Mixtures of polar lipids, production and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a lipid preparation which contains phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI), and sphyngomyelin (SM), a composition containing a mixture of said lipids and use thereof. The method involves steps of removing non-lipid material from bovine milk by dispersing the lipids in a mixture of a polar organic solvent and a nonpolar solvent, followed by separation of the lipid fraction and removing the solvent from said fraction, a step of de-oiling the obtained lipid fraction in order to remove nonpolar lipids by dissolving in acetone or supercritical CO2 and a step of filtering and drying the obtained lipids. In the lipid composition obtained using said method, the ratio of phospholipids is comparable with that of phospholipids in human breast milk. Disclosed is use of the composition obtained using the disclosed method as a source of human breast milk fat for making infant formula.

EFFECT: method enables to obtain a human breast milk substitute by processing readily available material and use thereof to make infant formula.

8 cl, 5 tbl, 1 ex

 

The technical field to which the invention relates.

The present invention relates to preparations of polar lipids, in particular to mixtures, including glycerophospholipids, optionally, together with sphingomyelin, to receive them and to their applications.

Prior art

All publications mentioned in the description, are fully included as references, including all mentioned links.

Fat milk (HMF) consists of about 30-40 g/l lipids. Among them, approximately 98% triglycerides, 0.3-1% phospholipids and 0.4% cholesterol. Phospholipids consist of four major components: sphingomyelin (SM), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI).

Although the glycerophospholipids, sphingomyelin, cholesterol and its derivatives have been detected in breast milk in relatively small quantities, they play an important role in the nutrition of the developing babies, and have a significant role in all physiological systems and cycles of the female body.

The total fat content increases gradually from colostrum (2.0%), through transitional milk (from 2.5% to 3.0%), to Mature milk (from 3.5% to 4.5%) [Bitman et al. (1983) Am. J. Clin. Nutr. 38: 300-312].

The role of phospholipids and, in particular, the role of the carbon skeleton of phospholipids in maternal human milk little to understand what. In most research phospholipids maternal breast milk was used as a test on the absorption and incorporation of different fatty acids in the carbon skeleton of phospholipids.

Phospholipids are involved in the formation of the structure of the membrane of fat globules of breast milk (HMFGM) and make up 23% of the total mass of the membrane. Interestingly, in contrast to the substantial changes in the composition of fatty acids from woman to woman, depending mainly on race and diet composition of phospholipids remains constant and does not change depending on diet. It is essential that the level of phospholipids in women's breast milk varies only with the age of the infant. This fact provides additional evidence that phospholipids are essential nutritional component of women's breast milk.

It was shown that the content of phospholipids is reduced from high levels in colostrum (1.1% of the total fraction of fat) to low levels in Mature milk (0.6%). This reduction in Soderini phospholipids is consistent with the increase in the size of fat globules [Ruegg et al. (1981) Biochim. Biophys. Acta 666, 7-14]. The composition of phospholipids of breast milk from mothers of full-term and premature infants during lactation has been thoroughly investigated in the work Bitman et al. [Bitman et al. (1984) Am. J. din. Nutr. 40, 1103-1119].

He was no visible p is slice in milk phospholipids, related to length of gestation after day 21. This is a striking consistency in the distribution of phospholipids indicates that the membrane composition of the milk fat globule identical at all stages of lactation.

The amount of phospholipids (sphingomyelin and glycerophospholipids) in the fat of breast milk is approximately 15-20 mg/DL. Found that sphingomyelin (SM) contains approximately 37% of the total content of polar lipids, phosphatidylcholine (PC) contains 28% of the total content of polar lipids, phosphatidylethanolamine (PE) contains approximately 19%, phosphatidylserine (PS) - 9% and phosphatidylinositol (PI) - 6%. Thus, the ratio between the polar lipids of HMF as follows: SM>PC>PE>PS>PI.

Some glycerophospholipids, and, in particular, those that were extracted from soybeans, is used as an additive to the diet, and their absorption is due to the many beneficial effects provided on health, including the improvement of cognitive functions and memory and ability to concentrate, maintaining the structure of cell membranes and contribute to maintaining overall health. Phospholipids and lectins are a source of choline, and they increase the bioavailability of other nutrients and therapeutic agents.

In addition, the glycerophospholipids was used as the e food emulsifiers, antioxidants, stabilizers, and other applications in the manufacture of food products, such as anti-mold and means for preventing sliianie. They give a unique physical properties of food products and products for personal care, and, therefore, their use as bases for drugs and delivery systems of drugs in formulations for the preparation of drugs.

In patent WO 03/105609 described phospholipid additive, which contains PS at a concentration of at least 1% of the total content of the phospholipids in the composition. In addition, the PS was produced from soybean lectin, lectin rapeseed or lectin egg yolk, and obtained by enzymatic method using phospholipase-D.

In the patent US 5709888 presents fat mixture comprising phospholipids and LC-PUFA, such as oleic acid, linoleic acid and alpha-linolenic acid, having a sufficient level of LC-PUFA in the series n6 and n3 series.

In the patent EP 484266 described mixture of phospholipids derived from such a source, as the marrow of domestic animals, in addition, at least one vegetable oil, animal fat, fish fat and/or triglycerides with a chain of medium length, in which the relationship between LC-PUFA and phospholipids was the same as against the giving of these compounds in human milk and in the Mediterranean diet.

Most sphingomyelin in milk fat is a building block of membrane globules of milk fat. Sphingomyelin is also an important building block needed by the baby for the development of the brain and other tissues, as well as important for the occurrence of certain biochemical pathways.

Myelin is a white substance that covers nerve cells, giving them the ability to conduct impulses from the brain to other parts of the body. It consists of a layer of proteins, Packed between two layers of lipids. Myelin is produced by specialized cells: oligodendrocytes in the Central nervous system and Schwann cells of the peripheral nervous system. The myelin sheath wrapped around axons, filiform outgrowths of neurons, which form the nerve fiber. Each oligodendrocyte can form the myelin sheath in multiple axons. Myelin consists of 80 percent of lipids and 20 percent from proteins. Sphingomyelin is a major lipid of this important tissue. This fatty substance that protects filiform axons and speeds up the conduction of electrical signals in the moment when they move along the nerve pathways, performing such a vital function as movement.

Various diseases and syndromes are associated with abnormalities caused by damage to myelin. Multiple IC is Eros, for example, leads to the disintegration of the myelin sheath, which leads to difficulty in the transfer of signals that gradually leads to loss of motor coordination, and other functions.

The development of myelin sheaths and neuronal network in infants is thus a key point and depends on the availability of suitable lipid building blocks, as well as from its own biosynthesis or from sources of nutrients, i.e. from women's breast milk.

Sphingomyelin (SM) consists of phosphocholine, which represents a polar group head, and sphingosine representing the carbon skeleton of the molecule, and therefore this connection klassifiziert as sphingolipid. These molecules are involved in the regulation of cell growth, cell differentiation, and many other functions, including the interaction of cell-substrate and signal transmission within the cell. Although many foods contain small amounts of SM, its role in nutrition and physiology are not fully understood.

The myelin of the Central nervous system (CNS-myelin) has a higher content of lipids (65-80%) compared with lipids in normal cell membranes. Metabolites SM and sphingolipid, such as cerebrosides and sulfatides, are essential components of the myelin sheath. This shell acts as isolator for nerve impulses and controls spasmodic (saltatory) method of conduction of the impulse through the interceptions Ranvier. The myelination in the CNS of man begins in the spinal cord with 12-th to 14-th week of pregnancy and continued during vnutrikorkovoj the fibers of the cerebral cortex in the third decade of life of the fetus, but the most rapid and significant changes occur between mid-pregnancy and the end of the second postnatal year [Brody BA et al. (1987) J. Neuropathol. Exp. Neurol. 46: 283-301; Kinney NA et al. (1988) J. Neuropathol. Exp. Neurol. 47: 217-234]. A threefold increase in the mass of the brain, which occurs in this period, due, for the most part, myelination.

The way of the metabolism of sphingolipids is described in the following paper [Luberto .and Hannun YA (1999) Lipids 34 (suppi): S5-S11]. SPT (EC 2.3.1.50) represents the first step in the biosynthesis of sphingolipid and rate-limiting enzyme that catalyzes the synthesis of 3-ketosteroid from L-serine and Palmitoyl-COA. This enzyme is localized in the endoplasmic reticulum or in the Golgi apparatus. A recent study showed that in rat hypothalamus SPT activity gradually increases from the third prenatal weeks until the third postnatal week. Because these animals myelination begins in the same period, it is likely that the increased activity of SPT can be one of the main factors involved in myelogenous.

The CNS myelin has a high content of cerebroside compared with its content in other tissues. Cerebroside is formed from ceramide with p the power of ceramide-UDP-galactosyltransferase, which is a key enzyme in the biosynthesis of cerebrosides and catalyzes the transfer of galactose from UDP-galactose to ceramide. It is difficult to determine the content of cerebroside in the brain of rats before the 10th day after birth, but the content cerebroside significantly increased from the second to third postnatal weeks, in particular, between 14 and 23 days of life. Since the period of maximum biosynthesis of cerebroside corresponds to the time of the most active myelination, cerebroside, generally considered to be a universal marker of CNS myelination.

Ceramides can be formed from L-serine and Palmitoyl-COA in the de novo synthesis by the enzyme SPT and SM using sphingomyelinase. Consequently, Oshida et al. (Pediatric Research 2003, 53: 589-593) suggested that in a period of low activity SPT, obrzovanie of cerebroside of CNS myelin in developing rats may occur mainly from SM in nutrient intake from milk, which is converted to ceramide and then cerebroside. Oshida et al., showed that, when the activity of SPT inhibited by injection of the appropriate inhibitor, leading to the reduction of cerebrosides in CNS myelin rats, the normal formation and the mass of the myelin tissue can be maintained using SM, administered with food. Adding SM in food restores a lot of the brain and the dry weight of myelin, the cat is who is reduced as a result of processing, leading to inhibition of SPT. Moreover, by electron microscopy, it was shown that the diameter of the axon in the group treated with the inhibitor, recovered after this the band started to get SM with food. These observations suggest that received oral SM is converted in the gut into ceramide or other metabolites that are absorbed from the digestive tract and entering the bloodstream, reach the CNS through the blood-brain barrier.

Although it is believed that sphingomyelin is an inert component of the cell membrane, the current study suggests that the metabolites of sphingomyelin involved in the transmission signal. SM plays a key role in the regulation of cellular processes. Dietary SM can contribute in the myelination of the developing CNS and protect in toxic or inhibitory conditions. SM is also a building block for other lipids, such as ceramides.

Breast-feeding seems to be contributing to the rapid growth of the brain mass, which mainly occurs as a result of myelination. At the moment of birth myelin very little, but for 3 years, most axons have myelin sheath.

As in human milk, the membrane of fat globules is similar in structure and/or function of the cell membrane, it is unclear why the level of SM in them so you is OK this fact suggests that the presence of SM may be due not only to its role as a building block of the membrane, but also as a source of SM from food. This role is very important in the early stages of pregnancy, is to provide a SM to build myelin before the end of the biosynthetic pathways of cerebrosides, as described above. Indeed, a higher content of phospholipids in General, and SM, especially in the early stages of pregnancy may not be random, but rather are necessary to increase dietary SM, with the aim to compensate for the newly formed biosynthetic apparatus of cerebrosides.

Sphingomyelin is usually not produced in industrial quantities, it is produced only from animal sources, such as cow's milk, eggs or animal brain. Animal sources, particularly those associated with the brain, of course, excluded from the diet of infants due to the risk of the disease pianoboy disease. In most cases, sphingomyelin from animal sources produced at a high level of purity, mainly for analytical standards and for research. These highly purified preparations of sphingomyelin extremely expensive and inaccessible, and therefore also not suitable for the General consumer.

Not avno, the dairy industry began to use waste milk production to produce food products containing milk proteins, carbohydrates and small amounts of lipids. The latter include both neutral lipids and polar lipids, including glycerophospholipids, and sphingolipids, and among them sphingomyelin. These products contain a very low amount of sphingomyelin and phosphatidylserine, which does not allow to use them as industrial sources for these nutrients. Typical drug (for example, SM3 Powder produced by Corman S.A. in Belgium), contains about 4% (wt./wt.) PC, 3.2% (wt./wt.) D, 1.6% (wt./wt.) PS, 0.9% (wt./wt.) PI and approximately 2.6% (wt./wt.) SM. Such low numbers entail the use of very large quantities of such drugs in order to put even a small amount of PS and sphingomyelin. Moreover, such large quantities will result in the delivery of unnecessary and unwanted proteins and carbohydrates, the latter mainly in the form of lactose.

The above commercial preparations of milk lipids, although having some similarities with the polar lipids HMF still different from them. The ratio between the polar lipids in the above-mentioned obtained from commercial milk products was as follows PC>PE>SM>PS>PI, whereas HMF ratio between the polar lipids is as follows SM> PC>PE>PS>PI. In particular, the content of sphingomyelin HMF was always higher than the content of the PC, their ratio is equal to about 1.3, while in the above-mentioned derived from milk commercial preparations of this ratio was equal to about 0.65.

Rombaut and co-authors has provided the phospholipid composition of some dairy products [Rombaut et al. (2005) J. Dairy Sci. 482:488]. None of the tested dairy products polar lipids were not given this attitude, which would correspond to the ratio of SM>PC>PE>PS>PI, shown for HMF.

As shown in Table 1, the lipid composition of the above derived from milk commercial drug differs from HMF mainly content sphingomyelin, which was lower than the content of PC, and a higher content RE.

Table 1
Class of lipidsCommercial dairy lipids (% from total polar lipids)Lipids HMF (% from total polar lipids)
SM21.137.5
PC32.528
D26.0PS13.09
PI7.46
Amount100100

In patent WO 2005/051091 the authors of the present invention described composition, which simulates the phospholipid composition of female milk. The present invention relates to a polar lipids women's breast milk and the importance of their recharge from other sources in the diet of children and adults nutrition. Thus, the aim of the present invention is the provision of drugs, lipids, particularly cost-effective drugs, with a high content of lipids, similar to the lipids of the brain for improved child nutrition and for use as food additives, functional food and pharmaceutical compositions for stimulating healthy brain.

In patent WO 2005/051091 described preparations of lipids that mimic the composition of the polar lipids of the fat womens breast milk (HMF), which include glycerophospholipids, such as PC, PE, PS and PI, as well as other polar lipids, such as sphingomyelin. These drugs lipids were mainly obtained from mixtures of phospholipids flora the CSOs origin, preferably, from soybeans, as well as of structured phospholipids, such as TRANS-phosphatidylcholine lectins. Other drugs lipids that mimic polar lipids HMF, is described in the publication included a bullish sphingomyelin obtained from milk. In this earlier application, the inventors have used pure bovine milk sphingomyelin, available as an analytical standard or chemical reagent for research purposes, which, in particular, is not suitable for use in baby food or food supplements, because of its high cost and extremely low availability, as mentioned earlier.

Thus, the aim of the present invention was to provide preparations of polar lipids that mimic polar lipids HMF, including optional SM, where the source of these polar lipid is a natural source of lipids, but not the brain.

Another objective of the present invention was to provide a dietary Supplement which guarantees sufficient and recommended consumption of phospholipids, particularly PS and sphingomyelin, in the form of Deputy imitating phospholipids lipid women breast milk used, in particular, for consumption by infants and young children, and pregnant women. Other uses and purposes of the invention will be clarified n the course of the description.

Brief description of the invention

The present invention relates to the preparation of lipids, which includes a mixture of polar lipids, in particular, glycerophospholipids, representing a phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI) and, optional or mandatory, including sphingolipids, or their predecessors or their metabolites, preferably sphingomyelin, where the level of each of these PC, PE, PS and PI was equal to at least 1% (wt./wt.), and where these polar lipids were obtained from a natural source of lipids of animal origin, but not from the brain.

The preparation of the lipids of the invention, where the quantitative relationship between the specified glycerophospholipids was basically equivalent to the specified relationship to the natural fat of breast milk (HMF), at any desired stage of lactation.

In one of the embodiments of the preparation of the lipids of the invention include sphingolipid or its predecessor or its metabolite, preferably sphingomyelin, where the quantitative relationship between the glycerophospholipids and sphingolipids in the specified drug was basically equivalent to the corresponding ratio of these compounds in the specified natural HMF, at any desired stage of lactation.

Thus, the relation between the polar lipids in the preparation of the lipid is in the invention was as follows PC> PE>PS>PI, or SM>PC>PE>PS>PI, or even SM=PC>PE>PS>PI.

In another embodiment of the specified polar lipids were obtained from the specified natural source of lipids of animal origin, but not from the brain, using fractionation and/or extraction, or using a method not included transpeptidation.

Mainly polar lipids contained in the mixture of lipids were obtained from the specified natural source of lipids of animal origin, but not from the brain, using fractionation and/or extraction, in particular, by using the method, not including transpeptidation.

The quantitative relationship between the specified glycerophospholipids may substantially mimic the ratio of these compounds in the natural fat of breast milk (HMF), at any desired stage of lactation. Moreover, when the drug contained sphingomyelin (SM) or its predecessor or its metabolite, quantitative relationship between the glycerophospholipids and sphingomyelin in the specified drug could significantly to simulate the corresponding ratio of these compounds in the specified natural HMF, at any desired stage of lactation.

In a particular embodiment the invention relates to the preparation of lipids enriched in PS containing about 5-99% (wt./wt.) PS, preferably, about 5-90% (wt./wt.), more FAV is preferably, about 7-60% (wt./wt.), most preferably, about 7-25% (wt./wt.), where PS was obtained from a natural source of lipids of animal origin, but not from the brain, using methods that did not include transpeptidation, and where the specified source of lipids represented, preferably, seafood, milk or eggs, more preferably cow's milk. This preparation could include additional polar lipids, preferably PC, more preferably, a mixture of PC, PE, PI, most preferably, a mixture of PC, PE, PI and SM. PS can be described by the characteristics of the profile of fatty acids source of animal from which it was obtained, preferably, on the profile of fatty acids PS cow's milk.

In another specific embodiment the invention relates to the preparation of lipids enriched in SM and containing about 5-99% (wt./wt.) SM, preferably, about 5-90% (wt./wt.), more preferably, about 10-60% (wt./wt.), most preferably, about 10-50% (wt./wt.), where SM was obtained from a natural source of lipids of animal origin, but not from the brain. SM can be described by the characteristics of the profile of fatty acids of the specified source animal, preferably on the profile of fatty acids SM cow's milk.

Additionally, the invention has come compared to the drug lipids, enriched as PS, SM, and containing about 5-99% (wt./wt.) PS and SM, preferably, about 5-90% (wt./wt.), more preferably, about 7-60% (wt./wt.), most preferably, about 7% to 50% (wt./wt.), where PS and SM were obtained from a natural source of lipids of animal origin, but not from the brain, using methods that do not include transpeptidation specified source of lipids was preferable, milk or eggs, more preferably cow's milk.

In an additional aspect, the invention relates to a method for the preparation of lipids, which includes a mixture of polar lipids, in particular, the glycerophospholipids were phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI), and optional or required, including sphingolipid or its predecessor, or its metabolite, preferably sphingomyelin, from a natural source of lipids of animal origin, but not of the brain, including the allocation of the above-mentioned mixture of lipids from the specified natural source of lipids of animal origin, but not from the brain, using methods that do not include transpeptidation.

The method of producing drug lipids of the invention, as described in this document involves the following stages:

(a) providing a natural source of lipids zivotnog the origin, but not the brain, which has a significantly low content of polar lipids;

(b) removal of non-lipid material from the specified source of lipids, a dispersion of lipids, preferably with stirring in a suitable organic solvent or mixture of organic solvents;

(c) separating the fraction of dissolved lipids obtained in stage (b), and the removal of this fraction of organic solvent to obtain fractions of lipids;

(d) degreasing fraction of lipids obtained in stage (C), at least, to remove any non-polar lipids; and

(e) filtering and drying the polar lipids obtained in stage (d).

Optionally, the method may optionally include the stage of processing of the source of the lipids in an aqueous medium both before and after said stage (b).

Suitable organic solvents may be mixtures of polar organic solvents, preferably lower alcohols, especially ethanol, and non-polar solvent, preferably hydrocarbons, particularly n-hexane. The organic solvent may optionally contain water.

The method of the invention can be carried out at a temperature of 15-100°C., preferably at 25-80°C., more preferably at 30 to 60°C.

A natural source of lipids of animal origin, but not the brain, was included at the ore, one source of lipids, preferably obtained, from seafood, more preferably, from a source animal, most preferably, from fat cow's milk, or eggs of poultry. The source of lipids could be a mixture of sources of lipids.

A natural source of lipids obtained, preferably, made from cow's milk could contain up to 5% (wt./wt.), preferably, 10% (wt./wt.), more preferably, 25% (wt./wt.), even more preferably, 35% (wt./wt.) of total lipids, in addition to other components, including proteins and carbohydrates, and where polar lipids was about 20%, preferably 30%, more preferably 50%, most preferably, 70% of these total lipids.

In a special embodiment of a natural source of lipids contained about 0.1-10% (wt./wt.) PC, about 0.1-5% (wt./wt.) RE, about 0.1-5% (wt./wt.) PS, about 0.1-5% (wt./wt.) PI and do not necessarily contain sphingomyelin, preferably in an amount of about 0.1-5% (wt./wt.). More precisely, the source of the lipids included approximately 2.6% (wt./wt.) SM, approximately 4% (wt./wt.) PC, about 3.2% (wt./wt.) RE, about 1.6% (wt./wt.) PS and about 0.9% (wt./wt.) PI.

The preparation of lipids resulting from the application of any of the described in this document ways, was characterized by the following ratio of polar lipids PC>PE>PS>PI Il the SM> PC>PE>PS>PI or SM=PC>PE>PS>PI.

The present invention additionally provides a method of enrichment of SM drug lipids obtained using any of the methods described in this document, the method including the additional evaluation of the specified drug at any one stage using alkaline hydrolysis, enzymatic hydrolysis, preparative chromatography, or extraction of polar.

In another embodiment the invention relates to a food additive or nutrient substance, which includes the preparation of the lipids of the invention. The drug is lipid may contain emulsified or dispersed form, preferably in the form of a substantially watered emulsion or dispersed form or in the form of dry matter.

The invention also relates to a method of obtaining nutritional supplements of the invention, by mixing the drug lipid of the invention, at least one of the additives, emulsifiers or foundations. This method may further include mixing the drug of lipids with liquid water environment, with the specified food additive, mainly in liquid water form. The method may additionally include a dispersion, preferably, the dissolution of the drug lipid environment consisting of organic compounds, preferably in the oil, the LEM for use in children mixtures, in particular, in oil, which mimics the HMF. Optionally, the method can include drying the dispersion liquid nutritional supplements to provide nutritional supplements in powder form.

Mixtures and preparations of the lipids of the invention, and nutritional supplementation, or nutrients, including them, can be used as an ingredient lipid component of infant formula or as an ingredient in infant formula.

Additionally, mixtures and preparations of the lipids of the present invention and dietary supplements, nutrients or food products comprising them, can be applied to improve the development of infants and/or children, in particular, cognitive development, and/or improve visual development.

Special food product in accordance with the invention is an infant formula, including the preparation of lipid, or a mixture, or food Supplement comprising the same drug lipids.

The invention also relates to the process of obtaining PS, originating from a natural source of lipids of animal origin, but not of the brain, including the extraction of the PS of the fraction of polar lipids obtained using the method of the invention. Specified natural source of lipids of animal origin, but not the brain, is preferably included at least one source of lipids, preferably, the C seafood, more preferably, the source of the lipids of animal origin, most preferably, from cow fat or eggs poultry.

The invention additionally relates to a method of obtaining SM originating from a natural source of lipids of animal origin, but not of the brain, including the extraction of SM of the fraction of polar lipids obtained using the method of the invention. Specified natural source of lipids of animal origin, but not the brain, is preferably included at least one source of lipids preferably, seafood, more preferably, from a source of lipids of animal origin, most preferably, from cow fat or eggs poultry.

In an additional aspect, the invention relates to the use of these enriched PS, SM or PS/SM preparations of the invention to improve cognitive function, particularly memory, concentration, attention and ability to learn.

Moreover, the invention relates to the use of these drugs of the invention, enriched PS, SM or PS/SM for the treatment of diseases associated with dysfunction of the brain, or for treatment of disorders or to improve cognitive function, for example, disorders and diseases associated with worsening of mood, memory, stress, or with the old is observed such as dementia and Alzheimer's disease, and memory loss and problems with sosredotochennosti and attention, and ability to learn.

In yet another embodiment the invention relates to the use of these enriched SM or PS/SM preparations of the invention for the treatment, prevention or improvement of myelin-related disorders and diseases, particularly disorders associated with de-myelination, such as, for example, MS. These drugs lipids can be applied also to maintain and enhance the subject, especially in infants and children, normal or improved development of the myelin sheath and other sphingomyelin-dependent tissues.

Detailed description of the invention

First of all, the present invention provides the preparation of a lipid, including a mixture of polar lipids, in particular, glycerophospholipids such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI), and optionally including sphingolipid, or its predecessor, or its metabolite, particularly sphingomyelin, where the content of each of these PC, PE, PS and PI were equal to at least 1% (wt./wt.), and where these polar lipids were obtained from a natural source of lipids of animal origin, but not from the brain.

In these preparations, the relationship between polarn the mi lipids was as follows: SM> PC>PE>PS>PI or SM=PC>PE>PS>PI. Thus, the relationship between SM and PC was equal to or >1, or 1:1, preferably 1.1, more preferably, 1.3. Alternatively, the relationship between SM and PC was equal to 1.5, preferably, it is 2.

The preparation of the lipids of the invention was obtained by the processing of the process and fractionation of mixtures of natural extracted polar lipids, preferably containing glycerophospholipids, most preferably, also contained sphingomyelin. In the preferred embodiment these natural lipids from animal sources, preferably from milk of domestic animals, especially the cow, and/or eggs of animals. In an additional embodiment, the mixture of natural lipids can be obtained from a source of plant origin, preferably containing sphingomyelin, or predecessor of sphingomyelin, or metabolite sphingomyelin.

In a particularly preferred embodiment of the preparation of the lipids of the invention can be obtained from drug commercial cow's milk containing low and even very low amounts of polar lipids (for example, a mixture described in Table 2), and in which lipids differed in their internal relationship from the relationship SM>PC>PE>PS>PI, which was discovered in HMF (Table is 1, above).

Table 2
Class of lipidsCommercial dairy lipids
(weight %)
Commercial dairy lipids (% from total polar lipids)
SM2.621.1
PC432.5
D3.226.0
PS1.613.0
PI0.97.4
Amount12.3100.00

In accordance with the present invention, the authors processed and selectively were extracted polar lipids from the mixture obtained from raw cow's milk, increasing, thus, the contents of the individual lipids and receiving the drug, suitable for use as a food additive or as a Supplement to the diet of infants. Importantly, the relative content of sphingomyelin was increased to the number of the output, or even exceeding, the contents of the PC, making, thus, the preparation of the lipids of the invention even more like polar lipids HMF. Additionally, the content of RE was low, again making it comparable to the relative level RE found in HMF. Table 3 shows an example of the preparation of the polar lipids of the invention and details concerning the relative content of polar lipids, namely SM, PC, PE, PS and PI, compared with lipids HMF. The ratio of SM>PC>PE>PS>PI found in HMF was obtained in the preparation of the lipids of the invention (table 3), even though the initial mixture, obtained from raw cow's milk, had a different attitude (PC>PE>SM>PS>PI).

PI
Table 3
Class of lipidsThe preparation of the lipids of the invention (% of the sum SM, PC, PE, PS, PI)Lipids HMF (% of the sum SM, PC, PE, PS, PI)
SM29.737.5
PC27.928
D19.619.5
PS13.39
9.56
Amount100100

The composition of glycerophospholipids drug lipids of the invention was also similar to the composition of glycerophospholipids HMF and imitated the glycerophospholipids HMF, as you can see from the example presented in Table 4.

Table 4
Class of lipidsThe preparation of the lipids of the invention (% of the amount of PC, PE, PS, PI)The fat milk (% of the amount of PC, PE, PS, PI)
PC39.745.4
D27.830.8
PS18.914.1
PI13.59.7
Amount100100

The composition of the special preparation of the lipids of the invention are described in Table 5. As you can see, the product mainly contains a large amount of HMF-like polar limes is Dov, in contrast to the low content of polar lipids detected in the original mixture. Thus, the product of the invention has reached such a content of polar lipids, which is equivalent to the concentration found in HMF. These high amounts are used to apply preparations of the invention in a variety of food babies, food supplements, functional foods and pharmaceutical compositions.

It is important to note that the product of the invention was artificial, and its components, even from natural sources, has undergone processing/structuring before application of the drug of the invention. Alternatively, these components are synthesized using chemical or enzymatic methods. Therefore, these components are included in the drug of the invention contain at least small amounts of substances which are endogenous sources of lipids, from which they were obtained (such trace amounts suitable for food and physiologically compatible). Trace amounts of this kind are absent in human milk (and HMF), which makes the preparation of the invention is similar, but not identical HMF.

In addition, HMF is a composition used to describe the full fraction of the lipids of breast milk. It definitely contains the components (phospholipids), especially mentioned the e in this document, and also contain other lipid components that are not present in the product of the lipids of the invention, such as, for example, fat-soluble vitamins. Thus, the most preferred embodiment of the preparation of the lipids of the present invention includes the combination of phospholipids, whose attitude is comparable with the ratio of HMF (SM>PC>PE>PS>PI or SM=PC>PE>PS>PI), and additionally includes trace amounts of compounds from sources of lipids, of which these phospholipids were obtained, whereas other lipid components present in HMF, was missing.

Table 5
Class of lipidsThe preparation of the lipids of the invention (% w/w)
SM22.7
PC21.4
D15.0
PS10.2
PI7.3
Amount76.6

In the preparation of the lipids of the invention can additionally be influenced to make it more similar to HMF by increasing SM content item is compared with the contents of glycerophospholipids. This can be achieved by using one of the following methods.

1. Given the advantage that gives a certain stability of the SM to alkaline hydrolysis, the product of lipid, e.g., one that presented in Table 5, were placed in an aqueous alkaline medium. The glycerophospholipids were subjected to hydrolysis, leading to the elimination of their fatty acids and the formation of free fatty acids and partially or completely hydrolyzed glycerophospholipids, which were well soluble in water. Thus, non-hydrolyzed, relatively hydrophobic SM could easily be separated and obtained by extraction with organic or oily environment. Received SM can then be combined with the drug are presented in Table 5 (or other drugs of the invention), to obtain the drug of lipids, in which the relative content of SM was higher and closer to the content of SM in HMF (approximately 38% of the total polar lipids). Optional alkaline hydrolysis partially gidrolizu only part of glycerophospholipids. Thus, the process of hydrolysis can be controlled so that the non-hydrolyzed glycerophospholipids and SM gave the drug to lipid, which resembled a polar lipids HMF even more closely than the drug is presented in Table 5.

2. The use of selective enzymatic hydroly is and glycerophospholipids, in the presence of selective glycerophospholipid lipase, in a mixture of polar lipids of the invention (for example, the drug is presented in Table 5). Applying one or more of the following enzymes: 1:3 lipase, phospholipase Al (PLA1) or phospholipase A2 (PLA2)was subjected to the hydrolysis of glycerophospholipids to release one or two fatty acids. Partially or fully hydrolyzed fatty acids can be separated from the SM, with subsequent alkali treatment. Then the SM can be combined with the drug are presented in Table 5 (or similar drug). Alternatively, selective enzymatic hydrolysis can be carried out partially, by making fewer enzymes and/or by reducing the reaction time. Thus, the remaining glycerophospholipids and SM give the drug of lipids, which resembles a polar lipids HMF even more closely than the original drug.

3. The use of the difference in polarity of the various components of the drug of the invention (SM>PC>PS>PI>PE) and carrying out purification using preparative chromatography normal phase. Then the SM could be combined with the drug are presented in Table 5 (or similar drug), to obtain the drug of lipids, in which the relative content of SM was higher and closer to the content of SM in HMF.

4. Carrying out the extraction of polarn the x lipids from the raw material (consisting of proteins/sugars/lipids) using a system of selective solvents, which increased SM content in the extract and the fraction remaining and not ekstragirovanie from the raw material fat. Examples of solvents for extraction can be any alcohol or a combination of alcohol and water. Thus, SM, representing the most polar component was enriched compared to its concentration in the raw material. As described earlier, the received SM could be combined with the original drug (e.g., drug, are presented in Table 5) for the preparation of lipids enriched in SM and more like the HMF.

Thus, the present invention provides the preparation of lipids, which was obtained without mixing multiple sources of lipids, but preferably by fractionation and processing of natural drugs of polar lipids containing glycerophospholipids, preferably, PC, PE, PS and PI, and optionally including sphingomyelin (or predecessors of sphingomyelin and/or metabolites of sphingomyelin). In accordance with the present invention, a mixture of polar lipids were obtained from the crude preparations of lipids extracted from natural sources, preferably, seafood, more preferably, from a source animal, and even more preferably from cow's milk or eggs poultry. Milk others who Lampedusa or eggs of other domesticated or wild birds can also be used as a source. Moreover, it can also be applied to the sources of plant origin, provided that they contain the glycerophospholipids in relative terms, which allows their use without additional mixing with other sources of lipids, and/or lipids from sources of plant origin, including PS and/or sphingomyelin (or precursors or metabolites of sphingomyelin). Examples of sources of plant origin are soybeans, sweet potatoes and groundnuts.

In preferred embodiments the drug is lipid in accordance with the invention included more than 1% (wt./wt.) each of PC, PE, PS and PI, and, optionally, more than 1% (wt./wt.) sphingomyelin, preferably more than 3% (wt./wt.) each of PC, PE, PS and PI, and, optionally, more than 3% (wt./wt.) sphingomyelin, more preferably more than 5% (wt./wt.) each of PC, PE, PS and PI, and, optionally, more than 5% (wt./wt.) sphingomyelin, most preferably more than 7% (wt./wt.) each of PC, PE, PS and PI, and need not be more than 7% (wt./wt.) sphingomyelin.

In an additional preferred embodiment the content of the PC is over 5% (wt./wt.), more preferably, more than 10% (wt./wt.), most preferably, more than 15% (wt./wt.). The contents of the PC was preferably about 5-50% (wt./wt.), more preferably, about 8 to 40% (wt./wt.), most prefer is Ino, 10-35% (wt./wt.).

In the preferred embodiment the content of PS was more than 2% (wt./wt.), more preferably, more than 4% (wt./wt.), most preferably, more than 7% (wt./wt.). The content of PS was preferably about 2-50% (wt./wt.), more preferably, about 4-40% (wt./wt.), most preferably, of about 5-25% (wt./wt.).

In the preferred embodiment the content of RE was more than 4% (wt./wt.), more preferably, more than 7% (wt./wt.), most preferably, more than 10% (wt./wt.). The content was RE preferably about 3-50% (wt./wt.), more preferably, about 5-40% (wt./wt.), most preferably, about 7-30% (wt./wt.).

In the preferred embodiment the content of PI was about 2-50% (wt./wt.), more preferably, about 3-40% (wt./wt.), most preferably, about 4-20% (wt./wt.).

In the preferred embodiment the content of SM was more than 3% (wt./wt.), more preferably, more than 5% (wt./wt.), more preferably, more than 10% (wt./wt.), most preferably, more than 15% (wt./wt.). The SM content was preferably about 5-50% (wt./wt.), more preferably, about 10-40% (wt./wt.), most preferably, about 15-35% (wt./wt.).

In a particular preferred embodiment the relative content of polar lipids (SM, PC, PE, PS, PI) simulated relative content this is x of lipids in HMF, where SM>PC>PE>PS>PI. Alternatively, these relative content were as follows SM=PC>PE>PS>PI. In more preferred embodiments, the relative content of the SM of the total polar lipids (SM, PC, PE, PS, PI) was between 5-60%, more preferably 10-50%, even more preferably 20-40%, most preferably 30-35%.

In other particularly preferred embodiments, the relative content of the PC of the total polar lipids (SM, PC, PE, PS, PI) was between 5-60%, more preferably 10-50%, more preferably 20-40%, even most preferably 25-35%.

In other particularly preferred embodiments, the relative content of PE of the total polar lipids (SM, PC, PE, PS, PI) was between 5-50%, more preferably 10-40%, most preferably 23-30%.

In other preferred embodiments, the relative content of PS from the overall content of polar lipids (SM, PC, PE, PS, PI) was between 3-40%, more preferably 5-35%, even more preferably 7-25%, most preferably 10-20%.

In other preferred embodiments of the proportion PI of the total polar lipids (SM, PC, PE, PS, PI) was between 2-40%, more preferably 3-35%, most preferably 5-20%.

In another preferred embodiment the relative content of polar glycerolipids (PC, PE, PS, PI) imit is informed of the relative content of these lipids in the HMF, in which PC>PE>PS>PI. In more preferred embodiments, the relative content of PC from the sum of the content of the polar glycerolipids (PC, PE, PS, PI) was between 5-60%, more preferably 10-55%, even more preferably 20-50%, most preferably 35-45%.

In other preferred embodiments, the relative content of PE of the amount of the polar glycerolipids (PC, PE, PS, PI) was between 5-60%, more preferably 10-50%, even more preferably 15-45%, most preferably 20-35%.

In another preferred embodiment, the relative content of PS from the amount of the polar glycerolipids (PC, PE, PS, PI) was between 3-50%, more preferably 5-45%, even more preferably 7-35%, most preferably 15-25%.

In another preferred embodiment, the relative content of PI from the amount of the polar glycerolipids (PC, PE, PS, PI) was between 3-50%, more preferably 5-40%, most preferably 7-30%.

The drug of the invention include a high number of PS, preferably more than 2% (wt./wt.), preferably, more than 5% (wt./wt.), more preferably, more than 8% (wt./wt.), most preferably, more than 10% (wt./wt.). The specified PS was from natural sources, but not from the brain, preferably, from milk or eggs, preferably, made from cow's milk or eggs poultry. It should be noted that the present invention can be applied is e natural source PS, comparable to transpeptidation PS soybeans, but safe from a natural source. The drug of the invention can serve as a good source PS, obtained by extraction and not using transpeptidation. This PS can be used for the same purposes as a commercial soy transpeptidation PS, in particular, as a dietary Supplement or functional food products or pharmaceutical products, to obtain the health benefits associated with the addition of PS.

The drug of the invention is also characterized by the inclusion of high amounts of SM, preferably more than 3% (wt./wt.), more preferably, more than 5% (wt./wt.) more preferably, more than 10% (wt./wt.), and most preferably more than 15% (wt./wt.). SM received from natural sources, but not from the brain, preferably, from milk or eggs, more preferably, from cow's milk or eggs poultry. Importantly, the drug of the invention served as the available source SM, who was not from the brain of animals, and its shape, price and quality were suitable for food additives, functional food and/or pharmaceutical compositions, which have health benefits for the brain.

Additionally, the invention relates to the combination of PS and SM, for use in the treatment of diseases or the breach is, work-related injuries or to improve cognitive functions (worsened mood, depression, stress, disorders, and diseases associated with aging, such as dementia, Alzheimer's disease, memory loss, problems with concentration and attention, problems with learning and so on).

Additionally, the invention relates to preparations of lipids, including PS and SM, optionally together with other polar lipids, in which PS and SM show a synergistic effect. As PS and SM represent the structural components of various tissues or parts of the human brain. PS - this is an important building block of cell membranes grey matter of the brain and nerve cells, whereas SM is the main component of myelin sheaths. Thus, the replenishment of these two important building blocks of the brain lipid nature has a higher positive effect on cognitive function, by treatment and maintain the structural integrity of the two systems of the brain at the same time, synergistic, and not just an additive way. These compositions PS and SM may contain more than 1%, preferably 5-90% (wt./wt.), more preferably 5-60% (wt./wt.), most preferably 5-40% (wt./wt.) each of the PS and SM.

The invention particularly relates to a method for the preparation of the lipids of the invention. This method includes the adiya's, providing suitable coarse source of lipids, removal of coarse source of lipids non-lipid material by selective dissolution of the lipids in a suitable organic solvent or mixture of organic solvents.

Gross source of lipids may be a mixture of different sources of lipids, for example, cow's milk, combined with lecithin eggs. Alternatively, each of the different sources can be processed independently using the process of the invention, and the resulting final mixture of lipids can be mixed to obtain the drug of lipids, including polar lipids from a variety of sources.

In the preferred embodiment the source of lipids were dispersively in a mixture of nonpolar and polar organic solvents, or one polar solvent. Preferred polar organic solvents represented alcohols, preferably lower alcohols, more preferably, ethanol, and the preferred non-polar solvents represented hydrocarbons, most preferably hexane. The solvent or solvent system optionally included water, or, alternatively, treatment with organic solvents were carried out in aqueous medium or treatment with organic solvents followed by processing in the aquatic environment. The above is the processing included the dispersion of the source of lipids in the specified environment with stirring. Processing was carried out at room temperature or, alternatively, under cooling or under heating. Preferably, processing, removal of non-lipid material was carried out at the temperatures at which the removal was optimal, and removed the minimum number of lipids. Preferably, the method could be carried out at elevated temperatures, preferably at 15-100°C., more preferably at 25-80°C., most preferably at 30 to 60°C. non-lipid material was filtered and then optionally processed by the specified solvent system in order to ensure the removal of the minimum number of polar lipids.

Organic solvents containing lipids were removed by conventional methods, preferably by evaporation under reduced pressure. Fraction of the lipids were then degreased (removal of non-polar lipids, mainly triglycerides) by conventional methods, preferably with acetone or supercritical CO2. In the case of acetone, for example, the stage degreasing was repeated several times, and polar lipids obtained was filtered and dried by conventional methods, preferably, under reduced pressure.

The drug of the invention is suitable in addition to or as an additive to infant formula as a light source is AC HMF-like polar lipids, making these infant formula more similar to breast milk, as well as for food, babies or small children, enriching their nutritional content of HMF-like polar lipids.

The term "infant formula"as it is used in this document covers infant formula (for babies from newborn to 6 months old), subsequent infant formula (for infants 6-12 months) and adults milk for children 1-3 years old).

The term "infant formula"as it is used in this document, covers the baby formula (for babies from newborn to 6 months old), mixtures (for babies 6-12 months) and adult formulas (for children 1-3 years old).

The drug of the invention can then be applied in order to simulate or create a globule of fat, which simulate the globules of fat in human milk.

The drug of the invention is also suitable for adding to the nutrition of pregnant women, either as additions to the diet or as supplements, functional foods or as a pharmaceutical preparation.

The drug of the invention can be applied for feeding preterm infants as a Supplement to their diet, or as a pharmaceutical preparation.

The drug of the invention can then be applied in ka is este active ingredient in dietary supplements, in functional food products or pharmaceutical products to improve the health of all people, children, teenagers, adults and especially the elderly.

A special aspect of the present invention is the use of the drug of the invention to improve the brain functions of any of the above populations, in particular, by improving their cognitive function, memory, alleviate stress, improve mood, recovery weakened by aging memory, struggle with dementia, prevention or treatment of Alzheimer's disease, etc.

The drug of the invention may also be applied for the treatment, prevention or improvement of disorders or diseases associated with myelin, particularly disorders associated with de-myelination, such as, for example, MS, by introducing (or consumption) of the drug by the subject who needs it.

The drug of the invention is suitable in order to enable a normal brain, and cognitive development of infants, young children and pre-school children, by ensuring normal or improved development of the myelin sheath and other tissues associated with the metabolism of sphingomyelin.

The preparation of pharmaceutical compositions is well known in this technical field and has been described in many articles and textbooks, see, e.g., A.R. Gennaro e. (1990) Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, and, in particular, s-1712 in this document.

In conclusion, the present invention also provides methods of treating and/or improving cognitive function, or job-related brain diseases or disorders, in need thereof of a subject, the method including the introduction of a specified subject a therapeutically effective amount of the drug lipids provided in the present invention. These cognitive functions are memory, stress concentration, attention and ability to learn. These violations are neurological disorders that are associated with mood, memory, stress, or aging, and neurological diseases such as dementia, Alzheimer's disease, memory loss, problems with concentrated and attention and ability to learn.

In addition, where the specified method of treatment was used drugs lipids of the invention, including SM, this method is suitable for subjects suffering from associated with myelin disorders or diseases, particularly disorders associated with de-myelination, such as multiple sclerosis (MS) and leukodystrophy.

Usually, a "therapeutically effective amount" is determined by the severity of the disease depending on the prophylactic or therapeutic objectives, the route of administration and obseg the condition of the patient (age, sex, weight and other factors known to the attending physician). The decision regarding the individual dose for receiving (and how many times a day should take the medicine), the physician is free to accept himself, and to achieve the desired therapeutic effect of this decision can be changed by the selection of doses in the specific conditions of the invention.

The present invention additionally provides the use of drugs lipids described in the invention in the preparation of pharmaceutical compositions for use in treating the above conditions.

It should be understood that the invention disclosed and described, is not limited to particular examples, phases and materials disclosed in this document, such as the stage or the materials will be a little different. It should also be understood that the terminology used in this document applies only to describe specific embodiments and not intended to be limiting, as the scope of the present invention is limited only by the attached claims and their equivalents.

It should be noted that applied in this description and in the appended claims, the singular forms of "a", "an" and "the" include the plural, if the content was not clearly defined in another way.

Throughout the description of the invention and forms the Les of the invention, which will be presented below, as long as the context requires, the definitions in a different way, the word "comprise", and variations such as "comprises" and "comprising"should be understood as the inclusion formulated an integer or stage, or whole groups or groups of stages, but not the exclusion of any other integer or any other stage, or any other whole groups or groups of stages.

The following Examples are examples of techniques used by the authors of the invention for the implementation approaches of the present invention. It should be appreciated that, since these techniques are typical in the preferred embodiments for carrying out the invention in practice, experts in the field of technology, in the light of the present disclosure should appreciate that numerous modifications can be made without deviating from the essence and the proposed scope of the invention.

Information confirming the possibility of carrying out the invention

Example 1 - Getting SM-containing mixture of polar lipids

50 g product of cow's milk (table 2) was added to 400 ml of a mixture of hexane: ethanol (80:20) and were mixed together at a temperature of 40-45°C. After 2 hours the suspension was filtered under reduced pressure, and the residue resuspendable in the same conditions, and again filtered. United faction rastvoritelyami under reduced pressure (< 10 mbar). Then the fractions obtained lipid twice degreased with acetone in the ratio of 1:6 (wt/vol.), and the powder obtained in the form of precipitation, filtered and dried under reduced pressure (<10 mbar in a vacuum drying. There was obtained 7 g of dry powder, the analysis of which showed the same distribution of polar lipids, which was shown in Table 3, above.

1. The method of obtaining the drug of polar lipids, which contains a mixture of glycerophospholipids, representing phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI) and sphingomyelin (SM), for use as a source of fat in human breast milk, which includes stages:
(a) removal of non-lipid material from cow's milk by dispersion of lipids, preferably with stirring, a mixture of a polar organic solvent, preferably a primary alcohol, more preferably ethanol, and non-polar solvent, preferably a hydrocarbon, more preferably n-hexane, optionally containing water;
(b) separating the fraction of lipids obtained in stage (a), and removal of this fraction of organic solvent to obtain fractions of lipids;
(c) at least once degreasing fraction of lipids obtained in stage (b), to remove any non-polar the lipids by dissolving the mixture in acetone or supercritical CO 2;
(d) filtering and drying the specified polar lipids obtained in stage (C).

2. The method according to claim 1, which additionally includes a step of processing the specified source of lipids in an aqueous medium either before or after stage (a).

3. The method according to claim 1, in which the specified stage (a) is conducted at a temperature of 15-100°C., preferably at 25-80°C., more preferably 30-60°C.

4. The method according to claim 1, wherein in stage (b) specified organic solvent is removed by evaporation, preferably under reduced pressure.

5. The composition of the polar lipids for use as a source of fat in human breast milk obtained according to the method according to claim 1, containing a mixture of glycerophospholipids, representing phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI) and sphingomyelin (SM), in which the content of PC is equal to at least 5% (wt./wt.), the content of PS is equal to at least 2% (wt./wt.), the content of RE is at least 4% (wt./wt.), the content of PI is at least 2% (wt./wt.).

6. The use of a composition of polar lipids according to claim 5 for the manufacture of infant formula.

7. The use according to claim 6, where this lipid composition is emulsified or dispersed form, preferably in the form of mainly water emulsion or dispersion./p>

8. The use according to claim 6, where this composition is in dry form.



 

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