Link:  Pharm/Biotech Resources

Title:  Tape material for transcutaneous absorption

United States Patent:  6,953,590

Issued:  October 11, 2005

Inventors:  Owaki; Yukino (Kashima, JP); Hashimoto; Michiyo (Kashima, JP); Sakamoto; Isamu (Kashima, JP); Takiguchi; Kunio (Kobe, JP); Toyoshima; Yoetsu (Nara, JP)

Assignee:  Yutoku Pharmaceutical Ind. Co., Ltd. (Kashima, JP); Maruho Kabushiki Kaisha (Osaka, JP)

Appl. No.:  786370

Filed:  September 9, 1999

PCT Filed:  September 9, 1999

PCT NO:  PCT/JP99/04905

371 Date:  March 15, 2001

102(e) Date:  March 15, 2001

PCT PUB.NO.:  WO00/19986

PCT PUB. Date:  April 13, 2000

A preparation for transdermal absorption is disclosed which is suited for alleviating lasting pains caused by herpes zoster or postherpetic neuralgia and is practical and more improved in drug efficacy, safety and application characteristics. This tape preparation for transdermal absorption is obtained by causing an adhesive mass prepared by incorporating 1-30 parts by weight of a local anesthetic as an active ingredient in 100 parts by weight of a nonaqueous adhesive mass base comprising 5-50% by weight of a styrene-isoprene-styrene block copolymer, 1-60% by weight of an alicyclic saturated hydrocarbon resin, 5-60% by weight of liquid paraffin and 1-30% by weight of butyl rubber to be supported on a backing.

DISCLOSURE OF INVENTION

The present inventors made investigations in an attempt to obtain a transdermal preparation which contains a local anesthetic, typically lidocaine, as an active ingredient and has high practicability.

Meanwhile, patches, which are transdermal preparations, are roughly classified into two types: poultices derived from an aqueous base comprising a water-soluble polymer, water and a water-retaining agent, among others, and tape preparations derived from an oleaginous (nonaqueous) base whose base is a elastomer selected from among styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, polybutenes, polyisoprenes, butyl rubbers, natural rubbers and the like. As a result of preliminary investigations made by the present inventors, it was found that poultices are relatively low in adhesion and difficult to retain on the affected part for a long period of time, hence are unsuitable for achieving the object of the present invention and, further, that since they contain water, they are, in an aspect, inferior in release and transdermal absorption of the main ingredient lidocaine. It was also found that they have more problems to solve as compared with oleaginous bases; for example, since their properties (which have influences on the drug release and adhesion as well) change as a result of evaporation of water after application, they are not suited for long-period application. Furthermore, it was judged that, in the case of HZ or PHN in which the pain maybe increased by external stimulation, the stimulation resulting from cooling of the affected part is also unfavorable and, therefore, water-free, oleaginous base-derived tape preparations are rather preferred.

However, tape preparations produced by merely incorporating a local anesthetic, such as lidocaine, in an oleaginous base comprising a elastomer such as mentioned above cannot attain sustained percutaenous absorbability or sufficient adhesion. Further contrivances were needed for obtaining a practical transdermal preparation for lasting pains.

Accordingly, the present inventors made intensive investigations for obtaining a nonaqueous system-based transdermal preparation which enables to prolong and sustain the effect of a local anesthetics, such as lidocaine, can be used repeatedly for a long period of time without causing abrasion of the stratum corneum and is suited for the alleviation of HZ pains or PHN and, as a result, they found that the above object can be accomplished when a adhesive mass is prepared by incorporating liquid paraffin as a release controlling agent and butyl rubber in a adhesive mass base comprising a styrene-isoprene-styrene block copolymer and an alicyclic saturated hydrocarbon resin as a tackifier component, and a local anesthetic, such as lidocaine, is incorporated in this mass, and they have now completed the present invention.

Thus, the present invention provides a tape preparation for transdermal absorption which is characterized by that a adhesive mass prepared by incorporating 1-30 parts by weight of a local anesthetic as an active ingredient in 100 parts by weight of a nonaqueous adhesive mass base comprising 5-50% by weight of a styrene-isoprene-styrene block copolymer, 1-60% by weight of an alicyclic saturated hydrocarbon resin, 5-60% by weight of liquid paraffin and 1-30% by weight of butyl rubber is supported on a backing.

BEST MODES FOR CARRYING OUT THE INVENTION

The tape preparation for transdermal absorption of the present invention is produced by preparing a adhesive mass by incorporating a local anesthetic, liquid paraffin and butyl rubber in a nonaqueous adhesive mass base comprising a styrene-isoprene-styrene block copolymer (hereinafter sometimes referred to also as "SIS"), which is a main adhesive component, and an alicyclic saturated hydrocarbon resin, which is a tackifier component, and causing the adhesive mass to be supported on a backing in the conventional manner.

The adhesive mass base component SIS is a component essential for providing adhesion required of a patch. This SIS is already available on the market as a adhesive mass base material and, in the practice of the present invention, such commercial product can be utilized. This SIS base is incorporated preferably at an amount of 5-50%, more preferably 10-40%, relative to the adhesive mass weight. When it is less than 5%, the cohesion will become reduced, which may cause such a problem as adhesive deposit after the application. When it is in excess of 50%, the mass becomes excessively hard, which may cause insufficient adhesion.

The alicyclic saturated hydrocarbon resin included in the nonaqueous adhesive mass base components is a resin capable of providing adhesion only when combined as a tackifier component with the adhesive base. If this tackifier component is absent, no adhesion can be generated, hence the function as a tape preparation cannot be performed. As examples of the alicyclic saturated hydrocarbon resin which are specifically utilizable, there may be mentioned those available on the market such as Arkon P series and Arkon M series (both being products of Arakawa Chemical Industries). This alicyclic saturated hydrocarbon resin is incorporated preferably at an amount of 1-60%, more preferably 10-50%. When the amount of this resin is smaller than 1%, the adhesion will be lost and peeling tends to occur. When it is in excess of 60%, the adhesion is so strong that pain may be caused on the occasion of peeling off, or abrasion of the stratum corneum may occur and cause skin irritation.

Further, the liquid paraffin, as an oleaginous component, controls the release of a local anesthetic, such as lidocaine, from the adhesive mass and at the same time softens the adhesive of the adhesive mass. By incorporating this, long-lasting release of the local anesthetic is realized and the tape form preparation is provided with flexible physical properties. Therefore, without using this oleaginous component, it is impossible to obtain an elastic and flexible tape preparation effective against such diseases as HZ and PHN and capable of remaining adhesive and releasing a local anesthetic, such as lidocaine, stably for along period of time. The liquid paraffin is incorporated preferably at an amount of 5-60%, more preferably 10-40%, relative to the weight of the adhesive mass. When it is less than 5%, the long-term releasability of the local anesthetic, such as lidocaine, and the ability to morphologically follow the skin will become reduced. When it is in excess of 60%, excessive flexibility will result, the cohesion will be lost and adhesive deposit may occur after the application.

Furthermore, the butyl rubber used in the tape preparation for transdermal absorption of the present invention is used to modify the flexibility of the adhesive mass, which is insufficient when the SIS is used alone, to a favorable level and prevent the cohesion of the adhesive mass from being decreased by the liquid paraffin.

By combinational using the above liquid paraffin and butyl rubber, it is intended that the long-lasting release of the local anesthetic, such as lidocaine, from the adhesive mass and an adequate level of adhesion be secured and that the stratum corneum be prevented from being abraded. For this purpose, the butyl rubber to be used in the practice of the present invention preferably has a molecular weight of about 400,000. The butyl rubber is incorporated preferably at an amount of 1-30%, more preferably 5-15% and, by doing so, an adhesive mass having high wettability and good adhesion can be obtained.

As the active ingredient local anesthetic which can be incorporated in the thus-obtained adhesive mass, there may be mentioned lidocaine, procaine, oxyprocaine, dibucaine, tetracaine, bupivacaine, mepivacaine, propitocaine, and salts of these. Such a local anesthetic is incorporated at the adhesive mass composition preferably at an amount of 1-30% by weight (hereinafter, "%" for short), more preferably 5-20%.

In the above adhesive mass composition, a filler may be incorporated for retaining the thickness of the adhesive mass layer and/or preventing the adhesive mass from becoming excessively soft and flexible and permeating through the backing. As the filler, there maybe mentioned, for example, kaolin, titanium oxide, talc, calcium carbonate, silicate salts, silicic acid, aluminum hydrate, barium sulfate, calcium sulfate and the like.

Further, an antioxidant, such as dibutylhydroxytoluene, and/or a perfume, such as peppermint oil, and other additives generally used in ordinary tape preparations may be added, when necessary, to the adhesive mass composition of the present invention.

The tape preparation for transdermal absorption of the present invention is prepared in the form of tape preparations by preparing an adhesive mass composition by mixing and dissolving the above essential components and then causing the composition to be supported on a flexible backing, as mentioned above. An example is now shown. First, an SIS and a butyl rubber base, liquid paraffin and an alicyclic saturated hydrocarbon resin, together with a filler and/or an optional ingredient or ingredients to be added where necessary, are melted and mixed up under the heat, and a local anesthetic is added thereto, followed by mixing for sufficient dissolution.

Then, this adhesive mass is casted over a flexible backing and cooled and then, if necessary, a release liner is applied, followed by cutting to an adequate surface area, whereby a tape preparation can be prepared.

The backing to be used here is preferably a flexible film- or sheet-like material so that the tape preparation for transdermal absorption can be provided with the ability to follow the movement of the skin when it is applied as a tape preparation, for instance, to such movable site. As suitable materials, there maybe mentioned, for example, nonwoven fabrics, vinyl chloride films, knitted fabrics, cotton cloths, polyurethane films and the like. Among them, nonwoven fabrics and knitted fabrics are preferred. The thickness of the adhesive mass formed on the backing is preferably 50-500 μm, more preferably 100-300 μm.

As preferred embodiments of the thus-obtainable tape preparation for transdermal absorption of the present invention, there maybe mentioned, for example, tape preparations produced by forming, on a nonwoven fabric (backing), a 100-300 μm thick layer of an adhesive mass with a lidocaine content of 5-20%, a styrene-isoprene-styrene block copolymer content of 10-40%, a liquid paraffin (oleaginous component) content of 10-40%, a butyl rubber content of 5-15% and an alicyclic saturated hydrocarbon resin (tackifier component) content of 20-50%.

The tape preparation for transdermal absorption of the present invention as explained hereinabove is highly effective not only against such diseases as HZ and PHN but also against pains on the occasion of high frequency therapy or laser therapy, pains in the treatment of liver spots or dark red birthmarks or on the occasion of biopsy, and pains at the time of skin grafting for the treatment of thermal burns or pains in the treatment of molluscum contagiosum. In addition to the above, it will be usable also against postoperative pains and pains on the occasion of dental treatment, and so forth.

The transdermal administration of a local anesthetic utilizing the tape preparation for transdermal absorption of the present invention is made either for the purpose of alleviating pains upon venipuncture or the like or for the purpose of alleviating pains caused by HZ or PHN. However, there is a great difference between both concepts of pain alleviating.

Thus, in the former case, an instantaneous action is first of all required of the preparation and it is only required that the pain alleviating effect be produced on the occasion of such treatment as venipuncture. In the latter case, on the contrary, the maintenance of effect, namely how long pains can be alleviated, is required rather than the immediate action. For meeting such requirement, from the viewpoint not only of efficacy but also of adhesion, long-period efficacy maintenance and long-period fixation on the affected part are required in the latter case while, in the former case, only about 1 hour of maintenance of such is sufficient. The period over which the effect lasts should preferably be as long as possible and the frequency of tape preparation exchange should preferably be as low as possible. For the symptom called allodynia in which mere contacting, for instance, evokes pain, such conditions are particularly favorable to the patients concerned.

The tape preparation for transdermal absorption of the present invention is characterized by that it is excellent not only in long-lasting pain-alleviating effect but also in adhesion to and ability to morphologically follow the site of application and, furthermore, the preparation is also effective for preventing the stratum corneum from being abraded. Therefore, it can be said to be a preparation very suited for the purpose of alleviating pains caused by HZ or PHN.

Although adhesive masses can also be obtained using other substances such as natural rubbers and acrylic rubbers as main adhesive components of tape preparations for transdermal absorption, it was found, as a result of investigations concerning the releasability of local anesthetics such as lidocaine, that SISs are most preferred. However, SISs alone are insufficient to provide the adhesive masses with flexibility. In attempts to modify them by conventional techniques, a phenomenon was observed that SISs, which have a molecular weight of only about 200,000, allowed the adhesive masses to penetrate through the backing, resulting in decreases in adhesion. For preventing this phenomenon, a butyl rubber with a high molecular weight, namely a molecular weight of not less than 400,000, is incorporated to thereby improve the physical properties of the adhesive mass base.

The incorporation of this butyl rubber was further found to be effective for suppressing the decrease in adhesive mass cohesion which otherwise results from the incorporation of liquid paraffin as a release controlling agent.

On the contrary, Japanese Patent Prepublication No. 02-300138 discloses examples in which a salicylate ester, such as methyl salicylate or glycol salicylate, is used as a solvent, namely as means of dissolving lidocaine in adhesive masses. When attempts were made to use such esters in the preparation of the present invention, the esters separated from adhesive masses, causing insufficient adhesion and failing to give the form of required preparations, hence they could not be used successfully.

As mentioned above, as a result of incorporation of butyl rubber in SIS, the tape preparation for transdermal absorption of the present invention has established a balance between the flexibility of the adhesive mass and the cohesion of the adhesive mass as well as the sustained release of local anesthetics and its safety in long-period application to the skin.
 

Claim 1 of 16 Claims

1. A non-aqueous tape preparation comprising a nonaqueous adhesive mass consisting essentially of 1-30 parts by weight of a local anesthetic in a base form in 100 parts by weight of the nonaqueous adhesive mass base, 5-50% by weight of a styrene-isoprene-styrene block copolymer, 1-60% by weight of an alicyclic saturated hydrocarbon resin, 5-60% by weight of liquid paraffin and 1-30% by weight of butyl rubber,

wherein the adhesive mass is supported on a backing, and

wherein the local anesthetic is at least one selected from the group consisting of lidocaine, procaine, oxyprocaine, dibucaine, bupivacaine, mepivacaine, and propitocaine.

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