Method and composition for improving reproductive health

Abstract

Disclosed in the present invention are a method and composition for improving reproductive health and related use thereof in preparing nutritional products, health-care products, foods, beverages, animal feeds, or drugs for improving reproductive health. The method and composition of the present invention can improve erectile dysfunction, increase testosterone level, ameliorate hypogonadism, and ameliorate decreased sexual desire.

Description

Methods and compositions for improving reproductive health TECHNICAL FIELD

[0001] The present invention belongs to the technical field of reproductive health, and particularly relates to methods and compositions for improving reproductive health and related applications thereof in the preparation of nutritional products, health care products, foods, beverages, animal feeds, or drugs for improving reproductive health. BACKGROUND

[0002] With the increasing aging of today's society and the increase in the population of the middle-aged and elderly, the population of sexual dysfunction has naturally increased. In addition, due to social factors, etc., the proportion of sexual dysfunction in young adults is also increasing. Male sexual dysfunction is generally related to erectile dysfunction (ED), which can be caused by both physical and psychological factors. Physical ED is usually caused by underlying vascular diseases, such as those associated with hypertension or diabetes; and by prescription drug therapy and / or psychiatric disorders. Psychological factors include fear, behavioral anxiety, and interpersonal conflict. ED has a significant negative impact on the quality of life of individuals and their partners, often leading to increased anxiety and tension, causing depression and low self-esteem, and inducing a series of problems.

[0003] There are some methods on the market to alleviate ED, but they often have side effects for some users, and there may be some contraindications. In addition, there are prostaglandin compounds for improving or treating ED by transurethral or via small needle injection, but they are very inconvenient or invasive. Therefore, it is necessary to find new methods and compositions that can improve ED and thus improve reproductive health.

[0004] Dihydroberberine (DHB) is an excellent anti-inflammatory and antibacterial substance. However, there is no research on DHB for improving reproductive health by regulating GLP-1 levels or stimulating GLP-1 secretion, and / or inhibiting PDE5 activity, and / or improving erectile dysfunction, increasing testosterone levels, improving hypogonadism, and improving decreased libido. SUMMARY

[0005] In one aspect, the present invention provides a method for improving reproductive health, comprising administering to a subject in need thereof a composition comprising an effective amount of dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog, or derivative thereof. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0006] In some embodiments, improving reproductive health comprises improving erectile dysfunction, increasing testosterone levels, improving hypogonadism, and improving decreased libido.

[0007] In some embodiments, the reproductive health is improved by modulating GLP-1 levels or stimulating GLP-1 secretion, and / or inhibiting PDE5 activity.

[0008] In some embodiments, the composition is prepared as a nutritional product, a health product, a food, a beverage, an animal feed, or a medicament.

[0009] In some embodiments, the composition is in the form of a suppository, a tablet, a pill, a granule, a powder, a film, a capsule, a drop, a functional food, a sublingual preparation, an aerosol, a tonic, a solution, a suspension, an injection, or a syrup.

[0010] In some embodiments, the dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog, or derivative thereof is formulated to be administered in an amount of 10-2000 mg per day. In some embodiments, the dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog, or derivative thereof can be formulated to be administered in an amount of 20-1500 mg, 40-1000 mg, 60-800 mg, 80-600 mg, 100-400 mg per day. In some embodiments, the administration is once or more times per day.

[0011] In some embodiments, the composition is administered orally, intravenously, intramuscularly, intraperitoneally, or sublingually.

[0012] In some embodiments, the subject is a human.

[0013] In another aspect, the present application provides a composition comprising dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog, or derivative thereof for use in improving reproductive health.

[0014] In some embodiments, the improvement of reproductive health comprises improving erectile dysfunction, increasing testosterone levels, improving hypogonadism, improving decreased libido.

[0015] In some embodiments, the reproductive health is improved by modulating GLP-1 levels or stimulating GLP-1 secretion, and / or inhibiting PDE5 activity.

[0016] In some embodiments, the composition is prepared as a nutritional product, a health product, a food, a beverage, an animal feed, or a medicament.

[0017] In some embodiments, the composition is in the form of a suppository, a tablet, a pill, a granule, a powder, a film, a capsule, a drop, a functional food, a sublingual preparation, an aerosol, a tonic, a solution, a suspension, an injection, or a syrup.

[0018] In some embodiments, dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof is formulated to be administered in an amount of 10-2000 mg per day. In some embodiments, dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof can be formulated to be administered in an amount of 20-1500 mg, 40-1000 mg, 60-800 mg, 80-600 mg, 100-400 mg per day. In some embodiments, administration is once or more times per day.

[0019] In another aspect, the present application provides use of a composition comprising an effective amount of dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof in the preparation of a nutritional product, health care product, food, beverage, animal feed or medicament for improving reproductive health.

[0020] In some embodiments, improving reproductive health comprises improving erectile dysfunction, increasing testosterone level, improving hypogonadism, improving decreased libido.

[0021] In some embodiments, reproductive health is improved by modulating GLP-1 level or stimulating GLP-1 secretion, and / or inhibiting PDE5 activity.

[0022] In some embodiments, the composition is in the form of a suppository, tablet, pill, granule, powder, film, capsule, drop, functional food, sublingual preparation, aerosol, tonic, solution, suspension, injection or syrup.

[0023] In some embodiments, dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof is formulated to be administered in an amount of 10-2000 mg per day. In some embodiments, dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof can be formulated to be administered in an amount of 20-1500 mg, 40-1000 mg, 60-800 mg, 80-600 mg, 100-400 mg per day. In some embodiments, administration is once or more times per day.

[0024] The methods and compositions of the present application can improve reproductive health, and / or improve erectile dysfunction, increase testosterone level, improve hypogonadism, improve decreased libido, improve quality of life, increase happiness; in addition, convenient to use and substantially no side effects.

[0025] The summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 is serum GLP-1 levels in rats in each group.

[0027] Figure 2 is NO levels in supernatant of genital homogenate in rats in each group.

[0028] Figure 3 is cGMP levels in supernatant of genital homogenate in rats in each group.

[0029] Figure 4 is PDE5 mRNA levels in supernatant of genital homogenate in rats in each group. DETAILED DESCRIPTION

[0030] Reference will now be made in detail to the preferred embodiments of the application, examples of which are illustrated in the accompanying drawings. While the application will be described in conjunction with the preferred embodiments, it will be understood that they are not intended to limit the application to these embodiments. On the contrary, the application is intended to cover alternatives, modifications, and equivalents, which can be included within the spirit and scope of the application as defined by the claims. Furthermore, in the following detailed description of the application, numerous specific details are set forth in order to provide a thorough understanding of the application. However, it will be apparent to one of ordinary skill in the art that the application can be practiced without these specific details. In other instances, well-known methods, procedures, components, and other features are not described in detail in order to avoid unnecessarily obscuring aspects of the application.

[0031] As used herein, the term "or" is intended to mean "and / or," unless otherwise indicated by context. In other words, the term "or" is used in the inclusive sense.

[0032] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0033] As used herein, the terms "comprises," "comprising," "includes," "including" and the like are meant to be interpreted as specifying the presence of stated features or components rather than precluding the presence of further features or components. They also encompass the more restrictive verbs 'consisting essentially of and 'consisting of.

[0034] As used herein, the terms "mammal" or "subject" are used interchangeably to refer to any animal to which the methods and compositions of the disclosure can be applied or administered. The animal can be suffering from an ailment or other disease, but the animal need not be ill in order to benefit from the methods and compositions of the disclosure. Thus, any animal can utilize the disclosed compositions or be the recipient of the disclosed methods. Although the animal subject is preferably a human, the methods and compositions of the present application are equally applicable to veterinary medicine, e.g., for treating domesticated species such as canids, felines, murids, and various other pets; farm animals, e.g., bovines, equines, ovines, caprines, porcines, etc.; and wild animals, e.g., non-human primates in the wild or in zoos, etc.

[0035] As used herein, the term "administering" refers to the process of delivering the disclosed compositions or active ingredients to a subject. The compositions of the present application can be administered in a variety of ways to exert the desired effect, including orally, intragastrically, and parenterally (i.e., intravenously and intra-arterially as well as other suitable parenteral routes), and the like.

[0036] As used herein, the term "effective amount" refers to the amount necessary to achieve the effect as taught herein. The effective amount herein includes, but is not limited to, the amount necessary to improve reproductive health, and / or the amount necessary to improve erectile dysfunction, to increase testosterone levels, to improve hypogonadism, to improve decreased libido; and / or the amount necessary to modulate GLP-1 levels or stimulate GLP-1 secretion, and / or the amount necessary to inhibit PDE5 activity. According to the present disclosure, a suitable single dose size is a dose that is capable of achieving the above effects when administered one or more times over a suitable period of time.

[0037] As used herein, the term "pharmaceutically acceptable" means pharmaceutically, physiologically, dietetically, and / or nutritionally acceptable, refers to those which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals, compatible with other ingredients of the composition, not excessively toxic, irritating, allergenic or otherwise inappropriate, and commensurate in risk with the potential benefits.

[0038] The methods of the present application include administering at least 5 mg, typically 5-3000 mg, preferably 10-2000 mg, 20-1500 mg, 40-1000 mg, 60-800 mg, 80-600 mg, 100-400 mg of DHB or a pharmaceutically acceptable salt, acid, ester or derivative thereof per day, depending on the specific formulation and form. The amount to be administered can also vary depending on factors such as the sensitivity of the subject, age, sex and weight, idiosyncrasy, and the like. One or more doses can be administered one or more times per day over any period of time or at a suitable frequency. For example, an effective dose can be administered daily for one day, several days, many days, or indefinitely.

[0039] The following examples are illustrative of selected embodiments of the application, and are not meant to limit the scope of the application. Example 1

[0040] 40 six-week-old male SD rats with normal erectile function, weighing 200±20g. Randomly divided into control group, model group and experimental groups 1, 2, 3, 8 in each group. The control group is fed with ordinary feed, with fat mass fraction not more than 5%, fat calories not more than 15%; the model group and the experimental group are fed with high-fat feed, with fat mass fraction not less than 35% and calorie ratio not less than 60%. After 8 weeks of feeding, all rats are subjected to overnight fasting and water deprivation, and the test group is injected with 50mg / kg streptozotocin (1% 0.1mol / L citric acid-sodium citrate buffer solution) to damage the islet β cells; the control group is injected with the same amount of citric acid-sodium citrate buffer solution. One week after injection, oral glucose tolerance test (OGTT) is performed, and fasting blood glucose (FBG)≥16.7mmol / L is considered to be successful. 2, animal intervention Table 1 is the intervention method of each group of animals, BBR is berberine, DHB is dihydroberberine. BBR or DHB is dissolved in corn oil, and after ultrasonic dissolution, the experimental group rats are gavaged; the control group and the model group are gavaged with corn oil. The rats are administered according to the above dose for 12 weeks, and then the erection test is performed. 3, erection test

[0041] Table 1 is the intervention method of each group of animals, BBR is berberine, DHB is dihydroberberine. BBR or DHB is dissolved in corn oil, and after ultrasonic dissolution, the experimental group rats are gavaged; the control group and the model group are gavaged with corn oil. The rats are administered according to the above dose for 12 weeks, and then the erection test is performed. 3, erection test

[0042] The rats after intervention are fixed at night for erection test, and the experimental environment is required to be dim and quiet without disturbance. After recording the body weight of the rats, they are placed in the test cage and adapted to the environment for 10min, then subcutaneously injected with apomorphine 100μg / kg. Apomorphine is a dopamine receptor agonist, and low-dose apomorphine can cause penile erection through dopamine receptors in the hypothalamic nucleus. It has been reported that injection of apomorphine can cause 100% penile erection in normal rats. Then observe for 30min and record the penile erection of the rats. Penile erection is considered to be penile erection when the glans penis is congested and the distal penile body appears, which is recorded as 1 penile erection. If the erection frequency is ≥1, the erection test is considered positive, otherwise it is negative. 4, collection and processing of samples

[0043] After the erection test, the rats are fasted overnight, and their body weight is recorded. The next day, blood is collected from the tail vein to measure GLP-1 levels. Then the rats are euthanized with CO2, the genital organs are dissected, weighed and homogenized, and the supernatant is collected by centrifugation. The samples are stored at -80℃. According to the kit instructions, NO and cGMP are detected, and PDE5 mRNA levels are detected by PCR. 5, statistical analysis

[0044] Data analysis was performed using Graphpad Prism 10 software, and the results were expressed as standard deviation (x±s).

[0045] Table 2 is the FBG level of each group of rats at 15 weeks of age. From the data in the table, the average FBG-15 of the model group and the experimental group rats is ≥ 16.7 mmol / L, which is significantly different from the control group, *P>0.05, indicating that the modeling is successful.

[0046] Table 3 is the observation results of the erection test of each group of rats. From the table, it can be seen that during the 30min observation period, the rats in the control group can be observed to have 2-3 erections within 30min due to injection of apomorphine, with an average erection frequency of 2.67 times; the model group has no reaction to apomorphine and no erection is observed within 30min. After 12 weeks of BBR intervention, the experimental group 1 has a reaction to apomorphine and 0-1 erections can be observed within 30min, with an average erection frequency of 0.54 times. After 12 weeks of DHB intervention, the experimental group 2 and the experimental group 3 have improved reactivity to apomorphine, and the erection frequency is significantly improved, with 1-3 erections observed within 30min, with an average erection frequency of 1.33 times and 1.92 times, respectively, which is 146% and 256% better than the experimental group 1, respectively.

[0047] Figure 1 is the serum GLP-1 level of each group of rats. From Figure 1, it can be seen that after 12 weeks of DHB intervention, the serum GLP-1 levels of the experimental group 2 and the experimental group 3 rats are improved by 27.6% and 42.6% compared with the model group, and by 17.6% and 31.4% compared with the experimental group 1. This indicates that DHB intervention can improve rat GLP-1 secretion.

[0048] Figure 2 is the NO level in the supernatant of the genital homogenate of each group of rats. From Figure 2, it can be seen that after 12 weeks of DHB intervention, the NO levels in the supernatant of the genital homogenate of the experimental group 2 and the experimental group 3 rats are improved by 34.0% and 100.0% compared with the model group, and by 21.1% and 80.8% compared with the experimental group 1. This indicates that DHB intervention can improve the NO level of the rat genitalia.

[0049] Figure 3 is the cGMP level in the supernatant of the genital homogenate of each group of rats. From Figure 3, it can be seen that after 12 weeks of DHB intervention, the cGMP levels in the supernatant of the genital homogenate of the experimental group 2 and the experimental group 3 rats are improved by 26.0% and 54.6% compared with the model group, and by 21.3% and 48.9% compared with the experimental group 1. This indicates that DHB intervention can improve the cGMP level of the rat genitalia.

[0050] Figure 4 is the PDE5 mRNA level in the genital homogenate supernatant of each group of rats. As shown in Figure 4, after 12 weeks of DHB intervention, the PDE5 mRNA level in the genital homogenate supernatant of the experimental group 2 and the experimental group 3 was all reduced by 17.9% and 33.9% compared with the model group, and by 10.4% and 25.4% compared with the experimental group 1. This indicates that the expression of PDE5 can be inhibited after DHB intervention.

[0051] The administration of DHB to the rats can increase the serum GLP-1 level of the rats. The NO level in the penile tissue is improved, thereby ensuring the local cGMP concentration of the tissue. At the same time, the PDE5 mRNA level is inhibited. As a signal molecule of the organism, NO can promote the secretion of the second messenger cGMP, so as to realize the vasodilation and the increase of the blood flow. PDE5 can degrade cGMP in the body, antagonizes the NO-cGMP effect, and the inhibition of PDE5 can maintain the NO-cGMP effect. The penile artery is small, and is more susceptible to the influence of NO, cGMP and PDE5, thereby promoting the relaxation of the cavernous smooth muscle, increasing the blood flow and realizing the penile erection.

[0052] In the embodiments of the present application, the subjects are administered with microcrystalline cellulose or DHB for 12 weeks of intervention, and the change in the result of the international erectile function score questionnaire before and after the intervention is observed. 1. Clinical data

[0053] The 12 male ED patients were aged 30-55 years, with an average age of 41.5±6.3 years. The 12 subjects were randomly divided into 3 groups, i.e., a control group, an intervention group 1 and an intervention group 2, with 4 people in each group.

[0054] The ED symptoms are judged according to the international ED diagnosis principle, i.e., a male does not continuously achieve or maintain a penile erection with sufficient hardness to complete satisfactory sexual intercourse under sexual stimulation, and the obstacle occurs for more than 3 months, and the international erectile function score questionnaire (IIEF-5) is ≤21 points, which is judged as ED.

[0055] (1) Diabetic patients; (2) Patients with severe heart, liver, kidney and other organ diseases; (3) Patients with severe prostate hyperplasia or prostate specific antigen (PSA) >4 μg / mL; (4) Patients with other mental diseases such as epilepsy; (5) Patients who have taken other ED treatment drugs within 3 months; (6) Patients with a history of severe infection or active infectious diseases.

[0056] The daily dose is shown in the above table, which is administered twice a day for 12 weeks. Before the treatment, after 6 weeks of intervention and after 12 weeks of intervention, the IIEF-5 is used to evaluate the improvement of ED, and the international penile erection hardness registration evaluation standard (EHGS) is used to evaluate the penile erection hardness after 12 weeks of intervention.

[0057] The EHGS evaluates the penile erection hardness condition into four levels, level I: the penile volume increases, and the hardness is poor; level II: the hardness is better, but cannot be inserted into the vagina; level III: can be inserted into the vagina, but not completely hard; level IV: completely hard erection and rigid. 5. Intervention results

[0058] The statistical results are analyzed by using the GraphPad Prism software, and the result data is expressed by standard deviation (x±s), and the t test is used for significance analysis.

[0059] The following table is the change result of IIEF-5 after intervention. Compared with the treatment before the group, *P<0.05; compared with the control group after treatment, # P<0.05. As can be seen from the results in the table, the IIEF-5 score of the subjects in the intervention group 1 is significantly improved after 12 weeks, which is increased by 36.1% compared with the control group, and is increased by 37.1% compared with before intervention; the IIEF-5 score of the subjects in the intervention group 2 is significantly improved at 6 weeks and 12 weeks, which is increased by 48.9% at the highest compared with the control group, and is increased by 45.9% at the highest compared with before intervention. It shows that after 6 weeks and 12 weeks of DHB intervention, the IIEF-5 score can be improved, and the ED symptoms can be improved. Table 5

[0060] The following table is the EHGS result after 12 weeks of intervention. As can be seen from the results in the table, compared with the control group, the penile erection hardness of the subjects in the intervention group 1 and the intervention group 2 is improved after 12 weeks, and the number of people in the II and III levels is increased by 200% at the highest. Table 6

[0061] The results show that the application of DHB can improve the erectile dysfunction of the subjects, and the method is simple and has no toxic side effects. Erectile dysfunction is closely related to the level of testosterone, gonadal function and sexual desire. Testosterone can improve the erectile function by promoting the synthesis of NO and regulating the relaxation function of the cavernous body smooth muscle of the penis. And the strength of the gonadal function affects the secretion of testosterone and the level of sexual desire. Therefore, DHB can improve erectile dysfunction, improve the level of testosterone, improve hypogonadism, improve decreased sexual desire, and achieve the improvement of the reproductive health of the subjects.

[0062] In the present application, after the application of dihydroberberine, the erectile dysfunction can be improved, the level of testosterone can be improved, the hypogonadism can be improved, the decreased sexual desire can be improved, the GLP-1 level can be regulated or the GLP-1 secretion can be stimulated, and / or the PDE5 activity can be inhibited, so as to improve the reproductive health and improve the quality of life.

[0063] While specific embodiments and examples of the application have been described herein, those skilled in the art will understand that any modification and variations therefrom fall within the principles of the application. The above examples and illustrations are not intended to limit the scope of the application. Any combination of the embodiments of the application, as well as any obvious extension or analogue thereof, are within the scope of the application. Furthermore, the application encompasses any arrangement which is intended to achieve the same purpose, as well as all such variations and modifications falling within the scope of the appended claims.

Claims

1. A method of improving reproductive health, the method comprising administering to a subject in need thereof a composition, characterized in that, The composition comprises an effective amount of dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof.

2. The method of claim 1, wherein, The improvement in reproductive health includes improvement in erectile dysfunction, improvement in testosterone levels, improvement in hypogonadism, improvement in decreased libido.

3. The method according to claim 1 or 2, characterized in that, The method modulates GLP-1 levels or stimulates GLP-1 secretion, and / or inhibits PDE5 activity to improve reproductive health.

4. The method according to any one of claims 1 to 3, characterized in that, The composition is prepared as a nutritional product, a health product, a food, a beverage, an animal feed or a medicament.

5. The method according to any one of claims 1 to 4, characterized in that, The composition is in the form of a suppository, a tablet, a pill, a granule, a powder, a film, a capsule, a drop, a functional food, a sublingual preparation, an aerosol, a tonic, a solution, a suspension, an injection or a syrup.

6. The method according to any one of claims 1 to 5, characterized in that, The dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof is formulated to be administered in an amount of 10-2000 mg per day.

7. The method according to any one of claims 1 to 6, characterized in that, The composition is administered orally, intravenously, intramuscularly, intraperitoneally or sublingually.

8. The method according to any one of claims 1 to 7, characterized in that, The subject is a human.

9. A composition comprising dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog, or derivative thereof, characterized in that, The composition is used to improve reproductive health.

10. The composition of claim 9, wherein, The improvement in reproductive health includes improvement in erectile dysfunction, improvement in testosterone levels, improvement in hypogonadism, improvement in decreased libido.

11. The composition according to claim 9 or 10, characterized in that, The composition modulates GLP-1 levels or stimulates GLP-1 secretion, and / or inhibits PDE5 activity to improve reproductive health.

12. The composition according to any one of claims 9 to 11, characterized in that, The composition is prepared as a nutritional product, a health product, a food, a beverage, an animal feed or a medicament.

13. The composition according to any one of claims 9 to 12, characterized in that, The composition is in the form of a suppository, a tablet, a pill, a granule, a powder, a film, a capsule, a drop, a functional food, a sublingual preparation, an aerosol, a tonic, a solution, a suspension, an injection or a syrup.

14. The composition according to any one of claims 9 to 13, characterized in that, The dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof is formulated to be administered in an amount of 10-2000 mg per day.

15. Use of a composition for the manufacture of a nutritional product, a health product, a food, a beverage, an animal feed or a medicament for improving reproductive health, characterized in that, The composition comprises an effective amount of dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof.

16. Use according to claim 15, characterized in that, The improvement in reproductive health includes improvement in erectile dysfunction, improvement in testosterone levels, improvement in hypogonadism, improvement in decreased libido.

17. Use according to claim 15 or 16, characterized in that, The use modulates GLP-1 levels or stimulates GLP-1 secretion, and / or inhibits PDE5 activity to improve reproductive health.

18. Use according to any one of claims 15 to 17, characterized in that, The composition is in the form of a suppository, a tablet, a pill, a granule, a powder, a film, a capsule, a drop, a functional food, a sublingual preparation, an aerosol, a tonic, a solution, a suspension, an injection or a syrup.

19. Use according to any one of claims 15 to 18, characterized in that, The dihydroberberine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof is formulated to be administered in an amount of 10-2000 mg per day.

Images