RU2342940C1 - Means for treatment of chronic prostatitis - Google Patents

Abstract

FIELD: medicine; pharmacology.

SUBSTANCE: means for treatment of chronic prostatitis contains the active substance including a complex of water-soluble peptides, allocated from prostate gland of livestock, and glycine in the ratio 1 : 2; the carrier including dimethyl sulfoxide and a softener, thus it is executed in the form of an ointment, the carrier contains an emulsive basis including softener, distilled monoglycerides and purified water, and in addition contains preservative.

EFFECT: organotropic action in relation to prostate gland, high biological availability and therapeutic effect, preservation of stability throughout long time.

4 cl, 3 ex, 2 tbl

Description

The present invention relates to medicine, namely to pharmaceuticals, and can be used in the pharmaceutical industry for the manufacture of a drug used to treat chronic prostatitis. The present invention relates to agents for the pathogenetic treatment of diseases of the prostate gland and organs functionally associated with it, and is indicated for chronic prostatitis.

In recent years, it has been noted that prostatitis is one of the most common diseases in men. It can be caused by various bacteria, viruses, protozoa, yeast. The infection enters the prostate gland from various infectious foci in the body. Prostatitis is divided into acute and chronic. Chronic prostatitis can be detected at the end of the acute process, or prostatitis from the very beginning takes a chronic course. With a long course, patients complain of premature ejection of the seed during intercourse or attempt to it, the weakening of ejaculation. In case of violation of the function of the prostate gland, increased nervousness, fatigue, digestive upset, poor sleep, decreased performance are observed. For the treatment of prostatitis, a wide range of preparations of synthetic, plant and animal origin is used. However, the problem of finding new reliable and at the same time safe means for the treatment of prostatitis is relevant.

One of the promising areas in the treatment of prostatitis is the use of drugs aimed at stimulating the nonspecific reactivity of the body, in particular the use of prostatotropic drugs of natural origin. Known use for the treatment of prostatitis funds in the form of various dosage forms containing a complex of bioregulatory peptides of the prostate gland of cattle (cattle). One of these well-known products is Raveron, which is an extract of the prostate gland of sexually mature animals, freed from extrogenic hormones and proteins. "Roveron" in the form of injections is used in the initial stage of the disease in chronic non-specific prostatitis (Mashkovsky MD Medicines. M., Medicine, 1994, v. 2, p. 190). However, the use of "Raveron" requires long-term courses of treatment, while allergic reactions to it are frequent

Known tool that is produced under the trade name "Prostatilen." It is a complex of bioregulatory peptides of the prostate gland of cattle (with a content of water-soluble peptides of at least 20%) in the form of a lyophilized sterile powder mixed with glycine in a ratio of 1: 2 before the lyophilization process. This product is available for injection intramuscularly (VFS 42-2077-91 "Prostatilen"). The use of prostatylene does not cause any danger of allergic reactions, nor the likelihood of atrophy of the prostate gland and other complications. The absence of side effects of the drug makes it possible to relatively freely vary dosages and courses of treatment. A disadvantage of the known means is that the dosage form of the drug is a solution for intramuscular injection. For the course of treatment requires qualified medical personnel, the use of sterile instruments and disinfectants. Due to the painfulness of the procedures and possible infection of patients, it became necessary to create an alternative to the injection solution of the dosage form of the drug with high bioavailability.

Known means for the treatment of diseases of the prostate gland, made in dosage form and containing a complex of peptides of the prostate gland of cattle. The tool is made in the form of a solid dosage form for oral administration containing a core and enteric coating, while the core contains the active substance in an amount of 4-75 wt.% And auxiliary substances, wt.%: A binder, in particular selected from the group including milk sugar or low molecular weight polyvinylpyrrolidone in an amount of 1-10, a disintegrator selected from the group comprising a starch derivative or polyvinyl polypyrrolidone in an amount of 1-4, a release agent selected from the group including stearic acid or e f salts, or talc, or silicon dioxide in an amount of 0.25-5.0, and a filler, in particular selected from the group comprising sugar or lactose and a starch derivative or microcrystalline cellulose in an amount of up to 100 wt.%, at their ratio 1: 4-1: 3, and the shell contains, in particular, acetylphthalyl cellulose or a polymer selected from the group comprising a copolymer of methacrylic acid, for example a copolymer of methacrylic acid and ethyl acrylate (RF Patent No. 2278681 for the invention of “Means for treating prostate diseases”, MPK A61K 35/48, A61K 9/20, A61 13/00, publ. 06/27/2006). The implementation of the known funds in the form of tablets, or pellets, or granules is a convenient dosage form for patients who prefer oral administration of the drug, and a particularly convenient form for patients in the postoperative period on the prostate gland. However, the known tool requires the presence of enteric membranes, preventing the release in the stomach of the active substance from orally administered dosage forms, which significantly increases the cost of the drug. In addition, the involvement of the gastric tract can cause an adverse reaction.

Known drugs used to treat acute and chronic prostatitis, complications after surgery on the prostate gland, as well as prostate adenoma, copulative dysfunction, urination disorders, containing a complex of water-soluble peptides isolated from the prostate gland of cattle (prostatilene), in the form of a drug forms - fat-based suppositories.

Closest to the invention according to the combination of essential features and the achieved therapeutic effect is a means for the treatment of diseases of the prostate gland "Vitaprost". The known tool is made in the form of a suppository, contains the active substance, which is a complex of water-soluble peptides isolated from the prostate gland of cattle, and a carrier, which is a fat base. Vitaprost contains the following ratio of components, g per candle: a complex of bioregulatory peptides of the prostate gland of cattle in the form of a powder with a content of water-soluble peptides of at least 20% - 0.04-0.06; the base is a sufficient amount to produce a candle weighing 1.15-1.35 g. The base is a mixture of mono-, di- and triglycerides of natural saturated fatty acids with a carbon chain length of C ₁₂ -C ₁₈ (RF patent No. 2112504 for the invention “MEANS FOR TREATMENT OF DISEASES OF THE PROSTATIVE GLAND "VITAPROST", class IPK А61К 9/02, А61К 38/00, publ. 06/10/1998). This tool, combining a therapeutic substance that has an organotropic effect on the prostate, with a base that ensures the rapid entry of a therapeutic substance into the blood, has high bioavailability, and provides a rapid onset of therapeutic effect. A known tool is characterized by low cost and does not involve gastric function. A disadvantage of the known agent is that a fat base is used in suppositories that does not facilitate the rapid penetration of active substances into tissues. The process of penetration of active substances is slowed down by the suppository melting stage. In addition, the storage of suppositories requires conditions with a narrow temperature range.

The problem to which the invention is directed, is the creation of a new pharmaceutical composition exhibiting organotropic action against the prostate, with high bioavailability and therapeutic effect, maintaining stability for a long time

The technical result that can be obtained by carrying out the claimed invention is:

- increasing the therapeutic effect of the drug for the treatment of prostatitis by accelerating the penetration of active substances into tissues and enhancing the penetration of drugs through biological barriers;

- increasing the shelf life of the stability of the physico-chemical properties due to the preservation of the biological activity of the drug and the absence of contamination by putrefactive bacteria and fungi during storage;

- reduction of restrictions on storage conditions.

The specified technical result is achieved in that the agent for the treatment of chronic prostatitis contains an active substance - a complex of water-soluble peptides isolated from the prostate gland of cattle, and a carrier. The tool is made in the form of an ointment and additionally contains a suction activator and a preservative, and as a carrier contains an emulsion base, in the following ratio, wt.%:

 Water-soluble peptides isolated from cattle prostate 2.0-10.0  Suction activator 5.0-15.0  Preservative 0.1-0.5  Emulsion base up to 100.0

Preferably, the agent for the treatment of chronic prostatitis contains Samprost as the active substance.

It is also preferred that the agent for the treatment of chronic prostatitis contains dimethyl sulfoxide as an absorption activator.

It is also preferred that the agent for the treatment of chronic prostatitis contains a mixture of nipagin and nipazole as a preservative.

It is also preferable that the agent for the treatment of chronic prostatitis as an emulsion base contains a mixture of emulsifier, plasticizer and purified water.

Preferably, the agent for treating chronic prostatitis contains distilled monoglycerins as an emulsifier.

In some cases, the implementation of the tool for the treatment of chronic prostatitis as a plasticizer may contain medical paraffin and petrolatum, or copolymers of acrylic and methacrylic acids, or a mixture of 1,2 propylene glycol and polyethylene oxide, or copolymers of acrylic and methacrylic acids, oil, twin-80 coemulsifier.

Preferably, the agent for the treatment of chronic prostatitis contains Samprost as an active substance, dimethyl sulfoxide as an absorption activator; as a preservative, a mixture consisting of nipagin and nipazole; as an emulsion base - a mixture of distilled monoglycerides, medical vaseline, liquid paraffin and purified water in the following proportions, wt.%:

Samprost, calculated on the dry matter 2.0-10.0 Dimethyl sulfoxide 5.0-15.0 Distilled monoglycerides 5.0-10.0 Vaseline medical 20.0-50.0 Vaseline oil 10.0-30.0 Nipagin 0.1-0.3 Nipazole 0.1-0.3 Purified water up to 100.0%

In all cases, the implementation of the proposed tool for the treatment of chronic prostatitis differs from the above known closest to him funds:

- execution in the form of ointment;

- the presence of a suction activator;

- the presence of a preservative;

- the implementation of the media containing the emulsion base;

- the following ratio of components, wt.%:

 water soluble peptides isolated from cattle prostate, calculated on dry matter 2.0-10.0  suction activator 5.0-15.0  preservative 0.1-0.5  emulsion base up to 100.0

In some cases, the implementation of the claimed drug for the treatment of chronic prostatitis differs from the known:

- the use of the drug "Samprost" as the active substance;

- using dimethyl sulfoxide as an activator of absorption;

- using as a preservative a mixture consisting of nipagin and nipazole;

- the implementation of the emulsion base containing a mixture of emulsifier, plasticizer and purified water.

- using distilled monoglycerins as an emulsifier;

- the use of vaseline plasticizer of medical and vaseline oil, or copolymers of acrylic and methacrylic acids, or a mixture of 1.2 propylene glycol and polyethylene oxide, or copolymers of acrylic and methacrylic acids, oil, twin-80 coemulsifier;

- content as the active substance - the drug "Samprost", as a promoter of absorption - dimethyl sulfoxide; as a preservative, a mixture consisting of nipagin and nipazole; as an emulsion base - a mixture of distilled monoglycerides, medical vaseline, liquid paraffin and purified water in the following ratios, wt.%:

Samprost, in terms of dry matter 2.0-10.0 Dimethyl sulfoxide 5.0-15.0 Distilled monoglycerides 5.0-10.0 Vaseline medical 20.0-50.0 Vaseline oil 10.0-30.0 Nipagin 0.1-0.3 Nipazole 0.1-0.3 Purified water up to 100.0%

The use of a complex of water-soluble peptides isolated from the prostate gland of cattle as the active substance normalizes microcirculation and hemostasis, regulates the tone of the bladder, helps to reduce swelling and infiltration of the prostate gland, and normalizes spermatogenesis. The presence of an emulsion base containing an emulsifier, plasticizer and purified water ensures that the product is in the form of an ointment, which simplifies the use and storage of the product, and also contributes to the rapid delivery of the therapeutic substance to the prostate. The presence of the absorption activator in the proposed composition, which is also able to penetrate biological barriers, provides a quick release of the therapeutic substance from the base and enhances the penetration of water-soluble peptides to the prostate, increasing the therapeutic effect. The use of dimethyl sulfoxide (DMSO) as an activator of absorption provides an additional anti-inflammatory, analgesic and fibrinolytic effect. The introduction of a preservative in the composition ensures the stability of the drug against microbial contamination. The use of a mixture of nipagin and nipazole as preservatives provides a suppression of the growth of mold and yeast fungi. The use of distilled monoglycerides as an emulsifier, medical paraffin and petroleum jelly as a plasticizer allows you to get a drug of the required consistency, ensures the stability of the dosage form and optimal fluidity. The proposed ratio of active, excipients and bases found experimentally, is optimal in qualitative and quantitative terms. The proposed ratio provides a high-quality drug with a high therapeutic effect, with high bioavailability and maintaining stability for at least two years. When the concentration in the composition of the active substance (Samprost substance) is less than 4%, the drug is pharmacologically ineffective, a concentration of more than 10% is technologically inappropriate. The concentration of DMSO (from 5 to 10%) is due to pharmacological efficacy and technological feasibility. The proposed ratio of preservatives in the composition ensures the preservation of biological activity and the absence of contamination of the drug with putrefactive bacteria and fungi during storage. With a decrease in the amount of any of the components, an opportunity arises for the growth of pathogenic microflora, with an increase in the occurrence of allergic reactions with the use of the composition.

Thus, the present invention is a new drug in the form of an ointment, having an organotronic effect on the prostate, with a base that ensures the rapid flow of the therapeutic substance to the prostate. The proposed tool has high bioavailability, provides a quick onset of therapeutic effect, does not require special temperature storage. The proposed technical solution is original, not known from the prior art.

The proposed composition is produced as follows:

Distilled monoglycerides and petroleum jelly, liquid paraffin and preservatives are placed in the reactor. Heat the mixture and mix. Next, water is poured into the reactor and an emulsion is obtained. At a temperature of about 60 ° C, dimethyl sulfoxide is introduced into the reactor. After cooling to 30 ° C, Samprost powder is introduced into the reactor; after stirring, the mixture is triturated in a maser.

Samprost is a complex of water-soluble peptides isolated from the prostate gland of cattle. Samprost can be used with the technical characteristics described, for example, in VFS 42-3243-98. As an activator of absorption, dimethyl sulfoxide (DMSO) can be used, for example, according to FS 42-2980-98. As preservatives, a mixture of nipagin and nipazole can be used, for example, according to FS No. 42-1460-89; 42-2079-91.

As an emulsifier, distilled monoglycerides can be used, for example, according to TU 10-1197-95. As a plasticizer in the proposed composition, medical vaseline (FS 42-2456-97 or GOST 3582-84) and liquid paraffin (VFS 42-2298-94) are used.

Examples of compositions of the proposed pharmaceutical composition:

Example 1

Wt%

Samprost, calculated on the dry matter  4.0 Dimethyl sulfoxide  5,0 Distilled monoglycerides  5,0 Vaseline medical  35.0 Vaseline oil  20,0 Nipagin  0.1 Nipazole  0.1 Purified water  up to 100.0%

This ratio of components, established experimentally, is preferable to solve the problem.

Example 2

Wt%

Samprost  4.0 Carbomer  1,5 Triethanolamine  1.8 Dimexide  5,0 1,2-propylene glycol  20,0 Polyethylene Oxide 400  20,0 Nipagin  0.1 Nipazole 0.1 Purified water up to 100.0 g

Example 3

Wt%

Samprost  4.0 Dimethyl sulfoxide  5,0 Carbomer  1,5 Triethanolamine  1.8 Olive oil  10.0 Twin 80  5,0 Nipagin  0.1 Nipazole  0.1 Purified water (FS 42-2619-97)  up to 100.0 g

Examples 2 and 3 with the indicated ratios of the ingredients provide a pharmacological composition that meets the requirements of GF XI (in appearance, microbiological purity and other indicators), stable during storage. The composition proposed as an invention is an effective drug for the treatment of chronic prostatitis.

A preclinical study of the action of the ointment with the Samprost substance was carried out on the basis of a clinical laboratory.

The pharmacological effect of the studied drug was studied in determining the specific activity of the drug in accordance with the "Guidelines for the experimental (preclinical) study of new pharmacological substances" [1, 2, 3, 4].

Given that the main role in the pathogenesis of the development of prostatic hypertrophy is played by hormonal imbalances, in modeling this pathological process we used techniques aimed at creating a hormonal imbalance in experimental animals.

Analysis of literature data showed that sulpiride is used to model experimental prostatopathy, the intraperitoneal administration of which to rats to males induces hyperprolactinemia and subsequent development of prostatic hyperplasia within 30 days. A compensatory increase in the lateral lobe of the prostate also occurs as a result of castration, with the administration of testosterone preparations to animals and with a combination of these effects [1, 2].

In our experiments, we used rats of males weighing 180-200 g. Animals of the experimental and control groups were castrated under general anesthesia. The next day, all operated animals were divided into two groups of 10 animals each.

Group 1 animals received testosterone propionate at a dose of 0.1 mg / kg (5% oil solution was diluted with olive oil and was administered to rats subcutaneously daily for 3 weeks).

Group 2 animals received testosterone propionate at a dose of 0.1 mg / kg (5% oil solution was diluted with olive oil and was administered to rats subcutaneously daily for 3 weeks) and the test drug daily at a dose of 4.3 mg / kg for 3 weeks

To assess the severity of the condition of the rats, histological control was used, as well as weighing the prostate before removal for histological examination and intravital assessment of diuresis at different stages of treatment. The choice of criteria for assessing the severity of the pathological process is justified primarily by the fact that in clinical conditions it is not only the severity of the disease, but also the effectiveness of its treatment that is judged by the change in the size of the prostate gland and the nature of urination.

The test drug was started after castration. The course of treatment was 21 days. After the expiration of the experiment, the rats were weighed, then they were killed by the dislocation of the cervical vertebrae, they were opened, the prostate gland was removed, examined and weighed, the weight coefficient was calculated (the ratio of the gland weight in mg to 100 g of the animal’s body weight) and preparations were prepared for histological examination [3].

Table 1 presents the results of a study of the effect of the preparation claimed as an invention on diuresis in male rats with experimental prostatitis.

Table 1
The effect of the study drug on the diuresis of male rats with experimental prostate hyperplasia (n = 10 in the group) Group Dates from the start of the experiment, days Hourly diuresis, ml Daily diuresis, ml The presence of protein and blood (% of animals with a positive sample) 1st hour 2nd hour Control (without treatment) 0
21 5.3 ± 0.1
0.4 ± 0.02 * 2.4 ± 0.4
0.05 ± 0.02 * 12.2 ± 3.6
0.9 ± 0.2 * 0
one hundred Test drug 0
21 4.2 ± 0.5
0.3 ± 0.07 * 2.4 ± 0.5
0.9 ± 0.1 * ^, ** 13.6 ± 1.6
4.8 ± 0.5 * ^, ** 0
40 Note: * - differences from the source data are statistically significant;
** - differences from control are statistically significant.

From the materials of Table 1 it can be seen that in the control (animals left without treatment) 21 days after the start of the experiment, diuresis drops sharply, and in the group receiving the study drug, diuresis disorders, although significant, are still less than in the control group. Table 2 shows the results of weighing the prostate of rats 21 days after treatment of experimental prostatic hyperplasia.

table 2
The effect of the study drug on prostate mass in male rats with experimental prostate hyperplasia (n = 10 in the group) Group, dose, mg / kg Prostate weight, mg / 100 g Control (without treatment) 184.8 ± 9.6 Test drug 159.6 ± 8.7

The results (Table 2) indicate that inflammatory edema of the prostate gland in rats not receiving treatment was more pronounced than in males from the experimental group. When the prostate was removed, it was noted that it looked looser in the control animals, was larger in volume than in the animals from the experimental group, and was much more difficult to separate from the bladder wall than in rats receiving specific therapy.

Obtained by weighing the prostate and assessing diuresis, the results were confirmed by microscopic examination of sections of the prostate gland of animals from two groups. Both in the control and in the experimental groups, the following morphological changes in the prostate were revealed:

- edema of the stroma of the gland;

- focal fibrinous swelling and stromal hyalinosis;

- atrophy and hypoplasia of the secretory departments.

Edema of the stroma of the gland was most pronounced in animals from the control group, in the experimental group - moderately. The prevalence of foci of fibrinous swelling and hyalinosis of the stroma of the prostate is subject to significant individual fluctuations within all groups, which makes it difficult to draw certain conclusions about the differences between groups by this criterion. The severity of atrophy and hypoplasia of the prostatic glands, as well as the presence of preserved functionally active glands are also subject to significant individual fluctuations, however, in this case, one can trace a tendency to an increase in the number of functionally active glands in animals from the experimental group compared to the control. So, in control functionally active glands are found only in 40% of animals, while they make up no more than 1/5 of all glands located in the plane of the histological section. Active rats were found in all animals in groups of rats receiving the test drug, and in 70% of cases they account for about 50% of all histological sections present in the plane.

Thus, in an experiment on male rats with experimental hyperplasia, the effectiveness of the test drug was proved.

In the study of the general toxic properties of the studied drug, it was revealed that the average lethal dose for rectal administration is more than 10 g / kg, which makes it possible to classify the studied substance as low-toxic means - 4th hazard class (GOST 12.1.007-76). To determine the LD ₅₀ when applied to mice, rectally once or several times during the day with an hour-long interval between applications (maximum 10 times).

In separate experiments, the effect of prolonged rectal administration of the studied drug on the physical condition of laboratory animals - male rats was studied [4]. Control animals received a placebo. The studied drug was administered in two doses - 4.3 mg / kg (therapeutic dose for rats) and 10 times greater (43 mg / kg). The number of animals in each group was 10.

The results of measurements of body weight of male rats during the experiment did not have significant differences between the control and experimental groups. The results of an electrocardiographic study of male rats receiving the study drug indicate that its administration in a therapeutic dose and in a dose 10 times higher than it does not significantly affect the ECG of animals. The introduction of the test drug in the tested doses did not cause significant changes in the picture of peripheral blood, as well as significant changes in the level of glucose, total protein, urea, cholesterol and creatinine in the blood serum. The studied drug in both doses did not significantly change the daily volume of urine, its density and pH. None of the animals showed the appearance of protein or sugar in the urine. The results of weighing the internal organs of male rats after the end of the experiment do not differ significantly for animals from all experimental and control groups. Pathological changes in the structure of internal organs were not detected. On preparations of the prostate gland, the lobular structure of the gland with elements of a thin connective tissue capsule is clearly visible. The parenchyma consists of numerous separate mucous glands (small, medium, prostate proper), the excretory ducts of which have a typical structure. The end sections of the alveolar-tubular prostate glands are formed by high mucous exocrinocytes, between the bases of which small insertion cells are visible. Each lobule is surrounded by longitudinal and circular layers of smooth muscle cells. No significant differences between the preparations from animals from different groups were found. On the preparations of the rectum, there were no signs of mucosal structure disorders.

Literature

1. Tkachuk V.N., Gorbachev A.G., Agulyansky L.I. Chronic prostatitis. - L., 1989.

2. Yunda I.F. Prostatitis. - Kiev, 1987.

3. Volkova OV, Yeletsky Yu.K. Basics of histology with a histological technique. - M .: Medicine, 1971. - 271 p.

Claims (4)

1. An agent for the treatment of chronic prostatitis containing the active substance, including a complex of water-soluble peptides isolated from the prostate gland of cattle, and glycine in a ratio of 1: 2; a carrier comprising dimethyl sulfoxide and a plasticizer, characterized in that it is in the form of an ointment, the carrier contains an emulsion base including a plasticizer, distilled monoglycerides and purified water, and additionally contains a preservative in the following ratio, wt.%:
water soluble peptides isolated from cattle prostate and glycine, calculated on the dry matter 2.0-10.0 dimethyl sulfoxide 5.0-15.0 preservative 0.1-0.5 emulsion base including plasticizer, distilled monoglycerides and purified water up to 100 2. The treatment for chronic prostatitis according to claim 1, characterized in that as a preservative contains a mixture consisting of nipagin and nipazole. 3. The agent for the treatment of chronic prostatitis according to claim 1, characterized in that the plasticizer contains petrolatum medical and petrolatum, or copolymers of acrylic and methacrylic acids, or a mixture of 1,2 propylene glycol and polyethylene oxide, or copolymers of acrylic and methacrylic acids, oil Co-emulsifier Twin-80. 4. The agent for the treatment of chronic prostatitis according to claim 1, characterized in that the plasticizer contains medical paraffin and petrolatum oil, nipagin and nipazole as a preservative in the following ratios of components, wt.%:
water soluble peptides isolated from cattle prostate and glycine, calculated on the dry matter 2.0-10.0 dimethyl sulfoxide 5.0-15.0 medical vaseline 20.0-50.0 Vaseline oil 10.0-30.0 distilled monoglycerides 5.0-10.0 nipagin 0.1-0.3 nipazole 0.1-0.3 purified water up to 100.0