The invention relates to improved pharmaceutical compositions for topical administration to a human or lower animal subject and methods for their use in treatment of disease.
The following patents to Rajadhyaksha issued from 1976 to 1984 disclose methods and compositions employing 1-alkylazacycloheptan-2-ones and homologs thereof for enhanced penetration of pharmacologically active agents through human and animal skin;
U.S. 3,989,816; U.S. 4,316,893; U.S. 4,405,616 and 4,444,762.
Stoughton, Arch. Derm., 118, 474-477 (1982) relates to 1-dodecylazacycloheptan-2-one, referred to herein as Azone, and its ability to enhance percutaneous penetration.
Cooper, U.S. 4,557,934 and 4,537,776, discloses topical compositions of nonsteroidal antiinflammatory compounds, antiviral agents, antitussives and other drugs containing ethanol, certain glycols, pyrrolidone, 1-(2-hydroxyethyl)-aza-cyclopentan-2-one and from 1-35% 1-dodecylazacycloheptan-2-one (Azone).
Cooper, J. Pharm. Sci., 73, 1153-1156 (1984) discloses a method for increased transport of nonpolar molecules like salicylic acid through skin by adding fatty alcohols or fatty acids to transdermal formulations in various glycol solvents.
Akhter and Barry, J. Pharm. Pharmacol., 36, 7P (1984), report that oleic acid and Azone enhance dermal penetration of flurbiprofen formulations in propylene glycol and other solvents.
EP43738 discloses a binary dermal penetration enhancing vehicle for antiinflammatory agents containing a C.sub.3 --C.sub.4 -diol, diol ester or diol ether and a cell envelope-disordering compound selected from, inter alia, the lower alkyl esters of C.sub.12 -C.sub.14 fatty acids, oleic acid, lauryl acetate and myristyl acetate.
Patel, et al., Journ. Soc. Cosmetic Chem. 36, 303-311 (1985) has noted that propylene glycol, a common constituent of prior art pharmaceutical formulations for transdermal use, causes irritation and/or sensitization when its concentration exceeds ten percent.
Walker et al., U.S. 4,711,888 disclose certain pyrimidine derivatives, including 5-hydroxy-4,6-dimethyl-2-(6-phenylhexyl)aminopyrimidine of the formula ##STR1## which inhibit leukotriene synthesis and so are useful in the treatment of certain pulmonary inflammatory, allergic, gastrointestinal, cardiovascular and dermatological diseases such as psoriasis.
Hoover et al., U.S. 4,814,342 disclose certain peptides, including compounds of the formula ##STR2## wherein X is O or C=O, there named, respectively, N-morpholinocarbonyl-L-phenylalanine-S-methyl-L-cysteine-norcyclostatine isopropyl ester or simply morpholinocarbonylPhe S-MeCysnor-C-Sta isopropyl ester, and N-(4-oxopiperidino)carbonyl-L-phenylalanine-S-methyl-L-cysteine-norcyclost atine isopropyl ester or simply 4-oxopiperidinocarbonylPhe S-MeCysnor-C-Sta isopropyl ester. These compounds inhibit the angiotensinogen-cleaving action of the enzyme renin and so are useful as antihypertensive agents.
In our prior applications, cited above, we generally disclose transdermal flux enhancing pharmaceutical compositions comprising a pharmaceutical agent, a solvent comprising water and a near optional level of a water miscible solvent and a penetration enhancing compound which is a 1-alkylazacycloheptan-2-one or a cis-olefinic fatty acid, ester, alcohol or amine. The specific pharmaceutical agents disclosed in these earlier applications, (e.g., salicylic acid, ubuprofen, glipizide, piroxicam) are generally hydrophilic (lipophobic).
It is known that hydrophobic (lipophilic) drugs containing readily metabolized groups, (e.g., polypeptides, and certain pyrimidine drugs proposed for topical use) are particular prone to metabolism intradermally and in other skin-like biomembranes, such as mucous membrane. See, for example, Tauber in "Transdermal Drug Delivery", Hadgraft and Guy, eds., Marcel Dekker, Inc., (New York) pp. 99-112; Banga et al., Intl. J. Pharmaceutics, v. 48, pp. 15-50 (1988). Surprisingly, we have now found that the lipophilic drugs in this type of formulation are not only better carried across these barriers, offering advantageous routes (e.g., transdermally) for maximal systemic delivery of certain readily metabolized lipophilic drugs (such as the renin inhibitors of the formula II above); but metabolism of these drugs within the biomembrane is inhibited and high intramembrane (e.g. intradermal) levels of such drugs can be achieved, particularly valuable where the site of action is in the skin (such as in the case of psoriasis) or in another such biomembrane (e.g., nasal, rectal, ophthalmic, buccal, etc.). Indeed, the present invention is also of value in oral, intramuscular or subcutaneous routes of administration when there is significant metabolism of a lipophilic drug at these alternative sites of absorption, e.g., in the lumen of the gut.