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United States Patent (19) 11 Patent Number: 5,955,459 Bradley Et Al

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United States Patent (19) 11 Patent Number: 5,955,459 Bradley Et Al USOO5955459A United States Patent (19) 11 Patent Number: 5,955,459 Bradley et al. (45) Date of Patent: Sep. 21, 1999 54 FATTY ACID-ANTIPSYCHOTIC 5,795,909 8/1998 Shashoua et al. ...................... 514/449 COMPOSITIONS AND USES THEREOF 5,827,819 10/1998 Yatvin et al. ............................... 514/2 75 Inventors: Matthews O. Bradley, Laytonsville, FOREIGN PATENT DOCUMENTS Md.; Victor E. Shashoua, Belmont, 0599 576 A1 1/1994 European Pat. Off.. Mass.; Charles S. Swindell, Merion; 693498 1/1996 European Pat. Off.. Nigel L. Webb, Bryn Mawr, both of Pa. 06 072868 3/1994 Japan. 6072868 3/1994 Japan. 73 Assignee: Neuromedica, Inc., Conshohocken, Pa. 81513347082146 6/19963/1996 Japan. 9030963 2/1997 Japan. 21 Appl. No.: 08/979,312 WO 98/17325 4/1998 WIPO. 22 Filed: Nov. 26, 1997 OTHER PUBLICATIONS (51) Int. Cl." ................................................... A61R 31/395 Schabitz, WR, et al., “The Effects of Prolonged Treatment 52 U.S. Cl. .......................... 514/220, 514/234, 514/255; With Citicoline in Temporary Experimental Focal 514/321 Ischemia", J NeurolSci, 1996, 138(1-2):21–25. (Abstract). 58 Field of Search ..................................... 514220, 234, D’Orlando KJ, et al., “Citicoline (CDP-Choline): Mecha 514/255,321 nisms of Action and Effects in Ischemic Brain Injury', s Neurol Res, 1995, 17(4): 281–284. Review. 56) References Cited Nishio K, et al., “Novel Water-Soluble Derivatives of Docosahexaenoic Acid Increase Diacyl-Glycerol Produc U.S. PATENT DOCUMENTS tion Mediated by Phosphatidylcholine-Specific Phospholi 3,539,573 11/1970 Schmutz et al. ........................ poss pase C", Proc Soc Exp Biol Med, 1993, 203(2): 200-208. 4,097,597 6/1978 Horrom et al. ... 514220 Marder, Stephen R., J. Clin. Psychiatry (suppl 3) 57:9-13 4,558,049 12/1985 Lazzari et al. .......................... 514/234 (1996). 4,692,441 9/1987 Alexander et al. ..................... 514/194 Copy of Office Action in related case U.S. Serial No. 4,939,174 7/1990 Shashoua ............. ... 514/549 08/978,541. 5,112,863 5/1992 Hashimoto et al. ... 514/534 5,214,062 5/1993 Mark et al. ....... 514,369 Primary Examiner James H. Reamer 5,223,263 6/1993 Hostetler et al. ....................... 424/450 Attorney, Agent, or Firm Wolf, Greenfield & Sacks, P.C. 5,308,832 5/1994 Garleb et al. ............................... 514/2 5,411,947 5/1995 Hostetler et al. ... 514/43 57 ABSTRACT 5,516,8005,466,841 11/19955/1996 Horrobin et....... al. ............................ 514/560554/79 The invention provides compositions that include conjuill 5.532,374 7/1996 Saii et all 544/368 gates of a fatty acid molecule, preferably cis 560419s 2/1997 also et al. .514.6 docosahexaenoic acid, and antipsychotic agents. The con 5604,216 2/1997 Horrobin ....... ... 514/182 jugates are usefull in treating psychotic conditions Such as 5,646,180 7/1997 Chaturvedi ... ... 514/471 Schizophrenia. 5,654,290 8/1997 Bayon et al. ............................. 514/77 5,750,572 5/1998 Bruzzese ................................. 514/560 32 Claims, 5 Drawing Sheets U.S. Patent Sep. 21, 1999 Sheet 1 of 5 5,955,459 HZ HN HN: H. ZZZZZZZZ o Ng - k 22 Ss N: h s 2 l N O N CO NO S. N s 2 2 r y C. o og N Co un Si n) () - C -- var O O O O O O O O O O Know Jo Ouoool U.S. Patent Sep. 21, 1999 Sheet 2 of 5 5,955,459 N ZZZZZZZZ N: ?o N\, \ 5 S : N 8. NZ 2 g : 3. NSZo W3S - KIA ow Jo Ouoool U.S. Patent Sep. 21, 1999 Sheet 3 of 5 5,955,459 NS Zi N: (Zii HNS sm HZZ d NigE N o 1 ZS O S. N: C HZS Ni H N 25 N2 c\! t d or ap N Co L S. no c. - C Y - - - O O o O O. O. O. O. O. O KA3W Jo OuJoool U.S. Patent Sep. 21, 1999 Sheet 4 of 5 5,955,459 O Nire N: N N O N k . s N:NO 9 N : o S top in C - Cd C) N 2 NE. U.S. Patent Sep. 21, 1999 Sheet 5 of 5 5,955,459 O Clozapine DHA-Clozapine O 5 O 15 2O 25 3O 35 Dose(umol/kg) Avg. 5 5,955,459 1 2 FATTY ACID-ANTIPSYCHOTC Seizure threshold and, in particular, agranulocytosis. The COMPOSITIONS AND USES THEREOF incidence of agranulocytosis in patients taking clozapine is about 1-2%. Agranulocytosis is a Serious condition charac RELATED APPLICATION terized by a precipitous drop in the white blood cell count; the seriousness of the condition mandates that white blood This application claims priority under 35 U.S.C. S 120 cell counts be measured each week for patients taking from U.S. patent application Ser. Nos. 08/651,428, and clozapine. Another patient compliance issue is the relatively 08/651,312, both filed May 22, 1996 the entire disclosures Short half life of clozapine in Vivo, which necessitates of which are incorporated herein 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 naturally-occurring, unbranched fatty acid that previously approximately 1 to 2% of all populations worldwide. 15 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. DHA is attached via the acid withdrawal, affect, and poverty of Speech). Abnormal activ group to hydrophilic drugs and renders these drugs more ity of the neurotransmitter dopamine is a hallmark of Schizo hydrophobic (lipophilic). DHA is an important constituent phrenia. Dopaminergic activity is reduced in the mesocor of the brain and recently has been approved as an additive tical System (resulting in negative symptoms) and is to infant formula. It is present in the milk of lactating enhanced in the mesolimbic System (resulting in positive or women. The mechanism of action by which DHA helps psychotic Symptoms). Several other neurotransmitters are drugs conjugated to it cross the blood brain barrier is involved, including Serotonin, glutamate, and GABA. 25 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, an antipsychotic, to dopamine receptors. The neuroleptics are effective for treat Stearic acid, palnitic acid, enanthic acid, undecylenic acid or ing the positive Symptoms of Schizophrenia, but have little 2,2-dimethyl-palmitic acid. Pipotiazine is a drug that acts or no effect on the negative Symptoms. The ability of these within the central nervous System. The purpose of conju drugs to antagonize dopamine receptors correlates with gating pipotiazine to the fatty acids was to create an oily antipsychotic efficacy. Neuroleptic drugs include phenothi Solution of the drug as a liquid implant for Slow release of azines including aliphatics (e.g., chlorpromazine), pip the drug when injected intramuscularly. The release of the eridines (e.g., thioridazine), and piperazines (e.g., drug appeared to depend on the particular fatty acid Selected, fluiphenazine); butyrophenones (e.g., haloperidol); thioxan 35 and the drug was tested for its activity in the central nervous thenes (e.g., flupenthixol); Oxoindoles (e.g., molindone); System. dibenzoxazepines (e.g., loxapine) and diphenylpiperidines Lipidic molecules, including the fatty acids, also have (e.g., pimozide). been conjugated with drugs to render the conjugates more Unfortunately, neuroleptics-resistant negative Symptoms lipophilic than the drug. In general, increased lipophilicity account for most of the Social and vocational disability 40 has been Suggested as a mechanism for enhancing intestinal caused by Schizophrenia. Further, neuroleptics cause uptake of drugs into the lymphatic System, thereby enhanc extrapyramidal Symptoms, including rigidity, tremor, ing the entry of the conjugate into the brain and also thereby bradykinesia (slow movement), and bradyphrenia (slow avoiding first-pass metabolism of the conjugate in the liver. thought), as well as tardive dyskinesias and dystonias. 45 The type of lipidic molecules employed have included The atypical antipsychotics are a different class of antip phospholipids, non-naturally occurring branched and Sychotic drugs which have a different receptor binding unbranched fatty acids, and naturally occurring branched profile and effectiveness against the Symptoms of Schizo and unbranched fatty acids ranging from as few as 4 carbon phrenia. Atypical antipsychotics bind central Serotonin2 atoms to more than 30 carbon atoms. In one instance, (5-HT2) receptors in addition to D2 dopamine receptors. enhanced receptor binding activity was observed (for an Unlike the neuroleptics, they improve negative as well as 50 adenosine receptor agonist), and it was postulated that the positive Symptoms. They cause minimal extrapyramidal pendant lipid molecule interacted with the phospholipid Symptoms and rarely cause tardive dyskinesias, akathisia, or membrane to act as a distal anchor for the receptor ligand in acute dystonic reactions. the membrane microenvironment of the receptor. This The first atypical antipsychotic drug approved for the 55 increase in potency, however, was not observed when the treatment of Schizophrenia was clozapine. Clozapine binds Same lipid derivatives of adenosine receptor antagonists D2 dopamine receptor weakly, but has a strong affinity for were used, and generalizations thus were not made possible the 5-HT2A receptor.
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