US005389.623A United States Patent (19) 11 Patent Number: 5,389,623 Bodor 45 Date of Patent: Feb. 14, 1995 (54) REDOX CARRIERS FOR BRAIN-SPECIFIC DRUG DELVERY OTHER PUBLICATIONS Wu et al., CA 77: 19978m (1972). 75) Inventor: Nicholas S. Bodor, Gainesville, Fla. Endo et al, CA 92: 21076y (1979). 73) Assignee: University of Florida, Gainesville, Endo et al, CA 87: 53561m (1977). Fla. Bodor et al, Science 190, 155-156 (1975). Shek et al., J. Med. Chem. 19, 113-117 (1976). 21 Appl. No.: 766,528 Bodor et al, in Design of Biopharmaceutical Properties through Prodrugs and Analogs, ed. Edward B. Roche, (22 Filed: Sep. 27, 1991 American Pharmaceutical Association, Washington, D.C., 98-135 (1977). Related U.S. Application Data Bodor et al, J. Pharm. Sci 67, 685-687 (1978). 60 Division of Ser. No. 295,663, Jan. 11, 1989, Pat. No. Bodor et al, Science 214, 1370-1372 (1981). 5,087,618, which is a division of Ser. No. 666,210, Oct. The Friday Evening Post, Health Center Communica 29, 1984, Pat. No. 4,829,070, which is a continuation-in tions, University of Florida, Gainesville, Fla., Aug. 14, part of Ser. No. 379,316, May 18, 1982, Pat. No. 1981. 4,479,932, and Ser. No. 461,543, Jan. 27, 1983, aban Chemical and Engineering News, pp. 24-25, Dec. 21, doned, and Ser. No. 475,493, Mar. 15, 1983, Pat. No. 1981. 4,622,218, and a continuation-in-part of Ser. No. Science News, vol. 121, #1, p. 7, Jan. 2, 1982. 516,382, Jul. 22, 1983, Pat. No. 4,540,564. Brewster III, Dis. Abst. Int. B., vol. 43, #9, p. 2910B (30) Foreign Application Priority Data (1983). Bodor et al., J. Med. Chem. 26, 313-318 (1983). May 12, 1983 WO WIPO ................. PCT/US83/00725 Bodor et al, J. Med. Chem. 26, 528-534 (1983). May 16, 1983 CA) Canada ................................... 428.192 Bodor et al, Pharmac. Ther. 19, 337-386 (1983). 51 Int. Cl. .................... A61K 31/56; A61K 31/455 Bodor et al, J. Pharm. Sci 73, 385-389 (1984). 52 U.S.C. .................................... 514/169; 514/170; Bodor et al, Science 221, 65-67 (1983). 514/356; 540/109; 540/110 Primary Examiner-John W. Rollins 58) Field of Search ................ 540/109, 110; 514/169, Assistant Examiner-James D. Wilson 514/170,356 Attorney, Agent, or Firm-Burns, Doane, Swecker & Mathis 56) References Cited 57 ABSTRACT U.S. PATENT DOCUMENTS Compounds of the formula 3,987,175 10/1976 Cousse ................................ 54.6/316 4,065,566 12/1977 Bodor.................................... 560/40 D--DHC (I) 4,083,996 4/1978 Tanaka et al. ...................... 546/316 4,143,146 5/1979 Saari.................................... 54.6/316 and the nontoxic pharmaceutically acceptable salt 4,152,521 5/1979 Cousse et al. .. 546/316 thereof, wherein D is the residue of a centrally acting 4,157,396 6/1979 Tanaka et al. 546/316 drug containing at least one reactive functional group 4,195,984 12/1980 Stein et al. .......................... 546/323 selected from the group consisting of amino, hydroxyl, 4,479,932 10/1984 Bodor ..................................... 424/9 mercapto, carboxyl, amide and imide, said residue being 4,532,251 7/1985 Spatz ...... 54/354 characterized by the absence of a hydrogen atom from 4,540,564 9/1985 Bodor ..................................... 424/9 4,555,520 11/1985 Misra et al. ......................... 514/546 at least one of said reactive functional groups in said 4,558,150 12/1985 Gordon et al. ..................... 54.6/316 drug; n is a positive integer equal to the number of said 4,727,079 2/1988 Bodor .................................. 514/307 functional groups from which a hydrogen atom is ab 5,087,618 2/1992 Bodor .................................... 514/45 (Abstract continued on next page.) 5,389,623 Page 2 sent; and DHC) is the reduced, biooxidizable, blood then the alkylene groups can be the same or different brain barrier penetrating lipoidal form of a dihy and the Ro radicals can be the same or different; said dropyridine-pyridinium salt redox carrier, said carrier bivalent radical being so positioned that the terminal comprising a bivalent radical of the formula carbonyl function of the bivalent radical is linked to the drug residue while the terminal amino function of the O bivalent radical is linked to the remaining portion of the I carrier moiety; are adapted for the site-specific/sus t-calypeNH; tained delivery of centrally acting drugs to the brain. R The corresponding pyridinium salt type drug/carrier wherein the alkylene group can be straight or branched entities D-(-QC) qY are also disclosed. and can contain 1 to 3 carbon atoms; R is a radical identical to the corresponding portion of a natural amino acid; and p is 1 or 2, provided that, when p is 2, 28 Claims, No Drawings 5,389,623 1. 2 barrier, BBB. Site-specific delivery and sustained deliv REDOX CARRIERS FOR BRAN-SPECIFIC ORUG ery of drugs to the brain are even more difficult. DELIVERY It has been previously suggested to deliver a drug species, specifically N-methylpyridinium-2-carbaldox CROSS-REFERENCE TO RELATED 5 ime chloride (2-PAM), into the brain, the active nucleus APPLICATIONS of which in and of itself constitutes a quaternary pyri This application is a division of application Ser. No. dinium salt, by way of the dihydropyridine latentiated 07/295,663, filed Jan. 11, 1989, now U.S. Pat. No. prodrug form thereof. Such approach was conspicu 5,087,618, which is a division of application Ser. No. ously delimited to relatively small molecule quaternary 06/666,210, filed Oct. 29, 1984, now U.S. Pat. No. 10 pyridinium ring-containing drug species and did not 4,829,070, which is a continuation-in-part of my earlier provide the overall ideal result of brain-specific, sus applications Ser. No. 06/379,316, filed May 18, 1982, tained release of the desired drug, with concomitant now U.S. Pat. No. 4,479,932; Ser. No. 06/461,543, filed rapid elimination from the general circulation, en Jan. 27, 1983, abandoned in favor of Ser. No. hanced drug efficacy and decreased toxicity. Hence, no 06/733,463, filed May 13, 1985, now U.S. Pat. No. 15 "trapping” in the brain of the 2-PAM formed in situ 4,727,079; Ser. No. 06/475,493, filed Mar. 15, 1983, now resulted, and obviously no brain-specific, sustained de U.S. Pat. No. 4,622,218, and Ser. No. 06/515,382, filed livery occurred as any consequence thereof: the 2-PAM Jul. 22, 1983, now U.S. Pat. No. 4,540,564. Each of said was eliminated as fast from the brain as it was from the earlier applications is hereby expressly incorporated by general circulation and other organs. Compare U.S. reference in its entirely and relied upon. 20 Pat. Nos. 3,929, 813 and 3,962,447; Bodor et al., J. Pharm. Sci, 67, No. 5, pp. 685-687 (1978); Bodor et al, FIELD OF THE INVENTION Science, Vol. 190 (1975), pp. 155-156; Shek, Higuchi The present invention relates to a dihydropyridine/- and Bodor, J. Med. Chem, Vol. 19 (1976), pp. 113-117. pyridinium salt type of redox system for the site-specific A more recent extension of this approach is described or sustained delivery (or both) of a wide variety of drug 25 by Brewster, Dissertation Abstracts International, Vol. species to the brain. More especially, this invention 43, No. 09, March 1983, p. 2910B. It has a also been relates to the discovery that a biologically active com speculated to deliver, e.g., an antitumor agent, into the pound coupled to a lipoidal carrier moiety comprising a brain by utilizing a dihydropyridine/pyridinium redox dihydropyridine nucleus readily and easily penetrates carrier moiety therefor, but this particular hypothesis the blood-brain barrier (“BBB”) and attains increased 30 necessarily entails derivatizing the dihydropyridine/- levels of concentration in the brain; oxidation of the pyridinium carrier with a substituent itself critically dihydropyridine carrier moiety in vivo to the ionic designed to control the release rate of the active drug pyridinium salt prevents its elimination from the brain, species itself; Bodor et al., J. Pharm. Sci, supra. See also while elimination from the general circulation is accel Bodor, "Novel Approaches for the Design of Mem erated, resulting in significant and prolongedly sus 35 brane Transport Properties of Drugs', in Design of tained brain-specific drug activity, whether ascribable Biopharmaceutical Properties Through Prodrugs and Ana to the cleavage of the drug/quaternary entity and sus logs, Roche, E. B. (ed.), APhAAcademy of Pharmaceu tained release of the drug in the brain and/or to the tical Sciences, Washington, D.C., pp. 98-135 (1976). drug/quaternary itself. More recently, the present inventor and his cowork ers, in Bodor et al, Science, Vol. 214, December 18, BACKGROUND OF THE INVENTION 1981, pp. 1370-1372, have reported on site-specific sus The delivery of drug species to the brain is ofttimes tained release of drugs to the brain. The Science publica seriously limited by transport and metabolism factors tion outlines a scheme for specific and sustained deliv and, more specifically, by the functional barrier of the ery of drug species to the brain, as depicted in the fol endothelial brain capillary wall deemed the blood-brain lowing Scheme: SCHEME (D) + (QC)+-Eš s (D-QC* section s(D-DHC) / DELVERY TO BODY ELMINATION D-DHC D-DHC) IN CIRCULATORY SYSTEM IN THE BRAIN AND ORGANS K IN VEVO K IN VIVO oxIDATION OXDATION 5,389,623 3. 4.