Transdermal methotrexate preparations

Details Transdermal methotrexate preparations Transdermal methotrexate preparations

2000-03-14

2002-11-26

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

C424S448000, C424S443000, C514S946000, C514S947000, C514S825000

Reexamination Certificate

active

06485740

ABSTRACT:

BACKGROUND OF THE INVENTION
a) Field of the Invention
This invention relates to percutaneously-applicable preparations (hereinafter called “transdermal preparations”) capable of administering methotrexate, which is at present considered to be most effective for rheumatoid arthritis (hereinafter abbreviated as “RA”), more safely than conventional oral preparations while permitting high compliance.
b) Description of the Related Art
As the cause of RA has not been ascertained yet -RA has neither appropriate preventive method nor radical treatment method and is a so-called inveterate disease. RA is a chronic constitutional inflammatory disease and develops characteristic articular lesions. Although RA begins from arthralgia in many cases, its continuation is accompanied by multi-articular destruction or deformity and results in problems of moving functions. It is also often accompanied by extra-articular lesions such as skin, blood vessel, nerve, heart and lung lesions. It is hence a systemic disease lesions of which are not confined to joints. RA patients in Japan are reported to reach as many as 300,000 even on a conservative estimate.
Principal therapeutic drugs for RA at present are non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDS) and, unless they can provide sufficient effects, immunosuppressants are used.
As first-choice drugs for RA, non-steroidal anti-inflammatory drugs such as salicylic acids, anthranilic acids, phenylacetic acids, indoleacetic acids, propionic acids, pyrazolones, phenacetins, oxycams or solantal type are used.
As second-choice drugs, DMARDs such as gold-containing agents (auranofin, gold sodium thiomalate), SH-containing agents (bucillamine, D-penicillamine), CCAs (disodium lobenzarit) and sulfa drugs (sulfasalazine) are used.
As third-choice drugs, various steroidal drugs are selected.
Further, as fourth-choice drugs, immunosuppressants such as mizoribine, azathioprine, cyclophosphamide, methotrexate and tacrolimus hydrate are used.
Methotrexate that is indicated to be extremely useful among these therapeutic drugs. This drug is indicated that, even when administered at low dosage level against RA, anti-inflammatory effects can be observed from a relatively early stage and remission may be maintained over an extended time. It is usually to RA patients at a dosage of from 2.5 to 7.5 mg/week.
Incidentally, methotrexate is classified as first-choice for RA in Europe and America.
Methotrexate is a metabolic antagonist which was initially developed as therapeutic drug for malignant tumors. For the first time in 1951, it was used for RA and was reported to have effectiveness. It was approved as therapeutic drug for RA in the United States (as early as 1988). Since then, it has been approved as therapeutic drug of RA in 17 countries outside Japan. In Japan, however, it was as late as in 1999 that the application of the national health insurance to methotrexate as a therapeutic drug for RA was approved, although it had already been widely used in clinical fields under the discretion of attending physicians.
Nonetheless, methotrexate is well known to induce various problems such as leukopenia and thrombocytopenia, hepatic problems, gastrointestinal ulcer, diarrhea, mucosal erosion, erythema and alopecia. Development of serious side effects such as bone marrow failure and interstitial pneumonia his arisen as an especially serious problem.
Administration of this drug to patients has conventionally been performed orally, for example, in the form of tablets or capsules. preparation is, however, accompanied by the problem of the first-pass effect at the liver in that upon passage through the liver, a drug is substantially metabolized there before it reaches an affected part. Further, methotrexate has a potential problem of development of side effects as mentioned above although its drug efficacy is strong. For its use, an utmost care is therefore needed. Under these circumstances, methotrexate is used only when an advantage which would be available from its administration is judged to surpass the risk of development of side effects.
If a transdermal preparation which would permit absorption of this drug into blood can be developed, it would then become possible to avoid the first-pass effect at the liver, which is unavoidable for oral preparations, and moreover, to avoid side effects such as gastrointestinal problems. In particular, plasters have some additional advantages. For example, control of percutaneous absorption of the drug makes it possible to maintain its blood at a constant level an extended time and further, to prevent side effects which would otherwise occur due to rapid absorption of the drug in a short time as is observed in the case of oral administration. On top of these, if any problem should arise, simple removal of the preparation makes it possible to immediately stop the supply of the drug, and further, it is also possible to obviate the potential problem of forgetting to give a dose or to give a dose twice. Methotrexate, however, has a high molecular weight and high polarity, so that its percutaneous absorption for transdermal preparations is poor. Therefore, no preparation of the percutaneous absorption type has been disclosed yet for the absorption of the drug into blood.
Incidentally, methotrexate has been confirmed to have therapeutic effect for psoriasis, and its topical preparation has been disclosed (JP 63-27432 A). This topical preparation is, however, effective only to an affected topical part to which the drug is applied, and no additional absorption can be achieved (namely, a topical treatment is intended). On the other hand, JP 55-149212 A states the incorporation of methotrexate in a particular water-insoluble hydrophilic polymer makes it possible to control the velocity of dissolution of the drug by relying upon its water content, and discloses a sustained release preparation useful as a villous tumor therapeutic agent for topical administration to the uterine cavity. However, this sustained release preparation is likewise not intended to achieve absorption of the drug into blood, so that absorption of the drug to the whole body has not been achieved yet.
Presently-available external preparations are intended primarily to give topical effects and under the current circumstances, are physically unable to exhibit the therapeutic effect of methotrexate where inflamed lesions spread at many sites as in RA. If it becomes possible to make the drug reach an effective concentration at the whole body level, its clinical usefulness will be assured. In particular, more people are expected to suffer from deteriorated kidney or liver function as the aging of population in the society advances. Here too, the merits of transdermal preparations are believed to be enjoyed.
SUMMARY OF THE INVENTION
To solve the above-described drawbacks of the conventional oral preparations of methotrexate, the present invention has as a theme thereof the completion of a technique for the delivery of methotrexate into blood, which has heretofore remained as a problem upon formulation of methotrexate into transdermal preparations, and as an object thereof the provision of a transdermal methotrexate preparation effective for RA.
As a result of extensive research on transdermal preparations, the present inventors have found that inclusion of an organic amine along with methotrexate in a base for an external preparation makes it possible to achieve delivery of methotrexate into blood although this delivery has heretofore been difficult.
The present inventors have also found that in an external preparation added with methotrexate, addition of an organic amine in a base leads to a significant improvement in the absorption of methotrexate as an active ingredient.
These findings have led to the completion of the present invention. In one aspect of the present invention, there is accordingly provided a methotrexate-containing transdermal preparation effective for rheumatoid arthritis, which comprises an organic amine.
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