COMPOSITION COMPRISING L-CARNITINE FOR THE TREATMENT OF MALE INFERTILITY

Abstract

The invention relates to a composition for the treatment of male infertility. The invention is characterized by a composition comprising L-carnitine and/or acetyl-L-carnitine or prodrugs thereof for the treatment of infertility in men with a sperm concentration of less than 5 million spermatozoa per milliliter.

Claims

1. A composition comprising: at least one selected from the group consisting of L-carnitine, acetyl-L-carnitine, active metabolic derivatives thereof, and combinations of two or more thereof and at least one selected from the group consisting of docosahexaenoic acid, eicosapentaenoic acid, and combinations of two or more thereof, wherein the composition is formulated to be effective in the treatment of infertility in men having a sperm concentration less than or equal to 5 million spermatozoa per milliliter.

2. The composition according to claim 1, further comprising: Coenzyme Q10, vitamin E, and vitamin B6.

3. The composition according to claim, 1 wherein the composition is formulated to be effective when the sperm concentration is less than or equal to 3 million spermatozoa per milliliter.

4. The composition according to claim 3, wherein the composition is formulated to be effective when the sperm concentration less than or equal to 0.1 million spermatozoa per milliliter.

5. The composition according to claim 1, wherein the composition is formulated to be effective when the sperm concentration s greater than 0.1 million spermatozoa per milliliter.

6. The composition according to claim 1, wherein the composition is formulated to be effective in the treatment of infertility in men having asthenospermia or oligoasthenospermia.

7. The composition according to claim 1, further comprising: at least one selected from the group consisting of vitamins, micronutrients, and combinations of two or more thereof, and at least one trace element.

8. The composition according to claim 7, wherein the one selected from the group consisting of vitamins, micronutrients, and combinations of two or more thereof is selected from the group consisting of vitamin E, vitamin C, vitamin A, vitamin B6, vitamin B8, vitamin B9, vitamin B12, vitamin D, lycopene, arginine, N-acetyl-cysteine, coenzyme Q10, and mixtures of two or more thereof.

9. The composition according to claim 7, wherein the trace element is selected from the group consisting of zinc, selenium, copper, magnesium, manganese, potassium, iodine, and mixtures of two or more thereof.

10. The composition according to claim 1, further comprising: coenzyme Q10, vitamin E, vitamin B6, selenium, zinc, and docosahexaenoic acid.

11. The composition according to claim 10, comprising: a first formulation containing coenzyme Q10, vitamin E, vitamin B6, and a second formulation containing selenium, zinc and L-carnitine.

12. The composition according to claim 11, wherein the first formulation is dosed for a daily administration corresponding to 15.0 to 200.0 mg/day of coenzyme Q10, 6.0 to 24.0 mg/day of vitamin E, 0.7 to 2.8 mg/day of vitamin B6 and 600.0 to 1000.0 mg/day of docosahexaenoic acid.

13. The composition according to claim 11, wherein the second formulation is dosed for a daily administration corresponding to an amount in a range of from 10.0 to 100.0 μg/day of selenium, an amount in a range of from 5.0 to 20.0 mg/day of zinc, an amount in range of from 0.5 to 2.0 g/day of sucrose and an amount in a range of from 1.0 to 5.0 g/day of L-carnitine.

14. The composition according to claim 11, wherein at least one selected from the group consisting of: the first formulation is in the form of a capsule, the second formulation is in the form of a sachet to be diluted in a volume of liquid.

15. The composition according to claim 1, wherein the composition is formulated to be administered orally.

16. The composition according to claim 11, wherein the first and second formulations are adapted to be administered with a time interval lying between 8 h and 16 h.

17. The composition according to claim 1, wherein the composition is formulated to be effective when administered for a period of at least 3 months.

18. The composition according to claim 1, further comprising: fructose, citric acid, selenium, Coenzyme Q, vitamin C, zinc, folic acid, and vitamin B12.

19. The composition according to claim 1, further comprising: prickly pear seed extract, fish oil, N-acetylcysteine, nopal fruit extract including betalain and quercetin, L-tyrosine, carnitine tartrate, marigold flower extract including lutein, Haematococcus pluvialis extract including astaxanthin, sweet orange fruit extract including hesperidin, green tea leaf extract including polyphenols, Dunaliella salina extract including carotenoids, olive leaf extract including hydroxytyrosol, acerola fruit extract, maritime pine bark extract including oligo-proanthocyanidins, zinc, vitamin B9, and vitamin B12.

20. The composition according to claim 1, further comprising: zinc, taurine, arginine, vitamin B9, vitamin C, vitamin E, selenium, Coenzyme Q10, and fish oil including omega 3.

Description

EXAMPLE 1

Compositions COMPRISING CARNITINE ACCORDING to the Invention for Combating Male Infertility

[0085] The quantities of ingredients of compositions 1, 2, and 4 described below are the daily quantities administered.

Composition 1

[0086] Composition 1 is in the form of two formulations: in a sachet and in capsules. The daily dose is one sachet in the morning and three capsules in the evening. Three capsules comprise 30.0 mg of coenzyme Q10, 12.0 mg of vitamin E, 1.4 mg of vitamin B6 and 1705 mg of fish oil, including 800.0 mg of docosahexaenoic acid. A sachet comprises 50.0 μg of selenium, 10.0 mg of zinc, 1.1 g of sucrose and 3.0 g of L-carnitine base. The treatment may for example have a duration of 30 days.

Composition 2

[0087] Composition 2 is solely in sachet form. The daily dosage is two sachets per day. Two sachets contain 3.5 g of carnitine fumerate, 1 g of acetyl-L-carnitine, 2 g of fructose, 100 mg of citric acid, 100 μg of selenium, 40 mg of coenzyme Q, 180 mg of vitamin C, 20 mg of zinc, 400 μg of folic acid and 3 μg of vitamin B12. The duration of treatment may for example be 15 days.

Composition 3

[0088] Composition 3 is in the form of two tablets: one non-colored tablet and one colored tablet. The daily dose is four tables per day, including one colored. One colored tablet contains 100 mg of prickly pear seed extract and 100 mg of fish oil, including 2.30 mg of docosahexaenoic acid and 18.20 mg of eicosapentaenoic. One non-colored tablet contains 250 mg of

[0089] N-acetylcisteine, 200 mg of nopal fruit extract (including 0.05 mg of betalain and 0.001 mg of quercetin), 150 mg of L-tyrosine, 134.41 mg of carnitine tartrate, 111.12 mg of marigold flower extract (including 5.71 mg of lutein), 85.71 mg of Haematococcus pluvialis extract (including 4.29 mg of astaxanthin), 83.73 mg of sweet orange fruit extract (including 50.24 mg of hesperidin), 67.47 mg of green tea leaf extract (including 20.24 mg of polyphenols), 48 mg of Dunaliella salina extract (including 1.20 mg of carotenoids), 47.19 mg of olive leaf extract (including 0.47 mg of hydroxytyrosol), 40.20 mg of acerola fruit extract (including 30 mg of coenzyme Q10), 20 mg of maritime pine bark extract (including 19 mg of oligo-proanthocyanidins), 15 mg of zinc, 12 mg of vitamin E, 1.40 mg of vitamin B6, 178.49 μg of vitamin B9 and 2.50 μg of vitamin B12. The treatment may last for example for 7 days.

Composition 4

[0090] Composition 4 is in sachet and capsule form. The daily dosage is one sachet and one capsule, preferably in the evening. One sachet contains 15 mg of zinc, 100 mg of taurine, 3 g of carnitine and 100 mg of arginine. One capsule contains 200 μg of vitamin B9, 90 mg of vitamin C, 15 mg of vitamin E, 27.5 mg of selenium, 30 mg of coenzyme Q10, 408 mg of fish oil including 230 mg of omega-3 and 200 mg of docosahexaenoic acid. The treatment may for example extend over 30 days.

EXAMPLE 2

Evaluation of the Efficacy of Composition 1 of Example 1 on Male Infertility

[0091] The invention is particularly illustrated by the results of the following multicentre observational study carried out in the context (i) of the Reproduction Center of the Pole of Obstetrics, Reproduction and Gynecology (ORG) of the Nice Hospital (Archet II Hospital), (ii) of the Pole of Gynecology-Obstetrics and Reproduction, Biology Department of Reproduction-CECOS of the Bordeaux Hospital (Pellegrin-Maternity Hospital Group) and (iii) of the Marseille Institute of Reproductive Medicine.

[0092] The objective of the study was to evaluate the impact of a 6 months treatment with the composition according to the invention as formulated in the above preparation example on the main sperm parameters, namely the sperm number and mobility, in a population of men obtained from three centers distributed in France, consulting for an infertility problem and presenting in particular with oligospermia, cryptospermia, azoospermia, or oligoasthenospermia.

[0093] The example focuses on the analysis of the impact of such a treatment with regard to the count in patients having fewer than 3 million spermatozoa per milliliter, and/or the sperm mobility in patients included in the study carried out during at least two spermograms done before the start-of-treatment visit. The need to do two different spermograms in order to determine the pathological character of the values of a spermogram takes account of the personal variability of the results and constitutes a WHO standard.

[0094] During the start-of-treatment visit, the composition according to the invention is handed to the patient for treatment of a daily dose for 6 months (1 sachet in the morning and 3 capsules in the evening). The dosages begin the same day.

[0095] During the end-of-protocol visit, a post-treatment spermogram is done. Observance is also evaluated.

[0096] If the spermogram has at least one non-evaluable result and/or observance has not been complied with, such results are not analyzed.

[0097] The sperm count was described and analyzed over 125 patients, including 73 patients presenting with oligospermia, 5 patients presenting with cryptozoospermia, patients presenting with azoospermia, 10 patients presenting with asthenospermia and 33 patients presenting with oligoasthenospermia.

TABLE-US-00001 TABLE 1 Results of the sperm count Inclusion visit Final visit p value* Count (M/ml) 7.35 ± 9.17 9.91 ± 13.01 0.0088 Av ± SD (Med [IQR]) (5,00 [1.50; 10.00] (6.00 [1.00; 12.00] *Student test for matched data

[0098] At inclusion, on average the patients had a sperm count of 7.35 M/ml±9.17 as against 9.91 M/ml±13.01 at the final visit, that is to say an average increase of 2.56 M/ml±10.76, corresponding to an average increase of 35%. This difference is statistically significant.

[0099] The main analysis was repeated for the purpose of evaluating the change in the number of spermatozoa in patient subgroups: men with a sperm count of less than or equal to one million/ml at inclusion, men with a sperm count of less than or equal to two million/ml at inclusion, men with a sperm count of less than or equal to three million/ml at inclusion, and men with a sperm count greater than three million/ml at inclusion.

[0100] The sperm count in men with a sperm count of less than or equal to one million/ml at inclusion was described and analyzed over 29 patients.

TABLE-US-00002 TABLE 2 Results of the sperm count in patients who had a count of less than or equal to one million/ml at inclusion Inclusion visit Final visit p value* Count (M/ml) 0.20 ± 0.28 2.34 ± 4.62 0.0171 Av ± SD (Med [IQR]) (0.10 [0.01; 0.20] (0.10 [0.01; 2.00] *Student test for matched data

[0101] At inclusion, on average the patients had a sperm count of 0.20 M/ml±0.28 as against 2.34 M/ml±4.62 at the final visit, that is to say an average increase of 2.14 M/ml±4.55, corresponding to an average increase of 1070%. This difference is statistically significant.

[0102] The sperm count in men with a sperm count of less than or equal to two million/ml at inclusion was described and analyzed over 45 patients.

TABLE-US-00003 TABLE 3 Results of the sperm count in patients who had a count of less than or equal to two million/ml at inclusion Inclusion visit Final visit p value* Count (M/ml) 0.75 ± 0.80 3.22 ± 5.00 0.0012 *Student test for matched data

[0103] At inclusion, on average the patients had a sperm count of 0.75 M/ml±0.80 as against 3.22 M/ml±5.00 at the final visit, that is to say an average increase of 2.47 M/ml±4.77, corresponding to an average increase of 329%. This difference is statistically significant.

[0104] The sperm count in men with a sperm count of less than or equal to three million/ml at inclusion were described and analyzed over 51 patients.

TABLE-US-00004 TABLE 4 Results of the sperm count in patients who had a count of less than or equal to three million/ml at inclusion Inclusion visit Final visit p value* Count (M/ml) 1.00 ± 1.02 3.70 ± 5.21 0.0002 *Student test for matched data

[0105] At inclusion, on average the patients had a sperm count of 1.00 M/ml±1.02 as against 3.70 M/ml±5.21 at the final visit, that is to say an average increase of 2.70 M/ml±4.89, corresponding to an average increase of 270%. This difference is statistically significant.

[0106] The sperm count in men with a sperm count greater than three million/ml at inclusion were described and analyzed over 74 patients.

TABLE-US-00005 TABLE 5 Results of the sperm count in patients who had a count greater than three million/ml at inclusion Inclusion visit Final visit p value* Count (M/ml) 11.73 ± 9.72 14.19 ± 14.94 0.1187 *Student test for matched data

[0107] At inclusion, on average the patients had a sperm count of 11.73 M/ml±9.72 as against 14.19 M/ml±14.94 at the final visit, that is to say an average increase of 2.47 M/ml±13.43, corresponding to an average increase of 21%. This difference is not statistically significant.

[0108] The results demonstrate clearly that the treatment taken daily for six months affords an increase in the production of spermatozoa in infertile patients. More particularly, this increase in the sperm concentration observed following the taking of the treatment is greater in the patients who had a sperm count of less than or equal to three million/ml than in patients who had a sperm count greater than three million/ml. More particularly, the effect on the production of spermatozoa is all the greater in men with a sperm concentration of less than or equal to two million/ml and even more particularly in men with a sperm concentration of less than or equal to one million/ml. This is because the mean increase in the sperm concentration is 1070% in men with a sperm concentration of less than or equal to one million/ml at inclusion, 329% in men with a sperm concentration of less than or equal to two million/ml at inclusion and 270% in men with a sperm concentration of less than or equal to three million/ml at inclusion, as against a mean increase in the number of spermatozoa of 21% in men with a sperm concentration of greater than three million/ml at inclusion.

[0109] These results make it possible to identify a subpopulation that is particularly receptive to the treatment. Infertile patients having a sperm concentration of less than or equal to three million/ml therefore represent a subpopulation of patients responding much more effectively to the treatment. The potentialized effect of the treatment on this subpopulation has a surprising and unexpected character.

[0110] Finally, the mobility of the spermatozoa was described and analyzed over 28 patients having mobility of less than or equal to 20% at inclusion.

TABLE-US-00006 TABLE 6 Results of the sperm mobility in patients who had a mobility of less than or equal to 20% at inclusion Inclusion visit Final visit p value* Mobility (%) 9.05 ± 7.22 24.61 ± 20.70 0.0002 Av ± SD (Med [IQR]) (9.00 [2.50; 15.00] (30.00 [1.50; 40.00] *Student test for matched data

[0111] At inclusion, on average the patients had a sperm mobility of 9.05%±7.22 against 24.61%±20.70 at the final visit, that is to say an absolute mean increase of 15.55%±19.30, corresponding to a relative mean increase of 172%. This difference is statistically significant.