IT201900007044A1 - Composition for use in the prevention and / or treatment of diseases associated with the prostate - Google Patents

Description

DESCRIPTION of the industrial invention entitled:

"Composition for use in the prevention and / or treatment of diseases associated with the prostate"

DESCRIPTION

The present invention relates to a composition of substances, preferably obtained from natural sources, effective in the prevention and / or treatment of prostatic pathologies. The prostate can run into a large number of pathologies, from inflammatory or infectious to degenerative, benign or malignant ones. In the composition of the present invention the synergistic action occurs between aescin and capsaicin. The composition may further contain an extract of Curcuma longa and / or an extract of a plant belonging to the genus Cucurbita and / or an extract of Serenoa Repens.

Background of the invention

Pelvic pain

Pelvic pain is one of the most disabling disorders with a high impact on the quality of life and which requires a multidisciplinary diagnostic and therapeutic approach. Pelvic pain in humans is an important symptom that can be secondary to physiological or pathological conditions.

The adjective "pelvic" discriminates the presence of pain in the lower abdomen, just below the abdominal region, including the pelvis area, the external genitals and the perineum.

The possible causes of male pelvic pain are numerous and can be related to disorders affecting different systems:

• gastrointestinal,

• urinary,

• genital,

• musculoskeletal and nervous.

Based on the mode of onset, pelvic pain can be classified as:

• Acute: appears suddenly but, once the triggering cause has been removed, the pain disappears;

• Chronic: it arises gradually, without it being possible to trace a specific cause and without the possibility of removing it; A particular nosological entity may emerge in this area, namely the Chronic Pelvic Pain Syndrome (acronym CPPS from English: Chronic Pelvic Pain Syndrome).

In the context of genitourinary causes, chronic nonspecific prostatitis is the most frequent cause of chronic pelvic pain syndrome. It is characterized by inflammation of the prostate gland, but without signs of infection. All investigations performed as a culture of urine or prostate fluid are negative, and on ultrasound or CT (Computed Tomography) the prostate is normal, despite the presence of pain and urinary symptoms that suggest its involvement. This clinical picture could be caused by an altered perception of pain with the presence of allodynia or hyperalgesia.

Diseases of the prostate can be of benign neoplastic, malignant and inflammatory origin.

Benign prostatic hyperplasia (BPH) is a benign disease characterized by a proliferation of prostate tissue resulting in an increase in the volume of the gland. This disease is very common, especially in men aged 40/50. In fact, with advancing age, the prostate tends to increase its volume; to explain this phenomenon, hormonal variations and the action of numerous growth factors during aging are called into question. The result of a significant enlargement of the prostate is the appearance of urinary disorders.

Prostate cancer includes a variety of forms, from those with very slow growth, which may not cause disturbances over a lifetime, to other more aggressive forms, which instead grow rapidly. Precisely the latter, the so-called malignant forms, are the most dangerous neoplasms. First of all they are dangerous because they can spread outside the gland, using the blood and the lymphatic system. Malignant tumors therefore have the potential to spread to other parts of the body, that is, they can lead to the onset of metastases. Prostate cancer is a pathology that is sometimes complicated to identify, because in the initial stages it tends to be asymptomatic. Furthermore, when symptoms are present, they can be confused with those resulting from benign prostatic hyperplasia or prostatitis. Inflammation of the prostate, better known in the medical field with the term prostatitis, can depend on infectious (specifically bacterial) or non-infectious causes.

There are 4 types of prostate inflammation and they correspond, to be precise, to:

• acute prostatitis of bacterial origin (type I),

• chronic prostatitis of bacterial origin (types II),

• chronic non-bacterial prostatitis (type III),

• asymptomatic prostatitis (type IV).

The typical symptoms and signs of type I prostatitis are: high fever with chills, pelvic pain, various types of urinary disorders. Chronic inflammation of the prostate of bacterial origin can be: the result of non-treatment of acute prostatitis of bacterial origin, the consequence of a urinary tract infection or, finally, the complication of epididymitis (infection whose symptoms appear testicularly). Acute bacterial inflammation of the prostate is a form of prostatitis caused by bacteria. Non-bacterial chronic inflammation of the prostate is prostatitis with a gradual onset and persistent character, which does not depend on the presence of bacteria in the prostate gland. Also known as type III prostatitis or chronic pelvic pain syndrome, it arises for reasons that doctors and researchers, despite numerous studies, have not yet fully clarified. Asymptomatic inflammation is also called type IV prostatitis or asymptomatic inflammatory prostatitis. Despite numerous studies regarding type IV prostatitis, doctors still do not understand the triggers and reasons for the lack of symptoms.

Chronic Pelvic Pain (CPP) is characterized by the persistence of pain, continuous or intermittent, with pelvic involvement, lasting more than six months. It progressively affects different pelvic organs, involving multiple functions.

The mast cell (MC) plays a cardinal role in chronic pelvic pain and in the comorbidities that underlie and feed it. In fact, it plays a cardinal role in acute and chronic inflammation, of which pain is the main symptom. The MC is ubiquitous in all vascularized organs and tissues, where it works as an immune sentinel and organizes the inflammatory response. MC contains multiple vasoactive, proinflammatory and neurotrophic substances, contained in vesicles that are released in the surrounding tissues in a differentiated way in response to the action of various "agonistic" factors (harmful or which in any case induce their release), coordinating the different phases of physiological and pathological inflammatory response. These factors over time modulate the body's inflammatory response to heterogeneous endogenous and exogenous harmful factors. The treatment of pelvic pain involves an etiological therapy based on the removal of the underlying cause.

When needed, it is possible to perform symptomatic therapy that aims to remove the pain alone, with classic pain relievers such as NSAIDs (ibuprofen, aspirin, ketoprofen) and paracetamol (Tachipirina). However, these drugs require numerous daily administrations to reach adequate therapeutic doses and often have serious side effects. There is therefore the need to provide treatments, alternative to those already existing, which are effective in the prevention and / or treatment of the aforementioned pathologies, but which do not have the side effects and / or disadvantages of the treatments present in the state of the art. These and other needs are satisfied by the present invention, which provides a composition characterized in that it comprises a synergistic combination of active substances, obtained from natural sources.

Detailed Description of the Invention

In the composition of the present invention, the synergistic action takes place between aescin and capsaicin in a mixture with one or more pharmaceutically acceptable carriers. The composition may further contain an extract of Curcuma longa and / or an extract of a plant belonging to the genus Cucurbita and / or an extract of Serenoa Repens.

Escin

Aescin is a vegetable compound obtained from the seeds, skins and leaves of the horse chestnut. Horse chestnut (Aesculus hippocastanum) is a plant of the Hippocastanaceae family. The seeds and bark of the horse chestnut contain saponins, the mixture of which is called aescin. Aescin exists in two alpha and beta forms, distinguished by their melting points, haemolytic activities and solubility in water. The beta form of aescin is the active component of the Indian chestnut extract. The complex mixture of triterpenoid saponins has proved to be very effective in the treatment of microcirculatory disorders. It acts by increasing the resistance of the capillaries (phlebotonic action) and reducing their permeability (anti-exudative action) and inflammation. Three types of pharmacodynamic actions have been attributed to escin: anti-edematous properties, anti-inflammatory activities and venotonic properties.

Aescin is traditionally used in the symptomatic treatment of functional disorders of skin capillary fragility, venous insufficiency (heavy legs), but also in the symptomatology of the hemorrhoidal crisis. Aescin acts on the factors that trigger inflammation / edema, that is, the hypoxia of the endothelial cells, followed by the reduction of ATP. The inflammatory reaction is triggered by the release of prostaglandins (signals of the inflammatory response) via phospholipase A2 and PAF (platelet activating factor). It is at the origin of edema and the adhesion of neutrophils to the endothelium. These neutrophils in turn release elastase-like enzymes, which degrade the vein wall and stimulate the production of FGF (fibroblast growth factors), causing the vein to widen. Finally, the adherence of neutrophils to the endothelium reduces blood flow and stimulates hypoxia. Aescin acts at an anti-inflammatory level by reducing the activity of lysosomal enzymes which, hyper-activated by inflammatory processes, produce a degradation of the capillary wall; in particular, aescin reduces the activity of elastase, collagenase, hyaluronidase and beta-glucuronidase, proteolytic enzymes which - during inflammatory processes - degrade the internal structure of the vessels and weaken the endothelium of the capillaries causing the formation edema.

Escin prevents and reduces edema. The anti-edematous effect is linked to a selective vascular permeability, which causes an increase in venous and arterial tone. Aescin reduces the fragility of the capillaries and thus allows to avoid the infiltration of liquid into the tissue interstitium (primary cause of edema). The therapeutic benefit is well supported by a series of experimental investigations on different animal models, indicative of anti-edema, anti-inflammatory and venotonic properties. Its properties are mainly related to the molecular mechanism of the agent, allowing a better entry of ions into the channels, causing an increase in venous tension both in in vitro and in vivo conditions. Other mechanisms, namely the release of PGF (prostaglandins) from the veins, the reduced catabolism of tissue mucopolysaccharides, further underline the wide-ranging mechanisms of the therapeutic activity of aescin. In particular, it has been shown that escin exerts a venotonic effect, mediated by the stimulation of prostaglandins F2 α in human veins. In vivo studies have demonstrated the efficacy of aescin in topical application in the treatment of hematoma and chronic venous insufficiency. In fact, after 6 weeks of topical treatment based on 2% aescin, patients suffering from chronic venous insufficiency found a significant reduction in the symptoms of heavy legs, pain and itching, as well as a significant decrease in the circumference of the ankles. Escin differs from other polyphenolic-type vaso-protectors (such as rutin) in its mode of action and profile. The amphiphilic character of their structure gives it an indisputable advantage for crossing the double membranous layers and the topical use is accredited by many drugs.

The improvement in the tonic (vasomotor) effect is more significant than the flavonoids (type diosmin, for example), which can be considered more "protective". The anti-edematous and anti-inflammatory effect (in the decisive sense of tissue infiltration) is relevant and proven. An interesting clinical study has demonstrated the anti-inflammatory properties against patients with negative prostate biopsy and with high PSA value (used in the early diagnosis of prostate cancer). The use of a blend of plant substances, aescin (30 mg), bromelain (50 mg) and baicalin (190 mg), revealed a significant reduction in PSA levels. In particular, the combination of the active ingredients in oral administration reduced the PSA values by 30%.

Other in vitro studies demonstrate the ability of aescin to arrest the growth of cancerous prostate cells by stopping the cell cycle in the G2 / M phase by inducing p21 and pro-apoptotic factors.

The present invention has highlighted the role of aescin with its vasoconstriction action and has found an innovative application in the treatment and prevention of pathologies associated with the prostate. In fact, this saponin has a peripheral vasoconstrictive action and increases diuresis through an increased excretion of sodium and chlorides. Although it causes vasoconstriction, aescin does not cause hypertension. Furthermore, this substance acts on the microcirculation by decreasing both the number and the diameter of the pores of the membranes of the arterial capillaries and reducing the passage of liquids from the capillaries to the tissues. Finally, aescin is converted in the adrenal gland into a corticoid-like substance that has a marked restorative action on edema and hematomas of traumatic and / or allergic origin.

Capsaicin

Capsaicin (8-methyl-N-vanillyl-6-noneamide) is the active ingredient of chilli, belonging to the genus Capsicum (among the most important species we remember the Capsicum annum) and responsible for its spicy flavor and spicy sensation.

"Capsaicin", the main component of chilli, was used in ancient times for the control of various forms of pain; of particular interest is the topical treatment of capsaicin in both inflammatory pain and neuropathic pain.

Capsaicin is a potent transient receptor potential vanilloid (TRPV1) agonist. This receptor is a non-selective cation channel, mainly expressed on sensory neurons, but has also been localized in other non-neuronal tissues; it is activated by multiple stimuli, both endogenous and exogenous (resiniferatoxin, anandamide, inflammatory mediators, high temperature> 43 ° C, acid pH <5.3). Exposure to capsaicin determines a biphasic response. The first phase is excitatory, due to the binding of capsaicin with TRPV1 with consequent opening of the channel that allows the passage of Na <+> and Ca <2+> ions, depolarizing the membrane; the resulting electrical impulses reach the brain and are responsible for the typical local burning sensation. This is followed by a phase of analgesia that lasts over time, in which the painful fibers become insensitive to nociceptive stimuli of any kind. The refractoriness to painful stimuli is not due only to receptor desensitization but to a more complex condition called "defunctionalization" which consists of functional and structural changes of the nerve fiber. Chilli contains more than 20 capsaicinoids. Each molecule is made up of three regions: A aromatic ring, B amide bond, C hydrophobic side chain. Capsaicinoids differ in the side chain (number of C atoms, presence of absence of double bonds); the different structure is responsible for the different biological effects, related to the binding affinity to TRPV1, to the agonist or antagonist action, to the spicy power. All capsaicinoids possess analgesic properties, the mechanisms of which are very different between the various molecules. Capsaicin and dihydrocapsaicin are the most powerful agonists of TRPV1 with an excitatory effect, responsible for an intense spicy and irritating effect. Other forms such as homocapsaicin have weak activity on TRPV1 with more inhibitory effects, resulting in a minimal irritating effect, but still an adequate analgesic effect.

The mechanisms are many and can be summarized in the following points:

I. Receptor inactivation.

II. Increase in the intracellular influx of Ca <2+>; this being a second messenger leads to the activation of Ca-dependent proteases with consequent activation of further biological pathways such as the depolymerization of microtubules that block axonal transport causing a dysfunction of the nerve fiber. III. Mitochondrial dysfunction with neurotransmitter synthesis defect.

The first commercial capsaicin products for topical use containing low concentrations of the active (0.025 / 0.1%) showed in addition to the mild analgesic effect, the annoying local irritation, the need for multiple applications, the contamination of the personal environment (mucous membranes, clothes , instruments, contact lenses, etc.) and therefore a poor therapeutic compliance.

To cope with these problems, a preparation containing capsaicin in high doses (8%) was created. In all studies, the results were positive. A single administration resulted in a reduction in pain, quantified by the NPRS (Numeric Pain Rating Scale), significantly larger than the control, and the analgesic effect lasted until the end of the observation period (12 wk. ).

Capsaicin is commonly used in the treatment of pelvic pain. In some studies, capsaicin has been shown to have a positive effect on increasing bladder function. While capsaicin is widely studied and known for its ability to reduce pain, many studies have also shown that it can help kill cancer cells, including those from prostate cancer. In fact, it has been shown that capsaicin causes cancer cells to "commit suicide" (a process called apoptosis). This substance does this by attacking the energy-producing portion of the cells, called the mitochondrion. Furthermore, it does this without affecting the healthy cells that surround the diseased cells. Capsaicin promotes the suicide of cancer cells (apoptosis) and also improves other factors that inhibit the development of prostate cancer.

In fact, capsaicin has been shown to have anti-cancer activity in several cancer cells, including prostate cancer. Several molecular mechanisms have been proposed on its chemopreventive action, including accumulation of ceramide, induction of endoplasmic reticulum stress, and inhibition of NFκB. However, the precise mechanisms by which capsaicin exerts its anti-proliferative effect in prostate cancer cells remain questionable. The involvement of autophagy on the mechanism of action of capsaicin on LNCaP and PC-3 cells of prostate cancer was then tested. The results showed that capsaicin induces prostate cancer cell death in a time- and concentration-dependent manner by increasing levels of microtubule-associated light chain protein (LC3-II, a marker of autophagy) and accumulation. of the p62 protein. Normal prostate cells were more resistant to capsaicin-induced cytotoxicity and did not accumulate p62 protein. These results suggest that ROS-mediated capsaicin-induced blockade of autophagy contributes to the non-proliferation in prostate cancer cells, thanks to the molecular anticancer mechanism of capsaicin.

In addition, the molecule has pain relieving activity on the urinary flow. Through its mechanism of action it acts by selectively blocking the unmyelinated C fibers, normally silent, which are activated in conditions of hypersensitivity and bladder hyperactivity, resulting in increased frequency and urgency of urination, incontinence and reduced bladder capacity. The interaction between capsaicin and vanilloid receptors induces desensitization of C fibers, both by interrupting responses to nociceptive stimuli and by inhibiting the hyperactivity of the detrusor muscle. In this way it carries out both a pain-relieving action and an action to regulate a correct urination flow.

Curcuma longa

Curcuma longa is a plant belonging to the Zingiberaceae family comprising a total of about 80 species. Commonly also called Indian saffron, or simply referred to as turmeric, it represents the most used species. Its name derives from the Sanskrit "Kum-kuma", and is the main ingredient of Indian curry. Most of the properties attributed to turmeric depend precisely on curcumin, which is its best-known active ingredient ally of well-being.

This molecule - which from a chemical point of view can be classified among the polyphenols - is responsible for the golden yellow color typical of turmeric and the curries that contain it, but not only.

In fact, turmeric would have been attributed antioxidant, anti-inflammatory, anti-infective, antimicrobial, hepatoprotective, thrombosuppressive, cardioprotective, antiarthritic, proapoptotic, antitumor and chemopreventive (ie cancer prevention) properties. Its protective action against tumors (for example in the colon or breast) would depend on the negative regulation of molecules involved in inflammation (inflammatory cytokines), of transcription factors, of some enzymes (protein kinases), of some genes involved in cancer and reactive oxygen species. In the case of breast cancer, for example, curcumin appears to exert its anticancer effect through an intricate mechanism involving the mechanisms of cell proliferation and apoptosis, estrogen receptors and the growth factor HER2.

The anti-inflammatory action of curcumin seems to depend on its ability to control various molecules promoting inflammation (such as interleukin-6, interleukin-1beta and Tumor necrosis factor-alpha), some growth factors and their receptors, protein kinases and other enzymes, molecules involved in cellular adhesion mechanisms and NF-kB, a fundamental transcription factor in inflammation.

Curcumin is a product of natural origin with mainly anti-inflammatory activity, which could be useful in the treatment of prostatitis and benign prostatic hyperplasia. In addition to being one of the most powerful anti-inflammatories of natural origin, it has chemical-physical properties suitable for its distribution in the prostate (being a lipophilic and relatively small molecule, it has no problems in overcoming the blood-prostate barrier). The mechanism of action of curcumin consists in the modulation of the expression of numerous proteins, including pro-inflammatory cytokines (TNF-α, IL-8, IL-1β, IL-6), apoptotic proteins, NF-kB, COX- 2, STAT3, MDA, etc ...

The main markers of prostate inflammation are TNF-α, IL-8, IL-1β, IL-6, as demonstrated by a study by Penna and collaborators, who found high concentrations of these pro-inflammatory cytokines and especially of the chemokine IL -8 in the seminal fluid of patients with prostatitis. One of the activities of curcumin is precisely to inhibit TNF-α, IL-1β, IL-6 and IL-8 (the latter to a lesser extent) and this could make it a valid active ingredient to be used in case of prostatitis, since which reduces its main markers. The same activity has been demonstrated in prostatitis models (induced by castration and the administration of 17βestradiol): the administration of curcumin, in this case, is able to reduce the expression of TNF-α, IL-6, IL-8.

A randomized, clinical trial with long-term patient follow-up evaluated the effect of the combination of Serenoa repens (160 mg), Urtica dioica (120 mg), curcumin (200 mg), quercetin (100 mg) and prulifloxacin ( 600 mg) compared to prulifloxacin alone for the treatment of chronic bacterial prostatitis. After one month of treatment, in 89% of patients in the first group, the disappearance of symptoms of prostatitis was observed, while in the second group the disappearance of symptoms was observed in only 27% of patients. This spice has a decidedly beneficial action in the treatment of chronic prostatitis (or pelvic pain syndrome) as well as bacterial prostatitis.

Turmeric combines well with other supplements and is often used as an ingredient in formulations. It can also be used in combination with traditional therapies and could even help improve the effectiveness of antibiotics when taken together for bacterial prostatitis.

Turmeric has been studied to: reduce pro-inflammatory cytokines interleukin-8 and tumor necrosis factor alpha in blood tissues and have efficacy on patients with prostate problems.

Several studies have highlighted the specific role in fighting bacterial prostatitis, especially in combination with other supplements and antibiotics. A combination of curcumin, quercetin, saw palmetto and nettle, together with the moderate use of an antibiotic, is excellent for chronic bacterial prostatitis.

In an effort to find a non-toxic alternative to prostate cancer therapy, the attention of researchers has turned to turmeric. Research results have shown that curcumin is a potent inducer of apoptosis (a form of programmed cell death) of both androgen-dependent and independent prostate cancer cells.

Plant belonging to the Cucurbitaceae family

Cucurbita is a genus of plants belonging to the Cucurbitaceae family originating from Central-South America. The generic term Cucurbita comes from the Latin name of the pumpkin and in turn from the Sanskrit curved, round arbor. In botany, pumpkins are divided into four species: Cucurbita maxima - Cucurbita moschata - Cucurbita pepo - Cucurbita melanosperma. The most studied varieties are represented by Cucurbita maxima Duchesne (yellow or sweet pumpkin) and Cucurbita pepo (commonly called courgette). Pumpkin seed oil is obtained by pressing the plant of the same name and varies in relation to the varieties and botanical species from which the seeds are obtained. Pumpkin is a natural antidote against free radicals, substances that are dangerous for our body and that speed up the cellular aging process. The beta-carotene contained in pumpkin has many anti-inflammatory and anticancer properties as discovered by the National Cancer Institute; lycopene, on the other hand, is more effective in cases of prostate, lung and stomach cancer. Interesting studies showing an important blood glucose lowering effect in the animal model, using both pulp and seed extracts. The effect could be due both to the presence in the pulp of the fruit of D-chiroinositol and other particular polysaccharides, substances that favor the action of insulin, and to substances such as trigonellin and nicotinic acid present in the seeds. The presence of vitamin E and other substances with antioxidant action, in particular some polysaccharides that are bound to proteins in the fruit pulp, can stimulate the activity of enzymes such as superoxide dismutase and glutathione peroxidase, essential enzymes in reducing oxidative damage in the cell.

Several studies have shown that diets rich in carotenoids, abundant in pumpkin, may have some role in reducing the incidence of prostate cancer. Furthermore, several substances isolated from the pulp and seeds of the pumpkin, moschatina and cucurmosina have been shown to have the ability to inhibit the growth of specific types of cancer cells, especially some types of melanoma. Pumpkin seeds contain substances such as cucurbitin, phytosterins and delta sterols, capable of inhibiting the aromatase enzyme that affect the tone of the pelvic floor.

In addition, pumpkin seed oil (extracted from both Cucurbita maxima and Cucurbita pepo) is widely used as a herbal remedy useful in the treatment of benign prostatic hypertrophy. Carotenoids and zinc (both useful for prostate health), manganese, magnesium, phosphorus and iron also abound, although the main constituent is still oleic acid (24-38%), linoleic (4356 %), tocopherols and carotenoids (lutein and β-carotene). Some substances of pumpkin seeds are useful in fighting benign prostatic hyperplasia, a condition that causes an increase in the volume of the prostate caused, in turn, by an increase in the number of (non-cancerous) cells in the gland. This condition usually presents with frequent urination, infections and recurrent inflammation of the urinary tract. It has been seen that pumpkin seeds can help relieve the symptoms of this pathology, thanks to their content of zinc and, above all, of phytosterols such as beta sitosterol, sitostanol, avenasterol. These phytosterols have a chemical structure very similar to that of the hormones androgens and estrogens. These would be able to inhibit the conversion of testosterone into dihydrosterone, responsible for cell growth at the base of prostatic hypertrophy. Zinc is also important for the proper functioning of the prostate and pumpkin seeds, being rich in it, also in this respect help to exert a protective action against this gland.

It has long been known that seeds contain betasterols that are structurally similar to androgens and estrogens. These substances have been shown to be useful for lowering cholesterol levels and improving the symptoms of prostatic hypertrophy, an effect that seems to be linked in part to the ability to inhibit the conversion of testosterone into dihydrotestosterone, and in part to the obstacle offered to the link between androgen receptors and dihydrotestosterone. The latter substance is a hormone derived from testosterone by the enzyme 5-alpha-reductase, involved - among other things - in the hyperproliferation of prostate cells.

In a randomized, double-blind, placebo clinical trial conducted on 47 Korean patients with a mean age of 53.3 years with benign prostatic hyperplasia, the efficacy of pumpkin seed oil administered for 12 months alone was tested. (320 mg / day) or in combination with Serenoa repens oil (320 mg / day of one 320 mg / day of the other); the results were compared with those of the group treated with placebo (320 mg of sweet potato starch) or with serenoa oil alone (320 mg / day). None of the proposed treatments guaranteed a significant reduction in prostate volume; the serum PSA values decreased in the group that took the two oils together, while the quality of life improved after 6 months. The two herbal medicines taken separately ensured an improvement in prostatic symptoms expressed through the IPSS (International Prostatic Symptom Score) over three months, while the maximum urinary flow improved after six months in the group treated with pumpkin seed oil. and after 12 months in the group treated with serenoa oil. The combination of Serenoa with another variety also belonging to the Cucurbita genus has shown a reduction in BPH symptoms with a very small amount of active ingredients (Cucurbita pepo 80 mg and Serenoa repens 80 mg).

Serenoa repens

Serenoa repens, called Saw Palmetto in English, is a dwarf palm of the Arecaceae family that grows mainly in the South-East of the United States along the Atlantic Ocean coast and in south tropical areas. Its fruits, dark brown to black in color and rich in active ingredients such as free fatty acids and sterols (in particular beta-sitosterol), are recognized the undisputed health properties previously reported for the benefit of the prostate and hair.

The sterolic lipid extract of Serenoa repens, highly titrated in fatty acids, not only helps to keep the prostate healthy but, as reported by numerous scientific evidences, contributes, thanks to the inhibition of the 5-alpha reductase enzyme, also to well-being and to the trophism of the hair of men with androgenetic alopecia. The sterol lipid extract of Serenoa repens, thanks to its composition and content in fatty acids including lauric acid, myristic acid and a plant sterol called beta-sitosterol, has an important selective antiandrogenic action that is mainly expressed through inhibition, of both isoforms I and II, of the key enzyme 5-alpha reductase (5AR) in the process of converting testosterone into dihydrotestosterone. Dihydrotestosterone is the hormone mainly responsible for prostate growth and the appearance of male androgenetic alopecia. Scientific evidence has revealed that lauric acid and myristic acid are also able to interact directly with testosterone, forming esters of this hormone which is thus no longer convertible into DHT. Studies on animal models have instead shown that beta-sitosterol limits the bioavailability of cholesterol and therefore the synthesis of testosterone, a substrate of 5-alpha reductase, in the prostate and in the hair follicle. An in vitro study shows that both ethanolic and hexane extracts, two types of serenoa repens sterolic lipid extract, are capable of inhibiting 5-alpha reductase in co-cultures of epithelial cells and prostatic fibroblasts. Another in vitro study shows that the serenoa repens sterol lipid extract is useful in treating BPH with inflammatory characteristics, presumably modulating the balance between apoptotic and proliferative factors. An in vivo study compares the efficacy of the sterol lipid extract of Serenoa repens (LSESR) with finasteride (5-alpha-reductase inhibitor) on prostatic hyperplasia induced by hyperprolactinaemia in rats. Hyperprolactinemia was induced by 30 daily injections of sulpiride. The rats received daily gavage of serenoa repens sterol lipid extract or finasteride. They were divided into the following groups: control, neutered, castrated rats with a replacement testosterone (T) or with 5alphahydrotestosterone (DHT) implantation. Hyperprolactinemia increases wet weight and induces hyperplasia in the lateral prostate. Unlike finasteride, LSESR significantly reduced growth and lateral prostate hyperplasia in neutered, DHT-treated, and sulpiride-treated rats. Finasteride was only able to inhibit the effect of androgens on the enlarged rat prostate. LSESR inhibited not only the androgenic effect but also the trophic effect of prolactin in rat lateral hyperplasia. Numerous clinical studies have then confirmed the efficacy of this plant sterol in improving the well-being of the prostate in men. Finally, further studies have shown that the extract of Serenoa repens has an inhibitory action against growth factors responsible for cell proliferation and the inflammatory process underlying benign prostatic hypertrophy. It is scientifically proven that the fruit of Serenoa repens contributes to the normal function of the prostate. In fact, clinical studies show that the sterol lipid extract from Serenoa repens fruits is effective in improving the symptoms of benign prostatic hypertrophy. Several double-blind, randomized and placebo-controlled clinical trials conducted on patients with benign prostatic hypertrophy (BPH) have confirmed the efficacy of Serenoa extracts. One of these studies, conducted on 176 patients with BPH and no-responders to placebo treatment in previous clinical studies, showed that the daily intake of 320 mg of Serenoa repens fruit extract already after 30 days contributes to normal prostatic function. In fact, it was possible to observe an evident improvement in dysuria, a reduction in polyuria and nocturia in patients treated with respect to placebo (32.5% vs 17.7%). In addition, patients who were administered the lipid-sterol extract of Serenoa experienced an increase in maximum urinary flow (28.9%) compared to patients who had received placebo (8.5%). There is evidence that the hexane extract of Serenoa repens (HESr) can antagonize the metabolites of lipoxygenases, resulting in an anti-inflammatory effect. This finding was recently confirmed by in vivo and in vitro studies, with the evidence that Serenoa can modulate the expression of multiple genes related to inflammation. Furthermore, randomized clinical trials evaluated the effect of Serenoa on the biomarkers of persistent chronic inflammation in patients with LUTS / BPH, using a non-invasive method (urine test after prostate massage), correlating the efficacy of the extract. exane of Serenoa in the inflammatory state of the patient. Recent acquisitions have also noted how using inflammation as a therapeutic target is also useful in promoting the therapeutic response of other treatments. In fact, it has been shown that during a state of chronic inflammation the effectiveness of 5-alpha-reductase (5-ARI) inhibitors decreases. Furthermore, this chronic inflammatory state, as mentioned, is able to stimulate the production of interleukins and growth factors that act independently of the presence of 5-ARI. Therefore it appears interesting for the present invention for its anti-inflammatory and antiproliferative capacities.

The present invention allows to obtain at the same time:

• Anti-inflammatory effect

• Analgesic effect

• Pro-apoptotic effect on cancer cells

In particular, the effectiveness of the aforementioned composition derives from the precise properties of its main components: the diuretic, anti-edematous and anti-inflammatory activities of aescin and the analgesic and pain-relieving action of capsaicin.

Furthermore, both compounds are able to induce apoptosis in prostatic cancer cells through different activities.

The aforesaid invention may further contain the following components: turmeric, a powerful anti-inflammatory of natural origin, possesses chemical-physical properties suitable for its distribution in the prostate; an extract from the plant belonging to the Cucurbita genus which, thanks to its variety of constituents (sitosterols, vitamin E, zinc, carotenoids, etc.) contributes to a complete well-being of the prostate. Finally, the extract of Serenoa repens, in addition to its anti-inflammatory and anti-androgenic activity, has a complete regulatory action on the functionality of the prostate.

As previously stated, in the present invention the synergistic action occurs between aescin and capsaicin in a mixture with one or more pharmaceutically acceptable carriers.

Suitable pharmaceutically acceptable carriers are those commonly known to those skilled in the art for the preparation of pharmaceutical compositions for oral administration such as solutions, suspensions, powders or granulates, tablets, capsules, pellets. By way of non-limiting example, these pharmaceutically acceptable carriers can consist of binders, diluents, lubricants, glidants, disaggregants, solubilizers (wetting agents), stabilizers, dyes, anti-caking agents, emulsifiers, thickeners and gelling agents, coating agents, humectants, sequestrants, sweeteners. Specifically, examples of diluents can be: magnesium carbonate, microcrystalline cellulose, starch, lactose, sucrose; the main lubricants used are magnesium stearate, stearic acid, sodium stearyl fumarate. As glidants, colloidal silica, magnesium silicate, cross-linked polyvinylpyrrolidones, starch sodium glycolate, surfactants such as TWEEN or sodium lauryl sulphate as solubilizers, and all classes of preservatives (sorbic acid and derivatives , benzoic acid and derivatives, parabens), antioxidants (ascorbic acid and derivatives, tocopherol), acidifiers (phosphoric acid, tartaric acid). The thickeners and gelling agents can be carrageenan, pectins, starches, the coating agents include for example waxes and derivatives, the anti-caking agents calcium or magnesium carbonate, the humectants sorbitol, mannitol, the sequestrants EDTA and derivatives, the dyes aspartame, acesulfame potassium. The composition object of the present invention is preferably a liquid or solid composition for oral use, even more preferably an aqueous solution, a suspension, a powder or granulate, a tablet, a capsule, pellet.

The composition may further contain an extract of Curcuma longa and / or an extract of a plant belonging to the genus Cucurbita and / or an extract of Serenoa Repens.

The synergy occurs when capsaicin is present in an amount comprised between 0.1 mg and 5000 mg, preferably between 1 mg and 3000 mg; escin is present between 0.1 mg and 5000 mg, preferably between 1 mg and 3000 mg. Curcuma longa extract, if present in the composition, is contained in an amount between 10 mg and 5000 preferably between 20 mg and 3000 mg. The extract of the plant belonging to the Cucurbita genus, if present in the composition, is contained in an amount between 1 mg and 5000 mg, preferably between 10 mg and 3000 mg. The extract of Serenoa repens, if present in the composition, is contained in an amount between 10 mg and 5000 mg, preferably between 20 mg and 3000 mg. The following examples are provided for illustrative and non-limiting purposes of the scope of the invention as defined by the attached claims.

EXAMPLE 1

Active ingredient Amount per dosage unit Capsaicin (Capsicum annum) 50 mg

Aescin (Aesculus hippocastanum) 50 mg

Pumpkin seeds (Cucurbita) 80 mg

Turmeric (Curcuma longa) 50 mg

Serenoa repens 320 mg

Pharmaceutical form: soft gel capsules

EXAMPLE 2

Active ingredient Amount per dosage unit Capsaicin (Capsicum annum) 60 mg

Aescin (Aesculus hippocastanum) 10 mg

Pumpkin seeds (Cucurbita) 100 mg

Turmeric (Curcuma longa) 100 mg

Serenoa repens 400 mg

Pharmaceutical form: soft gel capsules

EXAMPLE 3

Active ingredient Amount per dosage unit Capsaicin (Capsicum annum) 200 mg

Aescin (Aesculus hippocastanum) 200 mg

Pumpkin seeds (Cucurbita) 200 mg

Turmeric (Curcuma longa) 120 mg

Serenoa repens 320 mg

Pharmaceutical form: sachets

EXAMPLE 4

Active ingredient Quantity per dosage unit Capsaicin (Capsicum annum) 500 mg

Aescin (Aesculus hippocastanum) 400 mg

Pumpkin seeds (Cucurbita) 400 mg

Turmeric (Curcuma longa) 200 mg

Serenoa repens 400 mg

Pharmaceutical form: sachets

The dosage form can be a food supplement or medical device, a food supplement, a cosmetic, a nutraceutical, dietary and nutritional composition, a food product, a beverage, a nutraceutical, a medicament, a medicated food, a pharmaceutical composition or a food for special medical purposes including the aforementioned active ingredients in admixture with each other. The preferred route of administration is oral or topical.

EXPERIMENTAL PART

The synergistic action of the composition with respect to the individual active ingredients is evaluated using in vitro and / or in vivo experimental methods.

The susceptibility of the cellular system to proinflammatory stimuli can be evaluated with enzyme immunoassays (ELISA), detecting the quantity of cytokines involved in inflammatory processes and in particular the activity of bioactive compounds on the response, inhibition / activation, of cytokines (TNF- α, IL-1, IL-4, IL-6, IL-8, IL-10, IL-17, INF-ϒ, COMP), proinflammatory enzymes such as lipoxygenases (LOX) and cyclooxidases (COX2) involved during LPS-induced inflammatory diseases through the Whole Blood Assay (WBA) or the Peripheral Blood Mononuclear Cell (PBMC) test or other similar tests.

The pro-apoptotic activity of the active ingredients of the present invention can be evaluated by in vitro assays capable of demonstrating how the synergy of the two components significantly inhibits cell viability with respect to the individual active ingredients.

Cellular models known to those skilled in the art can be used such as PC-3, CRPC (castration-resistant prostate cancer), DU - 145, LNCap and / or other analogues cells.

As an in vivo test, a simple model of general inflammation is the carrageenan-induced edema model induced on mice or rats. In this test, the injection of carrageenan into the animal causes an acute inflammatory reaction with the appearance of the classic signs of inflammation. With this test, the response of the active ingredients to reduce inflammation in rats can be assessed.

The anti-inflammatory activity can be evaluated by demonstrating the efficacy of the compounds object of the present invention in promoting apoptosis in mice with experimentally induced BPH. The apoptosis system is a promising system for the medical treatment of benign prostatic hypertrophy. As part of the apoptotic cascade, apoptosis inhibitory proteins (IAPs) modulate apoptosis through the direct inhibition of the caspase cascade. The study can evaluate the effectiveness of the active ingredients, alone or in combination, on the ability to induce the expression of IAPs proteins in mice with BPH experimentally induced by injection with testosterone.

A more complex in vivo model involves testing the active ingredients of the present composition to demonstrate their anti-inflammatory and analgesic effect on rats in which experimental autoimmune prostatitis (EAP) is induced, through intradermal injection of rat prostate antigens and "Freund's adjuvant ”, A mixture of antigens emulsified in mineral oils used as immuno-enhancers.

This occurs on set days (for example 0-28 and 42) and after the injection both the level of inflammatory cytokines and chemokines and chronic pelvic pain are assessed. In particular, the recruited rats are tested in terms of allodynia and hyperalgesia at the preset day (for example 42) after immunization. Allodynia and hyperalgesia are tested using von Frey filaments with forces of 0.4 g. The filament is applied a total of 5 times for 1-2 seconds with an interstimulation interval of 2 minutes. Behaviors considered positive to the stimulation of the filament are: net retraction of the abdomen, licking or scratching immediately in the stimulation area of the filament or jumping. The control, each substance individually and then also the mixture of substances of interest for the present composition, are administered orally 2 hours before the mechanical stimulation, thus evaluating the role of the active ingredients in reducing the frequency of reactions to mechanical stimulation, with respect to to control and to substances administered individually.

Claims (10)

CLAIMS 1) A composition comprising an association of escin and capsaicin, in admixture with one or more pharmaceutically acceptable carriers. 2) Composition according to claim 1, wherein the escin is present in the composition in the form of an extract of Aesculus hippocastanum. 3) Composition according to claim 1, wherein the capsaicin is present in the composition in the form of an extract of a plant of the genus Capsicum, preferably Capsicum annum and / or Capsicum pubescens and / or Capsicum baccatum and / or Capsicum chinense and / or Capsicum frutescens . 4) Composition according to any one of the preceding claims, in which an extract of Curcuma longa and / or an extract of a plant belonging to the Cucurbita genus and / or an extract of Serenoa repens is present as a further active component. 5) Composition according to any one of the preceding claims, in which the extract of a plant belonging to the Cucurbita genus is an extract of Cucurbita maxima and / or Cucurbita pepo. 6) Composition according to any one of the preceding claims, wherein the escin is present in an amount comprised between 0.1 mg and 5000 mg, preferably between 1 mg and 3000 mg; capsaicin is present in an amount comprised between 0.1 mg and 5000 mg, preferably between 1 mg and 3000 mg. 7) Composition according to any one of the preceding claims in which, if present, the extract of Curcuma longa is contained in an amount of between 10 mg and 5000 mg, preferably between 20 mg and 3000 mg; the extract of a plant belonging to the Cucurbita genus is contained in an amount between 1 mg and 5000 mg, preferably between 10 mg and 3000 mg; Serenoa repens extract is contained in an amount between 10 mg and 5000 mg, preferably between 20 mg and 3000 mg. 8) Composition according to any one of the preceding claims, wherein the composition is a food supplement, a medical device, a food supplement, a cosmetic, a nutraceutical, dietary and nutritional composition, a food product, a beverage, a nutraceutical, a medicament , a medicated food, a pharmaceutical composition or a food for special medical purposes. 9) Composition according to any one of the preceding claims in the form of liquid, solid or semi-solid composition for oral or topical use. 10) Composition according to any one of the preceding claims for use in the prevention and / or treatment of prostate pathologies, in which the pathologies associated with the prostate are pelvic pain, chronic pelvic pain, acute prostatitis of bacterial origin, chronic prostatitis of bacterial origin, chronic non-bacterial prostatitis, asymptomatic prostatitis, overactive bladder, benign prostatic hypertrophy, prostate cancer.