DESC:FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition for use in controlling male infertility with special reference to oligospermia. More particularly, the invention relates to a synergistic combination or composition comprising cordycepin enriched Cordyceps militaris extract as an active ingredient and other ingredients.

BACKGROUND OF THE INVENTION
Infertility is always been a one of the most concerned clinical problem through ages and in present scenario affects 8–12% of the couples worldwide (Kumar & Singh, 2015). In humans, 40-50% of fertility accounts for “male factor” infertility and is demonstrated by deficiencies in the semen and its quality (Cooper et. al., 2010). Further, among a number of male infertility factors, oligospermia termed for low sperm concentration or count comprised of significant proportion (Sabra & Al-Harbi, 2014). As per WHO, the low reference limit of sperm concentration or total sperm number is 15 million spermatozoa/mL and 39 million spermatozoa per ejaculate respectively, below which the male is considered to have oligospermia. Based upon the stage at which spermatogenesis has been altered, oligospermia can be divided as pre-testicular, testicular, and post-testicular. While pre-testicular stage occurs due to impaired functioning of hypothalamic-pituitary-gonadal (HPG) axis resulting in aberrant to no stimulation of testes to produce sperm, testicular and post-testicular stage arises due to failure of testicular function and physical causes such as obstruction respectively.

A number of pharmacological agents are available as the first line of treatment of male infertility including gonadotropin releasing hormones, gonadotropins, dopamine agonists, aromatase inhibitors, and selective estrogen receptor modulators (Dabaja & Schlegel, 2014). However, these pharmacological therapies have questionable efficacy due to their success in smaller number of patients where the causes are relatively well-defined and understood with adverse effects. This leads to the development of holistic, complementary, and alternative approaches to treat male infertility.

In this context, an entomopathogenic fungus, Cordyceps sp. can serve as a potential candidate for ethno-pharmacological use. Cordyceps militaris, of phyla Ascomycota and order hypocreales is popularly known as ‘‘winter-worm summer-grass’’, as it grows parasitically on lepidopteron larvae and pupae of insects and spiders in winters while its fruiting body appears in summers (Wang et. al., 2008). Among a variety of pharmacologically bioactive compounds of Cordyceps sp., cordycepin has been reported to execute broad-spectrum biological activities over hepatic, renal, cardiovascular, respiratory, nervous, sexual, immunological systems. Cordycepin have also been recorded to exert anti-cancer, anti-oxidant, anti-inflammatory and anti-microbial activities (Zhou et. al., 2008; Wang et. al., 2011; Lee et. al., 2011a, b; Zhang et. al., 2012; Patel & Goyal 2012; Yue et. al., 2012). Further, greater yield of Cordycepin is found in Cordyceps militaris which is actually a synthetically cultivated species with similar benefits as that of naturally occurring species, Cordyceps sinensis (Shrestha et. al., 2012; Zhou et. al., 2009; Kim & Yun, 2005).

With respect to its effect over male reproductive system, a number of studies reported that supplementation of cordycepin enriched C. militaris resulted in enhanced sperm quality, quantity, and motility due to increased testosterone and estradiol-17 serum concentrations (Chang et. al., 2008; Hong et. al., 2011). Another study conducted by Patel and Ingalhalli (2013) revealed the increased semen production and sperm quality in boars after administration of Cordycepin militaris.

A wide variety of compositions with cordycepin as one of the main constituents have been constituted to improve sexual performance and fertility.
US9629866 refers the use of cordycepin or derivatives including pharmaceutically acceptable salts, esters of crodycepin or glycosides formed by cordycepin and saccharides thereof in manufacture of medicaments for anti-depression.

US9572847 discloses an herbal extract manufactured by mingling Antrodia cinnamomea and Cordyceps militaris in a weight ratio between 1:5 and 5:1 to obtain a herbal solution for treatment of a lung tumor in a subject in need thereof.
KR20150016795A discloses a pharmaceutical composition and a nutraceutical formulation for preventing and treating sub-infertility in rats using cordycepin as an active ingredient.

CN104887719A refers to the protective application of selenium-rich cordyceps in electromagnetic radiation induced reproductive system damage in mice.

CN108159265A discloses the composition development in the field of medicinal foods for male infertility using cordycepin. The invention relates to the preparation method and its use thereof for improving male infertility.

CN109222100A describes a tableting candy and preparation method thereof with radix ginseng and cordyceps militaris composition using the principles of homology of medicine and food along with scientific matching.

CN108452079A discloses the invention in the technical field of medical and health care products related to a preparation method of the composition, and the use thereof in delaying senescence, inhibiting tumor cell growth and improving cardiovascular microcirculation. The invention relates to a composition made of ginseng, cordyceps, rehmannia, epimedium, cistanche, and red deer.

The use of plant extracts in sexual disorders and also as fertility enhancers is on the rise because of the shifting of attention from western drugs to natural herbal products (Dada & Ajilore, 2009). Withania somnifera (WS) popularly known as ashwagandha or Indian ginseng is a reputed medicinal plant in Indian traditional system of medicine (Mishra et. al., 2000). In context of the impact of WS over reproductive system function, number of reports demonstrated improved fertility in sub-fertile male subjects due to the enhancement in semen quality. Withania root extract was proposed to increase enzymatic activity in seminal plasma and decrease oxidative stress suggesting its reversible spermicidal and infertilizing effects in male subjects (Azgomi et. al., 2018). Similarly, ginseng is often referred to as the King of all herbs in traditional Chinese medicine. Being a promising agent to improve general well-being, ginseng has also been used extensively to treat sexual dysfunction as well as to enhance sexual behavior. A number of animal studies and case-control studies in human reported the positive impact of ginseng over libido, copulatory performances, sperm quality and count (Leung & Wong, 2013).

Therefore, the present invention aims to provide a composition of Cordyceps militaris, with Withania and ginseng. Compared with the existing formulations of Cordyceps militaris, the composition has scientific therapeutic formula, good bioavailability, excellent product stability and quality with no side effects. The invented formulation has special medical uses, sufficient efficacy and short board problems with the capability to replace the toxic side effects of existing medicines and health foods.

OBJECT AND SUMMARY OF THE PRESENT INVENTION
The main objection of the present invention is to provide a synergistic combination/composition of cordycepin enriched Cordyceps militaris with natural medicinal components for use in preventing oligospermia.

Another object of the present invention is to provide a synergistic combination/composition of cordycepin enriched Cordyceps militaris with Withania somnifera and ginseng for alleviating male sub-fertility issues by promoting male sperm motility and improving reproductive performance.

Yet another object of the present invention is to provide a herbal formulation of Cordyceps militaris optionally combined with pharmaceutically acceptable carrier, a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative or a combination thereof.

Accordingly, in a first aspect, the present invention aims to provide a synergistic combination of cordycepin enriched Cordyceps militaris with natural medicinal components such as Withania somnifera and ginseng for alleviating male sub-fertility issues by promoting male sperm motility and improving reproductive performance. The synergistic combination is a herbal formulation optionally combined with pharmaceutically acceptable carrier, a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative or a combination thereof.

In an embodiment, the combination further comprises at least one herb or extracts of Withania somnifera and ginseng.

In a second aspect, the present invention provides a method of treating a male infertility conditions related to oligospermia by administering to a male subject suffering from male fertility issues, preferably orally.

Another aspect of the present invention is to provide a health functional food for alleviating male infertility including oligospermia.

In another embodiment, the formulation is in solid preparations for oral administration including a tablet, a pill, a powder, a granule, and a capsule, and these solid preparations are formulated by mixing it with acceptable pharmaceutical excipients.

The combination may comprise the herbal extracts of Cordecyps militaris, Withania somnifera, and ginseng in equal ratio and also in the ratio of 0.5:0.25:0.25 or 0.20:0.4:0.4 and similar combinations thereafter respectively.

The pharmaceutical composition of the invention optionally comprises vitamins, coenzymes, proteins or a combination thereof. The vitamins are selected from methylcobalamin, cyanocobalamin, benfotiamine or a combination thereof. The coenzymes are selected from ubidecarenone, thiamine pyrophosphate, Flavin adenine dinucleotide and a combination thereof. The proteins are selected from whey protein isolate, whey protein concentrate, soy protein and a combination thereof.

Compared with the existing formulations of Cordyceps militaris, the composition has scientific therapeutic formula, good bioavailability, excellent product stability and quality with no side effects. The invented formulation has special medical uses, sufficient efficacy and short board problems with the capability to replace the toxic side effects of existing medicines and health foods.

DETAILED DESCRIPTION OF THE INVENTION
The following is a detailed description of embodiments of the disclosure to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the scope of the present disclosure as defined by the appended claims.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of embodiments of the present invention. It will be apparent to one skilled in the art that embodiments of the present invention may be practiced without some of these specific details.
Embodiments of the present invention relates to a synergistic combination/composition of cordycepin enriched Cordyceps militaris extract with natural medicinal components for use in preventing oligospermia.
In an embodiment, the present invention provides a synergistic composition of cordycepin enriched Cordyceps militaris extract, herbal extracts of Withania somnifera and ginseng for alleviating male sub-fertility issues by promoting male sperm motility and improving reproductive performance.

In another embodiment, the present invention provides an herbal composition of cordycepin enriched Cordyceps militaris extract, herbal extracts of Withania somnifera and ginseng optionally combined with pharmaceutically acceptable carrier, a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative or a combination thereof.

In another embodiment, the composition of the present invention is administered orally.

In yet another embodiment, the composition of the present invention is a health functional food and capable of being added in other food stuffs for alleviating male infertility including oligospermia.

In yet another embodiment, the composition is formulated in solid preparations for oral administration including a tablet, a pill, a powder, a granule, and a capsule, and these solid preparations are formulated by mixing it with acceptable pharmaceutical excipients.

The composition comprises cordycepin enriched Cordecyps militaris extract and herbal extract of Withania somnifera and ginseng. The herbal extracts of Withania somnifera and ginseng are taken in equal ratio. The Cordecyps militaris and herbal extract ratio ranges from 1:1 to 1:4.
The pharmaceutical composition of the invention optionally comprises vitamins, coenzymes, proteins or a combination thereof. The vitamins are selected from methylcobalamin, cyanocobalamin, benfotiamine or a combination thereof. The coenzymes are selected from ubidecarenone, thiamine pyrophosphate, Flavin adenine dinucleotide and a combination thereof. The proteins are selected from whey protein isolate, whey protein concentrate, soy protein and a combination thereof.

Compared with the existing formulations of Cordyceps militaris, the composition has scientific therapeutic formula, good bioavailability, excellent product stability and quality with no side effects. The invented formulation has special medical uses, sufficient efficacy and short board problems with the capability to replace the toxic side effects of existing medicines and health foods.

While the foregoing describes various embodiments of the invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
,CLAIMS:We claim:
1. A Pharmaceutical Composition for Oligospermia, said composition comprises cordycepin enriched Cordyceps militaris extract and herbal extract of Withania somnifera root and ginseng root.
2. The Pharmaceutical Composition as claimed in claim 1, wherein said herbal extracts of Withania somnifera and ginseng are taken in equal ratio.
3. The Pharmaceutical Composition as claimed in claim 1, wherein ratio of Cordecyps militaris and herbal extract ranges from 1:1 to 1:4.
4. The pharmaceutical composition as claimed in claim 1, wherein said composition optionally comprises vitamins, coenzymes, proteins or a combination thereof.
5. The pharmaceutical composition as claimed in claim 4, wherein the vitamins are selected from methylcobalamin, cyanocobalamin, benfotiamine or a combination thereof, the coenzymes are selected from ubidecarenone, thiamine pyrophosphate, flavin adenine dinucleotide and a combination thereof, the proteins are selected from whey protein isolate, whey protein concentrate, soy protein and a combination thereof.
6. The pharmaceutical composition as claimed in claim 1, wherein said composition is a health functional food and capable of being added in other food stuffs for alleviating male infertility including oligospermia.
7. The pharmaceutical composition as claimed in claim 1, wherein said composition in solid preparation for oral administration including a tablet, a pill, a powder, a granule, and a capsule.
8. The pharmaceutical composition as claimed in claim 7, wherein said solid preparations are formulated by mixing the composition with acceptable pharmaceutical excipients.
9. The pharmaceutical composition as claimed in claim 1, wherein said composition is optionally combined with pharmaceutically acceptable carrier, a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative or a combination thereof.
10. The pharmaceutical composition as claimed in claim 1, wherein said composition is administered orally.