RU2444368C1 - Elton mud suppositories for gynaecological and urological diseases - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely a dosage form presented as suppositories for gynaecological and urological diseases. The suppositories for gynaecological and urological diseases contain a lipid complex of Elton lake mud dehydrated to 20-35%, PEG-1500 base, a preparation of Tykveol and T2 emulsifier in certain proportions, wt %.

EFFECT: suppositories present vaginal and rectal suppositories providing microbiological purity with no side and allergic reactions.

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Description

The invention relates to medicine, namely to dosage forms in the form of suppositories for the treatment of gynecological and urological diseases.

Reproductive health of the population is an important aspect of the country's well-being, and in connection with its deterioration, the development of new drugs is relevant. In the structure of gynecological and urological nosologies, inflammatory diseases of the genital organs take first place.

The undoubted advantage of natural ingredients over synthetic ones is a wide range of biological activity manifested along with the absence of toxicity.

Recently, rectal dosage forms in the form of suppositories are becoming increasingly popular. This is due to the fact that in treatment and rehabilitation measures for patients with urological and gynecological diseases, an important role is given to local treatment, because This dosage form provides the targeted action of a complex of biologically active substances.

The prior art composition of suppositories with natural producers in the following ratio of components, wt.%: Propolis extract 2.9-3.1, bee honey 2.9-3.1 or buckwheat honey 3.0, emulsifier T2 9.9- 10.1, cocoa butter enriched with lipids to a carotenoid content of not less than 1.0 mg% or Tambukan therapeutic mud lipids to a carotenoid content of not less than 1.0 mg% - the rest (RF Patent No. 2142789, published on December 20, 1999 BI No. 35). The composition has anti-inflammatory and antibacterial activity, provides rapid melting of the candles in the human cavity and the resistance of the candles to melting at room temperature. However, the inclusion of beekeeping products limits the number of patients in view of their possible intolerance.

Known suppositories for the treatment of chronic prostatitis, containing cocoa butter as a base and a medicinal substance, as a medicinal substance they contain a 1% aqueous solution of humic acids of low mineralized silt sulphide mud (pH 7.4) in the following ratio of components: 1% aqueous solution of humic acids (pH 7.4) 0.2 ml; cocoa butter - a sufficient amount to obtain suppositories weighing 2.0-2.2 g (RF Patent No. 2241471, publ. 10.12.2004, BI No. 34).

These suppositories have anti-inflammatory effects, but the low level of mineralization of silt sulfide mud does not have an effective therapeutic effect compared to highly mineralized mud of Lake Elton.

Known suppositories based on natural producers for the treatment of gynecological and urological diseases, containing the following ratio of components, wt.%: Stearic acid 15-20, mud of the Dead Sea 50-70, emulsifier 1-4, polyethylene oxide 1500 and 400 - the rest (RF Patent No. 2363446, published on 08/10/2009, BI No. 22).

Suppositories have anti-inflammatory, antibacterial and regenerative activity, but since sterilization is not provided for their manufacture, the microbiological purity requirements for vaginal suppositories have not been met accordingly.

Suppositories with natural producers on a hydrophilic-lipophilic basis were selected as the prototype, the composition of which was added mud from Lake Elton with lipids of plant origin of the following composition, wt.%: Hydrophilic base 71-74, mud from Lake Elton 24-26, lipids of plant origin 2- 3, as a lipid of plant origin use oil from melon seeds (Application for invention No. 2009114274, publ. 20.10.2010).

These suppositories are anti-inflammatory, immunomodulatory, improve cellular metabolism, but are limited in use in gynecology due to non-compliance with the requirements of microbiological purity when performing vaginal suppositories, the characterization of the dosage form is not plastic enough.

The problem solved by the invention is the creation of a dosage form for the treatment of urogenital diseases, which has improved therapeutic properties, improved characteristics of the dosage form, microbiological purity, low toxicity, good penetrating ability, and availability for use by the patient on his own.

The technical result from the use of the invention is to improve the therapeutic activity of the claimed dosage form for the treatment of urogenital diseases by enhancing anti-inflammatory, antibacterial and regenerating properties, the effectiveness of which increases from the combination of lipid complexes of Elton mud and Tykveol drug; improving the characteristics of the dosage form due to conditioning, dehydration of mud from Lake Elton and the introduction of T2 emulsifier; ensuring the microbiological purity of the drug by fulfilling the requirements of the State Pharmacopoeia XII (GF XII); low toxicity due to the introduction of atoxic components; good penetrating ability and the possibility of administering the drug by the patient independently due to the implementation of the dosage form in the form of suppositories.

The specified technical result according to the first embodiment is achieved by the fact that the dosage form for the treatment of gynecological and urological diseases in the form of a suppository contains mud from Lake Elton and a base - PEG-1500, in which the drug Tykveol was added to enhance therapeutic activity; as mud, use conditioned, dehydrated to 20-35% and containing the lipid complex of mud from Lake Elton; emulsifier T2 in the following components in wt.%:

Mud Lake Elton 24-26 Tykveol 2-3 PEG-1500 70-74 Emulsifier T2 0.5-1.5

The specified technical result according to the second embodiment is achieved in that the dosage form of the suppository is a vaginal suppository.

The specified technical result according to the third embodiment is achieved in that the dosage form of the suppository is a rectal suppository.

The difference of the claimed invention is the use of mud, conditioned, dehydrated to 20-35% and containing a complex of lipids, of mud Lake Elton, which in combination with the drug Tykveol forms a new dosage form with improved therapeutic activity for the treatment of gynecological and urological diseases, the effectiveness of which increases from aggregates of lipid complexes of Elton mud and Tykveol drug. All components are atoxic. Compliance with the requirements of the State Pharmacopoeia XII (GF XII) in the manufacture of vaginal and rectal suppositories ensures microbiological purity. The implementation of the dosage form in the form of suppositories provides good penetration and the ability to administer the drug to the patient on their own.

As a raw material for creating suppositories, silt highly mineralized, highly sulfide, salt-saturated mud from Lake Elton was used. The mud is conditioned, i.e. cleaned, thoroughly mixed to a homogeneous mass and dehydrated by arbitrary draining. It is this method of dehydration that allows you to save biologically active substances, sulfides and water-soluble salts, which are responsible for the healing properties of dirt.

The water content in the used mud should be in the range of 20-35%. An increase in water to more than 35% worsens the structure of the resulting suppositories. When the water content in the mud is less than 20%, the structure of the mud changes in the direction of its compaction, which negatively affects the uniform distribution of the mud when it is introduced into the suppository mass and the characteristics of the dosage form.

To create the claimed dosage form, the most lipid-rich part of the mud is used, which is characterized by a significant variety of biologically active substances that have anti-inflammatory and regenerative effects. The content of trace elements (bromine, boric acid, zinc) characterizes the dirt as antibacterial. Selective extraction is applied from areas and layers of the deposit that have the maximum mud indicators for the content of the lipid complex, the content of sulfides and water-soluble salts.

Table 1 shows the results of mud samples from Lake Elton for the content of lipid fatty acid composition. Samples were studied on a Kristallux-4000M chromatograph.

Table 1 Component PUFA index,% Oil 2.69 Kapron 1.09 Palmitic 2.24 Oleic 3.75 Linoleic 7.11 Gondoin 2.21 Geneikosanova 10.17 Cis-11,14,17-eicosatriene 14.00 Erukova 8.96 Arachidonic 15.86 Tricosan 4.14 Cis-13.16-docosadiene 2.92 Lignoceric 8.04 Nerve 12.83 Other components 3.99 TOTAL 100.00

The medicinal product Tykveol, introduced into the composition of the suppository mass, is a pumpkin seed oil obtained by cold pressing (RF Patent No. 2104028, publ. 02.10.1998). It is a battery of biologically active substances. Found its application, in particular, in gynecology (for the treatment of colpitis, cervical erosion) and urology (prostatic hyperplasia), which is proved by preclinical and clinical trials that were conducted at the Research Institute of Urology of the Ministry of Health of the Russian Federation, as well as at the Department of Obstetrics and Gynecology No. 1 KSMA, in the gynecological department RKB-3.

Tykveol has the following physicochemical parameters: it is easily soluble in chloroform, hexane and diethyl ether, the density is from 0.88 to 0.94, the acid number is not more than 1.25, the iodine number is from 100 to 140, the oxidation index is not more than 4, heavy metals - 0.001%, the content of the sum of carotenoids - not less than 6 mg% and α-tocopherol - not less than 4 mg%.

In addition, the complex of biologically active substances of Tykveol is composed of phospholipids, sterols, phosphatides, flavonoids, vitamins B1, B2, C, P, PP, F, saturated, monounsaturated and polyunsaturated fatty acids (palmitic, stearic, oleic, linoleic, linolenic, arachic) . Unlike the prototype, where melon seed oil is used, in particular pumpkin seed oil, Tykveol is pumpkin seed oil purified from ballast (inert) substances, which improves its therapeutic activity and speaks of its priority in quality and medicinal properties compared to the prototype. Tykveol is a drug. It has broad indications for use, in particular, in gynecologists and urology.

The total combination of pharmacological properties of biologically active substances in Tykveol determines its anti-inflammatory and regenerative effect. Tykveol has a direct effect on the structure of epithelial tissues, providing differentiation and physiological function of the epithelium, reduces edema and improves microcirculation in the stages of trophic disorders, stimulates metabolic processes in tissues, reduces the severity of inflammatory processes and has a bacteriostatic effect. Atoxic

The selected proportion of the drug Tykveol enhances the healing properties of Elton mud with its therapeutic properties. The healing properties of Tykveol are manifested in doses of 2-5%. A dosage of less than 2% and more than 3% affects the physical properties of the dosage form. Therefore, the dosage of Tykveol is taken in boundary doses of 2-3% of the content of the components.

The mud lipid complex of Lake Elton complements the complex of plant lipids of the Tykveol drug, which enhances and improves the therapeutic activity of the claimed dosage form, expressed in anti-inflammatory, antibacterial and regenerative effects.

The choice of PEG-1500 polyethylene glycol as the hydrophilic base for the preparation of suppositories was dictated by the fact that the hydrophilic bases are compatible with a large group of active substances and do not interfere with their absorption. Found that the polyethylene glycol base enhances the action of active active substances. Polyethylene glycol bases are resistant during storage, do not undergo contamination, release medicinal substances well, withstand sterilization, and have an optimal combination of physicochemical and structural-mechanical properties. The amount of PEG-1500, taken less than 70%, makes the structure of the suppository mass soft, and more than 74% - hard and increases the dissolution time of the suppository in the human cavity. Therefore, the borderline doses of PEG-1500 are taken in the range of 70-74%.

Emulsifier T2 provides the ability to obtain a high quality dosage form. The use of T2 emulsifier makes it possible to more easily achieve a uniform distribution of medicinal substances in molten suppository bases; to reduce the fragility of such bases, has a pronounced effect on such important characteristics of dosage forms as the release rate of active ingredients, the absorption rate of drugs. The border doses of 0.5-1.5% are sufficient to ensure a high quality dosage form.

Depending on the field of use according to the invention, suppositories can be made in the form of

- vaginal suppositories (Suppositoria vaginalia) (option 2), which are made in accordance with the requirements of microbiological purity of the State Pharmacopoeia XII (GF XII), according to which the total number of aerobic bacteria and fungi (total) is not more than 10 ² in 1 g or 1 ml ; no more than 10 ¹ enterobacteria and other gram-negative bacteria in 1 g or in 1 ml of other drugs;

- rectal suppositories (Suppositoria rectalia) (option 3), which are made in accordance with the requirements of microbiological purity of the State Pharmacopoeia XII (GL XII), according to which the total number of aerobic bacteria is not more than 10 ³ per 1 g or 1 ml; the total number of mushrooms is not more than 10 ² in 1 g or in 1 ml; the absence of Escherichia coli in 1 g or 1 ml.

Selected quantitative proportions of all components provide a melting point of suppositories below + 37 ° C, and preservation of their shape in the solid state is provided at a temperature of + 25 ° C, which is enough to store suppositories.

Thus, the introduction into the proposed dosage form of all components simultaneously in the stated quantitative proportions allows to obtain a dosage form with improved therapeutic activity for the treatment of gynecological and urological diseases by enhancing anti-inflammatory, antibacterial and regenerative properties, the effectiveness of which increases from the combination of lipid complexes of Elton mud and drug Tykveol drug; improved characteristics of the dosage form due to conditioning, dehydration of mud from Lake Elton up to 20-35% and the introduction of T2 emulsifier; ensuring the microbiological purity of the drug by fulfilling the requirements of the State Pharmacopoeia XII (GF XII); low toxicity due to the introduction of atoxic components; good penetrating ability and the possibility of administering the drug by the patient independently due to the implementation of the dosage form in the form of suppositories.

The high therapeutic activity of the claimed dosage form is due to a significant variety of biologically active substances that are part of the lipid complexes of the mud of Lake Elton and the drug Tykveol, which provide the necessary therapeutic effects.

The invention is as follows:

- preparation of raw materials;

- receiving suppository mass;

- filling containers with suppository mass;

- labeling and packaging.

An example of a specific implementation of vaginal suppositories.

The mud of Lake Elton is conditioned by purification and mixing to a homogeneous mass, followed by dehydration to 20-35% by arbitrary draining. Before introducing the components into the steam sterilizer VK 75, it is heated to a temperature of 120 ° C at a pressure of 0.11 MPa (1.1 kgf / cm ² ). The prepared components are loaded into a steam sterilizer BK 75 and sterilized at 120 ° C for 45 minutes, thereby achieving the necessary pharmacopoeial level of microbiological purity applied to vaginal suppositories. Then the sterilized components, PEG-1500, Tykveol preparation and T2 emulsifier, are placed in the hopper, where they are thoroughly mixed, and sterilized mud of Lake Elton is added in small doses. Mix the resulting suppository mass to a homogeneous mass without air bubbles. In the process of mixing, the suppository mass is cooled to a temperature of 45-50 ° C, which is optimal for the suppository mass, since at this temperature the suppository mass remains homogeneous, viscous, fluid during filling, helps to obtain suppositories of a given geometric shape, uniformity and prevents deformation of the packaging plate . The result is suppositories containing the contents of the components according to the invention. The mass of one suppository is 2.5 g.

An example of the implementation of rectal suppositories differs from the execution of vaginal suppositories in that the components are not sterilized, but melted at a temperature of 70-80 ° C and a pressure of 0.11 mPa for 45 min, which achieves the necessary pharmacopoeial level of microbiological purity applied to rectal suppositories. The result is suppositories containing the contents of the components according to the invention. The mass of one suppository is 2.5 g.

The resulting suppositories are packaged in 5 pcs. in plates and 2 plates in a pencil case. Store ready-made packages with suppositories in a dry place, protected from light, at a temperature not exceeding + 5 ° С.

From table 2 it can be seen that at an optimal process temperature of 120 ° C and a pressure of 0.11 MPa (1.1 kgf / cm ² ), the required level of microbiological purity for vaginal suppositories is achieved within 45 minutes, and at a temperature of 70-80 ° C and a pressure of 0.11 MPa (1.1 kgf / cm ² ) within 45 minutes, the necessary level of microbiological purity for rectal suppositories is achieved.

The results of a sanitary-biological study of suppositories

table 2 Indicators Recommended Requirements *
in 1 g Sample Content Vaginal suppositories The total number of aerobic bacteria and fungi ≤1 × 10 ² 5 × 10 ¹ Enterobacteria and others
gram negative bacteria ≤1 × l0 ¹ less than l × l0 ¹ Pseudomonas aeruginosa lack of lack of Staphylococcus aureus lack of lack of Rectal suppositories The total number of aerobic bacteria and fungi ≤1 × 10 ³ 5 × 10 ² Total number of mushrooms ≤1 × 10 ² less than l × l0 ¹ Escherichia coli lack of lack of * according to GF XII, issue 1, p. 160, category 2 and 3

The results of the analysis of the physicochemical properties of suppositories with mud from Lake Elton are shown in Table 3.

Physico-chemical properties of suppositories with mud from Lake Elton

Table 3 Indicators ND requirements Test results pr.1 pr.2 pr 3 one 2 3 four 5 Average weight g 2.5 ± 0.125 2,55 2,53 2,56 Presence Confirmed by Confirmed by Confirmed by Authenticity hydrogen sulfide (qual. r) Solution Time No more than 60 29th thirty 29th ny, min Medium reaction 6.0-8.0 7.4 7.6 7.5 (pH) 5% solution E No less -112 -110 -111 5% solution, mV -fifty Content Not less than 50 86 85 84 sulfides, mg% Lipids, mg per Not less than 60 74 76 74 suppository

The claimed dosage form is a source of biologically active substances that provide the basic processes of life. Due to the presence of fat-soluble bioantioxidants in their composition, they reduce the intensity of free radical processes and protect cell and subcellular membranes from damage. They stimulate reparative processes and accelerate the healing of damaged tissues, and also have anti-inflammatory and antibacterial effects.

A study of suppositories was carried out at the All-Russian Scientific Center for the Safety of Biologically Active Substances on 120 non-linear rats weighing 220-260 g. The anti-inflammatory effect of the claimed dosage form was studied on a model of carrageenin-induced edema of rat paw, on a model of the chronic inflammatory process, vaginitis in rats. According to the results of studies, the developed dosage form in the form of suppositories with a course of administration has a systemic and local anti-inflammatory, antibacterial and regenerative effect and can be recommended for the treatment of chronic inflammatory diseases of the pelvic organs.

The theoretical and experimental results made it possible to declare the presence of a therapeutic effect of the claimed suppositories, which is explained by the content in their composition of components that have anti-inflammatory, antibacterial and regenerating effects.

The clinical efficacy of suppository treatment was studied in 2 groups of patients suffering from urological and gynecological diseases.

The study of suppositories for urological diseases was carried out on 30 patients with a diagnosis of benign prostatic hyperplasia and chronic prostatitis. The course of treatment was carried out for 10 days, 1 suppository 2 times a day, morning and evening.

The criteria for the effectiveness of the claimed suppositories in this group of patients were a decrease in inflammatory processes in the tissues, a decrease in the phenomenon of edema, the disappearance of the phenomena of itching and burning.

Studies of suppositories for gynecological diseases were in a group of patients from 25 patients suffering from gynecological diseases (such as inflammatory diseases of the vagina, acute vaginitis, bacterial vaginosis). The course of treatment was carried out for 10 days, 1 suppository 2 times a day, morning and evening.

The criteria for the effectiveness of the claimed suppositories in this group of patients were a decrease in the intensity of the pain reaction and the severity of edema, a decrease in the number of leucorrhoea, an increase in the number of lactobacilli and an improvement in vaginal microbiocenosis.

A positive result from the use of suppositories at a given course of treatment in the study groups occurred on 3-4 days.

During the follow-up examination of patients of the first and second groups, after 10 days a stable positive therapeutic result was established, manifested in the relief of inflammatory processes, the removal of edema, itching, burning, subsidence of pain, and the cessation of bleeding.

During the examination, a positive result was achieved in all treated patients at the early stages of treatment, which indicates an increased therapeutic activity of the claimed suppositories, which is achieved due to the effective manifestations of anti-inflammatory, antibacterial and regenerative actions. Ultrasound examination confirmed the removal of inflammation and restoration of epithelial cells.

The choice of components with predetermined quantitative values makes it possible to obtain a technical result, which consists in improving the therapeutic activity of the claimed dosage form for the treatment of urogenital diseases, in improving the characteristics of the dosage form, in ensuring microbiological purity, in good penetration and the possibility of administering the drug by the patient on his own.

When using the claimed suppositories, patients did not have side effects and allergic reactions.

Thus, the claimed suppositories for the treatment of gynecological and urological diseases with mud from Lake Elton meets all the requirements for vaginal and rectal suppositories, are effective and safe and can be recommended for the treatment of patients with gynecological and urological diseases.

Claims (1)

Suppositories for the treatment of gynecological and urological diseases, containing the mud of Lake Elton and the base of PEG-1500, characterized in that they contain the lipid complex of mud of Lake Elton, dehydrated to 20-35%, and additionally contain the drug Tykveol and emulsifier T2 with the following components, wt.%:
Elton Lake Mud Lipid Complex 24-26 drug Tykveol 2-3 PEG-1500 70-74 emulsifier T2 0.5-1.5