Method for preparing substance possessing nootropic activity

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for preparing rosavine possessing the nootropic activity. Method for preparing rosavine involves three-fold extraction of rosewort (Rhodiola rosea L.) milled rhizomes with 70-90% ethyl alcohol in the definite ratio raw : extractant, evaporation of combined extracts under vacuum to obtain dense residue, chromatography separation on silica gel, evaporation of eluates and crystallization wherein the first extraction is carried out at definite temperature and two other extractions are carried out at definite temperature with reflux condenser. Proposed method provides increasing the yield of the end product from rosewort rhizomes and reducing duration of the technological process.

EFFECT: improved preparing method.

3 tbl, 3 ex

 

The invention relates to chemical-pharmaceutical industry, in particular the production of medicines in the form of substances and individual biologically active compounds (BASS), and concerns a method for obtaining rosavine from rhizomes of Rhodiola rosea (Rhodiola rosea L.).

Rhizomes of Rhodiola rosea contains as predominant biologically active compounds containing, including rosavin (1) [1, 4-8, 15, 16], and are a valuable raw material for the production of tonic, adaptogenic and immunomodulatory drugs [2-5, 7-12, 14, 18].

Known methods for producing rosavine with neurotropic activity [4, 6, 19], however, a disadvantage of known methods is the complexity of the process and low yield of the target product.

A prototype of the invention we have used the method of receiving Rosalina from rhizomes of Rhodiola rosea [6], however, the allocation of this substance is carried out with the use of cumbersome technology, consisting in the extraction of raw materials methanol, evaporation of the methanol extract to the syrup-like residue, chromatographic purification on polyamide using as eluent a mixture of solvents (methanol and chloroform), followed by rechromatography fractions containing the target product (rosavin), on silica gel (eluent:chloroform-the ethanol in different ratios), the process of evaporation of fractions containing the target product to the syrupy film, dissolution of the residue in boiling ethanol, filtration, crystallization, Department of technical rosavine by filtration and final purification of the target product by recrystallization from ethanol to yield target substance 3.2 g, or 0.64% of the air-dried raw materials [6].

This method is not only cumbersome and lengthy (143), but also gives a low yield of the target substance - rosavine (0,64%). In addition, at the stage of extraction of the raw materials used such a dangerous solvent like methyl alcohol. Given the enormous importance of Rosalina as the state standard sample [13], proposed by us for the purposes of standardization of raw materials and products of Rhodiola rosea[2, 7, 8, 11], very relevant are studies on the improvement of the method of obtaining rosavine.

The aim of the invention is to increase the output rosavine from rhizomes of Rhodiola rosea.

This goal is achieved by the fact that as the extractant used 70...90% ethyl alcohol, allowing exhaustively extract the target product - rosavin (1) from the rhizomes of Rhodiola rosea with subsequent chromatographic separation of extractives on silica gel and recrystallization technical target product.

Conducted by the applicant who feature on scientific, technical and patent information sources and selected from the list of analogues prototype [6], we were able to identify distinctive features in the claimed technical solution. Therefore, the inventive method of obtaining satisfies the criteria of the invention of "novelty."

Conducted by the applicant additional search of the known technical solutions[2, 4, 5, 7, 12, 14, 18, 19] to detect in them the characteristics similar to the characteristics of the proposed method of obtaining, showed that these signs are absent, therefore, the claimed technical solution meets the criterion of "inventive step".

The inventive method is illustrated by the following examples.

Example 1. Powdered air-dried rhizomes of Rhodiola rosea (500.0 g) extracted with 80% ethanol at a ratio of 1:6 at room temperature for 24 h and then spend two extraction (2×30 min) at a temperature of 80-85°With a reflux condenser. The combined aqueous alcoholic extracts evaporated under vacuum to a thick residue (500 ml)that was mixed with 100 g of silica gel L 40/100, dried for 24 h and applied to a column (8×10 cm)filled with silica gel in the form of a suspension in chloroform. The chromatographic column is washed with choroform (0.5 l) and a mixture of chloroform-ethyl alcohol in a ratio of 90:10 (2 liters). The target substance elute with chloroform-ethyl alcohol in a ratio of 85:15 (2 l) and 80:20 (1 liter). Control over the separation of substances was carried chromatographytandem on the plates "Silufol UV-254" in the solvent system: chloroform-marked the first alcohol-water(26:14:3).

Eluate containing rosavin, evaporated under vacuum to a syrup-like film, the residue is dissolved in ethyl alcohol when heated, filtered and leave at 10 o'clock after this time the resulting crystalline precipitate rosavine separated, received technical target product is dissolved by heating in ethanol and leave for 10 hours after this time the resulting crystalline precipitate rosavine was separated, washed with ethyl alcohol and dried in air. Get 5.3g target substance yield of 1.06% of air-dried raw materials (table 1).

Spectral and physico-chemical properties rosavine (cinnamyl-O-(6'-O-α-L-arabinopyranosyl)-β-D-glucopyranoside) (1). Colorless crystals of composition With20H28About10with so pl. 171-173°C; UV-range: λmaxEtOH- 252 nm. Range1H-NMR (200 MHz, C5D5N) δ, ppm: 7.4-7.2 (m, I-N). 6.82 (d, 16 Hz, H-7), 6.5 (dt, 6 and 16 Hz, H-8), 4.94 (d, 7 Hz, H-1'), 4.87 (d, 6 Hz, H-1"), 4.90 (m, 1N-9), 4.65 (DD, 6 and 12 Hz, 1H-9), 4.55-3.95 (m, 10H glucose), 3.7 (kV, 2 and 13 Hz, H-5"e). Quality rosavine meets the requirements of FS 42-0071-01 [13].

Example 2. Powdered air-dried rhizomes of Rhodiola rosea (500.0 g) extracted with 90% ethanol in the ratio of 1:6 at room temperature for 24 h and then spend two extraction (2×30 min) at a temperature of 80-85°With reverse cold what linecom. The combined aqueous alcoholic extracts evaporated under vacuum to a thick residue (500 ml)that was mixed with 100 g of silica gel L 40/100, dried for 24 h and applied to a column (8×10 cm)filled with silica gel in the form of a suspension in chloroform. Next process is carried out in accordance with example 1.

The yield of the desired product as individual rosavine is 4.35 g or 0,87% by weight of air-dry raw material. Physicochemical and spectral characteristics rosavine meet the requirements of FS 42-0071-01 [13].

Example 3. Powdered air-dried rhizomes of Rhodiola rosea (500.0 g) extracted with 70% ethanol in the ratio of 1:6 at room temperature for 24 h and then spend two extraction (2×30 min) at a temperature of 80-85°With a reflux condenser. The combined aqueous alcoholic extracts evaporated under vacuum to a thick residue (500 ml)that was mixed with 100 g of silica gel L 40/100, dried for 24 h and applied to a column (8×10 cm)filled with silica gel in the form of a suspension in chloroform. Next process is carried out in accordance with example 1.

The yield of the desired product as individual rosavine makes 4.75 g or 0.95% of the mass of air-dried material. Physicochemical and spectral characteristics rosavine meet the requirements of FS 42-0071-01 [13].

Studied the e beyond the parameters (examples 4-6), namely: implementation of the extraction of 60% and 96% ethanol, using chromatography on polyamide and rechromatography on silica gel leads to a marked reduction in the yield of the target product, respectively to 0.61%, 0.50% and 0.70 percent (table 1).

Therefore, the optimal parameters of the method of obtaining rosavine are: extraction of 70...90% ethyl alcohol in the ratio of raw materials-extractant 1:6 with subsequent chromatographic separation of extractives on silica gel and crystallization of the desired product from ethyl alcohol.

Table 1

Output rosavine depending on values of parameters of technological process
№№ p/pThe essential featuresThe optimal parametersBeyond the optionsOutput rosavine, in % by weight of air-dry raw
1.Extraction of raw material alcohols C1-C2,Methanol (prototype)0,64
The same80% ethanol1,06
2.The same90% ethyl alcohol0,87
3.The same70% of milovy alcohol 0,95
4.The same96% ethyl alcohol0,50
5.The same60% ethyl alcohol0,61
Chromatographic purificationPrototype (polyamide + silica gel)0,64
1.

The same

6.

The same
Silica gel1,06

0,70
Polyamide + silica gel

Use in the claimed method 70...90% ethyl alcohol can exhaustively extract the target product from the rhizomes of Rhodiola rosea. While the inventive method allows 1.77 times to increase the yield of the target product from the rhizomes of Rhodiola rosea compared to the prototype (table 2).

In addition, the inventive method allows 1.8 times to reduce the duration of the technological process, 1.8 times to reduce the consumption of expensive solvent (chloroform) and to exclude from the process flowsheet use in the extraction step of hazardous solvent methyl alcohol, and expensive sorbent - polyamide.

Table 2

ravnitelnaya characteristic ways of getting rosavine
№№ p/pThe parameters of the methodThe inventive methodThe placeholderThe advantages of the proposed method
1.The extractantEthyl alcohol (70%...90%)Methyl alcoholThe exception to the way hazardous solvent
2.Output rosavine,% 1,060,64Higher output rosavine (1.77 times)
3.Used sorbentsSilica gelPolyamide and silica gelThe exception to the way polyamide as expensive sorbent
4.Consumption of chloroform on stage chromatographic purification5 l 600 ml10 l 160 mlReducing consumption of chloroform as expensive solvent 1.8 times
5.The duration of the technological process79 h1431.8 times shorter

Nootropic activity rosavine investigated in terms of methodology open field, allowing to estimate approximately research responses in rats [17]. As the comparison drug studied the reference drug "Piracetam" [3, 12]. Research vypolneniya outbred rats of both sexes with initial mass, 170-210, contained in standard vivarium conditions on a normal diet. Used a square cell size of 100×100×40 see Her floor was divided into 25 squares with a hole in the center. Registration was carried out for 5 minutes. Calculated move from square to square (horizontal activity), both in 16 external and 9 internal, number of stevani on the hind feet (vertical activity), the number of surveyed holes (research activity), the number of washings (grooming) and the number of acts of defecation by the number of fecal balls (boles).

The study drugs were injected animals intragastrically through a tube, pre-dissolved in distilled water at different doses: 10 mg/kg (rosavin) and 200 mg/kg (piracetam) once a day from one to 5 days, last 30 minutes before the test.

The main purpose of the estimated response is to increase the excitability of analyzers for better perception of the actions on the nervous system stimuli to establish their biological significance. Any type of analysis takes place with the active participation of the indicative reflex. The reaction of addiction or negative doctrine protects the nervous system, removing the animal from unnecessary number of stimuli of the environment. At the same time, she too is tied to isolate biologically meaningful signal. Addiction is one of adaptive skills in rodents. In our experiments, the location of the animal in a new environment leads to exploratory behavior, which simultaneously prevents fear. Two antagonistic trends are characterized by different time course, and the best expression of the reduction of fear in animals is considered to be the study of their inner squares of the experimental setup.

The results of the study are presented in table 3, indicate that the greatest degree of General locomotor activity (total horizontal activity in the external, internal squares and vertical activity) was increased under the influence of rosavine - 26.0%, whereas in the case of piracetam, this figure was only 10% (table 3). Introduction rosavine significantly increased the release of animals into the inner squares: 0,16±0.1 in the control to 4.0±0,4* experience, that is, 25 times, whereas in the case of pyracetam this indicator increased only 6.7 times (table 3). This is evidenced by a decrease in emotionality and fear of animals under the influence of these drugs. With the introduction of rosavine increased vertical activity (from 15.1±4.7 rises up on its hind legs to 25.5±3,1* experience), as well as horizontal activity in the outer squares: 12.5±2,0 control to 15.0± 3,7* intersections of the squares in the experiment (table 3).

Table 3

The influence of Rosalina and pyracetam (drug comparison) the figures in the "open field" (the number of animals in each group - 12)
The drug dose in mg/kgHorizontal activity externalHorizontal activity internalVertical activityResearch activityGroomingBolesGeneral motor activity
Control12,5±2,00,16±0,115,1±4,75,0±0,94,5±0,61,3±0,317,6
Rosavin, 10 mg/kg15,0±3,7*4,0±1,4*25,5±3,1*3,1±0,51,7±0,42,8±0,522,1(126%)
Control10,0±1,80,3±0,16,6±1,75,5±1,21,0±0,22,6±0,615,5
Piracetam, 200 mg/kg16,5±0,9*2,0±0,4*2,8±0,50,5±0,21,6±0,81,2±0,1 17,1(110%)
* - P<0.05 compared with control

Thus, using the proposed method of obtaining rosavine provides the following benefits:

1. Use in the claimed method 70-90% ethyl alcohol can exhaustively extract the target product from the rhizomes of Rhodiola rosea.

2. The inventive method allows 1.77 times to increase the yield of the target product from the rhizomes of Rhodiola rosea in comparison with the prototype.

3. The inventive method enables 1.8 times to reduce the duration of the process.

4. The inventive method enables 1.8 times to reduce the consumption of expensive solvent and to exclude from the process flowsheet at the stage of extraction, the use of hazardous solvent methyl alcohol, and expensive sorbent - polyamide.

5. The inventive method allows to obtain the substance, far superior in the dose of 10 mg/kg by the pharmacological action reference nootropic drug Piracetam" (investigational dose of 200 mg/kg).

Sources of information:

1. Barnaul OD, Limarenko, A., Kurkin VA and other Comparative evaluation of biological activity of compounds isolated from species of Rhodiola L. // Chem.-formats. log. - 1986. - T.20, No. 9. - S-1112.

2. Bykov V.A., Zapesochnaya GG, Kurkin V.A. (Rhodiola rosea L.): Traditional and b is tehnologicheskie aspects of reception of medicines (review) // Chem.-formats. log. - 999. - V.33, no. 1. - P.28-37.

3. The state register of medicines. 1. Official publication. - M., 2002. - 1300 C.

4. Zapesochnaya GG, Kurkin VA Glycosides cinnamic alcohol from rhizomes of Rhodiola rosea II Chemistry natures. connect. - 1982. No. 6. - S-727.

5. Zapesochnaya GG, Kurkin VA, Boyko VP, etc. Containing promising biologically active substances of medicinal plants // Chem.-formats. log. - 1995. - T, No. 4. P.47 - 50.

6. Kurkin VA, Zapesochnaya GG, Sablinski A.N., Ivashin, V.M., Sokolov, SJ, schröter A.I. Way to obtain rosavine // A.S. No. 1168254 (USSR). - Publ. in B. I., 1985. No. 27.

7. Kurkin VA, Zapesochnaya, Chemical composition and pharmacological properties of plants of the genus Rhodiola (review) // Chem.-formats. log. - 1986. - T.20, No. 10. - S-1244.

8. Kurkin V.A. Containing promising natural biologically active compounds. - Samara: Samara state medical University, 1996. - 80 S.

9. Kurkin VA, Zapesochnaya GG, Avdeeva E.V. and other Method of obtaining funds, possessing immunomodulatory activity // Patent RF №2133620. - A 61 K 35/78. - Bull. No. 21 from 27.07.99,

10. Kurkin VA, Dobyshev A.V., I. Titov. and other Neurotropic activity of herbal remedies containing containing // the pharmacy. - 2003. - T, No. 6. P.30-31.

11. Kurkin V.A. Pharmacognosy: a textbook for students of pharmaceutical universities. - Samara: LLC "Etching", VPO "Samara state medical University", 2004. - 1180 C.

12. Mashkovsky PPM Lek is stennie funds. 1 and 2. - M.: New Wave, 2000.

13. Rosavin - standard sample. FS 42-0071-01. - M., 2001. - 4 S.

14. Saratikov A.S., Krasnov EA Rhodiola rosea (Golden root). - Tomsk: Publishing house of Tomsk University, 2004. - 292 S.

15. Sokolov, SJ; Ivashin, V.M., Zapesochnaya, and other Research neurotropic activity of new substances isolated from Rhodiola rosea // Chem.-formats. log. - 1985. - T, No. 11. - S-1371.

16. Sokolov, SJ, Boyko VP, Kurkin VA and other Comparative study of the stimulating properties of some containing // Chem.-formats. log. - 1990. - V.24, No. 10. - P.66-68.

17. Experimental study of drugs with neuroprotective action type. Edited Voronina T.A., Ostrovskaya RU // Vedomosti of the Pharmacological Committee. 1998. No. 2. P.21-38.

18.Kurkin VA Phenylpropanoids from Medicinal Plants: Distribution, Classification, Structural Analysis, and Biological Activity // Chemistry of Natural Compounds. - 2003. - Vol.39, No.2. - P.123-153.

19. Tolonen, A., Pakonen M., Hohtola A. et al. Phenylpropanoid glycosides from Rhodiola rosea II Chem. Pharm. Bull. - 2003. - Vol.51, No.4. - P.467-470.

The method of receiving Rosalina, including three-fold extraction with an organic solvent crushed rhizomes of Rhodiola rosea (Rhodiola rosea L.) at the ratio of raw material: solvent 1:6), evaporation of the combined extracts under vacuum to a thick residue, chromatographic separation on silica gel, evaporation of the eluates and crystallization, characterized in that the extraction is carried out 70-90%Adilov the m alcohol, the first extraction was performed at room temperature, and the other two extraction at a temperature of 80-85°With reflux.



 

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3 ex

FIELD: medicine, stomatology.

SUBSTANCE: invention relates to a gel composition used in treatment of stomatological diseases. The composition comprises an active component represented by diclofenac and chlorhexidine gluconate, mucoadhesive reagent, gel-forming agent and a pharmaceutically acceptable excipient wherein components are taken in the definite ratio. The composition is prepared by dissolving diclofenac in propylene glycol followed by addition of carboxyvinyl polymer and copolymer of methylvinyl ester with maleic anhydride and the following addition of prepared solution to a separately prepared system of solvents at continuous stirring, the following addition to the prepared gel of EDTA disodium salt aqueous solution, saccharin sodium salt and chlorhexidine gluconate up to the complete dissolution. Prepared composition provides retaining a medicinal preparation on the damaged site for the more long time and provides local delivery of the preparation for therapeutic effect.

EFFECT: improved preparing method, valuable medicinal properties of gel composition.

21 cl, 3 tbl, 3 ex

FIELD: medicine, stomatology.

SUBSTANCE: invention relates to a gel composition used in treatment of stomatological diseases. The composition comprises an active component represented by diclofenac and chlorhexidine gluconate, mucoadhesive reagent, gel-forming agent and a pharmaceutically acceptable excipient wherein components are taken in the definite ratio. The composition is prepared by dissolving diclofenac in propylene glycol followed by addition of carboxyvinyl polymer and copolymer of methylvinyl ester with maleic anhydride and the following addition of prepared solution to a separately prepared system of solvents at continuous stirring, the following addition to the prepared gel of EDTA disodium salt aqueous solution, saccharin sodium salt and chlorhexidine gluconate up to the complete dissolution. Prepared composition provides retaining a medicinal preparation on the damaged site for the more long time and provides local delivery of the preparation for therapeutic effect.

EFFECT: improved preparing method, valuable medicinal properties of gel composition.

21 cl, 3 tbl, 3 ex

FIELD: medicine, stomatology.

SUBSTANCE: invention relates to a gel composition used in treatment of stomatological diseases. The composition comprises an active component represented by diclofenac and chlorhexidine gluconate, mucoadhesive reagent, gel-forming agent and a pharmaceutically acceptable excipient wherein components are taken in the definite ratio. The composition is prepared by dissolving diclofenac in propylene glycol followed by addition of carboxyvinyl polymer and copolymer of methylvinyl ester with maleic anhydride and the following addition of prepared solution to a separately prepared system of solvents at continuous stirring, the following addition to the prepared gel of EDTA disodium salt aqueous solution, saccharin sodium salt and chlorhexidine gluconate up to the complete dissolution. Prepared composition provides retaining a medicinal preparation on the damaged site for the more long time and provides local delivery of the preparation for therapeutic effect.

EFFECT: improved preparing method, valuable medicinal properties of gel composition.

21 cl, 3 tbl, 3 ex

FIELD: medicine, stomatology.

SUBSTANCE: invention relates to a gel composition used in treatment of stomatological diseases. The composition comprises an active component represented by diclofenac and chlorhexidine gluconate, mucoadhesive reagent, gel-forming agent and a pharmaceutically acceptable excipient wherein components are taken in the definite ratio. The composition is prepared by dissolving diclofenac in propylene glycol followed by addition of carboxyvinyl polymer and copolymer of methylvinyl ester with maleic anhydride and the following addition of prepared solution to a separately prepared system of solvents at continuous stirring, the following addition to the prepared gel of EDTA disodium salt aqueous solution, saccharin sodium salt and chlorhexidine gluconate up to the complete dissolution. Prepared composition provides retaining a medicinal preparation on the damaged site for the more long time and provides local delivery of the preparation for therapeutic effect.

EFFECT: improved preparing method, valuable medicinal properties of gel composition.

21 cl, 3 tbl, 3 ex

FIELD: medicine, stomatology.

SUBSTANCE: invention relates to a gel composition used in treatment of stomatological diseases. The composition comprises an active component represented by diclofenac and chlorhexidine gluconate, mucoadhesive reagent, gel-forming agent and a pharmaceutically acceptable excipient wherein components are taken in the definite ratio. The composition is prepared by dissolving diclofenac in propylene glycol followed by addition of carboxyvinyl polymer and copolymer of methylvinyl ester with maleic anhydride and the following addition of prepared solution to a separately prepared system of solvents at continuous stirring, the following addition to the prepared gel of EDTA disodium salt aqueous solution, saccharin sodium salt and chlorhexidine gluconate up to the complete dissolution. Prepared composition provides retaining a medicinal preparation on the damaged site for the more long time and provides local delivery of the preparation for therapeutic effect.

EFFECT: improved preparing method, valuable medicinal properties of gel composition.

21 cl, 3 tbl, 3 ex

FIELD: pharmaceutical industry and technology, pharmacy.

SUBSTANCE: invention relates to the improved method for preparing dihydroquercitin. Invention involves preliminary separation of volatile nonpolar compounds with steam at rapid change of pressure from 0.1 to 0.3 MPa in reactor carried out before extraction stage and with reduced time of raw extraction being without milling wood under conditions of mild mechanical-chemical effect and without destruction of wood occurring in rapid change of pressure from 0.1 to 0.5 MPa using mixture of polar solvent with water or their mixtures as an extractant. Invention reduces extraction time in intensifying and optimization of the process of dihydroquercitin that provides reducing total time of process from 60-75 min to 7-9 min and to simplify technology in carrying out the process without milling wood.

EFFECT: improved method for preparing.

5 ex

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