JP2003321367A - Ointment - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an ointment capable of obtaining therapeutic effect of the same level as a peroral drug by enhancing percutaneous absorption of methotrexate having excellent therapeutic effect on proliferative dermatopathy such as chronic rheumatism and psoriasis. <P>SOLUTION: This ointment is obtained by incorporating methotrexate, an organic amine and a nonion surfactant in a base containing a gelatinized hydrocarbon. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an ointment.
More specifically, by increasing the transdermal absorbability of methotrexate, which has an excellent therapeutic effect on proliferative skin diseases such as rheumatoid arthritis and psoriasis, an ointment capable of obtaining the same level of therapeutic effect as an oral preparation. The agent is provided.

[0002]

BACKGROUND OF THE INVENTION Methotrexate is an antimetabolite developed as a therapeutic agent for malignant tumors, but in recent years it has been confirmed that it also has therapeutic effects on rheumatoid arthritis and proliferative skin diseases such as psoriasis. Has been done. This methotrexate is generally administered to the human body by oral administration such as tablets and capsules, but when methotrexate is used as an oral agent, the first-pass effect in the liver, that is, most of the drug is systemically circulated (in the blood) There is a problem that it is metabolized and excreted in the liver before reaching (1), and it has been necessary to administer an excessive dose over that required for treatment. However, excessive administration of methotrexate causes various disorders such as white blood cell / platelet reduction, liver damage, gastrointestinal ulcer, diarrhea, mucosal erosion, erythema and hair loss, and serious side effects such as bone marrow suppression and interstitial pneumonia. It is not preferable because it causes

On the other hand, if the administration of methotrexate to the human body can be performed by a transdermal absorption type external preparation instead of an oral preparation, the above-mentioned first-pass liver effect can be avoided and side effects such as digestive disorders can be avoided. It will be possible. Therefore, development of a transdermal absorption type external preparation using methotrexate has been demanded.

[0004] However, methotrexate has a large molecular weight and a high polarity, and when it is used as an external preparation, the drug release from the base and the transdermal absorbability are markedly deteriorated. The transdermal absorbability of methotrexate has been a major problem.

Various studies have been conducted to improve the transdermal absorbability of methotrexate. For example, JP-A-55-149212 discloses a sustained-release agent which contains methotrexate in a specific water-insoluble hydrophilic polymer, the drug dissolution rate is controlled by the water content, and is locally administered to the uterine cavity. It was Also, JP-A-63-27
Japanese Patent No. 432 discloses a preparation comprising methotrexate and the like, a skin permeation reagent and a carrier, for example, a local preparation for treating hyperproliferative epithelial diseases such as psoriasis.
However, the percutaneous absorbability of methotrexate such as the preparations disclosed therein is an action only on the local site of the affected area and is not always satisfactory in terms of systemic therapeutic effect.

Further, in WO98 / 31369,
There has been disclosed a transdermal external preparation containing methotrexate and having a systemic therapeutic effect on chronic inflammatory diseases such as autoimmune diseases and cancer diseases such as leukemia. However, the transdermal absorbability of this external preparation, methotrexate, was not sufficient. Further, in the publication, alcohol,
Although it is described that it is preferable to add various absorption promoters such as organic acids, higher fatty acid esters, hydroxycarboxylic acid esters, N-acyl sarcosine, and surfactants, the effect has not been clarified. .

On the other hand, the present inventors have developed a transdermal agent for treating rheumatoid arthritis, which contains methotrexate and an organic amine (Japanese Patent Laid-Open No. 2000-16938).
Although the present invention improves the transdermal absorbability of methotrexate by incorporating an organic amine, its transdermal absorption promoting effect varies, and it cannot be said that the maximum effect is obtained.

Further, the present inventors formed a complex having a high polarity of methotrexate and an organic amine, and in the production of a patch using a rubber-based pressure-sensitive adhesive base using a solvent method, the above-mentioned complex is a base. It has been found that it is not sufficiently compatible with the solution of the agent and becomes non-uniform in the base due to the high specific gravity of the complex. When the base composition containing this complex is spread on the release sheet and left standing, the complex in the base is localized on the release sheet side (skin application side) due to its high specific gravity. Found a mechanism whereby the drug release of methotrexate when applied to the skin was enhanced, and applied for a patent (Japanese Patent Application No. 20
01-140951). According to this method, the release of methotrexate can be maximized, and a patch with improved variation can be obtained, which is a very effective means, but in a form other than the patch, such as an ointment. Since the drug in the preparation is required to be uniform, it is a means that cannot be used with external preparations other than the patch.

[0009]

SUMMARY OF THE INVENTION Therefore, the present invention solves the above-mentioned drawbacks of the prior art and, when methotrexate is used in the form of an external preparation, particularly an ointment, the percutaneous absorbability of methotrexate, which is a medicinal ingredient. It is an object of the present invention to provide a technology capable of stably increasing the amount of ointment, and an object thereof is to provide a safe and highly compliant ointment.

[0010]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that gelled hydrocarbons are used as a base component, It was found that by incorporating a nonionic surfactant into the base to form an ointment, transdermal absorbability of methotrexate, which is a medicinal component, can be enhanced, and delivery of methotrexate into blood can be realized. Was completed.

That is, the present invention provides an ointment comprising a gelled hydrocarbon base and methotrexate, an organic amine and a nonionic surfactant.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Methotrexate, which is used as a medicinal component in the ointment of the present invention, is an antimetabolite originally developed as a therapeutic agent for malignant tumors, such as rheumatoid arthritis, psoriasis, and skin tumors (group Constant cell carcinoma, squamous cell carcinoma, melanoma, viral disease (warts, herpes simplex,
It is known as a drug for the treatment of proliferative skin diseases such as malignant diseases of apoplexy (condyloma acuminata) and mucous membrane (oral cavity).

The content of methotrexate in the ointment of the present invention is 0.1 to 10% by mass based on the whole ointment.
(Hereinafter, simply referred to as “%”) is preferable, and 1 to 5% is more preferable. When the amount of methotrexate is in this range, when the ointment is applied to the skin, the medicinal component is absorbed into the skin without waste, and good medicinal effect is obtained, which is preferable.

The organic amine used in the ointment of the present invention is used in combination with a nonionic surfactant or a gelling hydrocarbon as a base component to improve the absorbability of methotrexate from the skin. Those having an absorption promoting action, for example, alkylamines such as diethylamine and triethylamine, monoethanolamine,
Examples thereof include alkanolamines such as diethanolamine, triethanolamine, diisopropanolamine, and triisopropanolamine. Further, diamines such as ethylenediamine and amine salts such as triethanolamine hydrochloride can also be used. One of these organic amines may be used alone, or two or more thereof may be appropriately selected and used.

The content of the organic amine in the ointment of the present invention is preferably 2.0 to 10.0%, more preferably 2.0 to 5.0% based on the whole ointment. When the content of the organic amine is within this range, a complex is favorably formed with methotrexate which is a medicinal component, which is preferable.

The nonionic surfactant used in the ointment of the present invention is used in combination with an organic amine or a gelling hydrocarbon as a base component to promote transdermal absorption of methotrexate. It has an action. Examples of the nonionic surfactant include polyhydric alcohol ester type surfactants such as glycerin fatty acid ester and sorbitan fatty acid ester, and alkylene oxide addition ether type interface such as polyoxyethylene alkyl ether and polyoxyethylene alkyl allyl ether. Activator, alkylene oxide addition ester type surfactant such as polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, alkylene oxide addition ether ester type surfactant such as polyoxyethylene glycerin monofatty acid ester, polyoxyethylene fatty acid amide , Polyoxyethylene alkylamine, and other alkylene oxide-added nitrogen-containing compound type surfactants. One of these may be used alone, or two or more of them may be appropriately selected and used.

The content of the nonionic surfactant in the ointment of the present invention is 1.0 to 10.0% based on the whole ointment.
Is preferable and 1.0 to 5.0% is more preferable. If the content of the nonionic surfactant is within this range,
It is preferable because it exhibits a good effect of promoting percutaneous absorption.

In the ointment of the present invention, each of the above-mentioned compounding ingredients must be compounded with a base containing gelled hydrocarbon. This gelled hydrocarbon is obtained by blending polyethylene in liquid paraffin at a ratio of 5 to 10% and gelling it. For example, polyethylene having an average molecular weight of about 21,000 is dissolved by heating liquid paraffin. This solution is produced by means such as cooling from a temperature near the cloud point at 10 ° C./sec. This product is commercially available, for example, under the trade name of Plastibase (manufactured by Sankyo Co., Ltd.), and thus may be used.

In addition to the above-mentioned gelled hydrocarbon, white petrolatum, polyethylene glycol, wax, higher alcohols, fatty acids and the like can be supplementarily added to the base of the ointment of the present invention.

The content of gelled hydrocarbon in the ointment of the present invention is preferably 60.0-97.0%, more preferably 60.0-97.0%, based on the whole ointment. When the content of the gelled hydrocarbon is within this range, the complex of methotrexate and the organic amine can be stably maintained, which is preferable.

Further, in the ointment of the present invention, in addition to the above-mentioned essential components, various optional components used in ordinary ointments, such as crotamiton and myristic acid, are added within a range that does not impair the effects of the invention. One or more kinds of solubilizers such as isopropyl and stabilizers such as tocopherol can be appropriately mixed.

The ointment of the present invention can be prepared according to a conventional method taking into consideration the composition, content, etc. of each component. For example, the essential components of organic amine, nonionic surfactant and methotrexate and, if necessary, It can be prepared by adding the optional components to the gelled hydrocarbon as a base and thoroughly mixing and stirring the mixture.

The ointment of the present invention produced as described above has the efficacy of methotrexate contained as a medicinal component, for example, the growth of chronic rheumatism, psoriasis, skin tumors, viral diseases and malignant tumors of mucous membranes. It can be used as an ointment for the treatment of sexual skin diseases and the like.

[0024]

In the ointment of the present invention, the mechanism by which the transdermal absorbability of methotrexate is improved is still unknown, but the gelled hydrocarbon stably maintains the complex of methotrexate and the organic amine and is applied to the skin. It is speculated that the nonionic surfactant enhances the transdermal absorbability.

[0025]

The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1 Ointment: According to the formulation shown in Table 1, the components were thoroughly mixed and stirred to produce ointments of the present invention products 1 to 5 and comparative products 1 to 4.

(Method)

[Table 1]

Test Example 1 Skin Transparency Test: A skin permeation test using the back skin extracted from a hairless mouse was conducted using the following test method, and the ointments of the present invention product 1 and comparative products 1 to 4 were tested. The skin permeation was compared and evaluated.

(Test method) The skin on the back of the hairless mouse was removed, and the present invention product 1 or comparative products 1 to 4 were applied to the skin.
0.05 g / 1.74 cm ² of the ointment of Example ¹ was applied, and the ointment was attached to an in vitro membrane permeation tester. As a receptor solution of this membrane permeation tester, a phosphate buffer solution of pH 7.4 was used,
The amount of methotrexate transferred into the receptor fluid over time was measured. The results are shown in Fig. 1.

From the results of FIG. 1, the ointment of the product 1 of the present invention using gelled hydrocarbon as a base and adding an organic amine and an ionic surfactant as a percutaneous absorption promoter of methotrexate which is a medicinal component The agent is a comparative product 1 using white petrolatum as a base, a comparative product 2 not containing an organic amine and a nonionic surfactant, a comparative product 3 containing only an organic amine and a nonionic surfactant alone. The skin permeation was higher than that of the comparative ointment of Comparative Product 4. Therefore,
It was confirmed that the skin permeability of methotrexate can be improved by using a gelled hydrocarbon as a base and adding an organic amine and a nonionic surfactant to an external preparation containing methotrexate.

Test Example 2 Drug efficacy test (confirmation of edema inhibitory effect): With respect to the ointment of the product 1 of the present invention, the edema inhibitory effect on the adjuvant arthritis of rats used as a model of rheumatoid arthritis using the following test method. It was confirmed.

(Test method) 5 rats per group (Lew
is system, 6-week-old, male, 140 g to 180 g) was used as a test group, the back skin thereof was shaved, and an ointment of the present invention product 1 (4 m
g / kg) was applied. Further, as a comparison group, a group was prepared in which hair was removed and then no ointment was applied, as in the test group. Then, both groups were subjected to adjuvant inflammation, and the paw edema volume was measured over time. The results of comparing the edema inhibitory effects of the test group and the comparative group are shown in FIG.

From the results of FIG. 2, the ointment of the product 1 of the present invention is
It was possible to suppress the occurrence of edema even after 28 days had elapsed, and a remarkable edema suppressing effect was exhibited. Therefore,
It was confirmed that the ointment of the product 1 of the present invention had an excellent effect on the treatment of rheumatoid arthritis.

[0034]

INDUSTRIAL APPLICABILITY The ointment of the present invention uses a gelled hydrocarbon as a base component, and contains an organic amine and a nonionic surfactant in the base to give methotrexate as a medicinal component. It can improve the transdermal absorbability,
An excellent pharmacological effect can be obtained.

Further, the ointment of the present invention is not an oral preparation, but is capable of absorption of methotrexate into the blood in the form of an external preparation, so that it is safe for the human body and has high compliance. is there.

[Brief description of drawings]

FIG. 1 is a graph showing the skin permeability of the present invention product 1 and comparative products 1 to 4 in the hairless mouse skin penetration test of Test Example 1.

FIG. 2 is a graph showing the changes in the rate of adjuvant arthritis edema in the drug efficacy test of Test Example 2 in the product 1-administered group of the present invention and the comparative group. that's all

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 17/00 A61P 17/00 29/00 101 29/00 101 (72) Inventor Yu Sakamoto Kashima City, Saga Prefecture No. 2596, Otomi, 1 Yutoku Pharmaceutical Co., Ltd. (72) Yukio Yamaguchi Inventor, Yukio Yamaguchi 2596, No. 1, Tofu, Yutoku Pharmaceutical Co., Ltd. F term (reference) 4C076 AA09 BB31 CC21 DD07N DD34A DD50N EE23N EE26N EE51A FF34 FF35 4C086 AA01 AA02 CB09 MA03 MA05 MA28 MA63 NA05 NA10 ZA89 ZB15 ZB26

Claims (8)

[Claims] 1. An ointment comprising a gelled hydrocarbon base and methotrexate, an organic amine and a nonionic surfactant. 2. An organic amine is added to the entire ointment at 2.0.
~ 10.0% by mass, 1.0 to 1 nonionic surfactant
The ointment according to claim 1, which contains 0.0% by mass and 60.0 to 97.0% by mass of gelled hydrocarbon. 3. The ointment according to claim 1, wherein the organic amine is an alkylamine or an alkanolamine. 4. The ointment according to claim 3, wherein the alkylamine is one or more selected from the group consisting of ethylamine, diethylamine and triethylamine. 5. The ointment according to claim 3, wherein the alkanolamine is one or more selected from the group consisting of monoethanolamine, diethanolamine, triethanolamine and diisopropanolamine. 6. The nonionic surfactant is a polyhydric alcohol ester type surfactant, an alkylene oxide addition ether type surfactant, an alkylene oxide addition ester type surfactant, an alkylene oxide addition ether ester type surfactant and The ointment according to any one of claims 1 to 5, which is one or more selected from the group consisting of alkylene oxide-added nitrogen-containing compound type surfactants. 7. The ointment according to any one of claims 1 to 6, which is for treating rheumatoid arthritis. 8. The ointment according to any one of claims 1 to 6, which is used for treating proliferative skin diseases.