|||||||IIII US005607691A United States Patent (19) 11 Patent Number: 5,607,691 Hale et al. (45) Date of Patent: Mar. 4, 1997 54) COMPOSITIONS AND METHODS FOR 0559625 9/1993 European Pat. Off. ...... CO7C 229/22 ENHANCED DRUG DELIVERY 880 1615 3/1988 WIPO .......................... CO7C 103/30 9008128 7/1990 WIPO : 75) Inventors: Ron L. Hale, Woodside; Amy Lu, Los 9106556 5/1991 WIPO ............................ COTH 21100 9113631 '9/1991 WIPO ............................ A61K 39/00 Altos; Dennis Solas, San Francisco; 9114696 10/1991 WIPO ............................ CO7H 17/00 Harold E. Selick, Belmont; Kevin R. 9115259 10/1991 WIPO .............................. A61N 1/30 Oldenburg, Fremont; Alejandro C. 92/08459 5/1992 WIPO Zafaroni, Atherton, all of Calif. 92.17180 10/1992 WIPO .......................... A61K 3/505 92/22530 12/1992 WIPO. (73) Assignee: Affymax Technologies N.V., Middlesex, 93.07883 4/1993 WIPO ............................ A61K 31/70 England 93.17713 9/1993 WIPO ............................ A61K 47/48 OTHER PUBLICATIONS (21) Appl. No.: 449,188 Bodor, et al. Int. J. Pharm, 35(1-2) 47-59 1987 Improved 22) Filed: May 24, 1995 Delivery Through Biological Membranes. Pratt et al., 1990, Principles of drug action: The basis of Related U.S. Application Data pharmacology 203-227 Principles of drug action: The basis of pharmacology. (63) Continuation of Ser. No. 164,293, Dec. 9, 1993, abandoned, which is a continuation-in-part of Ser. No. 77,296, Jun. 14, Russell-Jones et al., 1988, Proceed Intern. Symp. Control. 1993, abandoned, which is a continuation-in-part of Ser. No. Rel. Bioact. Mater. 85: 142-143 Vitamin B12: A novel 898,219, Jun. 12, 1992, abandoned, and a continuation-in carrier for orally presented antigens. part of Ser. No. 9,463, Jan. 27, 1993, abandoned. Bodde et al., 1989, Biochemical Society 17 (3): 197-199 (51) Int. Cl." ........................... A61K 9/70; A61K 31/00 Transdermal peptide delivery. Sanderson et al., 1989, J. of Pharm. Sci. 78 (5): 361-364. 52 U.S. Cl. ................................. 424/449; 604/20; 514/1; Iontophoretic delivery of nonpeptide drugs: Formulation 514/2; 514/26; 514/183; 514/169; 514/553; optimization for maximum skin permeability. 514/556 Harris, Physical Medicine Library vol. IV, Therapeutic elec (58) Field of Search .............................. 424/22, 448, 449, tricity and ultraviolet radiation, pp. 146-149. 424/485, 486; 604/20; 514/1, 2, 26, 169, Foder et al., 1991, Science 251: 767-773 Light-Directed, 183,553,556 spatially addressable parallel chemical synthesis. Bioworld 29 Jan 92, 3 (20): p. 1 FDA approves Elan's (56) References Cited nicotine patch. U.S. PATENT DOCUMENTS Chien et al., 1989, J. Pharm. Sci. 78 (5): 376-383 Direct current iontophoretic transdermal delivery of peptide and 3,472,931 10/1969 Stoughton ............................... 424/180 protein drugs. 4,006,218 2/1977 Sipos ......................................... 424/54 4,144,328 3/1979 Vainshtein et al. ... 424/180 Srinivasan et al., 1989, J. of Pharm. Sci. 78(5): 370-375 4,195,172 3/1980 Falkowski et al. ................... 536/17 R Transdermal iontophoretic drug delivery : Mechanistic 4,294,958 10/1981 Falkowski et al. ....................... 536/17 analysis and application to polypeptide delivery. 4,427,660 1/1984 Schiffman et al. ..................... 424/177 West, Textbook of Biochemistry, Ch. 6: 169-170 Lipids. 4,454,065 6/1984 Gilvarget al. ...... ... 260/12 R Chien et al., 5 May 1989, J. Pharm. Sci. 78 (5): 353–354 4,588,580 5/1986 Gale et al. ................................ 424/21 Iontophoretic (transdermal) delivery of drugs: Overview of 4,645,502 2/1987 Gale et al. ................................ 604/89 historical development. 4,727,151 2/1988 Bodor .......... ... 546/174 Fix et al., 1986, The American Physiological Society: 4,788,062 11/1988 Gale et al. ...... ... 424/449 G332-G340 Acylccarnitines: drug absorption-enhancing 4,816,258 3/1989 Nedberg et al. ........................ 424/448 4,846,826 7/1989 Shaw et al. ..... 604/890. agents in the gastrointestinal tract. 4,900,555 2/1990 Cheng et al. ... ... 424/449 Banga et al., 1988, J. Controlled Release 7: 1-24 Ionto 4,904,475 2/1990 Gale et al. .............................. 424/449 phoretic delivery of drugs: Fundamentals, developments and 4,908,027 3/1990 Enscore et al. ...................... 604/890.1 biomedical applications. 4,927,408 5/1990 Haak et al. ............................... 604/20 Bernstein, 92, Bioworld 3 (105): p.1 Patch developers 4,963,367 10/1990 Ecanow ....... 424/485 extinguish suits. 4,978,337 12/1990 Theeuwes ................................. 604/85 5,011,686 4/1991 Pang............ ... 424/94.1 (List continued on next page.) 5,013,653 5/1991 Huston et al. .. ... 435/69.7 5,028,435 7/1991 Katz et al. ...... ... 424/484 Primary Examiner-Neil S. Levy 5,053,227 10/1991 Chiang et al. ... 424/484 Attorney, Agent, or Firm-Lauren L. Stevens 5,149,539 9/1992 Ledger et al. ...... ... 424/449 5,219,564 6/1993 Zalipsky et al. .... 424/78.17 (57) ABSTRACT 5,223,261 6/1993 Nelson et al. ... ... 424/443 The present invention relates to methods of delivering 5,246,967 9/1993 Zezza ...................................... 514/547 pharmaceutical agents across membranes, including the skin 5,270,472 12/1993 Taglialatela et al. ................... 560/251 layer or mucosal membranes of a patient. A pharmaceutical FOREIGN PATENT DOCUMENTS agent is covalently bonded to a chemical modifier, via a 0031722 7/1981 European Pat. Off. ........ COTH 17/08 physiologically cleavable bond, such that the membrane 0331391 9/1989 European Pat. Off. ....... A61K 45/00 transport and delivery of the agent is enhanced. 0351173 1/1990 European Pat. Off. ........ COTH 17/08 O385610 9/1990 European Pat. Off. ... A61K 39/295 5 Claims, No Drawings 5,607,691 Page 2 OTHER PUBLICATIONS Bodor et al., 18 Sep. 1992, Science 257: 1698–1700 A Behl et al., 1989, J. of Pharm. Sci. 78 (5): 355-360 Ionto strategy for delivering peptides into the central nervous phoretic drug delivery: Effects of physicochemical factors system by sequential metabolism. on the skin uptake of nonpeptide drugs. Benet et al., Pharmacokinetics: The dynamics of drug Jacobson et al., 1986, Mol. Pharmacol. 29: 126-133 A absorption, Distributuion, and elimination. Ch. 1: 3-10 fuctionalized congener approach to adenosine receptor Pharmacokinetics: The dynamics of drug absorption, distri antogonists: Amino Acid conjugates of 1,3-Dipropylxan bution, and elimination. thine. Phipps et al., 1989, J. of Pharm. Sci. 78 (5): 365-369 Iontophoretic delivery of model inorganic and drug ions. Jacobson et al., 1987, J. Med. Chem. 30: 1529-1532 Binary Ames et al., Feb. 1973, Proc. Natl. Acad. Sci., USA 70(2): Drugs: Conjugates of purines and a peptide that binds to 456-458 Illicit Transport: The Oligopeptide Permease. both adenosine and substance P receptors. 5,607,691 1. 2 COMPOSITIONS AND METHODS FOR dermal pharmaceutical agent delivery systems rely upon ENHANCED DRUG DELVERY pharmaceutical agents that are absorbed when admixed with inert carriers. See Cooper et al. (1987) “Penetration Enhanc This is a Continuation of application Ser. No. 08/164, ers', in Transdermal Delivery of Drugs, Vol. II, Kyodonieus 293, filed Dec. 9, 1993 now abandoned, which is a continu et al., Eds., CRC Press, Boca Raton, Fla. Few pharmaceu ation-in-part of application Ser. No. 08/077,296, filed Jun. tical agents fit this profile and those which do are not always 14, 1993 which is a continuation-in-part of applications Ser. predictably absorbed. Various forms of chemical enhancers, Nos. 07/898,219, filed Jun. 12, 1992 now abandoned, and such as those enhancing lipophilicity, have been developed 08/009,463, filed Jan. 27, 1993 now abandoned. Each of the to improve transdermal transport when physically mixed above identified applications are incorporated herein by 10 with certain therapeutic agents and provide more predictable reference for all purposes. absorption. See for example, U.S. Pat. Nos. 4,645,502; 4,788,062; 4,816,258; 4,900,555; 3,472,931; 4,006,218; and BACKGROUND OF THE INVENTION 5,053,227. Carriers have also been coupled to pharmaceu tical agents to enhance intracellular transport. See Ames et The present invention relates generally to methods for 15 al. (1973) Proc. Natl. Acad. Sci. USA, 70:456-458 and improving the transport and delivery of pharmaceutical (1988) Proc. Int. Symp. Cont. Rel. Bioact. Mater, 15:142. agents across membranes. More particularly, the invention Electric gradients also have been used to enhance trans relates to methods for enhancing the transport and delivery dermal pharmaceutical agent delivery. See Chien et al. of pharmaceutical agents through the addition of one or (1989) Journal of Pharmaceutical Sciences, 78(5):353–354 more chemical modifiers to the pharmaceutical agent. 20 and Banga et al. (1988) J. Controlled Release, 7:1-14. This The therapeutic efficacy of pharmaceutical or therapeutic technique, known as iontophoresis, uses an electric field to agents relies on the delivery of adequate doses of a phar enhance the rate of delivery of ionized pharmaceutical maceutical agent to the site of action. Many modes of agents through the skin. Typically, devices are used which delivery have been developed, including, for example, hold a pharmaceutical agent in a reservoir near the skin, enteral (oral), parenteral (intramuscular, intravenous, sub 25 generate an electric field surrounding the pharmaceutical cutaneous), and topical administration. In most instances the agent-dermal interface, and drive the agent through the skin. administration system is chosen for reliable dosage delivery For iontophoretic delivery, the drug molecules must be in and convenience. an ionized state with either a positive or negative charge. Typically, parenteral administration is the most reliable Nonionic drugs may also be delivered iontophoretically means of delivering a pharmaceutical to a patient. See, 30 provided that a charge can be induced on them, for example, Goodman et al., Goodman and Gilman's Pharmacological by adsorption of drug onto an ionic carrier or entrapment in Basis of Therapeutics, Pergamon Press, Elmsford, N.Y.