JP5369389B2 - Acupuncture composition - Google Patents

Description

  The present invention relates to a composition for treating hemorrhoids, and more particularly to a composition for treating hemorrhoids in which a vasoconstrictor is stably blended.

  When bleeding in or near the rectum due to diseases such as hemorrhoids, a vasoconstrictor having local hemostasis is administered. In addition to bleeding, pain, itchiness and inflammation also accompany, so products that are generally used in combination with local anesthetics and anti-inflammatory agents have been released.

  As the vasoconstrictor, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride and the like are generally used.

  However, when the vasoconstrictor and the local anesthetic lidocaine or dibucaine are formulated together, there is a problem that the vasoconstrictor becomes unstable, and by combining the carboxyvinyl polymer together, a stable composition for treating hemorrhoids Is disclosed (see Patent Document 1).

  Here, it is generally known that a carboxyvinyl polymer is difficult to swell unless it is neutral to basic, and it is generally said that it is not preferable to add an acid to a preparation containing a carboxyvinyl polymer. Yes.

Further, a salmon treatment ointment is disclosed, which contains a poorly water-soluble drug, a water-soluble drug, a polyhydric alcohol and an oily component in a cream and has a pH in the range of 4 to 7 (Patent Document 2). reference)
JP-A-7-304669 JP 2004-131472 A

  For the treatment of hemorrhoids, a composition for treating hemorrhoids that is effective against all symptoms of bleeding, pain, itching and inflammation is desired. Therefore, one or more selected from the group consisting of tetrahydrozoline hydrochloride, naphazoline hydrochloride and phenylephrine hydrochloride is selected as the vasoconstrictor, and selected from the group consisting of lidocaine and dibucaine as the local anesthetic because of its solubility in the suppository base. When one or more types are selected and glycyrrhetinic acid is added to a formulation containing carboxyvinyl polymer to improve drug stability, the vasoconstrictor becomes extremely unstable. I found.

  An object of the present invention is to provide a therapeutic agent for hemorrhoids in which glycyrrhetinic acid, a vasoconstrictor and a local anesthetic are simultaneously and stably blended.

  As a result of investigations to solve the problems, the present inventors have formulated a composition containing glycyrrhetinic acid, a vasoconstrictor, and a local anesthetic, and a carboxyvinyl polymer and an organic acid having high solubility in water. Has found that the stability of the vasoconstrictor is improved, and the present invention has been completed.

That is, the present invention provides (1), (a) one or more vasoconstrictors selected from the group consisting of tetrahydrozoline hydrochloride, naphazoline hydrochloride and phenylephrine hydrochloride,
(B) one or more local anesthetics selected from the group consisting of lidocaine and dibucaine;
(C) glycyrrhetinic acid,
(D) carboxyvinyl polymer,
(E) an organic acid having a high solubility in water;
A composition for treating hemorrhoids,
(2) The composition for treating hemorrhoids according to 1, wherein the compounding amount of the organic acid having high solubility in water is 0.01 to 10% by mass relative to the total amount of the composition,
(3) The composition for treating hemorrhoids according to 1, wherein the compounding amount of the organic acid having high solubility in water is 0.3 to 2.5% by mass with respect to the whole composition,
(4) The hemorrhoid treatment composition according to any one of 1 to 3, wherein the organic acid having a high solubility in water is one or more selected from the group consisting of citric acid, tartaric acid and adipic acid,
(5) The composition for treating hemorrhoids according to any one of 1 to 4, wherein the vasoconstrictor is one or two selected from the group consisting of tetrahydrozoline hydrochloride and naphazoline hydrochloride,
(6) The composition for treating hemorrhoids according to any one of 1 to 5, wherein the local anesthetic is lidocaine,
(7) The composition for treating hemorrhoids according to any one of 1 to 6, wherein the compounding amount of the vasoconstrictor is 0.005 to 0.5 mass% with respect to the total amount of the composition,
(8) The composition for treating hemorrhoids according to any one of 1 to 7, wherein the compounding amount of the local anesthetic is 0.05 to 6% by mass with respect to the total amount of the composition,
(9) The composition for treating hemorrhoids according to any one of 1 to 8, wherein the blending amount of glycyrrhetinic acid is 0.5 to 2% by mass with respect to the total amount of the composition,
(10) The composition for treating hemorrhoids according to any one of 1 to 9, wherein the compounding amount of the carboxyvinyl polymer is 0.2 to 15% by mass relative to the total amount of the composition,
(11) The composition for treating hemorrhoids according to any one of 1 to 10, wherein the composition for treating hemorrhoids is a suppository, an external ointment, or an injection ointment,
It is.

  Even when glycyrrhetinic acid, a vasoconstrictor, and a local anesthetic are blended, a vasoconstrictor can be blended stably.

  In the composition for treating hemorrhoids of the present invention, the amount of one or more vasoconstrictors selected from the group consisting of tetrahydrozoline hydrochloride, naphazoline hydrochloride and phenylephrine hydrochloride is 0.005 to 0.5% by mass relative to the total amount of the composition. Preferably, 0.01 to 0.1% by mass is more preferable. The most preferred vasoconstrictor is tetrahydrozoline hydrochloride.

  The blending amount of one or more local anesthetics selected from the group consisting of lidocaine and dibucaine of the present invention is preferably 0.05 to 6% by mass, more preferably 1.5 to 5% by mass, based on the total amount of the composition. is there.

  The blending amount of the anti-inflammatory agent glycyrrhetinic acid is preferably 0.5 to 2% by mass relative to the total amount of the composition.

  In the present invention, the carboxyvinyl polymer means a copolymer of acrylic acid. For example, there are several types having different viscosities such as viscosity of a 0.5% aqueous solution of 4000 to 10000 mPa · s and 40000 to 60000 mPa · s. However, in the present invention, it can be properly used depending on the purpose of use. For example, when a suppository is used, it is preferable to mainly use a type having a high viscosity, and when a cream is used, a type having a low viscosity is mainly used. 0.2-15 mass% is preferable with respect to whole quantity, and, as for the compounding quantity of a composition, 1-10 mass% is more preferable. This is because if the amount of the carboxyvinyl polymer is small, the drug release and effectiveness are lowered, and if the amount is too large, the mucous membrane region may be irritated.

  The organic acid having a high solubility in water in the present invention is an organic acid having a solubility of not less than “slightly soluble” in terms of solubility in Japanese Pharmacopoeia. Specifically, 20 ± 5 ° C. purified water is used as a solvent, and the amount of solvent required to dissolve 1 g of solute is less than 30 mL.

  Examples of such organic acids include citric acid, tartaric acid, adipic acid, acetic acid, butyric acid, lactic acid, benzoic acid, malic acid, sorbic acid, L-aspartic acid, aminoethylsulfonic acid, and salicylic acid. Citric acid, tartaric acid, and adipic acid can be mentioned as preferable from the track record of use.

  In the present invention, the blending amount of the organic acid having high solubility in water is preferably 0.01 to 10% by mass, more preferably 0.3 to 2.5% by mass, and 1.2 to 2% based on the total amount of the composition. More preferably, 2% by mass. If the amount of organic acid that is highly soluble in water is too large, the swellability of the carboxyvinyl polymer will deteriorate and the release may be reduced. If the amount of organic acid that is highly soluble in water is small, the stability of the drug This is because the sex is lowered.

  It is known that it is generally not preferable to add an acid to a preparation containing a carboxyvinyl polymer. However, in the present invention, there was no problem in the drug release property despite the addition of an acid.

In the composition for treating hemorrhoids of the present invention, other drugs that are usually used in the composition for treating hemorrhoids can be blended within a range that does not impair the effects of the present invention. Here, the drug is funnel extract, epinephrine solution, hydrocortisone acetate, prednisolone acetate, hydrocortisone, prednisolone, clobetasol propionate, diclazozone acetate, diflupredade, dexamethasone propionate, betamethasone propionate, diflucortron valerate, fluocinide, amsinide Steroids such as halsinonide, dexamethasone valerate, betamethasone valerate, beclomethasone propionate, prednisolone valerate acetate, fluocinolone acetonide, hydrocortisone butyrate propionate, triamcinolone acetonide, flumetasone vivalate, methylprednisolone acetate, zinc oxide, Astringents such as tannic acid, albumin tannate, acrinol, alkylpolyaminoethylglycine, isopropyl Sulpha drugs such as methylphenol, sulfazine, sulfisomidine, sodium sulfisomidine, homosulfamine, antihistamines such as diphenylpyraline hydrochloride, diphenhydramine hydrochloride, diphenhydramine, chlorfuniramine maleate, crotamiton, allantoin, aluminum chlorohydroxyalrantinate, ictamol, chloride Lysozyme, dry aluminum potassium sulfate, dimethylisopropylazulene, purified egg yolk lecithin, egg yolk oil, indomethacin, piroxicam, ampiroxicam, meloxicam, lornoxicam, suprofen, bufexamac, bendazac, ufenamate, ketoprofen, ibuprofen, ibuprofen piconol, flurbiprofen , Naproxen, loxoprofen, Luminoprofen, felbinac, diclofenac sodium, sulindac, flufenamic acid, mefenamic acid, glycyrrhetinic acid tolfenamic acid and its salts, antiseptics such as glycol salicylate, methyl salicylate, herbal medicines such as shikon, horse chestnut seeds, hamamelis, processed daisan, liver oil , retinol palmitate, tocopherol acetate, tocopherol, ascorbic acid, vitamin B _1, vitamin B _2, vitamin B _6, vitamin B _12, folic acid, niacin, biotin, pantothenic acid, vitamin a, vitamin D, vitamin K and derivatives thereof Vitamins such as menthol, camphor, peppermint oil, eucalyptus oil and the like.

  The composition for treating hemorrhoids of the present invention can be formulated into suppositories, external ointments, injectable ointments, creams, gels and the like by a general production method.

  The base used in the composition for treating hemorrhoids of the present invention is not particularly limited as long as it is generally used for suppositories, external ointments, injection ointments, creams, gels, and the like. Surfactants, solubilizers, preservatives, antioxidants, fragrances and the like can be blended.

  As fats and oils, soybean oil, soybean hardened oil, cacao butter, hardened oil, sesame oil, castor oil, cottonseed oil, wheat germ oil, rapeseed oil, peanut oil, olive oil, saflower oil, sunflower oil, phytosterol, kaunauba wax, beeswax, White beeswax, Owl, Medium chain fatty acid triglyceride, Tri (capryl / capric acid) glycerin, Triisoctanoic acid glycerin, Hard fat, Lanolin, Polyethylene ethylene lanolin, Squalane, Squalene, Liquid paraffin, Paraffin, Gelatinized hydrocarbon, Microcrystalline wax Petrolatum, white petrolatum, cetanol / polyoxyethylene cetyl ether mixed wax, cetanol / polyoxyethylene cetyl ether / sodium lauryl sulfate mixed wax, cetanol / polysorbate mixed Wax, myristyl alcohol, cetanol / polyethylene glycol fatty acid ester mixed wax, cetanol / polyoxyethylene sorbitan fatty acid ester mixed wax, cholesterol, myristic acid, stearic acid, palmitic acid, behenic acid, isostearic acid, isostearyl palmitate, oleic acid, Oleyl alcohol, stearyl alcohol, behenyl alcohol, octyldodecanol, isostearyl alcohol, cetanol, cetostearyl alcohol, octanediol, hexyldecanol, lauryl alcohol, isopropyl myristate, octyldodecyl myristate, cetyl myristate, myristyl myristate, isopropyl palmitate Cetyl palmitate, dextrin palmitate, Decyl oleate, diisopropyl adipate, diisobutyl adipate, dioctyl adipate, diglyceryl adipate mixed fatty acid ester, diethyl sebacate, diisopropyl sebacate, ethyl linoleate, isopropyl linoleate, cetyl octanoate, hexadecyl isostearate, cetyl alcohol Fatty acid ester, batyl monostearate, hexyl laurate, cetyl lactate, lanolin fatty acid isopropyl, dimethylpolysiloxane, methylphenylpolysiloxane, dimethylpolysiloxane / methyl (polyoxyethylene) siloxane copolymer, dimethylpolysiloxane / silicon dioxide mixture , Silicone oil, crotamiton and the like.

  Surfactants include glycerin fatty acid ester, propylene glycol fatty acid ester, polyethylene glycol fatty acid ester, sucrose fatty acid ester, fatty acid polyoxyl such as stearic acid polyoxyl, coconut oil fatty acid, coconut oil fatty acid diethanolamide, fatty acid diethanolamide, lecithin, sesquitin. Sorbitan fatty acid esters such as sorbitan oleate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid ether, polyoxyethylene behenyl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene alkyl ether , Polyoxyethylene palm oil fatty acid glyceryl, polyoxyethylene sorbitan fatty acid ester (polysorbate) Polyoxyethylene alkyl ether (cetomacrogol), sodium polyoxyethylene alkyl ether phosphate, polyoxyethylene octylphenyl ether, polyoxyethylene oleylamine, polyoxyethylene sorbid beeswax, polyoxyethylene lanolin, polyoxyethylene aralkyl ether Stearyl alcohol mixture, polyoxyethylene polycyclic phenyl ether ammonium sulfate, sodium lauryl sulfate, lauric acid diethanolamide, sodium lauroyl sarcosine, polyoxyethylene ethylene oleyl ether, sodium polyoxyethylene lauryl ether, alkylallyl polyether alcohol, Higher alcohol sulfate, N-cocoyl-L-arginine ethyl ester DL-pyrrole Carboxylate, sodium N-cocoyl-N-methylaminoethylsulfonate, polyethylene glycol N-methyl-2-pyrrolidone monostearate, sodium N-acyl-L-glutamate, allyl glycidyl ether, alkyldiaminoethylglycine hydrochloride, Alkylbenzenesulfonate, alkylbenzenesulfonate / alkylnaphthalenesulfonate mixed emulsifier, sodium dodecylbenzenesulfonate, ammonium nonylphenoxypolyoxyethylene ethane sulfate, phospholipid, ethylene glycol monomethyl ether, diethylene glycol monobutyl ether, dioctyl sodium sulfo Succinate, dibutate sodium, methyl acrylate / -2-ethylhexyl acrylate copolymer resin emulsion, silicone resin Marujon, pentaerythritol still citric acid higher fatty acid ester, beeswax, nonionic emulsifier mixture, and the like.

  Examples of solubilizers include purified water, ethanol, butanol, propanol, isopropanol, isobutanol, propylene glycol, 1,3-butylene glycol, dipropylene glycol, ethylene glycol, polyethylene glycol, fructose, glucose, sucrose, lactose, xylitol, Examples thereof include mannitol, sorbitol, trehalose, cyclodextrin and derivatives thereof.

  Examples of preservatives include parabens, phenoxyethanol, sodium benzoate, sodium dehydroacetate, hinokitiol, and benzyl alcohol.

  Antioxidants include sodium nitrite, sodium bisulfite, sodium sulfite, sodium pyrosulfite, ascorbic acid and salts or derivatives thereof, alpha thioglycerin, erythorbic acid, cysteine hydrochloride, citric acid, tocopherol and salts or derivatives thereof, Potassium isocyaninate, dibutylhydroxytoluene, butylhydroxyanisole, soy lecithin, sodium thioglycolate, sodium thiomalate, 1,3-butylene glycol, benzotriazole, pentaerythrityl-tetrakis [3- (3,5- Di-t-butyl-4-hydroxyphenyl) propionate], propyl gallate, 2-mercaptobenzimidazole and the like.

  Perfumes include menthol, camphor, bergamot, lavender, pine, rose otto, winter green, citronella, tea tree, peppermint, lemon, lemongrass, lemon eucalyptus, rosemary camphor, clove, geranium bourbon, marjoram sweet, lavandin, Rosewood, Palmarosa, Petit Goren, Cypress, Cinnamon, Juniper, Orange Sweet, Spike Lavender, Time Timor, Time Linalor, Basil, Hyssop, Helichrysum, Mandarin, Eucalyptus Davis, European Red Pine, Labansara Aromatica, Lemon Verbena, Lemon Balm, Roman Chamomile, Ylang Ylang, Chamomile German, Chamomile Roman, Cayupute, Clarisage, Grape Roots, Sandalwood, Cedarwood Atlas, Cedarwood Virginia, Jasmine Absolute, Spearmint, Time Tsuyanol, Niauri Cineall, Neroli, Basil Sweet, Patchouli, Palmarosa, Fennel Sweet, Petit Glen, Frankincense, Eucalyptus Globulus, Eucalyptus Radiata, Labansara, chamomile oil, cinnamon aldehyde, clove oil, clove oil, mint oil, piperonal, eucalyptus oil, rosin, rose water, roman chamomile oil, orange oil, turpentine oil and the like.

Examples 1-4
Hereinafter, the present invention will be described in more detail with reference to examples and test examples.
(Method for preparing suppository)
Suppositories were prepared with the compositions of Examples and Comparative Examples shown in Tables 1 and 2 below. The other components were sequentially dissolved or dispersed in a hard fat (40 ° C. to 60 ° C.) heated and melted and mixed. After cooling to about 50 ° C., the suppository container was filled and further cooled and molded to obtain a suppository. Unless otherwise specified, Carbopol 980NF manufactured by Noveon is used as the carboxyvinyl polymer, Erojil manufactured by Nippon Aerosil is used as the light silicic acid, and vitepsol E85 and witepsol W35 manufactured by Sasol are used as the hard fat. It was.

Test example 1
(Stability evaluation method)
The evaluation was carried out with reference to the evaluation method described in JP-A-7-304669. The suppository was stored for 2 weeks at a temperature of 65 ° C. and a humidity of 75%, and then the vasoconstrictor (tetrahydrozoline hydrochloride or naphazoline hydrochloride) was quantified by high performance liquid chromatography (HPLC method). The stability (%) of the vasoconstrictor contained in each specimen was calculated based on the residual ratio in the mass comparison with that immediately after production.

  The suppositories of Examples 1-3 and Comparative Examples 1-4 were evaluated with n = 3, and the suppositories of Example 4, Comparative Examples 5 and 6 were evaluated with n = 1.

  The composition and results are shown in the table. In addition, the number of the component in a table | surface shows mg / piece (1650 mg), and the number of stability shows%.

  As apparent from the table, the suppository (Comparative Example 2) having a composition containing a vasoconstrictor, a local anesthetic and an anti-inflammatory agent and not containing both a carboxyvinyl polymer and an organic acid has stability of the vasoconstrictor. It was shown to be extremely bad.

  In suppositories (comparative examples 1, 3, 4, 5 and 6) having a composition containing a vasoconstrictor, a local anesthetic and / or an anti-inflammatory agent and either a carboxyvinyl polymer or an organic acid, Increased stability of the shrink agent. Furthermore, suppositories (Examples 1, 2 and 3) containing both carboxyvinyl polymer and organic acid were proved to have extremely high stability of the vasoconstrictor (with stability of 95% or more). there were). In particular, it was proved that the suppositories of Examples 1 and 2 have significantly improved stability of the vasoconstrictor (tetrahydrozoline hydrochloride) as compared with Comparative Examples 3 and 4.

Examples 5-6
Suppositories of Examples 5 to 7 and Comparative Example 7 were produced in the same manner as in Examples 1 to 4 with the formulations shown in the following table.

Test example 2
The suppository was stored at a temperature of 50 ° C. for 2 months, and tetrahydrozoline hydrochloride was quantified by high performance liquid chromatography (HPLC method). The stability (%) of tetrahydrozoline hydrochloride contained in each specimen was calculated based on the residual ratio in comparison with mass immediately after production.

  The composition and results are shown in the table. In addition, the number of the component in a table | surface shows mg / piece (1650 mg), and the number of stability shows%.

  As is apparent from the table, it became clear that a suitable stability was exhibited depending on the amount of the acid.

Test Example 3 (Drug Release Test)
With respect to the drug release properties of the preparations obtained in Example 5 and Comparative Example 7, drug release properties were tested by the method described below.

  Dialysis membrane method (Katsu Yamazaki, Soichi Ito, Kazuhisa Tabe, “Comparison of suppository dissolution test methods”, pharmaceuticals using a suppository dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) equipped with a tube for encapsulating suppositories Research, 28, 232 (1997)). Specifically, it is as follows.

  As the release solution, a phosphate buffer solution (pH 7.2) was prepared by adding 34.7 mL of 0.2N sodium hydroxide test solution and water to 50 mL of 0.2 M potassium dihydrogen phosphate test solution for buffer solution to make 200 mL. The set temperature of the release solution was 37 ° C., and the measurement tube was a cellulose tube (Dialysis Membrene, Size 36 Viskase Sales Corporation) (about 15 cm). The lower end of the cellulose tube was stopped with a closer, and a suppository that had been weighed in advance from the upper end of the tube was placed, and sealed with a closer to prevent air from entering. After a certain time, 1 mL was sampled from the container. After sampling, the same amount of release solution was replenished. The results of drug release measured by the HPLC method are shown in the table.

  As is apparent from the table, in the present invention, although a carboxyvinyl polymer and an acid were blended at the same time, there was no significant difference in drug release properties from a formulation not blended with an acid.

Example 7
A suppository was produced in the same manner as in Example 4 except that naphazoline hydrochloride was replaced with phenylephrine hydrochloride.

Examples 8-9
A cream was prepared according to a conventional method with the formulation shown in the table. The numbers in the table indicate mass%.

  The composition for treating hemorrhoids of the present invention contains a vasoconstrictor, a local anesthetic, and an anti-inflammatory agent, and is effective for treating hemorrhoids and is effective for all symptoms of bleeding, pain, itching and inflammation. It can be used as an ointment, injectable ointment, cream or gel.

Claims (8)

(A) one or more vasoconstrictors selected from the group consisting of tetrahydrozoline hydrochloride, naphazoline hydrochloride and phenylephrine hydrochloride,
(B) one or more local anesthetics selected from the group consisting of lidocaine and dibucaine;
(C) glycyrrhetinic acid,
(D) carboxyvinyl polymer,
(E) one or more selected from the group consisting of citric acid, tartaric acid and adipic acid,
Contain,
A composition for treating hemorrhoids , wherein one or more compounding amounts selected from the group consisting of citric acid, tartaric acid and adipic acid are 0.3 to 2.5% by mass relative to the total amount of the composition .   The composition for treating hemorrhoids according to claim 1, wherein the vasoconstrictor is one or two selected from the group consisting of tetrahydrozoline hydrochloride and naphazoline hydrochloride. The composition for treating hemorrhoids according to claim 1 or 2 , wherein the local anesthetic is lidocaine. The composition for treating hemorrhoids according to any one of claims 1 to 3 , wherein the compounding amount of the vasoconstrictor is 0.005 to 0.5 mass% with respect to the total amount of the composition. The composition for treating hemorrhoids according to any one of claims 1 to 4 , wherein the compounding amount of the local anesthetic is 0.05 to 6% by mass with respect to the total amount of the composition. The composition for treating hemorrhoids according to any one of claims 1 to 5 , wherein the blending amount of glycyrrhetinic acid is 0.5 to 2% by mass with respect to the total amount of the composition. The composition for treating hemorrhoids according to any one of claims 1 to 6 , wherein the compounding amount of the carboxyvinyl polymer is 0.2 to 15% by mass relative to the total amount of the composition. The composition for treating hemorrhoids according to any one of claims 1 to 7 , wherein the composition for treating hemorrhoids is a suppository, an external ointment or an injection ointment.