Ephtiderm preparation method

FIELD: organic synthesis.

SUBSTANCE: invention provides a method for preparing water/glycerol complex of (2,3-dihydroxypropyl) ortho-titanate hydrochloride (chloride) having symbolic name "Ephtiderm", which is depicted by following empirical formula: Method consists in that glycerol is mixed with butyl ortho-titanate at molar ratio 12:1, whereupon butanol is distilled off in vacuum, residue is treated with water and aqueous hydrochloric acid to form reaction mass with pH 2.2-3.0, which is heated in vacuum. Method is characterized by that glycerol is mixed with low-grade butyl ortho-titanate and chloroform, reaction mass during the synthesis is maintained at temperature up to 100°C in vacuum 40-200 mm Hg, while chloroform is added at 40-50°C in amount corresponding to 1 L chloroform per 2 L low-grade butyl ortho-titanate.

EFFECT: reduced expenses due to use of low-grade butyl ortho-titanate and simplified technology.

1 tbl, 3 ex

 

The invention relates to methods for chemical substances of unknown structure, specifically to methods for water-glycerol complex (2,3-DIXIPAY)-orthotitanate chloride (hydrochloride), with the conditional name “Epiderm”, which is characterized by the following gross formula:

Epiderm may find application in medicine, cosmetics and veterinary medicine as anti-inflammatory agents and transcutaneous Explorer biologically active substances through the skin and mucous membranes[1, 2, 3].

A method of obtaining epiderma, which consists in the interaction of glycerol with purified utilitarianism (pre-made double distillation of technical butylacetoacetate in high vacuum at 2-5 mm Hg) at a molar ratio of 12:1, respectively, with distillation of the butanol under vacuum at temperatures up to 105° With not less than 8 h followed by barbotirovanie air through the reaction mass at a temperature of up to 30° With the addition of water and hydrochloric acid to a pH of 2.2 to 3.0 with keeping the reaction mass at a temperature of up to 95° C for 2-3 h (see RF patent No. 2053234, 1996 - prototype).

The disadvantages of the prototype should be attributed to the low productivity of the method and the relatively high cost of the resulting product. The above is not the key associated with the obligatory double distilled technical butylacetoacetate (BOT) in high vacuum (2-5 mm Hg). And thus we get a party epiderma may differ greatly from each other, which requires additional correcting tests.

Technical problem in the present invention is to simplify the production technology of epiderma without compromising its quality and medicinal properties, reducing its value.

The technical result is achieved in that in the method of obtaining epiderma-water-glycerol complex (2,3-DIXIPAY)-orthotitanate hydrochloride, characterized by gross formula

,

which can find application in medicine, cosmetics and veterinary medicine as anti-inflammatory agents and transcutaneous Explorer biologically active substances through the skin and mucous membranes, in the way in which mix the glycerin and utilitarianist when a molar ratio of twelve to one, respectively, butanol is distilled off from the mixture by heating under vacuum, add the remainder of water and hydrochloric acid to obtain a reaction mixture having a pH of pH from 2.2 to 3.0, which is then heated in vacuum, glycerin mixed with technical utilitarianism and chloroform, the reaction mass in the synthesis phase is maintained at a temperature of up to 100° With vacuum, equal 40-100 mm Hg Method characterized by the fact that chloroform was added when the fact is the temperature value of 40-50° With a rate of 1 liter of chloroform in 2 liters of technical butylacetoacetate (BOT).

New in the proposed method is the use of relatively inexpensive technical BOT, and provision of the synthesis when the vacuum 40-100 mm Hg unlike 2-25 mm Hg required in the known method. Obvious is the addition to the reaction mass of chloroform, which, acting on a cheap technical BOT, ensures epiderma, not inferior in quality to the product obtained with the use of expensive, purified by double distillation in high vacuum BOT. Industrial applicability of the proposed method is confirmed by the following examples.

To obtain epiderma the proposed method use technical utilitarianist, which is mixed with glycerol in a ratio of 1/12. The mixture is heated to 70-100° With vacuum. The vacuum level can be from 40 to 100 mm Hg In these conditions, of a mixture of butyl alcohol is distilled off until the end of the shoulder strap. Then to the reaction mass is added the calculated amount of 20% caustic soda and distilled water. The mixture is again stirred at a temperature of 70-100° the lower the air pressure to 40 mm Hg While completely Argonauts fraction butanol-water. After the end of a shoulder strap of the reaction mass is then cooled to 40-50° after which it add the chloroform at a ratio of 500 ml of chloroform per 1000 ml BOT. The mixture is stirred for 10-15 minutes and leave for delamination.

After complete separation of the receive two layers: the bottom - dark brown (chloroform and), upper - transparent, slightly yellowish (alkaline solution glycerate titanium). The bottom layer is separated and sent for regeneration of chloroform.

The top layer is filtered over a suction filter of coarse activated carbon and filter paper (number of layers is selected empirically). The filtrate was stirred at room temperature with addition of the calculated quantity of citric acid solution. Then the reaction mass is added experimentally determined on a sample quantity of a mixture consisting of 50% (vol.) hydrochloric acid and 50% (vol.) of distilled water. When this reaction mass becomes yellow and opalestiruet in transmitted light. The resulting liquid is again stirred and gradually heated to a temperature of 70-90° C. After a slight turbidity and increasing the viscosity of the fluid prior to the settlement of its discharge into the receiving container and cooled. The result is a gelatinous opalescent mass of yellowish or grayish - epiderm.

Preliminary experimental studies conducted on animals showed that epiderm received on the proposed patent method, and to preserve yet all properties of the drug, made previously known method.

Example 1. Water-glycerol complex (2,3-DIXIPAY)-orthotitanate hydrochloride gross formula C720H3729O1660TI20CL9

,

The synthesis is carried out in the three-neck flask with funnel, stirrer and reflux condenser. The flask of 63.7 g (0,69 mole) of glycerol, include a mixer and gradually add 19,2 g (0,058 mole) of technical butylacetoacetate in a molar ratio of 12:1, respectively. Change a reflux on the line and the reaction mass is heated to 70-100° With simultaneous vacuum at 40-100 mm Hg butyl alcohol is Distilled off until the termination of a shoulder strap.

Then to the reaction mass is added the calculated amount of 20% caustic soda and distilled water. The mixture is stirred with decreasing pressure to 40 mm Hg After the end of a shoulder strap of the reaction mass is then cooled to 40-50° C, after which it was added chloroform at a ratio of 500 ml of chloroform per 1000 ml BOT. The mixture is stirred for 10-15 minutes and leave for delamination. After complete separation of the layers the bottom layer is separated and sent for regeneration of chloroform. The top layer is filtered over a suction filter of coarse activated carbon and filter paper (number of layers is selected empirically). To the filtrate with stirring at ControlTemplate add the calculated amount of 21% solution of citric acid, then at room temperature the reaction mass is added experimentally determined on a sample quantity of the mixture: 50% vol. hydrochloric acid and 50 vol.% of distilled water. When this reaction mass becomes yellow and opalestiruet in transmitted light. The mixture with stirring is heated to a temperature of 70-90° C. After a slight turbidity of the reaction mass and increase in viscosity prior to the settlement it into the receiving container and cooled. The result is a gelatinous opalescent mass of yellowish - epiderm.

Example 2. Determination of the percutaneous conductivity epiderma.

For research transcutaneous activity epiderma was made polarographic cell, hermetically divided into equal parts skin of the newborn rat, which provodnikovym properties corresponds to the human skin. Both parts of the cell was filled 0,89% solution of sodium chloride, then in the part facing to the surface of the skin - the epidermis, made of various biologically active substances to obtain a 1% solution, was immersed in her reference electrode. The second part of the cell was immersed platinum working electrode and included polarograph. The emergence of the “peak” of the analyte matched his appearance in the second part of the cell. Transcutaneous activity was expressed in minutes. After each the determination both of the cell was thoroughly rinsed with saline solution of sodium chloride. The comparison was done with epidermal obtained in a known manner, and dimexide, as control was used saline. Table 1 presents the results of the study 20% epiderma obtained in different ways, and 20% solution of Dimexidum. Increasing the concentration of essential drugs to increase performance transcutaneous activity was not called.

Table 1

Comparative evaluation of transcutaneous activity 20% solutions of epiderma and Dimexidum (in minutes)
№№ p/p1% solution medicationSalineDimexideEpiderm (known way)Epiderm (proposed method)
1Salicylic acid25,612,42,32,2
2Ascorbic acid24,113,82,92,7
3Potassium iodide18,210,92,12,0
4Tetracycline33,019,14,85,0
5Mefenamovaya acid29,822,37,67,5
6Sulfur precipitatedwithin 2 h not found89,4a 12.712,6

On the basis of the data in table 1, we can conclude that epiderm obtained by the proposed method, has a transcutaneous activity exceeding the action Dimexidum 3.0-7.1 times that of saline in 4-11,6 times. Its activity is not inferior to the activity of epiderma obtained previously known method.

Example 3. To determine the viability of monocytes [4, 5]

The experiment was performed on 40 adult mice weighing 19,2±1,21, Mice were divided into 4 equal groups. All animals through the probe three times in 24 h were injected drugs podgruppe at the rate of 0.5 g/kg of body weight. group 1 - control, injected with a saline solution, group 2 - Dimexidum, group 3 - epiderm obtained by the proposed method, group 4 - epiderm obtained previously known method.

Dimexide and epiderm was used in dilution with water in the ratio 1:1. A day after the third injection, all mice were taken blood, isolated monocytes [4}. Suspension of monocytes were diluted with medium 199 to the content of the cells 107ml of the resulting suspension in sterile conditions were poured in Petri dishes based 2-3 million cells per Cup and placed for 1 h in a thermostat at 37° C, washed the cells with medium 199, and monocytes is stabalise attached to the bottom of the Petri dish. Used various extreme impact, incubated in Petri dishes in an incubator for 1 h at 37° With, again washed with medium 199, filled with 1%solution Trypanosoma blue for 3 min, washed away the paint with a saline solution of sodium chloride and counted directly in Petri dishes under a microscope the number of living cells per 100 monocytes. From each mouse were prepared in 5 Petri dishes. Used impact: 1 - control (saline), 2 - UFOs for 5 min, 3 - a 0.02% solution of cyclophosphamide in saline solution, 4 - 8000 units of penicillin in 2 ml of saline, 5 - 8000 units tetracycline in 2.0 ml of saline. All applied effects have a cytotoxic effect. The results are shown in table 2.

From the table 2 data, we can conclude that the greatest protective effect has epiderm both series: the difference between unreliable. Epiderm increases cell viability (functional activity), 1.8-7.1 times stronger saline, 2.1-8 times more Dimexidum. It should be noted that the Dimexidum has a toxic effect [6, 7], which is confirmed by the condition of the animals of the 2nd group. They bad eaten food, were sedentary, 8 of them was expressed diarrhea, 2 - hematuria. The difference of action epidermal obtained in different ways, should be considered unreliable.

Table 2

Assessment of viability of monocytes after extreme

impacts on the background of the protection of the studied drugs
Drug protectionExtreme exposure
 Control without exposureUFO 5 minCyclophosphamidePenicillinTetracycline
Control984973730
Dimexide984183427
Epiderm (known way)9886617976
Epiderm (proposed method)9888648275

Summarizing the results shown in examples 2,3, we can conclude that the results obtained by the proposed method epiderm is not inferior in its transcutaneous qualities of epidermo produced using a known method. Being a good conductor of biologically active additives, it significantly increases the vitality and resistance of cells to the effects of extreme external factors.

Given the above, it is possible in order to conclude, that the proposed solution meets the criteria of novelty, non-obviousness and industrial applicability, and therefore proposed to the legal protection of a patent for an invention.

Sources of information

1. RF patent №2042683 on August 27, 1995, application No. 93031251.

2. RF patent №2058319 dated April 20, 1996, application No. 93016862.

3. RF patent №2053234 of January 27, 1996, application No. 5012506/04.

4. Strizkov L.P. Cooperative cellular reaction in the hearth of aseptic inflammation, obtained by the method of “skin window” in healthy people. // Sat. “Etiology and pathology of connective tissue”, V all-Union conference. - Novosibirsk, 1980, p.21-22.

5. Privalova LI ABOUT the relationship of viability of various cell system faguoqitirute of mononuclear cells when exposed to quartz particles. // Prof. diseases caused by dust. Collection of scientific papers, 1984, p.31-35.

6. Yushkov astray freight, Glotov N.A., Barybin A.S., ALEXANDER Osipenko ON the influence of DMSO on the blood of irradiated and non-irradiated animals.” / Radiobiology”, T. XX, issue 1, 1980, No. 1, str-136.

7. Ashwood-Smith, M.J., Intern J. Radiat. Biol. 3, 101, 1961, Dimethilsulfoxide, vol.1. Basic concepts. New York, 1971, pp.149-189.

Annex a

physico-chemical properties epiderma

Physico-chemical characteristics and composition of water-glycerol complex (2,3-DIXIPAY)-orthotitanate hydrochloride (chloride): thick, translucent, gelatinous mA the sa light yellow with low specific smell. Mixed with water, glycerin, alcohol 95% in the ratio of 4:1, restoring the structure of the gel after 12 hours. Mixed with chloroform in a ratio of 1:4. Practically insoluble in ether and acetone. The composition of the water-glycerol complex (2,3-DIXIPAY)-orthotitanate hydrochloride (chloride) gross formula:

T(C3H7O3)4·160S3H8O3·N2O· 9l720H3729O1660Ti20CL9Mm 40209 confirmed by elementary analysis.

Calculated, %: C 21,49; N 9,27; Ti 2,39; Cl 0,79. Found, %: C 21,34-21,64; N 9,23-9,38; Ti 2,30-2,70; Cl Of 0.71 To 1.0.

The density of 25% aqueous solution of epiderma from 1,038 to 1,058 in GF XI, issue 1. p.24 (using the pycnometer). The viscosity of a 25% aqueous solution is from 1.40 to 2.80 for GF XI issue 1, St (using capillary viscometer glass type VPI-2 at 20°).

The refractive index from 1,351 to 1,355; pH from 2.6 to 4.0 and a density of from to 1,038 1,058; the relative viscosity of from 1.40 to 2.80. The refractive index of a 25% aqueous solution of 1,3515 to 1,3553 on GF XI, issue 1. p.29 (Abbe Refractometer).

The titanium content is from 2,150 to 2,800%. The content of Floridiana from 0.70 to 1.00%. UV spectrum obtained on a spectrophotometer Specord UV VIS diluted at epiderma water (GF XI, p.34). UV spectrum recorded in the region from 200 to 350 nm, has two intense broad overlapping absorption bands with m is xenomai about 227 nm, the coefficient of extinction ∈ 738 (lg∈ 2,87) and

approximately 250 nm, the extinction coefficient ∈ 676 (lg∈ 2,83).

The identity of the substance confirms the infrared spectrum. The IR spectrum obtained on a spectrophotometer Specord 75 of the criminal code in the field 500-4000 nm, the layer between the Windows has characteristic bands of fluctuation:

3380 (OH), 1045 (C-0 to C-O-N pri.), 1112 (C-O-N Deut.), 995, 1045, 1112 (Assoc. link Ti-0-C), 1640 (H-HE), 2880, 2935 (C-H), 1220 (CH2).

1. The method of obtaining epiderma - water-glycerol complex (2,3-DIXIPAY)-orthotitanate hydrochloride, characterized by gross formula

which can find application in medicine, cosmetics and veterinary medicine as anti-inflammatory agents and transcutaneous Explorer biologically active substances through the skin and mucous membranes, which mix the glycerin and utilitarianist when a molar ratio of 12:1, respectively, butanol is distilled off from the mixture by heating under vacuum, add the remainder of water and hydrochloric acid to obtain a reaction mixture with a pH of from 2.2 to 3.0, which is then heated in a vacuum, characterized in that the glycerol is mixed with technical utilitarianism and chloroform, while the reaction mass in the synthesis phase is maintained at a temperature of up to 100°With vacuum 40-100 mm Hg and after distillation bout the Nola add chloroform at a temperature of 40-50° With a rate of 1 l of chloroform to 2 l technical butylacetoacetate.



 

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