Europaisches Patentamt European Patent Office 00 Publication number: 0 335 545 B1 Office europeen des brevets © EUROPEAN PATENT SPECIFICATION © Date of publication of patent specification: 09.06.93 © Int. CI.5: A61 K 9/08, A61 K 47/00 © Application number: 89302719.3 @ Date of filing: 20.03.89 Pharmaceutical formulations for parenteral use. © Priority: 29.03.88 US 174945 PATENT ABSTRACTS OF JAPAN, vol. 12, no. 19.12.88 EP 88312016 410 (C-540)[3257], 28th October 1988, page 10 C 540; & JP-A-631 46861 @ Date of publication of application: 04.10.89 Bulletin 89/40 © Proprietor: UNIVERSITY OF FLORIDA 223 Grinter Hall © Publication of the grant of the patent: Gainesville, Florida 32611 (US) 09.06.93 Bulletin 93/23 @ Inventor: Bodor, Nicholas S. © Designated Contracting States: 6219 Southwest 93rd Avenue AT BE CH DE ES FR GB GR IT LI LU NL SE Gainesville Florida 32608(US) © References cited: Representative: Pendlebury, Anthony et al PATENT ABSTRACTS OF JAPAN, vol. 8, no. PAGE, WHITE & FARRER 54 Doughty Street 56 (C-214)[1493], 14th March 1984, page 128 London WC1N 2LS (GB) C 214; & JP-A-58213712 PROCEEDINGS OF THE FOURTH INTERNA- TIONAL SYMPOSIUM ON CYCLODEXTRINS, Munich, 20th-22nd April 1988, pages 399-404, Kluwer Academic Publishers, Dordrecht, NL; M.E. BREWSTER et al.: "Water soluble com- plexes of a brain-targeted drug delivery sys- 00 tem" PATENT ABSTRACTS OF JAPAN, vol. 13, no. 11 (C-558)[3359], 11th January 1989, page 94 m C 558; & JP-A-63218663 00 Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition Q_ shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee LLI has been paid (Art. 99(1) European patent convention). Rank Xerox (UK) Business Services (3. 10/3.6/3.3. 1) EP 0 335 545 B1 Description FIELD OF THE INVENTION: 5 The present invention relates to aqueous parenteral solutions of drugs which are insoluble or only sparingly soluble in water and/or which are unstable in water, combined with selected cyclodextrins. The solutions provide a means for alleviating problems associated with drug precipitation at the injection site and/or in the lungs or other organs following parenteral administration. w BACKGROUND OF THE INVENTION: Cyclodextrins are cyclic oligosaccharides. The most common cyclodextrins are a-cyclodextrin, which is composed of a ring of six glucose residues, /3-cyclodextrin, which is composed of a ring of seven glucose residues, and 7-cyclodextrin, which is composed of a ring of eight glucose units. The inside cavity of a 15 cyclodextrin is lipophilic, while the outside of the cyclodextrin is hydrophilic; this combination of properties has led to widespread study of the natural cyclodextrins, particularly in connection with pharmaceuticals, and many inclusion complexes have been reported. ^-Cyclodextrin has been of special interest because of its cavity size, but its relatively low aqueous solubility has limited its use in the pharmaceutical field. Attempts to modify the properties of the natural cyclodextrins have resulted in the development of 20 heptakis (2,6-di-0-methyl)-j8-cyclodextrin, heptakis (2,3,6-tri-0-methyl)-j8-cyclodextrin, hydroxypropyl-/3- cyclodextrin, /3-cyclodextrin-epichlorohydrin polymer and others. For a comprehensive review of cyclodex- trins and their use in pharmaceutical research, see Pitha et al, in Controlled Drug Delivery, ed. S.D. Bruck, Vol. I, CRC Press, Boca Raton, Florida, pp. 125-148 (1983). For an even more recent overview, see Uekama et al, in CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 3 (1), 1-40 (1987); Uekama, in 25 Topics in Pharmaceutical Sciences 1987, eds. D. D. Breimer and P. Speiser, Elsevier Science Publishers B.V. (Biomedical Division), 1987, 181-194; and Pagington, Chemistry in Britain, May 1987, pp. 455-458. Inclusion complexes of a-, 0- or 7-cyclodextrin or their mixtures with a variety of drugs have been described by numerous parties and various advantages have been attributed to the complexes. These descriptions include the following: 30 35 40 45 50 55 EP 0 335 545 B1 U.S. ACTIVE INVENTOR PATENT NO. INGREDIENT USE ADVANTAGE Noda et al 4,024.223 menthol */or antiphlogistic, reduced unpleasant methyl analgesic odor. Increased salicylate wet packing effect Szejtll et al 4,228.160 Indoaethacln anti-inflam- reduced ulcerative matory, pro- effect tective during pregnancy 70 Hayashl et al 4,232.009 »-halo-PGI2 hypotensive, Increased stability analogs uterine con- traction stimulating, blood platelet aggregation 75 inhibiting Matsumoto et al 4,351,846 3-hydroxy- and uterine contrac- Increased stability 3-oxo- tion stimulating prostaglandln analogs 20 Yamahira et al 4,352,793 bencyclane anticonvulsant, Increased stability fumarate vasodllatlve at strong add pH, faster gastric emptying, higher blood concentrations, less Irritation, 25 improved hemolytic activity L1par1 4,383,992 steroids-- hormonal Improved Mater corticosteroids, solubility. Increased androgens, therapeutic response anabolic In eye 30 steroids, estrogens, progestagens Nlcolau 4,407,795 p-hexadecyl- ant 1 athero- enhanced amlnobenzolc sclerotic bioavailability 35 add sodium salt 40 45 50 55 EP 0 335 545 B1 V.S. ACTIVE INVENTOR PATENT NO. INGREDIENT USE ADVANTAGE Tuttle1 4.424,209 3,4-dHsobutyr- cardiac yloxy-N-[3-(4- contractility Isobutyryloxy- agent phenyl )-l- methyl -n- propy1]-B- 70 phenethyl amine Tuttle 4.425,336 3 ,4-d1 hydroxy- cardiac capable of oral N-[3-(4-hydroxy- contractility administration phenyl agent methyl -n- 75 propyl]-6- phenethyl amine Wagu et al 4,438,106 EPA and OHA deodorized, (fatty adds) storage stable 20 Masuda et al2 4,474,811 2-(2-fluoro-4- ant1- reduced eye blphenylyl )pro- Inflammatory Irritation, plonlc add ophthalmic higher concen- or salt tratlons, no side effects, highly soluble, long 25 stability, excellent pharmacological effects Shi noda et al 4,478,995 add addition anti-ulcer excellent water salt of (2'- solubility, good 30 benzyloxycar- absorption 1n diges- bonyl ) phenyl tive tract, good trans-4-guan1- anti-ulcer activity dlnomethylcyclo- hexanecarboxylate 35 Hayashl et al 4,479,944 PGI2 analog for treatment of stabilization against artereosclerosls, decomposition cardiac failure or thrombosis 40 45 50 55 EP 0 335 545 B1 U.S. ACTIVE INVENTOR PATENT NO. INGREDIENT USE ADVANTAGE HayasM et al 4,479,966 6.9-methano- for hypertension. Increased stability PGIj analogs cerebral throm- bosis and the like 70 Harada et al 4,497,803 lankaddln- antibiotic for enhanced water group antibiotic swine dysentery solubility and stability. Increased rate and amount of absorption 75 Hasuda 4,499,085 prostaglandin treating anoxia ana 1 og of brain cells SzejtH et al 4,518,588 phendlHne, I.e. coronary dilator Improved water solu- N-(l-phenyl- calcium blllty, accelerated 20 ethylethyl)-3,3- )-3,3- antagonist and Increased U± dlphenylpro-d1 phenyl pro- vivo resorption pyl amine or Its ToTssolutlon at pH/ hydrochloride temperature of gastric acid 25 Szejtll et al 4,524,068 plperonyl synerglzes easily handled butoxlde pestlcldal effect crystalline solid; of known Insectl- Improved water solu- ddes and fungi- blllty. Increased ddes absorption & velocity of penetration 30 through biological membranes Jones 4,555,504 a cardiac cardiac effect high aqueous solu- glycoside bility, apparently better bioavail- 35 ability Uekama et al3 4,565,807 plrprofen ant 1 -Inflam- improved stability matory , to oxidation, analgesic, freedom from bitter less Irrita- 40 antipyretic taste, ting 45 50 55 EP 0 335 545 B1 U.S. ACTIVE INVENTOR PATENT NO. INGREDIENT USE ADVANTAGE Ueda et al 4,575,548 2-n1troxymethyl- for vascular non-volatile powder 6-chloropyrldlne disorders vs. volatlve oil Ohwakl et al4 4,598,070 trlpamlde ant 1 -hyper- Improved solubility tensive 70 Ch1es1 et al 4,603,123 plroxlcam. I.e. ant1-1nfl am- 4-hydroxy-2- matory, analgesic 75 methyl -N-2- pyr1dyl-2H-l,2- benzoth1azine-3- carboxamlde-1 ,1- dioxlde 20 Hasegawa et al 4,608,366 mobenzoxamlne. antiemetic, storage stability, I.e. l-[2-(4- antispasmodic better absorption methoxybenzhy- through digestive dryloxyjethyl]- tract 4-[3-(4-f1uoro- benzoyl )propyl]- 25 piperazine H1ra1 et al2 4,659.696 polypeptide improving drug absorption by non- oral and non- Injection routes 30 SzejtH et al 4,623,641 PGI2 methyl anti-ulcer Improved storage ester stability Nlnger et al 4,663,316 unsaturated antibiotic, enhanced stability oxidation 35 phosphorus- antifungal , against containing antitumor antibiotics, Including phosphotrlenin 40 45 50 55 EP 0 335 545 B1 U.S. ACTIVE INVENTOR PATENT NO. INGREDIENT USE ADVANTAGE Fukazawa et at 4.675.395 hlnokltlol bactericidal. improved water bacteriostatic solubility, less odor 70 1 Tuttle also describes use of 2,6-d1-0-methyl-6-cyclodextrin and 2,3,6-tr1-0- methyl-a-cyclodextrin to form the Inclusion complex. 2 This may not be an Inclusion complex, but simply a physical mixture. 3 75 This is a mixture and/or an Inclusion compound. 4 The Inventors also mention prior known solubility improvements of cyclodextrin Inclusions of barbituric acid derivatives, mefenamlc acid, indomethacin and chloramphenicol . 5 The inventors refer to this as an "occlusion" compound. 20 Inclusion complexes of 2,6-di-O-methyl-^-cyclodextrin with dibenzo[bd]pyran derivatives and salts having analgesic, antemetic and narcosis-potentiating activities have been described in Ndgradi et al U.S. 25 Patent No. 4,599,327; increased water solubility and thus improved biological activity have been claimed for the complexes. A review of the pharmaceutical applications of such methylated cyclodextrins has been published by Uekama, Pharm. Int., March 1985, 61-65; see also Pitha, Journal of Inclusion Phenomena 2, 477-485 (1984).