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
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(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. 3(1), l-40 (1987); Uekama, in Topics in Pharmaceu for increasing the ratio of initial brain to lung concentra tical Sciences 1987, eds. D. D. Breimer and P. Speiser, tions, thus leading to decreased toxicity. In selected 25 Elsevier Science Publishers B.V. (Biomedical Divi instances, complexation results in substantially im sion), 181-194 (1987); and Pagington, Chemistry in Brit proved water solubility of the redox systems as well. ain, pp. 455-458 (May 1987). BACKGROUND OF THE INVENTION: Inclusion complexes of a-, B- or 'y-cyclodextrin or Cyclodextrins are cyclic oligosaccharides. The most their mixtures with a variety of drugs have been de 30 scribed by numerous parties and various advantages common cyclodextrins are a-cyclodextrin, which is have been attributed to the complexes. These descrip composed of a ring of six glucose residues; B-cyclodex tions include the following: trin, which is composed of a ring of seven glucose resi
us. ACTIVE INVENTOR PAT. NO. INGREDIENT USE ADVANTAGE Noda et al 4,024,223 menthol &/or antiphlogistic, reduced unpleasant methyl analgesic odor, increased salicylate wet packing effect Szejtli et a1 4,228,160 indomethacin anti-in?am- reduced ulcerative matory, pro- effect tective during pregnancy Hayashi et al 4,232,009 w-halo-PGI; hypotensive, increased stability analogs uterine con traction stimulating, ‘blood platelet aggregation " inhibiting Matsumoto et al 4,351,846 3-hydroxy- and uterine contrac- increased stability 3-oxo- tion stimulating prostagiandin analogs Yamahira et al 4,352,793 bencyclane anticonvulsant, increased stability fumarate- vasodilative at strong acid pH, faster gastric emptying, higher blood concentra tions, less irritation improved hemolytic activity Lipari 4,383,992 steroids- hormonal improved water corticosteroids solubility, increased androgens, therapeutic response anabolic in eye steroids, estrogens, progestagens Nicolau 4,407,795 p-hexadecyl- antiathero- enhanced aminobenzoic sclerotic bioavailability acid sodium salt Tut‘tlcl 4,424,209 3,4-diisobutyr- cardiac yioxy-N-[3—(4- contractility isobutyryloxy- agent 5,017,566 3 -continued U.S. ACTIVE INVENTOR PAT. NO. INGREDIENT USE ADVANTAGE phenyl)~l methyl-n PwPyIl-B phenethylamine Tuttle 4,425,336 3,4-dihydroxy- cadiac capable of oral N-[3»(4-hydroxy- contractility administration phenyl)~l- agent methyl-m PYOPYIl-B phenethylarnine Wagu et al 4,438,106 EPA and DHA deodorized (fatty acids) storage stable Masada et al2 4,474,811 2-(2-?uoro-4- anti- reduced eye biphenylyl)pro- in?ammatory irritation, pionic acid ophthalmic higher concen or salt trations, no side . effects, highly soluble, long stability, excellent pharmacological effects Shinoda et al 4,478,995 acid addition anti-ulcer excellent water salt of (2’- solubility, good benzyloxycar- absorption in diges bonyl)phenyl tive tract, good trans-ll-guani- anti-ulcer activity dinomethylcyclo~ hexanecarboxylate Hayashi et a1 4,479,944 PGIZ analog for treatment of stabilization against artereosclerosis, decomposition cardiac failure or thrombosis Hayashi et al 4,479,966 6,9-methano- for hypertension, increased stability PGIZ analogs cerebral throm bosis and the like Harada et al 4,497,803 lankacidin- antibiotic for enhanced water group antibiotic swine dysentery solubility and stability, increased rate and amount of absorption Masuda 4,499,085 prostaglandin treating anoxia analog of brain cells Szejtli et al 4,518,588 phendiline, i.e. coronary dilator improved water solu N-(l-phenyl- calcium bility, accelerated ethyl)‘3,3— antagonist and increased in diphenylpro- vivo resorption pylamine or its & dissolution at pH/ hydrochloride temperature of gastric acid Szejtli et al 4,524,068 piperonyl synergizes easily handled butoxide pesticidal effect crystalline solid; of known insecti- improved water solu cides and fungi- bility, increased cides absorption & velocity of penetration through biological membranes Jones 4,555,504 a cardiac cardiac effect high aqueous solu glycoside bility, apparently better bioavajl ability Uekama et al3 4,565,807 pirprofen anti-inflam- improved stability matory, to oxidation, analgesic, frwdom from bitter antipyretic taste, less irritating Ueda et a] 4,575,548 Z-nitroxymethyl- for vascular non-volatile powder 6-chloropyridine disorders vs. volative oil Ohwaki et 814 4,593,070 triparnide anti-hyper- improved solubility tensive Chiesi et al 4,603,l23 piroxicam, i.e. anti-inflam 4-hydroxy-2- matory, analgesic methyl-N-Z pyridyl-2H-l,2 benzothiazine-S carboxamide-l,l dioxide Hasegawa et al 4,608,366 mobenzoxamine, antiemetic, storage stability i.e. l_[2‘(4- antispasmodic better absorption methoxybenzhy through digestive 5,017,566 5 6 -continued U.S. ACTIVE INVENTOR PAT. NO. INGREDIENT USE ADVANTAGE dryloxy)ethyl]- tract 4-[3-(4-?uoro benzoyl)propyl] piperazine Hirai a all 4,659,696 polypeptide improving drug absorption by non . oral and non injection routes Szejtli et a1 4,623,641 PGI; methyl anti-ulcer improved storage ester stability Ninger et a1 4,663,316 unsaturated antibiotic, enhanced stability pbosphorus- antifungal, against oxidation containing antitumor antibiotics, including phosphotrienin Fulrazawa et al 4,675,395 hinoltitiol bactericidal, improved water solu bacteriostatic bility, less odor Shimizu et al 4,728,509 2-amino-7- anti-allergic, improved water solu isopropyl-S- anti- bility to increase oxo~51-1-[l]- in?ammatory concentration to benzopyrano- therapeutic levels [2,3-b]pyridine— in nasal drops and 3-carboxylic acid eye drops Shibanai et al6 4,728,510 a milk bath improved stability component preparation Karl et al 4,751,095 aspartame dipeptide stabilization from ' sweetener hydrolysis lTurtle also describes use of 2,6-di-O-methyl-B-cyclodextrin and 2,3,6-tri-O-methyl B-cyclodextrin to form the inclu sion complex. 2This may not be an inclusion complex, but simply a physical mixture. is is a mixture and/or an inclusion compound. ‘The inventors also mention prior known solubility improvements of cyclodextrin inclusions of barbituric acid deriva tives, mefenamic acid, indomethacin and chloramphenicol. 5The inventors refer to this as an "occlusion" compound. "The inventors also mention a derivative of cyclodextrin and a cyclodextrin-containing starch decomposition product for use in forming the clathrate. Inclusion complexes of 2,6di-0-methyl-B-cyclodex trin with dibenzo[bd]pyran derivatives and salts having analgesic, anternetic and narcosispotentiating activities tion power of hydrophilic derivatives of cyclodextrins, have been described in Nogradi et al U.S. Pat. No. the non-aggregated structure of their complexes with 4,599,327; increased water solubility and thus improved steroids, and their low toxicity and irritancy of mouth biological activity have been claimed for the complexes. tissue”. Success with other cyclodextrins, including A review of the pharmaceutical applications of such poly-'y-cyclodextrin and hydroxypropyl-y-cyclodex methylated cyclodextrins has been published by trin, have also been noted in the Pitha patent. See also Uekama, Pharm Int., March 1985, 61-65; see also Pitha, Pitha et al, J. Pharm. Sci., Vol. 74, No. 9, 987-990 (Sep Journal of Inclusion Phenomena 2, 477-485 (1984). tember 1985), concerning the same and related studies. Cyclodextrin polymer has been reported by Fenyvesi Pitha et al also describe in the J. Pharm. Sci. article the et al, Chem. Pharm. Bull. 32 (2), 665-669 (1984) to im storage stability of tablets containing a testosterone prove the dissolution of furosemide. Improvements in hydroxypropyl-B-cyclodextrin complex and the lack of the dissolution and absorption of phenytoin using a toxicity of the cyclodextrin itself, as well as the impor water-soluble B-cyclodextrin epichlorohydrin polymer tance of the amorphous nature of the cyclodextrin de have been described by Uekama et al, International rivatives and their complexes with drugs in improving Journal of Pharmaceutics, 23, 35-42 (1985). dissolution properties. Hydroxypropyl-B-cyclodextrin (HPCD) and its The improved, optimized preparation and puri?ca preparation by propylene oxide addition to ,B-cyclodex tion of hydroxypropyl—B-cyclodextrin has been recently trin were described in Gramera et a1 U.S. Pat. No described by Pitha et al, International Journal of Phar 3,459,731 nearly 20 years ago. Gramera et al also de maceutics 29, 73-82 (1986). In the same publication, the scribed the analogous preparation of hydroxyethyl-B authors have described increased water solubility for 32 cyclodextrin by ethylene oxide reaction with B drugs in concentrated (40 to 50%) aqueous solutions of cyclodextrin. Much more recently, Pitha and co-work hydroxypropyl-B-cyclodextrin; improved solubilization ers have described the improved preparation of this of acetaminophen, apomorphine, butylated hydroxytol cyclodextrin derivative and its effects on the dissolution uene, chlorthalidone, cholecalciferol, dexamethasone, of various drug molecules. Pitha U.S. Pat. No. dicumarol, digoxin, diphenylhydantoin, estradiol, es 4,596,795, dated June 24, 1986, describes inclusion com triol, ethinylestradiol-3-methyl ether, ethisterone, furo plexes of sex hormones, particularly testosterone, pro semide, hydro?umethiazide, indomethacin, iproniazid gesterone, and estradiol, with speci?c cyclodextrins, phosphate, 17-methyltestosterone, nitroglycerin, nor preferably hydroxypropyl-B-cyclodextrin and poly-B ethindrone, ouabain, oxprenolol, progesterone, retinal, cyclodextrin. The complexes enable the sex hormones 65 retinoic acid (all trans and salt forms), retinol, spirono to be successfully delivered to the systemic circulation lactone, sulpiride, testosterone and theophylline was via the sublingual or buccal route; the effectiveness of noted. The authors indicated this to be an extension of this delivery is believed to be due to “the high dissolu their earlier work with hydroxypropyl-B-cyclodextrin, 5,017,566 7 8 which was previously found effective for oral adminis Japanese Kokai 88-2l8,663 (Kamikama et a1) de tration of the sex hormones to humans. Their later work scribes a pharmaceutical preparation containing reported in Pitha et al, International Journal of Pharma nimodipine solubilized with hydroxypropyl-Beyclodex ceutics 29, 73-82 (1986), has also been very recently trin. described in Pitha U.S. Pat. No. 4,727,064, dated Feb. Carpenter et al, The Journal of Pediatrics, 111, 23, 1988. That patent claims a composition containing 507-512 (October 1987) describe intravenous infusion an amorphous complex of cyclodextrin and a drug, and of Z-hydroxypropyl-B-cyclodextrin, prepared as a 5% a method of producing a stabilizing amorphous complex solution in water, to treat severe hypervitaminosis A. It ofa drug and a mixture of cyclodextrins comprising (1) was found that, during infusion, circulating retinyl es dissolving an intrinsically amorphous mixture of cy ters increased transiently, while total vitamin A ex clodextrin derivatives which are water soluble and ca creted in the urine was enhanced after infusion. Thus, pable of forming inclusion complexes with drugs in intravenous infusion of 5% HPCD was found to de water; and (2) solubilizing lipophilic drugs into aqueous crease in vivo levels of the vitamin, presumably by media to form a solution and form a solubilized drug/ complexing with the vitamin and removing some of the cyclodextrin complex. The patent describes the prepa 15 excess from the body. ration of various substituted amorphous cyclodextrins, _ The preparation of amorphous water-soluble cy including hydroxypropyl-B-cyclodextrin and hydroxy clodextrin derivatives, including 2-hydroxyethyl-B propyl-y-cyclodextrin, the latter by analogous conden cyclodextrin, 3-hydroxypropyl-B-cyclodextrin and 2 sation of propylene oxide and 'y-cyclodextrin. hydroxypropyl-y-cyclodextrin, is described by Irie et Uekama et a1, CRC Critical Reviews in Therapeutic a1, Pharmaceutical Research, Vol. 5, No. 11, 1988, 713 Drug Carrier Systems, Vol. 3 (1), pp. l-40 (1987), have 717. That report also addresses the distribution of the described the characteristics of various cyclodextrins, substituents among the glucose residues of the cy including hydroxypropyl-B-cyclodextrin. The authors clodextrin ring. have presented data showing improved solubilization in A pharmaceutical evaluation of hydroxyalkyl ethers 25 of B-cyclodextrins has been recently reported by Yo water in the presence of 15 mg/mL of HPCD for the shida et al, International Journal of Pharmaceutics 46, drugs carmofur, diazepam, digitoxin, digoxin, ?urbi 1988, 217-222. Aqueous solubilities, surface activities, profen, indomethacin, isosorbide dinitrate, phenytoin, hemolytic activity and local irritancy are reported. The prednisolone, progesterone and testosterone. In a dis data suggest that hydroxyalkyl-B-cyclodextrins over— cussion of the metabolism and toxicity of cyclodextrins, 30 come many of the undesirable characteristics of B Uekama et al have indicated that cyclodextrins at suffi cyclodextrin usage in pharmaceuticals. ciently high concentrations cause hemolysis, and that JANSSEN PHARMACEUTICA N.V.’s European the methylated cyclodextrins have higher hemolytic Patent Application No. 862003340, published under activity than the natural cyclodextrins. Hydroxypropyl EPO Publication No. 0197571 on Oct. 15, 1986, de B-cyclodextrin is said to cause hemolysis beginning at 35 scribes y-cyclodextrin derivatives which are 7 4.5 mM. The authors have further indicated that paren cyclodextrin substituted with C1-C6 alkyl, hydroxy teral administration of large .doses of cyclodextrins C1-C6 alkyl, carboxy C1-C6 alkyl or C1-C6 alkylox should be avoided, but that “'y-cyclodextrin and by ycarbonyl C1-C6 alkyl or mixed ethers thereof. Among droxypropyl-B-cyclodextrin seem to be useful in drug the speci?c derivatives named are hydroxypropyl-7 solubilization for injections and liquid preparations used cyclodextrin and hydroxyethyl-y-cyclodextrin. Com for mucous membranes.” positions comprising the cyclodextrin derivatives and a JANSSEN PHARMACEUTICA N.V.’s Interna drug are also described. See also corresponding Muller tional Patent Application No. PCT/EP84/0O4l7, pub US. Pat. No. 4,764,604, dated Aug. 16, 1988. lished under International Publication No. W085/02767 The inclusion characteristics of yet other derivatized on July 4, 1985, has described pharmaceutical composi 45 cyclodextrins have also been described in the literature. tions comprising inclusion compounds of drugs, which Studies of branched cyclodextrins which are glucosyl are unstable or only sparingly soluble in water, with and maltos'yl derivatives of a-, B-and 'y-cyclodextn'n partially etheri?ed B-cyclodextrin derivatives having and their inclusion complexes with drugs have recently hydroxyalkyl and optionally additional alkyl groups. been reported. Uekama, in Topics in Pharmaceutical Among the cyclodextrin derivatives contemplated are 50 Sciences 1987, eds. D. D. Breimer and P. Speiser, El hydroxypropyl-B-cyclodextrin and hydroxyethyl-Bcy sevier Science Publishers B.V. (Biomedical Division), clodextrin, while the drugs include non-steroidal anti 181-194 (1987), has described the effects on biophar rheumatic agents, steroids, cardiac glycosides and de maceutical properties of maltosyl and glucosyl cy rivatives of benzodiazepine, benzimidazole, piperidine, clodextrin derivatives, as well as hydroxypropyl and piperazine, imidazole and triazole. Preferred drugs in 55 other hydrophilic cyclodextrin derivatives, including clude etomidate, ketoconazole, tubulazole, enhanced drug absorption. The mechanism of enhanc itraconazole, levocabastine and flunarizine. The phar ing drug absorption is described and the apparent stabil maceutical compositions of the invention include oral, ity constants for inclusion complexes of various drugs parenteral and topical formulations, with 4 to 10% solu with B-cyclodextrin, dimethyl-B-cyclodextrin, hydrox tions of cyclodextrin derivatives being utilized to solu 60 ypropyl-B-cyclodextrin and maltosyl-B-cyclodextrin bilize various drugs. Improved solubilities of indometh are given. Drugs studied with these cyclodextrins in acin, digitoxin, progesterone, dexamethasone, hydro clude benoxaprofen, biphenyl acetic acid, carmofur, cortisone and diazepam using 10% HPCD are shown, clo?brate, chlorpromazine, diazepam, diclofenac, digi and an injectable formulation of diazepam in 7% HPCD toxin, digoxin, ethyl 4-biphenyl acetate, ?urbiprofen, is speci?cally described. The relatively low cyclodex 65 isosorbide dinitrate, indomethacin, menadione, nimodi trin concentrations used re?ect a desire to avoid or pine, nisoldipine, phenytoin, prednisolone, progester minimize the hemolytic effects observed at higher cy one, prostacyclin, various prostaglandins (E1, B2, A1, clodextrin concentrations. A2), protriptyline, spironolactone and testosterone. 5,017,566 9 10 Uekama also discussed the hemolytic effects of cy Japanese Kokai 62-106901 (NIKKEN CHEM KK), clodextrins. Summarizing the various studies using published May 18, 1987, describes the preparation of human erythrocytes, Uekama indicated that the natural diglucosyl-B-cyclodextrin and its general use for phar cyclodextn'ns at relatively high concentrations caused maceuticals. hemolysis in the order 7
CHEMICAL [D1 + [QCF COUPLING 9 [D'QC]+ REDUCTION 9 [D‘DHC]
K1
DELIVERY To BODY , AMINATION [D-DHC] [D-DHC] IN THE BRAIN IN CIRCULAToRY SYSTEM AND ORGANS K1 IN VIVO IN VIVO OXIDATION K1 OXIDATIQN
lD-QC] + — [D-QC] + IN THE BRAIN 55382;? IN cIRcULAToRY SYSTEM
K4 K4
K2 v K3
l [D] + IQClI+ [l3']+[QCl1+ K5 K6
BBB ' \l’ V V N ELIMINATION SCHEME 1: BBB, BLOOD-BRAIN BARRIER.
According to the scheme in Science, a drug [D] is cou pled to a quaternary carrier [QC]+ and the [D-QC]+ 60 which results is then reduced chemically to the lipoidal dihydro form [D-DHC]. After administration of [D DHC] in vivo, it is rapidly distributed throughout the (R = CH3 °Y CH2 ) body, including the brain. The dihydro form [D-DHC] is then in situ oxidized (rate constant, k1) (by the NAD 65 2 NADH system) to the ideally inactive original + quaternary salt which, because of its ionic, hydrophilic which were subsequently reduced by sodium dithionite character, should be rapidly eliminated from the gen to the corresponding compounds of the formula 5,017,566 13 14 -continued (T CONHCHZCHZ (1))
N l a
O (R = CH3 or CH ) 10 (c)
Testing of the N-methyl derivative in vivo supported the criteria set forth in Scheme I. Bodor et al speculated that various types of drugs might possibly be delivered using the depicted or analogous carrier systems and indicated that use of N-methylnicotinic acid esters and 3 amides and their pyridine ring-substituted derivatives \g was being studied for delivery of amino- or hydroxyl (R)... containing drugs, including small peptides, to the brain. No other possible speci?c carriers were disclosed. wherein the dotted line in formula (a) indicates the Other reports of this work with the redox carrier system presence of a double bond in either the 4 or 5 position of have appeared in The Friday Evening Post, Aug. 14, 25 the dihydropyridine ring; the dotted line in formula (b) 1981, Health Center Communications, University of indicates the presence of a double bond in either the 2 or Florida, Gainesville, Fla.; Chemical & Engineering 3 position of the dihydroquinoline ring system; m is zero News, Dec. 21, 1981, pp. 24-25; and Science News, Jan. or one; n is zero, one or two; p is zero, one or two, 2, 1982, Vol. 121, No. 1, page 7. More recently, the provided that when p is one or two, each R in formula redox carrier system has been substantially extended in 30 (b) can be located on either of the two fused rings; q is terms of possible carriers and drugs to be delivered. See zero, one, or two, provided that when q is one or two, International Patent Application No. each R in formula (c) can be located on either of the two PCT/US83/OO725, ?led May 12, 1983 and published fused rings; and each R is independently selected from the group consisting of halo, C1-C7 alkyl, C1-C7 alkoxy, Nov. 24, 1983 under International Publication No C2-C8 alkoxycarbonyl, C2-C3 alkanoyloxy, C1-C7 halo W083/03968. Also see Bodor et al, Pharmacology and alkyl, C1-C7 alkylthio, C1-C7 alkylsul?nyl, C1-C7 alkyl Therapeutics, Vol. 19, No. 3, 337-386 (1983); and Bodor sulfonyl, ——CH=NOR'” wherein R’” is H or C1-C7 US. Pat. No. 4,540,564, issued Sept. 10, 1985. alkyl, and --CONR’R" wherein R’ and R", which can The third approach for delivering drugs to the brain be the same or different, are each H or C1-C7 alkyl. using the redox system provides derivatives of centrally These dihydropyridine analogs act as a delivery system acting amines in which a primary, secondary or tertiary for the corresponding biologically active quaternary amine function has been replaced with a dihy compounds in vivo. Due to its lipophilic nature, the dropyridine/pyridinium salt redox system. These brain dihydropyridine analog will distribute throughout the speci?c analogs of centrally acting amines have been body and has easy access to the brain through the recently described in International Patent Application 45 blood-brain barrier. Oxidation in vivo will then provide No. PCT/US85/00236, ?led Feb. 15, 1985 and pub the quaternary form, which will be “locked” preferen lished Sept. 12, 1985 under International Publication tially in the brain. In contradistinction to the drug-car No. W085/03937. The dihydropyridine analogs are rier entities described in Bodor US. Pat. No 4,540,564 characterized by the structural formula and related publications, however, there is no readily 50 metabolically cleavable bond between drug and quater nary portions, and the active species delivered is not the original drug from which the dihydro analog was de rived, but rather is the quaternary analog itself. Each of the major dihydropyridine <—_> pyridinium 55 redox systems for brain-targeted drug delivery thus has its own unique characteristics but also has properties in wherein D is the residue of a cent acting primary, sec common with the other approaches. Common to the ondary or tertiary amine, and —I\Ois a radical of the various approaches is introduction of a dihydropyri formula dine-type nucleus into the drug molecule, which ren ders the dihydropyridine-containing drug derivative (a) substantially more lipophilic than the parent drug from I which it is derived. The increased lipophilicity enables N 1 the derivative to readily penetrate biological mem 2 s - branes, including the blood-brain barrier. Also common 3 51' ‘ I 65 to the various approaches is the fact that the “redox” nature of the dihydropyridine-type moiety means that (R), the lipophilic dihydropyridine form is oxidizable in vivo to the hydrophilic, ionic pyridinium salt form, thus 5,017,566 15 16 locking in the brain either the active drug or its quater~ tration of the reduced, dihydropyridine form of a dihy nary precursor, depending on which approach is em dropyridine :2 pyridinium salt redox system for brain ployed. targeted drug delivery. The dihydropyridine pyridinium salt redox carrier Yet another object of the present invention is to pro and analog systems have achieved remarkable success vide a method for improving the water solubility of the in targeting drugs to the brain in laboratory tests. This reduced, dihydropyridine form of selected dihydropyri success is, of course, due in part to the highly lipophilic dine <—_> pyridinium salt redox systems for brain-targeted nature of the dihydropyridine-containing derivatives, drug delivery. which allows brain penetration. At the same time, the Another object of the present invention is to provide increased lipophilicity makes it practically impossible to improved pharmaceutical formulations containing the formulate aqueous solutions of these derivatives for reduced, dihydropyridine form of a dihydropyridine injection; moreover, even when the dihydropyridines pyridinium salt redox system for brain-targeted drug are dissolved in organic solvents such as dimethylsulf delivery. oxide, they have a propensity for precipitating out of The foregoing objects are achieved by means of solution upon injection, particularly at higher concen 15 novel inclusion complexes of cyclodextrin selected trations, and especially at the injection site or in the from the group consisting of hydroxypropyl, hydroxy lungs. Indeed, even in the absence of noticeable crystal ethyl, glucosyl, maltosyl and maltotriosyl derivatives of lization, it has been found that the redox derivatives B-and 'y-cyclodextrins with the reduced, dihydropyri frequently display not only the desired concentration in dine form of the dihydropyridine 2 pyridinium salt the brain but undesired lung concentrations as well, so 20 redox system for brain-targeted drug delivery. Thus, that while the brain to blood ratios are at appropriate the present invention provides a novel method for stabi high levels, the initial lung to brain levels are high as lizing the reduced biooxidizable, blood-brain barrier well. Still further, the dihydropyridine-containing de penetrating lipoidal form of a dihydropyridine :2 pyri rivatives suffer from stability problems, since even in dinium salt redox system for brain-targeted drug deliv the dry state they are very sensitive to oxidation as well 25 ery, said method comprising complexing said reduced as to water addition. These problems must be overcome form with cyclodextrin selected from the group consist so that the dihydropyridine 2 pyridinium salt redox ing of hydroxypropyl, hydroxyethyl, glucosyl, maltosyl systems can be fully commercialized. and maltotriosyl derivatives of B- and 'y-cyclodextrin. Applicant’s parent US patent application Ser. No. The present invention further provides a novel method 07/139,755, ?led Dec. 30, 1987, incorporated by refer 30 for improving the water-solubility of the reduced, bi ence herein, relates to a method for stabilizing the re duced, dihydropyridine forms of dihydropyridine :2 ooxidizable, bloodbrain barrier penetrating lipoidal pyridinium salt redox systems for brain-targeted drug form of dihydropyridine :2 pyridinium salt redox sys delivery by forming inclusion complexes of the dihy tems for brain-targeted drug delivery, said method com dropyridine forms with HPCD. The redox inclusion 35 prising complexing said reduced form with cyclodex complexes also provide a means for increasing the ratio trin selected from the group consisting of hydroxypro of initial brain to lung concentrations, thus leading to pyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl decreased toxicity, and in selected instances provide derivatives of ,B- and 'y-cyclodextrin. The present inven improved water solubility as well. Formulation of a tion still further provides a novel method for increasing particular redox system for estradiol “in a water-soluble 40 the ratio of brain to lung concentrations of drug at early B-hydroxycyclodextrin” is reported by Bodor and co time points resulting from administration of the re workers in Estes et al, “Use of a Chemical Redox Sys duced, biooxidizable, blood-brain penetrating lipoidal tem for Brain Enhanced Delivery of Estradiol De form of a dihydropyridine <—_> pyridinium salt redox creases Prostate Weight,” in Biological Approaches to the system for brain-targeted drug delivery, said method Controlled Delivery of Drugs, ed. R. L. Juliano, Annals comprising administering said reduced form as its inclu of the New York Academy of Sciences, Volume 507, sion complex with cyclodextrin selected from the group 1987, 334-336. consisting of hydroxypropyl, hydroxyethyl, glucosyl, Applicant’s parent US. patent application Ser. No. maltosyl and maltotriosyl derivatives of B- and 'y 07/174,945, filed Mar. 29, 1988, incorporated by refer cyclodextrin. ence herein, relates to a method for decreasing the inci 50 BRIEF DESCRIPTION OF THE DRAWINGS dence of precipitation of a lipophilic and/or water labile drug (i.e. a drug which is insoluble or only spar Other objects and advantages of the present invention ingly soluble in water and/or which is unstable in wa will be apparent from the following detailed description ter) occurring at or near the injection site and/or in the and accompanying drawings, in which: lungs or other organs following parenteral administra $5 FIG. 1 is a phase-solubility diagram illustrating the tion, said method comprising parenterally administering increase in solubility of an estradiol-CD5, l7B-[(l-meth said drug in an aqueous solution containing from about yl-l,4-dihydro-3-pyridinyl)carbonyloxy]estral,3,5 (l0) 20% to about 50% hydroxypropyl-B-cyclodextrin. trien-3-ol, hereafter referred to as EZ-CDS (Q), with increasing concentrations of hydroxypropyl-B SUMMARY AND OBJECTS OF THE cyclodextrin in water; INVENTION FIG. 2 is a graph comparing the brain concentrations One object of the present invention is to provide a of the quaternary cation, l7B-[(l-methyl-3-pyridinium) method for stabilizing the reduced, dihydropyridine carbonyloxy-lestra-l,3,5(l0)-trien-3-ol, hereafter re form of a dihydropyridine :1 pyridinium salt redox ferred to as EzQ'l', in % dose per gram of brain tissue, system for brain-targeted drug delivery. 65 following systemic administration to rats of either 15 Another object of the present invention is to provide mg/kg E2-CDS in dimethylsulfoxide (c) or 5 mg/kg a method for increasing the ratio of brain to lung con Ez-CDS in aqueous hydroxypropyl-B-cyc1odextrin centrations at early time points resulting from adminis (A), corrected for dose; 5,017,566 17 18 FIGS. 3aand 3b are a pair of semi-logarithmic plots, Pat. No. 4,727,079, issued Feb. 23, 1988; Bodor U.S. FIG. 3a comparing the concentrations of Ez-CDS in Pat. No. 4,824,850, issued Apr. 25, 1989; odor U.S. Pat. lung tissue in ug per gram dose following systemic No. 4,829,070, issued May 9, 1989; and related publica administration to rats of either 15 mg/kg EZ-CDS in tions. All of said patents and the international publica dimethylsulfoxide (O) or 5 mg/kg EZ-CDS inclusion tion are incorporated by reference herein in their en complex with hydroxypropyl-Bcyclodextrin (A) in tirety and relied upon. water, corrected for dose, and FIG. 3b comparing the The redox analog system provides for braintargeted lung concentrations of the quaternary cation, E2Q+ or drug delivery by means of new compounds containing a Quat, following the same E2—CDS administration; dihydropyridine .—_> pyridinium salt portion which, un FIG. 4 is a bar graph illustrating, at selected time like the redox carrier, is not readily metabolically cleav points, the concentrations of the quaternary cation, able from the original drug molecule. E2Q+ or Quat, in the brain in ng per gram dose, follow One redox analog approach, which provides deriva ing systemic administration to rats of either 15 mg/kg tives of centrally acting amines in which a primary, E1-CDS in dimethylsulfoxide (U) or 5 mg/kg Ez-CDS secondary or tertiary amine function has been replaced inclusion complex with hydroxypropyl-B-cyclodextrin 15 with a dihydropyridine 2 pyridinium salt redox system, (I) in water, corrected for dose; and is discussed hereinabove in the section entitled “BACK FIG. 5 is a plot of first-order rate constants as a func tion of ferricyanide ion concentration, illustrating the GROUND OF THE INVENTION”; historically, this effect of added hydroxypropyl-B-cyclodextrin (HPCD) analog system is the third type of redox system devel on the rate of E2-CDS oxidation. oped for delivering drugs to the brain. Various aspects of this analog system are described in detail in UNI DETAILED DESCRIPTION OF THE VERSITY 0F FLORIDA’s International Application INVENTION No. PCT/US85/00236, published under International The term “lipoidal” as used herein is intended to Publication No. W085/03937 on Sept. 12, 1985, incor designate a redox moiety which is lipid-soluble or lipo porated by reference herein in its entirety and relied philic. 25 upon. The terms “redox carrier system” and “redox analog Another redox analog approach provides novel system” are intended to designate two different ap amino acids and peptides containing them which com proaches to targeting drugs to the brain using a dihy prise a dihydropyridine :2 pyridinium salt portion, the dropyridine a? pyridinium salt system; compounds rep redox system being appended directly or via an alkylene resenting either of these approaches are contemplated bridge to the carbon atom adjacent to the carboxyl for complexation with cyclodextrin selected from the carbon. These amino acids and peptides are described in group consisting of hydroxypropyl, hydroxyethyl, detail in copending Bodor patent application Ser. No. glucosyl, maltosyl and maltotriosyl derivatives of B-and 07/035,648, ?led Apr. 7, 1987, incorporated by refer ence herein in its entirety and relied upon. Brie?y, the 'y-cyclodextrin (especially hydroxypropyl-B-cyclodex 35 trin) and use in accord with the present invention. novel redox amino acids in the reduced form have the The redox carrier system provides for brain-targeted structural formula drug delivery by means of carrier-drugs,which in their reduced form, which is the form intended for adminis tration, can be represented by the formula wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain bar rier penetrating, lipoidal form of a dihydropyridine 2 pyridinium salt redox carrier. In their oxidized form, which is the form “locked” in the brain from‘which the active drug is ultimately released, the carrier-drugs can wherein Z is either a direct bond or C1-C6 alkylene and be represented by the formula can be attached to the heterocyclic ring via a ring car bon atom or via the ring nitrogen atom; R1 is C1-C7 50 alkyl, C1-C7 haloalkyl or C7-C1; aralkyl when Z is attached to a ring carbon atom; R1 is a direct bond when wherein X- is the anion of a non-toxic pharmaceuti Z is attached to the ring nitrogen atom; R2 and R3, cally acceptable acid, [D] is a centrally acting drug which can be the same or different, are selected from species and [QC]+ is the hydrophilic, ionic pyridinium the group consisting of hydrogen, halo, cyano, C1-C7 salt form of a dihydropyridine :2 pyridinium salt redox 55 alkyl, C1-C7 alkoxy, C2-C3 alkoxycarbonyl, C2-C3 al carrier. The redox carrier approach is discussed herein kanoyloxy, C1-C7 haloalkyl, C1-C7 alkylthio, C1~C7 above in the section entitled “BACKGROUND OF alkylsulfmyl, C1»C7 alkylsulfonyl, —CH=NOR"' THE INVENTION”; historically, the carrier system is wherein R’” is hydrogen or C1-C7 alkyl, and the second type of redox system developed for deliver --CONR’R" wherein R’ and R", which can be the same ing drugs to the brain. 60 or different, are each hydrogen or C1-C7 alkyl; or one Various aspects of the redox carrier system have been of R2 and R3 together with the adjacent ring carbon described in detail in Bodor U.S. Pat. No. 4,479,932, atom forms a benzene ring fused to the heterocyclic issued Oct. 30, 1984; Bodor U.S. Pat. No. 4,540,564, ring, which benzene ring may optionally bear one or issued Sept. 10, 1985; Bodor et al U.S. Pat. No two substituents, which can be the same or different, 4,617,298, issued Oct. 14, 1986; UNIVERSITY OF 65 selected from the group consisting of hydroxy, pro FLORIDA’s International Application No. tected hydroxy, halo, cyano, C1-C7 alkyl, C1-C7 alk PCT/U 583/00725, published under International Publi oxy, C1-C3 alkoxycarbonyl, C2-C3 alkanoyloxy, C1-C7 cation No. W083/03968 on Nov. 24, 1983; Bodor U.S. haloalkyl, C1-C7 alkylthio, C1-C7 alkylsul?nyl, C1-C7 5,017,566 19 20 alkylsulfonyl, —CH=NOR"' wherein R’” is hydrogen of the drug/carrier system as described in the afore or C1—C7.alkyl, and —CONR'R" wherein R’ and R", noted documents. which can be the same or each hydrogen or C1-C7 The term “drug” as used herein means any substance alkyl; R4 is different, are each hydrogen or C1-C7 alkyl; intended for use in the diagnosis, cure, mitigation, treat R4 is hydrogen or a carboxyl protective group; R5 is ment or prevention of disease or in the enhancement of hydrogen or an amino protective group; and the dotted desirable physical or mental development and condi lines indicate that the compound contains a l,4-'or 1,6 tions in man or animal. dihydropyridine, a 1,4- or 1,2-dihydroquinoline, or a By “centrally acting” drug species, active agent or 1,2-dihydroisoquinoline ring system. compound as utilized herein, there is of course intended The new dihydropyridine amino acid analogs de any drug species or the like, a signi?cant (usually, prin picted above and the corresponding oxidized forms are cipal) pharmacological activity of which is CNS and a useful in the preparation of novel redox peptides of the result of direct action in the brain. partial formulas: Exemplary such centrally acting drug species are the CNS-amines and other nervous system agents, whether —HN-—CH-CO— (A) 15 sympathetic or parasympathetic, e. g., phenylethylamine (a stimulant), dopamine (a neurotransmitter and dopam l inergic agent used, e g., in the treatment of Parkinson R2 ism or hyperprolactinemia), tyramine (a stimulant), ' N-R, L-DOPA (a dopamine precursor used, for example, in 20 the treatment of Parkinsonism); muscle relaxants, tran quilizers and antidepressants, e. g., benzodiazepine tran (reduced form) quilizers such as diazepam and oxazepam and phenothi azine tranquilizers such as carphenazine, ?uphenazine and the like; mild and strong analgesics and narcotics; 25 sedatives and hypnotics; narcotic antagonists; vascular agents; stimulants; anesthetics; small peptides, such as the di-, tri-, tetra and pentapeptides, and other small 2-20 amino acid unit containing peptides, e g. the enke phalins (for example, Tyr-Gly-Gly-Phe-Leu), which, 30 besides being analgesics, initiate epileptic activity in the brain at doses that are about tenfold lower than for effecting analgesic activity; growth-promoting sub (oxidized form) stances; antiepileptic and anticonvulsant drugs gener ally, including hydantoins such as phenytoin and etho the new peptide analogs of partial structure (A) act as a delivery system for the corresponding quaternary salts toin, barbiturates such as phenobarbital; hormones, such of partial structure (B) in vivo; the quaternary deriva as the steroid hormones, e.g., estradiol, testosterone, l7 tives, which also are chemical intermediates to the dihy a-ethynyl testosterone (ethisterone), and the like (re dro compounds, are pharmacologically active or con cent studies on histological mapping of hormone-sensi vertible in vivo to pharmacologically active peptides, 40 tive and speci?c steroid binding cells in the brain have and are characterized by site-speci?c and sustained underscored the importance of the steroid action in the delivery to the brain when administered via the cone brain on sexual behavior); amphetamine-like drugs; sponding dihydropyridine form. Methods for the prepa anticancer and anti-Parkinsonism agents; anti-hyperten ration of these analog amino acids and peptides utilize sives, agents to enhance learning capacity and the mem methods known in the art for introduction of the dihy 45 ory processes, including treatment of dementias, such as dropyridine :2 pyridinium salt moiety or a precursor Alzheimer’s disease, such as 9-amino-l,2,3,4-tetrahy thereof, e.g. from the aforementioned International droacridine; antibacterials; centrally acting hypotensive Publications Nos. W083/03968 and W085/O3937, ap agents; centrally acting prostaglandins, such as PGDZ; propriately combined with well-known methods for diagnostic agents, such as radiopharmaceuticals; mono peptide synthesis. Ultimately, the quaternary forms of SO amine oxidase (MAO) inhibitor drugs; CNS or brain the amino acids and peptides are subjected to reduction important/essential amino acids, such as tryptophan to afford the corresponding dihydropyridines, accord (which is an antidepressant as well as a nutrient); and ing to the methods of the Bodor US. patents and above any like centrally acting compounds. For the purposes mentioned published PCT applications. of this invention, dopa or L-DOPA is not classi?ed as In a preferred aspect of the present invention, the an amino acid but rather as a CNS amine and dopamin redox system selected for complexation with a hydroxy ergic agent used, e.g. in the treatment of Parkinsonism. propyl, hydroxyethyl, glucosyl, maltosyl or maltotrio Other illustrative ultimate species of centrally acting syl derivative of B- or 'y-cyclodextrin and use in accord drug entities are: amphetamine, dextroamphetamine, With the present invention is a redox carrier system. levamphetamine, aletamine, cypenamine, fencamfamin, The drug and carrier portions of the redox carrier sys fenozolone, zylofuramine, methamphetamine, phenmet tem are described in more detail below and of course in razine and phentermine, which are sympathomimetic the various carrier patents and patent applications iden amines/cerebral stimulants and appetite suppressants; ti?ed above and incorporated by reference herein. Se etryptamine, a cerebral stimulant; codeine, oxycodone, lection of appropriate drugs and carrier moieties need pentazocine, anileridine, hydromorphone, morphine not be limited to speci?c drugs and speci?c carriers 65 and oxymorphone, which are narcotic analgesics; desi disclosed in the aforementioned patents and applica pramine, nortriptyline, octriptyline, maprotiline, opi tions or in the present application, just so long as the pramol and protriptyline, which are cerebral stimu selected drug and carrier meet the general requirements lants/tricylic antidepressants of the dibenzazepine type 5,017,566 21 22 used, e.g., in endogenous depressions; clonidine and are narcotic antagonists or agonist-antagonists; norges methyldopa, which are sympatholytic agents used, e.g., trel and norethindrone, progestins; cephalothin, cepha in hypertension; biperiden, cycrimine and procyclidine, lexin, cefazolin, cefoxitin, moxalactam, ceforanide, ce which are centrally acting anticholinergics; tranylcy froxadine and cephapirin, cephalosporin antibiotics; promine, a sympathomimetic cerebral stimulant/MAO atenolol, nadolol, timolol and metoprolol, B-blockers/ inhibitor and antidepressant; acetophenazine, carphena hypotensives; ACTH (corticotropin), a hormone which zine, ?uphenazine, perphenazine and piperacetazine, stimulates glucocorticoid production; LHRH, a neuro which are phenothiazine-type tranquilizers; benzocta transmitter which stimulates secretion of the pituitary mine, a sedative/muscle relaxant which structurally is hormones, LH and FSH, and has been used to induce an' analogue of the phenothiazine tranquilizers; chlordi ovulation as well as for fertility control/contraception; azepoxide, clorazepate, nitrazepam and temazepam, sulfadiazine and other sulfonamide antibiotics; ribavirin which are benzodiazepine-type tranquilizers; and acyclovir, antiviral agents; chlorambucil and mel noracymethadol, a narcotic analgesic of the methadone phalan, nitrogen mustard-type anticancer/antitumor type piminodine, a narcotic analgesic of the meperidine agents; methotrexate and aminopterin, which are folic type; tracazolate, a sedative/hypotensive; prizidilol, a acid antagonist-type anticancer/antitumor agents; plati centrally acting hypotensive; sulpiride, an antidepress num coordination complexes, i.e. cisplatin analogue ant/psychotropic; haloperidol and clopenthixol, which type anticancer/antitumor agents; dactinomycin and are tranquilizers; norepinephrine, a sympathetic stimu mitomycin C, used in cancer chemotherapy; thiogua lant/adrenergic agent; nalorphine and naloxone, nar nine, a purine/pyrimidine antagonist used in cancer cotic antagonists; hydralazine, a hypotensive; ethotoin, 20 treatment; vincristine and vinblastine, anticancer alka phenobarbital and aminoglutethimide, anticonvulsants; loids; hydroxyurea and DON, anticancer urea deriva epinephrine, an adrenergic agent; ethamivan, a medul tives; FSH, HCG and HCS, pituitary and non-pituitary lary stimulant; bemegride, a barbiturate antagonist; ami gonadotropins, used, for example, in certain reproduc phenazole, a stimulant; iopydol, iodopyracet, iodouppu tive disorders; N,N'-bis(dichloracetyl)-1,8-octame rate (o-iodohippuric acid), iodamide and iopanoic acid, 25 thylenediamine (fertilysin), an agent for male fertility which are radiodiagnostics; ephedrine, pseudoephed inhibition; levorphanol, a narcotic analgesic; benzestrol rine, oxymetazoline and phenylephrine, which are sym and diethylstilbestrol, synthetic estrogens; ethyl B-car pathomimetic amines and decongestants; estradiol, es boline-3-carboxylate, a benzodiazepine antagonist; furo trone and estriol, the natural estrogens; amoxicillin, semide, a diuretic/antihypertensive; dipyridamole and oxacillin, carbenicillin, benzylpenicillin, phenoxyme 30 nifedipine, coronary vasodilators; and progabide, a thylpenicillin, methicillin, nafcillin, ticarcillin, bacam GABA-agonist and prodrug of GABA. Yet other ulti picillin, epicillin, hetacillin, pivampacillin, the methox mate species include non-steroidal antiinflammatory ymethyl ester of hetacillin, and ampicillin, which are agents/non-narcotic analgesics, e.g. propionic acid de- _ penicillin-type antibiotics; amobarbital, a sedative; tri rivatives, acetic acid derivatives, fenamic acid deriva hexyphenidyl, a centrally acting anticholinergic; hy 35 tives and biphenylcarboxylic acid derivatives. Speci?c droxyzine, a tranquilizer; chlortetracycline, demeclocy NSAID’s/non-narcotic analgesics contemplated for use cline, minocycline, doxycycline, oxytetracycline, tetra herein include ibuprofen, naproxen, flurbiprofen, cycline and methacycline, which are tetracycline-type zomepirac, sulindac, indomethacin, fenbufen, feno antibiotics; ?urazepam, bromazepam, demoxepam and profen, indoproxen, ketoprofen, ?uprofen, bucloxic lorazepam, benzodiazepine tranquilizers; phenytoin, an acid, tolmetin, alclofenac, fenclozic acid, ibufenac, anticonvulsant; glutethimide, a mild hypnotic/ sedative; flufenisal, pirprofen, ?ufenamic acid, mefenamic acid, clindamycin, lincomycin, nalidixic acid, oxolinic acid clonixeril, clonixin, meclofenamic acid, flunixin, di and phenazopyridine, antibacterials/antibiotics; be clofenac, carprofen, etodolac, fendosal, prodolic acid, thanidine and guanethidine, hypotensives/sympatholyt sermetacin, indoxole, tetrydamine, di?unisal, naproxol, ics; captopril, a hypotensive; methyprylon, a mild hyp 45 piroxicam, metazamide, flutiazin and tesicam. notic; amedalin, bupropion, cartazolate, daledalin, di Preferred classes of centrally acting drugs for use ?uanine, ?uoxetine and nisoxetine, which are cerebral herein are the central neurotransmitters, steroids, anti stimulants: propranolol, a B-blocker antihypertensive; cancer and antitumor agents, antiviral agents, tranquil cloxacillin and dicloxacillin, penicillin-type antibacteri izers, memory enhancers, hypotensives, sedatives, anti als; butalbital, a barbiturate sedative; GABA, 'y-vinyl ‘psychotics and cerebral stimulants (especially tricyclic GABA, 'y-acetylenic GABA, neurotransmitters for antidepressants). Among the neurotransmitters, there possible use in epilepsy; valproic acid and its metabo can be mentioned amino acids, such as GABA, GABA lites such as 5-hydroxy-Z-n-propylpentanoic acid, 4 derivatives and other omega-amino acids, as well as hydroxy-Z-n-propylpentanoic acid, 3-hydroxy-2-n glycine, glutamic acid, tyrosine, aspartic acid and other propylpentanoic acid, for use as anticonvulsants; val 55 natural amino acids; catecholamines, such as dopamine, promide, a valproic acid derivative for use as an anti norepinephrine and epinephrine; serotonin, histamine convulsant; apomorphine, a narcotic depressant/emetic and tryptamine; and peptides such as neurotensin, lute which has been used in the treatment of photosensitive inizing hormonereleasing hormone (LHRH), somato epilepsy; pholcodine, a narcotic antitussive; methotrex statin, enkephalins such as met5-enkephalin and lens ate, mitoxantrone, podophyllotoxin derivatives (etop 60 enkephalin, endorphins such as 7-, a- and B-endorphins, side, teniposide), doxorubicin, daunamycin and cyclo- - oxytocin M and vasopressin. Synthetic and semi-syn phosphamide, anti-cancer/antitumor agents; methyl thetic analogues, e.g. analogues of LHRH in which one phenidate, a stimulant; thiopental, an anesthetic; ethinyl or more amino acid(s) has/have been eliminated and/or estradiol and mestranol, estrogens; meptazinol, cyclazo replaced with one or more different amino acid(s), and cine, phenazocine, profadol, metopon, drocode and 65 which may be agonists or antagonists, are also contem myfadol, which are narcotic analgesics; buprenorphine, plated, e.g. the primary and secondary amine LHRH nalbuphine, butorphanol, levallorphan, naltrexone, analogues disclosed in US. Pat. Nos. 4,377,574, nalmefene, alazocine, oxilorphan and nalmexone, which 3,917,825, 4,034,082 and 4,338,305. Among the steroids, 5,017,566 23 24 there can be mentioned anti-in?ammatory adrenal corti triazole(l,5-a)pyrimidine, zidovudine (AZT), dideox cal steroids such as hydrocortisone, betamethasone, ycytidine, dideoxyadenosine, dideoxyinosine and cortisone, dexamethasone', ?umethasone, ?upredniso DHPG. Among the tranquilizers, there can be men‘ lone, meprednisone, methyl prednisolone, prednisolone, tioned benzodiazepine tranquilizers, such as diazepam, prednisone, triamcinolone, cortodoxone, ?udrocorti oxazepam, lorazepam, chlordiazepoxide, ?urazepam, sone, ?urandrenolone acetonide (?urandrenolide), par bromazepam, chlorazepate, nitrazepam and temazepam; amethasone and the like; male sex hormones (andro hydantoin-type tranquilizers/anticonvulsants such as gens), such as testosterone and its close analogues, e g phenytoin, ethotoin, mephenytoin; phenothiazine-type methyl testosterone (l7-methyltestosterone); and fe tranquilizers such as acetophenazine, carphenazine, male sex hormones, both estrogens and progestins, e.g. ?uphenazine, perphenazine and piperacetazine; and progestins such as norgestrel, norethindrone, nore others. Among the hypotensives, there can be men thynodrel, ethisterone, dimethisterone, allylestrenol, tioned clonidine, methyldopa, bethanidine, debrisoquin, cingestol, ethynerone, lynestrenol, norgesterone, nor hydralazine, and guanethidine and its analogues. vinisterone, ethynodiol, oxogestone and tigestol, and Among the sedatives, tranquilizers and antipsychotics, estrogens such as ethinyl estradiol, mestranol, estradiol, 15 there can be mentioned the many speci?c compounds of estriol, estrone and quinestrol and the like Among the this type disclosed above, especially the phenothiazines anticancer and antitumor agents, there can be men and benzodiazepines and their analogues. Among the tioned Ara-AC, pentostatin (2’-deoxycoformycin), cerebral stimulants, there also can be mentioned the Ara-C (cytarabine), 3-deazaguanine, dihydro-S-azacyti many speci?c compounds set forth hereinabove, partic dine, tiazofurin, sangivamycin, Ara-A (vitarabine), 6 ularly the sympathomimetic amine-type cerebral stimu MMPR, PCNU, FENU, HENU and other ni lants and the tricyclic antidepressants, especially pre trosoureas, spiromustine, bisbenzimidazole, L-alanosine ferred tricyclics being the dibenzazepines and their (6-diazo-5-oxo-L-norleucine), DON, L-ICRF, tri analogues. methyl TMM, 5-methyl-tetrahydrohomofolic acid, gly Also illustrative of the centrally acting drug species oxylic acid sulfonylhydrazone, DACH, SR-2555, SR 25 2508, desmethylmisonidazole, mitoxantrone, menoga contemplated by this invention are centrally active rol, aclacinomycin A, phyllanthoside, bactobolin, metabolites of centrally acting drugs. Such metabolites aphidocolin, homoharringtonine, levonantradol, acivi are typi?ed by hydroxylated metabolites of tricyclic cin, streptozotocin, hydroxyurea, chlorambucil, cyclo antidepressants, such as the E- and Z-isomers of 10 phosphamide, uracil mustard, melphalan, S-FU (5 30 hydroxynortriptyline, 2-hydroxyimipramine, 2-hydrox ?uorouracil), S-FUDR (?oxun'dine), vincristine, vin ydesipramine and 8-hydroxychloripramine; hydroxyl blastine, cytosine arabinoside, 6-mercaptopurine, thio ated metabolites of phenothiazine tranquilizers, e.g. guanine, 5-azacytidine, methotrexate, adriamycin (dox 7-_hydroxychlorpromazine; and desmethyl metabolites orubicin), daunomycin (daunorubicin), largomycine of N-methyl benzodiazepine tranquilizers, e.g. desme polypeptide, aminopterin, dactinomycin, mitomycin C, 35 thyldiazepam. Other CNS active metabolites for use and podophyllotoxin derivatives, such as etoposide herein will be apparent to those skilled in the art, e.g. (VP-l6) and teniposide Among the antiviral agents, SL 75102, which is an active metabolite of progabide, a there can be mentioned ribavirin; acyclovir (ACV); GABA agonist, and hydroxy-CCNU, which is an active amantadine (also of possible value as an anti-Parkinso metabolite of CCNU, an anticancer nitrosourea Typi nism agent); diarylamidines such as 5-amidino-2-(5 cally, these CNS active metabolites have been identi?ed amidino-Z-benzofuranyDindole and 4’,6-diimidazolino as such in the scienti?c literature but have not been 2-phenylbenzo(b)thiophene; 2-aminooxazoles such as administered as drugs themselves In many cases, the Z-guanidino-4,5-di-n-propyloxazole and Z-guanidino active metabolites are believed to be comparable in 4,5-diphenyloxazole benzimidazole analogues such as CNS activity to their parent drugs; frequently; how the syn and anti isomers of 6[[(hydroxyimino)phenyl] 45 ever, the metabolites have not been administered per se methyl]-l-[(l-methylethyl)sulfonyl]-lH-benzimidazol because they are not themselves able to penetrate the Z-amine; bridgehead C-nucleosides such as 5,7-dimeth blood-brain barrier. yl-2-B-Dlribofuranosyl-s-triazole(l,5-a)pyrimidine; As indicated hereinabove, diagnostic agents, includ glycosides such as Z-deoxy-D-glucose, glucosamine, ing radiopharmaceuticals, are encompassed by the ex 2-deoxy-2-fluoro-D-mannose and 6-amino-6-deoxy-D 50 pression “centrally acting drug” or the like as used glucose; phenyl glucoside derivatives such as phenyl-6 herein. Any diagnostic agent which can be derivatized chloro-6-deoxy-B-D-glucopyranoside; (S)-9-(2,3-dihy to afford a redox carrier system which will penetrate droxypropyDadenine; tiazofurin; selenazofuri'n; 3 the BBB and concentrate in the brain in its quaternary deazauridine; 3-deazaguanosine; DHPG; 6-azauridine; form and can be detected therein is encompassed by this idoxuridine; trifluridine (tri?uorothymidine); BDVU 55 invention. The diagnostic may be “cold” and be de (bisdihydroxyvinyluridine); zidovudine (AZT); dideox tected by X-ray (e.g radiopaque agents) or other means ycytidine; and 5,6-dichloro-l-B-D-ribofuranosylben such as mass spectrophotometry, NMR or other nonin~ zimidazole. Among the anticancer/antitumor and anti vasive techniques (e.g. when the compound includes viral agents, those of the nucleoside type (i e a purine or stable isotopes such as C13, N15, 018, S33 and S34). pyrimidine base~type structure bearing a singly or mul 60 The diagnostic alternatively may be “hot”, i e radi tiply hydroxylated substituent) are of particular interest olabelled, such as with radioactive iodine (I 123, I 125, This group includes such compounds as Ara-AC, pen I 131) and detected/imaged by radiation detection/i tostatin, Ara-C, dihydro-S-azacytidine, tiazofurin, san maging means. Typical “cold” diagnostics for deriva givamycin, Ara-A, 6-MMPR, desmethylmisonidazole, tion herein include o-iodohippuric acid, iothalamic acid, S-FUDR, cytosine arabinoside, S-azacytidine, ribavirin, 65 iopydol, iodamide and iopanoic acid. Typical radi acyclovir, (S)-9-(2,3-dihydroxypropyl)adenine, 6 olabelled diagnostics include diohippuric acid (I 125, I azauridine, 5,6-dichloro-l-B-D-ribofuranosylben 131), diotyrosine (I 125, I 131), o-iodohippuric acid (I zimidazole, 5,7-dimethyl—2-B-D-ribofuranosyl-s- I 131), iothalamic acid (I 125, I 131), thyroxine (I 125, I 5,017,566 25 26 131), iotyrosine (I 131) and iodometaraminol (I 123), toxic salts of the reduced, dihydropyridine forms of the which has the structural formula redox carrier or redox analog systems, formed with nontoxic, pharmaceutically acceptable inorganic or r"; organic acids HX. For example, the salts include those HO derived from inorganic acids such as hydrochloric, (IIHCHNHZ hydrobromic, sulfuric, sulfamic, phosphoric, nitric and OH the like; and the salts prepared from organic acids such 1. as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydrox In the case of diagnostics, unlike the case of drugs ymaleic, phenylacetic, glutamic, benzoic, salicylic, sul which are for the treatment of disease, the “locked in” fanilic, fumaric, methanesulfonic, toluenesulfonic and quaternary form will be the form that is imaged or the like. The expression “anion of a non-toxic pharma otherwise detected, not the original diagnostic itself. ceutically acceptable acid” as used herein, e.g. in con Moreover, any of the centrally acting drugs which are 15 nection with the oxidized, pyridinium salt forms of the intended for the treatment or prevention of medical redox carrier or redox analog systems, is intended to disorders but which can be radiolabelled, e.g. with a include anions of such inorganic or organic acids HX. radioisotope such as iodine, or labelled with a stable In the discussion to follow, the expression “at least isotope, can thus be converted to a diagnostic for incor one reactive functional group selected from the group poration into the redox carrier system. 20 consisting of amino, hydroxyl, mercapto, carboxyl, It will be apparent from the known structures of the amide and imide” or portions of that expression are many drug species exempli?ed above, that in many used. The functional groups designated in that expres cases the selected drug will possess more than one reac tive functional group, and, in particular, that the drug sion have the following meanings: may contain hydroxyl or carboxyl or amino or other The word “amino” means a primary or secondary H functional groups in addition to the groups to which the 25 amino function, i e. —NHZ or —NHR. The secondary carrier will be linked, and that these additional groups amino function is also represented herein as —NH—, will at times bene?t from being protected during syn particularly since the exact identity of the R portion of thesis and/or during administration. The nature of such —NHR is immaterial, R being a part of the drug residue protection is described in more detail in the various D itself whichv is left unchanged by conversion of the patents and patent applications incorporated by refer 30 drug to the redox carrier system. ence herein. Obviously, such protected drug species are The word “hydroxyl” means an —OH function. encompassed by the de?nition of “drug” set forth here The word “carboxyl” means a —COOH function. inabove, The word “mercapto” means an —SH function. It too will be appreciated that by “dihydropyridine ' The word “amide” means a carbamoyl (—CONH2) carrier” or “[OHC]“, there is intended any nontoxic 35 or substituted carbamoyl (—CONHR) or a sulfamoyl carrier moiety comprising, containing or including the (—SO2NH2) or substituted sulfamoyl (—sOgNHR) dihydropyridine nucleus, whether or not a part of any functional group. The —CONHR and —SOZNI-IR larger basic nucleus, and whether substituted or unsub groups may also be represented herein as --CONH— stituted, the only criterion therefor being capacity for and —SO2NH—, respectively, since the identity of R is BBB penetration and in vivo oxidation thereof to the 40 immaterial, R being a part of the drug residue 0 itself corresponding quaternary pyridinium salt carrier which is left unchanged by conversion of the drug to [QC]+. As aforesaid, the ionic pyridinium salt drug/ carrier prodrug entity [D-QC]+ which results from the redox carrier system. such in vivo oxidation is prevented from efflux from the The word “imide” means a functional group having brain, while elimination from the general circulation is the structure accelerated. Subsequently, the covalent or equivalent bond coupling the drug species [D] to the quaternary carrier [QC]+ is metaboically cleaved, which results in sustained delivery of the drug [D] in the brain and facile elimination of the carrier moiety [QC]+. Such “cova 50 lent or equivalent bond” between the drug and the quaternary carrier can be a simple direct chemical bond, e.g., an amide, an ester, or any other like bond, or same can even be comprised of a linking group of function, e. g., a thiazolidine bridge or a peptide linkage, typically 55 that is, the structure which characterizes imides (i.e. necessitated when the drug species is not susceptible to compounds having a succinimide-type or phthalimide direct chemical coupling to either the dihydropyridine type structure). carrier or the quaternary carrier. Nonetheless, the bond Many different dihydropyridine :2 pyridinium salt in the formulae [D-QC]+ and [D-DHC] s intended to redox carrier moieties are illustrated in the carrier pa be, and is hereby de?ned as inclusive of al such alterna tents and applications incorporated by reference herein tives. And the cleavage of the [D-QC]+prodrug to ~ above. The following is a list of representative major sustainedly delivery the drug species [D] in the brain classes of dihydros and the corresponding quaternaries, with concomitant facile elimination of the carrier moi but is not meant to be exhaustive: ety [QC]"‘ is characteristically enzymatic cleavage, e.g., (1) For linkage to a drug having at least one hydroxyl by esterase, amidase, cholinesterase, hydrolytic en or mercapto or primary or secondary amino functional zyme, or peptidase. grouping, replacing a hydrogen atom from at least one The expression “non-toxic pharmaceutically accept— of said functional groupings with one of the following able salts” as used herein generally includes the non [DHC] groupings: