USOO5994392A United States Patent (19) 11 Patent Number: 5,994,392 Shashoua (45) Date of Patent: Nov.30, 1999 54 ANTIPSYCHOTIC PRODRUGS COMPRISING 5,120,760 6/1992 Horrobin ................................. 514/458 AN ANTIPSYCHOTICAGENT COUPLED TO 5,141,958 8/1992 Crozier-Willi et al. ................ 514/558 AN UNSATURATED FATTY ACID 5,216,023 6/1993 Literati et al. .......................... 514/538 5,246,726 9/1993 Horrobin et al. ....................... 424/646 5,516,800 5/1996 Horrobin et al. ....................... 514/560 75 Inventor: Victor E. Shashoua, Brookline, Mass. 5,580,556 12/1996 Horrobin ................................ 424/85.4 73 Assignee: Neuromedica, Inc., Conshohocken, Pa. FOREIGN PATENT DOCUMENTS 30009 6/1981 European Pat. Off.. 21 Appl. No.: 08/462,820 009 1694 10/1983 European Pat. Off.. 22 Filed: Jun. 5, 1995 09 1694 10/1983 European Pat. Off.. 91694 10/1983 European Pat. Off.. Related U.S. Application Data 59-025327 2/1984 Japan. 1153629 6/1989 Japan. 63 Continuation of application No. 08/080,675, Jun. 21, 1993, 1203331 8/1989 Japan. abandoned, which is a continuation of application No. 07/952,191, Sep. 28, 1992, abandoned, which is a continu- (List continued on next page.) ation of application No. 07/577,329, Sep. 4, 1990, aban doned, which is a continuation-in-part of application No. OTHER PUBLICATIONS 07/535,812,tion of application Jun. 11, No. 1990, 67,375.734 abandoned, Eb3-1685, which is a continu-PEN. T. Higuchi et al. 66 Prodrugs as Noye Drug Delivery Sys 4,933,324, which is a continuation-in-part of application No. tems”, American Chem. Society, ACS Symposium Series, 07/160,667, Feb. 26, 1988, Pat. No. 4939,174. vol. 14, pp. 14–15 (1975). (51) Int. Cl." ..................................................... A61K 31/38 (List continued on next page.) 52 U.S. Cl. .......................... 514/437; 514/432; 514/546; 514/549, 514/552; 514/678; 514/688; 554/85; Primary Examiner-Gary Geist 554/101; 554/223; 554/224;554/229; 549/1; ASSistant Examiner Deborah D. Carr 549/23; 549/26; 568/303; 568/308; 568/335 Attorney, Agent, or Firm Wolf, Greenfield & Sacks, P.C. 58 Field of Search .............................. 554/78, 223, 224, 57 ABSTRACT 554/85, 101, 229; 564/204, 207; 560/144, 163; 514/2, 17, 284, 400, 415, 849, 627, The invention involves the formation of a prodrug from a 432, 437, 566,549, 554, 678, 688; 548/342, fatty acid carrier and a neuroactive drug. The prodrug is 504, 507; 568/303, 308,355; 549/1, 23, stable in the environment of both the stomach and the 26 bloodstream and may be delivered by ingestion. The prodrug passes readily through the blood brain barrier. Once in the 56) References Cited central nervous System, the prodrug is hydrolyzed into the fatty acid carrier and the drug to release the drug. In a U.S. PATENT DOCUMENTS preferred embodiment, the carrier is 4, 7, 10, 13, 16, 19 4,346,085 8/1982 Growdon et al..... ... 424/199 docosahexa-enoic acid and the drug is dopamine. Both are 4,351,831 9/1982 Growdon et al. ......................... 514/78 normal components of the central nervous System. The 4.550,109 10/1985 Folkers et al. ... ... 514/249 covalent bond between the drug and the carrier preferably is 4,554.272 11/1985 Bock et al. ...... ... 514/219 an amide bond, which bond may Survive the conditions in 2. 1. Ele al. ......................... s'. the Stomach. Thus, the prodrug may be ingested and will not 4,933,3242 - a? a 6/1990 Shashouaang et al................................... .... 514/17 be tly,teletely into the carrier molecule and drug 4,939,174 7/1990 Shashoua ......... s14540 molecule in Ine Slomacn. 4,968,672 11/1990 Jacobson et al. ......................... 514/46 5,116,624 5/1992 Horrobin ................................. 424/702 44 Claims, 2 Drawing Sheets A 5t A? J///WY 47 S 30 S &S 20 ar f (7 W A. A A5 ASA / / / 4) 5,994,392 Page 2 FOREIGN PATENT DOCUMENTS Oshima, M., et al., “Effects of Docosahexaenoic Acid 1287022 11/1989 Japan. (DHA) on Intestinal Polyp Development in APC Delta 716 6016548 1/1994 Japan. Knockout Mice', Carcinogenesis, (1995), 8027010 1/1996 Japan. 16(11):2605–2607. (Abstract). 8163991 6/1996 Japan. Deutsch, H.F., et al., “Cytotoxic Effects of Daunomycin 9025231 1/1997 Japan. -Fatty Acid Complexes on Rat Hepatoma', Cancer Res, 96.03433 10/1996 South Africa. (1983), 43(6):2668–2672. (Abstract). 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