U.S. patent application number 10/428020 was filed with the patent office on 2004-01-22 for pharmaceutical preparation comprising eicosapentaenoic acid and/or stearidonic acid.
This patent application is currently assigned to Scotia Holdings PLC.. Invention is credited to Horrobin, David Frederick.
Application Number | 20040014810 10/428020 |
Document ID | / |
Family ID | 26310221 |
Filed Date | 2004-01-22 |
United States Patent
Application |
20040014810 |
Kind Code |
A1 |
Horrobin, David Frederick |
January 22, 2004 |
Pharmaceutical preparation comprising eicosapentaenoic acid and/or
stearidonic acid
Abstract
A pharmaceutical preparation for the treatment of schizophrenia
and/or tardive dyskinesia using an oil comprising eicosapentaenoic
acid (EPA) and/or stearidonic acid (SA) in amounts of more than
20%, preferably more than 40% and very preferably more than 70% by
weight of the total (preferably of the total unsaturated) fatty
acids present.
Inventors: |
Horrobin, David Frederick;
(Stirling, GB) |
Correspondence
Address: |
JACOBSON HOLMAN PLLC
400 SEVENTH STREET N.W.
SUITE 600
WASHINGTON
DC
20004
US
|
Assignee: |
Scotia Holdings PLC.
|
Family ID: |
26310221 |
Appl. No.: |
10/428020 |
Filed: |
May 2, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10428020 |
May 2, 2003 |
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09956509 |
Sep 18, 2001 |
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09956509 |
Sep 18, 2001 |
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09284231 |
Jun 10, 1999 |
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6331568 |
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09284231 |
Jun 10, 1999 |
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PCT/GB97/02738 |
Oct 7, 1997 |
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Current U.S.
Class: |
514/547 ;
514/560 |
Current CPC
Class: |
A61K 31/20 20130101;
A61P 25/24 20180101; A61P 25/28 20180101; A61P 25/18 20180101; A61K
31/202 20130101; A61P 25/14 20180101; A61P 25/00 20180101; A61K
31/20 20130101; A61K 31/20 20130101; A61K 31/20 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/547 ;
514/560 |
International
Class: |
A61K 031/225; A61K
031/202 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 11, 1996 |
GB |
9621294.9 |
Dec 16, 1996 |
GB |
9626062.5 |
Claims
1. A pharmaceutical preparation for the treatment of schizophrenia
and/or tardive dyskinesia, using an oil comprising eicosapentaenoic
acid (EPA) and/or stearidonic acid (SA) in amounts of more than
20%, preferably more than 40% and very preferably more than 70% by
weight of the total (preferably of the total unsaturated) fatty
acids present and wherein the weight ratio of SA/EPA to n-6 EFAs
present is not less than 3:1 and is preferably 4:1 or more, or n-6
EFAs are absent:
2. A method of treating, or a method of preparation of a medicament
for treating, schizophrenia and/or tardive dyskinesia whereby EPA
and/or SA is provided in the form of an oil containing more than
20% of said acid(s), preferably more than 40% and very preferably
more than 70% by weight of the total (preferably total unsaturated)
fatty acids present and wherein the weight ratio of SA/EPA to n-6
EFAs present is not less than 3:1 and is preferably 4:1 or more, or
n-6 EFAs are absent.
3. A pharmaceutical preparation according to claim 1, or method
according to claim 2, wherein the weight ratio of SA/EPA to any DHA
present is not less than 3:1 and is preferably 4:1 or more.
4. A pharmaceutical preparation according to claim 1 or 3 or method
according to claim 2 or 3 but for the treatment of depression.
5. A pharmaceutical preparation according to claim 1 or 3 or method
according to claim 2 or 3 but for the treatment of Alzheimer's
disease or other dementias.
6. Pharmaceutical preparation or medicament prepared as above which
is suited to, or a method of treatment as above which employs,
administration of 10 mg to 100 g, preferably 100 mg to 20 g, very
preferably 500 mg to 10 g, EPA and/or SA daily.
7. Use of EPA and/or SA in the preparation of a medicament for the
treatment of schizophrenia and/or tardive dyskinesia, or
depression, or Alzheimer's disease or other dementias, in the forth
set out in claim 1, for the administration of 10 mg to 100 g,
preferably 100 mg to 20 g, very preferably 500 mg to 10 g, EPA
and/or SA daily, with the weight ratio of SA/EPA to n-6 EFAs if
present set out in claims 1 and 2 and desirably with the SA/EPA to
DHA ratio set out in claim 3; and such treatment itself.
Description
FIELD OF THE INVENTION
[0001] The invention relates to fatty acid treatment in
schizophrenia.
BACKGROUND
[0002] The essential fatty acids and their conversions in the body
are shown in the following table.
1 n-6 EFAs n-3 EFAs 18:2n-6 18:3n-3 Linoleic acid (LA)
.alpha.-linolenic acid (ALA) 1 .delta.-6-desaturase 2 18:3n-6
18:4n-3 .gamma.-Linolenic acid (GLA) Stearidonic acid (SA) 3
elongation 4 20:3n-6 20:4n-3 Dihomo-.gamma.-linolenic acid
Eicosatetraenoic acid (DGLA) 5 .delta.-5-desaturase 6 20:4n-6
20:5n-3 Arachidonic acid (AA) Eicosapentaenoic acid (EPA) 7
elongation 8 22:4n-6 22:5n-3 Adrenic acid (AdrA) 9
.delta.-4-desaturase 10 22:5n-6 Docosahexaenoic acid (DHA)
[0003] The acids, which in nature are of the all--cis
configuration, are systematically named as derivatives of the
corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. LA
z,z-octadeca-9,12-dienoic acid or D[4A
z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoic acid, but numerical
designations based on the number of carbon atoms, the number of
centres of unsaturation and the number of carbon atoms from the end
of the chain to where the unsaturation begins, such as,
correspondingly, 18:2 n-6 or 22:6 n-3, are convenient. Initials,
e.g. EPA, and shortened forms of the name e.g. eicosapentaenoic
acid, are used as trival names in some instances.
[0004] In previous patent applications EPA-0347856 and EPA-0599576
we have drawn attention to the action of various essential fatty
acids in schizophrenia and have claimed the use of these fatty
acids in treatment. We have particularly drawn attention to the low
red cell levels of arachidonic acid (AA) and docosahexaenoic acid
(DHA) and to the use of these fatty acids.
[0005] Present Work
[0006] We have now unexpectedly found that one particular essential
fatty acid which was previously accorded only a minor role is in
fact particularly effective in treatment. This is eicosapentaenoic
acid (EPA; 20:5n-3) which is present in the brain in only small
amounts compared to AA and DHA. However, in a trial of treatment we
have found that EPA is exceptionally effective in treatment of
schizophrenia. Particularly effective are preparations comprising
EPA in amounts of more than 20% of the total fatty acids present
(preferably the total unsaturated fatty acids present) preferably
more than 40% and very preferably more than 70%.
[0007] Studies of the use of omega-3 essential fatty acids in
treatment., using a mixture of DHA and EPA, have previously shown
modestly beneficial effects (Mellor et al, Human Psychopharmacology
11:39-46, 1996). The preparation used contained 18% of EPA and 12%
of DHA and so far as this disclosure goes the therapeutic effects
could have been caused by either component or both. An analysis of
the relationship between fatty acid change and schizophrenia
symptoms showed that a rise in the total omega-3 content of red
cell membranes was associated with a fall in schizophrenic
symptoms.
[0008] We therefore decided to try to determine the relative
importance of EPA and DHA in schizophrenia. A study was carried Out
with 30 schizophrenia patients, most of whom had both positive and
negative symptoms as shown by the positive and negative symptom
scale (PANSS) and also had some evidence of tardive dyskinesia as
shown by the abnormal involuntary movements scale (AIMS). Patients
were randomly assigned on a double blind basis to treatment with 20
ml of a placebo emulsion, 20 ml of a 40% emulsion providing 8 g of
oil containing approximately 2.0 g of EPA and 0.4 g of DHA per day
(`EPA group`), and 20 ml of an emulsion providing approximately 2.3
g of DHA and 0.5 g of EPA per day (`DHA group`) in 8 g of oil.
Patients were scored at baseline and at the end of 12 weeks of
treatment. In the placebo group, 9 patients were unchanged or
deteriorated on the PANSS and AIMS scores and one improved. In the
DHA group, seven patients were unchanged or deteriorated and three
patients improved. In contrast, in the EPA group one patient was
unchanged but nine patients showed improvement. The improvement was
seen in both the negative and positive symptom scores and in the
AIMS score. There was therefore a broad spectrum improvement in all
aspects of the schizophrenia syndrome. The DHA group was not
significantly different from placebo whereas the EPA group was
significantly better than both the DHA group and the placebo group
(p <0.02 in both cases).
[0009] It is therefore possible to conclude that the main
therapeutic effect of treatment with EFAs is attributable to the
effect of EPA. The other EFAs may contribute to some degree but
there can be no doubt that EPA is primarily responsible for the
positive effects of treatment with omega-3 EFA preparations. We
concluded that EPA should also be effective in other psychiatric
disorders such as Alzheimer's disease and depression since low
levels of n-3 fan, acids have been shown in the blood and/or the
brain of patients with these disorders also. Two patients with
severe depression not responsive to the usual anti-depressants were
therefore treated with the EPA formulation as used in the
schizophrenia trial. Within 4 weeks both had shown remarkable
improvement in their symptoms.
[0010] While we cannot be certain of the mechanism by which EPA is
working, one possibility is that it is inhibiting the enzyme,
phospholipase A2. There is considerable evidence that phospholipase
(PL) A2 activity is elevated in schizophrenia (Horrobin et al,
Schizophrenia Research 1994; 13: 195-207). Compounds which safely
inhibit PLA2 might therefore be expected to have a therapeutic
effect. In in vitro studies of the effects of fatty acids on PLA
activity we have found that EPA is a potent inhibitor, whereas the
relatively similar fatty acid, DHA is not. This might explain why
DHA did not prove effective in the clinical studies.
[0011] We have further found that another n-3 fatty acid,
stearidonic acid (18:4 n-3), is as effective in inhibiting PLA2 as
is EPA. EPA and SA are 20- and 18-carbon fatty acids which have in
fact been shown to inhibit the activity of phospholipase A,
(Finnen, Biochem Soc. Trans 1991; 19:915). In contrast, DHA is A
22-carbon fatty acid which like other 22-carbon acids does not
inhibit phospholipase. This may offer an explanation for the
differences between EPA and DHA since there is evidence for
overactivity of phospholipase A.sub.2 in schizophrenia. We
therefore propose that stearidonic acid will be effective in
treating schizophrenia and the other disorders and we include its
use for that purpose alone or with EPA.
[0012] The n-6 EFAs such as linoleic acid, gammalinolenic acid
(GLA) dihomogammalinolenic acid (DGLA) and arachidonic acid (AA)
are important in brain structure. GLA can be metabolised to DGLA
and AA. We therefore tried to see whether the addition of an oil
containing linoleic acid and GLA would be beneficial in two
individuals who had responded to EPA. In fact their condition
appeared to be less good with addition of the n-6 EFAs. It is
therefore better to treat with EPA preparations in which the levels
of n-6 EFAs are kept at a low level compared to the concentration
of EPA. Either n-6 EFAs should be absent or if present at a ratio
to EPA of not more than 1:3, preferably 1:4 or less.
[0013] In any case to ensure that the effects secured are not
countered the weight ratio of SA/EPA to any DHA present is
desirably not less than 3:1 by weight and desirably 4:1 or
more.
STATEMENT OF INVENTION
[0014] The invention is set out in the claims herein but inter alia
provides a pharmaceutical preparation for the treatment of
schizophrenia and/or tardive dyskinesia using an oil comprising
eicosapentaenoic acid (EA) and/or stearidonic acid (SA) in amounts
of more than 20%, preferably more than 40% and very preferably more
than 70% by weight of the total (preferably of the total
unsaturated) fatty acids present and wherein the weight ratio of
SA/EPA to n-6 EFAs present is not less than 1:1 and is preferably
4:1 or more, or n-6 EFAs are absent. Corresponding methods of
treatment, and methods of preparation of medicaments, wherein such
oils as used, are also within the invention, as are corresponding
treatments of depression or Alzheimer's disease or other
dementias.
[0015] The EPA can be provided in any appropriate way which will
elevate the levels of EPA in the blood. Mono-, di-, and
tri-glycerides, mono- or di-esters, salts, cholesterol esters,
amides, phospholipids, free acids or any other appropriate form may
be used to deliver the EPA. Mono or diesters of EPA as specified in
previous applications where the present inventor is a co-inventor
(PCT/GB96/01052 and 01053), published respectively as WO96/34855
and WO96/34846 are particularly convenient forms in which the EPA
may be administered. The EPA may be derived from fish or marine
mammal oils, microbial oils or even from total chemical synthesis.
The EPA dose used may range from 10 mg to 100 g/day, preferably 100
mg to 20 g/day and very preferably from. 500 mg to 10/day. Oral,
enteral, parenteral, topical, or any other appropriate route of
administration may be used. Stearidonic acid may be provided in
similar doses and in similar ways, alone or with the EPA.
EXAMPLES
[0016] The study described above illustrates treatment according to
the invention but examples of suitable formulations are as
follows:-
[0017] 1. Soft gelatine capsules, each containing 200 mg of EPA in
the form of one of the following:
[0018] a) An oil containing 22% EPA derived from marine or
microbial sources.
[0019] b) An oil containing 56% EPA derived from marine or
microbial sources.
[0020] c) An oil containing 75% of EPA derived from marine or
microbial sources.
[0021] d) An oil containing 95% of EPA derived from marine,
microbial or synthetic sources.
[0022] e) EPA 1-3 propane diol diester.
[0023] 2. Oils as in examples 1a to 1e but formulated as an
emulsion for oral administration. The emulsion may contain 5 to 50%
of the oil emulsified wvith emulsifying agents oknown to these
skilled in the art including natural, synthetic and semi-synthetic
agents such as phospholipids and galactolipids, the latter for
example as described in PCT SE95/00115 published as WO95/20943.
[0024] 3. Emulsions as in 2 but sterilised and appropriately
formulated for intravenous administration.
[0025] 4. Oils as in examples 1a to 1e. sterilised and formulated
for intramuscular or sub-cutaneous injection.
[0026] 5. Oils as in examples 1a to 1e formulated for topical
administration using patch or other technologies known to those
skilled in the art.
[0027] 6-10. As Examples 1-5 except that stearidonic acid is used
instead of EPA or in admixture with it e.g. half and half.
* * * * *