JPH05132415A - Anti-inflammatory analgesic external preparation - Google Patents

Abstract

PURPOSE:To obtain an anti-inflammatory analgesic external preparation having excellent percutaneous absorption, safety and stability by blending an anti- inflammatory agent analgesic with a specific base component. CONSTITUTION:An anti-inflammatory analgesic external preparation comprising 0.001-5wt.% non-steroid-based and/or steroid-based anti-inflammatory analgesic as a medicinal component and 0.1-30wt.% phosphatidylglycerol as a base component. Indomethacin, methyl salicylate, flufenamic acid, etc., may be cited as the non-steroid-based anti-inflammatory analgesic and hydrocortisone, predonisolone, dexamethasone, etc., as the steroid-based anti-inflammatory analgesic. The external preparation can be prepared into a dosage form such as solution, colloidal solution, emulsified lotion, hydrophilic cream, aqueous gel or lipophilic cream.

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) and steroidal anti-inflammatory and analgesic external preparations (hydrocortisone acetate and prednisolone) Dosage forms of those containing analgesic drugs include aqueous gel ointments, solutions, creams, tapes and the like. Solution agents are used because of their ease of use and convenience, cream agents are used because of their accompanying moisturizing and other tactile sensations, 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.

[0003]

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 this gel ointment is applied to the skin, the means for sealing the application surface is not usually adopted,
There is also a problem that the lower alcohol in the base immediately evaporates and crystals of the medicinal component are deposited, and as a result, the transdermal absorbability of the medicinal component is impeded.

On the other hand, studies have also been conducted to improve the transdermal absorbability of medicinal components by blending a transdermal absorption enhancer.
As a percutaneous absorption promoter, dimethyl sulfoxide (D
MSO) and dimethylformamide (DMF) are known. However, in order to improve the percutaneous absorption, it is necessary to add a large amount of percutaneous absorption enhancer, and therefore, like the alcohols, there are problems in terms of safety such as skin irritation of the percutaneous absorption enhancer. Moreover, it cannot be said that the effect of promoting percutaneous absorption is satisfactory, and it is the current situation that it has not yet been put to practical use.

[0006]

[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, if a specific base component is added to an anti-inflammatory analgesic drug,
The present invention has been completed by finding that an anti-inflammatory analgesic external preparation having excellent transdermal absorbability, safety and stability can be obtained.

That is, the present invention provides an anti-inflammatory analgesic external preparation containing a non-steroidal and / or steroidal anti-inflammatory analgesic drug as a medicinal component and phosphatidylglycerol as a base component.

The present invention will be described in detail below.

<1> Anti-inflammatory and analgesic drug of the present invention As the anti-inflammatory and analgesic drug used as a medicinal component of the external preparation of the present invention, non-steroidal drugs include, for example, indomethacin, methyl salicylate, glycol salicylate,
Diclofenac sodium, flufenamic acid, bufexamac, ibuprofen, naproxen, flurbiprofen, fenbufen, mefenamic acid, piroxicam and the like can be mentioned.

In the steroid type, for example, hydrocortisone, prednisolone, methylprednisolone, dexamethasone, triamcinolone, triamcinolone acetonide, flumethasone, fluocinonide, beclomethasone, fluocinolone, fluometron, fludoxycortide, clobetasone, clobetasol and these steroids. Examples thereof include esters, ketals, acetals and hemiacetal derivatives.

<2> Phosphatidylglycerol The phosphatidylglycerol used in the anti-inflammatory and analgesic external preparation of the present invention is derived from egg yolk, soybean and the nervous system of animals or the like, or is a chemical compound, and is extracted. When used in the form, the purity is 50% or more, preferably 70% or more,
In particular, 90% or more is preferably used.

<3> Anti-inflammatory and analgesic external preparation of the present invention To prepare the anti-inflammatory and analgesic external preparation of the present invention, basically, one of non-steroidal and / or steroidal anti-inflammatory analgesic drugs is used.
The seeds or more and phosphatidylglycerol may be uniformly mixed.

The amount of the anti-inflammatory and analgesic drug to be compounded varies depending on its component, but is generally 0.001 to 5% relative to the total amount of the external preparation.
(% By weight, the same applies below) is preferred.

The blending amount of phosphatidylglycerol varies depending on the intended indication, dosage form, type and amount of the anti-inflammatory and analgesic drug contained, etc., but is usually 0.1 to 30% with respect to the total amount of the external medicine, It is preferably 0.1 to 10%, particularly preferably 0.2 to 7%. If the amount of phosphatidylglycerol is less than this range, the percutaneous absorption effect of the drug is not sufficient, and even if it is used more than necessary, the effect is not enhanced proportionally and the skin becomes sticky and other undesirable effects are exhibited. Therefore, the above range is preferable. The blending amount of phosphatidylglycerol is determined based on the purity of phosphatidylglycerol.

In addition to the anti-inflammatory and analgesic drug, phosphatidylglycerol, the anti-inflammatory and analgesic external preparation of the present invention may contain other components depending on the intended use, and a preparation having various rheological properties by a conventional method. It is possible to manufacture

Examples of such dosage forms include an aqueous mixture having a continuous aqueous phase such as a solution, a chloride solution, an emulsion lotion, an O / W cream (hydrophilic cream), and an aqueous gel, a solution, and a W. / O cream (lipophilic cream),
For example, a gel base such as plastibase, a water-absorbing ointment in which an emulsifier is added to fats and oils, a hydrophilic ointment, and the like can be used to produce an oily mixture in which the oil phase is a continuous phase. The agent can be manufactured. It is also possible to produce suspension bases such as shaking lotions with the addition of solid dispersants.

As the oil / fat component, emulsifier, dispersant, and gelling agent used for producing these dosage forms, known substances usually used in cosmetics and pharmaceutical external preparations can be used.

As the oil and fat component, saturated fatty acids (C _{8 to} C
₁₉₎ triglyceride, an unsaturated fatty acid (C ₈ -C ₁₉₎ triglyceride, straight chain fatty acids (C ₈ -C ₁₉₎ triglycerides, triglycerides such as branched fatty acids (C ₈ -C ₁₉₎ triglyceride, solid paraffin, liquid paraffin, squalene , Squalane, pristane, vaseline,
Hydrocarbons such as microcrystalline wax and polyethylene powder, aliphatic higher alcohols such as cetyl alcohol, hexadecyl alcohol, stearyl alcohol and oleyl alcohol, palmitic acid, stearic acid,
Higher fatty acids such as oleic acid, linoleic acid and linoleic acid, beeswax, carnauba wax, spermaceti wax, lanolin, hydrogenated lanolin, hard lanolin, esters of higher alcohols and higher alcohols such as calderila wax, isopropyl myristate, isopropyl palmitate Esters of higher fatty acids such as and lower alcohols can be used.

As the emulsifier and the dispersant, anionic type,
Although both cationic and nonionic surfactants can be used, it is advantageous to use nonionic surfactants because they are less irritating to the skin. As the nonionic surfactant, for example, fatty acid monoglycerides such as glyceryl monostearate, sorbitan fatty acid esters such as sorbitan monolaurate, polyoxyethylene fatty acid esters such as polyoxyethylene stearate, polyoxyethylene cetyl ether, Examples thereof include polyoxyethylene higher alcohol ethers such as polyoxyethylene oleyl ether.

Examples of the gelling agent include carboxymethyl cellulose, cellulose gel, carbopol gel,
Examples thereof include polyvinyl alcohol, polyethylene glycol, and various gums. These oil and fat components, emulsifiers, dispersants and gelling agents can be used alone or in combination.

A moisturizing agent is added to the anti-inflammatory and analgesic external preparation of the present invention in order to increase the moisturizing action on the skin and further improve the transdermal absorbability of the drug. It is advantageous to add alcohol to provide a cooling effect. As the moisturizer, propylene glycol, glycerin, 1,3-butylene glycol, dipropylene glycol, ethylene glycol,
1,4-butylene glycol, diglycerin, polyglycerin such as triglycerin, glucose, maltose,
Maltitol, sucrose, fructose, threitol,
Examples thereof include erythritol, sorbitol, starch-decomposing sugar and the like. The moisturizer and alcohol are added in such an amount that they do not irritate the skin.

In order to further increase the stability, it is preferable to add an antioxidant, a chelating agent, a preservative and the like to the anti-inflammatory analgesic external preparation of the present invention, if necessary. Examples of the antioxidant include butylated hydroxytoluene, butylated hydroxyanisole, tocopherol sodium pyrosulfite, and acetone sodium bisulfate.
As preservatives, methyl-, ethyl-, propyl-, butyl esters of p-oxybenzoic acid (hereinafter referred to as methylparaben, ethylparaben, propylparaben, butylparaben, respectively), 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, or thioglycerin can be used.

In addition, it is preferable to adjust the pH by adding citric acid, lactic acid, tartaric acid or the like to the anti-inflammatory analgesic external preparation of the present invention. The pH to be adjusted is determined based on the stability of the preparation, but it is usually preferably neutral to weakly acidic. Further, a slight amount of fragrance can be added if necessary. Furthermore, the anti-inflammatory analgesic external preparation of the present invention, an antibiotic,
It is also possible to combine one or more antihistamines, bactericides and vitamins.

[0024]

The anti-inflammatory analgesic external preparation of the present invention can be formed into various dosage forms as described above by the action of phosphatidylglycerol as a base component. Moreover, in these dosage forms, the transdermal absorbability of non-steroids and steroids, which are anti-inflammatory and analgesic drugs contained, is significantly increased (bioavailability), and the action is also enhanced, so that eczema, lichen, ichthyosis,
By applying it to inflammatory diseases such as dryness, myalgia, and arthritis, the symptoms can be eliminated or relieved.

Further, the anti-inflammatory analgesic external preparation of the present invention, by using the above-mentioned base component, does not lose the anti-inflammatory analgesic non-steroids and steroids, which are the active ingredients, and allows them to be dispersed and stored in the skin for a long time. The effects of steroids and steroids can be effectively exerted. Furthermore, the anti-inflammatory analgesic external preparation of the present invention is stable over time and has little change in coloring and the like for the same reason.

[0026]

EXAMPLES Examples of the present invention will be described below.

[Examples 1 and 2, Comparative Examples 1 to 3] Oil Gels Examples containing indomethacin as an antiphlogistic and analgesic drug as an external antiphlogistic and analgesic agent of the present invention will be described. As comparative examples, those in which phosphatidylglycerol was substituted for phosphatidylglycerol and those in which phosphatidylglycerol was removed were used.

<Manufacturing Method> Each component shown in Table 1 is mixed,
An anti-inflammatory analgesic external preparation in the form of oil gel was produced.

[0029]

[Table 1]

<Percutaneous absorption test of anti-inflammatory analgesic drug> The percutaneous absorption of the anti-inflammatory analgesic drug of each of the above-mentioned Examples and Comparative Examples was measured by the diffusion cell test method. The depilated guinea pig dorsal skin is removed and this skin is sinked (Si
nk) type diffusion cell, the donor side was coated with the external preparation (specimen) of each Example or Comparative Example, and the receptor side was prepared by using phosphate buffered saline with pH 7.4.
A constant amount of the sample was sampled from the receptor side at a constant temperature of 7 ° C., and the amount of the drug percutaneously permeated to the receptor side was quantified by high performance liquid chromatography to obtain the transdermal absorption amount.
The transdermal absorption rate after 48 hours is shown in Table 2.

[0031]

[Table 2]

As is clear from these results, the anti-inflammatory analgesic external preparation of the present invention is superior in the effect of promoting percutaneous absorption of a drug as compared with the comparative product.

[Examples 3 to 4, Comparative Examples 4 to 6] O / W
Cream Next, as an anti-inflammatory analgesic external preparation of the present invention, an example of O / W cream will be described. As comparative examples, those in which phosphatidylglycerol was substituted for phosphatidylglycerol and those in which phosphatidylglycerol was removed were used.

<Manufacturing method> The components shown in Table 3 were mixed to give O /
Each anti-inflammatory analgesic external preparation in the form of W cream was produced.

[0035]

[Table 3]

<Percutaneous absorption test of anti-inflammatory analgesic drug> Example 3
For each of the anti-inflammatory analgesic external preparations of Comparative Examples 4 to 6 and Comparative Examples 4 to 6, the transdermal absorption rate of the anti-inflammatory analgesic drug was measured in the same manner as above. The results are shown in Table 4.

[0037]

[Table 4]

As is clear from these results, the anti-inflammatory analgesic external preparation of this example is superior in the effect of promoting the percutaneous absorption of the drug in the O / W cream as well as in the oil gel as compared with the comparative product.

[Examples 5-6, Comparative Examples 7-9] Aqueous gel Next, examples of an aqueous gel containing ketoprofen as an anti-inflammatory analgesic drug as an external drug for anti-inflammatory analgesia of the present invention will be described. As comparative examples, those in which phosphatidylglycerol was substituted for phosphatidylglycerol and those in which phosphatidylglycerol was removed were used.

<Manufacturing Method> Each component shown in Table 5 was mixed to manufacture an aqueous anti-inflammatory analgesic external preparation.

[0041]

[Table 5]

<Transdermal absorption test of anti-inflammatory analgesic drug> Example 5
For each of the anti-inflammatory analgesic external preparations of Comparative Examples 6 to 9 and Comparative Examples 7 to 9, the transdermal absorption rate of the anti-inflammatory analgesic drug was measured in the same manner as above. The results are shown in Table 6.

[0043]

[Table 6]

As is clear from these results, the anti-inflammatory analgesic external preparation of this example is also superior in the effect of promoting percutaneous absorption of the drug as compared with the comparative product.

[Examples 7 to 8 and Comparative Examples 10 to 12] W
/ O cream Next, an example of a W / O cream containing prednisolone acetate as an anti-inflammatory analgesic drug as an external anti-inflammatory analgesic agent of the present invention will be described. As comparative examples, those in which phosphatidylglycerol was substituted for phosphatidylglycerol and those in which phosphatidylglycerol was removed were used.

<Manufacturing Method> The respective components shown in Table 7 were mixed and W /
Each O cream type anti-inflammatory analgesic external preparation was produced.

[0047]

[Table 7]

<Percutaneous absorption test of anti-inflammatory analgesic drug> Example 7
For each of the anti-inflammatory analgesic external preparations of ~ 8 and Comparative Examples 10-12, the transdermal absorption rate of the anti-inflammatory analgesic drug was measured in the same manner as above. The results are shown in Table 8.

[0049]

[Table 8]

As is clear from these results, the anti-inflammatory analgesic external preparation of this example is also superior in the effect of promoting the percutaneous absorption of the drug as compared with the comparative product.

[Examples 9 to 10, Comparative Examples 13 to 15]
Ointment Next, an example of an ointment containing hydrocortisone as an anti-inflammatory analgesic drug as the external anti-inflammatory analgesic agent of the present invention will be described. As comparative examples, those in which phosphatidylglycerol was substituted for phosphatidylglycerol and those in which phosphatidylglycerol was removed were used.

<Manufacturing Method> The components shown in Table 9 were mixed to prepare ointment-shaped anti-inflammatory analgesic external preparations.

[0053]

[Table 9]

<Percutaneous absorption test of anti-inflammatory analgesic drug> Example 9
For each of the anti-inflammatory analgesic external preparations of Comparative Examples 10 to 10 and Comparative Examples 13 to 15, the transdermal absorption rate of the anti-inflammatory analgesic drug was measured in the same manner as above. The results are shown in Table 10.

[0055]

[Table 10]

As is clear from these results, the anti-inflammatory analgesic external preparation of this example is also superior in the effect of promoting percutaneous absorption of the drug as compared with the comparative product.

[Examples 11 to 12, Comparative Examples 16 to 18]
Hydrophilic Ointment Next, an example of a hydrophilic ointment containing ibuprofen as an anti-inflammatory analgesic drug as an external anti-inflammatory analgesic agent of the present invention will be described. As comparative examples, those in which phosphatidylglycerol was substituted for phosphatidylglycerol and those in which phosphatidylglycerol was removed were used.

<Manufacturing Method> The components shown in Table 11 were mixed to prepare a hydrophilic ointment-type external anti-inflammatory and analgesic external preparation.

[0059]

[Table 11]

<Transdermal absorption test of anti-inflammatory analgesic drug> Example 1
For each of the anti-inflammatory analgesic external preparations of 1 to 12 and Comparative Examples 16 to 18, the transdermal absorption rate of the anti-inflammatory analgesic drug was measured in the same manner as above. The results are shown in Table 12.

[0061]

[Table 12]

As is clear from these results, the anti-inflammatory and analgesic external preparation of this example is also superior in the effect of promoting percutaneous absorption of the drug as compared with the comparative product.

[0063]

INDUSTRIAL APPLICABILITY The anti-inflammatory analgesic external preparation of the present invention uses phosphatidylglycerol as a base component to promote percutaneous absorption of non-steroidal and steroidal anti-inflammatory analgesic drugs as active ingredients, It has improved availability and is excellent in safety, stability and usability of an external preparation.

[Procedure amendment]

[Submission date] April 27, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 2

[Correction method] Change

[Correction content]

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 3

[Correction method] Change

[Correction content]

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0009

[Correction method] Change

[Correction content]

<1> Anti-inflammatory and analgesic drug of the present invention As the anti-inflammatory and analgesic drug used as a medicinal component of the external preparation of the present invention, non-steroidal drugs include, for example, indomethacin, methyl salicylate, glycol salicylate,
Diclofenac sodium, flufenamic acid, Bufexamac, ibuprofen, zaltoprofen, naproxen, full Le Bipurofen, flurbiprofen Aki
Cetyl , fenbufen, mefenamic acid, piroxicam, ampiroxicam, lisipfen, tenoxicam,
Examples include felbinac and orsenone .

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0010

[Correction method] Change

[Correction content]

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 propionate butyrate , etc.) , ketals, acetals, hemiacetal derivatives and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location A61K 31/405 7252-4C 31/54 7252-4C 31/575 7252-4C 31/60 7252-4C 45/00 AAH 8415-4C ABE 47/24 E 7329-4C J 7329-4C N 7329-4C

Claims (4)

[Claims] 1. An anti-inflammatory analgesic external preparation containing a non-steroidal and / or steroid anti-inflammatory analgesic drug as a medicinal component and phosphatidylglycerol as a base component. 2. The nonsteroidal anti-inflammatory drug is indomethacin, methyl salicylate, glycol salicylate,
The anti-inflammatory analgesic external preparation according to claim 1, which is selected from diclofenac sodium, flufenamic acid, bufexamac, ibuprofen, naproxen, flurbiprofen, fenbufen, mefenamic acid and piroxicam. 3. The steroidal anti-inflammatory drug is hydrocortisone, prednisolone, methylprednisolone, dexamethasone, triamcinolone, triamcinolone acetonide, flumetasone, fluocinonide, beclomethasone, fluocinolone, fludoxycortide, clobetasone, clobetazetal and esters of these steroids. The anti-inflammatory analgesic external preparation according to claim 1, which is selected from the group consisting of acetal and hemiacetal derivatives. 4. The anti-inflammatory analgesic external preparation according to claim 1, wherein the content of phosphatidylglycerol is 0.1 to 30% by weight based on the total amount of the external preparation.