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Ep 0335545 B2 Patentamt Europaisches ||| || 1 1| || ||| || || || || ||| || || 1 1| (19) J European Patent Office Office europeen des brevets (1 1 ) EP 0 335 545 B2 (12) NEW EUROPEAN PATENT SPECIFICATION (45) Date of publicationation and mention (51) |nt. CI.6: A61 K 9/08, A61 K 47/00 of the opposition decision: 23.09.1998 Bulletin 1998/39 (45) Mention of the grant of the patent: 09.06.1993 Bulletin 1993/23 (21) Application number: 89302719.3 (22) Date of filing: 20.03.1989 (54) Pharmaceutical formulations for parenteral use Pharmazeutische Zusammensetzungen fur die parenterale Anwendung Formulations pharmaceutiques pour I'usage parenteral (84) Designated Contracting States: (56) References cited: AT BE CH DE ES FR GB GR IT LI LU NL SE EP-A- 327 766 WO-A-85/02767 US-A- 139 755 US-A- 174 945 (30) Priority: 29.03.1988 US 174945 US-A- 4 727 064 19.12.1988 EP 88312016 • PATENT ABSTRACTS OF JAPAN, vol. 8, no. 56 (43) Date of publication of application: (C-214)[1493], 14th March 1984, page 128 C 214; 04.10.1989 Bulletin 1989/40 & JP-A-58213712 • PROCEEDINGS OF THE FOURTH (73) Proprietor: INTERNATIONAL SYMPOSIUM ON UNIVERSITY OF FLORIDA CYCLODEXTRINS, Munich, 20th-22nd April Gainesville, Florida 32611-2037 (US) 1988, pages 399-404, Kluwer Academic Publishers, Dordrecht, NL; M.E. BREWSTER et Inventor: Nicholas S. (72) Bodor, al.: "Water soluble complexes of a brain- Gainesville Florida 32608 (US) targeted drug delivery system" • PATENT ABSTRACTS OF JAPAN, vol. 13, no. 11 (74) Representative: (C-558)[3359], 1 1th January 1 989, 94 C 558; Pendlebury, Anthony et al page & JP-A-63218663 PAGE, WHITE & FARRER • PATENT ABSTRACTS OF JAPAN, vol. 1 2, no. 41 0 54 Doughty Street (C-540)[3257], 28th October 1 988, 1 0 C 540; London WC1N2LS(GB) page & JP-A-631 46861 • Inclusion complexes of poorly water-soluble drugs with glucosyl-cyclodextrins, Chem. Pharm. Bull., 35(8), 3413-3418 (1987) • Some properties of the inclusion behaviour of branched cyclodextrins, Chem. Pharm. Bull., 36(6), 2176-2185(1988) • Proceedings of the Fourth International Symposium on Cyclodextrins, Munich, Germany, 20-22 April 1988, pp. 399-404 CM • Declaration of Mr. Van Cauteren of 3.1 1 .95 CO together with Protocol of a non-clinical IO laboratory study (experiment 2688) of 28.1 - 30.4.1992 IO IO CO CO o Q_ LU Printed by Xerox (UK) Business Services 2.16.3/3.4 EP 0 335 545 B2 Description FIELD OF THE INVENTION: 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. 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, p-cyclodextrin, which is composed of a ring of seven glucose residues, and y-cyclo- dextrin, which is composed of a ring of eight glucose units. The inside cavity of a cyclodextrin is lipophilic, while the out- side 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, p- 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 heptakis (2,6-di- 0-methyl)-p-cyclodextrin, heptakis (2,3,6-tri-0-methyl)-p-cyclodextrin, hydroxypropyl-p-cyclodextrin, p-cyclodextrin- epichlorohydrin polymer and others. For a comprehensive review of cyclodextrins 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 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-, p- or y-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 fol- lowing: P 0 335 545 BZ u.s. active INVENTOR PATENT NO. INGREDIENT oat loda et al 4,024.223 Menthol I/or intlphloglstic, >educed unpleasant methyl inalgeslc idor. Increased salicylate «t packing effect izejtll et al 4,228.160 indomethadn inti-inTiam- ■educed ulcerative ■atory, pro- iffect tective during jregnancy layashl et al 4,232.009 »-»»alo-WI2 hypotensive, ncreaseo shpimij analogs jterlne con- traction stimulating, >lood platelet iggregatlon Inhibiting iatsumoto et al 4,351,846 3-hydroxy- and iteMne contrac- ncreaseo scaoi 1 i tjr 3-oxo- tion stimulating prostaglandln analogs ramahira et al 4,352,793 bencyclane inticonvuisani, 1 ncreaseo simnuj fumarate rasodllatlve at strong add pH, faster gastric emptying, higher blood concentrations, less irritation. Improved hemolytic activity .1par1 4,383.992 steroids— i lormonai Improved water corticosteroids, solubility. Increased androgens, therapeutic response anabolic 1n eye steroids, estrogens , progestagens Hcolau 4,407,795 p-hexadecyl - antiatnero-i ennanicu amlnobenzolc scl< erotic bioavailability add sodium salt EP 0 335 545 B2 ACTIVE INVENTOR MiUl NO. INGREDIENT USE ADVANTAGE Tuttle1 4.424,209 3,4-dilsobutyr- cardiac yloxy-N-[3-(4- contractility Isobutyryloxy- agent phenyl )-l- methyl-n- propyl]-B- phenethyl amine Tuttle 4,425,336 3,4-dihydroxy- cardiac capable of oral N-[3-(4-hydroxy- contractility administration phenyl)-l- agent methyl-n- propyl]-e- phenethyl amine Wagu et al 4.438,106 EPA and OHA deodorized, (fatty acids) storage stable Masuda et al2 4.474,811 2-(2-fluoro-4- anti- reduced eye blphenylyl ) pro- inflammatory irritation, pionic add ophthalmic higher concen- or salt trations, no side effects, highly soluble, long stability, excellent pharmacological effects Shlnoda et al 4,478,995 acid addition ant1 -ulcer excellent water salt of (2'- solubility, good benryloxycar- absorption 1n diges-dlges- bonyl)phenyl tivetlve tract, good trans-4-guanl- ant 1 -ulcer activity dlnomethylcyclo- hexanecarboxyl ate Hayashl et al 4,479,944 P6I2 analog for treatment of stabilization against arteriosclerosis, decomposition cardiac failure or thrombosis EP 0 335 545 B2 U.S. ACTIVE INVENTOR PATENT NO. INGREDIENT USE ADVANTAGE layashl et al 4.479.966 6.9-methano- for hypertension. Increased stability PGI2 analogs :erebral throa- >os1s and the like Harada et al 4,497,803 lankacidin- antlblotlc for enhanced water group antibiotic swine dysentery solubility and stability. Increased rate and amount of absorption Hasuda 4,499,085 prostaglandin treating anoxia analog of brain cells Szejtll et al 4,518.588 phendlHne, I.e. coronary dilator Improved water solu- N-(l-phenyl- calcium bility, accelerated ethyl )-3,3- antagonist and Increased In dl phenyl pro- vivo resorption pyl amine or Its ToTssolutlon at pH/ hydrochloride temperature of gastric acid Szejtll et al 4,524.068 plperonyl synerglzes easily handled butoxlde pestlcidal effect crystalline solid; of known Insect 1- Improved water solu- cides and fungi- bllity. Increased ddes absorption • velocity of penetration through biological membranes Jones 4.555.504 a cardiac cardiac effect high aqueous solu- glycoside bility, apparently better bioavail- ability Uekama et al3 4.565.807 pirprofen ant 1 -Inflam- Improved stability matory, to oxidation, analgesic, freedom from bitter antipyretic taste, less Irrita- ting EP 0 335 545 B2 U.S. ACTIVE INVENTOR PATENT NO. INGREDIENT USE ADVANTAGE Ueda et al 4.575,548 2-nltroxyi2-n1troxymethy1- for vascular non-volatile powder 6-chlorop;6-chloropyr1d1nc disorders vs. volatlve oil Ohwakl et al4 4,598.070 trtpMlde ant 1 -hyper- lap roved solubility tensive Chiesi et al 4.603,123 plroxlcam. I.e. ant 1-1 nf law- 4-hydroxy-2- mat ory, analgesic methyl -H-2- pyridy1-2H-l,2- benzothiazine-3- carboxamlde-1 ,1- dioxlde Hasegawa et al 4,608,366 mobenzoxamine. antiemetic, storage stability, I.e. l-[2-(4- antispasmodic better absorption methoxybenzhy- through digestive dry1oxy)ethyl]- tract 4-[3-(4-f1uoro- benzoyl ) propyl ]- piperazine Hlral et al£ 4,659,696 polypeptide improving drug absorption by non- oral and non- Injection routes Szejtll et al 4,623,641 PGI2 « sthyl ant 1 -ulcer improved storage ester stability Mnger et al 4,663,316 unsaturated antibiotic, enhanced stability phosphorus- antifungal , against oxidation containing antitumor antibiotics. Including phosphotrlenln EP 0 335 545 B2 U.S. ACTIVE INVENTOR PATENT NO. INGREDIENT USE ADVANTAGE water Fukazawa et el 4 ,675,395 hlnokltlol bactericidal , improved bacteriostatic solubility, less odor 1 Tuttle also describes use of 2.6-d1-0-methyl-«-cyclodextr1n and 2,3,6-tr1-0- •ethyl-a-cyclodextrln to form the Inclusion complex. 2 This may not be an Inclusion complex, but simply a physical mixture. 15 , J 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, indomethadn and chloramphenicol . 20 5 The Inventors refer to this as an "occlusion" compound. Inclusion complexes of 2,6-di-O-methyl-p-cyclodextrin with dibenzo[bd]pyran derivatives and salts having analge- 25 sic, antemetic and narcosis-potentiating activities have been described in Nogradi et al U.S. Patent No. 4,599,327; increased water solubility and thus improved biological activity have been claimed for the complexes.
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