Preparation for transdermal drug administration

Abstract: A preparation for transdermal drug administration comprising a flexible backing layer and a pressure-sensitive adhesive layer containing a local anesthetic in a proportion of 40-65 weight%. Since the ratio of the amount of the undissolved local anesthetic (Ac) to that of the dissolved local anesthetic (As), Ac/As, in the pressure-sensitive adhesive layer is determined to be in the range of 0.1-1.8, the preparation for transdermal drug administration of the present invention is superior in self-adhesiveness and leaves no adhesive material upon removal from the skin. In addition, burst-like release of the undissolved drug from the pressure-sensitive adhesive layer immediately after application to the skin permits rapid appearance of the anesthetic effect, which enables wide clinical application of the preparations of the present invention.

Description: BACKGROUND OF THE INVENTION The present invention relates to a preparation for transdermal drug administration which contains a local anesthetic as a medicinal ingredient. There have been so far investigated various preparations aiming at transdermal administration of a local anesthetic, and some of them have been marketed as liquid- or ointment-form external preparations. However, application of such preparations to common integument poses problems such as difficulty in controlling the dose, possibility of staining clothes, and so on. While there has been proposed an analgesic composition aiming at longer retention of the drug at a local site (Japanese Patent Publication No. 130540/1988), such a composition is within the category of liquid or ointment preparations intended for administration to mucous membrane, which is not entirely suitable for application to common integument. Japanese Patent Publication No. 272521/1989 proposes a patch preparation for application to gum. This preparation has overcome the disadvantages of the conventional liquid or ointment preparations and has improved handling facility. Still, this preparation is unsuitable for application to common integument since it is originally designed for application to gum and the application site is required to have much moisture in order to secure the preparation tightly on the site. Also, there has been proposed an adhesive tape preparation as a device for transdermal administration of a local anesthetic (Japanese Patent Publication No. 299215/1989), which offers easy application and easy control of the dose. The self-adhesive matrix used therein comprises an adhesive material selected from among the group of poly(styrene-butadiene) block copolymer, poly(styrene-isoprene-stylene) block copolymer, high molecular weight polyisobutylene polymer, low molecular weight polyisobutylene polymer and ethylene-vinyl acetate copolymer, yet the use of such polymers or copolymers renders the rapid appearance of the anesthetic effect which is one of the expected properties of a local anesthetic unattainable. Moreover, the self-adhesive matrix used therein comprises an adhesion-imparting agent, a fluidity-imparting agent and an antioxidant besides a local anesthetic as a medicinal ingredient, and such inclusion is not only uneconomical but also may present problems in pharmaceutical stability due to potential reaction between those agents and the medicinal ingredient. Japanese Patent Publication No. 185713/1985 proposes a preparation for transdermal drug administration in which a transdermally absorbable drug is dispersed as recrystallized fine powder in a pressure-sensitive adhesive macromolecule copolymer and said percutaneously absorbable drug is contained in an amount corresponding to 1.2 times the saturation solubility of the pressure-sensitive adhesive macromolecule copolymer, or more. This preparation permits easy handling, and easy control of the dose. Yet, according to the description, the amount of the transdermally absorbable drug relative to the pressure-sensitive adhesive macromolecule copolymer is 40 weight% or less, which hardly enables the local anesthetic effect to appear in a short time. For the effect to appear in a short time, it is necessary to let the drug release burst at the initial stage upon application, and the balance between this drug release and the adhesiveness to the skin depends on the proportion of the amount of the dissolved drug to that of the undissolved drug in the pressure-sensitive adhesive macromolecule copolymer. However, this patent gives no description in this regard. SUMMARY OF THE INVENTION The present inventors have conducted intensive studies for the purpose of resolving the problems mentioned above, and as a result, newly found that in a preparation for transdermal drug administration comprising a flexible backing layer and a pressure-sensitive adhesive layer formed thereon containing a local anesthetic, the drug release and absorbability via the skin are greatly influenced by the concentration of the local anesthetic in the pressure-sensitive adhesive layer, the ratio of the amount of the dissolved local anesthetic (As) to that of the undissolved local anesthetic (Ac) contained therein, and the type of the pressure-sensitive adhesive to be used. Then, the inventors have eventually found that the preparation for transdermal drug administration of the present invention wherein the local anesthetic is contained in a certain range of amount in a specific pressure-sensitive adhesive shows an excellent local anesthetic effect and adhesiveness to the skin, and also is easy to handle, which resulted in the completion of the invention. That is, the present invention relates to a preparation comprising a flexible backing layer and a pressure-sensitive adhesive layer formed on the backing layer, wherein 1 ○ a local anesthetic is contained in the pressure-sensitive adhesive layer in a proportion of 40-65 weight% and the ratio of the amount of the undissolved local anesthetic (Ac) to that of the dissolved local anesthetic (As), Ac/As, is in the range of from 0.1 to 1.8, and 2 ○ an acrylate adhesive is used as the pressure-sensitive adhesive. DETAILED DESCRIPTION OF THE INVENTION The present invention is detailedly described in the following. The backing layer used in the present invention is subject to no particular limitation as long as it is flexible and impervious to drugs. Examples thereof include films and sheets made of polyolefin, polyester, poly(vinyl alcohol), poly(vinyl chloride), poly(vinylidene chloride), polyamide, polytetrafluoroethylene, etc. ; deposited metal films and sheets thereof; and laminated sheets using two kinds or more thereof, which are about 500 µm or less, preferably 5-150 µm in thickness. The pressure-sensitive adhesive layer of the present invention contains and sustains the local anesthetic in a proportion of 40-65 weight%, and releases the drug in a short time to promote absorption via the skin while securing the preparation of the present invention tightly on the skin. In the present invention, the pressure-sensitive adhesive is preferably an acrylic pressure-sensitive adhesive of a copolymer of (meth)acrylic acid alkyl ester and (meth)acrylic acid in view of the adhesiveness to the skin, stability of a local anesthetic to be used, and migration and absorption of the local anesthetic from the adhesive layer to the skin in a short time. Examples of the (meth)acrylic acid alkyl ester for forming said acrylic pressure-sensitive adhesive include copolymers of one or more of (meth)acrylic acid alkyl esters having an alkyl of 4 to 13 carbon atoms, such as butyl (meth)acrylate, pentyl (meth)acrylate, hexyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate, nonyl (meth)acrylate, decyl (meth) acrylate, undecyl (meth)acrylate, dodecyl (meth)acrylate and tridecyl (meth)acrylate. The (meth)acrylic acid alkyl ester of the present invention encompasses various isomers whose alkyl moiety is straight or branched, various isomers having different substitution sites and their derivatives. Such acrylic pressure-sensitive adhesive has a high degree of polymerization, improved cohesiveness and adhesiveness, and permits stable retention of a local anesthetic in a large amount and migration of the local anesthetic to the skin in a short time after application. It is desirable that the weight ratio of (meth)acrylic acid alkyl ester to (meth)acrylic acid contained in the acrylic pressure-sensitive adhesive be 65/35-99/1 in view of the balance between the adhesiveness to the skin and cohesiveness. In preparing said acrylic pressure-sensitive adhesive, another monomer may optionally replace a part of the above-mentioned monomers for the copolymerization to the degree that the efficacy of the drug and the adhesiveness to the skin are not impaired. Examples thereof include vinyl acetate, (meth) acrylic acid hydroxyalkyl ester, (meth)acrylic acid alkoxyalkyl ester, (meth)acrylic acid alkylaminoalkyl ester, (meth) acrylamide, derivatives thereof, N-vinylpyrrolidone and (meth) acrylonitrile. The amount of the local anesthetic to be contained in the above-mentioned pressure-sensitive adhesive layer should be in a proportion of 40-65 weight%, and the ratio of the amount of the undissolved local anesthetic (Ac) to that of the dissolved local anesthetic (As), Ac/As, in the pressure-sensitive adhesive layer be in the range of 0.1-1.8. Note that the undissolved local anesthetic means the crystalline precipitate or dispersed drug resulting from addition beyond the saturation solubility in the adhesive polymer, and the dissolved local anesthetic means the drug existing in molecule dispersion or noncrystalline state in the polymer, which can be confirmed by a microscope examination or an X-ray diffractometry. Where the Ac/As is below 0.1, the local anesthetic acts like a plasticizer to the acrylic adhesive in the pressure-sensitive adhesive layer of the present invention, resulting in gooey threads from the pressure-sensitive adhesive layer itself upon removal from the skin after application, which in turn results in remainder from the pressure-sensitive adhesive layer partially or in the entirety of the applied site on the skin, staining the common integument, and delayed appearance of the local anesthetic effect. On the other hand, where the Ac/As exceeds 1.8, self-adhesiveness of the pressure-sensitive adhesive layer decreases so that the layer cannot be adhered to the skin. Where the Ac/As is in the range of 0.1-1.8, most favorably 0.6 or above, the local anesthetic is in part undissolved in the pressure-sensitive adhesive layer, which contributes to the improved cohesiveness of the pressure-sensitive adhesive. In addition, the presence of the undissolved local anesthetic in a rather large amount leads to burst of the drug release soon after the application, causing prompt migration of the drug in an amount necessary for the exertion of the effect upon application of the preparation, which will eventually assure rapid appearance of the anesthetic effect which is expected of a local anesthetic. While the amount of the local anesthetic to be contained in the pressure-sensitive adhesive layer is determined to be in the range of from 40 to 65 weight%, it is preferably not less than 45 weight% to ensure the rapid appearance of the effect. The local anesthetic to be used in the present invention is selected from among amide anesthetics and ester anesthetics, and preferably selected from among cocaine, procaine, chloroprocaine, tetracaine, lidocaine, mepivacaine, prilocaine, bupivacaine and dibucaine. The preparation of the present invention contains one or more of the above-mentioned local anesthetics in the pressure-sensitive adhesive layer. The thickness of the pressure-sensitive adhesive layer containing local anesthetic is preferably in the range of from 5 to 30 µm in view of the short application time and economic feasibility. The preparation of the present invention has the components as described above and contains a local anesthetic in a proportion of 40-65 weight% in the pressure-sensitive adhesive layer. Since the ratio of the amount of the undissolved local anesthetic (Ac) to that of the dissolved local anesthetic (As), Ac/As, in the pressure-sensitive adhesive layer is determined to be in the range of 0.1-1.8, the preparation of the present invention is superior in self-adhesiveness and leaves no adhesive material upon removal from the skin. In addition, burst-like release of the undissolved drug from the pressure-sensitive adhesive layer immediately after application to the skin permits rapid appearance of the local anesthetic effect, which makes it possible to be utilized for the pre-operational treatment of needle indwelling in a vein or an artery, dura or lumbar puncture, arthrocentesis and minor dermic operation. As a result, pain of patients can be vastly reduced and many clinical applications become possible. The present invention is hereinbelow described in detail by illustrating working examples. In the following description, part(s) and % refer to part(s) by weight and weight%, respectively. Example 1 2-Ethylhexyl acrylate (95 parts) and acrylic acid (5 parts) were charged in a flask under an inert gas atmosphere and azobisisobutyronitrile (0.3 part) was added thereto as a polymerization initiator. The polymerization was conducted in ethyl acetate while maintaining the temperature at 60 °C to give the acrylic pressure-sensitive adhesive solution A (solids: 41.2%). Thereto was added lidocaine in a ratio of 60 parts thereof relative to 40 parts of the solids, after which ethyl acetate was added to give a solution containing 35% solids. The thus-obtained solution was coated on a polyester release paper to make the thickness after drying become 20 µm, which was then dried at 100°C for 5 minutes to form a pressure-sensitive adhesive layer containing 60% lidocaine. After the obtained pressure-sensitive adhesive layer containing 60% lidocaine was adhered onto a 12 µm-thick polyester backing layer, it was allowed to stand at room temperature for 24 hours to crystallize the lidocaine in the pressure-sensitive adhesive layer, by which a preparation of the present invention was obtained (Ac/As was about 1.6). Example 2 To the acrylic pressure-sensitive adhesive solution A as used in Example 1 was added lidocaine in a ratio of 40 parts thereof relative to 60 parts of the solids to give a solution containing 30% solids. The obtained solution was treated in the same manner as in Example 1 to give a preparation of the present invention (Ac/As was about 0.7). Example 3 To the acrylic pressure-sensitive adhesive solution A as used in Example 1 was added lidocaine in a ratio of 50 parts thereof relative to 50 parts of the solids, and ethyl acetate was further added to give a solution containing 33% solids. The obtained solution was treated in the same manner as in Example 1 to give a preparation of the present invention (Ac/As was about 1.2). Comparative Example 1 To the acrylic pressure-sensitive adhesive solution A as used in Example 1 was added lidocaine in a ratio of 70 parts thereof relative to 30 parts of the solids, and ethyl acetate was further added to give a solution containing 30% solids. The obtained solution was treated in the same manner as in Example 1 to give a preparation containing a local anesthetic (Ac/As was about 2.0). Comparative Example 2 To the acrylic pressure-sensitive adhesive solution A as used in Example 1 was added lidocaine in a ratio of 20 parts thereof relative to 80 parts of the solids, and ethyl acetate was further added to give a solution containing 25% solids. The obtained solution was treated in the same manner as in Example 1 to give a preparation containing a local anesthetic (Ac/As was 0). Reference Example 1 Carboxyvinyl polymer (Wako Junyaku Kogyo, Hibis Waco 105, 2.6 weight%), ethanol (40 weight%) and purified water (47.4 weight%) were mixed thoroughly to dissolve the carboxyvinyl polymer. Thereto was added lidocaine (10 weight%), and the mixture was mixed to dissolve lidocaine, by which there was obtained a gel ointment containing lidocaine. Experiment Example 1 A 3.17 × 3.17 (10 cm²) specimen cut out from each of the preparations as obtained in Examples 1-3 and Comparative Examples 1 and 2 was adhered onto the human inner forearm and maintained for 30 minutes. The adhesiveness, remaining adhesive material upon removal from the skin, and anesthetic effect were examined. The effect was examined by the pin pricking method. That is, after 30 minutes of adhesion, the specimen was removed and an intracutaneous pin was pricked on the applied area to see the degree of pain, based on which numerical evaluation of the anesthetic effect was made according to the evaluation criteria. As regards the Reference Example, 0.1 g of the lidocaine-containing gel ointment obtained therein was applied onto the area of 3.15 × 3.15 cm of the human inner forearm, and the similar experiment was conducted. Anesthetic effect evaluation criteria 0 : no pain was sensed on 5 points. 1 : pain was sensed on 1 of 5 points. 2 : pain was sensed on 2 of 5 points. 3 : pain was sensed on 3 of 5 points. 4 : pain was sensed on 4 of 5 points. 5 : pain was sensed on 5 points. The results are summarized in Table 1. Adhesiveness to the skin Adhesive material remaining on the skin Anesthetic effect Example 1 ○ none 0.9 Example 2 ○ partial remainder around the adhesion site 1.6 Example 3 ○ none 1.1 Comp. Ex. 1 X adhesion unattainable due to the residual adhesive material on the release paper - Comp. Ex. 2 ○ remainder on the entire site 3.1 Ref. Ex. - - 4.1 ○ : good adhesion X : adhesion unattainable Note that the anesthetic effect of the Reference Example was 1.9 after 3 hours' application.

Claims: Claims for the following Contracting States : AT, BE, CH, LI, DE, DK, FR, GB, IT, LU, NL, SE A preparation for transdermal drug administration comprising a flexible backing layer and a pressure-sensitive adhesive layer containing a local anesthetic in a proportion of 40-65 weight%, wherein the ratio of the amount of the undissolved local anesthetic (Ac) to that of the dissolved local anesthetic (As), Ac/As, is 0.1-1.8. A preparation for transdermal drug administration according to Claim 1, wherein the local anesthetic is at least one member selected from the group consisting of amide anesthetics and ester anesthetics. A preparation for transdermal drug administration according to Claim 1, wherein the local anesthetic is at least one member selected from the group consisting of cocaine, procaine, chloroprocaine, tetracaine, lidocaine, mepivacaine, prilocaine, bupivacaine, dibucaine and their pharmacologically acceptable salts. A preparation for transdermal drug administration according to Claim 1, wherein the pressure-sensitive adhesive layer is a layer of acrylic pressure-sensitive adhesive. A preparation for transdermal drug administration according to Claim 4, wherein the acrylic pressure-sensitive adhesive is a copolymer of (meth)acrylic acid alkyl ester and (meth)acrylic acid. A preparation for transdermal drug administration according to Claim 4, wherein the acrylic pressure-sensitive adhesive is obtained by polymerization of 65-99 weight% of (meth)acrylic acid alkyl ester and 1-35 weight% of (meth)acrylic acid. Claims for the following Contracting States : ES, GR A process for producing a preparation for transdermal drug administration comprising a flexible backing layer and a pressure-sensitive adhesive layer containing a local anesthetic in a proportion of 40-65 weight%, wherein the ratio of the amount of the undissolved local anesthetic (Ac) to that of the dissolved local anesthetic (As), Ac/As, is 0.1-1.8, which process comprises forming the pressure-sensitive adhesive layer on the backing layer. The process according to Claim 1, wherein the local anesthetic is at least one member selected from the group consisting of amide anesthetics and ester anesthetics. The process according to Claim 1, wherein the local anesthetic is at least one member selected from the group consisting of cocaine, procaine, chloroprocaine, tetracaine, lidocaine, mepivacaine, prilocaine, bupivacaine, dibucaine and their pharmacologically acceptable salts. The process according to Claim 1, wherein the pressure-sensitive adhesive layer is a layer of acrylic pressure-sensitive adhesive. The process according to Claim 4, wherein the acrylic pressure-sensitive adhesive is a copolymer of (meth)acrylic acid alkyl ester and (meth)acrylic acid. The process according to Claim 4, wherein the acrylic pressure-sensitive adhesive is obtained by polymerization of 65-99 weight% of (meth)acrylic acid alkyl ester and 1-35 weight% of (meth)acrylic acid.

Inventors: IKUO KISHI, KENICHIRO SAITO C O NITTO DENK, KOJI MARUYAMA C O NITTO DENKO, MASAKI SUNAMI, MITSUHIKO HORI C O NITTO DENKO, SHOICHI TOKUDA C O NITTO DENKO, IKUO, KISHI, KENICHIRO, SAITO, C/O NITTO DENKO CORPORATION, KOJI, MARUYAMA, C/O NITTO DENKO CORPORATION, MASAKI, SUNAMI, MITSUHIKO, HORI, C/O NITTO DENKO CORPORATION, SHOICHI, TOKUDA, C/O NITTO DENKO CORPORATION
Applicants: LEDERLE JAPAN LTD, NITTO DENKO CORP, LEDERLE (JAPAN), LTD., NITTO DENKO CORPORATION
Application year: 1991
Main classification: A61K9
IPC codes: A61P23, A61K9, A61K31, A61P25, A61K45