A preparation method for improving the stability of clopidogrel bisulfate tablets and a composition thereof

Abstract

This invention discloses a method for preparing clopidogrel bisulfate tablets and a composition thereof to improve their stability. This invention utilizes a novel porous silica carrier material and a specific process to achieve greater drug loading capacity. By employing a solid dispersion preparation technique, the exposure of clopidogrel bisulfate is reduced. The stability and feasibility of the sample preparation process are improved, and the preparation of a solid dispersion significantly enhances the drug's resistance to damp heat. The samples prepared by this invention are more suitable for production conditions and ensure the stability of the finished product during storage, thus improving the drug's resistance to damp heat.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical manufacturing, and specifically relates to the formulation process of clopidogrel bisulfate tablets. Background Technology

[0002] Atherosclerosis is the most common and important vascular disease among arteriosclerotic arteries. It has multiple causes, affects a wide range of populations, and presents with a variety of symptoms, such as: mental and physical decline, cerebral thrombosis, vascular dementia, refractory hypertension, and indigestion.

[0003] Clopidogrel bisulfate is a platelet aggregation inhibitor that inhibits platelet aggregation by binding to ADP receptors on the surface of platelets, preventing fibrinogen from binding to glycoprotein GPIIb / IIIa receptors. This helps prevent and treat cardiovascular, cerebrovascular, and other circulatory disorders caused by high platelet aggregation.

[0004] Clopidogrel bisulfate belongs to BCS Class II drugs, characterized by low solubility and high permeability.

[0005] Patent CN102462667A mentions using clopidogrel bisulfate crystal form I and excipients to make small pellets, which are then coated and compressed with magnesium stearate into tablets. This reduces the risk of tablet sticking and reduces the impact of magnesium stearate on product stability.

[0006] Patent CN101791309A mentions using a mixture of liquid paraffin and talc as a lubricant for tablets, thereby reducing the risk of sticking and brittleness of clopidogrel bisulfate tablets during formulation production.

[0007] Patent CN102058550A mentions that by adding granular microcrystalline cellulose and micronized silica to the formulation and performing dry granulation, the feasibility of product tableting is improved.

[0008] Patents CN102240269A and CN110339178A mention that clopidogrel bisulfate and polyethylene glycol are copolymerized through a melt process, and then mixed with other excipients and compressed into tablets to form the final product.

[0009] Patent CN102988321A mentions using β-cyclodextrin as a filler in wet granulation, and improving the tableting effect by encapsulating clopidogrel bisulfate with β-cyclodextrin. Summary of the Invention

[0010] To address the problems existing in the prior art, the present invention provides a clopidogrel bisulfate composition that reduces the risk of tablet sticking and increases drug solubility, addressing the issues of poor process stability, easy tablet sticking and punching during tablet compression, and poor formulation stability of the prior art. The process of the present invention is simpler and more practical.

[0011] This invention provides a method for preparing clopidogrel bisulfate tablets with improved stability. The method comprises the following steps: dispersing a porous silica support in water at a ratio of 1:5; dissolving clopidogrel bisulfate in ethanol or acetone to form a clopidogrel bisulfate solution at a ratio of 1:10; adding the clopidogrel bisulfate solution to the aqueous solution of the porous silica support, stirring and mixing thoroughly, removing the dissolving solvent to form a solid dispersion, mixing with excipients, pressing the mixture into tablets with a diameter of 8.5 mm and a hardness of 80–140 N, and coating with a coating machine to obtain the final sample.

[0012] According to one aspect of the present invention, a method for preparing clopidogrel bisulfate tablets with improved stability is also provided, wherein clopidogrel bisulfate is dissolved in ethanol medium in the above steps.

[0013] According to one aspect of the present invention, a method for preparing clopidogrel bisulfate tablets with improved stability is also provided, wherein the excipients are microcrystalline cellulose, polyethylene glycol 6000, low-substituted hydroxypropyl cellulose, and hydrogenated castor oil.

[0014] According to one aspect of the present invention, a method for preparing clopidogrel bisulfate tablets with improved stability is also provided, wherein the coating machine uses a film coating premix, preferably 32K140004-CN.

[0015] According to one aspect of the present invention, a method for preparing clopidogrel bisulfate tablets with improved stability is also provided, wherein the mass ratio of clopidogrel bisulfate, porous silica carrier, microcrystalline cellulose, polyethylene glycol 6000, low-substituted hydroxypropyl cellulose, hydrogenated castor oil, and film coating premix is ​​97.875:45.0:31.0:34.0:12.9:3.3:7.44.

[0016] According to one aspect of the present invention, a highly stable clopidogrel bisulfate tablet is also provided, which is prepared by any of the above-described methods for improving the stability of clopidogrel bisulfate tablets.

[0017] According to one aspect of the present invention, a highly stable clopidogrel bisulfate tablet is also provided, wherein the clopidogrel bisulfate tablet is composed of the following formulation:

[0018]

[0019] For drugs with low solubility, various methods and techniques are employed to improve their solubility, thereby increasing dissolution rate and concentration to achieve higher bioavailability in vivo. Methods for improving drug solubility, as described in the aforementioned patent, include using a hot-melt extrusion process with a hydrophilic carrier to increase the drug's hydrophilicity and surface wetting ability, thus enhancing its solubility; or adding surfactants to improve hydrophilicity. However, these processes are complex or unsuitable for clinical use, resulting in low practicality.

[0020] This invention employs a novel porous silica carrier material and a specific process to enhance its drug loading capacity. By using solid dispersion technology, the exposure of clopidogrel bisulfate is reduced, improving the stability and feasibility of the sample preparation process. Furthermore, preparing a solid dispersion significantly improves the drug's resistance to damp heat.

[0021] This invention employs a novel solid dispersion carrier, using clopidogrel bisulfate and a porous silica support to prepare samples through a solid dispersion process. This avoids the use of highly toxic solvents, simplifies the process, and reduces production costs. Attached Figure Description

[0022] Figure 1 The dissolution curves of clopidogrel bisulfate tablets prepared in the embodiments of the present invention are compared with those of commercially available products. Detailed Implementation

[0023] Example 1

[0024] 1.1 Composition

[0025]

[0026] 1.2 Preparation

[0027] All raw materials and excipients (except for the film coating premix) were sieved and then mixed. The mixture was compressed into tablets with a diameter of 8.5 mm and a hardness of 80–140 N. The tablets were then coated using a coating machine to obtain the final sample.

[0028] Example 2

[0029] 2.1 Composition

[0030]

[0031] 2.2 Preparation

[0032] Clopidogrel bisulfate, mannitol, microcrystalline cellulose, polyethylene glycol 6000, and low-substituted hydroxypropyl cellulose were sieved and then mixed. Granulation was performed using a dry granulator. The granulated particles were then mixed with hydrogenated castor oil. The mixture was compressed into tablets with a diameter of 8.5 mm and a hardness of 80–140 N. The tablets were then coated using a coating machine to obtain the final sample.

[0033] Example 3

[0034] 3.1 Composition

[0035]

[0036] 3.2 Preparation

[0037] Clopidogrel bisulfate and polyethylene glycol were melted at 80°C, and then microcrystalline cellulose and mannitol were added and stirred rapidly. The mixture was passed through a 60-mesh sieve, and then low-substituted hydroxypropyl cellulose and hydrogenated castor oil were added and mixed. The mixture was compressed into tablets with a diameter of 8.5 mm and a hardness of 80–140 N. The tablets were then coated using a coating machine to obtain the final sample.

[0038] Example 4

[0039] 4.1 Composition

[0040]

[0041] 4.2 Preparation

[0042] The porous silica support (preferably 120091 Parteck SLC) is fully dispersed in water at a ratio of 1:5. Clopidogrel bisulfate is dissolved in ethanol or acetone; in this embodiment, ethanol is used as the dissolving medium, with a mass ratio of clopidogrel bisulfate to ethanol of 1:10. The above clopidogrel bisulfate solution is added to the aqueous solution of the porous silica support, and the mixture is stirred and mixed thoroughly to ensure sufficient contact between the clopidogrel bisulfate and the porous silica support, thereby removing the dissolving solvent and forming a solid dispersion, which is then mixed with other excipients. The mixture is compressed into tablets with a diameter of 8.5 mm and a hardness of 80–140 N. The tablets are then coated using a coating machine to obtain the final sample.

[0043] Example 5: Commercially Available Product Plan

[0044] 5.1 Composition

[0045]

[0046] Comparison of properties in Example 6

[0047] 6.1 In vitro dissolution test

[0048] 6.1.1 Method for preparing the dissolution medium

[0049] pH 2.0 hydrochloric acid buffer: Take 250 ml of 0.2 mol / L potassium chloride solution, add 65.0 ml of 0.2 mol / L hydrochloric acid solution, dilute with water to 1000 ml, mix well, and obtain the buffer solution.

[0050] 6.1.2 Dissolution results are as follows Figure 1

[0051] 6.2 Crystal form comparison

[0052]

[0053] 6.3 Stability Comparison

[0054] The stability of the parameters under accelerated 6-month conditions and Example 4 was compared.

[0055]

[0056] In summary, Example 1 experienced severe sticking and punching during tablet compression, leading to production difficulties. Examples 2 and 3 also exhibited sticking and punching issues, resulting in slightly rough tablet surfaces. Example 4, however, had a smooth production process with stable parameters, producing smooth and intact tablets with stable weight and hardness, demonstrating the superior quality of the samples prepared using this process. Furthermore, the active pharmaceutical ingredient (API) used in Example 4 did not undergo any change in crystal form after processing into the final product. Additionally, the dissolution results of the sample in Example 4 showed higher similarity to the reference formulation compared to other samples, with a smaller RSD. Moreover, during a 6-month accelerated stability study, the increase trend of related substances in the sample was smaller than in Examples 1, 2, and 3, indicating that the sample prepared using this process better meets production conditions and ensures the stability of the finished product during storage, thus improving the API's resistance to damp heat.

[0057] It should be noted that the above preferred embodiments are merely illustrative of the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing clopidogrel bisulfate tablets with improved stability, characterized in that, The method steps are as follows: A porous silica support is fully dispersed in water at a ratio of 1:5; clopidogrel bisulfate is dissolved in ethanol or acetone to form a clopidogrel bisulfate solution at a ratio of 1:10; the clopidogrel bisulfate solution is added to the aqueous solution of the porous silica support, stirred and mixed thoroughly, and the dissolving solvent is removed to form a solid dispersion. After mixing with excipients, the mixture is pressed into tablets with a diameter of 8.5 mm and a hardness of 80–140 N, and then coated using a coating machine to obtain the final sample.

2. The method for preparing clopidogrel bisulfate tablets with improved stability according to claim 1, characterized in that, In the above steps, clopidogrel bisulfate is dissolved in ethanol.

3. The method for preparing clopidogrel bisulfate tablets with improved stability according to claim 2, characterized in that, The excipients are microcrystalline cellulose, polyethylene glycol 6000, low-substituted hydroxypropyl cellulose, and hydrogenated castor oil.

4. The method for preparing clopidogrel bisulfate tablets with improved stability according to claim 3, characterized in that, The coating machine uses a film coating premix.

5. The method for preparing clopidogrel bisulfate tablets with improved stability according to claim 4, characterized in that, The mass ratio of clopidogrel bisulfate, porous silica carrier, microcrystalline cellulose, polyethylene glycol 6000, low-substituted hydroxypropyl cellulose, hydrogenated castor oil, and film coating premix in the method is 97.875:45.0:31.0:34.0:12.9:3.3:7.

44.

6. A highly stable clopidogrel bisulfate tablet, characterized in that, The clopidogrel bisulfate tablets are prepared by any one of the methods described in claims 1 to 5.

7. A highly stable clopidogrel bisulfate tablet, characterized in that, The clopidogrel bisulfate tablets are formulated as follows: composition:

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