WO2008120214A2

WO2008120214A2 - Compositions containing phosphatidylserine in treating diabetes associated conditions

Info

Publication number: WO2008120214A2
Application number: PCT/IL2008/000455
Authority: WO
Inventors: Yael Richter; Gai Ben-Dror; Evgeny Ivanovich Sas
Original assignee: Enzymotec Ltd.
Priority date: 2007-04-01
Filing date: 2008-04-01
Publication date: 2008-10-09
Also published as: IL182372A0; WO2008120214A3

Abstract

Provided is a pharmaceutical and nutraceutical composition for oral delivery which contains at least 60 wt% of glycerophospholipids (GPLs), in which the ratio of esterified to free phosphatidic acid is between 6 and 7, and wherein phosphatidylserine constitutes more than 50 wt% of the phosphatidic esters. The composition mitigates diabetes-like conditions and boosts mental and bodily vigor.

Description

coMPOsiTiONS CONTAINING PHOSPHATIDΎLSERINE

IN TREATING DIABETES ASSOCIATED CONDITIONS

Field of the Invention The invention relates to an orally deliverable composition for mitigating or preventing conditions associated with diabetes, containing glycerophos- pholipids at a concentration of at least 60 wt%, particularly aimed at helping the patients suffering from diabetes mellitus type II.

Background of the Invention

An increase in the prevalence of diabetes mellitus (DM) of type II has become a real threat, being called "epidemic" by the WHO, who have used such term the first time in connection with a chronic degenerative disease. The estimated number of patients with DM in the world is expected to grow from 135 million in 1995 to 300 million by 2025. The therapy of DM is complicated by the fact that the diagnosis of DM and its treatment start usually only after the full manifestation of the disease, while some doctors still tend to underestimate the severity of the disease. Studies of the last years have shown that hyperglycemia plays dominant role in the pathogenesis of vascular complications in DM, and DM type II is further complicated by disturbances in the lipid exchange. The life expectancy of more than 60% of the type II DM patients is lowered due to rapidly progressing ischemic heart disease, or the development of vascular complications; as known, the heart vascular diseases remain the main death cause in the developed countries. According to the International Diabetes Federation, the cost of DM care consumes up to 10% of the public health funds. It is still more widely recognized that mitigating the conditions associated with the disease, comprising a variety of problems in the metabolism of carbohydrates and lipids, requires prevention as much as treatment of the acute symptoms. Prophylaxis should include, beside the elimination of etiological factors, strengthening the protective functions of the organism itself. It is therefore an object of the invention to provide a composition mitigating the conditions associated with DM, particularly relieving symptoms of perturbed lipid or sugar metabolism.

Due to their availability as nontoxic surfactants, lecithins and the phospholipids made therefrom have been largely used as delivery means for bioactive molecules, for example as a matrix for liposome formation. US2003/0215491, for example, employs the phospholipids as a carrier for systemic delivery of medicaments. WO 2005/044176 describes a composition comprising phosphatide acid (PA), particularly PA not exceeding three percent of the composition and devoid of physiologically effective amount of phosphatidylserine, for treating insulin resistance, and for improving glucose metabolism and mood.

It is an object of the invention to provide a composition for mitigating the conditions associated with DM, comprising glycerophospholipids.

Other objects and advantages of present invention will appear as description proceeds.

Summary of the Invention

The present invention provides an orally deliverable composition containing glycerophospholipids (GPLs) at a concentration of at least 60 wt% comprised of phosphatidic acid and esters thereof, for mitigating or preventing conditions associated with diabetes, wherein said esters constitute at least 80 wt% of said GPLs, and wherein more than 50 wt% of said esters are constituted by phosphatidylserine. Said esters may comprise phosphatidylserine (PS), phosphatidylcholine (PC), phosphatidylinositol (PI), and phosphatidylethanolamine (PE), and other phospholipids. In a preferred embodiment of the invention, said diabetes is diabetes mellitus (DM) type II. In a preferred embodiment of the invention, said concentration of the glycerophospholipids is at least 65 wt%, and said esters constitute at least about 85 wt% of said GPLs, and said phosphatidylserine (PS) constitutes at least 65 wt% of said esters, and may reach up to more than 90 wt%. Said conditions, to be preferably treated or prevented, comprise high plasma glucose level, high plasma levels of total cholesterol or triglycerides, low- serum level of HDL cholesterol or high serum level of LDL cholesterol, low antioxidant capacity in blood, or insulin resistance. The composition of the invention enables the mitigation of the diabetes inflictions or prophylaxis thereof, comprising reducing the plasma level of glucose, lowering the plasma levels of total cholesterol or triglycerides, enhancing the serum level of HDL cholesterol or lowering the serum level of LDL cholesterol, enhancing the anti-oxidant capacity in blood, reducing insulin resistance, and/or strengthening mental and bodily vigor. Said mitigation may result, for example, in lowering the plasma coefficient of atherogenicity, enhancing the erythrocyte level of catalase activity, enhancing the erythrocyte level of superoxide dismutase (SOD) activity, enhancing the serum testosterone level, enhancing bone density, or enhancing muscle mass, but is not limited to said effects. Said conditions treated by the composition of the invention may comprise disorders such as atherosclerotic disease, coronary artery disease, cerebrovascular disease, peripheral vascular disease, hypercholesterolemia, hypertriglyceridemia, diabetic lipemia, and obesity. The composition of the invention is administered orally, and preferably in a daily dose of from 0.4 to 10 g.

One of the important aspects of the invention is the use of said orally deliverable composition as a dietary supplement, or a functional food, being a food or beverage. Other important aspect of the invention is the use of said orally deliverable composition as a pharmaceutical composition, or in the preparation of a medicament for treating diabetes associated conditions. - A -

A imtraceutical composition according to the invention is, in an important aspect of the invention, used as a food or beverage additive, or it is used in the preparation of a health-promoting food or dietary supplement, wherein particularly benefited are users suffering from a disorder selected from a carbohydrate metabolism disorder, lipid metabolism disorder, cardiovascular disorder, and mood disorder, whether said disorder is presently in the acute or chronic stage, and said nutraceutical of the invention contributes to managing the symptoms; also in stabilized persons, the nutraceutical of the invention strengthens the mental and physical vigor. A GPL composition according to the invention is advantageously used as medicinal food or in medicinal food. The term medicinal food means in the context of the present text a food which has a health-promoting or disease-preventing effects, and which is to be consumed by subjects suffering from a condition associated with diabetes. A GPL composition according to the invention is effectively used as a vigor-boost composition.

The invention relates to an orally deliverable pharmaceutical antidiabetic composition comprising glycerophospholipids comprised of phosphatidic acid and esters thereof, and pharmaceutically acceptable additives, diluents, excipients and/or carriers, said esters comprising PC, PI, PE, and therapeutically active amount of PS, said glycerophospholipids constituting at least 60 wt% of said composition, said esters constituting at least 80 wt% of said GPLs, wherein said therapeutically active amount is at least 50 wt% of said esters. In a preferred embodiment of the invention, said orally deliverable pharmaceutical antidiabetic composition may further comprise another active agent selected from the group consisting of antihypertensive, antianginal, antihyperlipoproteinemic, antiinflammatory, antidiabetic, lipotropic, and vasoprotectant. The composition according to the invention may be used, for example, in simultaneously reducing blood levels of cholesterol and triglycerides, simultaneously lowering LDL and increasing HDL, rising testosterone levels, maintaining bone density and strength, maintaining muscle mass and strength levels, boosting body's antioxidant defense, and/or ameliorating insulin resistance.

The invention aims at use of the above described composition in the preparation of a medicament for treating or preventing a condition associated with carbohydrate or lipid metabolism, optionally in combination with an additional active agent selected from the group consisting of antihypertensive, antianginal, antihyperlipoproteinemic, antiinflammatory, antidiabetic, lipotropic, and vasoprotectant, and further with pharmaceutically acceptable additives, diluents, excipients and/or carriers. A skilled person will identify advantageous active agents that will benefit the patient, particularly a patient suffering from DM type II, when used with the glycerophospholipid composition of the invention, whether simultaneously or subsequently in any order, or whether admixed in the composition. An illustrative example of such agent is metformin in any of its commercial presentations. Said medicament in the use according to the invention may aim at treating or preventing a condition selected from diabetes, high blood level of triglycerides and/or LDL, cardiovascular disorder, reduced body's antioxidant defense, insulin resistance, and hyperlipidemia. The medicament obtained according to the invention may help in lowering serum glucose level, increasing testosterone serum level, increasing erythrocyte catalase activity, increasing erythrocyte SOD activity, lowering serum Cortisol level, increasing serum estradiol level, regulating serum level of somatotropic hormone (STH) and glucagon hormones, reducing anxiety and factor of vegetative tonus, reducing alarming, hypochondriac, apathetic, neurasthenic, melancholic, egocentric, and euphoric attitudes, elevating harmonic and ergopathic attitudes, increasing activity and fitness for work factors, elevating quality of life (physical, social, and emotional functioning, viability, general and mental health), and/or enhancing mental and bodily vigor. In another embodiment of the invention, the above GPL vigor-boost is combined with a drug that is aimed at treating a disease not associated with diabetes, which drug worsens or causes diabetes-like syndromes. Such combination may comprise separate use of said drug and the GPL vigor- boost, or their simultaneous use. A combined pharmaceutical composition may comprise said drug and phosphatidic acid with esters thereof at a total concentration of at least 60 wt%, wherein said esters constitute at least 80 wt% of said GPLs, and wherein more than 50 wt% of said esters are constituted by phosphatidylserine, helping a patient to balance the lipid metabolism or glucose intolerance, and improving her/his general well being. Examples of such drugs, without being limited to them, include antipsychotic medications, anti-HIV medications, and glucocorticosteroids. The invention, thus, enables mitigating or preventing diabetes associates symptoms which are caused or exacerbated by delivering drugs aimed at disorders other than diabetes.

The invention provides a method of treating or preventing conditions associated with diabetes, comprising administering to a person in need of such treatment an orally deliverable composition containing glycerophospholipids at a concentration of at least 60 wt% comprised of phosphatidic acid and esters thereof, wherein said esters constitute at least 80 wt% of said GPLs, and wherein more than 50 wt% of said esters are constituted by phosphatidylserine.

The GPL composition of the invention improves laboratory parameters in subjects suffering from diabetic syndromes, positively affects their subjective disposition, and enhancing their well-being and vigor. The invention provides an efficient GPL vigor-boost to be comprised in food or in pharmaceutical formulations. Brief Description of the Drawings

The above and other characteristics and advantages of the invention will be more readily apparent through the following examples, and with reference to the appended drawings, wherein: Fig. 1. shows the effect of a composition of the invention (denoted as PS- composition in the figures) on blood parameters in DM type II patients; Fig. IA is Table 1, showing the effect on blood serum lipoprotein levels (Example 1); Fig. IB is Table 2 showing the effect on the activity of catalase and superoxide dismutase (SOD) in the erythrocytes;

Fig. 2. shows dynamics of hormone levels in the blood serum upon the administration of the PS-composition; Fig. 2A relates to insulin levels; Fig. 2B relates to glucagons levels; Fig. 2C relates to STH levels; Fig. 3. shows the effect of the PS-composition on blood parameters; Fig. 3A is Table 3, showing the effect on the serum glucose levels; Fig. 3B is Table 4, showing the effect on the serum Cortisol levels; Fig. 3C is table 5, showing the effect of the PS-composition on testosterone and estradiol serum levels; and Fig. 4. shows the effects of the PS vigor-boosts of the invention on patients' well being; Fig. 4A relates to the dynamics of quality of life; Fig. 4B relates to the dynamics of the types of attitudes towards the disease; Fig. 4C is Table 6, showing the effect on psychological parameters.

Detailed Description of the Invention

It has now been found that a composition containing glycerophospholipids (GPLs) at high concentrations, such as GO wt%, have surprisingly mitigating effects on DM type II patients, particularly when phosphatidic acid esters constitute a substantial part, such as more than three quarters, of said glycerophospholipids mass, and where phosphatidylserine constitutes more than half of those esters. For example, daily doses of about 2 g of a composition of the invention improved simultaneously a plurality of parameters characterizing the patient's well being, including bodily and mental vigor, when measured by accepted characteristics. Said characteristics included blood levels of indicative biochemicals relevant for sugar and lipid metabolism and for hormonal balance, as well as psychological features used for scoring the patient's vigor. When using the shortened term "blood level", intended throughout may be the level in blood serum or in blood cells, according to the context.

A composition of the invention for mitigating or preventing conditions associated with diabetes is orally deliverable, and preferably contains GPLs comprised of phosphatidic acid and esters thereof at a total concentration of at least 60 wt%, more preferably at least 65 wt%, wherein said esters constitute at least 80 wt% of said GPLs, more preferably at least 85 wt%, and wherein more than 50 wt% of said esters are constituted by phosphatidylserine, more preferably at least 65 wt%. The composition comprises phosphatidylserine (PS), phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidylethanolamine (PE), and possibly other lipids or phospholipids, optionally in combination with additional active agent, and further with pharmaceutically acceptable additives, diluents, or carriers. A therapeutically or prophylactically effective dose may comprise from 0.4 to 10 gram composition a day, but, of course, in view of very low toxicity of the materials, a skilled person is granted even greater flexibility here. The GPL vigor-boost of the invention, to be comprised in medicinal food or in pharmaceutical formulations, may be dosed, for example as shown in the following table, in which also corresponding minimal contents of GPLs, GPL-esters, and PS are shown (all values being in grams).

The GPL vigor-boosting compositions of the invention contain at least 60 wt% of phosphatidic acid and its esters, the esters constituting at least 80 wt% of said GPLs, and PS constituting more than 50 wt% of said esters.

The GPLs minimal content in the GPL vigor-boosts is most preferably selected from the group of values consisting of: 65 wt%, 70 wt%, 75 wt%, and 80 wt%. The minimal content of the esters in the GPLs is most preferably selected from the group of values consisting of: 82 wt%, 84 wt%, 86 wt%, 88 wt%, 90 wt%, 92 wt%, and 94 wt%. The minimal content of PS in the GPL esters is most preferably selected from the group of values consisting of: 51 wt%, 61 wt%, 71 wt%, 81 wt%, and 91 wt%. In a preferred embodiment, a composition of the invention contains esterified GPL and free phosphatidic acid in a weight ratio of from 6 to 7.

When employing the term "associated with diabetes", the causative relations among the conditions and disorders, and among the involved symptoms, are not considered; some symptoms are often associated with several diseases, while precise mechanisms cannot be untangled; what is meant by the above term is "one accompanying the other", or "occurring simultaneously", which is the relevant meaning for practical therapeutic purposes. It is known that conditions occurring with diabetes, cardiovascular diseases, and lipid metabolism are interlinked. Without wishing to be bound by mechanistic considerations, it is known, for example, that hypertriglyceridemia is associated with diabetes, that macrovascular complications of diabetes include atherosclerotic coronary and atheral diseases, that for DM type II patients the most important thing is weight reduction, that obesity is associated with insulin resistance, that total cholesterol (TC) is correlated with coronary artery disease (CAD), and that hypercholesterolemia is associated with CAD and with peripheral vascular disease, and with cerebrovascular disease [The Merck Manual, 17^th Ed. 1999, pp 165-211]. The composition of the present invention can mitigate or prevent a diverse range of conditions associated with diabetes.

Further found has now been that said mitigating effects are observable even in patients who simultaneously get a classical diabetes treatment, for example treatments comprising metformin. According to one preferred embodiment of the invention, a patient who suffers from DM type II, or from symptoms associated with the disease, is delivered a composition comprising GPLs at high concentrations, such as preferably more than 60 wt%, in which phosphatidic acid esters prevail over the free acid, forming preferably 80 or more wt%, which esters contain more than 50 wt% of PS. In another preferred embodiment of the invention, said patient is delivered said composition together with a known antidiabetic agent, which agent may be administered to the patient separately or admixed in said composition as a part of it. In other preferred embodiment of the invention, said patient is administered together with said composition comprising the GPLs, also one or more additional therapeutic agents aiming at the symptoms to be prevented or treated, selected, for example, from antidiabetic, antihypertensive, antianginal, antihyperlipoprotein-emic, antiinflammatory, lipotropic, and vasoprotectant. Pharmaceutically acceptable additives, diluents, excipients and/or carriers may be included in a composition of the invention.

In one aspect of the invention, an orally deliverable composition is provided for preventing or relieving symptoms associated with diabetes, wherein the composition is a dietary supplement. Said supplement may be a stable formulation comprising the above said GPLs, and is consumed either separately or admixed in food or beverage. The supplement helps to keep a stabilized patient in a good physical and mental state, or it participates in supportive diet of a patient treated by other known methods. In another aspect of the invention, said glycerophospholipid composition is a pharmaceutical composition, optionally comprising additional therapeutic agents.

As mentioned above, lecithins have been often used as nutritious additives, or alternatively as vectors for drug delivery, and certain lecithin components were suggested for treating diabetic or other symptoms; however, the instant composition exhibits unexpectedly broad therapeutic and prophylactic effects due to the presence of concentrated glycerophospholipids comprising high ratio of esterified to free phosphatide acid, with PS representing the bulk of said esters, preferably constituting more than 50% of their mass or even up to nearly 100 % of their mass. PS in a mixture with said other phosphatidic esters and with lesser amount of the free acid operates either alone or in combination with standard therapeutic substances in mitigating the symptoms of disorders associated with carbohydrate and lipid metabolism. The composition of the invention may comprise from 30 wt% to 70 wt% PS, additional phosphatidic esters whose total mass does not exceed the mass of PS, and usually being much lower, the free phosphatidic acid not exceeding 1/3 of the PS mass and usually constituting about 10 wt% of the composition but exceeding 5 wt%, and optionally another material affecting metabolism of lipids or carbohydrates; such composition turns out to be highly effective in strengthening the body in the periods of remission from symptoms associated with metabolism of carbohydrates or lipids, and further in overcoming exacerbations of said symptoms. A good tolerance of the body to the glycerophospholipids, together with their low cost, make the composition of the invention a strong candidate for an efficient means in managing otherwise destructive, and at their ends fatal, conditions associated with metabolism of carbohydrates and lipids, which, composition is further able to enhance the user's bodily and mental vigor. Thus, diabetes, diabetic lipemia, and the diseases of cardiovascular system (ischemic heart disease, hypertonic disease), as well as various pathologic conditions, accompanied by early manifestations of metabolic syndrome, are now granted novel means for mitigating the symptoms or even, in new combined therapies, suppressing the acute form of the disease, and managing the disease during remission.

In a preferred embodiment of the invention, an orally administered composition for mitigating or preventing conditions associated with diabetes is provided that contains glycerophospholipids at a concentration of about from 60 wt% to about 80 wt%, comprised of esterified and free phosphatidic acid in a ratio of from about 6 to about 7, and wherein more than half of the ester mass is constituted by PS. Compositions according to the invention may be obtained by any method that provides pharmaceutically or nutritionally acceptable GPL mixtures, for example by a method capable to provide a mixture containing from 30 to 70 wt% PS, from less than 1 wt% to 30 wt% of

PC and PE and PI, and about 10 wt% PA. Said method may comprise any steps known in preparative biochemistry, including chemical or enzymatic reactions, one of such processes being disclosed, for example, in

WO2005/027822.

The invention provides compositions which alone or in combination with standard therapies improve glucose metabolism, lower insulin resistance, improve lipoprotein levels, and elevate the bodily antioxidant capacity in subjects suffering from diabetes, insulin resistance, diabetic lipemia, cardiovascular disease, metabolic syndrome, impaired glucose metabolism, dyslipidemia or abnormalities of lipoprotein metabolism, and obesity. Compositions of the invention, whether serving as a food additive or pharmaceutical formulation, may be prepared, for example, in the form of powder or suspension. A pharmaceutical composition of the invention may be prepared in various known forms suitable for oral use, for example, as tablets, granules, capsules, syrups, optionally with sweetening or flavoring or coloring agents, it may contain the active ingredients in admixture with nontoxic pharmaceutically acceptable excipients, inert diluents, wherein the tablets may be uncoated or coated.

Tablets, hard tablets, capsules, and soft gel capsules containing the combination of the invention may be preferred, either as dietary supplements or as pharmaceutical dosage forms. In essence, any pharmaceutical dosage form suitable for oral administration may be used for delivering the combination of the invention.

The composition of the invention, whether used as a food additive or as a pharmaceutical formulation, prevents or mitigates suffering from various diabetes symptoms, particularly in DM type II patients. Easily observable external improvements in the patient's state are usually accompanied by improved laboratory values in wide range of parameters. Beside the symptomatic progress, deeper health improvements can be often expected even in the parameters that are routinely not measured, such as bone and muscle strength and hormonal balance, as demonstrated in the following Examples. The composition of the invention exhibits a broad range of positive activities, and even when aiming at alleviating one certain symptom, usually a host of positive effects is achieved, comprising mitigating diabetes syndromes and enhancing bodily and mental vigor.

In an important aspect of the invention, GPLs comprised of phosphatidic acid and its esters at a total concentration of at least 60 wt% are used in a combined pharmaceutical composition with a drug that alters lipid metabolism and is associated with onset of diabetes, wherein said esters constitute at least 80 wt% of said GPLs, and wherein more than 50 wt% of said esters are constituted by phosphatidylserine. This preferred combination helps a patient to balance the lipid metabolism or glucose intolerance and in addition helps in improving the general well being. Said drug and said GPL composition may be delivered separately or simultaneously; said drug may be admixed in a homogeneous formulation with the GPLs. The invention, thus, also relates to a combined use of the GPL vigor-boost as described and a drug that may cause or exacerbate diabetes symptoms.

In one embodiment, said combined use comprises a GPL pharmaceutical composition as described and a drug selected from the group consisting of olanzapine, risperidone, aripiprazole, clozapine, quetiapine, and ziprasidone. New medications were developed to help in treating schizophrenia, bi-polar, or other psychotic disorders, which include said olanzapine (Zyprexa™), risperidone (Risperdal™), aripiprazole, clozapine, quetiapine, and ziprasidone; the drugs were observed to contribute to symptoms of diabetes- associated states. Combining these types of drugs with the PS composition of the invention benefit the patient, beside treating said psychic problem, in two ways: it helps in protecting from developing diabetic mellitus, and it improves the patient's well being.

In another embodiment, said combined use comprises said GPL pharmaceutical composition and an antiretroviral protease inhibitor. A highly active, protease inhibitor-based antiretroviral therapy, used in patients infected with HIV-I, has been implicated in eliciting dyslipidemia, peripheral insulin resistance, and abnormal adipose tissue deposition in the treated patients; a GPL/protease inhibitor combination according to the invention can successfully overcome the existing problems and reduce the side effects observed when said drug is used alone, enhancing general well- being of the HIV-I patients.

In a further embodiment of the invention, a combined use or combined composition comprises a GPL composition as described and further steroids. The administration of steroids such as glucocorticosteroids stimulates altered insulin secretion. The patients being administrated steroids will benefit from simultaneously or separately combining the drug with the GPL composition according to the invention.

In a still further embodiment of the invention, a combined GPL pharmaceutical composition includes an anti-diabetic drug known in the field; unbalanced diabetic patients will be helped to balance their insulin levels and lipid metabolism by combining said drug with said GPL composition.

The present invention thus relates to an orally administrable composition for strengthening the protective functions of the body, and suppressing the symptoms of disorders associated with sugar and lipid metabolism. The terms sugar and carbohydrate are used interchangeably throughout. The composition of the invention, whether used as a dietary supplement or a pharmaceutical composition affecting blood lipid levels, comprises GPLs in relatively high concentrations (more than 60 wt%, and up to about 80 wt%) among which prominent is PS (more than half mass of said GPL, but up to nearly 100 wt% of said GPL), wherein the ratio between esterified phosphatidic acid to non-esterified is from about 6 to about 7 (the esterification by an alcohol at the phosphate group is, of course, related to). When used as a pharmaceutical composition, additional active agents may be comprised, such as agents ameliorating symptoms typical for disorders associated with lipid and sugar metabolism. A composition according to the invention exhibits at least one of the following effects: i) mitigates or prevents diabetes symptoms; ii) elevates the total antioxidant capacity of the body; iii) improves blood lipids profile; and iv) increases mental well-being. A composition according to the invention preferably exhibits at least one of the following effects: i) it simultaneously reduces the blood levels of cholesterol and triglycerides; ii) it simultaneously lowers the serum LDL level and elevates the serum HDL level; and iϋ) it simultaneously elevates the total antioxidant capacity of the body and lowers insulin resistance. However, in various situations, the instant compositions may be useful in treating conditions associated with diabetes, obesity, atherosclerosis, high serum lipids, high serum triglycerides, high serum LDL, low serum HDL, etc. It is noted that the terms hyperlipidemia and hyperlipoproteinemia are sometimes used interchangeably, including also such terms as lipemia, lipidemia, hypercholesterolemia. A composition according to the invention may increase the serum testosterone levels, or it enhances bone density and strength, or it enhances muscle mass and strength. Said enhancing bone or muscle strength particularly relates to a body recuperating after an acute or chronic disease. As known, the body's ability to fight the pathological states is enhanced when the body's antioxidant defense is strengthened, and that is also one of the preferred effects attained through delivering the composition of the invention.

In one important aspect of the invention, a composition comprising PS with other PGLs is a dietary supplement, possibly being a food or beverage supplement. Said dietary supplement contains PS, in a physiologically effective amount and in physiologically effective ratios. When applied as a pharmaceutical formulation, optionally other active agents are used, such as materials affecting lipid metabolism or carbohydrate metabolism, possibly comprising carbohydrates and their homologues, lipids and their homologues, derivatives thereof, enzyme inhibitors, and known therapeutic agents. Other agents affecting lipid or carbohydrate metabolism may comprise antihypertensive, antianginal, antihyperlipoproteinemic, antiinflammatory, antidiabetic, lipotropic, and vasoprotectant. A non-limiting example of such an agent may be antidiabetics such as metformin, buformin, phenformin, or agents having other biochemical activities, but preferably synergistically managing said symptoms associated with the sugar or lipid metabolism diseases. The amount of the composition usually ranges from 0.4 to 10 grams. In a preferred embodiment, the composition of the invention comprises a physiologically effective amount of PS admixed with PGLs together with an agent affecting lipid or sugar metabolism, for use in simultaneously reducing blood levels of cholesterol and triglycerides, simultaneously lowering LDL and increasing HDL, rising testosterone levels, maintaining bone density and strength, maintaining muscle mass and strength levels, boosting body's antioxidant defense, and/or ameliorating insulin resistance.

A composition according to the invention exhibits at least one of the following effects in a subject who uses it: The composition i) mitigates or prevents diabetes symptoms; ii) elevates the total antioxidant capacity of the body; iϋ) improves blood lipids profile; and iv) increases mental well-being of said subject.

Examples

Preparing GPL-Compositions

In one embodiment, a composition according to the present invention may be prepared as described in WO 2005/027822. Shortly, an aqueous mixture of L- serine was mixed with lecithin in the presence of phospholipase D for a suitable period of time to give phosphatidylserine in the required amounts. Following the enzymatic reaction, the solid product is separated from the aqueous solution, purified and dried. Compositions of several mixtures thus obtained, adjusted to a precise PS value, and called PS30, PS40, etc., are presented in the following table, as wt% values.

In the following Examples, a composition close to the above "PS40" was employed, which contained 41 wt% PS, 9.6 wt% PA, 7.0 wt% PC, 6.3 wt% PI, and 5.2 wt% PE, and which is related to as "PS-composition" below.

Example 1

Effect of the GPL-composition on blood serum lipoprotein levels in patients with DM type II

In order to establish the effect of a composition according to the invention on blood serum lipoprotein levels, 36 diabetes mellitus type II patients received compositions containing either 2 g (corresponding to 800 mg PS) or 3.75 g (corresponding to 1.5 g PS) composition of the invention (study groups 1 and 2, respectively), in addition to the standard therapy (1.7 g/day Siofor or Glibomet 0.8 g/d) for four weeks. Control group was composed of 20 diabetes mellitus type II patients, which received only the standard therapy. Blood serum lipoprotein levels were measured at baseline and at treatment termination (4 weeks). Results are summarized in Table 1 (Fig. IA). The analysis of lipid metabolism parameters revealed decreased levels of both total cholesterol and its atherogenic fractions in all three groups of patients. However, patients who received the PS-composition in addition to standard therapy showed a significant increase in HDL cholesterol levels, decrease in total cholesterol and even larger decrease in LDL cholesterol. Thus, supplementation with PS-composition is useful for modulating lipoprotein levels.

Example 2

Antioxidant effect of GPL -composition in patients with DM type II In order to establish the antioxidant effect of PS-composition, 36 diabetes mellitus type II patients received PS-composition according to the same protocol as described in Example 1. Activities of catalase and superoxide disnαutase (SOD) in erythrocytes were measured at baseline and at treatment termination. From the results presented in Table 2 (Fig. IB), the addition of PS-composition to the complex therapy significantly increased the activities of catalase and superoxide dismutase in erythrocytes, demonstrating the potential of the composition in boosting body's antioxidant defense.

Example 3

Effect of GPL-composition on insulin, glucagon, and STH levels in DM type II patients

In order to establish the effect of PS-composition on blood serum insulin levels, 36 diabetes mellitus type II patients received PS-composition according to the same protocol as described in Example 1. Insulin, glucagon and somatotropic hormone (STH) levels were measured both pre- and postprandial at baseline and at treatment termination (Fig. 2A, 2B and 2C respectively). As indicated in Fig. 2A, levels of blood serum insulin (both pre- and post-prandial) decreased in both groups of diabetes mellitus type II patients receiving the PS-compositions. Together with the decrease in insulin levels, increased fasting levels of glucagon and STH, and a tendency towards decreased postprandial levels of glucagon and STH, within patients receiving the treatment of the invention were observed, as seen in Fig. 2B and 2C, respectively. These results suggest that supplementation with the PS- composition is useful in lowering insulin resistance in patients with DM type II. Specifically PS supplementation results in better regulation of insulin, glucagon and STH.

Example 4

Effect of GPL-composition on blood serum glucose levels in DM type II patients

In order to establish the effect of phosphatidylserine on blood serum glucose levels, 36 diabetes mellitus type II patients received phosphatidylserine according to the same protocol as described in example 1. Fasting and postprandial blood serum glucose levels were measured at baseline and at treatment termination. Results are summarized in Table 3 (Fig. 3A). As indicated in Table 3, a decrease in both fasting and post-prandial glucose levels was observed in study groups receiving phosphatidylserine in addition to the standard therapy. No significant glucose reduction was observed in the control group. Thus, supplementation with phosphatidylserine is useful in improving glucose metabolism.

Example 5

Effect of GPL-composition on blood serum hormone levels in DM type II patients

The patients receiving PS-composition, as described in Example 1, were checked for the hormonal status. Table 4 (Fig. 3B) shows the Cortisol levels. The administration of the PS-composition was accompanied by a decrease in hydrocortisone levels, demonstrating decreases of high stress tension of the patients. Table 5 (Fig. 3C) shows the testosterone and estradiol levels, demonstrating increase in testosterone levels in the male patients upon administering the PS-composition, in parallel with reduction of estradiol levels; testosterone levels are associated with maintaining of bone density and strength, as well as muscle mass and strength.

Example 6

Effect of GPL-comυosition on the well-being of DM type II patients The patients receiving a PS-composition according to the present invention, as described in Example 1, were checked for well-being parameters according to several accepted methods. The evaluation was performed by the analysis of patients' self-inspection diaries, type of attitude towards the disease (the LOBI method), and the paired control study by Lyusher color test.

1. Effect of the GPL-composition on quality of life In order to establish the effect of phosphatidylserine on quality of life, 36 diabetes mellitus type 2 patients were administrated the composition of the invention according to the same protocol as described in example 1. Results are presented in Fig. 4A. The results indicate that the addition of the PS- composition to the standard therapy leads to a significant improvement in all major parameters of the quality of life, especially on the scales of general health and physical role functioning, compared to baseline and the control group.

2. Effect of the GPL-composition on the attitude towards the disease

In order to establish the effect of the PS-composition on the attitude towards the disease, 36 diabetes mellitus type 2 patients were administrated phosphatidylserine according to the same protocol as described in example 1. The attitude toward the disease was assessed by the Personal Questionnaire of Bechterev's Institute. Results are presented in figure 4B. The study groups 1 and 2 were combined into one group, based on the results' similarity in both groups. PS-composition supplementation resulted in reduction of undesirable (alarming, hypochondriac, apathetic) types of attitude towards the disease, in parallel with almost 3-fold increase in balanced, harmonic type attitude in comparison to baseline values. These results corroborate the positive effects of the compositions according to the invention on bodily and mental vigor.

3. Effect of GPL-composition on psychological parameters.

In order to establish the effect of the PS-composition on psychological parameters, 36 diabetes mellitus type 2 patients were administrated phosphatidylserine according to the same protocol as described in example 1. Psychological parameters were assessed by Lyusher color test. Results are presented in Table 6 (Fig. 4C). The study groups 1 and 2 were combined into one group, based on the results' similarity in both groups. As can be seen from the data, the addition of biologically active additive - of PS-composition - into the standard therapy lead to a significant improvement in the psychological parameters, which characterize the activity levels and work fitness levels, together with decrease in the anxiety levels. Furthermore, the effects of the instant treatment on the short-term memory in the patients was characterized using standard tests comprising memorization of digits or word parts, and a positive change in patients receiving the instant composition was observed in the average length of a row in digits, in the percentage of correct answers in the numbers memorization test, and in the maximum length of a row in the syllables-memorization test.

While this invention has been described in terms of some specific examples, many modifications and variations are possible. It is therefore understood that within the scope of the appended claims, the invention may be realized otherwise than as specifically described.

Claims

1. An orally deliverable composition comprising glycerophospholipids (GPLs) at a concentration of at least 60 wt% comprised of phosphatide acid and esters thereof, for mitigating or preventing conditions associated with diabetes in a subject, wherein said esters constitute at least 80 wt% of said glycerophospholipids, and wherein more than 50 wt% of said esters are constituted by phosphatidylserine (PS).

2. An orally deliverable composition according to claim 1, said esters comprising phosphatidylserine (PS), phosphatidylcholine (PC), phosphatidylinositol (PI), and phosphatidylethanolamine (PE), wherein said concentration of the GPLs is at least 65 wt%, and said esters constitute at least about 85 wt% of said GPLs, and wherein said phosphatidylserine constitutes at least 65 wt% of said esters.

3. An orally deliverable composition according to claim 1, wherein said diabetes is diabetes mellitus (DM) type II.

4. An orally deliverable composition according to claim 1, wherein said conditions comprise high plasma glucose level, high insulin level, unregulated glucagon and STH level, high plasma levels of total cholesterol or triglycerides, low serum level of HDL cholesterol or high serum level of LDL cholesterol, low antioxidant capacity in blood, or insulin resistance.

5. An orally deliverable composition according to claim 1, wherein said conditions associated with diabetes are exacerbated or caused in said subject by a drug treating a disease other than diabetes.

6. An orally deliverable composition according to claim 1, wherein said mitigation results in lowering the plasma level of glucose, lowering the plasma levels of total cholesterol or triglycerides, enhancing the serum level of HDL cholesterol or lowering the serum level of LDL cholesterol, enhancing the anti-oxidant capacity in blood, reducing insulin resistance, or strengthening mental and bodily vigor.

7. An orally deliverable composition according to claim 5, wherein said mitigation results in lowering the plasma coefficient of atherogenicity, enhancing the erythrocyte level of catalase activity, enhancing the erythrocyte level of superoxide dismutase (SOD) activity, enhancing the serum testosterone level, enhancing bone density, or enhancing muscle mass.

8. An orally deliverable composition according to claim 1, wherein said conditions are associated with atherosclerotic disease, coronary artery disease, cerebrovascular disease, peripheral vascular disease, hypercholesterolemia, hypertriglyceridemia, diabetic lipemia, and obesity.

9. An orally deliverable composition according to claim 1, for use in a daily dose of from 0.4 to 10 g.

10. An orally deliverable composition according to claim 1, being a nutraceutical or pharmaceutical composition.

11. An orally deliverable composition according to claim 10, being functional food or medicinal food.

12. An orally deliverable composition according to claim 10, being a dietary supplement.

13. An orally deliverable composition according to claim 12, being a food or beverage supplement.

14. An orally deliverable composition according to any one of claims 10 to 13, which enhances well-being and vigor in a subject suffering from conditions associated with diabetes.

15. An orally deliverable composition according to claim 10, being a pharmaceutical composition.

16. An orally deliverable pharmaceutical composition according to claim 15, for treating or preventing a disorder selected from a carbohydrate metabolism disorder, lipid metabolism disorder, cardiovascular disorder, and mood disorder.

17. An orally deliverable pharmaceutical antidiabetic composition comprising glycerophospholipids (GPLs) comprised of phosphatidic acid and esters thereof, and pharmaceutically acceptable additives, diluents, excipients and/or carriers, said esters comprising PC, PI, PE, and therapeutically active amount of PS, said GPLs constituting at least 60 wt% of said composition, said esters constituting at least 80 wt% of said GPLs, wherein said therapeutically active amount is at least 50 wt% of said esters.

18. A composition according to claim 1, in which the minimal content of said GPLs has a value selected from the group consisting of 65 wt%, 70 wt%, 75 wt%, and 80 wt%.

19. A composition according to claim 1, in which the minimal content of said esters in said GPLs has a value selected from the group consisting of 82 wt%, 84 wt%, 86 wt%, 88 wt%, 90 wt%, 92 wt%, and 94 wt%.

20. A composition according to claim 1, in which the minimal content of said PS in said esters has a value selected from the group consisting of 51 wt%, 61 wt%, 71 wt%, 81 wt%, and 91 wt%.

21. A composition according to claim 1, in which said esterified GPL and said free phosphatidic acid are in a ratio of from 6 to 7.

22. An orally deliverable pharmaceutical antidiabetic composition according to claim 17, further comprising another active agent.

23. A composition according to claim 22, wherein said agent is selected from the group consisting of antihypertensive, antianginal, antihyperlipoproteinemic, antiinflammatory, antidiabetic, lipotropic, and vasoprotectant.

24. A composition according to claim 22, wherein said agent is a drug for treating a diseases not being diabetes but causing or exacerbating diabetes-associated symptoms.

25. An orally deliverable pharmaceutical antidiabetic composition according to claim 17, for use in simultaneously reducing blood levels of cholesterol and triglycerides, simultaneously lowering LDL and increasing HDL, rising testosterone levels, maintaining bone density and strength, maintaining muscle mass and strength levels, boosting body's antioxidant defense; or ameliorating insulin resistance.

26. Use of a composition according to claim 1 in the preparation of a medicament for treating or preventing a condition associated with carbohydrate or lipid metabolism, optionally in combination with additional active agent selected from the group consisting of antihypertensive, antianginal, antihyperlipoproteinemic, antiinflammatory, antidiabetic, lipotropic, and vasoprotectant, and further with pharmaceutically acceptable additives, diluents, excipients and/or carriers.

27. Use according to claim 26, wherein said additional agent is metformin.

28. Use according to claim 26, wherein said condition comprises high blood level of triglycerides or LDL.

29. Use according to claim 26, wherein said condition comprises a form of diabetes or diabetic lipemia.

30. Use according to claim 26, wherein said condition comprises cardiovascular disorder.

31. Use according to claim 26, wherein said condition comprises reduced body's antioxidant defense.

32. Use according to claim 26, wherein said condition comprises insulin resistance.

33. Use according to claim 26, wherein said condition comprises hyperlipidemia.

34. A method of treating or preventing conditions associated with diabetes, comprising administering to a patient in need of such treatment an orally deliverable composition containing glycerophospholipids at a concentration of at least 60 wt% comprised of phosphatidic acid and esters thereof, wherein said esters constitute at least 80 wt% of said glycerophospholipids, and wherein more than 50 wt% of said esters are constituted by phosphatidylserine.

35. A method according to claim 34, wherein said treating results in a lowered serum glucose level.

36. A method according to claim 34, wherein said treating results in an increased testosterone serum level.

37. A method according to claim 34, wherein said treating results in an increased erythrocyte catalase activity.

38. A method according to claim 34, wherein said treating results in an increased erythrocyte SOD activity.

39. A method according to claim 34, wherein said treating results in a lowered serum Cortisol level.

40. A method according to claim 34, wherein said treating results in an increased serum estradiol level.

41. A method according to claim 34, wherein said treating results in an elevated serum level of somatotropic hormone (STH).

42. A method according to claim 34, wherein said treating results in reduced anxiety.

43. A method according to claim 34, wherein said treating results in enhanced mental and bodily vigor.