Composition and preparation method of mactentan tablet

Abstract

The invention discloses a composition and a preparation method of a masutentan tablet, the formula comprises masutentan, lactose (monohydrate), microcrystalline cellulose, povidone K30, croscarmellose sodium, magnesium stearate, polysorbate 80, L-cysteine and purified water, and the use amount of L-cysteine is 0.1%-0.9% of the use amount of the main drug masutentan. The masutentan tablet disclosed by the invention is simple in composition, stable in quality and simple and convenient in preparation process, and L-cysteine is adopted as an antioxidant, so that the oxidative degradation of the masutentan can be inhibited under a strong oxygen condition, the level of impurities generated after the masutentan is degraded is lower, the toxic and side effects of the medicine are further reduced, and the medication safety is improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to the composition of a macitentan tablet and its preparation method. Background Technology

[0002] Macitentan, chemically known as N-[5-(4-bromophenyl)-6-[2-[(5-bromopyrimidin-2-yl)oxy]ethoxy]-pyrimidin-4-yl]-N'-propylsulfonyldiamine, is an endothelin receptor antagonist (ERA). Macitentan tablets are used to treat pulmonary arterial hypertension (PAH, WHO Group 1) to slow disease progression. Disease progression includes death, intravenous (IV) or subcutaneous administration of prostaglandins, or clinical deterioration of PAH (reduced 6-minute walk distance, worsening PAH symptoms requiring further PAH treatment). Furthermore, this product reduces hospitalizations for PAH patients.

[0003] Macitentan is a white to off-white crystalline powder with a melting point of 135°C. It is almost insoluble in water, sparingly soluble in methanol and ethanol, and slightly soluble in acetone, ethyl acetate, and acetonitrile. In biopharmaceutics, it belongs to Class BSCII, classifying it as a drug with low solubility and high permeability. Furthermore, analysis of the synthetic process of the raw material macitentan revealed that the main possible residual impurities in this product are impurities A through S. Among them, impurities G, I, M, R, and S are degradation impurities, while the remaining impurities are process impurities. Impurities T and U are degradation impurities mentioned in the references.

[0004] According to the requirements of General Chapter 0512 of Part IV of the Chinese Pharmacopoeia (2020 Edition), impurity content should be controlled during tablet quality evaluation. Based on the import registration standards for macitentan tablets and the results of product quality and stability studies, the impurity release limits for this product are set as follows: impurity G ≤ 0.20%; impurity T ≤ 0.20%; impurity R ≤ 0.20%; other individual impurities not exceeding 0.20%; total impurities not exceeding 1.0%. During testing, it was found that macitentan is quite sensitive to oxygen; under oxidative conditions, the content and quantity of various impurities generated by the oxidative degradation of macitentan significantly increase.

[0005] Therefore, it is necessary to find an antioxidant that can inhibit the oxidative degradation of macitentan under strong oxygen conditions, so that the level of impurities produced after degradation is lower and meets the release standards, thereby reducing the toxic side effects of the drug and increasing its safety. Summary of the Invention

[0006] The main objective of this invention is to overcome the shortcomings of existing technologies for macitentan tablets and provide an antioxidant with good antioxidant effects and safety, significantly reducing the content and quantity of impurities during quality control and increasing medication safety. This invention also provides the formulation and manufacturing process of the tablets, which is simple, efficient, and easily scalable for mass production.

[0007] The objective of this invention is achieved through the following means: A macitentan tablet characterized by containing L-cysteine ​​in its formulation.

[0008] The formulation of macitentan tablets consists of: macitentan, lactose (monohydrate), microcrystalline cellulose, povidone K30, croscarmellose sodium, magnesium stearate, polysorbate 80, L-cysteine, and purified water.

[0009] The preferred dosage of L-cysteine ​​is 0.1%-0.9% of the dosage of the active ingredient, macitentan; a more preferred dosage is 0.25%-0.7% of the dosage of the active ingredient, macitentan; and an even more preferred dosage is 0.5% of the dosage of the active ingredient, macitentan.

[0010] The preparation method of the macitentan tablets of the present invention includes the following steps: The prescribed amounts of macitentan, lactose (monohydrate), microcrystalline cellulose, povidone K30, croscarmellose sodium, and L-cysteine ​​were dry-mixed, granulated with polysorbate 80 aqueous solution, dried, granulated, premixed with microcrystalline cellulose and croscarmellose sodium, and then mixed with magnesium stearate. The mixture was then compressed into tablets and coated.

[0011] The ingredients described in this invention, including macitentan, lactose (monohydrate), microcrystalline cellulose, povidone K30, croscarmellose sodium, magnesium stearate, polysorbate 80, L-cysteine, and purified water, are all commercially available.

[0012] The antioxidant L-cysteine, when used in the product of this invention, effectively inhibits the oxidative degradation of macitentan, improves product stability, reduces impurity generation, and lowers drug toxicity. L-cysteine ​​is a precursor for the synthesis of glutathione. Glutathione is an important antioxidant that plays a crucial role in protecting the body from oxidative stress. Adding L-cysteine ​​to the drug effectively improves redox capacity and reduces oxidative stress. Furthermore, L-cysteine ​​is an amino acid drug, a natural antioxidant, readily soluble in water, and has a high safe dosage in vivo.

[0013] The following is a brief description of the concept of this invention: Impurity content is a crucial parameter for evaluating tablet quality standards. Given that macitentan is highly sensitive to oxygen and easily oxidizes and degrades under strong oxygen conditions, increasing the content and quantity of impurities, and considering that no antioxidants have been added to the excipients of marketed macitentan tablets, the inventors considered adding an antioxidant to increase tablet stability and inhibit the oxidative degradation of macitentan. Research revealed that L-cysteine ​​is a safe and effective natural antioxidant, a strong reducing agent. Upon encountering oxygen, it is first oxidized, consuming the surrounding oxygen and thus protecting the drug. Therefore, the inventors added an appropriate amount of L-cysteine ​​to the composition of macitentan tablets to ensure that the oxidative degradation of macitentan is inhibited under strong oxygen conditions, resulting in lower levels of impurities after degradation, thereby reducing the drug's toxic side effects and increasing medication safety. Detailed Implementation

[0014] The invention is further illustrated by the embodiments given below, but the invention is not limited to these embodiments.

[0015] Example 1 Based on a prescription dose of 10 mg for macitentan, the following ingredients are added in addition to the prescription dose: lactose (monohydrate), microcrystalline cellulose, povidone K30, croscarmellose sodium, and L-cysteine ​​0.01 mg. The mixture is then dry-mixed with an appropriate amount of polysorbate 80 aqueous solution, dried, granulated, and premixed with the prescription dose of microcrystalline cellulose and croscarmellose sodium. A small amount of magnesium stearate is then added for final mixing, followed by tableting and coating.

[0016] Example 2 The difference from Example 1 is that the amount of L-cysteine ​​used is 0.025 mg, while the amount of other excipients and the preparation steps are the same as in Example 1, to obtain macitentan tablets.

[0017] Example 3 The difference from Example 1 is that the amount of L-cysteine ​​used is 0.05 mg, while the amount of other excipients and the preparation steps are the same as in Example 1, and macitentan tablets are prepared.

[0018] Example 4 The difference from Example 1 is that the amount of L-cysteine ​​used is 0.07 mg, while the amount of other excipients and the preparation steps are the same as in Example 1, and macitentan tablets are prepared.

[0019] Example 5 The difference from Example 1 is that the amount of L-cysteine ​​used is 0.09 mg, while the amount of other excipients and the preparation steps are the same as in Example 1, and macitentan tablets are prepared.

[0020] Example 6 The difference from Example 1 is that L-cysteine ​​was not added, but the amount of other excipients and preparation steps were the same as in Example 1, and macitentan tablets were prepared.

[0021] The tablets prepared in Example 6 and the purchased raw materials were tested for impurity content in the untreated and oxidized forms, respectively. The specific data are shown in Table 1.

[0022] Table 1 Impurity Detection Results The experimental results in Table 1 show that after oxidation, the content of impurities T, R, and total impurities in both the macitentan raw material and macitentan tablets increased significantly, and the number of impurities also increased significantly, indicating that macitentan is relatively sensitive to oxygen. Furthermore, the content of impurity R in both the oxidized macitentan raw material and macitentan tablets exceeded the relevant regulatory limits (≤0.2%), and the total impurity content in the oxidized macitentan tablets also exceeded the relevant regulatory limits (≤1.0%). In summary, this indicates that macitentan is easily degraded under oxidative conditions, leading to a significant increase in its impurity levels.

[0023] The contents of relevant impurities in the macitentan tablets prepared in Examples 1-6 and after oxidation were tested. The specific data are shown in Table 2.

[0024] Table 2 Impurity Detection Results As shown in Table 2, compared with Example 6, the content of impurity R and total impurities in Examples 1-5 were significantly reduced, and the total impurity content all met the relevant regulatory limits (≤1.0%). Impurity T was not detected in Examples 1-4 compared with Example 6. However, only Examples 2 and 3 had impurities G, R, T, and total impurity content that met the relevant regulatory limits, and the total impurity content of Example 3 was even lower than that of Example 2, essentially equivalent to the total impurity content of the undamaged tablets of Example 6.

[0025] In summary, the macitentan tablets prepared in Example 3 exhibit better stability. The added antioxidants maximally inhibit the oxidative degradation of macitentan, resulting in relatively low impurity levels. Furthermore, the content of each impurity and the total impurity content all meet the relevant regulatory limits. Therefore, the optimal dosage of the antioxidant L-cysteine ​​is 0.5% of the dosage of the active pharmaceutical ingredient, macitentan.

Claims

1. A composition of macitentan tablets and its preparation method, characterized in that... The prescription contains L-cysteine.

2. The L-cysteine ​​according to claim 1, characterized in that... The dosage is 0.1%-0.9% of the dosage of the main drug, masitentan.

3. The L-cysteine ​​according to claim 1, characterized in that... The dosage is 0.25%-0.7% of the dosage of the main drug, masitentan.

4. The L-cysteine ​​according to claim 1, characterized in that... The dosage is 0.5% of the dosage of the main drug, masitentan.

5. The macitentan tablet according to claim 1, characterized in that... It is composed of macitentan, lactose (monohydrate), microcrystalline cellulose, povidone K30, croscarmellose sodium, magnesium stearate, polysorbate 80, L-cysteine ​​and purified water.

6. The complete preparation process of the macitentan tablet according to claim 1 includes the following steps: The prescribed amounts of macitentan, lactose (monohydrate), microcrystalline cellulose, povidone K30, croscarmellose sodium, and L-cysteine ​​were dry-mixed, granulated with polysorbate 80 aqueous solution, dried, granulated, premixed with microcrystalline cellulose and croscarmellose sodium, and then mixed with magnesium stearate. The mixture was then compressed into tablets and coated.

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