Composition for treating antiphospholipid syndrome

Abstract

The invention provides a pharmaceutical composition. The pharmaceutical composition is prepared from an oral anticoagulant drug, folic acid, 5-methyltetrahydrofolic acid and pharmaceutically acceptable auxiliary materials. The invention also provides application of the pharmaceutical composition in preparation of drugs for treating anti-phospholipid syndromes. The pharmaceutical composition has the advantages that the pharmaceutical composition is particularly suitable for patients with repeated thrombus formation, and the clinical benefit of the pharmaceutical composition is remarkably superior to that of single-use anti-oral coagulation drugs. In addition, a patient can take the medicine conveniently, and the medical cost is reduced.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition containing an oral anticoagulant, folic acid, and 5-methyltetrahydrofolate for the treatment of antiphospholipid syndrome. This invention belongs to the field of pharmaceutical science. Background Technology

[0002] Antiphospholipid syndrome (APS) is a non-inflammatory autoimmune disease characterized by recurrent arterial or venous thrombosis, pathological pregnancies (such as recurrent miscarriage and late-term stillbirth), and thrombocytopenia. This disease can occur alone (primary APS) or secondary to other autoimmune diseases, such as systemic lupus erythematosus.

[0003] The pathological mechanism of APS is not fully understood, but previous studies have shown that antiphospholipid antibodies play an important role. Antiphospholipid antibodies primarily target phospholipid-binding proteins, such as β2-glycoprotein 1 (β2-GP1), anticardiolipin antibody (ACL), and lupus anticoagulant (LA). The presence of these antibodies interferes with the normal coagulation process, leading to thrombosis. In addition, APS patients may also exhibit neuropsychiatric symptoms, such as cerebrovascular accidents and behavioral abnormalities.

[0004] The goal of APS treatment is to prevent recurrent thrombosis and morbid pregnancy. Common treatment methods include anticoagulation therapy, with antiplatelet agents and anticoagulants being the most frequently used drugs, both of which improve blood circulation. Antiplatelet agents include low-dose aspirin or clopidogrel, while anticoagulants include warfarin, heparin, and low molecular weight heparin. For APS patients with concurrent systemic lupus erythematosus, hydroxychloroquine may be administered; for APS patients with severe thrombocytopenia, glucocorticoids, immunosuppressants, or immunoglobulins are required. In severe cases, plasma exchange and intravenous immunoglobulin therapy are necessary. For refractory APS, the treatment regimen is more complex and may require the combination of multiple drugs.

[0005] The above-mentioned medications for APS each have their own limitations. For example, low molecular weight heparin can only be administered subcutaneously and has a rapid metabolism, requiring daily injections, which is inconvenient for pregnant women. Side effects of low molecular weight heparin include allergies, thrombocytopenia, bleeding, and abnormal liver function, posing certain risks. Traditional oral anticoagulants like warfarin require frequent monitoring of coagulation function indicators (INR values), limiting their clinical use. Furthermore, long-term use of aspirin or clopidogrel can lead to adverse reactions such as gastrointestinal damage.

[0006] Therefore, it is of great significance to explore a therapeutic drug for APS patients that is convenient to administer, has high compliance, few side effects, and is also beneficial to pregnant women and embryonic development, and its clinical application will be more advantageous. Summary of the Invention

[0007] To address the current limitations of clinical antiphospholipid syndrome treatments, this invention provides a superior pharmaceutical composition.

[0008] The specific technical solution is as follows:

[0009] A pharmaceutical composition comprising:

[0010] (1) Oral anticoagulants,

[0011] (2) Folic acid,

[0012] (3) 5-Methyltetrahydrofolate,

[0013] (4) Pharmaceutically acceptable excipients.

[0014] In the pharmaceutical composition described in this invention, the mass ratio of folic acid to 5-methyltetrahydrofolate is 2-10:2-8, preferably 2:1 or 1:1.

[0015] In the pharmaceutical composition provided by the present invention, the mass ratio of the oral anticoagulant, folic acid and 5-methyltetrahydrofolate is 1-220:0.2-1:0.1-0.8.

[0016] In the pharmaceutical composition provided by the present invention, the oral anticoagulant is selected from one of edosaban, dabigatran etexilate, rivaroxaban, apixaban, or edoxaban.

[0017] In the pharmaceutical composition provided by the present invention, the mass ratio of the oral anticoagulant edoxaban, folic acid and 5-methyltetrahydrofolate is 60-120:0.4-0.8:0.2-0.8.

[0018] In the pharmaceutical composition provided by the present invention, the mass ratio of the oral anticoagulant apixaban, folic acid and 5-methyltetrahydrofolate is 2.5-7.5:0.4-0.8:0.2-0.8.

[0019] In the pharmaceutical composition described in this invention, the dosage of the oral anticoagulant is 1 mg to 220 mg.

[0020] In the pharmaceutical composition described in this invention, the amount of 5-methyltetrahydrofolate used is 0.1 mg to 0.8 mg.

[0021] In the pharmaceutical composition described in this invention, the oral anticoagulant is selected from one of the following dosages: 60-120 mg of edosaban, 75-175 mg of dabigatran etexilate, 5-15 mg of rivaroxaban, 2.5-7.5 mg of apixaban, and 15-30 mg of edoxaban.

[0022] The pharmaceutical composition described in this invention comprises 60-120 mg of edoxaban, 0.4 mg-0.8 mg of folic acid, and 0.2 mg-0.8 mg of 5-methyltetrahydrofolate.

[0023] The pharmaceutical composition described in this invention comprises 2.5 to 7.5 mg of apixaban, 0.4 to 0.8 mg of folic acid, and 0.2 to 0.8 mg of 5-methyltetrahydrofolate.

[0024] The pharmaceutical composition described in this invention is characterized in that the dosage form of the pharmaceutical composition is an oral preparation, including tablets, capsules, or granules, etc.

[0025] The use of the pharmaceutical composition described in this invention in the preparation of products for the treatment of antiphospholipid syndrome, including primary and secondary antiphospholipid syndrome.

[0026] The present invention provides a pharmaceutical composition containing oral anticoagulants, folic acid, and 5-methyltetrahydrofolate. Its advantage lies in that, on the basis of oral anticoagulants inhibiting thrombus formation, the addition of folic acid and 5-methyltetrahydrofolate to form a compound drug produces a synergistic effect, which is more effective in preventing and treating antiphospholipid syndrome, and is especially suitable for women of childbearing age. Detailed Implementation

[0027] 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.

[0028] Example 1: Effects of the composition of the present invention on a rat model of antiphospholipid syndrome.

[0029] Female BALB / c mice, SPF grade, 8-10 weeks old, were included in the experiment after 7 days of quarantine.

[0030] APS model preparation process: 20 μg rhβ2-GP1 was mixed with an equal volume of Freund's adjuvant (CFA) until emulsified, and then injected subcutaneously into the paw of female BALB / c mice. Three weeks later, an equal volume of rhβ2-GP1 (dissolved in PBS) was injected as a booster injection. The blank control group was immunized with PBS / CFA solvent in the same way.

[0031] While establishing the model, the test substances in different doses were given by gavage according to the following table (FA represents folic acid and 5-MTHF represents 5-methyltetrahydrofolic acid). The gavage volume was calculated as 10 ml / kg body weight and given once a day by gavage.

[0032] After continuous administration for 10 weeks, another corresponding number of normal male BALB / c mice were taken. Female mice in each group were caged with male mice at a ratio of 2:1. The next morning, it was checked whether vaginal plugs were formed. The appearance of a vaginal plug was regarded as the first day of pregnancy. On the 15th day of pregnancy, anti-β 2- GP1, anticardiolipin antibody (ACA), activated partial thromboplastin time (aPTT), platelet count (PLTPBC) were detected, and the abortion rate (%) was calculated (abortion rate (%) = number of aborted embryos / (number of aborted embryos + number of non-aborted embryos)).

[0033] Effect analysis of the pharmacodynamic effects between two components was carried out using the Jin Zhengjun Q value method.

[0034] The Jin Zhengjun Q value method [Jin Zhengjun, Zhang Xiaowen, A new method for estimating the combined drug effect with equal probability sum curve and Q5e-, Acta Academiae Medicinae Shanghai Second, 1981] is also called the probability addition method. According to the pharmacological effects of the combination of two drugs and the pharmacological effects of the two drugs used alone in the dose-effect curve area, Q = E A+B / (E A + E B - E A * E B ) is calculated. In the formula, the numerator represents the "measured combined effect", and the denominator represents the "expected combined effect". (To meet the analysis of the pharmacological action relationship of the components and the composition, their pharmacological actions are transformed into effects that can intuitively reflect the strength of the pharmacological action. The calculation formula: E i = 1 - P i / P 模型组 , where Pi is the pharmacological index of each component and P 模型组 is the pharmacological index of the model group), and Q is the ratio of the two. When Q < 0.85, the combination of the two drugs is considered to have an antagonistic effect; when 0.85 < Q < 1.15, it is considered to have an additive effect; when Q > 1.15, it is considered to have a synergistic effect.

[0035] Experimental results:

[0036] Table 1: Effects of the composition of the present invention on the levels of anti-β 2- GP1 and ACA in APS model BALB / c mice ( n = 9 - 10)

[0037]

[0038]

[0039] Note: Compared with the control group: ## P<0.01, compared with the model group, * P<0.05, ** P<0.01.

[0040] Table 2: Effects of the composition of the present invention on PLTPBC and aPTT levels in APS model BALB / c mice ( n = 9 to 10)

[0041]

[0042]

[0043] Note: Compared with the control group: ## P<0.01, compared with the model group, * P<0.05, ** P<0.01.

[0044] The experimental results in Tables 1 and 2 show that, after establishing the antiphospholipid syndrome mouse model, compared with the control group, the model group mice exhibited significantly increased levels of anti-β2-glycoprotein 1 antibody (anti-β2-GP1), anticardiolipin antibody (ACA), platelet count (PLTPBC), and abortion rate (%), and significantly decreased activated partial thromboplastin time (aPTT), all with statistically significant differences (P<0.01), demonstrating that the mice developed obvious antiphospholipid syndrome symptoms after modeling. After administering the corresponding test substance of this invention during the modeling process, compared with the model group, apixaban or edoxaban alone showed significant decreases in anti-β2-GP1, ACA, PLTPBC, and abortion rate (%) only in the high-dose group (P<0.05), while aPTT significantly increased (P<0.05). However, there was no significant difference in the effect of administering folic acid + 5-methyltetrahydrofolate alone. In groups using apixaban or edoxaban alone, the addition of different proportions of folic acid and 5-methyltetrahydrofolate to the regimen showed significant differences compared to the model group in both low- and high-dose groups in reducing anti-β2-GP1, ACA, PLTPBC, miscarriage rate (%), and increasing aPTT (P<0.01). Compared to the single-dose regimens using the same dose, both low- and high-dose regimens showed a synergistic effect in reducing anti-β2-GP1, ACA, PLTPBC, miscarriage rate (%), and increasing aPTT (Q>1.15).

Claims

1. A pharmaceutical composition comprising: (1) an oral anticoagulant, (2) folic acid, (3) 5-methyltetrahydrofolic acid, (4) a pharmaceutically acceptable excipient.

2. The pharmaceutical composition of claim 1, wherein, The mass ratio of the folic acid to the 5-methyltetrahydrofolic acid is 2-10:1-8, preferably the mass ratio is 2:1 or 1:

1.

3. The pharmaceutical composition of claim 2, wherein, The mass ratio of the oral anticoagulant, the folic acid and the 5-methyltetrahydrofolic acid is 1-220:0.2-1:0.1-0.

8.

4. The pharmaceutical composition of claim 1, wherein, The amount of the oral anticoagulant is 1 mg-220 mg, the amount of the folic acid is 0.2 mg-1 mg, and the amount of the 5-methyltetrahydrofolic acid is 0.1 mg-0.8 mg.

5. The pharmaceutical composition of claim 1, wherein, The oral anticoagulant is selected from one of edoxaban with an amount of 60-120 mg, dabigatran with an amount of 75-175 mg, rivaroxaban with an amount of 5-15 mg, apixaban with an amount of 2.5-7.5 mg, and edoxaban with an amount of 15-30 mg.

6. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises edoxaban with an amount of 60-120 mg, folic acid with an amount of 0.4 mg-0.8 mg, and 5-methyltetrahydrofolic acid with an amount of 0.2 mg-0.8 mg.

7. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises apixaban with an amount of 2.5-7.5 mg, folic acid with an amount of 0.4 mg-0.8 mg, and 5-methyltetrahydrofolic acid with an amount of 0.2 mg-0.8 mg.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that, The dosage form of the pharmaceutical composition is an oral preparation, including tablets, capsules or granules, etc.

9. Use of the pharmaceutical composition according to any one of claims 1-7 in the preparation of a product for treating antiphospholipid syndrome, including primary antiphospholipid syndrome and secondary antiphospholipid syndrome.

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