JP3273805B2 - Anti-inflammatory analgesic external preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to an anti-inflammatory analgesic external preparation,
More specifically, the present invention relates to an antiphlogistic analgesic external preparation containing a nonsteroidal and / or steroidal antiphlogistic analgesic drug as a medicinal ingredient.

[0002]

2. Description of the Related Art Non-steroidal anti-inflammatory analgesic external preparations currently marketed (including non-steroidal anti-inflammatory analgesics such as indomethacin and ketoprofen as active ingredients) and steroidal anti-inflammatory analgesic external preparations (steroids such as hydrocortisone acetate and prednisolone) Water-based gel ointments, solutions, creams,
There is a tape agent and the like. Solution preparations are used because of their ease of use and simplicity, cream preparations are used because of their accompanying good touch such as moisturizing, and tape preparations are used because of their sustained release of drugs.

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

[0004]

However, the gel ointment as described above is used in a large amount for the purpose of improving the solubility and percutaneous absorption of the non-steroidal anti-inflammatory analgesic drug and the steroidal anti-inflammatory analgesic drug which are the active ingredients. Lower alcohols (ethanol, isopropanol, etc.) and polyhydric alcohols (propylene glycol, polyethylene glycol 300,
Since polyethylene glycol 400) is contained as an essential component, there is a problem in terms of safety, i.e., irritation to the skin.

[0005] In addition, when this gel ointment is applied to the skin, it usually does not take measures to seal the application surface,
There is a problem that the lower alcohol in the base is immediately volatilized and crystals of the medicinal ingredient are deposited, and as a result, there is a problem that the transdermal absorbability of the medicinal ingredient is hindered.

[0006] On the other hand, studies have been made to improve the transdermal absorbability of medicinal ingredients by blending a transdermal absorption enhancer. As transdermal absorption enhancers, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) are known. However, in order to effectively percutaneously absorb a medicinal ingredient, it is necessary to add a large amount of a percutaneous absorption enhancer. Therefore, like the alcohols, from the viewpoint of safety such as irritation to the skin of the percutaneous absorption enhancer. There is a problem, and the effect of promoting percutaneous absorption cannot be said to be satisfactory, and at present it has not yet been put to practical use.

[0007]

Under the circumstances described above, the present inventors have conducted various studies to solve the above problems, and as a result, a specific base component was added to an anti-inflammatory analgesic drug to make the oil phase continuous. The present invention was completed by finding that an anti-inflammatory analgesic external preparation excellent in percutaneous absorbability, safety and stability could be obtained by forming a dosage form comprising an oily mixture of phases.

[0008] That is, the present invention provides an anti-inflammatory analgesic comprising a non-steroidal and / or steroidal anti-inflammatory analgesic drug as a medicinal component, and a liquid fat and a solid fat of 70% by weight or more based on the total amount of an external preparation as a base component. It provides an external preparation.

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

Further, among steroids, for example, hydrocortisone, prednisolone, methylprednisolone, betamethasone, dexamethasone, triamcinolone, triamcinolone acetonide, flumethasone, fluocinonide, beclomethasone, fluocinolone, fluometron, fludoxycortide, mometasone, clobetasone And esters of these steroids (such as betamethasone propionate butyrate), ketals, acetals, and hemiacetal derivatives.

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

Triglycerides as liquid fats include saturated fatty acids (C8-C19) triglycerides, unsaturated fatty acids (C8-C19) triglycerides, and linear fatty acids (C8-C19).
19) Triglycerides, branched fatty acids (C8 to C19) triglycerides, and the like can be used. However, there is no problem as long as they are used for external preparations for medicines or cosmetics.

[0013] fatty acid ester as a liquid oil include isopropyl myristate, palmitic acid isopropyl, butyl stearate, hexyl laurate, octyldodecyl myristate, oleyl oleate, dimethyl octanoic acid hexyl decyl, myristyl lactate, diethyl phthalate, such as phthalate, di-butyl, and the like.

The hydrocarbon as the liquid fat includes liquid paraffin, squalene, squalane, pristane and the like. Triglycerides as solid fats include cocoa butter, palm fat, palm kernel oil, mokuro, coconut oil, tallow, lard,
Hardened oil, hardened castor oil, lanolin fatty acid triglyceride and the like can be mentioned.

Fatty acid esters as solid fats include beeswax, carnauba wax, spermaceti, lanolin, hydrogenated lanolin, hard lanolin, candelilla wax and the like. 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 is used for an external preparation for medicine or cosmetics.

The anti-inflammatory analgesic external preparation of the present invention is basically produced by blending at least one anti-inflammatory analgesic drug, at least one solid fat, and at least one liquid fat. Here, the amount of the antiphlogistic analgesic drug varies depending on the type thereof, but is generally 0.001 to 5% by weight based on the total amount of the external preparation.
(Hereinafter simply referred to as “%”).

The total amount of the liquid fat and the solid fat varies depending on the type of the liquid fat and the type of the dosage form (or the preferred hardness), but is generally 70% or more, preferably 70 to 99%, based on the total amount of the external preparation. %. If the total compounding amount is less than 70%, a remarkable increase in the transdermal absorbability of the anti-inflammatory analgesic drug cannot be expected, and it is difficult to obtain a preferable substance in terms of stability and safety.

The amount of each component in the external preparation is 5 to 80%, preferably 20 to 50% for fatty acid esters and 5 to 80% for triglycerides.
70%, preferably 20-45%, and the range of hydrocarbons is preferably 5-60%, preferably 10-20%, while the amount of water contained in the external preparation is determined by the dosage form ( For example, it is different depending on an anhydrous ointment or a W / O ointment, but generally ranges from 0 to 30%.

The anti-inflammatory and analgesic external preparation of the present invention may optionally contain, in addition to the above components, a humectant, an emulsifier, an antioxidant, a preservative, a chelating agent, a fragrance and the like.
Examples of the humectant include glycerin, 1,3-butylene glycol, propylene glycol, dipropylene glycol, ethylene glycol, 1,4-butylene glycol, polyglycerin such as diglycerin and triglycerin, glucose, maltose, maltitol, and sucrose. ,
Fructose, threitol, erythritol, starch-decomposing sugar and the like.

Examples of the emulsifier include sorbitan sesquiolate, dehimulus F, glycerin monooleate, glycerindiolate, sorbitan monooleate and the like. As antioxidants, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol,
Examples include sodium pyrosulfite, acetone sodium bisulfate, and the like.

Examples of the preservative include methyl, ethyl, propyl and butyl esters of p-oxybenzoic acid (hereinafter referred to as methylparaben, ethylparaben, propylparaben and butylparaben, respectively), o-phenylphenol, dehydroacetic acid and salts thereof and p-hydroxybenzoic acid. -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 and the like can be used. Further, it is preferable to add citric acid, lactic acid, tartaric acid and the like to the anti-inflammatory analgesic external preparation of the present invention to adjust the pH. PH to adjust
Is determined on the basis of the stability of the preparation, and is usually preferably neutral to weakly acidic.

Further, the antiphlogistic / analgesic external preparation of the present invention may be combined with at least one of an antibacterial substance, an antihistamine, a bactericide, and a vitamin.

[0024]

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

The cream is a W / O cream,
The ointment may be a W / O ointment or an anhydrous ointment.
As the gel, a polyethylene-microcrystalline wax-based gel is preferable. Where polyethylene-microphone
Locrystallin wax is a paraffin or petrolatum
Is substantially free from polyethylene oil from solid fatty hydrocarbons.
Use only wax and / or microcrystalline wax
Gel type.

In these dosage forms, the mixed system of the liquid fat and the solid fat has no irritating property to the skin, no change with time, and contributes to the improvement of transdermal absorption of nonsteroidal and steroidal anti-inflammatory analgesics. I do.

[0027]

Embodiments of the present invention will be described below.

[0028]

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

[0029]

[Table 1]

On the other hand, as a comparative example to the present invention, O / W type cream, gel and solution external anti-inflammatory analgesics containing indomethacin were produced, and these were named Comparative Examples 1 to 3.

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

Comparative Example 2 The following components were mixed to produce a gel-like anti-inflammatory analgesic external preparation. Diisopropyl adipate 10 g Propylene glycol 5 g Polyoxyethylene (60) sorbitol 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 produce a solution-based anti-inflammatory analgesic external preparation. Propylene glycol 99g Indomethacin 1g

<Transdermal Absorption Test of Pharmaceutical Ingredients> The transdermal absorbability of the medicinal components of the anti-inflammatory analgesic external preparations of the above Examples and Comparative Examples was examined by a diffusion cell test method. The skin was excised from the back of the guinea pig from which the hair had been removed, and the skin was attached to a sink type diffusion cell, and the external preparation (sample) of each example was applied to the donor side, and pH 7.4 was applied to the receptor side. Using a phosphate buffered saline solution, a constant amount was sampled from the receptor side at a constant temperature of 37 ° C., and the amount of indomethacin that had percutaneously penetrated to the receptor side was quantified as the transdermal absorption amount by high performance liquid chromatography. The transdermal absorption after 48 hours is shown in Table 2.

[0035]

[Table 2]

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

[0037]

Examples 5 to 8 Next, as an example of the present invention, an anti-inflammatory and analgesic external preparation containing prednisolone as a medicinal component will be described. <Production method> Each component shown in Table 3 was mixed to produce an oil gel-like anti-inflammatory analgesic external preparation.

[0038]

[Table 3]

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

Comparative Example 4 O / W
A cream-like anti-inflammatory analgesic external preparation was produced. Polyoxyethylene (60) sorbitol monostearate 5 g Cetanol 5 g Liquid paraffin 30 g Methyl paraben 0.2 g Butyl paraben 0.1 g Prednisolone 1 g Purified water 58.7 g

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

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

<Percutaneous Absorption Test of Pharmaceutical Ingredients> Examples 1-4
Percutaneous absorption of prednisolone was determined in the same manner as in.
Table 4 shows the transdermal absorption rates after 48 hours.

[0044]

[Table 4]

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

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

INDUSTRIAL APPLICABILITY In the anti-inflammatory analgesic external preparation of the present invention, the use of liquid fats and solid fats which do not irritate the skin as the base component significantly enhances the percutaneous absorption of non-steroids and steroids which are anti-inflammatory analgesics. Increase, and also increase the bioavailability effect, so eczema, moss, ichthyosis,
It can be applied to inflammatory diseases such as dryness, myalgia, arthritis and the like to effectively and safely eliminate or alleviate the symptoms.

For the same reason, the anti-inflammatory and analgesic external preparation of the present invention does not lose the non-steroids and steroids which are the active ingredients, and stores the non-steroids and steroids in the skin for a long time. It is excellent in usability, such as exhibiting its effects effectively.

Further, since the anti-inflammatory analgesic external preparation of the present invention has a water content of 30% or less, it is not easily hydrolyzed, is stable over time, and has little change in coloring and the like.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI A61K 47/32 A61K 47/32 47/44 47/44 (72) Inventor Hiroshi Macita 27-27 Takashimadai, Kanagawa-ku, Yokohama-shi, Kanagawa-ken 1 Polar Chemical Industry Co., Ltd. Yokohama Laboratory (56) References JP-A-4-308530 (JP, A) JP-A-4-275235 (JP, A) JP-A-4-74138 (JP, A) JP 61-68414 (JP, A) JP-A-62-36337 (JP, A) JP-A-61-275248 (JP, A) JP-A-58-150508 (JP, A) JP-A-58-189115 (JP, A) A) JP-A-57-98209 (JP, A) JP-A-62-215528 (JP, A) JP-A-57-171913 (JP, A) JP-A-58-39616 (JP, A) JP-A-204728 (JP, A) JP-A-60-41607 (JP, A) JP-A-63-188628 (JP, A) 63-25506 (JP, A) JP Akira 62-238261 (JP, A) Tokuoyake Akira 41-5467 (JP, B1) (58 ) investigated the field (Int.Cl. ^7, DB name) A61K 31/405 A61K 9/06 A61K 9/107 A61K 31/573 A61K 47/14 A61K 47/32 A61K 47/44 CA (STN)

Claims (2)

(57) [Claims] 1. Non-steroidal anti - inflammatory analgesic as a medicinal ingredient
A polyethylene-microcrystalline wax gel system containing indomethacin as a drug and / or prednisolone as an anti-inflammatory analgesic drug and 70% by weight or more of liquid fat and solid fat as base components based on the total amount of the external preparation. A topical anti-inflammatory analgesic agent, substantially free of alcohol , 0.001 to 5% by weight of indomethacin and / or prednisolone as the medicinal component, and 5 to 80% by weight of a fatty acid ester as a base component, 5 to 70% by weight of triglyceride and 5 to 60% of hydrocarbon
An antiphlogistic analgesic external preparation containing 1% by weight. 2. The fatty acid ester content is 20 to 50% by weight, the triglyceride content is 20 to 45% by weight, and the hydrocarbon content is 10 to 20% by weight. The anti-inflammatory and analgesic external preparation according to claim 1 ,