EP3972577A1 - Composition destinée à être utilisée dans la prévention et/ou le traitement de pathologies associées à la prostate - Google Patents

Composition destinée à être utilisée dans la prévention et/ou le traitement de pathologies associées à la prostate

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Publication number
EP3972577A1
EP3972577A1 EP20732318.9A EP20732318A EP3972577A1 EP 3972577 A1 EP3972577 A1 EP 3972577A1 EP 20732318 A EP20732318 A EP 20732318A EP 3972577 A1 EP3972577 A1 EP 3972577A1
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EP
European Patent Office
Prior art keywords
extract
composition
prostate
composition according
capsaicin
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EP20732318.9A
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German (de)
English (en)
Inventor
Umberto DI MAIO
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Neilos SRL
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Neilos SRL
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Publication of EP3972577A1 publication Critical patent/EP3972577A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/77—Sapindaceae (Soapberry family), e.g. lychee or soapberry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a composition of substances, preferably obtained from natural sources, effective in the prevention and/or treatment of prostate pathologies.
  • the prostate can incur in a huge number of pathologies, from the inflammatory or 15 infectious ones to the degenerative, benign or malignant ones.
  • the synergic action takes place between escin and capsaicin.
  • the composition can 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 pelvic pain represents one of the most disabling disorders highly impacting on the quality of life and requiring a multidisciplinary diagnostic and therapeutic approach.
  • the pelvic pain in man represents an important symptom which can be secondary to physiological or pathological conditions.
  • the “pelvic” adjective discriminates the presence of pain at the level of lower abdomen, immediately below the abdominal region, comprising the pelvis area, the external genitalia and perineum.
  • the pelvic pain can be classified as:
  • the non-specific chronic prostatitis represents the most frequent cause of syndrome from chronic pelvic pain. It is characterized by the inflammation of the prostate gland, but without signs of infection. All performed surveys such as culture of urine or prostate liquid result to be negative, and at the ultrasound or CT (Computed Tomography) the prostate results to be normal, notwithstanding the presence of pain and urinary symptoms suggesting its involvement. This clinical picture could be caused by an altered perception of pain with presence of allodynia or hyperalgesia.
  • the prostate diseases can be of benign neoplastic, malign neoplastic or inflammatory origin.
  • Benign prostatic hyperplasia is a benign disease characterized by a proliferation of the prostate tissue resulting in an increase in the gland volume. This disease is very frequent, above all in men after the age of 40/50 years. With increasing age, in fact, the prostate tends to increase its own volume; to explain such phenomenon, hormonal changes and the action of several growth factors during ageing get involved. The result of a significative prostate enlargement is the appearance of urinary disorders.
  • the prostate tumour includes a variety of forms, from those having a very slow growth, which may not cause disorders throughout life, to other more aggressive forms, which on the contrary grow quickly. Exactly the latter, the so-called malignant ones, are the most dangerous neoplasms.
  • the malignant tumours then have the power of spreading in other parts of organism, that is they may determine the onset of metastases.
  • the prostate tumour is a pathology which sometimes is difficult to be detected, since in the initial phases tends to be asymptomatic. Moreover, when the symptoms are present, they can be confused with those deriving from the benign prostatic hyperplasia or from prostatitis.
  • the prostate inflammation better known in medical field with the term of prostatitis, can depend upon infectious (to be precise, bacterial) or non-infectious causes.
  • the prostate inflammation types are 4 and, to be precise, correspond to:
  • the typical symptoms and signs of prostatitis of type I are: high fever with chills, pelvic pain, urinary disorders of various type.
  • the chronic prostate inflammation of bacterial type can be: the result of a failed treatment of an acute prostatitis of bacterial origin, the consequence of an infection of urinary tracts or, at last, the complication of an epididymitis (infection whose symptoms appear in a testicular manner).
  • the acute prostate inflammation, of bacterial origin is a form of prostatitis caused by bacteria.
  • the non-bacterial chronic prostate inflammation is the prostatitis appearing gradually and having persistent character, not depending from the presence of bacteria at the level of the prostate gland.
  • prostatitis of type III also known as prostatitis of type III or chronic pelvic painful syndrome, it occurs due to reasons that physicians and researchers, notwithstanding the several studies, have not yet cleared completely.
  • the asymptomatic inflammation is also called prostatitis of type IV or inflammatory asymptomatic prostatitis. Notwithstanding the several studies about prostatitis of type IV, the physicians have not yet understood the triggering causes thereof and the reasons of the lack of symptoms.
  • the Chronic Pelvic Pain is characterized by the pain persistence, continuous or intermittent pain, with pelvic involvement, lasting more than six months. It involves progressively different pelvic organs, by involving several functions.
  • MC mastocyte
  • MC is ubiquitous in all organs and vascularized tissues, wherein it works as immune sentinel and organizes the inflammatory response.
  • MC includes several vasoactive, proinflammatory and neurotrophic substances, included in vesicles which are released in the surrounding tissues in differentiated way in response to the action of different“antagonist” factors (dangerous or however which cause the release thereof), by coordinating the different phases of the physiological and pathological inflammatory response. These factors modulate in time the inflammatory response of the organism to endogenous and hexogen harmful heterogeneous factors.
  • the treatment of pelvic pain provides a therapy of aetiological type based upon the removal of the underlying cause.
  • composition of the present invention the synergic action takes place between escin and capsaicin in admixture with one or more pharmaceutically acceptable carriers.
  • the composition can further include 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 is a vegetable compound obtained from the seeds, peels and leaves of horse- chestnut.
  • the horse-chestnut ( Aesculus hippocastanum) is a plant of the family Ippocastanacee.
  • the seeds and the bark of the horse-chestnut include saponins, the mixture thereof is called escin.
  • the escin exists in two forms, alfa and beta, which can be distinguished for their melting points, haemolytic activities and solubility in water.
  • the beta form of escin is the active component of the extract of chestnut of India.
  • the complex mixture of triterpenoid saponins has revealed to be very effective in the treatment of the microcirculatory disorders.
  • Escin is traditionally used in the symptomatic treatment of the functional disorders of the skin capillary fragility, the venous insufficiency (heavy legs), but even in the symptoms of haemorrhoidal crisis. Escin acts upon the factors starting inflammation/oedema, that is hypoxia of endothelial cells, followed by the reduction in ATP. The inflammatory reaction is triggered by the release of prostaglandin (signals of the inflammatory response) through phospholipase A2 and PAF (platelet activating factor). It is at the origin of oedema and of the adherence of the neutrophils to endothelium.
  • neutrophils in turn release enzymes of elastase type, degrading the veins’ wall and stimulating the production of FGF (fibroblast growth factor), by causing a vein enlargement.
  • FGF fibroblast growth factor
  • Escin acts at the anti-inflammatory level through the reduction in the activity of the lysosomal enzymes which, since they are hyper-activated by the inflammatory processes, produce a degradation of the capillary wall; in particular, escin reduces the activity of elastase, of collagenase, of hyaluronidase and beta-glucuronidase, proteolytic enzymes which - during the inflammatory processes - degrade the internal structure of vessels and weaken endothelium of capillaries by determining the oedema formation.
  • Escin prevents and reduces oedema.
  • the anti-oedematous effect is linked to a selective vascular permeability, which causes an increase in the venous and arterial tone.
  • Escin reduces the fragility of capillaries and thus allows to avoid liquid infiltration in the tissue interstitium (first cause of oedema).
  • the therapeutic benefit is well supported by a series of experimental surveys on different animal models, indicative of anti-oedematic, anti-inflammatory and venotonic properties. Its properties are mainly correlated to the agent molecular mechanism, by allowing a better inlet of ions into the channels, it causes a raise in the venous tension both under in-vitro and in-vivo conditions.
  • Escin differs from other vasoprotectors of polyphenolic type (such as rutin) for its action mode and its profile.
  • the amphiphilic character of their structure confers an indisputable advantage to cross the double membrane layers and the topical use is supported by many drugs.
  • the improvement of the tonic effect is more significant with respect to the flavonoids (like diosmin, for example) which can be considered more“protective”.
  • the anti-oedematous and anti-inflammatory effect is relevant and demonstrated.
  • An interesting clinical study has demonstrated the anti-inflammatory properties against patients with negative biopsy at the prostate and with high value of PSA (used in the early diagnosis of the prostate cancer).
  • the use of a blend of vegetable substances, escin (30 mg), bromelain (50 mg) and baicalin (190 mg) detected a significative reduction in the PSA levels.
  • the combination of the active principles in the oral administration reduced by 30% the PSA levels.
  • the present invention has underlined the role of escin with its vasoconstriction action and it has detected an innovative application thereof in the treatment and in the prevention of pathologies associated to the prostate.
  • saponine has a peripheral vasoconstricting action and it increases diuresis by means of an increased excretion of Sodium and Chlorides. Even if it determines vasoconstriction, escin does not cause hypertension.
  • such substance acts onto the microcirculation by decreasing both then number and the diameter of the pores of the membranes of the arterial capillaries and by reducing the passage of the liquids from the capillaries to the tissues.
  • escin is converted in the adrenal gland into a substance having corticoid-like activity performing a strong reparatory action of oedema and of hematomas of traumatic and/or allergic origin.
  • Capsaicin (8-methyl-N-vanillyl-6-noneamide) is the active principle of chili pepper, belonging to the genus Capsicum (among the most important species we remind Capsicum annum) and responsible for its spiced flavour and spicy feeling.
  • Capsaicin main component of chili pepper, was used in past to control various pain forms; the topical treatment of capsaicin both in the inflammatory pain, and in the neuropathic pain is of particular interest.
  • Capsaicin is a powerful agonist of TRPV1 (transient receptor potential vanilloid) receptor.
  • TRPV1 transient receptor potential vanilloid
  • Such receptor is a not selective cationic channel, mainly expressed on the sensorial neurons, but it was localized even in other non-neuronal tissues: it is activated by several stimuli, both endogenous and exogenous ones (resiniferatoxin, anandamide, inflammation mediators, high temperature > 43°C, acid pH ⁇ 5.3).
  • the exposition to capsaicin determines a biphasic response.
  • the first phase is excitative, due to the bond of capsaicin with TRPB1 with consequent opening of the channel allowing the passage of Na + and Ca 2+ ions by depolarizing the membrane; the resulting electric pulses reach the brain and are responsible for the typical feeling of local burning.
  • An analgesia phase follows, lasting in time, in which the pain-producing fibres become insensitive to the nociceptive stimuli of any nature. The refractoriness to the pain-producing stimuli is not only due to receptor desensitisation, but to a more complex condition called “de-functionalization” consisting in functional and structural changes in the nervous fibre.
  • the chili pepper includes more than 20 capsaicinoids.
  • Each molecule is formed by three regions: A aromatic ring, B amidic bond, C hydrophobic lateral chain.
  • the capsaicinoids differ by the lateral chain (Nr. of C atoms, presence/absence of double bonds); the different structure is responsible for the different biological effects, related to the bond affinity to TRPV1 , to the agonist or antagonist action, to the spicy power. All capsaicinoids have analgesic proprieties, the mechanisms thereof are very different among the various molecules.
  • Capsaicin and dihydrocapsaicin are the most powerful agonists of TRPV1 with excitative effect, responsible for an intense spicy and irritating effect. Other forms such as homocapsaicin have weak activity on TRPV1 with more inhibiting effects, by determining a minimum irritating effect, but however an adequate analgesic effect.
  • the first commercial products of capsaicin for topical use containing active low concentrations showed, apart from the slight analgesic effect, the annoying local irritation, the need for several applications, the contamination of the personal environment (mucosae, clothes, instruments, contact lenses, etc.) and then a poor therapeutic compliance.
  • NPRS Numeric Pain Rating Scale
  • Capsaicin is commonly used in the treatment of pelvic pain. In some studies capsaicin demonstrated to have a positive effect on the increase in the bladder functionality. Whereas capsaicin is widely studied and known for its capability in reducing pain, several studies have even shown that it can help to kill tumour cells, including those of the prostate cancer.
  • capsaicin makes the tumour cells to “kill themselves” (a process called apoptosis). This substance succeeds in doing so by attacking the portion producing energy of cells, called mitochondrion. Moreover, it does this without affecting healthy cells surrounding the diseased cells. Capsaicin promotes the suicide of tumour cells (apoptosis) and improves even other factors inhibiting the development of the prostate cancer.
  • Capsaicin in fact, has demonstrated to have anti-cancer activities in different tumour cells, thereamong the prostate cancer.
  • Several molecular mechanisms were proposed on its chemo-preventive action, thereamong the accumulation of ceramide, the stress induction of the endoplasmic reticulum and NFkB inhibition.
  • the precise mechanisms therewith capsaicin exerts its anti-proliferative effect in the prostate cancer cells remain questionable. Then, the involvement of autophagia on the action mechanism of capsaicin on LNCaP and PC-3 cells of the prostate carcinoma was tested.
  • capsaicin induces the death of the prostate cancer cells independently from time and concentration, by increasing the levels of light-chain protein associated to the microtubules (LC3-II, an autophagia marker) and the accumulation of p62 protein.
  • LC3-II light-chain protein associated to the microtubules
  • the normal prostate cells were more resistant to cytotoxicity induced by capsaicin and did not accumulate p62 protein.
  • the molecule has pain-relieving activity on the urine flow.
  • it acts by locking selectively the unmyelinated C fibres, usually silent, which activate under conditions of hypersensitivity and bladder hyperactivity, by involving increased frequency and urine urgency, incontinence and reduced bladder capacity.
  • the interaction between capsaicin and vanilloid receptors induces desensitization of C fibres, both by interrupting the responses to the 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 for adjusting a correct urine flow.
  • Curcuma longa is a plant belonging to the family Zingiberaceae comprising a total of about 80 species. Commonly also called saffron from Indies, or simply designated as curcuma, it represents the most used species. Its name derives from the Sanskrit “Kum-kuma” and it is the main ingredient of the Indian curry. Most properties attributed to curcuma indeed depend upon curcumin, which is its most famous active principle ally of well-being.
  • This molecule - which from the chemical point of view can be classified among polyphenols - is responsible for the typical golden yellow colour of curcuma and of the curries containing it, but not only this.
  • tumours for example colon or breast tumour
  • curcumin seems to exert its anti-tumour effect through a complicated mechanism involving the mechanisms of cellular proliferation and apoptosis, the receptors of estrogens and the growth factor HER2.
  • curcumin seems to depend upon its capability of controlling different molecules promoting the inflammation (such as interleukin-6, interleukin-1 beta and the Tumour necrosis factor-alpha), some growth factors and their receptors, the protein kinases and other enzymes, the molecules involved in the mechanisms of cellular adhesion and NF-kB, fundamental transcription factor in inflammation.
  • promoting the inflammation such as interleukin-6, interleukin-1 beta and the Tumour necrosis factor-alpha
  • some growth factors and their receptors such as interleukin-6, interleukin-1 beta and the Tumour necrosis factor-alpha
  • some growth factors and their receptors such as interleukin-6, interleukin-1 beta and the Tumour necrosis factor-alpha
  • the protein kinases and other enzymes the molecules involved in the mechanisms of cellular adhesion and NF-kB, fundamental transcription factor in inflammation.
  • Curcumin is a product of natural origin mainly endowed with anti-inflammatory activity, which might be useful in the treatment of prostatitis and benign prostatic hyperplasia. Apart from being one of the most powerful anti-inflammatory drugs of natural origin, it has chemical-physical properties suitable to its distribution at prostate level (since it is a lipophile molecule and relatively small, it has no problems in overcoming the blood- prostate barrier).
  • the action mechanism of curcumin consists in modulating the expression of several proteins, thereamong pro-inflammatory cytokines (TNF-a, IL-8,
  • I L- 1 b I L- 1 b
  • IL-6 IL-6
  • apoptotic proteins NF-kB
  • COX-2 IL-6
  • STAT3 MDA
  • the main markers of prostate inflammation are TNF-a, IL-8, I L- 1 b , IL-6, as demonstrated by a study of Penna and collaborators, which have found high concentrations of these pro-inflammatory cytokines and above all of chemokine IL-8 .in the sperm of patients with prostatitis.
  • One of curcumin activities is exactly that of inhibiting TNF-a, I L- 1 b , IL-6 and IL-8 (the latter to a lesser extent) and this could make it a valid active principle to be used in case of prostatitis, since it reduces its main markers.
  • the same activity was demonstrated in prostatitis models (induced by castration and administration of 17b-ob3 ⁇ oI): the administration of curcumin, in this case, is capable of reducing the expression of TNF-a, IL-6, IL-8.
  • Curcuma combines well with other integrators and it is used often as ingredient in the formulations. It can also be used in combination with traditional therapies and it could even help to improve the effectiveness of antibiotics when they are taken together for the bacterial prostatitis. It was studied that curcuma: reduces the pro-inflammatory interleukin-8 cytokines and alfa tumour necrosis factor in the blood tissues and it is effective on the patients with prostate problems.
  • curcumin is a powerful inductor of apoptosis (form of programmed cell death) of the cells of both androgen-dependant and independent prostate tumour.
  • Cucurbita is a plant genus belonging to the family Cucurbitaceae originating from Centre-South America.
  • the general term Cucurbita comes from the Latin name of pumpkin and, in turn, from the Sanskrit c’arbata curved, rounded.
  • pumpkins divide into four species: Cucurbita maxima - Cucurbita moschata - Cucurbita pepo - Cucurbita melanosperma. The most studied varieties are represented by the Cucurbita maxima Duchesne (yellow or sweet pumpkin) and by Cucurbita pepo (commonly called zucchini).
  • the pumpkin seed oil is obtained by squeezing the homonymous plant and it varies in relation to the varieties and the botanic species therefrom the seeds are obtained.
  • the pumpkin is a natural antidote against the free radicals, dangerous substances for our organism and which speed-up the cell aging process.
  • Betacarotene contained in the pumpkin has several anti-inflammatory and anti-tumour properties as the National Cancer Institute discovered; on the contrary, lycopene is more effective in case of prostate, lung and stomach tumour.
  • the studies showing an important effect in reducing blood sugar in the animal model, by using extracts both of pulp and of the seeds, are interesting.
  • the effect could be due both to the presence in the fruit pulp of D-chiro-inositol and of other particular polysaccharides, substances promoting the action of insulin, and to substances such as trigonelline and nicotinic acid present in the seeds.
  • the presence of vitamin E and other substances with antioxidant action, particularly some polysaccharides which are bound to proteins in the fruit pulp, can stimulate the activity of enzymes such as superoxide dismutase and glutathione peroxidase, fundamental enzymes in reducing the oxidative damage in cell.
  • the pumpkin seeds include substances such as cucurbitin, phytosterine and delta sterols able to inhibit the aromatase enzyme influencing the tonicity of the pelvic floor.
  • pumpkin seed oil (extracted both from Cucurbita maxima and from Cucurbita pepo) is widely used as phyto-therapeutic remedy useful in the treatment of benign prostatic hypertrophy.
  • carotenoids and zinc both useful for the prostate’s health
  • manganese, magnesium, phosphorous and iron are abundant, even if the main constituent however remains oleic acid (24-38%)
  • linoleic acid (43-56%)
  • tocopherols and carotenoids lutein and b-carotene.
  • Some own substances of pumpkin seeds are useful in fighting benign prostatic hyperplasia, a condition which determines an increase in the prostate volume in turn caused by an increase in the number of (not tumour) cells of the gland.
  • This pathology usually appears with frequent urinations, recurrent infections and inflammations of the urinary tracts. It was shown that the pumpkin seeds can help in alleviating the symptoms of this pathology, thanks to their content of zinc and, above all, phytosterols such as beta sitosterol, sitostanol, avenasterol. Such phytosterols have a chemical structure very similar to that of the androgenic and estrogenic hormones. These would be capable of inhibiting the conversion of testosterone into dihydrotestosterone, responsible for the cell growth at the basis of the prostatic hypertrophy. Even zinc is important for the good operation of the prostate and the pumpkin seeds, since they are rich therein, even under this aspect contribute to explicate a protective action against this gland.
  • phytosterols such as beta sitosterol, sitostanol, avenasterol.
  • Such phytosterols have a chemical structure very similar to that of the androgenic and estrogenic hormones. These would be capable of inhibiting the conversion of testosterone into dihydrotestosterone, responsible
  • betasterols structurally similar to androgens and estrogens. These substances have demonstrated to be useful to lower the cholesterol levels and to improve the symptoms of prostatic hypertrophy, effect which seems to be partially linked to the capability of inhibiting the conversion of testosterone into dihydrotestosterone.
  • This latter substance is a hormone derived from testosterone thanks to 5-alfa-reductase enzyme, involved - among other things - in the hyperproliferation of the prostatic cells.
  • IPSS International Prostatic Symptom Score
  • Serenoa repens in English called Saw Palmetto, is a dwarf palm of the family Arecaceae growing mainly in South-East of United States along the coast of the Atlantic Ocean and in the South tropical areas. Its fruits, having colour from dark brown to black and rich in active principles such as free fatty acids and sterols (in particular beta-sitosterol), are recognized by the undisputed healthy properties reported previously to the advantage of prostate and hair.
  • the sterol lipid extract of Serenoa repens not only helps in keeping healthy the prostate, but as reported by a lot of scientific evidence, thanks to the inhibition of 5-alfa reductase, it contributes even to the well-being and the trophism of hair of men affected by androgenetic alopecia.
  • the lipido-sterolic extract of Serenoa repens thanks to its composition and content in fatty acids thereamong the lauric acid, the myristic acid and a vegetable sterol called beta-sitosterol, has an important selective antiandrogenic action which mainly explicates through the inhibition of both isoforms I and II of 5-alfa reductase (5AR), key enzyme in the process for transforming testosterone into dihydrotestosterone.
  • Dihydrotestosterone is the hormone mainly responsible for the prostate growth and the appearance of male androgenetic alopecia. Scientific evidence has shown that the lauric acid and the myristic acid are also capable of interacting directly with testosterone by forming esters of this hormone which then cannot be converted into DHT.
  • beta-sitosterol limits the bioavailability of cholesterol and then the synthesis of testosterone, substrate of 5-alfa reductase, in the prostate and capillary follicle.
  • An in-vitro study demonstrates that both the ethanolic and the hexane extract, two types of lipido-sterolic extract of Serenoa repense are capable of inhibiting 5-alfa reductase in co-cultures of epithelial cells and prostate fibroblasts.
  • Another in-vitro study demonstrates that the lipido-sterolic extract of Serenoa repens is useful in treating BPH with inflammation features, by modulating presumably the equilibrium between apoptotic factors and proliferative factors.
  • Hyperprolactinemia increases the humid weight and induces hyperplasia in the lateral prostate.
  • LSESR reduced significantly the growth and hyperplasia of the lateral prostate in the castrated rats, treated with DHT and treated with sulpiride. Finasteride was only capable of inhibiting the effect of androgens on the enlargement of the rat prostate. LSESR inhibited not only the androgenic effect but even the trophic effect of prolactin in the lateral hyperplasia of rat.
  • Several clinical studies then confirmed the effectiveness of this vegetable sterol in improving the well being of the prostate in man.
  • the present invention allows to obtain contemporarily:
  • the effectiveness of the above-mentioned composition derives from the precise properties of its main components: the diuretic, anti-oedematous and anti inflammatory activities of escin and the analgesic and pain-killing action of capsaicin.
  • both compounds are capable of inducing apoptosis in prostatic cancerous cells by means of different activities.
  • the above-mentioned invention can further include the following components: curcuma, powerful anti-inflammatory of natural origin, has chemical-physical properties suitable to its distribution and the prostatic level; an extract from the plant belonging to the genus Cucurbita which thanks to its variety of constituents (sitosterols, vitamin E, zinc, carotenoids, etc.) contributes to a complete well-being of the prostate. Al last, the extract of Serenoa repens, apart from its anti-inflammatory and anti-androgenic activity, has a complete regulating action on the prostate functionality.
  • the synergic action takes place between escin and capsaicin in admixture with one or more pharmaceutically acceptable carriers.
  • Suitable pharmaceutically acceptable carriers are those commonly known to the expert in the art for the preparation of pharmaceutical compositions for oral administration such as solutions, suspensions, powders or granulates, tablets, capsules, pellet.
  • such pharmaceutically acceptable carriers can consist of binders, diluents, lubricants, glidants, disaggregating agents, solubilizing (wetting) agents, stabilizing agents, colouring agents, anti-agglomerating agents, emulsifying agent, thickening and gelling agents, coating agents, wetting agents, sequestrants, sweeteners.
  • diluents they can be: magnesium carbonate, microcrystalline cellulose, starch, lactose, sucrose; the mainly used lubricants are magnesium stearate, stearic acid, sodium stearyl fumarate.
  • colloidal silica, magnesium silicate can be mentioned, as disaggregating agents the crosslinked polyvinylpyrrolidones, sodium starch glycolate can be mentioned, as solubilizing agents the surfactants such as TWEEN or sodium lauryl sulphate can be mentioned and as stabilizing agents all class of preservatives (sorbic acid and derivatives, benzoic acid and derivative, parabens), antioxidants (ascorbic acid and derivatives, tocopherol), acidifying agents (phosphoric acid, tartaric acid) can be mentioned.
  • preservatives sorbic acid and derivatives, benzoic acid and derivative, parabens
  • antioxidants ascorbic acid and derivatives, tocopherol
  • acidifying agents phosphoric acid, tartaric acid
  • the thickening and gelling agents can be carrageenan, pectin, starches, the coating agents include for example waxes and derivatives, the anti-agglomerating agents include calcium or magnesium carbonate, the wetting agents include sorbitol, mannitol, the EDTA sequestrants and derivatives, the colouring agents include aspartame, potassium acesulfame.
  • the composition, the present invention relates to, and preferably a liquid or solid composition for oral use, still more preferably an aqueous solution, a suspension, a powder or granulate, a tablet, a capsule, pellet.
  • the composition can further include an extract of Curcuma longa and/or an extract of a plant belonging to the genus Cucurbita and/or an extract of Serenoa Repens.
  • capsaicin is present in an amount ranging 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.
  • the extract of Curcuma longa if present in the composition, is contained in an amount ranging between 10 mg and 5000 preferably between 20 mg and 3000 mg.
  • the extract of the plant belonging to the genus Cucurbita if present in the composition, is contained in an amount ranging 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 ranging between 10 mg and 5000 mg, preferably between 20 mg and 3000 mg.
  • the dosage form can be a food supplement or a medical device, a food complement, a cosmetic, a nutraceutical, dietetic and nutritional composition, a food product, a beverage, a nutraceutical agent, a medicament, medicated food, a pharmaceutical composition or food for special medical purposes including the above-mentioned active ingredients in admixture therebetween.
  • the preferred administration route is the oral or topical one.
  • the synergic action of the composition with respect to the single active ingredients is evaluated by means of in-vitro and/or in-vivo experimental methods.
  • the susceptibility of the cell system to the pro-inflammatory stimuli can be evaluated with immuno-enzymatic essays (ELISA), by detecting the amount of cytokines involved in inflammatory processes and in particular the activity of bioactive compounds on the response, inhibition/activation, of cytokines (TNF-a, IL-1 , IL-4, IL-6, IL-8, IL-10, IL-17, INF-Y, COMP), proinflammatory enzymes such as lipoxygenase (LOX) and cyclooxidases (COX2) involved during inflammatory processes induced by LPS through the“Whole Blood Assay (WBA)” or the test with“mononucleated cells of the peripheral blood” (PBMC) or other similar tests.
  • ELISA immuno-enzymatic essays
  • the pro-apoptotic activity of the active principles, the present invention relates to, can be evaluated by means of in-vitro assays capable of demonstrating the way in which the synergy of the two components inhibits significantly the cell viability with respect to the single active principles.
  • Cell models known to the person skilled in the art can be used, such as for example PC-3 cells, CRPC (castration-resistant prostate cancer), DU-145, LNCap and/or other analogous ones.
  • the anti-inflammatory activity can be evaluated by demonstrating the effectiveness of the compounds, the present invention relates to, in favouring apoptosis in mouse with BPH induced experimentally.
  • the apoptosis system is a promising system as far as the medical treatment of benign prostate hypertrophy is concerned.
  • the apoptosis inhibiting proteins (lAPs) modulate apoptosis through the direct inhibition of the cascade of caspases.
  • the study can evaluate the effectiveness of the active principles, alone or in combination, on the capability of inducing the expression for the proteins lAPs in mice with BPH induced experimentally by injection with testosterone.
  • a more complex in-vivo model provides to test the active principles of the present composition to demonstrate their anti-inflammatory and analgesic effect on rats in which an experimental autoimmune prostatitis (EAP) is induced, through intradermic injection of prostatic antigens of rat and of “Freund’s adjuvant”, a mixture of antigens emulsified in mineral oils used as immuno-potentiating agents.
  • EAP experimental autoimmune prostatitis
  • control each substance singularly and then even the mixture of substances of interest for the present composition, are administered orally 2 hours before the mechanical stimulation, in this way the role of the active principles in reducing the frequency of reactions to the mechanical stimulation is evaluated, with respect to the control and to the substances administered singularly.

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Abstract

L'invention concerne une composition comprenant une association entre l'aescine et la capsaïcine. La composition peut en outre contenir un extrait de Curcuma longa et/ou un extrait d'une plante appartenant au genre Cucurbita et/ou un extrait de Serenoa Respens efficaces dans la prévention et/ou le traitement de pathologies associées à la prostate.
EP20732318.9A 2019-05-23 2020-05-19 Composition destinée à être utilisée dans la prévention et/ou le traitement de pathologies associées à la prostate Pending EP3972577A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT102019000007044A IT201900007044A1 (it) 2019-05-23 2019-05-23 Composizione per l’uso nella prevenzione e/o trattamento di patologie associate alla prostata
PCT/IB2020/054740 WO2020234770A1 (fr) 2019-05-21 2020-05-19 Composition destinée à être utilisée dans la prévention et/ou le traitement de pathologies associées à la prostate

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EP3972577A1 true EP3972577A1 (fr) 2022-03-30

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Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007141661A2 (fr) * 2006-02-22 2007-12-13 Tracey Anne Seipel Compositions galéniques pour la prévention ou le traitement d'une hypertrophie bénigne de la prostate
ITMI20080283A1 (it) * 2008-02-22 2009-08-23 Indena Spa Composizioni per il trattamento di ipertrofia prostatica benigna, prostatiti, prostatosi e carcinoma prostatico
ITMI20081404A1 (it) * 2008-07-29 2010-01-30 Velleja Res Srl Formulazioni topiche per il trattamento sintomatico delle patologie muscolo-scheletriche
US20140134261A1 (en) * 2012-08-21 2014-05-15 Trinity Laboratories, Inc. Pharmaceutical Compositions Comprising Capsaicin Esters for Treating Pain and Cold Sores
ITMI20130807A1 (it) * 2013-05-16 2014-11-17 Indena Spa Combinazioni di estratti di serenoa repens e di estratti lipofili di zingiber officinalis e di echinacea angustifolia, loro uso e formulazioni che li contengono

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IT201900007044A1 (it) 2020-11-23

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