Phospholipid complexes of proantocyanidine a2 as antiatherosclerotic agents

FIELD: medicine.

SUBSTANCE: the present innovation deals with phospholipid complexes of proanthocyanidine A2 and pharmaceutical compositions upon their basis as antiatherosclerotic agents, those for preventing and treating myocardial and cerebral infarction. Phospholipids of the above-mentioned complex should be preferably chosen out of lecithins, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl serine. The innovation provides the preparation to treat the above-mentioned diseases due to decreasing the quantity and burden of atheromatous plaque, decreased obstruction of carotid arteries and decreased thickness of vascular walls.

EFFECT: higher efficiency of prophylaxis and therapy.

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DESCRIPTION

The present invention relates to phospholipid complexes of proanthocyanidin A2 or extracts, enriched with proanthocyanidin A2, and to their use for producing drugs for the prevention and treatment of atherosclerosis and myocardial infarction and brain.

The proanthocyanidin A2 or 8,14-methane-2H,14N-1-benzopyran-[7,8-d][1,3]benzodioxole-3, 5, 11, 13, 15-pentol-2,8-bis-(3,4-dihydroxyphenyl) 3, 4-dihydro [2R-2α, 3α, 8β, 14β, 15R)] of the formula (I)

was isolated from the seeds of Aesculus hippocastanum (Tetrahedron Lett., 429, 1966). Therapeutic application of proanthocyanidin A2 as subcauses, chitosamine, antiulcer, venomotor, assamites and antiperoxidative agent are described in EP-A-210785 (4 February 1987).

Currently, it has been unexpectedly found that the phospholipid complexes of proanthocyanidin A2 have a pronounced anti-atherosclerotic activity in both animals and in humans with systemic administration, preferably oral.

The complexes of the present invention can be composed of natural and synthetic phospholipids, such as lecithin, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine. The ratio of proanthocyanidin A2 and phospholipids varies from 2:1 to 1:2, and preferably is about 1:1.5 mass/mass. This item is the preferred complex is a complex with soy phosphatidylcholine.

The complexes of the present invention is produced by interaction of a solution of phospholipid and mortar proanthocyanidin A2 in suitable solvents, such as acetone, ethyl acetate, ethanol, followed by concentration of the reaction mixture under reduced pressure, to obtain a thick residue, which you can grind.

The complexes of the present invention depending on the doses to prevent or reduce the formation of atherosclerotic plaques. This activity was observed in rabbits that received giperholesterinemiei diet in order to cause the formation of atherosclerotic plaques, such such damage in humans, on the vascular level, especially in the aortic arch, abdominal aorta, carotid arteries and cerebral vessels. On this model the aforementioned phospholipid complexes change the state of the vessels at the macro - and mikoranah, slimming, compared with untreated animals both the quantity and severity of atheromatous plaques, with a surprisingly favorable effect on blood vessels and tissue. In another model of atherosclerosis, with the aim of protecting the brain, when the lumen of the internal carotid artery of the rabbit was reduced surgically, and animals received giperholesterinemiei diet rich in saturated fats, there has been a decrease in obstruction of the carotid arteries, the mind is isenia thickness of the vascular walls, and increased survival of the animals. In patients suffering from atherosclerosis, after six months of treatment there was a decrease in obstruction of the carotid arteries, caused by atheromatous plaques, and improve blood flow through the carotid artery, which was estimated using Doppler ultrasound.

Phospholipid complexes of proanthocyanidin A2 can be applied in the form of dosage forms suitable for oral administration such as tablets, soft and hard gelatin capsules at doses in the range of from 50 to 500 mg, two to three times a day, depending on the severity of the disease. The preparative production of pharmaceutical forms can be implemented using conventional technologies and fillers.

The following examples illustrate the present invention in more detail.

Example 1

Obtaining a complex of proanthocyanidin A2 with phosphatidylcholine

To a solution of 1577 phosphatidylcholine in 5 liters of ethyl acetate with a temperature of 70° solution was added to 1 kg proanthocyanidine with a temperature of 70° solution was added to 1 kg of proanthocyanidin A2 in 5 liters of acetone.

The mixture was boiled under reflux with stirring and evaporated to dryness in vacuum. The residue was dried in vacuum at a temperature of 50°C for 24 h, and then grinded to obtain particles of the desired size.

Example 2

32 new Zealand rabbit R is sdelali into 4 groups of 8 animals each and treated as follows:

Group 1: control, normal diet

Group 2): giperholesterinemiei diet (0.2 wt.% cholesterol)

Group 3): giperholesterinemiei diet + phospholipid complex of proanthocyanidin A2, extract (0.2 wt.% cholesterol +2 wt.% complex of example 1).

Group 4): giperholesterinemiei diet + extract proanthocyanidin A2 (0.2 wt.% cholesterol + proanthocyanidin A2 in an amount equivalent to that available in 2 wt.% complex of example 1).

After 8 weeks of treatment, during which measured the levels of cholesterol, LDL/VLDL, HDL and triglyceride levels, animals were killed.

Estimated number, size and distribution of atherosclerotic lesions in the thoracic and abdominal aorta.

The aortic strips were fixed and stained with Sudan IV for visualization of damage and assessment of vascular cholesterol and content of oxidized cholesterol by gas chromatography.

The results presented in the following table, show that the treatment of phospholipid complexes of proanthocyanidin A2 diseases statistically significant way reduces atherosclerotic damage induced hypercholesterinemia ration.

Table
The treatmentThe percentage of the land damage
Group 10,5%
Group 234%
Group 37,5%*
Group 430%

*p<0,01 compared with group 2.

Example 3

Capsules containing 500 mg of phospholipid complex of proanthocyanidin A2.

Composition:

The complex of proanthocyanidin A2 with soybean phosphatidylcholine 150 mg

Lactose 57 mg

Modified starch 40 mg

Magnesium stearate 3.0 mg

Example 4

Intersolubility tablets

The complex of proanthocyanidin A2 with soybean phosphatidylcholine 200 mg

Microcrystalline cellulose 118 mg

Precipitated silicon dioxide 3 mg

Magnesium stearate 4 mg

Anionic polymer of methacrylic acid

and its esters 12mg

Talc 8 mg

Carbonate of magnesium 8 mg

Corn starch 5 mg

Arabian gum 159 mg

Example 5

Soft gelatin capsules

The complex of proanthocyanidin A2 with soybean phosphatidylcholine 216 mg

Peanut butter 209 mg

Partially hydrogenated vegetable oil 100 mg

Soy lecithin 5 mg

Example 6

Data of physico-chemical studies of the complex of proanthocyanidin A2 with phosphatidylcholine in the mass ratio 1:1.5 (mass/mass)

Designation

The proanthocyanidin A2 represents a dimer of epicatechin type, namely epicatechin-(2β→ 7, 2β→7)-epicatechin, in which two units of epicatechin linked through C-4 To C-8 and C-2 - O-7 connection.

Phosphatidylcholine (trade name (PhospholiponŽ 90G) is a purified phosphatidylcholine derived from soy lecithin.

The table below shows the solubility, thermogravimetric/differential thermal analysis (TG/DTA), IR spectroscopy,1H NMR and 13C NMR spectroscopy for the complex of proanthocyanidin A2 with phosphatidylcholine in the mass ratio 1:1.5 (mass/mass) of individual compounds proanthocyanidin A2 and phosphatidylcholine, as well as physical mixtures of phosphatidylcholine in the same weight ratio.

1. Profile solubility

The solubility of the complex of proanthocyanidin A2 with phosphatidylcholine in comparison with a mixture of proanthocyanidin A2/phosphatidylcholine tested in accordance with the methodology described in Eur.Ph., III Ed.

The results presented in the table.
toluenechloroformwater
the proanthocyanidin And2insolubleinsolubleinsoluble
phosphatidylcholinesolubleLes is corestore insoluble
the complex of proanthocyanidin A2 with phosphatidylcholineinsolublesolubleinsoluble
a mixture of proanthocyanidin And2/ phosphatidylcholineLABORATORIAinsolubleinsoluble

Thermococci analysis

Method and equipment

Installation for thermogravimetric/differential thermal analysis (TG/DTA) Seiko 6200 program EXTAR 6000 ver. 5.7 using an open aluminum crucible (⊘ 6 mm). The heat flow was recorded from 25°to 300°With a linear heating rate of 5°C/min under a stream of nitrogen at 200 ml/min TG/DTA were normalized on the basis of mass.

The proanthocyanidin And2

TG/DTA profile (thermogravimetric/differential thermal analysis) shows the release of solvent crystallization at 96°with a corresponding weight loss of 7.2%, which is consistent with megidramon. The process of decomposition observed after 240°with the peak of the DTA when 241,7° (Figure 1).

The complex of proanthocyanidin A2 with phosphatidylcholine

The profile does not show an endothermic peak due to loss of solvent of crystallization. Loss on drying, component to 2.57%, can be attributed to loss nesw the above solvent. The process of decomposition begins at about 200°with the transition when 258,3°S. Solid state proanthocyanidin And2in phytosome differs from the pure substance (Figure 2).

A mixture of proanthocyanidin And2/phosphatidylcholine

Although thermal profile shows behavior similar to those observed for proanthocyanidin And2observed loss of solvent of crystallization (8,15%) with the transition when 108,7°With the subsequent loss of solvent (e.g. water in lipids). The total mass loss amounted to 9.66%. Solid state is different, and no transition occurs at temperatures above 240°With (3).

3. The infrared spectrum

Method and equipment

IR spectra were recorded on a spectrometer Mada 550 Series II with Fourier transform. Spectra of proanthocyanidin A2 and complex of proanthocyanidin A2 with phosphatidylcholine was obtained with the use of a plate CVG (degree of purity for spectroscopy)spectra of phosphatidylcholine, and mixtures of proanthocyanidin And2/ phosphatidylcholine - cell NaCl. The equipment was supplied by the optical bench, standard DTGS detector, the beam splitter CVG and OMNIC program ver. 5.1. The spectrum was obtained as the result of the collection and conversion of the aggregate of 32 scans in the spectral range 4000-400 cm-1if resolution 4 cm-1.

Phosphatidylcholine

Infrared spectrum (Fig, 5) shows the symmetric and asymmetric elongated strip for groups of CH2at 2852 and 2924 cm-1deep absorption band group SN2at 1466 cm-1and an elongated band for C=O at 1736 cm-1symmetric and asymmetric stretches of the absorption bands of the phosphate group at 1088 and 1236 cm-1. At 968 cm-1there is also a bar that indicates out-of-plane bending ("coils") C-H on transvaginal communication. This is consistent with the composition of the acyl residues (oleic acid 10±3%, linoleic acid 66±5%, linolenic acid, 5±3%), known for this product.

The proanthocyanidin And2

The main absorption bands are strong curvature for H-O-N when 1630-1610 cm-1(this is consistent with megidramon), deep absorption band of CH2at about 1470 cm-1stretching absorption band of phenolic and alcoholic groups WITH IT at 1247 and 1112 cm-1respectively (6, 7).

The complex of proanthocyanidin A2 with phosphatidylcholine

The infrared spectrum shows an elongated strip of the absorption band of C=O at 1735 cm-1bending N-O-N at 1618 cm-1. Two strong absorption bands observed at 1076 and 1203-1179 cm-1. These bands are attributed to the shift to lower wavenumber of the symmetric and anti-symmetric elongated absorption bands of the phosphate group. Also p is outstay absorption band unsaturated acyl residue at 969 cm -1(Fig, 9).

A mixture of proanthocyanidin And2/ phosphatidylcholine

The infrared spectrum shows a broad absorption band in the region 1300-900 cm-1without the presence of two bands at 1076 and 1203-1179 cm-1. In addition, the absorption band at 1088 and 968 overlap the absorption bands of phosphatidylcholine (Figure 10, 11).

The IR spectra of the four considered products presented on Fig, 13.

4. Spectra1H-NMR

Method and equipment

NMR spectra were obtained in CDCl3or DMSO-d6(purity analysis NMR) at 300 MHz (1H) installing a VARIAN INOVA 300 MHz with VNMR programTMver. 6.1.b, equipped with a 5 mm switchable wideband sensor. Used tube, Wilmad 528-PP (7"×5 mm). Temperature 30°C.

Multipletness of carbon atoms was determined using DEPT experiment (undistorting amplification and polarization transfer).

Chemical shifts were correlated with tetramethylsilane was (purity analysis NMR) at 0 ppm as an external standard.

Spectra of phosphatidylcholine and complex of proanthocyanidin A2 with phosphatidylcholine can be obtained in CDCl3while the range of proanthocyanidin A2get in DMSO-d6in accordance with the solubility profile.

Phosphatidylcholine (Range1H-NMR Fig)

- terminal methyl group of 0.93 ppm

- CH2on the basis of the Noah long chain when 1,32, 1,64, 2,09, 2,34, and of 2.81 ppm

- NMe

+
3
the singlet at 3,45 ppm

the protons on the double linkages and ester group at about 5.3 and 5.4 ppm

the multiplets at 4,16 was 4.42 ppm: CH and CH2glycerol-part.

The proanthocyanidin And2(Range of1H-NMR Fig)

The proton spectrum obtained in DMSO-d6shows the following signals:

NPpmJ (Hz)
3a 3.87t (3,8)
3-HE5,22D (4,4)
44,33d(3,5)
6of 5.89D (2,2)
85,94D(2,2)
2'a 4.83
3'4,14M
3 ON4,65D(4,4)
6'6,01
4'-2,81DD (18,0; 4,6)
4'-Hb2,59DD (18,0; 1,8)
12, 12', 15,15',16'6,75D (8,0)
6,76D (8,2)
6,87DD (8,3 2,3)
7,01DD (8,8, 1,9)
7,03D (2,1)
7,09D (1,9)
HE (phenolic)8,10 8,69, 8,79,(user.)
8,90, 9,07, 9,29

The complex of proanthocyanidin A2 with phosphatidylcholine (Range1H-NMR Fig)

The spectrum shows a very broad signals with no permission, which is consistent with a strong change of the relaxation time of the protons. The signal corresponding polar head group NM

+
3
disappears, which suggests a strong interaction with the molecule of proanthocyanidin And2and the corresponding loss of mobility. All multiplets become wider singlets, in particular, signals the presence of the glycerol part of the CH and CH2give a broad resonance at about 4.2 ppm did Not observe any signals inherent in the dimer of epicatechin.

Spectrum of the complex obtained after adding DMSO-d6(Fig)shows the resonance and phosphatidylcholine and proanthocyanidin A2. The addition of polar solvent affects the interaction between the s between two molecules with obtaining a spectrum with narrow peaks, the appropriate mixture of two substances without interaction.

Spectrograms presented on Fig.

5. Spectra13With NMR

Method and equipment

NMR spectra were obtained in Dl3or DMSO-d6(purity analysis NMR) at 75 MHz (13C) installing a VARIAN INOVA 300 MHz with VNMR programTMver. 6.1.b, equipped with a 5 mm switchable wideband sensor. Used tube, Wilmad 528-PP (7"×5 mm). Temperature 30°C.

Multipletness of carbon atoms was determined using DEPT experiment (undistorting amplification and polarization transfer).

Chemical shifts were correlated with tetramethylsilane was (purity analysis NMR) at 0 ppm as an external standard.

Spectra of phosphatidylcholine and complex of proanthocyanidin A2 with phosphatidylcholine can be obtained in Dl3while the range of proanthocyanidin And2get in DMSO-d6in accordance with the solubility profile.

Phosphatidylcholine (Range13C-NMR Fig)

- carboxyl group when 173,8, 173,7 and 173,4 ppm

- olefinic carbon (the main long chain) when 128,1, 128,3, 129, 9mm, 130,2 and 130,4 ppm

- methine group of glycerol, doublet (linking phosphorus) when 70,8 and to 70.7 ppm (Jc-p=7,4 Hz)

- methylene group of glycerol, doublets (linking phosphorus) in 66.6% and up to 66.5 ppm (Jc-p=7.5 Hz) and when 63,7 and 63.6 ppm (Jc-p=5,5 Hz)/p>

the methylene on the carboxyl group (RO-CH2-CHOR-CH2-OP) at 63,2 ppm, without linking With-P

the methylene containing the group of nitrogen at 59,6 ppm (as-R associated doublet, Jc-p=4,8 Hz)

- a group of Tetramethylammonium when the 54.6 ppm

- methylene group on the main long chain in the area of 34.5 and 22.8 ppm

- terminal methyl group on long-chain primary chain when the 14.3 ppm

The proanthocyanidin And2(Range of13C-NMR Fig)

Spectrum obtained in DMSO-d6shows the following signals

8
ppmmultipletnessCppmMultipletness
2106,3g2'80,0D
366,8D3'65,2D
428,4D4'30,0T
5155,6a5'153,5
697,2D6'for 95.3D
7156,8a7'151,1a
93,5D8'101,8g
9157,2a9'to 151.8a
10103,4g10'99,2
11humidity 131.6c11'130,7c
12115,4eD12'115,4eD
13146,1b13'145, 2mmd
14145,4b14'145,0b
15115,6eD15'115,9eD
16118,6dD16'119,5dD

The complex of proanthocyanidin A2 with phosphatidylcholine (Range13C-NMR Fig)

The spectrum shows broad signals with no permission, which is consistent with a strong change of the relaxation time of carbon atoms. A sharp signal corresponding to a polar head group NHMe +3when the 54.6 ppm becomes broadened due to reduced spinoreticular relaxation time in the limited mobility of the molecules. The same effect was observed for carboxylic groups in the field of 173 ppm and methylene groups and Metin. The carbon signals corresponding to the main long chain, becoming more narrow with increasing their mobility. Therefore, the signals corresponding to the terminal methyl and methylene groups not involved in the interaction of proanthocyanidin And2/phosphatidylcholine.

As described in §4, adding DMSO-d6(Fig) provides a decomposition of the complex formed by two molecules, to obtain the spectrum in which these two substances legkonastraivaemy.

CONCLUSIONS

The data presented indicate that the complex of proanthocyanidin A2 with phosphatidylcholine is a product in which the polar head group of the lipid fraction takes a strong interaction with the molecule of proanthocyanidin And2. Acyl groups of a long chain of phosphatidylcholine not involved in complexation. A characteristic feature of the complex of proanthocyanidin A2 with phosphatidylcholine is increased lipophilicity, as demonstrated by the solubility profile that provides fast is the second dissolution of proanthocyanidin And 2in nonpolar solvents such as chloroform and toluene. The complex can be destroyed by adding a polar solvent, which changes the interaction between the two substances. The experimental data clearly show the difference between a complex and a mixture of proanthocyanidin And2/ phosphatidylcholine.

1. Complexes of phospholipids and proanthocyanidin A2.

2. The complexes according to claim 1, in which the phospholipids are selected from lecithins, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine.

3. The complexes according to claim 2, in which the phospholipid is a phosphatidylcholine.

4. The complexes according to any one of claims 1 to 3, in which the mass ratio of proanthocyanidin A2 and the phospholipid is in the range from 2:1 to 1:2.

5. The complexes according to any one of claims 1 to 4 as an active agent for the prevention or therapeutic treatment of atherosclerosis and myocardial infarction and brain.

6. Pharmaceutical composition for prophylaxis and therapeutic treatment of atherosclerosis and myocardial infarction and brain, comprising as the active ingredient complex according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6 in the form of standard doses ranging from 50 to 500 mg of active ingredient.

8. The pharmaceutical composition according to claim 6 or 7 for pearling the introduction.

9. The pharmaceutical composition according to any one of p-8 in the form of soft or hard gelatin capsules or tablets.



 

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