DESC:FIELD OF THE INVENTION
The present invention relates to a synergistic composition for improving hypothalamic pituitary gonadal (HPG) axis activity.

Particularly, the present invention relates to a synergistic composition comprising combination of 2-aminobutanedioic acid and one or more ROS inhibitors or salts thereof along with pharmaceutically acceptable excipients.

Particularly, the present invention relates to a synergistic bioactive composition comprising combination of 2-aminobutanedioic acid and one or more ROS inhibitors are selected from N,N,N-trimethylglycine and 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23, 27,31,35, 39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3-methyl benzene-1,4-diol or salts thereof either alone or in combination along with pharmaceutically acceptable excipients.

More particularly, the 2-aminobutanedioic acid in the present composition activates HPG axis; and one or more ROS inhibitors or salts thereof in the present composition protects HPG axis from oxidative stress and reactive oxygen species.

The present synergistic composition is useful in the treatment of disorders related to hypothalamic pituitary gonadal (HPG) axis activity such as male infertility. Moreover, the present composition improves sperm mortality, sperm morphology and spermatogenesis.

BACKGROUND OF THE INVENTION
Reproduction is necessary for the persistence of species and reproductive success is dependent on many neuropeptide and hormonal systems. Reproduction is mainly governed by the hypothalamic-pituitary-gonadal (HPG) axis. The hypothalamic pituitary gonadal axis (HPG axis) is also known as the hypothalamic–pituitary–ovarian/testicular axis comprises the hypothalamus, pituitary gland, and gonadal glands. The HPG axis plays a critical part in the development and regulation of the health systems, mainly in the reproductive and immune systems. Any disturbance in this axis cause changes in the hormones produced by each gland and have various local and systemic effects on the body. The main function of this axis is controlling development, reproduction, and aging in animals including humans.

The activation and deactivation of the HPG axis also helps to regulate life cycles. During puberty the HPG axis is activated by the secretions of estrogen from the ovaries in the female and testosterone from the testes in the male. This activation of estrogen and testosterone causes physiological and psychological changes.
Particularly, during the activation of HPG axis, the hypothalamus secretes Gonadotropin hormone-releasing hormone (GnRH). GnRH further travels down to the anterior pituitary gland and binds to receptors on the gland. This promotes the release of LH (luteinizing hormone) and FSH (follicle-stimulating hormone). In male, LH and FSH travel in the bloodstream to the testicles. LH stimulates Leydig cells in the testicles to produce testosterone (testosterone is required for spermatogenesis and many other important biological processes). Whereas in female, LH and FSH travel in the bloodstream to the ovaries. When LH bind to the ovaries they stimulate the production of estrogen. Estrogen helps to regulate the menstrual cycle and is an essential component in many other physiological processes in female.
Once activated, the HPG axis continues to function in male till death but becomes deregulated in female which leads to menopause. Although males remain fertile till rest of the life, the activity of the HPG axis decreases due to aging. In aging, the testes begin to produce less testosterone, leading to a condition known as post-pubertal hypogonadism. Post-pubertal hypogonadism results in progressive muscle mass decrease, increase in visceral fat mass, loss of libido, impotence, decreased attention, increased risk of fractures, and abnormal sperm production. Hence, the activation of HPG axis is an important part in male fertility.
To keep HPG axis activate, the continuous stimulation of GnRH secretion or LH secretion is very important. Previous studies states that an excitatory amino acid analog, N-methyl-D-aspartate (NMDA) stimulates GnRH secretion. Particularly, N-Methyl-D-Aspartate (NMDA) receptors mediate the release of gonadotropin-releasing hormone (GnRH) [Endocrinology, Volume 134, Issue 3, 1 March 1994, Pages 1023–1030].
It is also found that excitatory amino acid (EAA) neurotransmission is an essential component of the neuroendocrine transmission line that regulates anterior pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion [Frontiers in neuroendocrinology 15, 3—49 (1994)].
It is reported that activation of NMDA type glutamate receptor stimulates LH secretion in immature male. It is concluded that higher dose of NMDA activator required in aged subjects compared to young one. [Fronters in neuroendocrinology 15, 3-49 (1994)].
Excitatory amino acid transmitters are main reason for most of the fast synaptic transmission that occurs in the mammalian brain. The major excitatory amino acid neurotransmitters are glutamate, aspartate and acetylaspartylglutamate. [Ariel Y. Deutch, in Fundamental Neuroscience (Fourth Edition), 2013].
D-Aspartic acid is considered to play an important neuromodulating role in activating the HPG axis. For example, in males, this axis is responsible for synthesizing endogenous testosterone and occurs due to D-Aspartic acid converting to N-methyl d-aspartic acid (NMDA) by d-aspartate methyltransferase (NMDA synthetase). In the hypothalamus, NMDA binds to its receptor, a subtype of the l-glutamate receptor, and potentiates glutaminergic neurotransmission which results in the release of GnRH. [Nutrition Research, Volume 33, Issue 10, October 2013, Pages 803-810]
US11524031 describes the use of a mixture consisting of a mixture of D-aspartic and L-aspartic acids or salts thereof, preferably at least at ratio 1:1 in order to stimulate the man procreative activity by means of an increment of spermatozoon number and motility.
There are many reports of the increasing incidence of male infertility paired with decreasing sperm quality have triggered studies on the effects of lifestyle and environmental factors on the male reproductive potential. However, one of the major triggering factors is excessive production of reactive oxygen species (ROS) beyond that of cellular antioxidant capacity, thus causing oxidative stress. High ROS levels can disrupt the oxidative balance, thereby impacting the HPG axis resulting in reduced secretion of reproductive hormones, particularly GnRH.
Sperm also cause damage to themselves through generation of reactive oxygen species (ROS) mainly as a by-product of mitochondrial function [Antioxidants (Basel). 2021 Jan; 10(1): 98].
ROS cause loss of sperm motility and lipid peroxidation. The latter damage leads to alteration of the membrane properties such as flexibility and fluidity, and can also lead to lack of membrane integrity and/or decreased chromatin quality. Sperm are particularly sensitive to ROS-induced damage because of their membrane composition and their limited antioxidant defenses. The nature of the sperm cell, with limited cytoplasmic fluid, also constrains the availability of intracellular antioxidants [J Hum Reprod Sci. 2019 Jan-Mar; 12(1): 4–18].
In human sperm, at least, there exists a strong relationship between ROS production and antioxidant protection for determining the lifespan of sperm in the absence of external damaging agents [Animal Reproduction Science 71, Issues 1–2, 2002, 13-23].
There are very limiting prior arts which discloses about improving overall sperm health that includes spermatogenesis or sperm count, its motility, viability, sperm maturation and integrity that maintains sperm morphology. Further, there are very few articles demonstrates the sperm capacitation which is a crucial factor for penetration and fertilization in female egg.
The inventors of the present invention found that mere activation of HPG axis cannot be much effective for maintaining and improving the overall sperm health or male fertility. There is a need to find out some supplemental one or more active ingredients that can synergistically protects HPG axis activation from ROS and consequently improves sperm mortality, sperm morphology, spermatogenesis and moreover improves its capacitation. Hence, there is need of a composition which improves hypothalamic pituitary gonadal (HPG) axis activity by triggering its activity on one side, simultaneously protecting its damage from other side.
Hence, after extensive research and experimentation, the inventors of the present invention found an effective combination of therapeutically active ingredients which work concurrently to improve hypothalamic pituitary gonadal (HPG) axis activity by triggering its activity on one side and simultaneously protecting its damage from other side.

Concisely, the present invention provides a cost-effective, non-toxic, safe, and therapeutically active combination of NMDA activator that facilitates the release of gonadotropin-releasing hormone (GnRH) and ROS inhibitors that protect sperm from apoptosis to afford overall better sperm health.

OBJECTIVE OF THE INVENTION
The primary object of the present invention is to provide a novel therapeutical approach for improving HPG axis activity.

Another object of the present invention is to provide cost-effective, side-effect-free composition for regulating the reproductive axis.

Yet another object of the present invention is to provide effective combination of bioactive components to improve sperm health.

Another object of the present invention is to provide bioavailable oral composition(s) for treating male fertility problems.

SUMMARY OF THE INVENTION
To meet the above objects, the inventors of the instant invention carried out thorough experiments to establish significant effects of the active ingredients or vitamins or coenzymes or enzymes or amino acids or nutrients or methyl donors that ameliorate therapeutic efficacy in the treatment of male infertility.

In one aspect, the invention provides synergistic composition comprising combination of 2-aminobutanedioic acid and one or more ROS inhibitors or salts thereof, present in suitable weight ratio along with pharmaceutically acceptable excipients.

In a further aspect, the invention provides a synergistic composition comprising combination of active form of 2-aminobutanedioic acid and one or more ROS inhibitors, wherein ROS inhibitors are selected from N,N,N-trimethylglycine and 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3-methylbenzene-1,4-diol or salts thereof either alone or in combination along with pharmaceutically acceptable excipients.

In another aspect, the invention provides a synergistic composition comprising combination of active form of 2-aminobutanedioic which is present in the range of 0.1-1000 mg and one or more ROS inhibitors which are present in the range of 0.1-1000 mg along with pharmaceutically acceptable excipients/carriers.

In another aspect, the invention provides synergistic composition which is useful in the treatment of male infertility.

ABBREVIATIONS
ROS: Reactive Oxidative Species
HPG: Hypothalamic–pituitary–gonadal
LH: luteinizing hormone
FSH: follicle-stimulating hormone
GnRH: gonadotropin-releasing hormone
EAA: excitatory amino acid
NMDA: N-methyl d-aspartic acid

BRIEF DESCRIPTION OF THE FIGURES/DRAWINGS:
Figure 1 illustrates semen volume (in ml) for Group I to Group IX test groups.
Figure 2 illustrates sperm count (million/ml) for Group I to Group IX test groups.
Figure 3 illustrates sperm motility (%) for Group I to Group IX test groups.
Figure 4 illustrates sperm capacitation (%) for Group I to Group IX test groups.

DETAILED DESCRIPTION OF THE INVENTION
The present invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully interpreted and comprehended. However, any skilled person or artisan will appreciate the extent to which such embodiments could be generalized in practice.

It is further to be understood that all terminology used herein is for the purpose of describing particular embodiment only and is not intended to be limiting in any manner or scope. Unless defined otherwise, all technical and scientific expressions used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the invention pertain.

In describing and claiming the embodiments of the present invention, the following terminology will be used in accordance with the definitions set out below which are known in the state of art.

The singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Also, the term ‘composition’ does not limit the scope of the invention for multiple compositions that can be illustrated for best mode of the invention.

The term “pharmaceutically/nutraceutically acceptable salt,” as use herein, represents those salts which are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.

Particularly the term “pharmaceutically-acceptable salts” refers to the relatively non-toxic, inorganic, and organic acid addition salts of compounds, amino acid salt, halide salt, sugar-based salt, alkali or alkaline earth metal salts, as well as solvates, co-crystals, polymorphs and the like of the salts. The salts are preferably selected from chloride, bromide, calcium, sodium, hydroxide, aspartate, taurate, threonate, phosphate, acetate, fumarate, lactate, maleate, sulphate, tartrate, citrate, hydrates carbonate, gluconate, mesylate, hydrochloride, hydrobromide and glucosamine.

All modifications and substitutions that come within the meaning of the description and the range of their legal equivalents are to be embraced within their scope. A description using the transition “comprising” allows the inclusion of other elements to be within the scope of the invention.

As used herein, the term (HPG) pertains to hypothalamic-pituitary-gonadal (HPG) axis which is responsible for the onset and regulation of puberty.

The male hypothalamic-pituitary-gonadal (HPG) axis is a controlled system to promote spermatogenesis and androgen biosynthesis. The gonadotropin-releasing hormone (GnRH)-gonadotropic secretory unit stimulates the production and release of LH and FSH. Once in the blood, LH and FSH act on cells in the testes to initiate the release of steroid hormones (i.e., testosterone) and initiate the production of sperm.

In one embodiment, the present invention relates to a bioactive composition for improving HPG axis activity, comprising: a). 2-aminobutanedioic acid or salt thereof or isomer thereof; b). at least one ROS inhibitor or salt thereof; and c). at least one pharmaceutically acceptable excipient.

In an embodiment of the present invention, the ROS inhibitor is selected from N,N,N-trimethylglycine and 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3-methylbenzene-1,4-diol or salts thereof.

In yet another embodiment of the present invention, the 2-aminobutanedioic acid or salt thereof or isomer thereof is present in a range of 10% to 95% by weight of the total composition.

In another embodiment of the present invention, the ROS inhibitor or salt thereof is present in a range of 1% to 50% by weight of the total composition.

In an embodiment of the present invention, combination of the 2-aminobutanedioic acid or salt thereof and ROS inhibitor(s) or salt(s) thereof are present in the weight ratio of 1: 0.01 to 1:1 in the composition.

In an embodiment of the present invention, combination of the 2-aminobutanedioic acid, the N,N,N-trimethylglycine and the 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19, 23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol or salts thereof are present in the weight ratio of 1:0.1:0.01 to 1:1:1 in the composition.

In another embodiment of the present invention, the pharmaceutically acceptable excipient is selected from diluent, binder, surfactant, lubricant, glidant, additive, solvent or mixtures thereof.

In yet another embodiment of the present invention, the diluent is present in a range of 0.1 to 30%; the binder is present in a range of 0.1 to 25%; the lubricant is present in a range of 0.1 to 10.0 %; the glidant is present in a range of 0.1 to 5.0%; the additive is present in a range of 0.1 to 10%; the surfactant is present in a range of 0.1 to 5.0%; the stabilizer is present in a range of 0.1 to 5.0%; %; the antioxidant is present in a range of 0.01 to 5.0%; and the plasticizer is present in a range of 0.1 to 5.0%; by weight of total composition.

In an embodiment of the present invention, the composition increases the sperm volume by 0.48 ml as compared to normal control.

In an embodiment of the present invention, the composition increases the sperm count by 17.08 million/ml as compared to normal control.

In an embodiment of the present invention, the composition increases the sperm motility by 27.5% as compared to normal control.

In an embodiment of the present invention, the composition increases the sperm capacitation by 34.80 % as compared to normal control.

In an embodiment of the present invention, effective unit dose for an oral administration of the composition is formulated in a range of 1 to 1000 mg.

In a preferred embodiment, the present invention provides synergistic bioactive composition for improving HPG axis activity.

In another preferred embodiment, the present invention provides synergistic combination of biologically active compounds wherein the combination comprises exogenous blend of 2-aminobutanedioic acid and one or more ROS inhibitors or salts thereof, present in suitable weight ratio along with pharmaceutically acceptable excipients.

In another embodiment, the ROS inhibitors are selected from N,N,N-trimethylglycine; 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol or salts with pharmaceutically acceptable excipients. The ROS inhibitors not only protects from cell damage (apoptosis) but also reduce the ATP depletion and provide energy to the sperm cells.

Particularly 2-aminobutanedioic acid triggers the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, luteinizing hormone (LH) from the pituitary gland, and testosterone from the testes. On the other side, ROS inhibitors like 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol and N,N,N-trimethylglycine or salts thereof protects the sperm cells from oxidative damage and improve the sperm energy, thereby maintaining sperm quality and quantity and its activity. This synergistic effect ultimately improves male fertility.

In another embodiment, the present invention provides a synergistic bioactive composition comprising combination of 2-aminobutanedioic acid salts or enantiomers or isomers and salts thereof which is present in the range of 0.1-2000 mg and ROS inhibitors and salts thereof which is present in the range of 0.1-2000 mg along with pharmaceutically acceptable excipients/carriers.

In another embodiment, the present invention provides composition comprising synergistic combination, wherein 2-aminobutanedioic acid and salts thereof are present in the range of 0.1-2000 mg; preferably 0.1-1000 mg; more preferably 0.1-500 mg by weight of total composition.

In one more embodiment, the present invention provides composition comprising synergistic combination, wherein the ROS inhibitors and salts thereof are present in the range of 0.1-2000 mg; preferably 0.1-1000 mg; more preferably 0.1-500 mg by weight of total composition.

In another embodiment the invention provides male fertility composition comprising synergistic combination of 2-aminobutanedioic acid and one or more ROS inhibitors present in specific ratio along with pharmaceutically acceptable excipients, wherein the composition improves the sperm health via promoting HPG axis activity.

In a preferred embodiment, the present invention provides composition comprising synergistic combination of 2-aminobutanedioic acid or salts thereof and ROS inhibitors or salts thereof are present in the weight ratio of 1: 0.01 to 1:1 along with pharmaceutically acceptable excipients.

In one embodiment, the present invention provides composition comprising synergistic combination of 2-aminobutanedioic acid with N,N,N-trimethylglycine or 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol or salts thereof either alone or in combination thereof.

In some embodiment, the weight ratio of 2-aminobutanedioic acid with N,N,N-trimethylglycine and salts thereof ranges from 1:0.1 to 1:1 along with pharmaceutically acceptable excipients.

In some embodiment the weight ratio of 2-aminobutanedioic acid with 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol and salts thereof ranges from 1:0.01 to 1:1 along with pharmaceutically acceptable excipients.

In yet another embodiment, the present invention provides composition comprising synergistic combination of 2-aminobutanedioic acid, N,N,N-trimethylglycine and 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol or salts thereof are present in the weight ratio of 1:0.1:0.01 to 1:1:1 along with pharmaceutically acceptable excipients.

In one more embodiment, the present invention provides composition comprising 2-aminobutanedioic acid or its salt is present in a range of 10% to 95% by weight of the total composition.

In yet another embodiment, the invention provides composition wherein the ROS inhibitor or its salt is present in a range of 1% to 50% by weight of the total composition.

In another embodiment the present bioactive composition improves hypothalamic-pituitary-gonadal (HPG) axis activity that allows for the promotion of gonadal sex steroid secretion and function.

Gonadotropin-releasing hormone (GnRH) is secreted from the hypothalamus by GnRH-expressing neurons. The anterior portion of the pituitary gland produces luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and the gonads produce estrogen and testosterone.

In another embodiment, the present bioactive composition comprises 2-aminobutanedioic acid for HPG axis activation which can work concurrently with one or more ROS inhibitors such as N,N,N-trimethylglycine or 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39 -decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3-methylbenzene-1,4-diol or salts thereof either alone or in combination thereof which effectively improves hypothalamic pituitary gonadal (HPG) axis activity.

In another embodiment, the present invention provides stable composition that provides male fertility composition which is useful to enhance sperm health not only in oligospermia but also in azoospermia, teratospermia, necrospermia, asthenozoospermia, aspermia, hypospermia subjects.

In yet another embodiment, the present invention provides a method of treating the male fertility problems comprising oral administration of a composition comprising a synergistic combination of 2-aminobutanedioic acid, N,N,N-trimethylglycine and 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol or salts thereof in the weight ratio of 1:0.1:0.01 to 1:1:1 along with pharmaceutically acceptable excipients.

In another embodiment, the present invention provides synergistic composition wherein two ingredients work intracellularly in synergistic way to improve sperm health through promoting HPG axis activity.

Further, the present composition is useful in the treatment of male infertility, post-pubertal hypogonadism, and conditions related to poor sperm health.

In some embodiment, the present invention provides synergistic composition for male fertility where it is not only increases spermatogenesis but also to improve sperm capacitation. Sperm capacitation refers to physiological changes, spermatozoa must undergo in order to have the ability to penetrate and fertilize an egg.

In yet another embodiment, the present composition is useful to improve sperm count, sperm motility, sperm morphology and sperm capacitation.

The term "therapeutically effective amount " denotes an amount that reduces the risk, potential, possibility or occurrence of a disease or disorder, or provides advanced alleviation, mitigation, and/or reduction or restoration or modulation, regulation of at least one indicator/biomarker (e.g., blood or serum CRP level), and/or minimize at least one clinical symptom related to male infertility.

The term ‘subject in need thereof’ pertains to a subject preferably mammal, more preferably a
male with fertility issues including but not limited to male with abnormal sperm morphology, increase in the percentage of sperm with abnormal form in semen, low sperm count or negligible or no sperm count, and low aspartate level.

In the context of the present invention, the term “treatment” refers to alleviate, mitigate, prophylaxis, attenuate, manage, regulate, modulate, control, minimize, lessen, decrease, downregulate, up regulate, moderate, inhibit, restore, suppress, limit, block, decrease, prevent, inhibit, stabilize, ameliorate, cure, heal sperm disorders which include defects in quality or quantity of sperm produced and defects in sperm emission.

Notably, the instant composition is non-hazardous, non-toxic, and safe for human consumption without any severe adverse effects, therefore the present composition can also be used as preventive therapy/ adjuvant therapy/ add-on therapy/ combination/ adjunctive therapy in a subject in need thereof.

Certain compounds of the present invention exist in unsolvated forms as well as solvated forms, including hydrated forms. Further, some compounds of the present invention exist in multiple crystalline or amorphous forms (“polymorphs”). Compounds of the present invention are formulated in geometric or enantiomeric or stereoisomeric forms.

In general, all physical forms are of use in the methods contemplated by the present invention and are intended to be within the scope of the present invention.

Compound or pharmaceutically acceptable salts includes, hydrates, halides like chloride, bromide, metal salts like calcium, sodium, potassium, hydroxide, phosphate; polymorphs, solvates, enantiomers or racemates. Some of the crystalline forms of the compound exist as polymorphs and as such are intended to be included in the present disclosure. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are intended to be encompassed by some embodiments.

In one embodiment, the present invention provides composition(s) having effective amount of active ingredients along with pharmaceutically acceptable excipients.

As used herein, the term “pharmaceutically acceptable carriers, diluents or excipients” is purported to mean, without limitation, any adjuvant, carrier, excipient, sweetening agent, diluents, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, encapsulating polymeric delivery systems or polyethylene glycol matrix, which is acceptable for use in the subject, preferably humans. Excipients also include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colours), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, food additives, or waters of hydration, salts.

In another embodiment, the present invention relates to synergistic composition prepared in a manner well known in the pharmaceutical art and administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.

The preferable route of administration includes but is not limited to sublingual, rectal, topical, parenteral, nasal, or oral.

In some embodiment, the instant synergistic compositions are administered to a subject in need thereof, in the form which is suitable for oral use, such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release); hard gelatin capsules, soft gelatin capsules in an oily vehicle, veg capsule, hard or soft cellulose capsule, granulate for sublingual use, effervescent or carbon tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or reconstituted dry powdered form with a liquid medium or syrup; for topical use including transmucosal and transdermal use, such as a cream, ointment, gel, aqueous or oil solution or suspension, salve, parch or plaster; for nasal use, such as a snuff nasal spray or nasal drops; for vaginal or rectal use, such as a suppository; for administration by inhalation, such as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, such as a tablet, capsule, film, spray.

In a further embodiment, the present composition is formulated in the form of oral dosage forms such as syrup, inhalation, spray minitablets, chewable formulations, orodispersible films orodispersible tablets. It can also be prepared in the form of snack, confectionery food products, sachet and gummies.

In another embodiment, the synergistic composition of the present invention is non-toxic, cost effective, enriched with bioactive ingredients, and provides treatment against problems associated male infertility.

In another embodiment of the present invention, the diluents are selected from starches, hydrolyzed starches, partially pregelatinized starches, anhydrous lactose, cellulose powder, lactose monohydrate, sugar alcohols such as sorbitol, xylitol and mannitol, silicified microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium lactate, dibasic calcium phosphate (anhydrous/ dibasic dehydrate/ tribasic), calcium silicate, calcium sulphate, cellulose acetate, corn starch, pregelatinized starch, dextrin, ß-cyclodextrin, methylated-ß-cyclodextrin, dextrates, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sterilizable maize, sucrose, sugar spheres, talc, trehalose, xylitol, vehicles like petrolatum, dimethyl sulfoxide and mineral oil or the like.
In some embodiment of the present invention, the diluent in the composition/formulation is present in a range of 1% to 30% by weight of the total composition/formulation.

In yet another embodiment of the present invention, the binder is selected from disaccharides such as sucrose, lactose, polysaccharides and their derivatives like starches, cellulose, or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); hydroxypropyl methyl cellulose (HPMC); sugar alcohols such as xylitol, sorbitol, or mannitol; protein like gelatin; synthetic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, chitosan, copovidone, corn starch, pregelatinized starch, cottonseed oil, dextrates, dextrin, dextrose, ethyl cellulose, guar gum, hydrogenated vegetable oil, mineral oil, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyl ethyl methyl cellulose, hydroxypropyl cellulose, inulin, cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol, lactose, liquid glucose, hypromellose, magnesium aluminium silicate, maltodextrin, maltose, methyl-cellulose, microcrystalline cellulose, pectin, poloxamer, polydextrose, polymethacrylates, povidone, sodium alginate, stearic acid, sucrose, sunflower oil, various animal vegetable oils, and white soft paraffin, paraffin, flavorants, colorants and wax.

In a further embodiment of the present invention, the binder in the composition/formulation is present in a range of 0.1 to 30% by weight of the composition/formulation.

In some embodiment, the antioxidant is selected from tocopherol (vitamin E), sesamol, guaiac resin, methionine, beta-carotene, lycopene, lutein, zeaxanthin, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), sodium ascorbate, sodium metabisulfite (SMB), l-carnosine, propyl gallate (PG), tertiary butyl hydroquinone, cysteine (CYS), citric acid, tartaric acid, phosphoric acid and ascorbic acid.

In another embodiment of the present invention, the amount of antioxidant in the composition/formulation is present in the range of 0.1 to 10% by wt. of the composition/ formulation.
In another embodiment of the present invention, the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulphate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, potassium, or sodium benzoate or the like.
In another embodiment of the present invention, the lubricant in the composition/formulation is present in a range of 0.1% to 10.0% by weight of the total composition/formulation.

In another embodiment of the present invention, the solubilizing agent is selected from polysorbate 80, sodium lauryl sulphate, anionic emulsifying wax, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sorbitan esters, triethyl citrate, vitamin E, polyethylene glycol succinate, microcrystalline cellulose, carboxymethylcellulose sodium, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, hypromellose, hypromellose, acetate succinate, lecithin, polyethylene alkyl ethers, aluminum oxide, poly(methylvinyl ether/maleic anhydride), calcium carbonate, crospovidone, cyclodextrins, fructose, hydroxpropyl betadex, oleyl alcohol, povidone, benzalkonium chloride, benzethonium chloride, benzyl alcohol, benzyl benzoate, cetylpyridinium chloride, inulin, meglumine, poloxamer, pyrrolidone, sodium bicarbonate, starch, stearic acid, sulfobutylether beta cyclodextrin, tricaprylin, triolein, docusate sodium, glycine, alcohol, self-emulsifying glyceryl monooleate, cationic benzethonium chloride, cetrimide, xanthan gum, lauric acid, myristyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, sorbic acid or the like.

In another embodiment of the present invention, the amount of solubilizing agent or surfactant in the composition/formulation ranges from 0.1% to 10% by weight of the composition/formulation.

In a preferred embodiment of the present invention, the solubilizing agent or surfactant is present in a range of 0.1% to 5.0% by weight of the composition/formulation.

In one of the embodiments of the present invention, the glidant is selected from colloidal silicon dioxide, magnesium stearate, fumed silica (colloidal silicon dioxide), starch, talc, calcium phosphate tribasic, cellulose powdered, hydrophobic colloidal silica, magnesium oxide, zinc stearate, magnesium silicate, magnesium trisilicate, silicon dioxide or the like.

In another embodiment of the present invention, the glidant in the composition/formulation is present in a range of 0.1% to 5.0% by weight of the total composition/formulation.

In some embodiment of the present invention, the stabilizers are selected from the group consisting of alginate, agar, carrageen, gelatin, guar gum, gum arabic, locust bean gum, pectin, starch, xanthan gum, trehalose and likewise.

In some embodiment of the present invention, the stabilizer in the composition/formulation is present in a range of 0.1% to 10.0% by weight of the total composition/ formulation.

In some embodiment of the present invention, the plasticizers added to coating of the formulation are selected from the group consisting of propylene glycol, glycerol, glyceryl triacetate (triacetin), triethyl citrate, acetyl triethyl citrate, diethyl phthalate, acetylated monoglycerides, castor oil, mineral oil and like thereof.

In some embodiment of the present invention, the plasticizer in the composition/formulation is present in a range of 0.1% to 5.0% by weight of the total composition/ formulation.

In some embodiment of the present invention, the solvent is selected from water, alcohol, isopropyl alcohol, propylene glycol, mineral oil, benzyl alcohol, benzyl benzoate, flavored glycol, carbon dioxide, castor oil, corn oil (maize), cottonseed oil, dimethyl ether, albumin, dimethylacetamide, ethyl acetate, ethyl lactate, medium-chain triglycerides, methyl lactate, olive oil, peanut oil, polyethylene glycol, polyoxyl, castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, water-miscible solvents, organic polar or non-polar solvents or mixtures thereof.

In a preferred embodiment of the present invention, the solvent in the composition/formulation is used in a quantity sufficient to make the weight of the composition/formulation 100% by weight.

The additional additives include a polymer, a plasticizer, a sweetener, and a powdered flavor, a preservative, a colorant, a surfactant, and other excipients. The powdered flavor composition includes a flavourant associated with a solid carrier. Coating materials such as synthetic polymers, shellac, corn protein (zein) or other polysaccharides, gelatin, fatty acids, waxes, shellac, plastics, and plant fibers and like thereof are used.

In a preferred embodiment of the present invention, the additives are used in a range of 0.1 to 10% w/w of unit dose.

In yet another embodiment, the present invention provides the composition/formulation comprising a therapeutic blend of 2-aminobutanedioic acid or salts thereof and one or more ROS inhibitors or salts thereof along with pharmaceutical excipients, wherein the pharmaceutical excipients are selected from a diluent, a binder, a lubricant, a glidant, an additive, a surfactant, a stabilizer or mixtures thereof.

In a preferred embodiment, the present invention provides the composition/formulation wherein the pharmaceutically acceptable excipients are selected from a group consisting of the diluent is present in a range of 1 to 30%; the binder present is present in a range of 0.1 to 25%; the lubricant is present in a range of 0.1 to 10.0 %; the glidant is present in a range of 0.1 to 5.0%; the additive is present in a range of 0.1 to 10%; the surfactant is present in a range of 0.1 to 5.0%; the stabilizer is present in a range of 0.1 to 5.0%; %; the antioxidant is present in a range of 0.1 to 5.0%; and the plasticizer is present in a range of 0.1 to 5.0%; by weight of total composition.

In further embodiment, compositions containing compounds of the present invention, can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient, or a pharmaceutically acceptable salt thereof.

The magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient.

In general, the total daily dose (in single or divided doses) ranges from about 0.1 mg per day to about 5000 mg per day, preferably about 1mg per day to about 1000 mg per day.

In some embodiment, the total daily dose can be administered in the range of about 1 mg to about 3000 mg per day, and preferably about 2 mg to about 1000 mg per day.

It is further recommended that the dosage be titrated based on individual physiological responses and/or pharmacokinetics. It can be necessary to use dosages outside these ranges in some cases, as will be apparent to those in the art.

The present composition can be used as adult formula by varying the concentration of active ingredients. Further, it is noted that the dietician or nutritionist or certified physician, medical practitioner knows how and when to interrupt, adjust or terminate therapy in conjunction with an individual patient's response.

The use of any and all examples, or exemplary language (e.g., such as) provided herein, is intended merely to better illuminate the invention, and does not pose a limitation on the scope of the invention unless otherwise claimed.

Various other examples of compositions and modifications or adaptations thereof can be devised by a person skilled in the art after reading the foregoing preferred embodiments without departing from the spirit and scope of the invention. All such further examples, modifications and adaptations are included within the scope of the invention.

It will be appreciated by those versed in the art that the present invention makes available novel and useful compositions, which have effects in several administration forms. Also, it will be understood by those with knowledge in the dietary supplement and nutraceutical art, that many embodiments of this invention may be made without departing from the spirit and scope of the invention, and the invention is not to be construed as limited, as it embraces all equivalents therein.

The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in anyway.

The present disclosure is therefore to be considered as in all respects illustrative and not restrictive, the scope of the invention being indicated by the appended claims and examples, and all changes or alterations which come within the ambit of equivalency are intended to be encompassed therein.

EXAMPLES:
Having described the basic aspects of the present invention, the following non-limiting examples illustrate specific embodiments thereof. Those skilled in the art will appreciate that many modifications may be made in the invention without changing the essence of invention.

Example 1: Various compositions/formulations.

i. Composition 1: Tablet / Capsule.
Ingredient mg per unit dose
[R]2-aminobutanedioic acid 500
N,N,N-trimethylglycine hydrochloride 250
2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol acetate salt 50
Magnesium Stearate 0.1-10
Hydroxypropyl Methylcellulose 0.5-10
Microcrystalline Cellulose 0.1-10
Polyvinylpyrrolidone 0.1-10
Starch 0.1-5
Talc 0.1-5
Mannitol 0.1-2
Propylene Glycol QS
Water QS
Average weight 810-900 mg

ii. Composition 2: Tablet / Capsule.
Ingredient mg per unit dose
2-aminobutanedioic acid 500
N,N,N-trimethylglycine hydrochloride 300
2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol 100
Magnesium Stearate 0.1-5
Ascorbic acid 0.1-5
Microcrystalline Cellulose 0.1-10
Colloidal Silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-5
PVPP 0.1-5
Talc 0.1-5
Tween 80 0.1-5
Mannitol 0.1-1
Alcohol QS
Water QS
Average weight 910-1000 mg

iii. Composition 3: Tablet / Capsule.
Ingredient mg per unit dose
(R) 2-aminobutanedioic acid 400
N,N,N-trimethylglycine hydrochloride 250
2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol acetate salt 50
Microcrystalline Cellulose 0.1-10
Silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-5
Stearic acid 0.1-5
Pregelatinized starch 0.1-10
Talc 0.1-5
Tween 80 0.1-5
Polydextrose 0.1-5
PEG QS
Water QS
Average weight 710-760 mg

iv. Composition 4: Tablet / Capsule.
Ingredient mg per unit dose
(R) 2-aminobutanedioic acid 300
N,N,N-trimethylglycine hydrochloride 200
2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol acetate salt 50
Microcrystalline Cellulose 0.1-5
Silicon dioxide 0.1-5
Glycerin 0.1-5
Ethyl Cellulose 0.1-2
Hydroxypropyl Methylcellulose 0.1-10
Magnesium Stearate 0.1-5
Polyvinylpolypyrrolidone 0.1-10
Talc 0.1-5
Polysorbate 20 0.1-2
Mannitol 0.1-2
IPA QS
Water QS
Average weight 560-600 mg

v. Composition 5: Tablet / Capsule.
Ingredient mg per unit dose
(R)2-aminobutanedioic acid 500
N,N,N-trimethylglycine hydrochloride 250
Silicon Dioxide 0.1-2
Medium-chain triglycerides 0.1-5
Microcrystalline Cellulose 0.1-10
Magnesium Stearate 0.1-5
Polyvinylpyrrolidone 0.1-5
Talc 0.1-5
Corn Starch 0.1-5
Sodium ascorbate 0.1-2
Propylene glycol 0.1-1
Water QS
Average weight 760-800 mg

vi. Composition 6: Tablet / Capsule.
Ingredient mg per unit dose
2-aminobutanedioic acid 400
N,N,N-trimethylglycine 40
Microcrystalline Cellulose 0.1-10
Colloidal silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-5
Magnesium Stearate 0.1-5
Polyvinylpyrrolidone 0.1-5
Calcium Phosphate 0.1-5
Ascorbic Acid 0.1-1
Polysorbate 20 0.1-2
Talc 0.1-5
Sucrose 0.1-1
Mannitol 0.1-1
Glycerol 0.1-2
Average weight 450-470mg

vii. Composition 7: Tablet / Capsule.
Ingredient mg per unit dose
2-aminobutanedioic acid 300
N,N,N-trimethylglycine 150
Microcrystalline Cellulose 0.1-5
Silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-10
Magnesium Stearate 0.1-2
Zinc Stearate 0.1-5
Polyvinylpyrrolidone 0.1-3
Mineral Oil 0.1-2.5
Sodium benzoate 0.1-1
Ascorbic Acid 0.1-2
Polysorbate 20 0.1-1
Talc 0.1-1
Dextrose 0.1-1
Mannitol 0.1-1
Water QS
Average weight 460-500 mg

viii. Composition 8: Tablet / Capsule.
Ingredient mg per unit dose
2-aminobutanedioic acid 200
N,N,N-trimethylglycine hydrochloride 200
Microcrystalline Cellulose 0.1-5
Silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-5
Magnesium Stearate 0.1-5
Zinc Stearate 0.1-5
Polyvinylpyrrolidone 0.1-5
Mineral Oil 0.1-2
Sodium benzoate 0.1-1
Ascorbic Acid 0.1-2
Polysorbate 20 0.1-1
Talc 0.1-5
Mannitol 0.1-1
Water QS
Average weight 410-5450 mg

ix. Composition 9: Tablet / Capsule.
Ingredient mg per unit dose
(R) 2-aminobutanedioic acid 500
2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol acetate salt 50
Microcrystalline Cellulose 0.1-5
Silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-5
Magnesium Stearate 0.1-5
Zinc Stearate 0.1-5
Polyvinylpyrrolidone 0.1-5
Mineral Oil 0.1-2
Sodium Ascorbate 0.1-2
Polysorbate 20 0.1-1
Talc 0.1-5
Mannitol 0.1-1
Water QS
Average weight 560-600 mg

x. Composition 10: Tablet / Capsule.
Ingredient mg per unit dose
(R)2-aminobutanedioic acid 400
2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3-methylbenzene-1,4-diol acetate salt 40
Microcrystalline Cellulose 0.1-5
Silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-5
Magnesium Stearate 0.1-5
Zinc Stearate 0.1-5
Polyvinylpyrrolidone 0.1-5
Mineral Oil 0.1-2
Sodium benzoate 0.1-1
Ascorbic Acid 0.1-2
Polysorbate 20 0.1-1
Talc 0.1-5
Mannitol 0.1-1
Water QS
Average weight 460-550 mg

xi. Composition 11: Tablet / Capsule.
Ingredient mg per unit dose
(R)2-aminobutanedioic acid 500
2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol acetate salt 100
Microcrystalline Cellulose 0.1-5
Silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-5
Magnesium Stearate 0.1-5
Zinc Stearate 0.1-5
Polyvinylpyrrolidone 0.1-5
Mineral Oil 0.1-2
Sodium benzoate 0.1-1
Ascorbic Acid 0.1-2
Polysorbate 20 0.1-1
Talc 0.1-5
Mannitol 0.1-1
Water QS
Average weight 610-700 mg

xii. Composition 12: Tablet / Capsule.
Ingredient mg per unit dose
(R) 2-aminobutanedioic acid 250
2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol acetate salt 10
Magnesium Stearate 0.1-5
Ascorbic acid 0.1-5
Microcrystalline Cellulose 0.1-10
Colloidal Silicon dioxide 0.1-5
Hydroxypropyl Methylcellulose 0.1-5
Polyvinylpyrrolidone 0.1-5
Talc 0.1-5
Tween 80 0.1-5
Sucrose 0.1-2
Sorbitol 0.1-1
Alcohol QS
Water QS
Average weight 265-320 mg

Example: 2
A study to evaluate the effect of test substance in stimulating and promoting sperm production in men with low fertility.
Study Design and Participants:
The pivotal study was involved 90 patients which are suffering from one or more male infertility conditions such as oligospermia, teratozoospermia, asthenoteratospermia, azoospermia, asthenospermia and asthenozoospermic are divided in to 9 groups of 10 each dosed with test substance for 11 weeks.

Group Design:

Table I: Group 1 (Control)

Patients Diagnosis Age (Y)
1 Oligospermia 30
2 Teratozoospermia 32
3 Asthenoteratospermia 28
4 Oligospermia 35
5 Azoospermia 31
6 Asthenoteratospermia 29
7 Oligospermia 33
8 Teratozoospermia 34
9 Asthenoteratospermia 30
10 Oligospermia 31

Table II: Group 2 (Treated with 500mg of (R)2-aminobutanedioic acid)

Patients Diagnosis Age (Y)
11 Asthenozoospermic 28
12 Terato + Oligospermia 32
13 Azoospermia 31
14 Asthenoteratospermia 29
15 Oligospermia 33
16 Terato + Oligospermia 31
17 Asthenozoospermic 28
18 Teratozoospermia 30
19 Asthenoteratospermia 32
20 Terato + Oligospermia 29

Table III: Group 3 (Treated with 250 mg N,N,N-trimethylglycine hydrochloride)

Patients Diagnosis Age (Y)
21 Asthenozoospermic 31
22 Oligospermia 33
23 Asthenoteratospermia 34
24 Azoospermia 30
25 Terato + Oligospermia 31
26 Asthenozoospermic 29
27 Terato + Oligospermia 32
28 Azoospermia 31
29 Asthenoteratospermia 28
30 Oligospermia 30

Table IV: Group 4 (Treated with 50 mg of 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol acetate salt )

Patients Diagnosis Age (Y)
31 Terato + Oligospermia 33
32 Asthenoteratospermia 31
33 Oligospermia 29
34 Asthenozoospermic 32
35 Teratozoospermia 31
36 Asthenoteratospermia 28
37 Oligospermia 33
38 Terato + Oligospermia 34
39 Azoospermia 30
40 Asthenoteratospermia 31

Table V: Group 5 (Treated with combination of 500 mg of (R) 2-aminobutanedioic acid and 250 mg N,N,N-trimethylglycine)

Patients Diagnosis Age (Y)
41 Asthenospermia 29
42 Azoospermia 30
43 Oligospermia 31
44 Terato + Oligospermia 28
45 Teratozoospermia 33
46 Teratozoospermia 32
47 Asthenozoospermic 31
48 Oligospermia 29
49 Terato + Oligospermia 32
50 Azoospermia 30

Table VI: Group 6 (Treated with combination of 500 mg of (R) 2-aminobutanedioic acid and 50 mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyl tetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol) acetate

Patients Diagnosis Age (Y)
51 Azoospermia 32
52 Asthenospermia 29
53 Oligospermia 31
54 Teratozoospermia 28
55 Terato + Oligospermia 33
56 Teratozoospermia 30
57 Asthenozoospermic 31
58 Oligospermia 29
59 Azoospermia 30
60 Asthenoteratospermia 32

Table VII: Group 7 (Treated with combination of 250 mg of 2-aminobutanedioic acid, 25mg of N,N,N-trimethylglycine and 2.5 mg of 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate

Patients Diagnosis Age (Y)
61 Asthenospermia 29
62 Teratozoospermia 32
63 Oligospermia 31
64 Terato + Oligospermia 28
65 Teratozoospermia 33
66 Azoospermia 32
67 Asthenozoospermic 31
68 Oligospermia 29
69 Asthenospermia 32
70 Azoospermia 31

Table VIII: Group 8 (Treated with combination of 250 mg of (R) 2-aminobutanedioic acid, 250 mg N,N,N-trimethylglycine and 250 mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol aceate

Patients Diagnosis Age (Y)
71 Asthenospermia 29
72 Azoospermia 32
73 Oligospermia 32
74 Terato + Oligospermia 28
75 Teratozoospermia 33
76 Azoospermia 30
77 Asthenozoospermic 31
78 Oligospermia 29
79 Asthenospermia 32
80 Terato + Oligospermia 31

Table IX: Group 9 (Treated with combination of 500 mg of 2-aminobutanedioic acid, 250mg N,N,N-trimethylglycine and 50mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate.

Patients Diagnosis Age (Y)
81 Asthenospermia 29
82 Azoospermia 32
83 Oligospermia 31
84 Teratozoospermia 28
85 Asthenozoospermic 33
86 Teratozoospermia 30
87 Asthenozoospermic 31
88 Oligospermia 29
89 Asthenoteratospermia 32
90 Azoospermia 30

Inclusion Criteria:
1. Male partner of a couple presenting for infertility.
2. Moderate abnormalities of semen parameters (Mean sperm density <20 million, but = 3 million/ml), and/or motility < 50%, and/or < 4% abnormal morphology on at least two separate occasions.
3. Age 28-35 years.
4. Normal renal function defined as Glomerular filtration rate > 90

Exclusion Criteria:
1. Patients that are currently taking thiazide, cyclosporin, lithium, and allopurinol or the use of these medications in the last 2 weeks.
2. The frequent use of NSAIDS (3 or more times a week).
3. Vasectomy reversal.
4. Regular use of tobacco products.
5. Mean white blood cell count >1 million/ml in the ejaculate.
6. Inability or unwillingness to participate in evaluations required by the study.
7. Potassium > 5.0.
8. Systolic blood pressure < 90 mmHg.
9. Currently use of (ACEI)Angiotensin-converting enzyme inhibitors

Observations:
1. Semen Volume in milliliter (ml):

Table I: Group 1 (Control)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
1 Oligospermia 30 3.4 3.4 0

0.01
2 Teratozoospermia 32 3.3 3.3 0
3 Asthenoteratospermia 28 3 3 0
4 Oligospermia 35 2.5 2.5 0
5 Azoospermia 31 3.5 3.5 0
6 Asthenoteratospermia 29 3.2 3.2 0
7 Oligospermia 33 2.8 2.8 0
8 Teratozoospermia 34 2.6 2.6 0
9 Asthenoteratospermia 30 3.4 3.5 0.1
10 Oligospermia 31 3.2 3.2 0

Table II: Group 2 (Treated with 500mg of 2-aminobutanedioic acid)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
11 Asthenozoospermic 28 2.8 2.9 0.1

0.07
12 Terato + Oligospermia 32 2.6 2.65 0.05
13 Azoospermia 31 3.5 3.55 0.05
14 Asthenoteratospermia 29 3.3 3.4 0.1
15 Oligospermia 33 3.1 3.3 0.1
16 Terato + Oligospermia 31 2.4 2.5 0.1
17 Asthenozoospermic 28 3.6 3.6 0
18 Teratozoospermia 30 3.5 3.52 0.02
19 Asthenoteratospermia 32 2.9 3 0.1
20 Terato + Oligospermia 29 2.7 2.78 0.08

Table III: Group 3 (Treated with 250 mg N,N,N-trimethylglycine hydrochloride)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
21 Asthenozoospermic 31 3.3 3.33 0.03

0.02
22 Oligospermia 33 2.9 2.92 0.02
23 Asthenoteratospermia 34 3 3.1 0.1
24 Azoospermia 30 3.5 3.5 0
25 Terato + Oligospermia 31 2.8 2.81 0.01
26 Asthenozoospermic 29 3.3 3.31 0.01
27 Terato + Oligospermia 32 3.6 3.62 0.02
28 Azoospermia 31 2.5 2.51 0.01
29 Asthenoteratospermia 28 3 3.05 0.05
30 Oligospermia 30 3.7 3.7 0

Table IV: Group 4 (Treated with 50 mg of 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol acetate)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
31 Terato + Oligospermia 33 3.4 3.55 0.15

0.11
32 Asthenoteratospermia 31 3.3 3.5 0.2
33 Oligospermia 29 3 3.15 0.15
34 Asthenozoospermic 32 2.6 2.75 0.15
35 Teratozoospermia 31 3.5 3.6 0.1
36 Asthenoteratospermia 28 3.4 3.41 0.01
37 Oligospermia 33 2.7 2.82 0.12
38 Terato + Oligospermia 34 3.1 3.2 0.1
39 Azoospermia 30 3.6 3.62 0.02
40 Asthenoteratospermia 31 3.2 3.32 0.12

Table V: Group 5 (Treated with combination of 500 mg of (R)2-aminobutanedioic acid and 250 mg N,N,N-trimethylglycine hydrochloride)

Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
41 Asthenospermia 29 3.2 3.34 0.14

0.15
42 Azoospermia 30 2.7 2.88 0.18
43 Oligospermia 31 3.1 3.23 0.13
44 Terato + Oligospermia 28 3.4 3.56 0.16
45 Teratozoospermia 33 2.9 3.10 0.20
46 Teratozoospermia 32 3.5 3.68 0.18
47 Asthenozoospermic 31 3.1 3.23 0.13
48 Oligospermia 29 3.2 3.35 0.15
49 Terato + Oligospermia 32 3.4 3.59 0.19
50 Azoospermia 30 2.8 2.92 0.12

Table VI: Group 6 (Treated with combination of 500 mg of (R) 2-aminobutanedioic acid and 50 mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyl
tetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol acetate)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
51 Azoospermia 32 3.2 3.49 0.29

0.24
52 Asthenospermia 29 2.7 2.9 0.2
53 Oligospermia 31 3.6 3.81 0.21
54 Teratozoospermia 28 3.1 3.35 0.25
55 Terato + Oligospermia 33 3.2 3.44 0.24
56 Teratozoospermia 30 3.0 3.27 0.27
57 Asthenozoospermic 31 3.3 3.55 0.25
58 Oligospermia 29 3.1 3.38 0.28
59 Azoospermia 30 2.9 3.1 0.2
60 Asthenoteratospermia 32 3.5 3.72 0.22

Table VII: Group 7 (Treated with combination of 250 mg of (R) 2-aminobutanedioic acid, 25 mg of N,N,N-trimethylglycine and 2.5 mg of 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
61 Asthenospermia 29 3.2 3.51 0.31

0.32
62 Teratozoospermia 32 2.8 3.13 0.33
63 Oligospermia 31 3.6 3.9 0.3
64 Terato + Oligospermia 28 3.1 3.44 0.34
65 Teratozoospermia 33 2.6 2.97 0.37
66 Azoospermia 32 3.4 3.68 0.28
67 Asthenozoospermic 31 2.8 3.18 0.38
68 Oligospermia 29 3.5 3.71 0.21
69 Asthenospermia 32 3.0 3.32 0.32
70 Azoospermia 31 3.1 3.46 0.36

Table VIII: Group 8 (Treated with combination of 250 mg of (R)2-aminobutanedioic acid, 250mg N,N,N-trimethylglycine and 250mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
71 Asthenospermia 29 3.1 3.47 0.37

0.37
72 Azoospermia 32 3.4 3.75 0.35
73 Oligospermia 32 2.8 3.19 0.39
74 Terato + Oligospermia 28 3.2 3.55 0.35
75 Teratozoospermia 33 3.6 3.98 0.38
76 Azoospermia 30 3.1 3.5 0.40
77 Asthenozoospermic 31 2.9 3.29 0.39
78 Oligospermia 29 2.5 2.88 0.38
79 Asthenospermia 32 3.2 3.59 0.39
80 Terato + Oligospermia 31 3.5 3.87 0.37

Table IX: Group 9 (Treated with combination of 500 mg of (R) 2-aminobutanedioic acid, 250mg N,N,N-trimethylglycine and 50mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
81 Asthenospermia 29 3.2 3.71 0.51

0.48
82 Azoospermia 32 2.5 2.88 0.38
83 Oligospermia 31 3.7 4.27 0.57
84 Teratozoospermia 28 3 3.48 0.48
85 Asthenozoospermic 33 3.4 3.94 0.54
86 Teratozoospermia 30 2.6 3.01 0.41
87 Asthenozoospermic 31 3.5 4.05 0.55
88 Oligospermia 29 3.3 3.82 0.52
89 Asthenoteratospermia 32 3.1 3.58 0.48
90 Azoospermia 30 2.7 3.13 0.43

2. Sperm count in million per milliliter(ml):

Table I: Group 1 (Control)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
1 Oligospermia 30 27.2 28 0.8

0.22
2 Teratozoospermia 32 7.8 8.1 0.3
3 Asthenoteratospermia 28 15.2 15 -0.2
4 Oligospermia 35 13.8 14 0.2
5 Azoospermia 31 0 0 0
6 Asthenoteratospermia 29 8.3 8.6 0.3
7 Oligospermia 33 14.5 15 0.5
8 Teratozoospermia 34 17.56 18.2 0.64
9 Asthenoteratospermia 30 27.1 26 -1.1
10 Oligospermia 31 8.2 9 0.8

Table II: Group 2 (Treated with 500mg of (R)2-aminobutanedioic acid)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
11 Asthenozoospermic 28 14.1 19.2 5.1

7.51
12 Terato + Oligospermia 32 22.1 32.1 10
13 Azoospermia 31 0 9 9
14 Asthenoteratospermia 29 7.5 12.95 5.45
15 Oligospermia 33 15.3 21 5.7
16 Terato + Oligospermia 31 25.05 39.05 14
17 Asthenozoospermic 28 26.9 36 9.1
18 Teratozoospermia 30 7.3 11 3.7
19 Asthenoteratospermia 32 13.4 19 5.6
20 Terato + Oligospermia 29 15.48 23 7.52

Table III: Group 3 (Treated with 250 mg N,N,N-trimethylglycine hydrochloride)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
21 Asthenozoospermic 31 27.6 31 3.4

2.6
22 Oligospermia 33 8.2 11 2.8
23 Asthenoteratospermia 34 9 12 3
24 Azoospermia 30 10.1 14 3.9
25 Terato + Oligospermia 31 7.9 9.2 1.3
26 Asthenozoospermic 29 7.7 9.5 1.8
27 Terato + Oligospermia 32 27.4 32 4.6
28 Azoospermia 31 0 0 0
29 Asthenoteratospermia 28 13.2 16.2 3
30 Oligospermia 30 6.9 9.1 2.2

Table IV: Group 4 (Treated with 50 mg of (R)2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol acetate)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
31 Terato + Oligospermia 33 8.5 11.8 3.3

5.77
32 Asthenoteratospermia 31 17.33 24.33 7
33 Oligospermia 29 11.7 20.91 9.21
34 Asthenozoospermic 32 9.1 15.76 6.66
35 Teratozoospermia 31 11 16.48 5.48
36 Asthenoteratospermia 28 10.4 18.48 8.08
37 Oligospermia 33 9.7 15.01 5.31
38 Terato + Oligospermia 34 15.4 23.4 8
39 Azoospermia 30 0 0 0
40 Asthenoteratospermia 31 8.8 13.46 4.66

Table V: Group 5 (Treated with combination of 500 mg of (R) 2-aminobutanedioic acid and 250 mg N,N,N-trimethylglycine hydrochloride)

Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
41 Asthenospermia 29 12.9 26.02 13.12

12.34
42 Azoospermia 30 0 9.61 9.61
43 Oligospermia 31 8.5 20.48 11.98
44 Terato + Oligospermia 28 22.7 34.7 12
45 Teratozoospermia 33 12.1 24.27 12.17
46 Teratozoospermia 32 17.4 30.95 13.55
47 Asthenozoospermic 31 19.6 33.36 13.76
48 Oligospermia 29 12.4 28.2 15.8
49 Terato + Oligospermia 32 25.4 37.1 11.7
50 Azoospermia 30 0 10.01 10.01

Table VI: Group 6 (Treated with combination of 500 mg of (R) 2-aminobutanedioic acid and 50 mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyl
tetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3-methylbenzene-1,4-diol acetate)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
51 Azoospermia 32 0 10.48 10.48

14.92
52 Asthenospermia 29 12.4 28.65 16.25
53 Oligospermia 31 7.9 23.4 15.5
54 Teratozoospermia 28 9.8 26.69 16.89
55 Terato + Oligospermia 33 26.8 41.74 14.94
56 Teratozoospermia 30 12.6 29.56 16.96
57 Asthenozoospermic 31 20.13 35.32 15.19
58 Oligospermia 29 14.5 31.25 16.75
59 Azoospermia 30 0 10.17 10.17
60 Asthenoteratospermia 32 13.9 29.97 16.07

Table VII: Group 7 (Treated with combination of 250 mg of (R) 2-aminobutanedioic acid, 25 mg of N,N,N-trimethylglycine hydrochloride and 2.5 mg of 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
61 Asthenospermia 29 12.5 27.93 15.43

16.62
62 Teratozoospermia 32 17.9 33.67 15.77
63 Oligospermia 31 11.2 27.74 16.54
64 Terato + Oligospermia 28 22.3 36.62 14.32
65 Teratozoospermia 33 15.5 35.62 20.12
66 Azoospermia 32 0 16.19 16.19
67 Asthenozoospermic 31 24.7 39.88 15.18
68 Oligospermia 29 14.67 31.47 16.80
69 Asthenospermia 32 12.1 30.75 18.65
70 Azoospermia 31 0 17.26 17.26

Table VIII: Group 8 (Treated with combination of 250 mg of (R) 2-aminobutanedioic acid, 250 mg N,N,N-trimethylglycine hydrochloride and 250 mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate )
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
71 Asthenospermia 29 11.8 27.59 15.79

16.89
72 Azoospermia 32 0 17.65 17.65
73 Oligospermia 32 13.6 30.47 16.87
74 Terato + Oligospermia 28 24.9 43.35 18.45
75 Teratozoospermia 33 9.6 25.55 15.95
76 Azoospermia 30 0 16.22 16.22
77 Asthenozoospermic 31 14.32 31.15 16.83
78 Oligospermia 29 10.9 28.32 17.42
79 Asthenospermia 32 12.2 29 16.8
80 Terato + Oligospermia 31 23.2 40.12 16.92

Table IX: Group 9 (Treated with combination of 500 mg of (R) 2-aminobutanedioic acid, 250mg N,N,N-trimethylglycine HCl and 50mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
81 Asthenospermia 29 12.5 26.4 13.9

17.08
82 Azoospermia 32 0 16.5 16.5
83 Oligospermia 31 6.9 19.0 12.1
84 Teratozoospermia 28 14.845 29.9 15.05
85 Asthenozoospermic 33 26.7 50.1 23.4
86 Teratozoospermia 30 16.09 33.1 17.01
87 Asthenozoospermic 31 23.8 48.2 24.4
88 Oligospermia 29 7.6 19.0 11.4
89 Asthenoteratospermia 32 14.8 33.4 18.6
90 Azoospermia 30 0 18.5 18.5

3. Sperm Motility in PR (%):

Table I: Group 1 (Control)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
1 Oligospermia 30 16 15 -1

0
2 Teratozoospermia 32 26 24 -2
3 Asthenoteratospermia 28 9 10 1
4 Oligospermia 35 10 11 1
5 Azoospermia 31 0 0 0
6 Asthenoteratospermia 29 24 24 0
7 Oligospermia 33 18 18 0
8 Teratozoospermia 34 6 7 1
9 Asthenoteratospermia 30 18 18 0
10 Oligospermia 31 24 24 0

Table II: Group 2 (Treated with 500mg of (R) 2-aminobutanedioic acid)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
11 Asthenozoospermic 28 15 25 10

6.6
12 Terato + Oligospermia 32 7 9 2
13 Azoospermia 31 0 16 16
14 Asthenoteratospermia 29 24 28 4
15 Oligospermia 33 19 25 6
16 Terato + Oligospermia 31 8 11 3
17 Asthenozoospermic 28 18 25 7
18 Teratozoospermia 30 22 28 6
19 Asthenoteratospermia 32 17 25 8
20 Terato + Oligospermia 29 11 15 4

Table III: Group 3 (Treated with 250 mg N,N,N-trimethylglycine HCl)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
21 Asthenozoospermic 31 21 26 5

4.3
22 Oligospermia 33 21 28 7
23 Asthenoteratospermia 34 9 12 3
24 Azoospermia 30 0 0 0
25 Terato + Oligospermia 31 26 30 4
26 Asthenozoospermic 29 25 31 6
27 Terato + Oligospermia 32 18 22 4
28 Azoospermia 31 0 0 0
29 Asthenoteratospermia 28 16 26 10
30 Oligospermia 30 24 28 4

Table IV: Group 4 (Treated with 50 mg of 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol acetate)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
31 Terato + Oligospermia 33 16 23 7

4.6
32 Asthenoteratospermia 31 26 28 2
33 Oligospermia 29 9 15 6
34 Asthenozoospermic 32 10 14 4
35 Teratozoospermia 31 18 25 7
36 Asthenoteratospermia 28 24 28 4
37 Oligospermia 33 18 26 8
38 Terato + Oligospermia 34 6 10 4
39 Azoospermia 30 0 0 0
40 Asthenoteratospermia 31 24 28 4

Table V: Group 5 (Treated with combination of 500 mg of 2-aminobutanedioic acid and 250 mg N,N,N-trimethylglycine HCl)

Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
41 Asthenospermia 29 27 39 12

12.20
42 Azoospermia 30 0 16 16
43 Oligospermia 31 11 23 12
44 Terato + Oligospermia 28 13 23 10
45 Teratozoospermia 33 14 25 11
46 Teratozoospermia 32 27 39 12
47 Asthenozoospermic 31 10 22 12
48 Oligospermia 29 23 33 10
49 Terato + Oligospermia 32 9 19 10
50 Azoospermia 30 0 17 17

Table VI: Group 6 (Treated with combination of 500 mg of (R) 2-aminobutanedioic acid and 50 mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyl
tetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3-methylbenzene-1,4-diol acetate)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
51 Azoospermia 32 0 16 16

14.70
52 Asthenospermia 29 24 38 14
53 Oligospermia 31 25 39 14
54 Teratozoospermia 28 23 38 15
55 Terato + Oligospermia 33 21 35 14
56 Teratozoospermia 30 20 35 15
57 Asthenozoospermic 31 13 28 15
58 Oligospermia 29 17 31 14
59 Azoospermia 30 0 16 16
60 Asthenoteratospermia 32 22 18 14

Table VII: Group 7 (Treated with combination of 250 mg of (R) 2-aminobutanedioic acid, 25mg of N,N,N-trimethylglycine HCl and 2.5 mg of 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
61 Asthenospermia 29 25 44 19
62 Teratozoospermia 32 19 37 18
63 Oligospermia 31 21 40 19
64 Terato + Oligospermia 28 25 49 24
65 Teratozoospermia 33 12 30 18 20.2
66 Azoospermia 32 0 22 22
67 Asthenozoospermic 31 19 39 20
68 Oligospermia 29 14 37 23
69 Asthenospermia 32 22 40 18
70 Azoospermia 31 0 21 21

Table VIII: Group 8 (Treated with combination of 250 mg of (R) 2-aminobutanedioic acid, 250 mg N,N,N-trimethylglycine HCl and 250mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
71 Asthenospermia 29 21 44 23

22.9
72 Azoospermia 32 0 22 22
73 Oligospermia 32 23 44 21
74 Terato + Oligospermia 28 17 41 24
75 Teratozoospermia 33 16 37 21
76 Azoospermia 30 0 23 23
77 Asthenozoospermic 31 20 44 24
78 Oligospermia 29 18 44 26
79 Asthenospermia 32 24 46 22
80 Terato + Oligospermia 31 20 43 23

Table IX: Group 9 (Treated with combination of 500 mg of (R) 2-aminobutanedioic acid, 250mg N,N,N-trimethylglycine and 50mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
81 Asthenospermia 29 23 48 25

27.5
82 Azoospermia 32 0 41 41
83 Oligospermia 31 21 46 25
84 Teratozoospermia 28 12 33 21
85 Asthenozoospermic 33 0 39 39
86 Teratozoospermia 30 15 38 23
87 Asthenozoospermic 31 14 34 20
88 Oligospermia 29 26 54 28
89 Asthenoteratospermia 32 9 28 19
90 Azoospermia 30 0 34 34

4. Sperm Capacitation (% Sperms Binds with hyaluronic acid (HA))
Table I: Group 1 (Control)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
1 Oligospermia 30 47 47 0

-1.2
2 Teratozoospermia 32 37 36 -1
3 Asthenoteratospermia 28 49 44 -5
4 Oligospermia 35 55 51 -4
5 Azoospermia 31 0 0 0
6 Asthenoteratospermia 29 42 43 1
7 Oligospermia 33 51 51 0
8 Teratozoospermia 34 57 56 -1
9 Asthenoteratospermia 30 37 37 0
10 Oligospermia 31 38 36 -2

Table II: Group 2 (Treated with 500mg of 2-aminobutanedioic acid)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
11 Asthenozoospermic 28 48 58 10

10.6
12 Terato + Oligospermia 32 56 64 8
13 Azoospermia 31 0 26 26
14 Asthenoteratospermia 29 38 44 6
15 Oligospermia 33 50 60 10
16 Terato + Oligospermia 31 55 67 12
17 Asthenozoospermic 28 41 51 10
18 Teratozoospermia 30 44 47 3
19 Asthenoteratospermia 32 52 62 10
20 Terato + Oligospermia 29 54 65 11

Table III: Group 3 (Treated with 250 mg N,N,N-trimethylglycine HCl)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
21 Asthenozoospermic 31 35 49 14

7.2
22 Oligospermia 33 38 41 3
23 Asthenoteratospermia 34 49 61 12
24 Azoospermia 30 0 0 0
25 Terato + Oligospermia 31 42 53 11
26 Asthenozoospermic 29 38 46 8
27 Terato + Oligospermia 32 51 59 8
28 Azoospermia 31 0 0 0
29 Asthenoteratospermia 28 46 51 5
30 Oligospermia 30 46 57 11

Table IV: Group 4 (Treated with 50 mg of 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol acetate)
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
31 Terato + Oligospermia 33 48 57 9

8.8
32 Asthenoteratospermia 31 56 61 5
33 Oligospermia 29 38 54 16
34 Asthenozoospermic 32 41 44 3
35 Teratozoospermia 31 50 60 10
36 Asthenoteratospermia 28 55 68 13
37 Oligospermia 33 41 57 16
38 Terato + Oligospermia 34 38 44 6
39 Azoospermia 30 0 0 0
40 Asthenoteratospermia 31 54 64 10

Table V: Group 5 (Treated with combination of 500 mg of (R)2-aminobutanedioic acid and 250 mg N,N,N-trimethylglycine HCl)

Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
41 Asthenospermia 29 35 57 22

20.20
42 Azoospermia 30 0 23 23
43 Oligospermia 31 39 59 20
44 Terato + Oligospermia 28 54 78 24
45 Teratozoospermia 33 44 59 15
46 Teratozoospermia 32 48 65 17
47 Asthenozoospermic 31 42 60 18
48 Oligospermia 29 44 64 20
49 Terato + Oligospermia 32 43 61 18
50 Azoospermia 30 0 25 25

Table VI: Group 6 (Treated with combination of 500 mg of (R) 2-aminobutanedioic acid and 50 mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyl
tetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 -methylbenzene-1,4-diol acetate
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
51 Azoospermia 32 0 24 24

23.80
52 Asthenospermia 29 37 60 23
53 Oligospermia 31 38 63 25
54 Teratozoospermia 28 53 80 27
55 Terato + Oligospermia 33 49 70 21
56 Teratozoospermia 30 51 76 25
57 Asthenozoospermic 31 45 68 23
58 Oligospermia 29 47 72 25
59 Azoospermia 30 0 23 23
60 Asthenoteratospermia 32 50 72 22

Table VII: Group 7 (Treated with combination of 250 mg of (R) 2-aminobutanedioic acid, 25mg of N,N,N-trimethylglycine HCl and 2.5 mg of 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate

Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
61 Asthenospermia 29 38 70 32

29.50
62 Teratozoospermia 32 53 78 25
63 Oligospermia 31 40 71 31
64 Terato + Oligospermia 28 53 88 33
65 Teratozoospermia 33 47 74 27
66 Azoospermia 32 0 34 34
67 Asthenozoospermic 31 44 68 24
68 Oligospermia 29 54 85 31
69 Asthenospermia 32 34 62 28
70 Azoospermia 31 0 30 30

Table VIII: Group 8 (Treated with combination of 250 mg of (R) 2-aminobutanedioic acid, 250mg N,N,N-trimethylglycine HCl and 250mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
71 Asthenospermia 29 37 73 36

31.70
72 Azoospermia 32 0 29 29
73 Oligospermia 32 38 33 33
74 Terato + Oligospermia 28 56 91 35
75 Teratozoospermia 33 44 72 28
76 Azoospermia 30 0 35 35
77 Asthenozoospermic 31 41 70 29
78 Oligospermia 29 52 87 35
79 Asthenospermia 32 35 62 27
80 Terato + Oligospermia 31 52 82 30

Table IX: Group 9 (Treated with combination of 500 mg of (R) 2-aminobutanedioic acid, 250mg N,N,N-trimethylglycine HCl and 50mg 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol acetate
Patients Diagnosis Age (Y) Baseline Week 11 Improvement Mean Improvement
81 Asthenospermia 29 38 74 36

34.80
82 Azoospermia 32 0 33 33
83 Oligospermia 31 23 69 46
84 Teratozoospermia 28 43 82 39
85 Asthenozoospermic 33 38 68 30
86 Teratozoospermia 30 55 88 33
87 Asthenozoospermic 31 35 71 36
88 Oligospermia 29 32 42 10
89 Asthenoteratospermia 32 51 82 31
90 Azoospermia 30 0 54 54

Results:
Improvement in Mean
Semen Volume (ml) Sperm count (million/ml) Sperm Motility (%) Sperm Capacitation
(% )
Group I 0.01 0.22 0 -1.2
Group II 0.07 7.51 6.6 10.6
Group III 0.02 2.6 4.3 7.2
Group IV 0.11 5.77 4.6 8.8
Group V 0.15 12.34 12.20 20.20
Group VI 0.24 14.92 14.70 23.80
Group VII 0.32 16.62 20.20 29.50
Group VIII 0.37 16.89 22.90 31.70
Group IX 0.48 17.08 27.5 34.80

Conclusion:
In the present study, the compositions for combination of two ingredients, i.e., Group V and Group VI as well as the compositions for combination of three ingredients, i.e., Group VII, Group VIII and Group IX shows significant improvements in sperm volume, sperm count, sperm motility and sperm capcitation when compared it with individual ingredient. It is concluded that the compositions of the present invention significantly improve hypothalamic pituitary gonadal (HPG) axis activity and hence, overall male fertility. ,CLAIMS:1. A bioactive composition for improving hypothalamic pituitary gonadal (HPG) axis activity, comprising:
a. 2-aminobutanedioic acid or salt thereof or isomer thereof;
b. at least one ROS inhibitor or salt thereof; and
c. at least one pharmaceutically acceptable excipient.

2. The composition as claimed in claim 1, wherein the ROS inhibitor is selected from N,N,N-trimethylglycine and 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3-methylbenzene-1,4-diol or salts thereof.

3. The composition as claimed in claim 1, wherein the 2-aminobutanedioic acid or salt thereof or isomer thereof is present in a range of 10% to 95% by weight of the total composition.

4. The composition as claimed in claim 1, wherein the ROS inhibitor or salt thereof is present in a range of 1% to 50% by weight of the total composition.

5. The composition as claimed in claim 1, wherein combination of the 2-aminobutanedioic acid or salt thereof and ROS inhibitor(s) or salt(s) thereof are present in the weight ratio of 1: 0.01 to 1:1 in the composition.

6. The composition as claimed in claims 1 and 2, wherein combination of the 2-aminobutanedioic acid, the N,N,N-trimethylglycine and the 2-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19, 23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-5,6-dimethoxy-3 methylbenzene-1,4-diol or salts thereof are present in the weight ratio of 1:0.1:0.01 to 1:1:1 in the composition.

7. The composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient is selected from diluent, binder, surfactant, lubricant, glidant, additive, solvent or mixtures thereof.

8. The composition as claimed in claim 7, wherein the diluent is present in a range of 0.1 to 30%; the binder is present in a range of 0.1 to 25%; the lubricant is present in a range of 0.1 to 10.0 %; the glidant is present in a range of 0.1 to 5.0%; the additive is present in a range of 0.1 to 10%; the surfactant is present in a range of 0.1 to 5.0%; the stabilizer is present in a range of 0.1 to 5.0%; %; the antioxidant is present in a range of 0.01 to 5.0%; and the plasticizer is present in a range of 0.1 to 5.0%; by weight of total composition.

9. The composition as claimed in claim 1, wherein the composition increases the sperm volume by 0.48 ml as compared to normal control.

10. The composition as claimed in claim 1, wherein the composition increases the sperm count by 17.08 million/ml as compared to normal control.

11. The composition as claimed in claim 1, wherein the composition increases the sperm motility by 27.5% as compared to normal control.

12. The composition as claimed in claim 1, wherein the composition increases the sperm capacitation by 34.80 % as compared to normal control.

13. The composition as claimed in claim 1, wherein effective unit dose for an oral
administration of the composition is formulated in a range of 1 to 1000 mg.