WO2021136784A1

WO2021136784A1 - A composition for the treatment of male infertility

Info

Publication number: WO2021136784A1
Application number: PCT/EP2020/087987
Authority: WO
Inventors: Mónica Maria LABELLA LORITE; Jordi GONZÁLEZ PLÁGARO; Carlos Nieto Abad
Original assignee: Laboratorio Reig Jofré, S.A.
Priority date: 2019-12-30
Filing date: 2020-12-29
Publication date: 2021-07-08
Also published as: EP4084782A1

Abstract

The present invention relates to a composition comprising: a) an effective amount of an appropriate acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; b) an effective amount of Ginkgo Biloba extract; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines. It also relates to a process for its preparation and its use in the treatment of male infertility.

Description

A composition for the treatment of male infertility

This application claims the benefit of European Patent Application EP19383214.4 filed December 30th, 2019. The present invention relates to the field of male infertility. Particularly to a composition substantially free of calcium ion, manganese and xanthines, which comprises cyclodextrin complex of curcumin and Ginkgo Biloba extract. It also relates to a process for its preparation and its use in the treatment of male infertility.

Background Art

Infertility is defined as the absence of conception after 1 year of regular and unprotected sexual intercourse. There is a prevalence of about 15% of couples in reproductive age, which suffer from infertility. Its aetiology is divided equally between the male and female factor, being 20% to 30% only male and around 15% of idiopathic origin. More of the research has been focused on the male infertility diagnosis and treatment. Particularly, research on useful infertility biomarkers to aid in male infertility diagnosis, treatment, and counselling has been a topic of high interest in clinical practice. In this sense, the traditional microscopic analysis of the semen, which measures the concentration, motility and morphology of the sperm, does not allow to explain most infertility cases. In fact, it is well known in the state of the art that the maintenance of genomic integrity of spermatozoa is crucial for the treatment of male infertility. Particularly, the functional capacity of sperm depends not only on the ability to fertilize the oocytes but also on the capacity to transfer intact paternal genome. Sperm DNA integrity (i.e. genomic integrity) plays a vital role in embryogenesis since sperm DNA damage may lead to embryo pre- and post-implantation losses, early miscarriage and congenital malformations. In this respect, multiple studies have focused their research on analysing the effect of sperm DNA fragmentation (SDF) on male fertility. This DNA damage can be double-strand SDF (dsSDF) or single-strand SDF (ssSDF). Both SDF types have different origin and different effects on male fertility.

On one hand, single-strand SDF (ssSDF) is mainly produced by reactive oxygen species (ROS). It is known that ROS mediated sperm damage is the main cause of infertility pathologies in the 30-80% of infertile men. Actually, ssSDF has been associated to a reduced capacity of natural pregnancy. There are multiple endogenous and exogenous factors which contribute to ROS generation. In fact, reactive oxygen metabolites are necessary for common physiological processes such as sperm capacitation or apoptosis.

Notwithstanding, phenomena, such as leucocytospermia or dysfunctions in sperm mitochondria, can disrupt the balanced redox state equilibrium leading to oxidative stress (OS). Therefore, multiple antioxidants have been described and many of them have proven beneficial effects on fertility since antioxidants are substances that delay or inhibit cellular oxidation. Particularly, antioxidants can be non-enzymatic antioxidants with radical scavenging capacity, or enzymatic antioxidants capable of modifying the expression of the genes coding for the antioxidant enzymes. However, unfortunately, the use of antioxidants does not seem to have any beneficial effect for reducing or avoiding the double-stranded sperm DNA fragmentation.

On the other hand, double-stranded DNA fragmentation (dsSDF) are naturally produced and naturally repaired during meiosis process. The presence of not repaired dssDF is associated to repeated miscarriages during the first trimester of pregnancy in couples with unknown female factor. Unlike ssSDF that results in a loss of motility and fertilization capacity of sperm cells, the effects of dsSDF do not manifest until the zygote is formed or later. In fact, double-stranded SDF causes a delay in embryo development and impaired implantation, while single-stranded DNA damage does not significantly affect embryo kinetics and implantation. Thus, dsSDF is the most deleterious alteration that may occur in a zygote, since maternal and paternal pronuclei are kept, hence, no complementary chain would be available for DNA repair.

Spermatogenesis is a complex and highly ordered process that implies both meiosis and cell differentiation. During prophase I stage of meiosis, programmed DNA double-strand breaks (DSBs) take place at many places across the genome to enable DNA recombination of homologous chromosomes. The repair of these DSBs through homologous recombination creates a physical link between the homologous chromosomes essential for proper chromosomal segregation later in meiosis, which guarantees the production of healthy gametes with new combinations of parental alleles. These programmed DSBs are driven by Spo11 protein. The activity of Spo11 is controlled by multiple regulatory factors, so that the number of DSBs is restricted and DSBs are formed in different locations throughout the genome and at the right time. These programmed DSBs induce DNA repair machinery activation, being ATM protein kinase the cornerstone of this process.

After DSB induction, there is a spatial redistribution of ATM and a fraction of nuclear ATM shuttles to the DSBs it and gets positioned on the damaged sites to be then repaired by homologous recombination. DSBs activate this sensor kinase that in turn phosphorylate several downstream substrates to trigger checkpoint signalling and promote DSB repair. This mechanism is also activated in response to DNA damage which and depending on the extent results in cell-cycle checkpoint initiation and/or apoptosis. ATM also acquires a critical role in restraining the formation of further DSBs by Spo11. Loss of this control can affect genome integrity or cause meiotic arrest. In fact, ATM impairment has been associated with predisposition to chromosomal abnormalities and cancer. It has been described that ATM-based signalling, repair and/or apoptosis systems can be modulated by phytochemicals with competence to trigger ATM activation or inactivation.

Therefore, compounds that stimulate the ATM can be potential candidates for reducing the double-strand DNA breaks (DSBs)a and subsequent dsSDF. On the contrary, in this sense, it is known in the state of the art that some compounds that can caused some double-strand breaks to not be repair are calcium ion, manganese and xanthines such as caffeine. Particularly, caffeine (also called theine when this substance comes from tea-plants) is a well-known example among ATM inhibitors and not only inhibits ATM kinase but also alters homologous recombination. Therefore, caffeine may cause some double-strand breaks to not be repaired, which may cause mature sperm to present dsSDF.

Prevention of oxidative stress and DSB formation through the administration of an oral dietary supplements composed by antioxidants and ATM activators have been disclosed in the state of the art. Particularly,

Androferti is a dietary supplement commercially available by Q Pharma laboratories indicated to promote male fertility and improve sperm quality (such as the number, concentration, motility and speed of spermatozoa). However, at the hands of the inventors, it is demonstrated that Androferti only improve sperm quality in men having an abnormal seminogram, but not in men having normal seminogram. In fact, with men that had normal seminogram, a significantly decreased of the sperm quality was observed (even though these seminogram can still be considered normal) (of. section 2.3. of the experimental data).

Therefore, from what is known in the art, it is derived that there is still the need of providing an efficient composition for the treatment of male infertility.

Summary of Invention

Inventors have found that the composition of the invention containing cyclodextrin complex of curcumin and Ginkgo Bilola extract and being substantially free of calcium ion, manganese and xanthines is useful for the treatment of male infertility. Particularly, the inventors have surprisingly found that the composition of the invention allows reducing significantly the single-chain sperm DNA fragmentation (ssSDF) and the double chain sperm DNA fragmentation (dsSDF); and improving all the most important semen parameters (i.e. the volume of the ejaculate; the sperm concentration; the sperm cells total number; and the progressive motility of the sperm cells). It is remarkable that the seminal parameters were increased even in men having a normal semen parameters at the beginning of the study. As it is demonstrated in the experimental section, the compositions of the present invention showed a significant reduction of double-strand sperm DNA fragmentation between 19 to 27%; and a reduction of single-strand sperm DNA fragmentation between 7 and 20%. Furthermore, the seminal parameters were significantly increased with the use of the composition of the present invention. Particularly, the spermatozoa concentration showed a significant increase from 48 M/mL to 74 M/mL; and also, a significant improvement in their progressive motility from 37% to 45%.

In comparison, Androferti showed a lower percentage of reduction of single-strand sperm DNA fragmentation about 8% and a 16% of reduction of the double-strand sperm DNA fragmentation. Meanwhile, the seminal parameters were significantly decreased in terms of ejaculate volume, concentration of sperm cells, total number of sperm cells and progressive motility. Particularly, the spermatozoa concentration showed a significant reduction from 51 to 44%; and also, a significant decrease in their progressive motility from 36% to 31%. It means that, men having a normal seminogram, the administration of Androferti could allow reducing the percentage of miscarriages (due to the reduction of the sperm fragmentation) but could unwillingly reducing the percentage of pregnancy, due to the reduction of semen volume, spermatozoa total amount and their motility.

Without being bound to any theory, it seems that the combination of the curcumin, curcuminoids, or Curcuma Longa extract in form of cyclodextrin complex, in combination with the Ginkgo Biloba extract allows having a better bioavailability of the active ingredients due to their enhanced absorption; allowing the appropriate effective amount of active ingredients for being useful for the treatment of male infertility.

Therefore, the compositions of the present invention are advantageous because allows reducing both the double- and single strand DNA fragmentation allowing a reduction of the miscarriages and also enhancing significantly the semen parameters allowing also an increase in the percentage of pregnancy, and finally in an increase of the percentage of baby born without the need of assisted reproduction techniques.

Thus, the first aspect of the invention relates to a composition comprising: a) an effective amount of an appropriate acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; b) an effective amount of Ginkgo Biloba extract; and one or more appropriate acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines; and the complex is a pharmaceutically acceptable cyclodextrin complex. In particular, the present invention relates to a pharmaceutical composition comprising: a) a therapeutically effective amount of a pharmaceutically acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; b) a therapeutically effective amount of Ginkgo Biloba extract; and one or more pharmaceutically acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines and the complex is a pharmaceutically acceptable cyclodextrin complex; or alternatively, a dietary supplement comprising: a) an effective amount of an edible acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; b) an effective amount of Ginkgo Biloba extract; and one or more edible acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines and the complex is an edible acceptable cyclodextrin complex. The second aspect of the invention refers to the composition of the first aspect of the invention for use in the treatment of male infertility.

Finally, it is also part of the invention a process for the preparation of the composition of the first aspect of the invention. Detailed description of the invention All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.

For purposes of the present invention, any ranges given include both the lower and the upper endpoints of the range. Ranges given, such as temperatures, times, and the like, should be considered approximate, unless specifically stated.

The terms "percentage (%) by weight” or "% by weight” are used interchangeably and they refer to the percentage of each ingredient of the composition in relation to the total weight of the composition of the invention.

As mentioned above, the first aspect of the invention refers to a composition comprising: a) an effective amount of an appropriate acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; b) an effective amount of Ginkgo Biloba extract; and one or more appropriate acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines; and the complex is a pharmaceutically acceptable cyclodextrin complex.

For the purpose of the present invention, the term "effective amount" refers to the amount of each one of the components of the composition of the present invention which provides a beneficial effect after its application; particularly a beneficial effect for the male infertility.

In an embodiment, the composition of the invention is a pharmaceutical composition comprising: (a) a therapeutically effective amount of a pharmaceutically acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; b) a therapeutically effective amount of Ginkgo Biloba extract; and one or more pharmaceutically acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines and the complex is a pharmaceutically acceptable cyclodextrin complex.

In terms of the present invention, "pharmaceutical composition" refers to any composition of the invention that is intended for use in the treatment of a disease or condition. The pharmaceutical compositions according to the present invention are therefore referring in particular to the treatment of male infertility.

The expression "therapeutically effective amount" as used herein, refers to the amount of active ingredients that, when administered, which is enough to prevent development of, or alleviate to some extent, male treatment. The particular dose of the active ingredients administered according to this invention will of course be determined by the skilled in the art regarding the particular circumstances surrounding the case, including the particular condition being treated, and the similar considerations.

The term "pharmaceutically acceptable" refers to the complexes, excipients and carriers appropriate for use in pharmaceutical technology for the preparation of compositions for medical use. Particularly, the term "pharmaceutically acceptable salt" encompasses any salt formed from pharmaceutically acceptable non-toxic acids including inorganic or organic acids. There is no limitation regarding the salts, except that as they are used for therapeutic purposes, they must be pharmaceutically acceptable.

In an embodiment, the composition of the invention is a dietary supplement comprising: a) an effective amount of an edible acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; b) an effective amount of Ginkgo Biloba extract; and one or more edible acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines; and the complex is an edible acceptable cyclodextrin complex.

In terms of the present invention, the terms "dietary supplement”, "food supplement” or "nutritional supplement” as used herein interchangeably refer to a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantity in a person's diet.

The term "edible” refers to compounds, compositions, complexes, salts, esters, excipients and carriers that may be consumed by humans without significant deleterious health consequences, it means that is suitable for consumption. The particular dose of the active ingredients administered according to this invention will of course be determined by the skilled in the art regarding the particular circumstances surrounding the case. The term "edible acceptable ester” used herein encompasses an ester formed from edible acceptable non toxic acids including inorganic or organic acids. The term "edible acceptable excipients or carriers” refers to excipients or carriers suitable for use in the preparation of compositions which can be consumed by humans without significant deleterious health consequences. The term "edible acceptable salt" encompasses any salt formed from edible acceptable non-toxic acids including inorganic or organic acids. There is no limitation regarding the salts, except that as they are appropriate for human consumption.

The term "extract” refers to the conventional sense to concentrated preparations of plants or trees of the genus curcuma and Ginkgo and Black Pepper by removing the active constituents from the plant or tree with suitable means. Such actives constituents can be obtained from various parts of plants or trees like for example leaves, root, seed, rhizome, stem or germinated among others. Suitable means for removal of the active ingredients include, for example, use of organic solvents, microwave or supercritical fluids extraction. Active ingredients are sometimes directly incorporated in pharmaceutical compositions or dietary supplement in a variety of forms, including a pure or semi-pure component, a solid or liquid extract, a dry or wet form. Plants or tree extracts contain not only one but multiple constituents, many of them active. Often, the beneficial effect is derived from the combination of many of these active compounds, even though in some cases there is one particular compound that is mainly responsible for most of the activity.

The compositions of the present invention are substantially free of calcium ion, manganese and xanthines.

The term, "substantially free” refer to compositions, particularly pharmaceutical compositions or dietary supplement comprising such amount of calcium ion, manganese and xanthines which does not cause sperm DNA fragmentation. For the purpose of the invention, the term "substantially free” refers to a composition comprises less than 1 gram of calcium ion per unit dose, less than 1 mg of manganese and less than 30 mg of xanthines per unit dose (composition). In an embodiment, the composition of the invention is free of calcium ion, manganese and xanthines. The term "free of” refers to a composition whose content of ion calcium, manganese and xanthines is not detectable by any of the commonly used techniques defined in the state of the art. For the purpose of the invention, the method for determining the content of ion calcium, manganese and xanthines is well known in the state of the art. For the purpose of the invention, any method known in the state of the art for determining calcium ion, manganese and xanthines in a composition is appropriate for the present invention. In an embodiment, the composition of the invention is "substantially free” or "free” of methylated xanthines.

The term "xanthine” is the non-proprietary name of the purine base 3,7-dihydropurine-2,6-dione having the CAS number 69-89-6. For the purpose of the invention the term "xanthines” refers to those compounds containing the base-xanthine structure. The term "methylated xanthines” refers to a compound derivative of xanthine (i.e. 3,7-dihydropurine-2,6-dione) which includes one or more methyl groups. Examples of "methylated xanthines” are, but not limited to, 1,3,7-trimethylxanthine (caffeine, also known as theine), 1,3- dimethyl-7H-purine-2,6-dione, ethane-1, 2-diamine (aminophylline), 3-isobutyl-1 -methylxanthine (IBMX), 1,7- dimethyl-3H-purine-2,6-dione (paraxanthine), 3,7-dimethyl-1 -(5-oxohexyl)-3,7-dihydro-1 H-purine-2,6-dione (pentoxifylline), 3,7-dimethyl-1 H-purine-2,6-dione (theobromine) and 1 ,3-dimethyl-7H-purine-2,6-dione (theophylline). In an embodiment, the composition of the invention is "substantially free” or "free” of methylated xanthines selected from the group consisting of 1,3,7-trimethylxanthine (caffeine, also known as theine) and 3,7-dimethyl-1 H-purine-2,6-dione (theobromine).

As mentioned above, the composition of the invention comprises (a) an effective amount of an appropriate acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract . In an embodiment, the composition of the invention comprises (a) a therapeutically effective amount of a pharmaceutically acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; or alternatively the composition of the invention comprises (a) an effective amount of an edible acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract.

In an embodiment, the composition comprises from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract. In an embodiment, the composition comprises from 0.2 to 20 % by weight of a pharmaceutically or edible acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; . In an embodiment, the composition comprises from 0.5 to 20 % by weight of an appropriate acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract.

In an embodiment, the compositions of the present invention comprise an effective amount of "curcumin” as defined above. The term "curcumin” is the non-proprietary name of (1£,6£)-1,7-Bis(4-hydroxy-3- methoxyphenyl)hepta-1,6-diene-3,5-dione having the CAS number 458-37-7 of formula

For the purpose of the present invention the term "curcumin” refers to isolated curcumin. Isolated curcumin can be natural or semi- or totally-synthetically prepared. In any case, isolated curcumin is a curcumin having a chemical purity from 80 to 100% by weight. The measurement of the purity of the curcumin can be performed using the methods commonly used and disclosed in the state of the art. Particularly, for the purpose of the invention the measurement of the purity of the curcumin is performed by High-performance liquid chromatography (HPLC). The curcumin is commercially available or can be prepared following any of the processes disclosed in the state of the art.

In an embodiment, the composition of the invention comprises effective amount of "curcuminoids” as defined above. In an embodiment, the composition of the invention comprises a therapeutically effective amount of "curcuminoids”. The term "curcuminoids” is of common general knowledge. In particular, it refers to a mixture comprising curcumin, demethoxycurcumin and bisdemethoxyurcumin. In an embodiment, the composition comprises an effective amount of curcuminoids comprising from 10 to 100 % by weight of curcumin. The mixture of curcuminoids appropriate for the present invention is commercially available or can be prepared following any of the processes disclosed in the state of the art.

In an embodiment, the composition of the invention comprises effective amount of Curcuma Longa extract. In an embodiment, the composition of the invention comprises a therapeutically effective amount of Curcuma Longa extract. The terms “Curcuma Longa extract” and "turmeric extract” have the same meaning and they are used interchangeable. For the purpose of the invention, the extract of Curcuma Longa (I NCI name Curcuma Longa Root Extract, CAS number 84775-520) refers to the extract of rhizomes of Turmeric

(Curcuma longa L, Zingiberaceae) that is mainly composed of curcuminoids and particularly of curcumin. The extract of Curcuma Longa root comprises from 5 to 95 % by weight of curcuminoids. This extract is a dry extract. The process for its preparation are well known in the state of the art. For the purpose of the invention any of the processes disclosed in the state of the art are appropriate for the preparation of the Curcuma Longa extract of the present invention. Besides, Curcuma Longa extracts appropriate for the present invention are also commercially available.

The composition of the invention comprises effective amount of an appropriate acceptable complex selected from curcumin complex, curcuminoids complex or a Curcuma Longa extract complex.

In an embodiment, the composition of the invention comprises a therapeutically effective amount of a pharmaceutically acceptable complex selected from curcumin complex, curcuminoids complex or a Curcuma Longa extract complex. In an embodiment, the composition of the invention comprises an effective amount of an edible acceptable complex selected from curcumin complex, curcuminoids complex or a Curcuma Longa extract complex. In an embodiment, the composition of the invention comprises an effective amount of curcumin complex; particularly a therapeutically effective amount of curcumin complex. In an embodiment, the composition of the invention comprises an effective amount of curcuminoids complex; particularly a therapeutically effective amount of curcuminoids complex. In an embodiment, the composition of the invention comprises an effective amount of Curcuma Longa extract complex; particularly a therapeutically effective amount of Curcuma Longa extract complex. The composition of the invention comprises a therapeutically effective amount of a complex selected from curcumin complex, curcuminoids complex or a Curcuma Longa extract complex, wherein the complex is a pharmaceutically acceptable cyclodextrin complex. In an embodiment, the composition of the invention comprises an effective amount of a complex selected from curcumin complex, curcuminoids complex or a Curcuma Longa extract complex, wherein the complex is an edible acceptable cyclodextrin complex.

In an embodiment, the composition of the invention comprises an effective amount of a complex selected from curcumin complex, curcuminoids complex or a Curcuma Longa extract complex wherein the complex is selected form (alpha)-cyclodextrin, (beta)-cyclodextrin and (gamma)-cyclodextrin; particularly a therapeutically effective amount. In an embodiment, the composition of the invention comprises a therapeutically effective amount of a complex selected from curcumin complex, curcuminoids complex or a Curcuma Longa extract complex wherein the complex is a pharmaceutically acceptable gamma cyclodextrin complex. In an embodiment, the composition of the invention comprises an effective amount of a complex selected from curcumin complex, curcuminoids complex or a Curcuma Longa extract complex wherein the complex is an edible acceptable gamma cyclodextrin complex.

As used herein, the term "complex” refers to a combination of an active compound (i.e. curcumin, curcuminoids or Curcuma Longa extract) and an additional molecular specie that forms or produces a new chemical specie in a solid form. The term "cyclodextrin complex” refers to a structure in which one or more cyclodextrin molecules (the "host”) form a cavity within which one or more molecules of a second compound (the "guest”) are located. For the purpose of the invention, the host is the cyclodextrin and the guest is the curcumin, the curcuminoid or the Curcuma Longa extract. "Cyclodextrins” are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by a-1,4 glycosidic bonds. Cyclodextrins are produced from starch by enzymatic conversion. Cyclodextrins are composed of 5 or more a-D-glucopyranoside units linked 1->4, as in amylose (a fragment of starch). The largest cyclodextrin contains 32 1,4-anhydroglucopyranoside units, while as a poorly characterized mixture, at least 150-membered cyclic oligosaccharides are also known. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape. Particularly the (alpha)-cyclodextrin contains 6 glucose subunits, the (beta)-cyclodextrin contains 7 glucose subunits and the (gamma)-cyclodextrin contains 8 glucose subunits. Complexes of curcumin, curcuminoid or Curcuma Longa extract are commercially available such as cavacurmin supplied by Wacker Chemie AG, which comprises from 15 to 30% by weight of curcuminoids.

As it is mentioned above, the composition of the invention comprises (b) an effective amount of Ginkgo Biloba extract; particularly a therapeutically effective amount of Ginkgo Biloba extract. For the purpose of the invention, the extract of Ginkgo Biloba (I NCI name, CAS number 90045-36-6) refers to an extract of the leaf of maidenhair tree (also named Ginkgo Biloba, Ginkgoaceae) that is mainly composed of flavonoids, particularly flavonoids glycosides, specially Kaempferol and quercetin glycosides, with a content from 10 to 50 % by weight. This extract is a dry extract. The process for its preparation are well known in the state of the art. For the purpose of the invention any of the processes disclosed in the state of the art are appropriate for the preparation of the Ginkgo Biloba extract of the present invention. Besides, Ginkgo Biloba extract appropriate for the present invention are also commercially available. In an embodiment, the composition of the invention comprises from 0.1 to 10 % by weight of Ginkgo Biloba extract. In an embodiment, the composition of the invention comprises from 0.3 to 3 % by weight of Ginkgo Biloba extract.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract, and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.2 to 20 % by weight of pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above, particularly gamma cyclodextrin complex; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract, particularly from 0.2 to 20 % by weight; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.5 to 20 % by weight of pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above, particularly gamma cyclodextrin complex; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract, particularly from 0.2 to 20 % by weight; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention further comprises (c) an effective amount of Piper Nigrum extract. In an embodiment, the composition of the invention further comprises (c) a therapeutically effective amount of Piper Nigrum extract. For the purpose of the invention, the extract of Piper Nigrum (I NCI name,

CAS number 84929-41-9) refers to an extract of the seed of Black Pepper (also named Piper nigrum L, Piperaceae). This extract is a dry extract. The process for its preparation are well known in the state of the art. For the purpose of the invention any of the processes disclosed in the state of the art are appropriate for the preparation of the Piper Nigrum extract of the present invention. In an embodiment, the composition of the invention comprises from 0.01 to 1 % by weight of Piper Nigrum extract. In an embodiment, the composition of the invention comprises from 0.005 to 0.5 % by weight of Piper Nigrum extract.

Without being bound to any theory, it seems that the combination of the curcumin, curcuminoids, or Curcuma Longa extract in form of cyclodextrin complex, in combination with the Ginkgo Biloba extract and the Piper Nigrum extract allows having a better bioavailability of the active ingredients due to their enhanced absorption and reduced first- and second-pass metabolism; allowing the appropriate effective amount of the active ingredients for being useful for the treatment of male infertility.

In an embodiment, the composition of the invention comprises: a) an effective amount of an appropriate acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) an effective amount of Ginkgo Biloba extract; c) an effective amount of Piper Nigrum extract; and one or more appropriate acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above.

In an embodiment, the composition of the invention is a pharmaceutical composition comprising: a) a therapeutically effective amount of a pharmaceutically acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) a therapeutically effective amount of Ginkgo Biloba extract; c) a therapeutically effective amount of Piper Nigrum extract; and one or more pharmaceutically acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; or alternatively, the composition of the invention is a dietary supplement comprising: a) an effective amount of an edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) an effective amount of Ginkgo Biloba extract; c) an effective amount of Piper Nigrum extract; and one or more edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex, particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract; c) from 0.01 to 1 % by weight of Piper Nigrum extract; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight. In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of pharmaceutically or edible cyclodextrin acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above, particularly gamma cyclodextrin complex, particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention further comprises d) an effective amount of coenzyme Q10. In an embodiment, the composition of the invention further comprises d) a therapeutically effective amount of coenzyme Q10. For the purpose of the invention, the terms "coenzyme Q10”, "ubiquinone” and CoQ10” have the same meaning and are used interchangeable. They are non-proprietary name of 2-

In an embodiment, the composition of the invention comprises from 0.1 to 10 % by weight of coenzyme Q10. In an embodiment, the composition of the invention comprises from 0.5 to 5 % by weight of coenzyme Q10.

In an embodiment, the composition of the invention comprises: a) an effective amount of an appropriate acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) an effective amount of Ginkgo Biloba extract; c) an effective amount of Piper Nigrum extract; d) an effective amount of coenzyme Q10; and one or more appropriate acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above.

In an embodiment, the composition of the invention is a pharmaceutical composition comprising: a) a therapeutically effective amount of a pharmaceutically acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) a therapeutically effective amount of Ginkgo Biloba extract; c) a therapeutically effective amount of Piper Nigrum extract; d) a therapeutically effective amount of coenzyme Q10; and one or more pharmaceutically acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; or alternatively,

In an embodiment, the composition of the invention is a dietary composition comprising: a) an effective amount of an edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) an effective amount of Ginkgo Biloba extract; c) an effective amount of Piper Nigrum extract; d) an effective amount of coenzyme Q10; and one or more edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible cyclodextrin acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex, particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract; c) from 0.01 to 1 % by weight of Piper Nigrum extract; d) from 0.1 to 10 % by weight of coenzyme Q10; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex, particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention further comprises e) an effective amount of one or more vitamins or an appropriate acceptable salt thereof. In an embodiment, the composition of the invention further comprises e) a therapeutically effective amount of one or more vitamins or a pharmaceutically acceptable salt thereof. The term "vitamin” refers to an organic compound, which is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism.

In an embodiment, the composition of the invention comprises from 0.0005 to 15 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof. In an embodiment, the composition of the invention comprises from 0.8005 to 11.75 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof. In an embodiment, the composition of the invention comprises from 1 to 10 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof. In an embodiment, the composition of the invention comprises from 0.0005 to 11.75 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof selected from the group consisting of vitamin C, vitamin E and vitamin B9; particularly from 0.8005 to 11.75% by weight, more particularly from 1 to 10% by weight.

In an embodiment, the composition of the invention further comprises e) an effective amount of vitamin C or an appropriate acceptable salt thereof; particularly from 0.6 to 9.7 % by weight.

In an embodiment, the composition of the invention further comprises e) an effective amount of vitamin E or an appropriate acceptable salt thereof; particularly from 0.2 to 2 % by weight. In an embodiment, the composition of the invention further comprises e) an effective amount of vitamin B9 or an appropriate acceptable salt thereof; particularly from 0.005 to 0.05 % by weight. In an embodiment, the composition of the invention further comprises e) an effective amount of a mixture of vitamins or an appropriate acceptable salt thereof selected from a mixture of vitamin C and vitamin E, a mixture of vitamin C and vitamin B9, a mixture of vitamin E and vitamin B9, and a mixture of vitamin C, vitamin E and vitamin B9. In an embodiment, the composition of the invention further comprises e) an effective amount of a mixture of vitamin C, vitamin E and vitamin B9; particularly in an amount from 0.8005 to 11.75 %; more particularly from 1 to 10% by weight.

The terms "vitamin C" and "ascorbic acid" and "L-ascorbic acid” have the same meaning and are used interchangeable. Particularly, the chemical name for vitamin C is 2-oxo-L-threo-hexono-l,4-lactone-2,3-ene- diol. CAS numbers associated with ascorbic acid include CAS Numbers 50-81-7 (L-Form) and 62624-30-0. The chemical structure for stable vitamin C is:

The term "vitamin C” also encompasses a derivative thereof. The term "derivative" refers to a chemically modified compound that still retains the desired effects of the vitamin C prior to the chemical modification. Thus, derivatives of vitamin C appropriate for the present invention includes ascorbic acid polypeptide, ascorbyl dipalmitate, ascorbyl methylsilanol pectinate, ascorbyl palmitate, ascorbyl stearate, sodium ascorbyl palmitate, disodium ascorbyl sulfate, esters of ascorbic acid, magnesium ascorbate, magnesium ascorbyl phosphate, methylsilanol ascorbate, potassium ascorbyl tocopheryl phosphate, calcium ascorbate, sodium ascorbate, ascorbyl glucoside or ascorbyl tocopheryl maleate; particularly calcium ascorbate. Furthermore, for the purpose of the present invention, the term "derivative thereof also includes the addition or removal of (Cr C₆)al kyl alkanes such as methyl, ethyl, propyl, or substituted (CrCe) alkanes such as hydroxymethyl or amino methyl groups; carboxyl groups and carbonyl groups; hydroxyls; nitro, amino, amide, and azo groups; sulfate, sulfonate, sulfone, sulfhydryl, sulfonyl, sulfoxide, phosphate, phosphonic, phosphoryl groups, and halide substituents. Additional modifications can include an addition or a deletion of one or more atoms of the atomic framework, for example, substitution of an ethyl by a propyl; substitution of a phenyl by a larger or smaller aromatic group. Alternatively, in a cyclic or bicyclic structure, hetero atoms such as N, S, or 0 can be substituted into the structure instead of a carbon atom. In an embodiment, the composition further comprises (c) an effective amount of calcium ascorbate; particularly from 0.6 to 9.7 % by weight.

The term "Vitamin E” encompasses a group of eight compounds, including a, b, y, and d tocopherols and a, b, y, and d tocotrienols. Each compound contains a hydroxyl-containing chromanol ring with a varying number and position of methyl groups between the a, b, y, and d forms. The four tocotrienols (alpha, beta, gamma, delta) are similar in structure to the four tocopherols, with the main difference being that the former have hydrophobic side chains with three carbon-carbon double bonds, whereas the tocopherols have saturated side chains. For alpha(a)-tocotrienol each of the three "R" sites has a methyl group (CH3) attached. For beta®-tocotrienol: R1 = methyl group, R2 = FI, R3 = methyl group. For gamma(y)-tocotrienol: R1 = FI, R2 = methyl group, R3 = methyl group. For delta(b)-tocotrienol: R1 = FI, R2 = FI, R3 = methyl group. The general chemical structure of tocotrienols is as follows: The expression "vitamin E” encompasses all-rac-tocopherol, tocotrienols and derivatives thereof. Thus, derivatives of vitamin E appropriate for the present invention also includes water-dispersible derivatives such as tocopheryl acetate, tocopheryl succinate and tocopheryl phosphate. In an embodiment, the composition of the invention further comprises (c) an effective amount of tocopheryl acetate; particularly from 0.2 to 2 % by weight. The terms "vitamin B9” and "folic acid” have the same meaning and are used interchangeable. They refer to the non-proprietary name of (2S)-2-[[4-[(2-Amino-4-oxo-1H-pteridin-6- yl)methylamino]benzoyl]amino]pentanedioic acid having the CAS number 59-30-3 of formula:

In an embodiment, the composition of the invention further comprises (c) an effective amount of folic acid; particularly from 0.0005 to 0.05 % by weight.

In an embodiment, the composition of the invention comprises: a) an effective amount of an appropriate acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) an effective amount of Ginkgo Biloba extract; c) an effective amount of Piper Nigrum extract; d) an effective amount of coenzyme Q10; e) an effective amount of one or more vitamins or an appropriate acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; and one or more appropriate acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above.

In an embodiment, the composition of the invention is a pharmaceutical composition comprising: a) a therapeutically effective amount of a pharmaceutically acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) a therapeutically effective amount of Ginkgo Biloba extract; c) a therapeutically effective amount of Piper Nigrum extract; d) a therapeutically effective amount of coenzyme Q10; e) a therapeutically effective amount of one or more vitamins or a pharmaceutically acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; and one or more pharmaceutically acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; or alternatively the composition of the invention is an edible supplement comprising: a) an effective amount of an edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) an effective amount of Ginkgo Biloba extract; c) an effective amount of Piper Nigrum extract; d) an effective amount of coenzyme Q10; e) an effective amount of one or more vitamins or an edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; and one or more edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex, particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract; c) from 0.01 to 1 % by weight of Piper Nigrum extract; d) from 0.1 to 10 % by weight of coenzyme Q10; e) from 0.005 to 15 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.8005 to 11.75 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 1 to 10 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex, particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract; c) from 0.01 to 1 % by weight of Piper Nigrum extract; d) from 0.1 to 10 % by weight of coenzyme Q10; e) from 0.2 to 2 % by weight of vitamin E, particularly tocopheryl acetate; from 0.6 to 9.7 % by weight of vitamin C, particularly calcium ascorbate; and from 0.0005 to 0.05 % by weight of vitamin B9; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.2 to 2 % by weight of vitamin E, particularly tocopheryl acetate; from 0.6 to 9.7 % by weight of vitamin C, particularly calcium ascorbate; and from 0.0005 to 0.05 % by weight of vitamin B9; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention further comprises f) an effective amount of one or more minerals or an appropriate acceptable salt thereof. In an embodiment, the composition of the invention further comprises f) a therapeutically effective amount of one or more minerals or a pharmaceutically acceptable salt thereof. In an embodiment, the composition of the invention comprises from 0.1 to 10 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof. In an embodiment, the composition of the invention comprises from 0.2 to 5 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof. In an embodiment, the composition of the invention further comprises f) an effective amount of one or more minerals or an appropriate acceptable salt thereof selected from the group consisting of zinc and selenium; particularly in an amount from 0.2 to 5% by weight. In an embodiment, the composition of the invention further comprises f) an effective amount of zinc or an appropriate acceptable salt thereof; particularly from 0.1 to 2.5 % by weight. In an embodiment, the composition of the invention further comprises f) an effective amount of selenium or an appropriate acceptable salt thereof; particularly from 0.1 to 2.5 % by weight. In an embodiment, the composition of the invention further comprises f) an effective amount of an appropriate acceptable zinc salt. In an embodiment, the composition of the invention further comprises f) a therapeutically effective amount of a pharmaceutically acceptable zinc salt; particularly water-soluble zinc salts. Examples of appropriate zinc salts for the present invention include zinc acetate, zinc chloride, zinc gluconate, zinc lactate, zinc picolinate, zinc tartrate, zinc chloride, zinc sulfate, zinc acetate, zinc citrate, zinc ascorbate or zinc amino acid chelate (single or double chelates). In an embodiment, the composition of the invention further comprises f) an effective amount of zinc sulphate. In an embodiment, the composition of the invention further comprises f) from 0.1 to 2.5 % by weight of zinc sulphate.

In an embodiment, the composition of the invention further comprises f) an effective amount of an appropriate acceptable selenium salt. In an embodiment, the composition of the invention further comprises f) a therapeutically effective amount of a pharmaceutically acceptable selenium salt; particularly water-soluble selenium salts. Examples of appropriate selenium salts for the present invention include selenite salts and selenate salts such as alkali metal or alkali metal earth selenite or selenite. In an embodiment, the composition of the invention further comprises f) an effective amount of an appropriate acceptable selenium salt selected from the group consisting of potassium selenite, sodium selenite, sodium selenite and a mixture thereof; particularly sodium selenite. In an embodiment, the composition of the invention further comprises f) an effective amount of an appropriate acceptable selenium salt selected from the group consisting of potassium selenite, sodium selenite, sodium selenite and a mixture thereof; particularly sodium selenite. In an embodiment, the composition of the invention further comprises f) from 0.1 to 2.5 % by weight of sodium selenite.

In an embodiment, the composition comprises f) an effective amount of a mixture of an appropriate acceptable zinc salt and appropriate acceptable selenium salt; particularly zinc sulphate and sodium selenite; particularly from 0.2 to 5% by weight.

In an embodiment, the composition of the invention comprises: a) an effective amount of an appropriate acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) an effective amount of Ginkgo Biloba extract; c) an effective amount of Piper Nigrum extract; d) an effective amount of coenzyme Q10; e) an effective amount of one or more vitamins or an appropriate acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) an effective amount of one or more minerals or an appropriate acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; and one or more appropriate acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above.

In an embodiment, the composition of the invention is a pharmaceutical composition comprises: a) a therapeutically effective amount of a pharmaceutically acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) a therapeutically effective amount of Ginkgo Biloba extract; c) a therapeutically effective amount of Piper Nigrum extract; d) a therapeutically effective amount of coenzyme Q10; e) a therapeutically effective amount of one or more vitamins or a pharmaceutically acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) a therapeutically effective amount of one or more minerals or a pharmaceutically acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; and one or more pharmaceutically acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; or alternatively, the composition of the invention is a dietary supplement comprising: a) an effective amount of an edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) an effective amount of Ginkgo Biloba extract; c) an effective amount of Piper Nigrum extract; d) an effective amount of coenzyme Q10; e) an effective amount of one or more vitamins or an edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) an effective amount of one or more minerals or an edible acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; and one or more appropriate acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex, particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract; c) from 0.01 to 1 % by weight of Piper Nigrum extract; d) from 0.1 to 10 % by weight of coenzyme Q10; e) from 0.005 to 15 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) from 0.1 to 10 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.8005 to 11.75 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) from 0.2 to 5 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 1 to 10 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) from 0.2 to 5 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight. In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex, particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract; c) from 0.01 to 1 % by weight of Piper Nigrum extract; d) from 0.1 to 10 % by weight of coenzyme Q10; e) from 0.2 to 2 % by weight of vitamin E, particularly tocopheryl acetate; from 0.6 to 9.7 % by weight of vitamin C, particularly calcium ascorbate; and from 0.0005 to 0.05 % by weight of vitamin B9; f) from 0.1 to 2.5 % by weight of Zinc, particularly zinc sulphate; from 0.1 to 2.5 % by weight of Selenium, particularly sodium selenite; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.2 to 2 % by weight of vitamin E, particularly tocopheryl acetate; from 0.6 to 9.7 % by weight of vitamin C, particularly calcium ascorbate; and from 0.0005 to 0.05 % by weight of vitamin B9; f) from 0.1 to 2.5 % by weight of Zinc, particularly zinc sulphate; from 0.1 to 2.5 % by weight of Selenium, particularly sodium selenite; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight. In an embodiment, the composition of the invention further comprises g) an effective amount of one or more amino acids. In an embodiment, the composition of the invention further comprises g) a therapeutically effective amount of one or more amino acids. In an embodiment, the composition of the invention further comprises g) from 5 to 60 % by weight of one or more amino acids. In an embodiment, the composition of the invention further comprises g) from 10 to 60 % by weight of one or more amino acids. In an embodiment, the composition of the invention further comprises g) from 20 to 40 % by weight of one or more amino acids. In an embodiment, the composition of the invention further comprises g) an effective amount of one or more amino acids selected from the group consisting of L-carnitine and L-arginine; particularly in an amount from 5 to 60 % by weight; more particularly from 10 to 60 % by weight. In an embodiment, the composition of the invention further comprises g) from 20 to 40 % by weight of one or more amino acids selected from the group consisting of L-carnitine and L-arginine. In an embodiment, the composition of the invention further comprises g) an effective amount of a mixture of L-carnitine and L-arginine; particularly in an amount from 10 to 60 % by weight; more particularly from 20 to 60 % by weight. In an embodiment, the composition of the invention further comprises g) from 20 to 40 % by weight of a mixture of L-carnitine and L-arginine.

In an embodiment, the composition of the invention further comprises g) an effective amount of L-carnitine. In an embodiment, the composition of the invention further comprises g) an effective amount of L-arginine. In an embodiment, the composition of the invention further comprises g) an effective amount of a mixture L- carnitine and L-arginine.

In an embodiment, the composition of the invention further comprises g) a therapeutically effective amount of L-carnitine. In an embodiment, the composition of the invention further comprises g) a therapeutically effective amount of L-arginine. In an embodiment, the composition of the invention further comprises g) a therapeutically effective amount of a mixture L-carnitine and L-arginine.

The term "L-carnitine” is the non-proprietary of 3-hydroxy-4-W,W,W-trimethylaminobutyrate) having the CAS number 541-15-1 of formula

As used herein, the term "L-carnitine” also encompasses its salts and esters derivatives thereof. Examples of esters appropriate for the present invention include acetyl-L-carnitine, propionyl-L-carnitine and a mixture thereof. In an embodiment, the composition of the invention further comprises g) an effective amount of L- carnitine; particularly L-carnitine fumarate. In an embodiment, the composition of the invention further comprises g) from 5 to 30 % by weight of L-carnitine; particularly from 10 to 20% by weight. In an embodiment, the composition of the invention further comprises g) from 5 to 30 % by weight of L-carnitine fumarate; particularly from 10 to 20% by weight fumarate.

The term "L-arginine” is the non-proprietary name of (S)-2-amino-5-guanidinopentanoic acid having the CAS number 74-79-3 of formula

As used herein, the term "L-arginine” also encompasses its biochemical equivalents, precursors and its basic form, as well as its salts and esters derivatives thereof.

Examples of esters appropriate for the present invention include L-arginine ethyl ester, L-arginine methyl ester, and mixtures thereof. In an embodiment, the composition of the invention further comprises g) an effective amount of L-arginine; particularly of L-arginine hydrochloride. In an embodiment, the composition of the invention further comprises g) from 5 to 30 % by weight of L-arginine; particularly from 10 to 20% by weight of L-arginine. In an embodiment, the composition of the invention further comprises g) from 5 to 30 % by weight of L-arginine hydrochloride; particularly from 10 to 20% by weight of L-arginine hydrochloride.

The appropriate acceptable salts of L-carnitine and L-arginine refers to salts prepared from an appropriate acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.

Suitable non-toxic acids include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphor sulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluensulfonic, and the like. In an embodiment, the L-arginine is L-carnitine fumarate.

In an embodiment, the L-arginine is L-arginine hydrochloride.

In an embodiment, the composition of the invention further comprises g) an effective amount of a mixture of pharmaceutically acceptable salts of L-carnitine and L-arginine; particularly a mixture of L-carnitine fumarate and L-arginine hydrochloride. In an embodiment, the composition of the invention further comprises g) from 10 to 60 % by weight; more particularly from 20 to 60 % by weight of a mixture of L-carnitine fumarate and L- arginine hydrochloride. In an embodiment, the composition of the invention further comprises g) from 20 to 40 % by weight of a mixture of L-carnitine fumarate and L-arginine hydrochloride.

In an embodiment, the composition of the invention comprises: a) an effective amount of an appropriate acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) an effective amount of Ginkgo Biloba extract; c) an effective amount of Piper Nigrum extract; d) an effective amount of coenzyme Q10; e) an effective amount of one or more vitamins or an appropriate acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) an effective amount of one or more minerals or an appropriate acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; g) an effective amount of one or more amino acids; particularly selected from the group consisting of L- carnitine and L-arginine; and one or more appropriate acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above.

In an embodiment, the composition of the invention is a pharmaceutical composition comprising: a) a therapeutically effective amount of a pharmaceutically acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) a therapeutically effective amount of Ginkgo Biloba extract; c) a therapeutically effective amount of Piper Nigrum extract; d) a therapeutically effective amount of coenzyme Q10; e) a therapeutically effective amount of one or more vitamins or a pharmaceutically acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) a therapeutically effective amount of one or more minerals or a pharmaceutically acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; g) a therapeutically effective amount of one or more amino acids; particularly selected from the group consisting of L-carnitine and L-arginine; and one or more pharmaceutically acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; or alternatively, the composition of the invention is a dietary supplement comprising: a) an effective amount of an edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) an effective amount of Ginkgo Biloba extract; c) an effective amount of Piper Nigrum extract; d) an effective amount of coenzyme Q10; e) an effective amount of one or more vitamins or an edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) an effective amount of one or more minerals or an edible acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; g) an effective amount of one or more amino acids; particularly selected from the group consisting of L- carnitine and L-arginine; and one or more edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex, particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract; c) from 0.01 to 1 % by weight of Piper Nigrum extract; d) from 0.1 to 10 % by weight of coenzyme Q10; e) from 0.005 to 15 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) from 0.1 to 10 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; g) from 5 to 60 % by weight of one or more amino acids; particularly selected from the group consisting of L- carnitine and L-arginine; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.8005 to 11.75 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) from 0.2 to 5 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; g) from 10 to 60 % by weight of one or more amino acids; particularly selected from the group consisting of L- carnitine and L-arginine; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 1 to 10 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) from 0.2 to 5 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; g) from 20 to 40 % by weight of one or more amino acids; particularly selected from the group consisting of L- carnitine and L-arginine; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex, particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract; c) from 0.01 to 1 % by weight of Piper Nigrum extract; d) from 0.1 to 10 % by weight of coenzyme Q10; e) from 0.2 to 2 % by weight of vitamin E, particularly tocopheryl acetate; from 0.6 to 9.7 % by weight of vitamin C, particularly calcium ascorbate; and from 0.0005 to 0.05 % by weight of vitamin B9; f) from 0.1 to 2.5 % by weight of Zinc, particularly zinc sulphate; from 0.1 to 2.5 % by weight of Selenium, particularly sodium selenite; g) from 5 to 30 % by weight of L-carnitine; particularly L-carnitine fumarate; from 5 to 30 % by weight of L-arginine; particularly L-arginine hydrochloride; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.2 to 2 % by weight of vitamin E, particularly tocopheryl acetate; from 0.6 to 9.7 % by weight of vitamin C, particularly calcium ascorbate; and from 0.0005 to 0.05 % by weight of vitamin B9; f) from 0.1 to 2.5 % by weight of Zinc, particularly zinc sulphate; from 0.1 to 2.5 % by weight of Selenium, particularly sodium selenite; g) from 10 to 20 % by weight of L-carnitine; particularly L-carnitine fumarate; from 10 to 20 % by weight of L-arginine; particularly L-arginine hydrochloride; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention further comprises h) an effective amount of one or more sugars, carotenoids or mixtures thereof. In an embodiment, the composition of the invention further comprises h) a therapeutically effective amount of one or more sugars, carotenoids or mixtures thereof. In an embodiment, the composition of the invention further comprises h) an effective amount of one or more sugars, carotenoids or mixtures thereof from 0.5 to 70 % by weight. In an embodiment, the composition of the invention further comprises h) an effective amount of one or more sugars, carotenoids or mixtures thereof from 10.5 to 65 % by weight. In an embodiment, the composition of the invention further comprises h) an effective amount of one or more sugars, carotenoids or mixtures thereof from 20 to 40 % by weight.

In an embodiment, the composition of the invention further comprises h) an effective amount of one or more sugars, carotenoids or mixtures thereof selected from the group consisting of inositol, lycopene, isomaltulose and a mixture thereof. In an embodiment, the composition of the invention further comprises h) an effective amount of one or more sugars, carotenoids or mixtures thereof selected from the group consisting of inositol, lycopene, isomaltulose and a mixture thereof in an amount from 0.5 to 70 % by weight; Particularly from 10.5 to 65 % by weight; more particularly from 20 to 40 % by weight.

In an embodiment, the composition of the invention further comprises h) an effective amount of inositol; particularly from 5 to 30 % by weight of inositol. In an embodiment, the composition of the invention further comprises h) an effective amount of lycopene; particularly from 0.5 to 5 % by weight of lycopene. In an embodiment, the composition of the invention further comprises h) an effective amount of isomaltulose; particularly from 5 to 30 % by weight of isomaltulose. In an embodiment, the composition of the invention further comprises h) an effective amount of a mixture of inositol and lycopene; particularly in an amount from 5.5 to 35% by weight. In an embodiment, the composition of the invention further comprises h) an effective amount of a mixture of inositol and isomaltulose; particularly in an amount from 10 to 60% by weight. In an embodiment, the composition of the invention further comprises h) an effective amount of a mixture of inositol, lycopene and isomaltulose; particularly in an amount from 10.5 to 65%; more particularly from 20 to 40% by weight.

The term "inositol” is the non-proprietary name of the sugar cyclohexane-1,2,3,4,5, 6-hexol, which is a six-fold alcohol (polyol) of cyclohexane. "Inositol" according to the invention refers to any one of its possible stereoisomers, such as for example myo-, epi-, scyllo-, chiro-, muco-, alio-, or meso-inositol. The term "inositol” also encompasses its derivative thereof, wherein at least one of the hydroxyl functions has been modified or substituted. Examples of inositol derivatives are inositol phosphate, inositol sulphate or inositol methylate.

The terms "lycopene”, "leucopin" and "all-trans-lycopene" have the same meaning and are used interchangeable. As used herein, the term "lycopene" refers to the non-proprietary name of linear carotenoid (6£,8£,10£,12£,14£,16£,18£,20£,22£,24£,26£)- 2,6, 10, 14, 19,23,27,31 -Octamethyldotriaconta- 2,6,8, 10, 12, 14, 16, 18,20,22,24,26,30-tridecaene having the CAS number 502-65-8. The term "lycopene” also encompasses analogues and derivatives thereof.

The term "isomaltulose” is the non-proprietary name of the sugar 6-O-a-D-Glucopyranosyl-D-fructose having the CAS number 13718-94-0 of formula

The term "isomaltulose” also encompasses analogues and derivatives thereof. Examples of analogues and derivatives thereof. In particular, isomaltulose is commercially available for instance with the tradename Palatinose.

In an embodiment, the composition of the invention comprises: a) an effective amount of an appropriate acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) an effective amount of Ginkgo Biloba extract; c) an effective amount of Piper Nigrum extract; d) an effective amount of coenzyme Q10; e) an effective amount of one or more vitamins or an appropriate acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) an effective amount of one or more minerals or an appropriate acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; g) an effective amount of one or more amino acids; particularly selected from the group consisting of L- carnitine and L-arginine; h) an effective amount of one or more sugars, carotenoids or mixtures thereof, particularly a mixture of inositol, lycopene and isomaltulose; and one or more appropriate acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above.

In an embodiment, the composition of the invention is a pharmaceutical composition comprising: a) a therapeutically effective amount of a pharmaceutically acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) a therapeutically effective amount of Ginkgo Biloba extract; c) a therapeutically effective amount of Piper Nigrum extract; d) a therapeutically effective amount of coenzyme Q10; e) a therapeutically effective amount of one or more vitamins or a pharmaceutically acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) a therapeutically effective amount of one or more minerals or a pharmaceutically acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; g) a therapeutically effective amount of one or more amino acids; particularly selected from the group consisting of L-carnitine and L-arginine; h) a therapeutically effective amount of one or more sugars, carotenoids or mixtures thereof, particularly a mixture of inositol, lycopene and isomaltulose; and one or more pharmaceutically acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; or alternatively, the composition of the invention is a dietary supplement comprising: a) an effective amount of an edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex; b) an effective amount of Ginkgo Biloba extract; c) an effective amount of Piper Nigrum extract; d) an effective amount of coenzyme Q10; e) an effective amount of one or more vitamins or an edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) an effective amount of one or more minerals or an edible acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; g) an effective amount of one or more amino acids; particularly selected from the group consisting of L- carnitine and L-arginine; h) an effective amount of one or more sugars, carotenoids or mixtures thereof, particularly a mixture of inositol, lycopene and isomaltulose; and one or more edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex, particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract; c) from 0.01 to 1 % by weight of Piper Nigrum extract; d) from 0.1 to 10 % by weight of coenzyme Q10; e) from 0.005 to 15 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) from 0.1 to 10 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; g) from 5 to 60 % by weight of one or more amino acids; particularly selected from the group consisting of L- carnitine and L-arginine; h) from 0.5 to 70 % by weight of one or more sugars, carotenoids or mixtures thereof, particularly a mixture of inositol, lycopene and isomaltulose; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.8005 to 11.75 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) from 0.2 to 5 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; g) from 10 to 60 % by weight of one or more amino acids; particularly selected from the group consisting of L- carnitine and L-arginine; h) from 10.5 to 65 % by weight of one or more sugars, carotenoids or mixtures thereof, particularly a mixture of inositol, lycopene and isomaltulose; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 1 to 10 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) from 0.2 to 5 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof; particularly selected from the group consisting of zinc and selenium; g) from 20 to 40 % by weight of one or more amino acids; particularly selected from the group consisting of L- carnitine and L-arginine; h) from 10.5 to 65 % by weight of one or more sugars, carotenoids or mixtures thereof, particularly a mixture of inositol, lycopene and isomaltulose; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex, particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract; c) from 0.01 to 1 % by weight of Piper Nigrum extract; d) from 0.1 to 10 % by weight of coenzyme Q10; e) from 0.2 to 2 % by weight of vitamin E, particularly tocopheryl acetate; from 0.6 to 9.7 % by weight of vitamin C, particularly calcium ascorbate; and from 0.0005 to 0.05 % by weight of vitamin B9; f) from 0.1 to 2.5 % by weight of Zinc, particularly zinc sulphate; from 0.1 to 2.5 % by weight of Selenium, particularly sodium selenite; g) from 5 to 30 % by weight of L-carnitine; particularly L-carnitine fumarate; from 5 to 30 % by weight of L-arginine; particularly L-arginine hydrochloride; h) from 5 to 30 % by weight of inositol; from 0.5 to 5 % by weight of lycopene; from 5 to 30 % by weight of isomaltulose; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30 % by weight of a pharmaceutically or edible acceptable cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract as defined above; particularly gamma cyclodextrin complex particularly from 0.2 to 20% by weight; more particularly from 0.5 to 20% by weight; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.2 to 2 % by weight of vitamin E, particularly tocopheryl acetate; from 0.6 to 9.7 % by weight of vitamin C, particularly calcium ascorbate; and from 0.0005 to 0.05 % by weight of vitamin B9; f) from 0.1 to 2.5 % by weight of Zinc, particularly zinc sulphate; from 0.1 to 2.5 % by weight of Selenium, particularly sodium selenite; g) from 10 to 20 % by weight of L-carnitine; particularly L-carnitine fumarate; from 10 to 20 % by weight of L-arginine; particularly L-arginine hydrochloride; h) from 5 to 30 % by weight of inositol; from 0.5 to 5 % by weight of lycopene; from 5 to 30 % by weight of isomaltulose; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines as defined above; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.1 to 30% by weight of a pharmaceutically or edible cyclodextrin acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; particularly gamma cyclodextrin curcumin, curcuminoids or Curcuma Longa extract complex; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract; c) optionally, from 0.01 to 1 % by weight of Piper Nigrum extract; d) optionally, from 0.1 to 10 % by weight of coenzyme Q10; e) optionally, from 0.0005 to 15 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) optionally, from 0.1 to 10 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of Zinc and Selenium; g) optionally, from 5 to 60 % by weight of one or more of one or more amino acids, particularly a mixture of L- carnitine and L-arginine; h) optionally, from 0.5 to 70 % by weight of one or more sugars, carotenoids or mixtures thereof, particularly a mixture of inositol, lycopene and isomaltulose; one or more pharmaceutically or edible acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the invention comprises: a) from 0.2 to 20 % by weight of a cyclodextrin curcumin, curcuminoids or Curcuma Longa extract complex; particularly gamma cyclodextrin curcumin, curcuminoids or Curcuma Longa extract complex; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.8005 to 11.75 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) from 0.2 to 5 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of Zinc and Selenium; g) from 10 to 60 % by weight of one or more of one or more amino acids, particularly a mixture of L-carnitine and L-arginine; h) from 10.5 to 65 % by weight of one or more sugars, carotenoids or mixtures thereof, particularly a mixture of inositol, lycopene and isomaltulose; one or more pharmaceutically or edible acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthine, and the sum of the components is up to 100% by weight. In an embodiment, the composition of the invention comprises: a) from 0.5 to 20 % by weight of a cyclodextrin curcumin, curcuminoids or Curcuma Longa extract complex; particularly gamma cyclodextrin curcumin, curcuminoids or Curcuma Longa extract complex; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.2 to 2 % by weight of vitamin E, particularly acetate vitamin E; from 0.6 to 9.7 % by weight of vitamin C, particularly calcium ascorbate; and from 0.0005 to 0.05 % by weight of vitamin B9; f) from 0.1 to 2.5 % by weight of Zinc, particularly zinc sulphate; from 0.1 to 2.5 % by weight of Selenium, particularly sodium selenite; g) from 5 to 30 % by weight of L-carnitine, particularly L-carnitine fumarate; from 5 to 30 % by weight of L-arginine, particularly L-arginine hydrochloride; h) from 5 to 30 % by weight of inositol; from 0.5 to 5 % by weight of lycopene; from 5 to 30 % by weight of isomaltulose; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines; and the sum of the components is up to 100% by weight.

The composition of the present invention comprises one or more appropriate acceptable excipients or carriers. In an embodiment, the composition of the present invention comprises one or more pharmaceutically acceptable excipients or carriers. In an embodiment, the composition of the present invention comprises one or more edible acceptable excipients or carriers.

Example of appropriate excipients or carriers of the present invention include, but not limited to, glidant, binder, diluent, lubricant, taste modulator agent and flavouring agents.

"The term "glidant” refers to a substance which improves the flow characteristics of powder mixtures in the dry state. Materials commonly used as a glidant include magnesium stearate, colloidal silicon dioxide, cellulose, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, sodium stearate, starch, talc or a mixture thereof; particularly colloidal silicon dioxide. In an embodiment, the composition of the invention is one wherein the pharmaceutically or edible acceptable excipients or carriers comprises one or more glidant. In an embodiment, the composition of the invention is one wherein the pharmaceutically or edible acceptable excipients or carriers comprise one or more glidant; particularly colloidal silicon dioxide, in an amount from 1% to 20% by weight of the composition.

The terms "filler" and "diluent" have the same meaning and are used interchangeably. They refer to any pharmaceutically or edible acceptable excipient or carrier (material) that fill out the size of a composition, making it practical to produce and convenient for the consumer to use. Materials commonly used as filler include calcium carbonate, magnesium carbonate, calcium lactate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethyl cellulose, cellulose, cellulose products such as microcrystalline cellulose and its salts, dextrin and dextrin derivatives, dextrose, fructose, lactitol, lactose, starches or modified starches, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, mannitol, sorbitol, starch and starch derivatives, polydextrose, polyethylene glycol, sucrose, sugar, xylitol, inositol, isomalt, (cross)polyvinylpyrrolidone, erythritol, sucrose, sugar, trehalose and mixtures thereof. In an embodiment, the composition of the invention is one wherein the pharmaceutically or edible acceptable excipients or carriers comprises one or more filler selected from the group consisting of xylitol, mannitol, sorbitol, inositol, isomalt, maltitol, lactitol, lactose and povidone; particularly mannitol. In an embodiment, the composition of the invention is one wherein the pharmaceutically or edible acceptable excipients or carriers comprise one or more filler, preferably mannitol, in an amount from 1 to 30% by weight of the composition.

The term "lubricant" refers to a substance that prevents composition ingredients from clumping together and from sticking to the tablet punches or capsule filling machine and improves flowability of the composition mixture. Materials commonly used as a lubricant include sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, zinc stearate, stearic acid, sucrose stearate, talc, leucine, polyethylene glycol, glyceryl behenate, glyceryl monostearate, myristic acid, palmitic acid, poloxamer, potassium benzoate and mixtures thereof. The presence of a lubricant is particularly preferred when the composition is a tablet to improve the tableting process. The term "taste modulator agent" refers to any substance, compound or ingredient which is capable of modifying the taste and aroma perception of taste active ingredients or compounds, including sweeteners and flavouring agents. Materials commonly used as taste modulator agent include sucralose, acesulfame potassium, Neohesperidin, neotame, aspartame, cyclamic acid and cyclamic salts, saccharin and saccharin salts, tagatose, thaumatin, sucralose, citric acid, malic acid, tastegem, lemon flavour, orange flavour, among others. In an embodiment, the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprise one or more taste modulator agent, preferably sucralose, in an amount from 0.2 to 20% by weight of the composition.

In an embodiment, the composition of the present invention comprises; from 1 to 20 % by weight of glidants, particularly colloidal silicon dioxide; from 1 to 30 % by weight of diluent, particularly mannitol; optionally; from 0.2 to 20 % by weight of taste modulator agent, particularly sucralose; and the sum of the components is up to 100% by weight.

In an embodiment, the composition of the present invention comprises; from 1 to 20 % by weight of glidants, particularly colloidal silicon dioxide; from 1 to 30 % by weight of diluent, particularly mannitol; from 0.2 to 20 % by weight of taste modulator agent, particularly sucralose; and the sum of the components is up to 100% by weight.

It is also part of the invention, a process for the preparation of the compositions of the first aspect of the invention. The solid compositions of the present invention can be prepared according to methods well known in the state of the art. The method, experimental conditions, equipment as well as appropriate excipients and/or carriers (pharmaceutically or edible acceptable excipients or carriers), and their amounts, can readily be determined by those skilled in the art according to the type of formulation being prepared.

In an embodiment, the process for the preparation of the present invention comprises: i) mixing Ginkgo Biloba extract; one or more excipients of carriers (particularly glidants and diluents); optionally, vitamin E, one or more minerals, one or more taste modulator agent; and optionally a mixture comprising vitamin B9, Piper Nigrum extract, and one or more excipients (particularly glidant and diluent); and ii) mixing the mixture obtained in step i) with a mixture comprising a cyclodextrin complex of curcumin, curcuminoid, or Curcuma Longa extract, one or more excipients or carriers (particularly glidants and diluents); and optionally: vitamin C; one or more amino acids; one or more sugars, carotenoids or mixtures thereof; coenzyme Q10; and one or more taste modulator agent.

In an embodiment, the process for the preparation of the present invention comprises: mixing Ginkgo Biloba extract; a cyclodextrin complex of curcumin, curcuminoid, or Curcuma Longa extract; one or more excipients of carriers (particularly glidants and diluents); and optionally: vitamin C; one or more amino acids; one or more sugars, carotenoids or mixtures thereof; coenzyme Q10; and one or more taste modulator agent; vitamin E; one or more minerals; vitamin B9; Piper Nigrum extract; and one or more excipients (particularly glidant and diluent).

In an embodiment, the process for the preparation of the present invention comprises:

(i) mixing Ginkgo Biloba extract; a cyclodextrin complex of curcumin, curcuminoid, or Curcuma Longa extract ; one or more excipients of carriers (particularly glidants and diluents); and optionally: vitamin C; one or more amino acids; one or more sugars, carotenoids or mixtures thereof; coenzyme Q10; and one or more taste modulator agent,

(ii) mixing the mixture obtained in step i) with a mixture comprising one or more excipients (particularly glidant and diluent) and optionally vitamin E, one or more minerals, vitamin B9, Piper Nigrum extract, and one or more taste modulator agent.

As it is mentioned above, the second aspect of the invention relates to the use of the composition of the invention, the pharmaceutical compositions or the dietary supplement, as defined in the application in the treatment of male infertility. In an embodiment, the composition of the invention is useful for the treatment of male fertility caused by sperm double-stranded DNA fragmentation. In an embodiment, the composition of the invention is useful for the treatment of male infertility caused by sperm single-stranded DNA fragmentation. In an embodiment, the composition of the invention is useful for the treatment of male infertility caused by sperm double-stranded DNA fragmentation and sperm single-stranded DNA fragmentation. In an embodiment the composition of the invention is useful for the treatment of male infertility caused by abnormal sperm production or abnormal sperm function.

Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word "comprise” encompasses the case of "consisting of. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

Examples

Abbreviatures dsSDF: double-strand sperm DNA fragmentation ssSDF: single-strand sperm DNA fragmentation SDF: sperm DNA fragmentation 1. Composition

1.1. Compositions of the invention The components of compositions of the invention in form of sachets are shown in Table 1 , wherein the amounts of the components are expressed in weight percent. Particularly, the amount of each components of the compositions used to produce a batch of 5250 sachets containing 5g per sachet is disclosed below:

The compositions of the invention of Examples 1 and 2 as defined above were performed following the process disclosed above using the amounts of the ingredients specified in Table 1.

Preparation of the composition of Example 1 of the present invention:

Step 1. A mixture of vitamin B9, Piper Nigrum extract, colloidal silicon dioxide (0.75g), sucralose and mannitol (78.70g) were stirred and sifted through a stainless-steel sieve of 0.5mm of diameter. The resulting mixture was loaded in a stainless-steel mixer and stirred for 20 minutes until having a homogeneous mixture. Store the homogeneous mixture in a double plastic bag in an airtight container until it is used.

Step 2. Vitamin E, sodium selenite, zinc sulphate, citric acid, malic acid, colloidal silicon dioxide (10.00g), mannitol (1052.60g) and the mixture obtained in step 1 were stirred and sifted through a stainless-steel sieve of 0.5mm of diameter. The resulting mixture was loaded in a stainless-steel mixer and stirred for 20 minutes until having a homogeneous mixture. Store the homogeneous mixture in a double plastic bag in an airtight container until it is used.

Step 3. Calcium ascorbate, L-carnitine fumarate, L-arginine hydrochloride, inositol, lycopene, coenzyme Q10, cavacurmin, Ginkgo Biloba extract, isomaltulose, flavours, colloidal silicon dioxide (1564.25g), mannitol (639.95g) and the mixture obtained in step 2 were stirred and sifted through a stainless-steel sieve of 1.2 mm of diameter. The resulting mixture was loaded in Rulon type mixer and stirred for 45 minutes until having a homogeneous mixture. Store the homogeneous mixture in a double plastic bag in an airtight container until it is used.

Step 4. (Conditioning Step) The mixture obtained in step 3 was placed in sachets made of the complex OPP/Aluminium/PE of dimensions 65 x 90 mm with the automatic machine MESPACK. The sachets are dosed at a rate of 5 g per sachet (weight limits: 4.75 - 5.25 g); and the sachets were grouped in cardboard boxes.

Preparation of the composition of Example 2 of the present invention:

Step 2. Vitamin E, sodium selenite, zinc sulphate, Ginkgo Biloba extract, citric acid, malic acid, colloidal silicon dioxide (10.00g), mannitol (868.85g) and the mixture obtained in step 1 were stirred and sifted through a stainless-steel sieve of 0.5mm of diameter. The resulting mixture was loaded in a stainless-steel mixer and stirred for 20 minutes until having a homogeneous mixture. Store the homogeneous mixture in a double plastic bag in an airtight container until it is used. Step 3. Calcium ascorbate, L-carnitine fumarate, L-arginine hydrochloride, inositol, lycopene, coenzyme Q10, cavacurmin, isomaltulose, flavours, colloidal silicon dioxide (1564.25g), mannitol (2057g) and the mixture obtained in step 2 were stirred and sifted through a stainless-steel sieve of 1.2 mm of diameter. The resulting mixture was loaded in Rulon type mixer and stirred for 45 minutes until having a homogeneous mixture. Store the homogeneous mixture in a double plastic bag in an airtight container until it is used.

1.2. Comparative composition

As comparative composition falling outside the scope of the invention, the commercially available formulation Androferti was used. The qualitive composition available in the packaging of Androferti commercialized by Q Pharma laboratories is disclosed in Table 2.

Table 2

2. Fertility Study

2.1. Objectives of the study

-To evaluate the reduction in double-strand sperm DNA fragmentation values.

-To evaluate the reduction in single-strand sperm DNA fragmentation values.

-To evaluate variations in semen parameters.

2.2. Methodology

The fertility assay is a multicentric, prospective and randomized study.

Participants

A total of 80 patients was recruited between the four participants centres (26 patients for each treatment).

• Inclusion criteria: Infertile men having an altered double-strand sperm DNA fragmentation (>60%).

• Exclusion criteria: Normal double-strand sperm DNA fragmentation (<60%).

The main limitation of the study is that each recruitment centre cannot control if their patients are taking the treatment under the specifications. Nevertheless, some directed questions will be performed during the control analysis to detect if the intake is correct. In case of doubt, patients will be excluded from the study.

At the end of the study, two populations were established:

- ITT (I ntention-T o-T reat): Patients which have not performed the correct controls (T6 and T13), or which have not completed the treatment, or which has been excluded from the study because of adverse effects.

- PP (Per-Protocol): patients which completed the treatment and have all the diagnostic analysis.

Finally, patients which completed study were 71 patients and patients which withdrawn from the study were 9 patients.

Treatments

The patients were treated randomly by one of the oral treatments of the study for 13 weeks. The treatments were the following: i) Comparative composition Androferti (comparative treatment) twice daily (preferably morning/night with water after eating); ii) Composition Ex.1 of the present invention (Experimental treatment 1) once daily (preferably in the morning with water and after eating); and iii) Composition Ex.2 of the present invention (Experimental treatment 2) once daily (preferably in the morning with water and after eating). Samples analysis

During the study three sample analysis were performed:

- A first analysis of dsSDF, ssSDF and semen parameters was performed before starting the treatment (TO).

- A second analysis of dsSDF, ssSDF and semen parameters was performed six weeks after the treatment, initiation (T6). - A third analysis of dsSDF, ssSDF and semen parameters was performed 13 weeks after the treatment initiation (T13).

Methods

The measurement of the sperm DNA fragmentation was performed following the procedure reported by Casanovas et al. through the Comet Fertility assay (Casanovas et al. "Double-stranded sperm DNA damage is a cause of delay in embryo development and can impair implantation rates”. Fertility and Sterility. 2018, vol. 11, pp. 35). Double-strand sperm DNA fragmentation was analysed using the Neutral version of the Comet assay, while single-strand DNA fragmentation was analysed using the Alkaline version of the assay disclosed in Casanovas et al.. Semen parameters were evaluated using the CASA SCA software (available in Microptic S.L., Spain. In the website https://www.micropticsl.com/es/productos/sca-sistema-casa/ on November 11^th 2019) for volume, concentration, total sperm number and motility patterns.

Statistical methods

General aspects of statistical analysis

At the end of study, after the registration of all data of last subject included, the database was closed and prepared for statistical analysis. The statistical analysis is a synthesis of the methods used on the data collected, to respond to objectives of study. To carry out the analysis, SPSS v20 software was used which is commercially available.

Specific aspects of statistical analysis

A descriptive analysis of the characteristics of the included patients was carried out, depending on the nature of each variable. The evolution of the variables was studied for each treatment. If the variable presents a Normal distribution, the T-student test will be performed. If not, a Wilcoxon test will be performed. Differences between treatments were studied using the ANOVA test if variables present Normal distributions and the Kruskall-Wallis test if not. The non-parametrical Wilcoxon test for related samples was used to compare dsSDF between the initial sample, after 6 weeks of treatment and after 13 weeks of treatment. The level of statistical signification was 95%. 2.3. Results

Determination of DNA fragmentation and analysis of the semen parameters

The determination of sperm DNA fragmentation (SDF) including the double-strand SDF and single-strand SDF, as well as the analysis of the semen parameters observed before starting the treatment (TO) and after 13 weeks of treatment (T 13) are shown in T able below.

As it is shown in the results above, regarding the sperm DNA fragmentation (SDF), there are significant differences between TO and T13 weeks for all the groups showing a decrease of dsSDF at the end of the treatment. Particularly, the experimental treatment 1 (composition Ex.1) of the present invention has been the most effective in this reduction. Furthermore, the three treatments reduced ssSDF. Particularly, the experimental treatment 1 (composition Ex.1) of the present invention has been the most effective in this reduction. Regarding the Semen parameters, the above-disclosed results also shown that the compositions of the present invention (Experimental treatments 1 and 2) improved the volume of the ejaculate and the progressive motility of the sperm cells were observed. Particularly, the experimental treatment 2 (composition Ex.2) of the present invention has been the most effective in this improvement. Meanwhile, Androferti reduced this parameter. Furthermore, a significantly improvement in sperm concentration and sperm cells total number at the end of the treatment with the compositions of the present invention were observed. Particularly, the Experimental treatment 2 (composition Ex.2) of the present invention has been the most effective in this improvement. Meanwhile, Androferti significantly reduced this parameter.

To sum up, on one hand, the composition of Ex.1 of the present invention showed the best significant reduction of double-strand sperm DNA fragmentation between the initial sample (TO) and the final value (T13) (27,1%). Furthermore, composition of Ex.1 of the present invention was also the best treatment to reduce single-strand sperm DNA fragmentation (19,5%) and to improve sperm motility. On the other hand, the composition of Ex.2 showed the best significant improvements of semen parameters (sperm concentration and total number of sperm cells). Furthermore, composition Ex.2 of the present invention was also the best treatment to improve ejaculate volume. Regarding the DNA fragmentation, composition also showed a reduction of both single-strand sperm DNA fragmentation (6,8%) and double-strand sperm DNA fragmentation reduction (19,9%). In the contrary, comparative treatment (Androferti) showed the lower reduction of double strand sperm DNA fragmentation (15,8%) and the second reducing single-strand sperm DNA fragmentation (8,6%). Moreover, seminal parameters were significantly decreased in terms of ejaculate volume, concentration of sperm cells, total number of sperm cells and progressive motility.

Therefore, the compositions of the present invention allow reducing both the double- and single strand DNA fragmentation allowing a reduction of the miscarriages and also enhancing significantly the seminogram allowing an increase in the percentage of pregnancy. Unfortunately, the comparative composition (Androferti) allows a slight reduction of the strand DNA fragmentation but worsening the seminogram. It means that the administration of Androferti allows reducing the percentage of miscarriages (due to the reduction of sperm fragmentation) but unwillingly reducing the percentage of pregnancy, due to the reduction of semen volume, spermatozoa total amount and their motility.

Determination of pregnancy and baby born

The number of pregnancy and baby born expressed in absolute numbers and in percentage are summarised in the following table:

As it is shown in the results above, the percentage of pregnancy allowed after the treatment with the composition of the present invention is about 30%. Meanwhile, the comparative treatment with Androferti allow a percentage of pregnancy of about 14%. It means that the composition of the present invention allows having the double of pregnancy without assisted reproduction techniques in comparison with the comparative treatment of the state of the art.

Furthermore, the composition of the present invention also allows increasing the percentage of baby born until 20%, while the comparative treatment with Androferti only allows a 9.5% of baby born. It means that the composition of the invention allows having more than the double of baby born than the treatment disclosed in the state of the art.

To sum up, the compositions of the present invention are advantageous because allows reducing both the double- and single strand DNA fragmentation allowing a reduction of the miscarriages and also enhancing significantly the semen parameters having as a consequence a significantly increase in the percentage of pregnancy, and finally in a significantly increase of the percentage of baby born without the need of assisted reproduction techniques.

Citation List

1. Casanovas et al. "Double-stranded sperm DNA damage is a cause of delay in embryo development and can impair implantation rates”. Fertility and Sterility. 2018, vol. 11, pp. 35.

For reasons of completeness, various aspects of the invention are set out in the following numbered clauses: Clause 1. A composition comprising: a) an effective amount of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; or an appropriate acceptable complex thereof; b) an effective amount of Ginkgo Biloba extract; and one or more appropriate acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines.

Clause 2. The composition according to clause 1, which is: a pharmaceutical composition comprising: a) a therapeutically effective amount of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; or a pharmaceutically acceptable complex thereof; b) a therapeutically effective amount of Ginkgo Biloba extract; and one or more pharmaceutically acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines; or alternatively, a dietary supplement comprising: a) an effective amount of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; or an edible acceptable complex thereof; b) an effective amount of Ginkgo Biloba extract; and one or more edible acceptable excipients or carriers; wherein the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines. Clause 3. The composition according to any of the clauses 1 or 2, wherein the composition is free of calcium ion, manganese and xanthines; particularly methylated xanthines.

Clause 4. The composition according to any of the clauses 1-3, wherein the composition comprises a cyclodextrin curcumin complex; particularly a gamma cyclodextrin curcumin complex.

Clause 5. The composition according to any of the clauses 1-4, wherein the composition further comprises: c) a therapeutically effective amount of Piper Nigrum extract.

Clause 6. The composition according to any of the clauses 1-5, wherein the composition further comprises: d) a therapeutically effective amount of coenzyme Q10.

Clause 7. The composition according to any of the clauses 1-6, wherein the composition further comprises: e) an effective amount of one or more vitamins or a pharmaceutically acceptable salt thereof; particularly selected from the group consisting of vitamin C, vitamin E, vitamin B9.

Clause 8. The composition according to any of the clauses 1-7, wherein the composition further comprises: f) an effective amount of one or more minerals or a pharmaceutically acceptable salt thereof; particularly selected from the group consisting of zinc and selenium. Clause 9. The composition according to any of the clauses 1-8, wherein the composition further comprises: g) an effective amount of one or more amino acids; particularly selected from the group consisting of L-carnitine and L-arginine.

Clause 10. The composition according to any of the clauses 1-9, wherein the composition further comprises: h) an effective amount of one or more sugars; particularly selected from inositol, lycopene and isomaltulose.

Clause 11. The composition according to any of the clauses 1-10, which comprises: a) from 0.1 to 30% by weight of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; or a pharmaceutically or edible acceptable complex thereof; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract; c) optionally, from 0.01 to 1 % by weight of Piper Nigrum extract; d) optionally, from 0.1 to 10 % by weight of coenzyme Q10; e) optionally, from 0.0005 to 15 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) optionally, from 0.1 to 10 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of Zinc and Selenium; g) optionally, from 5 to 60 % by weight of one or more of one or more amino acids, particularly a mixture of L- carnitine and L-arginine; h) optionally, from 0.5 to 70 % by weight of one or more sugars, particularly a mixture of inositol, lycopene and isomaltulose; one or more pharmaceutically or edible acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines; and the sum of the components is up to 100% by weight.

Clause 12. The composition according to any of the clauses 1-11, which comprises: a) from 0.2 to 20 % by weight of a cyclodextrin curcumin, curcuminoids or Curcuma Longa extract complex; particularly gamma cyclodextrin curcumin, curcuminoids or Curcuma Longa extract complex; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.8005 to 11.75 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) from 0.2 to 5 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of Zinc and Selenium; g) from 10 to 60 % by weight of one or more of one or more amino acids, particularly a mixture of L-carnitine and L-arginine; h) from 10.5 to 65 % by weight of one or more sugars, particularly a mixture of inositol, lycopene and isomaltulose; one or more pharmaceutically or edible acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthine, and the sum of the components is up to 100% by weight.

Clause 13. The composition according to any of the clauses 1-12, which comprises: a) from 0.5 to 20 % by weight of a cyclodextrin curcumin, curcuminoids or Curcuma Longa extract complex; particularly gamma cyclodextrin curcumin, curcuminoids or Curcuma Longa extract complex; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.2 to 2 % by weight of vitamin E, particularly acetate vitamin E; from 0.6 to 9.7 % by weight of vitamin C, particularly calcium ascorbate; and from 0.0005 to 0.05 % by weight of vitamin B9; f) from 0.1 to 2.5 % by weight of Zinc, particularly zinc sulphate; from 0.1 to 2.5 % by weight of Selenium, particularly sodium selenite; g) from 5 to 30 % by weight of L-carnitine, particularly L-carnitine fumarate; from 5 to 30 % by weight of L-arginine, particularly L-arginine hydrochloride; h) from 5 to 30 % by weight of inositol; from 0.5 to 5 % by weight of lycopene; from 5 to 30 % by weight of isomaltulose; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines; and the sum of the components is up to 100% by weight.

Clause 14. The composition according to any of the clauses 1-13, wherein the one or more pharmaceutically or edible acceptable excipients or carriers comprises: from 1 to 20 % by weight of glidants, particularly colloidal silicon dioxide; from 1 to 30 % by weight of diluent, particularly mannitol; and from 0.2 to 20 % by weight of taste modulator agent, particularly sucralose.

Clause 15. The composition as defined in any of the clauses 1-14 for use in the treatment of male infertility.

Claims

1. A composition comprising: a) an effective amount of an appropriate acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; b) an effective amount of Ginkgo Biloba extract; and one or more appropriate acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines; and the complex is a pharmaceutically acceptable cyclodextrin complex.

2. The composition according to claim 1, which is: a pharmaceutical composition comprising: a) a therapeutically effective amount of a pharmaceutically acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; b) a therapeutically effective amount of Ginkgo Biloba extract; and one or more pharmaceutically acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines; and the complex is a pharmaceutically acceptable cyclodextrin complex; or alternatively, a dietary supplement comprising: a) an effective amount of an edible acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; b) an effective amount of Ginkgo Biloba extract; and one or more edible acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines; and the complex is an edible acceptable cyclodextrin complex.

3. The composition according to any of the claims 1 or 2, wherein the composition comprises: less than 1 gram of calcium ion; less than 1 mg of manganese; and less than 30 mg of xanthines.

4. The composition according to any of the claims 1-3, wherein the composition is free of calcium ion, manganese and xanthines; particularly methylated xanthines.

5. The composition according to any of the claims 1-4, wherein the composition comprises a cyclodextrin curcumin complex.

6. The composition according to any of the claims 1-5, wherein the composition comprises an appropriate acceptable gamma cyclodextrin complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract

7. The composition according to any of the claims 1-6, wherein the composition further comprises: c) a therapeutically effective amount of Piper Nigrum extract.

8. The composition according to any of the claims 1-7, wherein the composition further comprises: d) a therapeutically effective amount of coenzyme Q10.

9. The composition according to any of the claims 1-8, wherein the composition further comprises: e) an effective amount of one or more vitamins or a pharmaceutically acceptable salt thereof; particularly selected from the group consisting of vitamin C, vitamin E, vitamin B9.

10. The composition according to any of the claims 1-9, wherein the composition further comprises: f) an effective amount of one or more minerals or a pharmaceutically acceptable salt thereof; particularly selected from the group consisting of zinc and selenium.

11. The composition according to any of the claims 1-10, wherein the composition further comprises: g) an effective amount of one or more amino acids; particularly selected from the group consisting of L-carnitine and L-arginine.

12. The composition according to any of the claims 1-11, wherein the composition further comprises: h) an effective amount of one or more sugars, carotenoids or mixtures thereof; particularly selected from inositol, lycopene and isomaltulose.

13. The composition according to any of the claims 1-12, which comprises: a) from 0.1 to 30% by weight of a pharmaceutically or edible acceptable complex of curcumin, or alternatively curcuminoids, or alternatively a Curcuma Longa extract; b) from 0.1 to 10 % by weight of Ginkgo Biloba extract; c) optionally, from 0.01 to 1 % by weight of Piper Nigrum extract; d) optionally, from 0.1 to 10 % by weight of coenzyme Q10; e) optionally, from 0.0005 to 15 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) optionally, from 0.1 to 10 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of Zinc and Selenium; g) optionally, from 5 to 60 % by weight of one or more of one or more amino acids, particularly a mixture of L- carnitine and L-arginine; h) optionally, from 0.5 to 70 % by weight of one or more sugars, carotenoids or mixtures thereof, particularly a mixture of inositol, lycopene and isomaltulose; one or more pharmaceutically or edible acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines; and the sum of the components is up to 100% by weight.

14. The composition according to any of the claims 1-13, which comprises: a) from 0.2 to 20 % by weight of a cyclodextrin curcumin, curcuminoids or Curcuma Longa extract complex; particularly gamma cyclodextrin curcumin, curcuminoids or Curcuma Longa extract complex; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.8005 to 11.75 % by weight of one or more vitamins or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of vitamin E, vitamin C and vitamin B9; f) from 0.2 to 5 % by weight of one or more minerals or a pharmaceutically or edible acceptable salt thereof, particularly a mixture of Zinc and Selenium; g) from 10 to 60 % by weight of one or more of one or more amino acids, particularly a mixture of L-carnitine and L-arginine; h) from 10.5 to 65 % by weight of one or more sugars, carotenoids or mixtures thereof, particularly a mixture of inositol, lycopene and isomaltulose; one or more pharmaceutically or edible acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthine, and the sum of the components is up to 100% by weight.

15. The composition according to any of the claims 1-14, which comprises: a) from 0.5 to 20 % by weight of a cyclodextrin curcumin, curcuminoids or Curcuma Longa extract complex; particularly gamma cyclodextrin curcumin, curcuminoids or Curcuma Longa extract complex; b) from 0.3 to 3 % by weight of Ginkgo Biloba extract; c) from 0.05 to 0.5 % by weight of Piper Nigrum extract; d) from 0.5 to 5 % by weight of coenzyme Q10; e) from 0.2 to 2 % by weight of vitamin E, particularly acetate vitamin E; from 0.6 to 9.7 % by weight of vitamin C, particularly calcium ascorbate; and from 0.0005 to 0.05 % by weight of vitamin B9; f) from 0.1 to 2.5 % by weight of Zinc, particularly zinc sulphate; from 0.1 to 2.5 % by weight of Selenium, particularly sodium selenite; g) from 5 to 30 % by weight of L-carnitine, particularly L-carnitine fumarate; from 5 to 30 % by weight of L-arginine, particularly L-arginine hydrochloride; h) from 5 to 30 % by weight of inositol; from 0.5 to 5 % by weight of lycopene; from 5 to 30 % by weight of isomaltulose; and one or more pharmaceutically or edible acceptable excipients or carriers; wherein: the composition is substantially free of calcium ion, manganese and xanthines; particularly methylated xanthines; and the sum of the components is up to 100% by weight.

16. The composition according to any of the claims 1-15, wherein the one or more pharmaceutically or edible acceptable excipients or carriers comprises: from 1 to 20 % by weight of glidants, particularly colloidal silicon dioxide; from 1 to 30 % by weight of diluent, particularly mannitol; and from 0.2 to 20 % by weight of taste modulator agent, particularly sucralose.

17. The composition as defined in any of the claims 1-16 for use in the treatment of male infertility.