JPH05246892A - Antiphlogistic and analgesic external preparation - Google Patents

Abstract

PURPOSE:To obtain an antiphlogistic and analgesic agent, excellent in percutaneous absorbability of a pharmacodynamically effective ingredient and good in safety and stability. CONSTITUTION:The objective external preparation is obtained by blending a nonsteroidal and/or a steroidal antiphlogistic and analgesic medicine as a pharmacodynamically effective ingredient and a liquid fat selected from liquid triglycerides, liquid fatty acid esters and liquid hydrocarbons and a solid fat selected from solid triglycerides, solid fatty acid esters and solid hydrocarbons as a base ingredient with an external preparation.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an anti-inflammatory analgesic external preparation,
Specifically, it relates to an anti-inflammatory analgesic external preparation containing a non-steroidal and / or steroidal anti-inflammatory analgesic drug as a medicinal component.

[0002]

2. Description of the Related Art Non-steroidal anti-inflammatory and analgesic external preparations (including non-steroidal anti-inflammatory and analgesic drugs such as indomethacin and ketoprofen as active ingredients) and steroidal anti-inflammatory and analgesic external preparations such as hydrocortisone acetate and prednisolone (Including anti-inflammatory and analgesic drugs), aqueous gel ointments, solutions, creams,
There are tapes, etc. Solution agents are used because of their ease of use and ease of use, cream agents are used because of the accompanying feeling of moisturizing, and tape agents are used because of the advantage of sustained drug release.

Among them, gel ointments are widely used as a dosage form for non-steroidal and steroidal anti-inflammatory analgesic external preparations because of their particularly excellent transdermal absorbability.

[0004]

However, the gel ointment as described above contains a large amount of a non-steroidal anti-inflammatory analgesic drug or a steroidal anti-inflammatory analgesic drug, which is a medicinal component, for the purpose of improving solubility and transdermal absorbability. Lower alcohols (ethanol, isopropanol, etc.) and polyhydric alcohols (propylene glycol, polyethylene glycol 300,
Since it contains polyethylene glycol 400, etc.) as an essential component, there is a problem in terms of safety of irritation to the skin.

Further, when the gel ointment is applied to the skin, the means for sealing the application surface is not usually adopted,
There is a problem that the lower alcohol in the base is immediately volatilized and crystals of the medicinal component are broken out, and as a result, the transdermal absorbability of the medicinal component is hindered.

[0006] On the other hand, studies have also been conducted to improve the transdermal absorbability of medicinal components by blending a transdermal absorption enhancer. Dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and the like are known as transdermal absorption enhancers. However, in order to effectively percutaneously absorb the medicinal component, a large amount of percutaneous absorption enhancer needs to be added. There is a problem and it cannot be said that the effect of promoting percutaneous absorption is satisfactory, and the present situation is that it has not yet been put to practical use.

[0007]

[Means for Solving the Problems] Under the circumstances as described above, the present inventors have conducted various investigations to solve the above-mentioned problems, and as a result, as a result of blending a specific base component with an anti-inflammatory analgesic drug, an oil phase was continuously formed. It was found that an anti-inflammatory analgesic external preparation having excellent transdermal absorbability, safety and stability can be obtained by forming a dosage form comprising an oily mixture of two phases, and completed the present invention.

That is, the present invention provides an anti-inflammatory analgesic containing a non-steroidal and / or steroidal anti-inflammatory analgesic drug as a medicinal component, and 70% by weight or more of a liquid fat and a solid fat relative to the total amount of the external preparation as a base component. It is intended to provide an external preparation.

The anti-inflammatory analgesic drug used as a medicinal component in the external preparation of the present invention is a non-steroidal drug, for example, indomethacin, methyl salicylate, glycol salicylate, sodium diclofenac, flufenamic acid, bufexamac, ibuprofen, zaltoprofen. , Naproxen, flurbiprofen, flurbiprofen axetil, fenbufen, mefenamic acid,
Piroxicam, ampiroxicam, lysipphen, tenoxicam, felbinac, orsenone and the like can be mentioned.

Examples of the steroids include hydrocortisone, prednisolone, methylprednisolone, betamethasone, dexamethasone, triamcinolone, triamcinolone acetonide, flumethononide, beclomethasone, fluocinolone, fluometron, fludoxycortide, mometasone, clobetasol, And esters of these steroids (betamethasone butyrate propionate etc.), ketals, acetals and hemiacetal derivatives.

The liquid fat used as a base component in the external preparation of the present invention includes triglyceride, liquid fatty acid ester and liquid hydrocarbon, and the solid fat includes solid triglyceride, solid fatty acid ester and solid hydrocarbon. is there.

The triglyceride as the liquid fat includes saturated fatty acid (C8-C19) triglyceride, unsaturated fatty acid (C8-C19) triglyceride, straight-chain fatty acid (C8-C).
19) Triglyceride, branched fatty acid (C8-C19) triglyceride and the like can be mentioned, but there is no problem as long as they can be used in external pharmaceutical preparations and cosmetics.

Fatty acid esters as liquid fats include isopropyl myristate, isoprovir palmitate, butyl stearate, hexyl laurate, octyldodecyl myristate, oleyl oleate, hexyldecyl dimethyloctanoate, myristyl lactate, diethyl phthalate, Diptyl phthalate and the like can be mentioned.

Examples of the hydrocarbon as the liquid fat include liquid paraffin, squalene, squalane, pristane and the like. Triglyceride as a solid fat, cocoa butter, palm fat, palm kernel oil, mokuro, palm oil, beef tallow, lard,
Examples include hydrogenated oil, hydrogenated castor oil, lanolin fatty acid triglyceride, and the like.

Examples of the fatty acid ester as the solid fat include beeswax, carnauba wax, spermaceti wax, lanolin, hydrogenated lanolin, hard lanolin and candelilla wax. Hydrocarbons as solid fats include petrolatum, paraffin, ozokerite, ceresin, microcrystalline wax,
Polyethylene powder and the like can be mentioned, but there is no problem as long as it can be used in external pharmaceutical preparations and cosmetics.

The anti-inflammatory and analgesic external preparation of the present invention is basically produced by mixing one or more anti-inflammatory and analgesic drugs, one or more solid fats and one or more liquid fats. Here, the compounding amount of the anti-inflammatory analgesic drug varies depending on its type, but generally 0.001 to 5% by weight relative to the total amount of the external preparation.
(Hereinafter, simply referred to as “%”) is preferable.

Further, the total amount of the liquid fat and the solid fat varies depending on their type and the type of the dosage form (or preferable hardness), but generally 70% or more, preferably 70 to 99 with respect to the total amount of the external preparation. %. If this total content is less than 70%, a significant increase in the transdermal absorbability of the anti-inflammatory and analgesic drug cannot be expected, and it is difficult to obtain a preferable one in terms of stability and safety.

The blending amount of each component in the external preparation is 5 to 80%, preferably 20 to 50% for fatty acid ester, and 5 to 5 for triglyceride.
70%, preferably 20 to 45%, and 5 to 60%, preferably 10 to 20% for hydrocarbons, on the other hand, the amount of water contained in the external preparation depends on the dosage form ( Although it varies depending on, for example, anhydrous ointment or W / O ointment, it is generally in the range of 0 to 30%.

In addition to the above-mentioned components, a moisturizing agent, an emulsifying agent, an antioxidant, an antiseptic, a chelating agent, a perfume and the like can be appropriately added to the anti-inflammatory and analgesic external preparation of the present invention.
As the moisturizer, glycerin, 1,3-butylene glycol, propylene glycol, dipropylene glycol, ethylene glycol, 1,4-butylene glycol, diglycerin, polyglycerin such as triglycerin, glucose, maltose, maltitol, sucrose ,
Examples thereof include fructose, threitol, erythritol, and starch-decomposing sugar.

Examples of the emulsifier include sorbitan sesquioleate, dehymuls F, glycerin monooleate, glycerin dioleate and sorbitan monooleate. As the antioxidant, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol,
Examples include sodium pyrosulfite and acetone sodium bisulfate.

As preservatives, methyl, ethyl, propyl and butyl esters of p-oxybenzoic acid (hereinafter referred to as methylparaben, ethylparaben, propylparaben and butylparaben), o-phenylphenol, dehydroacetic acid and its salts and p. -Cresol, m-
Cresol, p-chlor-m-xylenol and the like can be used.

As the chelating agent, EDTA (ethylenediaminetetraacetic acid), thioglycolic acid, thiolactic acid,
Thioglycerin or the like can be used. In addition, it is preferable to add citric acid, lactic acid, tartaric acid, etc. to the anti-inflammatory analgesic external preparation of the present invention to adjust the pH. PH to be adjusted
Is determined based on the stability of the preparation, but it is usually preferably neutral to weakly acidic.

Furthermore, the antiphlogistic / analgesic external preparation of the present invention may be blended with one or more anti-substances, antihistamines, bactericides and vitamins in combination.

[0024]

The anti-inflammatory and analgesic external preparation of the present invention can be obtained as an oily mixture in which the oil phase is a continuous phase by using the liquid fat and the solid fat in combination as a base component. The dosage form of the external medicine comprising such an oily mixture may be any of solution, gel, cream and ointment.

The cream is a W / O cream,
The ointment may be either W / O ointment or anhydrous ointment.
As the gel, a polyethylene-microcrystalline wax-based gel is preferable.

In these dosage forms, the mixed system of liquid fat and solid fat has no irritating effect on the skin and does not change with time, and contributes to the improvement of percutaneous absorption of non-steroidal and steroidal anti-inflammatory analgesic drugs. To do.

[0027]

EXAMPLES Examples of the present invention will be described below.

[0028]

Examples 1 to 4 As an example of the present invention, an anti-inflammatory analgesic external preparation containing indomethacin as a medicinal component will be described. <Manufacturing Method> The components shown in Table 1 were mixed to manufacture an oil-gel anti-inflammatory analgesic external preparation.

[0029]

[Table 1]

On the other hand, as comparative examples for the present invention, O / W type cream-like, gel-like and solution-like anti-inflammatory analgesic external preparations containing indomethacin were produced and designated as Comparative Examples 1-3.

Comparative Example 1 The following ingredients were mixed to prepare an O / W cream-type anti-inflammatory analgesic external preparation. Polyoxyethylene (20) sorb monostearate 5g Cetanol 5g Liquid paraffin 30g Methylparaben 0.2g Butylparaben 0.1g Indomethacin 1g Purified water 58.7g

Comparative Example 2 The following ingredients were mixed to prepare a gel anti-inflammatory analgesic external preparation. Diisopropyl adipate 10 g Propylene glycol 5 g Polyoxyethylene (60) sorb monostearate 4 g Hibis 14 0.2 g Diisopropanolamine 0.05 g Indomethacin 1 g Purified water 79.75 g

Comparative Example 3 The following ingredients were mixed to prepare a solution-type anti-inflammatory analgesic external preparation. Propylene glycol 99g Indomethacin 1g

<Percutaneous absorption test of medicinal components> The transdermal absorbability of medicinal components of the anti-inflammatory and analgesic external preparations of the above Examples and Comparative Examples was examined by the diffusion cell test method. The skin is removed from the back of the depilated guinea pig, the skin is attached to a sink type diffusion cell, the external preparation (sample) of each Example is applied to the donor side, and the receptor side is adjusted to pH 7.4. Using phosphate buffered saline, a constant amount was sampled from the receptor side at a constant temperature of 37 ° C., and the amount of indomethacin percutaneously permeated to the receptor side by high performance liquid chromatography was quantified as the transdermal absorption amount. The transdermal absorption rate after 48 hours is shown in Table 2.

[0035]

[Table 2]

As is clear from these results, the anti-inflammatory analgesic external preparation of this example is superior to the comparative product in the effect of promoting the transdermal absorption rate of indomethacin.

[0037]

Examples 5 to 8 Next, as an example of the present invention, an anti-inflammatory analgesic external preparation containing prednisolone as a medicinal component will be described. <Manufacturing Method> The ingredients shown in Table 3 were mixed to manufacture an oil-gel anti-inflammatory analgesic external preparation.

[0038]

[Table 3]

On the other hand, as comparative examples to the present invention, O / W type cream-like, gel-like and solution-like anti-inflammatory analgesic external preparations containing prednisolone were prepared and designated as Comparative Examples 4 to 6.

(Comparative Example 4) The following components were mixed to give O / W.
A creamy anti-inflammatory analgesic external preparation was produced. Polyoxyethylene (60) sorb monostearate 5 g Cetanol 5 g Liquid paraffin 30 g Methylparaben 0.2 g Butylparaben 0.1 g Prednisolone 1 g Purified water 58.7 g

Comparative Example 5 The following ingredients were mixed to produce a gel anti-inflammatory analgesic external preparation. Diisopropyl adipate 10g Propylene glycol 5g Polyoxyethylene (60) sorb monostearate 4g Carboxyvinyl polymer 0.2g Diisopropanolamine 0.05g Prednisolone 1g Purified water 79.75g

Comparative Example 6 The following ingredients were mixed to prepare a solution-type anti-inflammatory analgesic external preparation. Propylene glycol 99g Prednisolone 1g

<Percutaneous absorption test of medicinal components> Examples 1 to 4
The transdermal absorption amount of prednisolone was determined in the same manner as in.
The transdermal absorption rate after 48 hours is shown in Table 4.

[0044]

[Table 4]

As is clear from these results, the anti-inflammatory analgesic external preparation of this example is superior to the comparative product in the effect of promoting the transdermal absorption rate of prednisolone.

[0046]

Examples 9 to 12 As an example of the present invention, a W / O cream-type anti-inflammatory analgesic external preparation containing indomethacin will be described. <Manufacturing Method> The components shown in Table 5 were mixed to manufacture a W / O cream-type anti-inflammatory analgesic external preparation.

[0047]

[Table 5]

Anti-inflammatory and analgesic external preparations of this example and Comparative Examples 1 to 1
Regarding the anti-inflammatory analgesic external preparation of No. 3, the transdermal absorption rate of indomethacin was determined in the same manner as above. The results are shown in Table 6.

[0049]

[Table 6]

As is apparent from these results, the anti-inflammatory analgesic external preparation of the present invention is superior in the effect of promoting the percutaneous absorption rate of the drug in the W / O form as in the oil gel form, as compared with the comparative product. There is.

[0051]

Examples 13 to 16 As an example of the present invention, an oil gel anti-inflammatory analgesic external preparation containing indomethacin will be described. <Manufacturing Method> The components shown in Table 7 were mixed to produce an oil-gel anti-inflammatory analgesic external preparation.

[0052]

[Table 7]

Anti-inflammatory and analgesic external preparations of the above Examples and Comparative Example 1
For the antiphlogistic / analgesic external preparations (3) to (3), the transdermal absorption rate of indomethacin was determined in the same manner as above. The results are shown in Table 8.

[0054]

[Table 8]

[0055]

Examples 17 to 20 As an example of the present invention, an oil-gel anti-inflammatory analgesic external preparation containing prednisolone will be described. <Manufacturing Method> The components shown in Table 9 were mixed to manufacture an oil-gel anti-inflammatory analgesic external preparation.

[0056]

[Table 9]

Anti-inflammatory and analgesic external preparations of the above Examples and Comparative Example 4
For the antiphlogistic / analgesic external preparations of ~ 6, the transdermal absorption rate of prednisolone was determined in the same manner as described above. The results are shown in Table 10.

[0058]

[Table 10]

[0059]

Examples 21 to 24 As an example of the present invention, an oil gel anti-inflammatory analgesic external preparation containing betamethasone propionate butyrate will be described. <Manufacturing Method> The ingredients shown in Table 11 were mixed to manufacture an oil-gel anti-inflammatory analgesic external preparation.

[0060]

[Table 11]

The transdermal absorption rate of betamethasone propionate butyrate was the same as the above for the topical anti-inflammatory and analgesic preparations of Examples 7 to 9 in which indomethacin in Examples and Comparative Examples 1 to 3 was replaced with betamethasone propionate butyrate. I asked. The results are shown in Table 12.

[0062]

[Table 12]

As is clear from the results shown in Tables 8, 10 and 12, the anti-inflammatory analgesic external preparations of the present invention were
It has an excellent effect of promoting the transdermal absorption rate of drugs.

[0064]

INDUSTRIAL APPLICABILITY In the anti-inflammatory analgesic external preparation of the present invention, the use of liquid fats and solid fats having no stimulative effect on the skin as the base component makes the transdermal absorbability of non-steroids and steroids, which are anti-inflammatory analgesics, remarkable. Increase, and also enhance bioavailability, eczema, lichen, ichthyosis,
It can be applied to inflammatory diseases such as psoriasis, myalgia, and arthritis to effectively and safely eliminate or relieve the symptoms.

Further, in the anti-inflammatory analgesic external preparation of the present invention, for the same reason, there is no loss of the non-steroids and steroids which are the active ingredients, and since the non-steroids and steroids are dispersed and stored in the skin for a long time, the non-steroids and steroids It excels in usability by effectively exerting its effects.

Furthermore, since the anti-inflammatory analgesic external preparation of the present invention has a water content of 30% or less, it is hardly hydrolyzed, is stable over time, and has little change in coloring or the like.

[Procedure amendment]

[Submission date] March 16, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0060

[Correction method] Change

[Correction content]

[0060]

[Table 11]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location A61K 31/195 8413-4C 31/405 ABE 7252-4C 31/54 7252-4C 31/56 7252- 4C 31/60 AAH 7252-4C (72) Inventor Hiroshi Machida 1-27, Takashimadai, Kanagawa-ku, Yokohama, Kanagawa Prefecture Polar Chemical Industry Co., Ltd. Yokohama Laboratory

Claims (7)

[Claims] 1. An anti-inflammatory analgesic external preparation containing a non-steroidal and / or steroid anti-inflammatory analgesic drug as a medicinal component, and 70% by weight or more of a liquid fat and a solid fat relative to the total amount of the external preparation as a base component. 2. The non-steroidal anti-inflammatory drug is indomethacin, methyl salicylate, glycol salicylate, sodium diclofenac, flufenamic acid, bufexamac, ibuprofen, zaltoprofen, naproxen, flurbiprofen, flurbiprofen axetil, The anti-inflammatory analgesic external preparation according to claim 1, which is selected from the group consisting of fenbufen, mefenamic acid, piroxicam, ampiroxicam, lisipphen, tenoxicam, felbinac and orsenone. 3. The steroidal anti-inflammatory drug is hydrocortisone, prednisolone, methylprednisolone, betamethasone, dexamethasone, triamcinolone, triamcinolone acetonide, flumethasone, fluocinonide, beclomethasone, fluocinolone, fludoxycortide, mometasone, clobetasol, and these. The anti-inflammatory analgesic external preparation according to claim 1, which is selected from the group consisting of steroid esters, ketals, acetals, and hemiacetal derivatives. 4. The anti-inflammatory analgesic external preparation according to claim 1, wherein the liquid fat is selected from one or more of triglyceride, fatty acid ester and hydrocarbon. 5. The anti-inflammatory analgesic external preparation according to claim 1, wherein the solid fat is selected from one or more of triglyceride, fatty acid ester, and hydrocarbon. 6. A non-steroidal and / or steroidal anti-inflammatory and analgesic drug 0.001 to 5% by weight as a medicinal component,
The anti-inflammatory analgesic external preparation according to claim 1, which contains 5 to 80% by weight of fatty acid ester, 5 to 70% by weight of triglyceride, and 5 to 60% by weight of hydrocarbon as a base component. 7. The anti-inflammatory analgesic external preparation according to claim 1, wherein the oil phase of the external preparation is an oily mixture forming a continuous phase.