Sulfonamide derivative sustained-release granules and a method for preparing the same
By preparing small-particle-size sulfonamide derivative sustained-release particles and employing a double-layer sustained-release coating technology, the problems of swallowing difficulties and dosage fractionation difficulties in pediatric patients were solved, achieving good palatability and smooth drug release.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- CHANGSHA JINGYI PHARM TECH CO LTD
- Filing Date
- 2026-03-30
- Publication Date
- 2026-07-03
AI Technical Summary
Existing sulfonamide derivative formulations, such as immediate-release tablets and sustained-release capsules, present problems such as difficulty in swallowing, difficulty in dose division, and inconvenience in administration in pediatric patients. In particular, the large particle diameter of sustained-release capsules leads to a noticeable gritty sensation.
Sulfonamide derivatives were prepared into small-particle-size sustained-release granules. A double-layer sustained-release coating technology was used, and by controlling the type and amount of excipients in each layer and combining flavoring excipients, a palatable and easy-to-swallow oral formulation for children was prepared.
It solves the problems of swallowing difficulties and dosage fractionation for pediatric patients. The particles have no gritty feel, are palatable, support dosage-based administration, and improve the convenience of medication and the smoothness of drug release.
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Figure CN122320918A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical formulation technology, and specifically relates to a sulfonamide derivative sustained-release granule and its preparation method. Background Technology
[0002] Epilepsy is a chronic neurological disorder caused by abnormal electrical discharges in the brain. It is characterized by recurrent, spontaneous seizures and is one of the most common neurological diseases. It has a higher incidence rate in children and adolescents, with nearly 60% of epilepsy patients in my country being children.
[0003] The sulfonamide derivative is an aminosulfonate derivative of natural D-fructose, chemically named 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructose pyranocyanate, with the structure shown below: Sulfonamide is an antiepileptic drug with multiple mechanisms of action, widely used in the treatment of neurological disorders such as epilepsy and migraines. Research results indicate that this drug is effective in long-term monotherapy for childhood epilepsy. Currently, marketed sulfonamide derivative formulations mainly include immediate-release tablets and extended-release capsules. However, for children with epilepsy, immediate-release tablets have drawbacks such as difficulty swallowing, difficulty in dose fractionation leading to uncontrollable dosage, and the need for multiple doses. The marketed extended-release capsule formulations also suffer from swallowing difficulties and difficulty in dose fractionation, and their contents have excessively large extended-release particles, easily producing a noticeable gritty sensation when taken, causing significant inconvenience for children.
[0004] Therefore, developing a dosage form suitable for children containing this sulfonamide derivative is a technical problem that needs to be solved in this field. Summary of the Invention
[0005] To solve the above-mentioned technical problems, the present invention prepares the sulfonamide derivative into sustained-release particles with a smaller particle size, and performs two sustained-release coatings on the outside of the drug-loaded layer, controls the type and amount of excipients in each layer, and selectively adds other flavoring excipients to obtain a more palatable, easier-to-swallow, easier-to-divide, and more precise and convenient oral formulation for children.
[0006] This invention provides a sulfonamide derivative sustained-release particle, comprising a drug-loaded layer, a sustained-release layer I, and a sustained-release layer II. The drug-loaded layer includes a blank pellet core and an active ingredient layer, wherein the active ingredient is a compound of formula I. .
[0007] In some embodiments, the blank pellet core includes one or more of the following: sucrose pellet core, microcrystalline cellulose pellet core, silica pellet core, starch pellet core, tartaric acid pellet core, and mannitol pellet core.
[0008] In some embodiments, the particle size D90 of the blank pellet core is 20–80 μm.
[0009] In some embodiments, the sustained-release particles have a particle size D90 of less than 150 μm.
[0010] During the research process, this invention discovered that when the particle size D90 of the sustained-release granules is controlled below 150 μm, the prepared sulfonamide derivative sustained-release granules have no obvious gritty feeling in the oral cavity, a delicate taste, and good patient compliance. This particle size range, combined with the aforementioned particle size control of the blank pellet core, can effectively improve the palatability of the formulation, making it particularly suitable for pediatric patients whose swallowing function is not yet fully developed.
[0011] In some embodiments, the active ingredient layer includes an active ingredient, an adhesive, and an anti-adhesive, wherein the adhesive includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and polyvinyl alcohol, and the anti-adhesive includes one or more of talc, silica, magnesium stearate, micronized silica, and sodium dodecyl sulfate.
[0012] Understandably, the role of the adhesive is to promote the firm adhesion of the drug layer to the surface of the blank pellet core, ensuring that the drug can be uniformly and stably coated on the pellet core, thereby ensuring the uniformity of drug loading; the anti-adhesion agent is mainly used to prevent the adhesion between materials during the formulation process, while improving the overall flowability of the excipients, ensuring the smooth progress of the coating process and the stability of the process.
[0013] In some embodiments, the sustained-release layer I includes a sustained-release material, a pore-forming agent, an anti-adhesion agent, and a plasticizer. The sustained-release material includes one or more of ethyl cellulose, methyl methacrylate copolymer, and ethylene-vinyl acetate copolymer. The pore-forming agent includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and polyvinyl alcohol. The anti-adhesion agent includes one or more of talc, silica, magnesium stearate, micronized silica, and sodium lauryl sulfate. The plasticizer includes one or more of triethyl citrate, polyethylene glycol, phthalate, and castor oil.
[0014] It is understandable that pore-forming agents are excipients used in the sustained-release layer to form a microporous structure, which can help the sustained-release layer form a pore network and regulate the release rate; plasticizers are excipients used to improve the mechanical properties of the polymer, which can help increase the flexibility of the sustained-release layer, regulate the swelling of the granules, and optimize film-forming properties.
[0015] In some embodiments, the components include the following by weight percentage: Drug-loaded layer: 60%~12% blank pellet core, 50%~10% active ingredient, 6%~1% binder and 20%~1.5% anti-adhesion agent; Sustained-release layer I: 22%~1% sustained-release material, 5%~0% pore-forming agent, 5%~0% anti-adhesion agent, 5%~0% plasticizer; Sustained-release layer II: 10%~1% sustained-release material, 2%~0% anti-adhesion agent, 2%~0% plasticizer.
[0016] The weight percentage of the blank pellet core is 60% to 12%, for example, it can be 60%, 50%, 40%, 30%, 20% or 12%, and specific values between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values included in the range.
[0017] The weight percentage of the active ingredient is 50% to 10%, for example, it can be 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15% or 10%, and specific values between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values included in the range.
[0018] The adhesive has a weight percentage of 6% to 1%, for example, it can be 6%, 5%, 4%, 3%, 2% or 1%, and specific values between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values included in the range.
[0019] The weight percentage of the anti-adhesion agent is 20% to 1.5%, for example, it can be 20%, 18%, 15%, 12%, 10%, 8%, 5%, 3%, 2% or 1.5%, and specific values between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values included in the range.
[0020] In the sustained-release layer I, the weight percentage of the sustained-release material is 22% to 1%, for example, it can be 22%, 20%, 18%, 15%, 12%, 10%, 8%, 5%, 3%, 2% or 1%, and specific values between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values included in the range.
[0021] The weight percentage of the pore-forming agent is 5% to 0%, for example, it can be 5%, 4%, 3%, 2%, 1% or 0%, and specific values between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values included in the range.
[0022] The weight percentage of the anti-adhesive is 5% to 0%, for example, it can be 5%, 4%, 3%, 2%, 1% or 0%, and specific values between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values included in the range.
[0023] The plasticizer has a weight percentage of 5% to 0%, for example, it can be 5%, 4%, 3%, 2%, 1% or 0%, and specific values between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values included in the range.
[0024] In the sustained-release layer II, the weight percentage of the sustained-release material is 10% to 1%, for example, it can be 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%, and specific values between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values included in the range.
[0025] The weight percentage of the anti-adhesion agent is 2% to 0%, for example, it can be 2%, 1.5%, 1%, 0.5% or 0%, and specific values between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values included in the range.
[0026] The plasticizer has a weight percentage of 2% to 0%, for example, it can be 2%, 1.5%, 1%, 0.5% or 0%, and specific values between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values included in the range.
[0027] In some embodiments, when the anti-adhesion agent in the drug-loaded layer is selected from talc, the weight percentage of talc in the drug-loaded layer is greater than 7%.
[0028] In some embodiments, the weight ratio of the pore-forming agent to the anti-adhesive in the sustained-release layer I should be greater than 0.9:1.
[0029] In some embodiments, the weight gain of the sustained-release layer II ranges from 3% to 4%. In some embodiments, the sustained-release particles further include excipients, which include 95% to 70% diluent, 30% to 5% suspending agent, and 9% to 0% flavoring agent.
[0030] In some embodiments, the diluent includes one or more of sucrose, lactose, sorbitol, and mannitol. The suspending agent includes one or more of xanthan gum, gum arabic, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, and a co-treated microcrystalline cellulose sodium carboxymethyl cellulose. The flavoring agent includes one or more of sucrose, lactose, glucose, sorbitol, mannitol, sucralose, strawberry flavor, sweet orange flavor, and milk flavor.
[0031] In some embodiments, the added excipients also include colorants, such as one or more of Sunset Yellow, Carmine, and Titanium Dioxide.
[0032] Another aspect of the present invention provides a method for preparing the sustained-release particles, comprising the following steps: Step 1: Preparation of drug-loaded layer. The active ingredient is dissolved in a solvent and then mixed with a binder and an anti-adhesion agent. The mixture is stirred to obtain a drug-loaded solution. Using a blank pellet core as a substrate, the drug-loaded solution is atomized and sprayed onto the blank pellet core through a fluidized bed powder coating process to obtain drug-loaded particles. Step 2: Preparation of sustained-release layer I. First, prepare a sustained-release coating solution with ethanol aqueous solution as the main component. Then, continue to use the powder coating process to atomize the sustained-release coating solution and spray it onto the drug-loaded particles prepared in step 1 for sustained-release coating. Step 3: Preparation of sustained-release layer II. Prepare a sustained-release coating solution with ethanol aqueous solution as the main component; continue to use the powder coating process, atomize the sustained-release coating solution and spray it onto the sustained-release particles prepared in step 2 for sustained-release coating; after coating, dry to obtain sustained-release particles.
[0033] In some embodiments, the preparation method further includes step four: the sustained-release granules are mixed with an external diluent, suspending agent, and flavoring agent, and then packaged.
[0034] In some embodiments, the solvent for dissolving the active ingredient and the sustained-release material comprises ethanol, and the solvent for dissolving the adhesive and the pore-forming agent comprises water. In step one, the ethanol-water ratio can be 7:3 to 1:1; in steps two and three, the ethanol-water ratio in the ethanol-water solution can be 4:1 to 1:0.
[0035] The sustained-release granules prepared by this invention have the following advantages: This invention solves the problem of gritty feeling in traditional granules by controlling the particle size distribution of blank pellet cores and final granules, so that the prepared sustained-release granules have no gritty feeling when taken, have good palatability and are easier to swallow. The granule dosage form prepared by this invention supports "dosage by dosage". In clinical use, the required volume can be accurately measured according to the child's actual weight or age, which solves the problem of difficulty in dividing tablets or capsules into doses. At the same time, relying on sustained-release formulation technology, it only needs to be taken once a day, which greatly improves the convenience of medication. This invention employs a "double-layer sustained-release coating" process. By synergistically controlling the types and amounts of excipients in the inner and outer sustained-release layers, it overcomes the problems of excessively rapid initial release or incomplete release in the later stages that may occur with single-layer coating, thus achieving sustained-release characteristics with a smoother drug release rate and a longer duration of action. Detailed Implementation
[0036] Numerous specific details are set forth in the following description to provide a full understanding of the invention. However, the invention can be practiced in many other ways different from those described herein, and similar modifications can be made by those skilled in the art without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.
[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
[0038] Examples 1-4: Screening of Anti-adhesion Agent Dosage in Drug-Loaded Layers Table 1 Prescription Table for Examples 1-4
[0039] Drug loading layer preparation: Preparation of ethanol solution of active ingredient: Add the active ingredient to 500-800g of 95% ethanol and stir until dissolved. Hydroxypropyl methylcellulose aqueous solution: Disperse hydroxypropyl methylcellulose in 220-350g of hot water, stir to dissolve, and set aside for later use; Mix the active ingredient ethanol solution with the hydroxypropyl methylcellulose aqueous solution and stir until homogeneous; optionally, continue to add talc powder and perform high shear for no less than 5 minutes to obtain the drug solution. Microcrystalline cellulose pellets are added to a fluidized bed. A suitable inlet air temperature and atomizing pressure are set, and the material temperature is controlled. A drug-loaded solution is sprayed in for drug coating. After drug coating, the drug-loaded pellets are sieved, and the pellets below the sieve are collected to obtain drug-loaded particles.
[0040] Table 2. Investigation of the particle content of the drug-loaded layer prepared in Examples 1-4
[0041] Content determination method: Take the drug-loaded particles prepared in Examples 1-4, transfer their contents to volumetric flasks in full, wash the packaging bag with diluent (50% methanol solution) several times, combine the washings into the volumetric flasks, add an appropriate amount of diluent to dissolve the sample, sonicate, dilute to the mark with diluent, shake well, filter with an organic nylon filter, discard 2 drops of the initial filtrate, and take the subsequent filtrate to obtain the test sample. Determine the content by referring to the high performance liquid chromatography method (General Chapter 0512, Part IV, Chinese Pharmacopoeia 2025).
[0042] Conclusion: Increasing the amount of talc can improve the problem of large electrostatic adsorption during the experiment, and the content is within the acceptable range and tends to be stable. When the amount of talc is greater than 7.69%, the electrostatic adsorption problem is significantly improved.
[0043] Examples 5-7 Screening of the Dosage of Pore-Inducing Agent in the Sustained-Release Layer Table 3 Prescription Table for Examples 5-7
[0044] The drug-loaded layer was prepared using the formulation and preparation method of Example 3.
[0045] Preparation of ethyl cellulose ethanol solution: Dissolve ethyl cellulose in 800-1000g of 95% ethanol; Hydroxypropyl methylcellulose aqueous solution: Disperse hydroxypropyl methylcellulose in 200-250g of hot water, stir to dissolve, and set aside for later use; Ethyl cellulose ethanol solution and hydroxypropyl methyl cellulose aqueous solution were mixed and stirred evenly. Triethyl citrate was added and dissolved and dispersed. Talc powder was added and subjected to high shear for at least 15 minutes to obtain a sustained-release coating solution. Take the drug-loaded particles obtained in the first step, set appropriate inlet air temperature and atomization pressure, control the material temperature, and spray in the sustained-release coating solution to perform the first sustained-release coating, obtaining sustained-release layer I particles.
[0046] Evaluation indicators: Dissolution behavior evaluation Since the preparation obtained in this invention is a sustained-release formulation, the in vitro dissolution behavior of the US-listed sustained-release capsule (QUDEXY® XR, specification: 25mg) was referenced during the formulation screening stage to evaluate the in vitro sustained-release effect of the self-developed formulation.
[0047] Take the sustained-release granules prepared in Examples 5-7, and perform dissolution and release assays according to the method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), using 250 mL of pH 6.8 phosphate buffer solution as the dissolution medium, and a rotation speed of 100 rpm. After 0.5, 1, 2, 3, 4, 6, and 8 hours, take approximately 5 mL of the solution, and immediately replenish with the same volume and temperature of dissolution medium. Filter, discard approximately 1 mL of the initial filtrate, and accurately measure 50 μL of the subsequent filtrate. Perform chromatographic determination according to the conditions under the Assay section. The results are as follows.
[0048] Table 4. Dissolution test results of the sustained-release particles prepared in Examples 5-7
[0049] Conclusions: (1) When the talc content is high, the dissolution behavior of the self-developed formulation tends to be slower in the later stages compared with the control formulation. In this case, it is necessary to increase the content of the water-soluble porogen hydroxypropyl methylcellulose to increase the porosity of the sustained-release membrane, thereby improving the dissolution rate; (2) When increasing the unit dosage of the porogen hydroxypropyl methylcellulose, the dissolution rate significantly accelerates when the weight ratio of hydroxypropyl methylcellulose to talc reaches 0.9:1 or higher. Based on this, using Example 7 as a benchmark, the effect of coating weight gain on dissolution behavior was further investigated to obtain a suitable sustained-release effect.
[0050] Examples 8-9: Screening process and results for the number of sustained-release layers The increase in weight of the sustained-release layer affects dissolution and thus the sustained-release effect. Therefore, it is necessary to investigate the increase in weight of the sustained-release layer. The formulation and dissolution investigation method are the same as in Example 7.
[0051] Table 5. Results of dissolution curve analysis for the formulation in Example 8 (different coating weight gain under the formulation of Example 7).
[0052] The dissolution rates of the three batches (15%, 20%, and 25% weight gain) were all relatively fast, failing to achieve the desired sustained-release effect. This is presumably due to the high proportion of porogen; upon contact with the dissolution medium, the porogen rapidly hydrates and dissolves, causing the ethyl cellulose membrane to quickly form numerous pores, resulting in excessively rapid drug release. Previous studies on the amount of porogen indicated that reducing the amount of porogen tends to lead to limited dissolution and a lower dissolution plateau in the later stages. Therefore, this application considers removing the porogen and adding a sustained-release coating layer on top of the sustained-release coating I. This dual-layer sustained-release membrane synergistically controls release, slowing down the medium penetration rate to achieve a stable and sustained drug release.
[0053] Table 6 Prescription Table for Example 9
[0054] Drug loading layer preparation: Preparation of ethanol solution of active ingredient: Add the active ingredient to 500-800g of 95% ethanol and stir until dissolved. Hydroxypropyl methylcellulose aqueous solution: Disperse hydroxypropyl methylcellulose in 220-350g of hot water, stir to dissolve, and set aside for later use; Mix the active ingredient ethanol solution with the hydroxypropyl methylcellulose aqueous solution and stir until homogeneous; optionally, continue to add talc powder and perform high shear for no less than 5 minutes to obtain the drug solution. Microcrystalline cellulose pellets are added to a fluidized bed. Appropriate inlet air temperature and atomizing pressure are set, and the material temperature is controlled. A drug-coating solution is then sprayed in. After drug coating, the drug-loaded pellets are passed through a sieve, and the pellets below the sieve are collected for later use, yielding drug-loaded particles.
[0055] Preparation of sustained-release layer I (weight gain 20%): Preparation of ethyl cellulose ethanol solution: Dissolve ethyl cellulose in 800-1000g of 95% ethanol; Hydroxypropyl methylcellulose aqueous solution: Disperse hydroxypropyl methylcellulose in 200-250g of hot water, stir to dissolve, and set aside for later use; Ethyl cellulose ethanol solution and hydroxypropyl methyl cellulose aqueous solution were mixed and stirred evenly. Triethyl citrate was added and dissolved and dispersed. Talc powder was added and subjected to high shear for at least 15 minutes to obtain a sustained-release coating solution. Take the drug-loaded particles, set the appropriate inlet air temperature and atomization pressure, control the material temperature, and spray in the sustained-release coating liquid to form the first sustained-release coating, thus obtaining sustained-release layer I particles.
[0056] Preparation of sustained-release layer II: Preparation of ethyl cellulose ethanol solution: Dissolve ethyl cellulose in 95% ethanol + 5% water; Add triethyl citrate to the ethyl cellulose ethanol solution to dissolve and disperse it; continue to add talc powder and apply high shear for at least 15 minutes to obtain a sustained-release coating solution; Set appropriate inlet air temperature and atomization pressure, control material temperature, and spray in the slow-release coating liquid to form the second slow-release coating layer. After coating, dry. Sieve through a sieve to obtain slow-release layer II particles.
[0057] Table 7. Results of dissolution curve analysis of different sustained-release layer II coatings for weight gain under the formulation of Example 9.
[0058] Conclusion: The dissolution of the double-layer sustained-release film was similar to that of the control formulation, exhibiting good sustained-release effect and achieving complete dissolution. Therefore, two-layer sustained-release coating was determined. The weight gain of sustained-release layer II coating was 3-4%.
[0059] Examples 10-12 Table 8 Prescription Table for Example 10
[0060] Table 9 Prescription Table for Example 11
[0061] Table 10 Prescription Table for Example 12
[0062] Table 11 Prescription Table for Examples 13-14
[0063] The preparation method is the same as in Example 9. In addition, Examples 11-14 also include total mixing: the slow-release layer particles are mixed with mannitol, sodium carboxymethyl cellulose microcrystalline cellulose co-treated product, sucralose, titanium dioxide and milk powder flavoring, and then packaged.
[0064] Evaluation indicators: particle size detection, taste evaluation Table 12 Particle size measurement parameters of laser particle size analyzer
[0065] In this embodiment of the invention, the particle size D90 of the blank pellet core is 20-80 μm.
[0066] The particle size of the sustained-release particles prepared in Example 10 was measured as follows: D10: 61.52 μm, D50: 78.921 μm, D90: 125.789 μm, not exceeding 150 μm. When placed on the tip of the tongue, the sustained-release particles were tested and found to be free of any gritty sensation.
[0067] The particle size of the sustained-release particles prepared in Example 11 was measured as follows: D10: 64.73 μm, D50: 87.896 μm, D90: 120.289 μm, not exceeding 150 μm. When placed on the tip of the tongue, the particles were tested and found to be free of any gritty sensation.
[0068] The particle size of the sustained-release particles prepared in Example 12 was measured to be D10: 53.237 μm, D50: 86.912 μm, and D90: 122.319 μm, not exceeding 150 μm. When placed on the tip of the tongue, the sustained-release particles were tested and found to be gritty.
[0069] Without disclosing the product details, the taste and palatability of the granules prepared in Examples 11-14 were evaluated in adult volunteers. The results are as follows: Table 13 Taste Evaluation of the Particles Prepared in Examples 11-14
[0070] Taste evaluation scoring criteria: Taste: 1. Sweet, widely accepted 2. No bitterness, relatively widely accepted 3. Slightly bitter, acceptable 4. Bitter, acceptable 5. Very bitter, difficult to accept; Aftertaste: 1. Suitable aftertaste, highly acceptable 2. Fairly suitable aftertaste, relatively acceptable 3. Slightly unpleasant aftertaste, acceptable 4. Unpleasant aftertaste, but still acceptable 5. Strong aftertaste, unpleasant, difficult to accept; Odor: 1. Pleasant odor, no odor, high acceptance 2. Pleasant odor, no odor, relatively high acceptance 3. Slight odor, acceptable 4. Odor present, acceptable 5. Strong odor, unacceptable; Texture: (gritty texture) 1. Very smooth, no gritty texture 2. Smooth with a slight gritty texture 3. Slightly less smooth, with a gritty texture 4. Poor smoothness, noticeable gritty texture 5. Very poor smoothness, very noticeable gritty texture; Overall rating: 1. Very good 2. Good 3. Average 4. Poor 5. Very poor
[0071] All volunteers reported that the drug preparations prepared in Examples 11 and 12 had an overall fragrant aroma, a sweet taste, good palatability, and were easy to swallow; at the same time, the preparation particles were fine and had no gritty feeling, making the experience of taking the drug comfortable, especially suitable for children whose swallowing function has not yet been fully developed.
[0072] Comparative Example 1 Except for the particle size of the blank pellet, the formulation was the same as in Example 9. The sustained-release layer I was increased by 20% and the sustained-release layer II by 3%. Comparative Example 1 used blank pellets with a D90 of 90 μm to prepare the sustained-release particles. The particle size of the sustained-release particles was measured using the parameters in Table 11. The results were: D10: 83.60 μm, D50: 108.06 μm, D90: 169.09 μm, exceeding 150 μm. When the sustained-release particles were placed on the tip of the tongue, a gritty sensation was felt.
[0073] Comparative Example 2 Except for the absence of the pore-forming agent hydroxypropyl methylcellulose, the formulation is the same as in Example 7.
[0074] Evaluation indicators: Dissolution behavior evaluation Take the sustained-release granules prepared in Comparative Example 2 and perform dissolution and release assay according to the method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). Use 250 mL of pH 6.8 phosphate buffer solution as the dissolution medium and a rotation speed of 100 rpm. Perform the procedure according to the method, taking approximately 5 mL of solution after 0.5, 1, 2, 3, 4, 6, and 8 hours, and immediately replenishing with the same volume and temperature of dissolution medium. Filter the solution, discarding approximately 1 mL of the initial filtrate, and accurately measure 50 μL of the subsequent filtrate. Perform the chromatographic determination according to the conditions under the Assay section. The results are as follows.
[0075] Table 14 Dissolution test results of the sustained-release particles prepared in Comparative Example 2
[0076] The results in the table above show that the active pharmaceutical ingredient cannot be dissolved without the addition of a pore-forming agent.
Claims
1. A sustained release granule of a sulfonamide derivative, characterized by, It includes a drug-loaded layer, a sustained-release layer I, and a sustained-release layer II. The drug-loaded layer includes a blank pellet core and an active ingredient layer, wherein the active ingredient is a compound of formula I. 。 2. The sustained-release granule according to claim 1, characterized by The blank pellet core includes one or more of the following: sucrose pellet core, microcrystalline cellulose pellet core, silica pellet core, starch pellet core, tartaric acid pellet core, and mannitol pellet core.
3. The sustained-release granule according to claim 1, wherein The blank pellet core has a particle size D90 of 20–80 μm, and the sustained-release particles have a particle size D90 of less than 150 μm.
4. The sustained-release granules according to claim 1, characterized in that, The active ingredient layer includes an active ingredient, an adhesive, and an anti-adhesion agent. The adhesive includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and polyvinyl alcohol. The anti-adhesion agent includes one or more of talc, silica, magnesium stearate, micronized silica, and sodium dodecyl sulfate.
5. The sustained-release granules according to claim 1, characterized in that, The sustained-release layer I comprises a sustained-release material, a pore-forming agent, an anti-adhesion agent, and a plasticizer. The sustained-release layer II comprises a sustained-release material, an anti-adhesion agent, and a plasticizer. The sustained-release material comprises one or more of ethyl cellulose, methyl methacrylate copolymer, and ethylene-vinyl acetate copolymer. The pore-forming agent comprises one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and polyvinyl alcohol. The anti-adhesion agent comprises one or more of talc, silica, magnesium stearate, micronized silica, and sodium lauryl sulfate. The plasticizer comprises one or more of triethyl citrate, polyethylene glycol, phthalate, and castor oil.
6. The sustained-release granules according to claim 1, characterized in that, The product comprises the following components by weight percentage: Drug-loaded layer: 60%~12% blank pellet core, 50%~10% active ingredient, 6%~1% binder and 20%~1.5% anti-adhesion agent; Sustained-release layer I: 22%~1% sustained-release material, 5%~0% pore-forming agent, 5%~0% anti-adhesion agent and 5%~0% plasticizer; Sustained-release layer II: 10%~1% sustained-release material, 2%~0% anti-adhesion agent and 2%~0% plasticizer.
7. The sustained-release granules according to any one of claims 1-6, characterized in that, When the anti-adhesion agent in the drug-loaded layer is selected from talc, the weight percentage of talc in the drug-loaded layer is greater than 7%.
8. The sustained-release granules according to any one of claims 1-7, characterized in that, The weight ratio of the porogen to the anti-adhesion agent in the sustained-release layer I should be greater than 0.9:
1.
9. The sustained-release granules according to any one of claims 1-8, characterized in that, The weight gain range of sustained-release layer II is 3%-4%.
10. The sustained-release granules according to claim 1, characterized in that, The sustained-release granules also include external excipients, which include 95%~70% diluent, 30%~5% suspending agent, and 9%~0% flavoring agent.
11. A method for preparing sustained-release particles according to any one of claims 1-10, characterized in that, Includes the following steps: Step 1: Preparation of drug-loaded layer. The active ingredient is dissolved in a solvent and then mixed with a binder and anti-adhesion agent dissolved in the solvent. The mixture is stirred to obtain a drug-loaded solution. Using a blank pellet core as a substrate, the drug-loaded solution is atomized and sprayed onto the blank pellet core through a fluidized bed powder coating process to obtain drug-loaded particles. Step 2: Preparation of sustained-release layer I. After dissolving the sustained-release material in a solvent, it is mixed with a pore-forming agent and a plasticizer dissolved in the solvent, and then mixed with an anti-adhesion agent. High shearing is then applied to obtain the sustained-release coating solution. The powder coating process is then used to atomize the sustained-release coating solution and spray it onto the drug-loaded particles prepared in Step 1 for sustained-release coating. Step 3: Preparation of sustained-release layer II. The sustained-release material is dissolved in a solvent, mixed with a plasticizer, then mixed with an anti-adhesion agent, and subjected to high shear to obtain a sustained-release coating solution. After coating, the mixture is dried to obtain sustained-release particles. Step 4: Optionally, mix the sustained-release granules obtained in Step 3 with the added excipients.
12. The preparation method according to claim 10, characterized in that, The solvent for dissolving the active ingredient and the sustained-release material includes ethanol, and the solvent for dissolving the adhesive and the pore-forming agent includes water. In step one, the ethanol-water ratio can be 7:3 to 1:1; in steps two and three, the ethanol-water ratio in the ethanol-water solution can be 4:1 to 1:0.