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Title:
HIGHLY PURIFIED ETHYL EPA AND OTHER EPA DERIVATIVES FOR PSYCHIATRIC AND NEUROLOGICAL DISORDERS
Document Type and Number:
WIPO Patent Application WO/2000/044361
Kind Code:
A2
Abstract:
A pharmaceutical preparation comprising EPA in an appropriately assimilable form, for example in the form of the ehtyl ester, where of all the fatty acids present in the preparation at least 90 %, and preferably at least 95 %, is in the form of EPA and where less than 5 %, and preferably less than 3 %, is in the form of DHA is provided for the treatment of a psychiatric or central nervous disorder. The preparation may be administered with conventional drugs to treat psychiatric or central nervous disorders, like schizophrenia, bipolar disorders, attention deficit, hyperactivity disorder, dementia, panic and anxiety disorders.

Inventors:
PEET MALCOLM (GB)
VADDADI KRISHNARAO SITAMRAO (AU)
Application Number:
PCT/GB2000/000164
Publication Date:
August 03, 2000
Filing Date:
January 21, 2000
Export Citation:
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Assignee:
LAXDALE LIMITED (GB)
PEET MALCOLM (GB)
VADDADI KRISHNARAO SITAMRAO (AU)
International Classes:
A61K31/00; A61K31/351; A61K31/20; A61K31/202; A61K31/38; A61K31/40; A61K31/4439; A61K31/445; A61K31/4515; A61K31/495; A61K31/4965; A61K31/505; A61K31/519; A61K31/54; A61K31/5415; A61K31/55; A61K31/551; A61K31/5513; A61P9/10; A61P21/00; A61P25/00; A61P25/08; A61P25/16; A61P25/18; A61P25/20; A61P25/22; A61P25/24; A61P25/28; A61P29/00; A61P43/00; (IPC1-7): A61K31/00
Domestic Patent References:
WO1998016216A11998-04-23
WO1997039759A21997-10-30
WO1999029316A11999-06-17
Foreign References:
JPH04182426A1992-06-30
EP0606012A11994-07-13
US5589508A1996-12-31
EP0406917A11991-01-09
EP0610506A11994-08-17
GB2229363A1990-09-26
Other References:
SHAH S ET AL: "EICOSAPENTAENOIC ACID (EPA) AS AN ADJUNCT IN THE TREATMENT OF SCHIZOPHRENIA" SCHIZOPHRENIA RESEARCH,XX,XX, vol. 29, no. 1/02, January 1998 (1998-01), page 158 XP000921338
YOSHIMURA, TOSHIHIRO ET AL: "Effects of highly purified eicosapentaenoic acid on plasma beta thromboglobulin level and vascular reactivity to angiotensin II" ARTERY (FULTON, MICH.) (1987), 14(5), 295-303 , XP000949940
YAMAZAKI, KATSUYA ET AL: "Changes in fatty acid composition in rat blood and organs after infusion of eicosapentaenoic acid ethyl ester" BIOCHIM. BIOPHYS. ACTA (1992), 1128(1), 35-43 , XP000949431
URAKAZE, MASAHARU ET AL: "Infusion of emulsified trieicosapentaenoylglycerol into rabbits. The effects on platelet aggregation, polymorphonuclear leukocyte adhesion, and fatty acid composition in plasma and platelet phospholipids" THROMB. RES. (1986), 44(5), 673-82 , XP000949433
BLACK, K. L. ET AL: "Effect of intravenous eicosapentaenoic acid on cerebral blood flow, edema and brain prostaglandins in ischemic gerbils" PROSTAGLANDINS (1984), 28(4), 545-56 , XP000946383
SATO M ET AL: "GENERAL PHARMACOLOGICAL STUDIES ON 5 8 11 14 17 EICOSAPENTAENOIC ACID ETHYL ESTER EPA-E." FOLIA PHARMACOL JPN, (1989) 94 (1), 35-48. , XP000949423
MADHAVI N ET AL: "Effect of n-6 and n-3 fatty acids on the survival of vincristine sensitive and resistant human cervical carcinoma cells in vitro." CANCER LETTERS, vol. 84, no. 1, 1994, pages 31-41, XP000949427 ISSN: 0304-3835 cited in the application
WATANABE, IKUYOSHI ET AL: "Usefulness of EPA-E (eicosapentaenoic acid ethyl ester) in preventing neointimal formation after vascular injury" KOKYU TO JUNKAN (1994), 42(7), 673-7 , XP000949430
Attorney, Agent or Firm:
Wakerley, Helen Rachael (16 Theobalds Road, London WC1X 9PL, GB)
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Claims:
CLAIMS
1. A pharmaceutical preparation comprising EPA in an appropriately assimilable form where of all the fatty acids present in the preparation at least 90%, and preferably at least 95%, is in the form of EPA, and where less than 5%, and preferably less than 3%, is in the form of docosahexaenoic acid (DHA).
2. A pharmaceutical preparation according to claim 1 characterised in that among the other fatty acids present there are less than 5%, and preferably less than 3%, of each of AA or DPAn3, individually.
3. A pharmaceutical preparation according to claim 1 or 2 in which the aggregate DHA, AA and/or DPAn3 content is less than 10%, of the total fatty acids present and preferably less than 5%.
4. A pharmaceutical preparation according to any preceding claim in which the EPA is in the form of ethylEPA, lithium EPA, mono, dior triglyceride EPA or any other ester or salt of EPA, or the free acid form of EPA, or other appropriate bioavailable derivative which raises EPA levels within the body.
5. A pharmaceutical preparation according to any preceding claim in which the EPA is in the form of a 2substituted derivative or other derivative which reduces the rate of oxidation without impairing its biological activity.
6. A pharmaceutical preparation according to any preceding claim for the treatment or prevention of a psychiatric or central nervous system disorder.
7. A pharmaceutical preparation according to claim 6 in which the disorder is schizophrenia, schizoaffective disorder or a schizotypal disorder.
8. A pharmaceutical preparation according to claim 6 in which the disorder is depression or manicdepression (bipolar disorder).
9. A pharmaceutical preparation according to claim 6 in which the disorder is anxiety or panic disorder or social phobia, or a sleep disorder or an attention deficit, conduct, hyperactivity or personality disorder.
10. A pharmaceutical preparation according to claim 6 in which the disorder is Alzheimer's disease or another dementia, including multiinfarct dementia, Lewy body disease and diseases attributable to prion disorders.
11. A pharmaceutical preparation according to claim 6 in which the disorder is Parkinson's disease, or other motor system disorder.
12. A pharmaceutical preparation according to claim 6 in which the disorder is multiple sclerosis.
13. A pharmaceutical preparation according to claim 6 in which the disorder is stroke, or the poststroke syndrome, or head injury or a posthead injury syndrome.
14. A pharmaceutical preparation according to claim 6 in which the disorder is epilepsy.
15. A pharmaceutical preparation according to claim 6 in which the disorder is Huntington's disease or any other neurodegenerative disorder, in particular any disorder due to trinucleotide repeats, including Friedreich's ataxia, myotonic dystrophy and fragile X syndrome.
16. Formulations for use in psychiatric and neurological disorders in which a drug which acts primarily on neurotransmitter metabolism or receptors is prepared for co administration with a pharmaceutical preparation according to any of claims 15.
17. A pharmaceutical formulation comprising a preparation according to any of claims 1 to 5 together with a drug which acts primarily on neurotransmitter metabolism or receptors.
18. A formulation according to claim 16 or 17 in which the drug is clozapine.
19. A formulation according to claim 16 or 17 in which the drug is any one of the class of typical or atypical neuroleptics, including chlorpromazine, haloperidol, risperidone, olanzapine, sertindole, ziprasidone, zotepine or amisulpiride.
20. A pharmaceutical preparation according to any of claims 1 to 5 for the treatment of inflammatory disorders of the joints, respiratory system, gastrointestinal system, kidneys, skins, reproductive system and all other organs.
21. Method of treatment of psychiatric and neurological disorders in which a drug which acts primarily on neurotransmitter metabolism or receptors is used in conjunction with a pharmaceutical preparation according to any of claims 15.
22. A method of treatment according to claim 21 in which the disorder to be treated is schizophrenia, schizoaffective disorder or a schizotypal disorder.
23. A method of treatment according to claim 21 in which the disorder to be treated is depression or bipolar disorder.
24. A method of treatment according to claim 21 in which the disorder to be treated is any other psychiatric disorder including sleep disorders, anxiety disorders, panic disorders, social phobias, conduct disorders, personality disorders and attentional and hyperactivity disorders.
25. A method of treatment according to claim 21 in which the disorder to be treated is any form of dementia, including Alzheimer's disease, Lewy body disease, vascular dementia and other dementias.
26. A method of treatment according to claim 21 in which the disorder to be treated is any form of neurological disease, including Parkinson's disease, Huntington's disease, multiple sclerosis, stroke, epilepsy and other disorders.
27. A method of treating or preventing the side effects of a drug used in treating psychiatric or neurological disorders by administration of the drug and a pharmaceutical preparation according to any one of claims 1 to 5.
Description:
INTERNATIONALSEARCHREPORT Ins stional AppileatonNo PCT/GB00/00164 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT Category Citationofdocument,withindication,whereappropriate,oftherele vantpassagesRelevanttoclaimNo. XYOSHIMURA,TOSHIHIROETAL:"Effectsof1-4, highlypurifiedeicosapentaenoicacidon6-16,20, plasmabetathromboglobulinleveland26 vascularreactivitytoangiotensinII" ARTERY(FULTON,MICH.)(1987),14(5), 295-303, XP000949940 abstract XYAMAZAKI,KATSUYAETAL:"Changesin1-4, fattyacidcompositioninratbloodand6-16,20, organsafterinfusionofeicosapentaenoic26 acidethylester" BIOCHIM.BIOPHYS.ACTA(1992),1128(1), 35-43, XP000949431 abstract page35,column1,paragraph1-page36, column1,paragraph3 XJP04182426A(MOCHIDAPHARMACEUTCOLTD)1-4, 30June1992(1992-06-30)6-16,20, 21,25-27 abstract XURAKAZE,MASAHARUETAL:"Infusionof1-4, emulsifiedtrieicosapentaenoylglycerol6-16,20, intorabbits.Theeffectsonplatelet26 aggregation,polymorphonuclearleukocyte adhesion,andfattyacidcompositionin plasmaandplateletphospholipids" THROMB.RES.(1986),44(5),673-82, XP000949433 abstract page674,paragraphs1-3;table1 XEP0606012A(SCOTIAHOLDINGSPLC)1-4, 13July1994(1994-07-13)6-16, 20-26 page4,line54-page5,line13;example 3 page8,line2;claims1-11 XWO9739759A(SEVERUSWOLFRAME;BRIGHAM1-4, &WOMENSHOSPITAL(US);STOLLANDREWL)6-16,21, 30October1997(1997-10-30)23,27 abstract page4,line15-21;claims1-4,12,15,24 XUS5589508A(SCHLOTZEREWALDETAL)1-4, 31December1996(1996-12-31)6-16,20 abstract 2 2 INTERNATIONALSEARCHREPORT In,jtional ApplicatlonNo PCT/GB00/00164 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT Category Citationofdocument,withindication,whereappropriate,oftherele vantpassagesRelevanttoclaimNo. XEP0406917A(TEKTRONIXINC)1-4, 9January1991(1991-01-09)6-16,20 abstract page1,line1-7;tables1,2 page7,line45-page8,line4 XBLACK,K.L.ETAL:"Effectof1-4,- intravenouseicosapentaenoicacidon6-16,20, cerebralbloodflow,edemaandbrain26 prostaglandinsinischemicgerbils" PROSTAGLANDINS(1984),28(4),545-56, XP000946383 abstract XSATOMETAL:"GENERALPHARMACOLOGICAL1-4, STUDIESON58111417EICOSAPENTAENOIC6-16,20, ACIDETHYLESTEREPA-E."26 FOLIAPHARMACOLJPN,(1989)94(1),35-48. , XP000949423 abstract XMADHAVINETAL:"Effectofn-6andn-31-4, fattyacidsonthesurvivalofvincristine6-17,19 sensitiveandresistanthumancervical carcinomacellsinvitro." CANCERLETTERS, vol.84,no.1,1994,pages31-41, XP000949427 ISSN:0304-3835 citedintheapplication abstract XWATANABE,IKUYOSHIETAL:"Usefulnessof1-4, EPA-E(eicosapentaenoicacidethylester)6-16,20, inpreventingneointimalformationafter26 vascularinjury" KOKYUTOJUNKAN(1994),42(7),673-7, XP000949430 abstract XEP0610506A(NIPPONSUISANKAISHALTD)1-4, 17August1994(1994-08-17)6-16,20 abstract page3,paragraph1 XGB2229363A(BECKSUSANANNE;CANCER1-4, RESCAMPAIGNTECH(GB);TISDALEMICHAEL6-16,20 JO)26September1990(1990-09-26) abstract page4,line18-26 2 INTERNATIONALSEARCHREPORT ImInx jtional ApplicatlonNo PCT/GB00/00164 C.(Continuation) DOCUMENTS CONSIDEREDTOBERELEVANT Category o Citationofdocument,withindication,whereappropnate,oftherelev antpassagesRelevanttoclaimNo. P,XWO9929316A(MISHRAAWADHESHK; MOUSSA 16,17,19 ISKANDAR(CA);CLARKENUALAM(IE);CYCL) 17June1999(1999-06-17) claims1,7,14,22,26,27 2 FURTHER INFORMATION CONTINUED FROM PCT/ISA/210 Continuation of Box 1.2 Claims Nos.: 5 Present claims 1-4,6-27 relate to a large number of possible preparations/therapeutic applications, that a lack of clarity (and/or conciseness) within the meaning of Article 6 PCT arises to such an extent as to render a meaningful search of the claims impossible.

Present claims 1-4,6-27 relate to a preparations/therapeutic applications defined (inter alia) by reference to the following parameter (s): P1: appropriately assimilable form of EPA.

P2: appropriate bioavailable derivative which raises EPA levels within the body.

The use of these parameters in the present context is considered to lead to a lack of clarity within the meaning of Article 6 PCT. It is impossible to compare the parameters the applicant has chosen to employ with what is set out in the prior art. The lack of clarity is such as to render a meaningful complete search impossible.

Consequently, the search has been restricted to the compound for which pharmacological data were provided (ethyl-EPA, EPA) in relation to the therapeutic applications which are supported by the pharmacological data: schizophrenia, bipolar disorders, attention deficit hyperactivity disorder, panic and anxiety disorders and Huntington's disease.

The search also covers pharmaceutical preparations containing EPA or ethyl-EPA in combination with the compounds specifically mentioned in claims 18,19.

Claim 5 was not searched because no support can be found in the description for the term EPA in the form of a 2-substituted derivative or other derivative which reduces the rate of oxidation without impairing its biological activity.

The applicant's attention is drawn to the fact that claims, or parts of claims, relating to inventions in respect of which no international search report has been established need not be the subject of an international preliminary examination (Rule 66.1 (e) PCT). The applicant is advised that the EPO policy when acting as an International Preliminary Examining Authority is normally not to carry out a preliminary examination on matter which has not been searched. This is the case irrespective of whether or not the claims are amended following receipt of the search report or during any Chapter II procedure. INTERNATIONALSEARCHREPORT IntItional AppilcatlonNo Information on patent family members PCT/GB 00/00164 PatentdocumentPublication Patent family Publication citedinsearchreportdate member (s) date WO9816216A23-04-1998AU 4566797 A 11-05-1998 BR 9713479 A 11-04-2000 CN 1233955 A 03-11-1999 CZ 9901154 A 11-08-1999 EP 0956013 A 17-11-1999 NO 991635 A 07-06-1999 PL 333423 A 06-12-1999 JP04182426A30-06-1992NONE EP0606012A13-07-1994AT 168267 T 15-08-1998 AU 673555 B 14-11-1996 AU 5276393 A 14-07-1994 CA 2112824 A 07-07-1994 CN 1096197 A 14-12-1994 DE 69319710 D 20-08-1998 DE 69319710 T 11-03-1999 DK 606012 T 19-04-1999 ES 2119871 T 16-10-1998 JP 6234644 A 23-08-1994 NO 940035 A 07-07-1994 NZ 250583 A 22-08-1997 RU 2142468 C 10-12-1999 US 5604216 A 18-02-1997 ZA 9400025 A 19-08-1994 WO9739759A30-10-1997AU 2738497 A 12-11-1997 US5589508A31-12-1996DE 4133694 A 15-04-1993 AT 157247 T 15-09-1997 AU 2671292 A 03-05-1993 DE 59208834 D 02-10-1997 DK 607231 T 06-04-1998 WO 9306812 A 15-04-1993 EP 0607231 A 27-07-1994 ES 2108763 T 01-01-1998 GR 3025216 T 27-02-1998 JP 7502491 T 16-03-1995 EP0406917A09-01-1991US 4727340 A 23-02-1988 DE 3688428 A 17-06-1993 DE 3688428 T 26-08-1993 EP 0248962 A 16-12-1987 JP 1280904 A 13-11-1989 JP 2019116 C 19-02-1996 JP 7036510 B 19-04-1995 JP 62262512 A 14-11-1987 EP0610506A17-08-1994JP 5222392 A 31-08-1993 AU 664866 B 07-12-1995 DE 69229480 D 29-07-1999 DE 69229480 T 17-02-2000 NO 941550 A 27-06-1994 US 5840944 A 24-11-1998 AT 181567 T 15-07-1999 AU 2873992 A 07-06-1993 ES 2132133 T 16-08-1999 WO 9309210 A 13-05-1993 INTERNATIONALSEARCHREPORT !tionalApplicationNo Information on patent family members PCT/GB 00/00164 PatentdocumentPublication Patent citedinsearchreportdate member(s)date GB2229363A26-09-1990AT 155037 T 15-07-1997 AU 643201 B 11-11-1993 AU 5331090 A 22-10-1990 DE 69031033 D 14-08-1997 DE 69031033 T 20-11-1997 DK 464084 T 11-08-1997 EP 0464084 A 08-01-1992 ES 2103738 T 01-10-1997 WO 9011073 A 04-10-1990 HK 2894 A 21-01-1994 JP 3010310 B 21-02-2000 JP 5504936 T 29-07-1993 SG 137193 G 31-03-1994 US 5457130 A 10-10-1995 WO9929316A17-06-1999AU 1809499 A 28-06-1999 AU 1817499 A 28-06-1999 EP 1039893 A 04-10-2000 NO 20002991 A 09-08-2000 WO 9929300 A 17-06-1999




 
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