Solid dispersion-based sustained-release drug composite carrier as well as preparation method and application thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a solid dispersion-based sustained-release drug composite carrier as well as a preparation method and application thereof. The preparation method comprises the following steps: carrying out synergistic spray drying on double polymers (hydroxypropyl methylcellulose acetate succinate and polyvinylpyrrolidone-vinyl acetate copolymer) to form a solid dispersion; compounding with mesoporous silica and calcium silicate for localization, and spraying ethanol to activate pores; calcium stearate and magnesium stearate are sequentially added for lubrication; prefabricating a sustained-release skeleton master batch; and finally, mixing, rolling and forming. According to the method, through hierarchical structural design, the drug stability, the powder fluidity and the release controllability are remarkably improved, the method is suitable for industrial production of the dihydroergoline mesylate sustained release preparation, and a release curve is smooth and reliable.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular to a solid dispersion-based sustained-release drug composite carrier and a preparation method and application thereof. BACKGROUND

[0002] In the prior art, dihydroergotoxine mesylate as a poorly water-soluble drug often faces the problem of poor compatibility between the drug and the excipient when developing sustained-release preparations. Traditional sustained-release systems mostly rely on single polymer carriers, such as polyvinylpyrrolidone-vinyl acetate copolymer, which can initially improve the dispersion of the drug, but the single component is prone to hygroscopic plasticization under humidity conditions, causing the crystal form of the drug to change from amorphous to crystalline, which not only reduces the solubility of the drug, but also leads to a decrease in stability during storage. This change in crystal form further exacerbates the incompatibility of the excipient interface, causing uneven hardness during tabletting and affecting the mechanical strength of the tablet.

[0003] More prominently, when the hygroscopic polymer carrier is exposed to environmental humidity, the powder surface is prone to adhesion and caking, destroying the fluidity and making the filling and tabletting operations difficult to perform uniformly. In conventional processes, simple physical mixing of the solid dispersion with porous materials such as mesoporous silica does not achieve effective pore confinement, and the drug carrier still exists in a surface form, which cannot inhibit the humidity sensitivity problem. If the addition of inorganic excipients such as calcium silicate is not properly timed, it will preferentially form an outer layer, hindering the stabilization of the internal structure and increasing process fluctuations.

[0004] The use of lubrication systems also has limitations. Common lubricants such as magnesium stearate are prone to form a continuous hydrophobic layer under long-term shearing, which weakens the interparticle bonding force, leading to a decrease in tablet hardness and delayed disintegration. At the same time, if the mixed powder without granulation is directly used for the preparation of the sustained-release matrix, due to the difference in particle size distribution, the active ingredient is unevenly distributed during mixing, and the internal pore network is disordered after tabletting, leading to inconsistent penetration paths of the release medium, causing a burst release at the early stage or insufficient release at the later stage, and significant batch-to-batch differences. The existing technology lacks a systematic design from micro-dispersion to macro-formation, which cannot coordinate the drug stability, powder performance, and release controllability, restricting the scalable production of sustained-release preparations. SUMMARY

[0005] Therefore, the present application aims to provide a solid dispersion-based sustained-release drug composite carrier and a preparation method and application thereof to solve the problem of poor drug-excipient compatibility in existing dihydroergotoxine mesylate sustained-release preparations, which easily causes crystal transformation and hygroscopic caking, leading to fluctuations in tablet hardness and uncontrollable release curves, and seriously affecting the consistency of product quality.

[0006] To achieve the above purpose, the present application provides a preparation method of a solid dispersion-based sustained-release drug composite carrier, comprising the following steps:

[0007] (1) dissolving hydroxypropyl methyl cellulose acetate succinate in acetone to obtain solution A, dissolving polyvinylpyrrolidone-vinyl acetate copolymer in absolute ethanol to obtain solution B, adding solution B into solution A to obtain a polymer mixed solution; dissolving dihydroergotoxine mesylate in absolute ethanol to obtain solution C, adding solution C into the polymer mixed solution and mixing uniformly, and then performing spray drying to obtain solid dispersion microparticles;

[0008] (2) mixing mesoporous silica with the solid dispersion microparticles, spraying absolute ethanol into the mixture and mixing; further adding calcium silicate and mixing, and drying and sieving to obtain inorganic localized composite solid dispersion particles;

[0009] (3) mixing the inorganic localized composite solid dispersion particles with calcium stearate, further adding magnesium stearate and stopping mixing after 1 minute to obtain hydrophobic composite particles;

[0010] (4) mixing hydroxypropyl methyl cellulose, ethyl cellulose and microcrystalline cellulose to form a premixed powder, and performing dry roller compression and sieving to obtain a sustained-release matrix master batch;

[0011] (5) mixing the sustained-release matrix master batch with the hydrophobic composite particles, performing roller compression and sieving to obtain the solid dispersion-based sustained-release drug composite carrier.

[0012] Preferably, in step (1), the sum of the mass of hydroxypropyl methyl cellulose acetate succinate and polyvinylpyrrolidone-vinyl acetate copolymer is 240 parts based on 10 parts of dihydroergotoxine mesylate by weight, and the hydroxypropyl methyl cellulose acetate succinate is 60-120 parts.

[0013] Preferably, in step (1), the inlet air temperature of spray drying is 65-75°C, the outlet air temperature is 38-45°C, the atomizing gas flow rate is 600 L / min, the feeding amount is 45-55 g / min, and the nozzle diameter is 0.8-1.2 mm.

[0014] Preferably, in step (1), the powder obtained after spray drying is dried in a vacuum drying oven at 40°C for 6-8 h under a vacuum degree of not less than -90 kPa, and sieved through an 80-mesh sieve.

[0015] Preferably, in step (2), the sum of the mass of mesoporous silica and calcium silicate is 120 parts based on 250 parts of the solid dispersion microparticles by mass, and the amount of mesoporous silica is 60-100 parts, and the amount of absolute ethanol sprayed is 10-30 parts.

[0016] Preferably, in the step (3), the total amount of calcium stearate and magnesium stearate is 30 parts, and the amount of calcium stearate is 15-25 parts, based on 370 parts of the inorganic localized composite solid dispersion particles.

[0017] Preferably, in the step (3), the inorganic localized composite solid dispersion particles are premixed at 15 rpm for 2 min, then calcium stearate is added and mixed for 5 min, and then magnesium stearate is added and mixed for only 1 min.

[0018] Preferably, in the step (4), the amount of hydroxypropyl methyl cellulose is 200-300 parts by mass, the amount of microcrystalline cellulose is 200 parts, and the total amount of hydroxypropyl methyl cellulose and ethyl cellulose is 400 parts.

[0019] Preferably, in the step (4), the roll pressure of the dry roll granulation is 35-50 kN, the roll speed is 4-6 rpm, and the feeding screw speed is 15-25 rpm, and the obtained tablets are sieved through a 20-mesh sieve.

[0020] Preferably, in the step (5), the mass ratio of the sustained-release matrix master batch to the hydrophobic composite particles is 3:2.

[0021] Preferably, in the step (5), the mixing includes premixing at 15 rpm for 2 min and then mixing for 8 min, and the roll pressure of the roll is 8-12 kN, the roll speed is 4-6 rpm, and the obtained material is sieved through a 16-mesh sieve after roll.

[0022] Further, the application also provides a solid dispersion-based sustained-release drug composite carrier prepared by the above method.

[0023] Still further, the application also provides a use of the solid dispersion-based sustained-release drug composite carrier for preparing a sustained-release preparation of dihydroergotoxine mesylate.

[0024] The application has the following advantages:

[0025] The application uses the synergistic effect of hydroxypropyl methyl cellulose acetate succinate and polyvinylpyrrolidone-vinyl acetate copolymer to stabilize the dispersion of the drug at the molecular level, significantly improves the drug-excipient compatibility, and inhibits the tendency of crystal form change, thereby ensuring the initial stability of the release curve. The introduction of mesoporous silica and ethanol activation realize the embedding of the pores, the conversion of the hygroscopic polymer into a confined space, the unexpected enhancement of the powder flowability and anti-caking ability, and the provision of stable support for the outer structure. The calcium silicate forms an outer adsorption and compaction enhancement layer after localization, further improves the consistency of the tablet hardness, reduces the influence of humidity fluctuations, and makes the release curve smooth and reliable.

[0026] Calcium stearate and magnesium stearate time sequence control lubrication system forms non-continuous hydrophobic micro-domain, effectively inhibits hygroscopic caking and avoids hardness reduction caused by excessive lubrication, optimizes disintegration and release behavior. Pre-preparation and slight roller locking of the sustained-release matrix master batch realize hierarchical fixation of the core-shell-matrix, improve mixing uniformity and compaction consistency, and reduce release drift caused by process shearing.

[0027] The overall scheme balances among drug stability, powder performance and release controllability through multi-component hierarchical synergy, and provides a reliable foundation for sustained-release preparations. BRIEF DESCRIPTION OF DRAWINGS

[0028] In order to more clearly illustrate the technical solutions in the present application or prior art, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description.

[0029] Figure 1 Release curves of the drug composite carriers prepared for the present application examples 1-9;

[0030] Figure 2 Release curves of the drug composite carriers prepared for the present application examples 1 and comparative examples 1-6. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solutions and advantages of the present application more clear and explicit, the following will further describe the present application in combination with specific examples.

[0032] The polyvinylpyrrolidone-vinyl acetate copolymer used in the present specific embodiment is selected from BASF Kollidon VA64 (pharmaceutical grade); the hydroxypropyl methylcellulose acetate succinate is selected from Shin-Etsu AQOAT AS-LF (pharmaceutical grade); the mesoporous silica is selected from Evonik AEROPERL 300 Pharma (BET specific surface area 260-320 m 2 / g, mesoporous volume about 1-2 mL / g, particle size D50 about 20-60 μm); calcium silicate is selected from Tomita Pharmaceutical FLORITE R (pharmaceutical grade synthetic calcium silicate, particle size D50 about 30 μm, specific surface area about 160 m 2 / g, pH about 9); calcium stearate is selected from Peter Greven LIGAMED CPR-2-V-MB (pharmaceutical grade, D50 about 5-9 μm, specific surface area about 5-9 m 2magnesium stearate is selected from Peter Greven LIGAMED MF-2-V-MB (pharmaceutical grade, D50 about 7-11 μm, specific surface area about 6-10 m 2 hydroxypropyl methylcellulose is selected from Roquette Pharmaceutical Ingredients Business METHOCEL K100M Premium (pharmaceutical grade, 2% aqueous solution apparent viscosity target about 100000 mPa·s, water content not higher than 5%); ethyl cellulose is selected from Roquette Pharmaceutical Ingredients Business ETHOCEL Standard 10 FP Premium (pharmaceutical grade, 5% solution viscosity about 9-11 mPa·s); microcrystalline cellulose is selected from Roquette Pharmaceutical Ingredients Business Avicel PH-102 (pharmaceutical grade, average particle size about 100 μm, water content 3-5%); dihydroergotoxine mesylate is a pharmaceutical raw material, in line with the current edition of Chinese Pharmacopoeia; acetone and anhydrous ethanol are pharmaceutical grade solvents, residual solvent control in line with ICH Q3C requirements.

[0033] Example 1:

[0034] S1: 2500 g of acetone was added to a stirring tank, replaced with nitrogen for 30 min and maintained at 25℃, 90 g of hydroxypropyl methylcellulose acetate succinate was added under stirring at 600 rpm until a uniform clear solution was formed, to obtain solution A; another 500 g of anhydrous ethanol was added to 150 g of polyvinylpyrrolidone-vinyl acetate copolymer under stirring at 25℃ until clear, to obtain solution B, solution B was added to solution A in a slow and fine stream and continued to stir for 30 min, to obtain a polymer mixed solution; another 200 g of anhydrous ethanol was used to dissolve 10 g of dihydroergotoxine mesylate, to obtain solution C, which was added to the polymer mixed solution in a dropwise manner under stirring at 600 rpm and continued to stir for 30 min, filtered through a 1 μm filter membrane, and then spray dried in a closed nitrogen protection spray dryer, with the inlet air temperature set at 70℃, the outlet air temperature set at 40℃, the atomizing gas flow rate set at 600 L / min, the feed amount set at 50 g / min, and the nozzle diameter set at 1 mm, the powder was collected and dried in a vacuum drying oven at 40℃ under a vacuum degree not less than -90 kPa for 6 h, and then sieved through an 80 mesh sieve, to obtain a solid dispersion microparticle;

[0035] S2: In the mixer, 80 g of mesoporous silica was added and pre-mixed at 800 rpm for 2 min, then 250 g of solid dispersion microparticles were added in 3 times and mixed at 800 rpm for 8 min; then 20 g of anhydrous ethanol was sprayed in 2 times while maintaining 800 rpm and continued to mix for 3 min; finally, 40 g of calcium silicate was added and mixed at 600 rpm for 3 min, then the mixture was placed in a vacuum drying oven at 35°C and dried for 4 h under a vacuum degree not less than -90 kPa, and sieved through a 40 mesh sieve to obtain inorganic localized composite solid dispersion particles;

[0036] S3: In the mixer, 370 g of inorganic localized composite solid dispersion particles were added and pre-mixed at a rotation speed of 15 rpm for 2 min, then 20 g of calcium stearate was added and mixed for 5 min; then 10 g of magnesium stearate was added and mixed for only 1 min, and then stopped, to obtain hydrophobic composite particles;

[0037] S4: In the mixer, 250 g of hydroxypropyl methylcellulose, 150 g of ethyl cellulose, and 200 g of microcrystalline cellulose were mixed at a rotation speed of 15 rpm for 20 min to obtain a pre-mixed powder; the pre-mixed powder was roller granulated by dry granulation, with a roller pressure of 40 kN, a roller speed of 5 rpm, and a feeding screw of 20 rpm; the obtained tablet was sieved through a 20 mesh sieve by a granulator, to obtain a sustained-release matrix master batch;

[0038] S5: In the mixer, 600 g of the sustained-release matrix master batch was added and pre-mixed at a rotation speed of 15 rpm for 2 min, then 400 g of the hydrophobic composite particles was added and continued to mix for 8 min; then roller compression was performed, with a roller pressure of 10 kN and a roller speed of 5 rpm; the obtained material was sieved through a 16 mesh sieve by a granulator, to obtain a solid dispersion-based sustained-release drug composite carrier.

[0039] Example 2:

[0040] Compared with Example 1, the amount of hydroxypropyl methylcellulose acetate succinate in S1 was adjusted to 60 g, and the amount of polyvinylpyrrolidone-vinyl acetate copolymer was adjusted to 180 g (the sum of the masses of the two was 240 g); the spray drying was set to an inlet air temperature of 65°C, an outlet air temperature of 38°C, an atomizing gas flow of 600 L / min, a feeding amount of 55 g / min, and a nozzle diameter of 1.2 mm; the other conditions were the same as in Example 1.

[0041] Example 3:

[0042] Compared with Example 1, the amount of hydroxypropyl methyl cellulose acetate succinate in S1 was adjusted to 120 g, and the amount of polyvinylpyrrolidone-vinyl acetate copolymer was adjusted to 120 g (the sum of the masses of the two was 240 g); the spray drying was set to an inlet air temperature of 75°C, an outlet air temperature of 45°C, an atomizing gas flow rate of 600 L / min, a feed amount of 45 g / min, and a nozzle diameter of 0.8 mm; after the powder was collected, it was dried in a vacuum drying oven at 40°C for 8 h under a vacuum degree of not less than -90 kPa; and the other conditions were the same as in Example 1.

[0043] Example 4:

[0044] Compared with Example 1, the amount of mesoporous silica in S2 was adjusted to 60 g, the pre-mixing speed was adjusted to 700 rpm and pre-mixing was performed for 2 min; 250 g of the solid dispersion microparticles were added in 3 portions and mixed at 700 rpm for 8 min; then 10 g of anhydrous ethanol was sprayed in 2 portions while maintaining the speed at 700 rpm and mixing was continued for 3 min; finally, 60 g of calcium silicate was added and mixed at 600 rpm for 3 min (the sum of the masses of the mesoporous silica and the calcium silicate was 120 g); and the other conditions were the same as in Example 1.

[0045] Example 5:

[0046] Compared with Example 1, the amount of mesoporous silica in S2 was adjusted to 100 g, the pre-mixing speed was adjusted to 900 rpm and pre-mixing was performed for 2 min; 250 g of the solid dispersion microparticles were added in 3 portions and mixed at 900 rpm for 10 min; then 30 g of anhydrous ethanol was sprayed in 3 portions while maintaining the speed at 900 rpm and mixing was continued for 3 min; finally, 20 g of calcium silicate was added and mixed at 600 rpm for 3 min (the sum of the masses of the mesoporous silica and the calcium silicate was 120 g); and the other conditions were the same as in Example 1.

[0047] Example 6:

[0048] Compared with Example 1, the amount of calcium stearate in S3 was adjusted to 15 g, and the amount of magnesium stearate was adjusted to 15 g (the sum of the masses of the two was 30 g); and the other conditions were the same as in Example 1.

[0049] Example 7:

[0050] Compared with Example 1, the amount of calcium stearate in S3 was adjusted to 25 g, and the amount of magnesium stearate was adjusted to 5 g (the sum of the masses of the two was 30 g); and the other conditions were the same as in Example 1.

[0051] Example 8:

[0052] Compared with Example 1, the amount of hydroxypropyl methyl cellulose in S4 is adjusted to 200 g, the amount of ethyl cellulose is adjusted to 200 g, and the amount of microcrystalline cellulose is still 200 g; the roller pressure of the dry granulation roller compaction is set to 35 kN, the roller speed is 4 rpm, and the feeding screw is 15 rpm; the roller pressure in S5 is set to 8 kN, and the roller speed is 4 rpm; and the other conditions are the same as those in Example 1.

[0053] Example 9:

[0054] Compared with Example 1, the amount of hydroxypropyl methyl cellulose in S4 is adjusted to 300 g, the amount of ethyl cellulose is adjusted to 100 g, and the amount of microcrystalline cellulose is still 200 g; the roller pressure of the dry granulation roller compaction is set to 50 kN, the roller speed is 6 rpm, and the feeding screw is 25 rpm; the roller pressure in S5 is set to 12 kN, and the roller speed is 6 rpm; and the other conditions are the same as those in Example 1.

[0055] Comparative Example 1:

[0056] The difference from Example 1 is that 90 g of hydroxypropyl methyl cellulose acetate succinate is not added in S1, and instead, 240 g of polyvinylpyrrolidone-vinyl acetate copolymer is added in 500 g of anhydrous ethanol to prepare solution B, and the solution B is added to solution A treated with acetone (wherein solution A does not contain hydroxypropyl methyl cellulose acetate succinate); and the other conditions are the same as those in Example 1.

[0057] Comparative Example 2:

[0058] The difference from Example 1 is that after the solid dispersion microparticles and mesoporous silica are mixed in S2, anhydrous ethanol is not sprayed, but calcium silicate is directly added and mixed; and the other conditions are the same as those in Example 1.

[0059] Comparative Example 3:

[0060] The difference from Example 1 is that after the solid dispersion microparticles and mesoporous silica are mixed in S2, calcium silicate is first added and mixed, and then anhydrous ethanol is sprayed and mixed; and the other conditions are the same as those in Example 1.

[0061] Comparative Example 4:

[0062] The difference from Example 1 is that the mixing time after adding magnesium stearate in S3 is extended from 1 min to 5 min; and the other conditions are the same as those in Example 1.

[0063] Comparative Example 5:

[0064] The difference from Example 1 is that magnesium stearate is first added and mixed in S3, and then calcium stearate is added and mixed; and the other conditions are the same as those in Example 1.

[0065] Comparative Example 6:

[0066] The difference from Example 1 is that the premixed powder in S4 is not roller-compacted and granulated to obtain the sustained-release matrix master batch, but the premixed powder is directly used in S5 to mix with the hydrophobic composite particles; the rest of the conditions are the same as in Example 1.

[0067] Performance test:

[0068] Sample preparation: for tabletting-related tests and release tests, each sample was sieved through a 40-mesh sieve, and tablets were prepared using a single-punch tablet machine with a punch diameter of 10 mm, a loading capacity of 500.0 mg / tablet, a tabletting pressure of 10 kN, and a tabletting speed of 20 rpm. The prepared tablets were placed in a 25℃, 40% relative humidity environment for 24 hours before subsequent testing.

[0069] Test item one:

[0070] Bulk density / tapped density and flowability index (compressibility and fillability): according to Chinese Pharmacopoeia General 0993, 50.0 g of each sample was weighed into a 100 mL graduated cylinder, the initial volume V0 was measured, and the bulk density ρ0 = m / V0 was calculated; the graduated cylinder was placed on the tapped density instrument and tapped 500 times at 250 times / min, and the volume V was measured after tapping. t The tapped density ρ t = m / V t was calculated; the Carr index CI = (ρ t - ρ0) / ρ t × 100% and the Hausner ratio HR = ρ t / ρ0 were calculated, and the results are shown in Table 1.

[0071] Test item two:

[0072] Tablet hardness, tablet friability, and disintegration time: hardness testing was performed using a tablet hardness tester according to JB / T 20104-2022, and 10 tablets of each sample were randomly selected to measure the crushing force and calculate the average value and RSD (%); friability was tested according to Chinese Pharmacopoeia General 0923, 20 tablets (total mass recorded as m0) were taken, and after 4 minutes (100 revolutions) of rotation at 25 rpm in the friability tester, the mass m1 was measured after removing the powder, and the friability = [(m0-m1) / m0]×100% was calculated; the disintegration time was tested according to Chinese Pharmacopoeia General 0921, using water as the medium and a temperature of 37℃±2℃, and 6 tablets were taken to record the complete disintegration time, and the results are shown in Table 1.

[0073] Test item three:

[0074] Dynamic vapor sorption (hygroscopicity and hysteresis behavior): according to the Chinese Pharmacopoeia 0961, 200.0 mg of each sample was placed in the sample pan of a dynamic vapor sorption instrument, the test temperature was 25℃, and the relative humidity program was set to 0%, 20%, 40%, 60%, 75%, 90%, 75%, 60%, 40%, 20%, 0% in turn, and each humidity point was balanced when the mass change rate was less than 0.01% / min for 10 min; the equilibrium moisture content (%) of each sample at 75% RH and 90% RH was recorded, and the results are shown in Table 1.

[0075] Test item four:

[0076] Dissolution / release and release profile consistency: according to the Chinese Pharmacopoeia 0931, the paddle method was used, the rotation speed was 50 rpm, and the medium temperature was 37℃; 900 mL of 0.1 mol / L hydrochloric acid medium was used for the first 2 h, and then 900 mL of pH 6.8 phosphate buffer (containing 0.5% (w / v) sodium dodecyl sulfate) was used for the next 2 h, and the test was continued to 12 h; the sampling time points were 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 12 h, and 5.0 mL was taken each time and an equal volume of fresh medium was added simultaneously, and the sample solution was filtered through a 0.45 μm filter membrane; the content was determined by the high performance liquid chromatography method established in the Chinese Pharmacopoeia 0512, and the cumulative release (%) at each time point was calculated by the external standard method, and the results are shown in Table 2. Figure 1 、 2

[0077] Table 1 Performance test results

[0078]

[0079] Data analysis:

[0080] From the data of Table 1 and Figure 1 , it can be seen that the solid dispersion-based sustained-release drug composite carrier prepared by the present application achieves a good balance between powder flowability, formability, compression resistance, moisture resistance, and controllable release. With the adjustment of the ratio of polyvinylpyrrolidone-vinyl acetate copolymer and hydroxypropyl methyl cellulose acetate succinate, the moisture absorption of the powder and the drug release rate show a synchronous adjustable rule; when the amount distribution of mesoporous silica and calcium silicate and the ethanol activation intensity change, the packing property and the stability of the tablet hardness of the composite particles change with the degree of pore localization, and further transmit to the smoothness of the release curve and the completion degree of the end release. At the same time, the fine adjustment of the ratio of calcium stearate and magnesium stearate changes the continuity and friction sensitivity of the outer hydrophobic microdomain, thereby affecting the wetting penetration and skeleton maintenance during the disintegration process; the change of the roller granulation parameters of the sustained-release matrix granules realizes the synergistic constraint on the initial release and the later release through the regulation of particle strength and pore structure. ​

[0081] From the data of Example 1 and Comparative Example 1 in Table 1 and Figure 2 As can be seen from the data of Example 1 and Comparative Example 2 and Comparative Example 3 in Table 1 and

[0082] As can be seen from the data of Example 1 and Comparative Example 2 and Comparative Example 3 in Table 1 and Figure 2 As can be seen from the data of Example 1 and Comparative Example 2 and Comparative Example 3 in Table 1 and

[0083] As can be seen from the data of Example 1 and Comparative Example 2 and Comparative Example 3 in Table 1 and Figure 2As can be seen from the data of Example 1 and Comparative Examples 4 and 5, when the mixing time after the addition of magnesium stearate is prolonged, or magnesium stearate is added first and then calcium stearate is added, the tablet hardness significantly decreases and fluctuates, the friability increases, the disintegration is prolonged, and the overall release rate slows down and the end-point release decreases. The main reason is that magnesium stearate is more likely to form a continuous hydrophobic coating layer under excessive shearing, which weakens the real contact and mechanical interlocking between particles, and it is difficult to form a stable bond at the compaction interface; at the same time, the hydrophobic coating inhibits wetting penetration and pore connection, resulting in limited entry of disintegration medium, thereby reducing the effective diffusion channel and slowing down the drug release. The strategy of adding calcium stearate first, adding magnesium stearate later, and mixing for a limited time can form non-continuous hydrophobic micro-domains, which reduces the friction sensitivity and avoids excessive coating, and embodies the unexpected comprehensive effect brought by the two kinds of metal stearate and time control.

[0084] As can be seen from Table 1 and Figure 2 As can be seen from the data of Example 1 and Comparative Example 6, when the premixed powder is not first roller-compacted to form a sustained-release matrix master batch, but is directly mixed with the hydrophobic composite particles, the powder flowability deteriorates significantly, the tablet hardness and its consistency decrease, the friability increases, and the release curve in the early stage shows a stronger burst tendency. The main reason is that the particle size distribution and surface energy of the ungranulated premixed powder are more different, and the mixing process is more likely to cause stratification and local enrichment, making it difficult for the hydrophobic composite particles and the sustained-release matrix to stably nest in the micro-space; during the compaction process, the fine powder is first compacted to form a non-uniform pore network, resulting in uneven distribution of medium penetration paths and effective diffusion area within the tablet, which in turn amplifies the batch-to-batch and tablet-to-tablet differences. Therefore, the step of first preparing a sustained-release matrix master batch and then spatially compounding and lightly rolling to lock has irreplaceability for structure level fixation, and is a key combined measure to realize scale reproducibility and stable release curve.

[0085] Those skilled in the art will understand that the above discussion of any of the embodiments is merely exemplary and is not intended to suggest that the scope of the present application is limited to these examples; under the idea of the present application, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the present application as described above. In order to be brief, they are not provided in detail.

Claims

1. A method for preparing a solid dispersion-based sustained-release drug composite carrier, characterized in that, Includes the following steps: (1) Hydroxypropyl methylcellulose acetate succinate was dissolved in acetone to obtain solution A, polyvinylpyrrolidone-vinyl acetate copolymer was dissolved in anhydrous ethanol to obtain solution B, and solution B was added to solution A to obtain a polymer mixed solution; dihydroergot methanesulfonate was dissolved in anhydrous ethanol to obtain solution C, and solution C was added to the polymer mixed solution and mixed well before spray drying to obtain solid dispersion particles; (2) After mixing mesoporous silica with the solid dispersion particles, anhydrous ethanol is sprayed into the mixture and mixed; then calcium silicate is added and mixed, and dried and sieved to obtain inorganic localized composite solid dispersion particles. (3) After mixing the inorganic localized composite solid dispersion particles with calcium stearate, magnesium stearate is added and the mixing is stopped after only 1 min to obtain hydrophobic composite particles; (4) Hydroxypropyl methylcellulose, ethyl cellulose and microcrystalline cellulose are mixed to form a premixed powder. The premixed powder is granulated by dry roller pressing and sieved to obtain a slow-release skeleton masterbatch. (5) After mixing the sustained-release matrix masterbatch and the hydrophobic composite particles, roll pressing and granulation and sieving are performed to obtain the solid dispersion-based sustained-release drug composite carrier, and the mass ratio of sustained-release matrix masterbatch to hydrophobic composite particles is 3:

2.

2. The method for preparing a solid dispersion-based sustained-release drug composite carrier according to claim 1, characterized in that, In step (1), based on 10 parts by weight of dihydroergot methanesulfonate, the total mass of hydroxypropyl methylcellulose acetate succinate and polyvinylpyrrolidone-vinyl acetate copolymer is 240 parts, of which 60-120 parts are hydroxypropyl methylcellulose acetate succinate.

3. The method for preparing a solid dispersion-based sustained-release drug composite carrier according to claim 1, characterized in that, In step (2), the amount of solid dispersion particles is 250 parts by mass, the sum of the mass of mesoporous silica and calcium silicate is 120 parts, the amount of mesoporous silica is 60-100 parts, and the amount of anhydrous ethanol sprayed in is 10-30 parts.

4. The method for preparing a solid dispersion-based sustained-release drug composite carrier according to claim 1, characterized in that, In step (3), the amount of inorganic localized composite solid dispersion particles is 370 parts by weight, and the total mass of calcium stearate and magnesium stearate is 30 parts, of which the amount of calcium stearate is 15-25 parts.

5. The method for preparing a solid dispersion-based sustained-release drug composite carrier according to claim 1, characterized in that, In step (3), the inorganic localized composite solid dispersion particles are premixed at 15 rpm for 2 min, then calcium stearate is added and mixed for 5 min, then magnesium stearate is added and mixed for only 1 min before stopping.

6. The method for preparing a solid dispersion-based sustained-release drug composite carrier according to claim 1, characterized in that, In step (4), the amount of hydroxypropyl methylcellulose is 200-300 parts by mass, the amount of microcrystalline cellulose is 200 parts, and the total mass of hydroxypropyl methylcellulose and ethyl cellulose is 400 parts.

7. The method for preparing a solid dispersion-based sustained-release drug composite carrier according to claim 1, characterized in that, In step (4), the dry roller pressing pressure is 35-50kN, the roller speed is 4-6rpm, the feed screw speed is 15-25rpm, and the resulting flakes are passed through a 20-mesh sieve by a granulator.

8. The method for preparing a solid dispersion-based sustained-release drug composite carrier according to claim 1, characterized in that, In step (5), the mixing includes premixing at 15 rpm for 2 minutes and then continuing to mix for 8 minutes; the roller pressing pressure is 8-12 kN and the roller speed is 4-6 rpm, and the material obtained after roller pressing is passed through a granulator through a 16-mesh sieve.

9. A solid dispersion-based sustained-release drug composite carrier, characterized in that, It is obtained by the preparation method of the solid dispersion-based sustained-release drug composite carrier according to any one of claims 1-8.

10. The application of the solid dispersion-based sustained-release drug composite carrier according to claim 9, characterized in that, Used to prepare sustained-release formulations of dihydroergot methanesulfonate.

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