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United States Patent [191 [11] Patent Number: 5,017,566 Bodor [45] Date of Patent: ' May 21, 1991

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United States Patent [191 [11] Patent Number: 5,017,566 Bodor [45] Date of Patent: ' May 21, 1991 United States Patent [191 [11] Patent Number: 5,017,566 Bodor [45] Date of Patent: ' May 21, 1991 [54] REDOX SYSTEMS FOR BRAIN-TARGETED FOREIGN PATENT DOCUMENTS DRUG DELIVERY 0197571 10/1986 European Pat. Off. [75] Inventor: Nicholas S. Bodor, Gainesville, Fla. 58-213712 12/1983 Japan . 60-054384 3/1985 Japan . [73] Assignee: University of Florida, Gainesville, 61-070996 4/1986 Japan . Fla. 61-197602 9/1986 Japan . 61-236802 10/1986 Japan . [ ' ] Notice: 7 The portion of the term of this patent 62-“)3795 1/1987 Japan . subsequent to Jan. 8, 2008 has been 62-106901 5/1987 Japan . disclaimed. 62-16470] 7/1987 Japan . 62-281855 12/1987 Japan . [21] Appl. No.: 431,222 63-027440 2/1988 Japan . [22] Filed: Nov. 3, 1989 63-036793 2/1988 Japan . 63-135402 6/1988 Japan . 63-146861 6/1988 Japan . Related US. Application Data 63-218663 9/1988 Japan. [63] Continuation-impart of Ser. No. 139,755, Dec. 30, WO83/03968 11/1983 PCT Int'l Appl. 1987, which is a continuation-in-part of Ser. No. WO85/02767 7/ 1985 PCT lnt'l App], . 174,945, Mar. 29, 1988. WO85/03937 9/1985 PCT Int’l Appl. [30] Foreign Application Priority Data OTHER PUBLICATIONS Dec. 13, 1988 [CA] Canada ........................ .. 585791 Brewster et al, J. Pharm. Sci, vol. 77, No. 11, Nov. Dec. 13, 1988 [IE] Ireland 3717/88 1988, 981-985. Mar. 14, 1989 Ireland ................................. .. 810/89 Brewster et al, in Proceedings of the Fourth International [51] Int. Cl.5 ................... .. A611! 31/735; C0813 37/16 Symposium on Cyclodextrins, Munich, 20th-22nd Apr. [52] US. Cl. .................................... .. 514/58; 536/ 103; 1988, pp. 399-404, Kluwer Academic Publishers, Dor 514/964; 514/965 drecht, NL. _ [58] Field of Search ....................... .. 514/58, 964, 965; (List continued on next page.) 536/103 Primary Examiner-Ronald W. Griffin [56] References Cited Attorney, Agent, or Firm-—Mary Katherine Baumeister U.S. PATENT DOCUMENTS [57] ABSTRACT 3,459,731 8/ 1969 Gramera et a1. .................. .. 536/103 Inclusion complexes of hydroxypropyl, hydroxyethyl, 4,024,223 5/ 1977 Noda et a1. .. 514/58 4,228,160 10/1980 Szejtliet a1. .................. .. 558/344 glucosyl, maltosyl and maltotriosyl derivatives of B 4,232,1XJ9 11/1980 Hayashi et a1. .. 514/58 and 'y-cyclodextrin with the reduced, biooxidizable, 4,351,846 9/1982 Matsumoto et a1. 514/530 blood-brain barrier penetrating, lipoidal forms of dihy 4,352,793 10/1982 Yamahira et a1. .. 514/58 dropyridinezzpyridinium salt redox systems for brain 4,383,992 5/1983 Lipari ................ .. 514/174 targeted drug delivery provide a means for stabilizing 4,407,795 10/1983 Nicolau .... .. 514/58 the redox systems, particularly against oxidation. The 4,424,209 1/ 1984 Tuttle . .. 514/58 redox inclusion complexes also provide a means for 4,425,336 1/ 1984 Tuttle . .. 514/58 4,438,106 3/1984 Wagu et a1. .. 514/58 decreasing initial drug concentrations in the lungs after 4,474,811 10/1984 Matsuda et a1. 514/570 administration of the systems, leading to decreased tox 4,478,995 10/1984 Shinoda et a1. .. icity. In selected instances, complexation results in sub 4,479,932 10/1984 Bodor ....................... .. 424/9 stantially improved water solubility of the redox sys 4,479,944 10/1984 Hayashi et a1. .. 514/58 tems as well. 4,479,966 10/1984 Hayashi et a1. ..................... .. 514/58 (List continued on next page.) 72 Claims, 5 Drawing Sheets 8288 SOLUBILITYOFL-CDSINHPCDMSDS” §:Ia. ‘A‘Al‘Amb-al-al SOLUImOFL-CDS(‘I.) Q (WIV) CYCIDDEXTRIN 5,017,566 Page 2 US. PATENT DOCUMENTS Irie et a1, Pharmaceutical Research, vol. 5, No. 11, 1988, 713-717. 4,497,803 2/ 1985 Harada et a1. .................... .. 514/450 Yoshida et al, International Journal of Pharmaceutics, 46, 4,499,085 2/ 1985 Masuda . .. 514/58 4,518,588 5/1985 Szejtli et a1. 514/58 1988, 217-222. 4,524,068 6/1985 Szejtli et a1. 514/58 Koizumi et a1, Chem. Pharm. Bull, 35 (8), 3413-3418 4,540,564 9/ 1985 Bodor ........ .. 424/9 (1987). 4,546,097 10/1985 Pitha ...... .. Okada et a1, Chem. Pharm. Bull, 36 (6), 2176-1185 4,555,504 11/1985 Jones .............. .. (1988). 4,565,807 1/ 1986 Uekama et a1. .. 536/103 Yamamoto et al, in International Journal of Pharmaceu 4,575,548 3/ 1986 Ueda et a1. .. 536/46 tics, 49, 163-171 (1981). 4,596,795 6/1986 Pitha . .. 514/58 Pitha et al, in Controlled Drug Delivery, ed. S. D. Bruck, 4,598,070 7/1986 Ohwaki et a1. 514/58 vol. I, CRC Press, Boca Raton, Florida, 125-148 (1983). 4,599,327 7/ 1986 Nogradi et a1 .. 514/58 Uekama, Pharm. Int., Mar. 1985, 61-65. 4,603,123 7/1986 Chiesi et a1. .. 514/58 4,608,366 8/1986 Hasegawa et a1. 514/58 Pitha, Journal of Inclusion Phenomena 2, 477-485 (1984). 4,617,298 10/1986 Bodor et a1. 514/176 Fenyvesi et a1, Chem. Pharm. Bull. 32(2), 665-669 4,623,641 11/1986 Szcjtli et a1. .... .. 514/58 (1984). 4,659,696 4/1987 Hirai et a1. .. 514/15 Uekama et al, International Journal of Pharmaceutics, 23, 4,663,316 5/ 1987 Ninger et a1. .. 514/99 35-42 (1985). 4,675,395 6/ 1987 Fukazawa et a1. .. 536/ 103 Pitha, J. Pharm. Sci, vol. 74, No. 9, Sep. 1985, 987-990. 4,727,064 2/1988 Pitha ....................... .. 514/58 Pitha et al, International Journal of Pharmaceutics, 29, 4,727,079 2/ 1988 Bodor 514/307 73-82 (1986). 4,728,509 3/ 1988 Shimizu et . .. 424/81 Uekama et al, in CRC Critical Reviews in Therapeutic 4,728,510 3/ 1988 Shibanai et a1. 424/945 4,751,095 6/ 1988 Karl et a1. ...... .. 426/548 Drug Carrier Systems, vol. 3(1), 1-40 (1987). 4,764,604 8/1988 Miiller .... .. 536/103 Uekama, in Topics in Pharmaceutical Sciences 1987, eds. 4,824,850 4/1989 Bodor 514/270 D. D. Breirner & P. Speiser, Elsevier Science Publishers 4,829,070 5/ 1989 Bodor ..... .. 514/307 B.V. (Biomedical Division), 181-194 (1987). 4,834,985 5/ 1989 Elger et a1. 424/488 Pagington, Chemistry in Britain, 455-458 (May 1987). 4,888,427 12/1989 Bodor ................................ .. 546/316 Carpenter et al, The Journal of Pediatrics, 111, 507-512 OTHER PUBLICATIONS (Oct. 1987). Estes et al, in Biological Approaches to the Controlled Chemical Abstracts, 110: 101755b (abstract of Japanese ,Delivery of Drugs, ed. R. L. Juliano, Annals of the New Kokai 88/218,663, published 09-12-88). York Academy of Sciences, vol. 507, 1987, 334-336. U.S._ Patent May 21, 1991 Sheet 1 of s ' 5,017,566 v 305no»:EmoE5533253e. , 83 1iQ1‘q A25@225M530: (um/3w) sao-‘s a0 m'namos US. Patent May 21, 1991 Sheet 2 of 5 5,017,566 6 5‘ 13 3% =2? dd .4 q. A “1. a n~ 2a 11 ‘c: bl?nv-l nan-18.228‘;QGQQQQQQQ :mssu ma ?/asoa as US, Patent May 21, 1991 Sheet 3 of 5 5,017,566 “ /”mv 3 :62 ad [8/311] a/‘a * OIIO8:5 u-U\IUMI.0 E. mA-U-NH M»4'4:2: O /1: O /0.1:: 3:: [8/8111 am U.S. Patel-1t May 21, 1991 Sheet 4 of 5 5,017,566 U82: I. .:2: w itM 364.2305£2»- w3 2.u abb ~$8 gm 2:j US. Patent May 21, 1991 Sheet 5 of 5 5,017,566 T bnPnbnPp aNevEa32an *Q2:23 Hu\x...“ HUM-EHm0awn-Q4QUm? zoE;Pin.3madzoriixo (1-H 1-9) .LNVLSNOD ELLVH 5,017,566 1 2 dues; and Y-cyclodextrin, which is composed of a ring REDOX SYSTEMS FOR BRAIN-TARGETED DRUG of eight glucose units. The inside cavity of a cyclodex DELIVERY trin is lipophilic, while the outside of the cyclodextrin is hydrophilic; this combination of properties has led to CROSS-REFERENCE TO RELATED 5 widespread study of the natural cyclodextrins, particu APPLICATIONS: larly in connection with pharmaceuticals, and many inclusion complexes have been reported. B-Cyclodex This application is a continuation-in-part of appli trin has been of special interest because of its cavity size, cant’s copending application Ser. No. 07/139,755, ?led but its relatively low aqueous solubility (about 1.8% Dec. 30, 1987, and of applicant’s copending application w/v at 25° C.) and attendant nephrotoxicity has limited Ser. No. 07/174,945, ?led Mar. 29, 1988. Ser. No. its use in the pharmaceutical ?eld. 07/ 174,945 is itself a continuation-in-part of Ser. No. Attempts to modify the properties of the natural cy 07/ 139,755. Both of said copending applications are clodextrins have resulted in the development of hepta incorporated by reference herein in their entirety and kis (2,6-di-O-methyl)-B-cyclodextrin, heptakis (2,3,6-tri relied upon. 15 O-methyD-B-cyclodextrin, hydroxypropyl-B-cyclodex FIELD OF THE INVENTION: trin, B-cyclodextrin-epichlorohydrin polymer and oth ers. For a comprehensive review of cyclodextrins and The present invention provides a method for stabiliz ing the reduced, dihydropyridine forms of dihydropyri their use in pharmaceutical research, see Pitha et al, in dine :2 pyridinium salt redox systems for brain-targeted Controlled Drug Delivery, ed. S. D. Bruck, Vol. I, CRC drug delivery by forming inclusion complexes of the Press, Boca Raton, Florida, pp. 125- 148 (1983). For an even more recent overview, see Uekama et al, in CRC dihydropyridine forms with selected cyclodextrins. Critical Reviews in Therapeutic Drug Carrier Systems, These redox inclusion complexes also provide a means Vol.
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