USE OF COPAIFERA OLEORESIN IN PROSTATE DISEASES

Abstract

The present invention relates to a use of Copaifera oleoresin to prevent and / or treat prostate pathologies, including benign prostatic hyperplasia or prostate cancer.

Description

The present invention relates to a use of Copaifera oleoresin to prevent and / or treat prostate pathologies, including benign prostatic hyperplasia or prostate cancer. The genus Copaifera comprises 35 species, all trees native to tropical America, specifically Mexico, northern Argentina, and primarily Brazil. Within the region, more than twenty species are found, the most abundant being C. officinalis, C. reticulata, and C. multijuga. Copaifera officinalis is a tree found mainly in Brazil, Colombia, and Venezuela. It grows up to 25 meters tall and has reddish-brown wood. The leaves are compound, paripinnate with 2 to 10 leaflets, alternate or sub-opposite, apiculate, and unevenly rounded at the base. They are 3 to 8 cm long and 2 to 4 cm wide. The white flowers, generally sessile, are grouped in inflorescences 7 to 14 cm across. The fruits are small, swollen pods at maturity, 20-25 mm in diameter, hairless, with apiculate tips, containing an ovoid seed. Oleoresin is a substance obtained by making incisions in the bark of several Copaifera species. Located in anastomosing secretory canals of the secondary wood and pith, its extraction therefore requires very deep incisions in the trunk, allowing it to flow naturally from the tree. After steam distillation, or hydro distillation, the oleoresin yields the essential oil of Copaiba, renowned in perfumery. Copaiba oleoresin has been used medicinally since the 16th century by the indigenous people of Brazil. It has a long history of use in traditional medicine. Brazilian oleoresin, used to treat wounds and fade scars, as a fever reducer, urinary tract antiseptic, and for treating leukorrhea and gonorrhea, was considered a general tonic. Its indications included venereal disease, respiratory illness, asthma, rheumatism, secondary skin lesions, and ulcers. In small doses, it acts as a direct stimulant on the stomach. Copaiba oleoresin reduces excessive mucus secretion caused by inflammation. Today, copaiba oleoresin is sold in capsule form in Brazilian pharmacies, where it is indicated for all types of internal inflammation and stomach ulcers. Applied topically, it is a powerful healing agent, both antiseptic and anti-inflammatory, aiding in the healing of even the most difficult wounds. Copaiba oleoresin is said to be very effective on joint pain, minor sprains, hematomas, and tendinitis.Oleoresin is applied directly to the skin. Oleoresin is also used as a massage oil for sore or inflamed muscles and joints. Copaiba oleoresin, distilled or undistilled, is also used in cosmetics, in the manufacture of soaps, bath foams, detergents, and creams, and as a fixative in perfumery. The oleoresin is sometimes used as a flavoring in food. Copaiba oleoresin is also used as an artist's material, particularly in oil paint recipes and decorative ceramics. Oleoresin is a colorless, slightly viscous liquid that acquires an oily consistency and a greenish-yellow color over time. Its consistency and color vary slightly depending on the tree from which it is derived and the essential oil it contains. Its odor is strong and unpleasant, and its taste is bitter and acrid. Oleoresin is insoluble in water but completely soluble in alcohol and ether. The oleoresin of C. officinalis consists of 2 fractions that differ in their volatility; each fraction is characterized by distinct chemical compounds: A "volatile" essential oil representing 50-90% of the oleoresin, which is mainly composed of sesquiterpenes. Among these sesquiterpenes, the most prominent are germacrene D, (E)-p-caryophyllene, p- and β-elemene, α-ylangene, α-gurjunene, α-humulene. The minority sesquiterpenes are the following a-cubebene, a-copaene, 7-epi-sesquithujene, cis- and trans-a-bergamotene, sesquisabinene-A and B, 4aH, lOaH-guaia-1(5),6-diene, allo-aromadendrene, y-uurolene, a-amorphene, p-selinene, bicycliosesquiphyllandrene, a-muurolene, p-bisabolene, y-cadinene, ô-cadinene, cis-calamene, zonarene, cakina-1'4-diene, a-cadinene, a-calacorene, selina-3,7(11)-diene, germacrene B. This volatile oil is very clear, colorless, with a very strong odor and flavor. pronounced. A "non-volatile" fraction representing 10-50% of the oleoresin, which is composed mainly of the following diterpenic acids and / or esters of diterpenic acids: copalic acid, copaiferolic acid, dimethyl ester of agathendioic acid, agathic acid, methyl ester of 3β-hydroxyanticopalic acid, hardwickiic acid, and 7α-acetoxyhardwickiic acid. This distillation residue is a viscous, aromatic, dark brown liquid. The inventors have quite surprisingly demonstrated that Copaifera oleoresin exhibits a particularly interesting anti-5a-reductase activity. The role of 5α-reductase inhibitors is established in the pathophysiology of the prostate (Rittmaster, Journal of Andrology, vol 18, no. 6, 1997), particularly in benign prostatic hyperplasia and prostate cancer. The prostate is the largest exocrine gland in the male urogenital system. It is located at the junction of the genital and urinary tracts. Along with the seminal vesicles, the prostate plays a crucial role in the synthesis and release of seminal fluid. Its smooth muscle component contributes more indirectly to the bladder-continence cycle. Finally, the prostate is surrounded by neurovascular bundles involved in the male sexual response. With age, anatomical changes in the prostate gland can sometimes lead to urinary problems and sexual dysfunction, resulting in a decreased quality of life. The prostate can be the site of three main diseases: prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer. However, the 5α-reductase enzyme is currently only implicated in BPH and prostate cancer. Benign prostatic hyperplasia (BPH) is a common condition associated with aging and linked to the development of a prostatic adenoma, which causes a chronic obstruction to bladder emptying. BPH is characterized by an increase in the size of the prostate gland. An enlarged prostate compresses the urethra and puts pressure on the bladder, leading to a frequent urge to urinate and various urinary problems, such as a weak and intermittent stream, pain, etc. Almost all men are susceptible to BPH as they age. In fact, more than 50% of men aged 60 are affected, and 90% of those over 80. However, all Many men suffer from it, in fact, one in two men is bothered by urinary symptoms. The causes of this condition are not clearly established; there is probably a hereditary predisposition, but other factors also play a role. This condition should not be taken lightly, however, as there are several possible complications such as urinary tract infections, acute urinary retention, bladder stones, and kidney damage. Prostate cancer is a common disease and the second most common cancer in men in industrialized countries. There is a known genetic predisposition. Most prostate cancers progress very slowly. Often, the tumor remains localized within the prostate and has limited effects on health, sometimes causing urinary or erectile dysfunction. However, some prostate cancers can progress and spread more rapidly. Adenocarcinoma is the most common form of prostate cancer, accounting for approximately 95% of cases. The severity of the cancer depends on the extent of the tumor and the type of cancer cells. Testosterone promotes prostate growth through one of its metabolites, dihydrotestosterone. Testosterone is converted to dihydrotestosterone by the action of 5α-reductase. Dihydrotestosterone has a high binding affinity for the androgen receptor. Compared to testosterone, dihydrotestosterone stimulates the transcriptional activity of prostate cells by 2 to 10 times. Ex vivo, dihydrotestosterone has a much more potent stimulatory effect on prostate tumor growth than testosterone. In men with symptomatic benign prostatic hyperplasia, inhibition of 5α-reductase decreases prostate volume, improves symptoms and urinary flow, and reduces the risk of acute urinary retention. There are two isoforms of 5α-reductase, 5αR1 and 5αR2, encoded by two distinct genes, SRD5A1 and SRD5A2, respectively, located on separate chromosomes. The 5αR2 isoenzyme is found primarily in male reproductive tissues, including the seminal vesicles, epididymis, and prostate gland. The 5αR1 isoenzyme is found mainly in the liver and skin. 5αR2 is present in high concentrations in prostate tissue and has a high affinity for testosterone. Finasteride is a potent inhibitor of 5αR2, with a mean inhibitory concentration (IC50) of 69 nM, but is much less effective at inhibiting 5αR1, with an IC50 of 360 nM. In contrast, dutasteride inhibits both 5aR1 and 5aR2 similarly, with IC50 values ​​of 6 and 7 nM, respectively. Dutasteride appears to be more effective than finasteride, with a reduction of 94.7% vs. 70.8% in reducing mean serum dihydrotestosterone levels.Intraprostatic levels, a greater reduction in dihydrotestosterone was observed with dutasteride, suggesting that 5α-reductase appears to contribute to intraprostatic dihydrotestosterone synthesis. The role of 5α-reductase in the inhibition of prostate cancer has been reported in animal models. According to a first embodiment, the invention relates to a Copaifera oleoresin for its use as a medicinal product for the treatment and / or prevention of benign prostatic hyperplasia and / or prostate cancer. In a second embodiment, the invention relates to a Copaifera oleoresin according to the first embodiment, characterized in that the oleoresin is derived from the Copaifera species chosen from the group consisting of C. officinalis, C. multijuga, C. reticulata. In a third embodiment, the invention aims at the fraction of acids diterpenic and / or esters of acids diterpenic oleoresin according to one of embodiments 1 or 2, characterized in that it contains at least 90% diterpenic acids and / or esters of diterpenic acids by weight. A fourth embodiment of the invention relates to a pharmaceutical composition characterized in that it contains as an active agent, a Copaifera oleoresin according to one of embodiments 1 or 2, or a fraction according to the third embodiment, and at least one pharmaceutically acceptable excipient, for its use as a medicinal product for the treatment or prevention of benign prostatic hyperplasia and / or prostate cancer. A fifth embodiment of the invention relates to a pharmaceutical composition according to the fourth embodiment, characterized in that the oleoresin is derived from the Copaifera species selected from the group consisting of C. officinalis, C. multijuga, C. reticulata. A sixth embodiment of the invention relates to a pharmaceutical composition according to one of embodiments 4 or 5, characterized in that it contains as an active agent a fraction according to the third embodiment. A seventh embodiment of the invention further relates to a pharmaceutical composition according to one of the embodiments 4 to 6, characterized in that it is presented in a form suitable for administration by oral or intravenous route. For the purposes of this invention, "Copaifera oleoresin" means an exudate from Copaifera tree(s) comprising a volatile fraction mainly consisting of sesquiterpene compounds and a non-volatile fraction mainly consisting of diterpenic acids and / or esters of diterpenic acids. For the purposes of this invention, the "diterpenic acid and / or diterpenic acid ester fraction of Copaifera oleoresin" refers to the "non-volatile" fraction of the oleoresin obtained after total or partial, preferably total, removal of the essential oil, particularly by hydrodistillation. This non-volatile fraction comprises at least 80%, and preferably between 80 and 90% by weight, of diterpenic acids and / or diterpenic acid esters. The mixture of diterpenic acids and / or diterpenic acid esters can also be obtained from a Copaifera oleoresin, or from the "non-volatile" fraction of the Copaifera oleoresin, notably by liquid-liquid extraction until a mixture is obtained having a diterpenic acid and / or diterpenic acid ester concentration of between 50 and 100%, particularly between 60 and 100%, and even more particularly between 80 and 100% by weight of diterpenic acids and / or diterpenic acid esters relative to the total weight of the liquid fraction obtained after extraction and removal of the extraction solvent. This liquid fraction obtained after extraction and removal of the solvent constitutes said mixture. The mixture of diterpenic acids and / or diterpenic acid esters comprises at least 2, or at least 3, or at least 4, or at least 5, or at least 6, or at least 7 diterpenic acids and / or diterpenic acid esters selected from the group consisting of: copalic acid, copaiferolic acid, dimethyl ester of agathendioic acid, agathic acid, methyl ester of 3beta-hydroxyanticopalic acid, hardwickiic acid, 7 alpha acetoxyhardwickiic acid. Table 1: Molecular formulas, structural formulas and CAS numbers of various diterpenic acids and / or esters of diterpenic acids Name Molecular formula m / z Structural formula Copalic acid C20H32O2 304 CCMM Copaiferolic acid C20H32O3 320 HO .0 ^ch3 ÇH3 1 \ ^CH2 \ H ch3 Dimethyl ester of agathendioic acid C22H34O4 362 ■ - . ,l; Agathic acid C20H30O4 334 Methyl ester of 3-beta-hydroxyanticopalic acid C20H30O4 334 * Hardwickian acid C20H28O3 316 7-alpha-acetoxyhardwickian acid C22H30O5 374 5V-0 P 14 1 H Jt 17 jl J 1«RH Preferably, the mixture of diterpenic acids and / or diterpenic acid esters comprises all of the following diterpenic acids and / or diterpenic acid esters: 5 Copalic acid, copaiferolic acid, agathendioic acid dimethyl ester, agathic acid, 3beta-hydroxyanticopalic acid methyl ester, hardwickiic acid, 7 alpha acetoxyhardwickiic acid. 10 In one embodiment of the invention, the oleoresin comprises, by weight percentage, between 7.5 and 40% of the 7 diterpenic acids and / or esters of diterpenic acids mentioned above. above, or preferably 10 to 30%. In one embodiment of the present invention, the oleoresin may be an oleoresin enriched in diterpenic acids and / or esters of diterpenic acids and the content of the 7 diterpenic acids and / or esters of diterpenic acids of such an enriched oleoresin shall be between 48 and 90%, preferably between 60 and 90%, preferably again between 60 and 85%. The term "enriched resin," as used in the present invention, refers to an oleoresin that has undergone treatment by a process designed to concentrate the content of these seven diterpenic acids and / or diterpenic acid esters relative to the other compounds and molecules in the oleoresin. Thus, the ratios between diterpenic acids and / or diterpenic acid esters and other molecules are modified, increasing their concentration and resulting in ratios different from those found in natural products or products extracted from the tree. Table 2: Mass content of the main diterpenic acids and / or esters of diterpenic acids Product Name Mass Content in Oleoresin Mass Content in Diterpene Fraction Copalic Acid _ „ __ _ _ „ _ _ Hardwickian Acid 0.5 to 1.5 2 to 15 Copaiferolic Acid 1 to 6 10 to 30 Agathic Acid and Methyl Ester of 3β-Hydroxyanticopalic Acid 1 to 6 8 to 30 Dimethyl Ester of Agathendioic Acid 1 to 6 10 to 30 7-Alpha Acetoxyhardwickian Acid 1 to 8 3 to 15 The present invention relates to Copaifera oleoresin for its use as a medicinal product for the treatment and / or prevention of benign prostatic hyperplasia and / or prostate cancer. In a specific method, the oleoresin is derived from a Copaifera species selected from the group consisting of Copaifera officinalis, Copaifera multijuga, or Copaifera reticulata, for use as a medicinal product for the treatment and / or prevention of benign prostatic hyperplasia and / or prostate cancer. Preferably, the oleoresin is derived from the Copaifera officinalis species. According to an equally advantageous embodiment of the invention, only a fraction of diterpenic acids and / or diterpenic acid esters of the oleoresin is used as a medicinal product for the treatment and / or prevention of benign prostatic hyperplasia and / or prostate cancer. The oleoresin fraction used consists of at least 90% diterpenic acids and / or diterpenic acid esters, advantageously at least 92% diterpenic acids and / or diterpenic acid esters, and even more advantageously at least 95% diterpenic acids and / or diterpenic acid esters by weight. One object of the invention relates to the use of Copaifera oleoresin to prevent and / or treat benign prostatic hyperplasia or prostate cancer. According to a preferred embodiment, the invention relates to the use of oleoresin from Copaifera officinalis, C. multijuga or C. reticulata to prevent and / or treat benign prostatic hyperplasia or prostate cancer. According to a particularly preferred mode, the invention relates to the use of Copaifera officinalis oleoresin to prevent and / or treat benign prostatic hyperplasia or prostate cancer. According to a particular embodiment, the invention relates to the use of a fraction of diterpenic acids and / or esters of diterpenic acids from Copaifera oleoresin, consisting of at least 90% diterpenic acids and / or esters of acids diterpenic acids, preferably of at least 92% diterpenic acids and / or diterpenic acid esters, and even more preferably of at least 95% diterpenic acids and / or diterpenic acid esters by weight, to prevent and / or treat benign prostatic hyperplasia or prostate cancer. By "treatment" according to the present invention, we mean the inhibition of the evolution, more particularly the regression, preferably the disappearance of hyperplasia or tumor of the prostate. "Prevention" according to the present invention means preventing or delaying the onset of prostate hyperplasia or tumor. The treatment or prevention according to the invention is understood to be in humans or animals. The present invention further relates to a pharmaceutical composition comprising Copaifera oleoresin and at least one pharmaceutically acceptable excipient. In the present invention, "pharmaceutically acceptable" means something that is useful in the preparation of a pharmaceutical composition, that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and that is acceptable for pharmaceutical use in humans. When used here, the term "pharmaceutically acceptable excipient" includes any adjuvant or excipient, such as solvents, solubilizers, preservatives, emulsifiers, consistency agents, spreading agents, water-fixing agents, colorants, flavors, sweeteners, the use of these excipients being well known to those skilled in the art. The present invention further relates to a composition pharmaceutical for its use as a medicine. The present invention also relates to a pharmaceutical composition characterized in that it contains as an active agent a Copaifera oleoresin according to the invention or a fraction of diterpenic acids and / or diterpenic acid esters of Copaifera oleoresin, and at least one pharmaceutically acceptable excipient, for its use as a medicinal product for the treatment or prevention of benign prostatic hyperplasia and / or prostate cancer. According to a particular embodiment of the invention, the composition contains as an active agent an oleoresin from the species of Copaifera selected from the group consisting of C. officinalis, C. multijuga, C. reticulata and at least one pharmaceutically acceptable excipient, for its use as a medicinal product for the treatment or prevention of benign prostatic hyperplasia and / or prostate cancer. According to another embodiment of the invention, the composition contains as an active agent a fraction of diterpenic acids and / or diterpenic acid esters of oleoresin which contains at least 90% of diterpenic acids and / or diterpenic acid esters by weight, preferably at least 92% of diterpenic acids and / or diterpenic acid esters and even more preferably at least 95% of diterpenic acids and / or diterpenic acid esters by weight and at least one pharmaceutically acceptable excipient, for its use as a medicinal product for the treatment or prevention of benign prostatic hyperplasia and / or prostate cancer. Pharmaceutical compositions according to the present invention can be formulated in a form suitable for Administration to mammals, including humans. Dosage The dosage varies depending on the treatment and the condition being treated. These formulations are designed for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, topical, or rectal administration. In this case, the active ingredient may be administered in unit-dose forms, mixed with conventional pharmaceutical carriers, to animals or humans. Suitable unit-dose forms include oral forms such as tablets, capsules, powders, granules, and oral solutions or suspensions; sublingual and buccal forms; subcutaneous, topical, intramuscular, intravenous, intranasal, or intraocular forms; and rectal forms. When preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, silica, or similar substances. The tablets may be coated with sucrose or other suitable materials, or they may be treated to provide prolonged or delayed action and to release a predetermined amount of active ingredient continuously. A capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard capsules. A preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, an antiseptic, as well as a flavoring agent and an appropriate color. Water-dispersible powders or granules may contain the active ingredient mixed with dispersing agents, wetting agents, or suspending agents, as well as with flavor enhancers or other additives. sweeteners. For rectal administration, suppositories are used which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols. For parenteral (intravenous, intramuscular, etc.), intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmacologically compatible dispersing and / or wetting agents are used. The active ingredient can also be formulated in the form of microcapsules, possibly with one or more additive carriers. Advantageously, the pharmaceutical composition according to the present invention is in a form suitable for oral or intravenous administration. The composition according to the present invention can be administered in association, simultaneously, separately or spread over time, with prostatectomy, radiotherapy, and / or hormone therapy, for the treatment or prevention of prostate cancer. The following examples illustrate the invention without limiting its scope. Example 1: Effects of different compounds on the activity of 5a-reductase of fibroblasts from human dermal papilla follicles. The aim of this study was to evaluate the potential inhibitory activity of different compounds on 5α-reductase. Materials and methods The study was performed on human cells derived from donor dermal papilla follicles. This model is of interest because dermal papillae express the 5aR2 isoform, as does prostate tissue. Cells were seeded into 24-well plates and cultured for 24 hours in DMEM culture medium supplemented with L-glutamine (2 mM), penicillin (50 U / ml), streptomycin (50 pg / ml), and Fetal Calf Serum (10%) under standard culture conditions (37°C and 5% CO2). The culture medium was then replaced with DMEM analysis medium supplemented with L-glutamine (2 mM), penicillin (50 U / ml), streptomycin (50 pg / ml), and Fetal Calf Serum (1%). This analysis medium may or may not contain (control conditions) the products to be tested and a reference compound, finasteride (1OpM), for 24 hours of pre-incubation.The cells were then treated with an analytical medium containing testosterone [C14] and either containing (control conditions) the products to be tested or reference products, and the cells were incubated for 24 hours under these conditions. After incubation, the supernatants were collected for testosterone metabolism analysis. All experiments were performed three times. Steroid molecules were extracted from the supernatants with a chloroform / methanol mixture. The organic phase was collected, and the different molecular species (testosterone metabolites) were separated by thin-layer chromatography using a solvent system containing dichloromethane, ethyl acetate, and methanol. Autoradiography was performed on the chromatogram, and the transformed testosterone was estimated by densitometric analysis. Thus, the metabolism of testosterone into dihydrotestosterone accounts for 5a-reductase activity, and is evaluated by the dihydrotestosterone / testosterone ratio. Results A first set of experiments highlights the Effects of Copaifera officinalis oleoresin (Table 3 below). Surprisingly, the inventors demonstrated significant and reproducible inhibition of 5α-reductase by Copaifera officinalis oleoresin; this inhibition even appears to be concentration-dependent. The significant inhibition of this enzyme by finasteride effectively validates all of these experiments. Table 3: Effects of Copaifera officinalis oleoresin and finasteride on testosterone metabolism / dihydrotestosterone production (5α-reductase activity; n=3) Finasteride Oleoresin (C officinalis) Control 10 pM 10 pg / ml 30 pg / ml 100 -77% -15% -27% ** P<0.01 * P<0.05 ** P<0.01 The statistical study is carried out versus the control group (Dunnett's test). The oleoresin tested was prepared according to the method described in example 2. For comparison, an extract of Serenoa repens was also tested in one of these experiments. Serenoa repens extract, derived from the fruit of the saw palmetto, is the most studied and frequently prescribed phytonutrient, alone or in combination, particularly in the treatment of benign prostatic hyperplasia (Gordon AE, Am. Fam. Physician, 67(06), 1281-1283, 2003). At 10 pg / ml, the Serenoa repens extract did not induce significant inhibition of 5α-reducatse; however, at 20 pg / ml, this extract induced inhibition by 23%, reaching statistical significance (p<0.05 versus control). A second series of experiments was conducted to evaluate whether the inhibitory activity on 5α-reductase was mediated by the The non-volatile fraction, or rather the volatile fraction corresponding to the essential oil, is analyzed. The results are summarized in Table 4 below. The preparation of the volatile and non-volatile fractions is carried out according to the method described in Example 4, using the diethyl ester as a nonpolar solvent. Table 4: Effects of non-volatile and volatile fractions from Copaifera officinalis oleoresin on testosterone metabolism / dihydrotestosterone production (5α-reductase activity) Control Non-volatile fraction Volatile fraction 0.3 pg / ml 1 pg / ml 3 pg / ml 7.7 pg / ml 23.1 pg / ml 100 0 -6% -14% + 2% + 9% P=NS P=NS * P<0.05 P=NS P=NS The statistical study is performed versus the control group (test (from Dunnett). It appears that the activity of Copaifera officinalis oleoresin is mediated by the non-volatile fraction; indeed, no activity of the volatile fraction was observed. Inhibition of 5α-reductase is only 14% with the non-volatile fraction, but this reduction reaches statistical significance (p<0.05). A third series of experiments was set up to demonstrate that other Copaifera species, notably C. multijuga, also exhibited interesting activity in inhibiting 5α-reductase. The inventors focused on the non-volatile fraction, the fraction carrying the inhibitory activity. The results are summarized in Table 5 below. Table 5: Effects of non-volatile fractions from Copaifera multijuga oleoresin on testosterone metabolism / dihydrotestosterone production (5α-reductase activity; n=2) Control Non-volatile fraction Copaifera multijuga 1 pg / ml 10 pg / ml 100 0 -31% P=NS ** P<0.01 The statistical study is carried out versus the control group (Dunnett's test). The preparation of the volatile and non-volatile fractions is carried out according to the method described in example 4 with the diethyl ester as the non-polar solvent. These results clearly show that several Copaifera species are of interest. Indeed, the non-volatile fraction of the C. multijuga species achieves 31% inhibition of 5α-reductase at 100g / ml. These results lead to the conclusion that Copaifera oleoresin exhibits highly interesting inhibitory activity on 5α-reductase. This activity is mediated by the non-volatile fraction of the oleoresin. Furthermore, the inventors have also demonstrated that this activity is observed in several Copaifera species. Example 2: Preparation of oleoresin The bark of the trunks of Copaifera officinalis and / or Copaifera multijuga and / or Copaifera reticulata trees is cut to extract the oleoresin. This is then homogenized and stabilized under nitrogen. The active ingredient is composed of 100% crude oleoresin from the trunk of Copaifera officinalis and / or Copaifera multijuga and / or Copaifera reticulata. LCMS analysis of a Copaifera officinalis oleoresin Each sample was analyzed by UHPLC-QTOFMS according to a classical linear gradient. Separation on Waters Acquity UHPLC system. 5 - Column 100 x 2.1 mm, 1.7 µm, Acquity BEH C18 equipped from a pre-column Mobile phase: Mobile phase A: LCMS grade water + 0.1% formic acid Mobile phase B: Acetonitrile LCMS grade + 0.1% formic acid 10 - Gradient: Time (min) %A %B 0-0.5 50 50 0.5-4 5 0^4 0 50 60 4-12 4 0^1 6 0 ^9 9 12-15 1 99 15-15.5 1 ^5 0 9 9^5 0 15.5-19 50 50 Acquisitions: UV 220 nm Structure m / z Content in oleoresin (% by mass relative to the weight of oleoresin) Copalic acid 304 5.69 Hardwickian acid 316 0.61 Copaiferolic acid 320 2.90 Agathic acid and methyl ester of 3 beta-hydroxyanticopalic acid 334 2.35 Dimethyl ester of agathendioic acid 362 2.92 7-Acetoxyhardwickian acid 374 0.79 Example 3: Preparation of the non-volatile fraction The oleoresin obtained according to Example 2 is suspended in 10 volumes of water heated to 100 °C for 4 hours to perform hydrodistillation. The volatile essential oil is recovered by condensation. After hydrodistillation, the distillation residue is collected. After drying by freeze-drying or other drying methods, the residue constitutes the non-volatile fraction. Example 4: Another possible preparation of the non-volatile fraction One volume of Copaifera oleoresin obtained according to Example 2 is diluted in 8 to 10 volumes of a lipophilic solvent immiscible with water (such as diethyl ether or ethyl acetate). This solution is extracted by liquid-liquid extraction with a 5% sodium hydroxide (NaOH) solution. The operation is repeated three times with 4 to 5 volumes of 5% NaOH. The lower phase (basic aqueous phase) is acidified by the addition of 1 N hydrochloric acid (HCl) and then extracted by liquid-liquid extraction with a nonpolar solvent immiscible with water (such as diethyl ether or ethyl acetate). The ethyl acetate phase is washed with water and then dehydrated over Na₂SO₄. After removal of the solvent by rotavapor or other drying means, the dry residue obtained corresponds to the mixture of diterpenic acids and / or esters of diterpenic acids according to the invention. Structure m / z Mass content in the non-volatile fraction Copalic acid 304 28.45 Hardwickian acid 316 3.05 Copaiferolic acid 320 14.52 Agathic acid and methyl ester 334 11.77 of 3-beta-hydroxyanticopalic acid Dimethyl ester of agathendioic acid 362 14.58 7-acetoxyhardwickiic acid 374 3.96

Claims

Demands 1. Copaifera oleoresin for its use as a medicinal product for the treatment and / or prevention of benign prostatic hyperplasia and / or prostate cancer.

2. Copaifera oleoresin for its use according to claim 1, characterized in that the oleoresin is derived from the Copaifera species selected from the group consisting of C. officinalis, C. multijuga, C. reticulata.

3. Fraction of diterpenic acids and / or diterpenic acid esters of oleoresin for its use according to one of claims 1 or 2, characterized in that it contains at least 90% of diterpenic acids and / or diterpenic acid esters by weight.

4. Pharmaceutical composition characterized in that it contains as an active agent an oleoresin of Copaifera according to one of claims 1 or 2 or a fraction according to claim 3, and at least one pharmaceutically acceptable excipient, for its use as a medicinal product for the treatment or prevention of benign prostatic hyperplasia and / or prostate cancer.

5. Pharmaceutical composition for its use according to claim 4, characterized in that the oleoresin is derived from the Copaifera species selected from the group consisting of C. officinalis, C. multijuga, C. reticulata.

6. Pharmaceutical composition for use according to any one of claims 4 or 5, characterized in that it contains as an active agent a fraction according to claim 3.

7. Pharmaceutical composition for use according to any one of claims 4 to 6, characterized in that it is presented in a form suitable for oral or intravenous administration.