WO2016052617A1 - Préparation pour application topique contenant de la nalfurafine - Google Patents

Préparation pour application topique contenant de la nalfurafine Download PDF

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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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English (en)
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/ja
Publication of WO2016052617A1 publication Critical patent/WO2016052617A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—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.

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Abstract

La présente invention cherche à résoudre le problème qui est de fournir une préparation pour application topique contenant de la nalfurafine, présentant une haute stabilité médicamenteuse lors de sa préparation et d'excellentes propriétés de transfert du médicament depuis la préparation vers un organisme vivant. La préparation pour application topique contenant de la nalfurafine, qui contient de la nalfurafine sous forme de composé libre et qui contient une base huileuse comprenant une base d'émulsion ou une huile provenant d'hydrocarbures et en conséquence présente un rapport résiduel de nalfurafine de 90 à 100 % après stockage pendant 2 semaines à 60 °C et une pénétration cumulée de la nalfurafine de 100 ng/cm2 ou plus par unité de surface 20 heures après l'application de la préparation dans un essai de pénétration de la peau de rat, présente une haute stabilité médicamenteuse lors de sa préparation et d'excellentes propriétés de transfert du médicament depuis la préparation vers un organisme vivant.
PCT/JP2015/077741 2014-09-30 2015-09-30 Préparation pour application topique contenant de la nalfurafine WO2016052617A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11185509B2 (en) 2016-07-29 2021-11-30 Toray Industries, Inc. Solid preparation having improved light stability

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998023290A1 (fr) * 1996-11-25 1998-06-04 Toray Industries, Inc. Agent antiprurigineux
WO2009107478A1 (fr) * 2008-02-27 2009-09-03 久光製薬株式会社 Timbre transdermique adhésif et produit conditionné
WO2013099835A1 (fr) * 2011-12-27 2013-07-04 帝國製薬株式会社 Timbre adhésif contenant de la toltérodine
JP2013147459A (ja) * 2012-01-19 2013-08-01 Mikasa Seiyaku Co Ltd そう痒症改善経皮吸収貼付剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998023290A1 (fr) * 1996-11-25 1998-06-04 Toray Industries, Inc. Agent antiprurigineux
WO2009107478A1 (fr) * 2008-02-27 2009-09-03 久光製薬株式会社 Timbre transdermique adhésif et produit conditionné
WO2013099835A1 (fr) * 2011-12-27 2013-07-04 帝國製薬株式会社 Timbre adhésif contenant de la toltérodine
JP2013147459A (ja) * 2012-01-19 2013-08-01 Mikasa Seiyaku Co Ltd そう痒症改善経皮吸収貼付剤

Non-Patent Citations (1)

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Title
MASAHIKO TAKANO: "Konnichi no Hifu Gaiyozai", KABUSHIKI KAISHA NANZANDO.4-1-11, 1981, Bunkyo-Ku, Tokyo, pages 235, ISBN: 4-525-77271-9 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11185509B2 (en) 2016-07-29 2021-11-30 Toray Industries, Inc. Solid preparation having improved light stability

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