IIIIUSOOS 183665A United States Patent (19) 11 Patent Number: 5,183,665 Hori 45 Date of Patent: Feb. 2, 1993 54 COMPOSITION FOR PERCUTANEOUS (56) References Cited ADMINISTRATION AND METHOD FOR U.S. PATENT DOCUMENTS ENHANCING PERCUTANEOUS ABSORPTION OF A PHYSIOLOGICALLY 4,522,826 6/1985 Sunshine et al. .................... 54/569 ACTIVE INGREDIENT EMPOLYING THE 4,585,783 4/1986 Sunshine et al. ................... 54/408 SAME 4,590,190 5/1986 Saito et al. .......................... 514/221 4,654,209 3/1987 Leslie et al. ......................... 514/152 4,683,243 7/1987 Sunshine et al..................... 514/557 (75) Inventor: Mitsuhiko Hori, San Francisco, 4,710,497 12/1987 Heller et al. ......... ... 54/221 Calif. 4,719,226 l/1988 Otsuka et al. ... 514/449 4,752,612 6/1988 Saito et al. ... ... 514/42O 4,765,974 8/1988 Tokuda et al. ...................... 424/443 (73) Assignee: Nitto Denko Corporation, Osaka, 4,847,260 7/1989 Abe et al. ............................ 514/279 Japan Primary Examiner-Thurman K. Page Assistant Examiner-Leon R. Horne Attorney, Agent, or Firm-Sughrue, Mion, Zinn, 21 Appl. No.: 299,506 Macpeak & Seas 57 ABSTRACT 22 Filed: Jan. 23, 1989 The present invention relates to a composition for per cutaneous administration which can enhance percutane (51) Int. Cl. .............................................. A61F 13/00 ous absorption of a physiologically active ingredient 52) U.S. C. .................................... 424/449; 424/447; and a method of enhancing percutaneous absorption of 424/448; 514/946 a physiologically active ingredient employing the same. (58 Field of Search ............................. 514/946, 947, ; 424/946, 947, 449 5 Claims, 2 Drawing Sheets 5 4. -- CONTROL -- CHLORPHENRAMINE -- PROMETHANE 2 -o- CEMASTINE -o- CYPROHEPTADNE -o- OPHENHYDRAM NE TIME thr) U.S. Patent Feb. 2, 1993 Sheet 1 of 2 5,183,665 t | 9 U.S. Patent Feb. 2, 1993 Sheet 2 of 2 5,183,665 10H1N00 5,183,665 2 nol, propylene glycol, pyrrolidones, dimethylsulfoxide, COMPOSITION FOR PERCUTANEOUS dimethylacetamide, dimethylformamide, alkyl sulfox ADMINISTRATION AND METHOD FOR ide, phosphine oxide, sugar esters and surfactants are ENHANCING PERCUTANEOUS ABSORPTION OF well known percutaneous delivery enhancers (Barry, B. A PHYSIOLOGICALLY ACTIVE INGREDIENT W., Dermatological Formulations, Marcel Dekker Inc., EMPOLYING THE SAME New York, pages 160-172 (1983)). One enhancer, 1 dodecylazacycloheptan-2-one (Azone), has been shown FIELD OF THE INVENTION to increase the absorption of antibacterial agents, anti The present invention relates to a composition for fungal agents, steroids, iododeoxyuridine and 5 percutaneous administration which can enhance percu O fluorouracil (Stoughton, R. B., Arch. Dermatol, taneous absorption of a physiologically active ingredi 118:474-477 (1982); Stoughton, R. B. et al, Drug Dev, ent and a method of enhancing percutaneous absorption Ind. Pharm., 9:725-744 (1983); Chow, D. S-L. et al., J. of a physiologically active ingredient employing the Pharm. Sci., 73:1794-1799 (1984); Wotton, P. K. et al, Sae. 5 Int. J. Pharm., 24:19-26 (1985); Barry, B. W., J. Contr. BACKGROUND OF THE INVENTION Rel, 6:85-97 (1987); and Barry, B. W. et al, J. Pharm. Percutaneous administration of physiologically ac Pharmacol, 39:535-546 (1987)). To date, the mechanism tive ingredients has been carried out in order to produce of Azone's action is not well understood. However, it is topical effects on the skin or subcutaneous tissues be believed that the site of action is the stratum corneum neath the skin. Examples of such topical effects include 20 (Sugibayashi, K. et al, J. Pharm. Sci, 37:578-580 sterilization, disinfection, analgesia, anti-pruritus, anti (1985)). Azone is minimally absorbed and that which is inflammation and the like. absorbed is removed rapidly from circulation (Wiech On the other hand, oral or intravenous administration ers, J. W. et al, Pharm. Res., 4:519-523 (1987)). of physiologically active ingredients has been carried In addition, is has been reported that the transport of out in order to produce systemic effects in the subject. 25 salicylic acid and acyclovir through skin can be in Oral administration is disadvantageous in that the creased by the addition of small amounts of fatty acids physiologically active ingredients so administered are or alcohols (Cooper, E. R., J. Pharm. Sci, 73:1153-1156 susceptible to first-order metabolism in the liver. Fur (1984); and Cooper, E. R. et al, J. Pharm. Sci, ther, in order to obtain a long-lasting effect, the concen 74:688-689 (1985)). tration of the physiologically active ingredients must be 30 The enhancing effect of N-decylmethylsulfoxide on initially higher than is normally necessary for effective skin permeation of 5-fluorouracil has also been reported ness. In addition, oral administration of some physiolog (Touitou, E. et al, Int, J. Pharm., 27:89-98 (1985)). ically active ingredients, like indomethacin, causes gas Moreover, the enhancing effects of several amides of trointestinal side effects. cyclic amines through hairless mouse skin have been Intravenous administration, although advantageous 35 reported (Mirejovsky, D. et al., J. Pharm. Sci, for obtaining rapid absorption of the physiologically 75:1089-1093 (1986)). Enhancers containing an azacy active ingredients disadvantageously requires a special clo ring and terpene chain have been found to promote ist, such as a physician. mitocymin C penetration through hairless mouse and Recently, methods for achieving systemic effects in a subject through percutaneous administration of physio rat skin (Okamoto, H. et al., J. Pharm. Pharmacol, logically active ingredients have been proposed in order 39:531-534 (1987)). to overcome the above-described problems associated SUMMARY OF THE INVENTION with oral and intravenous administration of physiologi Accordingly, an object of the present invention is to cally active ingredients. Percutaneous administration of provide a composition for percutaneous administration physiologically active ingredients has the following 45 advantages: which can enhance percutaneous permeability and per (1) the physiologically active ingredients enter from cutaneous absorbability of physiologically active ingre the skin directly into the blood stream and are not, dients. therefore, susceptible to first-order metabolism in Another object of the present invention is to provide the liver, 50 a method for enhancing percutaneous permeability and (2) the release of the physiologically active ingredi absorption of physiologically active ingredients. ents can be easily sustained, and These and other objects of the present invention will (3) the concentration of the physiologically active be apparent from the detailed description provided ingredients in the subject is controllable. hereinafter. However, the stratum corneum has long been consid 55 In one embodiment, the objects of the present inven ered a major barrier to the penetration of physiologi tion have been met by a composition for percutaneous cally active ingredients (Marzulli, A. N., J. Invest. Der administration comprising: matol, 39:387-393 (1963)). Studies have shown that (A) a pharmaceutically effective amount of a physio most physiologically active ingredients have a low per logically active ingredient, and meability through skin. As a result, transdermal drug (B) a percutaneous absorption enhancing effective delivery systems have been utilized to accelerate the amount of a member selected from the group con permeability of physiologically active ingredients sisting of an anti-histamine, an anti-depressant, a through skin (Gummer, C. L., Percutaneous Absorption, vasodilator, an anti-psychotic, an anesthetic and an Eds, Bronaugh, R. L. et al, Mercel Dekker Inc., New analgesic, York, pages 561-570 (1985)). 65 wherein component (A) is a different compound from Percutaneous delivery enhancers may offer a means component (B). of increasing penetration of physiologically active in In a second embodiment, the above-described objects gredients. For example, organic solvents such as etha have been met by a method for enhancing percutaneous 5, 183,665 3. 4. permeability and absorption of a physiologically active e.g., methylatropine bromide, methylanisotropine bro ingredient comprising percutaneously administering: mide, etc.; vasodilators, e.g.; isosorbide dinitrate, nitro (A) a pharmaceutically effective amount of a physio glycerin, pentaerythritol tetranitrate, propanyl nitrate, logically active ingredient, and dipyridamole, etc.; antibiotics, such as tetracyclines, (B) a percutaneous absorption enhancing effective e.g., tetracycline, oxytetracycline, metacycline, doxy amount of a member selected from the group con cycline, minocycline, etc., chloramphenicols, erythro sisting of an anti-histamine, an anti-depressant, a mycines, and central nervous system stimulants, such as vasodilator, an anti-psychotic, an anesthetic and an caffeine and amphetamine: and mixtures thereof. analgesic, The amount of physiologically active ingredient to be wherein component (A) is a different compound from 10 incorporated in the composition of the present inven component (B). tion to achieve the desired pharmaceutical effect can be readily determined depending upon the particular phys BRIEF DESCRIPTION OF THE DRAWINGS iologically active ingredient employed, the body FIG. 1 illustrates the penetration percentage per hour weight, the age, the sex and the symptoms of the Sub of propranolol through hairless mouse skin with or 15 ject. In general,