Pharmaceutical composition for preventing and treating preeclampsia

Abstract

The invention provides a pharmaceutical composition. The pharmaceutical composition is prepared from an anti-platelet medicine, folic acid, 5-methyltetrahydrofolic acid and acceptable auxiliary materials. The composition has the advantages that the composition can be used for preventing and treating preeclampsia, and is particularly suitable for primary lying-in women, hypertension pregnant women and diabetes pregnant women. The composition provided by the invention aims at specific pregnant women, realizes precise medical treatment, improves the curative effect, reduces the side effect and increases the medication compliance.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition containing an antiplatelet drug, folic acid, and 5-methyltetrahydrofolate, for the prevention and treatment of preeclampsia. This invention belongs to the field of pharmaceutical science. Background Technology

[0002] Preeclampsia refers to the onset of symptoms such as headache, blurred vision, nausea, vomiting, upper abdominal discomfort, and visual disturbances after 24 weeks of gestation, on the basis of hypertension and proteinuria. It can also affect the normal development of the fetus and even cause stillbirth. Preeclampsia is a continuation and aggravation of gestational hypertension, and the condition can continue to progress, seriously affecting the health and safety of both mother and baby.

[0003] The pathogenesis of preeclampsia is not fully understood, but it is generally considered to be a multifactorial, multi-pathway disease resulting from the combined effects of factors related to the pregnant woman, placenta, and fetus. Abnormalities in the uteroplacental vascular structure, specifically impaired remodeling of trophoblastic cells in the uterine spiral arteries, lead to placental ischemia and hypoxia, releasing various placental factors. These placental factors enter the maternal bloodstream, promoting systemic inflammatory responses and vascular endothelial damage, resulting in diverse clinical manifestations of preeclampsia. Age, family history, history of chronic hypertension or kidney disease, and multiple pregnancies are all high-risk factors for preeclampsia.

[0004] Although the incidence of preeclampsia in pregnant women is not high, it remains the second leading cause of maternal death worldwide due to the sheer size of the population. Treatment for preeclampsia, aside from terminating delivery and using medications such as magnesium sulfate injection, nifedipine tablets, and furosemide injection to control symptoms, lacks other more effective interventions, making prevention of preeclampsia particularly important.

[0005] Antiplatelet drugs are important for the prevention and treatment of thrombotic diseases such as myocardial infarction and ischemic stroke. They mainly include cyclooxygenase (COX) inhibitors (aspirin), platelet membrane adenosine diphosphate (ADP) receptor inhibitors (clopidogrel, ticagrelor, ticlopidine, etc.), platelet glycoprotein IIb / IIIa receptor antagonists (abcitumab, etifibrebide, tirofiban, etc.), and protease-activated receptor 1 antagonists. While these drugs inhibit thrombus formation, they also increase the risk of side effects such as bleeding. Therefore, their clinical application requires caution and a comprehensive assessment of the benefit / risk ratio.

[0006] Folic acid, an essential B vitamin for human growth and development, plays a vital role in promoting the development of the nervous system and providing nutrition. Folic acid deficiency in pregnant women can lead to adverse consequences such as neural tube defects in the fetus, placental abruption, and megaloblastic anemia. 5-Methyltetrahydrofolate, the active form of folic acid, converts homocysteine ​​(Hcy) to methionine through transmethylation, thus reducing the production of the harmful substance Hcy. Summary of the Invention

[0007] In view of the shortcomings of current products for the prevention and treatment of preeclampsia in pregnant women, the present invention provides a pharmaceutical composition for the prevention and treatment of preeclampsia.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] A composition comprising:

[0010] a) an antiplatelet drug or a derivative thereof; b) folic acid; c) 5-methyltetrahydrofolate; d) an acceptable excipient or carrier or a mixture thereof. The antiplatelet drug is selected from one of aspirin, clopidogrel, prasugrel, ticagrelor, dipyridamole, cilostazol, abciximab, tirofiban, and ticlopidine.

[0011] In this invention, derivatives include, but are not limited to, various salts, esters, hydrates, pharmaceutical precursors, and in vivo active metabolites of compounds.

[0012] In this invention, the mass ratio of folic acid to 5-methyltetrahydrofolate, based on equimolar folic acid mass (the same below), is 0.2-1.2:0.2-2.0, preferably 0.4-0.8:0.4-0.8.

[0013] In this invention, the ratio of antiplatelet drug or its derivative to folic acid to 5-methyltetrahydrofolate, based on content, ranges from 25 to 400: 0.2 to 1.2: 0.2 to 2.0.

[0014] In this invention, the ratio of antiplatelet drug or its derivative to folic acid to 5-methyltetrahydrofolate, based on content, ranges from 25 to 250: 0.4 to 0.8: 0.4 to 0.8.

[0015] In this invention, based on content, when the antiplatelet drug is aspirin, the ratio of the antiplatelet drug or its derivative: folic acid: 5-methyltetrahydrofolate is 35:0.4:0.4.

[0016] Alternatively, when the antiplatelet drug is aspirin, the ratio of the antiplatelet drug or its derivative to folic acid to 5-methyltetrahydrofolate is 75:0.8:0.8.

[0017] Alternatively, when the antiplatelet drug is clopidogrel, the ratio of the antiplatelet drug or its derivative to folic acid to 5-methyltetrahydrofolate is 25:0.4:0.4.

[0018] Alternatively, the antiplatelet drug may be clopidogrel, and the ratio of the antiplatelet drug or its derivative to folic acid to 5-methyltetrahydrofolate is 50:0.8:0.8.

[0019] Alternatively, the antiplatelet drug may be ticagrelor, and the ratio of the antiplatelet drug or its derivative to folic acid to 5-methyltetrahydrofolate is 60:0.4:0.4.

[0020] Alternatively, the antiplatelet drug may be ticagrelor, and the ratio of the antiplatelet drug or its derivative to folic acid to 5-methyltetrahydrofolate is 120:0.8:0.8.

[0021] In this invention, the content of the antiplatelet drug is 25-400 mg.

[0022] In this invention, the aspirin content is 35-150 mg, preferably 35-75 mg; the clopidogrel content is 25-75 mg, preferably 25-50 mg; the ticagrelor content is 60-180 mg, preferably 60-120 mg; the dipyridamole content is 40-400 mg, preferably 40-100 mg; the cilostazol content is 100-200 mg; and the ticlopidine content is 125-250 mg.

[0023] In this invention, the folic acid content is 0.2–1.2 mg, preferably 0.4–0.8 mg.

[0024] In this invention, the content of 5-methyltetrahydrofolate is 0.2-2.0 mg, preferably 0.4-0.8 mg.

[0025] In this invention, the content of the antiplatelet drug is 25-400 mg; and / or the content of folic acid is 0.2-1.2 mg; and / or the content of 5-methyltetrahydrofolate is 0.2-2.0 mg.

[0026] In this invention, the antiplatelet drug is aspirin with a content of 35 mg, the folic acid content is 0.4 mg, and the 5-methyltetrahydrofolate content is 0.4 mg.

[0027] Alternatively, the antiplatelet drug could be aspirin (75mg), folic acid (0.8mg), and 5-methyltetrahydrofolate (0.8mg).

[0028] Alternatively, the antiplatelet drug may be clopidogrel with a content of 25 mg, folic acid with a content of 0.4 mg, and 5-methyltetrahydrofolate with a content of 0.4 mg.

[0029] Alternatively, the antiplatelet drug may be clopidogrel with a content of 50 mg, folic acid with a content of 0.8 mg, and 5-methyltetrahydrofolate with a content of 0.8 mg.

[0030] Alternatively, the antiplatelet drug may be ticagrelor with a content of 60 mg, folic acid with a content of 0.4 mg, and 5-methyltetrahydrofolate with a content of 0.4 mg.

[0031] Alternatively, the antiplatelet drug mentioned is ticagrelor with a content of 120 mg, folic acid with a content of 0.8 mg, and 5-methyltetrahydrofolate with a content of 0.8 mg.

[0032] In this invention, acceptable excipients or carriers or mixtures thereof include one or more of sugars or functional sweeteners, fillers, wetting agents, binders and lubricants.

[0033] The pharmaceutical compositions provided by this invention are in the form of oral preparations, including but not limited to ordinary tablets, bilayer tablets, multilayer tablets, sustained-release tablets, single-compartment controlled-release tablets, dual-compartment controlled-release tablets, microporous controlled-release tablets, sublingual tablets, orally disintegrating tablets, dispersible tablets, enteric-coated tablets, granules, pills, enteric-coated capsules, delayed-release tablets, timed / positional release tablets, ordinary capsules, sustained-release capsules, controlled-release capsules, capsules containing microspheres or small pieces, pH-dependent capsules containing microspheres or small pieces, granules, oral liquids, films, or patches, among which tablets, capsules, or granules are preferred.

[0034] The mass of 5-methyltetrahydrofolate (calculated as an equimolar mass of folic acid) mentioned in this invention refers to the following: if 0.416 mg of 5-methyltetrahydrofolate, 0.451 mg of calcium 5-methyltetrahydrofolate, and 0.4 mg of folic acid are equimolar masses, then the mass of 5-methyltetrahydrofolate or calcium 5-methyltetrahydrofolate (calculated as an equimolar mass of folic acid) is recorded as 0.4 mg.

[0035] The compounds in the pharmaceutical compositions provided by this invention can be administered simultaneously to a patient in the same formulation or administered separately and sequentially. If administered sequentially, a delay in the administration of the second (or additional) active ingredient should not result in a loss of the beneficial effects of the combined active ingredients. If administered simultaneously, the compounds in the composition can be mixed in the same pharmaceutical formulation or exist independently in the same formulation. If exist independently in the same formulation, the pharmaceutical composition can be alternatively presented in a "combination kit." A "combination kit" is a box-shaped container containing one or more dosage forms of the pharmaceutical combination and its instructions for use. In this invention, aspirin, folic acid, and 5-methyltetrahydrofolate are preferred; clopidogrel, folic acid, and 5-methyltetrahydrofolate are preferred; and ticagrelor, folic acid, and 5-methyltetrahydrofolate are preferred.

[0036] In this invention, the composition is used in the preparation of products for the prevention and treatment of preeclampsia.

[0037] In this invention, the composition is used in the preparation of products for reducing maternal and infant complications.

[0038] The beneficial effects of the present invention are as follows: The pharmaceutical composition provided by the present invention has a significant synergistic effect, which can effectively reduce placental tissue oxidative stress and inflammatory damage, improve symptoms of hypertension and proteinuria in late pregnancy, and promote offspring survival and normal development. Therefore, it can be used to prevent preeclampsia, improve adverse pregnancy outcomes, and has an auxiliary effect on the treatment and reduction of complications of preeclampsia. It is especially suitable for primiparous women, pregnant women with hypertension, and pregnant women with diabetes. Detailed Implementation

[0039] The present invention will be further described below with reference to specific embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in the art in accordance with the content of the present invention shall fall within the protection scope of the present invention.

[0040] To verify the scientific validity of the pharmaceutical composition provided by this invention, and to demonstrate that the three components of the composition are rationally combined and can exert a synergistic effect rather than simply an additive pharmacological effect, the Jin Zhengjun Q-value method is introduced for analysis. The Jin Zhengjun Q-value method, also known as the probability addition method, calculates the pharmacological effects of the two drugs used in combination and the two drugs used alone within the dose-response curve region using the following formula: Q = E A+B / (E A +E B -E A *E B In the formula, the numerator represents the "measured combined effect," and the denominator represents the "expected combined effect." (To satisfy the analysis of the pharmacological relationship between components and compositions, their pharmacological effects are transformed into effects that can intuitively reflect the strength of pharmacological effects. The calculation formula is: E...) i =1-P i / P 模型组 P i For the pharmacological indicators of each component, P 模型组 (The pharmacological index of the model group), Q is the ratio of the two: when Q is less than 0.85, the two drugs are considered to have an antagonistic effect; when Q is less than 1.15 and greater than 0.85, it is considered to have an additive effect; when Q is greater than or equal to 1.15, it is considered to have a synergistic effect.

[0041] Example 1: Effects of the composition of the present invention on endotoxin-induced preeclampsia rats

[0042] I. Methods

[0043] Experimental animals and grouping: SD rats, weighing 220±20g, were purchased from Guangdong Provincial Medical Laboratory Animal Center. Male and female rats were housed in separate cages at a ratio of 2:1, in an environment with room temperature of 18–28℃ and relative humidity of 40%–70%, with free access to food and water. The day the vaginal plug was found was considered day 1 of gestation. Eighty female rats were selected as the research subjects and randomly divided into groups (n=10 per group) as shown in Table 1. Except for the blank control group, all experimental groups received endotoxin 1.0 μg / (kg·d) via tail vein infusion from day 14 of gestation at an infusion rate of 2 mL / h for 4 consecutive days. The blank control group received the same dose of physiological saline during the same period.

[0044] Administration method: The drug group was administered the drug by gavage at the dosage shown in Table 1 below daily from day 14 to day 21 of pregnancy. The blank control group and the model control group were given the same amount of normal saline. The administration was continued until day 21 of pregnancy.

[0045] The following indicators of rats were detected on day 21 of pregnancy: (1) Tail artery blood pressure: The tail artery blood pressure of rats was measured by a non-invasive blood pressure and heart rate meter with a rat tail sheath while the rats were in a stable respiratory state. Each rat was measured three times and the average value was taken. (2) 24-hour urinary protein content: The urinary protein concentration of rats was determined by colorimetric method after collecting 24 hours of urine. (3) Body weight and length of pups: Rats were anesthetized with ether, and the fetuses were removed by abdominal surgery. Their body weight and length were measured to obtain the average body weight and average length of pups.

[0046] II. Results

[0047] As shown in Tables 1 and 2, compared with the blank control group, the tail artery blood pressure and 24-hour urinary protein of the rats in the model control group were significantly increased, and the body weight and length of the pups were significantly decreased (P < 0.01), indicating that the model was successfully constructed.

[0048] Compared with the model control group, there were no significant changes in the low-dose aspirin + folic acid group and the low-dose 5-MTHF group, while the tail artery blood pressure and 24-hour urinary protein of rats in the low-dose aspirin + folic acid + 5-MTHF group were significantly reduced, and the body weight and length of the pups were significantly increased. The tail artery blood pressure and 24-hour urinary protein of rats in the high-dose aspirin + folic acid group and the high-dose 5-MTHF group were significantly reduced, while the tail artery blood pressure and 24-hour urinary protein of rats in the high-dose aspirin + folic acid + 5-MTHF group were further significantly reduced, and the body weight and length of the pups were further significantly increased. There were no significant differences compared with the blank control group, indicating that the above composition has a significant effect on reducing blood pressure and urinary protein elevation and inhibiting the occurrence of preeclampsia in endotoxin-induced preeclampsia rats.

[0049] Meanwhile, the Q values ​​for tail artery blood pressure, 24-hour urinary protein, pup body weight, and pup length in the low-dose aspirin + folic acid + 5-MTHF group compared to the corresponding low-dose aspirin + folic acid and low-dose 5-MTHF groups were 1.95, 2.14, 1.71, and 1.96, respectively. Similarly, the Q values ​​for the high-dose aspirin + folic acid + 5-MTHF group compared to the corresponding high-dose aspirin + folic acid and high-dose 5-MTHF groups were 1.24, 1.59, 1.23, and 1.44, respectively, with all Q values ​​> 1.15. This indicates that the triple combination group has a surprisingly synergistic effect compared to the single-drug or two-drug groups in improving the clinical symptoms of preeclampsia and reducing adverse pregnancy outcomes, and therefore can be used for the prevention and treatment of preeclampsia.

[0050] Table 1. Effects of the composition of the present invention on tail artery blood pressure and 24-hour urinary protein in rats ( n = 8 to 10)

[0051]

[0052] Note: Compared with the blank control group, aa P<0.01; compared with the model control group, b P<0.05, bb P<0.01.

[0053] Table 2. Effects of the composition of the present invention on the average body weight and average length of pups (indicating the influence of the composition of the present invention on the average body weight and average length of pups). n = 8 to 10)

[0054]

[0055] Note: Compared with the blank control group, aa P<0.01; compared with the model control group, b P<0.05, bb P<0.01.

[0056] Example 2: Effects of the composition of the present invention on L-NAME-induced preeclampsia rats

[0057] I. Methods

[0058] Experimental animals and grouping: SD rats, weighing 220±20g, were purchased from Guangdong Provincial Medical Laboratory Animal Center. Male and female rats were housed in separate cages at a ratio of 2:1 in an environment with a room temperature of 18–28℃ and a relative humidity of 40%–70%, with free access to food and water. The day the vaginal plug was found was considered day 1 of gestation. 120 female rats were selected as the research subjects and randomly divided into groups (see Table 3 below), with 10 rats in each group. Except for the blank control group, all experimental groups received subcutaneous injections of 100 mg / kg of N-nitro-L-arginine methyl ester (L-NAME) once daily from day 14 of gestation until day 21 of gestation. A significant increase in blood pressure at the base of the tail indicated successful model establishment. The blank control group received an equal volume of physiological saline subcutaneously.

[0059] Administration method: The drug group was administered the drug by gavage at the dosage shown in Table 3 below daily from day 14 to day 21 of pregnancy. The blank control group and the model control group were given the same amount of normal saline. The administration was continued until day 21 of pregnancy.

[0060] The following indicators were measured in rats on day 21 of gestation: (1) Tail artery blood pressure: The tail artery blood pressure of rats was measured using a rat tail-tie non-invasive blood pressure and heart rate meter when the rats were in a stable respiratory state. Each rat was measured three times and the average value was taken. (2) 24-hour urinary protein content: The urinary protein concentration of rats was measured by a fully automated biochemical analyzer after collecting 24 hours of urine. (3) Average number of offspring and pup body weight: The rats were anesthetized with ether, the fetuses were removed by opening the abdomen, the number of fetuses was counted and their weight was measured to obtain the average number of offspring and the average body weight of pups. (4) Placental GSH-Px and MDA levels: 1g of placental tissue was cut off, an appropriate amount of high-strength RIPA lysis buffer was added, homogenized, centrifuged, and the supernatant was aspirated. The GSH-Px and MDA in the placental tissue were measured according to the kit operation steps.

[0061] II. Results

[0062] As shown in Table 3-5, compared with the blank control group, the tail artery blood pressure, 24-hour urinary protein, and placental tissue oxidative factor MDA of rats in the model control group were significantly increased (P<0.01), while the number of offspring, the body weight of pups, and the content of placental tissue antioxidant factor GSH-Px were significantly decreased (P<0.01), indicating that the model was successfully constructed.

[0063] Compared with the model control group, rats in the high-dose 5-MTHF group had significantly higher tail artery blood pressure and 24-hour urinary protein levels (P < 0.05); rats in the high-dose clopidogrel + folic acid group, high-dose ticagrelor + folic acid group, low (high)-dose clopidogrel + folic acid + 5-MTHF group, and low (high)-dose ticagrelor + folic acid + 5-MTHF group had significantly lower tail artery blood pressure, 24-hour urinary protein levels, and placental MDA content, while offspring number, pup body weight, and placental GSH-Px content were significantly higher (P < 0.05 or P < 0.01). This indicates that the above-mentioned compositions have significant effects on reducing placental oxidative stress and inflammatory damage, improving symptoms of hypertension and proteinuria in late pregnancy, and promoting offspring survival in rats.

[0064] Meanwhile, the Q values ​​for six indicators—tail artery blood pressure, 24-hour urinary protein, offspring number, pup body weight, placental GSH-Px, and MDA—were all >1.15 in the low (high) dose clopidogrel + folic acid + 5-MTHF group, the corresponding low (high) dose clopidogrel + folic acid group, and the low (high) dose 5-MTHF group alone. Similarly, the Q value for ticagrelor was also >1.15. This indicates that the triple combination has a synergistic effect compared to the dual combination and the single-drug group in enhancing the antioxidant capacity of placental tissue in pregnant mice, alleviating their hypertension and proteinuria symptoms, and promoting normal fetal development. Therefore, it can be used to prevent or treat preeclampsia and improve adverse pregnancy outcomes.

[0065] Based on the experimental data, it can be seen that the low-dose clopidogrel + folic acid + 5-MTHF group and the low-dose ticagrelor + folic acid + 5-MTHF group are not significantly different from the high-dose group in improving preeclampsia symptoms. The synergistic effect of each drug is stronger, and the low-dose antiplatelet drug can significantly reduce the risk of bleeding, making it the better dosage combination.

[0066] Table 3. Effects of the composition of the present invention on tail artery blood pressure and 24-hour urinary protein in rats ( n = 8 to 10)

[0067]

[0068]

[0069] Note: Compared with the blank control group, aa P<0.01; compared with the model control group, b P<0.05, bb P<0.01.

[0070] Table 4. Effects of the composition of the present invention on the average number of offspring and body weight of rats. n = 8 to 10)

[0071]

[0072]

[0073] Note: Compared with the blank control group, aa P<0.01; compared with the model control group, b P<0.05, bb P<0.01.

[0074] Table 5. Effects of the compositions of the present invention on GSH-Px and MDA levels in rat placenta ( n = 8 to 10)

[0075]

[0076]

[0077] Note: Compared with the blank control group, aa P<0.01; compared with the model control group, b P<0.05, bb P<0.01.

Claims

1. A composition comprising: a) an anti-platelet agent or a derivative thereof; b) folic acid; c) 5-methyltetrahydrofolic acid; d) an acceptable excipient or carrier or a mixture thereof.

2. The composition of claim 1, wherein, The anti-platelet agent is selected from one of aspirin, clopidogrel, prasugrel, ticagrelor, dipyridamole, cilostazol, abciximab, tirofiban, ticlopidine.

3. The composition of claim 2, wherein, The ratio of the anti-platelet agent or a derivative thereof : folic acid : 5-methyltetrahydrofolic acid ranges from 25 to 400 : 0.2 to 1.2 : 0.2 to 2.0 by content.

4. The composition of claim 3, wherein, The ratio of the anti-platelet agent or a derivative thereof : folic acid : 5-methyltetrahydrofolic acid ranges from 25 to 250 : 0.4 to 0.8 : 0.4 to 0.8 by content.

5. The composition of claim 4, wherein, The anti-platelet agent is aspirin, the ratio of the anti-platelet agent or a derivative thereof : folic acid : 5-methyltetrahydrofolic acid is 35 : 0.4 : 0.4 by content; or the anti-platelet agent is aspirin, the ratio of the anti-platelet agent or a derivative thereof : folic acid : 5-methyltetrahydrofolic acid is 75 : 0.8 : 0.8 by content; or the anti-platelet agent is clopidogrel, the ratio of the anti-platelet agent or a derivative thereof : folic acid : 5-methyltetrahydrofolic acid is 25 : 0.4 : 0.4 by content; or the anti-platelet agent is clopidogrel, the ratio of the anti-platelet agent or a derivative thereof : folic acid : 5-methyltetrahydrofolic acid is 50 : 0.8 : 0.8 by content; or the anti-platelet agent is ticagrelor, the ratio of the anti-platelet agent or a derivative thereof : folic acid : 5-methyltetrahydrofolic acid is 60 : 0.4 : 0.4 by content; or the anti-platelet agent is ticagrelor, the ratio of the anti-platelet agent or a derivative thereof : folic acid : 5-methyltetrahydrofolic acid is 120 : 0.8 : 0.8 by content.

6. The composition of claim 3, wherein The anti-platelet agent content is 25 to 400 mg; wherein the content of aspirin is 35 to 150 mg, the content of clopidogrel is 25 to 75 mg, the content of ticagrelor is 60 to 180 mg, the content of dipyridamole is 40 to 400 mg, the content of cilostazol is 100 to 200 mg, the content of ticlopidine is 125 to 250 mg; as a preference, the content of aspirin is 35 to 75 mg, the content of clopidogrel is 25 to 50 mg, the content of ticagrelor is 60 to 120 mg, the content of dipyridamole is 40 to 100 mg.

7. The composition of claim 6, wherein, The content of folic acid is 0.2 to 1.2 mg, preferably 0.4 to 0.8 mg.

8. The composition of claim 6, wherein, The content of 5-methyltetrahydrofolic acid is 0.2 to 2.0 mg, preferably 0.4 to 0.8 mg.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein: the anti-platelet agent is aspirin with a content of 35 mg, the content of folic acid is 0.4 mg, the content of 5-methyltetrahydrofolic acid is 0.4 mg; or the anti-platelet agent is aspirin with a content of 75 mg, the content of folic acid is 0.8 mg, the content of 5-methyltetrahydrofolic acid is 0.8 mg; or the anti-platelet agent is clopidogrel in an amount of 25 mg, the folic acid is in an amount of 0.4 mg, and the 5-methyltetrahydrofolate is in an amount of 0.4 mg; or the anti-platelet agent is clopidogrel in an amount of 50 mg, the folic acid is in an amount of 0.8 mg, and the 5-methyltetrahydrofolate is in an amount of 0.8 mg. or the anti-platelet agent is ticagrelor in an amount of 60 mg, the folic acid is in an amount of 0.4 mg, and the 5-methyltetrahydrofolate is in an amount of 0.4 mg; or the anti-platelet agent is ticagrelor in an amount of 120 mg, the folic acid is in an amount of 0.8 mg, and the 5-methyltetrahydrofolate is in an amount of 0.8 mg.

10. Use of a composition according to any one of claims 1 to 9 for the manufacture of a product for the prevention or treatment of preeclampsia.

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