WO2005044176A2

WO2005044176A2 - Compositions containing phosphatidic acid, methods of use thereof, methods of manufacture thereof, and articles of manufacture containing same

Info

Publication number: WO2005044176A2
Application number: PCT/IL2004/001026
Authority: WO
Inventors: David Rutenberg
Original assignee: Lipogen Ltd.
Priority date: 2003-11-10
Filing date: 2004-11-10
Publication date: 2005-05-19
Also published as: WO2005044176A3

Abstract

Phosphatidic acid compositions, uses thereof and methods of manufacture thereof. Compositions include a physiologically effective amount of phosphatidic acid and carriers and excipients. Physiologic effectiveness is with regard to at least one of: amelioration of insulin resistance; improvement of glucose metabolism; reduction of cortisol level; treatment of depression; relief of stress associated symptoms; and improvement of mood. Preferably, phosphatidic acid is produced from lecithin by reaction with phospholipase-D. Compositions further including phosphatidylserine are also disclosed.

Description

COMPOSITIONS CONTAINING PHOSPHATIDIC ACID, METHODS OF USE THEREOF, METHODS OF MANUFACTURE THEREOF, AND ARTICLES OF MANUFACTURE CONTAINING SAME

FIELD AND BACKGROUND OF THE INVENTION The present invention relates to compositions containing phosphatidic acid, methods of use thereof, methods of manufacture thereof, nd articles of manufacture containing same and, more particularly, to compositions which are useful in regulation of cortisol levels and treatment of various types of stress (e.g. mental, psychological and physical), regulation of glucose metabolism and amelioration of insulin resistance. The present invention further relates to compositions containing a mixture of phosphatidic acid and phosphatidylserine, methods of use thereof, methods of manufacture thereof, and articles of manufacture containing same and, more particularly", to compositions which are useful in regulation of cortisol levels, regulation of glucose metabolism, and amelioration of insulin resistance. The influence of administration of brain cortex phosphatidylserine over time on the neuroendocrine responses to physical stress has been previously investigated (Monteleoni et al., Eur. J. Clin. Pharmacology, 385-388, 1992). Monteleoni determined that oral administration of phosphatidylserine at 800 mg per day for 10 days prior to exercise, reduced the ACTH and cortisol responses to physical exercise. Monteleoni et al. (Neuroendocrinology, 52, 243-248, 1990) also conducted a double blind study in which every participant received intravenously brain cortex phosphatidylserine or a placebo before starting a physical exercise. Blood samples were collected before and after the exercise for plasma ACTH, cortisol and growth hoπnone readings. In the placebo group the physical stress induced an increase in ACTH, cortisol and growth hormone while the phosphatidylserine group showed a reduction in production of ACTH and cortisol. Monteleoni failed to investigate the physiologic effect of phosphatidic acid, either alone or in combination with phosphatidylserine on production of ACTH and cortisol. Further, Monteleoni does not teach an economical means of producing phosphatidylserine and/or phosphatidic acid. PCT/IL97/00147 ( 097/41874) teaches that phosphatidic acid may alleviate withdrawal symptoms associated with addiction (cigarettes, alcohol, narcotics). Further, this patent is strictly limited to treatment of withdrawal and does not consider the broader physiologic implications of the observed response to phosphatidic acid. US 6,410,522 teaches a composition of phosphatidylserine and phosphatidic acid which improves mood and/or decreases depression. While the influence of the claimed composition on cortisol levels is mentioned, this patent fails to teach potential utility of the composition in regulation of glucose metabolism or amelioration of insulin resistance. Rosmond R. (Med. Sci. Monitor, RA35-RA39, 2003 Feb) outlines the role of the stress-induced neuro-endocrine response pattern in the pathogenesis of insulin resistance.

Rosmond concluded that stress induced disturbances of the hypothalamic-pituitary- adrenal (HPA) axis with elevated levels of circulating cortisol are the pathway to type 2 diabetes, involving two defects: peripheral insulin resistance and hyperinsulinemia, followed by the failure of insulin secretion to compensate for the insulin resistance.

However, Rosmond makes no hint or suggestion that phosphatidic acid, either alone or in combination with other phospholipids including phospatidylserine, has potential utility in regulating the HPA axis. There is thus a widely recognized need for, and it would be highly advantageous to have, compositions containing phosphatidic acid, methods of use thereof, methods of manufacture thereof, and articles of manufacture containing same devoid of the above limitation(s).

SUMMARY OF THE INVENTION It is an object of the present invention to provide a modifier having an effect of regulation of cortisol levels, alleviating symptoms associated with insulin resistance and the regulation of glucose metabolism. According to one aspect of the present invention there is provided a pharmaceutical composition, the composition includes, as an active ingredient, an amount of phosphatidic acid physiologically effective with regard to at least one parameter selected from the group consisting of: (a) amelioration of insulin resistance; (b) improvement of glucose metabolism; (c) reduction of cortisol level; (d) treatment of depression; (e) relief of stress associated symptoms; and (f) improvement of mood; and carriers and excipients. According to a further aspect of the present invention there is provided a method of preparing a composition efficacious in treating insulin resistance and in improving glucose metabolism. The method includes: (a) preparing phosphatidic acid; (b) combining the phosphatidic acid with carriers and excipients. According to still a further aspect of the present invention there is provided a method of preparmg a composition efficacious in treating depression, suppressing mental & emotional stress and improving mood, the method includes: (a) preparing phosphatidic acid; (b) combining the phosphatidic acid with carriers and excipients. According to another further aspect of the present invention there is provided a method of preparing a composition efficacious in reducing a cortisol level in a subject, the method includes: (a) preparing phosphatidic acid; (b) combining the phosphatidic acid with carriers and excipients. According to yet another further aspect of the present invention there is provided an article of manufacture including: (a) a pharmaceutical composition includes a physiologically active amount of phosphatidic acid and carriers or excipients; (b) instructions for use of the pharmaceutical composition in treatment of insulin resistance and in improving glucose metabolism; and (c) packaging material. According to still another further aspect of the present invention there is provided an article of manufacture including: (a) a pharmaceutical composition includes a physiologically active amount of phosphatidic acid and carriers or excipients; (b) instructions for use of the pharmaceutical composition in treating depression, for suppressing mental & emotional stress and for improving mood; and (c) packaging material. According to a further additional aspect of the present invention there is provided an article of manufacture including: (a) a pharmaceutical composition includes a physiologically active amount of phosphatidic acid and carriers or excipients; (b) instructions for use of the pharmaceutical composition in reducing cortisol level; and (c) packaging material. According to yet another further additional aspect of the present invention there is provided a method for treating depression, for suppressing mental & emotional stress and for improving mood in a subject. The method includes administering to the subject a physiologically effective amount of phosphatidic acid. According to still another further additional aspect of the present invention there is provided a method for reducing insulin resistance and for improving glucose metabolism in a subject. The method includes administering to the subject a physiologically effective amount of phosphatidic acid. According to yet another further additional aspect of the present invention there is provided a method for reducing the cortisol level of a subject. The method includes administering to the subject a physiologically effective amount of phosphatidic acid. According to an additional aspect of the present invention there is provided a pharmaceutical composition effective in reducing insulin resistance and in improving glucose metabolism. The composition includes, as an active ingredient, a physiologically effective amount of a phospholipid mixture. The mixture includes phosphatidic acid and phosphatidylserine and further includes carriers or excipients. The composition is effective in reducing insulin resistance and in improving glucose metabolism. According to another aspect of the present invention there is provided a method of preparing a composition efficacious in treating insulin resistance and in improving glucose metabolism from lecithin. The method includes: (a) providing a mixture of phospholipids including phosphatidic acid and phosphatidylserine; and (b) combining an amount of the mixture of phospholipids acid having physiologic activity in treating insulin resistance and in improving glucose metabolism with carriers and/or excipients. According to yet another aspect of the present invention there is provided a method for the use of lecithin in the manufacture of a composition efficacious in treating insulin resistance and in improving glucose metabolism. According to still another aspect of the present invention there is provided a method for the use of phosphatidic acid and phosphatidylserine in the manufacture of a composition efficacious in treating insulin resistance and in improving glucose metabolism. According to an additional aspect of the present invention there is provided an article of manufacture includes: (a) a pharmaceutical composition effective in reducing insulin resistance and in improving glucose metabolism, the composition includes, as an active ingredient, a physiologically effective amount of a mixture of phospholipids including phosphatidic acid and phosphatidylserine and further includes carriers or excipients; (b) instructions identifying the pharmaceutical composition for use in treatment of insulin resistance and in improving glucose metabolism ; and (c) packaging material. According to yet an additional aspect of the present invention there is provided a method for reducing insulin resistance and for improving glucose metabolism in a subject. The method includes administering to the subject a physiologically effective amount of a mixture of phospholipids including phosphatidic acid and phosphatidylserine, which further includes carriers or excipients. The mixture is effective in reducing insulin resistance and in improving glucose metabolism. According to still an additional aspect of the present invention there is provided a method for reducing the cortisol level of a subject. The method includes administering to the subject a physiologically effective amount of a mixture of phospholipids including phosphatidic acid and phosphatidylserine and further including carriers or excipients. The mixture is effective in reducing insulin resistance and in improving glucose metabolism. According to further features in preferred embodiments of the invention described below, the phospholipid mixture is a fraction of a reaction product of an enzymatic trans- phosphatidylation of at least one crude phospholipid source by Phospholipase-D. According to still further features in the described preferred embodiments the mixture includes at least 10%, more preferably at least 20% (w/w) Phosphatidylserine and at least 2% (w/w) of phosphatidic acid out of a total phospholipid content of the composition. According to still further features in the described preferred embodiments the at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipids concentrate. According to still further features in the described preferred embodiments the at least 2% (w/w) of phosphatidic acid does not exceed 3%. According to still further features in the described preferred embodiments the physiologically effective amount of the mixture is a daily dose in the range of 5mg to 5000mg, more preferably a daily dose of 300mg to 1500 mg, most preferably a daily dose of 500 to 700 mg. According to still further features in the described preferred embodiments the composition is formulated for oral administration. According to still further features in the described preferred embodiments at least one item selected from the group consisting of the phosphatidylserine and the phosphatidic acid is present in a form selected from the group consisting of a salt, an ester and another derivative. According to still further features in the described preferred embodiments the providing the mixture is accomplished by: (i) trans-phospatidylating a crude phospholipid source with phospholipase-D to produce a reaction product; and (ii) separating from the reaction product a fraction containing the mixture of phospholipids including phosphatidylserine and phosphatidic acid. According to still further features in the described preferred embodiments the phosphatidic acid includes a reaction product of an enzymatic trans-phosphatidylation of at least one crude phospholipid source by Phospholipase-D. According to still further features in the described preferred embodiments the at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipids concentate. According to still further features in the described preferred embodiments the phosphatidic acid includes at least 2% (w/w) of a total phospholipid content of the composition. According to still further features in the described preferred embodiments the at least 2% (w/w) of phosphatidic acid does not exceed 3%. According to still further features in the described preferred embodiments the amount of the phosphatidic acid is a daily dose in the range of 5mg to 5000mg, more preferably a daily dose of 300mg to 1500 mg, most preferably a daily dose of 500 to 700 mg. According to still further features in the described preferred embodiments the composition is formulated for oral administration. According to still further features in the described preferred embodiments the phosphatidic acid is present in a form selected from the group consisting of a salt, an ester and another derivative. According to still further features in the described preferred embodiments the composition is devoid of phosphatidylserine. According to still further features in the described preferred embodiments preparing the phosphatidic acid includes trans-phosphatidylating at least one crude phospholipid source with phospholipase-D. The present invention successfully addresses the shortcomings of the presently known configurations by providing effective compositions which are economical to produce, easily administered and safe. DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention relates to compositions having an effect of reduction of cortisol level, ameliorationg symptoms associated with insulin resistance and the regulation of glucose metabolism, treatment of depression, relief of stress associated symptoms and improvement of mood as well as to methods of use thereof and methods of manufacture thereof, phosphatidic acid is a key active ingredient in all of these compositions. Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting. For purposes of this specification and the accompanying claims "pharmaceutical composition" refers to a preparation of one or more of the active ingredients described herein with other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. The phrase "pharmaceutical composition", as employed in this specification and the accompanying claims, is to be interpreted in its broadest possible sense so that it includes nutraceutical compositions and other less rigidly defined compositions intended for administration of a compound to an organism. As used herein the phrase "nutraceutical composition" refers to a nutritional supplement, which may take the form of pill, capsule, liquid, food or drink. Nutraceutical compositions are preferably, but not exclusively, supplied in appetizing forms such as fruit drinks (e.g nectar), milk based beverages, candies, cakes, cookies crackers or breads. It will be appreciated that the standard ingredients of these items function as carriers and/or excipients (as defined hereinbelow) when an item becomes a nutraceutical composition. For example, the flour, cocoa, sugar, eggs and margarine typically employed in preparing a brownie may be considered carriers if the brownie is a nutraceutical composition containing active ingredients as detailed hereinabove and hereinbelow. For purposes of this specification and the accompanying claims, the teπn "carrier" refers to an inert ingredient or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of me administered compound. An adjuvant is included in this definition. For purposes of this specification and the accompanying claims, the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Techniques for formulation and administration of drugs may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference. The present invention is embodied by a pharmaceutical composition effective in reducing insulin resistance and in improving glucose metabolism. The composition includes, as an active ingredient, a physiologically effective amount of a phospholipid mixture. The mixture includes phosphatidic acid and phosphatidylserine and further includes carriers or excipients. The composition is effective in reducing insulin resistance and in improving glucose metabolism. A method of preparing the composition efficacious in treating insulin resistance and in improving glucose metabolism from lecithin constitutes an additional embodiment of the invention. The method includes providing a mixture of phospholipids including phosphatidic acid and phosphatidylserine and further includes combining an amount of the mixture with carriers and/or excipients. Optionally, but preferably, providing the mixture is accomplished by trans-phospatidylating a crude phospholipid source with phospholipase-D to produce a reaction product and separating from the reaction product a fraction containing the mixture of phospholipids including phosphatidic acid and phosphatidylserine. In simpler terms, the invention is embodied by a method for the use of lecithin in the manufacture of a composition efficacious in treating insulin resistance and in improving glucose metabolism. Alternately, or additionally, the invention is embodied by a method for the use of phosphatidylserine and phosphatidic acid in the manufacture of a composition efficacious in treating insulin resistance and in improving glucose metabolism. optionally, but preferably, the pharmaceutical composition is supplied as an article of manufacture including the pharmaceutical composition as described hereinabove, instructions identifying the pharmaceutical composition for use in treatment of insulin resistance and in improving glucose metabolism and packaging material. Use of the pharmaceutical composition constitutes a method for reducing insulin resistance and for improving glucose metabolism in a subject which further embodies the invention. The method includes administering to the subject a physiologically effective amount of a mixture of phospholipids including phosphatidic acid and phosphatidylserine which further includes carriers or excipients. The mixture is effective in reducing insulin resistance and in improving glucose metabolism. The invention is further embodied by a method for reducing the cortisol level of a subject. The method includes administering to the subject a physiologically effective amount of a mixture of phospholipids including phosphatidic acid and phosphatidylserine and further including carriers or excipients. The mixture is effective in reducing insulin resistance and in improving glucose metabolism. Preferably, the phospholipid mixture is a fraction of a reaction product of an enzymatic trans-phosphatidylation of at least one crude phospholipid source by

Phospholipase-D. Preferably at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, a milk phospholipids concentrate and egg yolk lecithin. Additional details are provided in Examples 2, 3 and 5 hereinbelow.

According to a most preferred embodiment of the invention the mixture includes at least

10%, more preferably at least 20% (w/w) phosphatidylserine and at least 2% (w/w) of phosphatidic acid out of a total phospholipid content of the composition. More preferably, the at least 2% (w/w) of phosphatidic acid does not exceed 3%. The physiologically effective amount of the mixture is preferably a daily dose in the range of 5mg to 5000mg, more preferably a daily dose of 300mg to 1500 mg, most preferably a daily dose of 500 to 700 mg. Results using a most preferred dose of 600 mg/day are presented in example 6 hereinbelow with regard to modifying insulin resistance and improving glucose metabolism in diabetic subjects. In Example 6, three 200 mg doses per day are employed. However, one of ordinary skill in the art of pharmacology will be capable of formulating a slow release form of the composition, preferably one that requires only once per day administration, most preferably less frequent administration. Similarly, the preferred embodiment of the composition employed in Example 6 is formulated for oral administration, although formulations for all routes of administration are within the scope of the invention. Other routes of administration may, for example, include, rectal, transmucosal, especially transnasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intravenous, inrtaperitoneal, intranasal, or intraocular injections. Pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions for use in accordance with the present invention thus may be foπnulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. For injection, the active ingredients of the pharmaceutical composition may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For oral administration, the pharmaceutical composition can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the pharmaceutical composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. Pharmaceutical compositions which can be used orally include push-fit capsules made of gelatin or vegetable products as well as soft, sealed capsules made of gelatin (e.g. soft or hard) and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For administration by nasal inhalation, the active ingredients for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in a dispenser may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. The pharmaceutical composition described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative. The compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily or water based injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder foπn for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water based solution, before use. The pharmaceutical composition of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides. Pharmaceutical compositions suitable for use in context of the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of active ingredients (nucleic acid construct) effective to prevent, alleviate or ameliorate symptoms of a disorder (e.g., ischemia) or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. For any preparation used in the methods of the invention, the therapeutically effective amount or dose can be estimated initially from in vitro and cell culture assays. For example, a dose can be formulated in animal models to achieve a desired concentration or titer. Such information can be used to more accurately determine useful doses in humans. Toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in viti-o, in cell cultures or experimental animals. The data obtained from these in vitro and cell culture assays and animal studies can be used in foπnulating a range of dosage for use in human. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.l). Dosage amount and interval may be adjusted individually to provide plasma or brain levels of the active ingredient are sufficient to induce or suppress angiogenesis (minimal effective concentration, MEC). The MEC will vary for each preparation, but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. Detection assays can be used to determine plasma concentrations. Depending on the severity and responsiveness of the condition to be treated, dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved. The amount of a composition to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc. Compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions comprising a preparation of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition, as is further detailed hereinabove and hereinbelow. According to some preferred embodiments of the invention, the phosphatidylserine and/or the phosphatidic acid is present in a form selected from the group consisting of a salt, an ester and another derivative. The invention is alternately embodied by a pharmaceutical composition including, as an active ingredient, an amount of phosphatidic acid physiologically effective with regard to at least a parameter and carriers and excipients. The parameter is preferably one or more of parameter selected from the group consisting of amelioration of insulin resistance, improvement of glucose metabolism, reduction of cortisol level, treatment of depression, relief of stress associated symptoms, and improvement of mood. Preferably, the composition is provided as part of an article of manufacture further including instructions for use of the pharmaceutical composition in treatment of insulin resistance and in improving glucose metabolism and packaging material. Alternately, but also preferably, the composition is provided as part of an article of manufacture further including instructions for use of the pharmaceutical composition in treating depression, for suppressing mental & emotional stress and for improving mood and packaging material. Alternately, but also preferably, the composition is provided as part of an article of manufacture further including instructions for use of the pharmaceutical composition in reducing cortisol level and packaging material. The invention is further embodied by a method of preparing a composition efficacious in treating insulin resistance and in improving glucose metabolism. The method includes preparing phosphatidic acid and combining the phosphatidic acid with carriers and excipients. The invention is further embodied by a method of preparing a composition efficacious in treating depression, suppressing mental & emotional stress and improving mood. The method includes preparing phosphatidic acid and combining the phosphatidic acid with carriers and excipients. The invention is further embodied by a method of preparing a composition efficacious in reducing a cortisol level in a subject. The method includes preparing phosphatidic acid and combining the phosphatidic acid with carriers and excipients. As detailed hereinbelow in Examples 1, 3 and 4 preparing the phosphatidic acid preferably includes trans-phosphatidylating at least one crude phospholipid source with phospholipase-D. The invention is further embodied by a method of treating depression, for suppressing mental & emotional stress and for improving mood in a subject. The method includes administering to the subject a physiologically effective amount of phosphatidic acid. The invention is further embodied by a method of a method for reducing insulin resistance and for improving glucose metabolism in a subject. The method includes administering to the subject a physiologically effective amount of phosphatidic acid. The invention is further embodied by a method of reducing the cortisol level of a subject. The method includes administering to the subject a physiologically effective amount of phosphatidic acid. Preferably at least a portion of the phosphatidic acid is provided as a reaction product of an enzymatic trans-phosphatidylation of at least one crude phospholipid source by Phospholipase-D. Preferably the at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipids concentrate (e.g. PSNU 18200; Aria Food Ingredients amba; Skanderborgvej; Viby J.; Denmark), alternately, or additionally, a milk phospholipids concentrate may be employed as a source of phosphatidylserine in cases where trans- phosphatidylation by Phospholipase-D is not employed. Preferably, the phosphatidic acid includes at least 2% (w/w) of a total phospholipid content of the composition. More preferably, the at least 2% (w/w) of phosphatidic acid does not exceed 3%. According to still further features in the described preferred embodiments the amount of the phosphatidic acid is a daily dose in the range of 5mg to 5000mg, more preferably a daily dose of 300mg to 1500 mg, most preferably a daily dose of 500 to 700 mg. Examples 7 and 8 illustrate the efficacy of the composition in treatment of diabetes type 2 patients and in subjects under stress respectively. These examples describe a most preferred dose of 600 mg/day provided as three 200 mg doses throughout the day. Slow release formulations are a most preferred embodiment of the invention and may be prepared as described hereinabove. Preferably the composition is formulated for oral administration although other formulations are within the scope of the invention as detailed hereinabove. The phosphatidic acid of the composition may be provided as a salt, an ester or another derivative without negatively impacting on the utility of the composition. According to a most preferred embodiment of the invention, the composition may be devoid of phosphatidylserine. For purposes of this specification and the accompanying claims, the phrase "devoid of phosphatidylserine" means that no physiologically effective amount of phosphatidylserine is present. While enzymatic production of phosphatidylserine and/or phosphatidic acid is employed in some preferred embodiments of the invention, these compounds may be synthesized and are available commercially, for example from Avanti Polar Lipids Inc (Alabaster, Al, USA). Phosphatidic acid is available as catalog numbers 840857-840864; 830841- 830845; 830855; 830856; 830865; 840875; 840885 through 840887. Phosphatidylserine is available as catalog numbers 840034; 830034; 840060 through 840062; 840039; 830039; 840063 through 840065; 840030; 830030; 840031; 830031; 840036; 830036; 840038; 830038; 840033; 830033; 840037; 830037; 850408P;

850408C; 830028P; 830028C; 830029; 840035; 830035; 840040; 840040; 840066; and

840067. These catalog numbers are provided as non-limiting examples of commercially available phosphatidic Acid and Phosphatidylserine. Their existence establishes the feasibility of synthesis of these materials on a commercial scale well as their availability for use in the context of the present invention. Alternately, as described above and further detailed in examples 1 through 4 presented hereinbelow, a crude phospholipid source (namely, phosphatidylcholine) preferably a vegetal lecithin, egg yolk lecithin or milk phospholipids fraction transphosphatidylated with phospholipase-D thereby substituting the choline group with the serine group or the hydroxyl group, to produce the rearranged phosphatidic acid. If L- serine or DL-serine or D-serine is added to the reaction, a mixture of phosphatidylserine and phosphatidic acid results. Any commercially available vegetal lecithin or egg yolk lecithin or milk phospholipid concentrate may be used, with no limitation, as the raw material. As phospholipase-D for use in the process of enzymatic conversion, use may be made of for example those from cabbage and actinomyces, if they have an activity on lecithin or hydrogenated lecithin or lysolecithin in the presence of L-serine or DL-serine or D-serine and water to produce phosphatidylserine and phosphatidic acid. A specific process of enzymatic conversion is known and described in for example the article by Eibl A. and Kovatchev S. "Preparation of phospholipids analogs by phospholipase-D." ("Methods in Enzymology" Vol. 72, pages: 632- 639, 1981). The composition of the present invention may be administered effectively orally, or by other routes as detailed hereinabove. The composition may further include additional phospholipids and lyso-phospholoipids, sugars and proteins which facilitate preparation of capsules and granules with improved handling and extended shelf life. Because of the absence of any safety problem, composition may be blended into foods and beverages, either in powder or liquid form or as hydrogenated substance for purposes set forth hereinabove and hereinbelow. Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

EXAMPLES Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non-limiting fashion. EXAMPLE 1: PRODUCTION OF PHOSPHATIDIC ACID FROM SOY LECITHIN Soybean lecithin (Soy HealthyMe; Central Soya GmbH, Germany) was employed to produce phosphatidic acid by the following process. Fifty grams of lecithin and ten grams of soybean oil were placed in a 300 ml vial. Ethyl acetate (50 ml) was added for solubilization of the substrate solution. The substrate solution was thoroughly blended and a 0.5ml solution of 500 U/ml phospholipase-D from cabbage (Sigma Chemical P-7758; St. Louis MO, USA) was added to the substrate solution to form a reaction solution. The reaction solution was incubated at 25 degrees centigrade for 5 hours with constant stirring. Inactivation of the enzyme in the reaction solution was accomplished by immersion of the vessel containing the reaction solution in water bath heated to 90 degrees centigrade for 1 hour. The reaction solution was then cooled in ice so that separation into two layers occurred. The separated reaction solution was left undisturbed for 30 minutes on ice. The upper ethyl acetate layer was discarded. The remaining lower layer containing phosphatidic acid was extracted in 200 ml of chloroform. Vacuum evaporation of the chloroform produced a phospholipid fraction which is typically 40% to 50% phosphatidic acid or more. While soy lecithin may contain trace amounts of phosphatidylserine, this method yields a product which is "devoid of phosphatidylserine" as the phrase is defined hereinabove. EXAMPLE 2: PRODUCTION OF PHOSPHATIDIC ACID AND PHOSPHATIDYLSERINE FROM SOY LECITHIN In order to produce a phospholipid fraction containing a mixture of phosphatidylserine and phosphatidic acid the method of Example 1 was employed with the addition of 20 ml of a solution of 0.30 g/ml L-serine dissolved in 0.1M sodium phosphate buffer, pH 7.0 to the substrate solution. Evaporation of chloroform at the end of the procedure yields a phospholipid fraction as in Example 1, but enriched in phosphatidylserine. EXAMPLE 3: PRODUCTION OF PHOSPHATIDIC ACID AND PHOSPHATIDYLSERINE FROM EGG LECITHIN Substitution of 50g egg yolk lecithin (DS-PL95E; Doosan Corp.; Venture BG Biotech BU. Korea) for soy lecithin as the substrate in the method of Example 1 produced a phospholipid fraction rich in phosphatidic acid as in Example 1. Addition of L-serine to the reaction mixture as in Example 2 produced a phospholipid fraction rich in phosphatidylserine and phosphatidic acid as in Example 2.

EXAMPLE 4: PRODUCTION OF PHOSPHATD3IC ACD3 FROM HYDROGENATED SOY LECITHIN Soybean lecithin (Soy HealthyMe; Central Soya GmbH, Germany) was hydrogenated by solubihzing in a mixture of n-hexane (15 g) and ethanol (3 g). Addition of 0.15 g of 10% palladium carbon to the solution was performed followed by hydrogenation for 5 hours with constant stirring at room temperature and ambient pressure. Using the hydrogenated soybean lecithin as the substrate, a phospholipid fraction rich in phosphatidic acid was produced as described in Example 1 and a phospholipid fraction rich in phosphatidic acid plus phosphatidylserine was produced by the method of Example 2.

EXAMPLE 5: HYDROGENATION OF PHOSPHATIDIC ACID AND PHOSPHATD3YLSERINE PRODUCED FROM SOY LECITHIN One gram of a phospholipid fraction rich in phosphatidylserine and phosphatidic acid produced by the method of Example 2 was solubilized in a mixture of n-hexane (15 g) and ethanol (3 g) and hydrogenated as in Example 4. EXAMPLE 6: ORALLY ADMINISTERED PHOSPHATIDIC ACID AND PHOSPHATD3YLSERINE IN DIABETIC SUBJECTS In order to establish the efficacy of orally administered phosphatidic acid and phosphatidylserine in modifying insulin resistance and improving glucose metabolism in diabetic subjects, five human volunteers suffering from type 2 diabetes were recruited (table 1). A phosphatidylserine-phosphatidic acid complex (1:1 molar ratio) was prepared from soy lecithin according to Example 2. Each of the volunteers received 200 mg. of the phosphatidylserine - phosphatidic acid complex three times per day for a period of one week. Blood glucose levels were measured using a commercially available glucometer (Roche Acutrend Sensor). Effect on blood glucose levels is summarized in table 1. Table 1: Influence ofphosphatidylserine-phosphatidic acid complex on blood glucose in subjects with type 2 diabetes.

0 Normal, fasting blood glucose level less than 110 mg/DL. + Slightly elevated, blood glucose level between 110 mg/DL - 150 mg/DL. Highly elevated, blood glucose level more than 150 mg/DL.

As indicated in Table 1, a significant improvement was observed in all five participants irrespective of age or gender. These results indicate that orally administered phosphatidic acid and phosphatidylserine is useful in improving the glucose metabolism and lowering insulin resistance in patients with type 2 diabetes. EXAMPLE 7: ORALLY ADMINISTERD PHOSPHATD3IC ACDD IN DIABETIC SUBJECTS In order to determine whether phosphatidic acid alone might be responsible for the effects on glucose metabolism in diabetes type 2 patients described in Example 6, phosphatidic acid was prepared from soy lecithin according to Example 1. Five human volunteers with diabetes type 2 received phosphatidic acid orally according to the same schedule employed in example 6. Results are summarized in table 3. Table2: Influence of phosphatidic acid on blood glucose in subjects with type 2 diabetes.

0 Normal, fasting blood glucose level less than 110 mg/DL. + Slightly elevated, blood glucose level between 110 mg/DL - 150 mg/DL. ++ Highly elevated, blood glucose level more than 150 mg/DL.

Results summarized in Table 2 indicate a significant improvement in response to phosphatidic acid treatment in three of five volunteers. No correlation to age or gender is postulated. These results suggest that phosphatic acid alone, perhaps at a higher dose, might be advantageously employed in care of type 2 diabetes patients. Because phosphatidic acid is less costly to prepare than the phospatidylserine-phosphatidic acid mixture, treatment with phosphatidic acid only may be preferable even if higher doses are required.

EXAMPLE 8: ORALLY ADMINISTERED PHOSPHATTDIC IN SUBJECTS UNDER STRESS In order to determine whether phosphatidic acid alone might be responsible for the effects on cortisol in patients under stress described in US 6,410,522, phosphatidic acid was prepared from soy lecithin according to Example 1. Four human volunteers under mental and emotional stress were recruited. The volunteers were students in a period of critical examination and reported stress symptoms. In addition, all four volunteers exhibited blood cortisol levels of 125 ng/ml or greater as measured by commercial enzyme immunoassay kit (IBL, Hamburg, Germany). phosphatidic acid was administered orally according to the same schedule employed in example 8. Results are summarized in table 3. Table 3: Influence of phosphatidic acid complex on blood cortisol in subjects under stress

Results summarized in table 3 indicate that phosphatidic acid reduced blood cortisol level in all four volunteers. Improvement was observed irrespective of age or gender. These results indicate the results presented in Example 7 are due in large part to phosphatidic acid. Because phosphatidic acid is less costly to prepare than the phosphatidylserine-phosphatidic acid mixture, treatment with phosphatidic acid only may be preferable even if higher doses are required. Because cortisol is known to be involved in mood regulation (see US 6,410,522), these results suggest that phosphatidic acid may be employed in controlling depression and improving mood.

REFERENCES

Eibl A. and Kovatchev S. "Preparation of phospholipids analogs by phospholipase D." ("Methods in Enzymology" Vol. 72, pages : 632- 639, 1981).

Monteleone, et al., "Effects of phosphatidylserine on the Neuroendocrine Response to Physical Stress in Humans", Neuroendocrinology, 52, 243-248, 1990.

Monteleone, et al., "Blunting by chronic phosphatidylserine administration of the stress- induced activation of the hypothalamo-pituitary-adrenal axis in healthy men", Eur. J. Clin. Pharmacology, 385-388, 1992.

Rosmond R. "Stress induced disturbances of the HPA axis: a pathway to Type 2 diabetes", ("Medical Science Monitor" Vol. 9 No.2, pages : RA35-RA39, 2003).

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition, the composition comprising, as an active ingredient, an amount of phosphatidic acid physiologically effective with regard to at least one parameter selected from the group consisting of: (a) amelioration of insulin resistance; (b) improvement of glucose metabolism; (c) reduction of cortisol level; (d) treatment of depression; (e) relief of stress associated symptoms; and (f) improvement of mood; and carriers and excipients.

2. The composition of claim 1, wherein said phosphatidic acid comprises a reaction product of an enzymatic trans-phosphatidylation of at least one crude phospholipid source by Phospholipase-D.

3. The composition of claim 1, wherein said at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipids concentrate.

4. The composition of claim 1, wherein said phosphatidic acid comprises at least 2% (w/w) of a total phospholipid content of the composition.

5. The composition of claim 1 , wherein said amount of said phosphatidic acid is a daily dose in the range of 5mg to 5000mg.

6. The composition of claim 1, wherein the composition is formulated for oral administration.

7. The composition of claim 1, wherein said phosphatidic acid is present in a form selected from the group consisting of a salt, an ester and another derivative.

8. The composition of claim 1, devoid of phosphatidylserine.

9. A method of preparing a composition efficacious in treating insulin resistance and in improving glucose metabolism, the method comprising: (a) preparing phosphatidic acid; (b) combining said phosphatidic acid with carriers and excipients.

10. A method of preparing a composition efficacious in treating depression, suppressing mental & emotional stress and improving mood, the method comprising: (a) preparing phosphatidic acid; (b) combining said phosphatidic acid with carriers and excipients.

11. A method of preparing a composition efficacious in reducing a cortisol level in a subject, the method comprising: (a) preparing phosphatidic acid; (b) combining said phosphatidic acid with carriers and excipients.

12. A method according to any one of claims 9, 10 or 11, wherein said preparing said phosphatidic acid comprises trans-phosphatidylating at least one crude phospholipid source with phospholipase-D.

13. The method of claim 12, wherein said at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipid concentrate.

14. A method according to any one of claims 9, 10 or 11„ further comprising formulating said phosphatidic acid in an orally administrable form.

15. A method according to any one of claims 9, 10 or 11„ further comprising preparing said phosphatidic acid in a daily dose in the range of 5mg to 5000mg.

16. An article of manufacture comprising: (a) a pharmaceutical composition comprising a physiologically active amount of phosphatidic acid and carriers or excipients; (b) instructions for use of said pharmaceutical composition in treatment of insulin resistance and in improving glucose metabolism ; and (c) packaging material.

17. The article of manufacture of claim 16, wherein said phosphatidic acid comprises a reaction product of a reaction between at least one crude phospholipid source and phospholipase-D.

18. The article of manufacture of claim 17, wherein said at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipid concentrate.

19. The article of manufacture of claim 16, wherein said pharmaceutical composition is formulated in an orally administrable form.

20. The article of manufacture of claim 16, wherein said pharmaceutical composition includes phosphatidic acid in a daily dose in the range of 5mg to 5000mg.

21. An article of manufacture comprising: (a) a pharmaceutical composition comprising a physiologically active amount of phosphatidic acid and carriers or excipients; (b) instructions for use of said pharmaceutical composition in treating depression, for suppressing mental & emotional stress and for improving mood; and (c) packaging material.

22. The article of manufacture of claim 21, wherein said phosphatidic acid comprises a reaction product of a reaction between at least one crude phospholipid source and phospholipase-D.

23. The article of manufacture of claim 22, wherein said at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipids concentrate.

24. The article of manufacture of claim 22, wherein said pharmaceutical composition is formulated in an orally administrable form.

25. The article of manufacture of claim 21, wherein said pharmaceutical composition includes phosphatidic acid in a daily dose in the range of 5mg to 5000mg.

26. An article of manufacture comprising: (a) a pharmaceutical composition comprising a physiologically active amount of phosphatidic acid and carriers or excipients; (b) instructions for use of said pharmaceutical composition in reducing cortisol level; and (c) packaging material.

27. The article of manufacture of claim 26, wherein said phosphatidic acid comprises a reaction product of a reaction between at least one crude phospholipid source and phospholipase-D. 1

28. The article of manufacture of claim 27, wherein said at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipid concentrate.

29. The article of manufacture of claim 26, wherein said pharmaceutical composition is formulated in an orally administrable form.

30. The article of manufacture of claim 26, wherein said pharmaceutical composition includes phosphatidic acid in a daily dose in the range of 5mg to 5000mg.

31. A method for treating depression, for suppressing mental & emotional stress and for improving mood in a subject, the method comprising administering to the subject a physiologically effective amount of phosphatidic acid.

32. The method of claim 31, further comprising preparing said phosphatidic acid by enzymatic trans-phosphatidylation of at least one crude phospholipid source with phospholipase-D.

33. The method of claim 32, wherein said at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipid concentrate.

34. The method of claim 31, wherein said physiologically effective amount of phosphatidic acid is administered orally.

35. The method of claim 31, wherein said physiologically effective amount of phosphatidic acid is administered in a daily dose in the range of 5mg to 5000mg.

36. A method for reducing insulin resistance and for improving glucose metabolism in a subject, the method comprising administering to the subject a physiologically effective amount of phosphatidic acid.

37. The method of claim 36, further comprising preparing said phosphatidic acid by enzymatic trans-phosphatidylation of at least one crude phospholipid source with phospholipase-D.

38. The method of claim 37, wherein said at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an gg yolk lecithin and a milk phospholipid concentrate.

39. The method of claim 36, wherein said physiologically effective amount of phosphatidic acid is administered orally.

40. The method of claim 36, wherein said physiologically effective amount of phosphatidic acid is administered in a daily dose in the range of 5mg to 5000mg.

41. A method for reducing the cortisol level of a subject, the method comprising administering to the subject a physiologically effective amount of phosphatidic acid.

42. The method of claim 41, further comprising preparing said phosphatidic acid by enzymatic trans-phosphatidylation of at least one crude phospholipid source with phospholipase-D.

43. The method of claim 42, wherein said at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipid concentrate.

44. The method of claim 41, wherein said physiologically effective amount of phosphatidic acid is administered orally.

45. The method of claim 41, wherein said physiologically effective amount of phosphatidic acid is administered in a daily dose in the range of 5mg to 5000mg.

46. A pharmaceutical composition effective in reducing insulin resistance and in improving glucose metabolism, the composition comprising, as an active ingredient, a physiologically effective amount of a phospholipid mixture including phosphatidylserine and phosphatidic acid and further comprising carriers or excipients; wherein the composition is effective in reducing insulin resistance and in improving glucose metabolism.

47. The composition of claim 46, wherein said phospholipid mixture is a fraction of a reaction product of an enzymatic trans-phosphatidylation of at least one crude phospholipid source by Phospholipase-D.

48. The composition of claim 46, wherein said mixture comprises at least 10% (w/w) Phosphatidylserine and at least 2% (w/w) of phosphatidic acid out of a total phospholipid content of the composition.

49. The composition of claim 47, wherein said at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipid concentrate.

50. The composition of claim 48, wherein said at least 2% (w/w) of phosphatidic acid does not exceed 3%.

51. The composition of claim 46, wherein said physiologically effective amount of said mixture is a daily dose in the range of 5mg to 5000mg.

52. The composition of claim 46, wherein the composition is formulated for oral administration.

53. The composition of claim 46, wherein at least one item selected from the group consisting of said phosphatidylserine and said phosphatidic acid is present in a form selected from the group consisting of a salt, an ester and another derivative.

54. A method of preparing a composition efficacious in treating insulin resistance and in improving glucose metabolism from lecithin, the method comprising: (a) providing a mixture of phospholipids including phosphatidylserine and phosphatidic acid; (b) combining an amount of said mixture phospholipids acid having physiologic activity in treating insulin resistance and in improving glucose metabolism with carriers and/or excipients.

55. The method of claim 54, wherein said providing said mixture is accomplished by: (i) trans-phosphatidylating a crude phospholipid source with phospholipase-D to produce a reaction product; and (ii) separating from said reaction product a fraction containing said mixture of phospholipids including phosphatidylserine and phosphatidic acid.

56. The method of claim 54, wherein said mixture comprises at least 10%

(w/w) Phosphatidylserine and at least 2% (w/w) of phosphatidic acid out of a total phospholipid content of the composition.

57. The method of claim 55, wherein said at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipid concentrate.

58. The method of claim 56, wherein said at least 2% (w/w) of phosphatidic acid does not exceed 3%.

59. The method of claim 54, wherein said amount having physiologic activity amount of said mixture is in the range of 5mg to 5000mg.

60. The method of claim 54, wherein said carriers and excipients are selected to produce a composition fonnulated for oral administration.

61. The use of lecithin in the manufacture of a composition efficacious in treating insulin resistance and in improving glucose metabolism.

62. The use of phosphatidylserine and phosphatidic acid in the manufacture of a composition efficacious in treating insulin resistance and in improving glucose metabolism.

63. An article of manufacture comprising: (a) a pharmaceutical composition effective in reducing insulin resistance and in improving glucose metabolism, the composition comprising, as an active ingredient, a physiologically effective amount of a mixture of phospholipids including phosphatidylserine and phosphatidic acid and further comprising carriers or excipients; (b) instructions identifying said phannaceutical composition for use in treatment of insulin resistance and in improving glucose metabolism ; and (d) packaging material.

64. The article of manufacture of claim 63, wherein said mixture of phospholipids comprises a fraction of a reaction product of an enzymatic trans- phosphatidylation of at least one crude phospholipid source by Phospholipase-D.

65. The article of manufacture of claim 63, wherein said mixture comprises at least 10% (w/w) Phosphatidylserine and at least 2% (w/w) of phosphatidic acid out of a total phospholipid content of the composition.

66. The article of manufacture of claim 64, wherein said at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipid concentrate.

67. The article of manufacture of claim 65, wherein said at least 2% (w/w) of phosphatidic acid does not exceed 3%.

68. The article of manufacture of claim 63, wherein said physiologically effective amount of said mixture is in the range of 5mg to 5000mg.

69. The article of manufacture of claim 63, wherein the composition is fonnulated for oral administration.

70. The article of manufacture of claim 63, wherein at least one item selected from the group consisting of said phosphatidylserine and said phosphatidic acid is present in a form selected from the group consisting of a salt, an ester and another derivative.

71. A method for reducing insulin resistance and for improving glucose metabolism in a subject, the method comprising administering to the subject a physiologically effective amount of a mixture of phospholipids including phosphatidylserine and phosphatidic acid and further comprising carriers or excipients; wherein said mixture is effective in reducing insulin resistance and in improving glucose metabolism.

72. The method of claim 71, wherein said mixture comprises a reaction product of an enzymatic trans-phosphatidylation of at least one crude phospholipid source by Phospholipase-D.

73. The method of claim 71, wherein said mixture comprises at least 10% (w/w) Phosphatidylserine and at least 2% (w/w) of phosphatidic acid out of a total phospholipid content of the composition.

74. The method of claim 72, wherein said at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipid concentrate.

75. The method of claim 73, wherein said at least 2% (w/w) of phosphatidic acid does not exceed 3%.

76. The method of claim 71, wherein said physiologically effective amount of said mixture is a daily dose in the range of 5mg to 5000mg.

77. The method of claim 71, wherein the composition is formulated for oral administration.

78. The method of claim 71, wherein at least one item selected from the group consisting of said phosphatidylserine and said phosphatidic acid is present in a fonn selected from the group consisting of a salt, an ester and another derivative.

79. A method for reducing the cortisol level of a subject, the method comprising administering to the subject a physiologically effective amount of a mixture of phospholipids comprising phosphatidylserine and phosphatidic acid and further comprising carriers or excipients; wherein the mixture is effective in reducing insulin resistance and in improving glucose metabolism.

80. The method of claim 79, wherein said mixture comprises a reaction product of an enzymatic trans-phosphatidylation of at least one crude phospholipid source by Phospholipase-D.

81. The method of claim 79, wherein said mixture comprises at least 10% (w/w) Phosphatidylserine and at least 2% (w/w) of phosphatidic acid out of a total phospholipid content of the composition.

82. The method of claim 80, wherein said at least one crude phospholipid source is selected from the group consisting of a vegetal lecithin, an egg yolk lecithin and a milk phospholipid concentrate.

83. The method of claim 81, wherein said at least 2% (w/w) of phosphatidic acid does not exceed 3%.

84. The method of claim 79, wherein said physiologically effective amount of said mixture is a daily dose in the range of 5mg to 5000mg.

85. The method of claim 79, wherein the composition is fonnulated for oral administration.

86. The method of claim 79, wherein at least one item selected from the group consisting of said phosphatidylserine and said phosphatidic acid is present in a foπn selected from the group consisting of a salt, an ester and another derivative.