常用いられる油溶性の物質であれば特に限定することはないが、たとえば、ジメチルポリシロキサン、ジメチルシクロポリシロキサン、メチルフェニルポリシロキサン、メチルハイドロジェンポリシロキサン、高級脂肪酸変性オルガノポリシロキサン、高級アルコール変性オルガノポリシロキサン、トリメチルシロキシシリケートなどのシリコーン系オイル、流動パラフィン、スクワラン、ワセリン、ポリエチレン、ポリイソブチレン、マイクロクリスタリンワックスなどの炭化水素、イソプロピルミリステート、ミリスチルオクチルドデカノール、ジ－（２－エチルヘキシル）サクシネートなどのエステル、ジイソオクタン酸ネオペンチルグリコール、モノステアリン酸グリセリン、イソステアリン酸トリグリセライド、ヤシ油脂肪酸トリグリセライド、ヒマシ油などのグリセライド、エタノールなどの低級アルコール、オクチルドデカノール、ヘキサデシルアルコール、セチルアルコール、オレイルアルコール、ステアリルアルコール、コレステロールなどの高級アルコール、プロピレングリコールなどの多価アルコール、ラウリン酸、パルミチン酸、オレイン酸、ステアリン酸、イソステアリン酸、ラノリン、ミツロウ、オリーブ油などの高級脂肪酸などが挙げられ、単独または２種以上組み合わせて使用することができるが、保湿性、使用感の観点から特にワセリンが好ましい。また油分の配合量としては、本発明の効果を発揮する配合量であれば特に制限されないが、保湿性、使用感の観点から乳剤性基剤の重量に対して、１０．０～９５．０重量％が好ましい。 The oil used in the emulsion base is not particularly limited as long as it is an oil-soluble substance usually used in the fields of pharmaceuticals, cosmetics, etc. For example, dimethylpolysiloxane, dimethylcyclopolysiloxane, methylphenylpolysiloxane. Silicone oils such as siloxane, methyl hydrogen polysiloxane, higher fatty acid-modified organopolysiloxane, higher alcohol-modified organopolysiloxane, trimethylsiloxysilicate, hydrocarbons such as liquid paraffin, squalane, petrolatum, polyethylene, polyisobutylene, and microcrystalline wax , Esters such as isopropyl myristate, myristyl octyldodecanol, di- (2-ethylhexyl) succinate, neopentyl glycol diisooctanoate, monostearate Glyceryl phosphate, isostearic acid triglyceride, palm oil fatty acid triglycerides, glycerides such as castor oil, lower alcohols such as ethanol, octyldodecanol, hexadecyl alcohol, cetyl alcohol, oleyl alcohol, stearyl alcohol, cholesterol and higher alcohols, propylene glycol Higher fatty acids such as polyhydric alcohols such as lauric acid, palmitic acid, oleic acid, stearic acid, isostearic acid, lanolin, beeswax, olive oil, etc., which can be used alone or in combination of two or more. Vaseline is particularly preferable from the viewpoints of properties and usability. The amount of oil is not particularly limited as long as it exhibits the effects of the present invention, but is 10.0 to 95.0 with respect to the weight of the emulsion base from the viewpoint of moisture retention and feeling of use. % By weight is preferred.
　乳剤性基剤に使用する界面活性剤としては、たとえば、陽イオン性界面活性剤、陰イオン性界面活性剤、両性界面活性剤、非イオン性界面活性剤などが挙げられ、単独または２種以上組合わせて使用することができるが、特に非イオン性界面活性剤が好ましい。 Examples of the surfactant used in the emulsion base include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant. Although it can be used in combination, a nonionic surfactant is particularly preferable.
　陽イオン性界面活性剤としては、たとえば、塩化アルキルトリメチルアンモニウム、塩化ステアリルトリメチルアンモニウム、臭化ステアリルトリメチルアンモニウム、塩化ジステアリルジメチルアンモニウム、塩化ステアリルジメチルベンジルアンモニウム、臭化ベヘニルトリメチルアンモニウムなどが挙げられ、単独または２種以上組み合わせて使用することができる。 Examples of the cationic surfactant include alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, and behenyltrimethylammonium bromide. Or it can be used in combination of two or more.
　陰イオン性界面活性剤としては、たとえば、リグニンスルホン酸塩、アルキルベンゼンスルホン酸塩、アルキルスルホン酸塩、ポリオキシエチレンアルキルスルホン酸塩、ポリオキシエチレンアルキルフェニルエーテルスルホン酸塩、ポリオキシエチレンアルキルフェニルエーテルリン酸エステル塩、ポリオキシエチレンアリールフェニルエーテルスルホン酸塩、アルキル硫酸エステル塩、ポリオキシエチレンアルキル硫酸エステル塩、ポリオキシエチレンアリールフェニルエーテルリン酸エステル塩、ナフタレンスルホン酸塩、ナフタレンスルホン酸ホルマリン縮合物、ポリオキシエチレントリベンジルフェニルエーテルスルホン酸塩、アルキルリン酸塩、ポリオキシエチレンアルキルリン酸塩、ポリオキシエチレントリベンジルフェニルエーテルリン酸エステル塩、ジアルキルスルホコハク酸塩、脂肪酸塩（石けん）、ポリオキシエチレンアルキルエーテル酢酸塩などが挙げられ、単独または２種以上組み合わせて使用することができる。 Examples of the anionic surfactant include lignin sulfonate, alkylbenzene sulfonate, alkyl sulfonate, polyoxyethylene alkyl sulfonate, polyoxyethylene alkyl phenyl ether sulfonate, polyoxyethylene alkyl phenyl ether. Phosphate salt, polyoxyethylene arylphenyl ether sulfonate, alkyl sulfate ester salt, polyoxyethylene alkyl phenyl sulfate ester salt, polyoxyethylene aryl phenyl ether phosphate ester salt, naphthalene sulfonate, naphthalene sulfonate formalin condensate , Polyoxyethylene tribenzyl phenyl ether sulfonate, alkyl phosphate, polyoxyethylene alkyl phosphate, polyoxyethylene tribenzyl pheny Ether phosphoric acid ester salts, dialkyl sulfosuccinates, fatty acid salts (soaps), such as polyoxyethylene alkyl ether acetate and the like, may be used alone or in combination of two or more.
　両性界面活性剤としては、たとえば、アルキルカルボキシメチルヒドロキシエチルイミダゾリニウムベタイン、アルキルジメチルアンモニウムプロピルスルホン酸塩、アシルアミノエチルヒドロキシエチルグリシン塩、アシルアミノエチルヒドロキシエチルプロピオン酸塩などが挙げられ、単独または２種以上組み合わせて使用することができる。 Examples of amphoteric surfactants include alkyl carboxymethyl hydroxyethyl imidazolinium betaine, alkyl dimethyl ammonium propyl sulfonate, acylaminoethyl hydroxyethyl glycine salt, acylaminoethyl hydroxyethyl propionate, and the like. Two or more types can be used in combination.
　非イオン性界面活性剤としては、たとえば、プロピレングリコールモノ脂肪酸エステル、エチレングリコールモノ脂肪酸エステル、グリセリンモノ脂肪酸エステル、ポリグリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ショ糖脂肪酸エステル、メチルグルコシド脂肪酸エステルなどの多価アルコール脂肪酸エステル、アルキルポリグルコシドなどの多価アルコールアルキルエーテル、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンアルキルフェニルエーテル、ポリオキシエチレンフィトステロール、ポリオキシエチレンフィトスタノール、ポリオキシエチレンコレステロール、ポリオキシエチレンコレスタノール、ポリオキシエチレンポリオキシプロピレンアルキルエーテルなどのポリオキシエチレンエーテル、ポリオキシエチレンモノ脂肪酸エステル、ポリエチレングリコールジ脂肪酸エステル、ポリオキシエチレングリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンソルビトール脂肪酸エステル、ポリオキシエチレンメチルグルコシド脂肪酸エステル、ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレン植物油、ポリオキシエチレンアルキルエーテル脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコールなどのエーテルエステルなどが挙げられ、単独または２種以上組み合わせて使用することができるが、好ましくはソルビタン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステルである。 Nonionic surfactants include, for example, polyvalent polyols such as propylene glycol monofatty acid ester, ethylene glycol monofatty acid ester, glycerin monofatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, and methylglucoside fatty acid ester. Alcohol fatty acid ester, polyhydric alcohol alkyl ether such as alkyl polyglucoside, polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene cholesterol, polyoxyethylene cholestanol, Polyoxyethylene ether such as polyoxyethylene polyoxypropylene alkyl ether, poly Xylethylene mono fatty acid ester, polyethylene glycol difatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene methyl glucoside fatty acid ester, polyoxyethylene castor oil, polyoxyethylene Hardened castor oil, polyoxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid ester, ether ester such as polyoxyethylene polyoxypropylene glycol, and the like can be used, and can be used alone or in combination of two or more, preferably sorbitan Fatty acid esters, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan fatty acid esters.
　また界面活性剤の配合量としては、本発明の効果を発揮する配合量であれば特に制限されないが、乳剤性基剤の全重量に対して０．１～１０重量％であることが好ましく、より好ましくは１～５重量％である。 Further, the blending amount of the surfactant is not particularly limited as long as the blending amount exerts the effects of the present invention, but is preferably 0.1 to 10% by weight with respect to the total weight of the emulsion base, More preferably, it is 1 to 5% by weight.
　乳剤性基剤に使用する水としては、たとえば、精製水、滅菌水、天然水、常水、注射水などが挙げられ、単独または２種以上組み合わせて使用することができるが、好ましくは精製水である。本発明に係る乳剤性基剤において、内相または外相を形成する水の配合量は、剤形により異なる。一般にＯ／Ｗ型乳剤性基剤の場合は、Ｏ／Ｗ型乳剤性基剤の全重量に対して、５．０～８０．０重量％であることが好ましい。また、Ｗ／Ｏ型乳剤性基剤の場合は、水を含まなくともよいため、Ｗ／Ｏ型乳剤性基剤の全重量に対して、０．０～７０．０重量％であることが好ましい。
　また、本発明において用いられる乳剤性基剤としては、親水ワセリン（Ｗ／Ｏ型乳剤性基剤、例えば、第十六改正日本薬局方に規定される親水ワセリン）、親水軟膏（Ｏ／Ｗ型乳剤性基剤、例えば、第十六改正日本薬局方に規定される親水軟膏）が挙げられる。 Examples of the water used for the emulsion base include purified water, sterilized water, natural water, normal water, and injection water. These can be used alone or in combination of two or more, but preferably purified water. It is. In the emulsion base according to the present invention, the amount of water forming the internal phase or the external phase varies depending on the dosage form. In general, in the case of an O / W type emulsion base, it is preferably 5.0 to 80.0% by weight based on the total weight of the O / W type emulsion base. In the case of a W / O type emulsion base, it may not contain water, so that it is 0.0 to 70.0% by weight based on the total weight of the W / O type emulsion base. preferable.
Examples of the emulsion base used in the present invention include hydrophilic petrolatum (W / O emulsion base, for example, hydrophilic petrolatum prescribed in the 16th revision Japanese Pharmacopoeia), hydrophilic ointment (O / W type). Emulsion bases, for example, hydrophilic ointments prescribed in the 16th revision Japanese Pharmacopoeia).
　本発明において、油脂性基剤は、炭化水素油分からなるものが好ましい。炭化水素油分からなる油脂性基剤としては、たとえば、ワセリン（たとえば、白色ワセリン（たとえば、第十六改正日本薬局方に規定される白色ワセリン））、ゲル化炭化水素（たとえば、プラスチベース（たとえば、重質流動パラフィンに平均分子量２１，０００のポリエチレンを５％の割合にゲル化させた固形パラフィン；登録商標））、流動パラフィン、α－オレフィンオリゴマー、マイクロクリスタリンワックス、パラフィン、イソパラフィン、イソヘキサデカン、スクワラン、スクワレン、ポリブテン、ポリエチレンなどが挙げられ、単独または２種以上組み合わせて使用することができる。 In the present invention, the oily base is preferably composed of a hydrocarbon oil. Examples of the oleaginous base composed of a hydrocarbon oil include petrolatum (for example, white petrolatum (for example, white petrolatum prescribed in the 16th revised Japanese Pharmacopoeia)), gelled hydrocarbon (for example, plastic base (for example, Solid paraffin in which polyethylene having an average molecular weight of 21,000 is gelled to 5% in heavy liquid paraffin (registered trademark)), liquid paraffin, α-olefin oligomer, microcrystalline wax, paraffin, isoparaffin, isohexadecane, squalane , Squalene, polybutene, polyethylene and the like, and can be used alone or in combination of two or more.
　本発明のナルフラフィン含有局所適用製剤には、上記の他に、本発明の効果を損なわない範囲で医薬品を製造するにあたって許容される各種成分、すなわち、湿潤剤、界面活性剤、キレート剤、香料・清涼化剤、酸化防止剤、防腐剤、ｐＨ調整剤、吸収促進剤などを適宜配合することができる。 In addition to the above, the nalflaphine-containing topical preparation of the present invention has various components that are acceptable in the production of pharmaceuticals within the range that does not impair the effects of the present invention, that is, a wetting agent, a surfactant, a chelating agent, a fragrance, A refreshing agent, an antioxidant, an antiseptic, a pH adjuster, an absorption accelerator and the like can be appropriately blended.
　湿潤剤としては、たとえば、プロピレングリコール、１，３－ブチレングリコール、ジプロピレングリコール、グリセリン、キシリトール、ソルビトール、マルチトール、トレハロース、エリスリトール、コンドロイチン硫酸およびこの塩類、ヒアルロン酸およびこの塩類、ポリエチレングリコール、ｄｌ－ピロリドンカルボン酸塩、フィッシュコラーゲン、フィトステリル－１２－ヒドロキシステアレートなどが挙げられ、単独または２種以上組み合わせて使用することができる。湿潤剤の配合量としては、ナルフラフィン含有局所適用製剤の全重量に対して、１０重量％以下であることが好ましい。湿潤剤が１０重量％よりも多いと皮膚刺激性が強くなる場合があるため好ましくない。 Examples of the wetting agent include propylene glycol, 1,3-butylene glycol, dipropylene glycol, glycerin, xylitol, sorbitol, maltitol, trehalose, erythritol, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, polyethylene glycol, dl -Pyrrolidone carboxylate, fish collagen, phytosteryl-12-hydroxystearate and the like can be mentioned, and these can be used alone or in combination of two or more. The blending amount of the wetting agent is preferably 10% by weight or less with respect to the total weight of the nalflavine-containing topical preparation. When the amount of the wetting agent is more than 10% by weight, the skin irritation may become strong, which is not preferable.
　界面活性剤としては、たとえば、陽イオン性界面活性剤、陰イオン性界面活性剤、両性界面活性剤、非イオン性界面活性剤が挙げられ、単独または２種以上組合わせて使用することができる。
　陽イオン性界面活性剤としては、たとえば、塩化アルキルトリメチルアンモニウム、塩化ステアリルトリメチルアンモニウム、臭化ステアリルトリメチルアンモニウム、塩化ジステアリルジメチルアンモニウム、塩化ステアリルジメチルベンジルアンモニウム、臭化ベヘニルトリメチルアンモニウムなどが挙げられ、単独または２種以上組み合わせて使用することができる。
　陰イオン性界面活性剤としては、たとえば、リグニンスルホン酸塩、アルキルベンゼンスルホン酸塩、アルキルスルホン酸塩、ポリオキシエチレンアルキルスルホン酸塩、ポリオキシエチレンアルキルフェニルエーテルスルホン酸塩、ポリオキシエチレンアルキルフェニルエーテルリン酸エステル塩、ポリオキシエチレンアリールフェニルエーテルスルホン酸塩、アルキル硫酸エステル塩、ポリオキシエチレンアルキル硫酸エステル塩、ポリオキシエチレンアリールフェニルエーテルリン酸エステル塩、ナフタレンスルホン酸塩、ナフタレンスルホン酸ホルマリン縮合物、ポリオキシエチレントリベンジルフェニルエーテルスルホン酸塩、アルキルリン酸塩、ポリオキシエチレンアルキルリン酸塩、ポリオキシエチレントリベンジルフェニルエーテルリン酸エステル塩、ジアルキルスルホコハク酸塩、脂肪酸塩（石けん）、ポリオキシエチレンアルキルエーテル酢酸塩などが挙げられ、単独または２種以上組み合わせて使用することができる。
　両性界面活性剤としては、たとえば、アルキルカルボキシメチルヒドロキシエチルイミダゾリニウムベタイン、アルキルジメチルアンモニウムプロピルスルホン酸塩、アシルアミノエチルヒドロキシエチルグリシン塩、アシルアミノエチルヒドロキシエチルプロピオン酸塩などが挙げられ、単独または２種以上組み合わせて使用することができる。
　非イオン性界面活性剤としては、たとえば、プロピレングリコールモノ脂肪酸エステル、エチレングリコールモノ脂肪酸エステル、グリセリンモノ脂肪酸エステル、ポリグリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ショ糖脂肪酸エステル、メチルグルコシド脂肪酸エステルなどの多価アルコール脂肪酸エステル、アルキルポリグルコシドなどの多価アルコールアルキルエーテル、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンアルキルフェニルエーテル、ポリオキシエチレンフィトステロール、ポリオキシエチレンフィトスタノール、ポリオキシエチレンコレステロール、ポリオキシエチレンコレスタノール、ポリオキシエチレンポリオキシプロピレンアルキルエーテルなどのポリオキシエチレンエーテル、ポリオキシエチレンモノ脂肪酸エステル、ポリエチレングリコールジ脂肪酸エステル、ポリオキシエチレングリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンソルビトール脂肪酸エステル、ポリオキシエチレンメチルグルコシド脂肪酸エステル、ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレン植物油、ポリオキシエチレンアルキルエーテル脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコールなどのエーテルエステルなどが挙げられ、単独または２種以上組み合わせて使用することができるが、好ましくはソルビタン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステルである。 Examples of the surfactant include cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants, which can be used alone or in combination of two or more. .
Examples of the cationic surfactant include alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, and behenyltrimethylammonium bromide. Or it can be used in combination of two or more.
Examples of the anionic surfactant include lignin sulfonate, alkylbenzene sulfonate, alkyl sulfonate, polyoxyethylene alkyl sulfonate, polyoxyethylene alkyl phenyl ether sulfonate, polyoxyethylene alkyl phenyl ether. Phosphate salt, polyoxyethylene arylphenyl ether sulfonate, alkyl sulfate ester salt, polyoxyethylene alkyl phenyl sulfate ester salt, polyoxyethylene aryl phenyl ether phosphate ester salt, naphthalene sulfonate, naphthalene sulfonate formalin condensate , Polyoxyethylene tribenzylphenyl ether sulfonate, alkyl phosphate, polyoxyethylene alkyl phosphate, polyoxyethylene tribenzylphenyl Terurin acid ester salts, dialkyl sulfosuccinates, fatty acid salts (soaps), such as polyoxyethylene alkyl ether acetate and the like, may be used alone or in combination of two or more.
Examples of amphoteric surfactants include alkyl carboxymethyl hydroxyethyl imidazolinium betaine, alkyl dimethyl ammonium propyl sulfonate, acylaminoethyl hydroxyethyl glycine salt, acylaminoethyl hydroxyethyl propionate, and the like. Two or more types can be used in combination.
Nonionic surfactants include, for example, polyvalent polyols such as propylene glycol monofatty acid ester, ethylene glycol monofatty acid ester, glycerin monofatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, and methylglucoside fatty acid ester. Alcohol fatty acid ester, polyhydric alcohol alkyl ether such as alkyl polyglucoside, polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene cholesterol, polyoxyethylene cholestanol, Polyoxyethylene ethers such as polyoxyethylene polyoxypropylene alkyl ether, Siethylene mono fatty acid ester, polyethylene glycol difatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene methyl glucoside fatty acid ester, polyoxyethylene castor oil, polyoxyethylene Hardened castor oil, polyoxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid ester, ether ester such as polyoxyethylene polyoxypropylene glycol, and the like can be used, and can be used alone or in combination of two or more, preferably sorbitan Fatty acid esters, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan fatty acid esters.
　キレート剤としては、たとえば、エデト酸、シュウ酸、クエン酸、ピロリン酸、ヘキサメタリン酸、グルコン酸およびこれらの塩などが挙げられ、単独または２種以上組み合わせて使用することができる。 Examples of the chelating agent include edetic acid, oxalic acid, citric acid, pyrophosphoric acid, hexametaphosphoric acid, gluconic acid, and salts thereof, and can be used alone or in combination of two or more.
　香料・清涼化剤としては、たとえば、ハッカ油、ハッカハク油、ケイヒ油、チョウジ油、ウイキョウ油、ヒマシ油、テレピン油、ユーカリ油、オレンジ油、ラベンダー油、レモン油、ローズ油、レモングラス油、ダイウイキョウ油、チミアン油、ヘノポジ油、ヤマジン油、トウカ油、ベルガモット油、シトロネラ油、樟脳油、ローズマリー、セージなどの香料、ｌ－メントール、カンフル、チモール、Ｎ－エチル－ｐ－メンタン－カルボキシアミド、ｐ－メンタン－３，８－ジオール、ｌ－イソプレゴール、ｌ－メンチルグリセリルエーテルなどの清涼化剤が挙げられ、単独または２種以上組み合わせて使用することができる。 Examples of fragrances and refreshing agents include mint oil, mint oil, cinnamon oil, clove oil, fennel oil, castor oil, turpentine oil, eucalyptus oil, orange oil, lavender oil, lemon oil, rose oil, lemongrass oil, Fragrances such as Daiwichi Oil, Chimian Oil, Henopoi Oil, Yamadine Oil, Touka Oil, Bergamot Oil, Citronella Oil, Camphor Oil, Rosemary, Sage, 1-Menthol, Camphor, Thymol, N-ethyl-p-menthane-carboxyl Examples of the cooling agent include amide, p-menthane-3,8-diol, 1-isopulegol, and 1-menthyl glyceryl ether, and these can be used alone or in combination of two or more.
　酸化防止剤としては、たとえば、アスコルビン酸、チオ硫酸ナトリウム、没食子酸プロピル、ブチルヒドロキシアニソール、ジブチルヒドロキシトルエン、ノルジヒドログアヤレチン酸、トコフェロール、酢酸トコフェロールなどが挙げられ、単独または２種以上組み合わせて使用することができる。 Examples of the antioxidant include ascorbic acid, sodium thiosulfate, propyl gallate, butylhydroxyanisole, dibutylhydroxytoluene, nordihydroguaiaretic acid, tocopherol, tocopherol acetate and the like alone or in combination of two or more. Can be used.
　防腐剤としては、たとえば、チモール、イソプロピルメチルフェノール、安息香酸およびこの塩、安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル、ベンジルアルコール、塩化ベンザルコニウム、塩化ベンゼトニウムなどが挙げられ、単独または２種以上組み合わせて使用することができる。 Examples of preservatives include thymol, isopropylmethylphenol, benzoic acid and its salts, methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, benzyl alcohol, benzalkonium chloride, and benzethonium chloride. Can be used alone or in combination of two or more.
　ｐＨ調整剤としては、たとえば、酢酸、ギ酸、乳酸、酒石酸、シュウ酸、グリコール酸、リンゴ酸、クエン酸、コハク酸、フマル酸、リン酸、塩酸、硝酸、硫酸およびこれらの塩、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、アルギニン、メチルアミン、エチルアミン、プロピルアミン、ジメチルアミン、ジエチルアミン、ジプロピルアミン、トリメチルアミン、トリエチルアミン、トリプロピルアミン、モノメタノールアミン、モノエタノールアミン、モノプロパノールアミン、ジメタノールアミン、ジエタノールアミン、ジプロパノールアミン、トリメタノールアミン、トリエタノールアミン、イソプロパノールアミン、ジイソプロパノールアミン、トリプロパノールアミン、アンモニア水、炭酸グアニジン、炭酸水素ナトリウム、炭酸アンモニウムなどが挙げられ、単独または２種以上組み合わせて使用することができる。 Examples of pH adjusters include acetic acid, formic acid, lactic acid, tartaric acid, oxalic acid, glycolic acid, malic acid, citric acid, succinic acid, fumaric acid, phosphoric acid, hydrochloric acid, nitric acid, sulfuric acid and their salts, sodium hydroxide , Potassium hydroxide, calcium hydroxide, arginine, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, dipropylamine, trimethylamine, triethylamine, tripropylamine, monomethanolamine, monoethanolamine, monopropanolamine, dimethanol Amine, diethanolamine, dipropanolamine, trimethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, tripropanolamine, aqueous ammonia, guanidine carbonate, bicarbonate Potassium, and ammonium carbonate and the like, may be used alone or in combination of two or more.
　吸収促進剤としては、たとえば、オリーブ油、スクワラン、プロピレングリコール、ラウリルアルコール、トリアセチン、イソステアリン酸、モノカプリル酸プロピレングリコール、Ｎ－メチル－２－ピロリドン、ミリスチン酸イソプロピル、パルミチン酸イソプロピル、アジピン酸ジイソプロピル、モノオレイン酸ソルビタン、炭酸プロピレン、オレイルアルコール、クロタミトン、ｌ－メントールなどが挙げられ、単独または２種以上組み合わせて使用することができる。 Absorption enhancers include, for example, olive oil, squalane, propylene glycol, lauryl alcohol, triacetin, isostearic acid, propylene glycol monocaprylate, N-methyl-2-pyrrolidone, isopropyl myristate, isopropyl palmitate, diisopropyl adipate, mono Examples include sorbitan oleate, propylene carbonate, oleyl alcohol, crotamiton, and l-menthol, and these can be used alone or in combination of two or more.
　本発明のナルフラフィン含有局所適用製剤の治療対象とする症状は、オピオイドκ（カッパー）受容体に作動性を示し治療効果が得られるものであれば特に限定されないが、たとえば、アトピー性皮膚炎、神経性皮膚炎、接触皮膚炎、脂漏性皮膚炎、自己感作性皮膚炎、毛虫性皮膚炎、皮脂欠乏症、老人性皮膚そう痒、虫刺症、光線過敏症、蕁麻疹、痒疹、疱疹、膿痂疹、白癬、苔癬、乾癬、疥癬、内臓疾患（悪性腫瘍、糖尿病、肝疾患、腎不全、腎透析、妊娠など）、尋常性座瘡などによるそう痒、侵害受容性疼痛（筋肉痛、関節痛、頭痛、口腔顔面痛、内臓痛など）、神経因性疼痛（糖尿病、アルコール依存症、抗がん剤の副作用、術後痛、幻肢痛、帯状疱疹後痛、三叉神経痛、中枢神経痛など）、心因性痛などの痛み、などが挙げられる。 The symptom to be treated by the topical preparation containing nalflaphine of the present invention is not particularly limited as long as it exhibits an effect on opioid κ (kappa) receptor and a therapeutic effect can be obtained. For example, atopic dermatitis, nerve Dermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis, sebum deficiency, senile skin pruritus, insect bite, photosensitivity, hives, urticaria, shingles, Impetigo, ringworm, lichen, psoriasis, scabies, visceral diseases (malignant tumor, diabetes, liver disease, renal failure, renal dialysis, pregnancy, etc.), pruritus due to acne vulgaris, nociceptive pain (muscle pain) , Joint pain, headache, orofacial pain, visceral pain, etc.), neuropathic pain (diabetes, alcoholism, side effects of anticancer drugs, postoperative pain, phantom limb pain, postherpetic pain, trigeminal neuralgia, central Neuralgia, etc.), psychogenic pain, etc. That.
　本発明のナルフラフィン含有局所適用製剤は、ヒト、哺乳動物（例えば、マウス、ハムスター、モルモット、ラット、ウサギ、イヌ、ネコ、ヤギ、ヒツジ、ウシ、ブタ、サル等）に、安全に使用することができる。本発明の製剤は、表皮（皮膚、粘膜および角膜）等の局所に適用することによって、経口投与における全身性の副作用が軽減される点で有利である。
　本発明のナルフラフィン含有局所適用製剤の適用方法は特に限定されず、例えば、直接患者の表皮等の局所に塗布してもよく、支持体等に積層して貼付剤として患者の表皮等の局所に適用してもよい。
　本発明のナルフラフィン含有局所適用製剤の投与量は、対象疾患、疾患の重篤度等により異なり、適宜選択することができる。 The topical preparation containing nalflavine of the present invention can be safely used for humans and mammals (eg, mouse, hamster, guinea pig, rat, rabbit, dog, cat, goat, sheep, cow, pig, monkey, etc.). it can. The preparation of the present invention is advantageous in that systemic side effects in oral administration are reduced by applying it locally to the epidermis (skin, mucous membrane and cornea).
The application method of the topical preparation containing nalflavine according to the present invention is not particularly limited, and may be applied directly to the patient's epidermis or the like, for example, or may be laminated on a support or the like and applied locally to the patient's epidermis or the like as a patch. You may apply.
The dosage of the nalflaphine-containing topical preparation of the present invention varies depending on the target disease, the severity of the disease, etc., and can be appropriately selected.
　本発明のナルフラフィン含有局所適用製剤の製造方法については特に制限されず、剤形に応じて、従来公知の方法または今後新しく提供される方法を参考にして製造することができる。
　局所適用製剤用基剤として油脂性基剤を選択する場合は、たとえば、炭化水素系油分および他の任意の成分を加熱溶解させ、冷却してからナルフラフィンおよび他の任意の成分と混合することで、または炭化水素系油分と、ナルフラフィンおよび他の任意の成分とを同時に加熱溶解させてから冷却することで製造することができる。
　局所適用製剤用基剤としてＷ／Ｏ型またはＯ／Ｗ型乳剤性基剤を選択する場合は、たとえば、ナルフラフィンを油性成分または水性成分に添加し、当該成分、油性または水性成分、界面活性剤および他の任意の成分を混合し、乳化することで、または油性成分、水性成分、界面活性剤および他の任意の成分を混合し、乳化してからナルフラフィンを混合することで製造することができる。
　なお、油性成分と水性成分との乳化方法としては、たとえば、ホモミキサーなどを用いて撹拌する方法を挙げることができるが、必要に応じて、得られたエマルションをさらにホモジナイザーなどを用いて微細化することもできる。 The method for producing the nalflavine-containing topical preparation of the present invention is not particularly limited, and can be produced by referring to a conventionally known method or a newly provided method according to the dosage form.
When selecting an oleaginous base as a base for a topical preparation, for example, by heating and dissolving the hydrocarbon oil and other optional ingredients, cooling, and mixing with narfrafin and other optional ingredients Alternatively, it can be produced by simultaneously heating and dissolving a hydrocarbon-based oil component, narfrafin and other optional components, and then cooling.
When a W / O type or O / W type emulsion base is selected as a base for a topical preparation, for example, nalfrafin is added to an oily component or an aqueous component, and the component, oily or aqueous component, surfactant And other optional components may be mixed and emulsified, or oily components, aqueous components, surfactants and other optional components may be mixed and emulsified before mixing with nalfurafine. .
In addition, as an emulsification method of the oil component and the aqueous component, for example, a method of stirring using a homomixer or the like can be mentioned, but if necessary, the obtained emulsion is further refined using a homogenizer or the like. You can also
　以下に、実施例によりさらに詳細に本発明を説明するが、本発明は、これに限定されるものではない。
（実施例１）
　表１に示す配合に基づき、後述する調製法１の方法により調製し、本発明のナルフラフィン含有局所適用製剤１を得た。得られたナルフラフィン含有局所適用製剤１を使用して、試験例１に従って安定性試験を実施した結果、６０℃で２週間保存後のナルフラフィン残存率は、９６％となり、製剤中薬物安定性が高かった。次に、試験例２に従って、ラット皮膚透過試験を実施した結果、製剤適用後２０時間の単位面積当たりのナルフラフィンの累積透過量は、４３２．６ｎｇ／ｃｍ２となり、製剤から生体への薬物移行性が高かった。結果を表１に示す。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
(Example 1)
Based on the formulation shown in Table 1, it was prepared by the method of Preparation Method 1 described later to obtain a nalflaphine-containing topical preparation 1 of the present invention. As a result of conducting a stability test according to Test Example 1 using the obtained nalflavine-containing topical preparation 1 obtained, the residual ratio of nalfurafine after storage at 60 ° C. for 2 weeks was 96%, and the drug stability in the preparation was high. It was. Next, as a result of conducting a rat skin permeation test according to Test Example 2, the cumulative permeation amount of narfrafin per unit area for 20 hours after application of the formulation was 432.6 ng / cm 2 , and the drug transferability from the formulation to the living body. Was expensive. The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
（調製法１）
　ナルフラフィンのフリー体に親水ワセリンを加え、乳鉢上で均一に混合し、ナルフラフィン含有局所適用製剤１を得た。 (Preparation method 1)
Hydrophilic petrolatum was added to the free form of nalfrafin, and mixed uniformly on a mortar to obtain a nalfrafin-containing topical preparation 1.
（試験例１）
安定性試験
　前述した実施例１のナルフラフィン含有局所適用製剤、後述する実施例２～４のナルフラフィン含有局所適用製剤および比較例１～６の局所適用製剤を使用し、次に示す方法で安定性試験を行った。
　各局所適用製剤を密閉容器に入れて、６０℃で保存した。保存開始時および保存開始２週間後に、各局所適用製剤中のナルフラフィン含有量を高速液体クロマトグラフィーによって定量した。保存開始時のナルフラフィン含有量に対する保存開始２週間後のナルフラフィン含有量を百分率で算出し、ナルフラフィン残存率（％）とした。また、測定の誤差により、ナルフラフィン残存率が１００％を超えたものに関しては、ナルフラフィン残存率を１００％とした。 (Test Example 1)
Stability test Using the above-mentioned topical preparation containing nalfurafine of Example 1, the topical preparation containing nalfurafine containing Examples 2 to 4 and the topical application preparations of Comparative Examples 1 to 6 described later, the stability test was carried out by the following method. Went.
Each topical formulation was placed in a sealed container and stored at 60 ° C. At the start of storage and 2 weeks after the start of storage, the content of nalflavin in each topical preparation was quantified by high performance liquid chromatography. The nalfuraffin content at 2 weeks after the start of storage relative to the nalfurafin content at the start of storage was calculated as a percentage, and was defined as the nalfurafin residual rate (%). In addition, for the case where the nalfurafin residual ratio exceeded 100% due to measurement error, the nalfurafin residual ratio was set to 100%.
（試験例２）
ラット皮膚透過試験
　前述した実施例１のナルフラフィン含有局所適用製剤、後述する実施例２～４のナルフラフィン含有局所適用製剤および比較例１～６の局所適用製剤を使用し、次に示す方法でラット皮膚透過試験を行った。
　ＨＷＹヘアレスラット（雄性、８週齢、体重約２５０ｇ）の腹部皮膚を摘出し、皮下組織を取り除いたものを、試験用皮膚とした。フランツ型拡散セルに先の試験用皮膚を装着し、試験用皮膚に各局所適用製剤０．１ｇを直径２ｃｍの円状に均一に塗り広げて適用した。フランツ型拡散セルのレシーバー側は、リン酸緩衝生理食塩水（ｐＨ７．４）（以下、「レシーバー溶液」という）で満たし、試験終了まで撹拌し続けた。フランツ型拡散セルのジャケット温度を約３８℃に保ち、各局所適用製剤適用２０時間後にレシーバー溶液をサンプリングした。サンプリングしたレシーバー溶液中のナルフラフィン量をＬＣ／ＭＳ／ＭＳ（Ｌｉｑｕｉｄ　Ｃｈｒｏｍａｔｏｇｒａｐｈｙ－ｔａｎｄｅｍ　Ｍａｓｓ　Ｓｐｅｃｔｒｏｍｅｔｒｙ）により測定し、皮膚を透過したナルフラフィン量とした。この皮膚を透過したナルフラフィン量を製剤の適用面積で除して単位面積当たりのナルフラフィンの累積透過量を算出した。 (Test Example 2)
Rat skin permeation test Using the above-described topical preparation containing nalfurafine of Example 1, the topical preparation containing nalflaphine of Examples 2 to 4 and the topical preparation of Comparative Examples 1 to 6, which will be described later, rat skin was tested in the following manner. A permeation test was performed.
Abdominal skin of a HWY hairless rat (male, 8 weeks old, body weight about 250 g) was removed and the subcutaneous tissue was removed was used as test skin. The previous test skin was attached to a Franz diffusion cell, and 0.1 g of each topical preparation was uniformly spread and applied to the test skin in a circular shape having a diameter of 2 cm. The receiver side of the Franz diffusion cell was filled with phosphate buffered saline (pH 7.4) (hereinafter referred to as “receiver solution”), and stirring was continued until the end of the test. The jacket temperature of the Franz diffusion cell was kept at about 38 ° C., and the receiver solution was sampled 20 hours after application of each topical formulation. The amount of nalfurafine in the sampled receiver solution was measured by LC / MS / MS (Liquid Chromatography-Tandem Mass Spectrometry) to obtain the amount of nalfurafine that permeated the skin. The amount of nalflaphine permeated through the skin was divided by the application area of the preparation to calculate the cumulative amount of nalflaphine per unit area.
（実施例２）
　実施例１において、親水ワセリンの代わりに親水軟膏を用いた以外は実施例１と全く同じ調製法を繰り返して、ナルフラフィン含有局所適用製剤２を得た。得られたナルフラフィン含有局所適用製剤２を使用して、試験例１に従って安定性試験を実施した結果、６０℃で２週間保存後のナルフラフィン残存率は、９２％となり、製剤中薬物安定性が高かった。次に、試験例２に従って、ラット皮膚透過試験を実施した結果、製剤適用後２０時間の単位面積当たりのナルフラフィンの累積透過量は、１６０．６ｎｇ／ｃｍ２となり、製剤から生体への薬物移行性が高かった。結果を表１に示した。 (Example 2)
In Example 1, except for using hydrophilic ointment instead of hydrophilic petrolatum, exactly the same preparation method as Example 1 was repeated to obtain a nalflaphine-containing topical preparation 2. As a result of conducting a stability test according to Test Example 1 using the obtained nalflavine-containing topical preparation 2 obtained, the residual ratio of nalfurafine after storage at 60 ° C. for 2 weeks was 92%, and the drug stability in the preparation was high. It was. Next, as a result of conducting a rat skin permeation test according to Test Example 2, the cumulative permeation amount of nalfrafin per unit area for 20 hours after application of the formulation was 160.6 ng / cm 2 , and the drug transferability from the formulation to the living body. Was expensive. The results are shown in Table 1.
（実施例３）
　実施例１において、親水ワセリンの代わりに白色ワセリンを用いた以外は実施例１と全く同じ調製法を繰り返して、ナルフラフィン含有局所適用製剤３を得た。得られたナルフラフィン含有局所適用製剤３を使用して、試験例１に従って安定性試験を実施した結果、６０℃で２週間保存後のナルフラフィン残存率は、９８％となり、製剤中薬物安定性が高かった。次に、試験例２に従って、ラット皮膚透過試験を実施した結果、製剤適用後２０時間の単位面積当たりのナルフラフィンの累積透過量は、２２２．７ｎｇ／ｃｍ２となり、製剤から生体への薬物移行性が高かった。結果を表１に示した。 (Example 3)
In Example 1, the same preparation method as Example 1 was repeated except that white petrolatum was used in place of hydrophilic petrolatum to obtain a nalfrafin-containing topical preparation 3. As a result of conducting a stability test according to Test Example 1 using the obtained nalfurafine-containing topical preparation 3 obtained, the residual ratio of nalfurafin after storage at 60 ° C. for 2 weeks was 98%, and the drug stability in the preparation was high. It was. Next, as a result of conducting a rat skin permeation test according to Test Example 2, the cumulative permeation amount of nalfurafine per unit area for 20 hours after application of the formulation was 222.7 ng / cm 2 , and the drug transferability from the formulation to the living body. Was high. The results are shown in Table 1.
（実施例４）
　実施例１において、親水ワセリンの代わりにプラスチベース（登録商標）を用いた以外は実施例１と全く同じ調製法を繰り返して、ナルフラフィン含有局所適用製剤４を得た。得られたナルフラフィン含有局所適用製剤４を使用して、試験例１に従って安定性試験を実施した結果、６０℃で２週間保存後のナルフラフィン残存率は、１００％となり、製剤中薬物安定性が高かった。次に、試験例２に従って、ラット皮膚透過試験を実施した結果、製剤適用後２０時間の単位面積当たりのナルフラフィンの累積透過量は、１６７．２ｎｇ／ｃｍ２となり、製剤から生体への薬物移行性が高かった。結果を表１に示した。 Example 4
In Example 1, the same preparation method as Example 1 was repeated except that Plastibase (registered trademark) was used in place of hydrophilic petrolatum to obtain a nalflaphine-containing topical preparation 4. As a result of conducting a stability test according to Test Example 1 using the obtained nalflavine-containing topical preparation 4 obtained, the residual ratio of nalfrafin after storage at 60 ° C. for 2 weeks was 100%, and the drug stability in the preparation was high. It was. Next, as a result of conducting a rat skin permeation test according to Test Example 2, the cumulative permeation amount of nalfrafin per unit area for 20 hours after application of the formulation was 167.2 ng / cm 2 , and the drug transferability from the formulation to the living body. Was expensive. The results are shown in Table 1.
（比較例１）
　実施例１において、ナルフラフィンのフリー体の代わりにナルフラフィン塩酸塩を用いた以外は実施例１と全く同じ調製法を繰り返して、局所適用製剤１を得た。なお、ナルフラフィン塩酸塩の配合量は、製剤中のナルフラフィン含有量がナルフラフィンのフリー体として０．１重量％となるように調節した。得られた局所適用製剤１を使用して、試験例１に従って安定性試験を実施した結果、６０℃で２週間保存後のナルフラフィン残存率は、８５％となり、製剤中薬物安定性が低かった。次に、試験例２に従って、ラット皮膚透過試験を実施した結果、製剤適用後２０時間の単位面積当たりのナルフラフィンの累積透過量は、３６．２ｎｇ／ｃｍ２となり、製剤から生体への薬物移行性が低かった。結果を表１に示した。 (Comparative Example 1)
In Example 1, the preparation for topical application 1 was obtained by repeating exactly the same preparation method as in Example 1 except that nalfurafine hydrochloride was used instead of the free form of nalfurafine. In addition, the blending amount of nalfurafine hydrochloride was adjusted so that the content of nalfurafine in the preparation was 0.1% by weight as a free form of nalfurafine. As a result of carrying out a stability test according to Test Example 1 using the obtained topical preparation 1, the residual ratio of nalfrafin after storage at 60 ° C. for 2 weeks was 85%, and the drug stability in the preparation was low. Next, as a result of conducting a rat skin permeation test according to Test Example 2, the cumulative permeation amount of nalfrafin per unit area for 20 hours after the formulation application was 36.2 ng / cm 2 , and the drug transferability from the formulation to the living body. Was low. The results are shown in Table 1.
（比較例２）
　実施例２において、ナルフラフィンのフリー体の代わりにナルフラフィン塩酸塩を用いた以外は実施例２と全く同じ調製法を繰り返して、局所適用製剤２を得た。なお、ナルフラフィン塩酸塩の配合量は、製剤中のナルフラフィン含有量がナルフラフィンのフリー体として０．１重量％となるように調節した。得られた局所適用製剤２を使用して、試験例１に従って安定性試験を実施した結果、６０℃で２週間保存後のナルフラフィン残存率は、９２％となり、製剤中ナルフラフィン安定性が高かった。次に、試験例２に従って、ラット皮膚透過試験を実施した結果、製剤適用後２０時間の単位面積当たりのナルフラフィンの累積透過量は、９６．９ｎｇ／ｃｍ２となり、製剤から生体への薬物移行性が低かった。結果を表１に示した。 (Comparative Example 2)
In Example 2, a preparation for topical application 2 was obtained by repeating exactly the same preparation method as in Example 2 except that nalfurafine hydrochloride was used instead of the free form of nalfurafine. In addition, the blending amount of nalfurafine hydrochloride was adjusted so that the content of nalfurafine in the preparation was 0.1% by weight as a free form of nalfurafine. As a result of conducting a stability test according to Test Example 1 using the obtained topical preparation 2, the nalfurafin residual ratio after storage at 60 ° C. for 2 weeks was 92%, and the stability of nalfurafine in the preparation was high. Next, as a result of conducting a rat skin permeation test according to Test Example 2, the cumulative permeation amount of nalfrafin per unit area for 20 hours after the formulation application was 96.9 ng / cm 2 , and the drug transferability from the formulation to the living body. Was low. The results are shown in Table 1.
（比較例３）
　実施例３において、ナルフラフィンのフリー体の代わりにナルフラフィン塩酸塩を用いた以外は実施例３と全く同じ調製法を繰り返して、局所適用製剤３を得た。なお、ナルフラフィン塩酸塩の配合量は、製剤中のナルフラフィン含有量がナルフラフィンのフリー体として０．１重量％となるように調節した。得られた局所適用製剤３を使用して、試験例１に従って安定性試験を実施した結果、６０℃で２週間保存後のナルフラフィン残存率は、７８％となり、製剤中薬物安定性が低かった。次に、試験例２に従って、ラット皮膚透過試験を実施した結果、製剤適用後２０時間の単位面積当たりのナルフラフィンの累積透過量は、８０．０ｎｇ／ｃｍ２となり、製剤から生体への薬物移行性が低かった。結果を表１に示した。 (Comparative Example 3)
In Example 3, a preparation for topical application 3 was obtained by repeating exactly the same preparation method as in Example 3 except that nalfurafine hydrochloride was used instead of the free form of nalfurafine. In addition, the blending amount of nalfurafine hydrochloride was adjusted so that the content of nalfurafine in the preparation was 0.1% by weight as a free form of nalfurafine. As a result of conducting a stability test according to Test Example 1 using the obtained topical preparation 3, the residual ratio of nalfurafin after storage at 60 ° C. for 2 weeks was 78%, and the drug stability in the preparation was low. Next, as a result of conducting a rat skin permeation test according to Test Example 2, the cumulative permeation amount of nalfrafin per unit area for 20 hours after application of the formulation was 80.0 ng / cm 2 , and the drug transferability from the formulation to the living body. Was low. The results are shown in Table 1.
（比較例４）
　実施例４において、ナルフラフィンのフリー体の代わりにナルフラフィン塩酸塩を用いた以外は実施例４と全く同じ調製法を繰り返して、局所適用製剤４を得た。なお、ナルフラフィン塩酸塩の配合量は、製剤中のナルフラフィン含有量がナルフラフィンのフリー体として０．１重量％となるように調節した。得られた局所適用製剤４を使用して、試験例１に従って安定性試験を実施した結果、６０℃で２週間保存後のナルフラフィン残存率は、８８％となり、製剤中薬物安定性が低かった。次に、試験例２に従ってラット皮膚透過試験を実施した結果、製剤適用後２０時間の単位面積当たりのナルフラフィンの累積透過量は、１０．９ｎｇ／ｃｍ２となり、製剤から生体への薬物移行性が低かった。結果を表１に示した。 (Comparative Example 4)
In Example 4, topical application formulation 4 was obtained by repeating exactly the same preparation method as in Example 4 except that nalfurafine hydrochloride was used in place of the free form of nalflafine. In addition, the blending amount of nalfurafine hydrochloride was adjusted so that the content of nalfurafine in the preparation was 0.1% by weight as a free form of nalfurafine. As a result of conducting a stability test according to Test Example 1 using the obtained topical preparation 4, the residual ratio of nalfurafin after storage at 60 ° C. for 2 weeks was 88%, and the drug stability in the preparation was low. Next, as a result of conducting a rat skin permeation test according to Test Example 2, the cumulative permeation amount of narfrafin per unit area for 20 hours after application of the formulation was 10.9 ng / cm 2 , indicating that drug transfer from the formulation to the living body was achieved. It was low. The results are shown in Table 1.
（比較例５）
　実施例１において、親水ワセリンの代わりにマクロゴール軟膏を用いた以外は実施例１と全く同じ調製法を繰り返して、局所適用製剤５を得た。得られた局所適用製剤５を使用して、試験例１に従って安定性試験を実施した結果、６０℃で２週間保存後におけるナルフラフィン含有量が検出限界以下であったため、製剤中薬物安定性が低かった。次に、試験例２に従ってラット皮膚透過試験を実施した結果、製剤適用後２０時間の単位面積当たりのナルフラフィンの累積透過量は、１．８ｎｇ／ｃｍ２となり、製剤から生体への薬物移行性が低かった。結果を表１に示した。 (Comparative Example 5)
In Example 1, the same preparation method as Example 1 was repeated except that Macrogol ointment was used instead of hydrophilic petrolatum, thereby obtaining a topical preparation 5. As a result of carrying out a stability test using the obtained topical preparation 5 according to Test Example 1, the drug stability in the preparation was low because the content of nalflaphine after storage at 60 ° C. for 2 weeks was below the detection limit. It was. Next, as a result of conducting a rat skin permeation test in accordance with Test Example 2, the cumulative permeation amount of narfrafin per unit area for 20 hours after application of the formulation was 1.8 ng / cm 2 , indicating that the drug transferability from the formulation to the living body was high. It was low. The results are shown in Table 1.
（比較例６）
　比較例５において、ナルフラフィンのフリー体の代わりにナルフラフィン塩酸塩を用いた以外は比較例５と全く同じ調製法を繰り返して、局所適用製剤６を得た。なお、ナルフラフィン塩酸塩の配合量は、製剤中のナルフラフィン含有量がナルフラフィンのフリー体として０．１重量％となるように調節した。得られた局所適用製剤６を使用して、試験例１に従って安定性試験を実施した結果、６０℃で２週間保存後におけるナルフラフィン含有量が検出限界以下であったため、製剤中薬物安定性が低かった。次に試験例２に従ってラット皮膚透過試験を実施した結果、製剤適用後２０時間の単位面積当たりのナルフラフィンの累積透過量は、１．１ｎｇ／ｃｍ２となり、製剤から生体への薬物移行性が低かった。結果を表１に示した。 (Comparative Example 6)
In Comparative Example 5, a preparation for topical application 6 was obtained by repeating exactly the same preparation method as in Comparative Example 5 except that nalfurafine hydrochloride was used instead of the free form of nalfurafine. In addition, the blending amount of nalfurafine hydrochloride was adjusted so that the content of nalfurafine in the preparation was 0.1% by weight as a free form of nalfurafine. As a result of carrying out a stability test according to Test Example 1 using the obtained topical preparation 6, the drug stability in the preparation was low because the content of nalfrafin after storage at 60 ° C. for 2 weeks was below the detection limit. It was. Next, as a result of conducting a rat skin permeation test according to Test Example 2, the cumulative permeation amount of nalfrafin per unit area for 20 hours after application of the formulation was 1.1 ng / cm 2 , and the drug transfer from the formulation to the living body was low. It was. The results are shown in Table 1.
　本発明は、製剤中薬物安定性と製剤から生体への薬物移行性のいずれも高いナルフラフィン含有局所適用製剤に関するものであり、産業上十分に利用可能である。 The present invention relates to a nalflaphine-containing topical preparation having both high drug stability in the preparation and drug transfer from the preparation to the living body, and can be sufficiently used industrially.
　本出願は、日本で出願された特願２０１４－２０１２３７を基礎としており、その内容は本明細書にすべて包含されるものである。 This application is based on Japanese Patent Application No. 2014-201237 filed in Japan, the contents of which are incorporated in full herein.

Claims (5)

  1. 　ナルフラフィンのフリー体を含有する局所適用製剤。 Topically applied formulation containing a free form of narfraphine.
  2. 　ナルフラフィンのフリー体の含有量が、局所適用製剤の全重量に対して０．００１～１重量％であることを特徴とする請求項１に記載のナルフラフィン含有局所適用製剤。 2. The topical preparation containing nalflavine according to claim 1, wherein the content of the free form of nalflavine is 0.001 to 1% by weight based on the total weight of the topical preparation.
  3. 　局所適用製剤の基剤が乳剤性基剤または炭化水素油分からなる油脂性基剤であることを特徴とする請求項２に記載のナルフラフィン含有局所適用製剤。 3. The topical preparation containing nalflavine according to claim 2, wherein the base of the topical preparation is an oily base comprising an emulsion base or a hydrocarbon oil.
  4. 　炭化水素油分からなる油脂性基剤がワセリンおよびゲル化炭化水素からなる群より選ばれた少なくとも１種を含むことを特徴とする請求項３に記載のナルフラフィン含有局所適用製剤。 4. The topical preparation containing nalflaphine according to claim 3, wherein the oily base comprising a hydrocarbon oil contains at least one selected from the group consisting of petrolatum and gelled hydrocarbon.
  5. 　安定性試験における６０℃で２週間保存後のナルフラフィン残存率が９０～１００％であり、および、ラット皮膚透過試験における製剤適用後２０時間の単位面積当たりのナルフラフィンの累積透過量が１００ｎｇ／ｃｍ２以上であることを特徴とする請求項４に記載のナルフラフィン含有局所適用製剤。 In the stability test, the residual rate of nalfurafine after storage at 60 ° C. for 2 weeks is 90 to 100%, and the cumulative permeation amount of nalfurafine per unit area for 20 hours after application of the preparation in the rat skin permeation test is 100 ng / cm 2. The nalflaphine-containing topical preparation according to claim 4, which is as described above.
PCT/JP2015/077741 2014-09-30 2015-09-30 Nalfurafine-containing preparation for topical application WO2016052617A1 (en)

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WO2009107478A1 (en) * 2008-02-27 2009-09-03 久光製薬株式会社 Adhesive skin patch and packaged product
WO2013099835A1 (en) * 2011-12-27 2013-07-04 帝國製薬株式会社 Tolterodine-containing adhesive patch
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Publication number Priority date Publication date Assignee Title
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