PRETREATING AGENT FOR PERCUTANEOUS ADMINISTRATION

Abstract: A pre-treatment agent for skin areas to be used for percutaneous drug absorption, comprises a support on the surface of which are distributed uniformly small areas of keratin-removing material to a density of 0.001-5% (pref. 0.01-5%). The keratin-removing material may be an adhesive such as natural adhesive, microcapsular adhesive, thermoplastic adhesive or synthetic rubber. The support may be a plastic sheet or stiff board; the keratin-remover regions may be circular (diameter 10-300 micron) or linear (width 10-300 micron).

Description: The present invention relates to a material for an endermic administration pre-treatment, which material is pressed against the skin and removed therefrom prior to endermic administration, to produce fissures, for example, fine openings or microcracks, on the stratum corneum which forms a surface layer of the skin, to an extent such that no substantial irritation occurs. The administration of a medicament through endermism is considered to be the best means of providing considerable pharmaceutical effects without causing side effects, i.e., gastrointestinal disorders which occur upon a peroral administration. Recently, an iontophoresis treatment, which enhances the absorption through endermism by an electric means, has attracted particular attention. Reference is made to, for example, J.M. Glass et al, Int. J. Dermatol., 19,519 (1980); J. Russo et al, Am. J. Hosp. Pharm., 37, 843 (1980); L.P. Gangarosa et al, J. Pharmacol. Exp. Ther., 212,377 (1980); B.S. Kwon et al, J. Infect. Dis., 140, 1014 (1979); J.M. Hill et al, Ann. NY. Acad. Sci., 284, 604 (1977); and M. Tannebaum, Phys. Ther., 60,792 (1980). In endermism, which is a passive-diffusive system, the endermic absorbability of a pharmaceutically active component has not been sufficiently elucidated, and thus the selection of an effective medicament is made on the basis of experience, but there are few medicaments which can be employed for this purpose. Medicaments which can exhibit sufficient effects in iontophoresis are also limited. As a preliminary to endermic administration of a drug it is known, see JP-A-57-123117 and JP-B-60-54284, to remove skin surface to allow easier penetration of the drug. Moreover, according to US-A-4340586 adhesive tape is repeatedly applied to the skin to remove the stratum corneum before the pharmaceutical preparation described therein is applied. It is an object of the present invention to provide for efficient endermic administration pre-treatment without pain or irritation to the patient. It has been found that if a very few microcracks or fine openings are produced on the stratum corneum of the skin at a place to be treated through endermism, before carrying out a usual endermism operation, the physical and electrical resistances inherently shown by the skin tissue against the endermic absorption of the medicaments can be considerably reduced, and thus the endermism can be efficiently enhanced. The object of the invention is thus achieved by providing a device which comprises a support and a substance capable of removing corneum substantially uniformly distributed on the support in the form of small areas discontinuous to each other and at a density of 0.001 to 5 %. This device can be pressed against the skin and removed therefrom to thereby produce microcracks or fine openings on the stratum corneum, substantially without pain or irritation. As the support, a flexible material may be employed, in which case the device may simply consist of an adhesive-bearing tape or film, as described in Manufacturing Examples 1 to 3. Alternatively, the support may be rigid, in which case the support may be provided with a handle on a surface opposite to the surface carrying the corneum-removing substance. In the drawings Figure 1 is a plan view of one embodiment of material forming a pre-treatment device according to the present invention. Figure 2 is a sectional view on an enlarged scale of a portion of the material of Figure 1. Figure 3 is a plan view of another embodiment of material forming a pre-treatment device according to the present invention. Figure 4 is a sectional view on an enlarged scale of a portion of the material of Figure 3. Figure 5 is a plan view of another embodiment of material forming a pre-treatment device according to the present invention. Figure 6 is a plan view of still another embodiment of a pre-treatment device according to the present invention. Figure 7 is a plan view of yet another embodiment of a pre-treatment device according to the present invention. In the figures the meaning of the reference numerals is the following: 1 device for pre-treatment of endermic administration 2 support 3 substance capable of removing corneum 4 handle The device for an endermic administration pre-treatment according to the present invention comprises a support and a substance capable of removing corneum. As the support, any materials including a flexible material or a rigid material may be employed. The flexible materials which may be used are, for example, a plastic film, cellophane, cloth, paper or the like. Examples of the plastic film are films made of polyvinyl chloride, polyester, polyethylene or cellulose acetate. A laminated film formed from a combination thereof also may be used. The rigid materials which may be used are, for example, plastic or metallic plates. The term "substance capable of removing corneum" as used herein means a substance which can adhere to a scleroprotein, which is a constituent of the stratum corneum forming the surface layer of the human skin, and remove at least a portion of said screloprotein from the skin. The substance should be essentially harmless to the skin except for the removal of corneum, which is the purpose of the present invention. Typical of the substances capable of removing corneum is an adhesive, particularly a pressure sensitive adhesive. The adhesive strength of the pressure sensitive adhesive used in the present invention is generally 30 kgf/cm² or more, preferably 50 kgf/cm² or more, particularly 100 kgf/cm² or more. The pressure sensitive adhesives which may be used in the present invention are, for example, rubber adhesives such as those containing natural rubber, regenerated rubber, or synthetic rubber such as isoprene rubber, styrene-butadiene rubber, nitrile-butadiene rubber, chloroprene rubber or butyl rubber; acrylic adhesives such as those containing mainly acrylate of aliphatic alcohol having 2 to 12 carbon atoms; water-based adhesives such as polyvinyl alcohol, isobutene-maleic anhydride copolymer, polyacrylamide, polyethylene oxide, polyvinyl pyrrolidone, vinyl acetate copolymer, acrylic copolymer, vinyl methyl ether-maleic anhydride copolymer; or polyvinyl ether, polyisobutyl ether or the like. In the present invention, non-solvent based pressure sensitive adhesives also may be used. The non-solvent based pressure sensitive adhesives are, for example, emulsion based adhesives such as synthetic rubber latex, polyvinyl acetate based, vinyl acetate-ethylene copolymer based, polyacrylate based or polyvinyl chloride based adhesives; oligomer based adhesives such as rubber oligomer based, acrylic oligomer based or urethane oligomer based adhesives. Further, curable type pressure sensitive adhesives also may be used. As the curable type adhesives, there may be mentioned, for example, a hygroscopic curable adhesive such as cyanoacrylate based adhesive; or an anaerobic curable adhesive such as tetraethylene glycol dimethacrylate. Further, solvent-activating adhesives, for example, a water-activating adhesive such as glue, gum arabic, dextrin, polyvinyl alcohol, acrylics, polyacrylamide, polyethylene oxide or the like, and an organic solvent-activating adhesive also can be used. Furthermore, capsular adhesives can be employed. When the capsular adhesive is used, any adhesive can be encapsulated in microcapsule several to tens of microns thick. Alternatively, a curing agent such as peroxide (e.g., hydrogen peroxide) can be encapsulated in microcapsule several to tens of microns thick, and dispersed in an adhesive such as acrylic monomer. The pressure sensitive adhesive of the present invention can be classified in view of the chemical composition thereof, as follows: a natural adhesive such as a starch based adhesive (e.g., dextrin), protein based adhesive (e.g., glue) or natural rubber based adhesive; a thermoplastic adhesive such as a vinyl acetate, polyvinyl alcohol, vinyl chloride, acrylic compound, polyamide, polyethylene, cellulose, polyisobutylene or polyvinyl ether based adhesive; a synthetic rubber based adhesive such as a chloroprene, nitrilo rubber, styrene rubber or butyl rubber based adhesive. According to the present invention, the above substance capable of removing corneum is substantially uniformly distributed on the support in the form of small areas discontinuous to each other. The shape of the small area is not limited. For example, the area can be a circle about 10 - 300 µm in diameter (or an ellipse having a similar square measure), a strip about 10 - 300 µm in width (straight or curved), or any other shape. A combination of various shaped small areas may be formed on the support. The small areas can be formed by applying the above substance capable of removing corneum on the support by a conventional printing technique, spraying technique or the like. The density of the small areas is 0.001 - 5%, preferably 0.01 - 1%. The term "density of the small areas" means a ratio of effectively active portions in the above substance forming the small areas to the support surface pressed against the skin. When the density of the small areas is less than 0.001%, the sheet of the present invention does not achieve the required purpose. When the density is above 5%, disadvantages such as erythrochromia or irritation occur. The pre-treatment device according to the present invention is, for example, a sheet such as a tape (including a roll) or a label, and is used by appropriately selecting the size or shape thereof in accordance with the site to which it is to be applied. Further, the pre-treatment device according to the present invention also may be a relatively thick plate. Particularly, when the rigid pre-treatment plate is used, preferably, for the pre-treatment, a handle is provided which can be grasped by hand, on the surface opposite to the surface carrying the substance capable of removing corneum. The pre-treatment device according to the present invention can carry a protective film layer on the surface having the substance capable of removing corneum to avoid drying of said substance prior to use. The pre-treatment device according to the present invention can be employed before carrying out the endermic administration. The endermic administration is carried out, for example, by putting a plaster on the skin or by iontophoresis. The present invention now will be illustrated by, but is by no means limited to, the following Examples. EXAMPLES Manufacturing Example 1 On a surface of a polyvinyl chloride film (10 cm x 10 cm x 3 mm), dotting pits (diameter about 100 µm and depth about 50 µm) were dug uniformly at a ratio of 200 pits/cm². An adhesive based on an emulsion of vinyl acetate ethylene was poured into the pits to obtain the pre-treatment sheet according to the present invention (adhesive density: 1.5%). As shown in Figure 1, the pre-treatment sheet 1 produced in this Example uses an adhesive 3, based on an emulsion of vinyl acetate ethylene, on the polyvinyl chloride film 2. Figure 2 is an enlarged sectional view of a part of the above sheet. Manufacturing Example 2 On a surface of a polyvinyl chloride film, as in the above Manufacturing Example 1, a cyanoacrylate based adhesive was applied uniformly in the form of dots (diameter: about 80 µm) at a ratio of 200 dots/cm² to obtain the pre-treatment material of the present invention (adhesive density: 1.0%). Figure 3 shows the pre-treatment sheet 1 manufactured in this example. The sheet 1 carries a cyanoacrylate based adhesive 3 on a polyvinyl chloride film 2. Figure 4 is an enlarged sectional view of a part of the above sheet. Manufacturing Example 3 A vinyl acetate emulsion based adhesive having the following composition was applied on a surface of a cellophane tape, in the form of strips (width: 30 µm, space: 3 mm), to obtain the pre-treatment tape of the present invention (adhesive density: 0.9%). Composition Parts by weight H₂O 1,050 H₂O₂ (40%) 3 Polyvinyl alcohol 52 Vinyl acetate monomer 1,050 Formic acid 2.0 Figure 5 shows the tape 1 of this example carrying a vinyl acetate emulsion based adhesive 3 on a cellophane support 2. Manufacturing Example 4 A capsular adhesive based on cyanoacrylate (Sumitomo 3M: Scotch-Grip Fastener Adhesive 2353) was scatteringly and uniformly applied on a surface of a celluloid plate (7 cm x 8 cm x 10 mm), at a density of 0.1%, to obtain the pre-treatment device of the present invention. Figure 6 shows the pre-treatment material 1 of this example. The material 1 carries microcapsules 3 on a celluloid support 2. Manufacturing Example 5 As shown in Figure 7, the pre-treatment device 1 was manufactured by applying the adhesive as in the Manufacturing Example 4 on the surface of a rigid polyvinyl chloride plate 2 (5 cm x 10 cm x 5 mm) opposite to the surface having the cylindrical handle 4. Use Example 1 The pre-treatment material produced in the Manufacturing Example 1 according to the present invention was put on a facies lateralis brachii of a human and then peeled therefrom. Before and after the operation by the pre-treatment material of the present invention, the impedances were determined by applying a voltage at a frequency of 10 Hz, with a function generator (oscilloscope), and a reduction of resistance to one fifth due to the operation of the pre-treatment material of the present invention, was observed. Use Examples 2 - 4 The same tests as in the Use Example 1 were performed, using the pre-treatment devices produced in the Manufacturing Examples 2 - 4 according to the present invention. The results are shown as follows: Use Example Pre-treatment device used Reduction in impedance (After operation/before operation) 2 Sheet of Manufacturing Example 2 1/10 3 Tape of Manufacturing Example 3 1/7 4 Plate of Manufacturing Example 4 1/8 In each of the Use Examples 2 - 4, irritation such as erythrochromia was not found on the skin. The effect on the skin of the material for endermic administration pre-treatment according to the present invention resulted in a remarkable reduction of the physical and electrical resistances inherently exhibited by skin tissue against absorption of the medicament, without substantial irritation of the skin, thereby allowing a subsequent particularly efficient endermic administration to be carried out.

Claims: A device for endermic administration pre-treatment comprising a support and, substantially uniformly distributed on the support, a substance capable of removing corneum, characterized in that the substance is distributed in the form of small areas discontinuous to each other and at a density of 0.001 to 5 %. A device according to claim 1, wherein said substance capable of removing corneum is an adhesive substantially non-toxic to skin. A device according to claim 2, wherein said adhesive is a pressure sensitive adhesive. A device according to claim 3, wherein said pressure sensitive adhesive is a capsular adhesive. A device according to claim 3, wherein said pressure sensitive adhesive is a natural adhesive, thermoplastic adhesive or synthetic rubber adhesive. A device according to any preceding claim. wherein said small areas are circles with a diameter of 10 - 300 µm. A device according to any of claims 1 to 5, wherein said small areas are strips having a width of about 10 - 300 µm. A device according to any preceding claim, wherein said small areas are at a density of 0.01 to 1 %. A device according to any preceding claim, wherein the support is a flexible sheet. A device according to any of claims 1 to 8, wherein the support is a rigid plate. A device according to claim 10, wherein the rigid plate has a handle on a surface opposite to a surface carrying the substance capable of removing corneum. A device according to Claim 9, being a composition for use in endermic administration pre-treatment. A device according to claim 9, being a composition for use in iontophoresis pre-treatment.

Inventors: OTA MIDORI, OTA, MIDORI
Applicants: ADVANCE KK, KABUSHIKI KAISYA ADVANCE
Application year: 1987
Main classification: A61M37
IPC codes: A61K9, A61M35