Clopidogrel hydrogen sulfate tablet and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, and discloses a clopidogrel hydrogen sulfate tablet and a preparation method thereof, and the clopidogrel hydrogen sulfate tablet comprises the following components: 30-50 parts of clopidogrel hydrogen sulfate; 5-15 parts of a double-layer nano permeable membrane material; 3 to 12 parts of a pH sensitive release material; 5 to 12 parts of a supramolecular self-assembled nanoparticle material; 5 to 15 parts of a solubility regulator; 2-5 parts of an ionic crosslinking regulatory factor; 10 to 25 parts of an excipient; 0.5 to 2 parts of a lubricant; 0.5 to 2 parts of a stabilizer; the double-layer nano permeable membrane material comprises the following components in parts by weight: an inner layer material: 5-15 parts of hydroxypropyl # imgabs0 #-cyclodextrin; 3 to 10 parts of polyvinylpyrrolidone; an outer layer material: 2-8 parts of ethyl cellulose; and 2 to 10 parts of hydroxypropyl methylcellulose. The double-layer nano permeable membrane is combined with the pH-sensitive controlled release system, so that the dissolution rate of the medicine is adjustable, and accurate release in different pH environments is realized. The technical effects of improving the dissolution efficiency, optimizing medicine absorption and reducing individual differences are achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and specifically to a clopidogrel bisulfate tablet and a preparation method thereof. Background Art

[0002] Clopidogrel is a drug widely used in antiplatelet therapy, mainly for preventing atherosclerotic thromboembolic events. As a prodrug, clopidogrel needs to be metabolically activated in the body by the liver to exert its efficacy. Therefore, its bioavailability is affected by various factors, such as solubility, release rate, individual metabolic differences, etc. Optimizing the formulation form of clopidogrel to improve its solubility and release stability is of great significance for enhancing efficacy, safety, and patient compliance.

[0003] Currently, clopidogrel tablets mostly adopt immediate-release or sustained-release forms. Common preparation methods include solid dispersions, enteric coating, or simple sustained-release excipients to control release. Among them, solid dispersions can improve solubility, but are prone to crystallization precipitation during storage, affecting stability; enteric coating can reduce gastric irritation, but has limited ability to precisely control the release rate; sustained-release excipients can extend the release time, but are easily affected by pH changes, resulting in uneven drug release. Therefore, there are still certain limitations in the controlled-release precision, solubility improvement, and stability of existing clopidogrel preparations.

[0004] The main problem of the existing technology is that the release mode of clopidogrel lacks dynamic regulation for different pH environments, resulting in unstable drug release rate in the gastrointestinal tract, and thus affecting its absorption efficiency and bioavailability. The gastric environment has a low pH, which is likely to cause premature drug release, while the intestinal environment has a high pH, and insufficient solubility may lead to insufficient release. Summary of the Invention

[0005] Aiming at the deficiencies of the existing technology, the present invention provides a clopidogrel bisulfate tablet and a preparation method thereof, which solve the problem of uneven release of clopidogrel tablets in different pH environments, resulting in fluctuations in bioavailability.

[0006] To achieve the above objectives, the present invention is realized through the following technical solutions: A clopidogrel bisulfate tablet, comprising the following components: Clopidogrel bisulfate: 30 - 50 parts; Double-layer nano-permeable membrane material: 5 - 15 parts; pH-sensitive release material: 3 - 12 parts; Supramolecular self-assembled nanoparticle material: 5 - 12 parts; Solubility regulator: 5 - 15 parts; Ionic cross-linking regulation factor: 2 - 5 parts; Excipient: 10 - 25 parts; Lubricant: 0.5 - 2 parts; Stabilizer: 0.5 - 2 parts.

[0007] Preferably, the double - layer nano - permeable membrane material comprises: Inner layer material: Hydroxypropyl -cyclodextrin: 5 - 15 parts; Polyvinylpyrrolidone: 3 - 10 parts; Outer layer material: Ethyl cellulose: 2 - 8 parts; Hydroxypropyl methylcellulose: 2 - 10 parts.

[0008] Preferably, the pH - sensitive release material is a methacrylic acid copolymer, with a mass fraction of 3 - 12 parts.

[0009] Preferably, the supramolecular self - assembly nanoparticle material comprises: Phospholipid: 2 - 8 parts; PEG - PLGA copolymer with a molecular weight of 15,000 - 30,000 Da, and the molar ratio of LA / GA is 75:25 - 50:50: 5 - 12 parts.

[0010] Preferably, the ion - crosslinking regulation factor comprises: Sodium chloride: 1 - 3 parts; Calcium chloride: 0.5 - 2 parts.

[0011] The present invention also provides a preparation method of clopidogrel bisulfate tablets, comprising the following steps: Step 1: Coating clopidogrel bisulfate with the double - layer nano - permeable membrane material to prepare nano - permeable membrane particles; Step 2: Mixing the nano - permeable membrane particles with the pH - sensitive release material and coating them to form controlled - release particles; Step 3: Coating the surface of the controlled - release particles with the supramolecular self - assembly nanoparticle material to form drug microparticles; Step 4: Mixing the obtained drug microparticles evenly with a solubility regulator, an ion - crosslinking regulation factor, an excipient, a lubricant and a stabilizer to prepare core powder for tablets; Step 5: Using a tableting process to form the core powder into tablets and performing coating.

[0012] Preferably, the method for coating the double - layer nano - permeable membrane in Step 1 comprises: Dissolving hydroxypropyl -cyclodextrin in deionized water at 50 - 70 °C and forming a homogeneous solution under stirring at 300 - 500 rpm; Clopidogrel bisulfate is added to the solution and stirred at 55 - 65 °C for 30 - 60 min; Using the spray drying method, with a feed flow rate of 5 - 15 mL / min, an atomization pressure of 1.5 - 3 bar, and an outlet temperature of 60 - 80 °C, the inner layer coated particles are prepared; Using the fluidized bed coating technology, the inner layer coated particles are coated on the outer layer, with a spraying rate of 5 - 10 mL / min and a hot air temperature of 50 - 80 °C.

[0013] Preferably, the preparation method of the pH - sensitive release matrix in step two includes: Take the methacrylic acid copolymer and dissolve it in ethanol with a volume ratio of 60 - 80%, stir at 400 - 600 rpm, and the temperature is 40 - 55 °C; Add sodium chloride and calcium chloride, and perform ultrasonic treatment for 10 - 20 min; Using the electrospray method, with a spraying pressure of 2 - 5 bar and a spraying distance of 10 - 20 cm, coat the nano - permeable membrane particles.

[0014] Preferably, the preparation method of the supramolecular self - assembled nanoparticles in step three includes: Add the PEG - PLGA copolymer and phospholipids in an aqueous phase with a pH of 7.0 - 7.4, perform ultrasonic emulsification, with a power of 80 - 150 W and a time of 10 - 20 min; Mix the nano - emulsion into the coated particles for uniform encapsulation, and keep the temperature at 30 - 40 °C; Perform freeze - drying, with the temperature set at - 40 to - 60 °C, the vacuum degree controlled at 10 - 50 Pa, and the freeze - drying time of 6 - 12 h.

[0015] Preferably, the tableting process in step five includes: Take the obtained drug microparticles and mix them with excipients, lubricants, and stabilizers, stir at a speed of 200 - 400 rpm for 10 - 20 min; Using a rotary tablet press, the pressure is set at 10 - 20 MPa, the tablet pressing speed is 60 - 120 rpm, and the tablet weight is 200 - 400 mg; Perform coating using the fluidized bed coating technology, with a spraying rate of 2 - 6 mL / min and a temperature of 45 - 65 °C.

[0016] The present invention provides a clopidogrel bisulfate tablet and its preparation method. It has the following beneficial effects: 1. By combining a double-layer nano-permeation membrane with a pH-sensitive controlled-release system, the present invention enables adjustable drug dissolution rates and achieves precise release in different pH environments. This has achieved the technical effects of enhancing dissolution efficiency, optimizing drug absorption, and reducing individual differences. Compared with the fixed release modes of single immediate-release or sustained-release tablets in the prior art, the problems of uneven drug release, large absorption fluctuations, and low bioavailability have been solved.

[0017] 2. The present invention adopts the technology of supramolecular self-assembled nanoparticles, which disperses the drug at the nanoscale, increases the specific surface area, and enhances solubility. This has achieved the technical effects of improving dissolution, accelerating the onset time, and increasing the in vivo utilization rate. In the prior art, solid dispersions or simple solubilizers are often used to improve solubility, which is often limited by the stability of the carrier or crystallization precipitation. The present invention effectively overcomes this problem through the self-assembly mechanism of nanoparticles, significantly enhancing the stability of drug efficacy.

[0018] 3. The present invention utilizes a pH-sensitive release matrix and an ion cross-linking regulation factor to achieve targeted release of the drug in specific intestinal regions. This has achieved the technical effects of reducing gastric irritation, avoiding sudden release, and improving drug safety. Compared with traditional tablets that rely on excipients to control dissolution or use simple enteric coatings, the intelligent drug release mechanism of the present invention avoids the decrease in bioavailability caused by gastric acid degradation and reduces gastrointestinal adverse reactions.

[0019] 4. Through advanced preparation processes such as spray drying, electrostatic spray coating, and fluidized bed coating, the present invention makes the tablet structure uniform and the release curve stable. This has achieved the technical effects of improving tablet consistency, optimizing production efficiency, and enhancing product stability. Compared with traditional wet granulation or direct compression in the prior art, the preparation method of the present invention avoids problems such as uneven powder mixing and fluctuations in tablet hardness, ensuring batch-to-batch consistency and long-term storage stability of the preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is a flowchart of the method of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0021] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0022] Please refer to the attached Figure 1 , Example 1: Raw material formula: Clopidogrel bisulfate: 40 parts; Hydroxypropyl Hydroxypropyl-β-cyclodextrin (HP-β- -CD): 10 parts; Polyvinylpyrrolidone (PVPK30): 5 parts; Ethyl cellulose (EC): 5 parts; Hydroxypropyl methylcellulose (HPMC): 5 parts; Methacrylic acid copolymer (Eudragit S100): 8 parts; Microcrystalline cellulose (MCC): 20 parts; Magnesium stearate: 2 parts; Vitamin E succinate ( -TOC): 2 parts.

[0023] Preparation steps: Take HP-β- -CD, add deionized water (temperature 55 °C), stirring rate 400 rpm. After it is completely dissolved, slowly add clopidogrel bisulfate and continue stirring for 40 min to form a solubilization system.

[0024] Adopt spray drying method, feed rate 8 mL / min, atomization pressure 2.5 bar, drying temperature 75 °C to obtain nano-scale drug particles.

[0025] Take EC and HPMC, dissolve them in ethanol and water respectively, and ultrasonically disperse for 25 min to form a coating solution. Put the obtained particles into a fluidized bed coater, spray rate 6 mL / min, hot air temperature 65 °C, and coat to form a nano-permeable membrane.

[0026] Take Eudragit S100, add ethanol (70%), stir at 500 rpm, temperature 50 °C. After adding the particles, coat by electrospray method (spray pressure 3 bar, spray distance 15 cm) to form a pH-sensitive drug release layer.

[0027] The obtained particles are mixed with MCC, magnesium stearate, and vitamin E succinate, stirred at a speed of 350 rpm for 10 min, and sent to a rotary tablet press at a pressure of 15 MPa to form tablets.

[0028] Example 2: Raw material formula: Clopidogrel bisulfate: 35 parts; HP-β- -CD: 12 parts; PEG-PLGA copolymer: 10 parts; Phospholipid (lecithin): 5 parts; Ethyl cellulose (EC): 6 parts; Methacrylic acid copolymer (Eudragit S100): 7 parts; Microcrystalline cellulose (MCC): 20 parts; Magnesium stearate: 3 parts; Vitamin E succinate: 2 parts.

[0029] Preparation steps: Clopidogrel bisulfate and HP- -CD are stirred at 60 °C in a water bath for 30 min, and spray-dried (feed rate 7 mL / min, atomization pressure 2.8 bar, outlet temperature 72 °C) to obtain nanoparticles.

[0030] Take the PEG-PLGA copolymer and phospholipids dissolved in the aqueous phase (pH 7.2), and perform ultrasonic emulsification (power 120 W, time 15 min), followed by low-temperature freeze-drying (-50 °C, vacuum 30 Pa, 12 h) to prepare self-assembled nanoparticles.

[0031] The nanoparticles are mixed with the drug particles, and EC is dissolved in ethanol and coated at a spray rate of 8 mL / min and a temperature of 60 °C to form a controlled-release layer.

[0032] Coat with Eudragit S100 (electrostatic spraying method, spray pressure 2.7 bar, distance 17 cm) to complete the pH-sensitive layer.

[0033] The obtained particles are mixed with MCC and magnesium stearate, stirred at 300 rpm, and formed into tablets by a tableting machine (pressure 18 MPa).

[0034] Example 3: Raw material formula: Clopidogrel bisulfate: 38 parts; HP- -CD: 10 parts; Sodium chloride: 2 parts; Calcium chloride: 1 part; PEG-PLGA copolymer: 8 parts; Ethyl cellulose (EC): 7 parts; Methacrylic acid copolymer (Eudragit S100): 8 parts; Microcrystalline cellulose (MCC): 22 parts; Magnesium stearate: 2 parts; Vitamin E succinate: 2 parts.

[0035] Preparation steps: HP- -CD solubilizes clopidogrel bisulfate (50 °C, stir at 500 rpm, 30 min), and spray-dries (feed rate 9 mL / min, atomization pressure 2.5 bar, outlet temperature 70 °C) to prepare nanoscale drug particles.

[0036] Take the PEG-PLGA copolymer and phospholipids and dissolve them in the aqueous phase (pH 7.4). Perform ultrasonic emulsification (power 100 W, time 18 min), and then perform low-temperature freeze-drying (-45 °C, vacuum degree 20 Pa, 10 h) to obtain supramolecular self-assembled nanoparticles.

[0037] Dissolve NaCl and CaCl2 in deionized water to form an ionic cross-linking solution, and spray-coat the nano-drug particles (spray rate 5 mL / min, temperature 58 °C).

[0038] Apply a Eudragit S100 coating (electrostatic spraying method, spraying pressure 3.2 bar, distance 18 cm) to enhance pH sensitivity.

[0039] Mix the particles with MCC and magnesium stearate, stir at 250 rpm, and use a tableting machine to form tablets (pressure 16 MPa).

[0040] Example 4: Raw material formula: Clopidogrel bisulfate: 42 parts; HP- -CD: 9 parts; Sodium chloride: 2 parts; Calcium chloride: 2 parts; PEG-PLGA copolymer: 6 parts; Ethyl cellulose (EC): 6 parts; Methacrylic acid copolymer (Eudragit S100): 8 parts; Microcrystalline cellulose (MCC): 20 parts; Magnesium stearate: 3 parts; Vitamin E succinate: 2 parts.

[0041] Preparation steps: HP- -CD is dissolved in water (temperature 55 °C, stirring rate 450 rpm), add clopidogrel bisulfate, stir for 40 min, and perform spray drying (feed rate 7 mL / min, atomization pressure 2.6 bar, outlet temperature 73 °C) to form uniform particles.

[0042] Use PEG-PLGA and phospholipids to prepare supramolecular self-assembled nanoparticles (ultrasonic power 110 W, emulsification 15 min), and perform freeze-drying (-48 °C, vacuum degree 22 Pa, 12 h) to obtain a nano-carrier.

[0043] Use a sodium chloride and calcium chloride solution (concentration 2%) to spray-coat the particles (spray rate 4.5 mL / min, temperature 60 °C) to form an ionic cross-linked controlled-release layer.

[0044] Coated with Eudragit S100 (electrostatic spraying method, spraying pressure 3 bar, distance 16 cm) to optimize the dissolution rate.

[0045] The granules were mixed with MCC and magnesium stearate, stirred at 280 rpm, and tableted by a tableting machine (pressure 17 MPa).

[0046] Comparative Example 1: (Nanopermeable membrane technology not adopted) Comparison direction: Without using a double-layer nanopermeable membrane, investigate its effect on the dissolution rate.

[0047] Raw material formula: Clopidogrel bisulfate: 40 parts; HP- -CD: 10 parts; Methacrylic acid copolymer (Eudragit S100): 10 parts; Microcrystalline cellulose (MCC): 35 parts; Magnesium stearate: 3 parts; Vitamin E succinate: 2 parts.

[0048] Preparation process: The solubilized granules of clopidogrel bisulfate and HP- -CD were prepared in the same manner, with a spray drying temperature of 75 °C, an atomization pressure of 2.5 bar, and a feed rate of 8 mL / min.

[0049] Coated with Eudragit S100 by electrostatic spraying (pressure 3 bar, spraying distance 15 cm) to form a pH-sensitive layer.

[0050] The granules were mixed with MCC and magnesium stearate (stirring rate 300 rpm), directly tableted (pressure 15 MPa), and not treated with a nanopermeable membrane coating.

[0051] Comparative Example 2: (pH-sensitive controlled release layer not adopted) Comparison direction: Without using a pH-sensitive release matrix, investigate its effect on the drug release curve.

[0052] Raw material formula: Clopidogrel bisulfate: 40 parts; HP- -CD: 10 parts; PEG-PLGA copolymer: 10 parts; Phospholipid: 5 parts; Ethyl cellulose (EC): 10 parts; Microcrystalline cellulose (MCC): 20 parts; Magnesium stearate: 3 parts; Vitamin E succinate: 2 parts.

[0053] Preparation process: Use HP- -CD to prepare the solubilized particles of clopidogrel bisulfate, and spray drying (temperature 70 °C, atomization pressure 2.5 bar).

[0054] Ultrasonic emulsification of PEG-PLGA and phospholipids (power 120 W, 15 min), and freeze drying (-50 °C, vacuum degree 30 Pa, 12 h) to obtain supramolecular self-assembled nanoparticles.

[0055] Coat the nanoparticles with EC (spray rate 6 mL / min, temperature 60 °C).

[0056] Mix the particles with MCC and magnesium stearate (stirring rate 350 rpm), and directly press tablets (pressure 15 MPa), without using a pH-sensitive coating layer.

[0057] Comparative example 3: (Without using supramolecular self-assembled nanoparticles) Comparison direction: Do not use supramolecular self-assembled nanoparticles, and investigate its effect on drug solubility.

[0058] Raw material formula: Clopidogrel bisulfate: 40 parts; HP- -CD: 10 parts; Ethylcellulose (EC): 10 parts; Methacrylic acid copolymer (Eudragit S100): 10 parts; Microcrystalline cellulose (MCC): 25 parts; Magnesium stearate: 3 parts; Vitamin E succinate: 2 parts.

[0059] Preparation process: Use HP- -CD to prepare the solubilized particles of clopidogrel bisulfate, and spray drying (temperature 75 °C, atomization pressure 2.5 bar).

[0060] Coat the nanoparticles with EC (spray rate 5 mL / min, temperature 65 °C) to form a permeable membrane.

[0061] Coat with Eudragit S100 (electrostatic spraying method, spray pressure 3 bar, distance 15 cm).

[0062] Mix the particles with MCC and magnesium stearate (stirring rate 350 rpm), and directly press tablets (pressure 16 MPa).

[0063] Comparative example 4: (Without using an ion cross-linking regulator) Comparison direction: Without adopting the ionic cross - linked controlled - release strategy, investigate its influence on the release stability of drugs in different pH environments.

[0064] Raw material formula: Clopidogrel bisulfate: 38 parts; HP - -CD: 10 parts; PEG - PLGA copolymer: 10 parts; Phospholipid: 5 parts; Ethyl cellulose (EC): 7 parts; Methacrylic acid copolymer (Eudragit S100): 8 parts; Microcrystalline cellulose (MCC): 20 parts; Magnesium stearate: 2 parts; Preparation process: Use HP - -CD to prepare solubilized particles of clopidogrel bisulfate, and spray - dry (temperature 75°C, atomization pressure 2.5 bar).

[0065] Ultrasonically emulsify PEG - PLGA and phospholipid (power 110 W, time 15 min), and freeze - dry (-50°C, vacuum degree 30 Pa, 12 h) to obtain supramolecular self - assembled nanoparticles.

[0066] Coat the nanoparticles with EC (spray rate 5 mL / min, temperature 65°C).

[0067] Coat with Eudragit S100 (electrostatic spraying method, spraying pressure 3 bar, distance 15 cm).

[0068] Mix the particles with MCC and magnesium stearate (stirring rate 300 rpm), and directly compress into tablets (pressure 15 MPa).

[0069] Experiment 1: Influence of nano - permeable membrane on drug dissolution.

[0070] Experiment purpose: This experiment aims to evaluate the influence of the nano - permeable membrane on drug dissolution. By comparing the dissolution curves of Example 1 (containing the nano - permeable membrane) and Comparative Example 1 (without the nano - permeable membrane), analyze the influence of the nano - permeable membrane on the drug release rate.

[0071] Experiment materials and instruments: Drug samples: 6 tablets each of Example 1 and Comparative Example 1 Dissolution medium: pH 6.8 phosphate buffer solution (900 mL) Experiment instruments: Dissolution apparatus (basket method, 50 rpm); HPLC (detection = 220 nm); Thermostatic water bath (37.0 ± 0.5 °C); Sampling needle, filter membrane (0.45 m).

[0072] Experimental procedure: Add pH 6.8 buffer solution to the dissolution apparatus and maintain the temperature at 37 °C.

[0073] Take 6 tablets each of Example 1 and Comparative Example 1 and place them separately into different dissolution cups.

[0074] Set the rotation speed at 50 rpm, start the dissolution apparatus, and sample at regular intervals.

[0075] Take 1 mL of solution at 0, 15, 30, 45, 60, 90, 120, and 180 min. After each sampling, replenish an equal amount of fresh dissolution medium.

[0076] The sampled solution is filtered through a 0.45 m filter membrane, and the drug content is determined using HPLC.

[0077] Calculate the cumulative dissolution percentage, plot the dissolution curve, and perform data analysis.

[0078] Table 1: Influence of the nano-permeable membrane on the drug dissolution rate The function of the nano-permeable membrane is obviously not just to increase the drug release rate. It not only affects the initial dissolution rate but also changes the entire release curve. Experimental data show that the release amount of Example 1 in the first 30 min is nearly 2 times higher than that of Comparative Example 1, indicating that the permeable membrane can effectively regulate the hydration rate and improve the drug diffusion ability. In addition, the subsequent release also remains stable, reducing the risk of sudden drug release.

[0079] Mechanistically, the structural design of this nano-permeable membrane may form a semi-permeable network. It allows the dissolution medium to gradually penetrate, making the drug release more controllable. In Comparative Example 1, due to the lack of this structure, the drug release is limited by the particle solubility, and the diffusion process is relatively slow. Therefore, the nano-permeable membrane is not just a simple coating layer but a key factor for dynamically regulating the release rate.

[0080] However, it should be noted that although the nano-permeable membrane improves the drug dissolution rate, its actual influence is affected by various factors, such as the thickness of the permeable membrane and the proportion of the hydrophilic matrix. The future optimization direction may be to adjust the composition ratio of the coating material or introduce new nano-carrier technologies to further improve the uniformity and stability of the release.

[0081] Experiment 2: Influence of the nano-permeable membrane on drug stability Purpose of the experiment: By comparing Example 2 (with a nano-permeable membrane) and Comparative Example 2 (without a nano-permeable membrane), evaluate the effect of the nano-permeable membrane on the drug stability under different storage conditions. Examine the change of drug content during long-term storage and verify the inhibitory effect of the permeable membrane on drug degradation.

[0082] Experimental materials and instruments: Drug samples: 6 tablets each of Example 2 and Comparative Example 2 Storage conditions: 25°C ± 2°C, relative humidity 60% ± 5% 40°C ± 2°C, relative humidity 75% ± 5% Experimental instruments: High-performance liquid chromatography (HPLC) Precision balance Thermostatic and humidostatic chamber Sample bottles, filter membranes (0.45 μm) Experimental procedures: Weigh 6 tablets each of Example 2 and Comparative Example 2 and place them under different storage conditions: 25°C ± 2°C, 60% ± 5% RH 40°C ± 2°C, 75% ± 5% RH Take samples at 0, 15, 30, 60, 90, and 180 days and detect the drug content respectively.

[0083] When sampling, crush the tablets and accurately weigh an appropriate amount of powder, add an appropriate amount of solvent to dissolve, and ultrasonicate for 20 min.

[0084] After filtering through a 0.45 μm filter membrane, inject it into the HPLC for analysis, detect the main peak area, and calculate the drug content.

[0085] Record the content retention rate and analyze the drug content change curve under different conditions.

[0086] Table 2: Effect of the nano-permeable membrane on drug stability The experimental results show that in a high-temperature and high-humidity environment, the drug content retention rate of Example 2 is significantly better than that of Comparative Example 2. This difference becomes more significant during long-term storage, especially after 90 days, and the content gap gradually widens. This indicates that the nano-permeable membrane can not only isolate water vapor but may also prevent the penetration of water molecules at the molecular level through its dense structure, thereby slowing down the drug degradation rate.

[0087] In further analysis, it was found that the nano-permeable membrane exhibited a unique barrier effect in the diffusion of water molecules. In particular, the hydrophobic groups introduced into the membrane structure might form an effective barrier through the close arrangement of molecules, restricting the occurrence of hydration. This property is particularly crucial for thermosensitive drugs, helping to extend the shelf life of the drugs. However, under low-temperature and low-humidity conditions, although this protective effect still exists, it is relatively less significant, perhaps because the environmental impact is smaller and the protective effect of the membrane is not easily manifested.

[0088] Experiment 3: Experimental method Experimental materials: Four examples (Example 1, Example 2, Example 3, Example 4).

[0089] Four comparative examples (Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4).

[0090] Experimental equipment: High-temperature and high-humidity incubator, drug content analyzer, electronic balance, etc.

[0091] Analysis method: High-performance liquid chromatography (HPLC).

[0092] Experimental steps: Sample preparation: The raw drug of the same batch was used for preparation, and the nano-permeable membrane-coated drugs were prepared according to the formulations of the examples and comparative examples respectively.

[0093] Ensure that the preparation process is consistent to avoid human errors.

[0094] Storage condition setting: High-temperature and high-humidity environment (60 °C, relative humidity 75%), low-temperature and dry environment (4 °C, relative humidity 20%).

[0095] Placement period: 0 days, 30 days, 60 days, 90 days.

[0096] Drug content detection: Samples were taken at each time point for content detection, and the drug content was determined by high-performance liquid chromatography.

[0097] Each group of samples was detected in parallel 3 times, and the average value was taken.

[0098] Data statistics and analysis: Compare the drug content retention rates of different examples and comparative examples, and perform variance analysis and significance test.

[0099] Table 3: Comparison table of drug content retention rates The nano-permeation membrane shows significant advantages in protecting drug stability. The experimental results show that the drug content retention rates of the four examples are generally higher than those of the comparative examples under high temperature and high humidity conditions, especially for Example 2 and Example 4. After 90 days of long-term storage, the content retention rates of the examples are still above 86%, while those of the comparative examples generally drop to about 70%. This difference lies in the barrier effect of the nano-membrane structure on the intrusion of water vapor, which significantly reduces the penetration rate of water molecules in the membrane layer.

[0100] Structural analysis shows that the compactness and hydrophobicity of the nano-membrane layer are its core advantages. In particular, the dense arrangement of molecules within the membrane and the intermolecular interactions further block the migration path of water molecules. This mechanism enables the drug to maintain stable activity in harsh environments. In contrast, due to the lack of an effective barrier in the comparative example samples, a large amount of water molecules flood in within a short time, resulting in rapid drug degradation.

[0101] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A clopidogrel bisulfate tablet, characterized in that, It comprises the following components: Clopidogrel bisulfate: 30 - 50 parts; Double-layer nano-permeable membrane material: 5 - 15 parts; pH-sensitive release material: 3 - 12 parts; Supramolecular self-assembled nanoparticle material: 5 - 12 parts; Solubility regulator: 5 - 15 parts; Ionic cross-linking regulation factor: 2 - 5 parts; Excipient: 10 - 25 parts; Lubricant: 0.5 - 2 parts; Stabilizer: 0.5 - 2 parts.

2. The clopidogrel bisulfate tablet according to claim 1, wherein The double-layer nano-permeable membrane material comprises: Inner layer material: Hydroxypropyl -Cyclodextrin: 5-15 parts; Polyvinylpyrrolidone: 3 - 10 parts; Outer layer material: Ethylcellulose: 2 - 8 parts; Hydroxypropyl methylcellulose: 2 - 10 parts.

3. A clopidogrel bisulfate tablet according to claim 1, wherein The pH-sensitive release material is a methacrylic acid copolymer, with a mass fraction of 3 - 12 parts.

4. A clopidogrel bisulfate tablet according to claim 1, characterized in that, The supramolecular self-assembled nanoparticle material comprises: Phospholipid: 2 - 8 parts; PEG-PLGA copolymer with a molecular weight of 15,000 - 30,000 Da and a LA / GA molar ratio of 75:25 - 50:50: 5 - 12 parts.

5. A clopidogrel bisulfate tablet according to claim 1, characterized in that, The ionic cross-linking regulation factor comprises: Sodium chloride: 1 - 3 parts; Calcium chloride: 0.5 - 2 parts.

6. A method for preparing a clopidogrel bisulfate tablet, according to any one of claims 1 to 5, characterized in that: It comprises the following steps: Step 1: Coating clopidogrel bisulfate with the double-layer nano-permeable membrane material to prepare nano-permeable membrane particles; Step 2: Mixing the nano-permeable membrane particles with the pH-sensitive release material and performing coating to form controlled-release particles; Step 3: Coating the surface of the controlled-release particles with the supramolecular self-assembled nanoparticle material to form drug microparticles; Step 4: Uniformly mixing the obtained drug microparticles with the solubility regulator, ionic cross-linking regulation factor, excipient, lubricant and stabilizer to prepare tablet core powder; Step 5: Using a tableting process to form the core powder into tablets and performing coating.

7. The preparation method of the clopidogrel bisulfate tablet according to claim 6, characterized in that, The method for coating the double-layer nano-permeable membrane in Step 1 includes: Dissolve hydroxypropyl -cyclodextrin in deionized water at 50-70 °C and form a homogeneous solution under stirring at 300-500 rpm; Adding clopidogrel bisulfate to this solution and stirring at 55 - 65 °C for 30 - 60 min; Adopting spray drying method, with a feed flow rate of 5 - 15 mL / min, an atomization pressure of 1.5 - 3 bar and an outlet temperature of 60 - 80 °C to prepare inner layer coated particles; Adopting fluidized bed coating technology to perform outer layer coating on the inner layer coated particles, with a spray rate of 5 - 10 mL / min and a hot air temperature of 50 - 80 °C.

8. The preparation method of a clopidogrel bisulfate tablet according to claim 6, characterized in that, The method for preparing the pH-sensitive release matrix in Step 2 includes: Dissolving the methacrylic acid copolymer in ethanol with a volume ratio of 60% - 80%, stirring at 400 - 600 rpm and a temperature of 40 - 55 °C; Adding sodium chloride and calcium chloride and performing ultrasonic treatment for 10 - 20 min; Adopting electrostatic spraying method, with a spray pressure of 2 - 5 bar and a spray distance of 10 - 20 cm to coat the nano-permeable membrane particles.

9. The preparation method of a clopidogrel bisulfate tablet according to claim 6, characterized in that, The method for preparing the supramolecular self-assembled nanoparticles in Step 3 includes: Adding the PEG-PLGA copolymer and phospholipid to an aqueous phase with a pH of 7.0 - 7.4, performing ultrasonic emulsification, with a power of 80 - 150 W and a time of 10 - 20 min; Mixing the nanoemulsion into the coated particles for uniform encapsulation, and maintaining the temperature at 30 - 40 °C; Freeze-drying, with the temperature set at -40 to -60 °C, the vacuum degree controlled at 10 - 50 Pa, and the freeze-drying time of 6 - 12 h.

10. The preparation method of a clopidogrel bisulfate tablet according to claim 6, characterized in that, The tabletting process in Step 5 includes: Take the obtained drug particles and mix them with excipients, lubricants and stabilizers, with a stirring speed of 200 - 400 rpm and a time of 10 - 20 min; Use a rotary tablet press, set the pressure at 10 - 20 MPa, the tabletting speed at 60 - 120 rpm, and the tablet weight at 200 - 400 mg; Use the fluidized bed coating technology for coating, with a spraying rate of 2 - 6 mL / min and a temperature of 45 - 65 °C.

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