JP6684327B2 - Method for producing external medicine exhibiting foam when used - Google Patents

Description

  TECHNICAL FIELD The present invention relates to a method for producing an external medicine, and more particularly, to a method for producing an external medicine that is foamy when used.

  Topical pharmaceutical formulations are roughly classified into five types: lotion formulations, ointment formulations, cream formulations, spray aerosol formulations, and foam aerosols. Among them, a dosage form that exhibits a foamy shape when used, such as a spray aerosol formulation or a foam aerosol formulation, can obtain a large surface area during administration and can deliver the composition to a fine portion, so that the composition is uniform. In addition, it has attracted attention because it is possible to administer a drug in a wide area to the affected area with a reduced amount of embedded stimulation (see, for example, Patent Document 1). Examples of such a dosage form that exhibits a foamy shape during use include an aerosol dosage form that forms bubbles using a propellant such as liquefied gas (see, for example, Patent Document 2), and a pump foam without using a propellant. Non-aerosol dosage forms are known which form bubbles by taking in air using a non-aerosol former container such as a mer or squeeze foamer. The aerosol dosage form has a high possibility of irritating the skin to the gas composition itself for ejecting the aerosol, and due to the heightened awareness of environmental problems in recent years, it is possible to switch to a dosage form that does not use volatile gas. There is a growing interest in non-aerosol dosage forms, which is a means of forming foam and the like with a pump-former without being filled with a gas for foaming. However, as compared with aerosol foaming, in which the vaporization pressure and the physicochemical properties of the gas itself contribute greatly to foaming, the non-aerosol is greatly affected by the physicochemical properties of the surfactant, and the anionic surfactant and cationic Most of them are rinsed and used with a surfactant. That is, in the field of cosmetics, studies have been conducted to improve the foam quality and feeling in non-aerosol dosage forms centering on hair cosmetics, detergents, etc., and non-aerosol foam containing a surfactant and a polymer compound. Cosmetic compositions (for example, refer to Patent Document 3), foamy cosmetics containing a water-soluble alcohol, a nonionic surfactant and N-alkylpyrrolidone (for example, refer to Patent Document 4), etc. have been reported. ing. However, in the foamy cosmetic, the alkyl chain length of N-alkylpyrrolidone preferably has 8 to 18 carbon atoms, and it has been known that when the alkyl chain length is short, the foamability deteriorates. .

  On the other hand, studies on non-aerosol dosage forms in the pharmaceutical field have not been conducted much, and in an antipruritic composition containing paraben as a preservative applicable to a water-soluble drug, a fatty acid is used as a surfactant. A foaming agent characterized by being blended with an alkylolamide and a polyoxyalkylene aliphatic ether having an aliphatic group having 11 to 18 carbon atoms and having 7 to 40 repeating units of polyoxyalkylene. A composition (for example, refer to Patent Document 5) and a water-based composition for non-aerosol type foam agent capable of stably solubilizing a poorly water-soluble drug have been reported (for example, refer to Patent Document 6). ). However, the solvent used to solubilize a water-soluble or sparingly water-soluble drug is greatly affected by the chemical structure of the drug, etc. Therefore, when the drug is different, the usable solvent also greatly changes. Furthermore, the amount of solvent required to solubilize the drug is not necessarily small, and the surfactants that exert preferable properties in the non-aerosol foam composition are also very limited depending on the type and amount of the solubilizing solvent used. It becomes a thing.

  The present invention is a non-aerosol externally applied pharmaceutical composition containing a poorly water-soluble solvent (polar solvent), while containing a solvent amount capable of sufficiently dissolving a poorly water-soluble active ingredient, foam forming property, Agents such as foam quality / sustainability such as fineness of foam during use, feeling of use such as stickiness and tightness, discharge failure due to clogging, occurrence of liquid dripping (foam dripping), side effects related to safety such as skin irritation, etc. The present invention relates to a topical pharmaceutical composition for the purpose of solving the problems in form.

JP, 2007-314494, A JP, 10-158122, A JP, 10-273415, A JP 2002-161020 A JP, 2007-137813, A JP2012-214422A

  The present invention has been made under such circumstances, in an external pharmaceutical composition containing a polar solvent in an amount sufficient to solubilize a poorly water-soluble drug, and exhibiting a foamy state at the time of use. It solves the problems that occur in the relationship between the solvent and the surfactant, and has foam forming properties, foam quality and sustainability such as fineness of the foam, stickiness, feeling of use such as tightness, poor discharge due to clogging, liquid It is an object to solve the problems in the dosage form such as the occurrence of sagging (foam sagging) and the like during use, and the side effects on safety such as skin irritation.

In view of such a situation, the present inventors, in the pharmaceutical composition for external use characterized by being foamy at the time of use, the problems that occur in the relationship between the polar solvent and the surfactant, especially the foam-forming property and As a result of earnest research efforts in search of means for solving problems relating to persistence, feeling of use, skin irritation, etc., 1) a polar solvent and 2) a nonionic surfactant are contained, and they are foamy when used. The present invention has been completed by finding such characteristics in a pharmaceutical composition for external use that exhibits That is, the present invention relates to the following method for producing a pharmaceutical composition for external use.
<1> An external pharmaceutical composition containing 1) a polar solvent and 2) a nonionic surfactant, which is in the form of foam when used.
<2> The polar solvent is one or more selected from N-alkyl-2-pyrrolidone having an alkyl chain having 1 to 4 carbon atoms, carbonic acid diester, crotamiton, acylated product and etherified product of polyhydric alcohol. The external pharmaceutical composition according to <1>, which is
<3> The nonionic surfactant is a fatty acid monoglyceride to which polyoxyethylene may be added, a fatty acid ester of polyglycerin, a sorbitan fatty acid ester to which polyoxyethylene may be added, a polyoxyethylene fatty acid ester. , An alkyl or alkenyl ether of polyoxyethylene, a polyoxyethylene polyoxypropylene alkyl ether, a fatty acid diethanolamide, and a polyoxyethylene castor oil which may be hydrogenated, <1> or the external pharmaceutical composition described in <2>.
<4> The external pharmaceutical composition according to any one of <1> to <3>, which further contains an anionic surfactant.
<5> The external pharmaceutical composition according to any one of <1> to <4>, wherein the foam formed during use is due to a pump former.

  ADVANTAGE OF THE INVENTION According to this invention, in the external pharmaceutical composition which shows a foamy state at the time of use, especially, the external pharmaceutical composition for pump type | formula, the means which solves the problem which arises in the relationship between a polar solvent and a nonionic surfactant. Can be provided.

<1> Polar solvent which is an essential component of the pharmaceutical composition for external use of the present invention The pharmaceutical composition for external use which is foamy when used in the present invention contains 1) a polar solvent and 2) a nonionic surfactant. It is characterized by being a pharmaceutical composition for external use. The polar solvent of the present invention is not particularly limited as long as it is a drug that can be contained in a pharmaceutical composition for external use that is foamy at the time of use, in particular, a polar solvent in an amount sufficient to solubilize a poorly water-soluble drug. Suitable examples include N-alkyl-2-pyrrolidone having an alkyl chain having 1 to 4 carbon atoms, carbonic acid diester, crotamiton, acylated products and etherified products of polyhydric alcohols, and the like. It is preferable to select and contain one or more solvents selected from such polar solvents. These polar solvents, by containing the nonionic surfactant described below in the pharmaceutical composition for external use, while containing a polar solvent for solubilizing a poorly water-soluble drug, foam formation and sustainability, It is possible to provide a pharmaceutical composition for external use which is excellent in usability and skin irritation. In order for the polar solvent of the present invention to exhibit the above-mentioned action, the polar solvent is preferably contained in a total amount of 0.1 to 12 mass% with respect to the total amount of the pharmaceutical composition for external use, and 0.5 to 10 mass. % Is more preferable. This is because if the amount is too small, it is difficult to sufficiently solubilize the drug, and if the amount is too large, the foaming property, sustainability, and usability may be impaired. Suitable examples of the N-alkyl-2-pyrrolidone of the present invention include N-alkyl-2-pyrrolidone having an alkyl group having 1 to 4 carbon atoms, and particularly N-methyl-2-pyrrolidone and N-ethyl- 2-pyrrolidone can be preferably exemplified. N-methyl-2-pyrrolidone is a polar solvent having excellent properties, can be mixed with most organic solvents and water, and has a track record of being used as a pharmaceutical additive. Suitable examples of the carbonic acid diester of the present invention include alkylene carbonate having a cyclic structure, dialkyl carbonate having two linear or branched hydrocarbon groups bonded to each other, and propylene carbonate is particularly preferable. Crotamiton, which is the polar solvent of the present invention, is a polar solvent having excellent solubility and can suppress the decomposition of active ingredients such as steroids and vitamins and improve the stability. As the acylated product of the polyhydric alcohol of the present invention, triglycerides of short-chain or medium-chain fatty acids or esters of short-chain or long-chain fatty acids and (poly) ethylene glycol can be preferably exemplified, and more preferably triacetin and trica Examples thereof include prillin, glycerin trioctanoate and glycerin tri (caprylic / capric acid), (poly) ethylene glycol monoacetate, polyethylene glycol monolaurate and polyethylene glycol monooleate. As the etherified product of the polyhydric alcohol of the present invention, polyethylene glycol alkyl ether, polyoctyethylene alkyl ether and polyoxyethylene / polyoxypropylene alkyl ether can be preferably exemplified, and more preferable ones are diethylene glycol monoethyl ether and diethylene glycol. Examples include monobenzyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, polyoxyethylene lauryl ether, and polyoctyethylene cetyl ether.

<2> Nonionic surfactant which is an essential component of the external pharmaceutical composition of the present invention The external pharmaceutical composition of the present invention is characterized by containing a nonionic surfactant as an essential component. Examples of the nonionic surfactant of the present invention include fatty acid monoglyceride to which polyoxyethylene may be added, fatty acid ester of polyglycerin, polyoxyethylene fatty acid ester, and sorbitan fatty acid ester to which polyoxyethylene may be added. , 1 or 2 selected from nonionic surface active agents such as polyoxyethylene alkyl or alkenyl ether, polyoxyethylene polyoxypropylene alkyl ether, fatty acid diethanolamide and optionally hydrogenated polyoxyethylene castor oil. It is preferable to select one or more species to be contained in the external pharmaceutical composition of the present invention. Here, the average addition mole number of polyoxyethylene or polyoxypropylene is preferably 2 to 90. The average number of carbon atoms of the fatty acid constituting the fatty acid ester is preferably 6 to 24, more preferably 6 to 22. The alkyl group and the alkenyl group preferably have an average carbon number of 10 to 22. The fatty acid constituting the fatty acid diethanolamide preferably has 10 to 18 carbon atoms, and particularly preferably 10 to 14 carbon atoms. Furthermore, a particularly preferred embodiment of the nonionic surfactant in the present invention is polyoxyethylene (average addition mole number 6 to 10) fatty acid (average carbon number 6 to 14) glyceryl or fatty acid diethanolamide, and polyoxyethylene (average Addition mole number 2 to 50) Alkyl or alkenyl ether and / or polyoxyethylene (average addition mole number 30 to 90) Hardened castor oil-containing form, polyoxyethylene (average addition mole number 2 to 50) alkyl or In addition to alkenyl ether, fatty acid monoglyceride to which polyoxyethylene may be added, polyglycerin fatty acid ester, polyoxyethylene (average addition mole number: 5 to 70) fatty acid ester, polyoxyethylene (average addition mole number: 10 to 50) ) May be added to sorbitan fatty acid (carbon 12-18) ester, polyoxyethylene (average addition mole number 2-50) polyoxypropylene (average addition mole number 2-50) alkyl ether, optionally hydrogenated polyoxyethylene (average addition mole number 30- 90) A form in which one or more selected from castor oil is selected and contained is preferable. In the above preferred embodiment, the mass ratio of polyoxyethylene fatty acid glyceryl or fatty acid diethanolamide to polyoxyethylene alkyl or alkenyl ether and / or polyoxyethylene which may be hydrogenated is 1: 4 to 4: 1. Is particularly preferable in the sense of stabilizing the solubilization system. Furthermore, in the above preferred embodiment, polyoxyethylene (average addition mole number 2 to 50) alkyl or alkenyl ether, fatty acid monoglyceride to which polyoxyethylene may be added, fatty acid ester of polyglycerin, polyoxyethylene ( Fatty acid ester having an average addition mole number of 5 to 70), sorbitan fatty acid (having a carbon number of 12 to 18) ester to which polyoxyethylene (average addition mole number of 10 to 50) may be added, polyoxyethylene (average addition mole number of 2) To 50) polyoxypropylene (average addition mole number 2 to 50) alkyl ether, polyoxyethylene which may be hydrogenated (average addition mole number 30 to 90), one or more selected from castor oil. A mass ratio of nonionic surfactants of 1: 4 to 4: 1 stabilizes the solubilized system. Preferred in the sense that. Further, the nonionic surfactant of the present invention may be used alone as one type of nonionic surfactant, but since it is difficult to obtain a good foam quality, two or more types of nonionic surfactants are combined. It is preferable to use. The external pharmaceutical composition of the present invention contains only a nonionic surfactant because it may be used in a mode that does not involve a washing action when it is administered to skin that may be damaged. Preferably. The content of the nonionic surfactant in the external pharmaceutical composition of the present invention is preferably 0.5 to 10% by mass, more preferably 1 to 8% by mass, based on the total amount of the pharmaceutical composition.

  Furthermore, in the external pharmaceutical composition of the present invention, a form in which an anionic surfactant is added to the nonionic surfactant is also preferable. Only one anionic surfactant can be selected and contained in the external pharmaceutical composition, or a plurality of surfactants can be selected and contained. In the external pharmaceutical composition of the present invention, a preferable state of the active ingredient and the formulation ingredient can be created by adding an anionic surfactant to the nonionic surfactant. On the other hand, it is preferable that the cationic surfactant and the amphoteric surfactant are not substantially contained.

<3> Anionic Surfactant of External Pharmaceutical Composition of the Present Invention The external pharmaceutical composition of the present invention preferably contains an anionic surfactant in addition to the above essential components. Examples of the anionic surfactant include fatty acid salts having 12 to 24 carbon atoms such as sodium laurate, potassium palmitate and arginine stearate; alkyl sulfate ester salts such as sodium lauryl sulfate, potassium lauryl sulfate and sodium cetyl sulfate. Alkyl ether sulfates such as polyoxyethylene lauryl sulfate triethanolamine; N-acyl sarcosine salts such as lauroyl sarcosine sodium; fatty acids such as N-stearoyl-N-methyl taurine sodium, N-myristoyl-N-methyl taurine sodium Amidosulfonates; alkyl phosphates such as sodium monostearyl phosphate; sodium polyoxyethylene oleyl ether phosphate, sodium polyoxyethylene stearyl ether phosphate, poly Polyoxyethylene alkyl ether phosphates such as sodium xyethylene cetyl ether phosphate; long-chain sulfosuccinates such as sodium di-2-ethylhexyl sulfosuccinate; monosodium N-lauroyl glutamate, sodium N-stearoyl-L-glutamate, Examples include long-chain N-acylglutamates such as arginine N-stearoyl-L-glutamate, sodium N-stearoylglutamate, and sodium N-myristoyl-L-glutamate. Such an anionic surfactant, by containing the nonionic surfactant in the pharmaceutical composition for external use of the present invention, the problems that occur in the relationship between the polar solvent and the surfactant, among them, foam such as fineness of foam. It is possible to solve problems such as quality, sustainability, and feeling of use. The preferable content of the anionic surfactant in the external pharmaceutical composition of the present invention is 0.001 to 5% by mass, more preferably 0.01 to 3% by mass, based on the total amount of the pharmaceutical composition. . This is because, if the content of the anionic surfactant is too low or too high, the foam properties and the feeling of use with favorable characteristics cannot be obtained, and particularly when it is high, the action such as skin irritation occurs. is there.

<4> Drug that can be contained in the external pharmaceutical composition of the present invention The external pharmaceutical composition of the present invention may contain a drug that can be solubilized in the polar solvent, in particular, a poorly water-soluble drug. I can. As the poorly water-soluble drug, any drug that can be solubilized in the polar solvent can be applied without particular limitation, and steroids, vitamins, heparin-like substances and the like can be preferably exemplified. The steroids are not particularly limited as long as they have a steroid skeleton, and sex hormones, glucocorticoids (glucocorticoids), mineralocorticoids and the like can be preferably exemplified, and glucocorticoids are particularly preferable. . Examples of the glucocorticoid include cortisone, hydrocortisone, cortisone such as fludrocortisone acetate, prednisolone, prednisolone such as methylprednisolone, dexamethasone and its derivative, betamethasone and its derivative, clobetasol and its derivative. Examples thereof include phosphoric acid ester, valeric acid ester, butyric acid ester, and propyroic acid ester. Suitable examples of the vitamins include vitamin A or its derivative, vitamin B or its derivative, oil-soluble vitamin C or its derivative, vitamin D or its derivative, vitamin E or its derivative, vitamin K or its derivative. The heparin-like substance means a substance obtained by sulfating a mucopolysaccharide, and preferred examples thereof include chondroitin sulfates such as heparin, chondroitin sulfate D, and chondroitin sulfate E. Other drugs include, for example, antifungal agents such as terbinafine and butenafine, anti-inflammatory agents such as suprofen, ketotifen, ketoprofen and indomethacin, antibiotic agents such as azithromycin, immunosuppressive agents such as tacrolimus and cyclophosphamide, and nalfurafine. The antipruritic agent and the like can be preferably exemplified. A topical pharmaceutical composition which exhibits a foamy state when used in the present invention has excellent foam properties by solubilizing the poorly water-soluble drug in a polar solvent and incorporating it into a topical pharmaceutical composition together with a nonionic surfactant, It is possible to provide a pharmaceutical composition for external use having a feeling of use, skin safety and the like.

<5> External pharmaceutical composition of the present invention The external pharmaceutical composition of the present invention contains 1) a polar solvent and 2) a nonionic surfactant as essential components, and exhibits a foamy external pharmaceutical composition when used. Is. The topical pharmaceutical composition of the present invention may contain, in addition to the above-mentioned essential components, any components for formulation which are usually used in pharmaceutical compositions. Such components include, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, palm oil, palm oil, liquid lanolin, hardened palm oil, Oils, waxes such as hydrogenated oil, mokuro, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, carrot wax, lanolin, reduced lanolin, hard lanolin, jojoba wax; liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, vaseline, Hydrocarbons such as microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid; cetyl alcohol, stearyl alcohol, isostearyl Higher alcohols such as rucol, behenyl alcohol, octyldodecanol, myristyl alcohol, cetostearyl alcohol; etc .; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, ethylene glycol di-2-ethylhexanoate, neopentyl glycol dicaprate, di Synthetic ester oils such as glycerin-2-heptylundecanoate, glyceryl tri-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate and pentane erythritol tetra-2-ethylhexanoate Chains; chain polysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane, diphenylpolysiloxane; octamethylcyclotetrasiloxane, deca Cyclic polysiloxanes such as tylcyclopentasiloxane and dodecamethylcyclohexanesiloxane; Oil agents such as silicone oil such as amino-modified polysiloxane, alkyl-modified polysiloxane, modified polysiloxane such as fluorine-modified polysiloxane; polyethylene glycol, glycerin, 1, 3-butylene glycol, erythritol, sorbitol, xylitol, maltitol, propylene glycol, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol, 1, Polyhydric alcohols such as 2-octanediol; Moisturizing ingredients such as lactic acid and sodium lactate; Mica, talc, kaolin, synthetic mica, calcium carbonate, macamate which may be surface-treated Powders of gnesium, silicic acid anhydride (silica), aluminum oxide, barium sulfate, etc .; surface-treated, red iron oxide, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine blue, dark blue, titanium oxide, Inorganic pigments of zinc oxide; Mica titanium, fish phosphorus foil, bismuth oxychloride, and other pearl agents, which may be surface-treated; Red 202, Red 228, Red 226, which may be laked , Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204, etc .; Organic powders such as polyethylene powder, polymethylmethacrylate, nylon powder, organopolysiloxane elastomer, etc .; para-aminobenzoic acid type External line absorber; Anthranilic acid type UV absorber; Salicylic acid type UV absorber ;; Cinnamic acid type UV absorber ;; Benzophenone type UV absorber; Sugar type UV absorber; 2- (2'-hydroxy-5'-t Preferred examples include ultraviolet absorbers such as -octylphenyl) benzotriazole and 4-methoxy-4'-t-butyldibenzoylmethane; lower alcohols such as ethanol and isopropanol; antibacterial agents such as phenoxyethanol. Furthermore, a polyhydric alcohol can be preferably exemplified as a solvent other than the polar solvent, and the polyhydric alcohol can be used alone or in combination with a plurality of polyhydric alcohols in a pharmaceutical composition. Preferable examples of the polyhydric alcohol include 1,3-butylene glycol, propylene glycol, and 1,2-pentanediol, and 1,3-butylene glycol is particularly preferable. The content of the polyhydric alcohol is 5 to 40% by mass, more preferably 8 to 35% by mass. By using these, according to a conventional method, a solubilized pharmaceutical composition is processed, and a pharmaceutical composition for external use that exhibits a foamy state at the time of use, in particular, is processed into a non-aerosol pharmaceutical external preparation by filling a pump type former. can do. In addition, the external pharmaceutical composition exhibiting a foam-like state during use of the present invention can be applied without particular limitation as long as it is a pharmaceutical external preparation exhibiting a foam-like state during use. For example, it is filled in a gas-filled type former container. The external pharmaceutical composition and the external pharmaceutical composition to be filled in the non-gas type former container can be preferably exemplified, and the external pharmaceutical composition of the type to be filled in the non-gas type former container is particularly preferable. This is because the external preparation of the type filled in the non-gas type pump former container has excellent foam quality and uniformity during use.

The external pharmaceutical composition thus obtained is excellent in feeling of use such as fineness of foam, foam quality such as sustainability and good feel, and can be used in the form of foam at the time of use, without causing irritation smoothly. It can be spread over the affected area and the active ingredient can be evenly distributed over the affected area. According to such an aspect, when the drug is contained, the pharmacological action of the drug can be exerted at all. Further, the evaluation of the foam quality and the feeling of use of the present invention can be applied without particular limitation as long as the above characteristics can be evaluated, and is not limited to the sensitivity test described below.
Hereinafter, the present invention will be described in more detail with reference to examples.

  According to the formulation shown in Table 1 below, the external pharmaceutical composition 1 of the present invention was prepared. That is, the prescription ingredients were heated and stirred at 80 ° C., solubilized, and cooled to room temperature with stirring to obtain the external pharmaceutical composition 1 of the present invention. The external pharmaceutical composition 1 was filled in a pump former to obtain the external pharmaceutical 1 of the present invention. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition.

<Comparative Example 1>
Among the formulation ingredients shown in Table 1, a formulation (external pharmaceutical composition of Comparative Example 1) having a formulation excluding N-methyl-2-pyrrolidone and diisopropyl adipate, which are polar solvents, was prepared. The external preparation pharmaceutical composition of Comparative Example 1 was filled in a pump former to obtain the external preparation pharmaceutical composition of Comparative Example 1. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition.

<Comparative example 2>
The external pharmaceutical composition of Comparative Example 2 was prepared according to the following formulation. That is, the portion (1) was heated and solubilized at 80 ° C., and the components (2) whose temperature had been adjusted to 80 ° C. were mixed and dispersed under stirring. Then, the mixture was cooled to room temperature with stirring to obtain a pharmaceutical composition for external use of Comparative Example 2. The external preparation pharmaceutical composition of Comparative Example 2 was filled in a pump former to obtain the external preparation pharmaceutical composition of Comparative Example 2. The external medicine of Comparative Example 2 was an external medicine having a foamy form different from that of the external medicine of the present invention. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition.

<Comparative test 1>
The foam quality (foaming property, sustainability) and the feeling of use (stickiness, moist feeling) of the external medicine 1 of Example 1 and the external medicines of Comparative Examples 1 and 2 were evaluated according to the following methods.
(1) Foam quality (foaming property, persistence): Each of 10 subjects discharged each sample in a room kept at 25 ° C. and picked up to observe the foam quality (foaming property, persistence). went. The evaluation criteria are as follows.
◎ Very good (more than 8 subjects answered good)
○ Good (6 or more and less than 8 subjects answered good)
△ Somewhat bad (4 or more and less than 6 subjects answered good)
× Poor (less than 4 subjects answered good)
(2) Feeling of use (feeling of stickiness, feeling of moistness): Ten test subjects discharged each sample in a room kept at 25 ° C. and picked up by hand to evaluate feeling of use (feeling of stickiness, feeling of moistness). The evaluation criteria are as follows.
◎ Very good (more than 8 subjects answered good)
○ Good (6 or more and less than 8 subjects answered good)
△ Somewhat bad (4 or more and less than 6 subjects answered good)
× Poor (less than 4 subjects answered good)

  When the foam quality and the feeling of use of the external medicine 1 of Example 1 and the external medicines of Comparative Examples 1 and 2 were evaluated, the external medicine 1 of the present invention was a topical medicine excellent in foam quality and feeling of use. I understood. On the other hand, it was found that when the polar solvent was removed from the external medicine 1 of the present invention, the foam quality and the feeling of use were significantly reduced.

  Similar to Example 1, the external pharmaceutical compositions 2 to 19 of the present invention were prepared according to the formulations shown in Table 4 below. This was filled in a pump former to obtain external medicines 2 to 19 of the present invention. Furthermore, according to the test method shown in Example 2, the quality of foam (foaming property, sustainability) and the feeling of use (moist feeling) of the external medicines 2 to 19 were evaluated. It was found that the external medicines 2 to 19 of the present invention are external medicine compositions excellent in foam quality and feeling in use. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition.

  Similar to Example 1, the external pharmaceutical compositions 20 to 22 of the present invention were prepared according to the formulations shown in Table 5 below. This was filled in a pump former to obtain external medicines 20 to 22 of the present invention. Further, according to the test method shown in Example 2, the foam quality (foaming property, sustainability) and the feeling of use (moisturizing feeling, sticky feeling) of the external medicines 20 to 22 were evaluated. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition. It was found that the external medicines 20 to 22 of the present invention are external medicine compositions excellent in foam quality and feeling in use.

  External pharmaceutical compositions 23 and 24 of the present invention and external pharmaceutical compositions of Comparative Example 4 were prepared according to the formulations shown in Table 6 below. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition. The state immediately after preparation of the pharmaceutical composition for external use was visually observed (no turbidity: ◯, with turbidity: x). Furthermore, the external pharmaceutical compositions 23 and 24 and the external pharmaceutical composition 100 (g) of Comparative Example 4 were put into a beaker, stirred at 3000 rpm for 1 minute, and allowed to stand for 2 minutes, whereby the boundary line between the foam and the solution became clear. The height (mm) of the generated foam was measured, and the foam quality (foam with fine texture was obtained after stirring (○), coarse foam was obtained after stirring (Δ), and no foam was obtained after stirring ( X)) was visually confirmed. The results are shown in Table 6. The external pharmaceutical composition of the present invention showed excellent foam-forming ability. On the other hand, the external use pharmaceutical composition of Comparative Example 3 had poor foaming and foam quality as compared with the external use pharmaceutical composition of the present invention.

  Topical pharmaceutical compositions 25 and 26 of the present invention were prepared according to the formulations shown in Table 7 below. In addition, the content of the formulation component in the table is shown by mass% with respect to the total amount of the composition. The state immediately after preparation of the pharmaceutical composition for external use was visually observed (no turbidity: ◯, with turbidity: x). Further, 100 (g) of the external pharmaceutical compositions 25 and 26 were placed in a beaker, stirred at 3000 rpm for 1 minute, and allowed to stand for 2 minutes, and the height of the foam generated when the boundary line between the foam and the solution became clear ( mm) was measured to visually confirm the foam quality (fine bubbles were obtained after stirring (○), coarse bubbles were obtained after stirring (Δ), and no bubbles were obtained after stirring (×)). . The results are shown in Table 7. The external pharmaceutical composition of the present invention showed excellent foam-forming ability.

  The external pharmaceutical compositions 27 and 28 of the present invention and the external pharmaceutical composition of Comparative Example 4 are prepared according to the formulations shown in the following table. According to the method described in Example 6, foaming and foam quality of the external pharmaceutical compositions 27 and 28 of the present invention and the external pharmaceutical composition of Comparative Example 4 are examined. The topical pharmaceutical composition of the present invention is superior to the topical pharmaceutical composition of Comparative Example 4 in stability, foaming, sustainability, foam quality such as texture of foam, and feeling of use.

The present invention can be applied to medicine.

Claims (1)

A method for producing an external medicine, comprising 1) a polar solvent, 2) a nonionic surfactant, and 3) a polyhydric alcohol, which is foamy when used and which is used in a mode without cleaning action. hand,
A heating and stirring step of heating and stirring a mixture containing 1) to 3) to solubilize the mixture ;
A cooling step of cooling the mixture that has undergone the heating and stirring step to room temperature with stirring;
A filling step of filling the mixture having undergone the cooling step into a non-gas type former container,
The polar solvent is one or more selected from N-alkylpyrrolidone having an alkyl chain having 1 to 4 carbon atoms and carbonic acid diester,
The nonionic surfactant is a fatty acid monoglyceride to which polyoxyethylene may be added, a fatty acid ester of polyglycerin, a sorbitan fatty acid ester to which polyoxyethylene may be added, a polyoxyethylene fatty acid ester, polyoxy One or more selected from the alkyl or alkenyl ethers of ethylene, polyoxyethylene polyoxypropylene alkyl ether, fatty acid diethanolamide, and optionally hydrogenated polyoxyethylene castor oil,
The polyhydric alcohol is one or more selected from 1,3-butylene glycol, propylene glycol and 1,2-pentanediol,
A method for producing a pharmaceutical for external use, which comprises, as a surfactant, only the nonionic surfactant.