A sustained-release tablet of dihydroergotoxine mesylate resin composite matrix and a preparation method thereof
By constructing a multi-level composite structure, the problems of poor content uniformity and initial burst release in dihydroergot mesylate sustained-release formulations at low doses were solved, achieving stable drug release in different gastrointestinal environments and improving the safety and efficacy of the formulation.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-05-08
- Publication Date
- 2026-07-21
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical technology, and in particular to a sustained-release tablet with a dihydroergot methyl sulfonate resin composite matrix and its preparation method. Background Technology
[0002] Dihydroergotamine mesylate, a classic drug for improving cerebral microcirculation and cognitive function, places stringent requirements on formulation homogeneity and release stability due to its low-dose characteristics. Current mainstream sustained-release technologies mostly employ direct compression, physically mixing the drug with hydrophilic gel materials (such as hydroxypropyl methylcellulose), binders, and lubricants. While this process is simple, at low drug loadings, uneven mixing due to differences in material density and electrostatic effects can easily occur, leading to fluctuations in content uniformity and directly affecting the safety window for clinical use.
[0003] For controlling release behavior, relying solely on mechanisms such as hydrophilic skeleton dissolution or pore diffusion is insufficient to withstand the drastic changes in pH and ionic strength within the human gastrointestinal tract. When drugs move between the acidic environment of the stomach and the neutral environment of the intestines, the release rate often exhibits unpredictable drift, manifesting as a significant initial burst release or incomplete release in the later stages, making it impossible to maintain a stable blood drug concentration.
[0004] To overcome these problems, the industry has attempted to introduce ion exchange resin technology, utilizing its electrostatic adsorption to slow drug diffusion. However, conventional resin-loaded drug delivery processes still have significant limitations: first, the drug tends to accumulate on the resin surface, lacking an internal gradient distribution mechanism, leading to excessively rapid initial release; second, the resin's hygroscopic expansion can damage the integrity of the external coating film, thus accelerating drug leakage; and third, a single barrier structure cannot simultaneously address the contradictory needs of "preventing burst release" and "promoting release," meaning that while reducing the initial release peak, it is difficult to guarantee complete drug release within 12 hours. Therefore, how to construct a multi-stage release system that can synergistically address content uniformity, initial burst release, and environmental resistance under low-dose conditions has become a pressing challenge in this formulation field. Summary of the Invention
[0005] In view of this, the purpose of this invention is to propose a dihydroergotamine mesylate resin composite sustained-release tablet and its preparation method, so as to solve the problems of poor content uniformity, severe initial burst release and weak gastrointestinal adaptability of existing dihydroergotamine mesylate sustained-release formulations at low doses.
[0006] To achieve the above objectives, the present invention provides a sustained-release tablet with a dihydroergot methanesulfonate resin composite matrix, the sustained-release tablet comprising composite encapsulated drug-loaded resin particles and a hydroxypropyl methylcellulose matrix dispersing the composite encapsulated drug-loaded resin particles.
[0007] Based on a total weight of 260 tablets, the sustained-release tablets comprise: 34.2-43.3 parts of a composite-encapsulated drug-loaded resin particle containing 2 parts of dihydroergot mesylate, 68-92 parts of hydroxypropyl methylcellulose, 5.6-8.4 parts of povidone K30, 0.8-1.2 parts of colloidal silica, 2.4-3.6 parts of magnesium stearate, and the balance of microcrystalline cellulose, wherein the microcrystalline cellulose comprises 111.5-149.0 parts.
[0008] The composite encapsulated drug-loaded resin particles include gradient drug-loaded resin particles, a calcium alginate encapsulation layer on the surface of the gradient drug-loaded resin particles, and an ethyl cellulose membrane layer on the surface of the calcium alginate encapsulation layer.
[0009] The gradient drug-loaded resin particles comprise an exchange capacity pre-occupying resin and dihydroergot methanesulfonate loaded in the exchange capacity pre-occupying resin. The exchange capacity pre-occupying resin is obtained by acidifying a sulfonic acid-type cation exchange resin obtained through sieving to a hydrogen form and then neutralizing it with sodium ions. In the sulfonic acid-type cation exchange resin obtained through sieving, particles with a diameter of 75-125 μm account for no less than 90%, and the sodium neutralization equivalent of the exchange capacity pre-occupying resin accounts for 50.6% to 59.6% of the total exchange capacity.
[0010] The gradient drug-loaded resin particles, as measured by the sodium chloride fractional desorption method according to claim 2, have an outer layer weakly bound drug content of 15.3%-21.8% of the total drug load, an internally bound drug content of 76.5%-82.2% of the total drug load, and a remaining drug content of 1.7%-2.9% of the total drug load. The sum of the outer layer weakly bound drug content, the internally bound drug content, and the remaining drug content is 100% of the total drug load.
[0011] Preferably, the sodium chloride fractional desorption method includes: taking 1g of graded drug-loaded resin particles, adding them to 10g of a 50mmol / L sodium chloride solution, stirring at 120r / min for 10min at 25℃, filtering, and determining the content of dihydroergotamine mesylate in the filtrate as the amount of weakly bound drug in the outer layer; then adding the filter cake to 10g of a 1mol / L sodium chloride solution, stirring at 120r / min for 120min at 25℃, filtering, and determining the content of dihydroergotamine mesylate in the filtrate as the amount of internally bound drug.
[0012] Preferably, each sustained-release tablet has a theoretical weight of 260 mg, contains 2 mg of dihydroergot methyl methacrylate, and has a tablet hardness of 85-100 N.
[0013] Preferably, the sulfonic acid cation exchange resin is a pharmaceutical-grade strong acid dry powder type sodium polystyrene sulfonate cation exchange resin with a total cation exchange capacity of 5.0 meq / g.
[0014] Preferably, the composite encapsulated drug-loaded resin particles are prepared from the following raw materials excluding the solvent: 24-32 parts of exchange capacity pre-occupying resin, 2.12-2.25 parts of dihydroergot methanesulfonate, 0.210-0.225 parts of citrate monohydrate, 2.4-3.6 parts of sodium alginate, 0.8-1.2 parts of calcium lactate pentahydrate, 4.8-7.2 parts of ethyl cellulose, and 0.8-1.2 parts of triethyl citrate.
[0015] Preferably, the 1% aqueous solution of sodium alginate has a viscosity of 35 mPa·s at 20°C; the hydroxypropyl methylcellulose is K100M grade hydroxypropyl methylcellulose; and the colloidal silica has a specific surface area of 210 m². 2 / g.
[0016] Preferably, when the release rate of the sustained-release tablet is determined in pH 6.8 phosphate buffer using the paddle method, the medium volume is 900 mL, the medium temperature is 37.0 ± 0.5 °C, and the paddle speed is 50 r / min. The cumulative release rate is 5.6%-10.6% at 0.5 h, 21.7%-29.8% at 2 h, 58.9%-69.6% at 6 h, and 90.8%-95.8% at 12 h.
[0017] Preferably, the content uniformity acceptance value (AV) of the sustained-release tablet is 3.9-6.4; the release fluctuation factor of the sustained-release tablet measured in pH 1.2 sodium chloride hydrochloride solution, pH 6.8 phosphate buffer and pH 6.8 phosphate buffer containing 100 mmol / L sodium chloride is 3.2%-6.1%.
[0018] Furthermore, the present invention also provides a method for preparing a dihydroergot methyl sulfonate resin composite sustained-release tablet, comprising the following steps:
[0019] (1) The sulfonic acid type cation exchange resin was screened to obtain resin particles with a particle size of 75-125μm. After being converted to hydrogen form by acid treatment, it was partially neutralized by sodium hydroxide to obtain a pre-occupied resin with a sodium neutralization equivalent of 50.6%-59.6% of the total exchange capacity.
[0020] (2) Add dihydroergot methanesulfonate solution to the pre-occupied resin dispersion with vacuum assistance for drug loading, and then treat with sodium chloride solution to obtain gradient drug-loaded resin particles.
[0021] (3) The gradient drug-loaded resin particles are added to sodium alginate solution, and then calcium lactate pentahydrate solution is added for cross-linking to obtain calcium alginate-encapsulated drug-loaded resin particles.
[0022] (4) The ethyl cellulose film-forming solution is sprayed onto the surface of the calcium alginate-coated drug-loaded resin particles to obtain composite-coated drug-loaded resin particles.
[0023] (5) Take the composite encapsulated drug-loaded resin particles, mix them with hydroxypropyl methylcellulose, microcrystalline cellulose, povidone K30, colloidal silica and magnesium stearate, and compress them into tablets to obtain dihydroergot methanesulfonate resin composite sustained-release tablets.
[0024] Preferably, in step (4), the spraying is carried out using a fluidized bed coating method, the material temperature is controlled at 31-33℃, the atomizing air pressure is 0.16-0.20MPa, and the spraying speed is 1.8-2.2g / min.
[0025] The beneficial effects of this invention are:
[0026] (1) This invention achieves precise regulation of drug release behavior by constructing a multi-level composite structure consisting of exchange capacity pre-occupancy, gradient drug loading, calcium alginate gating, ethyl cellulose outer membrane, and hydroxypropyl methyl cellulose backbone. Data show that the initial release rate of Example 1 at 0.5 h was only 7.8%, which is 5.4 percentage points lower than that of Comparative Example 7 without a calcium alginate layer and 11.7 percentage points lower than that of Comparative Example 6 with the outer layer desorption step removed, effectively suppressing the burst release effect. At the same time, the release fluctuation factor of this structure in pH 1.2 hydrochloric acid solution, pH 6.8 buffer solution, and high ionic strength medium is as low as 4.4%, which is far superior to the single resin drug loading system (19.0% in Comparative Example 1), proving that each level has a significant synergistic effect in buffering resin swelling, extending diffusion path, and stabilizing gel backbone.
[0027] (2) By limiting the resin particle size to the range of 75-125 μm and combining vacuum-assisted drug loading with a low-concentration sodium chloride desorption process, this invention significantly improves the mixing uniformity and binding stability of low-dose drugs. Testing showed that the content uniformity acceptance value (AV) of Example 3 decreased to 3.9, significantly better than Comparative Example 3 (AV=16.1), which had a wider particle size distribution. Furthermore, the gradient drug loading design increased the proportion of internally bound drug to 82.2%, ensuring sufficient drug release within 12 hours (reaching over 90.8%). This solves the problem of incomplete or uncontrollable release caused by external coating rupture in traditional resin formulations, greatly improving the clinical safety and efficacy consistency of the formulation.
[0028] (3) The invention does not simply employ ion exchange resin or ethyl cellulose coating. Instead, after partial sodium neutralization at the resin exchange sites, the drug preferentially forms internal bonds during the drug loading stage. Then, a short-term treatment with low-concentration sodium chloride selectively reduces the amount of weakly bound drug on the outer layer. Subsequently, a calcium alginate layer buffers the resin hydration swelling and ion impact, an ethyl cellulose membrane layer extends the diffusion path, and a hydroxypropyl methylcellulose backbone forms a tablet-grade gel diffusion barrier. This multi-level structure allows for simultaneous control of 0.5h release, 12h release, and release fluctuations in different media, which cannot be achieved with a single coating or a single backbone. Detailed Implementation
[0029] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments.
[0030] Raw material source and quality requirements:
[0031] The active pharmaceutical ingredient (API) of dihydroergotoxine mesylate is sourced from Teva Pharmaceutical Industries Ltd. (TAPI) or from the same API registered on the API registration platform of the National Medical Products Administration (NMPA) in accordance with the requirements for formulation registration. Before administration, the API is inspected and released in accordance with the current edition of the Chinese Pharmacopoeia, national drug standards, or registration approval standards.
[0032] The sulfonic acid type cation exchange resin is DuPont's AmberLite IRP69 sodium polystyrene sulfonate sodium cation exchange resin, pharmaceutical grade, strongly acidic, dry powder type, with a total cation exchange capacity controlled at 5.0 meq / g according to the supplier's quality standards.
[0033] Sodium alginate, specifically KIMICA ALGIN AL20 from KIMICA Corporation, has a viscosity of 35 mPa·s at 20°C for a 1% aqueous solution.
[0034] Ethyl cellulose is Ashland's Aqualon EC-N10 Pharm.
[0035] Hydroxypropyl methylcellulose is IFF's METHOCEL K100M Premium CR.
[0036] The microcrystalline cellulose was Ceolus PH-102 from Asahi Kasei.
[0037] Povidone K30 is BASF's Kollidon 30.
[0038] The colloidal silica was Evonik's AEROSIL 200 Pharma, with a specific surface area of 210 m². 2 / g.
[0039] Magnesium stearate is Peter Greven's LIGAMED MF-2-V-MB.
[0040] Triethyl citrate is from Jungbunzlauer's CITROFOL AI Pharma.
[0041] Hydrochloric acid, sodium hydroxide, sodium chloride, citric acid monohydrate, ethanol, and purified water all meet the requirements of current valid drug standards or pharmaceutical excipient standards.
[0042] Example 1:
[0043] Step 1: Take sodium polystyrene sulfonate cation exchange resin. First, remove coarse particles that do not pass through the sieve using a 125μm sieve. Then, sieve the resin that has passed through the 125μm sieve onto a 75μm sieve and collect the particles remaining on the 75μm sieve. Add 28g of the sieved resin to 600g of purified water and stir at 150r / min for 30min at 25℃. Filter. Add 300g of 1mol / L hydrochloric acid solution to the filter cake and stir at 150r / min for 60min at 25℃. Filter. Add another 300g of 1mol / L hydrochloric acid solution to the filter cake and stir at 150r / min for 60min at 25℃. Filter to convert the sodium form resin to the hydrogen form resin. Wash the filter cake six times with 1200g of purified water, using 200g of purified water each time. The wet resin was then added to a sodium hydroxide solution prepared with 3g sodium hydroxide and 177g purified water. The mixture was stirred at 150r / min for 60min at 25℃, filtered, and washed three times with 600g purified water (200g purified water each time). The resulting resin was dried at 40℃ until the loss on drying was ≤8%, yielding a pre-filled exchange capacity resin. 1g of this pre-filled resin was added to 100g of a 1mol / L sodium chloride solution, shaken at 25℃ for 120min, filtered, and the pH of the filtrate was titrated to 7.0 with 0.1mol / L sodium hydroxide solution. The exchange equivalent of the resin still in the hydrogen form was calculated. Another 1g of the completely hydrogen form resin was taken and its total exchange capacity was determined using the same method. The proportion of sodium neutralization equivalent to the total exchange capacity was calculated to be 56.4%.
[0044] Step 2: Add 220 mg of citrate monohydrate and 2.20 g of dihydroergotamine mesylate to 2000 g of purified water. Stir at 150 r / min for 30 min at 25 °C under light-protected conditions to obtain a dihydroergotamine mesylate solution. Add 28 g of the exchange capacity pre-occupied resin obtained in Step 1 to 300 g of purified water. Stir at 120 r / min for 20 min at 25 °C. Then, evacuate to an absolute pressure of 40 kPa and maintain for 10 min, then restore to normal pressure for 5 min. Repeat the above evacuation and restoration to normal pressure operation once, maintaining 25 °C and stirring at 150 r / min. Add the above dihydroergotamine mesylate solution to the resin dispersion at a rate of 20 g / min. After the addition is complete, continue stirring for 360 min. Filter and collect the drug-loaded resin. At the same time, take the filtrate to determine the residual amount of dihydroergotamine mesylate. The residual drug amount in the filtrate is 3.1% of the feed amount. Add 1 g of sodium chloride and 1 g of ergotamine mesylate to the drug-loaded resin within 5 min after filtration. A sodium chloride solution prepared with 99g of purified water was stirred at 120r / min for 6 min at 25℃, filtered, and washed once with 200g of purified water within 3 min after filtration. The resulting resin was dried at 40℃ until the loss on drying was ≤5%, and passed through a 250μm sieve to obtain gradient drug-loaded resin particles. 1g of gradient drug-loaded resin particles were added to 10g of a 50mmol / L sodium chloride solution, stirred at 120r / min for 10 min at 25℃, filtered, and the content of dihydroergot methyl sulfoxide in the filtrate was determined as the amount of weakly bound drug in the outer layer. The filter cake was then added to 10g of a 1mol / L sodium chloride solution, stirred at 120r / min for 120 min at 25℃, filtered, and the content of dihydroergot methyl sulfoxide in the filtrate was determined as the amount of internally bound drug. The proportion of weakly bound drug in the outer layer to the total drug load of the particles was 18.4%, and the proportion of internally bound drug to the total drug load of the particles was 78.7%.
[0045] Step 3: Add 3g of sodium alginate to 297g of purified water, stir at 100r / min for 30min at 25℃, and let stand for hydration for 8h to obtain sodium alginate solution. Add all the graded drug-loaded resin particles obtained in Step 2 to the sodium alginate solution, stir at 120r / min for 20min at 25℃. Add 1g of calcium lactate pentahydrate to 99g of purified water, stir until dissolved, and add it to the sodium alginate dispersion containing the resin particles within 15min. Continue stirring at 120r / min for 30min. After filtration, dry the particles at 40℃ until the loss on drying is ≤6%, and pass through a 250μm sieve to obtain calcium alginate-coated drug-loaded resin particles.
[0046] Step 4: Add 6g of ethyl cellulose and 1g of triethyl citrate to 113g of ethanol, and stir at 150r / min for 60min at 25℃ to obtain ethyl cellulose film-forming solution. Take all the calcium alginate-coated drug-loaded resin particles obtained in Step 3, and process them using fluidized bed coating method. Control the material temperature at 32℃ and the atomizing air pressure at 0.18MPa. Spray the ethyl cellulose film-forming solution onto the particle surface at 2g / min. After spraying, continue drying at 40℃ until the ethanol residue is ≤5000ppm and the drying loss is ≤5%. Pass through a 250μm sieve to obtain composite-coated drug-loaded resin particles.
[0047] Step 5: Take the composite encapsulated drug-loaded resin particles obtained in Step 4, and take particles equivalent to 2g of dihydroergot methyl sulfoxide for total mixing; under the theoretical dry basis conditions in this embodiment, the amount of these particles is 38.6g. Add the above particles, 80g of hydroxypropyl methylcellulose, 130.4g of microcrystalline cellulose, and 7g of povidone K30 to a mixing container and mix at 20r / min for 15min; add 1g of colloidal silica and mix at 20r / min for 5min; then add 3g of magnesium stearate and mix at 20r / min for 3min; compress the total mixture into tablets to make 1000 tablets of dihydroergot methyl sulfoxide resin composite matrix sustained-release tablets, each with a theoretical tablet weight of 260mg and each containing 2mg of dihydroergot methyl sulfoxide, and the tablet hardness is controlled at 90N.
[0048] Example 2:
[0049] Step 1: Take sodium polystyrene sulfonate cation exchange resin. First, remove coarse particles that do not pass through the sieve using a 125μm sieve. Then, place the resin that has passed through the 125μm sieve onto a 75μm sieve for further sieving, collecting the particles remaining on the 75μm sieve. Next, add 24g of the sieved resin to 520g of purified water and stir at 150r / min for 30min at 25℃, then filter. Add 260g of a 1mol / L hydrochloric acid solution to the filter cake and stir at 150r / min for 60min at 25℃, then filter. Add another 260g of a 1mol / L hydrochloric acid solution to the filter cake and stir at 150r / min for 60min at 25℃, then filter. Stir for 60 min, filter to convert sodium-form resin to hydrogen-form resin; wash the filter cake five times with 1000 g purified water, using 200 g purified water each time; then add the wet resin to a sodium hydroxide solution prepared with 2.4 g sodium hydroxide and 142 g purified water, stir at 150 r / min for 60 min at 25 °C, filter, and wash three times with 600 g purified water, using 200 g purified water each time; dry the resulting resin at 40 °C until the loss on drying is ≤8%, to obtain the pre-occupied exchange capacity resin; determine the proportion of sodium neutralization equivalent to the total exchange capacity according to the method described in step 1 of Example 1, which is 50.6%;
[0050] Step 2: Add 210 mg of citrate monohydrate and 2.12 g of dihydroergot methyl sulfonate to 2000 g of purified water. Stir at 150 r / min for 30 min at 25 °C under light-protected conditions to obtain a dihydroergot methyl sulfonate solution. Add 24 g of the pre-occupied exchange capacity resin obtained in Step 1 to 260 g of purified water. Stir at 120 r / min for 20 min at 25 °C. Then, evacuate to an absolute pressure of 45 kPa and maintain for 10 min, followed by restoring to normal pressure for 5 min. Repeat the above evacuation and restoration to normal pressure operation once, maintaining 25 °C and stirring at 150 r / min. Add the above dihydroergot methyl sulfonate solution to the resin dispersion at a rate of 15 g / min. After the addition is complete, continue stirring for 300 min. Filter and collect the drug-loaded resin. The filtrate was used to determine the residual amount of dihydroergotamine mesylate. The residual drug amount in the filtrate was 3.8% of the feed amount. Within 5 minutes after filtration, the drug-loaded resin was added to a sodium chloride solution prepared with 0.8 g sodium chloride and 159.2 g purified water. The solution was stirred at 120 r / min for 4 minutes at 25°C, filtered, and washed once with 200 g purified water within 3 minutes after filtration. The resulting resin was dried at 40°C until the loss on drying was ≤5%, and passed through a 250 μm sieve to obtain gradient drug-loaded resin particles. The amount of weakly bound drug in the outer layer and the amount of bound drug in the inner layer were determined according to the method described in step 2 of Example 1. The proportion of weakly bound drug in the outer layer to the total drug load of the particles was 21.8%, and the proportion of bound drug in the inner layer to the total drug load of the particles was 76.5%.
[0051] Step 3: Add 2.4g of sodium alginate to 237.6g of purified water, stir at 100r / min for 30min at 25℃, and let stand for hydration for 8h to obtain sodium alginate solution. Add all the graded drug-loaded resin particles obtained in Step 2 to the sodium alginate solution, stir at 120r / min for 20min at 25℃. Separately, add 0.8g of calcium lactate pentahydrate to 79.2g of purified water, stir until dissolved, and add it to the above sodium alginate dispersion containing resin particles within 15min. Continue stirring at 120r / min for 30min. After filtration, dry the particles at 40℃ until the loss on drying is ≤6%, and pass through a 250μm sieve to obtain calcium alginate-coated drug-loaded resin particles.
[0052] Step 4: Add 4.8g of ethyl cellulose and 0.8g of triethyl citrate to 90.4g of ethanol, and stir at 150r / min for 60min at 25℃ to obtain ethyl cellulose film-forming solution. Take all the calcium alginate-coated drug-loaded resin particles obtained in Step 3, and process them using a fluidized bed coating method. Control the material temperature at 31℃ and the atomizing air pressure at 0.16MPa. Spray the ethyl cellulose film-forming solution onto the particle surface at 1.8g / min. After spraying, continue drying at 40℃ until the ethanol residue is ≤5000ppm and the drying loss is ≤5%. Pass through a 250μm sieve to obtain composite-coated drug-loaded resin particles.
[0053] Step 5: Take the composite encapsulated drug-loaded resin particles obtained in Step 4, and take particles equivalent to 2g of dihydroergot methyl sulfoxide for total mixing; under the theoretical dry basis conditions in this embodiment, the amount of these particles is 34.2g. Add the above particles, 68g of hydroxypropyl methylcellulose, 149g of microcrystalline cellulose, and 5.6g of povidone K30 to a mixing container and mix at 20r / min for 15min; add 0.8g of colloidal silica and mix at 20r / min for 5min; then add 2.4g of magnesium stearate and mix at 20r / min for 3min; compress the total mixture into tablets to make 1000 tablets of dihydroergot methyl sulfoxide resin composite matrix sustained-release tablets, each with a theoretical tablet weight of 260mg and each containing 2mg of dihydroergot methyl sulfoxide, and the tablet hardness is controlled at 85N.
[0054] Example 3:
[0055] Step 1: Take sodium polystyrene sulfonate cation exchange resin. First, remove coarse particles that do not pass through the sieve using a 125μm sieve. Then, place the resin that has passed through the 125μm sieve onto a 75μm sieve for further sieving, collecting the particles remaining on the 75μm sieve. Next, add 32g of the sieved resin to 680g of purified water and stir at 150r / min for 30min at 25℃. Filter. Add 340g of a 1mol / L hydrochloric acid solution to the filter cake and stir at 150r / min for 60min at 25℃. Filter. Add 340g of a 1mol / L hydrochloric acid solution to the filter cake again and stir at 150r / min at 25℃. Stir for 60 min, filter to convert sodium-form resin to hydrogen-form resin; wash the filter cake seven times with 1400 g purified water, using 200 g purified water each time; then add the wet resin to a sodium hydroxide solution prepared with 3.8 g sodium hydroxide and 225 g purified water, stir at 150 r / min for 60 min at 25 °C, filter, and wash three times with 600 g purified water, using 200 g purified water each time; dry the resulting resin at 40 °C until the loss on drying is ≤8%, to obtain the pre-occupied exchange capacity resin. The proportion of sodium neutralization equivalent to the total exchange capacity was determined according to the method described in step 1 of Example 1, and the proportion was 59.6%.
[0056] Step 2: Add 225 mg of citrate monohydrate and 2.25 g of dihydroergotamine mesylate to 2200 g of purified water. Stir at 150 r / min for 30 min at 25 °C under light-protected conditions to obtain a dihydroergotamine mesylate solution. Add 32 g of the exchange capacity pre-occupied resin obtained in Step 1 to 340 g of purified water. Stir at 120 r / min for 20 min at 25 °C. Then, evacuate to an absolute pressure of 35 kPa and maintain for 10 min, followed by restoring to normal pressure for 5 min. Repeat the above evacuation and restoration to normal pressure operation once, maintaining 25 °C and stirring at 150 r / min. Add the above dihydroergotamine mesylate solution to the resin dispersion at a rate of 25 g / min. After the addition is complete, continue stirring for 420 min. Filter and collect the drug-loaded resin. The filtrate was used to determine the residual amount of dihydroergot methyl sulfonate. The residual drug amount in the filtrate was 2.8% of the feed amount. Within 5 minutes after filtration, the drug-loaded resin was added to a sodium chloride solution prepared with 1.2 g sodium chloride and 238.8 g purified water. The solution was stirred at 120 r / min for 8 minutes at 25°C, filtered, and washed once with 200 g purified water within 3 minutes after filtration. The resulting resin was dried at 40°C until the loss on drying was ≤5%, and passed through a 250 μm sieve to obtain gradient drug-loaded resin particles. The amount of weakly bound drug in the outer layer and the amount of bound drug in the inner layer were determined according to the method described in step 2 of Example 1. The proportion of weakly bound drug in the outer layer to the total drug load of the particles was 15.3%, and the proportion of bound drug in the inner layer to the total drug load of the particles was 82.2%.
[0057] Step 3: Add 3.6g of sodium alginate to 356.4g of purified water, stir at 100r / min for 30min at 25℃, and let stand for hydration for 8h to obtain sodium alginate solution. Add all the graded drug-loaded resin particles obtained in Step 2 to the sodium alginate solution, stir at 120r / min for 20min at 25℃. Separately, add 1.2g of calcium lactate pentahydrate to 118.8g of purified water, stir until dissolved, and add it to the above sodium alginate dispersion containing resin particles within 15min. Continue stirring at 120r / min for 30min. After filtration, dry the particles at 40℃ until the loss on drying is ≤6%, and pass through a 250μm sieve to obtain calcium alginate-coated drug-loaded resin particles.
[0058] Step 4: Add 7.2g of ethyl cellulose and 1.2g of triethyl citrate to 135.6g of ethanol, and stir at 150r / min for 60min at 25℃ to obtain ethyl cellulose film-forming solution. Take all the calcium alginate-coated drug-loaded resin particles obtained in Step 3, and process them using fluidized bed coating method. Control the material temperature at 33℃ and the atomizing air pressure at 0.20MPa. Spray the ethyl cellulose film-forming solution onto the particle surface at 2.2g / min. After spraying, continue drying at 40℃ until the ethanol residue is ≤5000ppm and the drying loss is ≤5%. Pass through a 250μm sieve to obtain composite-coated drug-loaded resin particles.
[0059] Step 5: Take the composite-encapsulated drug-loaded resin particles obtained in Step 4, and take particles equivalent to 2g of dihydroergot methyl sulfonate for total mixing; under the theoretical dry basis conditions in this embodiment, the amount of these particles is 43.3g. Add the above particles, 92g of hydroxypropyl methylcellulose, 111.5g of microcrystalline cellulose, and 8.4g of povidone K30 to a mixing container and mix at 20r / min for 15min; add 1.2g of colloidal silica and mix at 20r / min for 5min; then add 3.6g of magnesium stearate and mix at 20r / min for 3min; compress the total mixture into tablets to make 1000 tablets of dihydroergot methyl sulfonate resin composite matrix sustained-release tablets, each with a theoretical tablet weight of 260mg and each containing 2mg of dihydroergot methyl sulfonate, and the tablet hardness is controlled at 100N.
[0060] Example 4:
[0061] Step 1: Take sodium polystyrene sulfonate cation exchange resin. First, remove coarse particles that do not pass through the sieve using a 125μm sieve. Then, place the resin that has passed through the 125μm sieve onto a 75μm sieve for further sieving, collecting the particles remaining on the 75μm sieve. Next, add 26g of the sieved resin to 560g of purified water and stir at 150r / min for 30min at 25℃. Filter. Add 280g of a 1mol / L hydrochloric acid solution to the filter cake and stir at 150r / min for 60min at 25℃. Filter. Add 280g of a 1mol / L hydrochloric acid solution to the filter cake again and stir at 150r / min at 25℃. Stir for 60 min, filter to convert sodium-form resin to hydrogen-form resin; wash the filter cake 6 times with 1200 g purified water, using 200 g purified water each time; then add the wet resin to a sodium hydroxide solution prepared with 2.75 g sodium hydroxide and 162 g purified water, stir at 150 r / min for 60 min at 25 °C, filter, and wash 3 times with 600 g purified water, using 200 g purified water each time; dry the resulting resin at 40 °C until the loss on drying is ≤8%, to obtain the pre-occupied exchange capacity resin. The proportion of sodium neutralization equivalent to the total exchange capacity was determined according to the method described in step 1 of Example 1, and the proportion was 52.8%.
[0062] Step 2: Add 216 mg of citrate monohydrate and 2.16 g of dihydroergotamine mesylate to 2000 g of purified water. Stir at 150 r / min for 30 min at 25 °C under light-protected conditions to obtain a dihydroergotamine mesylate solution. Add 26 g of the pre-occupied exchange capacity resin obtained in Step 1 to 280 g of purified water. Stir at 120 r / min for 20 min at 25 °C. Then, evacuate to an absolute pressure of 40 kPa and maintain for 10 min, followed by restoring to normal pressure for 5 min. Repeat the above evacuation and restoration to normal pressure operation once, maintaining 25 °C and stirring at 150 r / min. Add the above dihydroergotamine mesylate solution to the resin dispersion at a rate of 18 g / min. After the addition is complete, continue stirring for 330 min. Filter and collect the drug-loaded resin. The filtrate was used to determine the residual amount of dihydroergotamine mesylate. The residual drug amount in the filtrate was 3.4% of the feed amount. Within 5 minutes after filtration, the drug-loaded resin was added to a sodium chloride solution prepared with 0.9 g sodium chloride and 179.1 g purified water. The solution was stirred at 120 r / min for 5 minutes at 25°C, filtered, and washed once with 200 g purified water within 3 minutes after filtration. The resulting resin was dried at 40°C until the loss on drying was ≤5%, and passed through a 250 μm sieve to obtain gradient drug-loaded resin particles. The amount of weakly bound drug in the outer layer and the amount of bound drug in the inner layer were determined according to the method described in step 2 of Example 1. The proportion of weakly bound drug in the outer layer to the total drug load of the particles was 19.9%, and the proportion of bound drug in the inner layer to the total drug load of the particles was 78.0%.
[0063] Step 3: Add 2.7g of sodium alginate to 267.3g of purified water, stir at 100r / min for 30min at 25℃, and let stand for hydration for 8h to obtain sodium alginate solution. Add all the graded drug-loaded resin particles obtained in Step 2 to the sodium alginate solution, stir at 120r / min for 20min at 25℃. Separately, add 0.9g of calcium lactate pentahydrate to 89.1g of purified water, stir until dissolved, and add it to the above sodium alginate dispersion containing resin particles within 15min. Continue stirring at 120r / min for 30min. After filtration, dry the particles at 40℃ until the loss on drying is ≤6%, and pass through a 250μm sieve to obtain calcium alginate-coated drug-loaded resin particles.
[0064] Step 4: Add 5.4g of ethyl cellulose and 0.9g of triethyl citrate to 101.7g of ethanol, and stir at 150r / min for 60min at 25℃ to obtain ethyl cellulose film-forming solution. Take all the calcium alginate-coated drug-loaded resin particles obtained in Step 3, and process them using fluidized bed coating method. Control the material temperature at 32℃ and the atomizing air pressure at 0.18MPa. Spray the ethyl cellulose film-forming solution onto the particle surface at 2.0g / min. After spraying, continue drying at 40℃ until the ethanol residue is ≤5000ppm and the drying loss is ≤5%. Pass through a 250μm sieve to obtain composite-coated drug-loaded resin particles.
[0065] Step 5: Take the composite-encapsulated drug-loaded resin particles obtained in Step 4, and take particles equivalent to 2g of dihydroergot methyl sulfonate for total mixing; under the theoretical dry basis conditions in this embodiment, the amount of these particles is 36.4g. Add the above particles, 76g of hydroxypropyl methylcellulose, 137.7g of microcrystalline cellulose, and 6.3g of povidone K30 to a mixing container and mix at 20r / min for 15min; add 0.9g of colloidal silica and mix at 20r / min for 5min; then add 2.7g of magnesium stearate and mix at 20r / min for 3min; compress the total mixture into tablets to make 1000 tablets of dihydroergot methyl sulfonate resin composite matrix sustained-release tablets, each with a theoretical tablet weight of 260mg and each containing 2mg of dihydroergot methyl sulfonate, and the tablet hardness is controlled at 88N.
[0066] Example 5:
[0067] Step 1: Take sodium polystyrene sulfonate cation exchange resin. First, remove coarse particles that do not pass through the sieve using a 125μm sieve. Then, place the resin that has passed through the 125μm sieve onto a 75μm sieve for further sieving, collecting the particles remaining on the 75μm sieve. Next, add 30g of the sieved resin to 640g of purified water and stir at 150r / min for 30min at 25℃. Filter. Add 320g of a 1mol / L hydrochloric acid solution to the filter cake and stir at 150r / min for 60min at 25℃. Filter. Add 320g of a 1mol / L hydrochloric acid solution to the filter cake again and stir at 150r / min at 25℃. Stir for 60 min, filter to convert sodium-form resin to hydrogen-form resin; wash the filter cake 6 times with 1200 g purified water, using 200 g purified water each time; then add the wet resin to a sodium hydroxide solution prepared with 3.5 g sodium hydroxide and 207 g purified water, stir at 150 r / min for 60 min at 25 °C, filter, and wash 3 times with 600 g purified water, using 200 g purified water each time; dry the resulting resin at 40 °C until the loss on drying is ≤8%, to obtain the pre-occupied exchange capacity resin. The proportion of sodium neutralization equivalent to the total exchange capacity was determined according to the method described in step 1 of Example 1, and the proportion was 58.1%.
[0068] Step 2: Add 220 mg of citric acid monohydrate and 2.20 g of dihydroergotamine mesylate to 2100 g of purified water. Stir at 150 r / min for 30 min at 25 °C under light-protected conditions to obtain a dihydroergotamine mesylate solution. Add 30 g of the exchange capacity pre-occupied resin obtained in Step 1 to 320 g of purified water. Stir at 120 r / min for 20 min at 25 °C. Then, evacuate to an absolute pressure of 38 kPa and maintain for 10 min, followed by restoring to normal pressure for 5 min. Repeat the above evacuation and restoration to normal pressure operation once, maintaining 25 °C and stirring at 150 r / min. Add the above dihydroergotamine mesylate solution to the resin dispersion at a rate of 22 g / min. After the addition is complete, continue stirring for 390 min. Filter and collect the drug-loaded resin. The filtrate was used to determine the residual amount of dihydroergotamine mesylate. The residual drug amount in the filtrate was 3.0% of the feed amount. Within 5 minutes after filtration, the drug-loaded resin was added to a sodium chloride solution prepared with 1.1 g sodium chloride and 218.9 g purified water. The solution was stirred at 120 r / min for 7 minutes at 25°C, filtered, and washed once with 200 g purified water within 3 minutes after filtration. The resulting resin was dried at 40°C until the loss on drying was ≤5%, and passed through a 250 μm sieve to obtain gradient drug-loaded resin particles. The amount of weakly bound drug in the outer layer and the amount of bound drug in the inner layer were determined according to the method described in step 2 of Example 1. The proportion of weakly bound drug in the outer layer to the total drug load of the particles was 17.0%, and the proportion of bound drug in the inner layer to the total drug load of the particles was 80.6%.
[0069] Step 3: Add 3.3g of sodium alginate to 326.7g of purified water, stir at 100r / min for 30min at 25℃, and let stand for hydration for 8h to obtain sodium alginate solution. Add all the graded drug-loaded resin particles obtained in Step 2 to the sodium alginate solution, stir at 120r / min for 20min at 25℃. Separately, add 1.1g of calcium lactate pentahydrate to 108.9g of purified water, stir until dissolved, and add it to the above sodium alginate dispersion containing resin particles within 15min. Continue stirring at 120r / min for 30min. After filtration, dry the particles at 40℃ until the loss on drying is ≤6%, and pass through a 250μm sieve to obtain calcium alginate-coated drug-loaded resin particles.
[0070] Step 4: Add 6.6g of ethyl cellulose and 1.1g of triethyl citrate to 124.3g of ethanol, and stir at 150r / min for 60min at 25℃ to obtain ethyl cellulose film-forming solution. Take all the calcium alginate-coated drug-loaded resin particles obtained in Step 3, and process them using fluidized bed coating method. Control the material temperature at 32℃ and the atomizing air pressure at 0.19MPa. Spray the ethyl cellulose film-forming solution onto the particle surface at 2.1g / min. After spraying, continue drying at 40℃ until the ethanol residue is ≤5000ppm and the drying loss is ≤5%. Pass through a 250μm sieve to obtain composite-coated drug-loaded resin particles.
[0071] Step 5: Take the composite-encapsulated drug-loaded resin particles obtained in Step 4, and take particles equivalent to 2g of dihydroergot methyl sulfonate for total mixing; under the theoretical dry basis conditions in this embodiment, the amount of these particles is 41.5g. Add the above particles, 88g of hydroxypropyl methylcellulose, 118.4g of microcrystalline cellulose, and 7.7g of povidone K30 to a mixing container and mix at 20r / min for 15min; add 1.1g of colloidal silica and mix at 20r / min for 5min; then add 3.3g of magnesium stearate and mix at 20r / min for 3min; compress the total mixture into tablets to make 1000 tablets of dihydroergot methyl sulfonate resin composite matrix sustained-release tablets, each with a theoretical tablet weight of 260mg and each containing 2mg of dihydroergot methyl sulfonate, and the tablet hardness is controlled at 96N.
[0072] Comparative Example 1:
[0073] The difference from Example 1 is that: in step 1, hydrochloric acid hydrogenation treatment and sodium hydroxide pre-occupation treatment are not performed. 28g of sodium polystyrene sulfonate cation exchange resin after being sieved from 75μm to 125μm is taken, washed with 600g of purified water and dried at 40°C until the loss on drying is ≤8% and then directly used in step 2; the other conditions are the same as in Example 1.
[0074] Comparative Example 2:
[0075] The difference from Example 1 is that the amount of sodium hydroxide used in step 1 was adjusted from 3g to 4.5g, the amount of purified water used to prepare the sodium hydroxide solution was adjusted from 177g to 265.5g, and the sodium neutralization equivalent of the resulting resin accounted for 74.8% of the total exchange capacity; the other conditions were the same as in Example 1.
[0076] Comparative Example 3:
[0077] The difference from Example 1 is that: in step 1, the particle size range of 75μm to 125μm is not used. Instead, the coarse particles that do not pass through the sieve are first removed by a 250μm sieve. Then, the resin that has passed through the 250μm sieve is placed on a 45μm sieve for sieving, and the particles remaining on the 45μm sieve are collected. The other conditions are the same as in Example 1.
[0078] Comparative Example 4:
[0079] The difference from Example 1 is that in step 2, when preparing the dihydroergot methanesulfonate solution, 2000g of purified water is replaced with a sodium chloride solution prepared by 1g of sodium chloride and 1999g of purified water; the other conditions are the same as in Example 1.
[0080] Comparative Example 5:
[0081] The difference from Example 1 is that in step 2, 28g of the pre-occupied exchange capacity resin obtained in step 1 is added to 300g of purified water and stirred at 120r / min for 20min at 25℃. The process of pumping to an absolute pressure of 40kPa and then restoring to normal pressure is not performed. Instead, dihydroergot methanesulfonate solution is added directly under the conditions of 25℃ and stirring at 150r / min. The other conditions are the same as in Example 1.
[0082] Comparative Example 6:
[0083] The difference from Example 1 is that in step 2, the drug-loaded resin is added to 200g of purified water within 5 minutes after filtration, and stirred at 120r / min for 6 minutes at 25°C. The sodium chloride solution prepared by 1g of sodium chloride and 199g of purified water is not added; the other conditions are the same as in Example 1.
[0084] Comparative Example 7:
[0085] The difference from Example 1 is that step 3 is omitted, and in step 4, all the gradient drug-loaded resin particles obtained in step 2 are directly subjected to ethyl cellulose film formation treatment. In step 5, the particles obtained in step 4 are used to make a total mixture with particles equivalent to 2g of dihydroergot methanesulfonate. Under theoretical dry basis conditions, the amount of this particle is 34.8g, and the amount of microcrystalline cellulose is adjusted from 130.4g to 134.2g. The remaining conditions are the same as in Example 1.
[0086] Comparative Example 8:
[0087] The difference from Example 1 is that step 4 is omitted. In step 5, the calcium alginate-coated drug-loaded resin particles obtained in step 3 are used, and particles containing 2g of dihydroergot methanesulfonate are used for total mixing. Under theoretical dry basis conditions, the amount of these particles is 32g, and the amount of microcrystalline cellulose is adjusted from 130.4g to 137g. The remaining conditions are the same as in Example 1.
[0088] Comparative Example 9:
[0089] The difference from Example 1 is that 80g of hydroxypropyl methylcellulose is not added in step 5, and the amount of microcrystalline cellulose is adjusted from 130.4g to 210.4g; the other conditions are the same as in Example 1.
[0090] Performance testing:
[0091] Sample Preparation: 1000 tablets of dihydroergot methanesulfonate resin composite sustained-release tablets were prepared according to Examples 1-5 and Comparative Examples 1-9, respectively. After compression, the tablets were equilibrated at 25°C and 40% relative humidity for 24 hours before the following tests were performed. Intermediate samples used for resin pre-occupancy, particle size, and drug loading distribution tests were taken from the resin particles obtained in the corresponding steps of each example and comparative example; samples used for content uniformity, release rate, and release fluctuation tests were all tablets that had been compressed and equilibrated for 24 hours.
[0092] Resin particle size and sodium neutralization equivalent ratio test: According to the Pharmacopoeia 2025 edition, Part IV, General Chapter 0982, Particle Size and Particle Size Distribution Determination Method, take 10.0g of resin particles obtained in step 1 of each sample and place them in a standard sieve group consisting of a 125μm sieve and a 75μm sieve. Mechanically vibrate the sieve for 10min, weigh the particles that remain on the 75μm sieve and pass through the 125μm sieve, and calculate the proportion of 75μm to 125μm particle size. According to the 2025 edition of the Pharmacopoeia, Part IV, General Chapter 0701, potentiometric titration and permanent stop titration method, 1.000 g of the resin particles obtained in step 1 was added to 100 g of 1 mol / L sodium chloride solution, shaken at 25°C for 120 min, filtered, and the filtrate was titrated with 0.1 mol / L sodium hydroxide solution to pH 7.0. The exchange equivalent of the resin still in the hydrogen form was calculated. Another 1.000 g of the same batch of completely hydrogen form resin was taken and the total exchange capacity was determined using the same method. The proportion of sodium neutralization equivalent to the total exchange capacity was calculated.
[0093] Testing of the amount of weakly bound drug in the outer layer and the amount of drug bound internally of the drug-loaded resin particles: The content of dihydroergot methanesulfonate was determined by high performance liquid chromatography (HPLC) according to General Chapter 0512 of the 2025 edition of the Chinese Pharmacopoeia. The chromatographic column was an octadecylsilane-bonded silica column with dimensions of 250 mm × 4.6 mm and a packing particle size of 5 μm. The mobile phase was a solution of water, acetonitrile, and triethylamine in a volume ratio of 150:50:5. The flow rate was 1.5 mL / min. The detection wavelength was 280 nm. The column temperature was 30 °C. The injection volume was 20 μL. Take 1.000 g of the gradient drug-loaded resin particles obtained in step 2 of each sample, add 10 g of 50 mmol / L sodium chloride solution, stir at 120 r / min for 10 min at 25℃, filter, and use the filtrate as the test solution for the weakly bound drug in the outer layer; then add the filter cake to 10 g of 1 mol / L sodium chloride solution, stir at 120 r / min for 120 min at 25℃, filter, and use the filtrate as the test solution for the internally bound drug. The proportion of weakly bound drug in the outer layer is calculated by dividing the amount of weakly bound drug in the outer layer by the total drug load of the particles, and the proportion of internally bound drug is calculated by dividing the amount of internally bound drug by the total drug load of the particles. The total drug load of the particles is the sum of the amount of weakly bound drug in the outer layer, the amount of internally bound drug, and the amount of remaining drug measured by complete extraction using the same method.
[0094] Tablet content uniformity test: The content uniformity test was performed according to the General Rules 0941 (Content Uniformity Test Method) and 0512 (High Performance Liquid Chromatography) of the 2025 edition of the Pharmacopoeia. Ten tablets were randomly selected from each sample and placed in 50 mL volumetric flasks. 10 mL of 1 mol / L sodium chloride solution was added, and the mixture was shaken for 20 min. Then, 30 mL of acetonitrile was added, and the mixture was sonicated for 15 min. After cooling to 25°C, the mixture was diluted to the mark with acetonitrile, shaken well, and centrifuged at 5000 r / min for 10 min. The supernatant was filtered through a 0.45 μm microporous membrane, and the filtrate was used as the test solution. The content of dihydroergotamine mesylate in each tablet was determined according to the chromatographic conditions described in Test Item II. The percentage, average value, standard deviation, and content uniformity acceptance value of each tablet relative to the labeled amount were calculated. Since the labeled amount of dihydroergotamine mesylate per tablet is 2 mg, which is a low-dose tablet, the content uniformity acceptance value was calculated according to General Rules 0941.
[0095] In vitro release rate test: The test was conducted according to the second method (paddle method) of Dissolution and Release Rate Determination Method 0931 in the General Chapter IV of the 2025 edition of the Chinese Pharmacopoeia. Six tablets were used for each sample. The release medium was 900 mL of pH 6.8 phosphate buffer, with the medium temperature controlled at 37.0℃ ± 0.5℃ and the paddle speed at 50 r / min. 5 mL samples were taken at 0.5 h, 2 h, 6 h, and 12 h, and an equal volume of fresh release medium at the same temperature was immediately added. After filtering the samples through a 0.45 μm microporous membrane, the concentration of dihydroergot methanesulfonate in the filtrate was determined by high-performance liquid chromatography (HPLC) under the conditions described in Test Item II, and the cumulative release rate was calculated based on the sample replenishment correction.
[0096] Ionic strength and pH release fluctuation tests: The tests were performed according to the second method (paddle method) of the General Chapter 0931, Dissolution and Release Determination, Part IV, 2025 Pharmacopoeia. Each sample was tested in three release media, with six tablets taken from each medium: 900 mL of pH 1.2 sodium chloride hydrochloride solution for the first medium, 900 mL of pH 6.8 phosphate buffer for the second medium, and 900 mL of pH 6.8 phosphate buffer containing 100 mmol / L sodium chloride for the third medium. The medium temperature was controlled at 37.0℃ ± 0.5℃, and the paddle speed was 50 r / min. 5 mL samples were taken at 0.5 h, 2 h, 6 h, and 12 h, and the corresponding release medium was immediately added at the same temperature. After filtration through a 0.45 μm microporous membrane, the concentration of dihydroergot methyl sulfonate in the filtrate was determined. The release fluctuation factor is calculated as the maximum difference between the maximum and minimum cumulative release rates of the same sample at each sampling time point in three media. It is used to characterize the influence of changes in external pH and ionic strength on release behavior. The smaller the release fluctuation factor, the stronger the sample's resistance to changes in the gastrointestinal fluid environment.
[0097] Table 1 Performance Test Results
[0098] Example 1 93.4 56.4 18.4 78.7 4.7 7.8 27.4 65.8 93.4 4.4 Example 2 92.1 50.6 21.8 76.5 6.4 10.6 29.8 69.6 95.8 6.1 Example 3 94.2 59.6 15.3 82.2 3.9 5.6 21.7 58.9 90.8 3.2 Example 4 92.7 52.8 19.9 78.0 5.6 9.6 28.9 68.4 95.1 5.4 Example 5 93.9 58.1 17.0 80.6 4.2 6.8 24.2 62.7 92.2 3.8 Comparative Example 1 93.2 99.1 33.8 58.6 12.6 22.1 49.4 83.2 97.0 19.0 Comparative Example 2 92.9 74.8 27.6 67.5 9.5 15.7 38.6 76.4 96.3 14.4 Comparative Example 3 42.8 56.1 22.7 74.6 16.1 13.4 33.1 69.9 93.1 10.8 Comparative Example 4 93.3 56.3 30.4 64.2 9.0 18.8 44.7 80.1 96.8 18.3 Comparative Example 5 93.0 56.4 26.1 70.3 8.2 16.5 40.6 76.8 95.6 13.5 Comparative Example 6 93.4 56.4 32.0 66.0 7.5 19.5 46.2 81.4 96.2 15.8 Comparative Example 7 93.5 56.4 18.5 78.5 6.3 13.2 36.1 73.4 94.6 12.7 Comparative Example 8 93.4 56.4 18.4 78.6 6.9 17.4 43.5 79.0 96.4 16.7 Comparative Example 9 93.4 56.4 18.6 78.4 7.8 20.7 50.6 84.8 97.3 21.3
[0099] As shown in Table 1, the proportion of 75-125μm particles in Examples 1-5 was 92.1%-94.2%, the sodium neutralization equivalent was 50.6%-59.6%, the proportion of weakly bound drug in the outer layer was only 15.3%-21.8%, the proportion of internally bound drug reached 76.5%-82.2%, the content uniformity acceptance value AV was 3.9-6.4, the cumulative release rate at 0.5h was 5.6%-10.6%, the cumulative release rate at 12h was 90.8%-95.8%, and the release fluctuation factor was 3.2%-6.1%. This indicates that the examples exhibited good comprehensive performance in terms of content uniformity of low-dose tablets, initial burst release control, and release stability in different media.
[0100] Compared with Example 1, Comparative Example 1 did not undergo hydrochloric acid hydrogenation and sodium hydroxide pre-occupation treatment. The sodium neutralization equivalent ratio increased to 99.1%, the outer weakly bound drug amount ratio increased to 33.8%, the internal bound drug amount ratio decreased to 58.6%, the cumulative release rate at 0.5 h increased to 22.1%, and the release fluctuation factor increased to 19.0%, indicating that directly using sodium-type resin is not conducive to forming a stable internally bound drug-loaded structure.
[0101] Comparative Example 2 increased the sodium neutralization equivalent to 74.8%, and its outer layer weakly bound drug amount, 0.5h release rate and release fluctuation factor were all higher than those of Example 1, indicating that an excessively high sodium pre-occupancy ratio can also weaken the stable binding of the drug to the micropores inside the resin.
[0102] Comparative Example 3 did not specify a particle size range of 75-125 μm, and its target particle size ratio decreased to 42.8%, while the content uniformity acceptance value increased to 16.1, indicating that an excessively wide particle size would have an adverse effect on the content uniformity of low-dose dihydroergot mesylate tablets.
[0103] Comparative Example 4 added sodium chloride to the drug-loading solution, Comparative Example 5 did not undergo vacuuming and restoration to normal pressure treatment, and Comparative Example 6 did not use a low-concentration sodium chloride solution for short-term outer layer desorption. The proportion of weakly bound drug in the outer layer of the above samples increased to 30.4%, 26.1%, and 32.0%, respectively, and the cumulative release rate at 0.5 h increased to 18.8%, 16.5%, and 19.5%, respectively. This indicates that competing ions during the drug loading stage, insufficient liquid replacement in the resin channels, and the lack of selective removal of weakly bound drug in the outer layer all increase the initial release of the tablet.
[0104] Comparative Example 7 did not have a calcium alginate coating layer, Comparative Example 8 did not have an ethyl cellulose outer membrane, and Comparative Example 9 did not have a hydroxypropyl methylcellulose backbone. Their cumulative release rate and release fluctuation factor at 0.5 h were significantly higher than those of Example 1. Among them, the release fluctuation factor of Comparative Example 9 reached 21.3%, indicating that it is difficult to resist changes in pH and ionic strength at the same time by relying solely on resin-loaded drugs or a single coating structure.
[0105] The results of the combined embodiments and comparative examples show that this application, through the synergistic effects of moderate pre-occupancy of exchange capacity, internal gradient drug loading, weakly bound drug control in the outer layer, calcium alginate gating, ethyl cellulose diffusion barrier, and hydroxypropyl methyl cellulose gel skeleton, enables dihydroergot methanesulfonate to form a multi-level release control structure in the tablet. While maintaining a basically sufficient release over 12 hours, it significantly reduces release fluctuations caused by initial burst release and media disturbances, demonstrating a comprehensive sustained-release effect superior to single resin drug loading, single coating, or single hydrophilic skeleton systems.
[0106] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity.
Claims
1. A sustained-release tablet with a dihydroergot methanesulfonate resin composite matrix, characterized in that, The sustained-release tablet comprises composite-encapsulated drug-loaded resin particles and a hydroxypropyl methylcellulose backbone dispersing the composite-encapsulated drug-loaded resin particles. Based on a total weight of 260 tablets, the sustained-release tablets comprise: 34.2-43.3 parts of a composite-encapsulated drug-loaded resin particle containing 2 parts of dihydroergot mesylate, 68-92 parts of hydroxypropyl methylcellulose, 5.6-8.4 parts of povidone K30, 0.8-1.2 parts of colloidal silica, 2.4-3.6 parts of magnesium stearate, and the balance of microcrystalline cellulose, wherein the microcrystalline cellulose comprises 111.5-149.0 parts. The composite encapsulated drug-loaded resin particles include gradient drug-loaded resin particles, a calcium alginate encapsulation layer on the surface of the gradient drug-loaded resin particles, and an ethyl cellulose membrane layer on the surface of the calcium alginate encapsulation layer. The gradient drug-loaded resin particles comprise an exchange capacity pre-occupying resin and dihydroergot methanesulfonate loaded in the exchange capacity pre-occupying resin. The exchange capacity pre-occupying resin is obtained by acidifying a sulfonic acid-type cation exchange resin obtained through sieving to a hydrogen form and then neutralizing it with sodium ions. In the sulfonic acid-type cation exchange resin obtained through sieving, particles with a diameter of 75-125 μm account for no less than 90%, and the sodium neutralization equivalent of the exchange capacity pre-occupying resin accounts for 50.6% to 59.6% of the total exchange capacity. The gradient drug-loaded resin particles, as measured by the sodium chloride fractional desorption method according to claim 2, have an outer layer weakly bound drug content of 15.3%-21.8% of the total drug load, an internally bound drug content of 76.5%-82.2% of the total drug load, and a remaining drug content of 1.7%-2.9% of the total drug load. The sum of the outer layer weakly bound drug content, the internally bound drug content, and the remaining drug content is 100% of the total drug load.
2. The sustained-release tablet with dihydroergot methanesulfonate resin composite matrix according to claim 1, characterized in that, The sodium chloride fractional desorption method includes: taking 1g of graded drug-loaded resin particles, adding them to 10g of a 50mmol / L sodium chloride solution, stirring at 120r / min for 10min at 25℃, filtering, and determining the content of dihydroergot methyl sulfoxide in the filtrate as the amount of weakly bound drug in the outer layer; then adding the filter cake to 10g of a 1mol / L sodium chloride solution, stirring at 120r / min for 120min at 25℃, filtering, and determining the content of dihydroergot methyl sulfoxide in the filtrate as the amount of internally bound drug.
3. The sustained-release tablet with dihydroergot methanesulfonate resin composite matrix according to claim 1, characterized in that, Each of the sustained-release tablets has a theoretical weight of 260 mg, contains 2 mg of dihydroergot methyl methacrylate, and has a tablet hardness of 85-100 N.
4. The sustained-release tablet with dihydroergot methanesulfonate resin composite matrix according to claim 1, characterized in that, The sulfonic acid cation exchange resin is a pharmaceutical-grade strong acid dry powder sodium polystyrene sulfonate cation exchange resin with a total cation exchange capacity of 5.0 meq / g.
5. The sustained-release tablet with dihydroergot methanesulfonate resin composite matrix according to claim 1, characterized in that, The composite encapsulated drug-loaded resin particles are prepared from the following raw materials excluding the solvent: 24-32 parts of exchange capacity pre-occupying resin, 2.12-2.25 parts of dihydroergot methanesulfonate, 0.210-0.225 parts of citrate monohydrate, 2.4-3.6 parts of sodium alginate, 0.8-1.2 parts of calcium lactate pentahydrate, 4.8-7.2 parts of ethyl cellulose, and 0.8-1.2 parts of triethyl citrate.
6. The sustained-release tablet with dihydroergot methanesulfonate resin composite matrix according to claim 1, characterized in that, The 1% aqueous solution of sodium alginate has a viscosity of 35 mPa·s at 20°C; the hydroxypropyl methylcellulose is K100M grade hydroxypropyl methylcellulose; the specific surface area of the colloidal silica is 210 m². 2 / g.
7. The sustained-release tablet with dihydroergot methanesulfonate resin composite matrix according to claim 1, characterized in that, When the release rate of the sustained-release tablets was determined using the paddle method in pH 6.8 phosphate buffer, the medium volume was 900 mL, the medium temperature was 37.0 ± 0.5 °C, and the paddle speed was 50 r / min. The cumulative release rate was 5.6%-10.6% at 0.5 h, 21.7%-29.8% at 2 h, 58.9%-69.6% at 6 h, and 90.8%-95.8% at 12 h.
8. The sustained-release tablet with dihydroergot methanesulfonate resin composite matrix according to claim 1, characterized in that, The content uniformity acceptance value (AV) of the sustained-release tablets is 3.9-6.
4.
9. A method for preparing a sustained-release tablet with a dihydroergot methanesulfonate resin composite matrix according to any one of claims 1-8, characterized in that, Includes the following steps: (1) The sulfonic acid type cation exchange resin was screened to obtain resin particles with a particle size of 75-125μm. After being converted to hydrogen form by acid treatment, it was partially neutralized by sodium hydroxide to obtain a pre-occupied resin with a sodium neutralization equivalent of 50.6%-59.6% of the total exchange capacity. (2) Add dihydroergot methanesulfonate solution to the pre-occupied resin dispersion with vacuum assistance for drug loading, and then treat with sodium chloride solution to obtain gradient drug-loaded resin particles. (3) The gradient drug-loaded resin particles are added to sodium alginate solution, and then calcium lactate pentahydrate solution is added for cross-linking to obtain calcium alginate-encapsulated drug-loaded resin particles. (4) The ethyl cellulose film-forming solution is sprayed onto the surface of the calcium alginate-coated drug-loaded resin particles to obtain composite-coated drug-loaded resin particles. (5) Take the composite encapsulated drug-loaded resin particles, mix them with hydroxypropyl methylcellulose, microcrystalline cellulose, povidone K30, colloidal silica and magnesium stearate, and compress them into tablets to obtain dihydroergot methanesulfonate resin composite sustained-release tablets.
10. The method for preparing the dihydroergot methanesulfonate resin composite sustained-release tablet according to claim 9, characterized in that, In step (4), the spraying is carried out using a fluidized bed coating method, the material temperature is controlled at 31-33℃, the atomizing air pressure is 0.16-0.20MPa, and the spraying speed is 1.8-2.2g / min.