CN113069549B - Methyl donor composition for improving sperm quality - Google Patents
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Abstract
The present invention relates to a methyl donor composition for improving sperm quality, the composition comprising: 5-methyltetrahydrofolic acid and betaine. The invention also relates to a combination composition comprising a 5-hydroxytryptamine reuptake inhibitor with improved sperm quality, said combination composition comprising a 5-hydroxytryptamine reuptake inhibitor and a composition of 5-methyltetrahydrofolate and betaine. The composition provided by the invention not only can effectively overcome the side effect of reducing the sperm quality when the 5-hydroxytryptamine reuptake inhibitor is applied as a premature ejaculation treatment drug, but also has a synergistic effect with the 5-hydroxytryptamine reuptake inhibitor in the aspect of preventing or treating depression.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a methyl donor composition for improving male sperm quality, and also relates to a pharmaceutical composition containing the methyl donor composition and a 5-hydroxytryptamine reuptake inhibitor.
Background
Premature Ejaculation (PE) is a common sexual disorder, which belongs to the ejaculation disorder. As the modern life rhythm is accelerated, the pressure from all aspects is gradually increased, and the premature ejaculation is more and more common in the male population in China. Premature ejaculation can not only affect the quality of sexual life, but also affect the life of couples along with the lapse of time, which leads to anxiety, tension, fear and the like in the spirit of patients, and the adverse mental states can further aggravate PE, gradually lead the patients to lose confidence and have poor spirit, seriously affect the life and the working quality of the patients, and gradually receive wide attention of the whole society.
Premature ejaculation is a pathological phenomenon with excessively short vaginal ejaculation latency time (IELT) and is closely related to the regulation of ejaculation disorder and penis hypersensitiveness. The ejaculation process involves reflex activity of the receptors, central nervous system and spinal nerves. In this process, various neurotransmitters, central neurotransmitters and their receptors play important roles. The relevant neurotransmitters are involved in this process, and mainly include: 5-hydroxytryptamine (5-HT), leptin (leptin), dopamine (dopamine), etc.
The current drugs for treating premature ejaculation in clinic are 5-hydroxytryptamine reuptake inhibitor (SSRIs) drugs, such as paroxetine, dapoxetine, fluoxetine, citalopram, clomipramine, sertraline and the like, which are originally antidepressants, but the clinical treatment finds that the drugs are useful for treating premature ejaculation. The medicine mechanism of the antidepressant for treating premature ejaculation is that 5-hydroxytryptamine reuptake is inhibited, and then 5-hydroxytryptamine concentration in synaptic cleft is increased, so that 5-hydroxytryptamine related receptors behind synapses are activated, ejaculation threshold is obviously increased, and ejaculation is delayed.
Selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) have recently become first line treatments for primary premature ejaculation due to their remarkable effect in treating premature ejaculation, but have a side effect: resulting in a decreased sperm quality in men. Therefore, there is a certain concern about the safety of SSRIs when taken by young men who have fertility requirements. SSRIs reduce male sperm quality, possibly by a variety of routes: such as breaking hormone homeostasis, down-regulating 5-HT1 alpha receptor, inhibiting spermatogenesis and sperm metabolism, blocking sperm transport, and damaging sperm DNA, etc., which are time and dose dependent on the effects of male sexual function and fertility.
At present, researches show that folic acid and betaine have certain effects on improving the sperm quality, and the betaine and the folic acid are closely related in the aspect of organism metabolism and jointly participate in one-carbon metabolism as methyl donors/transporters. In addition, folic acid can improve sperm quality by reducing the degree of sperm oxygenation; betaine also improves sperm motility and sperm function via cyclic production of S-adenosylmethionine (SAM).
However, the effect of folic acid and betaine on improving sperm quality is still not ideal. 5-Methyltetrahydrofolate is the natural active form of folic acid, and it was found herein that 5-methyltetrahydrofolate, when used in combination with betaine, produces unexpectedly superior results in improving male sperm quality.
Disclosure of Invention
In view of the above, the present invention provides a methyl donor composition capable of effectively improving sperm quality, the methyl donor composition comprising 5-methyltetrahydrofolic acid and betaine-type compounds. The methyl donor composition can simultaneously improve the number of sperms and the motility of the sperms, and particularly can overcome or even reverse the problem of sperm quality reduction caused by 5-hydroxytryptamine reuptake inhibitors (SSRIs) when the methyl donor composition is used together with the SSRIs.
Accordingly, in a first aspect, the present invention provides a methyl donor composition for improving sperm quality, the methyl donor composition comprising: 0.4-20 parts of 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, and 10-500 parts of betaine compounds or pharmaceutically acceptable salt thereof.
In a second aspect, the present invention provides the use of a methyl donor composition as described above in the manufacture of a medicament for improving sperm quality.
In a third aspect, the present invention provides a combination composition of a methyl donor composition in combination with a 5-hydroxytryptamine reuptake inhibitor, said combination composition comprising: the invention relates to a methyl donor composition and 5-200 parts of 5-hydroxytryptamine reuptake inhibitor.
The combined use of the 5-methyltetrahydrofolic acid and the SSRIs not only can improve the sperm quality, but also has the synergistic effect on the aspect of anti-depression: patients with low plasma folate levels have poor efficacy in treating depression with SSRIs, as folate deficiency leads to poor metabolic activity in the production of serotonin, further leading to poor patient response to SSRIs treatment. Oral administration of 5-methyltetrahydrofolic acid can increase the level of oxindole acetic acid in cerebrospinal fluid and produce an antidepressant-like effect. In addition, many depressed patients present themselves with sexual dysfunction, such as premature ejaculation. It is sometimes difficult to distinguish whether premature ejaculation sexual dysfunction is an independent condition or due to depression. For depression patients with premature ejaculation and sexual dysfunction, the combination of 5-methyltetrahydrofolate, betaine and SSRIs has multiple synergistic effects: resisting depression, improving premature ejaculation treatment effect, and improving sperm quality.
To this end, in a fourth aspect, the present invention also provides the use of a combination composition as described above for the manufacture of a medicament for the treatment of depression, premature ejaculation and/or sperm quality.
In a fifth aspect, the present invention provides a method for preparing a methyl donor composition and a combination composition.
The invention has the beneficial effects that:
1. the methyl donor composition of the invention has the functions of increasing the number of sperms and improving the motility of the sperms, can overcome the problem of sperm proton reduction caused by SSRIs when being combined with the SSRIs, and can prevent sperm malformation caused by the SSRIs.
2. In the methyl donor composition, 5-methyltetrahydrofolic acid and betaine have a synergistic effect, and the lower the concentration is, the stronger the synergistic effect is. In particular, the synergistic effect of 5-methyltetrahydrofolate and betaine is not only effective in increasing sperm count, but also has similar effect in enhancing sperm motility, and compared with the composition of folic acid and betaine which is mainly used for improving sperm count and has serious antagonism problem in enhancing sperm motility, the methyl donor composition of the present invention is obviously more suitable for enhancing sperm quality.
3. The combined composition of the methyl donor composition and the SSRIs can generate the synergistic effect in aspects of depression resistance, premature ejaculation treatment effect improvement and sperm quality reduction improvement due to the complementary action among the 5-methyltetrahydrofolic acid, the betaine and the SSRIs, so the combined composition is particularly suitable for preparing the medicaments for depression resistance, premature ejaculation improvement and/or sperm quality improvement.
Detailed Description
In a first aspect, the present invention provides a methyl donor composition for improving sperm quality, the methyl donor composition comprising: 0.4-20 parts of 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, and 10-500 parts of betaine compounds or pharmaceutically acceptable salt thereof.
In one embodiment, the betaine compound or a pharmaceutically acceptable salt thereof is selected from at least one of anhydrous betaine, hydrated betaine, and betaine hydrochloride.
In one embodiment, the present invention provides a methyl donor composition comprising 0.4-20 parts of 5-methyltetrahydrofolic acid or a pharmaceutically acceptable salt thereof, preferably any value between 0.4 parts, 0.5 parts, 1 part, 2 parts, 4 parts, 6 parts, 10 parts, 15 parts, 20 parts, or 0.4-20 parts; the betaine compound or the pharmaceutically acceptable salt thereof is 10-500 parts, preferably 10 parts, 20 parts, 30 parts, 40 parts, 50 parts, 60 parts, 80 parts, 100 parts, 200 parts, 400 parts, 500 parts or any value between 10-500 parts.
In one embodiment, the methyl donor composition comprises: 1-10 parts of 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, and 10-200 parts of betaine compounds or pharmaceutically acceptable salt thereof.
Preferably, the methyl donor composition comprises: 1-5 parts of 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, and 20-100 parts of betaine compounds or pharmaceutically acceptable salt thereof.
Preferably, the methyl donor composition comprises: 1 part of 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, and 60 parts of betaine compounds or pharmaceutically acceptable salt thereof.
In one embodiment, the methyl donor composition consists of the following components: 0.4-20 parts of 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, and 10-500 parts of betaine compounds or pharmaceutically acceptable salt thereof.
In the present invention, the methyl donor composition may further include a pharmaceutically acceptable carrier.
Taking the dosage form of the drug as a tablet as an example, the pharmaceutically acceptable carrier is a type of carrier well known to those skilled in the art. Wherein the carrier comprises excipient and adjuvant for preparing active compound into medicinal preparation, such as one or more of starch, microcrystalline cellulose, inorganic salts, sucrose, dextrin, lactose, sugar powder, glucose, sodium chloride, citric acid and sodium sulfite.
Thus, in one embodiment, the methyl donor composition comprises: 0.4-20 parts of 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, 10-500 parts of betaine compounds or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carriers.
In one embodiment, the methyl donor composition comprises: 0.4-20 parts of 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof as an active ingredient, 10-500 parts of betaine compounds or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In one embodiment, the methyl donor composition consists of the following components: 0.4-20 parts of 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof as an active ingredient, 10-500 parts of betaine compounds or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In a second aspect, the present invention provides the use of a methyl donor composition as described above in the manufacture of a medicament for improving sperm quality.
In a third aspect, the present invention provides a combination composition of a methyl donor composition in combination with a 5-hydroxytryptamine reuptake inhibitor, said combination composition comprising: the invention relates to a methyl donor composition and 5-200 parts of 5-hydroxytryptamine reuptake inhibitor.
In one embodiment, the 5-hydroxytryptamine reuptake inhibitor is selected from at least one of dapoxetine hydrochloride, fluoxetine (including its monomeric isomers), paroxetine, sertraline, citalopram and escitalopram, fluvoxamine.
In one embodiment, the 5-hydroxytryptamine reuptake inhibitor varies according to its particular species, and when present in the combination composition, is in an amount that is each independently:
dapoxetine hydrochloride: 30-60 parts
Fluoxetine: 5-60 parts
Paroxetine: 10-50 parts of
Sertraline: 5 to 200 portions of
Citalopram: 5-20 parts of
Escitalopram: 5-20 parts.
In the present invention, the combination composition may further comprise a pharmaceutically acceptable carrier.
In one embodiment, the combination composition comprises a methyl donor composition and a pharmaceutically acceptable carrier.
Taking the dosage form of the drug as a tablet as an example, the pharmaceutically acceptable carrier is a type of carrier well known to those skilled in the art. Wherein the carrier comprises excipient and adjuvant for preparing active compound into medicinal preparation, such as one or more of starch, microcrystalline cellulose, inorganic salts, sucrose, dextrin, lactose, sugar powder, glucose, sodium chloride, citric acid and sodium sulfite.
In the present invention, the "part" is used to mean the weight part without other descriptions, which is mainly used to indicate the relative amount of each component, and may also indicate the absolute amount of each component, and the unit of weight includes mg, g, kg and any other weight units.
The methyl donor compositions and combination compositions provided herein may be formulated for single or multiple dose administration. For an individual of about 50-70kg, the presently disclosed methyl donor compositions and combination compositions may be in unit dosage form containing from about 1-1000mg, or from about 1-500mg, or from about 1-250mg, or from about 1-150mg, or from about 0.5-100mg, or from about 1-50mg of the active ingredient. The therapeutically effective amount of the composition will depend on the species, weight, age and condition of the individual, the disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of the disease.
In one embodiment, the therapeutically effective dose of the methyl donor compositions and combination compositions disclosed herein is from about 0.1mg to about 2000mg per day of 5-methyltetrahydrofolic acid, or a pharmaceutically acceptable salt thereof, and from about 1mg to about 5000mg per day of the betaine compound, or a pharmaceutically acceptable salt thereof.
In a fourth aspect, the invention also provides the application of the combination composition in preparing a medicament for resisting depression, improving premature ejaculation and/or improving sperm quality.
In a fifth aspect, the present invention provides a method for preparing a methyl donor composition and a combination composition.
In some embodiments of the present invention, when the dosage form of the methyl donor composition or the combination composition is a tablet, the preparation method comprises the following preparation steps:
(1) respectively sieving 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, betaine compounds or pharmaceutically acceptable salt thereof and optional 5-hydroxytryptamine reuptake inhibitor with 100 mesh sieve for use;
(2) weighing 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, betaine compounds or pharmaceutically acceptable salt thereof, optional 5-hydroxytryptamine reuptake inhibitor, starch, microcrystalline cellulose, sodium carboxymethyl starch (CMS-Na) and magnesium stearate according to the prescription amount;
(3) mixing: dispersing 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, betaine compounds or pharmaceutically acceptable salt thereof, optional 5-hydroxytryptamine reuptake inhibitor and microcrystalline cellulose, adding into a wet granulating machine, and adding starch and CMS-Na; stirring at 3-5 rpm, preferably 4rpm, and cutting knife at 20-40 rpm, preferably 30rpm for 4-8 min, preferably 6 min;
(4) preparing a soft material: granulating by taking a povidone K30 solution as an adhesive, stirring at 4-6 rpm preferably at 5rpm, cutting at 30-50 rpm preferably at 40rpm for 2-5 min preferably at 3 min;
(5) and (3) granulating: sieving and granulating the soft material, preferably adopting a 24-mesh screen;
(6) and (3) drying: drying the wet particles in a fluidized bed at 45-70 ℃ until the moisture content is 1.0% -3.0%, and then sieving the particles with a 20-mesh sieve for finishing;
(7) total mixing: mixing the obtained granules and magnesium stearate by a mixer at the rotating speed of 13rpm for 5-10 min, preferably 8 min;
(8) tabletting: pressing the mixture into tablets by using phi 8 round shallow recesses, wherein the hardness is 5-11 kgf;
(9) inner packaging: and carrying out aluminum-plastic packaging by using PVC.
The invention is further illustrated with reference to specific examples. It should be understood that the specific embodiments described herein are illustrative only and are not limiting upon the scope of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products which are not known to manufacturers and are available from normal sources.
The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.
Example 1: improvement of sperm quality by methyl donor compositions
A plurality of adult male Kunming mice (with a weight of 26-28 g and a grade of SPF (specific pathogen free) and purchased from Liaoning Biotechnology Ltd.) were randomly divided into 10 groups by 10 individuals per group, namely a blank control group, a folic acid administration group, a 5-methyltetrahydrofolic acid administration group, a betaine administration group, a folic acid + betaine administration group, a 5-methyltetrahydrofolic acid + betaine administration group, a fluoxetine administration group, a sertraline administration group, fluoxetine + 5-methyltetrahydrofolic acid + betaine administration group, and a sertraline + folic acid + betaine administration group.
The administration modes of each group are as follows:
blank control group: normal feed and normal drinking water, free diet and drinking water, and the same amount of distilled water for intragastric administration every day, and intragastric administration once a day; for 45 consecutive days.
Administration group: the normal feed and the normal drinking water are given every day, the food and the water are freely taken, and the medicine with the amount shown in the stomach is infused every day; for 45 consecutive days.
After 45 days of continuous oral administration, the epididymis is killed, picked up, placed in liquid nitrogen overnight, and then transferred to a refrigerator at-80 ℃ for freezing. Before measurement, the epididymis is transferred into PBS phosphate buffer solution, the epididymis is cut into pieces, the pieces are lightly squeezed, semen is squeezed out, and the mixture is incubated for 1 hour to enable the sperms to freely emerge. Sucking the supernatant to obtain sperm suspension.
Smear microscopic examination is carried out on the sperm suspension which is incubated and dispersed preliminarily, and the quantity, the vitality and the aberration rate of the sperms of the mice are detected.
Wherein, for the number of sperm: the mouse sperm was counted using a blood counting chamber of 25 × 16 size, and the number of sperm in the top left, bottom left, top right, bottom right, and central 5 squares was counted, and the number of sperm was calculated according to the following formula:
number of sperm/(piece/ml) ═ n/80X 400X dilution factor X104
Wherein n is the number of sperms in the upper left, lower left, upper right, lower right and middle regions.
For sperm motility: detecting the activity of mouse sperms by using a blood counting chamber, dripping the sperm suspension on the blood counting chamber, firstly counting the number of sperms which move linearly, then placing the counting chamber in a water bath kettle at 55 ℃ to heat for 15min to kill the sperms, counting the total number of sperms, repeatedly counting for three times, and taking an average value. Sperm motility was calculated according to the following formula:
sperm motility/(%) ═ n1/n
In the formula n1The number of sperms moving linearly is shown, and n is the total number of sperms.
For sperm teratogenicity rate: dripping the mouse sperm suspension on a glass slide, dispersing and pushing away, drying in the air, fixing with methanol for 10min, dyeing with 1% eosin dye solution for 3min, washing off redundant dye with distilled water, drying in the air, and performing microscopic examination. 500 sperm cells were observed per specimen and the number of various teratospermia were recorded. The sperm teratogenesis rate is calculated according to the following formula:
sperm teratogenicity/(%) n2/n
In the formula n2The number of teratospermia and n is the total number of sperms.
The experimental data were analyzed for variance using SPSS 20.0 software, and the experimental results were expressed as mean ± standard deviation (χ ± s), with differences in statistical significance being either p <0.05 or p < 0.01.
The method for calculating the synergistic effect comprises the following steps: judging by adopting a gold positive mean q value method, wherein the q value is obtained by the following formula: q ═ PA+B/(PA+PB-PA×PB). In the formula PA、PBAnd PA+BRespectively the action rates of the A-medicine group, the B-medicine group and the combined group. q. q.s<1, the two medicines are used together to generate antagonism; q. q.s>l, the synergistic effect of the two medicines is demonstrated; the result is that the two drugs are combined to produce the additive effect.
The results are shown in table 1 below:
table 1:
note: comparison with blank group: p <0.05, P <0.01
From the above results, it can be seen that folic acid, 5-methyltetrahydrofolic acid and betaine all have the function of increasing sperm motility, folic acid and 5-methyltetrahydrofolic acid can not increase the number of sperm significantly, and betaine can increase the number of sperm significantly. Whereas when folic acid or 5-methyltetrahydrofolic acid was combined with betaine, both combinations showed similar synergistic effects in increasing sperm number (q of 1.58 and 1.54, respectively), the combination of folic acid and betaine showed antagonistic effects on sperm motility (q of 0.41), while the combination of 5-methyltetrahydrofolic acid and betaine showed additive effects (q of 1.01). In sperm teratogenicity, it can be seen that folic acid, 5-methyltetrahydrofolic acid, betaine, and combinations thereof have little effect on sperm teratogenicity in normal mice, but also have no teratogenicity.
When a 5-hydroxytryptamine reuptake inhibitor (such as fluoxetine or troxerutin) is administered, the number of sperms in rats is remarkably reduced, the sperm motility is remarkably reduced, the proportion of abnormal-form sperms is remarkably increased, and the damage of the 5-hydroxytryptamine reuptake inhibitor on all aspects of the sperm quality is shown. By simultaneously administering the composition of 5-methyltetrahydrofolic acid and betaine, the phenomena of significantly reduced sperm number, significantly reduced sperm motility and significantly increased abnormal sperm proportion of rats are inhibited and improved, and even the sperm number and the sperm motility are better than those of a blank control; on the other hand, in the sperm teratospermia rate, although the composition of 5-methyltetrahydrofolic acid and betaine is not helpful for improving the sperm teratospermia rate of normal rats, the composition can play a role in preventing the sperm teratospermia when being administered with fluoxetine or trastuzumab.
Example 2: synergistic effect of different concentration combinations
An experiment was performed similarly to example 1, except that different concentrations of 5-methyltetrahydrofolate, betaine and combinations thereof were selected, and the results are shown in table 2 below:
table 2:
as can be seen from the above results, at low concentrations, 5-methyltetrahydrofolate and betaine tend to be synergistic, either in increasing sperm count or increasing sperm motility; at high concentrations, however, the synergistic effect is suppressed or even antagonism is produced. Therefore, low concentrations of 5-methyltetrahydrofolate and betaine are sufficient to produce the desired effect. However, high concentrations of 5-methyltetrahydrofolate and betaine still contribute to higher sperm counts and higher sperm motility.
Formulation examples
1. Prescription
See Table 3
Table 3:
2. the preparation process comprises the following steps:
(1) 5-methyltetrahydrofolic acid, betaine and dapoxetine hydrochloride are respectively sieved by a 100-mesh sieve for later use.
(2) Weighing 5-methyltetrahydrofolic acid, betaine, dapoxetine hydrochloride, starch, microcrystalline cellulose, sodium carboxymethyl starch (CMS-Na) and magnesium stearate according to the formula;
(3) mixing: dispersing 5-methyltetrahydrofolic acid, betaine, dapoxetine hydrochloride and microcrystalline cellulose, adding into a wet granulating machine, and adding starch and CMS-Na; stirring at 4rpm, cutting at 30rpm for 6 min;
(4) preparing a soft material: granulating with polyvidone K30 solution as binder, stirring at 5rpm, cutting at 40rpm, and standing for 3 min;
(5) and (3) granulating: sieving and granulating the soft material, preferably adopting a 24-mesh screen;
(6) and (3) drying: drying the wet granules in a boiling bed at 60 ℃ until the moisture is 1.0-1.5%, and then sieving the granules by a 20-mesh sieve for finishing the granules;
(7) total mixing: mixing the obtained granules and magnesium stearate by a mixer at the rotating speed of 13rpm for 8 min;
(8) tabletting: pressing the mixture into tablets by using phi 8 round shallow recesses, wherein the hardness is 6-7 kgf;
(9) inner packaging: and carrying out aluminum-plastic packaging by using PVC.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (10)
1. A methyl donor composition for improving sperm quality, the methyl donor composition comprising: 0.5-1 part of 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, and 20-60 parts of betaine compounds or pharmaceutically acceptable salt thereof.
2. The methyl donor composition according to claim 1, wherein the betaine compound or the pharmaceutically acceptable salt thereof is selected from at least one of anhydrous betaine, hydrated betaine, and betaine hydrochloride.
3. The methyl donor composition according to claim 1, wherein the amount of 5-methyltetrahydrofolic acid or a pharmaceutically acceptable salt thereof is 0.5 parts or 1 part; the amount of the betaine-type compound or a pharmaceutically acceptable salt thereof is 20 parts, 30 parts, 40 parts, 50 parts, or 60 parts.
4. Use of a methyl donor composition according to any one of claims 1 to 3 in the manufacture of a medicament for improving sperm quality.
5. A combination composition comprising a 5-hydroxytryptamine reuptake inhibitor, said combination composition comprising: the methyl donor composition according to any one of claims 1 to 3, and 5 to 200 parts of a 5-hydroxytryptamine reuptake inhibitor.
6. The combination composition according to claim 5, wherein the 5-hydroxytryptamine reuptake inhibitor is at least one selected from dapoxetine hydrochloride, fluoxetine, paroxetine, sertraline, citalopram and escitalopram, fluvoxamine.
7. The combination composition according to claim 6, wherein the following 5-hydroxytryptamine reuptake inhibitors, when present in the combination composition, are each independently in an amount of:
dapoxetine hydrochloride: 30-60 parts
Fluoxetine: 5-60 parts
Paroxetine: 10 to 50 portions of
Sertraline: 5 to 200 portions of
Citalopram: 5-20 parts of
Escitalopram: 5-20 parts.
8. Use of a combination composition according to any one of claims 5 to 7 for the preparation of a medicament for the treatment of depression, for the improvement of premature ejaculation and/or for the improvement of sperm quality.
9. A preparation method of a pharmaceutical composition is characterized in that the pharmaceutical composition is in the form of tablets, and the preparation method comprises the following preparation steps:
(1) respectively sieving 0.5-1 part of 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, 20-60 parts of betaine compound or pharmaceutically acceptable salt thereof and optional 5-hydroxytryptamine reuptake inhibitor with 100 mesh sieve for later use; wherein, when the 5-hydroxytryptamine reuptake inhibitor is contained, the dosage is 5-200 parts;
(2) weighing 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, betaine compounds or pharmaceutically acceptable salt thereof, optional 5-hydroxytryptamine reuptake inhibitor, starch, microcrystalline cellulose, sodium carboxymethyl starch (CMS-Na) and magnesium stearate according to the prescription amount;
(3) mixing: dispersing 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, betaine compounds or pharmaceutically acceptable salt thereof, optional 5-hydroxytryptamine reuptake inhibitor and microcrystalline cellulose, adding into a wet granulating machine, and adding starch and CMS-Na; stirring at 3-5 rpm, and cutting at 20-40 rpm for 4-8 min;
(4) preparing a soft material: granulating by taking a povidone K30 solution as an adhesive, stirring at 4-6 rpm, and cutting at 30-50 rpm for 2-5 min;
(5) granulating: sieving and granulating the soft material;
(6) and (3) drying: drying the wet particles in a fluidized bed at 45-70 ℃ until the moisture content is 1.0% -3.0%, and then sieving the particles with a 20-mesh sieve for finishing;
(7) total mixing: mixing the obtained granules and magnesium stearate by a mixer at the rotating speed of 13rpm for 5-10 min;
(8) tabletting: pressing with a phi 8 circular shallow concave tablet, wherein the hardness is 5-11 kgf;
(9) inner packaging: and carrying out aluminum-plastic packaging by using PVC.
10. The method of claim 9, wherein the (3) mixing comprises: dispersing 5-methyltetrahydrofolic acid or pharmaceutically acceptable salt thereof, betaine compounds or pharmaceutically acceptable salt thereof, optional 5-hydroxytryptamine reuptake inhibitor and microcrystalline cellulose, adding into a wet granulating machine, and adding starch and CMS-Na; stirring at 4rpm, cutting at 30rpm for 6 min; the soft material (4) includes: granulating with polyvidone K30 solution as binder, stirring at 5rpm, cutting at 40rpm, and standing for 3 min; the (5) granulating comprises: sieving and granulating the soft material by adopting a 24-mesh screen; the (7) total mixing comprises: the resulting granules were mixed with magnesium stearate using a mixer at 13rpm for 8 min.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3269389A1 (en) * | 2016-07-11 | 2018-01-17 | Laboratoire des Granions | Composition comprising l-carnitine for the treatment of male infertility |
| CN111132679A (en) * | 2017-07-10 | 2020-05-08 | 努瑞比尔公司 | Food supplement for protecting fertility in women and men |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3269389A1 (en) * | 2016-07-11 | 2018-01-17 | Laboratoire des Granions | Composition comprising l-carnitine for the treatment of male infertility |
| CN111132679A (en) * | 2017-07-10 | 2020-05-08 | 努瑞比尔公司 | Food supplement for protecting fertility in women and men |
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| Title |
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| 口服叶酸与甜菜碱提高小鼠精子质量的作用及其机制研究;于炎巧;《中国优秀博硕士学位论文全文数据库（硕士） 工程科技Ⅰ辑》;20190115;B024-1233页 * |
| 口服叶酸与甜菜碱提高小鼠精子质量的作用及机制研究;于炎巧;《中国优秀博硕士学位论文全文数据库（硕士）工程科技Ⅰ辑》;20190115;B024-1233页 * |
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