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(12) United States Patent (10) Patent No.: US 6,197,764 B1 Bradley Et Al

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(12) United States Patent (10) Patent No.: US 6,197,764 B1 Bradley Et Al USOO6197764B1 (12) United States Patent (10) Patent No.: US 6,197,764 B1 Bradley et al. (45) Date of Patent: *Mar. 6, 2001 (54) CLOZAPINE COMPOSITIONS AND USES FOREIGN PATENT DOCUMENTS THEREOF 0599 576A1 1/1994 (EP). (75) Inventors: Matthews O. Bradley, Laytonsville, 693498 1/1996 (EP). MD (US); Victor E. Shashoua, 61204136 11/1984 (JP). Belmont, MA (US); Charles S. 06-072868 3/1994 (JP). Swindell, Merion; Nigel L. Webb, 6072868 3/1994 (JP). Bryn Mawr, both of PA (US) 7082146 3/1996 (JP). 8151334 6/1996 (JP). (73) Assignee: Protarga, Inc., Conshohocken, PA (US) 9030963 2/1997 (JP). (*) Notice: Subject to any disclaimer, the term of this WO 89/07938 9/1989 (WO). patent is extended or adjusted under 35 WO 96/04001 2/1996 (WO). U.S.C. 154(b) by 0 days. WO 96/22303 7/1996 (WO). WO 96/27380 9/1996 (WO). This patent is Subject to a terminal dis WO98/17325 4/1998 (WO). claimer. OTHER PUBLICATIONS (21) Appl. No.: 08/978,541 (22) Filed: Nov. 26, 1997 Bourat, et al., "Long Chain Esters of Pipotiazine as Lon g-Acting Psychotropic Pro-Drug, Med. Chem. Proc. Int. (51) Int. Cl. .............................................. A61K 31/00 Symp. 5th (1976) pp. 105-114. (52) U.S. Cl. ........................... 514/218; 514/219; 514/220 Lohr, et al., “Neuroleptic-Induced Movement Disorders . (58) Field of Search ..................................... 514/218, 219, ..", Psychiatry, vol. 3, (1989). 514/220 Makino, et al., Chemical Abstracts, vol. 106, No. 12, (56) References Cited (90.177x) issued Mar. 23, 1987, “Pharmaceuticals Permeable to Blood-Brain Barrier'. U.S. PATENT DOCUMENTS 3,539,573 11/1970 Schmutz et al. ..................... 260/268 Marder, Stephen R., J. Clin. Psychiatry (Supp 3) 57: 9-13 4,097,597 * 6/1978 Horrom et al. ...................... 514/220 (1996). 4,346,085 8/1982 Growdon et al. .................... 424/199 4,351,831 9/1982 Growden et al. ... ... 424/199 Schabitz, WR, et al., “The Effects of Prolonged Treatment 4,558,049 12/1985 Bernardi et al. ... ... 514/234 with Citicoline in Temporary Experimental Focal Ischemia', 4,636,494 1/1987 Growden et al. ...................... 514/78 J Neurol Sci, 1996, 138(1-2): 21–25. (Abstract). 4,684,646 8/1987 Chang et al. ...... ... 514/221 4,692,441 9/1987 Alexander et al. ... 514/194 D’Orlando KJ, et al., “Citicoline (CDP-CHOLINE): 4,788,063 11/1988 Fisher et al. ....... ... 424/449 Mechanisms of Action and Effects in Ischemic Brain 4,933,324 6/1990 Shashoua ............................... 514/17 4,939,174 7/1990 Shashoua ....... ... 514/549 Injury”, Neurol Res, 1995, 17(4): 281–284. Review. 4,968,672 11/1990 Jacobson et al. ...................... 514/46 Nishio K, et al., “Novel Water-Soluble Derivatives of 5,112,863 5/1992 Hashimoto et al. .. ... 514/534 5,116,624 5/1992 Horrobin et al. ... ... 424/702 Docosahexaenoic Acid Increase Diacyl-Glycerol Produc 5,120,760 6/1992 Horrobin ........ ... 514/458 tion Mediated by Phosphatidylcholine-Specific Phospholi 5,214,062 5/1993 Mark et al. .... ... 514/369 pase C", Proc Soc Exp Biol Med, 1993, 203(2): 200–208. 5,223.263 6/1993 Hostetler et al. ... ... 424/450 5,284,876 2/1994 Shashoua ....... ... 514/549 5,308,832 5/1994 Garleb et al. ............................ 514/2 * cited by examiner 5,411947 5/1995 Hostetler et al. ... ... 514/43 5,466,841 11/1995 Horrobin et al. ...................... 554/79 5,516,800 5/1996 Horrobin .... ... 514/560 Primary Examiner Dwayne C. Jones 5,532,374 7/1996 Lee et al. ....... ... 546/167 ASSistant Examiner-C. Delacroix-Muirheid 5,604,198 2/1997 Poduslo et al. .......................... 514/6 (74) Attorney, Agent, or Firm Wolf, Greenfield & Sacks, 5,604,216 2/1997 Horrobin ........ ... 514/182 P.C. 5,646,180 7/1997 Chaturvedi ........................... 514/471 5,654,290 8/1997 Bayon et al. .......................... 514/77 (57) ABSTRACT 5,716,614 2/1998 Katz et al. ..... ... 424/94.3 5,750.572 5/1998 Bruzzese ........ ... 514/560 5,795,909 8/1998 Shashoula et al. ... 514/449 The invention provides compositions that include conju 5,827,819 10/1998 Yatvin et al. ............................ 514/2 gates of a fatty acid molecule, preferably cis 5,925,669 7/1999 Katz et al. ........................... 514/449 docosahexaenoic acid, and clozapine. The conjugates are 5,955.459 * 9/1999 Bradley et al. ... 514/220 useful in treating psychological disorderS Such as Schizo 5,977,174 11/1999 Bradley et al. ... 514/549 phrenia. 5,994,392 11/1999 Shashoua ....... ... 514/437 6,005,004 12/1999 Katz et al. ... 514/549 6,024,977 2/2000 Yatvin et al. ........................ 424/450 45 Claims, 5 Drawing Sheets U.S. Patent Mar. 6, 2001 Sheet 1 of 5 US 6,197,764 B1 HZNg ZdsRN H. ZZZZZZZZZZ N. - 2S N: 9 ho N s ZZZZZ (v : N K 2 M y O) S. no cy C . e O O. O. O. O. O. O. O d O Ali Aliovi Jo OuJooo U.S. Patent Mar. 6, 2001 Sheet 2 of 5 US 6,197,764 B1 O O ) 2 O S. N s re O s N 2 N ZZ O - NO n N N. N. N - - - O (P 9 e < 2. C () () ? s 2 NN Ns N 4. NN W NS4. W3S - KA:40w Jo OuJoool U.S. Patent Mar. 6, 2001 Sheet 3 of 5 US 6,197,764 B1 HN C o ap d HNS on -N. g NS i H * Z. & N ZZR N2 O CO. N. CO u?) St N) (N - O e e d d c. c. c. c. d d d d Know Jo OuJoool U.S. Patent Mar. 6, 2001 Sheet 4 of 5 US 6,197,764 B1 -NKZ H2 HN H2/ZZ N O up(s - B S Q 9 C) n 2 Q ns.- N & i U.S. Patent Mar. 6, 2001 Sheet 5 of 5 US 6,197,764 B1 O Clozopine DHA-Clozopine - - -- - - -- -- - - - r m - - - - - -- --- - - - - - -- - -- - - - -- -- --- -- --- - - - - road O 5 1O 15 2O 25 3O 35 Dose(umol/kg) Afg. 5 US 6,197,764 B1 1 2 CLOZAPINE COMPOSITIONS AND USES Sedation, orthoStatic hypotension, hypersalivation, lowered THEREOF Seizure threshold and, in particular, agranulocytosis. The incidence of agranulocytosis in patients taking clozapine is RELATED APPLICATIONS about 1-2%. Agranulocytosis is a Serious condition charac 5 terized by a precipitous drop in the white blood cell count; This application claims priority under 35 U.S.C. S 120 the seriousness of the condition mandates that white blood from U.S. patent application Ser. Nos. 08/651,428, and cell counts be measured each week for patients taking 08/651,312, now U.S. Pat. No. 5,795,909 both filed May 22, clozapine. Another patient compliance issue is the relatively 1996 the entire disclosures of which are incorporated herein Short half life of clozapine in Vivo, which necessitates by reference. multiple doses each day to maintain therapeutic effective BACKGROUND OF THE INVENTION CSS. Fatty acids previously have been conjugated with drugs to Psychotic conditions Such as Schizophrenia and related help the drugs as conjugates cross the blood brain barrier. disorders (e.g. Schizoaffective disorder), are complex and For example, DHA (docosahexaenoic acid) is a 22 carbon heterogeneous diseases of uncertain etiology that afflict 15 naturally-occurring, unbranched fatty acid that previously approximately 1 to 2% of all populations worldwide. has been shown to be unusually effective in crossing the Schizophrenia is characterized as having both “positive blood brain barrier. When DHA is conjugated to a drug, the Symptoms” (hallucinations, delusions, and conceptual entire drug-DHA conjugate is transported across the blood disorganization) and “negative Symptoms” (apathy, Social brain barrier and into the brain. withdrawal, affect, and poverty of Speech). Abnormal activ DHA is attached via the acid group to hydrophilic drugs ity of the neurotransmitter dopamine is a hallmark of Schizo and renders these drugs more hydrophobic (lipophilic). phrenia. Dopaminergic activity is reduced in the mesocor DHA is an important constituent of the brain and recently tical System (resulting in negative symptoms) and is has been approved as an additive to infant formula. It is enhanced in the mesolimbic System (resulting in positive or present in the milk of lactating women. The mechanism of psychotic Symptoms). Several other neurotransmitters are 25 action by which DHA helps drugs conjugated to it croSS the involved, including Serotonin, glutamate, and GABA. blood brain barrier is unknown. For many years, Schizophrenia was treated with classical Another example of the conjugation of fatty acids to a antipsychotic drugs, the neuroleptics, that block central drug is the attachment of pipotiazine to Stearic acid, palmitic dopamine receptors. The neuroleptics are effective for treat acid, enanthic acid, undecylenic acid or 2,2-dimethyl ing the positive Symptoms of Schizophrenia, but have little palmitic acid. Pipotiazine is a drug that acts within the or no effect on the negative Symptoms. The ability of these central nervous System. The purpose of conjugating pipo drugs to antagonize dopamine receptors correlates with tiazine to the fatty acids was to create an oily Solution of the antipsychotic efficacy. Neuroleptic drugs include phenothi drug as a liquid implant for slow release of the drug when azines including aliphatics (e.g., chlorpromazine), pip injected intramuscularly. The release of the drug appeared to eridines (e.g., thioridazine), and piperazines (e.g., 35 depend on the particular fatty acid Selected, and the drug was fluiphenazine); butyrophenones (e.g., haloperidol); thioxan tested for its activity in the central nervous System. thenes (e.g., flupenthixol); Oxoindoles (e.g., molindone); dibenzoxazepines (e.g., loxapine) and diphenylpiperidines Lipidic molecules, including the fatty acids, also have (e.g., pimozide).
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