Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1998-08-04
2001-05-29
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S568000
Reexamination Certificate
active
06239177
ABSTRACT:
This application is 371 of PCT/JP97/00283 filed on Feb. 6. 1997.
FIELD OF THE INVENTION
The present invention relates to a preparation for external application containing tranilast as an active ingredient, more specifically to a preparation for topical application giving good transdermal absorbability of the active ingredient in the preparation due to improvement of the base and capable of sufficiently keeping an effective drug concentration in the skin tissue after application, which preparation is directed to treat keloid having little skin irritation, hypertrophic scar, psoriasis, palmoplantar pustulosis, prurigo nodularis including urticaria perstans, allergic dermatitis (e.g., atopic dermatitis, contact dermatitis, dutaneous pruritus, sting of an insect, priurigo simplex acuta, etc.), the other eczema and dermatitis including progressive palmoplantar keratoderma and lichen symplex chronicus.
BACKGROUND OF THE INVENTION
An antiallergic drug, tranilast, has been commercially available as a therapeutic agent for allergic diseases. It has also been reported to show excellent pharmaceutical effect on keloid and hypertrophic scar (Kiyoshi Ichikawa et al., Oyo Yakuri (Pharmacometrics) 43(5), 401 (1992), Haruo Suzawa et al., Nichi Yakuri-shi (Folio Pharmacol Japan) 99, 231 (1992)). Tranilast has been used in the dosage form for oral administration such as capsules, tablets, dry syrup, fine granules, and the like. However, the drug orally taken is absorbed from the digestive tract through portal vein to liver where the drug is metabolized to give a so-called first passing effect. Thereafter, a part of the drug is transferred to local sites and its biological availability is decreased. Accordingly, it is necessary to administer a relatively large amount of the drug so as to maintain the effective drug concentration in blood, which increases manifestation of side effects. Further, preparations for external application directly applied to local sites of skin, particularly patches, have been considered favorable for the treatment of keloids, hypertrophic scar, and allergic dermatitis so that it is necessary to maintain an effective drug dosage sufficiently in the skin.
Attention has been paid to patches as preparations for topical application as well as a new route for applying systemic drugs as transdermal drug delivery system (TDS). In other words, in TDS, a drug absorbed from its preparation through epidermis is taken into blood stream via subcutaneous capillary vessels while a portion of the drug is transferred directly to local skin tissues without being taken into blood stream. Aiming at such a topical application effect, a number of patches utilizing non-steroid anti-inflammatory drug systems (NSAIDS) have been already developed and commercially available.
Further, subcutaneous application by patches is effective as the controlled release method of drugs by which effects of drugs can be prolonged and the concentration of drugs in blood can be controlled. Thus, it is possible to suppress manifestation of side effects.
However, skin inherently has a property to defend the inside of body from foreign substances that may invade from the outside. Keratolytic agents such as Azone are sometimes used as a base in order to increase transdermal absorption of a drug. Such agents give high skin irritation and thus may possibly cause side effects such as an eruption on the skin. Transdermal absorbability depends on characteristics of the molecule, which extremely limits formulation of the drugs that can give effective transdermal absorption.
Tranilast is sparingly soluble in water. Among organic solvents, it is hardly soluble in methanol, ethanol, ethyl acetate, while it is soluble in dimethyl formamide, pyridine, dioxane, and acetone though these solvents are not suitable for the base of preparations for external application. The drug can be solved to some extent in a kind of fatty acid and its ester, animal and vegetable oils and fats, terpene compounds, and alcohols, but the solubility is not sufficient and the drug cannot be dispersed well in the preparations. This affects transdermal absorbability of tranilast and the solubility of the drug makes it difficult to formulate the drug into a patch.
As a preparation containing tranilast for external application, a patch containing tranilast has been developed, which contains a kind of fatty acid and alcohols as absorption aids to improve cutaneous absorbability (Japanese Patent Application Laid-Open No. Hei 4-99719). However, this patch requires a large amount of absorption aids, such as fatty acid ester or alcohols, which might possibly cause skin irritation.
A tranilast-containing ointment has also been developed, which contains a basic aqueous solution as an absorption aid (Japanese Patent Application Laid-Open No. Hei 6-128153). This preparation for external application has basic pH due to the basic aqueous solution contained as an absorption aid. The basic substance itself might possibly cause skin irritation. Thus, there are problems that make it difficult to put the preparations into practical use.
SUMMARY OF THE INVENTION
An object of the present invention is to solve the above described problems in the prior art to achieve the practical use of the preparation for external application containing tranilast as an active ingredient, which has good transdermal absorbability of the active ingredient in the preparation, sufficiently keeps a drug concentration effective in the skin tissues, and shows little skin irritation.
The earlier report (Toyomi Waseda, The Japanese Journal of Dermatology, 99 (11), 1159 (1989)) describes that the effective concentration of tranilast in the skin tissue for treatment of keloid patients is about 8 to 10 &mgr;g/g when it is orally administered in a dose of 300 mg/day in three divided doses for three days. Another earlier report (Yasuo Goto et al., Kiso to Rinsho (The Clinical Report), 25(15), 69 (1991)) discloses that in the experiment using rat carrageenan-induced granulation tissue model a dose-dependent inhibitory effect was observed when tranilast was orally administered in a dose of 50, 100, and 200 mg/kg for consecutive 14 days and the drug concentration in the skin tissue one hour after the final administration was 4.2±0.4, 10.3±0.9, and 23.17±1.7 &mgr;g/g, respectively. Consequently, the tranilast concentration in the skin tissue after its application to the skin should desirably be comparable to or higher than the values as described above.
Keloid, hypertrophic scar, and allergic dermatitis are diseases giving some appearance on the skin surface that is not only apparently ugly but also sometimes accompanied by strong itchiness or pain as subjective symptoms. Accordingly, it is preferable that preparations for external application to be directly applied to the diseased part should not produce irritation by contact and the base in the preparation does not cause skin irritation. Particularly, patches are preferably elastic and do not have undue strong adhesiveness so that little resistance occur when they are detached. In this connection, a cataplasm containing water or a soft type of plasters is desired.
The present invention provides a preparation for external application and a method of producing it to achieve the above object, which preparation contains an aqueous base comprising tranilast, its salt, or a mixture thereof as an active ingredient, in which the aqueous base comprises a dissolution medium, a dispersant, an absorption aid, an adhesive, and/or a form-keeping agent, and water, the active ingredient is dissolved in the dissolution medium, and dispersed in the aqueous base by means of the dispersant. The present invention provides such a preparation for external application comprising tranilast and a patch for external application which comprises a support having the preparation for external application coated thereon.
Further, the present invention relates to a method of producing a preparation for external application containing tranilast, which comprises dissolv
Mori Masao
Saito Noriyasu
Jarvis William R. A.
Kim Vickie
Lead Chemical Co., Ltd.
Nath Gary M.
Nath & Associates PLLC
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