(12) United States Patent
`Horrobin
`
`USOO6479544B1
`US 6,479,544 B1
`(10) Patent No.:
`Nov. 12, 2002
`(45) Date of Patent:
`
`(54) THERAPEUTIC COMBINATIONS OF FATTY
`ACDS
`
`(75) Inventor: David Frederick Horrobin, Stirling
`(GB)
`(73) Assignee: Laxdale Limited, Stirling (GB)
`(*) Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/893,473
`(22) Filed:
`Jun. 29, 2001
`(30)
`Foreign Application Priority Data
`Jun. 29, 2001
`(GB) ............................................. OO16045
`(51) Int. Cl." ................................................ A61K 31/23
`(52) U.S. Cl. ........................................ 514/552; 514/558
`(58) Field of Search .................................. 514/558,552
`(56)
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,526.902 A 7/1985 Rubin ........................ 514/560
`4977,187 A 12/1990 Horrobin ...
`... 514/560
`5,120,760 A * 6/1992 Horrobin ...
`... 514/458
`5,198.468 A * 3/1993 Horrobin ..........
`... 514/558
`5,223.285 A * 6/1993 DeMichele et al. ........... 426/72
`5,252,333 A 10/1993 Horrobin ..........
`... 424/422
`5,260,067 A 11/1993 Zheng ..............
`... 424/450
`5,378,732 A
`1/1995 Horrobin et al. ........... 514/560
`5,466,841. A 11/1995 Horrobin et al. ............. 554/79
`5,516,800 A 5/1996 Horrobin ..........
`... 514/560
`5,516.801 A 5/1996 Horrobin et al. .
`... 514/560
`5,562.913 A * 10/1996 Horrobin ..........
`... 424/401
`5,658,767 A * 8/1997 Kyle .........
`... 435/434
`5.993,221. A * 11/1999 Bistrian ........
`... 435/.429
`5.998.476 A * 12/1999 Sleigh et al. .....
`... 514/560
`6,184,251 B1 * 2/2001 Stordy et al. ..
`... 514/560
`6.274,747 B1 * 8/2001 Strelchenok ................. 554/40
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`WO
`WO
`WO
`
`8/1994
`O609078 A1
`5/1996
`O 711 SO3
`5/1996
`O 713 653
`7/1999
`99/33355
`4/2000
`WOOO/21524
`8/2000
`WOOO/44361
`OTHER PUBLICATIONS
`Ann Nutr Metab, Meeting Report No. 43, Simopoulos et al.,
`“Essentiality of and Recommended ... pp. 127-130, 1999.
`ISSFAL Newsletter reporting on the International Society
`for the Study of Fatty Acids and Lipids, pp. 1-5, 1999
`Workshop.
`WPI Japanese Abstract No. 1989–290735 (JP 010215245),
`1989.
`XP-002181361; Song; Sep. 27, 1994; Derwent Publications
`Ltd., London, GB; Section Ch, Week 199932.
`XP-002181362; Tokiwa Yakuhin Kogyo KK; Sep. 27, 1994;
`Derwent Publications Ltd., London, GB; Section Ch, Week
`199443.
`XP-002181364; Tokiwa Yakuhin Kogyo KK; Jun. 29, 1993;
`Derwent Publications Ltd., London, GB, Section Ch, Week
`1993.30.
`XP-002181363; Nissei Marine Kogyo KK; Jun. 17, 1992;
`Derwent Publications Ltd., London, GB; Section Ch, Week
`1992.31.
`Patent Abstracts of Japan; 60 132916; Jul. 16, 1985; vol.
`009; No. 187 (C-314); Fujita Tadashi.
`* cited by examiner
`Primary Examiner James H. Reamer
`(74) Attorney, Agent, or Firm-Jacobson Holman PLLC
`(57)
`ABSTRACT
`Eicosapentaenoic acid or any appropriate derivative (EPA)
`is disclosed in combination with arachidonic acid (AA) or an
`AA precursor, Selected from DGLA and GLA, to give a
`pharmaceutical formulation.
`15 Claims, 1 Drawing Sheet
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1041, p. 1 of 6
`
`

`

`U.S. Patent
`
`Nov. 12, 2002
`
`US 6,479,544 B1
`
`
`
`
`
`WSTOEVIEW (VHE) GIOV XLIV) TWILNESSE
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`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1041, p. 2 of 6
`
`

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`1
`THERAPEUTIC COMBINATIONS OF EATTY
`ACDS
`
`There are two series of essential fatty acids (EFAs) in
`humans. They are termed "essential” because they cannot be
`Synthesised de novo in mammals. Their metabolic pathways
`are shown in FIG.1. These fatty acids can be interconverted
`within a Series, but the omega-6 (n-6) Series cannot be
`converted to the omega-3 Series nor can the omega-3 (n-3)
`Series be converted to the omega-6 Series in humans. The
`main EFAS in the diet are linoleic acid of the omega-6 Series
`and alpha-linolenic acid of the omega-3 Series. However, to
`fulfil most of their biological effects these “parent' EFAS
`must be metabolised to the other fatty acids shown in FIG.
`1. Each fatty acid probably has a specific role in the body.
`Particularly important in the n-6 Series are dihomogamma
`linolenic acid (DGLA, 20:3n-6) and arachidonic acid (AA,
`20:4n-6), while particularly important in the n-3 Series are
`eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic
`acid (22:6n-3). This patent specification particularly con
`cerns combinations of AA and EPA.
`AA is found as an important constituent of all cell
`membranes and particularly of cell membranes of nerve
`cells. It is an important component of many Signal trans
`duction Systems which are activated by many different forms
`of cell stimulation. AA is usually found in cells in the form
`of phospholipids. Cell activation generates a range of active
`phospholipases which can release AA as the free acid. The
`free acid has many direct actions of its own in regulating
`protein kinases and other enzymes, in modulating move
`ments of calcium and other ions, in activating receptorS Such
`as peroxisome proliferator activated receptors (PPARS), and
`in modulating gene function. Furthermore AA can be con
`verted to an enormous range of even more active derivatives
`known by the general name of eicosanoids. These include
`prostaglandins, leukotrienes, thromboxanes, various types
`of hydroxy acids, lipoxins, hepoxilins and many other
`compounds. These Substances are often involved in inflam
`matory and thrombotic reactions and are frequently regarded
`as harmful in their overall effects. This harmful image is
`illustrated by the fact that intravenous AA is frequently
`lethal because of its thrombotic effects, and by the fact that
`the Steroids which are widely used, in particular for their
`anti-inflammatory effects, block the release of AA by phos
`pholipases. Moreover, the class of drugs known as cyclo
`oxygenase inhibitors, which include aspirin and many other
`well known compounds, known for their antithrombotic and
`anti-inflammatory effects, inhibit the conversion of AA to
`prostaglandins and thromboxanes.
`This concept of the potential toxicity of AA has become
`well established. The expert organisation in the field, the
`International Society for the Study of Fatty Acids and Lipids
`(ISSFAL) in 1999 organised a workshop in association with
`the US National Institutes of Health. The remit of the
`Workshop was to make recommendations concerning the
`human uses of EFAS. The participants, all leading experts in
`the field, had no doubts about the harmful effects of AA, and
`emphasised this in their final statement (APSimopoulos et
`al, Essentiality of and recommended dietary intakes for
`omega-6 and omega-3 fatty acids, Nutrition and Metabolism
`1999; 43:127-130). The ISSFAL newsletter reporting on
`this workshop Stated that "after much discussion, consensus
`was reached on the importance of reducing the omega-6
`polyunsaturated fatty acids (PUFAs) even as the omega-3
`PUFAS are increased in the diet of adults and newborns for
`optimal brain and cardiovascular function. This is necessary
`to reduce adverse effects of arachidonic acid and its
`eicosanoid products.
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`In contrast to this general view of AA toxicity, the experts
`of ISSFAL and NIH were keen to promote the value of the
`n-3 EFAS, particularly EPA and DHA for human health. The
`view was taken that EPA and DHA would replace AA in cell
`membrane phospholipids and also reduce AA Synthesis from
`linoleic acid. The lowering of AA levels by EPA and/or DHA
`was expected to have widespread beneficial effects on
`human health.
`The present invention results from recent Surprising
`observations of the inventor which Suggest that this view
`may be wrong. Contrary to the general expert opinion, it has
`now been found that AA is highly desirable rather than
`undesirable and it may be helpful to administer AA in
`association with EPA. The present invention provides this
`combination treatment.
`The present invention provides pharmaceutical formula
`tions containing eicosapentaenoic acid or any appropriate
`derivative (hereinafter collectively referred to as EPA) and
`arachidonic acid (AA), as set out in the claims attached
`hereto. AA may be replaced by one or more of its precursors,
`DGLA or GLA. The ratio of EPA to AA is preferably
`between 1:1 and 20:1.
`The EPA is preferably provided in a dose of between 100
`mg and 10,000 mg/day. The formulation may be a single
`preparation comprising 100-10,000 mg EPA. An alternative
`upper limit is 5,000 mg EPA. Preferably, the formulations of
`the invention comprise 1-4g EPA and 0.1-2.0 g arachidonic
`acid (AA). Still preferred amounts are 1.5-3 g EPA and
`0.2-1 g AA.
`The formulation may be a Single daily dose preparation
`to give in one dose the above intakes, or may be in
`convenient divided doses, for example, a daily dose formed
`of four Soft gelatin or other capsules, each containing 500
`mg of EPA in an appropriate form and 150 mg of AA in an
`appropriate form.
`The compositions of the first aspect of the present
`invention are prepared by combining EPA in biologically
`assimilable form in which the EPA is at least 50% pure,
`preferably at least 90% pure, and arachidonic acid (AA) in
`any biologically assimilable form. The Starting materials
`must include one containing Substantial amounts of the EPA.
`The same can apply for the AA, which may be at least 30%
`pure, preferably at least 90% pure.
`Still preferably, the active ingredient of the formulations
`of the present invention consists essentially wholly of the
`EPA and AA or AA precursor. In that case, no significant
`amounts of other EFAS are present.
`Flavourants or emulsifiers may be included to make the
`preparation palatable. Other conventional additives, diluents
`and excipients may be present. The preparation for ingestion
`may be in the form of a capsule, a dry powder, a tablet, an
`oil, an emulsion or any other appropriate form. The capsules
`may be hard or Soft gelatin capsules, agar capsules, or any
`other appropriate capsule.
`The EPA is preferably composed of a triglyceride or ethyl
`ester which is 50% pure or purer, more preferably more than
`90% pure. Other forms of the fatty acids which may be
`useful include the free acids, Salts, esters of any type,
`amides, mono-, di- or triglycerides, phospholipids or any
`other form which can lead to the incorporation of EPA into
`body tissues. If phospholipids are considered, it is Specifi
`cally excluded from the present invention that a phospho
`lipid containing two different fatty acids, that is containing
`both EPA and AA (or AA precursor) is used. Phospholipids
`containing EPA may however be used in the present formu
`lations when combined with phospholipids containing AA or
`AA precursor.
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1041, p. 3 of 6
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`

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`US 6,479,544 B1
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`The formulations of the present invention may be used
`for the treatment of a wide range of diseases and disorders
`including:
`any psychiatric, neurological or other central or peripheral
`nervous System disease-in particular Schizophrenia,
`depression, bipolar disorder and degenerative disorders
`of the brain including Alzheimer's disease and other
`dementias and Parkinson's disease;
`asthma and other respiratory diseases,
`diseases of the gastrointestinal tract including inflamma
`tory bowel diseases and irritable bowel syndrome;
`inflammatory disease affecting any System;
`cardiovascular disease,
`dyslipidaemia, any form of diabetes or any form of
`metabolic diseases,
`dermatological diseases,
`kidney or urinary tract diseases,
`liver diseases,
`disease of the male or female reproductive organs Such as
`the breast or the prostate gland;
`cancer or cancer cachexia;
`diseases of the head and neck, including disease of the
`mouth and teeth, of the eyes or of the ears,
`infection with viruses, bacteria, fungi, protozoa or other
`organisms.
`They may also be taken as a general nutritional Supple
`ment.
`The present invention further provides a method of treat
`ment or prevention of any of the aforesaid diseases or
`conditions, in particular neurological and psychiatric
`disorders, especially Schizophrenia, depression, bipolar dis
`order and degenerative disorders of the brain including
`Alzheimer's disease and other dementias and Parkinson's
`disease. The treatment or preventative method is, for
`example, by the combined application of EPA and AA at the
`dosage regime of between 100 mg and 10,000 mg/day EPA
`and a ratio of EPA to AA of between 1:1 and 20:1. A
`40
`precursor to AA, selected from DGLA and GLA, may be
`used instead of AA. The preferred range of EPA to AA (or
`its precursor) is between 1:1 and 5:1.
`The present invention still further provides a method of
`treatment or prevention of any disease Selected from:
`asthma and other respiratory diseases,
`diseases of the gastrointestinal tract including inflamma
`tory bowel diseases and irritable bowel syndrome;
`inflammatory disease affecting any System;
`cardiovascular disease,
`any form of dyslipidaemia, any form of diabetes or any
`form of metabolic diseases,
`any form of dermatological diseases,
`any form of kidney or urinary tract disease;
`any form of liver disease;
`any form of disease of the male or female reproductive
`System or related Secondary Sexual organs Such as the
`breast or prostate gland; any form of cancer or for
`cancer cachexia;
`any disease of the head and neck including diseases of the
`mouth and teeth, of the eyes or of the ears, and
`any form of infection with viruses, bacteria, fungi, pro
`toZoa or other organisms
`by, for example, the combined application of EPA and AA at
`the dosage regime of between 100 mg and 10,000 mg/day
`EPA and a ratio of EPA to AA of between 1:1 and 20:1. A
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`precursor to AA, DGLA or GLA, may be used instead of
`AA. The preferred range of EPA to AA (or its precursor) is
`between 1:1 and 5:1.
`Use of the formulations of the invention in the manufac
`ture of a medicament for the treatment or prevention of any
`disease or disorder, including those mentioned above, is
`included in the present invention.
`The Specific therapeutic compositions proposed are ones
`which provide not less than 100 mg and not more than
`10,000 mg of EPA/day combined with AA, DGLA or GLA,
`in doses of between 100 mg and 10,000 mg/day. An alter
`native upper limit is 5,000 mg/day of the fatty acids.
`Particularly preferred amounts are 1-4 g per day EPA
`combined with 0.1-2.0 g per day arachidonic acid, or one of
`its precursors, GLA or DGLA. A Still preferred composition
`comprises 1.5-3 g EPA and 0.2-1 g AA. The present
`invention further provides a formulation, for example, in a
`one-a-day dose comprising 1.5-3 g EPA and 0.1-2.0 g
`arachidonic acid or one of its precursors.
`The ratio of EPA to the omega-6 fatty acid is important
`because too much EPA is likely to lead to the loss of AA
`from membranes, while too much AA may lead to adverse
`effects because of excessive conversion of AA to eicosanoid.
`The ratio of EPA to AA or DGLA or GLA should therefore
`never be less than 1:1, should preferably be in the range
`between 20:1 and 1:1, and should still preferably be in the
`range of between 5:1 and 1:1. These combinations will
`ensure that the beneficial effects of EPA are enhanced and
`maintained even at relatively high EPA doses, because the
`provision of AA and its precursors will prevent AA depletion
`which may occur when too much EPA is given alone.
`During absorption from the gut and within the body, EPA
`moieties are readily transformed intact from one chemical
`form to another. Simple esterS Such as ethyl or methyl esters
`are readily split by esterases and the freed fatty acids can
`then be bound by albumin or other binding or transport
`proteins or incorporated into complex lipids Such as
`phospholipids, cholesterol ester or glycerides. The fatty
`acids in the present formulations can therefore be adminis
`tered in any form Such as glycerides, esters, free acids, Salts,
`phospholipids, amides or any other form which leads to their
`incorporation into the blood and cell membranes.
`The EPA, AA, DGLA or GLA may be derived from any
`appropriate Source including plant Seed oils, microbial oils
`from algae or fungal or marine oils from fish or other marine
`animals. They may be used in the form of the natural oil, if
`that oil meets the required purity requirements of the Starting
`material, or may be purified to give products containing
`30%, 40%, 50%, 60%, 70%, 80%, 90% or more of the fatty
`acid. A particularly useful form of EPA is the highly purified
`ethyl ester described in patent filings based on the prelimi
`nary UK filing 9901809.5. Synthetic routes to the fatty acids
`are also possible although at present are not economically
`feasible.
`Once the oils containing the individual fatty acids have
`been obtained, and purified as necessary, the Starting mate
`rials may be blended to give the desirable ratios of EPA to
`AA, DGLA or GLA described above.
`The blended fatty acid compositions may then be incor
`porated into any appropriate dosage form for oral, enteral,
`parenteral, rectal, vaginal, dermal or other route of admin
`istration. Soft or hard gelatin capsules, flavoured oil blends,
`emulsifiers or other liquid forms, and microencapsulate
`powders or other dry form vehicles are all appropriate ways
`of administering the products.
`Example Formulations
`(a) Soft or hard gelatin capsules each containing 500 mg
`or 1000 mg of a mix of 10 parts 95% pure ethyl-EPA
`to 2 parts of 95% pure AA;
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1041, p. 4 of 6
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`(b) As in (a) but where the AA and EPA ethyl esters are
`replaced with the fatty acids in any other appropriate
`bioassimilable form Such as the free acid, tri-, di- or
`monoglyceride, other esters, Salts. Such as the Sodium,
`potassium or lithium Salts, amides, phospholipids or
`any other appropriate derivatives,
`(c) As in (a) or (b) but where the EPA or EPA derivative
`is 50%, 60%, 70%, 80% or 90% pure and where the AA
`or AA derivative is 30%, 40%, 50%, 60%, 70%, 80%
`or 90% pure;
`(d) As in (a)-(c) but where the ratio of EPA to AA is
`anywhere in the range from 1:1 to 20:1;
`(e) As in (a)-(d) but where the material is in the form of
`a microencapsulated powder which can be used as a
`powder or compressed into tablets. Such powderS may
`be prepared by a variety of technologies known to those
`skilled in the art;
`(f) As in (a)-(d) but where the formulation is a liquid or
`emulsion, appropriately flavoured for palatable oral
`administration;
`(g) AS in (a)-(d) but where the material is formulated in
`to material appropriate for topical application Such as a
`cream or ointment;
`(h) AS in (a)-(g) but where the AA is replaced by one of
`its precursors, GLA or DGLA.
`BRIEF DESCRIPTION OF THE FIGURES
`FIG. 1. the metabolic pathways of the two series of
`essential fatty acids.
`EXPERIMENTAL DATA
`A trial was conducted of the administration of a placebo
`and three different doses of EPA, 1 g, 2 g and 4 g/day in the
`treatment of Schizophrenia in patients who were also taking
`the antischizophrenic drug clozapine. Previous pilot Studies
`had suggested that EPA would have desirable effects and the
`expectation was that the higher the dose of EPA, the better
`would be the effect. 31 patents were entered into the study
`and followed for 12 weeks. They were assessed at baseline
`and 12 weeks using the Positive and Negative Symptom
`Scale for Schizophrenia (PANSS). The percentage improve
`ments from baseline are shown in table 1. Placebo produced
`a Small effect, 1 g/day produced a larger effect, 2 g/day
`produced a large effect of 26.0% compared to the usual
`15-20% improvements on this Scale generated by existing
`drugs for Schizophrenia. It was expected that 4 g/day would
`produce the best effect but this did not happen. The effect of
`4 g/day while there, was substantially less than the effect of
`2 g/day, and comparable to that of 1 g/day.
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`rise in EPA which was greater the greater the dose. It was
`also expected that there would be a progressive decline in
`AA, the larger the EPA dose, the greater the fall in AA.
`However, this did not happen. 1 g/day of EPA produced a
`Small rise in AA while 2 g/day produced a large rise. 4 g/day
`EPA produced the expected fall in AA.
`
`TABLE 2
`
`Changes from baseline to 12 weeks in red cell
`concentrations (in lugg) of eicosapentaenoic acid (EPA)
`and arachidonic acid (AA) in red blood cells in tour
`groups of schizophrenic patients given placebo or 1 g/d,
`2 g/d or 4 g/d ethyl-EPA, it means a rise and - means a fall
`
`Placebo
`
`-0.6
`-12.6
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`1 g
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`+2.4
`+2.7
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`2 g
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`+33.7
`+29.4
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`4g
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`+49.0
`-26.5
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`EPA
`AA
`
`It appeared that the improvement in Schizophrenic Symp
`toms was more related to the changes in AA than to the
`changes in EPA. This was tested in a larger Series of patients
`where the improvement in PANSS was correlated with the
`changes in all the major EFAS. The values for r, the
`correlation coefficient, are shown in table 3 as is the Statis
`tical Significance of the relationship. An r value of 1.0 means
`that the two parameters are perfectly related while one of 0.0
`means that there is no relationship whatsoever.
`
`TABLE 3
`
`Correlations between the change from baseline to
`12 weeks on the total PANSS score and the change from
`baseline to 12 weeks in the red cell concentration of
`various essential fatty acids. r, the correlation
`coefficient from a linear regression analysis, is shown.
`p is the statistical significance of the relationship.
`
`Fatty acid
`
`Dihomogammalinolenic
`(DGLA)
`Arachidonic (AA)
`Eicosapentaenoic
`(EPA)
`DocOsapentaenoic
`(DPA)
`Docosahexaenoic (DHA)
`
`Correlation
`coefficient r
`
`Significance p=
`
`-0.51
`
`-0.81
`-O.O7
`
`-0.12
`
`-0.35
`
`O.09
`
`O.OO1
`O.84
`
`O.76
`
`O.13
`
`From the table it is clear that by far the strongest rela
`tionship is with AA, and the Second strongest relationship is
`with DGLA. Rises in these two fatty acids are strongly
`asSociated with improvement in Schizophrenic Symptoms, as
`indicated by a fall in the PANSS score, hence the negative
`correlations. In contrast there is almost no relationship with
`EPA because high doses of EPA are associated with falls in
`red cell AA levels and the loss of clinical effect.
`These results were completely unexpected. Far from EPA
`itself being the most desirable fatty acid in cell membranes
`it seems that AA and DGLA are more helpful. The likeliest
`interpretation of this is that AA is desirable when it is
`retained in membrane phospholipids and not converted to
`potentially dangerous eicosanoids. The effect of EPA may be
`to inhibit phospholipases and So keep AA in the phospho
`lipid form. Very high does of EPA, however, displace AA
`and the therapeutic effect is lost.
`This interpretation was Supported by a pilot Study in
`which AA itself was given to five patients with Schizophre
`nia. The expectation was that they would improve, but in
`fact their condition deteriorated. The administration of AA,
`
`TABLE 1.
`
`Percentage improvements from baseline to 12
`weeks on the Positive and Negative Symptom Scale for
`Schizophrenia (PANSS) in patients given placebo, 1 g/day,
`2 g/day or 4 g/day ethyl eicosapentaenoate
`
`Placebo
`
`1 g
`
`7
`6.0%
`
`9
`18.3%
`
`2 g
`
`9
`26.0%
`
`4g
`
`6
`16.3%
`
`Improvement
`
`In these patients, and also in a further Series of patients,
`the levels of DGLA, AA, EPA and DHA were measured in
`human red cells before Starting treatment and after 12 weeks.
`The results were partly expected and partly Surprising and
`are shown in table 2. AS expected there was a dose-related
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`without EPA to inhibit phospholipases, may lead to
`increased formation of eicosanoids rather than to incorpo
`ration of AA into phospholipids.
`The conclusion to be drawn from these studies is that EPA
`is desirable, not in itself but because it raises the AA level
`in membrane phospholipids. High doses of EPA, far from
`being valuable in themselves, may be undesirable because
`they lead to excessive loss of AA from membranes. The way
`to get around this issue, and to boost the clearly desirable
`effects of EPA, is to keep to relatively low doses of EPA, but
`also to boost the level of AA by administering the EPA with
`either AA or one of its precursors, DGLA or gamma
`linolenic acid GLA. When AA in a dose of 1 g/day was given
`to two patients who had already been taking 2 g/day EPA for
`3 months, they experienced a Substantial further improve
`ment without any of the worsening Seen when AA was given
`alone.
`U.S. Pat. No. 4,977,187 provided for combinations of n-3
`fatty acids and n-6 fatty acids and Vitamin E in the treatment
`of Schizophrenia. However, that patent did not direct atten
`tion to AA specifically or to EPA specifically, or to the
`specific combination of EPA with AA or its immediate
`precursors or to the Specific doses and ratios of EPA and AA
`described in this specification. Any n-6 fatty acid could be
`25
`combined with any n-3 fatty acid in any ratio in U.S. Pat. No.
`4,977,198 and corresponding patents.
`A review of the literature Suggests that the phenomenon
`described here is not only true of schizophrenia but of
`several disorders where EPA is therapeutically useful. There
`are many studies describing the value of low doses of EPA
`containing products in cardiovascular diseases, in inflam
`matory disease and in other disorders. However, when
`investigators have gone to higher doses, these desirable
`therapeutic effects have been lost. To take two examples,
`high doses of EPA completely failed to exert beneficial
`effects in patients undergoing angioplasty for coronary vas
`cular disease, or in patients with inflammatory bowel
`disease, even though earlier Studies with Smaller EPA doses
`had given Strong evidence of benefit. The authors had no real
`explanation for the trial failure and did not consider the
`possibility that exceSS depletion of AA may have been the
`CalSc.
`The use of the formulations of the present invention could
`be very wide-ranging.
`What is claimed is:
`1. A pharmaceutical composition comprising a combina
`tion of a) a biologically assimilable eicosapentaenoic com
`pound (EPA) having a purity of at least 90% with b) a
`biologically assimilable arachidonic compound (AA) or a
`precursor thereof having a purity of at least 90%.
`2. A pharmaceutical composition according to claim 1 in
`which the ratio of EPA to AA or a precursor thereof is
`between 1:1 and 20:1.
`3. A pharmaceutical composition according to claim 1 in
`which the EPA is provided in a dose of between 100 mg and
`10,000 mg/day.
`
`35
`
`8
`4. A pharmaceutical composition according to claim 1
`comprising from 1 to 4 g. EPA and from 0.1 to 2.0 g
`arachidonic acid.
`5. A pharmaceutical composition according to claim 1
`comprising from 1.5 to 3 g of EPA and from 0.1 to 2.0 g of
`AA or a precursor thereof.
`6. A pharmaceutical composition according to claim 1
`which consists essentially of a combination of (a) and (b).
`7. A pharmaceutical composition according to claim 1
`wherein the AA precursor is in the form of DGLA.
`8. A pharmaceutical composition according to claim 1
`wherein the AA precursor is in the form of GLA.
`9. A pharmaceutical composition according to claim 1
`wherein the AA precursor is a member Selected from the
`group consisting of DGLA and GLA, and the EPA is
`provided in a dose of between 100 mg and 10,000 mg/day,
`and the ratio of EPA to AA precursor is between 1:1 and
`20:1.
`10. A pharmaceutical composition according to claim 1
`further comprising a flavourant or emulsifier.
`11. A pharmaceutical composition according to claim 1
`wherein the EPA is in triglyceride or ethyl ester form.
`12. A method of treating or preventing a psychiatric,
`neurological or other central or peripheral nervous System
`disease which comprises administering to a Subject prone to
`or afflicted with Such disease an effective amount of a
`composition according to claim 1.
`13. A method according to claim 12 wherein the disease
`is Schizophrenia, depression, bipolar disorder, Alzheimer's
`disease, other dementia or Parkinson's disease.
`14. A method of treating or preventing a disease which
`comprises administering an effective amount of a composi
`tion according to claim 1 to a Subject prone to or afflicted
`with Such disease, and wherein the disease is an amenable
`disease Selected from the group consisting of:
`asthma or other respiratory disease;
`a disease of the gastrointestinal tract,
`an inflammatory disease,
`a cardiovascular disease;
`a dyslipidaemia, diabetes or other form of metabolic
`disease;
`a dermatological disease;
`a kidney or urinary tract disease;
`a liver disease;
`a disease of the male or female reproductive System or
`related Secondary Sexual organs,
`a cancer,
`a disease of the head or neck, and
`an infection caused by a virus, bacterium, fungus, proto
`Zoa or other organism.
`15. A pharmaceutical composition according to claim 1
`wherein its Sole active ingredient consists essentially of the
`combination of (a) with (b).
`
`k
`
`k
`
`k
`
`k
`
`k
`
`US 6,479,544 B1
`
`5
`
`15
`
`40
`
`45
`
`50
`
`55
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1041, p. 6 of 6
`
`