PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`(51) International Patent Classification 6 5
`
`(21) International Application Number:
`
`PCT/U897/06712
`
`(81) Designated States: AU, CA, JP, US, European patent (AT. BE,
`CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL,
`PT, SE).
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
`
`
`(11) International Publication Number:
`WO 97/39759
`
`
`A61K 33/14, 31/66, 31/20
`
` (43) International Publication Date:
`30 October 1997 (30.10.97)
`
`
`
`
`(22) International Filing Date:
`23 April 1997 (23.04.97)
`
`Published
`
`(30) Priority Data:
`Without international search report and to be republished
`
`60/016, 1 40
`24 April 1996 (24.04.96)
`US
`
`
`upon receipt of that report.
`
`
`
`
`(71) Applicant (for all designated States except US): BRIGHAM
`AND WOMEN'S HOSPITAL [US/US]; 75 Francis Street,
`Boston, MA 02115 (US).
`
`
`
`(72) Inventors; and
`
`
`STOLL. Andrew, L.
`(75) Inventors/Applicants (for US only):
`[US/US]; 35 Old Winter Street, Lincoln, MA 01773 (US).
`SEVERUS, Wolfram, E. [DE/DE]; Badensche Strasse 7, D-
`10825 Berlin (DE).
`
`
`
`(54) Title: OMEGA-3 FAI I Y ACIDS AND OMEGA-3 PHOSPHATIDYLCHOLINE IN THE TREATMENT OF BIPOLAR DISORDER
`
`
`
`
`
`
`(74) Agent: SANZO, Michael, A.; Vinson & Elkins, 1455 Pennsyl-
`vania Avenue, N.W., Washington, DC 20004 (US).
`
`
`
`(57) Abstract
`
`The present invention is directed to a method of treating patients with bipolar disorder by administering omega-3 fatty acids. These
`may be administered in a substantially purified form, as part of a pharmaceutical composition, or as part of a larger molecule, e.g.
`a
`triacylglycerol, which releases free fatty acid after ingestion by a patient. The present invention is also directed to triacylglycerols which
`are esterified at the gamma carbon of glycerol to phosphocholine and at either the alpha or beta carbon of glycerol to an omega-3 fatty
`acid. These “omega-3 phosphatidylcholines” are also used in the treatment of patients with bipolar disorder.
`
`Petition for Inter Partes Review
`Of U.S. Patent 8,278,351
`Exhibit
`
`ENZYMOTEC - 1010
`
`000001
`
`000001
`
`

`

`Codes used to identify States patty to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`
`Zimbabwe
`
`SI
`
`SN
`51
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`
`UZ
`VN
`YU
`ZW
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Albania
`Armenia
`Austria
`Australia
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`COte d'lvoite
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`China
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`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`
`LC
`Ll
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`
`[’1‘
`RO
`RU
`SD
`SE
`80
`
`000002
`
`000002
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`

`

`WO 97/39759
`
`PCT/US97/06712
`
`Omega—3 Fatty Acids and Omega-3 Phosphatidylcholine
`in the Treatment of Bipolar Disorder
`fl
`
`Field of the Invention
`
`The present invention relates to medical treatments for psychiatric disorders. More
`
`specifically, it is concerned with novel methods and compositions for treating patients with
`
`bipolar disorder.
`
`Background of the Invention
`
`Patients with bipolar disorder suffer recurrent, alternating cycles of mania and
`
`depression.
`
`In a controlled clinical study performed more than a decade ago, it was reported
`
`10
`
`that lecithin (phosphatidylcholine) has anti—manic properties when administered to such patients
`
`(Cohen et al. , Am. J. Psychiatry 139:1162-1164 (1982); see also Cohen et al., Am. J.
`
`Psychiatry 137:242-243 (1980); Schreier, Am. J. Psychiatry [39:108—110 (1982)). More recent
`
`reports, have suggested that the beneficial effects observed for lecithin are due primarily to the
`
`metabolic release of free choline (Stoll et al. , Biol. Psychiatry 3 7:170-174 (1995)).
`
`15
`
`Although effective in reducing mania, lecithin is not widely used in treating bipolar
`
`patients. One of the main reasons for this is that 15-30 grams of lecithin per day must typically
`
`be given to a patient in order to obtain a beneficial effect and the intake of such a large quantity
`
`of lipid would, over time, tend to promote cardiovascular disease. An ideal solution to this
`
`problem would be to administer a therapeutic agent that has the same beneficial effect as lecithin
`
`20
`
`in controlling mania but which does not have the same adverse effect with respect
`
`to
`
`cardiovascular disease.
`
`The present invention is directed to phosphatidylcholines in which the a or [3 carbon of
`
`glycerol is esterifted to an omega-3 fatty acid. These fatty acids are unique among dietary fats
`
`in that they inhibit thrombosis and platelet aggregation and can lower blood pressure (see
`
`25
`
`Dimmitt, Clin. Exp. Pharmacol. Physiol. 22:204-208 (1995)). Thus,
`
`the
`
`"omega-3
`
`phosphatidylcholines" disclosed herein produce the same effects as lecithin in bipolar patients
`
`due to the release of free choline but reduce, rather than increase, the risk that a patient will
`
`suffer a stroke or coronary thrombosis.
`
`In addition, the present invention is directed to a method of treating bipolar disorder
`
`30
`
`using omega-3 fatty acids themselves,
`
`i.e. apart from phosphatidylcholine. These may be
`
`administered in a purified state, as part of a composition containing other therapeutic agents or
`
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`PCT/US97/06712
`
`-2-
`
`as part of another compound, e.g. a triacylglyeerol, which is metabolized to release free fatty
`
`acid in viva.
`
`Summary of the Invention
`
`An evaluation of mood stabilizing agents indicates that all such agents presently used
`
`to treat bipolar patients have an inhibitory effect on neuronal signal transduction systems. The
`present invention is based, in part, upon this discovery and the upon the recognition that omega-
`3 fatty acids are useful in treating pathological conditions involving excessive cell signal
`transduction (see e.g., Sperling, Rheum. Dis. Clinics 17(1991); Sperling, et al. , J. Clin. Invest.
`
`91:651-660 (1993)).
`
`10
`
`Thus, a method has been developed for treating a human patient for bipolar disorder by
`
`administering omega—3 fatty acids at a dosage sufficient to reduce or eliminate the symptoms
`
`associated with the disorder,
`
`i.e. at a dosage sufficient to reduce the frequency of mood
`
`fluctuations or lessen the severity of the mania or depression experienced by such patients. The
`
`omega-3 fatty acids should be administered at a dosage of between about 1 and about 30 grams
`
`15
`
`per day. The two most preferred omega-3 fatty acids are eicosapentanoic acid and docosa—
`hexanoic acid and these should typically be administered at daily dosages of 2-10 grams and 1-5
`
`grams respectively. The fatty acids may be administered as the sole therapeutic agent or in
`
`conjunction with other agents known to be useful in the treatment of bipolar patients. In
`
`particular, the fatty acids may be administered either with a source of lithium or choline. In
`
`20
`
`addition, omega-3 fatty acids may be taken by patients as a component of another molecule, e.g.
`
`a triacylglyeerol, and be metabolically released after ingestion.
`
`The present invention is also directed to an omega-3 phosphatidylcholine useful in the
`
`treatment of bipolar disorder, consisting of glycerol esterified at both its a and [3 carbons to fatty
`
`acids. At least one, and preferably both, of these fatty acids is an omega-3 fatty acid and the y
`
`25
`
`position of the glycerol must be esterified to phosphocholine. It is preferred that at least one of
`
`the esterified fatty acids be either eicosapentanoic acid or docosahexanoic acid. Omega-3
`
`phosphatidylcholines with eicosapentanoic acid esterified to the a carbon and docosahexanoic
`
`acid esterified to the [3 carbon and vice versa are the most preferred.
`
`In all cases, the v position
`
`of the triacylglyeerol is esterified to phosphocholine.
`
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`WO 97/39759
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`PCT/US97/06712
`
`-3-
`
`In another aspect, the present invention is directed to a pharmaceutical composition
`comprising one or more of the omega-3 phosphatidylcholines discussed above. The composition
`should contain sufficient triacylglycerol so that one or more unit doses provides enough agent
`to reduce or eliminate the symptoms associated with bipolar disorder.
`In some instances,
`lithium may be also incorporated into the composition in order to improve therapeutic effects.
`The present invention is also directed to a method for treating bipolar disorder in a
`human patient by administering an omega-3 phosphatidylcholine.
`It
`is expected that this
`phosphatidylcholine will typically be administered at a dosage sufficient to provide between 1
`and 30 (preferably between 2 and 8) grams of free omega-3 fatty acid to the patient. Again,
`administration may be carried out concurrently with the administration of other therapeutic
`
`10
`
`agents such as lithium.
`
`Detailed Description of the Invention
`
`In the following description, reference will be made to various methodologies well-
`
`known to those skilled in the art of medicine and pharmacology. Such methodologies are
`
`15
`
`described in standard reference works setting forth the general principals of these disciplines.
`
`Included among the relevant references are: Goodwin, PK. and Jamison, K.R., Manic
`
`W, Oxford University Press (1990); and Bloom, F. and Kupfer, D.,
`
`W, Raven Press (1994).
`
`A.
`
`Definitions
`
`20
`
`W: Bipolar disorder refers to a form of psychosis characterized by
`
`adnormally severe mood swings. The patient alternates between episodes of mania and episodes
`
`of depression.
`
`WHEELS: Fatty acids are long chain aliphatic molecules beginning with a
`
`methyl group and ending with a carboxyl group. Omega-3 fatty acids contain a double bond in
`
`25
`
`the third position from the methyl group. Two common, long chain omega-3 fatty acids are
`
`eicosapentanoic acid (20 carbons in length) and docosahexanoic acid (22 carbons in length).
`
`These are both found in fish oils
`
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`.4-
`
`oxyl groups of fatty acids are esterified
`
`e referred to as triacylglycerols or
`
`W: Compounds in which the carb
`to the hydroxyls of all three carbons found in glycerol ar
`triglycerides. Triacylglycerols in which the terminal carbon of glycerol (the "y carbon") is
`esterified to phosphocholine are called phosphatidylcholines. The next carbon in the glycerol
`is referred to herein as the "B carbon" and the following carbon is referred to as the "a carbon. "
`WW: As used herein the term "omega-3 phosphatidylcholine"
`refers to a triacylglycerol in which the 7 carbon of glycerol is esterified to phosphocholine and
`at least one of the other carbons of glycerol is esterified to an omega-3 fatty acid.
`choline: Choline (hydroxyethyl trimethyl ammonium hydroxide) is considered to be a
`vitamin of the B complex and is derivable from many foods. Unless otherwise indicated, the
`term "choline" as used herein, refers not only to the isolated choline molecule (i.e. free choline)
`but also to any biologically compatible salt of choline (e.g. , choline bitartrate).
`Lithium: Unless otherwise indicated, the term "lithium" refers to any salt containing
`
`5
`
`10
`
`lithium as the cationic component.
`
`15
`
`B.
`
`Method of Treating Patients For Bipolar Disorder Using Omega-3
`Fatty Acids
`
`20
`
`25
`
`The present invention is directed to a method for treating human patients for bipolar
`disorder by administering omega-3 fatty acids. Although the method is not restricted to any one
`particular type of omega-3 fatty acid,
`it
`is preferred that eicosapentanoic acid (EPA) or
`docosahexanoic acid (DHA) be used. Both EPA and DHA are found in a variety of fish oils and
`
`are commercially available in an essentially pure form.
`
`Dosage
`The total daily dosage of omega—3 fatty acid administered to a human patient should be
`at least the amount required to reduce or eliminate the symptoms associated with bipolar
`disorder. Specifically, the dosage should be high enough to either reduce the severity of the
`manic and depressive episodes experienced by patients or decrease the frequency at which such
`episodes occur. Physicians may begin by administering relatively small doses of omega-3 fatty
`acid (e. g. 1 gram per day) and then adjust the dosage upward as it becomes clear that the patient
`can tolerate the treatment. The final daily dosage should be between 1 and 30 grants of fatty acid
`
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`WO 97/39759
`
`PCT/US97/06712
`
`-5-
`
`per day with typical doses ranging between 2 and 10 grams per day. Dosages may be provided
`in either a single or multiple dosage regiment.
`These are simply guidelines since the actual dose must be carefully selected and titrated
`by the attending physician based upon clinical factors unique to each patient. The optimal daily
`dose will be determined by methods known in the art and will be influenced by factors such as
`
`the age of the patient and other clinically relevant factors. In many cases, a patient will already
`be taking medications for the treatment of bipolar disorder at the time that treatment with
`omega—3 fatty acid is initiated. In addition, patients may be taking medications for other diseases
`or conditions. The other medications may be continued during the time that omega-3 fatty acid
`
`10
`
`is given to the patient but it is particularly advisable in such cases to begin with low doses to
`
`determine if adverse side effects are experienced.
`
`Dosage Forms and Route of Administration
`
`The present
`
`invention is not
`
`limited to any particular dosage form or route of
`
`administration. Oral administration will generally be most convenient, however, the invention
`
`15
`
`is compatible with parenteral,
`
`transdermal, sublingual, buccal or implantable routes of
`
`administration as well.
`
`Omega—3 fatty acids may be given in a substantially purified form or as part of a
`
`pharmaceutical composition containing one or more excipients or
`
`flavoring agents.
`
`Compositions may also include other active ingredients for the treatment of bipolar disorder,
`
`20
`
`e. g. lithium.
`
`Preparations may be solid or liquid and take any of the pharmaceutical forms
`
`presently used in human medicine, e.g.
`
`tablets, gel capsules, granules, suppositories,
`
`transdermal compositions or injectable preparations.
`
`The active ingredient or ingredients may be incorporated into dosage forms in
`
`conjunction with any of the vehicles which are commonly employed in pharmaceutical
`
`25
`
`preparations, e. g. talc, gum arabic, lactose, starch, magnesium searate, cocoa butter, aqueous
`
`or non-aqueous solvents, oils, paraffin derivatives or glycols. Emulsions such as those
`
`described in US. 5,434,183, may also be used in which vegetable oil (e.g., soybean oil or
`
`safflower oil), emulsifying agent (e.g., egg yolk phospholipid) and water are combined with
`
`glycerol. Fatty acids may be incorporated into preparations either in the form of the free acid
`
`30
`
`or as a pharrnaceutically acceptable salt. Methods for preparing appropriate formulations are
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`WO 97/39759
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`PCT/US97/06712
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`well known in the art (see e.g.,W, 16th Ed., A. Oslo Ed.,
`
`—6-
`
`Easton, PA (1980)).
`
`Manner of Treatment
`
`In order to determine the effect of administered omega—3 fatty acid on mood alteration,
`
`1 to 4
`patients should be evaluated on a regular basis over an extended period of time, e.g.
`weeks. One good manner of carrying out evaluations is for patients to keep a daily diary in
`
`which they chart their moods. For example, patients may keep a daily record in which they rate
`
`their best and worst moods as either normal, mildly, moderately or severely depressed; and
`
`mildly, moderately, or severely manic. These records should help the patient and their physician
`
`10
`
`determine if moods fluctuate less frequently or become less extreme in intensity.
`
`Ideally, such
`
`a diary should be kept both before and after the administration of omega-3 fatty acid is begun.
`
`The evaluation of mood alterations by the patient should also be supplemented with periodic
`
`clinical evaluations carried out by a physician.
`
`In some cases, the evaluation discussed above may indicate that mood fluctuations have
`
`15
`
`become so stabilized in a patient as the result of administering omega—3 fatty acid at the initial
`
`concentration that no further adjustment in dosage is necessary.
`
`In other cases, the dosage of
`
`omega-3 fatty acid may be increased in order to obtain a more efficacious result. In general,
`
`dosage should not be increased beyond the point at which further stabilization of mood alteration
`
`is observed. If adverse side effects are experienced by patients, then dosages may be adjusted
`
`20
`
`in a downward direction accordingly.
`
`The process of adjusting dosage in an upward or downward direction and evaluating the
`
`effect of the adjustment on mood changes should be continued until an optimum dosage is
`
`discovered, i. e. the dosage at which the patient experiences the best balance between therapeutic
`
`effectiveness and discomfort due to side effects. In cases where adverse side effects are not
`
`25
`
`experienced, the optimal dosage is the lowest dose resulting in maximum stabilization of mood
`
`fluctuation.
`
`Omega-3 fatty acids may be used in combination with other agents effective at treating
`
`bipolar disorder, e. g. lithium or choline. These other agents may either be given together with
`
`omega-3 fatty acid in a single dosage form or they may be administered separately. Choline
`
`30
`
`should be administered at an initial dose of about 50 mg of free choline per kg of body weight
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`WO 97/39759
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`-7-
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`supplied either as a single unit dose or, preferably, divided into multiple doses during the day.
`The choline may be administered either as a free base or in the form of a pharrnaceutically
`acceptable salt. The final dosage of choline should typically be between about 2 and about 8
`grams of free choline per day.
`Patients taking lithium should continue taking the drug during the time at which choline
`and/or omega-3 fatty acid treatment is begun. Optimal dosages for each of the drugs may then
`be determined sequentially. For example, choline administration may be initiated and then
`optimized followed by the initiation and optimization of omega-3 fatty acid treatment. The
`problem of adjusting the dosages of multiple therapeutic agents is one that
`is routinely
`encountered by physicians and can be solved using well-established procedures similar to those
`
`discussed herein.
`
`Kits
`
`Individual preparations containing omega-3 fatty acid and other therapeutic agents for
`bipolar disorder, such as choline or lithium, may be provided in the form of a kit, comprising
`a carrier (e.g. a box or bag) compartmentalized to receive one or more components (bottles,
`vials, packets, etc.) in close confinement. Such a kit will be carried by patients with bipolar
`disorder and will typically contain written instructions concerning the way in which the enclosed
`drugs should be taken, potential side effects, etc. The kit should be portable, and be generally
`
`convenient for use by patients.
`
`10
`
`15
`
`20
`
`C.
`
`Omega-3 Phosphatidylcholines
`
`The present invention is also directed to omega-3 phosphatidylcholines in which glycerol
`
`is esterified at its y carbon to phosphocholine and at least one of the fatty acids esterified to
`
`either the a or B carbons is an omega—3 fatty acid. It is preferred that both the a carbon and {3
`
`carbon of glycerol be esterified to an omega-3 fatty acid, with the preferred fatty acids being
`
`25
`
`EPA and DHA. The most preferred phosphatidylcholines contain both DHA and EPA, one
`
`esterified at the a carbon of glycerol and the other at the 0 carbon.
`
`The phosphatidylcholines of the present invention may be synthesized using standard
`
`techniques well known in the art, see e.g. U.S. No. 4,701,468. One suitable method is to
`
`synthesize the "omega-3 phosphatidylcholines" from commercially available precursor lyso-
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`-8-
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`phosphatidylcholines. Specifically, a lyso-phos-phatidylcholine is acylated by combining the
`desired omega-3 fatty acid anhydride (e.g. from EPA or DHA) and 4-pyrrolidinopyridine as a
`catalyst (1.2 equivalents) in alcohol-free chloroform. Depending on the reaction conditions and
`the relative proportions of fatty acid, several different omega-3 phosphatidylcholine species will
`
`species will occur: dieicosapent-
`four major
`be generated. Using EPA and DHA,
`anoylphosphatidylcholine, didocosahexanoylphosphatidylcholine, l-eicosapentanoyl, 2-docosa-
`hexanoylphosphatidylcholine, and 1-docosahexanoyl, 2-eicosapentanoylphosphatidylcholine.
`The specific phosphatidylcholines of interest may then be isolated by well—established
`
`chromatographic methods.
`
`10
`
`D.
`
`of Treating Bipolar Disorder Using Omega-3
`Method
`Phosphatidylcholines
`
`The omega-3 phosphatidylcholines described above may be used for treating humans with
`
`bipolar disorder in the same manner and following the same procedures as those discussed in
`
`connection with omega-3 fatty acids. The phosphatidylcholines may be given in a substantially
`
`15
`
`purified fortn or as part of a pharmaceutical composition, It is expected that optimized dosages
`
`will have sufficient omega-3 phosphatidylcholine to deliver between about one and about 30
`
`grants of free omega-3 fatty acid per day, with the preferred daily dose being between 1 and 10
`
`grams. Patients should keep diaries of daily mood fluctuations and be evaluated by a physician
`
`on a regular basis to determine the effect of treatment. Based upon such evaluations dosages
`
`20
`
`may be increased or decreased as needed.
`
`As with omega-3 fatty acids, the omega-3 phosphatidylcholines may be delivered by any
`
`route and are compatible with any dosage form. Oral dosage forms such as tablets, capsules,
`
`powder packets and liquid solutions will generally be preferred. Therapeutically inert agents
`
`may be added to improve the palatability of preparations and additional therapeutic agents may
`
`25
`
`be included. It will be appreciated that one particularly attractive composition would include
`
`both a source of lithium as well as omega-3 phosphatidylcholine.
`
`In cases where parenteral administration is elected as the route of administration,
`
`preparations containing omega-3 phosphatidylcholine may be provided to patients in combination
`
`with pharmaceutically acceptable sterile aqueous or non-aqueous solvents, suspensions or
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`WO 97/39759
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`-9-
`
`emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol,
`vegetable oil, fish oil, and injectable organic esters. Aqueous carriers include water, water-
`alcohol solutions, emulsions or suspensions, including saline and buffered medical parenteral
`vehicles including sodium chloride solution, Ringer's dextrose solution, dextrose plus sodium
`chloride solution, Ringer's solution containing lactose, or fixed oils.
`Intravenous vehicles may
`include fluid and nutrient replenishers, electrolyte replenishers, such as those based upon
`
`Ringer's dextrose, and the like.
`in treating bipolar patients,
`Omega-3 phosphatidylcholine and other agents useful
`preferably lithium or choline ,may be provided as separate components in the form of a kit
`designed to be carried and used by bipolar patients. The kit would contain written instructions
`concerning the way in which the enclosed agents should be taken and other pertinent
`
`10
`
`information.
`
`All references cited herein are fully incorporated by reference. Having now fully
`
`described the invention, it will be understood by those of skill in the art that the invention may
`
`15
`
`be performed within a wide and equivalent range of conditions, parameters and the like, without
`
`affecting the spirit or scope of the invention or any embodiment thereof.
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`0000011
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`WO 97/39759
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`PCT/US97/06712
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`What is Claimed is:
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`-10-
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`1. A method of treating a human patient for bipolar disorder, comprising administering an
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`omega—3 fatty acid to said patient at a dosage sufficient to reduce or eliminate the symptoms of
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`said disorder.
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`2. The method of claim 1, wherein said omega-3 fatty acid is administered at a dose of between
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`about 1 and about 30 grams per day.
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`3. The method of claim 1, wherein said omega—3 fatty acid is in a substantially pure form.
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`4. The method of claim 1, wherein said omega-3 fatty acid is eicosapentanoic acid.
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`5. The method of claim 4, wherein said eicosapentanoic acid is administered at a dose of
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`between about 2 and about 10 grams per day.
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`6. The method of claim 1, wherein said omega-3 fatty acid is docosahexanoic acid.
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`7. The method of claim 6, wherein said docosahexanoic acid is administered at a dose of
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`between about 1 and about 5 grams per day.
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`8. The method of claim 1, fiirther comprising administering a source of lithium to said patient
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`at a dose sufficient to reduce or eliminate the symptoms of said disorder.
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`9. The method of claim 1, further comprising administerin
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`source of choline to said patient
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`at a dose effective at reducing or eliminating the symptoms of said disorder.
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`10. An omega-3 phosphatidylcholine useful in the treatment of bipolar disorder consisting of
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`glycerol, wherein:
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`WO 97/39759
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`PCT/US97IO6712
`
`-11-
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`a)
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`b)
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`the a and B carbons of said glycerol are both esterified to a fatty acid, at
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`least one of which is an omega-3 fatty acid; and
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`the Y carbon of said glycerol is esterified to phosphocholine.
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`11. The omega-3 phosphatidylcholine of claim 10, wherein both the a and [5 carbons of said
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`glycerol are esterified to an omega-3 fatty acid.
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`12. The omega-3 phosphatidylcholines of either claim 10 or 11, wherein eicosapentanoic acid
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`is esterified to either the on or [3 carbon of said glycerol.
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`13. The omega-3 phosphatidylcholine of either claim 10 or 11, wherein docosahexanoic acid
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`is esterified to either the 0: or [3 carbon of said glycerol.
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`14. The omega-3 phosphatidylcholine of claim 10, wherein eicosapentanoic acid is esterified
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`to the a carbon of said glycerol and docosahexanoic acid is esterified to the [3 carbon of said
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`glycerol.
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`15. The omega-3 phosphatidylcholine of claim 10, wherein docosahexanoic acid is esterified
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`to the a carbon of said glycerol and eicosapentanoic acid is esterified to the [3 carbon of said
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`omega-3 phosphatidylcholines.
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`16. A pharmaceutical composition comprising the omega-3 phosphatidylcholine of claim 10,
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`wherein one or more unit doses of said composition provides an amount of said omega-3
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`phosphatidylcholine sufficient to reduce or eliminate the symptoms of said bipolar disorder.
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`17. The pharmaceutical composition of claim 16, further comprising a source of lithium.
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`18. A method of treating bipolar disorder in a human patient, comprising administering the
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`omega-3 phosphatidylcholine of claim 10 to said patient at a dose sufficient to reduce or
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`eliminate the symptoms of said disorder.
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`0000013
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`0000013
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`WO 97/39759
`
`PCT/US97/06712
`
`-12-
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`19. The method of claim 18, further comprising administering a source of lithium to said
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`patient at a dosage sufficient to reduce or eliminate the symptoms of said disorder.
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`20. A kit comprising a carrier containing enclosed confinement
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`therein one or more
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`components, wherein:
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`a)
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`b)
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`a first component contains an omega-3 fatty acid; and
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`a second component contains a therapeutic agent useful in the treatment
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`of bipolar disorder.
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`21.
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`The kit of claim 20 wherein:
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`a)
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`b)
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`said first component contains an omega-3 fatty acid selected from the
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`group consisting of eicosapentanoic acid and docosahexanoic acid; and
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`said second component is selected from the group consisting of a source
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`of choline and a source of lithium.
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`22. A kit comprising a carrier containing in close confinement therein, none or more
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`components wherein:
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`a)
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`b)
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`a first component contains an omega-3 phosphatidyl-choline; and
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`a second component contains a therapeutic agent useful in the treatment
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`of bipolar disorder.
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`23. The kit of claim 22, wherein the a carbon of said glycerol is esterified to eicosapentanoic
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`acid and the [3 carbon of said glycerol is a esterified to docosa-hexanoic acid.
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`24. The kit of claim 22, wherein the a carbon of said glycerol is esterified to docosahexanoic
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`acid and the [3 carbon of said glycerol is a esterified to eicosapentanoic acid
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`24. The kit of any one of claims 22-24, wherein said second component is selected from the
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`group consisting of a source of choline and a source of lithium.
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`0000014
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`0000014
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