RU2764850C1 - Method and remedy for treatment and prevention of benign prostatic hyperplasia - Google Patents

Abstract

FIELD: medicine; urology.

SUBSTANCE: group of inventions relates to the field of medicine, namely urology, and it is intended for the treatment or prevention of benign prostatic hyperplasia (hereinafter – BPH). For the treatment or prevention of BPH, a remedy containing iodized whey milk proteins or their hydrolysates is used. A method for the treatment or prevention of BPH includes taking the specified remedy by a man of any age with a daily dose of iodine as part of iodized whey milk proteins or their hydrolysates from 200 mcg to 1000 mcg. Taking is carried out one, two or three times a day during the established course, which is at least 3 months and up to 5 years. The remedy can be taken without breaks or with breaks between courses for 1-2 months.

EFFECT: use of a group of inventions makes it possible to increase the efficiency and safety of treatment or prevention of BPH.

4 cl, 2 tbl, 5 ex

Description

The field of technology to which the invention belongs

The invention relates to medicine, in particular to urology - to agents for the treatment and prevention of benign prostatic hyperplasia (BPH) and a method for the treatment and prevention of BPH.

State of the art

Benign prostatic hyperplasia (BPH) is the most common pathology in older and older men. By the age of 60, histologically, BPH is detected in 50% of men, and by the age of 85 - in 90%; about 30% of men over the age of 65 have lower urinary tract symptoms caused by BPH [Prostate Disease / Ed. SOUTH. Alyaev. - M.: GEOTAR-Media, 2009. - S. 126-152]. A meta-analysis of more than 30 studies on the incidence of BPH in different countries showed that approximately 1 in 4 men suffer from lower urinary tract symptoms caused by BPH during their lifetime [Lee S.W.H., Chan E.M.C., Lai Y.K. The global burden of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A systematic review and meta-analysis // Sci. Rep. - 2017. - 7(1): 7984,].

The main goals of the treatment of BPH is to improve the quality of life of patients suffering from dysuric disorders, and to prevent the progression of the disease [Practical urology. A guide for doctors / ed. P.V. Glybochko, Yu.G. Alyaev. - M.: Medforum, 2012. - 352 p.]. Treatment of BPH should be carried out for a long time. Therefore, one of the main requirements for drugs for the treatment of BPH is low toxicity and the absence of significant adverse events.

Currently used 6 main groups of drugs for the treatment of BPH [Urology. Russian clinical guidelines / Ed. SOUTH. Alyaeva, P.V. Glybochko, D.Yu. Pushkar. - M.: GEOTAR-Media, 2016. - S. 15-38; Oelke M., Bachmann A., Descazeaud A. et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction // Eur. Urol. - 2013. - Vol. 64. - P. 118-140].

1. Antagonists of alpha-1-adrenergic receptors (alpha-1-blockers): alfuzosin, doxazosin, silodosin, tamsulosin, terazosin [Andrology. Pharmacotherapy without mistakes. A guide for doctors / ed. A.A. Kamalova. - M.: E-noto, 2017. - S. 21-120]. The main adverse events of this group of drugs are asthenia, dizziness, orthostatic hypotension, ejaculation disorder [Shum C.F., Lau W., Theo C.P.C. Medical therapy for clinical benign prostatic hyperplasia: α1 Antagonists, 5α reductase inhibitors and their combination // Asian J. Urol. - 2017. - Vol. 4. - P. 185-190; Thomas D., Chughtai B., Kini M., Te A. Emerging drugs for the treatment of benign prostatic hyperplasia // Expert Opin. Emerg. drugs. - 2017. - Vol. 22. - P. 201-212].

2. 5-alpha reductase inhibitors: dutasteride and finasteride [Andrology. Pharmacotherapy without mistakes. A guide for doctors / ed. A.A. Kamalova. - M.: E-noto, 2017. - S. 21-120]. The main adverse effects of 5-alpha reductase inhibitors are decreased libido, erectile dysfunction, ejaculation disorders, gynecomastia, and even breast cancer in men [Corona G., Tirabassi G., Santi D. et al. Sexual dysfunction in subjects treated with inhibitors of 5α-reductase for benign prostatic hyperplasia: a comprehensive review and meta-analysis // Andrology. - 2017. - Vol. 5. - P. 671-678; Jun J.E.J., Kinkade A., Tung A.C.H., Tejani A.M. 5α-Reductase inhibitors for treatment of benign prostatic hyperplasia: a systematic review and meta-analysis // Can. J. Hosp. Pharm. - 2017. - Vol. 70. - P. 113-119].

3. Antagonists of muscarinic receptors (M-anticholinergics): solifenacin, tolterodine, trospium chloride darifenacin, fesoterodine, oxybutynin, propiverine [Andrology. Pharmacotherapy without mistakes. A guide for doctors / ed. A.A. Kamalova. - M.: E-noto, 2017. - S. 21-120]. The main adverse effects of M-anticholinergics are dry mouth, dizziness, constipation, difficulty urinating, nasopharyngitis [Ng K.K., Ng F.C. The use of antimuscarinics, phosphodiesterase type V inhibitors and phytotherapy for lower urinary tract symptoms in men // Asian J. Urol. - 2017. - Vol. 4. - P. 191-194].

4. Type 5 phosphodiesterase inhibitors: sildenafil, tadalafil, vardenafil [Andrology. Pharmacotherapy without mistakes. A guide for doctors / ed. A.A. Kamalova. - M.: E-noto, 2017. - S. 21-120]. The most common adverse events with type 5 phosphodiesterase inhibitors are headaches, back pain, dizziness, dyspepsia, gastroesophageal reflux, diarrhea, myalgia, nasopharyngitis [Sun H.Y., Lee B., Kim J.H. Factors affecting the efficacy and safety of phosphodiesterase 5 inhibitor and placebo in treatment for lower urinary tract symptoms: meta-analysis and meta-regression // Int. Urol. Nephrol. - 2018. - Vol. 50. - P. 35-47; Thomas D., Chughtai B., Kini M., Te A. Emerging drugs for the treatment of benign prostatic hyperplasia // Expert Opin. Emerg. drugs. - 2017. - Vol. 22. - P. 201-212].

5. Analogues of vasopressin: desmopressin [Andrology. Pharmacotherapy without mistakes. A guide for doctors / ed. A.A. Kamalova. - M: E-noto, 2017. - S. 21-120]. The most common adverse events of vasopressin analogues are hyponatremia, peripheral edema, hypertension, headache, dizziness, nausea, diarrhea, abdominal pain, dry mouth [Rembratt A., Riis A., Norgaard J.P. Desmopressin treatment in nocturia: an analysis of risk factors for hyponatremia // Neurourol. Urodyne. 2006 Vol. 25. No. 2. P. 105-109].

6. Phytotherapy. Of the herbal remedies, the most commonly used alcoholic extract of the fruits of the creeping palm (Serenoa repens): the original drug (Prostamol Uno) and its generics [Ooi S.L., Rak S.C. Serenoa repens for lower urinary tract symptoms/benign prostatic hyperplasia: current evidence and its clinical implications in naturopathic medicine // J. Altern. complement. Med. - 2017. - Vol. 23. - P. 599-606]. Phytopreparations meet the safety requirements and the possibility of long-term use in patients with BPH. However, the common disadvantages of herbal remedies used in the treatment of BPH are the difficulty of standardization and quality control; different series of the same drug may differ in the quantitative composition of active ingredients; difficulty in determining the mechanisms of action due to the multicomponent composition of plant complexes; instability of clinical effects; growth of raw materials outside of Russia.

The closest analogue to the invention in terms of the totality of common essential features is a plant extract of the fruits of the creeping palm tree Serenoa repens (original drug "Prostamol Uno" in capsules of 320 mg). Serenoa repens extract has antiandrogenic, antiproliferative, decongestant and anti-inflammatory effects; indications for use - BPH stage I and II; apply 320 mg 1 time per day, the duration of the course of treatment is not limited in time, the recommended duration of the course of therapy is at least three months [Diseases of the prostate gland / Ed. SOUTH. Alyaev. - M.: GEOTAR-Media, 2009. - S. 126-152]. This analogue has a number of significant drawbacks. Serenoa repens extract has an unstable clinical effect. Meta-analyses of numerous clinical studies of Serenoa repens extract have yielded conflicting results. An early meta-analysis showed that Serenoa repens extract has a moderate beneficial effect in patients with BPH [Wilt T., Ishani A., Mac Donald R. Serenoa repens for benign prostatic hyperplasia // Cochrane Database Syst. Rev. - 2002. - No. 3.-CD001423]. However, subsequent meta-analyses have shown that the therapeutic effects of Serenoa repens extract do not exceed those of placebo [Tacklind J., Macdonald R., Rutks I. et al. Serenoa repens for benign prostatic hyperplasia // Cochrane Database Syst. Rev. - 2012. - 12:CD001423]. Serenoa repens extract has a multicomponent composition, which makes standardization and quality control difficult; which of the components of the extract are responsible for the mechanisms of action has not been determined. Medicinal plant materials for the production of preparations from Serenoa repens extract grow mainly in the United States, and therefore are exotic, expensive and inaccessible for processing in Russia. In the domestic pharmaceutical market, both original and generic drugs (generics) are represented by products produced abroad (Germany, France, etc.), which makes the drug from Serenoa repens extract more expensive for the domestic consumer.

Disclosure of invention

The objective of the present invention is to create a new effective and safe agent and method for the treatment of BPH, expanding the list of drugs of organic origin for the treatment of BPH without side effects with the possibility of long-term use.

In the present invention, for the first time, it is proposed to use iodized whey proteins of cow's milk or iodized hydrolysates of whey proteins of cow's milk as an agent for the treatment of BPH. The dried concentrate of iodinated whey proteins or their hydrolysates contains 2.2% iodine (22000 mcg per 1 g of powder). Iodine in the concentrate is covalently bound to amino acids (mainly tyrosine) in the form of monoiodotyrosine and diiodotyrosine, which form a structural isometric shape similar to the natural compound of iodine.

Until now, the possibility of using iodinated whey proteins or their hydrolysates for the treatment of BPH has not been known. To date, the authors of the present invention have obtained evidence of the effectiveness of iodinated whey proteins or their hydrolysates as a treatment for BPH. The possibility of using iodinated whey proteins or their hydrolysates for the treatment of BPH has never before been considered by anyone and was not obvious. The advantage of iodized whey milk proteins or their hydrolysates is that in the covalently bound (so-called "organic") form in the composition of amino acids, the safety and biomedical availability of iodine significantly increase, and iodized whey proteins or their hydrolysates do not have undesirable phenomena characteristic for inorganic iodine compounds. Another advantage of iodized whey protein (or hydrolysates of iodized whey proteins of cow's milk) is the availability of raw materials, which creates the possibility of creating a sufficient amount of iodized whey proteins or their hydrolysates, and from them - agents for the treatment of BPH.

The second object of the present invention is a pharmaceutical composition for the treatment of BPH, which contains iodized whey milk proteins or their hydrolysates in an effective amount as an active ingredient and the rest - pharmaceutically acceptable carriers, excipients. The pharmaceutical composition may be in the form of an oral dosage form, an oily solution, a suspension, a gel, a capsule, a tablet, a liposome, or a rectal suppository. The pharmaceutical composition is intended for men of any age for the prevention and treatment of BPH.

The third object of the present invention is a method for the treatment and prevention of BPH, since iodinated whey proteins have been found to have positive therapeutic effects in relation to BPH. Why were selected doses of iodinated whey milk proteins and schemes for their use, necessary and sufficient to obtain a therapeutic or prophylactic effect. Thus, a method for the treatment and prevention of BPH includes taking a man of any age of the above-mentioned agent in an effective amount and for a course of sufficient duration. The method provides that the daily dose of the above-mentioned agent is from 200 μg to 1000 μg of iodine in the composition of iodized whey milk proteins or their hydrolysates, and its intake would be carried out one or two, or three times a day during the established course, which is at least 3 months and up to 5 years, the remedy can be taken without interruptions or with breaks between courses for 1-2 months.

The technical result of the claimed group of inventions are the following advantages that have been identified as a result of scientific and practical research:

1. Iodized whey proteins or their hydrolysates contain iodine as an amino acid, which makes iodine safe for long-term use.

2. Iodized whey proteins have more pronounced curative effects on BPH than Serenoa repens extract.

3. Comparative studies conducted by the authors proved that in the model of BPH induced in male rats by testosterone, the therapeutic effects of iodinated whey milk proteins are more pronounced than those of Serenoa repens extract

4. Compared to Serenoa repens extract, iodized whey proteins have a better safety profile. Serenoa repens extract has infrequent and not very pronounced side effects, but their list is quite large: abdominal pain, diarrhea, nausea, weakness, headaches, rhinitis, decreased libido [Agbabiaka T.V., Pittler M.N., Wider B ., Ernst E. Serenoa repens (saw palmetto): a systematic review of adverse events // Drug Saf. - 2009. - Vol. 32. - P. 637-647].

5. Compared to Serenoa repens extract, there are significantly more affordable and cost-effective raw materials for the production of iodized whey proteins or their hydrolysates. Serenoa repens - an exotic plant of the south of the USA [Sosnowska J., Balslev H. American palm ethnomedicine: a metaanalysis // J. Ethnobiol. Ethnomed. - 2009. - 5:43]. Iodized whey proteins or their hydrolysates are produced from the inorganic compound of iodine and whey protein by enzymatic synthesis.

All the identified properties of iodized whey proteins or their hydrolysates compare favorably with their analogue - Serenoa repens extract - with greater efficiency and a wider therapeutic and prophylactic effect on BPH, greater safety, the possibility of long-term use, and the availability of raw materials.

Implementation of the invention

Below, the applicants present examples of embodiments of the invention that will be understandable to specialists working in the field of creation and use of drugs for the treatment of BPH, primarily urologists, andrologists and pharmacologists, but they are not intended to limit the scope of claims.

The authors for the first time revealed the ability to treat BPH with the help of iodized whey milk proteins. The inventors proposed to use iodinated whey proteins or their hydrolysates as an active ingredient for the production of an agent for the treatment or prevention of BPH.

In addition, a pharmaceutical composition for the treatment of BPH is proposed, which includes an effective amount of iodinated whey milk proteins or their hydrolysates and pharmaceutically acceptable excipients, including carriers, processing aids. The composition may be in the form of a tablet, capsule, oil solution, suspension, gel, suppository for rectal administration, in liposomal form.

In addition, a method for the treatment and prevention of BPH is proposed, which includes taking by a man of any age suffering from BPH, an agent in an effective amount and a course of sufficient duration, which has a therapeutic and prophylactic effect on BPH. At the same time, the daily dose of the mentioned agent is from 200 μg to 1000 μg of iodine in the composition of iodized whey milk proteins or their hydrolysates, and its administration is carried out once or twice or three times a day during the established course, which is at least 3 months and up to 5 years, the drug is taken without interruptions or with breaks between courses for 1-2 months.

The studies were carried out on male Wistar rats bred at the laboratory animal nursery "Rappolovo" of the Russian Academy of Medical Sciences. The study used the following drugs.

Dried iodized whey protein powder; the powder was obtained from the domestic company Chemical Technologies LLC (Moscow, Russia). Contains 2.2% iodine (22,000 mcg per 1 g of powder).

A mixture of testosterone esters - Omnadren 250 (Jelfa, Poland) in the form of a sterile oil solution of 1 ml, testosterone (a mixture of esters), in 1 ml of testosterone propionate (30.0 mg), testosterone phenylpropionate (60.0 mg), testosterone isocaproate ( 60.0 mg), testosterone capronate (100.0 mg), benzyl alcohol (50.0 mg), peanut oil for injection.

Serenoa repens fruit extract, 320 mg capsules (Prostamol Uno, Berlin-Chemie AG, Germany).

Example 1 Treatment of testosterone-induced BPH with iodinated whey milk proteins versus Serenoa repens extract in a population of 43 animals.

The experiment was carried out on 43 mature male Wistar rats with an initial weight of 380-420 g obtained from the Federal State Unitary Enterprise "Nursery of laboratory animals "Rappolovo" (Russia, Leningrad region). BPH was induced according to the following protocol: surgical castration, on the 7th day after castration testosterone ester mixture was started subcutaneously at a dose of 0.1 ml (25 mg)/kg body weight every other day (every second day) for 20 days. The animals were randomized and divided into 4 groups: group 1 - intact control, 7 rats did not receive any treatment until the end of the experiment; group 2 - BPH-control, 13 rats, castration and induction of BPH, injection refined vegetable oil for 4 weeks; 3rd group - BPH + iodized whey milk proteins, 13 rats, castration and induction of BPH, administration of iodized whey milk proteins proteins in refined vegetable oil for 4 weeks at a daily dose of 200 µg iodine/kg body weight; 4th group - BPH + Serenoa repens, 10 rats, castration and induction of BPH, administration of an alcoholic extract of Serenoa repens fruits, previously mixed with vegetable oil, for 4 weeks at a daily dose of 200 mg/kg of body weight. At the end of the drug administration, the animals of all groups were euthanized with chloroform vapors. The results were evaluated by the effect of drugs on the prostatic index of various parts of the prostate and the entire gland. At autopsy, the rat prostate gland was removed as a complex of the dorsolateral section, two ventral lobes, and two anterior lobes. The sections of the prostate gland were weighed, for each of the sections and for the entire gland, the prostatic index was calculated as the ratio of the mass of the prostate section or the entire gland (in mg) to 100 g of the animal's body weight. The results were subjected to statistical processing using the standard set of functions of the STATISTICA program. Numerical data are given as M±m, where M is the arithmetic mean; m is the standard error of the arithmetic mean. To assess statistical significance, Student's t-test was used with a 95% significance level.

Table 1 shows the data on the effect of the tested agents on the prostatic index of various sections and the entire prostate of rats.

As can be seen from Table 1, the administration of a prolonged form of testosterone causes BPH in male rats. Compared with the intact control, rats from the "BPH-control" group showed a statistically significant increase in the prostatic indices of the dorsolateral region by 225%, ventral lobes - by 262%, anterior lobes - by 300%, and the entire prostate - by 229%. Compared with BPH control, iodized whey milk proteins statistically significantly reduced the prostatic indices of the dorsolateral region by 29%, ventral lobes - by 26%, anterior lobes - by 33%, and the entire prostate - by 32%. The curative effects of Serenoa repens extract on BPH were weaker. Compared with BPH control, Serenoa repens extract reduced the prostatic indices of the dorsolateral section by 15% (p<0.05), ventral lobes - by 7% (p>0.05), anterior lobes - by 20% (p<0.05). 05), the entire prostate - by 12% (p<0.05). Moreover, compared with the Serenoa repens extract, iodized whey milk proteins statistically significantly more effectively reduced the prostatic indices of the dorsolateral region by 18%, the ventral lobes - by 15%, and the entire prostate - by 16% (Table 1).

The following are examples of pharmaceutical compositions based on iodinated whey proteins or their hydrolysates.

Example 2. From iodinated whey milk proteins or their hydrolysates, tablets are obtained (drug, biologically active food supplement) according to the recipe indicated in table 2.

Example 3 Capsules weighing 0.6-0.7 g are obtained from iodized whey milk proteins or their hydrolysates. Capsules have the same granulate composition as tablets. The content of iodine in 1 capsule is 200 mcg ± 10%.

Example 4 An oil solution is obtained from iodinated whey proteins or their hydrolysates. Iodized whey milk proteins or their hydrolysates are dissolved in vegetable oil (peach, stone, corn, sunflower and / or other edible oil) at a ratio of iodized whey proteins or their hydrolysates: oil = 0.1: 8-10). The content of iodine in 3 drops of oil is 200 mcg ± 10%.

Example 5. Suppositories are made from iodized whey milk proteins or their hydrolysates by dissolving it in cocoa butter when heated to 45-50 degrees Celsius and stirring at a ratio of iodized whey milk proteins or their hydrolysates: cocoa butter = 0.05-0.1: 90, pouring into molds and subsequent cooling of the mass directly in the molds to room temperature. The content of iodine in 1 candle is from 200 to 400 mcg.

The method for the treatment and prevention of BPH is used in men of any age. Iodine in the composition of iodized whey proteins or their hydrolysates is used in a daily dose of 200 mcg to 1000 mcg. Iodized whey milk proteins or their hydrolysates are prescribed in the form of tablets of 0.01 g of the active substance, 1-3 tablets 2-3 times a day; in the form of capsules of 0.01 g of the active substance, 1-3 capsules 2-3 times a day; in the form of an oil solution of 0.01 g of the active substance in 3 drops, 3-5 drops 2-3 times a day; in the form of suppositories, 0.01-0.02 g of the active substance, 1-2 suppositories 2 times a day in the morning and evening, or 2 suppositories containing 0.01-0.02 g of the active substance, in the evening at night. Reception of iodinated whey proteins or their hydrolysates is carried out once or twice or three times a day during the established course, which is at least 3 months and up to 5 years, the agent can be taken without interruptions or with breaks between courses for 1-2 months.

Iodized whey milk proteins or their hydrolysates are superior in a number of parameters to the closest analogue - plant extract of Serenoa repens palm fruits. Compared to Serenoa repens extract, iodized whey proteins or their hydrolysates have a more pronounced therapeutic effect on BPH, have a better safety profile, and there are much more affordable and cost-effective raw materials for the production of iodized whey proteins or their hydrolysates.

Claims (4)

1. The use of an agent containing iodinated whey proteins or their hydrolysates for the treatment or prevention of benign prostatic hyperplasia. 2. The use of the agent according to claim 1, characterized in that it contains iodized whey milk proteins or their hydrolysates in an effective amount as an active ingredient and the rest is pharmaceutically acceptable carriers, excipients. 3. The use of the agent according to claim 1, characterized in that the agent is made in the form of a dosage form for oral administration: tablets, capsules, oil solution, gel, suspension; or rectal suppositories. 4. A method for the treatment or prevention of benign prostatic hyperplasia, characterized in that it includes taking the agent according to claim 1 by a man of any age with a daily dose of iodine in the composition of iodized whey milk proteins or their hydrolysates from 200 μg to 1000 μg, and its administration is carried out one , or two or three times a day during the established course, which is at least 3 months and up to 5 years; the remedy can be taken without interruptions or with breaks between courses for 1-2 months.