Meloabalin besylate double-release preparation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a meloabalin besylate double-release preparation and a preparation method thereof. Comprising a quick-release pellet and a sustained-release pellet, and the quick-release pellet and the sustained-release pellet are wrapped in a hollow capsule; the quick-release pellet comprises a quick-release blank pellet core, a quick-release drug layer and a quick-release film coating layer; the sustained-release pellet comprises a sustained-release blank pellet core, a sustained-release drug layer, a sustained-release layer and a sustained-release film coating layer. According to the invention, the stable blood concentration is obtained while the medicine effect takes effect quickly, the medicine taking frequency is reduced, convenience is brought to patients, and the compliance is improved. The invention also provides a preparation method thereof.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a milobalin besylate dual-release preparation and a preparation method thereof. Background Art

[0002] Milobarline is a GABA (γ-aminobutyric acid) analog that can bind to and regulate the α2-δ1 subunit of the voltage-sensitive calcium channel complex (widely present in the nervous system that mediates pain transmission and processing throughout the body). It has the characteristics of high affinity and slow dissociation, can reduce neuronal excitability and inhibit pain signals, reduce the influx of calcium ions at presynaptic terminals, inhibit the release of excitatory neurotransmitters in pain-related nerve endings, reduce the generation and conduction of pain signals, thereby showing an analgesic effect and playing a role in treating chronic neuropathic pain.

[0003] Gabapentin-type anticonvulsant drugs have always been the standard drugs for treating neuropathic pain. Pregabalin was developed after gabapentin and has the advantages of rapid peak blood concentration and better bioavailability. Milobalin besylate shows a more sustained analgesic effect due to its high affinity and slow dissociation from the α2-δ1 subunit of the dorsal root ganglion (DRG). The daily equivalent analgesic dose of 30 mg of milobalin is 600 mg of pregabalin and more than 1200 mg of gabapentin.

[0004] Milobarlin besylate, molecular formula C 18 H 25 NO5S, chemical name [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]heptane-3-ene-6-yl]acetic acid monobenzenesulfonate, the structural formula is as follows:

[0005]

[0006] Neuropathic pain (NP) is pain directly caused by damage or disease of the somatic sensory nervous system, and is divided into central pain and peripheral pain. Peripheral neuropathic pain (PNP) is a pathological pain caused by peripheral nerve damage or dysfunction caused by various reasons. Common PNP in clinical practice include diabetic peripheral neuropathy (DPNP), postherpetic neuralgia (PHN), trigeminal neuralgia (TN), etc.

[0007] Diabetic peripheral neuropathic pain (DPNP) is a common chronic complication in people with diabetes and prediabetes. The most common symptom of patients is symmetrical peripheral neuropathic pain mainly affecting the distal limbs, which can also manifest as mononeuralgia or brachial plexus and lumbar plexus neuralgia. Milobarbitaline can act on voltage-sensitive calcium ion complexes in the nervous system that mediate pain transmission and processing in various regions of the body, thereby reducing pain and playing an analgesic role.

[0008] Milobarbitalin Besylate Tablets independently developed by Daiichi Sankyo Co., Ltd., has a fasting peak time of about 1 hour (0.5 to 2.5 hours) and a postprandial peak time of about 1.5 hours (1.0 to 3.5 hours). 1 / 2 The half-life is approximately 2.96 to 3.37 hours, and Cmax and AUCinf increase proportionally with the administered dose.

[0009] Chinese invention patent authorization publication number CN104334169B contains a solid composition of milopalpine besylate containing an aminocarboxylate, and discloses a conventional rapid-release formulation prepared by a powder direct compression method, which mainly includes a filler D-mannitol, a disintegrant calcium carboxymethyl cellulose, and a lubricant magnesium stearate or sodium stearyl fumarate, and is a conventional tablet dosage form.

[0010] China's invention patent authorization announcement number CN110917164B is a milobarlin besylate sustained-release tablet and a preparation method thereof. The sustained-release preparation is prepared by using high and low viscosity hydroxypropyl methylcellulose and fillers, and the wet granulation process is adopted, which is a sustained-release tablet dosage form.

[0011] China's invention patent authorization announcement number CN117860707B protects a method for preparing a milobalin besylate sustained-release capsule, which uses a multi-granular dosage unit membrane pore technology to prepare the sustained-release capsule, the inner filler is a sustained-release micro-pellet, and the drug diffuses into the release medium through the membrane pore. The sustained-release micro-pellet is composed of a drug-containing pellet and a sustained-release coating. The drug-containing pellet includes milobalin besylate, a sucrose pellet core, hydroxypropyl methylcellulose, and vitamin E. The sustained-release coating includes ethyl cellulose, hydroxypropyl methylcellulose, and triethyl citrate. The prepared milobalin besylate sustained-release capsule has a sustained-release characteristic and can slowly release the drug, but it does not achieve a rapid-release effect after taking it, and the analgesic effect is slow.

[0012] Milobalin besylate has a short half-life and cannot maintain blood drug concentration for a long time, so it needs to be taken multiple times. At present, the milobalin besylate sustained-release preparations prepared by existing technologies can ensure the continuous, uniform and slow release of the drug. However, neuropathic pain such as diabetic peripheral neuropathy and persistent pain day and night cannot be relieved quickly after taking conventional sustained-release preparations because there is no rapid release of the drug. In addition, milobalin besylate is very susceptible to environmental conditions such as light and high temperature during storage, resulting in oxidative degradation and impurities, which cause changes in drug content exceeding the prescribed limit, thereby posing a hidden danger to the safety and stability of the drug. Summary of the invention

[0013] In order to solve the above technical problems, the present invention provides a milobarlin besylate dual-release preparation, which can achieve rapid onset of efficacy and stable blood drug concentration, reduce the number of medications, facilitate patients, and improve compliance. The present invention also provides a preparation method thereof.

[0014] The milobalin besylate dual-release preparation of the present invention comprises quick-release pellets and sustained-release pellets, wherein the quick-release pellets and the sustained-release pellets are wrapped in hollow capsules; the quick-release pellets comprise quick-release blank pellet cores, quick-release drug layers and quick-release film coating layers; the sustained-release pellets comprise sustained-release blank pellet cores, sustained-release drug layers, sustained-release layers and sustained-release film coating layers.

[0015] Preferably, the rapid-release drug layer and the sustained-release drug layer are both made of milopalpine besylate, a binder and a stabilizer;

[0016] The sustained-release layer is made of sustained-release material, binder, plasticizer and lubricant.

[0017] Preferably, the total weight of the immediate-release blank pellet core and the immediate-release drug layer is 100%, and the immediate-release pellets include:

[0018] Immediate-release blank pellets, 68% to 81%;

[0019] Immediate-release drug layer, 19% to 32%;

[0020] The quick-release film coating layer is coated by weight gain of 2.99% to 3.02% of the total weight of the quick-release blank pill core and the quick-release drug layer;

[0021] Taking the total mass of the sustained-release blank pellet core, the sustained-release drug layer and the sustained-release layer as 100%, the sustained-release pellets include:

[0022] Sustained-release blank pellet core, 17% to 36%,

[0023] Sustained-release drug layer, 32% to 51%,

[0024] Sustained-release layer, 30% to 37%;

[0025] The sustained-release film coating layer is coated by weight gain of 2.99% to 3.02% of the total weight of the sustained-release blank pill core, the sustained-release drug layer and the sustained-release layer;

[0026] The immediate-release drug layer and the sustained-release drug layer are both made of the following ingredients in percentage by weight:

[0027] Milobarlin besylate 80%-85%, binder 14%-20%; stabilizer 1%-1.1%;

[0028] The mass ratio of milobarlin besylate in the immediate-release drug layer and the sustained-release drug layer is 1:2;

[0029] The sustained-release layer is made of the following ingredients in percentage by weight:

[0030] The sustained-release material comprises 62% to 85.5%, the adhesive comprises 0% to 7.5%, the plasticizer comprises 5.8% to 6.1%, and the lubricant comprises 1.5% to 31.5%.

[0031] Preferably, both the immediate-release blank pill core and the sustained-release blank pill core are microcrystalline fiber pill cores with a particle size of 300-500 μm; and the hollow capsule is a hypromellose capsule.

[0032] Preferably, the binder is one or both of hydroxypropyl cellulose and hypromellose.

[0033] Preferably, the stabilizers are ascorbyl palmitate and DL-alpha tocopherol.

[0034] Preferably, the sustained-release material is one or both of ethyl cellulose and polymethacrylate (Euterpe).

[0035] Preferably, the plasticizer is one or both of polyethylene glycol 4000 and triethyl citrate.

[0036] Preferably, the lubricant is one or both of talc and sodium stearyl fumarate.

[0037] Preferably, the quick-release film coating layer and the sustained-release film coating layer are both made of the following raw materials in percentage by weight:

[0038] Film-forming materials, 79.5%-80.5%;

[0039] sunscreen, 9.9%-10.1%;

[0040] Propylene glycol alginate, 9.9%-10.1%.

[0041] Preferably, the film-forming material is hypromellose; and the sunscreen is titanium dioxide.

[0042] The preparation method of the milobarlin besylate dual-release preparation of the present invention comprises the following steps:

[0043] (1) Preparation of immediate-release pellets:

[0044] a. Dissolving milopalline besylate, a binder and a stabilizer in water to prepare a quick-release drug layer coating solution;

[0045] b. Spraying the quick-release drug layer coating liquid onto the quick-release blank pill cores through a fluidized bed, and drying to obtain quick-release drug-containing pellets;

[0046] c. dissolving the film-forming material, the sunscreen, and propylene glycol alginate in water to obtain a quick-release film coating solution, and coating the quick-release drug-containing pellets;

[0047] (2) Preparation of sustained-release pellets:

[0048] S1, dissolving milopalline besylate, a binder, and a stabilizer in water to prepare a sustained-release drug layer coating solution;

[0049] S2, spraying the sustained-release drug layer coating liquid onto the sustained-release blank pill cores through a fluidized bed, and drying to obtain sustained-release drug-containing pellets;

[0050] S3, dissolving the sustained-release material, adhesive, plasticizer, and lubricant in an ethanol solution to obtain a sustained-release layer coating solution, spraying the sustained-release layer coating solution onto the sustained-release drug-containing pellets through a fluidized bed, and drying to obtain sustained-release pellets;

[0051] S4, dissolving the film-forming material, the sunscreen, and propylene glycol alginate in water to obtain a sustained-release film coating solution, and coating the sustained-release pellets;

[0052] (3) Mix the immediate-release pellets and the sustained-release pellets and put them into hollow capsules to obtain the product.

[0053] In step a, the total mass of milopalpine besylate, the binder and the stabilizer accounts for 22% of the mass of the quick-release drug layer coating solution.

[0054] In step c, the total mass of the film-forming material, the sunscreen and propylene glycol alginate accounts for 10% of the mass of the quick-release film coating solution.

[0055] In step S1, the total mass of milopalpine besylate, the binder and the stabilizer accounts for 22% of the mass of the sustained-release drug layer coating solution.

[0056] In step S3, the ethanol solution is a 90% ethanol solution; the total mass of the sustained-release material, the binder, the plasticizer, and the lubricant accounts for 7% of the mass of the sustained-release layer coating solution.

[0057] In step S4, the total mass of the film-forming material, the sunscreen, and propylene glycol alginate accounts for 10% of the mass of the sustained-release film coating liquid.

[0058] Compared with the prior art, the present invention has the following beneficial effects:

[0059] 1. The high bioavailability dual-release preparation of the present invention adopts a specific mass ratio of the rapid-release micropellets and the sustained-release micropellets, so that it can reach a high blood drug concentration within 1 hour, take effect quickly, and can quickly relieve symptoms. At the same time, the sustained-release part is slowly released, and the 24-hour release rate reaches more than 90%;

[0060] 2. The milobarlin besylate dual-release preparation provided by the present invention can prolong the drug action time. After entering the gastrointestinal tract, the rapid-release part of the drug can be rapidly dissolved, with high bioavailability, rapid absorption, and rapid onset of action. The subsequent sustained-release part is gradually released to maintain the blood drug concentration within the effective drug concentration range, reduce drug fluctuations, provide a stable blood drug concentration, reduce adverse drug reactions, greatly reduce the number of drug administrations, and is easy to take;

[0061] 3. Ascorbyl palmitate and DL-α tocopherol overcome the instability of milobarlin besylate under high temperature and light conditions. Ascorbyl palmitate has strong antioxidant properties and is resistant to high temperatures. The synergy of the two can significantly enhance the antioxidant effect, effectively control the oxidative degradation of drugs and the generation of impurities, improve the safety and effectiveness of drugs, extend the shelf life of drugs, and reduce the difference between drug contents;

[0062] 4. Propylene glycol alginate and titanium dioxide are used as the outer isolation layer film coating. Propylene glycol alginate can form a uniform and stable film layer that is not easy to break and fall off. When used in combination with titanium dioxide, it can effectively protect the drug from external factors such as oxidation and light, improve the stability of the drug and reduce the possibility of component decomposition;

[0063] 5. The preparation method of the present invention has a simple process, can be scaled up for industrial production, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 The in vitro cumulative release percentage-time curve of the rapid-release pellets in the milobalin besylate dual-release preparations of Examples 1 to 4;

[0065] Figure 2 The in vitro cumulative release percentage-time curve of the sustained-release pellets in the milobalin besylate dual-release preparations of Examples 1 to 4;

[0066] Figure 3 The in vitro cumulative release percentage-time curve of the milobarlin besylate dual-release capsule preparations of Examples 1 to 4; DETAILED DESCRIPTION

[0067] The technical solution of the present invention will be clearly and completely described below in conjunction with embodiments.

[0068] Unless otherwise specified, all raw materials used in the examples are commercially available.

[0069] The formulations of Examples 1 to 4 are shown in Table 1 below.

[0070] Table 1: Formula of Examples 1 to 4

[0071]

[0072]

[0073] The preparation method of the dual-release preparations of Examples 1 to 4 comprises the following steps:

[0074] Asahi Kasei CP-305 microcrystalline fiber pellets (particle size 300-500 μm) were selected as quick-release blank pellets and sustained-release blank pellets.

[0075] (1) Preparation of immediate-release pellets:

[0076] a. Measure pure water into a plastic cup, add the binder while stirring to dissolve, place the plastic cup in a water bath and heat to 40°C; slowly add milobalin besylate and stabilizer while stirring, pass through a 60-mesh sieve for later use, and prepare a quick-release drug layer coating solution; wherein the total mass of milobalin besylate, binder and stabilizer accounts for 22% of the mass of the quick-release drug layer coating solution.

[0077] b. Add the immediate-release blank pellet core into the fluidized bed, adjust the guide tube height to 15 mm, control the material temperature at 35°C, slowly spray the immediate-release drug layer coating solution, and dry for 10 minutes to obtain the immediate-release drug-containing pellets;

[0078] c. Dissolve the film-forming material, sunscreen and propylene glycol alginate in water to obtain a quick-release film coating solution, use a fluidized bed to coat the quick-release drug-containing pellets, and dry for 10 minutes to obtain quick-release micropellets; wherein the total mass of the film-forming material, sunscreen and propylene glycol alginate accounts for 10% of the mass of the quick-release film coating solution.

[0079] (2) Preparation of sustained-release pellets:

[0080] S1. Measure pure water into a plastic cup, add the binder to dissolve while stirring, place the plastic cup in a water bath and heat to 40°C; slowly add milobarlin besylate and stabilizer while stirring, pass through a 60-mesh sieve for later use, and prepare a sustained-release drug layer coating solution;

[0081] S2. Add the sustained-release blank pellet core into the fluidized bed, adjust the guide tube height to 15 mm, control the material temperature at 35°C, slowly spray the sustained-release drug layer coating liquid, and dry for 10 minutes to obtain sustained-release drug-containing pellets;

[0082] S3. Dissolve the sustained-release material, adhesive, plasticizer and lubricant in 90% ethanol solution to obtain a sustained-release layer coating solution, add the sustained-release drug-containing pellets into the fluidized bed, adjust the height of the guide tube to 15 mm, control the material temperature at 42°C, slowly spray the sustained-release layer coating solution, and obtain the sustained-release pellets after drying for 12 minutes; wherein, the total mass of the sustained-release material, adhesive, plasticizer and lubricant accounts for 7% of the mass of the sustained-release layer coating solution.

[0083] S4. Dissolve the film-forming material, sunscreen and propylene glycol alginate in water to obtain a sustained-release film coating solution, coat the sustained-release pellets using a fluidized bed, and dry for 10 minutes to obtain sustained-release micropellets; wherein the total mass of the film-forming material, sunscreen and propylene glycol alginate accounts for 10% of the mass of the sustained-release film coating solution.

[0084] (3) The immediate-release pellets and the sustained-release pellets are mixed at a mass ratio of 1:2 containing milobalin besylate, and loaded into hollow capsules to obtain a milobalin besylate dual-release preparation.

[0085] The formulations of Comparative Examples 1 to 4 are shown in Table 2 below, and the preparation methods of Comparative Examples 1 to 4 are the same as those of Examples 1 to 4.

[0086] Table 2 Comparative Examples 1 to 4 Formula Table

[0087]

[0088]

[0089] Results review

[0090] The stability of the milobarlin besylate dual-release capsules prepared in Examples 1 to 4 and Comparative Examples 1 to 4 was investigated, including the following contents:

[0091] Samples of milobarlin besylate dual-release capsules were placed in ziplock bags and placed under light (4500 lux ± 500 lux) and high temperature (60°C) for 30 days. Samples were taken for testing at 0 day and 30 days, and the dissolution, content, and related substances were tested by HPLC.

[0092] Dissolution test method: small cup method, paddle method, 200mL phosphate buffer solution (pH6.8) as dissolution medium, rotation speed 50r / min. Octadecylsilane bonded silica gel as filler (C18, 4.6×250mm, 5μm chromatographic column), 0.01mol / L phosphate buffer solution (pH6.5)-acetonitrile-methanol (75:18:7) as mobile phase, column temperature 20℃, detection wavelength 210nm.

[0093] Content detection method: Octadecylsilane bonded silica gel was used as filler (C18, 4.6×250mm, 5um chromatographic column), 0.01mol / L phosphate buffer solution (pH6.0)-acetonitrile (78:22) was used as mobile phase, column temperature was 20°C, and detection wavelength was 210nm.

[0094] Detection method for related substances: polysaccharide derivative solvent-resistant chiral chromatographic column (4.6×250mm, 5μm chromatographic column), with 0.02mol / L phosphate buffer solution (pH6.5)-acetonitrile (62:38) as the fluidity, column temperature 20℃, detection wavelength 210nm.

[0095] Example 1 to 4 Dissolution Results Investigation:

[0096] The specific data results of the dissolution curves of the rapid-release pellet samples in the milobalin besylate dual-release capsule preparations of Examples 1 to 4 are shown in Table 3.

[0097] Table 3 Dissolution curve data of instant release pellets of Examples 1 to 4

[0098]

[0099] The specific data results of the dissolution curves of the sustained-release pellet samples in the milobalin besylate dual-release capsule preparations of Examples 1 to 4 are shown in Table 4.

[0100] Table 4 Dissolution curve data of sustained-release pellets of Examples 1 to 4

[0101]

[0102] The specific data results of the dissolution curves of the milobalin besylate dual-release preparation samples of Examples 1 to 4 are shown in Table 5.

[0103] Table 5 Dissolution curve data of dual-release capsule preparations of Examples 1 to 4

[0104]

[0105] Table 3~5 combined Figures 1 to 3 The dissolution test results of the samples obtained in Examples 1 to 4 show that the release amount of the quick-release pellets is greater than 85% in 15 minutes, the release amount of the sustained-release pellets is less than 20% in 2 hours, the release amount is greater than 85% in 16 hours, and the release amount is greater than 95% in 24 hours. The preparation of the present invention can reach a high blood drug concentration within 1 hour, has a rapid onset, and relieves symptoms the fastest. At the same time, the sustained-release part is slowly released, prolongs the drug action time, maintains the blood drug concentration, and improves the bioavailability.

[0106] After the content and related substance detection of Examples 1 to 4 and Comparative Examples 1 to 4, the stability test results of the dual-release capsule preparations are shown in Table 6.

[0107] Table 6 Stability test table of Examples 1 to 4 and Comparative Examples 1 to 4

[0108]

[0109]

[0110] The samples obtained in Examples 1 to 4 above were subjected to stability tests and found that in Examples 1 to 4 of the present invention, by adding stabilizers ascorbyl palmitate and DL-α-tocopherol, and adding propylene glycol alginate and a sunscreen titanium dioxide to the outer isolation coating, the obtained milobarlin besylate dual-release preparation can have good stability under high temperature and light conditions, extend the shelf life of the drug, reduce the difference between the contents, and ensure the safety of the patient's medication.

Claims

1. A milobalin besylate dual-release preparation, characterized in that: It includes quick-release micro-pellets and sustained-release micro-pellets, which are encapsulated in hollow capsules; The immediate-release pellets include an immediate-release blank pellet core, an immediate-release drug layer and an immediate-release film coating layer; The sustained-release micropellets include a sustained-release blank pellet core, a sustained-release drug layer, a sustained-release layer and a sustained-release film coating layer.

2. The milobarlin besylate dual-release preparation according to claim 1, characterized in that: The immediate-release drug layer and the sustained-release drug layer are both made of milobarlin besylate, a binder and a stabilizer; The sustained-release layer is made of sustained-release material, binder, plasticizer and lubricant.

3. The milobarlin besylate dual-release preparation according to claim 2, characterized in that: Taking the total mass of the immediate-release blank pellet core and the immediate-release drug layer as 100%, the immediate-release pellets include: Immediate-release blank pellets, 68% to 81%; Immediate-release drug layer, 19% to 32%; The quick-release film coating layer is coated by weight gain of 2.99% to 3.02% of the total weight of the quick-release blank pill core and the quick-release drug layer; Taking the total mass of the sustained-release blank pellet core, the sustained-release drug layer and the sustained-release layer as 100%, the sustained-release pellets include: Sustained-release blank pellet core, 17% to 36%, Sustained-release drug layer, 32% to 51%, Sustained-release layer, 30% to 37%; The sustained-release film coating layer is coated by weight gain of 2.99% to 3.02% of the total weight of the sustained-release blank pill core, the sustained-release drug layer and the sustained-release layer; The immediate-release drug layer and the sustained-release drug layer are both made of the following ingredients in percentage by weight: Milobarlin besylate 80%-85%, binder 14%-20%; stabilizer 1%-1.1%; The sustained-release layer is made of the following ingredients in percentage by weight: The sustained-release material comprises 62% to 85.5%, the adhesive comprises 0% to 7.5%, the plasticizer comprises 5.8% to 6.1%, and the lubricant comprises 1.5% to 31.5%.

4. The milobarlin besylate dual-release preparation according to claim 1, characterized in that: Both the immediate-release blank pill core and the sustained-release blank pill core are microcrystalline fiber pill cores with a particle size of 300-500 μm; the empty capsule is a hypromellose capsule.

5. The milobalin besylate dual-release preparation according to claim 2, characterized in that: The binder is one or two of hydroxypropyl cellulose and hydroxypropyl methyl cellulose; the stabilizer is ascorbyl palmitate and DL-α-tocopherol.

6. The milobarlin besylate dual-release preparation according to claim 2, characterized in that: The mass ratio of milobarlin besylate in the immediate-release drug layer and the sustained-release drug layer is 1:

2.

7. The milobarlin besylate dual-release preparation according to claim 2, characterized in that: The sustained-release material is one or both of ethyl cellulose and polymethacrylate; the plasticizer is one or both of polyethylene glycol 4000 and triethyl citrate; and the lubricant is one or both of talc and sodium stearyl fumarate.

8. The milobarlin besylate dual-release preparation according to claim 1, characterized in that: The quick-release film coating layer and the sustained-release film coating layer are both made of the following raw materials in percentage by weight: Film-forming materials, 79.5%-80.5%; sunscreen, 9.9%-10.1%; Propylene glycol alginate, 9.9%-10.1%.

9. The milobarlin besylate dual-release preparation according to claim 8, characterized in that: The film-forming material is hypromellose; the sunscreen is titanium dioxide.

10. A method for preparing the milobalin besylate dual-release preparation according to claim 8 or 9, characterized in that: The steps include: (1) Preparation of immediate-release pellets: a. Dissolving milopalline besylate, a binder and a stabilizer in water to prepare a quick-release drug layer coating solution; b. Spraying the quick-release drug layer coating liquid onto the quick-release blank pill cores through a fluidized bed, and drying to obtain quick-release drug-containing pellets; c. dissolving the film-forming material, the sunscreen, and propylene glycol alginate in water to obtain a quick-release film coating solution, and coating the quick-release drug-containing pellets; (2) Preparation of sustained-release pellets: S1, dissolving milopalline besylate, a binder, and a stabilizer in water to prepare a sustained-release drug layer coating solution; S2, spraying the sustained-release drug layer coating liquid onto the sustained-release blank pill cores through a fluidized bed, and drying to obtain sustained-release drug-containing pellets; S3, dissolving the sustained-release material, adhesive, plasticizer, and lubricant in an ethanol solution to obtain a sustained-release layer coating solution, spraying the sustained-release layer coating solution onto the sustained-release drug-containing pellets through a fluidized bed, and drying to obtain sustained-release pellets; S4, dissolving the film-forming material, the sunscreen, and propylene glycol alginate in water to obtain a sustained-release film coating solution, and coating the sustained-release pellets; (3) Mix the immediate-release pellets and the sustained-release pellets and put them into hollow capsules to obtain the product.

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