Miscarriage prevention medicine for inhibiting uterine contraction and preparation method of miscarriage prevention medicine

Abstract

The invention belongs to the field of pharmaceutical preparations, and provides a miscarriage prevention medicine for inhibiting uterine contraction and a preparation method of the miscarriage prevention medicine. According to the invention, a double-layer tablet design of a nifedipine-nicotinamide eutectic nanocrystalline quick-release layer and a nifedipine-loaded calcium alginate sustained-release pellet sustained-release layer is adopted, and the median particle size of nifedipine in the quick-release layer is controlled to be 0.10-0.40 [mu] m through a nanocrystallization eutectic technology so as to realize quick effect; meanwhile, nifedipine in a sustained-release layer is continuously released by utilizing a calcium alginate ion cross-linked sustained-release pellet drug-loading technology, so that precise regulation and control of a two-phase release curve and collaborative optimization of interlayer bonding strength are realized, the in-vitro dissolution performance of nifedipine is improved, a release time window is prolonged, the batch-to-batch consistency is improved, and the sustained-release effect of nifedipine is improved. The problems that an existing double-layer preparation is difficult to give consideration to layering resistance and drug release differentiation, the processability and the stability of the eutectic nanocrystalline dispersoid are mutually restricted, the contradiction exists between high drug loading and release controllability of the sustained-release pellet and the like are solved, and wide clinical application value is achieved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a tocolytic drug for inhibiting uterine contractions and its preparation method. Background Technology

[0002] Threatened abortion and premature birth are common pregnancy complications in obstetrics and gynecology, seriously threatening the health and safety of mothers and infants. In clinical treatment, effectively inhibiting abnormal uterine contractions is a key measure to reduce the rates of miscarriage and premature birth. Nifedipine, as a calcium channel blocker, relaxes uterine smooth muscle by inhibiting calcium ion influx and has been widely used in the treatment of threatened abortion and premature birth. However, traditional nifedipine formulations suffer from low solubility, insufficient bioavailability, and long onset of action, making it difficult to meet the clinical needs of acute tocolytic therapy. Meanwhile, while conventional immediate-release formulations can act quickly, they exhibit large fluctuations in peak and trough blood drug concentrations and short duration of action, requiring frequent dosing, leading to poor patient compliance and a high risk of adverse reactions such as hypotension. Therefore, developing novel nifedipine formulations that combine rapid onset of action with long-lasting effect is of significant clinical value and practical importance for improving the efficacy of tocolytic therapy, reducing adverse reactions, and improving patients' quality of life. Furthermore, while existing technologies achieve biphasic release regulation, ensuring batch-to-batch quality stability and process scalability are also critical technical issues that urgently need to be addressed.

[0003] To achieve rapid onset and long-lasting effect of nifedipine, researchers have developed various biphasic release formulation technologies, but many shortcomings remain. For example, Chinese patent CN117797112A discloses a nifedipine controlled-release tablet, but its single-layer matrix sustained-release technology makes it difficult to achieve precise differentiation between fast and slow biphasic release, resulting in a slow onset time and insufficient initial blood drug concentration. Chinese patent CN103211788B discloses a nifedipine membrane-controlled sustained-release microcapsule, which controls the release rate through coating, but the microcapsule preparation process is complex, the drug loading is limited, and the coating layer thickness is difficult to control precisely, leading to large batch-to-batch differences in the release curve. Chinese patent CN102114004B discloses a nifedipine bilayer sustained-release tablet and its preparation method, attempting to achieve biphase release through a combination of a fast-release layer and a sustained-release layer. However, it fails to address the fundamental problems of low drug solubility in the fast-release layer and poor stability of the nano-dispersion. Furthermore, the insufficient interlayer bonding strength of the bilayer tablets easily leads to delamination, affecting the reproducibility of the release curve. In addition, while existing co-crystallization technology can improve drug solubility, the nano-dispersion after co-crystallization is prone to agglomeration under high solids content conditions, resulting in particle size rebound and batch-to-batch instability. Although alginate sustained-release carriers possess good biocompatibility, under high drug loading conditions, the microsphere morphology is uneven, mechanical strength decreases, and the release mechanism is significantly affected by the internal structure of the microspheres, making it difficult to achieve precise and controllable long-term release. Summary of the Invention

[0004] The purpose of this invention is to provide a tocolytic drug for inhibiting uterine contractions and its preparation method, which solves the problems of existing bilayer oral formulations, such as the difficulty in balancing anti-stratification of bilayer structure and rapid differentiation of biphase drug release, the mutual constraint between the high solids content and processability of eutectic nanocrystal dispersions and the stability of nanoparticle size, and the natural mechanism contradiction between high drug loading and microsphere morphology and strength consistency and long-term release controllability of calcium alginate sustained-release microspheres, resulting in release curve drift and insufficient batch-to-batch consistency.

[0005] This invention employs a synergistic design concept of a bilayer tablet consisting of a nifedipine-nicotinamide co-crystal nanocrystalline fast-release layer and a nifedipine-loaded calcium alginate sustained-release microsphere layer. Co-crystal technology enhances the drug solubility of the fast-release layer, while nanotechnology accelerates dissolution. Simultaneously, calcium alginate ion-crosslinked sustained-release microspheres precisely control the release kinetics of the sustained-release layer. The two release mechanisms do not interfere with each other and work synergistically, achieving dual-phase release regulation that balances rapid onset and long-lasting effect. Furthermore, by optimizing the tableting process parameters of the mixture of fast-release particles and sustained-release layer, the interlayer bonding strength and anti-stratification performance of the bilayer tablets are significantly improved, ensuring batch-to-batch reproducibility of the release curve and process scale-up stability. This overcomes the technical bottleneck of a single release system being unable to simultaneously meet the needs of both fast and slow release phases.

[0006] To achieve the above objectives, the present invention provides the following technical solution: A tocolytic drug that inhibits uterine contractions, said drug being a bilayer tablet comprising an immediate-release layer and a sustained-release layer, wherein: (1) The fast-release layer comprises nifedipine, nicotinamide, hydroxypropyl methylcellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone and magnesium stearate; in the fast-release layer, nifedipine and nicotinamide exist in the form of nifedipine-nicotinamide co-crystal nanocrystal dispersion, and the median particle size D50 of the co-crystal nanocrystal dispersion is 0.10-0.40µm; (2) The sustained-release layer comprises nifedipine-loaded calcium alginate sustained-release microspheres, microcrystalline cellulose, and magnesium stearate; the particle size of the sustained-release microspheres is 100-600µm, which is the particle size obtained by sieving the dried microspheres through a standard sieve; based on the total mass of the dried microspheres, the drug loading of nifedipine in the sustained-release microspheres is 1.00-20.00wt%; (3) The mass ratio of the fast-release layer to the sustained-release layer is 1:2-1:5; the total content of nifedipine in the bilayer tablets is 0.10-10.00wt% based on the total mass of the bilayer tablets.

[0007] Furthermore, the nifedipine-nicotinamide eutectic is prepared by the following steps: A1. Raw material preparation: Weigh nifedipine and nicotinamide, and control the molar ratio of nifedipine to nicotinamide to be 0.95-1.05:1; add anhydrous ethanol, and control the liquid-solid ratio to be 5-30 mL / g. Based on the total mass of nifedipine and nicotinamide, stir at 200-600 rpm for 5-30 min at 15-30℃ under light-protected conditions to obtain a mixed solution. A2. Crystallization: Stir at 300-800 rpm for 0.5-2.0 h at 40-60℃ until no visible solids are visible and the solution is clear; then cool the clear solution to 0-20℃; add the clear solution dropwise to purified water pre-cooled to 0-20℃ as an antisolvent at a dropping rate of 1-20 mL / min for crystallization, wherein the volume ratio of purified water to the ethanol solution is 2:1-20:1, and maintain the temperature of the mixing system at 0-20℃ and stir at 300-800 rpm during the dropwise addition; after the dropwise addition is completed, continue stirring and aging at 0-20℃ for 0.5-4.0 h; A3. Separation and post-processing: The obtained solid was separated by centrifugation at 3000-10000g for 5-30min at 4-25℃; washed 1-3 times with purified water, each time using 5-50mL of purified water per 1g of solid; and dried at 30-50℃ and 5-30kPa absolute pressure for 6-24h until the moisture content was 0.10-5.00wt%, to obtain the nifedipine-nicotinamide cocrystal. A4. Endpoint Criteria and Quality Control: Based on the total mass of the dried eutectic, the residual ethanol in the eutectic is ≤5000ppmw / w and the moisture content is 0.10-5.00wt%.

[0008] Furthermore, the nifedipine-nicotinamide eutectic nanocrystal dispersion is prepared through the following steps: B1. Raw materials: Nifedipine-nicotinamide cocrystal; hydroxypropyl methylcellulose is added to purified water and stirred at 300-800 rpm for 30-120 min at 20-30℃ until completely dissolved to obtain a stabilizer aqueous solution, wherein the mass fraction of hydroxypropyl methylcellulose in the stabilizer aqueous solution is 0.10-3.00 wt%; according to the initial pH of the stabilizer aqueous solution, the pH of the stabilizer aqueous solution is adjusted to 5.0-8.0 by adding 0.1-1.0 mol / L hydrochloric acid aqueous solution or 0.1-1.0 mol / L sodium hydroxide aqueous solution dropwise, and the pH is measured at 25℃ using a calibrated pH meter; B2. Nanoforming: The eutectic is added to the stabilizer aqueous solution, so that the mass fraction of the eutectic in the mixed system is 1.0-20.0 wt%; wet grinding is performed at 5-25℃ using a bead mill for 0.5-6.0 h, wherein the bead mill uses zirconia grinding beads with a diameter of 0.1-0.6 mm, a grinding bead filling rate of 50-80%, a grinding speed of 800-3000 rpm, and the system temperature is maintained at 5-25℃ by jacket circulation cooling; B3. Endpoint Criteria and Quality Control: When the median particle size D50 of the eutectic nanocrystals in the obtained dispersion reaches the range defined as 0.10-0.40µm and the solid content of the dispersion is 1.0-20.0wt%, the nifedipine-nicotinamide eutectic nanocrystal dispersion is obtained; wherein, D50 is the median particle size of the volume distribution measured by dynamic light scattering method after diluting the dispersion with purified water to a solid content of 0.05-0.50wt% and ultrasonically dispersing it at 25℃ for 5-20min; the solid content is the mass fraction of non-volatile solids measured by drying the dispersion sample at 105℃ to constant weight.

[0009] Furthermore, based on nifedipine, the mass ratio of nifedipine in the rapid-release layer to the mass of nifedipine in the sustained-release layer is 1:1 to 1:10.

[0010] Furthermore, based on the total mass of the rapid-release layer, the content of the hydroxypropyl methylcellulose in the rapid-release layer is 0.10-3.00 wt%.

[0011] Furthermore, based on the total mass of the fast-release layer, the content of magnesium stearate in the fast-release layer is 0.20-2.00 wt%; and based on the total mass of the slow-release layer, the content of magnesium stearate in the slow-release layer is 0.20-2.00 wt%.

[0012] Furthermore, the nifedipine-loaded calcium alginate sustained-release microspheres are prepared through the following steps: D1. Preparation of sodium alginate solution: Add sodium alginate to purified water, stir at 300-800 rpm for 1-4 hours at 20-30℃ until completely dissolved, and let stand for 0.5-2 hours to remove bubbles, to obtain sodium alginate solution with a mass fraction of 1.0-5.0 wt%; adjust the pH to 5.5-7.5 by adding 0.1-1.0 mol / L hydrochloric acid aqueous solution or 0.1-1.0 mol / L sodium hydroxide aqueous solution dropwise according to the initial pH of the sodium alginate solution. D2. Drug dispersion: Nifedipine was added to the sodium alginate solution and dispersed at 5-25°C using high-speed shear dispersion at a rotation speed of 10,000-20,000 rpm for 5-30 minutes to obtain a uniform sodium alginate suspension containing the drug; the mass fraction of nifedipine in the total mass of the sodium alginate suspension containing the drug was 0.10-5.00 wt%. D3. Ion crosslinking into pellets: A crosslinking solution is prepared with purified water, wherein the calcium chloride concentration in the crosslinking solution is 0.05-0.50 mol / L; the volume ratio of the crosslinking solution to the drug-containing sodium alginate suspension is controlled at 5:1-20:1; the mixture is stirred at 200-600 rpm at 5-30℃; the drug-containing sodium alginate suspension is added dropwise to the crosslinking solution through a nozzle with an inner diameter of 0.10-1.00 mm at a dropping rate of 0.5-10 mL / min, with a dropping height of 1-10 cm; after the addition is completed, the mixture is stirred and crosslinked at 5-30℃ for 0.5-4.0 h. D4. Post-processing and quality control: Wash the obtained microspheres with purified water 1-3 times, each time using 10-100 mL of purified water per 1 g of wet microspheres, and dry them at 30-50℃ and 5-30 kPa absolute pressure for 6-24 h until the water content of the microspheres is 0.50-8.00 wt%; after drying, sieve the microspheres and collect the microspheres with a particle size of 100-600 µm to obtain the nifedipine-supported calcium alginate sustained-release microspheres.

[0013] As a concept of this invention, the design of nifedipine-nicotinamide co-crystal nanocrystals is mainly used to enhance the dissolution rate and bioavailability of nifedipine in the rapid-release layer. Nifedipine belongs to the BCSII class of drugs, and its poor water solubility severely limits the rate and extent of oral absorption. This invention forms a co-crystal with nifedipine and nicotinamide in a specific molar ratio. Utilizing the hydrophilicity and hydrogen bond donor-acceptor properties of nicotinamide, the lattice structure and solvation energy of nifedipine are altered at the molecular level, significantly reducing the lattice energy and improving solubility. Simultaneously, nicotinamide, as a co-crystal former, can effectively inhibit recrystallization of nifedipine during dissolution, maintaining its high-energy amorphous or metastable state, thereby accelerating the dissolution rate. Building upon this foundation, the present invention further employs wet bead milling technology to nanoscale the eutectic crystals to a median particle size of 0.10-0.40 µm. According to the Noyes-Whitney equation, reducing the particle size significantly increases the specific surface area, further enhancing the dissolution rate. The nanoscaled eutectic particles form a stable dispersion under the protection of hydroxypropyl methylcellulose stabilizer, preventing nanocrystal aggregation and particle size rebound, ensuring rapid drug release after rapid disintegration of the fast-release layer in vivo. The synergistic application of eutectic and nanoscale technologies enables the fast-release layer of nifedipine to achieve high dissolution rates in a short time, achieving the design goal of rapid onset of action and meeting the clinical needs of acute tocolytic therapy.

[0014] This invention also discloses a method for preparing a tocolytic drug that inhibits uterine contractions, comprising the following steps: S1. Preparation of nifedipine-loaded calcium alginate sustained-release microspheres; S2. Preparation of fast-release layer particles: Microcrystalline cellulose and cross-linked polyvinylpyrrolidone were mixed, and then nifedipine-nicotinamide co-crystal nanocrystal dispersion was added. After wet granulation and drying, magnesium stearate was added and mixed to obtain fast-release layer particles. S3. Preparation of sustained-release layer mixture: The nifedipine-loaded calcium alginate sustained-release microspheres are mixed with microcrystalline cellulose, and magnesium stearate is added and mixed to obtain a sustained-release layer mixture; S4. Double-layer tableting: The mixture of the fast-release granules and the sustained-release granules is compressed into a double-layer tablet using a double-layer tableting process to obtain the drug.

[0015] Further, in step S2, the nifedipine-nicotinamide eutectic nanocrystalline dispersion is added at a feeding rate of 1-20 mL / min at 10-30℃ for granulation, with the endpoint being the wet particle moisture content reaching 15-30 wt%. The moisture content of the wet particles is determined by sampling and using the loss-in-weight method or Karl Fischer method. Once the target range is reached, feeding is stopped and granulation is completed. The total granulation time is 2-30 min. The obtained wet particles are dried at 30-60℃ for 1-12 h until the particle moisture content is ≤3.0 wt%. In step S4, the tableting main compression is 5-30 kN, and the target tablet weight is 100-1000 mg.

[0016] Furthermore, in step S4, the mass ratio of the fast-release layer to the sustained-release layer is controlled to be 1:2-1:5.

[0017] As another aspect of this invention, the design of nifedipine-loaded calcium alginate sustained-release microspheres primarily aims to enhance the sustained release performance and controllability of the release kinetics of the drug in the sustained-release layer. Calcium alginate, as a natural polysaccharide biomaterial, possesses excellent biocompatibility, non-toxicity, and pH-responsive swelling properties, making it an ideal material for constructing oral sustained-release carriers. This invention utilizes ion crosslinking technology to form an "egg-box" structure between the carboxyl groups on the sodium alginate molecular chain and calcium ions, enabling rapid pellet formation under mild conditions. This avoids the damage to the drug caused by traditional organic solvents or high-temperature processes, maintaining the chemical stability of nifedipine. The microsphere particle size is controlled within the range of 100-600 µm, ensuring both good flowability and compressibility while preventing excessive fragmentation of the microspheres during bilayer tablet compression, thus maintaining the intact sustained-release microsphere structure. The drug loading design of 1.00-20.00 wt% balances drug loading efficiency and microsphere mechanical strength. Lower loading results in a dense and strong calcium alginate matrix but a slow release rate, while higher loading leads to more uniform drug dispersion and faster initial release but decreased microsphere strength. This invention achieves the optimal balance between microsphere morphology uniformity, mechanical strength, and release rate within this loading range by optimizing sodium alginate concentration, cross-linking conditions, and drug dispersion methods. In the gastrointestinal environment, the calcium alginate network swells and partially dissolves under pH > 5 conditions, allowing for continuous drug release through a dual mechanism of diffusion and matrix dissolution. The release curve conforms to a zero-order or Higuchi model, achieving stable release for 8-12 hours, meeting the needs of long-term maintenance therapy.

[0018] Furthermore, the median particle size D50 of the eutectic nanocrystals is the median particle size of the volume distribution measured by dynamic light scattering after the fast-release layer sample is pulverized and mixed with purified water to prepare a dispersion with a solid content of 0.10-1.00wt%, ultrasonically dispersed at a temperature of 25℃, an ultrasonic frequency of 40kHz, an ultrasonic power of 200-500W, and an ultrasonic time of 5-20min.

[0019] Furthermore, the crystallization step of the nifedipine-nicotinamide eutectic is carried out under light-protected conditions.

[0020] Furthermore, the separation method of the nifedipine-nicotinamide eutectic also includes filtration separation, wherein the filtration separation adopts a vacuum filtration method and selects a filter membrane with a pore size of 0.22-5.0µm.

[0021] Furthermore, the hydroxypropyl methylcellulose is pharmaceutical grade hydroxypropyl methylcellulose, and the viscosity grade of the hydroxypropyl methylcellulose is 3-100 mPa·s.

[0022] Furthermore, the nifedipine is sieved through a standard sieve with a mesh size of 60-200 before preparing the drug-containing sodium alginate suspension.

[0023] Furthermore, the drug loading of the sustained-release microspheres was determined by high-performance liquid chromatography, and the drug loading was calculated with the total mass of the dried sustained-release microspheres as the denominator.

[0024] Furthermore, the hardness of the bilayer tablet is 30-150N, the brittleness is no more than 1.0wt%, and the interlayer peeling force is used as the quality control index for interlayer bonding.

[0025] Furthermore, the washing endpoint of the microparticles is characterized by conductivity or chloride ion residue until the conductivity of the washing liquid is less than 20-100 μS / cm or the chloride ion residue is less than 50-200 ppm.

[0026] Furthermore, the residual ethanol in the eutectic was determined by gas chromatography, and the moisture content was determined by Karl Fischer method.

[0027] Furthermore, based on the total mass of the fast-release layer, the content of magnesium stearate in the fast-release layer is 0.20-2.00 wt%; and based on the total mass of the slow-release layer, the content of magnesium stearate in the slow-release layer is 0.20-2.00 wt%.

[0028] Furthermore, the mass ratio of microcrystalline cellulose to cross-linked polyvinyl ketone in the rapid-release layer is 2:1-20:1.

[0029] Furthermore, the mass ratio of nifedipine-loaded calcium alginate sustained-release microspheres to microcrystalline cellulose in the sustained-release layer is 1:0.1-1:5.

[0030] The synergistic effect of the nifedipine-nicotinamide co-crystal nanocrystal fast-release layer and the nifedipine-loaded calcium alginate sustained-release microsphere layer in this invention is manifested in the following aspects: First, the fast-release layer co-crystal nanocrystals, through improved solubility and nano-sizing, ensure that nifedipine is rapidly dissolved and absorbed within 15-30 minutes after administration, quickly reaching an effective blood drug concentration, achieving rapid onset of action and controlling acute uterine contractions; the sustained-release layer calcium alginate microspheres, through a slow swelling and diffusion release mechanism, continuously release nifedipine over the following 6-10 hours, maintaining a stable blood drug concentration and prolonging the duration of efficacy. Second, the fast-release layer and the sustained-release layer are physically separated in the bilayer tablet, avoiding mutual interference between the two phases of drugs during preparation and storage. The nanocrystals in the fast-release layer will not agglomerate due to the presence of the sustained-release layer matrix, and the sustained-release microspheres will not have their release kinetics affected by the hygroscopicity of the fast-release layer excipients. The two release mechanisms are independent and complementary. Furthermore, the bilayer tablets, through optimized compression process parameters, ensure a strong interlayer bond between the rapid-release and sustained-release layers, avoiding release curve instability caused by delamination. Simultaneously, the bilayer structure allows the rapid-release layer to disintegrate before the sustained-release layer, resulting in an ideal release curve that is initially rapid and then slows down, aligning with the clinical medication logic of controlling symptoms first and then maintaining long-term health in acute tocolytic therapy. In addition, the combination of cocrystal nanocrystal technology and calcium alginate sustained-release technology overcomes the limitations of single-dose formulations in terms of bioavailability, release rate, and batch-to-batch stability, achieving synergistic optimization of biphasic release and significantly improving the clinical efficacy and safety of nifedipine formulations.

[0031] Beneficial technical effects 1. Significantly improves the bioavailability and onset of action of nifedipine: By using nifedipine-nicotinamide cocrystallization technology, the crystal structure and solvation properties of nifedipine are improved at the molecular level, significantly enhancing its water solubility; combined with nanotechnology, the median particle size of the cocrystallization is controlled at 0.10-0.40µm, significantly increasing the dissolution rate according to the Noyes-Whitney equation; the cocrystallized nanocrystals form a stable dispersion under the protection of hydroxypropyl methylcellulose stabilizer, ensuring rapid release after rapid disintegration in vivo, enabling nifedipine to achieve high dissolution in a short time and rapid onset of action to meet the needs of acute tocolytic therapy. Compared with traditional formulations, it is expected to shorten the onset time and increase the peak concentration level.

[0032] 2. Achieving a precise and controllable biphasic release curve and long-term maintenance therapy: Utilizing calcium alginate ion-crosslinked sustained-release microsphere technology, by controlling the microsphere particle size to 100-600µm and the drug loading to 1.00-20.00wt%, and leveraging the swelling and dissolution characteristics of the calcium alginate network under pH>5 conditions, a dual sustained-release mechanism of drug diffusion and matrix dissolution is achieved. Release data can be fitted and analyzed using zero-order models or Higuchi models, etc. Within the in vitro dissolution test time window, it exhibits continuous release. The physical separation of the fast-release layer and the sustained-release layer in the bilayer tablet, along with optimized tableting technology, ensures that rapid onset and long-term maintenance release do not interfere with each other and work synergistically, forming an ideal biphasic release curve that is initially fast and then slows down. This prolongs the duration of drug efficacy to 8-12 hours, reduces the frequency of administration, and improves patient compliance.

[0033] 3. Significantly improved batch-to-batch consistency and process scale-up stability: The eutectic nanocrystal dispersion is stabilized using wet bead milling and hydroxypropyl methylcellulose (HMC) technology, effectively inhibiting nanocrystal agglomeration and particle size rebound, ensuring stable particle size under high solid content conditions of 1.0-20.0 wt%, with a batch-to-batch D50 coefficient of variation of <5%; the calcium alginate sustained-release microspheres are produced through a mild pelleting process via ion crosslinking, avoiding damage from organic solvents and high temperatures, resulting in uniform microsphere morphology, stable mechanical strength, and a batch-to-batch coefficient of variation of drug loading of <3%; the bilayer compression process optimizes interlayer bonding strength, with an interlayer peeling force >30 N and friability <1.0 wt%, ensuring that the bilayer tablets do not separate during production, transportation, and storage, exhibiting excellent batch-to-batch reproducibility of the release curve, with a relative standard deviation of <8%, meeting the requirements for industrial scale-up production and quality control.

[0034] 4. Reduced incidence of adverse reactions and improved drug safety: The biphasic release design significantly reduces the peak-to-trough fluctuations in nifedipine blood concentration, avoiding adverse reactions such as hypotension, headache, and facial flushing caused by a sudden increase in blood concentration in traditional immediate-release formulations; after the rapid onset of action of the rapid-release layer, the sustained-release layer continuously releases and maintains a stable blood concentration, reducing the risk of cumulative toxicity caused by frequent dosing; calcium alginate, as a natural biomaterial, has good biocompatibility and safety, with no organic solvent residue, reducing excipient-related adverse reactions, making it suitable for pregnant women who need long-term medication, and improving the safety and tolerability of clinical medication.

[0035] 5. Simplified production process and reduced manufacturing costs: The preparation of eutectic crystals adopts anti-solvent crystallization technology, which is simple, mild, and easy to scale up, avoiding the complex processes such as grinding or hot-melt extrusion in traditional eutectic preparation; nano-sizing adopts wet grinding with bead milling, which has high continuous production efficiency and low energy consumption; the ion cross-linking of calcium alginate microspheres is carried out in a room temperature aqueous system, which does not require organic solvents or high-temperature equipment, making it environmentally friendly and low-cost; the double-layer tableting adopts a conventional double-layer tableting machine, which does not require special equipment modification, has good process compatibility, and the overall production process is simple and efficient, reducing manufacturing costs and facilitating industrialization and clinical application. Attached Figure Description

[0036] Figure 1 XRPD diffraction pattern superimposed to confirm the eutectic crystal form.

[0037] Figure 2 This is a volume distribution curve of eutectic nanocrystalline DLS.

[0038] Figure 3 The statistical indices D10, D50, and D90 of eutectic nanocrystals are plotted against a Span diagram.

[0039] Figure 4 The dissolution curves for Example 1 and Comparative Example 2 are shown from 0 to 12 hours.

[0040] Figure 5 This is a partial view of the phase before dissolution in Example 1 and Comparative Example 2 from 0 to 2 hours.

[0041] Figure 6 Laser-guided particle size distribution curve of calcium alginate microspheres for sustained release.

[0042] Figure 7 Mass distribution diagram of calcium alginate microspheres after standard sieving.

[0043] Figure 8 Box plot of drug loading distribution in sustained-release microspheres plus original point plot.

[0044] Figure 9 The dissolution curves for Example 1 and Comparative Example 4 are shown for 2 to 12 hours. Detailed Implementation

[0045] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Example 1

[0046] This embodiment prepares a tocolytic drug that inhibits uterine contractions. The drug in this embodiment is a bilayer tablet, including a fast-release layer and a sustained-release layer.

[0047] First, a nifedipine-nicotinamide cocrystal was prepared. 10.00 g of nifedipine and 3.53 g of nicotinamide were weighed, controlling the molar ratio of nifedipine to nicotinamide to be 1.00:1. 170 mL of anhydrous ethanol was added, controlling the liquid-to-solid ratio to be 12.5 mL / g. The mixture was stirred at 400 rpm for 15 min at 22°C under light-protected conditions to obtain a mixed solution. The solution was then stirred at 550 rpm for 1.2 h at 50°C until no visible solids were observed and the solution became clear. The clear solution was then cooled to 10°C. The clear solution was then added dropwise at 8 mL / min to 1700 mL of purified water pre-cooled to 10°C as an antisolvent for crystallization. The volume ratio of purified water to the ethanol solution in this example was 10:1. During the dropwise addition, the temperature of the mixed system was maintained at 10°C and the stirring speed was 550 rpm. Stirring; after the addition is complete, continue stirring and aging at 10℃ for 2.0h; the obtained solid is separated by centrifugation at 6500g, 15min, and 15℃; washed twice with purified water, each time using 25mL of purified water per 1g of solid, the washing endpoint is characterized by conductivity until the conductivity of the washing solution is less than 20μS / cm; and dried at 40℃ and 15kPa absolute pressure for 12h until the moisture content is 2.50wt%, to obtain the nifedipine-nicotinamide cocrystal of this embodiment. Based on the total mass of the dried cocrystal, the residual ethanol in the cocrystal of this embodiment is 2500ppmw / w and the moisture content is 2.50wt%. The residual ethanol in the cocrystal of this embodiment is determined by gas chromatography, and the moisture content is determined by Karl Fischer method.

[0048] Next, a nifedipine-nicotinamide co-crystal nanocrystalline dispersion was prepared. Hydroxypropyl methylcellulose was added to purified water and stirred at 500 rpm for 60 min at 25°C until completely dissolved, yielding a stabilizer aqueous solution. In this embodiment, the mass fraction of hydroxypropyl methylcellulose in the stabilizer aqueous solution was 1.50 wt%. The hydroxypropyl methylcellulose in this embodiment was pharmaceutical grade, and its viscosity was 15 mPa·s. Based on the initial pH of the stabilizer aqueous solution, the pH was adjusted to 6.5 by adding 0.5 mol / L sodium hydroxide aqueous solution dropwise. The pH of this embodiment was measured at 25°C using a calibrated pH meter. The nifedipine-nicotinamide co-crystal was added to the stabilizer aqueous solution, making the mass fraction of the co-crystal in the mixed system 10.0 wt%. The mixture was wet-milled at 15°C for 3.0 h using a bead mill. In this embodiment, zirconia grinding beads with a diameter of 0.35 mm and a filling rate of 65% were used. The milling speed was 1900 rpm, and the system temperature was maintained at 15°C by jacketed cooling. When the median particle size D50 of the eutectic nanocrystals in the dispersion reached 0.25 µm and the solid content of the dispersion was 10.0 wt%, the nifedipine-nicotinamide eutectic nanocrystal dispersion of this embodiment was obtained. In this embodiment, D50 is the median particle size of the volume distribution after diluting the dispersion with purified water to a solid content of 0.20 wt% and ultrasonically dispersing it at 25°C for 10 min, measured by dynamic light scattering. In this embodiment, the ultrasonic frequency was 40 kHz, the ultrasonic power was 350 W, and the ultrasonic time was 10 min. The solid content of this embodiment is the mass fraction of non-volatile solids measured after drying the dispersion sample at 105°C to constant weight.

[0049] Then, nifedipine-supported calcium alginate sustained-release microspheres were prepared. Sodium alginate was added to purified water and stirred at 500 rpm for 2.5 h at 25 °C until completely dissolved. The mixture was then allowed to stand for 1.0 h to remove bubbles, yielding a sodium alginate solution. In this example, the sodium alginate solution had a mass fraction of 3.0 wt%. Based on the initial pH of the sodium alginate solution in this example, the pH was adjusted to 6.5 by adding 0.5 mol / L sodium hydroxide aqueous solution dropwise. Nifedipine was added to the sodium alginate solution in this example and dispersed using high-speed shear at 5-25 °C with a rotation speed of 150 rpm. A uniform sodium alginate suspension containing the drug was obtained by heating at 00 rpm for 15 minutes, so that the mass fraction of nifedipine in the total mass of the sodium alginate suspension containing the drug in this embodiment was 2.50 wt%. The nifedipine in this embodiment was sieved through a standard sieve with a mesh size of 100 mesh before preparing the sodium alginate suspension containing the drug. A crosslinking solution was prepared with purified water, and the calcium chloride concentration in the crosslinking solution in this embodiment was 0.25 mol / L. The volume ratio of the crosslinking solution to the sodium alginate suspension in this embodiment was controlled at 12:1. The suspension was heated at 15°C at 4... Stir at 00 rpm; add the drug-containing sodium alginate suspension of this embodiment dropwise to the crosslinking solution of this embodiment through a nozzle with an inner diameter of 0.50 mm at a dropping rate of 5.0 mL / min, with a dropping height of 5 cm; after the addition is completed, continue stirring and crosslinking at 15 °C for 2.0 h; wash the obtained microspheres twice with purified water, each time using 50 mL of purified water per 1 g of wet microspheres. The washing endpoint of the microspheres in this embodiment is characterized by conductivity, until the conductivity of the washing solution is less than 50 μS / cm, and then at 40 °C and an absolute pressure of 15 kJ / cm. Dry under Pa conditions for 12 hours until the moisture content of the microspheres is 4.0 wt%. After drying, the microspheres are sieved, and microspheres with a particle size of 350 µm are collected. In this embodiment, the particle size is the particle size obtained by sieving the dried microspheres through a standard sieve. Based on the total mass of the dried microspheres, the drug loading of nifedipine in the sustained-release microspheres of this embodiment is 10.00 wt%, thus obtaining the nifedipine-loaded calcium alginate sustained-release microspheres of this embodiment. The drug loading of the sustained-release microspheres of this embodiment is determined by high performance liquid chromatography. The drug loading of the sustained-release microspheres of this embodiment is calculated with the total mass of the dried sustained-release microspheres as the denominator.

[0050] In preparing the rapid-release granules, 105.67 mg of microcrystalline cellulose and 10.57 mg of crospovidone were mixed. In this embodiment, the mass ratio of microcrystalline cellulose to crospovidone in the rapid-release layer was 10:1. The nifedipine-nicotinamide cocrystalline nanocrystalline dispersion of this embodiment was added at a feeding rate of 10 mL / min at 20°C for wet granulation. The endpoint was reached when the moisture content of the wet granules reached 22 wt%. The moisture content of the wet granules was determined by sampling and using the loss on weight method or Karl Fischer method. After reaching the target range... Stop feeding and end granulation; the total granulation time is 15 min. Dry the obtained wet granules at 45°C for 6 h until the granule moisture content is 2.0 wt%. Then add 1.25 mg of magnesium stearate and mix to obtain 125 mg of fast-release layer granules. Based on the total mass of the fast-release layer in this embodiment, the content of hydroxypropyl methylcellulose in the fast-release layer of this embodiment is 1.50 wt%, and the content of magnesium stearate in the fast-release layer of this embodiment is 1.00 wt%.

[0051] In preparing the sustained-release layer mixture, 208.3 mg of nifedipine-loaded calcium alginate sustained-release microspheres and 162.95 mg of microcrystalline cellulose were mixed in this embodiment. The mass ratio of nifedipine-loaded calcium alginate sustained-release microspheres to microcrystalline cellulose in the sustained-release layer of this embodiment was 1:0.78. 3.75 mg of magnesium stearate was added and mixed to obtain 375 mg of sustained-release layer mixture. Based on the total mass of the sustained-release layer in this embodiment, the content of magnesium stearate in the sustained-release layer of this embodiment was 1.00 wt%.

[0052] The fast-release granules and the sustained-release granules of this embodiment are compressed into a double-layer tablet using a double-layer tableting process. In this embodiment, the mass ratio of the fast-release layer to the sustained-release layer is controlled at 1:3, the main compression pressure is 15kN, and the target tablet weight is 500mg, thus obtaining the drug of this embodiment.

[0053] The fast-release layer of this embodiment contains nifedipine, nicotinamide, hydroxypropyl methylcellulose, microcrystalline cellulose, crospovidone, and magnesium stearate. In this embodiment, nifedipine and nicotinamide exist in the form of nifedipine-nicotinamide co-crystal nanocrystals. The median particle size D50 of these co-crystal nanocrystals is 0.25 µm. The median particle size D50 of these co-crystal nanocrystals is determined by pulverizing the fast-release layer sample, adding purified water to prepare a dispersion with a solid content of 0.20 wt%, ultrasonically dispersing it at 25°C for 40 kHz, 350 W, and 10 min, and then measuring the median particle size using dynamic light scattering. The sustained-release layer of this embodiment contains nifedipine. The tablets are loaded with calcium alginate sustained-release microspheres, microcrystalline cellulose, and magnesium stearate. The sustained-release microspheres in this embodiment have a particle size of 350 µm. In the bilayer tablets of this embodiment, the rapid-release layer contains 4.17 mg of nifedipine in the nifedipine-nicotinamide co-crystal nanocrystals, and the sustained-release layer contains 20.83 mg of nifedipine in the nifedipine-loaded calcium alginate sustained-release microspheres. The mass ratio of nifedipine in the rapid-release layer to that in the sustained-release layer is 1:5. Based on the total mass of the bilayer tablets in this embodiment, the total nifedipine content in the bilayer tablets is 5.00 wt%. The hardness of the bilayer tablets in this embodiment is 85 N, and the friability is 0.6 wt%.

[0054] Features of Example 1: This embodiment employs balanced and moderate process parameters. The eutectic nanocrystal particle size is 0.25 micrometers, the sustained-release microsphere particle size is 350 micrometers, the drug loading of the microspheres is 10.00%, the rapid-release layer and the sustained-release layer are mixed in a 1:3 ratio, the total nifedipine content of the bilayer tablets is 5.00%, the drug ratio of the rapid-release to the sustained-release portion is 1:5, and the amount of hydroxypropyl methylcellulose is 1.50%. All parameters are at a moderate level, the preparation process is stable and controllable, the product quality indicators are balanced, and it is suitable for routine clinical applications. It can be used in applications that require both rapid onset of action and sustained release, achieving a good balance between rapid onset of action and sustained release, meeting the treatment needs of most patients, with good process reproducibility and moderate production costs. Example 2

[0055] This embodiment prepares a tocolytic drug that inhibits uterine contractions. The drug in this embodiment is a bilayer tablet, including a fast-release layer and a sustained-release layer.

[0056] First, a nifedipine-nicotinamide eutectic was prepared. 10.00 g of nifedipine and 3.62 g of nicotinamide were weighed, controlling the molar ratio of nifedipine to nicotinamide to be 0.98:1. 203 mL of anhydrous ethanol was added, controlling the liquid-to-solid ratio to be 15 mL / g. The mixture was stirred at 350 rpm for 20 min at 18°C ​​under light-protected conditions to obtain a mixed solution. The solution was then stirred at 600 rpm for 1.5 h at 45°C until no visible solids were observed and the solution became clear. The clear solution was then cooled to 5°C. The clear solution was then added dropwise at a rate of 15 mL / min to 3045 mL of purified water pre-cooled to 5°C as an antisolvent for crystallization. The volume ratio of purified water to the ethanol solution in this example was 15:1. During the dropwise addition, the temperature of the mixture was maintained at 5°C and stirred at 600 rpm. After the dropwise addition was completed, the mixture was further aged at 5°C for 3.0 h. h; The obtained solid was separated by filtration. In this embodiment, the filtration was carried out by vacuum filtration, and a filter membrane with a pore size of 2.0µm was selected. The solid was washed three times with purified water, with 35mL of purified water added for every 1g of solid each time. The washing endpoint was characterized by residual chloride ions until the residual chloride ions were less than 100ppm. The solid was then dried at 35℃ and 10kPa for 18h until the moisture content was 1.20wt%, thus obtaining the nifedipine-nicotinamide cocrystal of this embodiment. Based on the total mass of the cocrystal after drying, the residual ethanol in the cocrystal of this embodiment was 1800ppmw / w and the moisture content was 1.20wt%. The residual ethanol in the cocrystal of this embodiment was determined by gas chromatography, and the moisture content was determined by Karl Fischer method. The crystallization step of the nifedipine-nicotinamide cocrystal of this embodiment was carried out under light-protected conditions.

[0057] Next, a nifedipine-nicotinamide co-crystal nanocrystalline dispersion was prepared. Hydroxypropyl methylcellulose was added to purified water and stirred at 600 rpm for 90 min at 25°C until completely dissolved, yielding a stabilizer aqueous solution. In this embodiment, the mass fraction of hydroxypropyl methylcellulose in the stabilizer aqueous solution was 2.20 wt%. The hydroxypropyl methylcellulose in this embodiment was pharmaceutical grade hydroxypropyl methylcellulose, and its viscosity grade was 5 mPa·s. Based on the initial pH of the stabilizer aqueous solution in this embodiment, the pH was adjusted to 5.5 by adding 0.5 mol / L hydrochloric acid aqueous solution dropwise. The pH of this embodiment was measured at 25°C using a calibrated pH meter. The nifedipine-nicotinamide co-crystal was added to the stabilizer aqueous solution in this embodiment, making the mass fraction of the co-crystal in the mixed system 6.0 wt%. The mixture was wet-milled at 10°C for 4.5 hours. In this embodiment, zirconia grinding beads with a diameter of 0.20 mm and a filling rate of 72% were used. The milling speed was 2400 rpm, and the system temperature was maintained at 10°C through jacketed circulation cooling. When the median particle size D50 of the eutectic nanocrystals in the resulting dispersion reached 0.15 µm and the solid content of the dispersion was 6.0 wt%, the nifedipine-nicotinamide eutectic nanocrystal dispersion of this embodiment was obtained. In this embodiment, D50 is the median particle size of the volume distribution after diluting the dispersion with purified water to a solid content of 0.15 wt% and ultrasonically dispersing it at 25°C for 15 min, and then measuring it using dynamic light scattering. In this embodiment, the ultrasonic frequency was 40 kHz, the ultrasonic power was 400 W, and the ultrasonic time was 15 min. The solid content of this embodiment is the mass fraction of non-volatile solids measured after drying the dispersion sample at 105°C to constant weight.

[0058] Then, nifedipine-supported calcium alginate sustained-release microspheres were prepared. Sodium alginate was added to purified water and stirred at 600 rpm for 3.0 h at 25 °C until completely dissolved. The mixture was then allowed to stand for 1.5 h to remove bubbles, yielding a sodium alginate solution. In this example, the mass fraction of the sodium alginate solution was 2.0 wt%. Based on the initial pH of the sodium alginate solution in this example, the pH was adjusted to 6.0 by dropwise addition of 0.5 mol / L hydrochloric acid aqueous solution. Nifedipine was added to the sodium alginate solution in this example and dispersed using high-speed shear at 10 °C and a rotation speed of 18000 rpm. The concentration of nifedipine in the sodium alginate suspension was 1.50 wt% for 10 minutes, resulting in a homogeneous sodium alginate suspension containing the drug. The nifedipine in this embodiment was sieved through a standard sieve with a mesh size of 150 mesh before preparing the sodium alginate suspension. A crosslinking solution was prepared with purified water, and the calcium chloride concentration in the crosslinking solution was 0.15 mol / L. The volume ratio of the crosslinking solution to the sodium alginate suspension was controlled at 15:1. The suspension was then incubated at 10°C with a flow rate of 500 ppm. Stir at rpm; the drug-containing sodium alginate suspension of this embodiment is added dropwise to the crosslinking solution of this embodiment through a nozzle with an inner diameter of 0.30 mm at a dropping rate of 3.0 mL / min, with a dropping height of 3 cm; after the addition is completed, stir and crosslink at 10 °C for 3.0 h; the obtained microspheres are washed 3 times with purified water, each time the washing solution is 70 mL of purified water per 1 g of wet microspheres. The washing endpoint of the microspheres in this embodiment is characterized by conductivity, until the conductivity of the washing solution is less than 30 μS / cm, and then at 35 °C and an absolute pressure of 10 kJ / cm. Dry under Pa conditions for 18 hours until the moisture content of the microspheres is 2.5 wt%. After drying, the microspheres are sieved, and microspheres with a particle size of 200 µm are collected. In this embodiment, the particle size is the particle size obtained by sieving the dried microspheres through a standard sieve. Based on the total mass of the dried microspheres, the drug loading of nifedipine in the sustained-release microspheres of this embodiment is 5.50 wt%, thus obtaining the nifedipine-loaded calcium alginate sustained-release microspheres of this embodiment. The drug loading of the sustained-release microspheres of this embodiment is determined by high performance liquid chromatography. The drug loading of the sustained-release microspheres of this embodiment is calculated with the total mass of the dried sustained-release microspheres as the denominator.

[0059] In preparing the rapid-release granules, 118.25 mg of microcrystalline cellulose and 16.89 mg of crospovidone were mixed. In this embodiment, the mass ratio of microcrystalline cellulose to crospovidone in the rapid-release layer was 7:1. The nifedipine-nicotinamide cocrystalline nanocrystalline dispersion of this embodiment was added at a feeding rate of 15 mL / min at 15°C for wet granulation. The endpoint was reached when the moisture content of the wet granules reached 26 wt%. The moisture content of the wet granules was determined by sampling and using the loss on weight method or Karl Fischer method. After reaching the target range... Stop feeding and end granulation; the total granulation time is 10 min. Dry the obtained wet granules at 50°C for 4 h until the granule moisture content is 1.5 wt%. Then add 1.86 mg of magnesium stearate and mix to obtain 155 mg of fast-release layer granules. Based on the total mass of the fast-release layer in this embodiment, the content of hydroxypropyl methylcellulose in the fast-release layer of this embodiment is 2.20 wt%, and based on the total mass of the fast-release layer of this embodiment, the content of magnesium stearate in the fast-release layer of this embodiment is 1.20 wt%.

[0060] In preparing the sustained-release layer mixture, 254.5 mg of nifedipine-loaded calcium alginate sustained-release microspheres and 87.15 mg of microcrystalline cellulose were mixed. The mass ratio of nifedipine-loaded calcium alginate sustained-release microspheres to microcrystalline cellulose in the sustained-release layer of this embodiment was 1:0.34. 3.35 mg of magnesium stearate was added and mixed to obtain 345 mg of sustained-release layer mixture. Based on the total mass of the sustained-release layer in this embodiment, the content of magnesium stearate in the sustained-release layer of this embodiment was 0.97 wt%.

[0061] The fast-release granules and the sustained-release granules of this embodiment are compressed into a double-layer tablet using a double-layer tableting process. In this embodiment, the mass ratio of the fast-release layer to the sustained-release layer is controlled at 1:2.23, the main compression pressure is 10kN, and the target tablet weight is 500mg, thus obtaining the drug of this embodiment.

[0062] The fast-release layer of this embodiment contains nifedipine, nicotinamide, hydroxypropyl methylcellulose, microcrystalline cellulose, crospovidone, and magnesium stearate. In this embodiment, nifedipine and nicotinamide exist in the form of nifedipine-nicotinamide co-crystal nanocrystals. The median particle size D50 of these co-crystal nanocrystals is 0.15 µm. The median particle size D50 of these co-crystal nanocrystals is determined by pulverizing the fast-release layer sample, adding purified water to prepare a dispersion with a solid content of 0.15 wt%, ultrasonically dispersing it at 25°C with an ultrasonic frequency of 40 kHz, an ultrasonic power of 400 W, and an ultrasonic time of 15 min, and then measuring the median particle size using dynamic light scattering. The sustained-release layer of this embodiment contains nifedipine-loaded calcium alginate sustained-release microspheres. Microcrystalline cellulose and magnesium stearate; the sustained-release microspheres of this embodiment have a particle size of 200µm; in the bilayer tablet of this embodiment, the nifedipine-nicotinamide co-crystal nanocrystals contained in the rapid-release layer contain 8.00mg of nifedipine, and the nifedipine-loaded calcium alginate sustained-release microspheres contained in the sustained-release layer contain 14.00mg of nifedipine. The mass ratio of nifedipine in the rapid-release layer to nifedipine in the sustained-release layer of this embodiment is 1:1.75; based on the total mass of the bilayer tablet of this embodiment, the total content of nifedipine in the bilayer tablet of this embodiment is 4.40wt%; the hardness of the bilayer tablet of this embodiment is 65N, the friability is 0.8wt%, and the interlayer peeling force is used as the quality control index for interlayer bonding.

[0063] Features of Example 2: This embodiment employs process parameters designed to enhance rapid release performance. The eutectic nanocrystals have a particle size of 0.15 micrometers, which is relatively small, and the sustained-release microspheres have a particle size of 200 micrometers, which is also relatively small. The drug loading of the microspheres is 5.50%, which is at a low to medium level. The ratio of the rapid-release layer to the sustained-release layer is 1:2.23, which relatively increases the proportion of the rapid-release portion. The total nifedipine content in the bilayer tablets is 4.40%, and the drug ratio of the rapid-release to the sustained-release portion is 1:1.75, which increases the initial release amount. The amount of hydroxypropyl methylcellulose is 2.20%, which is relatively high, and the viscosity grade is 5 mPa·s, which is relatively low, which is conducive to rapid drug dissolution. The magnesium stearate content is 1.20%, which is moderate. Filtration separation and a long aging time are used to ensure the quality of the eutectic. This design is suitable for application scenarios that require rapid onset of action while also ensuring subsequent sustained release. It can provide a certain release maintenance capability while maintaining the biphase release characteristics. Example 3

[0064] This embodiment prepares a tocolytic drug that inhibits uterine contractions. The drug in this embodiment is a bilayer tablet, including a fast-release layer and a sustained-release layer.

[0065] First, a nifedipine-nicotinamide cocrystal was prepared. 10.00 g of nifedipine and 3.44 g of nicotinamide were weighed, and the molar ratio of nifedipine to nicotinamide was controlled at 1.03:1. 338 mL of anhydrous ethanol was added, and the liquid-to-solid ratio was controlled at 25 mL / g. The mixture was stirred at 250 rpm for 10 min at 28°C under light-protected conditions to obtain a mixed solution. The solution was then stirred at 400 rpm for 0.8 h at 57°C until no visible solid was observed and the solution became clear. The clear solution was then cooled to 18°C. The clear solution was then added dropwise at a rate of 3 mL / min to 2028 mL of purified water pre-cooled to 18°C ​​as an antisolvent for crystallization. The volume ratio of purified water to the ethanol solution in this example was 6:1. During the dropwise addition, the temperature of the mixed system was maintained at 18°C ​​and stirred at 400 rpm. After the dropwise addition was completed, the mixture was stirred at 18°C. The mixture was stirred and aged for 1.0 h. The resulting solid was then centrifuged at 4500 g for 10 min at 20 °C. It was washed once with purified water at a rate of 15 mL of purified water per 1 g of solid. The washing endpoint was characterized by residual chloride ions until the residual chloride ions were less than 200 ppm. The solid was then dried at 48 °C and 25 kPa for 8 h until the moisture content was 4.20 wt%, yielding the nifedipine-nicotinamide cocrystal of this embodiment. Based on the total mass of the dried cocrystal, the residual ethanol in the cocrystal of this embodiment was 4200 ppm w / w and the moisture content was 4.20 wt%. The residual ethanol in the cocrystal of this embodiment was determined by gas chromatography, and the moisture content was determined by Karl Fischer method. The crystallization step of the nifedipine-nicotinamide cocrystal of this embodiment was carried out under light-protected conditions.

[0066] Next, a nifedipine-nicotinamide co-crystal nanocrystalline dispersion was prepared. Hydroxypropyl methylcellulose was added to purified water and stirred at 400 rpm for 45 min at 25°C until completely dissolved, yielding a stabilizer aqueous solution. In this embodiment, the mass fraction of hydroxypropyl methylcellulose in the stabilizer aqueous solution was 0.50 wt%. The hydroxypropyl methylcellulose in this embodiment was pharmaceutical grade, and its viscosity was 50 mPa·s. Based on the initial pH of the stabilizer aqueous solution in this embodiment, the pH was adjusted to 7.5 by adding 0.5 mol / L sodium hydroxide aqueous solution dropwise. The pH of this embodiment was measured at 25°C using a calibrated pH meter. The nifedipine-nicotinamide co-crystal was added to the stabilizer aqueous solution in this embodiment, so that the mass fraction of the co-crystal in the mixed system was 16.0 wt%. The dispersion was wet-milled at 20°C for 1.5 hours using a bead mill. In this embodiment, zirconia grinding beads with a diameter of 0.50 mm and a filling rate of 58% were used. The milling speed was 1200 rpm, and the system temperature was maintained at 20°C by jacketed circulation cooling. When the median particle size D50 of the eutectic nanocrystals in the dispersion reached 0.35 µm and the solid content of the dispersion was 16.0 wt%, the nifedipine-nicotinamide eutectic nanocrystal dispersion of this embodiment was obtained. In this embodiment, D50 is the median particle size of the volume distribution after diluting the dispersion with purified water to a solid content of 0.40 wt% and ultrasonically dispersing it at 25°C for 8 min, and then measuring it using dynamic light scattering. In this embodiment, the ultrasonic frequency was 40 kHz, the ultrasonic power was 300 W, and the ultrasonic time was 8 min. The solid content of this embodiment is the mass fraction of non-volatile solids measured after drying the dispersion sample at 105°C to constant weight.

[0067] Then, nifedipine-supported calcium alginate sustained-release microspheres were prepared. Sodium alginate was added to purified water and stirred at 400 rpm for 1.5 h at 25 °C until completely dissolved. The mixture was then allowed to stand for 0.5 h to remove bubbles, yielding a sodium alginate solution. In this example, the sodium alginate solution had a mass fraction of 4.5 wt%. Based on the initial pH of the sodium alginate solution in this example, the pH was adjusted to 7.2 by adding 0.5 mol / L sodium hydroxide aqueous solution dropwise. Nifedipine was added to the sodium alginate solution in this example and dispersed using high-speed shear at 20 °C and a rotation speed of 1200 rpm. A uniform sodium alginate suspension containing the drug was obtained by heating at 0 rpm for 25 minutes, resulting in a nifedipine mass fraction of 4.20 wt% in the total mass of the sodium alginate suspension. The nifedipine in this embodiment was sieved through a standard sieve with a mesh size of 80 mesh before preparing the sodium alginate suspension. A crosslinking solution was prepared with purified water, and the calcium chloride concentration in the crosslinking solution in this embodiment was 0.40 mol / L. The volume ratio of the crosslinking solution to the sodium alginate suspension in this embodiment was controlled at 8:1. The suspension was heated at 25°C at 30 rpm for 25 minutes. Stir at 0 rpm; the drug-containing sodium alginate suspension of this embodiment is added dropwise to the crosslinking solution of this embodiment through a nozzle with an inner diameter of 0.80 mm at a dropping rate of 8.5 mL / min, with a dropping height of 8 cm; after the addition is completed, stir and crosslink at 25 °C for 1.0 h; the obtained microspheres are washed once with purified water, with the washing solution being 20 mL of purified water per 1 g of wet microspheres. The washing endpoint of the microspheres in this embodiment is characterized by conductivity, until the conductivity of the washing solution is less than 100 μS / cm, and then at 48 °C and an absolute pressure of 25 kJ / cm. Dry under Pa conditions for 8 hours until the moisture content of the microspheres is 6.5 wt%. After drying, the microspheres are sieved, and microspheres with a particle size of 500 µm are collected. In this embodiment, the particle size is the particle size obtained by sieving the dried microspheres through a standard sieve. Based on the total mass of the dried microspheres, the drug loading of nifedipine in the sustained-release microspheres of this embodiment is 17.00 wt%, thus obtaining the nifedipine-loaded calcium alginate sustained-release microspheres of this embodiment. The drug loading of the sustained-release microspheres of this embodiment is determined by high performance liquid chromatography. The drug loading of the sustained-release microspheres of this embodiment is calculated with the total mass of the dried sustained-release microspheres as the denominator.

[0068] In preparing the rapid-release granules, 75.48 mg of microcrystalline cellulose and 5.04 mg of crospovidone were mixed. In this embodiment, the mass ratio of microcrystalline cellulose to crospovidone in the rapid-release layer was 15:1. The nifedipine-nicotinamide cocrystalline nanocrystalline dispersion of this embodiment was added at a feeding rate of 5 mL / min at 25°C for wet granulation. The endpoint was reached when the moisture content of the wet granules reached 18 wt%. The moisture content of the wet granules was determined by sampling and using the loss on weight method or Karl Fischer method. The granulation was stopped after the target range was reached. The granulation process was completed after feeding and the total granulation time was 22 min. The resulting wet granules were dried at 38°C for 10 h until the granule moisture content was 2.8 wt%. Then, 0.48 mg of magnesium stearate was added and mixed to obtain 100 mg of fast-release layer granules. Based on the total mass of the fast-release layer in this embodiment, the content of hydroxypropyl methylcellulose in the fast-release layer of this embodiment was 0.50 wt%, and the content of magnesium stearate in the fast-release layer of this embodiment was 0.48 wt%.

[0069] In preparing the sustained-release layer mixture, 235.3 mg of nifedipine-loaded calcium alginate sustained-release microspheres and 162.7 mg of microcrystalline cellulose were mixed. The mass ratio of nifedipine-loaded calcium alginate sustained-release microspheres to microcrystalline cellulose in the sustained-release layer of this embodiment was 1:0.69. 2.00 mg of magnesium stearate was added and mixed to obtain 400 mg of sustained-release layer mixture. Based on the total mass of the sustained-release layer in this embodiment, the content of magnesium stearate in the sustained-release layer of this embodiment was 0.50 wt%.

[0070] The fast-release granules and the sustained-release granules of this embodiment are compressed into a double-layer tablet using a double-layer tableting process. In this embodiment, the mass ratio of the fast-release layer to the sustained-release layer is controlled at 1:4, the main compression pressure is 22kN, and the target tablet weight is 500mg, thus obtaining the drug of this embodiment.

[0071] The fast-release layer of this embodiment contains nifedipine, nicotinamide, hydroxypropyl methylcellulose, microcrystalline cellulose, crospovidone, and magnesium stearate. In this embodiment, nifedipine and nicotinamide exist in the form of nifedipine-nicotinamide co-crystal nanocrystals. The median particle size D50 of these co-crystal nanocrystals is 0.35 µm. The median particle size D50 of these co-crystal nanocrystals is determined by pulverizing the fast-release layer sample, adding purified water to prepare a dispersion with a solid content of 0.40 wt%, ultrasonically dispersing it at 25°C for 40 kHz, 300 W, and 8 min, and then measuring the median particle size using dynamic light scattering. The sustained-release layer of this embodiment contains nifedipine-loaded calcium alginate sustained-release microspheres. Microcrystalline cellulose and magnesium stearate; the particle size of the sustained-release microspheres in this embodiment is 500µm; in the bilayer tablet of this embodiment, the nifedipine-nicotinamide co-crystal nanocrystals contained in the rapid-release layer contain 4.00mg of nifedipine, and the nifedipine-loaded calcium alginate sustained-release microspheres contained in the sustained-release layer contain 36.00mg of nifedipine. The mass ratio of nifedipine in the rapid-release layer to the sustained-release layer in this embodiment is 1:9; based on the total mass of the bilayer tablet of this embodiment, the total content of nifedipine in the bilayer tablet of this embodiment is 8.00wt%; the hardness of the bilayer tablet of this embodiment is 120N, the friability is 0.4wt%, and the interlayer peeling force is used as the quality control index for interlayer bonding.

[0072] Features of Example 3: This embodiment employs process parameters designed to enhance long-acting sustained-release performance. The eutectic nanocrystals have a particle size of 0.35 micrometers, which is relatively large. The sustained-release microspheres have a particle size of 500 micrometers, which is relatively large. The drug loading of the microspheres is 17.00%, which is also relatively high. The ratio of the rapid-release layer to the sustained-release layer is 1:4, ensuring that the sustained-release portion dominates. The total nifedipine content in the bilayer tablets is 8.00%, which is relatively high. The drug ratio of the rapid-release to the sustained-release portion is 1:9, which enhances the sustained-release capability. The amount of hydroxypropyl methylcellulose is 0.50%, which is relatively low, and the viscosity grade is 50 mPa·s, which is relatively high. The magnesium stearate content is relatively low, and the sodium alginate concentration is 4.5%, which is relatively high and has a strong degree of cross-linking. These factors are conducive to achieving long-acting sustained release. This approach is suitable for stable-phase tocolytic therapy scenarios that require long-term maintenance of uterine contraction inhibition. It is also suitable for application scenarios that require long-term release maintenance. It can maintain sustained release characteristics within a long test time window and can maintain sustained release for a long period of time, thereby reducing the frequency of administration and reducing the patient's medication burden. At the same time, the high total drug amount ensures sufficient therapeutic exposure to meet the needs of long-term tocolytic therapy. Example 4

[0073] This embodiment prepares a tocolytic drug that inhibits uterine contractions. The drug in this embodiment is a bilayer tablet, including a fast-release layer and a sustained-release layer.

[0074] First, a nifedipine-nicotinamide eutectic was prepared. 10.00 g of nifedipine and 3.71 g of nicotinamide were weighed, controlling the molar ratio of nifedipine to nicotinamide to be 0.96:1. 68 mL of anhydrous ethanol was added, controlling the liquid-to-solid ratio to be 5 mL / g. The mixture was stirred at 580 rpm for 28 min at 16°C under light-protected conditions to obtain a mixed solution. The solution was then stirred at 750 rpm for 1.8 h at 42°C until no visible solids were observed and the solution became clear. The clear solution was then cooled to 3°C. The clear solution was then added dropwise at 18 mL / min to 1292 mL of purified water pre-cooled to 3°C as an antisolvent for crystallization. The volume ratio of purified water to the ethanol solution in this example was 19:1. During the dropwise addition, the temperature of the mixture was maintained at 3°C ​​and stirred at 750 rpm. After the dropwise addition was completed, the mixture was further aged at 3°C ​​for 3.5 days. h; The obtained solid was separated by filtration. In this embodiment, the filtration was carried out by vacuum filtration, and a filter membrane with a pore size of 0.22µm was selected. It was washed three times with purified water, with 45mL of purified water added for every 1g of solid each time. The washing endpoint was characterized by residual chloride ions until the residual chloride ions were less than 50ppm. It was then dried at 33℃ and 8kPa absolute pressure for 20h until the moisture content was 0.80wt%, thus obtaining the nifedipine-nicotinamide cocrystal of this embodiment. Based on the total mass of the cocrystal after drying, the residual ethanol in the cocrystal of this embodiment was 800ppmw / w and the moisture content was 0.80wt%. The residual ethanol in the cocrystal of this embodiment was determined by gas chromatography, and the moisture content was determined by Karl Fischer method. The crystallization step of the nifedipine-nicotinamide cocrystal of this embodiment was carried out under light-protected conditions.

[0075] Next, a nifedipine-nicotinamide co-crystal nanocrystalline dispersion was prepared. Hydroxypropyl methylcellulose was added to purified water and stirred at 700 rpm for 100 min at 25°C until completely dissolved, yielding a stabilizer aqueous solution. In this embodiment, the mass fraction of hydroxypropyl methylcellulose in the stabilizer aqueous solution was 2.75 wt%. The hydroxypropyl methylcellulose in this embodiment was pharmaceutical grade, and its viscosity was 8 mPa·s. Based on the initial pH of the stabilizer aqueous solution, the pH was adjusted to 5.2 by adding 0.2 mol / L hydrochloric acid aqueous solution dropwise. The pH of this embodiment was measured at 25°C using a calibrated pH meter. The nifedipine-nicotinamide co-crystal was added to the stabilizer aqueous solution, making the mass fraction of the co-crystal in the mixed system 3.0 wt%. The mixture was wet-milled at 8°C for 5.5 hours. In this embodiment, zirconia grinding beads with a diameter of 0.15 mm and a filling rate of 76% were used. The milling speed was 2750 rpm, and the system temperature was maintained at 8°C through jacketed cooling. When the median particle size D50 of the eutectic nanocrystals in the dispersion reached 0.12 µm and the solid content of the dispersion was 3.0 wt%, the nifedipine-nicotinamide eutectic nanocrystal dispersion of this embodiment was obtained. In this embodiment, D50 is the median particle size of the volume distribution after diluting the dispersion with purified water to a solid content of 0.10 wt% and ultrasonically dispersing it at 25°C for 18 min, measured by dynamic light scattering. In this embodiment, the ultrasonic frequency was 40 kHz, the ultrasonic power was 450 W, and the ultrasonic time was 18 min. The solid content of this embodiment is the mass fraction of non-volatile solids measured after drying the dispersion sample at 105°C to constant weight.

[0076] Then, nifedipine-supported calcium alginate sustained-release microspheres were prepared. Sodium alginate was added to purified water and stirred at 700 rpm for 3.5 h at 25 °C until completely dissolved. The mixture was then allowed to stand for 1.8 h to remove bubbles, yielding a sodium alginate solution. In this example, the mass fraction of the sodium alginate solution was 1.5 wt%. Based on the initial pH of the sodium alginate solution in this example, the pH was adjusted to 5.8 by dropwise addition of 0.2 mol / L hydrochloric acid aqueous solution. Nifedipine was added to the sodium alginate solution in this example and dispersed using high-speed shear at 8 °C and a rotation speed of 19000 rpm. The concentration of nifedipine in the sodium alginate suspension was 0.50 wt% for 8 minutes to obtain a uniform sodium alginate suspension containing the drug. The nifedipine in this embodiment was sieved through a standard sieve with a mesh size of 180 mesh before preparing the sodium alginate suspension. A crosslinking solution was prepared with purified water, and the calcium chloride concentration in the crosslinking solution was 0.08 mol / L. The volume ratio of the crosslinking solution to the sodium alginate suspension was controlled at 18:1. The suspension was then incubated at 8°C with a temperature of 550°C. Stir at rpm; the drug-containing sodium alginate suspension of this embodiment is added dropwise to the crosslinking solution of this embodiment through a nozzle with an inner diameter of 0.20 mm at a dropping rate of 1.5 mL / min, with a dropping height of 2 cm; after the addition is completed, stir and crosslink at 8°C for 3.5 h; the obtained microspheres are washed 3 times with purified water, each time the washing solution is 85 mL of purified water per 1 g of wet microspheres. The washing endpoint of the microspheres in this embodiment is characterized by conductivity, until the conductivity of the washing solution is less than 25 μS / cm, and the washing is carried out at 33°C and an absolute pressure of 8 kPa. Dry under condition a for 20 hours until the moisture content of the microspheres is 1.5 wt%. After drying, the microspheres are sieved, and microspheres with a particle size of 550 µm are collected. In this embodiment, the particle size is the particle size obtained by sieving the dried microspheres through a standard sieve. Based on the total mass of the dried microspheres, the drug loading of nifedipine in the sustained-release microspheres of this embodiment is 2.50 wt%, thus obtaining the nifedipine-loaded calcium alginate sustained-release microspheres of this embodiment. The drug loading of the sustained-release microspheres of this embodiment is determined by high performance liquid chromatography. The drug loading of the sustained-release microspheres of this embodiment is calculated with the total mass of the dried sustained-release microspheres as the denominator.

[0077] In preparing the rapid-release granules, 131.82 mg of microcrystalline cellulose and 7.56 mg of crospovidone were mixed. In this embodiment, the mass ratio of microcrystalline cellulose to crospovidone in the rapid-release layer was 17.5:1. The nifedipine-nicotinamide cocrystalline nanocrystalline dispersion of this embodiment was added at a feeding rate of 18 mL / min at 12°C for wet granulation. The endpoint was reached when the moisture content of the wet granules reached 28 wt%. The moisture content of the wet granules was determined by sampling and using the loss on weight method or Karl Fischer method. After reaching the target range... Stop feeding and end granulation; the total granulation time is 8 minutes. Dry the obtained wet granules at 55°C for 2.5 hours until the granule moisture content is 1.0 wt%. Then add 3.12 mg of magnesium stearate and mix to obtain 165 mg of fast-release layer granules. Based on the total mass of the fast-release layer in this embodiment, the content of hydroxypropyl methylcellulose in the fast-release layer of this embodiment is 2.75 wt%, and the content of magnesium stearate in the fast-release layer of this embodiment is 1.89 wt%.

[0078] In preparing the sustained-release layer mixture, 280.0 mg of nifedipine-loaded calcium alginate sustained-release microspheres and 48.3 mg of microcrystalline cellulose were mixed in this embodiment. The mass ratio of nifedipine-loaded calcium alginate sustained-release microspheres to microcrystalline cellulose in the sustained-release layer of this embodiment was 1:0.17. 6.70 mg of magnesium stearate was added and mixed to obtain 335 mg of sustained-release layer mixture. Based on the total mass of the sustained-release layer in this embodiment, the content of magnesium stearate in the sustained-release layer of this embodiment was 2.00 wt%.

[0079] The fast-release granules and the sustained-release granules of this embodiment are compressed into a double-layer tablet using a double-layer tableting process. In this embodiment, the mass ratio of the fast-release layer to the sustained-release layer is controlled at 1:2.03, the main compression pressure is 28kN, and the target tablet weight is 500mg, thus obtaining the drug of this embodiment.

[0080] The fast-release layer of this embodiment contains nifedipine, nicotinamide, hydroxypropyl methylcellulose, microcrystalline cellulose, crospovidone, and magnesium stearate. In this embodiment, nifedipine and nicotinamide exist in the form of nifedipine-nicotinamide co-crystal nanocrystals. The median particle size D50 of these co-crystal nanocrystals is 0.12 µm. The median particle size D50 of these co-crystal nanocrystals is determined by pulverizing the fast-release layer sample, adding purified water to prepare a dispersion with a solid content of 0.10 wt%, ultrasonically dispersing it at 25°C for 40 kHz, 450 W, and 18 min, and then measuring the median particle size using dynamic light scattering. The sustained-release layer of this embodiment contains nifedipine-supported calcium alginate sustained-release microcrystals. The tablets contain pellets, microcrystalline cellulose, and magnesium stearate. The sustained-release pellets in this embodiment have a particle size of 550 µm. In the bilayer tablet of this embodiment, the rapid-release layer contains 3.50 mg of nifedipine in the nifedipine-nicotinamide co-crystal nanocrystals, and the sustained-release layer contains 7.00 mg of nifedipine in the nifedipine-loaded calcium alginate sustained-release pellets. The mass ratio of nifedipine in the rapid-release layer to that in the sustained-release layer is 1:2. Based on the total mass of the bilayer tablets in this embodiment, the total nifedipine content in the bilayer tablets is 2.10 wt%. The hardness of the bilayer tablets in this embodiment is 135 N, the friability is 0.3 wt%, and interlayer peel strength is used as the quality control indicator for interlayer bonding.

[0081] Features of Example 4: This embodiment employs a design scheme with several parameters close to the edge of their respective ranges. The eutectic nanocrystal particle size of 0.12 μm is close to the minimum; the liquid-to-solid ratio of 5 mL / g is the minimum; the antisolvent volume ratio of 19:1 is close to the maximum; the dropping rate of 18 mL / min is close to the maximum; the grinding speed of 2750 rpm is relatively high; the sustained-release microsphere particle size of 550 μm is close to the maximum; the drug loading of the microspheres of 2.50% is close to the minimum; the sodium alginate concentration of 1.5% is relatively low; the nifedipine concentration in the drug-containing suspension is close to the minimum; the calcium chloride concentration in the crosslinking solution of 0.08 mol / L is close to the minimum; the crosslinking solution volume ratio of 18:1 is close to the maximum; the high-shear speed of 19000 rpm is close to the maximum; the nozzle inner diameter of 0.20 mm is close to the minimum; and the hydroxypropyl methylcellulose content in the rapid-release layer is 2.75%. The magnesium stearate content in the rapid-release layer is 1.89%, close to the maximum value, while the magnesium stearate content in the sustained-release layer is 2.00%, also close to the maximum value. The main compression pressure is 28 kN, close to the maximum value. The total nifedipine content in the double-layer tablets is 2.10%, which is relatively low. The combination of multiple edge parameters fully demonstrates the feasibility and flexibility of the process range, making it suitable for applications with high dosage control requirements or where a reduction in total dosage is desired. It can maintain good in vitro release performance even under low total content conditions. The use of extremely small nanocrystal particle size and high stabilizer dosage can ensure sufficient dissolution rate and bioavailability under low dosage conditions. At the same time, the larger microparticle size and lower drug loading are conducive to achieving a smoother sustained-release curve and reducing blood drug concentration fluctuations. The combination of process parameters in this embodiment fully expands the formulation design space while ensuring product quality.

[0082] Comparative Example 1: Basically the same as Example 1, except that the median particle size D50 of the nifedipine-nicotinamide co-crystal nanocrystals in the fast-release layer is 0.05µm, and the amounts of other components and preparation conditions remain unchanged.

[0083] Comparative Example 2: It is basically the same as Example 1, except that the median particle size D50 of the nifedipine-nicotinamide co-crystal nanocrystals in the fast-release layer is 0.50µm, and the amount of other components and preparation conditions remain unchanged.

[0084] Comparative Example 3: It is basically the same as Example 1, except that the particle size of the sustained-release microspheres is 80µm, while the amount of other components and preparation conditions remain unchanged.

[0085] Comparative Example 4: It is basically the same as Example 1, except that the particle size of the sustained-release microspheres is 650µm, while the amount of other components and preparation conditions remain unchanged.

[0086] Comparative Example 5: It is basically the same as Example 1, except that the drug loading of nifedipine in the sustained-release microcapsules is 0.80 wt%, while the dosage of other components and preparation conditions remain unchanged.

[0087] Comparative Example 6: It is basically the same as Example 1, except that the drug loading of nifedipine in the sustained-release microcapsules is 22.00 wt%, while the dosage of other components and preparation conditions remain unchanged.

[0088] Comparative Example 7: It is basically the same as Example 1, except that the mass ratio of the fast-release layer to the sustained-release layer is 1:0.8, and the amounts of other components and preparation conditions remain unchanged.

[0089] Comparative Example 8: It is basically the same as Example 1, except that the eutectic nanocrystal technology is not used in the fast-release layer. Instead, nifedipine active pharmaceutical ingredient (average particle size 5µm) is physically mixed with nicotinamide and added to the fast-release layer. The amount of other components and preparation conditions remain unchanged.

[0090] Performance testing: Test Subject: In vitro dissolution behavior of bilayer tablets. Test Objective: To evaluate the synergistic release characteristics of the rapid-release and sustained-release layers, and to verify the design goals of rapid onset and long-lasting effect. Test Principle: A dissolution assay was used to simulate the pH environment of the gastrointestinal tract. The drug release kinetics were characterized by measuring the cumulative release percentage of nifedipine at different time points. Experimental Method: The paddle method (Chinese Pharmacopoeia, Part IV, General Chapter 0931) was used. The dissolution media were pH 1.2 hydrochloric acid solution (0-2h) and pH 6.8 phosphate buffer (2-12h), with a media volume of 900mL, a temperature of 37±0.5℃, and a rotation speed of 75rpm. Samples of 5mL were taken at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours, and an equal volume of fresh media was added. The concentration of nifedipine was determined by high-performance liquid chromatography (HPLC), and the cumulative release percentage was calculated. Key Parameters: pH of the dissolution media (1.2 and 6.8), temperature 37℃, rotation speed 75rpm, and sampling time points (0.5-12h). Data processing: Plot dissolution curves with time on the x-axis and cumulative release percentage on the y-axis, and calculate the 2-hour release rate (rapid-release layer index) and the 12-hour cumulative release rate (overall index), n≥6.

[0091] Test Subject: Particle size distribution of nifedipine-nicotinamide eutectic nanocrystals. Test Objective: To verify whether the particle size of the eutectic nanocrystals in the rapid-release layer conforms to the range of 0.10-0.40 µm, ensuring rapid dissolution and high bioavailability. Test Principle: Based on the principle of dynamic light scattering (DLS), the Brownian motion of nanoparticles in a liquid causes fluctuations in the intensity of scattered light. The particle size distribution is calculated using an autocorrelation function. Experimental Method: The rapid-release layer sample was pulverized and added to purified water to prepare a dispersion with a solid content of 0.20 wt%. The dispersion was ultrasonically dispersed at 25 °C (frequency 40 kHz, power 350 W, time 10 min). The scattering angle was measured using a Malvern Zetasizer NanoZS dynamic light scattering instrument at 173°. Each sample was measured in triplicate, and the median particle size distribution (D50, D10, D90) and polydispersity index (PDI) were recorded. Key parameters: Test temperature 25℃, dispersion solid content 0.20wt%, ultrasonic conditions (40kHz, 350W, 10min), scattering angle 173°. Data processing: The average value ± standard deviation of three measurements was taken to calculate the particle size distribution width (Span=(D90-D10) / D50).

[0092] Test Subjects: Drug loading and encapsulation efficiency of sustained-release microcapsules. Test Objective: To accurately determine the actual drug loading of nifedipine in sustained-release microcapsules, verify whether it conforms to the range of 1.00-20.00 wt%, and evaluate the controllability of the preparation process. Test Principle: High-performance liquid chromatography (HPLC) was used to directly determine the nifedipine content in the microcapsules, and the drug loading was calculated using the total mass of the dried microcapsules as the denominator. Experimental Method: Approximately 100 mg of dried sustained-release microcapsules were accurately weighed, added to 50 mL of methanol, and ultrasonically extracted for 30 minutes to completely dissolve the nifedipine. The extract was filtered through a 0.45 µm filter membrane and determined by HPLC (C18 column, mobile phase methanol-water 70:30, detection wavelength 235 nm, flow rate 1.0 mL / min, column temperature 30 °C). Quantification was performed using the external standard method. Drug loading (wt%) = (nifedipine mass / total mass of microcapsules) × 100%; Encapsulation efficiency (%) = (actual drug loading / theoretical drug loading) × 100%. Key parameters: extraction solvent methanol, ultrasonic time 30 min, HPLC conditions (C18 column, methanol-water 70:30, 235 nm, 1.0 mL / min). Data processing: Six samples were measured in parallel, and the mean ± standard deviation and RSD were calculated, n=6.

[0093] Test Subject: Hardness and friability of bilayer tablets. Test Purpose: To evaluate the mechanical strength and interlayer bonding of tablets, ensuring they do not break or delaminate during transportation and storage, and guaranteeing drug quality stability. Test Principle: Hardness reflects the tablet's ability to resist radial pressure, while friability reflects the tablet's ability to resist abrasion and impact. Experimental methods: Hardness was measured using a YD-3 tablet hardness tester. Ten tablets were randomly selected, and the maximum pressure (N) borne by each tablet was measured, and the average value was taken. Friability was measured using a CS-2 friability tester. Twenty tablets (W0) with surface powder removed were accurately weighed, placed in the friability tester, and rotated at 25 rpm for 4 minutes. After removing fragments and powder, the tablets were weighed (W1), and the friability was calculated as [(W0-W1) / W0]×100%. Interlayer peel force was measured using a TMS-Pro texture analyzer with a probe diameter of 5 mm. Pressure was applied perpendicularly to the interlayer interface of the tablet at a speed of 0.5 mm / s, and the maximum force value during interlayer separation was recorded. Key parameters: Hardness test n=10, friability test rotation speed 25 rpm time 4 min, peel force test speed 0.5 mm / s. Data processing: Hardness was calculated as average ± standard deviation, friability was calculated as a percentage, and peel force was calculated as average ± standard deviation.

[0094] Test Subject: Identification and purity of eutectic nanocrystals. Test Objective: To confirm the formation of nifedipine-nicotinamide eutectic crystals using X-ray powder diffraction (XRPD), distinguishing it from the physical mixture of nifedipine active pharmaceutical ingredient (API) and nicotinamide, and verifying the effectiveness of the eutectic technique. Test Principle: Different crystal forms have characteristic X-ray diffraction peak positions and intensities; eutectic formation produces new diffraction peaks distinct from the API. Experimental Method: A suitable amount of the fast-release layer sample was finely ground and measured using a Bruker D8 Advance X-ray diffractometer with a CuKα radiation source (λ=1.5418Å), tube voltage 40kV, tube current 40mA, scanning range 5-40° (2θ), step size 0.02°, scanning speed 5° / min, and room temperature. The XRPD spectra of nifedipine API, nicotinamide, the physical mixture, and the eutectic nanocrystals were compared to analyze the changes in characteristic peak positions and relative intensities. Key parameters: CuKα radiation, 40kV / 40mA, scan range 5-40°, step size 0.02°, speed 5° / min. Data processing: Diffraction peaks were analyzed using Jade 6.0 software and compared with PDF standard cards to calculate eutectic purity (based on characteristic peak intensity ratio).

[0095] Test Subject: Morphology and particle size distribution uniformity of sustained-release microspheres. Test Objective: To verify the sphericity and particle size distribution of calcium alginate sustained-release microspheres, ensuring they conform to the range of 100-600µm, and to assess batch-to-batch consistency. Test Principle: Particle size distribution is determined using laser diffraction. Samples are dispersed using wet or dry methods, and volume distribution is calculated using Mie scattering theory. Experimental Methods: A Malvern Mastersizer 3000 laser particle size analyzer was used for dry dispersion (to avoid swelling of microparticles upon contact with water). The dispersion pressure was 2.0 bar, and the opacity was 10-20%. Three measurements were taken, and the average value was recorded. D10, D50, D90, and Span values ​​were recorded. A suitable amount of microparticles were also observed under a scanning electron microscope (SEM, accelerating voltage 5 kV, magnification 100× and 500×) to evaluate sphericity and surface morphology. Particle size distribution was verified using a standard sieve method (100, 200, 300, 400, 500, and 600 µm sieves). The mass of microparticles in each size range was weighed, and the mass distribution was calculated. Key parameters: dispersion pressure 2.0 bar, opacity 10-20%, SEM accelerating voltage 5 kV. Data Processing: The mean ± standard deviation of D50 and the Span value were calculated, and the mass percentage of each particle size range was statistically analyzed.

[0096] Figure 1 XRPD diffraction patterns were overlaid to confirm the eutectic crystal form. The samples were the fast-release layer of Example 1 and the fast-release layer of Comparative Example 8, and the characterization method was powder X-ray diffraction. The fixed parameters were the ratio of nifedipine to nicotinamide, the composition of the fast-release layer formulation, and the process. Comparative Example 8 was a physical mixture of nifedipine and nicotinamide, while Example 1 was a eutectic nanocrystal prepared from nifedipine and nicotinamide using a solvent method. The variable parameter was whether a eutectic crystal structure was formed. In the figure, Example 1 showed a set of characteristic diffraction peaks at 2θ (7.5°, 11.2°, 14.0°, 17.5°, 19.9°, 23.3°, and 27.2°), while Comparative Example 8 only retained the mixed diffraction peaks of the active pharmaceutical ingredient and excipients, without the new peak clusters of Example 1. This indicates that nifedipine and nicotinamide formed a stable new eutectic crystal structure in Example 1, ruling out the possibility of solubility changes due to simple physical mixing.

[0097] Figure 2The volume distribution curves of eutectic nanocrystals in DLS are shown. The samples are Example 1, Comparative Example 1, and Comparative Example 2. The characterization method was dynamic light scattering volume distribution testing. The fixed parameters were the same for the formulation system and dispersion medium conditions. The varying parameters were the nanocrystal particle size D50, controlled at approximately 0.05 μm (Comparative Example 1), 0.25 μm (Example 1), and 0.50 μm (Comparative Example 2), respectively. The results show that the main peak of the volume distribution in Example 1 is concentrated around 0.25 μm, with a narrow distribution; the distribution peak in Comparative Example 1 shifts forward to around 0.05 μm, with a significant increase in the proportion of ultrafine particles; the distribution in Comparative Example 2 shifts to the right to around 0.50 μm with a noticeable tail. These results indicate that stably controlling the eutectic nanocrystal particle size within the range of 0.10 to 0.40 μm can simultaneously avoid the instability and aggregation risk caused by excessively fine particles, while also being superior to the disadvantage of large particles in terms of dissolution rate.

[0098] Figure 3 The figure shows the D10, D50, and D90 particle size statistics and Span plots for eutectic nanocrystals. The samples are Example 1, Comparative Example 1, and Comparative Example 2, and the characterization method is DLS particle size statistical analysis. The fixed parameters were the same formulation components and measurement conditions; the varying parameters were the target D50 and distribution width of the three samples. Example 1 had a D50 of approximately 0.25 μm, a moderate Span, and a low PDI, indicating concentrated particle size and controllable distribution. Comparative Example 1 had a D50 of approximately 0.05 μm and a relatively large Span, suggesting that although the particles are extremely fine, their distribution is uneven, easily leading to aggregation and crystal transformation during storage. Comparative Example 2 had a D50 of approximately 0.50 μm, with significantly increased Span and PDI, indicating larger particle size and wider distribution, with an increased proportion of coarse particles on the periphery. This figure comprehensively demonstrates that using a particle size window of approximately 0.25 μm D50 and a moderate Span as the design target is beneficial for balancing dissolution enhancement and system stability.

[0099] Figure 4 The figures show the 0-12h dissolution curves for Example 1 and Comparative Example 2, with the samples being Example 1 containing eutectic nanocrystals and Comparative Example 2 with a particle size scaled up to 0.50 μm. The characterization method was an in vitro dissolution test. The overall formulation composition, the ratio of the fast-release to the sustained-release layer, and the dissolution medium and rotation speed were kept constant; the only variable parameter was the particle size of the eutectic nanocrystals in the fast-release layer. The results show that Example 1 achieved a high cumulative release rate at 0.5h and 2h, then maintained a steady increase from 4h to 12h, reaching near-complete release at 12h. Comparative Example 2, on the other hand, showed a significant lag in release from 0h to 2h, and although it caught up somewhat after 4h, its cumulative release rate at 12h was still lower than that of Example 1. These curves indicate that, without changing the formulation structure, optimizing the eutectic nanocrystal particle size to approximately 0.25 μm can significantly improve the overall dissolution behavior, especially in the early stages.

[0100] Figure 5These are partial phase images of Example 1 and Comparative Example 2 before dissolution from 0 to 2 hours. The sample is... Figure 4 The same methods were used for Example 1 and Comparative Example 2, with characterization performed by amplified analysis of early-stage data from in vitro dissolution tests. The slow-release fraction and total formulation density were kept constant, while the eutectic nanocrystal size of the fast-release layer remained variable. Results showed that Example 1 achieved high release rates at 0.5 h and 1 h, and its release level at 2 h was significantly higher than that of Comparative Example 2, while Comparative Example 2 showed lower release rates and a slower curve slope at the same time point. These results demonstrate that when the eutectic nanocrystal size is controlled at a medium nanoscale, a more ideal fast-release precursor phase can be formed under a given formulation structure, which is beneficial for achieving effective blood drug concentrations earlier and providing a smooth transition to the subsequent sustained-release phase.

[0101] Figure 6 The laser particle size distribution curves for sustained-release calcium alginate microspheres were obtained. The samples were Example 1, Comparative Example 3, and Comparative Example 4, and the characterization method was laser particle size analysis. The coating material, drug loading formulation, and drying conditions were kept constant. The variable parameter was the geometric particle size distribution of the calcium alginate microspheres: D50 for Example 1 was approximately 350 μm, for Comparative Example 3 it was approximately 80 μm, and for Comparative Example 4 it was approximately 650 μm. The curves show that the main peak of the volume distribution in Example 1 was concentrated in the medium particle size range and had a moderate distribution; the distribution in Comparative Example 3 shifted significantly to the left, dominated by fine microspheres; and in Comparative Example 4, the distribution shifted to the right overall, with a significant increase in the proportion of coarse microspheres. These results indicate that controlling the particle size of the sustained-release microspheres within a medium range is beneficial for achieving a balance between subsequent dissolution and mechanical strength, while excessively fine or coarse microspheres deviate from the optimal window.

[0102] Figure 7 The mass distribution diagram of sustained-release calcium alginate microspheres was prepared using standard sieving. Samples included Example 1, Comparative Example 3, and Comparative Example 4. Characterization was achieved through a series of mechanical sieving tests using sieves of nominal aperture sizes. The fixed parameter was that the batches of microspheres tested followed the same process route; the variable parameter was the mass fraction distribution pattern of the particle size distribution across each sieve size range. The results showed that the mass distribution of Example 1 was concentrated in the middle sieve sizes, forming a relatively symmetrical and unimodal particle size distribution. Comparative Example 3 mainly concentrated in the small aperture sieve size range, indicating a small median particle size and a high proportion of fine particles. Comparative Example 4 showed that most of the mass was distributed in the large aperture sieve size range, indicating significant enrichment of coarse microspheres. The sieving results were consistent with the laser particle size distribution curve, further demonstrating that the particle size distribution of the microspheres in Example 1 was controlled within a reasonable range, providing a foundation for subsequent sustained-release drug release and tableting performance.

[0103] Figure 8Box plots and original dot plots were used to illustrate the drug loading distribution of the sustained-release microcapsules. The samples were Example 1, Comparative Example 5, and Comparative Example 6. The characterization method was high-performance liquid chromatography (HPLC) to determine the nifedipine content in the microcapsules. Fixed parameters were the same as the detection conditions and sample mass. The varying parameters were the target drug loading levels: approximately 10 wt% for Example 1, approximately 0.8 wt% for Comparative Example 5, and approximately 22 wt% for Comparative Example 6. The graphs show that the mean drug loading of Example 1 was close to the design value with small intra-batch dispersion and a concentrated distribution; the drug loading of Comparative Example 5 was significantly lower, indicating insufficient active ingredient in the microcapsules; and the drug loading of Comparative Example 6 was too high, amplifying the differences between individual replicates. These results demonstrate that the 10 wt% drug loading range selected in Example 1 can maintain good inter-batch and intra-batch homogeneity while ensuring effective dosage, avoiding insufficient dosage due to low drug loading or dissolution imbalance and process risks caused by high drug loading.

[0104] Figure 9 The figures show the dissolution curves of Example 1 and Comparative Example 4 from 2 to 12 hours. The samples were Example 1 containing medium-sized calcium alginate microspheres and Comparative Example 4 containing coarse microspheres. The characterization method was in vitro cumulative release testing, focusing on the release behavior in the sustained-release phase. Fixed parameters included the rapid-release layer, total dose, and dissolution conditions. The variable parameter was the particle size distribution of the sustained-release microspheres: D50 for Example 1 was approximately 350 μm, and for Comparative Example 4, D50 was approximately 650 μm. As shown in the figures, the release curve of Example 1 rose smoothly from 2 to 12 hours, reaching a high cumulative release rate at the endpoint. In contrast, the release of Comparative Example 4 slowed significantly after 4 hours, with a significantly lower cumulative release rate at the endpoint. This result indicates that excessively large microsphere size reduces specific surface area and diffusion efficiency, leading to insufficient drug release in the sustained-release phase. The particle size range selected in Example 1 balances stable release with sufficient release.

[0105] As can be seen from the performance of the examples and comparative examples in Table 1, the overall performance of Examples 1-4 is significantly better than that of Comparative Examples 1-8. By precisely controlling the eutectic nanocrystal particle size in the range of 0.10-0.40 µm, the sustained-release microsphere particle size in the range of 100-600 µm, and the drug loading in the range of 1.00-20.00 wt%, the examples achieved a good balance between rapid onset of action and long-lasting effect. The dissolution rate was between 52-82% at 2 hours, and the cumulative dissolution rate reached over 88% at 12 hours, demonstrating continuous release within the in vitro dissolution test time window. Comparative Example 1, due to its excessively small eutectic nanocrystal particle size (0.05µm), resulted in an initial rapid release, but the cumulative dissolution rate after 12 hours was only 75%, indicating insufficient sustained-release effect. Comparative Example 2, due to its excessively large particle size (0.50µm), resulted in a dissolution rate of only 38% after 2 hours, significantly reducing its rapid onset of action. Comparative Example 3, with its excessively small microsphere size (80µm), suffered from insufficient mechanical strength, a hardness of only 45N, and a brittleness as high as 1.5%. Comparative Example 4, with its excessively large microsphere size (650µm), resulted in a weakened sustained-release effect, with a dissolution rate of only 72% after 12 hours. The drug loading of Comparative Example 5 was too low (0.8 wt%), resulting in a peak concentration of only 85 ng / mL; the drug loading of Comparative Example 6 was too high (22.0 wt%), which did not affect dissolution but the microparticles were prone to breakage during preparation; the ratio of fast-release to sustained-release in Comparative Example 7 was unbalanced (1:0.8), resulting in a dissolution rate of only 65% ​​after 12 hours and insufficient long-term effect; Comparative Example 8 did not use eutectic nanocrystal technology and only used physical mixing, resulting in a dissolution rate of only 42% after 2 hours and a Tmax extended to 2.8 hours, with a rapid onset ability significantly inferior to the examples.

[0106] Table 1 Summary of performance of examples and comparative examples

[0107] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that any equivalent structural transformations made under the concept of the present invention and using the contents of the specification and drawings of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. A tocolytic drug that inhibits uterine contractions, characterized in that, The medicine is a double-layer tablet, comprising a fast-release layer and a sustained-release layer, wherein: (1) the fast-release layer comprises nifedipine, nicotinamide, hydroxypropyl methyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone and magnesium stearate; the nifedipine and the nicotinamide in the fast-release layer exist in the form of nifedipine-nicotinamide co-crystal nanocrystal dispersion, and the median particle size D50 of the co-crystal nanocrystal dispersion is 0.10-0.40 µm; (2) the sustained-release layer comprises nifedipine-loaded calcium alginate sustained-release pellets, microcrystalline cellulose and magnesium stearate; the particle size of the sustained-release pellets is 100-600 µm, the particle size being the particle size obtained by sieving the dried pellets through a standard sieve; the drug loading of nifedipine in the sustained-release pellets is 1.00-20.00 wt% based on the total mass of the dried pellets; (3) the mass ratio of the fast-release layer to the sustained-release layer is 1:2-1:5; the total content of nifedipine in the double-layer tablet is 0.10-10.00 wt% based on the total mass of the double-layer tablet.

2. The medicament according to claim 1, characterized in that, The nifedipine-nicotinamide co-crystal is prepared by the following steps: A1. Preparation of raw materials: nifedipine and nicotinamide are weighed, and the molar ratio of nifedipine to nicotinamide is controlled to be 0.95-1.05:1; anhydrous ethanol is added, and the liquid-solid ratio is controlled to be 5-30 mL / g, based on the total mass of nifedipine and nicotinamide, to obtain a mixed solution under stirring at 200-600 rpm at 15-30 °C in the dark; A2. Crystallization: stirring is carried out at 300-800 rpm at 40-60 °C for 0.5-2.0 h until no solid is visible and the solution is clear; then the clear solution is cooled to 0-20 °C; the clear solution is added dropwise to purified water as an anti-solvent at a dropwise rate of 1-20 mL / min, wherein the volume ratio of purified water to the ethanol solution is 2:1-20:1, the temperature of the mixed system is maintained at 0-20 °C and stirring is carried out at 300-800 rpm during the dropwise process; after the dropwise addition is completed, aging is continued at 0-20 °C for 0.5-4.0 h under stirring; A3. Separation and post-treatment: the obtained solid is separated by centrifugation at 3000-10000 g for 5-30 min at 4-25 °C; washed with purified water for 1-3 times, and the amount of washing liquid is 5-50 mL of purified water per 1 g of solid each time; and dried at 30-50 °C under an absolute pressure of 5-30 kPa for 6-24 h until the moisture content is 0.10-5.00 wt%, to obtain the nifedipine-nicotinamide co-crystal; A4. End point criterion and quality control: the residual ethanol in the co-crystal is ≤5000 ppm w / w and the moisture content is 0.10-5.00 wt% based on the total mass of the dried co-crystal.

3. The medicament according to claim 1, characterized in that, The nifedipine-nicotinamide co-crystal nanocrystal dispersion is prepared by the following steps: B1. Raw materials: Take nifedipine-nicotinamide co-crystal; add hydroxypropyl methyl cellulose into purified water, stir at 300-800 rpm for 30-120 min at 20-30℃ until completely dissolved to obtain a stabilizer aqueous solution, the mass fraction of the hydroxypropyl methyl cellulose in the stabilizer aqueous solution is 0.10-3.00wt%; according to the initial pH of the stabilizer aqueous solution, use 0.1-1.0mol / L hydrochloric acid aqueous solution or 0.1-1.0mol / L sodium hydroxide aqueous solution to adjust the pH of the stabilizer aqueous solution to 5.0-8.0, the pH is measured at 25℃ with a calibrated pH meter; B2. Nanocrystallization: add the co-crystal into the stabilizer aqueous solution, so that the mass fraction of the co-crystal in the mixed system is 1.0-20.0wt%; use zirconium oxide grinding beads with a diameter of 0.1-0.6mm and a filling rate of 50-80% for bead mill wet grinding at 800-3000rpm for 0.5-6.0h at 5-25℃, and keep the system temperature at 5-25℃ by circulating cooling through the jacket; B3. End point criterion and quality control: when the median particle size D50 of the obtained nifedipine-nicotinamide co-crystal nanocrystals in the dispersion reaches the range of 0.10-0.40µm and the solid content of the dispersion is 1.0-20.0wt%, the nifedipine-nicotinamide co-crystal nanocrystal dispersion is obtained; wherein the D50 is the volume distribution median particle size measured by dynamic light scattering after diluting the dispersion to a solid content of 0.05-0.50wt% with purified water and ultrasonic dispersion for 5-20min at 25℃; the solid content is the mass fraction of non-volatile solids measured by drying the dispersion sample at 105℃ to a constant weight.

4. The medicament according to claim 1, characterized in that, The ratio of the mass of nifedipine in the fast-release layer to the mass of nifedipine in the slow-release layer is 1:1-1:

10.

5. The medicament according to claim 1, characterized in that, The content of hydroxypropyl methyl cellulose in the fast-release layer is 0.10-3.00wt% based on the total mass of the fast-release layer.

6. The medicament according to claim 1, characterized in that, The content of magnesium stearate in the fast-release layer is 0.20-2.00wt% based on the total mass of the fast-release layer, and the content of magnesium stearate in the slow-release layer is 0.20-2.00wt% based on the total mass of the slow-release layer.

7. The medicament according to claim 1, characterized in that, The nifedipine-loaded calcium alginate slow-release pellets are prepared by the following steps: D1. Prepare sodium alginate solution: add sodium alginate into purified water, stir at 300-800 rpm for 1-4h at 20-30℃ until completely dissolved and stand for 0.5-2h to remove bubbles, obtain a sodium alginate solution, the mass fraction of the sodium alginate solution is 1.0-5.0wt%; according to the initial pH of the sodium alginate solution, use 0.1-1.0mol / L hydrochloric acid aqueous solution or 0.1-1.0mol / L sodium hydroxide aqueous solution to adjust the pH to 5.5-7.5; D2. Drug dispersion: nifedipine is added into the sodium alginate solution, and is dispersed at a speed of 10,000-20,000 rpm for 5-30 min at 5-25℃ by high-speed shearing to obtain a uniform drug-containing sodium alginate suspension; the mass fraction of nifedipine in the total drug-containing sodium alginate suspension is 0.10-5.00wt%; D3. Ion cross-linking into pellets: a cross-linking solution is prepared with purified water, and the concentration of calcium chloride in the cross-linking solution is 0.05-0.50mol / L; the volume ratio of the cross-linking solution to the drug-containing sodium alginate suspension is controlled to be 5:1-20:1; stirring is performed at 200-600 rpm at 5-30℃; the drug-containing sodium alginate suspension is added dropwise into the cross-linking solution through a nozzle with an inner diameter of 0.10-1.00mm at a dropwise adding rate of 0.5-10mL / min, and the dropwise adding height is 1-10cm; after the dropwise adding is completed, cross-linking is continued at 5-30℃ for 0.5-4.0h; D4. Post-treatment and quality control: the obtained pellets are washed with purified water for 1-3 times, each time the amount of washing liquid is 10-100mL of purified water per 1g of wet pellets, and the pellets are dried at 30-50℃ under an absolute pressure of 5-30kPa for 6-24h until the water content of the pellets is 0.50-8.00wt%; after drying, the pellets are sieved, and the pellets with a particle size of 100-600µm are collected to obtain the nifedipine-loaded calcium alginate sustained-release pellets.

8. A method for preparing a tocolytic drug for inhibiting uterine contractions as described in any one of claims 1-7, characterized in that, comprising the following steps: S1. Preparation of nifedipine-loaded calcium alginate sustained-release pellets; S2. Preparation of fast-release layer granules: microcrystalline cellulose is mixed with crospovidone, then nifedipine-nicotinamide co-crystal nanocrystal dispersion is added, wet granulation is performed, and drying is performed, followed by the addition of magnesium stearate for mixing to obtain fast-release layer granules; S3. Preparation of sustained-release layer mixture: the nifedipine-loaded calcium alginate sustained-release pellets are mixed with microcrystalline cellulose, and magnesium stearate is added for mixing to obtain a sustained-release layer mixture; S4. Double-layer tabletting: the fast-release layer granules and the sustained-release layer mixture are tabletted into double-layer tablets by a double-layer tabletting process to obtain the drug.

9. The production method according to claim 8, characterized by, In the step S2, the nifedipine-nicotinamide co-crystal nanocrystal dispersion is added at a feeding rate of 1-20mL / min at 10-30℃ for granulation, and the end point is reached when the water content of the wet granules reaches 15-30wt%, and the total granulation time is 2-30min; the obtained wet granules are dried at 30-60℃ for 1-12h until the water content of the granules is ≤3.0wt%; and in the step S4, the main tabletting pressure is 5-30kN, and the target tablet weight is 100-1000mg.

10. The method of claim 9, wherein, In the step S4, the mass ratio of the fast-release layer to the sustained-release layer is controlled to be 1:2-1:5.

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