Medicine for treating infertility and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and provides a medicine for treating infertility and a preparation method thereof. According to the invention, a biphase controlled release tablet design is adopted, a quick release layer contains 0.8-2.0 wt% of polyethylene glycol-hemisuccinic acid choline salt as an ion pair auxiliary release agent, and the polyethylene glycol-hemisuccinic acid choline salt has accurately regulated number-average molecular weight of 1000-2000, terminal group substitution degree of 1.8-2.0, neutralization degree of more than or equal to 95% and low acid value of less than or equal to 5.0 mg KOH / g; the surfaces of letrozole particles are micro-coated with a fluidized bed to form 1.0-1.5 wt% of a uniform weight-increasing coating layer, and diffusion control of 15-45 wt% of hydroxypropyl methylcellulose in a slow-release layer is combined, so that double-time-window stable drug release of 45-60% of accumulated release within 2 hours and 85-95% of accumulated release within 24 hours is realized; triple contradictions between tablet densification and double-time window release channel maintenance, micro-coating process window and initial release consistency, low water-containing stability of a formula and ion pair assisted release hydration requirements are solved, and the tablet is suitable for treating ovulation disorder related infertility and has wide clinical application value.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to a drug for the treatment of infertility and a preparation method thereof. BACKGROUND

[0002] Female infertility, especially ovulation disorder-related infertility, seriously affects the reproductive health and family happiness of women of childbearing age. In clinical treatment, aromatase inhibitors such as letrozole have become the first-line drug for inducing ovulation by selectively inhibiting estrogen synthesis, relieving hypothalamic-pituitary negative feedback inhibition, and promoting the release of gonadotropin. However, the stability of the clinical efficacy highly depends on the in vivo release behavior of the drug: it needs to quickly reach an effective blood drug concentration in the early stage of administration (about 2 hours) to start the feedback regulation of the hormone axis, and it needs to maintain stable drug release within 24 hours to ensure a continuous biological action window. Precise control of this dual-time window release characteristic is of great clinical significance for reducing the number of daily drug administrations for patients, improving drug compliance, and reducing the risk of side effects caused by blood drug concentration fluctuations. At the same time, the preparation must have excellent mechanical strength and stability to meet the needs of industrial production, packaging and transportation, and long-term storage. Therefore, the development of letrozole controlled-release tablets with dual-time window stable release, high mechanical reliability, and good storage stability is of great significance for improving the clinical benefits of ovulation disorder treatment and promoting technological progress in the field of women's reproductive health.

[0003] Currently, the development of letrozole controlled-release preparations faces three essential contradictions and technical bottlenecks. For example, Chinese Patent Publication No. CN106580907A discloses a preparation method for letrozole sustained-release tablets, but has the following shortcomings. First, to ensure a hardness of 90 N or more and a friability of less than 1.0%, high-pressure tabletting force and densification formulation design are required. However, the dense tablet core structure severely hinders the penetration of the medium and the diffusion of the drug, making it difficult to achieve an initial release of more than 45% within 2 hours, resulting in a loss of control of the front section of the dual-time window release curve. Second, although fluidized bed micro-coating technology can improve the flowability and mixing uniformity of the particles, the process window of the coating liquid viscosity, spraying speed, and bed temperature and humidity is extremely narrow. Overly high coating liquid concentration or spraying speed can easily cause particle sticking and uneven weight gain, while overly low coating can result in incomplete coating, with an initial release difference between batches of more than 15%, seriously affecting the quality stability of the product. Third, ion-pair release enhancers can accelerate release by enhancing drug solubility and membrane permeability, but they need a certain degree of hydration and diffusion flux in the tablet to function, which conflicts with the requirement that the tablet moisture content be strictly controlled at ≤3.0 wt% to ensure chemical stability and avoid microbial contamination. The above three contradictions make it difficult for existing technologies to simultaneously achieve stable dual-time window release, high mechanical reliability, and batch consistency under industrial conditions. SUMMARY

[0004] The present application aims to provide a drug for treating infertility and a preparation method thereof, and to solve the triple technical contradictions between the densification of the tablet and the maintenance of the double-time window release channel, the process window of the fluidized bed micro-coating and the consistency of the initial release, the low water content stability of the formula and the ion-pair hydration requirement of the release aid.

[0005] The present application breaks through the above triple contradictions through precise coordination of prescription design and process parameters. Specifically, low-acid-value and high-neutralization-degree polyethylene glycol-hemisuccinate choline salt is used as the ion-pair release aid of the immediate-release layer, and the choline cation and carboxylate anion thereof rapidly dissociate in the microenvironment of the tablet, and the choline cation enhances the wetting and interfacial dissolution flux of letrozole particles through cation-π and polar interactions, thereby significantly accelerating the initial dissolution without relying on a large amount of hydration of the tablet core; through optimization of the ethanol / water ratio and spraying rate in the fluidized bed liquid spraying, the coating layer is uniformly increased by 1.0-1.5 wt% and particle sticking is avoided; combined with the concentration gradient diffusion control of the hydroxypropyl methyl cellulose in the sustained-release layer, the double-time window release targets of 45-60% at 2 hours and 85-95% at 24 hours are simultaneously met under the premise of maintaining the tablet at a high hardness of 90-120 N and low water content, realizing the three-in-one of mechanical reliability, process robustness and release accuracy.

[0006] In order to achieve the above-mentioned purpose, the present application provides the following technical solutions:

[0007] A drug for treating infertility, which is a biphasic controlled-release tablet, comprises an immediate-release layer and a sustained-release layer; letrozole 2.5-7.5 mg / tablet; the immediate-release layer contains 0.8-2.0 wt% of polyethylene glycol-hemisuccinate choline salt, the polyethylene glycol-hemisuccinate choline salt has a number average molecular weight of 1000-2000, an end group substitution degree of 1.8-2.0, a neutralization degree of ≥95%, and an acid value of ≤5.0 mg KOH / g; the drug has a cumulative release of 45-60% at 2 h and a cumulative release of 85-95% at 24 h.

[0008] Further, the content of the polyethylene glycol-hemisuccinate choline salt in the immediate-release layer is 1.2-1.6 wt%.

[0009] Further, the preparation method of the polyethylene glycol-hemisuccinate choline salt is as follows: under inert atmosphere, polyethylene glycol with number average molecular weight of 1000-2000 is reacted with succinic anhydride at a hydroxyl end group equivalent ratio of 1.05-1.10:1 at 80-90 °C for 2-4 h to obtain a hemi-ester with an acid value of 45-60 mg KOH / g; dissolved in isopropyl alcohol / water with a mass ratio of 95 / 5, decolorized, filtered and the solvent removed; in an ethanol / water medium with a mass ratio of 90 / 10, choline hydroxide or choline bicarbonate is added to neutralize the carboxyl group at a molar ratio of 1.00-1.05:1 to pH 6.8-7.2, and dried at 40-50 °C to a moisture content of ≤0.5 wt% to obtain the polyethylene glycol-hemisuccinate choline salt;

[0010] Further, the sustained-release layer contains hydroxypropyl methyl cellulose 15-45 wt%, and is adjusted to obtain a cumulative release of 85-95% in 24 h.

[0011] Further, the diluent of the immediate-release layer is selected from at least one of microcrystalline cellulose and lactose monohydrate, with a total content of 20-70 wt%.

[0012] Further, the disintegrant of the immediate-release layer is selected from crospovidone or sodium carboxymethyl starch, with a content of 2.0-6.0 wt%.

[0013] Further, the cumulative release of the drug is preferably 48-58% in 2 h and 88-94% in 24 h;

[0014] The tablet hardness of the drug is 90-120 N, the friability is ≤0.8%, and the disintegration time is ≤15 min.

[0015] As one of the concepts of the present application, the present application adopts a dual-phase controlled-release tablet design and a prescription strategy of polyethylene glycol-hemisuccinyl choline salt ion pair release aid, which is mainly used to enhance the stable release performance of letrozole in the 2-hour and 24-hour dual time windows, while ensuring the high mechanical strength and storage stability of the tablet. As a key excipient of the immediate-release layer, the choline cation and carboxylate anion of the polyethylene glycol-hemisuccinyl choline salt rapidly dissociate in the instant contact of the tablet and the dissolution medium, and the choline cation forms a soluble ion pair with the aromatic ring π electron cloud in the letrozole molecule through electrostatic interaction, significantly reducing the apparent hydrophobicity of the drug in the aqueous phase, accelerating the initial dissolution to achieve a 2-hour release target of 45-60%, without relying on the hydration and pore formation of the tablet core, thereby breaking through the contradiction between the densification of the tablet high-pressure tabletting force and the maintenance of the initial release channel. The polyethylene glycol-hemisuccinyl choline salt has precise molecular parameters: a number average molecular weight of 1000-2000 ensures a moderate chain length and hydrophilicity, an end group substitution degree of 1.8-2.0 ensures nearly 2 carboxylate active sites per molecule, a neutralization degree of ≥95% ensures ion pair formation efficiency, and a low acid value of ≤5.0 mg KOH / g avoids the adverse effects of residual free acid on drug stability. 15-45 wt% hydroxypropyl methyl cellulose in the sustained-release layer takes over the sustained release process after the rapid release of the drug in the immediate-release layer through concentration gradient diffusion and gel matrix controlled-release mechanisms, making the 24-hour cumulative release reach 85-95%, and achieving precise connection of the dual-time window release curve. The tablet has a high hardness of 90-120 N and a low friability of ≤0.8% obtained by a double-layer tabletting process, a disintegration time of ≤15 min ensures the rapid disintegration of the immediate-release layer, and the overall design meets multiple clinical requirements for initial rapid effect, sustained stable drug release, and mechanical reliability of the tablet.

[0016] The present application also discloses a preparation method of the above-mentioned drug for treating infertility, comprising the following steps:

[0017] S1. Microencapsulating and granulating letrozole particles: spraying polyethylene glycol-hemisuccinyl choline salt in a 2 wt% ethanol / water solution into a fluidized bed to make letrozole particles gain 1.0–1.5 wt% weight, and the moisture content of the outfeed is ≤2.0 wt%;

[0018] S2. Mixing and tabletting the immediate-release layer and the sustained-release layer: mixing the gain-weighted particles with the immediate-release layer diluent, disintegrant and lubricant for 3–10 min, the lubricant is magnesium stearate with a content of 0.2–1.5 wt%, and the tabletting force is 8–18 kN, and then the immediate-release layer is compressed and dried with the sustained-release layer containing hydroxypropyl methyl cellulose to a tablet moisture content of 1.0–5.0 wt%, thereby obtaining the drug.

[0019] Further, the spraying liquid of S2 is a 2 wt% ethanol / water solution of the polyethylene glycol-hemisuccinyl choline salt, the mass ratio of ethanol / water is 80 / 20, and the spraying speed is 20–30 g / min.

[0020] As another concept of the present application, the present application adopts the preparation process of fluidized bed microencapsulation and double-layer compression, which is mainly used for enhancing the performance of the double-phase controlled-release tablets in batch release consistency, mechanical reliability and process robustness. The fluidized bed microencapsulation step forms a uniform weight gain coating layer of 1.0-1.5 wt% on the surface of letrozole particles by spraying a 20-30 g / min spray rate of a 2 wt% polyethylene glycol-hemisuccinate choline salt ethanol / water solution into the fluidized bed, which quickly dissolves and releases ion pair release aids at the initial stage of dissolution, ensuring the formation of a high solubility microenvironment on the particle surface, thereby ensuring the batch stability of 2-hour release. The spray liquid formulation of ethanol / water mass ratio 80 / 20 significantly optimizes the fluidized bed process window: ethanol reduces the surface tension and viscosity of the spray liquid, promotes droplet refinement and particle surface spreading, and avoids particle sticking and uneven weight gain caused by too high spray liquid viscosity; 20% moisture ensures that polyethylene glycol-hemisuccinate choline salt is fully dissolved and quickly forms a film on the particle surface, and the moisture content ≤2.0 wt% ensures the flowability and stability of the subsequent process. The spray rate of 20-30 g / min ensures the coating efficiency while avoiding the problem of local over-wetting and particle agglomeration caused by too fast spray rate, achieving a batch relative standard deviation of microencapsulation weight gain ≤5%. In the double-layer compression step, the compression force of 8-18 kN of the immediate-release layer and the sustained-release layer precisely balances the interlayer bonding strength and the porosity of each layer: too low pressure leads to the risk of interlayer separation, and too high pressure compresses the pores of the immediate-release layer, affecting the initial release. This pressure window makes the tablet have both 90-120 N hardness to meet the packaging and transportation requirements, and the dual functions of fast disintegration of the immediate-release layer within 15 min and stable diffusion of the sustained-release layer for 24 hours. The tablet moisture content is controlled at 1.0-5.0 wt%, which ensures the chemical stability and microbial control, and provides the necessary hydration channels for the dissociation and diffusion of ion pair release aids in the tablet microenvironment, achieving a dynamic balance between storage stability and release aid efficiency.

[0021] The present application also discloses the use of a drug for treating infertility in the treatment of infertility, wherein the infertility is ovulation disorder-related infertility.

[0022] In the present application, polyethylene glycol-hemisuccinate choline salt and hypromellose exhibit a dual mechanism of time-complementary and functional synergy in the present biphasic controlled-release system. The main function of polyethylene glycol-hemisuccinate choline salt focuses on initial dissolution acceleration and microenvironment pH buffering of the immediate-release layer: its choline cation rapidly dissociates upon contact with the dissolution medium, forms a water-soluble complex with letrozole molecules through ion-dipole interaction, increases the apparent solubility of the drug by 3-5 times, and at the same time, the carboxylate anion improves the local ionic strength and hydrophilicity, which is beneficial to wetting and dissolution under neutral conditions; initial release can be achieved without relying on massive hydration of the tablet core, avoiding the adverse effects of acid conditions on drug stability, so that 45-60% of the drug is released rapidly within 2 hours under the dense structure of the tablet. The function of hypromellose focuses on sustained diffusion control and gel matrix formation in the sustained-release layer: the concentration gradient of 15-45 wt% of hypromellose gradually hydrates and swells to form a gel layer after the penetration of the dissolution medium, controls the release rate of the drug from the sustained-release layer to the body fluid through the Fickian diffusion mechanism, ensures that the 24-hour cumulative release reaches 85-95%, and realizes a sustained and stable blood drug concentration. The synergistic effect of the two is reflected in three aspects: first, time-complementary synergy, polyethylene glycol-hemisuccinate choline salt dominates the immediate-release stage in 0-2 hours, and hypromellose dominates the sustained-release stage in 2-24 hours, forming a smooth connection rather than superimposed interference of the double-time window release curve; second, spatial distribution synergy, the former is concentrated in the immediate-release layer and the drug particle surface coating layer, and the latter is concentrated in the sustained-release layer matrix, avoiding the mutual competition of functional components and the mutual interference of release mechanisms; third, physicochemical property synergy, the ionic hydrophilicity of polyethylene glycol-hemisuccinate choline salt and the non-ionic gelation property of hypromellose exhibit complementary stability under different pH and ionic strength conditions, so that the biphasic controlled-release tablet still maintains consistent release behavior under the changes of gastrointestinal physiological environment. Based on the above synergistic mechanism, the present application breaks through the technical bottleneck that single controlled-release material is difficult to balance double-time window release and tablet mechanical strength.

[0023] Beneficial technical effects

[0024] 1. Precise realization of double-time window stable drug release, improving the controllability of clinical efficacy

[0025] By the time sequence coordination of the ion pair release-aids release mechanism and the concentration gradient diffusion of hydroxypropyl methyl cellulose, the application achieves the dual time window drug release target of 45-60% cumulative release in 2 hours and 85-95% cumulative release in 24 hours, and the relative standard deviation of the release curve between batches is ≤8%. The initial rapid release ensures that the effective blood concentration is reached within 2 hours after administration to start the hypothalamus-pituitary-ovary axis feedback regulation, the sustained stable release maintains the 24-hour treatment window concentration, reduces the number of daily medication to once a day, significantly improves the patient's medication compliance, reduces the risk of side effects caused by blood concentration fluctuations, and has better clinical benefits than the single time phase release preparation of the prior art.

[0026] 2. Breakthrough of the contradiction between tablet densification and release channel retention, taking into account mechanical reliability and drug release performance

[0027] The application adopts the ion pair release-aids surface coating strategy, which accelerates drug dissolution without relying on a large amount of hydration and pore formation of the tablet core, thereby allowing the use of 8-18 kN high pressure tabletting force to obtain a dense tablet structure with a hardness of 90-120 N and a friability of ≤0.8%, meeting the mechanical strength requirements of industrial packaging, transportation and long-term storage. At the same time, the disintegration time of the immediate release layer is ≤15 min, and the sustained release layer still maintains stable diffusion release under the dense structure of the tablet, breaking through the technical dilemma of traditional controlled release tablets "high hardness and slow release, fast release and poor mechanical strength", achieving the dual optimization of mechanical reliability and drug release performance.

[0028] 3. Optimization of fluidized bed micro-coating process window, improvement of batch consistency and process robustness

[0029] By precise control of the ethanol / water mass ratio 80 / 20 spray liquid formulation and 20-30 g / min spray rate, the application reduces the batch-to-batch relative standard deviation of fluidized bed micro-coating weight gain to ≤5%, which is significantly better than the 12-18% level of the prior art. Ethanol reduces the viscosity of the spray liquid to promote droplet refinement and particle surface spreading, and 20% moisture ensures the dissolution and film formation of the release-aids, avoiding process defects such as particle sticking, uneven weight gain and incomplete coating, reducing the batch-to-batch difference of 2-hour release from the prior art of 15% to ≤8%, significantly improving the product quality stability and process controllability, and reducing the batch rejection rate and cost of industrial production.

[0030] 4. Coordination of low moisture stability of formula and hydration demand of ion pair release-aids, extension of storage period

[0031] The present application avoids the catalytic effect of residual free acid on drug degradation by precisely controlling the polyethylene glycol-hemisuccinyl choline salt to a low acid value of ≤5.0 mg KOH / g and a high neutralization degree of ≥95%. The tablet water content is controlled at 1.0-5.0 wt%, which not only meets the requirements of chemical stability and microbial control, but also provides the necessary hydration channel for the rapid dissociation of ion pair release aids in the initial stage of dissolution, without relying on the hydration of the tablet core to start the release effect. Accelerated testing (40°C / 75% RH, 6 months) shows that the related substance of the present application increases by ≤0.3%, and the content retention rate is ≥98%, which is significantly better than the related substance of the prior art, which increases by ≥0.8% and the content retention rate is ≤95%, and the estimated room temperature storage period is more than 36 months.

[0032] 5. Simplified preparation process, reduced production cost and energy consumption

[0033] The present application uses a fluidized bed micro-coating one-step method to realize the distribution of release aids on the surface of particles, avoiding the multi-step processing technology of traditional spray drying or co-milling, and reducing equipment investment and energy consumption by about 40%. The double-layer tabletting process completes the complex molding of the immediate-release layer and the sustained-release layer at one time, which is about 30% shorter than the multi-layer coating or step-by-step granulation-tableting-coating process of the prior art, and the yield is increased to ≥95%, the labor cost and quality control cost are reduced, and it is suitable for industrial scale production. At the same time, the prescription components are all conventional excipients collected in the pharmacopoeia, and the raw material cost is reduced by about 50% compared with the controlled release technology using new high molecular materials or nano carriers, which has good economic benefits and market prospects. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 Figure 4 is the effect of the content of polyethylene glycol-hemisuccinyl choline salt on the 2-hour and 24-hour cumulative release rate.

[0035] Figure 2 Figure 5 is the effect of the content of hydroxypropyl methyl cellulose in the sustained-release layer on the 2-hour and 24-hour cumulative release rate.

[0036] Figure 3 Figure 6 is the effect of the content of letrozole on the 2-hour and 24-hour cumulative release rate.

[0037] Figure 4 Figure 7 is the infrared Fourier spectrum of letrozole in Example 1 of the present application

[0038] Figure 5 Figure 8 is the infrared Fourier spectrum of polyethylene glycol hemisuccinyl choline salt in Example 1 of the present application

[0039] Figure 6 Figure 9 is the infrared Fourier spectrum of microcrystalline cellulose in Example 1 of the present application

[0040] Figure 7Infrared Fourier spectrum of cross-linked povidone in Example 1 of the present application

[0041] Figure 8 Infrared Fourier spectrum of hydroxypropyl methyl cellulose in Example 1 of the present application

[0042] Figure 9 Infrared Fourier spectrum of magnesium stearate in Example 2 of the present application

[0043] Figure 10 Infrared Fourier spectrum of the composition of the immediate release layer in Example 1 of the present application

[0044] Figure 11 Infrared Fourier spectrum of the composition of the sustained release layer in Example 1 of the present application

[0045] Figure 12 Infrared Fourier spectrum of the whole composition of the bilayer tablet in Example 1 of the present application. DETAILED DESCRIPTION

[0046] In order to make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme of the embodiments of the present application will be described clearly and completely below with reference to the drawings of the embodiments of the present application.

[0047] Example 1

[0048] A medicament for treating infertility, which is a biphasic controlled-release tablet, comprising an immediate release layer and a sustained release layer.

[0049] Preparation of polyethylene glycol-hemisuccinate choline salt:

[0050] Under nitrogen protection, 150.0 g of polyethylene glycol with a number average molecular weight of 1500 and 10.8 g of succinic anhydride were mixed in a proportion of 1.075:1 based on the end hydroxyl equivalent, and reacted at 85°C for 3 hours to obtain a polyethylene glycol hemiester with an acid value of 52.5 mg KOH / g. The obtained hemiester was dissolved with an isopropyl alcohol / water (mass ratio 95 / 5) solution, activated carbon was added for decolorization for 30 minutes, and then filtered and the solvent was removed under reduced pressure. The purified hemiester was dissolved in a mixed solvent of ethanol / water (mass ratio 90 / 10), and choline hydroxide aqueous solution was added dropwise at 25°C, with a molar ratio of carboxyl to choline of 1.025:1, the pH was adjusted to 7.0, and the neutralization degree reached 97%. The obtained solution was dried at 45°C to a moisture content of 0.3 wt%, to obtain a polyethylene glycol-hemisuccinate choline salt with an acid value of 3.0 mg KOH / g, an end group substitution degree of 1.9, and a neutralization degree of 97%.

[0051] Preparation of the medicament:

[0052] S1. Micro-coating and granulation of letrozole particles: The above prepared PEG-hemisuccinate choline salt was formulated into a 2 wt% ethanol / water solution (mass ratio of ethanol / water 80 / 20), and sprayed into the fluidized bed at a spraying rate of 25 g / min to make the letrozole particles gain 1.25 wt% weight, and the moisture content of the discharged material was 1.5 wt%.

[0053] S2. Preparation of immediate-release layer: The letrozole particles after weight gain 5.0 mg were mixed with microcrystalline cellulose 67.5 mg (45 wt%), cross-linked polyvinylpyrrolidone 6.0 mg (4.0 wt%), PEG-hemisuccinate choline salt 2.1 mg (1.4 wt%) and magnesium stearate 1.2 mg (0.8 wt%) for 6 minutes, and the rest of the excipients were supplemented to make the total weight of the immediate-release layer 150 mg.

[0054] S3. Preparation of sustained-release layer: Hydroxypropyl methyl cellulose 45.0 mg (30 wt%), microcrystalline cellulose 95.0 mg, magnesium stearate 1.0 mg and other excipients were mixed, and the total weight was 150 mg.

[0055] S4. Double-layer tabletting: On the rotary tablet press, the sustained-release layer mixture was added first, followed by the immediate-release layer mixture, and the tabletting force was 13 kN to press into double-layer tablets. Drying at 50°C to a tablet moisture content of 3.0 wt% resulted in a total weight of 300 mg of biphasic controlled-release tablets.

[0056] Quality detection:

[0057] The tablet hardness was 105 N, the friability was 0.4%, and the disintegration time was 8 minutes. In vitro release rate determination showed that the cumulative release was 52% at 2 hours and 91% at 24 hours.

[0058] Features of Example 1: This example uses moderate parameter configuration, and the selection of each parameter is in the middle range of the scope of the claims, ensuring process stability and reproducibility of product quality. The molecular weight of PEG is selected as 1500, and the end group substitution degree is 1.9, both of which are the median values in the range, which is conducive to obtaining stable physicochemical properties. The content of PEG-hemisuccinate choline salt in the immediate-release layer is 1.4 wt%, which is in the middle of the preferred range, and it is combined with 30 wt% hydroxypropyl methyl cellulose to achieve an ideal release curve of 52% at 2 hours and 91% at 24 hours, which meets the preferred release requirements. This formulation ensures the immediate-release effect while achieving sustained release for 24 hours through a moderate sustained-release layer composition, which is suitable for infertile patients who need stable blood drug concentration, especially for dose adjustment and clinical observation in the initial treatment stage. The tablet hardness is 105 N, the friability is 0.4%, and the disintegration time is 8 minutes, and each physical index is in the middle level of the standard range, with good mechanical strength and stability, which is convenient for industrial production and quality control.

[0059] Example 2

[0060] A medicine for treating infertility, which is a biphasic controlled release tablet comprising a fast release layer and a slow release layer.

[0061] Preparation of polyethylene glycol-hemisuccinate choline salt:

[0062] Polyethylene glycol with number average molecular weight of 1200 g, 120.0 g, was mixed with succinic anhydride, 10.2 g, in a ratio of 1.06:1 of hydroxyl end group equivalent, and reacted at 83 °C for 2.5 hours to obtain polyethylene glycol hemiester with acid value of 48.0 mg KOH / g. The obtained hemiester was dissolved with isopropanol / water (mass ratio 95 / 5) solution, and activated carbon was added for decolorization for 30 minutes. After filtration, the solvent was removed under reduced pressure. The purified hemiester was dissolved in ethanol / water (mass ratio 90 / 10) mixed solvent, and choline bicarbonate aqueous solution was added dropwise at 25 °C for neutralization with molar ratio of carboxyl group to choline of 1.01:1. The pH was adjusted to 6.9, and the neutralization degree reached 96%. The obtained solution was dried at 43 °C to moisture content of 0.4 wt%, to obtain polyethylene glycol-hemisuccinate choline salt with acid value of 2.5 mg KOH / g, end group substitution degree of 1.85, and neutralization degree of 96%.

[0063] Preparation of medicine:

[0064] S1. Microencapsulation and granulation of letrozole particles: The polyethylene glycol-hemisuccinate choline salt prepared above was formulated into a 2 wt% ethanol / water solution (ethanol / water mass ratio 80 / 20), and sprayed into a fluidized bed at a spraying rate of 22 g / min to make the letrozole particles gain weight by 1.1 wt%, and the moisture content of the discharged material was 1.8 wt%.

[0065] S2. Preparation of fast release layer: The letrozole particles after weight gain, 3.5 mg, were mixed with microcrystalline cellulose, 42.0 mg (30 wt%), lactose monohydrate, 35.0 mg (25 wt%), sodium carboxymethyl starch, 7.0 mg (5.0 wt%), polyethylene glycol-hemisuccinate choline salt, 1.4 mg (1.0 wt%), and magnesium stearate, 0.7 mg (0.5 wt%), for 4 minutes, and the rest of the excipients were added to make up the total weight of the fast release layer to 140 mg.

[0066] S3. Preparation of slow release layer: hydroxypropyl methyl cellulose, 28.0 mg (20 wt%), microcrystalline cellulose, 100.0 mg, magnesium stearate, 0.7 mg, and other excipients were mixed to a total weight of 140 mg.

[0067] S4. Double-layer tabletting: On a rotary tablet press, the slow release layer mixture was first added, followed by the fast release layer mixture, and the tabletting force was 10 kN to press into double-layer tablets. Drying was carried out at 50 °C to a tablet moisture content of 2.0 wt%, to obtain biphasic controlled release tablets with a total weight of 280 mg.

[0068] Quality test:

[0069] The tablet hardness is 95 N, friability is 0.6%, and disintegration time is 6 minutes. In vitro release test shows that the cumulative release is 55% at 2 hours and 90% at 24 hours.

[0070] Features of Example 2: This example uses a lower dose of letrozole 3.5 mg, which is suitable for initial treatment or patients with lower body weight. A lower molecular weight of polyethylene glycol (1200) and a lower degree of substitution of end groups (1.85) are selected to make the polyethylene glycol-hemisuccinate choline salt have better water solubility. Combined with 20 wt% hydroxypropyl methyl cellulose and a higher content of disintegrant (5.0 wt%), a fast initial release profile is achieved, with a release of 55% at 2 hours, which is higher than the median of the standard range, which is beneficial to rapid onset. This formulation uses a microcrystalline cellulose and lactose monohydrate composite diluent system with a total content of 55 wt%, which not only ensures the tabletability of the tablet, but also improves the dissolution rate of the drug. Sodium carboxymethyl starch is selected as the disintegrant, and its super water absorption and swelling properties shorten the tablet disintegration time to 6 minutes, and the rapid release characteristics are obvious. The cumulative release is 90% at 24 hours, which is at the median level of the range, ensuring sufficient absorption of the drug. This formulation is particularly suitable for patients with ovulation disorders who need rapid onset, especially for patients with polycystic ovary syndrome in the initial stage of ovulation induction treatment, which can quickly reach an effective blood drug concentration, and at the same time maintain a sustained effect for 24 hours through the sustained-release layer. The tablet hardness is 95 N, which is at the lower limit of the standard, but the friability is 0.6%, which is still within the qualified range, and is suitable for industrial production.

[0071] Example 3

[0072] A medicine for treating infertility, which is a biphasic controlled-release tablet containing a rapid-release layer and a sustained-release layer.

[0073] Preparation of polyethylene glycol-hemisuccinate choline salt:

[0074] Polyethylene glycol with number average molecular weight of 1800, 180.0 g, was mixed with succinic anhydride, 11.0 g, in a ratio of 1.09:1 of hydroxyl end group equivalent, and reacted at 88°C for 3.5 hours to obtain a polyethylene glycol hemi-succinate with an acid value of 57.0 mg KOH / g. The obtained hemi-ester was dissolved in isopropyl alcohol / water (mass ratio 95 / 5) solution, and decolorized with activated carbon for 30 minutes. After filtration, the solvent was removed under reduced pressure. The purified hemi-ester was dissolved in a mixed solvent of ethanol / water (mass ratio 90 / 10), and choline hydroxide aqueous solution was added dropwise at 25°C to neutralize the hemi-ester in a molar ratio of carboxyl group to choline of 1.04:1. The pH was adjusted to 7.1, and the neutralization degree reached 98%. The obtained solution was dried at 48°C to a moisture content of 0.2 wt%, to obtain a polyethylene glycol-hemi-succinate choline salt with an acid value of 1.5 mg KOH / g, an end group substitution degree of 1.95, and a neutralization degree of 98%.

[0075] Drug preparation:

[0076] S1. Micro-coating and granulation of letrozole particles: The polyethylene glycol-hemi-succinate choline salt prepared above was formulated into a 2 wt% ethanol / water solution (ethanol / water mass ratio 80 / 20), and sprayed into a fluidized bed at a spraying rate of 28 g / min to make the letrozole particles gain a weight of 1.4 wt%, and the moisture content of the outflow was 1.2 wt%.

[0077] S2. Preparation of immediate-release layer: The letrozole particles after weight gain, 6.5 mg, were mixed with lactose monohydrate, 96.0 mg (60 wt%), crospovidone, 4.8 mg (3.0 wt%), polyethylene glycol-hemi-succinate choline salt, 2.56 mg (1.6 wt%), and magnesium stearate, 1.92 mg (1.2 wt%), for 8 minutes, and the rest of the excipients were added to make the total weight of the immediate-release layer 160 mg.

[0078] S3. Preparation of sustained-release layer: hydroxypropyl methylcellulose, 60.8 mg (38 wt%), microcrystalline cellulose, 85.0 mg, magnesium stearate, 1.5 mg, and other excipients were mixed to make a total weight of 160 mg.

[0079] S4. Double-layer tabletting: On a rotary tablet press, the sustained-release layer mixture was first added, followed by the immediate-release layer mixture, and the tabletting force was 16 kN to press into double-layer tablets. The tablets were dried at 50°C to a moisture content of 4.0 wt% to obtain double-phase controlled-release tablets with a total weight of 320 mg.

[0080] Quality detection:

[0081] The tablet hardness was 115 N, the friability was 0.3%, and the disintegration time was 12 minutes. In vitro release rate determination showed that the cumulative release was 50% at 2 hours and 92% at 24 hours.

[0082] Example 3 Features: This example adopts a high dose of letrozole 6.5 mg configuration, suitable for patients who need strong ovulation induction effect or patients who are weakly responsive to the drug. A higher molecular weight of polyethylene glycol (1800) and a higher degree of end group substitution (1.95) are selected to make the polyethylene glycol-hemisuccinate choline salt have better biocompatibility and sustained release effect. The content of polyethylene glycol-hemisuccinate choline salt in the immediate-release layer is increased to 1.6 wt% (upper limit of preferred range), combined with a high content of hydroxypropyl methyl cellulose of 38 wt%, to form a strengthened sustained-release system, achieving a moderate initial release of 50% in 2 hours and a high cumulative release of 92% in 24 hours, ensuring sufficient drug absorption and sustained effect. This formulation uses lactose monohydrate as a single diluent, with a content as high as 60 wt%, which not only meets the needs of tablet molding, but also promotes drug dissolution due to the good solubility of lactose. The disintegrant content is reduced to 3.0 wt%, combined with a higher tabletting force of 16 kN, to make the tablet have higher hardness (115 N) and longer disintegration time (12 minutes), which is beneficial to achieve sustained release. A high content of hydroxypropyl methyl cellulose (38 wt%) forms a gel matrix in the sustained-release layer, effectively controlling the drug release rate and avoiding the phenomenon of burst release. This formulation is particularly suitable for patients with refractory ovulation disorders, such as patients who do not respond well to regular doses, or patients who need to maintain a high blood drug concentration. The friability is only 0.3%, showing excellent tablet mechanical strength, which is convenient for packaging, transportation and patient administration. The lubricant content is 1.2 wt% and the mixing time is 8 minutes, which ensures good flowability and tabletting performance, suitable for large-scale industrial production.

[0083] Example 4

[0084] A drug for treating infertility, which is a biphasic controlled-release tablet containing an immediate-release layer and a sustained-release layer.

[0085] Preparation of polyethylene glycol-hemisuccinate choline salt:

[0086] Under nitrogen protection, polyethylene glycol with a number average molecular weight of 1900 190.0 g and succinic anhydride 11.1 g were mixed in a ratio of 1.10:1 of end hydroxyl equivalent, and reacted at 90°C for 4 hours to obtain a polyethylene glycol hemisuccinate with an acid value of 60.0 mg KOH / g. The obtained hemiester was dissolved with isopropanol / water (mass ratio 95 / 5) solution, activated carbon was added for decolorization for 30 minutes, and then filtered and the solvent was removed under reduced pressure. The purified hemiester was dissolved in a mixed solvent of ethanol / water (mass ratio 90 / 10), and choline hydroxide aqueous solution was added dropwise at 25°C, with a molar ratio of carboxyl to choline of 1.05:1, the pH was adjusted to 7.2, and the neutralization degree reached 99%. The obtained solution was dried at 50°C to a moisture content of 0.1 wt%, to obtain a polyethylene glycol-hemisuccinate choline salt with an acid value of 0.8 mg KOH / g, an end group substitution degree of 2.0, and a neutralization degree of 99%.

[0087] Drug preparation:

[0088] S1. Micro-coating and granulation of letrozole granules: The above prepared PEG-hemisuccinate choline salt was formulated into a 2 wt% ethanol / water solution (mass ratio of ethanol / water 80 / 20), and sprayed into a fluidized bed at a spraying rate of 30 g / min to increase the weight of letrozole granules by 1.5 wt%, with an output moisture content of 1.0 wt%.

[0089] S2. Preparation of immediate-release layer: Letrozole granules after weight gain 7.5 mg were mixed with microcrystalline cellulose 39.1 mg (23 wt%), cross-linked polyvinylpyrrolidone 4.25 mg (2.5 wt%), PEG-hemisuccinate choline salt 3.23 mg (1.9 wt%), and magnesium stearate 2.38 mg (1.4 wt%) for 9 minutes, and the remaining excipients were supplemented to a total weight of 170 mg of the immediate-release layer.

[0090] S3. Preparation of sustained-release layer: Hydroxypropyl methylcellulose 73.1 mg (43 wt%), microcrystalline cellulose 82.0 mg, magnesium stearate 1.5 mg, and other excipients were mixed to a total weight of 170 mg.

[0091] S4. Double-layer tabletting: On a rotary tablet press, the sustained-release layer mixture was first added, followed by the immediate-release layer mixture, and compressed into a double-layer tablet at a compression force of 17 kN. Drying was performed at 50°C until the tablet moisture content was 4.8 wt%, resulting in a total weight of 340 mg of the biphasic controlled-release tablet.

[0092] Quality testing:

[0093] The tablet hardness was 118 N, the friability was 0.5%, and the disintegration time was 14 minutes. In vitro release rate determination showed that the cumulative release was 45% at 2 hours and 94% at 24 hours.

[0094] Example 4 Features: This example adopts higher parameter configuration, systematically verifies the implementability of multiple core parameters in the claims at higher values, fully proves the authenticity and effectiveness of the patent protection range. The content of letrozole is 7.5 mg, which verifies the feasibility of high-dose formula, which is suitable for patients with refractory ovulation disorders or patients who need intensive treatment. The 2-hour cumulative release is 45%, which cooperates with the high content of hydroxypropyl methyl cellulose 43 wt%, forming a strong sustained-release system, which ensures the initial effect while realizing a more gentle and persistent release curve, especially suitable for patients who need long-acting and stable blood drug concentration. The 24-hour cumulative release of 94% ensures the full absorption and utilization of the drug. The content of polyethylene glycol-hemisuccinate choline salt is 1.9 wt% and the end group substitution degree is 2.0, which verifies the performance and stability of the auxiliary material under high substitution degree conditions. The molecular weight of polyethylene glycol is 1900, cooperated with the end hydroxyl equivalent ratio of 1.10:1, the reaction temperature of 90°C and the reaction time of 4 hours, which systematically verifies the feasibility of the preparation process of polyethylene glycol-hemisuccinate choline salt under higher parameter conditions, proves that high-quality products (acid value 0.8 mg KOH / g) can still be prepared under these process parameters. The neutralization process adopts the carboxyl to choline molar ratio of 1.05:1, pH 7.2, drying temperature 50°C, which obtains the super high neutralization degree of 99%, which proves the robustness of the process. In the tabletting process, the micro-coating weight gain is 1.5 wt%, the mixing time is 9 minutes, the tabletting force is 17 kN, the spraying speed is 30 g / min, etc. Multiple process parameters verify the operability and equipment adaptability of industrial production. The tablet hardness is 118 N and the disintegration time is 14 minutes, which proves that the high hardness formula can still maintain good disintegration performance. The friability is 0.5% in the middle level of the qualified range, which shows that under the combination of higher parameters, it still has good tablet quality. This example verifies the implementability of multiple core parameters in the claims at higher values through systematic verification of multiple parameters, which fully proves the rationality of the patent protection range, provides a solid technical support for the rationality of the patent protection range, and also provides a high-dose, strong sustained-release treatment option for clinical, especially suitable for infertile patients who do not respond well to conventional treatment and need intensive treatment.

[0095] Comparative Example 1

[0096] Basically the same as Example 1, except that the number average molecular weight of polyethylene glycol-hemisuccinate choline salt is 800, and the use amount and preparation conditions of other components remain unchanged.

[0097] Comparative Example 2

[0098] Basically the same as Example 1, except that the number average molecular weight of polyethylene glycol-hemisuccinate choline salt is 2300, and the use amount and preparation conditions of other components remain unchanged.

[0099] Comparative Example 3

[0100] The same as example 1, except that the content of polyethylene glycol-hemisuccinyl choline salt in the immediate-release layer is 0.5 wt%, and the dosages of other components and the preparation conditions are unchanged.

[0101] Comparative example 4

[0102] The same as example 1, except that the content of polyethylene glycol-hemisuccinyl choline salt in the immediate-release layer is 2.5 wt%, and the dosages of other components and the preparation conditions are unchanged.

[0103] Comparative example 5

[0104] The same as example 1, except that the end-group substitution degree of polyethylene glycol-hemisuccinyl choline salt is 1.6, and the dosages of other components and the preparation conditions are unchanged.

[0105] Comparative example 6

[0106] The same as example 1, except that the neutralization degree of polyethylene glycol-hemisuccinyl choline salt is 90%, and the dosages of other components and the preparation conditions are unchanged.

[0107] Comparative example 7

[0108] The same as example 1, except that the content of hydroxypropyl methyl cellulose in the sustained-release layer is 10 wt%, and the dosages of other components and the preparation conditions are unchanged.

[0109] Comparative example 8

[0110] The same as example 1, except that the content of hydroxypropyl methyl cellulose in the sustained-release layer is 50 wt%, and the dosages of other components and the preparation conditions are unchanged.

[0111] Comparative example 9

[0112] The same as example 1, except that conventional polyethylene glycol 6000 is used instead of polyethylene glycol-hemisuccinyl choline salt, and the dosage is 1.4 wt%, and the dosages of other components and the preparation conditions are unchanged.

[0113] Comparative example 10

[0114] The same as example 1, except that the content of disintegrant in the immediate-release layer is 1.0 wt%, and the dosages of other components and the preparation conditions are unchanged.

[0115] Comparative example 11

[0116] The same as example 1, except that the tabletting force is 6 kN, and the dosages of other components and the preparation conditions are unchanged.

[0117] Comparative example 12

[0118] The same as Example 1, except that the fluidized bed spray coating weight of letrozole particles is 0.5 wt%, and the use amount and preparation conditions of other components remain unchanged.

[0119] Comparative Example 13

[0120] The same as Example 1, except that the fluidized bed spray coating process is not performed, and the letrozole is directly mixed with other excipients of the immediate-release layer for granulation, and the use amount and preparation conditions of other components remain unchanged.

[0121] Performance test:

[0122] Experiment 1: In vitro release test

[0123] The in vitro release test takes the letrozole biphasic controlled-release tablet as the test object, aiming to evaluate the release characteristics of the immediate-release layer and the sustained-release layer in two time windows, and verify whether the cumulative release at 2 hours and 24 hours meets the design requirements, directly proving that the technical contradiction of "tablet densification and maintaining of double time window release channel" is solved. The test adopts the principle of paddle method dissolution test, and the cumulative release amount of the drug at different time points is determined by ultraviolet spectrophotometry to evaluate the release characteristics of the biphasic controlled-release tablet. The experimental method refers to the dissolution test method (paddle method) in the fourth part of Chinese Pharmacopoeia 2020 edition 0931, and 6 tablets of the product are placed in the dissolution cup of the dissolution tester. The pH 6.8 phosphate buffer 900 mL is used as the dissolution medium, the temperature is 37±0.5℃, the rotation speed is 100 rpm, and the samples are taken at 0.5, 1, 2, 4, 6, 8, 12 and 24 hours. 5 mL (after sampling, the same volume of dissolution medium is immediately supplemented), filter through a 0.45 μm microporous filter, and take the filtrate as the test solution. The concentration of letrozole is determined by high performance liquid chromatography (HPLC) (detection wavelength 240 nm, mobile phase acetonitrile-water 60:40), and the cumulative release percentage at each time point is calculated by the standard curve method and the release curve is drawn, focusing on the requirements of 45-60% cumulative release at 2 hours and 85-95% cumulative release at 24 hours. The data processing adopts the external standard method to calculate the cumulative release percentage at each time point, and the results are expressed as mean ± standard deviation (n=6), and the time-cumulative release curve is drawn.

[0124] Experiment 2: Tablet physical property test

[0125] The physical property test of the tablet takes the biphasic controlled-release tablet of letrozole as the test object, aiming to evaluate the hardness, friability and disintegration time of the tablet, verify that the tablet can still maintain good physical properties and rapid disintegration characteristics under high densification tabletting conditions, and prove that the technical scheme solves the contradiction of "tablet densification and release channel maintenance". The mechanical strength, anti-fracture ability and disintegration performance of the tablet are determined by hardness tester, friability tester and disintegration tester respectively. The hardness test refers to the fourth part of Chinese Pharmacopoeia 2020 edition 0101 tablets, and the radial hardness of 10 tablets is determined by tablet hardness tester (YD-35 type) at random, and the result is expressed as mean ± standard deviation, which is required to be 90-120 N; the friability test refers to the fourth part of Chinese Pharmacopoeia 2020 edition 0101, and 20 tablets are precisely weighed after removing the surface dust, and then placed in the friability tester with a rotating speed of 25 rpm for 4 minutes (100 turns), and then the tablets are weighed again after removing the fragments and surface dust, and the weight loss percentage is calculated (required to be ≤0.8%); the disintegration time test refers to the fourth part of Chinese Pharmacopoeia 2020 edition 0921 disintegration time limit inspection method, and 6 tablets are taken and placed in the disintegration instrument basket with pH 6.8 phosphate buffer 900 mL as the medium, temperature 37±1℃, and the disintegration test is carried out according to the first method (basket method), and the total disintegration time is recorded (required to be ≤15 min). In the data processing, the hardness result is expressed as mean ± standard deviation (n=10), the friability is calculated according to the formula friability (%)=(weight before test-weight after test) / weight before test×100%, and the disintegration time is recorded as the average time of 6 tablets ± standard deviation.

[0126] Experiment 3: Polyethylene glycol-hemisuccinate choline salt mass detection

[0127] Polyethylene glycol-hemisuccinate choline salt quality detection The polyethylene glycol-hemisuccinate choline salt excipient synthesized by the self was used as the test object, aiming to determine the number average molecular weight, end group substitution degree, neutralization degree and acid value, verify that the synthesis process can stably prepare the key excipient meeting the design requirements, and prove that the solution of the contradiction between the low water content stability of the formula and the ion pair water release and hydration demand depends on the specific specification of polyethylene glycol-hemisuccinate choline salt. Gel permeation chromatography (GPC) was used to determine the number average molecular weight, 1H-nuclear magnetic resonance (1H-NMR) was used to determine the end group substitution degree, potentiometric titration method was used to determine the neutralization degree, and acid-base titration method was used to determine the acid value. The number average molecular weight was determined by GPC method, the chromatographic column was TSKgel G3000HXL, the mobile phase was tetrahydrofuran, the flow rate was 1.0 mL / min, the column temperature was 40°C, and the differential refractive index detector was used, and the calibration curve was established with polyethylene glycol standard. The end group substitution degree was determined by 1H-NMR method (Bruker 400 MHz nuclear magnetic resonance instrument), deuterated chloroform was used as the solvent, and the substitution degree was calculated by the integral ratio of the methylene proton peak (δ 3.6-3.7 ppm) of the polyethylene glycol main chain and the methylene proton peak (δ 2.5-2.7 ppm) of the succinate end group; the neutralization degree was determined by potentiometric titration method, about 0.5 g of the sample was accurately weighed and dissolved in 50 mL of ethanol / water (1:1) mixed solvent, 0.1 mol / L hydrochloric acid standard solution was used for titration until pH 4.5, and the volume V1 of hydrochloric acid consumed was recorded. The same amount of sample was titrated with 0.1 mol / L sodium hydroxide standard solution until pH 9.5, and the volume V2 of sodium hydroxide consumed was recorded. The neutralization degree (%) = (V2-V1) / V2 x 100%; the acid value was determined according to the acid value determination method in Chinese Pharmacopoeia 2020 edition four, 2-3 g of the sample was accurately weighed and dissolved in 50 mL of neutral ethanol-ether mixed solution (1:1), phenolphthalein was used as the indicator, 0.1 mol / L potassium hydroxide ethanol solution was used for titration until the end point of 30 seconds without fading, and the acid value (mg KOH / g) was calculated. In the data processing, the number average molecular weight was calculated by GPC calibration curve, the end group substitution degree was calculated by NMR integral ratio, the neutralization degree and the acid value were calculated according to the formula, and the results were represented as mean ± standard deviation (n=3).

[0128] Experiment 4: Coating layer uniformity characterization

[0129] Coating uniformity characterization takes the letrozole particles after fluidized bed microencapsulation as the test object, aiming to evaluate the uniformity and reproducibility of the fluidized bed spray coating process, verify the uniform distribution of the coating layer under the condition of particle weight gain of 1.0-1.5 wt%, and prove the solution of the "fluidized bed microencapsulation process window and initial release consistency" problem. The coating uniformity is analyzed by observing the coating morphology and thickness by scanning electron microscope (SEM), combined with coating weight gain and particle size distribution. The experimental method uses scanning electron microscope (SEM, Hitachi S-4800) to observe the surface morphology of the particles before and after coating, acceleration voltage 5 kV, working distance 8 mm, after vacuum gold plating treatment of the sample, SEM images of different magnifications (500x, 2000x, 5000x) are taken, 20 particles are randomly selected to measure the coating thickness and calculate the average value and relative standard deviation (RSD); laser particle size analyzer (Malvern Mastersizer 3000) is used to determine the particle size distribution of the particles before and after coating, the dispersion medium is anhydrous ethanol, ultrasonic dispersion for 3 minutes, D10, D50, D90 values are determined, and the change and uniformity of the particle size distribution are evaluated; coating weight gain uniformity verification takes 100 g of coated particle sample and divides it into 10 parts by quartering method, each part is accurately weighed about 10 g and dissolved in appropriate amount of methanol for ultrasonic extraction for 30 minutes, after filtration, HPLC method is used to determine the content of letrozole, and the drug content of each sample is calculated to evaluate the intra-batch uniformity (RSD should be ≤5.0%). In data processing, the coating thickness is expressed as mean ± standard deviation and RSD is calculated, the particle size distribution gives D10, D50, D90 values and particle size distribution curve, and the coating weight gain uniformity is expressed by the RSD of drug content (required ≤5.0%).

[0130] Experiment 5: Moisture content determination

[0131] The moisture content determination takes polyethylene glycol-hemisuccinyl choline salt raw materials and finished tablets as the test objects, aiming to determine the moisture content of polyethylene glycol-hemisuccinyl choline salt raw materials and finished tablets, verify that the process can realize low moisture control (auxiliary materials ≤0.5 wt%, tablets ≤5.0 wt%), and prove the solution to the contradiction between the low water content stability of the formula and the demand for ion pair water release and hydration. The test uses the Karl Fischer method to determine the moisture content in the sample, and calculates the moisture content according to the volume or electric quantity of the consumed reagent through the quantitative reaction of Karl Fischer reagent and water. The experimental method refers to the first method (Fisher method) of moisture determination method 0832 in Chinese Pharmacopoeia 2020 edition, and uses Karl Fischer moisture meter (Metrohm 831 type) with anhydrous methanol as the solvent. The polyethylene glycol-hemisuccinyl choline salt raw material is precisely weighed 0.5-1.0 g and directly added into the titration cell for coulometric titration to record the moisture content (wt%). The determination is carried out in parallel for 3 times. The tablet moisture is determined by grinding the finished tablets into fine powder, precisely weighing about 1.0 g and adding into the titration cell for determination. The results are expressed in wt% and determined in parallel for 3 times. The polyethylene glycol-hemisuccinyl choline salt moisture is required to be ≤0.5 wt%, and the tablet moisture is required to be 1.0-5.0 wt%. At the same time, the effects of drying temperature (40-50℃) and drying time on the moisture content are investigated to optimize the drying process. In the data processing, the moisture content is expressed in wt%, and the results are the average value ± standard deviation of 3 determinations, and the relative standard deviation (RSD should be ≤5%).

[0132] Experiment 6: Accelerated stability test

[0133] The accelerated stability test takes the finished product of the bifacial controlled-release tablets of letrozole as the test object, aiming to evaluate the stability of the preparation under accelerated conditions, investigate the influence of polyethylene glycol-hemisuccinyl choline salt on the stability of the preparation, verify the realization of "low water content formula stability", and provide the basis for determining the shelf life. The preparation is stored under high temperature and high humidity accelerated conditions, and the changes of indicators such as appearance, content, impurities, and dissolution are detected regularly to evaluate the stability of the preparation. The experimental method refers to the Guiding Principles for Stability Testing of Raw Materials and Preparations in Chinese Pharmacopoeia 2020 Edition Part 4 9001, and the accelerated test conditions are temperature 40±2℃, relative humidity 75±5% RH (drug stability test box model LHH-150SD). Three batches of samples are packaged with high-density polyethylene bottles, and samples are taken at 0, 1, 2, 3, and 6 months for the following tests: appearance (visual recording of color, presence or absence of spots, cracking, etc.), content determination (HPLC method according to the letrozole content determination method in Chinese Pharmacopoeia 2020 Edition, 90.0-110.0% of the labeled amount), related substances (HPLC method, single impurity ≤0.5%, total impurities ≤2.0%), dissolution (2 hours and 24 hours cumulative release according to the method of experiment 1), moisture (Karl Fischer method according to the method of experiment 5), tablet hardness, friability, and disintegration time (according to the method of experiment 2), and a long-term stability test (25±2℃, 60±5% RH for 12 months) is set as a control. In data processing, the results of each index are represented as mean ± standard deviation (n=3), the curves of the index changes with time are drawn to evaluate the stability trend, and the content degradation rate (%) = (initial content-t time content) / initial content × 100%.

[0134] Figure 1: Effect of PEG-HSC content on release behavior, Under the basic conditions of fixed letrozole amount 5.0 mg / tablet, HPMC content 30 wt%, tabletting force 13 kN and coating weight gain 1.25 wt%, the effect of PEG-HSC (number average molecular weight 1500 Da, end group substitution degree 1.9) content in the immediate-release layer from 0.5 wt% to 2.4 wt% on the cumulative release was systematically investigated. The results showed that when the content of the excipient was in the range of 1.2-2.0 wt%, the 2-hour cumulative release could be controlled between 45-55%, and the 24-hour cumulative release was stable in the range of 91-93%, which could achieve the ideal dual-time window release characteristics. When the content was less than 1.0 wt%, the initial release rate was significantly accelerated, and the 2-hour release exceeded 55%, indicating that the ion pair release aid was too strong, resulting in too fast drug release from the immediate-release layer; while when the content was higher than 2.0 wt%, the 24-hour release slightly increased but the change tended to be flat, indicating that increasing the amount of the excipient had limited contribution to the release extension. Standard deviation data showed that within the optimized range of 1.2-2.0 wt%, the batch-to-batch variation of 2-hour release (RSD 1.8-2.3%) and 24-hour release (RSD 1.3-1.6%) both remained at a low level, proving that the concentration window could not only accurately control the biphasic release behavior, but also ensure the process reproducibility. This result showed that as an ion pair type release aid, the accurate control of PEG-HSC content played a key role in balancing the rapid release requirement of the immediate-release layer and the sustained release characteristics of the sustained-release layer.

[0135] Figure 2Effect of HPMCAS content on release behavior, under the premise of keeping the amount of letrozole 5.0 mg / tablet, the content of PEG-CHS in the immediate-release layer 1.4 wt%, the tabletting force 13 kN and the coating weight gain 1.25 wt%, the effect of HPMCAS content in the sustained-release layer from 8 wt% to 50 wt% on the double-time window release characteristics was studied. The experimental data showed that when the HPMCAS content was in the range of 20-40 wt%, the design goal of 45-60% release in 2 hours and 86-95% release in 24 hours could be effectively achieved, and the release curve in the concentration range of 25-35 wt% was most consistent with the clinical requirements. When the content was less than 20 wt%, the gel matrix strength was insufficient, resulting in weakened sustained-release effect, with 2-hour release exceeding 60%, showing that the initial drug release was too fast; while when the content was higher than 40 wt%, the overstrong gel matrix significantly slowed down the drug diffusion, resulting in 24-hour cumulative release falling below 86%, which could not meet the requirement of complete release throughout the day. It is worth noting that in the low content range of 8-15 wt%, the 2-hour release was as high as 65-75% and the 24-hour release was close to 98%, showing the release characteristics similar to that of immediate-release tablets; while in the high content range of 45-50 wt%, the 24-hour release decreased to 77-84%, showing an excessive sustained-release tendency. Standard deviation analysis showed that the batch-to-batch variation in the optimized range of 20-40 wt% was well controlled (RSD≤3%), proving the stability of the process. These findings fully demonstrate that as a hydrophilic gel matrix material, the accurate control of the amount of HPMCAS is the core element to achieve the dual-phase release characteristics of immediate-release and sustained-release, and to avoid initial burst release or insufficient release later.

[0136] Figure 3The effect of letrozole content on release behavior was investigated using the standard formulation system of Example 1 (immediate-release layer: polyethylene glycol-hemisuccinate choline salt 1.4 wt%, sustained-release layer: hydroxypropyl methylcellulose 30 wt%, compression force: 13 kN, coating weight gain: 1.25 wt%). The effect of varying letrozole dosage from 1.5 mg to 8.5 mg on cumulative release was systematically evaluated, while maintaining the relative proportions of excipients. The results showed that within a broad dose range of 2.5–7.5 mg, the 2-hour cumulative release remained stable at 50–53%, and the 24-hour cumulative release remained at 90–92%. The morphology of the release curve was largely unaffected by changes in drug loading. Even when the dose was reduced to 1.5 mg or increased to 8.5 mg, the release characteristics remained within a reasonable range, with a 2-hour release variation of only 49–54% and a 24-hour release variation of 88–92%, demonstrating good dose adaptability. Standard deviation data showed that the inter-batch variation was controlled within RSD of 2.0-2.8% throughout the entire study range, demonstrating the robustness of the formulation design. When the dosage exceeded 8.0 mg, the 24-hour release showed a slight decreasing trend, but the decrease was limited (down to 88-89%), which may be related to slight changes in the tablet microstructure under high drug content, but this change does not affect the feasibility of clinical application. This result fully demonstrates that the release mechanism of this biphasic controlled-release tablet is mainly controlled by the release channels and gel skeleton constructed by the excipient system, rather than simply relying on drug solubility or diffusion rate. Therefore, it has excellent dosage flexibility, and the dosage can be adjusted according to clinical needs without re-optimizing release parameters, providing technical support for the development of individualized treatment plans.

[0137] comprehensive Figures 4 to 12 Infrared Fourier transform spectroscopy results show that each component of the formulation of this invention has clear and distinguishable fingerprint peaks, and these peaks are reasonably retained and linearly superimposed in the immediate-release layer, sustained-release layer, and the overall bilayer tablet composition. This demonstrates that the formulation and process did not introduce any adverse chemical interactions and met the expected design of the formulation: letrozole in Figure 4 The middle section is 2230 cm -1 The characteristic strong peak of C≡N is located at... Figure 10 – Figure 12 The same displacement method can be used to identify it, and no significant displacement or peak distortion is observed; Figure 5 The 1735 cm of polyethylene glycol hemisuccinate choline salt shown -1 Ester group C=O and 1105 cm -1 C–O–C signal in the quick release layer combination spectrum ( Figure 10 Appearing proportionally in ( ); Figure 6 and Figure 8 Corresponding to microcrystalline cellulose and hydroxypropyl methylcellulose at 1058 / 1020 cm⁻¹, respectively. -1polysaccharide C-O backbone peaks at ca. 1050 cm Figure 11 predominate in the sustained release layer (SRL) Figure 12 and coexist with other peaks in the overall composition (OC) Figure 7 Cross-linked povidone 1655 cm -1 lactam C=0 and 1290 / 1019 cm -1 C-N peaks maintain their positions in the combined spectra; Figure 9 Magnesium stearate 1540 / 1415 cm -1 carboxylate salt pair with 2918 / 2849 cm -1 alkane signals appear weak to moderate in intensity in each combined spectrum without new peaks being generated. Overall, the combined spectra do not show new strong absorptions or systematic shifts in key peak systems, the baselines and peak intensities are reasonably additive at the prescription mass fractions, and there is no evidence of chemical reactions such as esterification or amidation, thus demonstrating that the prescription composition and process route of the examples are reasonable and feasible.

[0138] The performance of the example and comparative example drugs is summarized in Table 1, and the data of Examples 1-4 systematically demonstrate the superiority of the technical solution. In terms of release kinetics, the 2-hour cumulative release of the four examples is concentrated in the 45-55% range (45±1.8% to 55±2.3%), and the 24-hour cumulative release is stable in the 90-94% range (90±1.8% to 94±1.4%), accurately achieving the dual-time-window release target, and the standard deviation is controlled within 1.4-2.3%, showing excellent batch-to-batch consistency. In terms of tablet physical properties, the hardness is maintained in the high-strength range of 90-120 N (95±2.8 N to 118±3.8 N), while the friability is all below 0.7% (0.3±0.06% to 0.6±0.09%), proving that high-density compression does not compromise tablet integrity; although the disintegration time is prolonged with increasing hardness (6±0.4 min to 14±0.7 min), it is still controlled within 15 minutes, ensuring that the rapid release path of the immediate-release layer is not blocked. The gradient setting of the coating weight gain of 1.10-1.50 wt% verifies the operability of the fluidized bed micro-coating process window, and the control range of the tablet moisture of 2.0-4.8 wt% proves the balance between low moisture stability and ion pair release hydration requirements. Comparative Examples 1-13 verify the necessity of key technical parameters from different angles: Comparative Example 1 has a 2-hour release of up to 68±3.2%, Comparative Example 2 (with too high a molecular weight) has a 24-hour release of only 78±2.8%, Comparative Example 11 (with insufficient compression force) has a hardness of 68±2.5 N and a friability of 1.2±0.15%, and Comparative Example 13 (without a coating layer) has a 2-hour release of up to 78±3.8%, clearly revealing that any parameter deviating from the optimized range will result in significant performance degradation, and from the negative side, confirming the indispensability of each element of the example technical solution and the importance of their synergistic effect.

[0139] Table 2 is the conclusion of the quality index of PEG-hemisuccinyl choline salt. The data of the quality index of the excipients of Examples 1-4 fully prove the decisive influence of the structural parameters of ion pair type release aid on the performance of the preparation. The four samples with number average molecular weight in the range of 1200-1900 Da (1195±22 Da to 1892±30 Da) show a good performance gradient: the 2-hour release of Example 2 (1195 Da) is the fastest at 55%, and the release of Example 4 (1892 Da) is the slowest at 45%, showing a regularity of delayed release with increasing molecular weight, which is due to the longer PEG chain enhancing the thickness of the hydration film and moderately delaying the drug diffusion rate. The accurate control of the end group substitution degree of 1.85-2.00 ensures that each PEG chain end carries enough hemisuccinic acid groups to form an ion pair with choline to achieve the effect of solubilization and dissolution, and the neutralization degree of the four examples is more than 96% (96.1±0.6% to 99.0±0.3%), and the corresponding acid value is reduced to 0.8-3.0 mg KOH / g, proving that the ion pair is formed completely and stably. The moisture content is strictly controlled below 0.1-0.4 wt%, which not only avoids the hygroscopic degradation of the excipient, but also retains the necessary crystallization water to promote the hydration release. The data of Comparative Examples 1, 2, 5, and 6 prove the rationality of the parameter window from the opposite side: Comparative Example 1 (molecular weight 798 Da) has a chain length that is too short, resulting in a 2-hour release that is too fast at 68%, Comparative Example 2 (molecular weight 2285 Da) has a chain length that is too long, resulting in a 24-hour release of only 78%, Comparative Example 5 (substitution degree 1.60) has an ion pair density that is too low, resulting in an unsatisfactory release, and Comparative Example 6 (neutralization degree only 90%) has too much free acid (acid value 8.5 mg KOH / g) that may affect the stability of the formula, these control experiments clearly define the scientific basis of the quality control standards of number average molecular weight 1200-1900 Da, end group substitution degree 1.8-2.0, neutralization degree ≥95%, acid value ≤5.0 mg KOH / g, moisture ≤0.5 wt%.

[0140] Table 3 is a conclusion of accelerated stability test data. The continuous tracking data of Example 1 under harsh conditions of 40°C / 75% RH for 6 months systematically proves the long-term stability of the formulation and the effective solution of the triple technical contradictions. From the chemical stability, the content of letrozole slowly decreases from the initial 100.0 ± 0.8% to 96.5 ± 1.3% at the 6th month, with a cumulative degradation of only 3.5%, far below the acceptable limit of 5%, proving that the ion pair structure of polyethylene glycol-hemisuccinate choline salt does not cause the degradation of the main drug in a high humidity environment, and the low water content formulation design (initially 3.0 wt%, rising to 4.0 wt% after 6 months) successfully inhibits the hydrolysis reaction. In terms of release kinetics stability, the 2-hour cumulative release rate decreases slightly from 52 ± 2.1% to 49 ± 2.5% (change range 5.8%), and the 24-hour cumulative release rate decreases from 91 ± 1.5% to 89 ± 1.9% (change range 2.2%), with the standard deviation always controlled within the range of 1.5-2.5%, indicating that the dual-time-window release characteristics are not affected by environmental stress, the uniformity of the micro-coating layer and the integrity of the gel matrix are maintained, and the technical contradiction of "fluidized bed micro-coating process window and initial release consistency" is successfully solved. In terms of tablet physical properties, the hardness decreases from the initial 105 ± 3.2 N to 100 ± 3.6 N (decrease 4.8%), and the moisture increases from 3.0 ± 0.2 wt% to 4.0 ± 0.28 wt% (increase 1.0 percentage points), but the disintegration time and friability do not show significant signs of deterioration, proving that the high densification tablets still maintain mechanical strength under hygroscopic conditions, while the hygroscopicity of polyethylene glycol-hemisuccinate choline salt causes a slight increase in moisture, but the final moisture of 4.0 wt% is still far below the upper limit of 5.0 wt%, and the hydration release effect provided by the ion pair structure is retained, successfully achieving the balance of "low water content stability of the formulation and the need for ion pair hydration release". This set of time series data fully proves that the triple technical contradictions are not independent of each other but are interrelated, and through the precise molecular design of polyethylene glycol-hemisuccinate choline salt, the optimization control of the fluidized bed coating parameters, and the reasonable adjustment of the tablet densification process, the multiple requirements of chemical stability, controllable release, and physical strength can be met simultaneously under long-term storage conditions.

[0141] Table 1 Performance comparison data of examples and comparative examples

[0142]

[0143] Table 2 Quality indicators of polyethylene glycol-hemisuccinate choline salt

[0144]

[0145] Table 3 Accelerated stability test data (40°C / 75% RH)

[0146]

[0147] It should be pointed out finally that the above embodiments are only used to illustrate the technical solutions of the present application but not to limit it. Although the present application has been described in detail with reference to the above embodiments, it should be understood by those of ordinary skill in the art that any equivalent structure transformation made under the concept of the present application and by using the content of the present application specification and drawings should be covered within the protection scope of the claims of the present application.

Claims

1. A drug for treating infertility, characterized in that, This is a biphasic controlled-release tablet comprising an immediate-release layer and a sustained-release layer; letrozole 2.5–7.5 mg / tablet; the immediate-release layer contains 0.8–2.0 wt% polyethylene glycol-hemisuccinate choline salt, wherein the polyethylene glycol-hemisuccinate choline salt has a number-average molecular weight of 1000–2000, a degree of terminal substitution of 1.8–2.0, a degree of neutralization ≥95%, and an acid value ≤5.0 mg KOH / g; the cumulative release of the drug is 45–60% at 2 h and 85–95% at 24 h.

2. A drug for treating infertility according to claim 1, characterized in that, The content of polyethylene glycol-hemisuccinate choline salt in the immediate-release layer is 1.2–1.6 wt%.

3. A drug for treating infertility according to claim 1, characterized in that, The preparation method of the polyethylene glycol-hemisuccinate choline salt is as follows: under an inert atmosphere, polyethylene glycol with a number average molecular weight of 1000–2000 is reacted with succinic anhydride at a terminal hydroxyl equivalent ratio of 1.05–1.10:1 at 80–90 °C for 2–4 h to obtain a hemiester with an acid value of 45–60 mg KOH / g; the hemiester is dissolved, decolorized, filtered, and the solvent is removed by isopropanol / water mass ratio of 95 / 5. Choline hydroxide or choline bicarbonate was added to a medium with an ethanol / water mass ratio of 90 / 10 and neutralized to pH 6.8–7.2 at a carboxyl to choline molar ratio of 1.00–1.05:

1. The mixture was then dried at 40–50 °C until the moisture content was ≤0.5 wt% to obtain the polyethylene glycol-hemisuccinate choline salt.

4. A drug for treating infertility according to claim 1, characterized in that, The sustained-release layer contains 15–45 wt% hydroxypropyl methylcellulose and is adjusted to achieve a cumulative release of 85–95% over 24 h.

5. A drug for treating infertility according to claim 1, characterized in that, The immediate-release layer diluent is selected from at least one of microcrystalline cellulose and lactose monohydrate, with a total content of 20–70 wt%.

6. A drug for treating infertility according to claim 1, characterized in that, The immediate-release layer disintegrant is selected from crospovidone or sodium carboxymethyl starch, with a content of 2.0–6.0 wt%.

7. A drug for treating infertility according to claim 1, characterized in that, The cumulative release of the drug at 2 h is preferably 48–58%, and the cumulative release at 24 h is preferably 88–94%. The tablets of the drug have a hardness of 90–120 N, a friability of ≤0.8%, and a disintegration time of ≤15 min.

8. A method for preparing a medicament for treating infertility as described in any one of claims 1 to 7, characterized in that, Includes the following steps: S1. Micro-coating and granulation of letrozole granules: Polyethylene glycol-hemisuccinate choline salt was sprayed into a fluidized bed in a 2 wt% ethanol / water solution to increase the weight of letrozole granules by 1.0–1.5 wt%, with an output water content ≤2.0 wt%; S2. Mixing and tableting of immediate-release and sustained-release layers: Mix the weight-adding granules with the immediate-release layer diluent, disintegrant, and lubricant for 3–10 min. The lubricant is magnesium stearate with a content of 0.2–1.5 wt%. The tableting force is 8–18 kN. The mixture is then pressed with a sustained-release layer containing hydroxypropyl methylcellulose and dried until the tablet contains 1.0–5.0 wt% water to obtain the drug.

9. The method for preparing a drug for treating infertility as described in claim 8, wherein the spray liquid in S2 is a 2 wt% aqueous solution of polyethylene glycol-hemisuccinate choline salt in ethanol / water, the ethanol / water mass ratio is 80 / 20, and the spraying speed is 20–30 g / min.

10. The application of the medicament for treating infertility as described in any one of claims 1 to 7, or the medicament for treating infertility obtained by the preparation method as described in claims 8 to 9, in the treatment of infertility, characterized in that, In the stated uses, infertility refers to infertility related to ovulation disorders.

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