Solvent of compounds poorly soluble in water

FIELD: chemistry.

SUBSTANCE: claimed is application of fat emulsion for parenteral feeding as solvent for compounds which are poorly soluble in water. Fat emulsion contains in 1 l of solution: 30 g of refined soybean oil, 30 g of triglycerides with the average chain length, 25 g of olive refined oil, 15 g of purified fish oil.

EFFECT: obtaining solvent for compounds, poorly soluble in water, which makes it possible to determine parameters and spectrum of biological activity of novel compounds of chemical nature at the stages of pre-clinical and clinical tests, which does not change basic biological constants and possesses biological inertness.

2 tbl, 2 ex

 

The invention relates to medicine, namely to pharmaceutical chemistry and pharmacology, and can be used as a solvent for preclinical and clinical trials of newly synthesized compounds, the creation of new medicines.

There is a wide variety of organic solvents traditionally used for the dissolution of poorly soluble in water chemical substances to analyze their biological activity.

The closest analogue of the invention is a bipolar aprotic solvent is dimethyl sulfoxide, widely used as a solvent, including poorly soluble in water chemical compounds [Dimethyl sulfbxide (dmso) a "new" clean, unique, superior solvent / American Chemical Society. - Annual meeting. - August 20-24, 2000].

The objective of the invention is to expand the Arsenal of solvents soluble in water compounds to identify metrics and the spectrum of biological activity at the stages of pre-clinical and clinical trials of potential drugs.

Technical result - receiving solvent, allowing to define the metrics and the spectrum of biological activity of new compounds chemical nature on the stages of preclinical and clinical trials does not affect the main biological constants and possessing biological inertness.

Indicated the p technical result is achieved by as a solvent for the poorly soluble in water compounds used fat emulsion for parenteral nutrition containing 1 l of solution:

soya-bean oil (refined) - 30 g,

triglycerides medium chain length - 30 g

olive oil (refined)- 25 g,

fish oil purified - 15,

Known 20% fat emulsion for parenteral nutrition SMOFlipid®company Fresenius Kabi, Germany, which is the source of energy and essential fatty acids, including omega-3 fatty acids, and contains 1 l of solution:

- soya-bean oil (refined) - 60 g

- triglycerides medium chain length - 60 g

- olive oil (refined)- 50 g

- fish oil purified - 30 g; and auxiliary substances: the phospholipids of egg yolk, glycerol anhydrous, D,L-α-tocopherol, sodium oleate, sodium hydroxide (to maintain pH 8), water for injection [http://grls.rosminzdrav.ru/Grls_View.aspx?idReg=6659&t=cf01452f-40fb-49-846-14b7db6e9715].

We offer the solvent is partially soluble in water compounds produced by breeding a 20% fat emulsion for parenteral nutrition SMOFlipid®distilled sterile water at a ratio of 1:1 (vol/vol). Thus, the proposed as solvent soluble compounds in water fat emulsion for parenteral nutrition contains 1 l of solution:

- soya-bean oil (affilirovannogo) - 30 g

- triglycerides medium chain length - 30 g

- olive oil (refined)- 25 g,

- fish oil purified - 15 g; and auxiliary substances: the phospholipids of egg yolk, glycerol anhydrous, D,L-α-tocopherol, sodium oleate, sodium hydroxide, water for injection.

Determination of the dilution capacity of the stated solvent.

Determination of the dilution capacity of traditional solvents and the fat emulsion was evaluated by the solubility of poorly soluble in water substances. As poorly soluble substances were selected acetylsalicylic acid (2-acetyloxybenzoic acid, Farmacevticheskaja factory Shandong, Huadu pharmaceutical Co., Co., LTD., China), benzoic acid (benzoic acid, LLC Scientific-production Kama Chemical Company, Russia), PABA (4-aminobenzoic acid, Yurui Chemical Co., Ltd, China), papaverine hydrochloride (6,7-Dimethoxy-1-(3,4-dimethoxybenzyl)-isoquinoline hydrochloride, JSC "Dalkhimpharm", Russia), estradiol dipropionate (Estratrien-1,3,5(10)-diol-3,17 b dipropionate. Pharmaceutical factory Shandong, Huadu pharmaceutical Co., Co., LTD., China).

Example 1. The use of fat emulsions for parenteral nutrition as a solvent.

The ability to dissolve poorly soluble in water substances studied for distilled water, 95% (vol/vol) dimethyl what sulfoxide (DMSO), N,N-dimethylformamide (DMF), ethanol, and a solution of fat emulsions for parenteral nutrition of the claimed composition. The concentration of soluble substances in water after dissolution must be 2×10-3M/L. the Volume of solvent 1 ml of the Dissolution took place under standard conditions (SATP) is at atmospheric pressure 750,06 mm RT.article and a temperature of 25°C.

It is established that under these conditions, the dissolution of all the studied poorly soluble in water substances precipitate when dissolved in distilled water. Para-aminobenzoic acid (PAS), benzoic acid, papaverine hydrochloride (GHG) dissolved in 95% ethanol. Ethanol can dissolve this amount of acetylsalicylic acid (ASA) and estradiol dipropionate only when heated, which does not meet the conditions SATP, and when returning to the original indicators of substance precipitates. Other solvents, including declared equivalent to it effectively dissolved the selected partially soluble in water substances (table.1).

The biological activity of solvents and their impact on biological constants in terms of preclinical and clinical trials of potential drugs.

According to the manual [Manual on experimental (preclinical) study of new pharmacological substances under the General editorship of member-correspondent of the Russian Academy of medical Sciences, Professor R. U. Khabriev. - M., 2005. - S. 461-476.] solvents with its own biological activity, should not be used as a solvent medium for studying the effects of potential drugs. However, the high dissolving ability of a number of commonly used solvents combined with their high biological activity.

The biological activity of solvents has been studied for its ability to inhibit coagulation estramboticos plasma.

Experimental work was performed on the blood of healthy donors-men. The average age of the donors was 18-24 year. Blood sampling was performed from the cubital vein using a vacuum blood collection BD Vacutainer®(Dickinson and Company, USA). Samples estramboticos plasma was obtained by centrifugation citrate blood at 300g for 15 minutes.

The study of the effects of solvents on coagulation component of hemostasis in a cuvette containing depleted platelet plasma was introduced under stirring with 10 μl of a solution of the analyte, and incubated for 5 minutes at 37°C. Next determined the coagulation activity of the solvents in vitro standard clothingbaby tests turbidimetrically hemocoagulase Solar CGL (Belarus). In connection with the original difference of optical density lipid emulsions and is lazmi blood definition of these indicators for the suspension of lipid emulsions was carried out on mechanical coagulometer ASKA 2-01-Astra (Russia). Was carried out the determination of activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen concentration in A. Clauss [Manual on experimental (preclinical) study of new pharmacological substances under the General editorship corresponding member of RAMS, Professor R. U. Khabriev. - M.: Medicine, 2005. - 327 S.].

The research results were processed using the statistical package Statistica For 10.0 (StatSoft Inc, USA). Check for the normality of distribution of the actual data was performed using the criterion Shapiro-Fork. For a description of the groups used the median and interquartile range. Analysis of variance was performed using criteria Kruskal-Wallis. The critical significance level p for statistical tests was taken equal to 0.05.

Example 2. Coagulation activity of solvent.

The results of these studies demonstrate that all conventional solvents significantly prolong the clotting time estramboticos plasma. 95% (vol/vol) solution of DMSO lengthens the time of the APTT in average by 50% in comparison with the control. DMF in the initial concentration prolong all tested parameters by more than 200% in comparison with the control. 95% ethyl alcohol exhibits anticoagulant activity of all studied indicators, extending tested parameters in the CPE is it 5%. The solution of the fat emulsion for parenteral nutrition on the coagulation parameters estramboticos plasma effect is not rendered.

Thus, the claimed means for dissolving chemical substances characterized by good solubility, comparable with analog solvents. Long-term use of lipid emulsions as a means of nutritional support helped to ensure biological inertness, security and the absence of biological activity as when bolus, and with long-term use [Traul, K. A. Review of the toxicologic properties of medium-chain triglycerides / K. A. Traul, A. Driedger, D. L. Ingle, D. Nakhasi // Food Chem. Toxicol. - 2000. - Vol.38. - P. 79-98]. For example, coagulation estramboticos plasma revealed no effect of fat emulsion for parenteral nutrition on the performance of the APTT, PV and fibrinogen concentration.

The use of fat emulsions for parenteral nutrition containing 1 l of solution:
soya-bean oil (refined) - 30 g,
triglycerides medium chain length - 30 g
olive oil (refined)- 25 g,
fish oil purified - 15 g,
as solvent for the poorly soluble in water connections.



 

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