The way to obtain the thick extract of propolis and the drug based on it

 

(57) Abstract:

The invention relates to medicine, in particular the production of medicinal substances from the funds of plant origin. The way to obtain the thick extract of propolis is that propolis raw crushed, extracted with 96% ethanol and filtered, and the extraction is carried out at the boiling temperature of ethanol, and the extract obtained is cooled to a temperature of 60°C and filtered, then cooled to a temperature of -8 to -12°C, filtered at this temperature, the alcohol is distilled off under vacuum at 78°C to obtain propolis extract with alcohol content not more than 25%. The invention is also a pharmaceutical preparation containing the active substance and pharmaceutical base, which contains as active substance a thick propolis extract obtained by the claimed method. Effect: method allows to completely separate from propolis raw whole range of extractives, while simplifying the technological process, as well as to remove from the propolis extract all soluble and spironalactone waxes and thus get the propolis extract with improved technological properties, abused and antibacterial effect. 2 N. and 9 C.p. f-crystals, 5 PL.

The invention relates to medicine, in particular the production of medicinal substances from the funds of plant origin.

A method of obtaining liquid propolis extract, which consists in the fact that propolis raw fill in 96% ethyl alcohol, insist for three days, stirring occasionally, then put in the cold at a temperature of from 0 to -5°C, stand two hours, then filtered through filter paper (KN. "Propolis", ed. IV, Bucharest: in this respect, Apimondia, 1988, pp. 192-194).

The known method of extraction is not possible to distinguish from propolis raw whole range contained biologically active substances, in addition, it is not possible to completely clean the extract from the dissolved resins and waxes found in the extract. In this regard, the liquid extract is insufficiently active, and due to the presence of resins and wax poorly miscible with the basics and unevenly distributed them in the production of such dosage forms, such as ointments and suppositories.

A method of obtaining the drug from propolis by extraction of propolis absolute Dimexidum at a temperature of 60-70°and With vigorous stirring. Then the extract is settled and filtered pravednyh forms (RF patent No. 2083216).

The known method does not sufficiently allow for the extract from propolis main active ingredients are flavonoids, which are maximally extracted only 96% ethyl alcohol. In addition, the filtrate remain dissolved waxes, which, basically, ballast in the form of drug that interfere with uniform distribution of active ingredients in medicinal form.

Known way to obtain the thick extract of propolis by processing propolis raw 96% ethanol at a temperature of 40°C under reduced pressure, followed by filtration and evaporation. The result is a dense extract of propolis, which is used to obtain the dosage forms (RF patent No. 2073519).

In a known way from the extract is not fully extracted dissolved waxes, which further complicates the process of obtaining medical forms and, in addition, reduces the activity of the extract. The presence in the extract of waxy components complicates the uniform distribution of the extract and degrades the quality of the dosage forms may also complicate the process. In addition, wax-like components are the ballast and red eye reduction is the first way to obtain the thick extract of propolis, which would be completely isolated from propolis raw whole range of extractives, while simplifying the extraction process, and also to remove from the propolis extract all low-melting and high-melting waxes, thus to improve the quality of the final product, to obtain an extract of propolis with improved technological properties, more plastic, with a high content of extractives, with no mechanical impurities, which has anti-inflammatory, wound healing and antibacterial properties, as well as the development of drugs based on it.

The problem is solved by the fact that in a method of producing a thick extract, which consists in the fact that propolis raw crushed, extracted with 96% ethanol and filtered, according to the invention the extraction is carried out at the boiling temperature of the alcohol, and then the extract is cooled to a temperature of -8 to -12°C, and then filtered at a temperature of -8 to -12°C.

The obtained dense extract of propolis has anti-inflammatory, wound healing and antibacterial action.

The invention is also a pharmaceutical preparation consisting of a thick extract of propolis and pharmaceutically acceptable OS which are present in the following ratio (wt.%):

Dense extract of propolis 1-10

Pharmaceutically acceptable base the Rest

The drug according to the invention may contain as pharmaceutically acceptable bases of a mixture of glycerine and Na-carboxymethylcellulose (Na-CMC) in the ratio 2:3.

The drug according to the invention may contain as pharmaceutically acceptable bases of a mixture of glycerine and Na-alginate in a ratio of 2:3.

The drug according to the invention may contain as pharmaceutically acceptable bases of a mixture of witepsol and distilled monoglycerides (MHD) in the ratio of 1:19.

The drug according to the invention may contain as pharmaceutically acceptable bases of the mixture of emulsifier No. 1 and witepsol in the ratio of 1:9.

The drug according to the invention may contain as pharmaceutically acceptable bases of a mixture of polyethylene glycol 400 (PEG 400 and PEG 1500 in the ratio of 1:9.

The drug according to the invention may contain as pharmaceutically acceptable bases of the mixture is apart according to the invention may contain as pharmaceutically acceptable bases of a mixture of MHD and TKJ in the ratio of 1:19.

The drug according to the invention may contain as pharmaceutically acceptable bases of the mixture of emulsifier No. 2, paraffin and TKJ in the ratio of 1:2:17.

The drug according to the invention may contain as pharmaceutically acceptable bases of the mixture of emulsifier (distilled monoglycerides, T-2) and vaseline in the ratio of 1:16.

In the present method extract of propolis dense extraction process occurs at the boiling temperature of the alcohol, which makes it possible to select all extractive substances from propolis raw and, in addition, to exclude the elements of constructive mechanical mixing, since the mixing of the extract is due to the boiling point of the alcohol. At a temperature of -8 to -12°there is a complete separation of the extract of waxy components. The extract obtained after cold filtering is completely free of wax-like components. Therefore when creating dosage forms is a more uniform distribution of the extract on volume basis.

The extract obtained contains the maximum amount of extractives, which leads to increase karianna activity of propolis extract thick, as well as its high technological quality allow you to create medicines of high quality with a uniform distribution of the active substance in the dosage form with a high therapeutic activity. A large temperature difference of the boiling point (78°C) to a temperature of -8 - -12°With the high quality of the final product, its great plasticity, elasticity and uniformity, making a thick propolis extract more technological in the production of dosage forms. High elasticity and plasticity thick extract of propolis allows you to get the dosage form of high quality with a uniform distribution of the active substance in the basis.

The invention is illustrated by the following examples.

Example 1.

Pre-cooled and crushed to particle size of 1-3 mm weight propolis raw in the amount of 500 g is placed in the extractor. There also fill in 96% ethyl alcohol in a quantity of 2500 ml of the extraction Process is carried out at a temperature of 78°C (boiling point of ethanol), which excludes the additional mixing process, since the mixing occurs by boiling alcohol. The time of extraction costs is aema temperature extraction can reduce the extraction time while obtaining the maximum extraction of the extractive substances.

Hot filtered through filter cloth. The filtering 15 minutes. When hot filter is cleaned extract from mechanical impurities.

Thus obtained extract, not containing mechanical impurities, but containing significant amounts of dissolved wax, placed in the freezer and maintained at a temperature of -8C, while the wax precipitates. The cooled extract is fed to the cold filtering. Filter under low vacuum takes place in two stages. Thus obtained thick extract of propolis contains no solids, no beeswax.

To obtain the thick extract separate part extractive solvent (ethyl alcohol). This process occurs in the evaporation apparatus. The Stripping process is carried out at a temperature of 78°C under slight vacuum to obtain the extract with alcohol content not more than 25%.

The yield of the final product 312 ml, which is 62%. The dry residue 72,3%, no mechanical impurities, wax-like substances are absent.

Example 2.

The extraction was carried out analogously to example 1. The temperature of the cooling of the extract to -12&#ye matter is absent.

Example 3.

The extraction was carried out analogously to example 1. The temperature of the cooling of the extract to -10°C.

The yield of the final product 62%. The dry residue from 71.3%, no mechanical impurities, wax-like substances are absent.

Example 4.

The extraction was carried out analogously to example 1. The extractor download 500 g of propolis raw and 5000 ml of ethyl alcohol 96%.

The yield of the final product 64%. The dry residue 72,0%, no mechanical impurities, wax-like substances are absent.

Example 5.

The extraction was carried out analogously to example 2. The extractor download 500 g of propolis raw and 5000 ml of alcohol.

The yield of the final product 65%. The dry residue of 70.8%, no mechanical impurities, wax-like substances are absent.

Example 6.

The extraction was carried out analogously to example 3. The extractor download 500 g of propolis raw and 5000 ml of alcohol.

The yield of the final product 65,5%. The dry residue 71,9%, no mechanical impurities, wax-like substances are absent.

The results of the comparison of the quality of propolis extract thick (PGE) obtained by the present technology.

Higher dry matter content in the inventive PGE (in the complete absence of waxy components) shows a higher content of extractives than in the well-known extract, which naturally increases the pharmacological activity of the extract.

The claimed medicinal preparation contains the active substance in the amount of 1-10 wt.% any suitable pharmaceutical basis.

The choice of the concentration of the active substance due to the fact that in the specified concentration range shows high anti-inflammatory, wound healing and antibacterial effect in the absence of side effects.

The claimed medicinal preparation may be in the form of films. When choosing the basis for the film was used, the optimum composition of the film matrix in the following ratio, wt.%:

Given the sharply hydrophobic extract thick and the resulting technological complexity, we investigated the rational conditions of its introduction in the hydrophilic base. Experimentally it was found that regardless of the composition of the matrix (1 and 2), the optimal is the introduction of a thick extract propol is of the claimed medicinal product - the film was studied by the method of disks in the ratio 4 pharmacopoeial strains of test organisms. The study was performed with two films with different content of thick extract of propolis in the 1 and 10%. The results are presented in table 2.

The results showed the presence of strong bactericidal action of the claimed preparation in the form of a film with respect to all investigated strains of microorganisms.

Characterization of anti-inflammatory action of the claimed preparation in the form of a film.

In the experiment in vivo 90 white mongrel rats the study of anti-inflammatory action films on carragenine model exudative aseptic inflammation caused subplanetary the introduction of 0.1 ml of 1% solution carragenin. The film was applied on the surface of the rear extremity of the experimental group, the control group used the film to placebo. Immediately after the introduction carragenine and at 30, 60 minutes prior to its introduction ecometrics measured the growth of the limbs in relation to the original value. The results of the study indicate the presence of the anti-inflammatory action films, it is more pronounced when applied films 60 protivovospalitelnoe action films was studied in the clinic for the treatment of chronic catarrhal gingivitis, generalized periodontitis, erosive-ulcerous form of the red flat lichen (KPL).

In the treatment of periodontal gingivitis film was applied on mucous membranes of the gums, while patients reported comfort, pleasant taste, good adhesion.

Films were used for prolonging the local application of treatment fluids, anti-inflammatory, antiseptic action main (47 children) and control (24) groups. 23 patients of the main group of films were used during the first year, 14 patients in the intervals between the first and second courses, 22 - during the second year, 10 - between the second and third courses. In the control group the distribution was as follows (similar): 12, 5, 22, 14. The effectiveness of therapy films was estimated by the value of index PMA, Fedorova-Volodkina, green-Vermilion.

Compared with children who had conducted local treatment applications solutions, 71 patient after applying films of the proposed structure hygienic indexes already normalized to 4-6 days of treatment in the control group respectively to 10-15 days.

Film of the claimed composition used in the complex treatment of chronic Catral tcov aged 10 to 16 years (boys 12, girls 20).

Before treatment all patients were examined clinically, laboratory, x-ray. The clinical examination was taken into account complaints, medical history, genetic predisposition, unhealthy habits, General somatic pathology, concomitant diseases of the maxillofacial area. During the examination of periodontal tissues to determine the level of hygiene of the oral cavity using index green-Vermilion, Fedorova-Volodkina. The hygienic condition of the mouth was unsatisfactory in all children and adolescents. Index green-Vermilion ranged from 1.2 to 2.8 (normal 0-0,5). Index Fedorov-Volodkina was 2.0 to 3.8 (normal 1.0 to 1.5). Determined the severity of the process, using the index of the RMA. Its fluctuations ranged from 15 to 61%. Investigated the existence and nature of periodontal pockets, examining them using a graduated probe.

Given that the index system for assessing the severity of the inflammatory process is based on visual perception of the physician, i.e., can be subjective to diagnose applied the method of reproduktory (RPG). Analysis RPG was performed using kontulainen vascular tone and the periodic index resistance increased and reached respectively 19 and 87.5%.

Since the early loss of mineral salts from bone tissue of the alveolar process is detected using conventional radiography, performed reference radiography with subsequent micrograph of x-ray images. The detected decrease in the amount of hydroxyapatite in the alveolar ridge in children with chronic catarrhal gingivitis, up to 0,89 mg/mm3(in the norm of 1.15 mg/mm3).

The shelf life of films 2 years at a temperature of 20°C in the standard package.

Clinical and laboratory studies confirmed the specific antimicrobial and anti-inflammatory activity in the treatment of chronic catarrhal gingivitis, generalized periodontitis, erosive-ulcerous form of the red flat lichen.

The claimed medicinal preparation may be in the form of suppositories, which may include the components shown in table 3.

Propolis extract thick dissolved in 10 ml of 96% ethyl alcohol and gently dropwise with constant stirring, add 5 ml of purified water. When using such a reception is obtained thin fine combined system, which evenly speedwireless the results of quantitative determination of polyphenolic compounds.

In a water bath alloys weighed quantity of the components of the framework and emuleret approximately half of the mass of the dissolved extract the number of bases, then add the remaining basis, thoroughly mixed and poured into the nest suppozitornoj forms greased with alcohol soap (for hydrophobic bases) or vaseline oil (for hydrophilic bases). After cooling, the tubes are removed from the mold, wrap and decorate.

Suppositories with PGE are light yellow, torpedo-shaped form, the characteristic smell of propolis.

Study the degree of liberation of the amount of biologically active substances from the suppositories were evaluated by the method based on the diffusion of phenolic compounds in vivo in agar gel, with the formation of the colored zone in the result of the interaction of phenolic compounds of propolis with a 1% solution of chloride ferric iron.

Anti-inflammatory, wound healing and antibacterial effectiveness of the proposed suppositories investigated on the model of artificial proctitis. The study was performed with the suppositories, the composition of the basics presented in table 3, with dense content of propolis extract in the composition of 1 and 10 wt.%.

has been created). The control group was given a placebo. Evaluation of the effectiveness of treatment by suppositories were carried out in dynamics (to inflammation, three days after the introduction of logogen, at the end of treatment, 20 days) on the General status of the animals, peripheral blood, healing of the mucosa and correction of violations used (a study in the dynamics of the microflora of the rectum).

Visual inspection of the rectum showed a significant improvement of the mucosa (the absence of serous discharge, hyperemia, the severity of the vascular mesh).

Assessment of the microbial ecology of the intestine was performed by the classical method. Three days after the introduction of logogen estimated species composition of microorganisms. During the examination of smears under a microscope and found that the faeces were present additional microflora: fungi of the genus Candida, Staphylococcus aureus, Escherichia coli, bacteria of the genus Proteus, and was absent bifidobacteria and lactobacilli, lactic acid streptococci, enterococci and bacteroids, which indicates the presence of strong inflammatory process.

After the treatment pattern of microbial colonization has changed: a small number of bifido - and lactab the animal's at the end of the course of treatment.

The experimental data confirmed the anti-inflammatory effect of the suppositories of the proposed structure. A comparison of the proposed suppositories used in proctology and gynecology drugs (rosehip oil, suppositories with sea-buckthorn oil) shows superior anti-inflammatory and antimicrobial properties of the proposed drug. Healing caused by experimental proctitis in the treatment claimed by suppositories is celebrated on the 10th day, wild rose oil is on the 14th, suppositories with sea-buckthorn oil - 16-E. the Advantage of the proposed suppositories is also the fact that they contribute to the restoration normoflora intestines, as they have selective bactericidal effect and does not inhibit the growth of Escherichia coli.

Anti-inflammatory suppositories with PGE investigated as follows.

The analyzed composition was applied to the hind paw of the rat for 1 h prior to the introduction of carragenin, before the introduction and after 1 h, 3 h, 5 h after administration at a dose of 0.2 g Data anti-inflammatory activity are shown in table 4.

The results of the study indicate that the claimed suppositories are protevtive differences in the weights of the brain, heart, liver, thymus, spleen, kidneys, adrenal glands of animals from the control and experimental groups; the lack of effect on the Central nervous system of rats in the test "open field"; did not have a significant impact on leucopoiesis; on the liver cells, as evidenced by the absence of any significant changes in the activity of aminotransferases Alp and other biochemical parameters; on the pancreas (the absence of significant differences in the activity of amylase serum); on the functional state of the kidneys, cellularity and viability of the thymus and spleen (no immunotoxic action). Suppositories with PGE did not cause the reaction of hypersensitivity of the delayed type.

The use of suppositories is accomplished by injecting into the rectum or vagina after carrying out hygienic measures. Preliminary studies suppositories with PGE on volunteers from among the patients of the city and region in the treatment of proctologic (hemorrhoids, paraproctitis, cracks anal canal and others) and gynecological diseases (atrophic colpitis, violation of the integrity of the epithelium, hypoestrogyny any Genesis) resistance is stvennoi form.

In the Perm oblast clinical hospital outpatient during the examination of 23 patients aged from 21 to 32 years with complaints of vaginal discharge method extended colposcopy revealed cervicitis in all patients, ectopia - 6 (26.1 per cent), leukoplakia - 11 (47.8 percent). Therapy of these diseases has not previously been conducted. Were used for treatment claimed suppositories with PGE once a day for 10 days. The criteria for assessing the effectiveness of therapy was a change in subjective feelings and condition of the mucous membrane in the expanded colposcopy. Upon completion of the course, all patients indicated a decrease in vaginal discharge and itching. Regression of the pathological lesions observed in 8 (34.8 per cent) women, full cure in 12 (52.2 per cent). Therapy was ineffective in 3 cases (13%). No side effects were noted.

Thus, the obtained data testify to the effectiveness of conservative treatment of benign diseases of the cervix using the proposed suppositories with PGE. Under these conditions the drug can also be used to pre-training.

The drug may be in the form of ointment.

Give 80,0 g vaseline, 5.0 g of amalgam is stricta propolis thick.

Propolis extract thick dissolved in 96% ethyl alcohol and gently dropwise with constant stirring add purified water. When using such a reception is obtained thin fine combined system, which is uniformly mixed with the ointment base, precipitation does not occur, and active substances PGE almost not lost, as evidenced by the results of quantitative determination of polyphenolic compounds. In a water bath melt weighed quantity of the components of the framework and emuleret approximately half of the mass of the dissolved extract the number of bases, then add the remaining basis, thoroughly stirred using a mechanical stirrer until completely cooled, placed in a container.

The study was carried ointment with dense content of propolis extract in the composition of 1 and 10 wt.%.

Anti-inflammatory activity of the claimed ointment investigated as follows.

The study ointment was applied to the hind paw of the rat for 1 h prior to the introduction of carragenin, before the introduction and after 1 h, 3 h, 5 h after administration at a dose of 0.2 g Data anti-inflammatory activity are given in table 5.

1. The way to obtain the thick extract of propolis, which consists in the fact that propolis raw crushed, extracted with 96% ethanol and filtered, characterized in that the extraction is carried out at the boiling temperature of ethyl alcohol, and then the extract is cooled to a temperature of 60°C and filtration is carried out at a temperature of 60°C, then the extract is cooled to a temperature of from(-8)-(-12)°With and filtered at a temperature of(-8)-(-12)°With, then the alcohol is distilled off under vacuum at a temperature of 78°C to obtain the thick extract of propolis with alcohol content not more than 25%.

2. Medicinal preparation consisting of a thick extract of propolis and pharmaceutically acceptable bases, characterized in that a thick propolis extract obtained by the method according to p. 1, and the components are present in the following ratio, wt.%:

Dense extract of propolis 1-10

Pharmaceutically acceptable base the Rest

3. Drug under item 2, characterized in that it contains as the pharmaceutical basis of a mixture of glycerine and Na-carboxymethyl cellulose in the ratio 2:3.

4. Drug under item 2, characterized in that it contains as farmaceuticas under item 2, characterized in that it contains as the pharmaceutical basis of a mixture of witepsol and distilled monoglycerides in the ratio of 1:19.

6. Drug under item 2, characterized in that it contains as the pharmaceutical basis of the mixture of emulsifier No. 1 and witepsol in the ratio of 1:9.

7. Drug under item 2, characterized in that it contains as the pharmaceutical basis of a mixture of polyethylene glycol 400 and polyethylene glycol 1500 in the ratio of 1:9.

8. Drug under item 2, characterized in that it contains as the pharmaceutical basis of the mixture of emulsifier 1 and solid cooking fat in a ratio of 1:9.

9. Drug under item 2, characterized in that it contains as the pharmaceutical basis of a mixture of distilled monoglycerides and solid cooking fat in a ratio of 1:19.

10. Drug under item 2, characterized in that it contains as the pharmaceutical basis of the mixture of emulsifier No. 2, paraffin and solid cooking fat in a ratio of 1:2:17.

11. Drug under item 2, characterized in that the sod is

 

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