JP3527103B2 - Methotrexate transdermal application agent - Google Patents

Description

Detailed Description of the Invention

[0001]

[Industrial application] Methotrexate, which is currently the most effective against rheumatoid arthritis (RA),
It is provided as a transdermal application agent that is safer and more highly compliant than conventional oral agents.

[0002]

2. Description of the Related Art At present, RA is a so-called intractable disease for which the etiology is unknown and thus there is no appropriate preventive method or curative cure.
It is a chronic systemic inflammatory disease with characteristic joint lesions.
Many RAs start with joint pain, but if sustained, they are accompanied by joint destruction and deformation, resulting in motor dysfunction. Skin, blood vessels,
It is a systemic systemic disease that often involves extra-articular lesions such as nerves, heart, and lungs, and the lesions do not stop at the joints. It is said that the number of patients in Japan is 300,000 at the least.

Currently, the main treatments are non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMAR).
Ds), but an immunosuppressant is used when it is not sufficiently effective.

Non-steroids such as salicylic acid, anthranilic acid, phenylacetic acid, indoleacetic acid, propionic acid, pyrazolone, phenacetin, oxicam, and solantal (basic) are used as first-line drugs for RA. Anti-inflammatory agents are used. Second-line drugs include gold preparations (auranophine, gold thiomalate N
a), SH agent (bucilamine, D-penicillamine), CC
DMARDs such as A (lobenzarit disodium) and sulfa drug (sulfasalazine) are used. Various steroid drugs are selected as the third-choice drug. As the fourth-selective drug, an immunosuppressive drug such as mizoribine, azathioprine, cyclophosphamide, methotrexate, tacrolimus hydrate is used.

[0005] Among these, methotrexate has been pointed out to be extremely useful, and it is pointed out that administration of a small amount of RA may have an anti-inflammatory effect from a relatively early stage, and that maintenance of long-term remission may be possible. Has been done. Usually, a method of administration at 2.5 to 7.5 mg / week is used. In Europe and America, methotrexate is the drug of choice. However, mizoribine is the only fourth-line immunosuppressant that currently has RA as an indication (covered by insurance).

[0006] Methotrexate is an antimetabolite originally developed as a therapeutic agent for malignant tumors, and was first used in RA in 1951 and was announced to be effective. It has already been approved in the United States for the treatment of RA (1988).
Since then, it has been approved as an RA treatment drug in 17 countries overseas. In Japan, when clinical trials have started since 1994, although it has not yet been officially approved for RA, it is in widespread use in clinical settings at the discretion of the attending physician. . However, it is well known to induce various disorders such as decrease in white blood cells and platelets, liver disorder, gastrointestinal ulcer, diarrhea, erosion of mucous membrane, erythema and hair loss, and bone marrow suppression and interstitial pneumonia. The occurrence of serious side effects is a particular problem.

When administering this drug to a patient,
Conventionally, oral administration such as tablets and capsules has been performed. However, oral agents suffer from a hepatic first-pass effect, namely the inevitable consumption of much of the drug there as it passes through the liver before it reaches the blood. Further, methotrexate has a strong medicinal effect, but on the other hand, it may cause the above-mentioned side effects, so that it is necessary to exercise caution when using it. Therefore, it is used only when the efficacy of this drug exceeds the risk of developing side effects.

Therefore, if a transdermal preparation capable of absorbing the drug into the blood can be developed, it is possible to avoid the hepatic first-pass effect, which cannot be avoided by the oral preparation, and further avoid side effects such as digestive disorders. It becomes possible. In addition, especially the patch has some advantages in addition to that. For example, by controlling the transdermal absorbability of a drug, it is possible to maintain a constant blood concentration in the drug over a long period of time, and to avoid side effects caused by rapid and rapid absorption of the drug, such as oral administration. It becomes possible to prevent it. Further, even if a disorder occurs, the drug supply can be immediately stopped by removing the preparation, and there is no risk of forgetting to administer or repeated administration. However, because methotrexate has a large molecular weight and a high polarity, it has poor transdermal absorbability from the base of ordinary transdermal preparations, and a transdermal formulation for the purpose of drug absorption into blood is still disclosed. Was not done.

It has been confirmed that methotrexate has a therapeutic effect on psoriasis, and a topical application agent has been disclosed (JP-A-63-27432). However, the effect was only on the local site where the drug was administered, and further absorption was not achieved (the purpose was local treatment). In addition, Japanese Patent Laid-Open No. 55-149212 discloses that
By containing methotrexate in a specific water-insoluble hydrophilic polymer, the drug dissolution rate can be controlled by the water content, and a sustained-release agent useful as a villous tumor therapeutic agent to be locally administered to the uterine cavity is disclosed, Similarly, it is not intended to absorb the drug into the blood and has not been reached to the whole body.

The current topical formulations are mainly for local action,
At present, it is physically impossible when there are many inflamed lesions such as RA. If it can bring the drug to an effective concentration at the systemic level, its clinical utility will be confirmed. In addition, especially since the aging of society will progress in the future, many people will inevitably have poor renal and hepatic functions. Therefore, the merit of transdermal application also comes out here.

[0011]

In order to solve the above-mentioned drawbacks of the oral preparation, it is necessary to complete the delivery technology of methotrexate into blood, which has been a problem in transdermal application of methotrexate. Is an issue and RA
The purpose is to obtain an effective transdermal application agent.

[0012]

[Means for Solving the Problems] Therefore, as a result of intensive studies on the percutaneous absorption type preparations, the present inventors have found it difficult to add methotrexate and an organic amine to the base of the external preparation. Furthermore, we have come to the finding that the delivery of methotrexate into the blood is realized.

The present inventors have found that in an external preparation containing methotrexate, the drug absorbability of methotrexate is remarkably improved by adding an organic amine to the base.

Examples of the organic amine used in the present invention include alkylamines such as diethylamine and triethylamine,
Examples include alkanolamines such as monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine and triisopropanolamine, ethylenediamine, triethanolamine hydrochloride and the like.

For the transdermal application agent of the present invention, dosage forms such as ointments, creams, lotions, gels and patches can be used.
A patch is a more preferable dosage form in consideration of a preparation intended for absorption of a drug into blood, and controllability of drug absorption and handling.

The base components to be blended as ointments, creams and lotions include bases, emulsifiers and preservatives. As the base, white petrolatum, hydrocarbons such as liquid paraffin, oils and fats such as soybeans, Examples thereof include waxes such as beeswax and lanolin, fatty acids such as stearic acid and oleic acid, higher alcohols such as lanolin alcohol and cetostearyl alcohol and esters thereof, macrogol, and the like, and the emulsifier includes a nonionic surfactant. Examples of the preservative include thymol, methyl paraoxybenzoate, propyl paraoxybenzoate, and the like.

Among the patches, the base components to be added in the case of a poultice are thickeners, moisturizers, fillers, crosslinking agents,
Examples include solubilizers and emulsifiers. Specifically, thickeners include sodium alginate, gelatin, methyl cellulose, carboxyvinyl polymer, sodium polyacrylate, etc., moisturizers such as glycerin, macrogols, etc., and fillers. Is kaolin, titanium dioxide, zinc white, etc., as a cross-linking agent, acetaldehyde, dimethyl ketone, aluminum sulfate, etc., as a dissolving agent, alcohols such as ethanol and 2-propanol, macrogol, etc., and as an emulsifier, an anion Examples thereof include a nonionic surfactant and a nonionic surfactant.

In the plaster, as its adhesive base,
Rubber-based elastomers, acrylic pressure-sensitive adhesives, etc. are used. Specific rubber-based elastomers include natural rubber,
Isoprene rubber, styrene-butadiene rubber (SBR),
Styrene-isoprene-styrene block copolymer (S
IS), styrene-butadiene-styrene block copolymer (SBS), butyl rubber, polyisobutylene and the like. Also, as an acrylic adhesive, (meth)
Examples thereof include alkyl acrylate (co) polymers, polyacrylic acid esters, and methacrylic acid esters.

The rubber-based elastomer described above can be prepared by impregnating a plasticizer such as liquid paraffin and kneading it with a tackifying resin and a filler.

The amount of methotrexate used in the present invention is
When the preparation is applied to the skin, the amount of the drug is absorbed without waste, and high absorbency is obtained in order to obtain good drug efficacy, which is 0.1-10% by weight, preferably 1-5% by weight. .

[0021]

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

(Plastic) Based on the formulation shown in Table 1, a plaster was produced by the following method.

[0023]

[Table 1]

The organic amine was dissolved in ethanol, to which methotrexate was added and mixed. This mixed solution was mixed with a toluene solution of the base components (rubber-based elastomer, tackifying resin, plasticizer, etc.) described in the respective Examples and Comparative Examples. Then, it was spread on a release sheet and dried, and a vinyl chloride support was attached to the plaster surface to produce a patch. Comparative Example 1 was prepared in the same manner as in Example 1 except that liquid paraffin was used instead of diisopropanolamine of Example 1.

(Poultice) Based on the formulations shown in Table 2, the poultices of Example 7 and Comparative Example 4 were produced by the following method.

[0026]

[Table 2]

The organic amine and methotrexate were mixed with purified water. This mixture was mixed with an aqueous solution of the base components (sodium polyacrylate, gelatin and glycerin) described in the examples. Then, after spreading on a release sheet, a non-woven fabric support was attached to the plaster surface to produce a poultice.

(Ointment) Based on the formulations shown in Table 3, the ointments of Example 8 and Comparative Example 5 were produced by the following method.

[0029]

[Table 3]

The organic amine and methotrexate were mixed with the gelled hydrocarbon and stirred to prepare an ointment.

(Cream) Based on the formulations shown in Table 4, creams of Example 9 and Comparative Example 6 were produced by the following method.

[0032]

[Table 4]

The organic amine and methotrexate are mixed with a portion of purified water, and the mixture is mixed with stearic acid, behenyl alcohol, squalane, polyethylene glycol monostearic acid, glycerin monostearic acid, butylparaben and methylparaben, 1,3. -Warming with a mixture of butylene glycol and purified water, followed by cooling to prepare a cream.

(Lotion) Based on the formulation shown in Table 5,
Lotions of Example 10 and Comparative Example 7 were manufactured by the following method.

[Table 5]

An organic amine and methotrexate are mixed with a part of purified water, and the mixture is mixed with stearic acid, behenyl alcohol, polyoxyethylenesorbitan monostearic acid, glycerin monostearic acid and butylparaben and methylparaben, 1,3. -Warming with a mixture of butylene glycol and purified water, followed by cooling. Then, the mixture was mixed with an aqueous dispersion of carboxyvinyl polymer and stirred to produce a lotion.

Test Example 1 Skin Permeation Test A skin permeation test was carried out using the back skin of the hairless mouse, and the skin permeation of methotrexate of each preparation was compared.

Each preparation was attached to the skin of the hairless mouse, which was attached to an in vitro membrane permeation tester, and p was applied to the receptor fluid.
Using H7.4 phosphate buffer, the amount of methotrexate transferred into the receptor fluid was measured. The result is shown in FIG.

As is apparent from FIG. 1, the formulations of Examples 1 to 3 and Example 7 to which the organic amine was added showed higher skin permeability than the formulations of Comparative Examples 1 to 4 to which the organic amine was not added. It was The skin permeability was also examined for Examples 8 to 9 and Comparative Examples 5 to 7. Similarly, the examples to which the organic amine was added showed higher skin permeability than the comparative examples to which no organic amine was added. It was

(Test Example 2) Transdermal absorption test rat (Wistar strain, 7 weeks old, male, 200 g to 25)
Hair of the back skin (0 g) was removed, and the preparations of Example 1 and Comparative Example (4 cm ² ) were applied. Blood was collected after a certain period of time from the start of the test, and the blood concentration was measured. The preparation was peeled off after 48 hours, and the blood concentration was traced until 54 hours later. The result is shown in FIG.

As is clear from FIG. 2, the preparation of Example 1 to which the organic amine was added exhibited higher transdermal absorbability than the preparation of Comparative Example 1 to which no organic amine was added, and the blood concentration was sustained. Also showed. In addition, the blood concentration rapidly decreased after the preparation was peeled off.

Test Example 3 Drug Efficacy Test An edema inhibitory effect on adjuvant arthritis in rats used as a model of RA was carried out. Rat
The back skin of an is system, 7-week-old, male, 200 g to 250 g) was shaved, and the preparation (4 cm ² ) of Example 1 and Comparative Example 1 was applied. Then, adjuvant inflammation was performed and the paw edema volume was measured over time to evaluate the drug efficacy. The results are shown in Fig. 3.

As is clear from FIG. 3, the preparation of Example 1 to which the organic amine was added showed a stronger edema suppressing effect than the preparation of Comparative Example 1 to which the organic amine was not added. The formulation of Comparative Example 1 had no difference from the control (untreated).

[0043]

As described above, according to the present invention, methotrexate, which is currently the most effective against RA, can be used as a transdermal therapeutic agent that is safer and more compliant than conventional oral agents.

[Brief description of drawings]

FIG. 1 is a diagram showing the skin permeability of Examples and Comparative Examples by a hairless mouse skin permeation test.

FIG. 2 is a diagram showing blood levels when the patches of Examples and Comparative Examples were applied to rats.

FIG. 3 is a diagram showing changes in the rate of adjuvant arthritis edema in rats to which the examples and comparative examples are applied.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A61P 29/00 A61P 29/00 (56) References JP-A-9-143062 (JP, A) Arthritis & Rheum atism, 1990, Vol ． 33, No. 10, pp. 1449-1456 (58) Fields surveyed (Int.Cl. ⁷ , DB name) A61K 31/519 A61K 9/06 A61K 9/70 A61K 47/18 A61P 19/02 A61P 29/00 BIOSIS (STN) CAPLUS (STN) ) MEDLINE (STN) EMBASE (STN)

Claims (8)

(57) [Claims] 1. A transdermal preparation characterized by containing methotrexate and an organic amine . 2. The use for treating rheumatoid arthritis.
Transdermal application agent as described . 3. 0.1 to 10 parts by weight of methotrexate
%, An organic amine of 2.0 to 5.0% by weight.
The transdermal application agent according to claim 1 or 2. 4. The transdermal application agent according to claim 1, claim 2 or claim 3, wherein the organic amine is an alkanolamine or an alkylamine. Claims wherein the alkanolamine is monoethanolamine, diethanolamine, selected from the group consisting of triethanolamine and diisopropanolamine
Item 4. The transdermal application agent according to Item 4 . 6. A contract wherein the alkylamine is selected from the group consisting of ethylamine, diethylamine, triethylamine.
The transdermal application agent of claim 4 . 7. The transdermal application agent according to claim 1, claim 2, claim 3, claim 4, claim 5 or claim 6 , wherein the dosage form is a plaster or a poultice. 8. The formulation according to claim 1, wherein the formulation is any one of an ointment, a cream and a lotion.
The transdermal application agent according to claim 3, claim 4, claim 5, or claim 6 .