Lipid composition for oral, enteral or parenteral feeding.

The subject of the present invention is a lipid composition intended for oral, enteral or parenteral nutrition.

Many pathological situations in humans require a large intake of lipids to remedy abnormalities in lipid metabolism or to compensate for a specific deficit (eg various disorders of digestion and nutrition, specific needs for resuscitation, in shock and intensive care).

It has been mentioned, p. ex. in French patent application No. 2,490,631, lipid compositions intended for use in this type of situation comprising an oil containing gamma-linolenic acid (C₁₈: 3ω6) mixed with glycerol esters of C fatty acids₆-VS₁₂. The gamma-linolenic acid oil proposed comes from oenothera biennis and oenothera Lamarckiana (evening primrose or evening primrose) seeds, the only source currently available.

In addition, the C fatty acid glycerol esters₆-VS₁₂ constitute at least 50% by weight of the lipid composition. Such a composition does not optimally meet the needs mentioned above because it contains an excess of C triglycerides₆-VS₁₂ which are known to be highly ketogenic, and that it does not contain C lipid fractions₁₂-VS₁₈ which are however essential to the nutritional balance during a prolonged feeding of the seriously ill.

The object of the invention is a lipid composition which does not have the drawbacks of known compositions and which allows the daily supply of lipids providing:<ul id="ul0001" list-style="none"><li>- caloric energy substrates for the balanced functioning of internal metabolism,</li><li>- essential fatty acids whose role is to participate in the regulation of many metabolisms and cellular structures including the composition of membranes and the synthesis of many active substances (prostaglandins, leukotrienes and thromboxanes).</li></ul>

The lipid composition according to the invention is characterized in that it consists of:<ul id="ul0002" list-style="none"><li>a) from 10 to 30% by weight of an oil containing gamma-linolenic acid in the form of triglycerides,</li><li>b) from 20 to 40% by weight of triglycerides of C fatty acids₆-VS₁₂ and</li><li>c) from 50 to 70% by weight of an oil containing triglycerides of fatty acids, at least 80% of which are C fatty acids₁₂at C₁₈, the sum of components a) and b) not exceeding 50% by weight of the composition.</li></ul>

The oil containing gamma-linolenic acid according to the invention will in particular be a fruit seed oil of the genus Ribes which contains at least 4% by weight of this acid in the form of triglycerides. This is obtained by solvent extraction from fruit seeds of the genus Ribes, that is to say in practice blackcurrant (Ribes nigrum), currants (Ribes rubrum) and gooseberries (Ribes ova- crispa or grossularia) or hybrids of these fruits, e.g. ex. according to the method described in the parallel patent application. These seeds are found in residues from the production of juices, jams and jellies or brandies, leaguers and schnapps.

Their lipid content is 12 to 30% by weight depending on the raw material. The lipid phase in turn contains 4 to 19% by weight of gamma-linolenic acid.

As an indication, the seed oil of these fruits consists of the following fatty acids, by weight:<tables id="tabl0001" num="0001"><img file="EP0092076A2_D0001.tif" /></tables>

Blackcurrant oil, which is preferred because of its high gamma-linolenic acid content, also contains 1 to 2% by weight of unsaponifiable bodies, such as aliphatic alcohols, hydrocarbons, tocopherols, squalene, β-sitosterol, campesterol. and Δ-7 stigmasterol.

Gamma-linolenic acid is a polyunsaturated fatty acid which is metabolized by the body into prostaglandins via dihomo-gamma-linolenic acid and arachidonic acid (5, 8, 11, 14 - eicosatetraenoic acid), which is even a constituent of cell membranes while alpha-linolenic acid does not contribute in the same way to this metabolic process. The conversion of linoleic acid (C 18: 2 ω 6) + gamma-linolenic acid in the tissues is incomplete (4 - 20% compared to 90 - 98% for the transformation gamma-linolenic acid + arachidonic acid) and may even be nonexistent in absence or inactivation of the enzyme A-6-desaturase. Gamma-linolenic acid therefore becomes essential in pathological situations (e.g. stress, serious medical and surgical conditions, cancer, prematurity, senescence, etc.) where it has been shown that this enzyme is deficient. A lack of essential fatty acids leads in fact to a nutritional deficiency affecting all the metabolic processes mentioned above and which can lead to biochemical disorders or organic lesions (e.g. bleeding disorders, dermatological lesions, endocrine disorders, myocardial lesions, liver, joint, neurological and mental disorders). We therefore see the value of a gamma-linolenic acid intake for the prevention or treatment of these anomalies.

C fatty acid triglycerides₆-VS₁₂ and in particular in C₈-VS₁₀, commonly called "medium chain triglycerides", whether industrially prepared or extracted from natural products, of a Cuphea species containing 80 to 90% C fatty acid₁₀, constitute an immediate energy supply. Industrially, they are obtained from coconut and palm kernel fats, not hydrolysis, fractionation of fatty acids, mainly in C₈-VS₁₀, by distillation and re-esterification of these with glycerol.

The fatty acids provided by food, once crossed the digestive tract, or directly when injected intravenously, are used at catabolic sites (or possibly stored). They undergo an oxidation at the level of the mitochondria (β-oxidation) leading to the formation of acetyl radicals which enter the Krebs cycle or, in case of lack of oxaloacetic acid, are transformed into ketone bodies (hydroxybutyric acid and acetoacetic acid ) in the liver. Thus, they will provide a significant amount of energy maintaining the main synthetic functions of the organism.

In certain pathological situations, the lipids ingested are not or insufficiently absorbed by the digestive tract (hepatic insufficiency, insufficient biliary secretion, pancreatic insufficiency, functional or organic insufficiency of small intestine).

In these situations it is a good idea to provide medium chain triglycerides which are absorbed by the intestine much easier than long fatty acids.

In addition, medium chain triglycerides penetrate directly into the mitochondria (oxidation site). They do not need a specific vector system which allows the transfer of long chain fatty acids. Finally, recent work has highlighted a sparing effect of medium chain triglycerides on polyunsaturated fatty acids. (SC Frost and MA Wells, Archives of Biochemistry and Biophysics, 1981, 211, 2, 537-546; D. Sailer and M. Muller, Medium chain triglycerides in parenteral nutrition, JPEN, 1981, 5, 2, 115-119). Thus, the medium chain triglycerides are preferentially oxidized, preserving the polyunsaturated fatty acids from oxidation, for their functions of synthesis and structure.

The lipid composition according to the invention also contains an oil participating in the energy supply and providing at least 80% of C fatty acids.₁₂-VS₁₈, calculated on the total number of fatty acids, in the form of triglycerides.

It can be an oil of animal or vegetable origin providing in particular palmitic, stearic, oleic, linoleic and a-linolenic acids.

For oral or enteral use, the oil will be a vegetable oil commonly used in nutrition such as p. ex. Safflower, wheat, sunflower, peanut, cottonseed oil and more particularly corn, soybean oil and grape seed oil. One can also use an oil of animal origin such as p. ex. anhydrous milk fat, butter oil or fractions thereof providing at least 80% C fatty acids₁₂-VS₁₈, calculated on the total number of fatty acids. One can naturally use a mixture of the preceding oils.

For parenteral use, a vegetable oil particularly rich in unsaturated fractions will be preferred, supplying in particular oleic, linoleic and α-linolenic acids such as p. ex. soybean oil or grapeseed oil.

Soybean oil contains the following fatty acids by weight:<tables id="tabl0002" num="0002"><img file="EP0092076A2_D0002.tif" /></tables><tables id="tabl0003" num="0003"><img file="EP0092076A2_D0003.tif" /></tables>

Grapeseed oil contains the following fatty acids by weight:<tables id="tabl0004" num="0004"><img file="EP0092076A2_D0004.tif" /></tables>

Α-linolenic acid (C 18: 3 w 3) cannot be synthesized by mammals, but it does not seem to reduce the damage caused in animals by deficiency of essential fatty acids. In fact, a recent publication (RT Holman, SB Johnson, TF Hatch, A case of human linolenic acid deficiency involving neurological abnormalities, The Amer. Journal of Clinical Nutrition, 1982, 35, 617-623), describes the case of a young child receiving a lipid infusion without a-linolenic acid who developed signs of a deficiency in this fatty acid (torpor, paresthesias, delay in learning to walk, pain in the lower limbs) which were totally decreasing when a-linolenic acid was added to the parenteral diet).

It should be noted that α-linolenic acid is a precursor of prostaglandins of series 3 by eicosapentaenoic acid (C₂₀: 5 w 3) which it allows the synthesis.

It is generally accepted that the intracellular transport of these C fractions₁₂-VS₁₈ is provided by a specific vector called carnitine, the endogenous synthesis of which is ensured from lysine and methionine provided by food. In the above-mentioned medical conditions it is possible that the synthesis of carnitine may be depressed. In these cases an exogenous intake of carnitine by enteral or parenteral route could be of great benefit for the patient. It can therefore be added to the lipid composition if the patient's condition requires it.

The minimum needs of a healthy adult<ul id="ul0003" list-style="none"><li>- in linoleic acid are around 3% of the daily calorie intake</li><li>- in α-linolenic acid of the order of 0.5% of the daily caloric ration</li><li>- in gamma-linolenic acid of about 2 g / 24 hours.</li></ul>

When it is intended for parenteral nutrition and taking into account these various considerations relating to the absorption of essential fatty acids and medium chain triglycerides, the lipid composition of the invention preferably has the following constitution:<ul id="ul0004" list-style="none"><li>a) from 10 to 20% by weight of the oil containing gamma-linolenic acid in the form of triglycerides,</li><li>b) from 20 to 30% by weight of medium chain triglycerides and</li><li>c) from 60 to 70% by weight of a vegetable oil containing the C lipid fractions₁ at C₁₈ and in particular oleic, linoleic and a-linolenic acids in the form of triglycerides, the sum of components a) and b) not exceeding 40% by weight of the composition.</li></ul>

The lipid compositions according to the invention will be presented in a form suitable for the mode of administration.

When they are intended for oral or enteral nutrition, they can be p. ex. in the form of capsules or capsules containing the lipid mixture or in the form of emulsions in which the lipids are emulsified in the presence of an aqueous phase containing p. ex. proteins, amino acids, carbohydrates, mineral salts and vitamins and if necessary antioxidants and emulsifiers. Such emulsions will advantageously be dried in the form of powder which can be reconstituted in liquid form by dispersion in water at the time of use.

For parenteral administration, the lipid compositions will be in the form of emulsions which are physically stabilized (fineness of the lipid particles) and chemically (protection against oxidation, for example with tocopherols). In this form, lipids will be emulsified with soy, egg phosphatides, fractions thereof or any other natural emulsifier. The emulsions may contain carbohydrates such as p. ex. glucose, polyols - p. ex. xylitol, sorbitol or glycerol and / or amino acids or proteins (eg carnitine) in their aqueous phase. The emulsions obtained will be isotonic or hypertonic, pyrogen-free and will be presented in sterile form.

The following examples in which the percentages are by weight unless otherwise indicated, illustrate the invention:

Example 1

An isotonic aqueous emulsion for parenteral nutrition is prepared from the following lipids:<tables id="tabl0005" num="0005"><img file="EP0092076A2_D0005.tif" /></tables>

The lipids are mixed and 6% of soy phosphatides are added therein as emulsifier, calculated on the weight of lipids and the mixture is sterilized.

The sterile water supplement is added in sufficient quantity to obtain 100 g of lipids per liter of water after emulsification.

Is emulsified, preferably in a closed circuit under conditions as close as possible to sterility, in a homogenizer at a temperature below the phase inversion temperature, eg. ex. from 20 to 60 ° C and preferably at 55 ° C, at 140-180 bars until the lipid particles are less than 0.5 μm in size.

1 liter flakes are filled under aseptic conditions and sterilized for 20 to 30 min at 110-130 ° C.

Alternatively, the emulsification can be carried out in a colloid mill.

Example 2

The procedure is as in Example 1 to prepare a hypertonic emulsion for parenteral nutrition containing xylitol, sorbitol and glycerol in place of glucose in amounts resulting in a final concentration of 25, 50 and 100 g / 1 respectively , by adding one of these compounds to the water before emulsification.

Example 3

A hypertonic emulsion for parenteral nutrition is prepared from the following ingredients using the procedure indicated in Example 1:<tables id="tabl0006" num="0006"><img file="EP0092076A2_D0006.tif" /></tables>

Example 4

A hypertonic emulsion for parenteral nutrition is prepared from the following ingredients using the procedure indicated in Example 1:<tables id="tabl0007" num="0007"><img file="EP0092076A2_D0007.tif" /></tables><tables id="tabl0008" num="0008"><img file="EP0092076A2_D0008.tif" /></tables>

Example 5

A milk powder for premature babies is prepared as indicated on p. ex. in French Patent No. 2,388,503, from the following ingredients:<tables id="tabl0009" num="0009"><img file="EP0092076A2_D0009.tif" /></tables>as well as the minimum quantities of the following vitamins and trace elements:<tables id="tabl0010" num="0010"><img file="EP0092076A2_D0010.tif" /></tables>

To reconstitute the product, 15 g of powder are dispersed in 90 ml of water.

Example 6

A powder composition is prepared for the enteral feeding of old people from the following ingredients:

Fat

<tables id="tabl0011" num="0011"><img file="EP0092076A2_D0011.tif" /></tables>

Proteins:

Whey lactalbumin degraded by pancreatin containing 20% ​​free amino acids and 18% peptides of lower molecular weight<tables id="tabl0012" num="0012"><img file="EP0092076A2_D0012.tif" /></tables>10 kg of pregelatinized starch are dissolved in 333 kg of cold water. 117.5 kg of degraded lactalbumin powder is dissolved separately in 500 kg of water at 65 ° C. and the mineral salts are added thereto, followed by the starch solution, 270 kg of dextrin-maltose, 94.5 kg of sucrose and vitamins, these in the form of a 10% aqueous solution. To this aqueous phase is added 120 kg of the lipid mixture previously heated to 65 ° C, the two phases are stirred, they are passed through a colloid mill and then through a homogenizer at 65 ° C and under a pressure of 300 bars. The homogenized mixture is pasteurized at 105 ° C for 1 min, cooled to 65 ° C and homogenized again under a pressure of 400 bar. The mixture is then spray dried and the powder is conditioned in airtight containers gassed with nitrogen. The product is reconstituted by dissolving 15 g of it in 90 ml of water.