DESC:FIELD OF INVENTION:
The present invention relates to the field of nutraceutical composition, more particularly the present invention relates to oral nutraceutical composition comprising synergistic combination of 15 essential male fertility nutrients for effective management of male infertility. 5
BACKGROUND OF THE INVENTION:
Infertility is becoming a global clinical concern among millions of people of reproductive age. As per WHO, statistics between 48 million couples and 186 million individuals suffering from infertility issue. The infertility can occur in man, women or 10 both while the social stigma burdens more on women, however males also experience infertility. Low sperm concentration and/or low sperm motility and/or poor sperm morphology are known to be common reason for male infertility.
The study has shown that oxidative stress can be a leading cause of sperm dysfunction causing recurrent pregnancy loss, low fertility, congenital malformations and 15 malfunctions, complex metabolic diseases, cardiovascular and neurologic degeneration. Oxidative stress occurs when there is an imbalance between oxidants or reactive oxygen species (ROS) and body’s natural antioxidant defenses. There are several other factors such as obesity, pollution, inflammation and smoking also affects sperm quality but oxidative stress plays a major role in increasing ROS levels and affect 20 fertility in men.
Currently used treatments include pharmacotherapy approach including oral therapies such as use of Clomiphene or Anastrazole; parenteral therapy such as use of hCG (human chorionic gonadotropin) or hMG (human menopausal gonadotropin). But still nutraceutical approach is being preferred owing to less side effects, low cost 25
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and more patient compliance. Antioxidant based nutraceutical approach is gaining increasing attention in reducing oxidative stress.
Various studies and researches on antioxidant composition have been patented or published. Following are some of examples which illustrate the role of antioxidant in improving male fertility and reduces oxidative stress: 5
WO2004/056370 A1 discloses the use of fatty acid composition preferably EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) for preventing and treating male infertility. The prior art shows that the supplement comprising EPA and DHA improves sperm motility and increases sperm count, thus combination of EPA and DHA can potentially use in the treatment and prophylaxis of male infertility or 10 multiple factors with influence on male infertility, such as asthenozoospermia, teratozoospermia.
Malik Adewoyin et. al. had reviewed and reported that herbal plant with antioxidant activity and phytocompounds have a beneficial role in spermatogenesis and exogenous administration of antioxidants including enzymes, vitamins and 15 biomolecules helps in maintaining a healthy balance between ROS and antioxidant and reduces oxidative stress.
EP3269389 B1 discloses a dietary supplement comprising L-carnitine and/or acetyl-L-carnitine with docohexaenoic acid and/or eicosapentaenoic acid used for the treatment of male infertility. Carnitine exerts a role of antioxidants by protecting the 20 DNA and the cell membrane against free radicals and promotes stability of the mitochondrial membrane while allowing the acetylation of the membrane phospholipids, thus improves the level of the spermatozoa, to produce energy for their mobility, to fight against oxidative stress and to limit the degradation of the mitochondrial membranes. 25
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Although the role of antioxidant for treating and preventing male infertility is known in the art, there still exist need in the art to further provide a synergistic combination of antioxidants or phyto-constituents formulated in a single-dose form called fixed-dose combinations (FDCs) which compliments each other functions and thereby provide a safe and tolerable composition. FDC formulations have unique advantages 5 such as complementary mechanism of action, synergistic effects, better tolerability, elongated product life-cycle management, and cost savings. Use of FDCs is a rational approach for achieving optimal therapeutic benefits while minimizing pill-burden. Greater convenience with decreased pill-burden leads to improved adherence, resulting in superior clinical outcomes and greater cost-effectiveness. Thus the 10 present invention provides a synergistic combination of different male fertility nutrients which exerts anti-oxidant activity which helps in managing and improving male fertility.
The present invention provides a novel nutraceutical fixed dose combination of antioxidants which can improves sperm count, sperm morphology and sperm motility 15 and helps in management of male fertility. Object of Invention An object of the present invention is to provide a composition comprising combination of different anti-oxidants for management of male infertility. An another object of the present invention is to provide a nutraceutical composition 20 comprising fixed dose combination of different antioxidants which will improves sperm count and sperm motility. In another objective of the present invention is to provide synergistic nutraceutical composition comprising an effective amount of different anti-oxidants which is safe
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and tolerable for human consumption wherein the composition in the form of oral dosage form. Yet another objective of the present invention is to provide nutraceutical composition comprising synergistic combination of 15 unique essential male fertility nutrients for effective management of male infertility wherein 15 essential nutrients are 5 combination of different antioxidants. Yet another objective of the present invention is to provide nutraceutical composition of 15 blend of different nutrients which exert antioxidants activity which is safe and effective for managing male infertility and is formulated to reduce oxidative stress and ameliorate sperm count, sperm morphology and sperm motility. 10 Summary of the Invention Accordingly, the present invention provides a synergistic composition comprising combination of different anti-oxidants wherein the synergistic composition is a nutraceutical based combination of antioxidants for the management of male fertility. In one embodiment, the present invention provides a unique formula of 15 essential 15 male fertility nutrients which provide a comprehensive solution for male infertility to improve sperm count, sperm morphology and sperm motility. In another embodiment, the present invention provides an oral nutraceutical composition for the effective management of male infertility and method of preparation thereof. 20 Detailed Description of the invention The present invention provides a fixed dose combination of 15 essential antioxidants for effective management of male fertility wherein the essential antioxidants are: Coenzyme Q10, Astaxanthin, zinc in form of zinc oxide, Selenium in form of L-selenomethionine, Vitamin B 12, Folic Acid, L-Aginine, L- Citruline, L- Carnitine, N- 25
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Acetyl Cysteine (NAC), D- Aspartic Acid (DAA), vitamin E acetate, Vitamin C, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and Lycopene. In an embodiment antioxidant is Coenzyme Q10 also known as ubiquinone or CoQ-10. It is a naturally occurring antioxidant produced in the body. CoQ10 improves sperm motility, concentration and semen antioxidant content in male experiencing 5 infertility. In Ahmad Almahar, a study on patients with idiopathic OAT received 200 mg/day (n = 35) or 400 mg/day (n = 30) of CoQ10 orally for 3 months were carried out. Total antioxidant capacity (TAC), catalase (CAT) activity, and superoxide dismutase (SOD) activity were measured both before and after treatment. Results shows that treatment with CoQ10 resulted in a significant increase in sperm 10 concentration from baseline. [Ahmed T Alahmar, Clinical and Experimental Reproductive Medicine, 2019 Sep; 46(3): 112–118.] In an embodiment another antioxidant is Astaxanthin, Astraxanthin is a photo-protective red pigment known widely used in many dietary supplements. It helps to decrease the production of endogenous sperm reactive oxygen species (ROS) and 15 improves sperm concentration, thus improves male fertility. In an another embodiment, antioxidant is Zinc and pharmaceutical acceptable salt thereof. Zinc is an essential element and plays an important role in organization of DNA, RNA and proteins, as well as in the stability of cell membranes and cell division. Deficiency of zinc are known to cause low sperm quality and male infertility, therefore 20 supplementing adequate amount of zinc concentration helps in maintaining normal sperm function and fertilization. [Deborah Allouche Fitoussi et.al, International Journal of Molecular Sciences, 2020 Oct; 21(20): 7796.] In an another embodiment, antioxidant is selenium or derivatives thereof. Selenium is a trace element and reported to have anti-oxidant activity, selenium protects the 25
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sperm from oxidative damage and helps in maintaining morphology of sperm and its mobility. In an another embodiment, another antioxidant is Vitamin B12 also known as cobalamin. Several studies have suggested that vitamin B12 can improve or enhance semen quality. Oral antioxidant therapy of Vitamin B12 have reported to improve 5 sperm vitality, motility, and DNA integrity. Hu et al. had investigated the effects of vitamin B12 supplementation on standard bovine semen quality parameters and anti-oxidative enzyme activities and found that Vitamin B12 have iimproved spermatozoa quality and prevent oxygen generation and membrane lipid peroxidation. [J-H Hu. et.al, Reproduction in Domestic Animals., 2011 Feb;46(1):66-73] 10
In one embodiment, another antioxidant is Folic Acid also called as Folate, vitamin B9 and folacin is a natural form of vitamin B9. Breanne G. Swayne studied the effects of folic acid deficiency and supplementation on male germ cell integrity and reported that folic acid deficiency in adult male mice causes decreases in sperm numbers, and increases in germline chromatin damage and DNA mutation and further concluded 15 that adequate intake of folic acid may improve male fertility and prevent DNA mutation in the germline. In one embodiment, another antioxidant is L-Arginine. L-arginine is an essential amino acid which helps in making proteins in the body, dietary supplementation improved semen antioxidant capacity and have ameliorate effect on semen quality. 20 In another embodiment, antioxidant is L- Citruline. L-citrulline is non-essential amino acid with antioxidant activity and increases NOx concentrations and significantly improves semen parameters. In another embodiment, another antioxidant is carnitine and acceptable stereoisomers thereof more preferably L-carnitine. Carnitine is an amino acid 25
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derivatives and exists in two stereoisomers: d-carnitine and l-carnitine. Antioxidant activity of l-carnitine have a beneficial effect on semen parameters. As sperm contain high level of unsaturated fatty acid content, so it is highly prone to oxidative stress, l-carnitine protect the sperm plasma membrane with high level of unsaturated fatty acid, thus can be potentially exploited in managing male infertility. 5 In another embodiment, antioxidant is N-acetyl cysteine (NAC). N-acetyl cysteine is a natural supplement comes from amino acid and L-cysteine. NAC is a strong anti-oxidant which function as free radical scavenger and is a potent molecule for treating any disorder resulting due to high concentration of free oxygen radicals. Due to high anti-oxidant activity of NAC, it has positive effects on sperm parameter. 10 In one embodiment, antioxidant is aspartic acid and acceptable stereoisomers thereof more preferably D-aspartic acid (D-AA). Supplementing D-AA have significantly increased the concentration and motility of sperm. In another embodiment, another antioxidant is vitamin E acetate also known as a-Tocopheryl acetate or alpha-tocopherol acetate. Vitamin E is a water insoluble 15 antioxidant which inhibits ROS and protect the sperm from oxygen free radicals, thereby enhance sperm motility and quality. In another embodiment, another antioxidant is vitamin C. Vitamin-C is a powerful antioxidant and have positive effect on semen quality. Mohammed Akmal et. al. studied and reported the effect of oral supplementation of Vitamin-C on the sperm 20 count and morphology in infertile patients. The study concluded that vitamin C have beneficial effect in infertile male patients who were taking oral supplementation. [Mohammed Akmal et. al., Journal of Medicinal Food, 2006 ;9(3):440-2] In another embodiment, antioxidant is combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Eicosapentaenoic acid (EPA) is an omega-3 fatty 25
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acid found along with docosahexaenoic acid (DHA) derived from marine source. The plasma membrane of sperm is composed of high amount of fatty acid including EPA and DHA which are responsible for sperm motility and other sperm morphology. As fatty acids are prone to high level of ROS and oxidative stress resulting in lipid peroxidation leading to sperm damage, therefore supplementing infertile men with 5 omega-3 fatty acids can result in improved sperm motility and concentration of DHA in seminal plasma.
In another embodiment, another antioxidant is Lycopene. Lycopene is a natural pigment and is a carotenoid antioxidant. Lycopene is a strong antioxidant which protect the spermatozoa from oxidative stress by neutralizing ROS and decreasing 10 oxidative damage to lipids, proteins and DNA. In an embodiment the present invention provides a composition comprising synergistic combination of 15 anti-oxidants, wherein composition is an oral dosage form. In another embodiment oral dosage form is selected from group consisting of tablet, 15 powder, capsule, pills or granules preferably powder. In an another embodiment the powdered formulation of present invention can be formulated in granules forms or can directly compressed to form tablet. In an another embodiment the present invention provides a method of providing powdered formulation in a packaging means in the form of bottle container, 20 packaging bags, sachets, sticks, flowpacks, pouches most preferably in form of sachet. In an another embodiment the present invention provides a synergistic nutraceutical composition used for effective management of male infertility, wherein said composition comprises:
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Ingredients Percentage
Coenzyme Q-10
0-10%
Astaxanthin
0.05-0.5%
Zinc (Zinc Oxide)
0-5%
Selenium (l-selenomethionine)
0.0002-0.05%
Vitamin B 12
0.00001-0.0006%
Folic Acid
0.002-0.5%
L-Aginine
10-20%
L- Citruline
20-50%
L- Carnitine
0-20%
N- Acetyl Cysteine (NAC)
0-10%
D- Aspartic Acid (DAA)
0.005-0.05%
Vitamin E Acetate
0.005-0.05%
Vitamin C
0.5-1%
EPA & DHA
0-20%
Lycopene
0.005-0.5%
In another embodiment of the present invention comprises at least one or more excipients selected from the group consisting of citric acid, sucralose, flavoring agent, coloring agent, microcrystalline cellulose, mannitol and combination thereof. In another embodiment of the present invention provides a method of preparation 5 by blending different antioxidants into granules or powder conventionally know in the art and filling the granules/powder into sachets. In an another embodiment of the present invention provides a synergetic composition of unique blend of 15 antioxidants for the management of male infertility which improves sperm count, sperm morphology and sperm motility. 10 While the invention has been described with respect to specific composition which include presently preferred modes of carrying out the invention, those skilled in the art will appreciate that there are numerous variations and permutations of the above described embodiments that fall within the spirit and scope of the invention. It should
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be understood that the invention is not limited in its application to the details of construction and arrangements of the components set forth herein. The invention is described in detail with reference to the example given below. The example is provided just to illustrate the invention and therefore, should not be construed to limit the scope of the invention. 5
EXEMPLARY FORMULATIONS
Example 1:
Nutraceutical composition of 15 essential male fertility nutrients Ingredients Percentage
Coenzyme Q-10
2%
Astaxanthin
0.08%
Zinc (Zinc Oxide)
1.8%
Selenium (l-selenomethionine)
0.0004%
Vitamin B 12
0.00002%
Folic Acid
0.003%
L-Aginine
14%
L- Citruline
30%
L- Carnitine
10%
N- Acetyl Cysteine (NAC)
6%
D- Aspartic Acid (DAA)
0.028%
Vitamin E Acetate
0.075%
Vitamin C
0.8%
EPA & DHA
10%
Lycopene
0.04%
Citric acid
3.6%
Sucralose
0.1%
Flavoring agent
0.5%
Coloring agent
0.025%
Microcrystalline cellulose (MCC PH 112)
Q.S.
Mannitol (Pearlitol SD 200)
Q.S
Total
100%
,CLAIMS:1. A nutraceutical composition comprising synergistic combinations of 15 blend of different antioxidants.
2. A nutraceutical composition as claimed in claim 1 wherein the composition further comprises one or more excipients selected from the group consisting 5 of citric acid, sucralose, flavoring agent, coloring agent, microcrystalline cellulose, mannitol and combination thereof.
3. A nutraceutical composition as claimed in previous claims, the composition further comprises following:
Ingredients
Percentage
Coenzyme Q-10
2%
Astaxanthin
0.08%
Zinc (Zinc Oxide)
1.8%
Selenium (l-selenomethionine)
0.0004%
Vitamin B 12
0.00002%
Folic Acid
0.003%
L-Aginine
14%
L- Citruline
30%
L- Carnitine
10%
N- Acetyl Cysteine (NAC)
6%
D- Aspartic Acid (DAA)
0.028%
Vitamin E Acetate
0.075%
Vitamin C
0.8%
EPA & DHA
10%
Lycopene
0.04%
Citric acid
3.6%
Sucralose
0.1%
Flavoring agent
0.5%
Coloring agent
0.025%
Microcrystalline cellulose (MCC PH 112)
Q.S.
Mannitol (Pearlitol SD 200)
Q.S
10
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4. A nutraceutical composition as claimed in claim 1 the nutraceutical composition is an oral dosage form.
5. A nutraceutical composition as claimed in claim 4, the oral dosage form is selected from group consisting of tablet powder, capsule, pills or granules preferably powder or granules. 5
6. A nutraceutical composition as claimed in claim 5, the formulation is packed in form of bottle container, packaging bags, sachets, sticks, flowpacks, pouches most preferably in form of sachet.
7. A nutraceutical composition as claimed in previous claims wherein the synergetic composition of 15 antioxidants are used for the management of male infertility which improves sperm count, sperm morphology and sperm motility.
Dated this 14th October’2022
For Akums Drugs & Pharmaceutical Ltd.
Siddhartha Dulakakhoria
(Authorized Signatory)