A mixture comprising a plant extract of gastrodia elata and a coenzyme q10 or use in the treatment and / or prevention of prostate diseases and / or disorders

Abstract

The present invention relates to a composition comprising a mixture comprising or, alternatively, consisting of i) an extract of Gastrodia elata and ii) at least one ingredient selected from the group comprising or, alternatively, consisting of a coenzyme Q10, plant extracts and preparations (so-called botanicals) and / or mixtures thereof. Said mixture comprising or, alternatively, consisting of i) an extract of Gastrodia elata and iia) a coenzyme Q10. Furthermore, the present invention relates to said mixture and the composition containing it for use in the treatment and / or prevention of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation, preferably inflammation due to BPH, and / or other functional disorders affecting the urinary tract, bladder, testicles and prostate.

Description

[0001] A MIXTURE COMPRISING A PLANT EXTRACT OF GASTRODIA ELATA AND A COENZYME Q10 OR USE IN THE TREATMENT AND / OR PREVENTION OF PROSTATE DISEASES AND / OR DISORDERS

[0002] DESCRIPTION

[0003] The present invention relates to a composition comprising a mixture that comprises or, alternatively, consists of I) an extract of Gastrodia elata and ii) at least one ingredient selected from the group comprising or, alternatively, consisting of a coenzyme Q10, plant extracts and preparations (so-called botanicals) and / or mixtures thereof.

[0004] Preferably, said mixture comprising or, alternatively, consisting of I) an extract of Gastrodia elata and iia) a coenzyme Q10.

[0005] Furthermore, the present invention relates to said mixture, and to the composition containing it, for use in the treatment and / or prevention of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation, preferably inflammation due to BPH, and / or other functional disorders affecting the urinary tract, bladder, testicles and prostate.

[0006] BACKGROUND OF THE INVENTION

[0007] The prostate is a glandular organ of the male genital system that extends around the initial portion of the urethra and has two ejaculatory ducts passing through it; it is cone-shaped and is situated between the medial margins of the two levator ani muscles.

[0008] Prostate-related diseases or symptoms are a public health problem with a considerable impact from an epidemiological, clinical and economic standpoint. From 35% to 50% of men report having been affected by symptoms attributable to prostatitis during their lifetime.

[0009] A relevant disease of the prostate is benign prostatic hyperplasia (indicated in the present invention by the acronym "BPH”), also known as prostatic adenoma or prostatic hypertrophy, a condition characterised by an increase in the volume of the prostate gland. The increase in volume is due not to a hypertrophy (hence the name "prostatic hypertrophy" is going out of use), but rather a hyperplasia of the parenchymal and stromal components of the gland. Although both conditions lead to an overall increase in volume, the term hypertrophy indicates an increase in the volume of the individual cells making up an organ, whose number remains unchanged, whereas hyperplasia indicates an increase in the number of cells. In this case, the increase in the number of cells occurs in the central zone of the prostate, which is in contact with the prostatic urethra, or in the periurethral glands and in the transition zone.

[0010] On an anatomical level, the increase in size of the prostate brings about a compression and distortion of the urethra, causing a greater resistance in the urinary flow at the bladder outlet.

[0011] There are two types of symptoms: urinary symptoms of an obstructive type and ones of an irritative type. Among the obstructive symptoms it is worth mentioning difficulty in starting urinating, intermittence of flow, incomplete bladder emptying, a weak flow of urine and straining when urinating.

[0012] The irritative symptoms include frequency of urination (poll akiuria), nocturia, i.e. an increased need during the night, urgency of urination (a pressing need to empty the bladder) and a burning sensation when urinating.

[0013] BPH can be a progressive disease, especially if it is not treated. Incomplete bladder emptying can lead to an accumulation of bacteria, increasing the risks of urethritis, and also to the formation of stones due to the crystallisation of salts in the post-void residual. Urinary retention, acute or chronic, is another form of progression of the disease. Acute urinary retention is the inability to completely empty the bladder, whilst the chronic form sees a progressive increase in the residual and bladder muscle relaxation. Those who suffer from chronic urinary retention may be subject to a kidney disorder called obstructive uropathy.

[0014] Benign prostatic hyperplasia (BPH) is a chronic condition associated with lower urinary tract symptoms (LUTS) and affects nearly 3 out of 4 men during the seventh decade of life. The mechanism leading to the onset of BPH is not wholly clear; however, it is by now evident that the occurrence of BPH is not due to a single mechanism. On the contrary, the process underlying the onset of BPH is cumulative and involves androgen stimulation, oxidative stress and inflammatory agents, just to name a few.

[0015] Therefore, a combined therapy could represent the solution for an effective treatment.

[0016] The pharmacological treatments for BPH that have been developed provide for an initial monotherapy based on alpha-1 -adrenergic receptor antagonists, 5-alpha-reductase inhibitors, anticholinergic agents and phosphodiesterase 5 inhibitors, and, in the most serious cases, a combination thereof. The pharmacological treatments for BHP have a whole range of side effects that force many patents to take into consideration alternatives such as, for example, the use of drugs of plant origin.

[0017] The technical problem that the present invention addresses and solves is to provide an effective, side-effect-free mixture, and a composition containing it, for use in a method of treatment, preventive and / or curative, of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation and / or other functional disorders affecting the urinary tract, bladder, testicles and prostate.

[0018] It can by no means be taken for granted that combining different active ingredients will lead to a reasonable expectation of obtaining therapeutic success. In fact, there are various technical problems to be overcome in order that an association / combination may be effective. In particular, the ideal association / combination must: I) have good bioavailability of the active substances, ii) be well tolerated, ill) show very low toxicity, iv) be suitable for extended and repeated use, v) be easy to administer, vi) have a pleasing odour and flavour, vii) be easy to prepare, viii) have affordable costs and ix) be easy to prepare and stable over time.

[0019] It is therefore understood that there is a need to find novel therapeutic approaches and novel, effective solutions for maintaining the wellbeing and functionality of the urinary tract, bladder, testicles and prostate, in particular in the case of benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation and / or other functional disorders, said novel approaches and novel associations / combinations and compositions containing them being effective, well tolerated and free of side effects and / or adverse reactions.

[0020] CN105902840 discloses a composition comprising liposoluble components of Gastrodia elata, coenzyme Q10, vitamin E and walnut oil for the preventive treatment of cardiovascular diseases and dementia caused by a deficiency of apolipoprotein E.

[0021] CN105902840 does not disclose the use of a composition comprising an association of extract of Gastrodia elata and coenzyme Q10 in a method of treatment, preventive and / or curative, of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation and / or other functional disorders affecting the urinary tract, bladder, testicles and prostate.

[0022] JP2001187742A discloses a testosterone-5-alpha-reductase inhibitor comprising, among other things, an extract of Gastrodia elata Blume, for use in the prevention and treatment of alopecia, acne, benign prostatic hyperplasia, prostate cancer and the like.

[0023] Said JP2001187742A does not disclose the use of a composition comprising an association of extract of Gastrodia elata and coenzyme Q10 in a method of treatment, preventive and / or curative, of prostate diseases and / or disorders, in particular benign prostatic hyperplasia.

[0024] CN 105327151 A discloses a composition comprising, among other things, Gastrodia for the treatment of impotence, prostatitis and menopause syndrome.

[0025] Said CN 105327151 A does not disclose the use of a composition comprising an association of extract of Gastrodia elata and coenzyme Q10 in a method of treatment, preventive and / or curative, of prostate diseases and / or disorders, in particular benign prostatic hyperplasia.

[0026] IT201800002889 discloses a composition for the treatment of prostatic hyperplasia and urinary tract infections, as well as of neurological diseases (Alzheimer's, Parkinson's and ALS), cardiovascular diseases, arthritis and related diseases. The composition disclosed in IT 20180000 2889 is in the form of lipid nanoparticles consisting of a cocoa butter-based coating comprising curcumin and lactoferrin. Said coating includes a water-soluble component comprising a) a plant extract (which can be, among other things, an extract of Serenoa repens) and b) glucosamine sulphate, chondroitin sulphate, hydrolysed collagen and lycopene. The cocoa butter-based coating can further comprise coenzyme Q10. Coenzyme Q10, among the various options, is present only in the cocoa butter-based coating.

[0027] The composition disclosed in IT 2018 0000 2889 does not comprise an extract of Gastrodia elata.

[0028] WO2019 / 186355 discloses a composition comprising at least one cannabinoid receptor type-2 selective agonist, at least one substance with antioxidant properties and at least one tissue function modulator. The compositions of examples 7, 8 and 9 for use in the treatment of prostatic hyperplasia comprise an extract of Serenoa Repens in association with a cannabinoid receptor type-2 selective agonist. However, such compositions do not comprise an extract of Gastrodia elata and coenzyme Q10.

[0029] In particular, the compositions of the prior art do not act simultaneously in reducing prostate inflammation or on the proliferation of prostate epithelial and stromal cells, which, together with the formation of nodules, characterise benign prostatic hyperplasia.

[0030] It is thus necessary to provide mixtures and / or compositions that are free of side effects and have high tolerability and are capable of acting simultaneously in reducing the proliferation of prostate cells and on the prostate inflammation present, in particular, in the case of benign prostatic hypertrophy. Following an intense research activity, the applicant has developed and fine-tuned a mixture (also referred to as association or combination) of active ingredients, and pharmaceutical compositions and / or compositions for medical devices (Regulation (EU) 2017 / 745) and / or nutraceutical and / or food compositions (the composition(s) of the present invention) that are effective, free of side effects and with high tolerability. Said association / combination and composition having been developed for maintaining the wellbeing and functionality of the urinary tract, bladder, testicles, and prostate, in particular in the case of benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation, preferably inflammation due to BPH, and / or other functional disorders.

[0031] The novel associations or combinations of active ingredients, and the pharmaceutical compositions and / or compositions for medical devices (Regulation (EU) 2017 / 745) and / or nutraceutical and / or food compositions (the composition(s) of the present invention) containing them, due to the presence of natural ingredients, do not have significant adverse effects, are free of side effects and have high tolerability, and can be administered to a broad category of individuals.

[0032] Furthermore, the novel associations or combinations of active ingredients, and pharmaceutical compositions and / or compositions for medical devices (Regulation (EU) 2017 / 745) and / or nutraceutical and / or food compositions (the composition(s) of the present invention) containing them are easy to prepare and inexpensive, and can be prepared using techniques, methods and apparatus known to the person skilled in the art.

[0033] These purposes and still others, which will be clear from the detailed description below, are achieved by the novel associations or combinations of active ingredients, and the pharmaceutical compositions and / or compositions for medical devices (Regulation (EU) 2017 / 745) and / or nutraceutical and / or food compositions (the composition(s) of the present invention) containing them, by virtue of the technical features claimed in the appended claims.

[0034] DESCRIPTION OF THE FIGURES

[0035] Figure 1 shows the results of an assay on cell viability of the intestinal epithelium over time, in relation to the tested compounds / formulations indicated in the figure.

[0036] Figure 2 shows the results regarding the evaluation of ROS production in the intestinal epithelium, in relation to the tested compounds / formulations indicated in the figure.

[0037] Figure 3 shows the results regarding transepithelial resistance, in relation to the tested compounds / formulations indicated in the figure.

[0038] Figure 4 shows the results regarding the evaluation of cell proliferation in the 3D model of benign prostatic hyperplasia, in relation to the tested compounds / formulations indicated in the figure.

[0039] Figures 5 and 6 show the ROS production and oxidative stress, in relation to the compounds / formulations indicated in the figures which passed through the intestinal barrier after 24h of treatment, as measured in the 3D model of benign prostatic hyperplasia.

[0040] Figure 7 shows the results of the analysis of the activation of pro-inflammatory cytokines NFkp, TNFo, IL-1 p and IL-10 obtained through the treatment of the 3D model of prostatic hyperplasia with the various compounds / formulations indicated in the figure. Figure 8 shows a) the testosterone levels and b) dihydrotestosterone levels obtained after treatment of the in vitro model of BPH with the compounds / formulations indicated in the figure.

[0041] Figure 9 shows the activity of the enzyme 5o-reductase obtained after treatment of the in vitro model of BPH with the compounds / formulations indicated in the figure.

[0042] Figure 10 shows a) the activity of the androgen receptor (AR) and b) serotonin production obtained after treatment of the in vitro model of BPH with the compounds / formulations indicated in the figure.

[0043] Figure 11 shows the data of a screening on prostate cells aimed at establishing which form and concentration of extract of Epilobium parviflorum Schreb. Herba should be used to continue the experiments (example 3).

[0044] Figure 12 shows the cell viability and ROS production data for the tested compounds / formulations and indicated in the figure.

[0045] Figure 13 shows the results regarding the transepithelial resistance of the tested compounds / formulations indicated in the figure.

[0046] Figure 14 shows the results regarding the evaluation of cell proliferation in the 3D model of benign prostatic hyperplasia, in relation to the tested compounds / formulations indicated in the figure.

[0047] Figure 15 shows the ROS production and oxidative stress, in relation to the compounds / formulations which passed through the intestinal barrier after 24h of treatment, as measured in the 3D model of benign prostatic hyperplasia. Figure 16 shows the results of the analysis of the activation of pro-inflammatory cytokines NFkp, TNFo, IL-1 p and IL-10 obtained through the treatment of the 3D model of prostatic hyperplasia with the various compounds / formulations indicated in the figures.

[0048] Figure 17 shows the testosterone and dihydrotestosterone levels obtained after treatment of the in vitro model of BPH with the compounds / formulations indicated in the figure.

[0049] Figure 18 shows the activity of the enzyme 5o-reductase obtained after treatment of the in vitro model of BPH with the compounds / formulations indicated in the figure.

[0050] Figure 19 shows the activity of the androgen receptor (AR) and serotonin production obtained after treatment of the in vitro model of BPH with the compounds / formulations indicated in the figure.

[0051] Figure 20 shows the testosterone and dihydrotestosterone levels obtained after treatment of the in vitro model of BPH with the formulations indicated in the figure.

[0052] DETAILED DESCRIPTION OF THE INVENTION

[0053] It is an object of the present invention to provide a mixture (association or combination of ingredients) comprising or, alternatively, consisting of I) an extract of Gastrodia elata and ii) at least one ingredient selected from the group comprising or, alternatively, consisting of iia) a coenzyme Q10, lib) plant extracts and preparations (so-called botanicals), and / or mixtures thereof.

[0054] Preferably, said mixture (association or combination of ingredients) comprises or, alternatively, consists of I) an extract of Gastrodia elata and iia) a coenzyme Q10, and / or mixtures thereof. Preferably, said mixture (association or combination of ingredients) comprises or, alternatively, consists of i) an extract of Gastrodia elata, iia) a coenzyme Q10 and iib) at least one plant extract or preparation selected from the group G comprising or, alternatively, consisting of:

[0055] - Agathosma betulina (P.J. Bergius) Pillans folium,

[0056] - Cucurbita maxima Duch. semen, oleum,

[0057] - Cucurbita pepo L. var. styriaca Greb. semen, oleum,

[0058] - Epilobium angustifolium L herba,

[0059] - Epilobium parviflorum Schreb. Herba,

[0060] - Eryngium aguaticum L. radix,

[0061] - Hydrangea arborescens L. rhizoma,

[0062] - Opuntia ficus- indica (L.) Mill. Cladodium,

[0063] - Populus alba L. cortex, folium, gemma,

[0064] - Populus balsamifera L. cortex, folium, gemma,

[0065] - Populus nigra L. cortex, folium, gemma,

[0066] - Populus tremuloides Michx. cortex, folium, gemma,

[0067] - Pyrus communis L. folium,

[0068] - Seguoiadendron giganteum (Lindl.) J. Buchholz gemma,

[0069] - Serenoa repens (W. Bartram) Small fructus,

[0070] - Solanum lycopersicum L. fructus,

[0071] - Urtica dioica L. folium, summitas,

[0072] - Urtica urens L. folium, or

[0073] - Zea mays L. stigmata.

[0074] Preferably, said iib) can be Serenoa repens, Epilobium angustifolium L. herba, Epilobium parviflorum Schreb. Herba and / or mixtures thereof listed in said group G, in association with i) and iia).

[0075] Preferably, said iib) is Serenoa repens in association with i) and iia).

[0076] Preferably, said iib) is selected in the group comprising or, alternatively, consisting of Epilobium angustifolium L. herba and Epilobium parviflorum Schreb. Herba or mixtures thereof, in association with i) and iia).

[0077] Even more preferably said iib) is Epilobium parviflorum Schreb. Herba, in association with i) and iia).

[0078] Preferably, said iib) is a mixture of Serenoa repens and Epilobium parviflorum Schreb. Herba, in association with i) and iia).

[0079] It is an object of the present invention to provide a composition comprising a mixture (association or combination of ingredients) comprising or, alternatively, consisting of i) an extract of Gastrodia elata and ii) at least one ingredient selected from the group comprising or, alternatively, consisting of iia) a coenzyme Q10, iib) plant extracts and preparations (so-called botanicals) and / or mixtures thereof.

[0080] Preferably, said composition comprises said mixture (association or combination of ingredients) comprising or, alternatively, consisting of i) an extract of Gastrodia elata and iia) a coenzyme Q10, and / or mixtures thereof. Preferably, said composition comprises said mixture (association or combination of ingredients) comprising or, alternatively, consisting of i) an extract of Gastrodia elata, iia) a coenzyme Q10 and iib) at least one plant extract or preparation selected from the group G comprising or, alternatively, consisting of:

[0081] - Agathosma betulina (P.J. Bergius) Pillans folium,

[0082] - Cucurbita maxima Duch. semen, oleum,

[0083] - Cucurbita pepo L. var. styriaca Greb. semen, oleum,

[0084] - Epilobium angustifolium L herba,

[0085] - Epilobium parviflorum Schreb. Herba,

[0086] - Eryngium aguaticum L. radix,

[0087] - Hydrangea arborescens L. rhizoma,

[0088] - Opuntia ficus- indica (L.) Mill. Cladodium,

[0089] - Populus alba L. cortex, folium, gemma,

[0090] - Populus balsamifera L. cortex, folium, gemma,

[0091] - Populus nigra L. cortex, folium, gemma,

[0092] - Populus tremuloides Michx. cortex, folium, gemma,

[0093] - Pyrus communis L. folium,

[0094] - Seguoiadendron giganteum (Lindl.) J. Buchholz gemma,

[0095] - Serenoa repens (W. Bartram) Small fructus,

[0096] - Solanum lycopersicum L. fructus,

[0097] - Urtica dioica L. folium, summitas,

[0098] - Urtica urens L. folium, or

[0099] - Zea mays L. stigmata.

[0100] Preferably, said iib) can be Serenoa repens, Epilobium angustifolium L. herba, Epilobium parviflorum Schreb. Herba and / or mixtures thereof listed in said group G, in association with i) and iia).

[0101] Preferably, said iib) is Serenoa repens in association with i) and iia).

[0102] Preferably, said iib) is selected in the group comprising or, alternatively, consisting of Epilobium angustifolium L. herba and Epilobium parviflorum Schreb. Herba or mixtures thereof, in association with i) and iia).

[0103] Even more preferably said iib) is Epilobium parviflorum Schreb. Herba, in association with i) and iia).

[0104] Preferably, said iib) is a mixture of Serenoa repens and Epilobium parviflorum Schreb. Herba, in association with i) and iia).

[0105] It is an object of the present invention to provide a mixture (association or combination of ingredients) comprising or, alternatively, consisting of i) an extract of Gastrodia elata and ii) at least one ingredient selected from the group comprising or, alternatively, consisting of iia) a coenzyme Q10, iib) plant extracts and preparations (so-called botanicals) and / or mixtures thereof, said mixture and said composition containing it being both for use in the treatment and / or prevention of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation and / or other functional disorders affecting the urinary tract, bladder, testicles and prostate. More preferably, said mixture and said composition comprising it are for use in the treatment and / or prevention of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH and inflammation due to BPH.

[0106] Preferably, said mixture (association or combination of ingredients) comprises or, alternatively, consists of I) an extract of Gastrodia elata and iia) a coenzyme Q10 and / or mixtures thereof, said mixture and said composition containing it being both for use in the treatment and / or prevention of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation and / or other functional disorders affecting the urinary tract, bladder, testicles and prostate.

[0107] Preferably, said mixture (association or combination of ingredients) comprises or, alternatively, consists of I) an extract of Gastrodia elata, iia) a coenzyme Q10 and lib) at least one plant extract or preparation selected from the group G comprising or, alternatively, consisting of:

[0108] - Agathosma betulina (P.J. Bergius) Pillans folium,

[0109] - Cucurbita maxima Duch. semen, oleum,

[0110] - Cucurbita pepo L. var. styriaca Greb. semen, oleum,

[0111] - Epilobium angustifolium L herba,

[0112] - Epilobium parviflorum Schreb. Herba,

[0113] - Eryngium aguaticum L. radix,

[0114] - Hydrangea arborescens L. rhizoma,

[0115] - Opuntia ficus- indica (L.) Mill. Cladodium,

[0116] - Populus alba L. cortex, folium, gemma,

[0117] - Populus balsamifera L. cortex, folium, gemma,

[0118] - Populus nigra L. cortex, folium, gemma,

[0119] - Populus tremuloides Michx. cortex, folium, gemma,

[0120] - Pyrus communis L. folium,

[0121] - Seguoiadendron giganteum (Lindl.) J. Buchholz gemma,

[0122] - Serenoa repens (W. Bartram) Small fructus,

[0123] - Solanum lycopersicum L. fructus,

[0124] - Urtica dioica L. folium, summitas,

[0125] - Urtica urens L. folium, or

[0126] - Zea mays L. stigmata,' said mixture and said composition containing said mixture both being for use in the treatment and / or prevention of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation and / or other functional disorders affecting the urinary tract, bladder, testicles, and prostate. More preferably, said mixture and said composition comprising it are for use in the treatment and / or prevention of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH and inflammation due to BPH.

[0127] Preferably, said iib) can be Serenoa repens, Epilobium angustifolium L. herba, Epilobium parviflorum Schreb. Herba and / or mixtures thereof listed in said group G, in association with i) and iia); more preferably said iib) is selected in the group comprising or, alternatively, consisting of Epilobium angustifolium L. herba and Epilobium parviflorum Schreb. Herba, or mixtures thereof.

[0128] Preferably, the mixture comprising or, alternatively, consisting of i) an extract of Gastrodia elata and iia) a coenzyme Q10, and / or mixtures thereof, comprises iib) at least one plant extract or preparation selected from the group G described above.

[0129] More preferably, said mixture comprising or, alternatively, consisting of i) an extract of Gastrodia elata and iia) a coenzyme Q10, and / or mixtures thereof, comprises iib) Epilobium angustifolium L. herba, Epilobium parviflorum Schreb. Herba and / or mixtures thereof.

[0130] More preferably, said mixture comprising or, alternatively, consisting of i) an extract of Gastrodia elata and iia) a coenzyme Q10, and / or mixtures thereof, comprises iib) Serenoa repens.

[0131] More preferably, said mixture comprising or, alternatively, consisting of i) an extract of Gastrodia elata and iia) a coenzyme Q10, and / or mixtures thereof, comprises iib) Epilobium parviflorum Schreb. Herba.

[0132] More preferably, said mixture comprising or, alternatively, consisting of i) an extract of Gastrodia elata and iia) a coenzyme Q10, and / or mixtures thereof, comprises iib) Epilobium parviflorum Schreb. Herba, wherein said Epilobium parviflorum Schreb. Herba comprises or consists of oenothein B.

[0133] Preferably, "combination” means each of the various possible ways in which two or more elements can be joined or found together. For example, ingredients i) and ii), e.g., iia) and / or iib), are found joined together in the combination and are administered together when the combination is administered.

[0134] Preferably, "association” means the act of associating distinct elements that are administered at the same time or at short intervals (first one and then the other). For example, ingredients i) and ii), e.g., iia) and / or iib), are administered at the same time, but in a distinct manner, or are administered a short distance apart, first one and then the other, but still in a distinct manner.

[0135] In the context of the present invention the terms "association”, "combination” and "mixture” may be used interchangeably with each other.

[0136] Gastrodia elata belongs to the Orchidaceae family. The part of the plant that shows activity is its rhizome (Rhizoma Gastrodiae) from which, for example, phenols, polysaccharides, organic acids and sterols, and gastrodin, which is one of the phenolic glycosides, can be isolated. Each of these categories of compounds may contain within them several specific compounds or specific chemical entities such as, for example, gastrodin.

[0137] Gastrodia extract, preferably extract of Gastrodia elata, is therefore understood to comprise an extract comprising or consisting of one or more of said categories of isolated compounds, each of which may be present in said extract in an amount comprised from zero to 100% by weight, relative to the weight of the extract. For example, said extract may comprise or consist of gastrodin, or may comprise or consist of a mixture of said specific compounds or specific chemical entities belonging to one or more of said categories of compounds. We shall note that it has become customary in the marketplace to call an "extract” of Gastrodia, preferably an extract of Gastrodia elata, by the term "gastrodin extract 10:1”. In practice, even though the word gastrodin refers to a specific compound isolated from the rhizome of the plant (gastrodin, from Gastrodia alata >98%; (2R,3S,4S,5R,6S)-2-hydroxymethyl-6-(4- hydroxymethyl-phenoxy)-tetrahydro-pyran-3,4,5-triol, 4-p-D-glucopyranosyloxybenzyl alcohol, 4-hydroxybenzyl alcohol 4-O-p-D-glucoside, CAS 62499-27-8), in the marketplace the word gastrodin is also used to refer to an extract, e.g., a 10:1 extract or a 5:1 extract, which may contain not only gastrodin as such, but also other specific compounds.

[0138] In the context of the present invention Gastrodia extract is meant to comprise all types of extracts containing gastrodin, e.g., 20: 1 or 15:1 or 10:1 or 5:1 or 3: 1, but also gastrodin as such, without any limitation.

[0139] As mentioned above, the Gastrodia extracts, preferably the extracts of Gastrodia elata, contain active ingredients (specific compounds or specific chemical entities) that include not only molecular compounds of small dimensions such as, for instance, gastrodin, i.e. 4-hydroxybenzyl alcohol-4-O-p-D-glucopyranoside [CAS RN: 62499-27-8], of formula (I): which is the active ingredient of Gastrodia Elata that has been most extensively studied, Parishin, phenolic compounds, 4-hydroxybenzyl alcohol and p-sitosterol, but also active polysaccharide macromolecules.

[0140] In the context of the present invention, "an extract of Gastrodia elata" is intended to refer to, and include, any extract (and / or mixtures of extracts) of Gastrodia elata, obtained, from any source, with methods and apparatus well known to the person skilled in the art.

[0141] Preferably, the extract of Gastrodia elata may, for example, be a 10:1 extract of Gastrodia elata, i.e., standardized to contain, for example, a concentration 10 times higher than the concentration of active substances present in the tuber of Gastrodia elata.

[0142] For example, the extract of Gastrodia elata may for example be a 5: 1 , or also a 3:1 extract of Gastrodia elata.

[0143] In the context of the present invention, 10: 1 extract means the ratio [drug:extract] (1 gram of extract corresponds to the active ingredients contained in 10 grams of plant).

[0144] Said extract of Gastrodia elata, preferably a dry extract of Gastrodia elata, can be obtained by extraction with an extraction solvent, e.g., water or a water / alcohol solution (e.g., ethyl alcohol or ethanol), at a temperature, for example, comprised from 20°C to 70°C. Subsequently, a powder is obtained, preferably by drying or spraying with a spray-drying system to yield a nebulized dry extract, in which, for example, the extract is nebulized in a stream of superheated steam. The short contact time between the extract and the steam causes instant drying without damaging the active ingredients. Highly concentrated extracts can be obtained.

[0145] Preferably, the extract of Gastrodia elata, for example, a dry extract of Gastrodia elata, at a drug:extract ratio of 10:1 , may have a phytochemical profile of the following type:

[0146] - a total polysaccharide content comprised from 40% to 90%, preferably comprised from 50% to 80%, more preferably comprised from 60% to 70%; for example, alpha-glucans and / or maltodextrins may be present in an amount from greater than zero to less than 10%, preferably from greater than 0.1 % to less than 7.5%, more preferably from greater than 2% to less than 5%;

[0147] - a triterpene content comprised from 0.5% to 5%, preferably comprised from 1 % to 4%, more preferably comprised from 1 .5% to 3%;

[0148] - a total polyphenol content comprised from 0.05% to 3%, preferably comprised from 0.1 % to 2%, more preferably comprised from 0.2% to 1%.

[0149] In addition, lignans in an amount greater than zero to less than 0.01%, e.g., less than 0.05%, and triterpenes in an amount comprised from greater than zero to less than 0.01%, e.g., less than 0.05%, may also be present in said extract. Preferably, said triterpenes and polyphenols may be of a low molecular weight and belong to the class of phenolic glycosides.

[0150] As a further example, the extract of Gastrodia elata may be an extract of Gastrodia elata prepared from rhizome or root, for example, by extraction with water and ethanol having a polysaccharide content (measured with the UV Phenol Sulfuric Acid method, 490 nm) from 50% to 90%, preferably 60% to 80%; a particle size of 80 mesh (min. 95% passes through 80 mesh) and a bulk density CP <2020> comprised from 0.3 g / ml to 0.6 g / ml.

[0151] As a further example, an extract of Gastrodia elata may be Gastrodia elata rhizome P.E. 10: 1 (dry extract in the presence of dextrin as an excipient) and having a polysaccharide content (measured with the UV Phenol Sulfuric Acid method, 490 nm) of 10% to 40%, preferably from 15% to 20%; a particle size of 100 mesh (100% passes through 100 mesh), a water solubility of 100% at a temperature of 25°C and a tap density comprised from 0.35 to 0.55 g / cm3.

[0152] Preferably, said extract of Gastrodia elata is an extract of Gastrodia elata Blume,' preferably, said extract of Gastrodia elata Blume comprises or consists of gastrodin. The experiments included in the experimental part that follows were performed with the commercial product having the name "OXIBLUME”, which may be of the 10:1 type comprising, for example, a 10:1 extract of gastrodin.

[0153] Coenzyme Q10 (or CoQ10 or ubidecarenone or ubiquinone) is a molecule belong to the ubiquinone group, liposoluble benzoquinones involved in electron transport in mitochondria and cellular oxidative phosphorylation. Coenzyme Q10 is a 1 ,4-benzoquinone consisting of a 2,3-dimethoxy-5-methylbenzochinone nucleus, attached to which there is a terpenoid side chain containing 10 trans-isoprenoid monounsaturated units. Coenzyme Q10 acts as a free-radical acceptor with antioxidant (reducing) and membrane-stabilizing properties. Accordingly, it preserves cell integrity. In general, CoQ10 is well tolerated. A typical daily dose may be, for example, about 100-200 milligrams.

[0154] In the context of the present invention, coenzyme Q10 can be present in an oxidated or reduced form. The oxidated form is also known as "ubiquinone”, whereas the reduced form of coenzyme Q10 is also known as "ubiquinol”.

[0155] Preferably, the mixture of the invention comprises or, alternatively, consists of gastrodin and / or a derivate thereof and coenzyme Q10.

[0156] As shown in example 1 , the mixture according to the invention is capable of reducing the inflammatory response typical of benign prostatic hyperplasia, in particular by modulating the activity of 5o-reductase and reducing the production of dihydrotestosterone (DHT). These results were further confirmed in a 3D model of benign prostatic hyperplasia (Example 1 , Figure 7), effectively showing that a mixture comprising gastrodin and coenzyme Q10 is capable of reducing the oxidative stress typical of prostate inflammation, thus improving the antioxidant activity, also under pathological conditions of benign prostatic hyperplasia. Serenoa repens (or American dwarf palm or saw palmetto) is a small palm endemic to the subtropical and tropical zones of the USA. The extract of Serenoa repens (extract of dried ripe fruit, globe-shaped berries that are dark blue to black in colour upon ripening) is a well- tolerated herbal medicinal product.

[0157] Preferably, Serenoa repens extracts comprise a complex mixture of compounds including: fatty acids (such as oleic, lauric, myristic, linoleic, linolenic, palmitic, caprylic and capric acids, of which 2 / 3 in free form and 1 / 3 esterified); steroids (such as p-sitosterol, p-sitosterol-3-O-glucoside, campesterol and stigmasterol); flavonoids; polysaccharides; triglycerides; and terpenes.

[0158] Although Serenoa repens extract is indicated in cases of BPH, the clinical success obtained is still limited. Though numerous Serenoa repens extracts are available on the market, it has been demonstrated that such extracts differ greatly from the viewpoint of their makeup and, consequently, efficacy. When Serenoa-based preparations are used, the doses of the product to be taken and the effectiveness obtained can vary depending on the content of fatty acids and phytosterols. When Serenoa is used for therapeutic purposes, it is essential to use preparations that are defined and standardized in terms of active ingredients (free fatty acids and phytosterols), because only in this way is it possible to know the exact amount of pharmacologically active substances being taken.

[0159] A standardized lipidosterolic extract of Serenoa repens constitutes the active ingredient of a drug that was used in the present experimental part. For example, a soft capsule of said drug comprising said standardized lipidosterolic extract of Serenoa repens contains 320 mg of lipidosterolic extract of Serenoa repens* (7-11 : 1) *Oily extract originating from the fruit of Serenoa repens (Bartram) Small. The other components are gelatine, glycerol, titanium dioxide, ferric oxide yellow, sodium ethyl paraoxybenzoate, sodium propyl paraoxybenzoate), used precisely to counter the functional disorders tied to BPH.

[0160] Preferably, said iib) can be selected from the group comprising or, alternatively, consisting of Serenoa repens, Epilobium angustifolium L. herba, Epilobium parviflorum Schreb. Herba and / or mixtures thereof listed in said group G, in association with i) and iia). Preferably, said iib) can be Serenoa repens listed in said group G, in association with i) and iia). More preferably, said lib) is Epilobium angustifolium L. herba or Epilobium parviflorum Schreb. Herba, or mixtures thereof.

[0161] Even more preferably, said iib) is Epilobium parviflorum Schreb. Herba.

[0162] Preferably, said iib) Epilobium parviflorum Schreb. Herba is in addition to or a replacement for iib) Serenoa repens, again in association with i) and iia).

[0163] It is an object of the present invention to provide pharmaceutical compositions and / or compositions for medical devices (Regulation (EU) 2017 / 745) and / or nutraceutical and / or food compositions and / or a dietary supplement and / or a food for special medical purposes (FSMP) which comprise an association or combination of the present invention, optionally, together with one or more pharmaceutically acceptable excipients and / or vehicles.

[0164] Preferably, said compositions are for use in therapy, in particular in a method of treatment, preventive and / or curative, of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation and / or other functional disorders affecting the urinary tract, bladder, testicles and prostate, more preferably for use in the treatment and / or prevention of benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH and inflammation due to BPH.

[0165] According to one embodiment, the pharmaceutical and / or nutraceutical composition or supplement composition of the invention comprises: i) an extract of Gastrodia elata and ii) at least one ingredient selected from the group comprising or, alternatively, consisting of iia) a coenzyme Q10, iib) an extract of Serenoa repens and / or mixtures thereof, together with at least one pharmaceutically acceptable excipient and / or vehicle. According to one embodiment, the pharmaceutical and / or nutraceutical composition or supplement composition of the invention comprises: an extract of Gastrodia elata and a coenzyme Q10, together with at least one pharmaceutically acceptable excipient and / or vehicle.

[0166] According to one embodiment, the pharmaceutical and / or nutraceutical composition or supplement composition of the invention comprises: an extract of Gastrodia elata and an extract of Serenoa repens, together with at least one pharmaceutically acceptable excipient and / or vehicle.

[0167] According to one embodiment, the pharmaceutical and / or nutraceutical composition or supplement composition of the invention comprises: an extract of Gastrodia elata and a coenzyme Q10 and an extract of Serenoa repens, together with at least one pharmaceutically acceptable excipient and / or vehicle.

[0168] According to one embodiment, the pharmaceutical and / or nutraceutical composition or supplement composition of the invention comprises or, alternatively, consists of: i) an extract of Gastrodia elata and iia) a coenzyme Q10, iib) an extract of Epilobium parviflorum Schreb. Herba and / or mixtures thereof, together with at least one pharmaceutically acceptable excipient and / or vehicle.

[0169] According to one embodiment, the pharmaceutical and / or nutraceutical composition or supplement composition of the invention comprises or, alternatively, consists of: i) an extract of Gastrodia elata and iia) a coenzyme Q10, iib) an extract of Serenoa repens and an extract of Epilobium angustifolium L. herba and / or Epilobium parviflorum Schreb. Herba and / or mixtures thereof, together with at least one pharmaceutically acceptable excipient and / or vehicle. The composition of the invention is a composition for oral use, preferably a solid-state composition, preferably formulated in dosage units. "Solid state” means that the composition may exist in the form of granules or powders. The granular or powder compositions are mixed with pharmacologically acceptable additives and excipients to provide a final product such as, for example, a supplement product, medical device or pharmaceutical composition. The final product may be in pharmaceutical dosage units such as, for example, granules in a sachet, stick, orodispersible stick, tablet, gel or capsule.

[0170] The tablets may have different shapes among those known in the field of pharmaceutical forms, such as a cylindrical or spheroidal shape. The tablets may be coated or filmed with one or more layers of coating or film capable of passing through the gastric barrier, according to known methods.

[0171] The gel capsules may consist of hard gelatine or soft gelatine or soft gel.

[0172] Preferably, the oral composition of the invention is a solid or semi-solid (gel) composition as described above. However, if desired or necessary, the composition may be formulated in liquid form, for example by dissolution or suspension in water.

[0173] The solid compositions of the invention may contain, as mentioned above, physiologically acceptable conventional excipients and / or vehicles, such as diluents, bulking agents, binders, disaggregating agents, flow aids, lubricants, etc. Non-limiting examples of suitable vehicles and excipients are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins. Compositions of the invention may, for example, include cellulose derivatives, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, glycol, water, ethanol, and the like. The composition may also contain pH buffering reagents and wetting or emulsifying agents.

[0174] In addition to the above-described components, if desired or necessary, the composition of the invention may comprise further active components, for example components capable of assisting the active ingredients in performing their action in the body of the treated individual, provided that said further components are physically and chemically compatible with the active ingredients of the composition.

[0175] Preferably, the compositions of the present invention may be in the form of a capsule, a tablet, a sachet, a stick, an orodispersible stick, an oral gel or granules.

[0176] The composition of the invention, preferably formulated in dosage units, may be administered once or several times a day, for example once or twice or three times a day.

[0177] Preferably, the pharmaceutical and / or nutraceutical composition of the invention preferably comprises from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of I) extract of Gastrodia elata] and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of Ila) coenzyme Q10 and, optionally, together with one or more pharmaceutically acceptable excipients and / or vehicles.

[0178] Preferably, the pharmaceutical and / or nutraceutical composition of the invention preferably comprises from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of I) extract of Gastrodia elata] and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of Ila) coenzyme Q10 and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of lib) at least one extract selected from Serenoa repens, Epilobium angustifolium L. herba, Epilobium parviflorum Schreb. Herba and / or mixtures thereof and, optionally, together with one or more pharmaceutically acceptable excipients and / or vehicles.

[0179] Preferably, the pharmaceutical and / or nutraceutical composition of the invention preferably comprises from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of i) extract of Gastrodia elata] and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of Ila) coenzyme Q10 and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of lib) at least one extract of Serenoa repens and, optionally, together with one or more pharmaceutically acceptable excipients and / or vehicles.

[0180] More preferably, the pharmaceutical and / or nutraceutical composition of the invention preferably comprises from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of I) extract of Gastrodia elata] and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of Ila) coenzyme Q10 and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of lib) at least one extract of Epilobium parviflorum Schreb. Herba and, optionally, together with one or more pharmaceutically acceptable excipients and / or vehicles.

[0181] Preferably, the pharmaceutical and / or nutraceutical composition of the invention preferably comprises from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of I) extract of Gastrodia elata] and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of Ila) coenzyme Q10 and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of lib) at least one extract of Epilobium parviflorum Schreb. Herba and Serenoa Repens and, optionally, together with one or more pharmaceutically acceptable excipients and / or vehicles.

[0182] The compositions of the invention may be prepared by mixing the single components, and any conventional excipients and / or vehicles.

[0183] The daily dosage depends on the patient's health status, weight, gender and age. In general, the compositions of the invention are well tolerated and can be administered once or several times a day, even over an extended period of time.

[0184] The Applicant has found that the association or combination or mixture of the invention and the pharmaceutical and / or nutraceutical compositions containing it are useful for maintaining the wellbeing and functionality of the urinary tract, bladder, testicles and prostate, in particular in the case of benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation, preferably inflammation due to BPH, and / or other functional disorders.

[0185] According to another aspect thereof, it is an object of the invention to provide the association and / or composition of the invention for use in therapy, in particular to maintain the wellbeing and functionality of the urinary tract, bladder, testicles and prostate, in particular in the case of benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation and / or other functional disorders, more preferably for use in the treatment and / or prevention of benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH and inflammation due to BPH.

[0186] According to another aspect thereof, it is an object of the invention to provide a method of treatment, preventive and / or curative, of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation and / or other functional disorders affecting the urinary tract, bladder, testicles and prostate, which comprises administering, to an individual in need thereof, the association and / or composition of the invention, preferably in a dose effective for the purpose.

[0187] Preferably, 1 tablet or 1 sachet, for example, weighing 100 mg, or 200 mg, or 500 mg, is administered, preferably from 1 to 3 times a day according to need and the individual in need.

[0188] Furthermore, the association or combination of the invention and the pharmaceutical and / or nutraceutical compositions containing it, due to the presence of natural ingredients do not have significant adverse effects, are free of side effects and have high tolerability, and can be administered to a broad category of individuals.

[0189] Finally, the associations and / or compositions of the invention are easy to prepare and inexpensive.

[0190] Representative forms of the compositions of the invention are described in the Experimental Section below solely by way of illustration and are in no way limiting.

[0191] As will be shown in the Experimental Section that follows and by the figures illustrating the results of the experimental assays conducted, the association / composition of the invention has been demonstrated to be effective in the treatment of benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation and / or other functional disorders affecting the urinary tract, bladder, testicles and prostate.

[0192] It is an object of the invention to provide a method of treatment, preventive and / or curative, of prostate diseases and / or disorders, preferably benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation and / or other functional disorders affecting the urinary tract, bladder, testicles and prostate, which comprises administering, to an individual in need thereof, the association and / or composition of the invention, preferably in a dose effective for the purpose.

[0193] Preferably, said mixture and / or said composition can be advantageously administered to an individual having benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH and / or inflammation due to PBH.

[0194] The mixture and / or composition as disclosed in the present invention can be used in a method of treatment, therapeutic or non-therapeutic, for an individual having one or more of the above-mentioned disorders or symptoms associated therewith.

[0195] Said mixture and / or said composition may be used individually or in combination with at least one drug conventionally used in the treatment of benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation, preferably inflammation due to BPH, and / or other functional disorders affecting the urinary tract, bladder, testicles, and prostate. For example, said at least one drug is preferably selected from the group comprising or, alternatively, consisting of Finasteride, Dutasteride and Tadalafil, more preferably selected from Dutasteride and Finasteride. Even more preferably, said mixture and / or said composition are used in combination with both Finasteride and Dutasteride.

[0196] In fact, as shown in example 4, the mixture comprising gastrodin and coenzyme Q10, tested alone and in combination with the drugs Finasteride, Dutasteride or Tadur (Tadalafil), can reduce the inflammatory response typical of BPH in more effective manner than the drugs administered individually and promote and amplify the effect of the drugs themselves.

[0197] The results obtained have drawn attention to the ability of the mixture to be compatible with the drugs conventionally used in the treatment of the BPH.

[0198] Therefore, the mixture comprising or, alternatively, consisting of i) gastrodin and iia) coenzyme Q10, optionally in association with iib) at least one plant extract or preparation selected from the group G, preferably Serenoa Repens and / or Epilobium, can be advantageously used in combination with at least one drug conventionally used in the treatment of the benign prostatic hyperplasia, selected from the group comprising or, alternatively, consisting of Finasteride, Dutasteride and Tadalafil, preferably in combination with Dutasteride, even more preferably in combination with Finasteride and Dutasteride.

[0199] Experimental section

[0200] EXAMPLE 1

[0201] Experimental protocol

[0202] PHASE 1 : ANALYSIS OF ABSORPTION AND BIOAVAILABILITY

[0203] An absorption and bioavailability study was carried out using well-designed in vitro models, called Transwell®, which involve the use of human intestinal epithelial cells, specifically a Caco-2 cell line widely used and validated as a human intestinal epithelial cell model for studies on the absorption of orally administered compounds. The same 3D in vitro model (approved by the FDA and EMA) was used to test absorption and the mechanisms of transport across the intestinal barrier, by performing:

[0204] • an analysis of cell viability through an MTT assay;

[0205] • an analysis of oxidative stress;

[0206] • an analysis of permeability by means of a fluorescent probe and measurement of transepithelial resistance (TEER);

[0207] • an analysis of tight junction activity.

[0208] The cells seeded into the Transwell® insert were maintained in a complete medium changed every other day for 21 days before the stimulations in order to ensure the maturation and formation of intestinal microvilli. Maturation was complete when a transepithelial resistance (TEER) value >400 l / cm2 was reached.

[0209] All the above-mentioned investigations were carried out over a period of 1 h to 6h, the physiological absorption time of the small intestine; at the end of every stimulation the basolateral environment was collected and administered to the BPH model. PHASE 2: BIOLOGICAL ACTIVITY

[0210] A study on the biological activity and beneficial effect of the associations / combinations of the invention, after intestinal absorption, was carried out with a 3D in vitro prostate culture (model of gut-prostate axis). In this phase, in fact, a 3D in vitro prostate model was set up as described in the literature; this model was pretreated overnight with 0.5 pM testosterone to simulate BHP in vitro.

[0211] At the end of the pre-stimulation period, the following were analysed:

[0212] • cell viability and mitochondrial metabolism;

[0213] • absence of oxidative stress and ROS production;

[0214] • modulation of serotonin levels and the relevant markers involved (5-HTr1 a and 5-HTr1 b);

[0215] • activity of androgen receptors;

[0216] • modulation of testosterone, dihydrotestosterone and 5a-reductase levels;

[0217] • molecular pathways involved in cell proliferation, e.g., RAF / MAPK and Ki67;

[0218] • evaluation of the inflammatory state, and specifically NFkB and TNFo;

[0219] • analysis of the main cytokines involved, namely IL1 b, IL6 and IL10, mimicking acute inflammation;

[0220] • evaluation of the correlation between the prostate antigen, functional activity of cells and evolution of hyperplasia. Conclusions

[0221] In conclusion, based on the data obtained it is possible to observe that Gastrodia and Q10, or also Gastrodia, Q10 and Serenoa repens, stimulate gut wellbeing and ensure an activity in maintaining the integrity of TJ dynamics in intestinal cells, thus demonstrating the safety of their use. Gastrodia and Q10, or Gastrodia, Q10 and Serenoa repens can reduce the inflammatory response typical of BPH in a more effective manner than Serenoa repens alone, by modulating the activity of 5o-reductase and reducing the production of DHT. The results pointed out that treatment with testosterone, which imitates BPH, has a role in the development of hyperproliferation and hyperplasia, as it increases various parameters, including inflammatory mediators, inflammatory genes and oxidative stress; furthermore, prostate inflammation can cause the generation of free radicals such as ROS and activate the nuclear transcription factor NFkB through the TNFo signalling pathway.

[0222] In contrast, oral supplementation with Gastrodia and Q10, or Gastrodia, Q10 and Serenoa repens, compared to Serenoa repens alone, reduced oxidative stress, improving the antioxidant activity. Furthermore, not only the levels of TNF-a activity, but also the interleukins produced, such as IL-1 p and IL-10, are reduced, demonstrating their ability to reduce the inflammatory environment characteristic of BPH and suggesting their ability to modulate the damage induced by BPH. Furthermore, Gastrodia and Q10, or Gastrodia, Q10 and Serenoa repens, regulate AR activity, which underscores the ability thereof to operate not only in the majority of the key processes of the prostate function, but also under pathological conditions such as BPH.

[0223] Furthermore, the mixture of OXI BLUME and Q10 combined with Epilobium also gave surprising results, showing its effectiveness against BPH (see example 3). EXAMPLE 2

[0224] For the purpose of testing the mixture comprising gastrodin and coenzyme Q10, an in vitro study was carried out, divided into two phases:

[0225] (1) analysis of the absorption and bioavailability mechanisms underlying the passage of the mixture through the intestinal tract, by exploiting a 3D model of the intestinal barrier validated in the literature and approved by regulatory agencies; and

[0226] (2) analysis of the biological activity and beneficial effect of the new formulation, after intestinal absorption, with a 3D in vitro prostate culture.

[0227] The examples that follow relied on the use of the product OXIBLUME 10: 1 , 100 mg comprising gastrodin. In addition to gastrodin, the product OXI BLUME also comprises maltodextrin, fibres and inulin.

[0228] Phase 1 - Intestinal absorption and bioavailability

[0229] Materials and methods

[0230] The study on intestinal absorption was conducted using well-designed in vitro models, called Transwell®, which envisage the use of human intestinal epithelial cells, the Caco-2 cell line, widely used and validated as a human intestinal epithelial cell model for studies on the absorption of orally administered compounds. This 3D in vitro model 3D is approved by the FDA and EMA (https: / / www.fda.gOv / media / 117974 / download).

[0231] In particular, in order to test absorption and the mechanisms of transport through the intestinal barrier, the following analyses were performed:

[0232] • Analysis of cell viability through the MTT assay;

[0233] • Analysis of oxidative stress;

[0234] • Analysis of permeability by means of a fluorescent probe and measurement of TEER; and

[0235] • Tight junction activity.

[0236] The cells seeded into the Transwell® insert were maintained in a complete medium changed every other day for 21 days before the stimulations in order to ensure the maturation and formation of intestinal microvilli. Maturation was complete when a transepithelial resistance (TEER) value >400 l / cm2 was reached.

[0237] All the above-mentioned investigations were carried out over a period of 1 h to 6h, the physiological absorption time of the small intestine.

[0238] Results Phase 1

[0239] 1 - Evaluation of cell viability and ROS production of the intestinal epithelium over time to exclude toxicity

[0240] Cell viability of the intestinal epithelium over time was evaluated to exclude the toxicity of the mixture of gastrodin and coenzyme Q10. The analyses were performed with OXIBLUME 10: 1 at a dosage of 100 mg.

[0241] In particular, the following compounds were tested: the active ingredient gastrodin (indicated in the figures as "OXIBLUME 10: 1 100 mg”); mixture of gastrodin and coenzyme Q10 (indicated in the figures as "OXIBLUME 10:1 100 mg + Q10”); drug, gastrodin and coenzyme Q10;

[0242] Serenoa repens (oil);

[0243] Serenoa repens 2 (powder);

[0244] Coenzyme Q10; and drug.

[0245] In the experiment described in example 2, the drug tested alone and in association with gastrodin and coenzyme Q10 is a drug based on a lipidosterolic extract of Serenoa repens.

[0246] The mixture according to the invention comprising gastrodin and coenzyme Q10 (indicated in the figures as "OXIBLUME 10:1 100 mg + Q10”) increases the beneficial effect exerted by OXI BLUME alone.

[0247] The results of the present experiment are shown in figures 1 and 2, in which the reported data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. For all the tested forms, the results obtained are statistically significant vs control (p<0.05)). "SD” is meant to indicate standard deviation.

[0248] 2 - TEER

[0249] The evaluation of transepithelial resistance is useful for the purpose of determining that the integrity of intestinal tissues is preserved.

[0250] Based on the TEER analyses performed, the combination of OXIBLUME 10:1 with coenzyme Q10 exerts the best effect in terms of intestinal integrity.

[0251] The results of the present experiment are shown in figure 3, in which the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. In the case of TEER, all substances are p<0.05 vs control.

[0252] 3 - Evaluation of absorption through the intestinal epithelium

[0253] Table 1 shows the percentage values of absorption through the intestinal epithelium, calculated for the compounds / associations specified below. In particular, the percentage values specified below were derived by applying the formula:

[0254] J = Jmax [C] / (Kt + [C])

[0255] C: initial concentration of fluorescein

[0256] Jmax: maximum permeation rate

[0257] Kt: Michaelis-Menten constant

[0258] Table 1

[0259] OXI BLUME + Q10 in association with the drug shows positive effects in terms of greater permeability at the intestinal level compared to the single active components.

[0260] In the drug + OXI BLUME 10:1 + Q10 sample, one observes better results in terms of permeability at intestinal level (p<0.05).

[0261] Phase 2 - Assays performed on a 3D in vitro prostate model

[0262] Materials and methods

[0263] In order to test the effectiveness of the mixture according to the invention in treating benign prostatic hyperplasia, a 3D in vitro prostate model as reported in the literature was obtained (Fontana et al., Three-Dimensional Cell Cultures as an In vitro Tool for Prostate Cancer Modeling and Drug Discovery, Int. J. Mol. Sci, 2021, 21; and Takir et al., 3D Cell Culture Model for Prostate Cancer Cells to Mimic Inflammatory Microenvironment, Proceedings 2018, 2, 1555).

[0264] This model was pretreated overnight with 0.5pi M testosterone to simulate benign prostatic hyperplasia in vitro.

[0265] At the end of the pre-stimulation period, the following were analysed:

[0266] • cell viability and mitochondrial metabolism

[0267] • absence of oxidative stress and ROS production

[0268] • modulation of serotonin levels and the relevant markers involved (5-HTr1a and 5-HTr1b)

[0269] • activity of androgen receptors

[0270] • modulation of testosterone, dihydrotestosterone and 5o-reductase levels

[0271] • evaluation of the inflammatory state and specifically NFkb and TNFa

[0272] • analysis of the main cytokines involved, namely IL1p, and IL10, by mimicking acute inflammation.

[0273] Results of phase 2 1- Evaluation of cell proliferation in the 3D model of benign prostatic hyperplasia

[0274] A cell proliferation analysis was performed for the various formulations which passed through the intestinal barrier after 24h of treatment.

[0275] The results are shown in figure 4, in which the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<0.05 vs control; p<0.05 vs testosterone 0.5uM; # p<0.05 vs Serenoa repens (oil); 5 p<0.05 vs Serenoa repens 2 (powder); 9 p<0.05 vs Coenzyme Q10 a p<0.05 vs OXIBLUME 10: 1 ; ip p<0.05 vs drug; bars p<0.05 between the combinations.

[0276] All the tested combinations show to reduce cell proliferation compared to the prostatic inducer.

[0277] In the OXIBLUME sample, results similar to the pharmacological activity in terms of cell proliferation are appreciated, tending to to bring the values back to the level of the control (sample not treated with the inducer).

[0278] The combined use with coenzyme Q10 increases the beneficial effect exerted by OXIBLUME.

[0279] The combination of OXIBLUME with Q10 in association with the pharmacological treatment improves the activity of the drug itself without inhibiting its effectiveness.

[0280] 2- Evaluation of cell viability in 3D model of benign prostatic hyperplasia exclude toxicity

[0281] In order to evaluate cell viability in the 3D model of benign prostatic hyperplasia following treatment with the various formulations which passed through the intestinal barrier after 24h of treatment, ROS production was guantified, and the oxidative stress was assessed.

[0282] In particular, it was observed that in the drug + OXI BLUME + Q10 sample better results could be noted in terms of reducing oxidative stress with lower irritability.

[0283] The results are shown in figures 5 and 6, in which the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<0.05 vs control; p<0.05 vs testosterone 0.5uM; # p<0.05 vs Serenoa repens (oil); 5 p<0.05 vs Serenoa repens 2 (powder); 9 p<9.95 vs coenzyme Q19 a p<9.95 vs OXI BLUME 19:1 ; ip p<9.95 vs drug; bars p<9.95 between the combinations.

[0284] 3 - Evaluation of NFkB, TNFa, IL-113 and IL-19 production to establish anti-inflammatory capacity

[0285] The results of the analysis of the activation of proinflammatory cytokines NFkB, TNFa, IL-1 p and IL-19 are shown in figure 7, where the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<9.95 vs control; p<9.95 vs testosterone 9.5uM; # p<9.95 vs Serenoa repens (oil); 5 p<9.95 vs Serenoa repens 2 (powder); 9 p<9.95 vs coenzyme Q19 a p<9.95 vs OXIBLUME 19:1 ; ip p<9.95 vs drug; bars p<9.95 between the combinations.

[0286] In particular, it was observed that:

[0287] • In the sample of OXIBLUME combined with coenzyme Q19, better results are noted (p<9.95)

[0288] • The combined use with coenzyme Q19 in addition to the pharmacological treatment further increases the beneficial effect exerted by OXIBLUME combined with coenzyme Q19. 4 - Evaluation of OXI BLUME in attenuating the mechanism of benign prostatic hyperplasia in vitro on testosterone and dihydrotestosterone levels

[0289] During a condition of BPH, the levels of testosterone decrease because the latter is converted by 5a-reductase into dihydrotestosterone (DHT).

[0290] As may be observed in figures 8 a) and b), pretreatment with testosterone increases the DHT levels, while reducing the testosterone level, thus confirming the mechanisms present in BPH (p<0.05).

[0291] All the tested formulations, by contrast, reduce the production of DHT and the testosterone levels are conseguently maintained; in particular, OXIBLUME + Q10 in combination with the drug shows to have a better effect than the single components (p<0.05).

[0292] In figures 8 a) and b), the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<0.05 vs control; p<0.05 vs testosterone 0.5uM; # p<0.05 vs Serenoa repens (oil); 5 p<0.05 vs Serenoa repens 2 (powder); 9 p<0.05 vs coenzyme Q10 a p<0.05 vs OXIBLUME 10:1 ; ip p<0.05 vs drug; bars p<0.05 between the combinations.

[0293] 5 - Evaluation of OXIBLUME in attenuating the mechanism of benign prostatic hyperplasia in vitro - analysis of the activity of the enzyme 5a-reductase

[0294] During the condition of BPH, the enzyme 5a-reductase possesses a very high activity, as it is necessary for converting testosterone as shown by the previous results.

[0295] The formulations show an inhibitory capacity, since they are capable of shutting down the enzymatic activity of 5a- reductase

[0296] OXI BLUME + Q10 in combination with the drug seem to shut down the activity of the enzyme, thus confirming the previous data regarding the maintenance of testosterone levels and reduction in the production of DHT.

[0297] The results are shown in Figure 9, in which the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<0.05 vs control; p<0.05 vs testosterone 0.5uM; # p<0.05 vs Serenoa repens (oil); 5 p<0.05 vs Serenoa repens 2 (powder); 9 p<9.95 vs coenzyme Q19 a p<9.95 vs OXI BLUME 19:1 ; ip p<9.95 vs drug; bars p<9.95 between the combinations.

[0298] 6 - Evaluation of OXIBLUME in attenuating the mechanism of benign prostatic hyperplasia in vitro - analysis of the activity of the androgen receptor (AR) and serotonin production

[0299] During the condition of BPH, the androgen receptor (AR) is overexpressed due to the excess production of DHT (p<9.95). In this case as well, the formulations show an inhibitory capacity, since they are capable of reducing AR activity; in particular, OXI BLUME + Q19 in combination with the drug seem to shut down the activity of the enzyme, thus confirming the previous data. Furthermore, the data regarding serotonin confirm that AR activity increases, and serotonin decreases following treatment with testosterone (condition of BPH), but a balance is restored following treatment with OXIBLUME + Q19 in combination with the drug. Figure 10 shows a) AR activity and b) serotonin production obtained after treatment of the in vitro model of BPH with the specified formulations.

[0300] In Figures 10 a) and b), the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<0.05 vs control; # p<0.05 vs Serenoa repens (oil); 5 p<0.05 vs Serenoa repens 2 (powder); i p<0.05 vs drug; a p<0.05 vs OXIBLUME 50% polysaccharides; p p<0.05 vs OXIBLUME 10: 1 ; y p<0.05 vs respective OXI BLUME 200 mg.

[0301] Example 2 Conclusions

[0302] Based on the results obtained, it may be affirmed that OXI BLUME combined with coenzyme Q10 (mixture according to the invention): stimulates gut wellbeing by ensuring an activity in maintaining integrity in intestinal cells, demonstrating the safety of its use; can reduce the inflammatory response typical of BPH, activity of 5 o-reductase and production of DHT; can be used in combination with the classic pharmacological treatment, as it demonstrates a synergistic and non-competitive activity.

[0303] The results emphasise that treatment with testosterone, which imitates the conditions of BPH, has a role in the development of hyperproliferation and hyperplasia, increasing various parameters, including inflammatory mediators, inflammatory genes and oxidative stress; furthermore, prostate inflammation can cause the generation of free radicals such as ROS and activate the nuclear transcription factor NF-KB through the TNF-o signalling pathway.

[0304] Furthermore, OXI BLUME, in association with the drug, regulates AR activity, as it has demonstrated its ability to operate not only in the majority of the key processes of prostate function, but also under pathological conditions such as BPH.

[0305] EXAMPLE 3

[0306] Mixture comprising OXIBLUME, Q10 and Epilobium

[0307] The mixture for use according to the invention (extract of Gastrodia elata and coenzyme Q10) was tested in association with an extract of Epilobium parviflorum - Schreb, an herbaceous plant of the family Oenotheraceae. The principal tannic component of Epilobium parviflorum - Schreb is oenothein B.

[0308] Before the mixture of OXIBLUME and coenzyme Q10 with Epilobium extract was tested, a screening was performed on the prostate cells in order to select the best form and concentration of Epilobium to be used for the combination. Following the screening it emerged that, for all the forms of Epilobium tested, the best concentration was the one equal to 50pig / mL, compared to the other two tested (p<0.05). In addition, the form of Epilobium that the screening showed to be the best is Epilobium 15%, compared to all the other forms (p<0.05). The results of the screening are shown in figure 11 . In particular, in Figure 11 , the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<0.05 vs control; a p<0.05 vs other concentrations

[0309] The experiments proceeded with Epilobium 15% 50 pg / ml.

[0310] 1 - Analysis of OXI BLUME at a dosage of 100 mg supplemented with Q10 and Epilobium or Serenoa repens

[0311] It emerged from the data that OXIBLUME+Q10+Epilobium performs better, in terms of both increasing viability and reducing oxidative stress, compared to the combination alone, the single components, the combination of OXIBLUME+Q10 and the combination of OXIBLUME+Q10+Serenoa Repens (p<0.05).

[0312] The results of the experiment on cell viability and ROS production, performed to exclude toxicity, are shown in figure 12, in which the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. All substances are p<0.05 vs control.

[0313] 2 - TEER

[0314] Based on the TEER analyses performed, the combination of OXI BLUME+Q10 supplemented with Epilobium exerts a better effect in terms of maintaining intestinal integrity (Figure 13). In Figure 13, the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. In the case of TEER: all substances are p<0.05 vs control.

[0315] 3 - Evaluation of absorption through the intestinal epithelium

[0316] Table 2 shows the percentage values of absorption through the intestinal epithelium, calculated for the compounds / associations specified below. In particular, the percentage values specified below have been derived by applying the formula:

[0317] J = Jmax [C] / (Kt + [C])

[0318] C: initial concentration of fluorescein

[0319] Jmax: maximum permeation rate

[0320] Kt: Michaelis-Menten constant

[0321]

[0322] Table 2

[0323] Based on the absorption results, it may be observed that OXIBLUME+Q10 in association with Epilobium shows positive effects in terms of greater permeability at the intestinal level.

[0324] 4 - Evaluation of OXIBLUME+Q10+Ep / 7ob / i / m in attenuating the mechanism of proliferation in a 3D in vitro model of BPH.

[0325] The analysis of cell proliferation in relation to the various formulations which passed through the intestinal barrier after 24h of treatment is reported in Figure 14, in which the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<0.05 vs control; a p<0.05 vs testosterone; p p<0.05 vs OXIBLUME+Q10; y p<0.05 vs respective single agent; 5 p<0.05 vs OXIBLUME+Q10+Serenoa repens.

[0326] In particular, it was observed that all the tested combinations reduce cell hyperproliferation by decreasing the activation of proliferative mechanisms compared to the condition of BPH induced by testosterone and the single agents (p<0.05).

[0327] In the OXIBLUME+Q10+Ep / 7ob / um sample better results are observed in terms of reducing proliferation than with the combination OXIBLUME+Q10 and OXIBLUME+Q10+Serenoa repens (p<0.05).

[0328] 5 - Evaluation of cell viability in a 3D model of benign prostatic hyperplasia to exclude toxicity - Analysis of ROS production and oxidative stress in relation to the various formulations which passed through the intestinal barrier after 24h of treatment

[0329] The results of the present experiment are shown in figure 15, in which the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<0.05 vs control; a p<0.05 vs testosterone; p p<0.05 vs OXIBLUME+Q10; y p<0.05 vs respective single agent; 5 p<0.05 vs OXIBLUME+Q10+Serenoa repens.

[0330] In particular, it can be observed that:

[0331] • All the tested combinations show to reduce oxidative stress compared to the single agents.

[0332] • In the OXI BLUME +Q10 + Epilobium sample better results are noted in terms of reducing oxidative stress. 6 - Evaluation of the production of NFkB, TNFo, IL-1 P and IL-10 to establish the anti-inflammatory capacity

[0333] The results of the analysis of the activation of proinflammatory cytokines NFkB, TNFo, IL-1 p and IL-10 are shown in figure 16, where the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<0.05 vs control; a p<0.05 vs testosterone; p p<0.05 vs OXIBLUME+Q10; y p<0.05 vs respective single agent; 5 p<0.05 vs OXIBLUME+Q10+Serenoa repens.

[0334] In particular, it was observed that:

[0335] OXIBLUME+Q10 promotes a reduction of the inflammatory process

[0336] 7 - Evaluation of OXI BLUME in attenuating the mechanism of benign prostatic hyperplasia in vitro on testosterone and dihydrotestosterone levels

[0337] Analysis of the inhibition of crucial mechanisms of prostatic hyperplasia after 24h of treatment with OXIBLUME+Q10 with Epilobium under a condition of BPH in vitro.

[0338] During a condition of BPH, the levels of testosterone decrease because the latter is converted by 5o-reductase into dihydrotestosterone (DHT). As may be observed from the figure, pretreatment with testosterone increases the DHT levels, while reducing the testosterone level, thus confirming the mechanisms present in BPH (p<0.05).

[0339] All the tested formulations, by contrast, reduce the production of DHT and the testosterone levels are consequently maintained; in particular, OXIBLUME+Q10+Ep / 7ob / um shows to have a better effect than the single components (p<0.05). The results are shown in Figure 17, in which the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<0.05 vs control; a p<0.05 vs testosterone; p p<0.05 vs OXIBLUME+Q10; y p<0.05 vs respective single agent; 5 p<0.05 vs OXIBLUME+Q10+Serenoa repens.

[0340] The various compounds / formulations were tested to evaluate their ability to inhibit the enzyme 5o-reductase (Figure 18) of the androgen receptor and to stimulate the serotonin production (Figure 19).

[0341] The analysis of the activity of the enzyme 5o-reductase was carried out after 24h of treatment with OXIBLUME+Q10+Ep / 7ob / um under a condition of BPH in vitro (0.5 pM of testosterone). The formulations show an inhibitory capacity, since they are capable of shutting down the enzymatic activity of 5o-reductase. The combination OXI BLUME+Q10 with Epilobium shows to have a better effect compared to the single agents (p<0.05).

[0342] In Figure 18 the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<0.05 vs control; a p<0.05 vs testosterone; p p<0.05 vs OXIBLUME+Q10; y p<0.05 vs respective single agent; 5 p<0.05 vs OXIBLUME+Q10+Serenoa repens.

[0343] As regards the activity of the androgen receptor and the stimulation of serotonin production, it was observed that the formulations show an ability to inhibit AR activity. OXIBLUME+Q10+Ep / 7ob / um seem to act on AR activity, as OXIBLUME+Q10 amplifies the inhibitory activity of Epilobium on AR.

[0344] The data regarding serotonin confirm that AR activity increases, and serotonin decreases in the condition of BPH (p<0.05); a balance is restored following treatment with OXI BLUME + Q10 in combination with Epilobium. In figure 19, the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<0.05 vs control; a p<0.05 vs testosterone; p p<0.05 vs OXIBLUME+Q10; y p<0.05 vs respective single agent;

[0345] 5 p<0.05 vs OXIBLUME+Q10+Serenoa repens.

[0346] Example 3 Conclusions

[0347] Based on the results obtained, it may be affirmed that OXIBLUME+Q10 combined with Epilobium: ensures gut wellbeing, as it maintains the integrity of the monolayer of intestinal cells, demonstrating the safety of its use; can reduce the inflammatory response typical of BPH by modulating the activity of 5 o-reductase and reducing the production of DHT;

[0348] The results obtained underscored that treatment with testosterone is capable of mimicking the condition of BPH by stimulating hyperproliferation and hyperplasia and increasing various parameters, including inflammatory mediators and oxidative stress; furthermore, prostate inflammation can cause the generation of free radicals such as ROS and activate the nuclear transcription factor NFkB through the TNF-a signalling pathway.

[0349] The combination of OXIBLUME+Q10+Epilobium reduced oxidative stress, improving the antioxidant activity. Furthermore, it reduced the levels of NFkB and TNF-a and the production of interleukins IL-1 p, demonstrating its ability to reduce the inflammatory environment characteristic of BPH and suggesting its ability to modulate the damage induced by BPH.

[0350] Furthermore, the combination OXIBLUME+Q10+Epilobium was capable of amplifying the inhibition of AR activity, which underscores its ability to operate not only in the majority of the key processes of the prostate function, but also under pathological conditions such as BPH.

[0351] EXAMPLE 4

[0352] OXIBLUME+Q10 supplemented with Finasteride, Dutasteride and Tadur (Tadalafil)

[0353] After evaluating the cell viability and ROS production in relation to the mixture of the invention alone and in combination with the drugs Finasteride, Dutasteride and Tadur (Tadalafil), also comparing the results of the single drugs on their own, and the TEER analysis, experiments as described below were carried out on the in vitro BPH model.

[0354] In the studies carried out, Finasteride, Dutasteride and Tadur (Tadalafil) were used at a concentration of 1 piM. Furthermore, Finasteride and Dutasteride were tested in combination, both at a concentration of 1 piM.

[0355] The analysis of cell viability and ROS production was performed using OXI BLUME at a dosage of 100 mg with Q10 and Finasteride, OXIBLUME+Q10 supplemented with Finasteride, Dutasteride and Tadalafil (CIALIS) and Finasteride+Dutasteride.

[0356] It emerged that OXIBLUME+Q10 supplemented with Finasteride, Dutasteride and CIALIS performed better compared to the combination of CXIBLUME+Q10 alone and to the single components (p<0.05). In particular, the formulation that showed to be better is the one containing Dutasteride and Finasteride+Dutasteride compared to the formula with Finasteride and CIALIS (p<0.05).

[0357] The analysis of TEER demonstrates that the combination of OXIBLUME+QIO with Finasteride, Dutasteride, CIALIS and Finasteride+ Dutasteride is capable of increasing the rate of absorption of the drugs, thus demonstrating their compatibility.

[0358] CXIBLUME+Q10 supplemented with Finasteride, Dutasteride and Tadur (Tadalafil) in attenuating the mechanism of BPH in vitro

[0359] The effect of the combination of the mixture of the invention with at least one drug conventionally used in the treatment of benign prostatic hyperplasia was assessed by testing the mixture of the invention (OXIBLUME + Q10) alone and in combination with the drugs Finasteride, Dutasteride and Tadur (indicated as "CIALIS” in the figures) and comparing the results of the single drugs on their own.

[0360] Furthermore, the mixture of CXIBLUME+Q10 with Finasteride + Dutasteride was tested.

[0361] For the present experiment, an analysis was performed of the crucial mechanisms in prostatic hyperplasia after 24h of treatment under a condition of BPH in vitro.

[0362] Pretreatment with testosterone increases the DHT levels, while reducing testosterone, thus confirming the mechanisms present in BPH (p<0.05).

[0363] It was observed that all the tested formulations reduce the production of DHT and the testosterone levels are consequently maintained; in particular, CXIBLUME+Q10 seems to behave in a similar manner to Finasteride because, if combined with Finasteride alone, the effect obtained is identical, but if it is combined with dutasteride, it seems to amplify the activity of the drug to a larger extent.

[0364] Furthermore, if CXIBLUME+Q10 is combined with Finasteride+Dutasteride the effect increases further; this could be analogous to a double dose of Finasteride administered as Finasteride as such and CXIBLUME+Q10.

[0365] The results of this experiment are shown in figure 20, in which the data are expressed as the mean ± SD (%) of 5 independent experiments normalized to the control. * p<0.05 vs control; a p<0.05 vs testosterone; p p<0.05 vs OXIBLUME+Q10; y p<0.05 vs Finasteride; 5 p<0.05 vs Dutasteride; E p<0.05 VS Finasteride+Dutasteride; # p<0.05 vs OXIBLUME+Q10+Finasteride; q p<0.05 vs OXIBLUME+Q10+Dutasteride; 0 p<0.05 vs OXIBLUME+Q10+TDIALIS.

[0366] The results regarding the activity of the enzyme 5o-reductase in prostatic hyperplasia confirm that if OXIBLUME+Q10 is combined with Finasteride+Dutasteride, the effect increases; this might confirm that OXIBLUME+Q10 may act like a second administration of Finasteride.

[0367] The same results are confirmed by the data regarding AR and serotonin: OXIBLUME+Q10 analogous to Finasteride, since it better reduces AR activity and increases serotonin levels if administered with Dutasteride alone and with Finasteride+Dutasteride.

[0368] Example 4 Conclusions Based on the results obtained it may be affirmed that OXIBLUME+Q10 combined with Finasteride, Dutasteride, CIALIS or Finasteride+Dutasteride: ensures gut wellbeing, as it maintains the integrity of the monolayer of intestinal cells, demonstrating the safety of its use; - can reduce the inflammatory response typical of BPH in a more effective manner than the drugs administered individually and than OXIBLUME+Q10, by modulating the activity of 5 o-reductase and by reducing the production of DHT.

[0369] The results obtained have drawn attention to the ability of OXIBLUME+Q10 to be compatible with the drugs most commonly used in the treatment of this type of disease; specifically, if combined with Finasteride, Dutasteride or Tadur it promotes and amplifies the effect of the drugs themselves.

[0370] Furthermore, the data would suggest a behaviour of OXIBLUME+Q10 similar to that of Finasteride; therefore, it could be non-competitive analogue of Finasteride.

Claims

AMENDED CLAIMS received by the International Bureau on 13 May 2025 (13.05.2025)1. A mixture comprising or, alternatively, consisting of I) an extract of Gastrodia elata and iia) a coenzyme Q10, wherein said mixture is for use in a method of treatment, preventive and / or curative, of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation and / or other functional disorders affecting the urinary tract, bladder, testicles and prostate.

2. The mixture for use according to claim 1 , wherein said extract of Gastrodia elata is preferably an extract of Gastrodia elata Blume,' preferably, said extract of Gastrodia elata Blume comprises or consists of gastrodin.

3. The mixture for use according to claim 1 or 2, wherein said mixture further comprises lib) at least one plant extract or preparation selected from the group G comprising or, alternatively, consisting of:- Agathosma betulina (P.J. Bergius) Pillans folium,- Cucurbita maxima Duch. semen, oleum,- Cucurbita pepo L. var. styriaca Greb. semen, oleum,- Epilobium angustifolium L herba,- Epilobium parviflorum Schreb. Herba,- Eryngium aguaticum L. radix,- Hydrangea arborescens L. rhizoma,- Opuntia ficus- indica (L.) Mill. Cladodium,- Populus alba L. cortex, folium, gemma,- Populus balsamifera L. cortex, folium, gemma,- Populus nigra L. cortex, folium, gemma,- Populus tremuloides Michx. cortex, folium, gemma,- Pyrus communis L. folium,- Seguoiadendron giganteum (Lindl.) J. Buchholz gemma,- Serenoa repens (W. Bartram) Small fructus,- Solanum lycopersicum L. fructus,- Urtica dioica L. folium, summitas,- Urtica urens L. folium, or- Zea mays L. stigmata.

4. The mixture for use according to any one of claims 1-3, wherein said mixture comprises or, alternatively, consists of I) an extract of Gastrodia elata, iia) a coenzyme Q10 and lib) at least one plant extract or preparation selected from the group G comprising or, alternatively, consisting of: Serenoa repens, Epilobium angustifolium L. herba, Epilobium parviflorum Schreb. Herba and / or mixtures thereof.

5. The mixture for use according to any one of claims 1-4, wherein said mixture comprises or, alternatively, consists of I) an extract of Gastrodia elata, iia) a coenzyme Q10 and lib) Epilobium parviflorum Schreb. Herba.

6. The mixture for use according to any one of claims 1-5, wherein said lib) Epilobium parviflorum Schreb. Herba is a plant extract or preparation comprising oenothein B.

7. The mixture for use according to any one of claims 1-6, wherein said mixture comprises or, alternatively, consists of I) an extract of Gastrodia elata, iia) a coenzyme Q10 and lib) a plant extract or preparation of Serenoa repens, and / or mixtures thereof.

8. The mixture for use according to any one of claims 1-7, wherein said mixture is for use in a method of treatment, preventive and / or curative, of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation due to BPH and / or other functional disorders affecting the urinary tract, bladder, testicles and prostate.

9. A composition comprising the mixture according to any one of claims 1-7, and at least one pharmaceutically acceptable excipient and / or vehicle, wherein said composition is for use in a method of treatment, preventive and / or curative, of prostate diseases and / or disorders, in particular benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, inflammation and / or other functional disorders affecting the urinary tract, bladder, testicles and prostate.

10. The composition for use according to claim 9, wherein said composition comprises from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of I) extract of Gastrodia elata] and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of iia) coenzyme Q10 and, optionally, together with one or more pharmaceutically acceptable excipients and / or vehicles.

11. The composition for use according to claim 9, wherein said composition comprises from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of I) extract of Gastrodia elata and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of iia) coenzyme Q10 and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of lib) at least one extract selected from Serenoa repens, Epilobium angustifolium L herba, Epilobium parviflorum Schreb. Herba and / or mixtures thereof and, optionally, together with one or more pharmaceutically acceptable excipients and / or vehicles.

12. The composition for use according to claim 9, wherein said composition comprises from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of I) extract of Gastrodia elata] and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of iia) coenzyme Q10 and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of lib) at least one extract of Serenoa repens and, optionally, together with one or more pharmaceutically acceptable excipients and / or vehicles.

13. The composition for use according to claim 9, wherein said composition comprises from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of I) extract of Gastrodia elata] and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of iia) coenzyme Q10 and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of lib) at least one extract of Epilobium parviflorum Schreb. Herba and, optionally, together with one or more pharmaceutically acceptable excipients and / or vehicles.

14. The composition for use according to claim 9, wherein said composition comprises from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of I) extract of Gastrodia elata; and from 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of iia) coenzyme Q10 andfrom 10 to 500 mg, preferably from 50 to 300 mg, even more preferably from 100 to 200 mg of lib) at least one extract of Epilobium parviflorum Schreb. Herba and Serenoa Repens and, optionally, together with one or more pharmaceutically acceptable excipients and / or vehicles.

15. The composition for use according to any one of claims 9-14, wherein said composition is for oral use, preferably in the form of a capsule, a tablet, a sachet, a stick, an orodispersible stick, a gel for oral use or granules.

16. The composition for use according to any one of claims 9-15, wherein said composition is administered in the form of 1 tablet or 1 sachet, for example, weighing 100 mg, or 200 mg, or 500 mg, preferably 1 to 3 times a day depending on need and the subject in need thereof.

17. The composition for use according to any one of claims 9-16, wherein said composition is for use in a method of treatment, preventive and / or curative, of benign prostatic hyperplasia (BPH), LUTS (lower urinary tract symptoms) due to BPH, and inflammation due to BPH.

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