RU2740946C1 - Agent for reducing pathological changes in prostatic hyperplasia - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention refers to an agent for reducing pathological changes in prostatic hyperplasia, including dihydroquercetin, characterized by that it additionally contains oxidised dextran, dimexide, EDTA, polyethylene oxide in the following proportions: oxidised dextran - 1.25 wt %; dimexide - 5.0 wt %; EDTA - 2.5 wt %; dihydroquercetin - 2.5 wt %; polyethylene oxide 6000 - 88.75 wt %.

EFFECT: obtained agent improves efficiency of reducing pathological manifestations of prostatic hyperplasia.

1 cl, 1 tbl, 4 ex

Description

The present invention relates to experimental pharmacology, experimental medicine, in particular, the search for ways to reduce pathomorphological changes in experimental prostatic hyperplasia and can be used to create pharmacological agents for the treatment of infectious and non-infectious inflammatory-proliferative diseases of the prostate gland, in particular prostatic hyperplasia.

Currently, prostatic hyperplasia and chronic prostatitis are among the most common diseases in modern urology and andrology. Both diseases have common pathomorphological symptomatic complexes, while chronic prostatitis, both infectious and non-infectious etiology is one of the leading causes of the development of benign prostatic hyperplasia, and with prostatic hyperplasia, pathomorphological changes of an inflammatory nature (swelling of the gland tissue, microbleeds , cellular inflammatory infiltrates, changes in the structure of reticulin fibers of the connective tissue of the gland), characteristic of prostatitis. In this regard, therapeutic approaches in the drug treatment of chronic prostatitis and prostatic hyperplasia are largely general in nature. In particular, in chronic prostatitis and prostatic hyperplasia, drugs are used to suppress the activity of 5α-reductase isoenzymes, which are responsible for the process of converting testosterone into 5α-dihydrotestosterone (finasteride, dutasteride), to reduce the tone of the bladder neck and prostate ducts, selective competitive blockers of postsynaptic α1-adrenergic receptors (doxazazin, tamsulosin, alfazosin, etc.), while antibiotic therapy, mainly with broad-spectrum antibiotics, for example, fluoroquinolone derivatives, is often used in the treatment of prostatic hyperplasia, accompanied by infectious and inflammatory symptoms. Recently, for the treatment of chronic prostatitis and hyperplasia of the prostate gland, plant extracts have been used very often, in particular, the extract of the fruit of the creeping palm Serenoa repens. Among the pharmacological preparations containing creeping palm extract, the most famous are such preparations as Prostamol Uno, Palprotes, and Permikson. All of these drugs, according to their pharmacological action, belong to non-competitive type 1 5-alpha reductase inhibitors and disrupt the conversion of testosterone to dihydrotestosterone, which stimulates the proliferation of prostate cells. Preparations based on creeping palm extract have antiandrogenic properties that selectively manifest themselves at the level of the prostate gland, do not cause changes in the hormonal balance in the blood, do not affect the hypothalamic-pituitary system and have an anti-inflammatory effect, reducing the synthesis of prostaglandins by inhibiting the activity of phospholipase A-2 and release of arachidonic acid, reduce vascular permeability and edema of the gland tissue, have antiestrogenic activity, help to reduce the intensity of symptoms of benign prostatic hyperplasia and reduce its size. Despite such an extensive arsenal of pharmacological agents, the treatment of prostatitis and prostatic hyperplasia still remains a very difficult task, and even with long-term treatment of these diseases, it is difficult to achieve stable remission, therefore, both diseases are in the nature of a chronic disease and the search for new therapeutic approaches to reduce pathological manifestations in the prostate gland in these diseases is one of the urgent tasks of modern andrology.

In the patent WO 2019133022 (A1), 07/04/2019, for the treatment of prostatic hyperplasia, it is proposed to use a multkinase inhibitor, for example, sunitinib or panatinib, which are used as antineoplastic agents. The disadvantage of the claimed group of anticancer drugs is their high toxicity, which is expressed in a large number of side effects, in particular thrombosis and damage to the cardiovascular and nervous system. Recently, for the treatment of proliferative diseases of the prostate gland, reports began to appear on the use of dimethylase-1 (LSD-1) inhibitors and histone dimethylase inhibitors, which are used as an antitumor agent [US patent 10597376, 03.24.2020 and US patent 10597379, 03.24.2020 respectively]. A close technical solution is the use of apoptosis modulators for the treatment of prostatic hyperplasia [US patent 8618155, 12/31/2013]. All of the above technical solutions are not selective for the treatment of prostate diseases and their effectiveness is not high enough with a large number of side effects characteristic of all anticancer drugs.

There are isolated reports on the use of peptides with antiandrogenic activity [patent US 5389613, 14.02.1995], the disadvantage of which is the need for a predominantly injection method of administration into the systemic circulation and the effect on the balance of sex hormones, which can be accompanied by significant side effects. Also, for the treatment of diseases of the prostate gland, a mixture of carotenoids is used, the main therapeutic effect of which is aimed at removing inflammatory reactions [US patent 10561696, 02/18/2020], surfactants with isothiocyanate groups by a mechanism of action close to antitumor agents and having high toxicity [US patent 10583107, 03/10/2020], an insulin-like growth factor inhibitor together with androgen [US patent 10377828, 08.13.2019], which has side effects associated with hormonal imbalance; phosphodiesterase-9 inhibitors, which are used in the treatment of Alzheimer's disease [US patent 10513524, 24.12.2019], are non-specific for the treatment of prostate diseases in terms of their pathogenesis and do not have a sufficiently high therapeutic efficacy.

Basically, for the treatment of prostate diseases, drugs containing 5-alpha-reductase inhibitors are used, which inhibit the transition of testosterone to dihydrotestosterone, which is considered the main factor in prostate tissue hyperplasia: US patent 7744935, 06/29/2010, US patent 8513422, 08/20/2013, patent US 7776921, 17.08.2010. The main disadvantage of all such drugs is that they cause hormonal imbalance and an increase in the level of hepatic transaminases (hepatotoxic effect). In addition to 5-alpha reductase inhibitors for the treatment of prostatic hyperplasia, alpha-blockers are widely used, for example, presented in US patent 9737517, 08.22.2017 and RU 2538615, publ. 10.01.2015, Bul. # 1. All inhibitors of alpha-adrenergic receptors, such as tamsulosin and doxazosin, cause tachycardia, greatly reduce blood pressure and are contraindicated in atherosclerosis. They are used for long periods, over 6 months, and the therapeutic effect is insufficiently expressed.

In patent RU 2160114, publ. 10.12.2000, Bul. No. 34 describes a rectal agent for the treatment of chronic prostatitis. It contains bovine prostate extract and alpha-interferon as the main active ingredients. The disadvantage of the presented drug is its low therapeutic efficacy and duration of treatment. Close technical solutions are described in patent RU 2408378, publ. 10.01.2011, Bul. No. 1, in which the treatment of chronic prostatitis includes a combination of antibiotic therapy and the use of α-interferon in the form of ointments or suppositories, and in patent RU 2408399, publ. 10.01.2011, Bul. No. 1, in which for the treatment of benign prostatic hyperplasia using the drug "Vitaprost Forte" in the form of suppositories, which is based on the extract of the prostate gland of animals. In patent RU 2525182, publ. 08/10/2014, Bul. No. 22 provides means of treating patients with chronic prostatitis with partial androgen deficiency. According to the patent, the treatment is carried out by androgen replacement therapy under the control of testosterone levels. The main disadvantage of this agent is the complications characteristic of hormone replacement therapy with androgens, which in some cases can become pronounced and irreversible. In patent RU 2453347, publ. 06/20/12, Bul. No. 17 for the treatment of chronic infectious urethritis, complicated by prostatitis, take 1.0 g of azithromycin (sumamed) once a day on the 1st, 7th, 14th days in combination with complex therapy. Complex therapy includes rectal suppositories dalargex 1 suppository daily at night No. 10, prostate massage, rectal laser therapy and daily use of fluoroquinolone-hemifloxacin (faktiv) 1 tab. (320 mg) per day for 14 days. These funds allow to prolong the period of remission of the disease, improve the quality of life of patients, restore reproductive function by increasing the eradication of opportunistic flora in the contents of the secretion of the prostate gland. The disadvantage of these treatments is their symptomatic nature and relatively low efficiency, especially in the treatment of prostatic hyperplasia. In patent RU 2568369, publ. 20.11.2015, Bul. No. 32 describes the treatment of prostate adenoma in combination with chronic abacterial prostatitis. According to the patent, drug therapy is carried out with a 5α-reductase inhibitor and an α1-blocker. The therapy is mainly symptomatic and has little effect on the compensation of pathomorphological changes in the prostate gland in these diseases. In addition, drug therapy with 5α-reductase inhibitors and α1-adrenergic blockers is long-term (from several months or more) and is mainly aimed at increasing the period of remission. In patent RU 2331434, publ. 08/20/2008, Bul. No. 23 describes a medicinal product obtained from the fruits of the royal palm (roystonea regia), and a method of its use for the treatment and prevention of prostatic hyperplasia and prostatitis. The main disadvantage of the drug is its low efficacy, symptomatic nature of the treatment and its high duration. In patent RU 2612268, publ. 03.03.2017, Bul. No. 7 describes an agent for the prevention and treatment of benign prostatic hyperplasia. As the main active ingredient, a borneol terpenoid derivative, in particular 4-hydroxymethyl-2,6-diisobornylphenol, was used at a dose of 10 mg / kg of body weight. The use of the claimed agent for the treatment of benign hyperplasia makes it possible to increase the effectiveness of the prevention and treatment of benign prostatic hyperplasia. The disadvantage of the presented agent is its low therapeutic efficacy. In addition, it is known that the terpenoids contained in turpentine, including borneol, at high doses, can themselves provoke the proliferation of the glandular epithelium of the prostate gland and cause chronic inflammation in it. In patent RU 2306145, publ. 20.09.2007, Bul. No. 26 proposed the use of a medicinal mixture containing 50 mg of the enzyme preparation "Karipazim" containing a complex of proteolytic enzymes, 5 mg of hydrocortisone and 2 ml of a 20% aqueous solution of Dimexide for the treatment of chronic calculous prostatitis. In patent RU 2534857, publ. 10.12.2014, Bul. No. 34 describes a method for the treatment of chronic calculous prostatitis. According to the described method, a course of 5-7 procedures of transrectal ultrasound exposure is carried out in a pulsed mode, with an intensity of 0.2-0.4 / cm2 W. for 5-7 minutes daily. Also, enzyme therapy is carried out with Longidaza at a dose of 3000 U 2 times a week for 1 month. In addition, the patient is administered rectal suppositories containing 1000 mg of Trilon B and 200 mg of Dimexidum daily at night for 3 months. At the same time, after detecting bacteria by microbiological examination of the ejaculate, antibacterial therapy is carried out for 4-6 weeks, introducing an antibacterial drug according to the sensitivity of the microflora to it. The use of these means of treatment ensures the disappearance of stones in the prostate gland or a decrease in their number, a decrease in the likelihood of recurrence of the inflammatory process in the prostate gland, a differentiated approach to treatment by identifying a group of patients who are indicated for antibiotic therapy.

For the treatment of chronic prostatitis, especially with rectal administration, various pharmaceutical compositions are used in the form of solutions containing dimethyl sulfoxide (DMSO) as an anti-inflammatory agent: patent RU 2128052, publ. 03/27/1999, patent RU 2140265, publ. 27.10.1999, patent RU 2271203, publ. 10.03.2006, Bul. No. 7, patent RU 2306145, publ. 20.09.2007, Bul. No. 26. The main disadvantage of the claimed funds is their low therapeutic efficacy in prostatic hyperplasia.

In patent RU 2534853, publ. 10.12.2014, Bul. No. 34 provides a new method for the treatment of chronic calculous prostatitis. For this, a course of 5-7 procedures of transrectal ultrasound exposure is carried out in a pulsed mode, with an intensity of 0.2-0.4 W / cm2 for 5-7 minutes daily. The drug "Longidaza" (active ingredient - bovgialuronidase azoxymer) is used as the main pharmacological agent at a dose of 3000 U 2 times a week for 1 month. In addition, the patient is administered rectal suppositories containing 1000 mg of Trilon B and 200 mg of Dimexidum daily at night for 3 months. In this case, after identifying bacteria by microscopic and microbiological examination of the ejaculate, antibacterial therapy is carried out for 4-6 weeks, introducing an antibacterial drug according to the sensitivity of the microflora to it. This implementation of the method ensures the disappearance of stones in the prostate gland or a decrease in their number, reducing the likelihood of recurrence of the inflammatory process in the prostate gland. The disadvantage of the presented method of treatment is its relatively low efficiency, aimed primarily at lengthening the period of remission, symptomatic nature of treatment and its duration.

Recently, antioxidants have been widely used for the treatment of prostatic hyperplasia. In particular, with this purpose in the patent RU 2612268, publ. 03.03.2017, Bul. No. 7 as an antioxidant proposed 4-hydromethyl-2,6-diisobornylphenol, and in patent RU 2122422, publ. 11/27/1998 - traditional antioxidants such as quercetin and dihydroquercetin. The main disadvantage of products containing antioxidants is low efficiency, since basically the therapeutic effect is realized mainly through the anti-inflammatory effect.

In patent RU 2671488, publ. 01.11.2018, Bul. No. 31, taken as a prototype, describes a pharmaceutical combination containing metroformin and dihydroquercene, and its use for the treatment of cancer, including precancerous diseases, which include prostatic hyperplasia. In the composition, metformin acts as the main agent for the prevention of cancer, and dihydroquercetin acts as a hepatoprotector that reduces the toxicity of metformin, and also as an additional component with antioxidant and anti-inflammatory properties, which enhances the therapeutic effect of the pharmaceutical composition as a whole. The pharmaceutical composition can be used as rectal suppositories. The main disadvantage of the pharmaceutical composition (prototype) is its low efficiency in prostatic hyperplasia and its effect is mainly aimed at preventing cancer and has little effect on the compensation of pathomorphological changes in the prostate gland.

The objective of the present invention is to improve the efficiency of reducing the pathomorphological manifestations of prostatic hyperplasia.

The solution to this problem is achieved by the fact that to reduce the pathomorphological manifestations of prostatic hyperplasia, the following composition is used:

Oxidized dextran - 1.25 mass. % Dimexide - 5.0 mass. % EDTA - 2.5 mass. % Dihydroquercetin - 2.5 mass. % Polyethylene oxide 6000 - 88.75 mass. %

The main pharmacological characteristics of the components of the claimed agent

1. Oxidized dextran - has antifibrotic, anti-inflammatory effect, activates macrophages, due to which they express the synthesis of metalloproteinases and anti-inflammatory cytokines, stimulate interferonogenesis and phagocytosis, increase the frequency of phagososmotic-lysosomal fusions and increase the microbicidal potential of urogenital infections, which is especially important for with intracellular persistence of the pathogen (candidiasis, mycoplasmosis, trichomoniasis, ureaplasmosis, chlamydia), which are most common in chronic prostatitis and prostatic hyperplasia.

2. Dimexide - is a solvent for oxidized dextran, in addition, it has a moderate antimicrobial effect and promotes the penetration of pharmacological drugs through cell membranes.

3. EDTA - is a universal complexing agent for calcium ions, dissolves calcium calculi and improves hemorheological parameters in the tissue of the prostate gland, prevents the development of microthrombosis.

4. Dihydroquercetin - a flavonoid that protects cell membranes (membrane stabilizing effect) under conditions of ischemia and oxidative stress in chronic inflammatory processes, has a venotonic and anti-inflammatory effect.

5. Polyethylene oxide 6000 - a form-building component for rectal suppositories, improves tissue hemodynamics at the level of the microvasculature, reduces the risk of microthrombosis.

Studies have shown that all the components of the agent individually have a very weak therapeutic effect in the treatment of experimental prostatic hyperplasia (sulpiride model) in mice, while the combination of components selected experimentally, due to their synergism, has a pronounced therapeutic effect and clearly reduces pathomorphological changes in the prostate gland under experimental conditions, which proves the non-obviousness of the proposed technical solution. The composition of the agent is experimentally selected taking into account the maximum possible amount of the introduced components and with an increase in any component, above the specified value, the mechanical strength decreases and the heterogeneity of the suppositories increases. With a decrease in the amount of components administered, the therapeutic efficacy of the combination as a whole decreases. In terms of therapeutic effect, the claimed agent using a combination of the above components and its rectal administration is significantly superior to the agent used in the prototype.

The data of a comparative study of the therapeutic efficacy of individual pharmacological components, their combinations in accordance with the claimed agent and a combination of pharmacological components indicated in the prototype are shown in the table. To create a model of prostatic hyperplasia, BALB / c mice with an average body weight of 30-35 g were injected daily for 20 days with a solution of sulpiride at a concentration of 25 mg / ml based on a dose of 40 mg per 1 kg of body weight. Then the tested samples of the claimed agent, its individual components and the prototype agent indicated in the table, were administered rectally to mice within 7 days in the form of solutions with concentrations of 100 mg / ml in an amount of 50 μl. As can be seen from the table, the claimed agent most effectively reduces pathomorphological changes in the prostate gland under experimental conditions in terms of such indicators as the thickness of the muscle layer of the bladder, the thickness of the prostate gland, the nuclear-cytoplasmic coefficient of the prostate epithelium.

Examples of specific implementation:

Example 1. 2.5 g of EDTA (disodium salt of ethylenediamine tetraacetic acid), 2.5 g of dihydroquercetin, 5 ml of a 25% solution in oxidized dextran dimexide (with an average mass of 60 kDa) and 100 g of polyethylene oxide 6000 are placed in a glass beaker with a capacity of 200 ml, mix. Then the glass is placed in a boiling water bath until the polyethylene oxide 6000 is completely melted, the mixture is thoroughly mixed and poured into a mold for rectal suppositories with an average weight of 1 suppository of 2 g. The content of active components in 1 rectal suppository: EDTA (disodium salt of ethylenediamine tetraacetic acid) - 50 mg , dihydroquercetin - 50 mg, dimexide - 100 mg, oxidized dextran - 25 mg, polyethylene oxide 6000 - up to 2 g. After 7 days of rectal administration of the claimed agent in the form of a solution with concentrations of 100 mg / ml in an amount of 50 μl to BALB / c mice with with an average body weight of 30-35 g, the following pathomorphological manifestations of prostatic hyperplasia improved: the thickness of the epithelium of the prostate gland in mice, decreased to 15.0 ± 1.4 μm in the sulpiride model of prostatic hyperplasia in mice.

Example 2. 2.5 g of EDTA (disodium salt of ethylenediamine tetraacetic acid), 2.5 g of dihydroquercetin, 5 ml of a 25% solution in oxidized dextran dimexide (with an average mass of 40 kDa) and 100 g of polyethylene oxide 1500 are placed in a glass beaker with a capacity of 200 ml, mix. Then the glass is placed in a boiling water bath until polyethylene oxide 1500 is completely melted, the mixture is thoroughly mixed and poured into a mold for rectal suppositories with an average weight of 1 suppository of 2 g. The content of active components in 1 rectal suppository: EDTA (disodium salt of ethylenediamine tetraacetic acid) - 50 mg , dihydroquercetin - 50 mg, dimexide - 100 mg, oxidized dextran - 25 mg, polyethylene oxide 1500 - up to 2 g. After 7 days of rectal administration of the claimed agent in the form of solutions with concentrations of 100 mg / ml in an amount of 50 μl, the thickness of the prostate epithelium in mice on the sulpiride model, prostatic hyperplasia in mice decreased to 14.9 ± 0.9 μm.

Example 3. 2.5 g of EDTA (disodium salt of ethylenediamine tetraacetic acid), 2.5 g of dihydroquercetin, 5 ml of a 25% solution in oxidized dextran dimexide (with an average mass of 40 kDa) and 100 g of polyethylene oxide 6000 are placed in a glass beaker with a capacity of 200 ml, mix. Then the glass is placed in a boiling water bath until polyethylene oxide 1500 is completely melted, the mixture is thoroughly mixed and poured into a mold for rectal suppositories with an average weight of 1 suppository of 2 g. The content of active components in 1 rectal suppository: EDTA (disodium salt of ethylenediamine tetraacetic acid) - 50 mg , dihydroquercetin - 50 mg, dimexide - 100 mg, oxidized dextran - 25 mg, polyethylene oxide 6000 - up to 2 g. After 7 days of rectal administration of the claimed agent in the form of solutions with concentrations of 100 mg / ml in an amount of 50 μl, the thickness of the prostate epithelium in mice on the sulpiride model of prostatic hyperplasia, the thickness of the prostatic epithelium decreased to 16.1 ± 1.7 μm.

Example 4. 2.5 g of EDTA (disodium salt of ethylenediamine tetraacetic acid), 2.5 g of dihydroquercetin, 5 ml of a 25% solution in oxidized dextran dimexide (with an average mass of 60 kDa) and 100 g of polyethylene oxide 1500 are placed in a glass beaker with a capacity of 200 ml, mix. Then the glass is placed in a boiling water bath until polyethylene oxide 1500 is completely melted, the mixture is thoroughly mixed and poured into a mold for rectal suppositories with an average weight of 1 suppository of 2 g. The content of active components in 1 rectal suppository: EDTA (disodium salt of ethylenediamine tetraacetic acid) - 50 mg , dihydroquercetin - 50 mg, dimexide - 100 mg, oxidized dextran - 25 mg, polyethylene oxide 1500 - up to 2 g. Thickness of the prostate epithelium in mice, μm (after 7 days of rectal administration in the form of solutions with concentrations of 100 mg / ml in an amount of 50 μl) on a sulpiride model of prostatic hyperplasia in mice - 15.4 ± 0.8.

Claims (2)

An agent for reducing pathomorphological changes in prostatic hyperplasia, including dihydroquercetin, characterized in that it additionally contains oxidized dextran, dimexide, EDTA, polyethylene oxide in the following proportions: Oxidized dextran 1.25 mass. % Dimexide 5.0 mass. % EDTA 2.5 mass. % Dihydroquercetin 2.5 mass. % Polyethylene oxide 6000 88.75 mass. %