JP6322169B2 - Topical skin preparation - Google Patents

Description

  The present invention relates to a skin external preparation containing an arylacetic acid-based anti-inflammatory analgesic compound.

Conventionally, a skin external preparation containing an arylacetic acid-based non-steroidal anti-inflammatory component such as 4-biphenylacetic acid is known. For example, an anti-inflammatory analgesic gel ointment (Patent Document 1) containing 4-phenylacetic acid, an alkali containing a phenylacetic acid derivative-type anti-inflammatory analgesic agent, a water-soluble organic amine, a lower alcohol, and the like. And a water-soluble organic amine, the pH is 6
~ 7 anti-inflammatory analgesic patches (Patent Document 2), anti-inflammatory analgesics containing phenylacetic acid derivatives and menthols (Patent Document 3), and topical skin containing non-steroidal anti-inflammatory agents and refreshing agents An agent (Patent Document 4) and the like are known.
JP 59-222409 A JP-A 64-85913 JP 2003-286161 A JP-A-11-199522

Aryl acetate anti-inflammatory analgesic compounds such as 4-biphenylacetic acid have low solubility in solvents such as water, alkylene glycols such as propylene glycol, and alcohols such as ethanol under acidic conditions of pH 7 or less. Containing acidic solution (pH 4 to 6.5)
Is prepared, the precipitation of the compound from the solution is observed over time. For this reason, the preparation containing the compound usually has an alkaline pH (7 to 7) as in Patent Document 1.
9). However, human skin is slightly acidic (pH
4.5 to 6.5), when a preparation having a higher pH is applied to the skin, itching and redness may occur.

Patent Document 2 describes a patch containing 4-biphenylacetic acid and having a pH of 6 to 7. When preparing the patch, the pH of the 4-biphenylacetic acid solution is once adjusted to the alkaline region. The preparation was very complicated. Patent Document 3 discloses that 4
-Although the weakly acidic lotion agent (formulation example 2) and aerosol agent (formulation example 5) containing a biphenylacetic acid are described, there existed a problem in the stability of the agent.

Therefore, there has been a demand for a preparation that contains an arylacetic acid anti-inflammatory analgesic compound such as 4-biphenylacetic acid at a pH of 7 or less.

As a result of intensive studies in developing a preparation containing an arylacetic acid-based anti-inflammatory analgesic compound, the present inventors have suppressed the precipitation of the compound even at a pH of 7 or lower by using an alkylene glycol and a polyalkylene glycol together as a solvent. The present inventors have found that a stable preparation can be obtained, and have reached the present invention.

That is, the present invention includes the following aspects.
1. A skin external preparation containing an arylacetic acid anti-inflammatory analgesic compound or a pharmaceutically acceptable salt thereof, an alkylene glycol and a polyalkylene glycol, and having a pH of 7 or less,
2. The skin external preparation according to 1, wherein the polyalkylene glycol is 500 parts by mass or more with respect to 100 parts by mass of the arylacetic acid anti-inflammatory analgesic compound,
3. The external preparation for skin according to 1 or 2, wherein the arylacetic acid anti-inflammatory analgesic compound is 4-biphenylacetic acid,
4). The external preparation for skin according to any one of 1 to 3, which is a liquid agent or a gel agent,
5. The external preparation for skin according to any one of 1 to 4, which is for application.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a skin external preparation containing an arylacetic acid-based anti-inflammatory analgesic compound that can be easily prepared and has stable precipitation even at a pH of 7 or less. According to the present invention, an external preparation for skin having a pH close to that of human skin can be provided.

BEST MODE FOR CARRYING OUT THE INVENTION

The skin external preparation of the present invention contains an arylacetic acid anti-inflammatory analgesic compound or a pharmaceutically acceptable salt thereof, an alkylene glycol and a polyalkylene glycol as essential components.
It is an external preparation for skin having the following pH. And the external preparation for skin of this invention can contain other medicinal components and additives (humectant, pigment, fragrance, surfactant, antioxidant, etc.) as necessary in addition to the above essential components. .

The arylacetic acid anti-inflammatory analgesic compound that can be used in the present invention is not particularly limited as long as it is an anti-inflammatory analgesic compound, but examples thereof include indole acetic acid such as indomethacin, diclofenac, ibufenac, alkfenac, methazidic acid, ampenac And phenylacetic acid series such as 4-biphenylacetic acid, indenylacetic acid series such as sulindac, pyrroleacetic acid series such as tolmetine, and naphthylacetic acid series such as nabumetone.

In the present invention, a pharmaceutically acceptable salt of the arylacetic acid anti-inflammatory analgesic compound can also be used. Examples of the pharmaceutically acceptable salt include sodium salt, potassium salt, lithium salt, calcium salt and magnesium salt of the above compound. In the present specification, arylacetic acid anti-inflammatory analgesic compounds and pharmaceutically acceptable salts thereof are referred to as “
It may be referred to as “aryl acetate anti-inflammatory analgesic compound”. In the external preparation for skin of the present invention, only one kind of arylacetic acid anti-inflammatory analgesic compound can be used, or two or more kinds of compounds can be used in combination. A preferred arylacetic acid-based anti-inflammatory analgesic compound is 4-biphenylacetic acid because it is superior in stability as a skin external preparation of the present invention.

The content of the arylacetic acid anti-inflammatory analgesic compound in the external preparation for skin of the present invention is not particularly limited as long as it is an amount exhibiting anti-inflammatory analgesic action when applied to human skin, and the dosage form and use of the external preparation for skin It can be appropriately selected according to the purpose and the like. The amount of the arylacetic acid anti-inflammatory analgesic compound in the external preparation for skin of the present invention is, for example, 0.1 to 20% by mass or 0
. It is 5-15 mass% or 1-10 mass%.

In the external preparation for skin of the present invention, the arylacetic acid anti-inflammatory analgesic compound is dissolved in alkylene glycol and polyalkylene glycol. The type and amount of alkylene glycol and polyalkylene glycol that can be used in the present invention are not particularly limited as long as the arylacetic acid anti-inflammatory analgesic compound can be dissolved.

Examples of the alkylene glycol include ethylene glycol, propylene glycol, 1,3-butylene glycol, diethylene glycol, dipropylene glycol, triethylene glycol, 1,3-butanediol, isopropylene glycol, 1,2-pentanediol, 2- Examples include methyl-2,4-pentanediol and hexylene glycol. These can use only 1 type or can also be used in combination of 2 or more type. Propylene glycol and 1,3-butylene glycol are preferred from the viewpoint of satisfactorily dissolving the arylacetic acid anti-inflammatory analgesic compound.

Examples of the polyalkylene glycol include polyethylene glycol, polypropylene glycol, and polybutylene glycol. These can use only 1 type or can also be used in combination of 2 or more type. From the viewpoint of satisfactorily dissolving the arylacetic acid anti-inflammatory analgesic compound, polyethylene glycol and polypropylene glycol are preferred. Although there is no restriction | limiting in particular in the molecular weight (polymerization degree) of polyalkylene glycol, For example, the polyalkylene glycol whose molecular weight is 150-3000, or 150-1000, or 150-500 can be used.

In the external preparation for skin of the present invention, the polyalkylene glycol is 500 parts by mass or more, or 500 to 3000 parts by mass, or 1 with respect to 100 parts by mass of the arylacetic acid anti-inflammatory analgesic compound.
000 to 3000 parts by mass. Moreover, in the skin external preparation of this invention, polyalkylene glycol is 20 mass% or more, or 20-60 mass%, or 30-60 mass% in 100 mass% of skin external preparations.

In the skin external preparation of the present invention, the alkylene glycol can be used at a ratio of, for example, 10 to 350 parts by mass or 25 to 100 parts by mass with respect to 100 parts by mass of the polyalkylene glycol.

In the present invention, the use of alkylene glycol and polyalkylene glycol as a solvent for dissolving an arylacetic acid-based anti-inflammatory analgesic compound prevents the precipitation of the arylacetic acid-based anti-inflammatory analgesic compound even at a pH of 7 or less. It is an agent.

The pH of the external preparation for skin of the present invention is not particularly limited as long as it is 7 or less. The pH of the external preparation for skin of the present invention depends on the content ratio of the arylacetic acid anti-inflammatory analgesic compound and optional additives, but the pH is, for example, 3 to 7, or 4 to 6.5. . In consideration of the pH of human skin, the pH is preferably 4.5 to 6.5. Moreover, an acid or a base can be added to the external preparation for skin of the present invention to adjust the pH of the external preparation.

As long as the external preparation for skin of the present invention contains the above essential components, its dosage form is not particularly limited,
For example, it can be in the form of liquids (lotions and emulsions), ointments, creams, plasters, gels and aerosols. A preferable dosage form is a gel or a liquid because the effects of the present invention are remarkably exhibited.

When the external preparation for skin of the present invention is prepared as a liquid preparation, it can be prepared by an ordinary liquid preparation method. For example, it can be prepared by adding an arylacetic acid anti-inflammatory analgesic compound to alkylene glycol and polyalkylene glycol, and heating and dissolving as necessary. In addition, in addition to arylacetic acid-based anti-inflammatory analgesic compounds, other medicinal ingredients, additives (humectants, pigments, fragrances, surfactants, antioxidants, etc.), other solvents, etc., may be optionally used during the preparation. Can do.

Other medicinal ingredients include, for example, non-acid vanillylamide, nicotinic acid benzyl ester, capsicoside, capsaicin, capsaicinoid, capsaicin analogs such as dihydroxycapsaicin and capsanthin, and pepper-derived substances such as pepper extract, pepper pepper and pepper powder. Accelerators, p-menthane such as limonene, terpinolene, menthane and terpinene, and terpene hydrocarbon compounds such as monocyclic monoterpene hydrocarbon compounds derived therefrom, l-menthol, isopulegol, 3-l-mentoxy Propane-1,2-diol, 1- (2-hydroxydiphenyl) -4- (3-nitrophenyl) -1,2,3,6-tetrahydroxypyrimidin-2-one, ethylmenthane carboxamide, p-menta -3,8-diol, 3,8-dihydroxy-p-menthane-3-9-diol, a cooling agent that imparts a cooling sensation such as menthol-related compounds such as trialkyl-substituted cyclohexanecarboxyamide, procaine hydrochloride, and lidocaine Local anesthetics such as, penicillins, cephalosporins, aminoglycosides and macrolides, antibiotics such as griseofulvin and amphotericin B, arylacetic acids such as glycyrrhetinic acid, dipotassium glycyrrhizinate, piroxicam and methyl salicylate Non-steroidal analgesic / anti-inflammatory drugs, steroidal anti-inflammatory drugs such as hydrocortisone and bradnisolone, antiallergic / antihistamines such as chlorpheniramine and oxatomide, antihypertensive drugs such as clonidine and captopril Coronary vasodilators such as nitroglycerin and isosorbite nitrate, calcium antagonists such as nifedipine and nicardipine, β-blockers such as pindolol and propranol, antihypertensive diuretics such as deophylline and hydrothiazide, cardiotonic agents such as dopamine hydrochloride and diquitaris, Antiepileptic agents such as sodium valproate and phenytoin, anti-vertigo agents such as scopolamine, antipsychotic agents such as haloperidol, sleep regulators such as flurazepam hydrochloride and phenobarbital, anti-neoplastic agents such as 5-fluorouracil, mitomycin C and bleomycin , Hormone agents such as estradiol and insulin, vitamins such as vitamin E, and the like.

Other additives include humectants such as sorbitol, sodium pyrrolidonecarboxylate and sodium lactate, sorbitan fatty acid esters (for example, sorbitan monostearate,
Sorbitan sesquioleate), glycerin fatty acid esters (eg, glyceryl monostearate, glyceryl isooctanoate, glyceryl monomyristate), polyglycerin fatty acid esters (eg, diglyceryl monooleate, tetraglyceryl monostearate), propylene glycol Fatty acid esters (eg, propylene glycol monostearate) and polyoxyethylene hydrogenated castor oil (eg, polyoxyethylene (
5) surfactants such as hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil), pH adjusters such as monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine, sodium hydroxide, citric acid and hydrochloric acid, Examples thereof include powders such as kaolin, bentonite, montmorillonite, titanium oxide, zinc oxide, anhydrous silicic acid, synthetic aluminum silicate and corn starch.

Examples of the other solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and benzyl alcohol, and water. When such other solvents are used, the amount used is, for example, 1 to 50 parts by weight, preferably 1 to 30 parts by weight, based on 100 parts by weight of the total mass of polyalkylene glycol and alkylene glycol.

When the external preparation for skin of the present invention is prepared as a gel, the gel is prepared by using a gelling agent such as carboxyvinyl polymer, glycerin monooleate and hydroxypropylcellulose in addition to the components at the time of preparing the solution. Can do. For example, it can prepare by adding a gelatinizer to the solution of the liquid agent prepared as mentioned above, and making it gelatinize.

In the case of an ointment, a surfactant, a water-soluble polymer compound, and the like can be blended as a base. Specifically, water-soluble polymer compounds such as carboxyvinyl polymer, sodium carboxymethylcellulose, polyvinyl alcohol, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose and polyacrylic acid, and lanolin alcohol, hydrogenated oil , Lecithin, plastibase, liquid paraffin, beeswax, paraffin wax, microcrystalline wax, silicone oil, and the like. When it is prepared as an ointment, it can be produced by a conventional method, for example, it can be prepared by sequentially adding the components at the time of preparation of the solution to the solvent and kneading as appropriate.

The external preparation for skin of the present invention can be applied to the skin by application or the like. And since the pH of the external preparation for skin of the present invention is 7 or less (preferably pH 4.5 to 6.5), it can exert anti-inflammatory analgesic action without causing itching or redness to the skin. .

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
Preparation of external preparation for skin Each component was mixed in the proportions shown in Table 1 and Table 2 below, and 4-biphenylacetic acid was dissolved to prepare solutions (Examples 1 to 12, Comparative Examples 1 to 9, and Reference Examples 1 to 3). ) Was prepared. Moreover, each component was mixed in the ratio shown in Table 3, 4-biphenylacetic acid was melt | dissolved, and the gel agent (Examples 13-22) was prepared.

4-biphenylacetic acid is manufactured by Wako Pure Chemical Industries, Ltd., ethanol is manufactured by Konishi Co., Ltd.
Polyethylene glycol 200 and polyethylene glycol 400 are manufactured by Sanyo Chemical Industries, polypropylene glycol 400 is manufactured by Pure Chemicals, propylene glycol is manufactured by ADEKA, and 1,3-butylene glycol is manufactured by Kyowa Hakko Chemical Co., Ltd. Sodium hydroxide manufactured by Asahi Glass Co., Ltd., glycerin manufactured by Sakamoto Yakuhin Kogyo Co., Ltd., and hydroxypropyl cellulose manufactured by Shin-Etsu Chemical Co., Ltd. were used.

The pH of each example was measured using a pH meter F-52 manufactured by Horiba, Ltd. according to the instruction manual.
In addition, the numerical value of each component in each table | surface is a mass part.

Evaluation of solubility The solubility of 4-biphenylacetic acid was evaluated for each example.
In the evaluation, each component was mixed at a ratio shown in Tables 1 to 3, and 4-biphenylacetic acid was dissolved at 45 ° C. to prepare a liquid or gel. Then, it performed by observing the state of each agent after leaving still at 20 degreeC for 12 hours and 24 hours visually. The results are shown in Tables 1 to 3 when the solution of each agent is transparent, and when the precipitate is confirmed as x.

In Comparative Examples 1 to 9 using only one of alkylene glycol (propylene glycol or 1,3-butylene glycol) or polyalkylene glycol (polyethylene glycol 200, 400 or polypropylene glycol 400), the pH was 3.9 to 5.8.
The precipitate was observed after 12 hours or 24 hours, and was inferior in stability. Reference Examples 1 to 3 made alkaline (pH 7.5) with sodium hydroxide
Then, no precipitate was observed even after 24 hours.

On the other hand, Example 1 which used together alkylene glycol and polyalkylene glycol.
~ 22 is acidic with a pH of 4.6 to 5.7, but 24 like the reference example (alkaline).
No precipitate was observed even after time, and the formulation was stable.

In Example 1, precipitation could be similarly suppressed by using indomethacin or diclofenac instead of 4-biphenylacetic acid, but 4-biphenylacetic acid was more prominent in its effect.

Further, a composition containing 3 parts by mass of 4-biphenylacetic acid, 12 parts by mass of polyethylene glycol 400 and 38 parts by mass of propylene glycol (4-biphenylacetic acid: polyethylene glycol 400 = 100: 400, and polyethylene glycol 400: propylene glycol = 100: 320), and 3 parts by mass of 4-biphenylacetic acid, 45 parts by mass of polyethylene glycol 400 and 5 parts by mass of propylene glycol (4-biphenylacetic acid: polyethylene glycol 400 = 100: 1500, and polyethylene Glycol 400: Propylene glycol = 100: 11) was prepared, and similarly, precipitation of 4-biphenylacetic acid could be suppressed, but Examples 1 to 3 (4-biphenylacetic acid: polyethyleneglycol) Lumpur 400 = 100: 833-1333, and polyethylene glycol 400: propylene glycol = 100: 25 to 100) found the following was superior more for its effect.

Evaluation of feeling of use When the solutions and gels of Examples 1 to 22 were applied to the skin, itching and redness were not produced, and a good feeling of use was obtained.

Since Examples 1-9 did not contain ethanol, there was no strong cooling feeling (feeling hot) when the preparation was applied to the skin, and the feeling of use was better than in Examples 10-12.
Formulation Examples 1-14 and 19-34: According to the formulation examples described in Solution Formulation Examples 1-14 and 19-34, they were prepared in the usual manner to obtain a solution. Each solution was adjusted to pH described in Tables 4 to 7 with hydrochloric acid or sodium hydroxide.

Formulation Examples 15 and 16: Gel preparations were prepared according to conventional methods according to Gel Formulation Examples 15 and 16. Each gel was adjusted to the pH shown in Table 5 with hydrochloric acid or sodium hydroxide.

Formulation Example 17: An ointment was prepared according to a conventional method according to Ointment Formulation Example 17. The ointment was adjusted to the pH shown in Table 5 with hydrochloric acid or sodium hydroxide.

Formulation Example 18: Aerosol preparation was prepared in accordance with Formulation Example 18 in the usual manner. The aerosol was adjusted to the pH shown in Table 5 with hydrochloric acid or sodium hydroxide.

Claims (4)

4-biphenyl acetic acid or a pharmaceutically acceptable salt thereof, contain alkylene glycols and polyalkylene glycols, pH is Ri der 6.5, with respect to 100 parts by weight of polyalkylene glycol, alkylene glycol 25-100 An external preparation for skin which is part by mass . The skin external preparation of Claim 1 whose polyalkylene glycol is 500 mass parts or more with respect to 100 mass parts of 4-biphenylacetic acid or its pharmaceutically acceptable salt .   The external preparation for skin according to claim 1 or 2, which is a liquid or gel.   The external preparation for skin according to any one of claims 1 to 3, which is for application.