RU2571818C2 - Medication (versions), pharmaceutical composition and method of chemoprophylaxis of prostate pre-cancer and cancer - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the pharmaceutical industry, in particular to the application of a coniferous provitamin concentrate, to a medication based on the coniferous provitamin concentrate, a pharmaceutical composition, containing the coniferous provitamin concentrate, and to a method of the prophylaxis and treatment of benign prostate hyperplasia.

EFFECT: coniferous provitamin concentrate possesses the rich composition of active substances, more expressed therapeutic and prophylactic effect with respect to benign prostate hyperplasia, as well as it has a better safety profile and a possibility of long-term application.

9 cl, 4 tbl, 8 ex

Description

FIELD OF THE INVENTION

The invention relates to medicine, in particular to oncourology - to means for the prevention of precancer and prostate cancer (PCa), and a method for the prevention of PCa.

State of the art

PCa is a global social problem, one of the most common oncological diseases in men in developed countries. In the XXI century, prostate cancer has become one of the main culprits of the death of men from malignant neoplasms. PCa is the second most common cancer among men. In general, every sixth man will be diagnosed with prostate cancer throughout his life, about 3% of men have a chance to die from prostate cancer. The American Center for Disease Control and Prevention estimates the likelihood of men to develop prostate cancer by the age of 45 as 1 in 2,500, 50 on 1 in 476, 55 on 1 in 120, 60 on 1 in 43, 65 on 1 of 21, 70 - 1 out of 13, 75 years - 1 out of 9. However, the development of prostate cancer begins at a much earlier age. The number of men suffering from the so-called indolent (latent, latent) prostate cancer significantly exceeds the number of diagnosed cases. The problem of prostate cancer prevention in men with indolent forms is especially important and relevant. The precursor of invasive prostate cancer is pre-cancerous pathology - prostatic intraepithelial neoplasia (IDU), which is characterized by dysplasia and hyperplasia of epithelial cells lining the acini and ducts of the prostate [Epstein J.I. Precursor lesions to prostatic adenocarcinoma // Virchows Arch. - 2009 .-- Vol.454. - P.1-16].

Cancer prophylaxis with prolonged use of drugs or natural substances is defined as chemoprophylaxis, and agents that prevent the onset and development of malignant tumors are defined as chemoprophylaxis or reducing the risk of the disease [Davis J.S., Wu X. Current state and future challenges of chemoprevention // Discov. Med. - 2012 .-- Vol.13. P.385-390.

Chemoprophylaxis of prostate cancer should be the main method of combating this disease, the targets for which are precancer, benign prostatic hyperplasia, chronic inflammation, as well as age. Chemoprophylaxis of prostate cancer can be: a) primary (in practically healthy men from a certain age and in patients with background prostate pathology): b) secondary (in patients with precancerous changes in the prostate).

Several herbal remedies are known that in preclinical studies prevented the development of prostate cancer. In transgenic and combined models (carcinogen initiation and promotion with testosterone), soy isoflavones — genistein, a mixture of isoflavones — prevented prostate carcinogenesis; tea catechins - epigallocatechin-3-gallate, a mixture of catechins; polyphenolic compounds and extracts containing them - resveratrol, cocoa polyphenol extract, grape seed extract; plant extracts of Serenoa repens, Pygeum africanum, Roystonea regia and Scutellaria barbata. The above herbal remedies have a number of significant drawbacks, due to which they are not brought to clinical practice. In the experiments, all the above herbal remedies showed the ability to inhibit either IDUs or only prostate cancer, but did not simultaneously affect all stages of prostate carcinogenesis from IDUs to invasive and metastatic prostate cancer [Bespalov V.G., Murazov Y.G., Panchenko A.V. . Chemoprophylaxis of prostate cancer // Medline Express. - 2011. - No. 1. - S. 57-64].

Currently, in clinical practice, only synthetic drugs are used for chemoprophylaxis of prostate cancer.

The best known use for the chemoprophylaxis of prostate cancer is the synthetic drugs Finasteride (N-tert-Butyl-3-oxo-4-aza-5alpha-androst-1-ene-17beta-carboxamide in 5 mg tablets, an inhibitor of 5-α-reductase Type II) and Dutasteride (5 alpha, 17 beta) -N- {2,5-bis (trifluoromethyl) phenyl} -3-oxo-4-azaadrost-1-en-17-carboxamide in 0.5 mg capsules , an inhibitor of 5-α-reductase as I. and type II). In a randomized study called "PCRT" in 18882 men 55 years of age and older, finasteride reduced the risk of developing prostate cancer by 24.8% compared with placebo [Thompson I.M., Klein E.A., Lippman S.M. et al. Prevention of prostate cancer with finasteride: US / European perspective // Eur Urol. - 2003. - Vol. 44. - P.650-655]. Finasteride, taken for chemoprophylaxis of prostate cancer for 4 years or more, is known to reduce the risk of its development by 26% [Wilt T.J., MacDonald R., Hagerty K. etal. Five-alpha-reductase inhibitors for prostate cancer prevention // Cochrane Database Syst. Rev. - 2008 Apr 16; (2): CD007091]. In the experiments, finasteride reduced the frequency of prostate adenocarcinomas in transgenic rats SV-40 Tag [Cho Y.M., Takahashi S., Asamoto M. et al. Suppressive effects of antiandrogens, finasteride and flutamide on development of prostatic lesions in a transgenic rat model // Prostate Cancer Prostatic Dis. - 2007 .-- Vol.10. - P.378-383], as well as in Wistar rats exposed to methyl nitrosourea and testosterone [Esmat A.Y., Refaie P.M., Shaheen M.H., Said M.M. Chemoprevention of prostate carcinogenesis by DFMO and / or finasteride treatment in male Wistar rats // Tumori. - 2002 .-- Vol.88. - P.513-521]. It is known that the drug "Dutasteride", taken as a chemoprophylactic agent at 0.5 mg daily for 4 years, significantly reduced the risk of developing prostate cancer by 22.8% [Andriole G.L., Bostwick D.G., Brawley O.W. et al. Effect of dutasteride on the risk of prostate cancer // N. Engl. J. Med. - 2010 .-- Vol.362. - P.1192-1202].

However, 5-α-reductase inhibitors (finasteride, dutasteride) have a number of significant side effects, primarily a violation of sexual function: erectile dysfunction, decreased libido, decreased ejaculate volume, gynecomastia [Prostate Diseases / Ed. SOUTH. Alyaeva. - M .: GEOTAR-Media, 2009. - 240 p.]. The use of 5-α-reductase inhibitors for chemoprophylaxis of prostate cancer may lead to late diagnosis of prostate cancer, when the patient will be diagnosed with prostate cancer with a high Gleason index [Walsh P.C. Chemoprevention of prostate cancer // NEJM. - 2010 .-- Vol.362. - P.1237-1238]. A meta-analysis of randomized clinical trials of finasteride showed that finasteride does not reduce the risk of prostate cancer in men with a prostate-specific antigen (PSA) in the blood> 4 ng / ml [Wilt T.J., MacDonald R., Hagerty K. et al. Five-alpha-reductase inhibitors for prostate cancer prevention // Cochrane Database Syst. Rev. - 2008 Apr 16; (2): CD007091], namely elevated blood PSA levels are a serious risk factor for prostate cancer. The above disadvantages limit the possibility of using 5-α-reductase inhibitors for chemoprophylaxis of prostate cancer and call into question their use in practically healthy men, while finasteride reduces the risk of prostate cancer in healthy men with a PSA level in the blood of <4 ng / ml.

In addition to 5-α-reductase inhibitors, synthetic agents are known which in preclinical studies on transgenic and combined models (carcinogen initiation and testosterone promotion) inhibit prostate carcinogenesis. These include, first of all, hormonal preparations - antiandrogens (doxazosin, tamsulosin, flutamide), analogs of releasing hormones (leuroprorelin), estrogens and antiestrogens (2-methoxyestradiol, estradiol, tamoxifen, toremifene), steroid hormones, dermosterone (degermoneronone, dermoneron degoneron) , histone deacetylase inhibitor. Prostate carcinogenesis was also inhibited by antiproliferative drugs (α-difluoromethylornithine), non-steroidal anti-inflammatory drugs (sulindac, celecoxib, flurbiprofen), retinoids (phenretinide, 9-cis-retinoic acid), vitamins and antioxidants such as vitamin D, carotenoid lycopene isolated from garlic (diallyl trisulfide, diallyl disulfide, sulforaphane), soybean Bowman-Birk protease inhibitor, inositol hexaphosphate, omega-3 polyunsaturated fatty acids. However, almost all of these synthetic agents have serious side and toxic effects; in addition, in the experiments they showed the ability to inhibit either only IDUs or only prostate cancer, but did not simultaneously affect all stages of prostate carcinogenesis from IDUs to invasive and metastatic prostate cancer [Bespalov V.G., Murazov Y.G., Panchenko A.V. . Chemoprophylaxis of prostate cancer // Medline Express. - 2011. - No. 1. - S. 57-64].

For chemoprophylaxis of prostate cancer, the presence of only 5-α-reductase inhibitors is clearly not enough. Therefore, the search for funds for the prevention and treatment of precancerous forms and cancer of the prostate continues.

The closest analogue to the invention in terms of common essential features is a plant extract of the palm fruit of the creeping Serenoa repens (Prostamol Uno drug in 320 mg capsules) [Wadsworth T.L., Worstell T.R., Greenberg N.M., Roselli CE. Effects of dietary saw palmetto on the prostate of transgenic adenocarcinoma of the mouse prostate model (TRAMP) // Prostate. - 2007. - Vol. 67. - P.661-673]. However, it has much less advantages than disadvantages (this will be discussed below). In addition, this raw material does not grow on the territory of the Russian Federation, therefore it is exotic, expensive and inaccessible for processing.

Disclosure of invention

The present invention is the creation of new effective and safe means and methods for the prevention of prostate cancer and prostate cancer, expanding the list of herbal preparations instead of synthetic medicines for the prevention of prostate cancer without side effects with the possibility of long-term use. In addition, it became possible to make the most efficient use of available plant materials obtained from logging waste.

In the present invention, it is proposed for the first time to use provitamin coniferous concentrate (CPC), produced by wood chemical enterprises in accordance with OST 56-32-78, as an agent for the prevention of prostate precancer and prostate cancer.

CPC is obtained from pine and spruce needles (coniferous paws). The chopped needles are loaded into a reactor with a reflux condenser and a heating jacket, extraction BR-1 or BR-2 brand gasoline is poured there (boiling point 80-120C), the extraction process is carried out at a boiling point for 4-6 hours with a liquid module 4- 6. The hot extract is drained through a filter, cooled to freeze the waxes, separated from the waxes by decantation and filtration, then treated with an aqueous solution of sodium hydroxide to remove the water-alkaline phase of the saponified substances in the form of sodium salts. An unsaponifiable gasoline extract in the same reactor is washed with water until the washings are neutral to remove residual sodium hydroxide. Unsaponifiable substances (CPC) are obtained as bottoms by distillation of the solvent. To remove traces of solvent, the CPC is treated with deaf and hot steam, then poured into containers in hot form and analyzed for compliance with OST 56-32-78. The yield of CPC is 6-7% of the loaded coniferous paw.

KPH contains unsaponifiable substances of pine and spruce needles. In the CPC phytol, sterols, carotenoids, vitamin E, squalene, prenols are defined. CPC - a thick oily product from yellow to orange in color, with a specific coniferous smell, mass fraction,%: volatiles - not more than 3, water - not more than 9, phytol - 12-25, phytosterol - 2-3, vitamin E - 0 , 5-0.6, carotenoids - 0.4-0.6 [Yagodin V.I. Fundamentals of chemistry and technology for processing green wood. - L .: Leningrad State University, 1981. - P.116].

The main components of CH are high molecular weight alcohols (sterols, aliphatic alcohols) - more than 50% - and their esters with high molecular weight fatty acids - more than 30%. The remaining components,%: polyoxy compounds - 8.7; hydrocarbons - 4.9 (alkanes, terpenes); aldehydes - 2.8; oxides - 0.2. The chemical composition of the main ingredients of the CPC [Roshchin V.I. Composition, structure and biological activity of terpenoids from the greenery of coniferous plants: Abstract. dis. Dr. chem. sciences. - SPb., 1995. - 35 p .; Roshchin V.I. The chemical composition of the lipid fraction of pine and spruce needles // Study and use of therapeutic and prophylactic preparations based on natural biologically active substances / Ed. V.G. Bespalova and V.B. Nekrasova. - St. Petersburg: Aesculapius, 2000. - S.114-116] is given in table 1.

Table 1. The chemical composition of the CPC Component Name Content in% Alcohols up to 35 Aldehydes and Ketones up to 30 Hydrocarbons up to 30 Phytol 20-22 Carotenoids to 10 including β-carotene up to 0.4 Sterols 2.6-3.0 Vitamin E about 1

The most valuable biologically active substances in the composition of the CPC are phytosterols (β-sitosterol, campesterol, stigmasterol); vitamin E (α-tocopherol, beta, gamma, delta tocopherols, alpha, beta, gamma, delta tocotrienols); carotenoids (β-carotene, α-carotene, lutein, xanthophils); polyprenols, phytol, squalene, vitamin K.

Since the middle of the last century, CPH has been used as a useful additive to the perfumery and cosmetic industry [V. Yagodin. Fundamentals of chemistry and technology for processing green wood. - L .: Leningrad State University, 1981. - P.116].

Provit based on CPC is used in cardiology as an inhibitor of lipid peroxidation (RU 2408382 C1). The use of Provitam based on FIR is known to prevent lung carcinogenesis [Bespalov VG, Nekrasova VB Medical and prophylactic agents from wood biomass. - SPb .: Publishing house of the Polytechnic. University, 2007. - S.112-117]. However, to date, the possibility of using CPC for the prevention of prostate cancer has not been known. To date, the authors of the present invention obtained evidence of the effectiveness of the use of CPC as a means for the prevention of prostate cancer and prostate cancer. The possibility of using CPC for the prevention of prostate precancer and prostate cancer has never been considered by anyone and was not obvious, especially due to the fact that CPC is a complex multicomponent mixture made from non-food raw materials (needles). The advantage of this composition is that the raw material for the production of CPC is the needles - a waste of the logging industry, which supplies wood for the pulp and paper, furniture, construction industry. World reserves of raw materials - pine and spruce needles are concentrated precisely in Russia and are practically inexhaustible renewable resources. This is a prerequisite for creating a sufficient amount of CPC, and from it - means for the prevention of prostate precancer and prostate cancer.

The second object of the present invention is a means for the prevention of prostate cancer and prostate cancer, in which a provitamin coniferous concentrate is used as a plant extract. It can be made in the form of dietary supplements (for example, tablets) or a medicine (in any form for oral administration or in the form of rectal suppositories).

A third aspect of the present invention is a pharmaceutical composition for the prevention of precancer and prostate cancer, which contains an active amount of provitamin coniferous concentrate as an active ingredient and the rest are pharmaceutically acceptable carriers, excipients and / or solvents.

The pharmaceutical composition may be in the form of an oral dosage form, oil solution, suspension, gel, capsule, tablet, liposome or rectal suppository.

The pharmaceutical composition is intended for healthy men over the age of 40 who have a history of blood relatives with prostate cancer; healthy men over the age of 50 who have risk factors for prostate cancer (excessive calorie intake, increased intake of fat, meat, animal products, insufficient intake of plant foods, vegetables and fruits; obesity, diabetes mellitus, metabolic syndrome; physical inactivity; exposed to chemical carcinogens and ionizing radiation), patients over the age of 50 years, suffering from benign prostatic hyperplasia and prostatitis; patients of any age who have prostate precancer (IDU).

A fourth object of the present invention is a method for the prevention of precancerous pathology of the prostate and prostate cancer, since CPC has revealed positive effects in relation to the prevention of precancerous prostate pathology and the prevention of prostate cancer. Why were selected doses of CPC necessary and sufficient to obtain a prophylactic effect. Thus, a method for chemoprophylaxis of prostate cancer or prostate cancer involves the administration by a man of the aforementioned agent in an effective amount.

As used herein, prostate precancer refers to prostatic intraepithelial neoplasia (IDU).

The method has been successfully used in patients with prostate cancer risk factors, background prostate pathology, precancerous changes in the prostate, indolent micro-focal prostate cancer.

The method provides that the daily dose of the aforementioned agent is from 0.2 mg to 1 mg, and it should be taken one, or two, or three times a day for a specified course, which is at least 3 months and up to 5 years with a break between courses for 1-2 months.

The present method is indicated for healthy men over the age of 40 who have a history of blood relatives with prostate cancer; healthy men over the age of 50 who have risk factors for prostate cancer (excessive calorie intake, increased intake of fat, meat, animal products, insufficient intake of plant foods, vegetables and fruits; obesity, diabetes mellitus, metabolic syndrome; physical inactivity; exposed to chemical carcinogens and ionizing radiation), patients over the age of 50 years, suffering from benign prostatic hyperplasia and prostatitis; patients of any age who have prostate precancer (IDU).

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. CPC has a richer composition of active substances than Serenoa repens extract. As mentioned above, the active ingredients of the CPC are phytosterols, polyprenols, vitamin E, carotenoids, phytol, squalene, vitamin K, while the analogue is a liposterol extract from the fruit of the creeping palm Serenoa repens, the main active ingredients of which are lauric, myristic, oleic fatty acids and phytosterols [Sosnowska J., Balslev H. American palm ethnomedicine: a meta-analysis // J. Ethnobiol. Ethnomed. - 2009. - 5:43].

2. CPC has more pronounced therapeutic and prophylactic effects against prostate disease than Serenoa repens extract. The specific pharmacological effects of the extract of Serenoa repens on prostate disease are little known, it is assumed that the therapeutic and prophylactic activity of the extract of Serenoa repens is manifested mainly as a result of the antiproliferative and anti-inflammatory effects on the cells and tissue of the prostate, respectively [Magri V., Trinchieri A., Perletti G., Marras E. Activity of Serenoa repens. lycopene and selenium on prostatic disease: evidences and hypotheses // Arch. Ital. Urol. Androl. - 2008. - Vol.80. - P.65-78]. Due to the richer composition of the CPC, in addition to the antiproliferative and anti-inflammatory effects on the prostate, there are several more specific therapeutic and prophylactic mechanisms of action on the prostate. CPH polyprenols affect gene expression in prostate cancer cells; there is a prostin-1 gene in the genome of prostate cancer cells, the expression of which is associated with the absence of invasion of prostate cancer cells; protein production by this gene is regulated by the metabolite of polyprenols [Manos E.J., Kim M.L., Kassis J. et al. Dolichol-phosphate-mannose-3 (DPM3) / prostin-1 is a novel phospholipase C-gamma regulated gene negatively associated with prostate tumor invasion // Oncogene. - 2001 .-- Vol.20. - P.2781-2790]. In a meta-analysis of randomized trials, prolonged intake of vitamin E as a dietary supplement significantly reduces the risk of prostate cancer [Alkhenizan A., Hafez K. The role of vitamin E in the prevention of cancer: a meta-analysis of randomized controlled trials // Ann. Saudi Med. - 2007. - Vol. 27. - P.409-414]. In human prostate cancer cells, vitamin E inhibits growth and suppresses the function of androgen receptor and the expression of prostate-specific antigen [Zhang Y., Ni J., Messing E.M. et al. Vitamin E succinate inhibits the function of androgen receptor and the expression of prostate-specific antigen in prostate cancer cells // Proc. Natl. Acad. Sci. USA - 2002. - Vol. 99. - P.7408-7413], causes apoptosis of tumor cells of prostate cancer by activating various forms of caspases [Zu K., Ip C. Synergy between selenium and vitamin E in apoptosis induction is associated with activation of distinctive initiator caspases in human prostate cancer cells // Cancer Res. - 2003. - Vol. 63. - P.6988-6995]. In epidemiological studies, increased intake of carotenoids contained in the CPC: beta-carotene [IARC Working Group on the Evaluation of Cancer Preventive Agents. Carotenoids. - IARC Handbooks of Cancer Prevention. - Vol. 2. - France: International Agency for Research on Cancer, 1998. - 326 ps], lutein and zeaxanthin [Ribaya-Mercado J.D., Blumberg J.B. Lutein and zeaxanthin and their potential roles in disease prevention // J. Am. Coll. Nutr. - 2004 .-- Vol.23 (Suppl. 6). - P.567S-587S] reduces the risk of PCa. Lutein inhibits cell proliferation of androgen-independent and androgen-dependent prostate cancer [Gunasekera R.S., Sewgobind K. Desai S. et al. Lycopene and lutein inhibit proliferation in rat prostate carcinoma cells // Nutr Cancer. - 2007. - Vol. 58. - P.171-177]. Phytol is a ligand for PPAR cellular nuclear receptors and activates these receptors; activation of PPAR receptors in cells is an antiproliferative, antiangiogenic, and differentiating signal for prostate tissues [Ondrey F. Peroxisome proliferator-activated receptor gamma pathway targeting in carcinogenesis: implications for chemoprevention // Clin. Cancer Res. - 2009 .-- Vol.15. - P.2-8].

3. Compared with the extract of Serenoa repens, CPC has a more pronounced and wider prophylactic effect on precancer and prostate cancer. Serenoa repens extract is able to inhibit only the development of prostate cancer in genetically modified mice, while it does not affect precancerous changes in the prostate - IDU [Wadsworth T.L., Worstell T.R., Greenberg N.M., Roselli CE. Effects of dietary saw palmetto on the prostate of transgenic adenocarcinoma of the mouse prostate model (TRAMP) // Prostate. - 2007. - Vol. 67. - P.661-673]. CPH inhibits the development of both prostate cancer and IDU caused by testosterone. It is known that in the human population, the proportion of prostate cancer caused by genetic mutations and having a hereditary nature is very small [E. Imyanitov. Epidemiology and biology of prostate cancer // Practical Oncology. - 2008. - T. 9, No. 2. - S. 57-64]. Most cases of prostate cancer occur as a result of prolonged exposure to testosterone [Clinical Oncourology / Edited by Matveeva B.P. Moscow: Russian Society of Oncourologists, 2011. S.495-560]. That is why Serenoa repens extract, taken for 10 years in a large population of men (35171 men aged 50-76 years), did not prevent the occurrence of PCa [Bonnar-Pizzomo RM, Littman AJ, Kestin M., White E. Saw palmetto supplement use and prostate cancer risk // Nutr. Cancer - 2006 .-- Vol.55. - P.21-27], since most cases of prostate cancer in the general population are not associated with genetic risk.

4. Compared to Serenoa repens extract, CPC has a better safety profile. As a natural complex, Serenoa repens extract has not frequent and not very pronounced side effects [MacDonald R., Tacklind J.W., Rutks I., Wilt T.J. Serenoa repens monotherapy for benign prostatic hyperplasia (BPH): an updated Cochrane systematic review // BJU Int. - 2012 .-- Vol.109. - P.1756-1761], but their list is quite large: Serenoa repens extract causes abdominal pain, diarrhea, nausea, weakness, headaches, rhinitis, reduces libido [Agbabiaka TB, Pittler MH, Wider B., Ernst E. Serenoa repens (saw palmetto): a systematic review of adverse events // Drug Saf. - 2009 .-- Vol.32. - P.637-647]. CPH - a natural product in any commodity / preparative form does not give side effects with the exception of individual intolerance to the components of the needles [Bespalov VG, Nekrasova VB Medical and prophylactic agents from wood biomass. - SPb .: Publishing house of the Polytechnic. unta, 2007. - S.112-117], which is an indisputable advantage of the product of the invention over the Serenoa repens extract, and even more so over the synthetic drugs finasteride and dutasteride.

5. Compared to the Serenoa repens extract, there is a much more affordable and economically advantageous raw material for the production of CPC. Serenoa repens is an exotic plant in the south of the United States [Sosnowska J., Balslev H. American palm ethnomedicine: a meta-analysis // J. Ethnobiol. Ethnomed. - 2009. - 5:43]. KPH is produced from pine and spruce needles, widely available raw materials obtained from logging waste.

All the revealed properties of the CPC distinguish it from the analogue - Serenoa repens extract - with greater efficiency, safety, the possibility of long-term use, and availability of raw materials.

The implementation of the invention

Below, the applicant presents examples of embodiments of the invention that will be understandable to specialists working in the field of creating and using means for the prevention of prostate cancer and prostate cancer, especially urologists and oncologists, but they are not intended to limit the scope of claims.

The authors first revealed the ability to prevent the occurrence of foci of precancerous prostate (IDU), to prevent the occurrence of aggressive (invasive and metastatic) prostate cancer using CPC.

The inventors proposed the use of CPC as an active ingredient for the production of chemoprophylaxis for prostate cancer and prostate cancer.

In addition, a pharmaceutical composition is proposed for the chemoprophylaxis of prostate cancer and prostate cancer, which includes an effective amount of CPC and pharmaceutically acceptable excipients, including carriers and / or solvents, processing aids and / or lubricants. The pharmaceutical composition may be in the form of a tablet, capsule, oil solution, suspension, gel, suppository for rectal administration, in liposome form.

In addition, a method for the chemoprophylaxis of prostate cancer is proposed, which includes taking an effective amount of an agent to prevent prostate precancer (prostatic intraepithelial neoplasia) and prostate cancer. In the chemoprophylaxis of patients with prostate cancer risk factors, background prostate pathology, precancerous changes in the prostate, indolent micro-focal prostate cancer, CPC is used as the aforementioned agent in the form of dietary supplements or in the form of a pharmaceutical composition that additionally includes auxiliary components. In this case, the daily dose of the aforementioned agent is from 0.2 mg to 1 mg, and its administration is carried out one, or two, or three times a day for the prescribed course, which is at least 3 months and up to 5 years with a break of 1- 2 months.

Research conducted on the basis of the FSBI Research Institute of Oncology. N.N. Petrova of the Ministry of Health of Russia. The experiments were carried out on male rats Wistar wiring of the laboratory animal nursery "Rappolovo" RAMS. The following drugs and reagents were used in the study.

N-methyl-N-nitrosourea (MNM) in the form of a white powder was purchased from Sigma-Aldrich, Co (USA, Germany).

Coniferous provitamin concentrate (CPC) in the form of a paste of greenish-orange color was obtained from Fitolon-Med (St. Petersburg, Russia.

A mixture of testosterone esters (SET) - Omnadren 250 in the form of a 1 ml sterile oil solution, testosterone (ester mixture), 1 ml testosterone propionate (30.0 mg), testosterone phenylpropionate (60.0 mg), testosterone isocapronate (60, 0 mg), testosterone capronate (100.0 mg), benzyl alcohol (50.0 mg), peanut butter for injection.

Example 1. Prevention of precancerous prostate (IDU) using CPC in a population of 68 animals.

In 68 male rats, IDUs were induced according to the following scheme: surgical castration, 21 days after castration, administration of CET once at a dose of 833 mg / kg body weight was induced; 3 days after the SET injection, administration of a single intravenous MNM at a dose of 50 mg / kg body weight, dissolved in sterile saline at a concentration of 10 mg / ml; 7 days after the MNM injection, the administration of SET is intraperitoneal at a dose of 16.7 mg / kg body weight for 60 days with an interval between administrations of 3 days, a total of 15 injections; after this, the administration of SET is intraperitoneal at a dose of 16.7 mg / kg body weight, 1 time per week until the end of the experiment. KPH was introduced into the phases of promotion and progression of carcinogenesis of the prostate: daily, carefully mixed into the feed at the rate of 2 g / kg of the feed mixture. CPC began to be given 7 days after the introduction of MNM and was given until the end of the experiment. The experiment lasted for 55 weeks, the planned slaughter of the surviving animals was carried out in pairs of chloroform at the 56th week.

At the end of the experiment, as well as in animals who died before, a complete autopsy was performed. The prostate was removed as a complex of the dorsolateral, ventral and anterior lobes (coagulation glands) with seminal vesicles. In all rats, the prostate glands, regardless of macroscopic changes, were taken for histological examination. Fixation of tissues and their histological processing was carried out by standard methods. Serial sections of all prostate lobes were prepared with a microtome pitch of 500 μm. The diagnosis of IDU was made if the preparations revealed common structural changes: multiple or at least single foci (clusters) of acini with the presence of IDUs.

The results of a study of the impact of CPC on the development of IDUs are presented in table 2.

Table 2. The effect of CPC on the frequency and multiplicity of IDUs in rats exposed to castration, MNM and SET Indicator Group Control: MNM + SET MNM + SET + KPH The number of effective rats in the group 34 34 The number of rats with IDU total: abs. (%) 26 (76.5%) 19 (55.9%) The number of identified sections of the prostate with IDU 52 thirty The average number of departments of the prostate with IDUs per rat from the group, M ± m 1.53 ± 0.19 0.88 ± 0.16 ^{* *} The difference with the Castration CMA group is statistically significant.

In 76.5% of the rats from the control group and in 55.9% of the rats from the group with exposure to CP, IDU was diagnosed, which most often developed in the dorsolateral part of the prostate, less often in the ventral or anterior lobes. In one rat, IDUs were often detected in several parts of the prostate, i.e., there were multiple cases of IDUs. In most cases, in rats diagnosed with IDU, there were observed widespread structural changes in the tissue of the prostate, accumulations of acini with IDU in the foci. As a rule, when detecting common IDU in rats in the prostate, IDU was simultaneously severe and mild. Most often, IDUs were presented in a beam-like form, less commonly in micro-papillary and cribiform forms. When identifying single foci, the IDU was usually flat and beam-like. With extensive damage to prostate tissue, IDUs observed all its forms: flat, bundle-shaped, micro-papillary and cribiform.

As can be seen from table 2, in comparison with the control, CPC reduced the frequency of IDUs by 20.6% (p> 0.05), the multiplicity of IDUs - by 42.5% (p <0.05). In rats from the group with exposure to CPC, which were diagnosed with IDUs, in comparison with rats from the control group, prostate tissue lesions were less extensive, and sections of the more severe form of IDUs were more rare: micro-papillary and cribiform.

Example 2. Complete prevention of prostate precancer (IDU) using CPC in an individual.

In 2 male rats, IDUs were induced according to the scheme described in Example 1. 7 days after the injection of the MNM, rat No. 1 was injected with CPI: daily, they were thoroughly mixed into the feed at the rate of 2 g / kg of the feed mixture; rat No. 2 (control) received the same food without the addition of CPC. Rats were sacrificed 55 weeks after castration, the prostate glands were removed, subjected to standard histological processing, serial sections of all sections of the prostate were made, and the presence of IDUs was detected by light microscopy.

When analyzing serial sections of all sections of the prostate, rat No. 1, which received CPC, did not identify IDUs in any section of prostate tissue: the dorsolateral, ventral, and anterior prostate lobes looked the same as normal intact rats.

A male rat No. 2 (control) showed severe and mild IDUs in all parts of the prostate: dorsolateral, ventral, and anterior. Acinuses with IDUs accumulated in multiple foci. All forms of IDU were diagnosed: flat, beam-shaped, micro-papillary and cribiform.

Consequently, the CPC completely prevented the development of IDU in male rat No. 1. Male rats No. 1 and No. 2 were subjected to the same effects of castration, MNM and SET, which in male No. 2, who did not receive treatment and prophylactic agents, led to the development of multiple foci of IDUs of severe and mild degrees in all three departments of the prostate, including forms of IDU - micro-papillary and cribiform. In male rat No. 1, CPC completely warned the effects of castration, MNM, and omnadren; IDUs did not develop in any part of the prostate.

Example 3. Prevention of invasive prostate cancer using CPC in a population of 68 animals.

In 68 male rats, IDUs were induced according to the following scheme: surgical castration, 21 days after castration, administration of CET once at a dose of 833 mg / kg body weight was induced; 3 days after the SET injection, administration of a single intravenous MNM at a dose of 50 mg / kg body weight, dissolved in sterile saline at a concentration of 10 mg / ml; 7 days after the MNM injection, the administration of SET is intraperitoneal at a dose of 16.7 mg / kg body weight for 60 days with an interval between administrations of 3 days, a total of 15 injections; after this, the administration of SET is intraperitoneal at a dose of 16.7 mg / kg body weight, 1 time per week until the end of the experiment. KPH was introduced into the phases of promotion and progression of carcinogenesis of the prostate: daily, carefully mixed into the feed at the rate of 2 g / kg of the feed mixture. CPC began to be given 7 days after the introduction of MNM and was given until the end of the experiment. The experiment lasted for 55 weeks, the planned slaughter of the surviving animals was carried out in pairs of chloroform at the 56th week.

At the end of the experiment, as well as in animals who died before, a complete autopsy was performed. The prostate was removed as a complex of the dorsolateral, ventral and anterior lobes with seminal vesicles. In all rats, the prostate glands, regardless of macroscopic changes, were taken for histological examination. Fixation of tissues and their histological processing was carried out by standard methods. Serial sections of all prostate lobes were prepared with a microtome pitch of 500 μm. The diagnosis of prostate cancer was made taking into account the degree of differentiation according to the Gleason index.

The results of a study of the effect of CPC on the development of prostate cancer are presented in table 3.

Table 3. The effect of CPC on the frequency and multiplicity of prostate cancer in rats exposed to castration, MNM and SET Indicator Group Control: MNM + SET MNM + SET + KPH The number of effective rats in the group 34 34 The number of rats with prostate cancer: abs. (%) 22 (64.7%) 15 (44.1%) The number of detected prostate cancer 38 twenty The average number of prostate cancer in the rat from the group, M ± m 1.12 ± 0.18 0.59 ± 0.12 ^{* *} The difference with the Castration MNM Control group is statistically significant.

In 64.7% of the rats from the control group and in 44.1% of the rats from the group with exposure to CP, prostate cancer was diagnosed, which most often developed in the dorsolateral part of the prostate, less often in the ventral or anterior lobes. In one rat, prostate cancer was often detected in several parts of the prostate, that is, there were multiple cases of prostate cancer. In most cases, prostate cancer macroscopically looked like dense nodes with a tuberous surface. Some rats with prostate cancer had severe symptoms of lower urinary tract: impaired or blocked urination, hematuria, distended and tightly filled bladder during palpation of the abdominal cavity. Such rats were killed in a terminal state, with autopsy, large tumor lesions of the prostate were found in the lower abdominal cavity and pelvis, sometimes the tumor sprouted all sections of the prostate and looked like a single conglomerate, the bladder was distended and full, with signs of hematuria. By histological type, all cases of prostate cancer were adenocarcinomas, mainly with a high Gleason index (low degree of differentiation). In 32.4% of the rats from the control group and in 23.5% of the rats from the group with CPC exposure, PCa was metastatic. The most characteristic metastatic prostate cancer was metastases in the visceral peritoneum, omentum, mesentery of the intestine, diaphragm, various groups of lymph nodes.

As can be seen from table 2, in comparison with the control, CPC reduced the frequency of prostate cancer by 20.6% (p> 0.05), the multiplicity of prostate cancer - by 47.3% (p <0.05).

Example 4. Complete prevention of invasive metastatic cancer of the prostate using CPC in an individual.

In 2 male rats, invasive and metastatic prostate cancer was induced according to the scheme described in Example 3. 7 days after the injection of CMA, rat No. 3 was injected with CPC: daily, they were thoroughly mixed into the feed at the rate of 2 g / kg of the feed mixture; rat No. 4 (control) received the same food without the addition of CPC. Rats were sacrificed 55 weeks after castration, the prostate glands were removed, subjected to standard histological processing, serial sections of all sections of the prostate were made, and the presence of cancer was detected by light microscopy; metastatic nodes in rats No. 4 were subjected to standard histological processing and their histological nature was evaluated by light microscopy.

A male rat No. 3, which was given CPC, did not show pathological changes in the prostate and abdominal organs at autopsy. Histological analysis of serial sections of all sections of the prostate showed no tumor changes in any section of prostate tissue: the dorsolateral, ventral, and anterior prostates looked the same as normal intact rats.

An autopsy of rat No. 4 (control), which did not receive treatment and prophylactic agents, revealed a tumor lesion of all three sections of the prostate, a distended, overflowing urine with blood, and a bladder as a result of an obstruction of the urethra by a tumor; ascites, multiple metastases of the visceral peritoneum, omentum, mesentery of the intestine. Histological examination in rat No. 4 was diagnosed with three separate malignant tumors of the dorsolateral prostate, which affects more than half of the dorsolateral part, the ventral prostate, which affects the entire right ventral lobe, and the anterior prostate, which affects the entire left front lobe. All three tumors are high Gleason adenocarcinomas. Histological examination of metastatic nodes confirmed that metastases originate from prostate adenocarcinoma, all metastatic nodes were diagnosed with tumor lesions of the prostate adenocarcinoma with a high Gleason index.

Therefore, CPC completely prevented the development of invasive metastatic prostate cancer in male rat No. 4. Male rats No. 3 and No. 4 were subjected to the same effects during carcinogenesis (castration, MNM and SET), however, in male rat No. 3, CPC completely prevented carcinogenesis, and cancer did not develop in any part of the prostate, whereas in male No. 4, it did not receiving treatment and prophylaxis, the effects led to the development of cancer in all three departments of the prostate and multiple metastatic lesions of the abdominal cavity.

The following are examples of pharmaceutical compositions and dietary supplements based on KPH. Example 5. From KPH receive tablets according to the recipe indicated in table 4.

Table 4. The formulation of tablets with KPH without shell and with a shell №№ pp Name of components The dry matter content in 1 tablet, g A. Composition of the tablet core one KPH 0,100 2 Microcrystalline Cellulose (MCC) 0.365 3 Lactose (milk sugar) 0,120 four Potato starch 0,030 5 Excipients for tablet formation 0.015 Total: tablet core weight (uncoated tablet) 0.630 ± 10% B. Shell composition 6 Polyvinylpyrrolidone (PVP) 0.00600 7 Twin 80 0,00031 8 Cellulose-16 (MTs-16) 0.01000 9 Titanium dioxide pigment 0.0030 10 Dye: copper derivatives of chlorophyll (MPC) or food coloring (beta-carotene) 0.00009 eleven Talc Medical 0,00060 Total: tablet weight, g 0.650 ± 10%

Example 6. From KPH receive capsules weighing 0.3-0.4 g. Capsules have the same granulate composition as tablets. But given the lower weight of the contents of the capsules, the daily dose of capsules should be doubled in relation to the tablets.

Example 7. From the CPC receive an oil solution. KPH is dissolved in vegetable oil (peach, kernel, corn, sunflower and / or other edible oil) with a ratio of KPH: oil = 1: 8-10. With a lower oil content, the drops lose fluidity and do not flow out of the pipette. With a larger ratio - excess oil consumption and a large dose of drops.

Example 8. Candles are made from CPC by dissolving CPC in cocoa butter when heated to 45-50 degrees Celsius and stirring at a ratio of CPC: cocoa butter = 5-10: 90, pouring into molds and then cooling the mass directly in molds to room temperature. The content of the CPC in 1 candle is from 0.3 to 0.6 g.

The method of chemoprophylaxis of CPC can be applied at all stages of prostate carcinogenesis: in practically healthy men, patients with prostate cancer risk factors, patients with background prostate pathology (benign prostatic hyperplasia, prostatitis), patients with precancerous prostate pathology (IDU) and micro-focal latent (indolent) ) prostate cancer. Chemoprophylaxis of prostate cancer is indicated primarily for healthy men over the age of 40 who have a history of blood relatives who have prostate cancer; healthy men over the age of 50 who have risk factors for prostate cancer (excessive calorie intake, increased intake of fat, meat, animal products, insufficient intake of plant foods, vegetables and fruits; obesity, diabetes mellitus, metabolic syndrome; physical inactivity; exposed to chemical carcinogens and ionizing radiation), patients over the age of 50 years, suffering from benign prostatic hyperplasia and prostatitis; patients of any age who have prostate precancer (IDU).

KPH in the form of tablets is prescribed for 1-2 tablets 2-3 times a day. KPH in the form of capsules is prescribed 2-4 capsules 2-3 times a day, taking into account the same mass with granulate tablets. KPH in the form of an oil solution is prescribed based on the content of KPH in tablets of 0.1 g / tablet, that is, up to 0.6 g / day. If the solution is, then with a ratio of CPC: oil = 1: 10 and the solution content in 1 drop is 0.03 g, in each drop - 0.03 g. To obtain 0.6 g per day: 0.03 = 20 drops or 6-7 drops 3 times a day. KPH in the form of suppositories is prescribed intrarectally for 1 suppository containing 0.3 g of KPH, 2 times a day in the morning and evening, or 1 suppository containing 0.6 g of KPH in the evening at night. The duration of taking funds with CPC is at least 3 months and up to 5 years with a break between courses of 1-2 months.

The CPC is superior in a number of parameters to the closest analogue - plant extract of the palm fruit of the creeping Serenoa repens. Compared to Serenoa repens extract, CPC has a richer composition of active substances and more pronounced specific therapeutic and prophylactic effects in relation to prostate disease, has a more pronounced and wider prophylactic effect on precancer and prostate cancer, has a better safety profile for the production of CPC there is a much more affordable and economically more profitable raw material.

Claims (9)

1. The use of provitamin coniferous concentrate as a means for the prevention or treatment of benign prostatic hyperplasia. 2. Means for the prevention or treatment of benign prostatic hyperplasia based on a plant extract, characterized in that a coniferous provitamin concentrate is used as a plant extract. 3. The tool according to p. 2, characterized in that for prophylaxis it is a biologically active food supplement. 4. The tool according to p. 2, characterized in that it is a drug. 5. A pharmaceutical composition for the prevention or treatment of benign prostatic hyperplasia, characterized in that the active ingredient contains the agent of claim 2 in an effective amount and the rest is pharmaceutically acceptable carriers, excipients and / or solvents. 6. The pharmaceutical composition according to p. 5, characterized in that it is made in the form of a dosage form for oral administration, an oil solution, gel, suspension, capsule, tablet, liposome or rectal suppository. 7. The pharmaceutical composition according to claim 5 or 6, characterized in that it is intended for men over the age of 50 years suffering from benign prostatic hyperplasia. 8. A method for the prevention or treatment of benign prostatic hyperplasia, characterized in that it involves the administration of an agent or pharmaceutical composition according to any one of paragraphs. 2-7 men in an effective amount. 9. The method according to p. 8, characterized in that the funds are taken one, or two, or three times a day for an established course, which is at least 3 months and up to 5 years with a break between courses of 1-2 months.