CA1117041A - Lipoproteic complex stabilizing the effect of vitamin e and synthesis antioxidants - Google Patents

Abstract

PRECISION OF DISCLOSURE:
The invention relates to a lipoprotein complex.
normalizing the effectiveness of vitamin E and antioxidants of synthesis. The complex according to the invention is characterized in that it contains vitamin E or synthetic antioxidant, a selenium compound, at least one lipolytic enzyme having affinity for lipid-water interfaces, and lipids polar. The lipoprotein complex of the invention is applicable to the production of medicines for internal use or external for humans and animals, as well as products cosmetological.

Description

~ L7 ~ 1 The invention relates to a normal lipoprotein complex.
combining the effectiveness of vitamin E and antioxidants synthesis.
The present invention provides a lipopro- complex standardizing the effectiveness of vitamin E, a derivative suitable vitamin E or an antioxidant compound of synthesis characterized in that it contains the components following;
- vitamin E, a suitable derivative vitamin E or an antioxidant compound synthesis,.
- a selenium compound, -- at least one lipolytic enzyme with affinity -nity for lipid-water interfaces, and - at least one polar lipid said complex being pharmaceuti ~ uement acceptable.
The present invention also provides a method for the realization of a normalizing lipoproteic complex the effectiveness of vitamin E, a suitable derivative of Vitamin E or an antioxidant compound of synthesis characterized in that it contains the following components;
- vitamin E, a suitable derivative . ~ Vitamin E or an antioxidant compound of synthesis, - a compound of selenium, : - at least one lipolytic enzyme having :: nity for lipid-water interfaces, and - at least one polar lipid said complex is pharmaceutically acceptable, characterized in that it is obtained by aggregation at the level a structured lipid-water interface; vitamin E, a suitable aerative of vitamin E or an anti-hydroxy compound , '~ i.
-.

~ 7 ~
~ ...
dant de synthe ~ se; selenium compound; at least one lipolytic enzyme with finite for interfaces llids-water, and at least one polar lipid.
We have ~ wave, for ten years, large hopes for the therapeutic use of vitamin E and derivative tocopherols, especially in prevention and trafficking ~ 4 senescence, cardiovascular disease and Cancer.
These hopes were dashed, in part because the vitamin E may or may not be absorbed from the intestine, or its accelerated destruction by ox ~ dation. In this last case, not only does it lose its ant ~ oxidative properties, _ but it can produce reverse effects. However, this risk is currently increased, due to the vogue for prescription in the dietetics of hyperlipemies, of fatty food res containing a high percentage of polyunsaturated fatty acids.
It is well known that polyunsaturated fatty acids long chains ~ AGPLC) are major constituents of phospholipids and sterids of cell membranes, as well than serum lipoproteins.
The best studied AGPLCs are: linoleic acid on the one hand ~ and arachidonic acid on the other hand ~ ~ organism can perform the synthesis of the latter from acid linolei ~ ue, whose presence in food is mandatory, hence its former denomination of "vitamin F" and its denomina-~ 17 ~ 4 ~ L

ac tion ~ uell ~ of essential fatty acid (EFA).
It is also known that AGPLC can give rise, in vitro as in vivo, to the formation of hydroperoxides and toxic substances (e.g. malonaldehyde), these reactions that can be initiated and self-sustained by unstable free radicals and we accept that the antioxidant role of vitamin E would consist in a "trapping" of said radicals free.
The vitamin E - selenium association is also known in veterinary prophylaxis and therapeutics to be more effective than vitamin E alone. Selenium, which is a essential trace element, would act as a coenzy of the glutathione peroxidase (reduced form), which can be an acceptor of peroxidic oxygen.
Good internal absorption of AGPLC (acids linoleic and arachidonic) is therefore of major importance, as well as that of vitamin E. This absorption takes place in same time as that of edible fats and necessities, therefore, the presence in the intestine of bile salts and pancreatic lipase in sufficient quantities. Now, a selenium deficiency leads to a drying up of the secretion of pancreatic lipase, therefore malabsorption of ~ GPLC and Vitamin E. This results in serious disorders in membrane lipid structures, reflected, in particular, by lipid overload and liver necrosis, hyper-and dyslipemias and waxy degenerations of the muscles skeletal or myocardial.
Certain changes in acid composition fat from different lipid fractions of blood plasma and tissues, as well as fatty acid turnover, accompany the aforementioned affections. This is mainly the case for arachidonic acid. However, plasma lipid fractions , ~. .

.

~ 7 ~

or tissue richest ep this acid, are equal ~ ent in vitamin E and seleniu ~.
It was in 1957, for the first time, that SCHWARZ
and FOLZ (J. Am. Chem. Soc., 79, 3292-3293) highlighted the role of selenium in preventing degeneration necrotic liver of rats. Since then, mus-cular and hepatic following a selenium deficiency, have been observed in other animal species, examples:
pigs, calves, chickens, lambs. Prevention and therapy tick of said affections consist in the administration of selenium animals, either in mineral form: selenite or sodium selenate, either in organic form: selenoamino-acids free or included in polypeptide structures.
In this latter organic form, the rate of incorporation of ; selenium in plasma lipoproteins is higher, as well as its tissue retention rate (muscles, liver, kidney, pancreas).
However, in addition to these compounds of nature water-soluble selenium, we can easily highlight fat-soluble selenium compounds, especially in the mem-cellular and subcellular branes (reticulum membranes endoplasmic and cellular organelles). Now, selenium, as well as vitamin E, being strongly linked to these structures membranes, there is the problem of the stability of the vita-mine E and therefore AGPLC, at more or less interfaces hydrophobic. Indeed, the high affinity of lipolytic enzymes ticks for such interfaces, so ~ they can be still active in poorly hydrated environments and release AGPLC. particularly threats of peroxidation by radicals free in such environments.
The invention consists in the discovery that ~ es ~ GPL ~ and vitamin E are not the seat of re ~ ctions ~ 17 ~ 4 ~

destructive radicals, for themselves and other structures cells, especially at the lipid-water interfaces, a provided they are protected by a selenium compound (selenite, selenate, amino acids selenies, in particular) and a or lipolytic enzymes with affinity for these inter ~
faces.
On this subject, it should be recalled that lipolytic enzymes nonspecific are hydrolases which can be classified as follows in front of a hierarchical order going from the lysophospholipase of brain which attacks a monomolecular substrate in the aqueous phase (= "true esterase" ~, with pancreatic lipase which acts surface of oily droplets completely insoluble in water (= "true lipase"). "Intermediate" hydrolases acting at relatively hydrated interfaces like those that are micelles. Among these hydrolases one can quote: cholesterol, esterase, monoglycerides hydrolases, certain phospholipases and galactolipases, as well as lipo-protein lipase.
The hydrolases contracting the most strong with polar lipids and more specifically claimed are:
- the lipolytic enzymes of the digestive glands; glycerol-ester hydrolase (EC 3.II3); phosphoglyceride 2 and I-acyl-hydrolase (EC 3.II4) -e ~ sterol-ester hydrolase (EC 3.II13).
- glycerol-ester hydrolases of molds genera Mucor, Rhizopus, Penicillium, Aspergillus, Geotrichum, as well as to the higher plants: ~ wheat, rice bran, castor, olive.
~ 'aggregation of these hy ~ rolases with lipids polar is done in aqueous phase. The temperatures to respect are given in the examples below illustrating the invention.

The molecular association of proteins endowed with lipo- activity .

~ 7 ~ 4 ~

Lytic is carried out by mechanical agitation with two to ten times their weight of polar lipids. These are represented phospholipids (phosphatidylcholine, phosphatidyl-thanolamine, phosphatidylinositol, phosphatidylserine) or esters of fatty acids (with 16-20 carbon atoms) and glycerol (monoglycerides) or sorbitol (tweens) or sucrose (sucroglycerides) or other sugars (glucolipids).
Alpha-tocopherol (vitamin E) or its renal derivatives trant in the drug composition, benefit from being incorporated first brought to the lipid phase, as well as selenium compounds (mineral salts or selenized amino acids) gain ae ~ re incorporated at first in the phase above-mentioned aqueous.
The amounts of vitamin E and selenium to incorporate are calculated on the weight of the medicinal composition liar finished ready for clinical use. The amount of vitamin E thus calculated is between 20 and 30 mg (22 and 23 IU) per gram and that of selenium ~ Se = 78.96 g) is 0.40 mg per gram of pxet medication for use.
It results from intermolecular associations between polar lipids and lipolytic enzymes, the formation of sufficiently stable molecular lipoprotein plexes to be dehydrated by cryodessication.
After spraying, the freeze-dried product is -- divided into capsules, these can be gastroresistant.
A second mode of drug preparation consists to incorporate the lipoprotein complex obtained above (vita-mine E, selenium compound, polar lipids and lipolytic enzymes) apolar lipids for the prot ~ er of oxidative reactions radicals which can occur during dehydration pushed ration. We mean by 'apolar lipids':

neutral triglycerides; cholesterol and its acid esters , ~ _ 5 _ fat from C16 to C20; long chain free yras acids when they are not ionizable. The weight of lipids apolar that can be emulsified with the lipoprotein complex above is equal to 0.5 - once the weight of this complex.
A third mode of drug preparation consists in incorporating therein, in addition to non-polar lipids, or still to replace them; globin (side chain of hemo-globins) and / or phytol (chlorophyll side chain) or derivatives with phytyle chalne.
The following examples illustrate the invention:
Example I
The selenie compound is sodium selenate (Na2SeO4 IO ~ 20); Vitamin E is alphatoco succinate pherol grading 250 IU / g; the polar lipid is a phospha-tidylcholine (alpha, dimyristoyl-lecithin); apolar lipid is a triglyceride (trimyristine) and the hydrolase is glycerol-ester hydrolase (EC 3.II3) provided by a pancreatic extract purifies pork containing co-lipase and grading 150,000 IU / g.
Operating mode: We operate in a thermos-taté equipped with an agitator. The selenate (2 g) is dissolved in 2.100 ml of distilled water, the lecithin (350 g) is introduced under moderate but constant agitation and the temperature is brought to 70 - 80C for the formation of a homogeneous gel.
Vitamin E (100 g) is dissolved separately in the trigl ~ ceride (350 g) which is heated to 70 80C and introduced in the reactor to achieve a homogeneous emulsion with the lecithin. Then allowed to cool to 30C.
In parallel, we introduced into a mixer 900 ml of eaudistilled re ~ stiffness a - ~ 2C in which we dissolve the equal to 10 mg of calcium in the form of calcium chloride and 5 g of an equimolar buffer mixture of phosphates (PO4H2K, PO4HNa2) of pH 7.5. The pancrea extract is added to the mixer.

tick (150 g) under agitation, then the suspension obtained is also introduced into the reactor with stirring.
When the emulsion obtained is homogeneous, we check the pH which must not be lower than 6.5, otherwise it is adjusted between 6.5 and 7.0 with the phosphate-based buffer.
Between 10 and 20 minutes from the time of the introduction duction of the pancreatic extract in the reactor, the content of it is cooled to a temperature of + 2C and it is kept at this temperature for about 24 hours to to obtain the structure of the lipid-water interface.
The comple ~ e lipoprotein obtained is homogenized a new, then frozen and dehydrated by freeze-drying until a residual water content of between 3 and 5 per 100.
After spraying and sieving, the powder obtained is divided into capsules containing 500 mg of lipopro- complex dehydrated tea.
In this example I, the constituents of the phase lipids were chosen taking into account, on the one hand, that we know the brake effect of chalnes triglycerides means (trimyristin in particular) on the development of certain ; on the other hand, the results of an established survey-a negative relationship between selenium blood level and human mortality due to cancer (Nutrition ~ e ~ iews, 1970, 28, 3, 75) and more generally of the protective role assigned to antioxidants vis-à-vis cocarcinogenic agents (Canad. Med.
Ass. J. 1969, 100, 682).
Example II
The only differences from Example I
point on the following points:
- the lipid phase consists, on the one hand, of Grade I egg yolk L-alpha-lecithin (350 g) and other hand, glycerol monostearate palmitate (200 g).
, , f ~, ............

- EC 3.II3 lipase is from fungal origin (150 g). It ti ~ re 200 ~ 000 IU ~ / g and o ~ ~ 'additio ~ e extract pancreatic beef (150 g) as a source of co-lipase.
Example III
The only differences compared to ~ 'example I
relate to the following points:
- the lipid phase consists of, a paxt, fluid soy lecithin (350 g) containing 80 percent phospholipids and, on the other hand, cholesterol palmitate (350 g).
- hydrolases are lipases, phospholipases and esterases, contained in a mixture (150 g) pa ~ parts of pancreatins delipidés of pork and beef.
- we replace the vitamin E di ~ tertio ~ butyl-hydroxy-toluene, antioxidant of syn-thesis co ~ inu under the ~ om of BHT (100 g).
~ "In this example III, the constituents of the form ~ e have been chosen for a full use of the complex lipoprotein for external use in dermatology and cosmetics house.
;:
Toxicological data Selenium (Se !, in the forms stated, is the only compound included in the composition of the drug object dP
- the invention, which can be considered, in isolation, as likely to be toxic at certain doses. It is indeed through the into-acute and chronic xications due to this trace element, which have started studies on the 5th in biology. Today the Se is considered co ~ not being a trace element among the most important (WHO, Publication offset, N 5, 1974). However, deficiencies or insufficient food intake is possible, given its uneven distribution in food, its levels variables and relative needs, function of losses and intakes of vitamin E and AGPLC. Se deficiency may be detected by its dosage in the blood, or its rate is around 0.05 - 0.1 mcg / ml, or by determining the activity of the glytathion peroxidase in red cells or whole blood, this enzyme having Se as a co-factor.
Human needs for Se are still enough imprecise. By extrap ~ lation of known data in food animal, they are estimated at 0.1 - 0.2 ppm of the dry matter of the food ration, ie 2-3 mcg per kg body and per day.
The tolerance limit (long-term toxic dose) would be

2 to 5 ppm of the dry matter of the ration and the toxic level from 7 to 15 ppm. Acute toxicology of selenite and selenate sodium was determined orally, intravenously, sub-cutaneous, in ten animal species. There are big differences between the species. ~ so, the minimum dose oral lethal ~ arie of 2.2 to 15 mg / kg body and lethal-50 dose of 3 to 5 mg / kg body for the rat.
The elimination of Se takes place through urine, feces and expired air. This is how the cycle, very toxic for humans, methylmercury, can be detoxified by salts of Se because dimethylselenium is formed which is exhaled.
Based on its Se content (0.40 mg / ~ of medi-ready to use), the therapeutic index for men - ~ drug object of the invention, that is to say the report:
effective dose / toxic dose, can be estimated to be l to 100.
Pharmacological data Numerous works carried out over the past 20 years on the pharmacology of AGPLC, vitamin E and Se and their inter-relationships, we can basically remember that the couple synergistic vitanine E ~ Se, plays a crucial role in the regulation lation of carbohydrate-lipid metabolism, control of oxy-AGPLC dating and membrane ion fluxes, note _ g _ , ~, calcium ions. I, a pextu ~ batio ~ ~ e these ~ 1UY ~ can a ~ outir asthenia, even pathway to dystrophy, muscle. The contribution essential fatty acids (which are only well assimilated in presence of vitamin E, pancreatic lipase and bile salts or other emulsifiers), is not enough to restore tone muscular. The contribution of Se is also essential. The im-muscle pact and hepatic vitamin E deficiency and / or Has been specially studied on rats, chicken, lamb, veal and pork. Deficiency in Se results in muscular dystrophies with elevated enzymes in the blood characteristics of muscle physiology, as a consequence probable rupture of lysosome and other membranes cell membranes. These enzymes are: transaminase glutamic-oxaloacetic ~ SGOT): glutamic transaminase-pyruvic (SGPT) and creatine phosphokinase (CP).
The concept of relative deficiency emerges from tests on - animals which have shown that 0.1 ppm of dry tbase from the ration) was sufficient in the presence of 100 ppm of vitamin E, while that 0.2 ppm of Se was required in the presence of 10 ppm of ~ itamine E ~ From this relative Se deficiency, it can also result acceleration of glucose catalobism with elevation of the ratio lactate / pyruvate in muscle and blood serum. In case of very rapid glycogenolysis, as it can occur in pork, there may be a rise in muscle temperature and bodily. This is the so-called malignant hyperthermia syndrome "
experimentally reproducible in predisposed animals - - ^ by simple halothane narcosis (fluothane). More precisely, this anesthetic promotes the release of calcium ions in the muscle, at the same time as it activates ATPase there and elevates the Serum CP. However, halothane is also known to cause liver damage when it is found to be dehalogenated by enzymes that detoxify drugs and are feared to alleviate o ~

activity through the Cytochrome-P450 assay. We explain as well as a relative deficiency in Se can weaken the cell membranes of muscle and liver and lead to the muscular dystrophy and / or hepatic necrosis. As example, the pharmacological study of the drug o ~ jet the invention was made on Belgian Landrace piglets from mothers assumed to be under vitamin deficient E - Se.
The cumulative percentage of mortality from dystrophy muscle and liver necrosis was 50 to 80 percent at the age of 2 months. The classic treatment consisting of a intramuscular injection of 5 IU of vitamin E and 0.05 mg of If, per kg body, failed to save more than half of the piglets. On the other hand, the drug object of the -vention, administered daily orally at a dose 0.05 percent of the food ~ basic know ?, reduced the rate cumulative mortality referred to less than 2 percent.
Clini tests ~ _s dear man The medicament subject of the invention corresponding to the NI preparation example was administered to 25 subjects - (8 men and 17 women) ages 30 to 70 and over. The dosage was 500 mgday (divided into 5 capsules) and the duration of treatment of 8 days for 5 subjects; of 2 series of 8 d, interspersed with the same period of time for 17 subjects; of

- 3 series of 3 days interspersed with intervals of 5 days without medication-ment for 2 subjects, finally 5 series of 8 days interspersed with 8 days without medication for a subject who thus received the medication for 2 and a half months. This last subject presented with asthenia with hypothyroidism, hyperlipemia and painful arthritis. Of clinically, there has been a general tonic effect of medication and analgesic for joint pain. Of biologically: serum cholesterol has dropped from ~ 7 ~

3.80 m / l at Z, 25 g / l and stayed at this rate for both month and a half of treatment with the ~ drug as the only hypolipe-miant. After treatment, the levels of transaminases were particularly low: 8 mU / ml for SGOY and 1 mU / ml for SGPT.
~ none of the suje-ts had transaminases abnormally high serum at the start, but every time that they were dosed, we found very low levels in end of treatment. Examples for 3 subjects in whom, moreover, treatment results have been good on the syndrome depressive: SGOT (mU / ml) Before treatment After treatment Subject N 14 l9 4;
Subject N 20 4 2 Subject N 24 16 6 CGPT (mU / ml Before treatment After treatment Subject N 14 13 Subject N 20 2 Subject N 24 4 The diagnoses for the 25 subjects who received the were:
Tolerance test on a healthy subject .. ~ ......... 1 subject Involutional depression ................................. ... 2 "
~ Astheno-depressive syndrome ......................., ......... 7 "
; - Astheno-depressive syndrome plus painful arthritis ....... 7 "
Hypothyrolde, asthenia and arthritis ......................... 2 "
Late fatty diabetes .................... u .......................... .... 5 "
~ anxiety and hyperlipemia ................................. ............. . 1 "
3 ~ A total of 21 patients reviewed were recorded:
Very good results: 3 Good results: 9

4; ~ L

Quite a few results: 4 Doubtful results: 2 Drawn results: 2 Major intolerance: 1 (generalized erythema and edema of Quincke).
In the latter case, it was an obese Eemme, hyperlipemic and hypothyroldian of 60 years, already known for be allergic to aspirin, dust and mold.
Regarding the results in fatty diabetes late, we can cite the following case (observation N 13).
Drop in serum cholesterol: from 3.70 g / l to 3.10 g Total lipid drop: 12.50 to 8.50 Triglyceride drop: from 4.60 to 1.43 ~ in one month).
On a general clinical level, we could note the effect drug tonic, as well as anti-inflammatory effects, anti-depressants and eutrophics. We can also count on hepatotropic, anti ~ atheromatous and vasculotropic effects.
The lipoprotein complex of the invention is applicable to the production of drugs for internal use or external for humans and animals, as well as products cosmetics.

".

~ ,. . -:

'./'~.
. . .
'' .

Claims (34)

The embodiments of the invention, about which an exclusive right of property or privilege is claimed, are defined as follows: 1. Lipoprotein complex normalizing the effectiveness of vitamin E, a suitable derivative of vitamin E or a synthetic antioxidant compound characterized in that it contains the following components;
- vitamin E, a suitable derivative vitamin E or an antioxidant compound synthesis, - a selenium compound, - at least one lipolytic enzyme having nity for lipid-water interfaces, and - at least one polar lipid said complex being pharmaceutically acceptable. 2. Complex according to claim 1 characterized in that that it contains at least one apolar lipid. 3. Complex according to claim 1 characterized in that it contains globin. 4. Complex according to claim 1 characterized in that that it contains at least one phytyl chain derivative. 5. Lipoprotein complex normalizing the effectiveness of vitamin E or a suitable derivative of vitamin E charac-terized in that it contains the following components;
- Vitamin E or a suitable derivative of Vitamin E
- a selenium compound - at least one lipolytic enzyme having affinity for lipid-water interfaces, and - at least one polar lipid said complex being pharmaceutically acceptable. 6. Complex according to claim 5 characterized in that that it contains at least one apolar lipid. 7. Complex according to claim 5 characterized in that it contains globin. 8. Complex according to claim 5 characterized in that that it contains at least one phytyl chain derivative. 9. Complex according to claim 5 characterized in that that said lipolytic enzyme is selected from the group consisting of glycerol ester hydrolase; phosphoglyceride 2 and I-acyl hydrolases and sterol-ester hydrolase. 10. Complex according to claim 5 characterized in that whether it contains Vitamin E or Vitamin Succinate mine E. 11. Complex according to claim 10 characterized in that Said lipolytic enzyme is glycerol-ester-hydrolase. 12. Lipoprotic complex normalize the effectiveness of a synthetic antioxidant compound characterized in that it contains the following components:
- a synthetic antioxidant compound, - a selenium compound, - at least one lipolytic enzyme having The fineness for the lipid-water interfaces, and - at least one polar lipid said complex being pharmaceutically acceptable. 13. Complex according to claim 12 characterized in that that it contains at least one apolar lipid. 14. Complex according to claim 12 characterized in that it contains globin. 15. Complex according to claim 12 characterized in that that it contains at least one phytyl chain derivative. 16. Complex according to claim 12 characterized in that that said lipolytic enzyme is selected from the group consisting of glycerol ester hydrolase; phosphoglyceride 2 and I-acyl hydrolases and sterol-ester hydrolase. 17. Complex according to claim 16 characterized in that said synthetic antioxidant compound is di-tertiobutyl hydroxy-toluene. 18. Method for producing a lipoprotein complex normalizing the effectiveness of vitamin E, a derivative venable vitamin E or a synthetic antioxidant compound characterized in that it contains the following components;
- vitamin E, a suitable derivative vitamin E or an antioxidant compound synthesis, - a selenium compound, - at least one lipolytic enzyme having nity for lipid-water interfaces, and - at least one polar lipid said complex being pharmaceutically acceptable, characterized in that it is obtained by aggregation at the level a structured lipid-water interface; vitamin E, a suitable vitamin E derivative or an anti-hydroxy compound dant of synthesis; selenium compound; at least one lipolytic enzyme with affinity for interfaces lipids-water, and at least one polar lipid. 19. The method of claim 18 for the realization of a complex as defined in claim 18 which contains at least one non-polar lipid, characterized in that it is obtained by aggregation of at least one non-polar lipid into in addition to the other components. 20. The method of claim 18 for carrying out of a complex as defined in claim 18 which contains globin, characterized in that it is obtained by aggregation of globin in addition to the other compounds health. 21. The method of claim 18 for carrying out of a complex as defined in claim 18 which contains at least one characterized phytyl chain derivative in that it is obtained by aggregation of at least one derivative to phytyl chain in addition to the other components. 22. Process for the production of a lipoprotein complex normalizing the effectiveness of vitamin E or a derivative suitable vitamin E characterized in that it contains the following components;
- vitamin E or a suitable derivative of Vitamin E
- a selenium compound - at least one lipolytic enzyme having affinity for lipid-water interfaces, and - at least one polar lipid said complex being pharmaceutically acceptable, characterized in that it is obtained by aggregation at the level a structured lipid-water interface; vitamin E
or a suitable vitamin E derivative; of the compound of selenium; at least one lipolytic enzyme with affinity for lipid-water interfaces and at least one polar lipid. 23. The method of claim 22 for carrying out of a complex as defined in claim 22 which contains at least one non-polar lipid characterized in that it is obtained by aggregation of at least one non-polar lipid in addition to the other components. 24. The method of claim 22 for carrying out of a complex as defined in claim 22 which contains globin, characterized in that it is obtained by aggregation of globin in addition to the other compounds health. 25. The method of claim 22 for the realization.
of a complex as defined in claim 22 which contains at least one characterized phytyl chain derivative in that it is obtained by aggregation of at least one derivative to phytyl chain in addition to the other components. 26. The method of claim 22 characterized in that said lipolytic enzyme is chosen from the group consisting of kills with glycerol-ester hydrolase; phosphoglyceride 2 and I-acyl hydrolases and sterol ester hydrolase. 27. Method according to claim 22 characterized in that said complex contains vitamin E or succinate vitamin E. 28. The method of claim 27 characterized in that Said lipolytic enzyme is glycerol-ester-hydrolase. 29. Method for producing a lipoprotic complex normalize the effectiveness of a synthetic antioxidant compound characterized in that it contains the following components:
- a synthetic antioxidant compound, - a selenium compound, - at least one lipolytic enzyme having offinity for lipid-water interfaces, and - at least one polar lipid said complex being pharmaceutically acceptable characterized in that it is obtained by aggregation at the level a structured interface; of an antioxidant compound of synthesis, of the selenium compound; at least one enzyme lipolytic with affinity for lipid interfaces-water and at least one polar lipid. 30. The method of claim 29 for carrying out of a complex as defined in claim 29 which contains at least one non-polar lipid, characterized in that it is obtained by aggregation of at least one non-polar lipid into in addition to the other components. 31. Method according to claim 29 for carrying out of a complex as defined in claim 29 which contains globin, characterized in that it is obtained by aggregation of globin in addition to the other compounds health. 32. The method of claim 29 for carrying out of a complex as defined in claim 29 which contains at least one characterized phytyl chain derivative in that it is obtained by aggregation of at least one derivative to phytyl chain in addition to the other components. 33. Method according to claim 29 characterized in that said lipolytic enzyme is chosen from the group consisting of killed by glycerol-ester hydrolase; phosphoglyceride 2 and I-acyl hydrolases and sterol ester hydrolase. 34. Method according to claim 29 characterized in that said synthetic antioxidant compound is di-tertio-butyl hydroxy-toluene.