Sustained-release oral dissolution film and preparation method therefor

Abstract

A sustained-release oral dissolution film, comprising a sustained-release pellet core, a film-forming material, a plasticizer, and a flavoring agent. Further provided is a method for preparing a sustained-release oral dissolution film. By providing a multi-unit drug delivery system, first preparing a film-controlled sustained-release pellet core with a small particle size as an intermediate, and then adding the film-controlled sustained-release pellet core into a film-forming material to form an oral dissolution film formulation, the method overcomes the limitation that an oral dissolution film is generally only used as an immediate-release formulation, and provides a sustained-release oral dissolution film formulation which facilitates precise dosage division, has a better mouthfeel, and is capable of improving medication convenience for a patient, compliance, and a stable and sustained blood drug concentration.

Description

A sustained-release orally dissolving film and its preparation method Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a sustained-release orally disintegrating film and its preparation method. Background Technology

[0002] For pediatric and elderly patients, conventional solid dosage forms such as tablets and capsules are insufficient to meet the clinical needs for individualized dosage. Furthermore, young children and elderly patients with swallowing difficulties may experience swallowing difficulties when taking conventional solid dosage forms. In addition, the inconvenience of frequent dosing can further lead to poor patient adherence, while administering a single daily dose can result in excessively high blood drug concentrations, which can easily cause adverse reactions. Therefore, to ensure consistent dosing frequency, achieve stable and effective blood drug concentrations, and provide a good medication experience, it is necessary to develop a safer and more convenient sustained-release dosage form.

[0003] Oral dispersible films (ODFs), also known as orally dissolving films, are thin-film formulations made by mixing, coating, drying, and slitting drugs with suitable film-forming materials. As a precise drug delivery method, they offer accurate and flexible dosage division, disperse rapidly in the mouth, and can be swallowed without water, simply by normal saliva. They also have a pleasant taste. In recent years, as a novel drug delivery form, they have received widespread attention and research due to their significant safety and good patient compliance. This is especially true for young children under 12 years old and elderly patients with swallowing difficulties, who have not yet fully developed the ability to swallow safely or have swallowing difficulties due to illness. Therefore, using orally dispersible films as an alternative to ordinary solid dosage forms is of great significance, helping to improve patient compliance. However, currently marketed orally dispersible films are only limited to immediate-release formulations and cannot reduce the frequency of drug administration. Therefore, achieving sustained drug release in small, thin orally dispersible film formulations remains a challenge.

[0004] The prior art CN113490485A discloses an oral film that forms a resin salt with an active ingredient and an ion exchange resin, and further adds "free" ion exchange resin to obtain a film in which the first and / or second active ingredients are released in a constant mode over a period of time. However, its sustained-release capacity is limited, with more than 80% release within 1 to 6 hours, failing to provide a more stable and effective blood drug concentration.

[0005] Therefore, providing a drug dosage form that facilitates precise dosage division, has a better taste, and can improve patient convenience, compliance, and stable and sustained blood drug concentration is a technical problem that needs to be solved in this field. Summary of the Invention

[0006] To address the aforementioned issues, this invention proposes a multi-unit drug delivery system. First, small-particle-size membrane-controlled sustained-release pellets are prepared as intermediates, which are then added to a film-forming material to form an orally disintegrating film formulation. This overcomes the limitation that orally disintegrating films are generally only used as immediate-release formulations, providing a sustained-release orally disintegrating film formulation that facilitates precise dosage division, has a better taste, and improves patient convenience, compliance, and stable and sustained blood drug concentrations.

[0007] The present invention provides a sustained-release oral dissolving film, comprising a sustained-release pellet core, a film-forming material, a plasticizer, and a flavoring agent.

[0008] In some embodiments, the sustained-release pellet core comprises at least three layers, namely, a blank pellet core, an active ingredient layer, and a sustained-release layer.

[0009] It is understood that the main structure of the membrane-controlled sustained-release pellet design, from the inside out, consists of: a blank pellet core, an active ingredient layer, and a sustained-release layer. This invention uses the sustained-release pellet core as an intermediate to coat and form an orally disintegrating film, thereby precisely controlling its drug release behavior to achieve a sustained-release effect with once-daily administration. After the sustained-release orally disintegrating film is taken, it rapidly disintegrates in the oral cavity, reverting to the sustained-release pellet core. In the gastrointestinal tract, the drug is slowly released through the insoluble sustained-release coating.

[0010] In some embodiments, the blank pellet core includes one or more of sucrose pellet core, microcrystalline cellulose pellet core, silica pellet core, starch pellet core, tartaric acid pellet core, and mannitol pellet core.

[0011] In some embodiments, the particle size of the blank pellet core is 40–150 μm.

[0012] Understandably, to ensure that there is no gritty feeling after the sustained-release orally disintegrating film disintegrates in the mouth, the particle size of the blank pellet core should be small enough to achieve a particle size of less than 250μm in the final sustained-release pellet core intermediate, so as not to cause an uncomfortable gritty feeling in the patient's mouth.

[0013] In some embodiments, the active ingredient layer includes an active ingredient, a binder, and a solvent.

[0014] In some embodiments, the weight ratio of the active ingredient, binder, and solvent is 1:0:3 to 7:1:22.

[0015] In some embodiments, the adhesive comprises one or more of hydroxypropyl methylcellulose (HPMC E5, HPMC E6), hydroxypropyl cellulose (HPC ELF, HPC EF, HPC EXF, HPC LF, HPC LXF), polyvinylpyrrolidone (PVPK25, PVP K30), and / or the solvent comprises one or more of ethanol, acetone, isopropanol, and water.

[0016] In some embodiments, the active ingredient includes one or more of the following: topiramate, methylphenidate hydrochloride, atomoxetine hydrochloride, guanifaxine hydrochloride, risperidone, olanzapine, melatonin, diphenhydramine, baclofen, seclorazine, promethazine, zarostazine, propafenone hydrochloride, captopril, isosorbide mononitrate, felodipine, glipizide, and gliclazide.

[0017] It is understandable that while epilepsy can occur in people of any age, region, and ethnicity, its incidence is higher in children and adolescents. Nearly 60% of epilepsy patients in my country are children, making them the group most attentive to this disease. Antiepileptic drugs can cause a series of adverse central nervous system reactions in the first few weeks of use. To reduce these adverse reactions in the initial treatment phase and improve patient compliance so that treatment can continue, clinical drug treatment should start with a low dose and gradually increase until seizures are controlled or the maximum tolerable dose is reached. For example, topiramate (TPM), as a natural D-fructose sulfamate derivative, has been well-established in its antiepileptic efficacy in various epilepsy subtypes. It has significant clinical effects in treating partial and generalized tonic-clonic seizures, and studies have shown that long-term monotherapy with topiramate is effective in children with epilepsy, with an efficacy rate of 55.73% and a seizure-free rate of 48.85%. According to the *Chinese Clinical Practice Guidelines—Epilepsy Section*, the initial dose of topiramate for children is 0.5–1 mg / (kg·d), with escalation doses of 0.5–1 mg / (kg·d) and a maintenance dose of 3–6 mg / (kg·d), administered twice daily. Currently, only immediate-release tablets and capsules are available in China. These common solid dosage forms are insufficient to meet the individualized dosage requirements for children, and young children may experience swallowing difficulties with these medications. Furthermore, the inconvenience of frequent administration can further lead to poor medication adherence. Although topiramate has a half-life of 21 hours, its narrow therapeutic window prevents the administration of a single daily dose. Excessively high blood concentrations can easily cause adverse reactions in the central nervous system, such as drowsiness, dizziness, speech disorders, and visual abnormalities. While extended-release topiramate capsules are available internationally, their large particle size can cause an uncomfortable gritty sensation in the mouth, making administration equally inconvenient for children.

[0018] It is understandable that methylphenidate hydrochloride, a central nervous system stimulant, atomoxetine hydrochloride, a selective norepinephrine reuptake inhibitor, and guanifacin hydrochloride, an α2 receptor agonist, are used to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents. Modifying them into sustained-release orally disintegrating films can improve children's medication compliance, reduce the frequency of medication, and avoid adverse reactions caused by excessively high blood drug concentrations due to the destruction of the sustained-release tablet structure.

[0019] Melatonin is a hormone secreted by the pineal gland that regulates circadian rhythms. It can reduce sleep latency in patients with primary insomnia, benefit patients with delayed sleep syndrome, and help regulate sleep-wake patterns in blind patients. Under the guidance of a doctor, melatonin can be used to treat autism and neurogenetic disorders in children (Smith-Magilli syndrome, Ritter syndrome, Angelman syndrome, tuberous sclerosis). Modifying it into a sustained-release orally disintegrating film can improve medication compliance in children.

[0020] Baclofen, as a derivative of gamma-aminobutyric acid (GABA), can stimulate GABA β-receptors, thereby inhibiting the release of excitatory neurotransmitters such as glutamate and aspartate, thus achieving an antispasmodic effect. When using this medication in children, it is necessary to start with a low dose and titrate it, and divide the daily dose into 2-4 times. Modifying it into a sustained-release orally disintegrating film can improve patient compliance and reduce the frequency of administration.

[0021] It is understandable that risperidone and olanzapine, as second-generation antipsychotic drugs, can be improved by being modified into sustained-release orally disintegrating films to help improve patient medication adherence, avoid patients hiding or vomiting their medication, and ensure stable blood drug concentrations to better control symptoms and reduce treatment discontinuation rates.

[0022] It is understandable that isosorbide mononitrate and felodipine are commonly used cardiovascular drugs for elderly patients, glipizide and gliclazide are commonly used hypoglycemic drugs for elderly patients, and donepezil, rivastigmine and galantamine are drugs for the treatment of Alzheimer's disease. Modifying them into sustained-release orally disintegrating films can help avoid the inconvenience of taking medication caused by swallowing difficulties due to disease progression or loss of swallowing function in elderly patients.

[0023] It is understandable that the purpose of preparing drugs into sustained-release orally disintegrating films is to address medication adherence issues in pediatric and elderly patients, ensuring both convenient drug administration and minimizing the frequency of dosing. Therefore, both pediatric and elderly patients with swallowing difficulties can use these as active ingredients. Because the sustained-release orally disintegrating film provided by this invention first prepares small-particle-size membrane-controlled sustained-release pellets from blank pellets as intermediates, and then adds them to a film-forming material to form an orally disintegrating film formulation, the structure, formulation, and process of the sustained-release orally disintegrating film described in this invention can be applied to sustained-release orally disintegrating film dosage forms of various active ingredients.

[0024] In some embodiments, the sustained-release layer includes a sustained-release film-forming material, a plasticizer, a pore-forming agent, an anti-adhesion agent, and a solvent.

[0025] It is understandable that the purpose of selecting sustained-release film-forming materials in the sustained-release layer is to form an insoluble membrane structure, which separates the drug from the gastrointestinal fluid. This ensures that the drug solution formed after the gastrointestinal fluid permeates into the sustained-release coating through the pores between polymer molecules in the coating structure or the aqueous pores formed by the pore-forming agent can be slowly diffused and released through the sustained-release membrane.

[0026] In some embodiments, the sustained-release film-forming material includes one or more of cellulose acetate, ethyl cellulose, and polyacrylic resins, and / or the plasticizer includes one or more of triacetin, triethyl citrate, tributyl citrate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, and dibutyl sebacate, and / or the porogen includes one or more of the active ingredient, sucrose, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyurethane, urea, polyvinylpyrrolidone, and talc, and / or the anti-adhesive includes one or more of talc, micronized silica gel, and magnesium stearate, and / or the solvent includes one or more of ethanol, acetone, isopropanol, and water.

[0027] It is understandable that highly soluble small molecule compounds (or active pharmaceutical ingredients) are added to the sustained-release layer as pore-forming agents. When the sustained-release layer comes into contact with gastrointestinal fluid, these small molecule compounds can dissolve rapidly and form countless micropores in the sustained-release coating, allowing more water to enter the core of the pellet, forming a saturated solution of the drug and then releasing it.

[0028] In some embodiments, the particle size of the sustained-release pellet core is 60–180 μm.

[0029] It is understandable that, in order to ensure that there is no gritty feeling after the sustained-release orally disintegrating film disintegrates in the mouth, in addition to controlling the particle size of the blank pellet core, the particle size of the sustained-release microspheres should also be ensured to be small enough.

[0030] In some embodiments, the film-forming material includes one or more of chitosan, hyaluronic acid, gelatin, pectin, agar, sodium alginate, amylopectin, pullulan, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyoxyethylene, polyvinyl alcohol, and polyvinyl alcohol-polyethylene glycol copolymer, and / or the plasticizer includes one or more of glycerol, propylene glycol, sorbitol, and polyethylene glycol, and / or the flavoring agent includes one or more of fructose, sucrose, lactose, sucralose, aspartame, and neotame.

[0031] In some embodiments, the product comprises the following components by weight percentage: drug-loaded pellet core: 20-30% blank pellet core, 10-30% active ingredient, 0-3% binder, and 47-70% active ingredient layer solvent; sustained-release layer: 3-10% sustained-release film-forming material, 0.3-2.5% plasticizer, 0.5-1.5% pore-forming agent, 0-2% anti-adhesion agent, and 84-96.2% sustained-release layer solvent; sustained-release oral dissolving film: 35-60% sustained-release pellet core intermediate, 40-60% film-forming material, 0-10% plasticizer, and 0-5% flavoring agent.

[0032] It is understood that, in addition to its excellent taste in the oral cavity, the sustained-release orally disintegrating film provided by this invention, as a multi-unit drug delivery system, offers prolonged drug release, which is highly beneficial for improving drug treatment adherence and safety. As a small-dose unit, the drug is uniformly dispersed in the orally disintegrating film and exhibits good reproducibility of drug release in vivo, with minimal individual variability and minimal impact of the digestive tract's food transport rhythm on drug absorption. Most importantly, it can reduce drug burst release; damage to the coating of individual microparticles does not alter the overall drug release behavior, resulting in high safety.

[0033] In some embodiments, the product comprises, by weight, the following components: Drug-loaded pellet core: 20-30% blank pellet core, 10-30% active ingredient, 0-3% HPMC E5, 47-70% 70% ethanol; Sustained-release layer: 3-10% ethyl cellulose 20pre, 0.3-2.5% triethyl citrate, 0.5-1.5% PVP K30, 0-2% talc, 84-96.2% 95% ethanol; Sustained-release orally dissolving membrane: 35-60% sustained-release microcapsule intermediate, 40-60% PEO N80 and HPMC E5, 0-10% propylene glycol, 0-5% sucralose.

[0034] In another aspect, the present invention provides a method for preparing sustained-release pellet cores, comprising the following steps:

[0035] Step 1: Mix the active ingredients, thickener and solvent, spray the drug solution onto the surface of the blank pellet core using a fluidized bed, perform drug deposition, and sieve to obtain the drug-loaded pellet core;

[0036] Step 2: Mix the sustained-release film-forming material, plasticizer, pore-forming agent, and anti-adhesion agent with the solvent, and use a fluidized bed to spray the coating solution onto the surface of the drug-loaded pellet core. Then, sieve and retain the sustained-release pellet core.

[0037] The present invention also provides a method for preparing a sustained-release orally dissolving film, comprising the following steps:

[0038] Step 1: Mix the active ingredients, thickener and solvent, spray the drug solution onto the surface of the blank pellet core using a fluidized bed, perform drug deposition, and sieve to obtain the drug-loaded pellet core;

[0039] Step 2: Mix the sustained-release film-forming material, plasticizer, pore-forming agent, and anti-adhesion agent with the solvent, and use a fluidized bed to spray the coating solution onto the surface of the drug-loaded pellet core. Then, sieve and retain the sustained-release pellet core.

[0040] Step 3: Mix the film-forming material, plasticizer, flavoring agent and solvent, then add the sustained-release pellet core, stir and disperse evenly to obtain the drug-containing gel solution;

[0041] Step 4: Take the medicated gel, spread it evenly using a solution coating machine, and cut it after it is completely dried to obtain a sustained-release oral dissolving film formulation.

[0042] The sustained-release orally dissolving membrane and its preparation method described in this invention have the following advantages:

[0043] 1. The sustained-release oral dissolving film of the present invention has a small volume and thin thickness, which facilitates precise dosage division. It can disintegrate rapidly in the oral cavity within 30 seconds. The sustained-release pellet core formed in the oral cavity has a maximum particle size of less than 180μm, which will not cause an uncomfortable gritty feeling in the oral cavity and has a better taste, which helps to improve the convenience and compliance of medication for children and elderly patients.

[0044] 2. The sustained-release orally disintegrating membrane described in this invention, as shown in the human pharmacokinetic curve, can provide a stable and sustained blood drug concentration;

[0045] 3. The sustained-release oral dissolving film of the present invention is prepared by first preparing small-particle-size membrane-controlled sustained-release pellets from blank pellets as intermediates, and then adding them to the film-forming material to form an oral dissolving film formulation. It does not require a separate granulation step for the active ingredients, nor does it require exploring the granulation process for each active ingredient. The sustained-release oral dissolving film structure, formulation and process of the present invention can be applied to sustained-release oral dissolving film dosage forms of various active ingredients. Attached Figure Description

[0046] Figure 1 is a schematic diagram of the sustained-release microsphere structure;

[0047] Figure 2 shows the appearance of the sustained-release orally soluble films prepared in Examples 24-29;

[0048] Figure 3 shows the effect of disintegration time and folding endurance on the sustained-release orally soluble films prepared in Examples 24-29;

[0049] Figure 4 shows the appearance of the sustained-release orally dissolving films prepared in Examples 30-33;

[0050] Figure 5 shows the effect of disintegration time and folding endurance on the sustained-release orally soluble films prepared in Examples 30-33;

[0051] Figure 6 shows the appearance of the sustained-release orally dissolving films prepared in Examples 34-37;

[0052] Figure 7 shows the effect of disintegration time and folding endurance on the sustained-release orally soluble films prepared in Examples 34-37;

[0053] Figure 8 shows the appearance of the sustained-release orally dissolving films prepared in Examples 38-41;

[0054] Figure 9 shows the effect of disintegration time and folding endurance on the sustained-release orally soluble films prepared in Examples 38-41;

[0055] Figure 10 shows the appearance of the sustained-release orally dissolving films prepared in Examples 42-46;

[0056] Figure 11 shows the effect of disintegration time and folding endurance on the sustained-release orally soluble films prepared in Examples 42-46;

[0057] Figure 12 shows the appearance of the sustained-release orally dissolving films prepared in Examples 47-49;

[0058] Figure 13 shows the effect of disintegration time and folding endurance on the sustained-release orally soluble films prepared in Examples 47-49;

[0059] Figure 14 shows the effect of disintegration time and folding endurance on the sustained-release orally soluble films prepared in Examples 50-55;

[0060] Figure 15 is a comparison chart of the cumulative release rates of the sustained-release orally soluble films prepared in Examples 11-13;

[0061] Figure 16 is a comparison chart of the cumulative release rates of the sustained-release orally soluble films prepared in Examples 14-17;

[0062] Figure 17 is a comparison chart of the cumulative release rates of the sustained-release orally soluble films prepared in Examples 18-20;

[0063] Figure 18 is a comparison chart of the cumulative release rates of the sustained-release orally soluble films prepared in Examples 21-23;

[0064] Figure 19 is a comparison chart of the cumulative release rates of the sustained-release orally dissolving films prepared in Examples 56-59.

[0065] Figure labels: 1: Blank pellet core; 2: Active ingredient layer; 3: Sustained-release layer. Detailed Implementation

[0066] 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.

[0067] 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.

[0068] Folding endurance test method: Take a single-dose drug-containing sustained-release oral dissolving film and repeatedly fold it in the same position until the film breaks. Record the number of folds required for the film to just break; this number represents the folding endurance of the film.

[0069] Disintegration time limit test method: Disintegration time limit: Prepare pH 6.8 phosphate buffer. Dissolution medium: Weigh 1.36g potassium dihydrogen phosphate, dissolve and dilute to 50mL with purified water, add 22.4mL of 0.2mol / L NaOH solution (weigh 0.4g NaOH dissolved in 50mL purified water), mix, and then dilute to 200mL with water (add 127.6mL purified water). Stir well. Measure 25mL of PBS buffer (37℃) into a petri dish, place the petri dish in a 37℃ constant temperature shaker, adjust the speed to 30min⁻¹, place the membrane to be tested on the water surface and start timing. Record the disintegration time of the membrane with a stopwatch. Repeat the test on 3 tablets of drug-containing sustained-release oral dissolution membrane and calculate the average value.

[0070] In vitro dissolution method: paddle dissolution method; rotation speed: 50 rpm; medium: water (degassed); volume: 500 ml (±5.0 ml); temperature: 37℃ (±0.5℃); sampling time: 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h; sampling volume: 5 ml; replenishment volume: 5 ml.

[0071] Screening of binders for the active ingredient layer of sustained-release pellet cores (Examples 1-4)

[0072] Table 1 Prescription Table for Examples 1-4

[0073] Table 2 Prescription Table for Examples 5-10

[0074] Preparation method:

[0075] 1. Preparation of the above-mentioned solution: ① Weigh the prescribed amount of purified water, heat it to 80°C in a water bath, and slowly add the different amounts of binder to it. Stir thoroughly until completely dissolved, and let it cool to room temperature for later use; ② Weigh the prescribed amount of anhydrous ethanol and place it in a beaker. Add all the prescribed amount of active ingredients, completely cover the mouth of the beaker with plastic wrap to prevent ethanol evaporation, and sonicate until the active ingredients are completely dissolved; ③ Mix the solutions in 1 and 2 to obtain the above-mentioned solution.

[0076] 2. Weigh 300g of blank pellet cores into a bottom-side spray multifunctional fluidized bed for drug loading. The drug-loaded pellet cores prepared with different binder formulations are shown in the table below:

[0077] Table 3 Results of drug application to pellet cores with different adhesive formulations

[0078] As shown in Table 3, when topiramate is selected as the active ingredient, and HPMC E5, HPC ELF and PVP K30 are selected as the binders, the ratio of binder to active ingredient should preferably be 5%-10%.

[0079] Examples 11-17: Screening of sustained-release film-forming materials for sustained-release pellet core sustained-release layers

[0080] Table 4 Prescription Table for Examples 11-13

[0081] Preparation method:

[0082] 1. Preparation of coating solution: ① Weigh the prescribed amount of anhydrous ethanol, and slowly add the prescribed amount of sustained-release film-forming material to it while stirring until completely dissolved; ② Weigh the prescribed amount of water, and add the prescribed amounts of plasticizer and pore-forming agent in sequence, stirring until completely dissolved; ③ While stirring, mix the ethanol solution in ① and the aqueous solution in ② evenly, then add the prescribed amount of anti-adhesion agent, and stir to disperse evenly to obtain the sustained-release coating solution.

[0083] 2. Core coating: Weigh 180g of drug-loaded core and place it in a bottom-side spray multi-functional fluidized bed for core coating.

[0084] As shown in Figure 15, the three sustained-release film-forming materials, cellulose acetate, Eudragit RL (polyacrylic acid resin), and ethyl cellulose 20pre, can all exert a sustained-release effect and can basically meet the sustained-release requirements.

[0085] Table 5 Prescription Table for Examples 14-17

[0086] The preparation method is the same as in Examples 11-13.

[0087] As shown in Figure 16, the optimal range for sustained-release coating weight gain is 20-30%. The sustained-release microcapsules exhibited good sustained-release effects and sufficient dissolution plateaus in in vitro release tests. (The coating weight gain ratio is calculated by dividing the total mass of all solids in the formulation (excluding solvent) by the weight of the drug-loaded core.)

[0088] Examples 18-24: Screening of the type and amount of pore-forming agent for the sustained-release layer of the sustained-release pellet core.

[0089] Table 6 Prescription Table for Examples 18-20

[0090] The preparation method is the same as in Examples 11-13.

[0091] As shown in Figure 17, the type of pore-forming agent has little effect on drug release. It does not cause sudden drug release in the early stage of drug release, and the sustained release effect is obvious. In the end, the sustained release of the pellet core can reach the ideal plateau. PEG 400, PVP K30 and HPC EXF all meet the requirements.

[0092] Table 7 Prescription Table for Examples 21-23

[0093] The preparation method is the same as in Examples 11-13.

[0094] As shown in Figure 18, when the proportion of pore-forming agent is higher than 1.5%, the sustained-release microspheres release too quickly in the first 2 hours, which can easily lead to burst release; while when the proportion of pore-forming agent is lower than 0.5%, the final drug release plateau of the sustained-release microspheres is too low and cannot meet the requirements. Therefore, the preferred proportion of pore-forming agent is 0.5% to 1.25%.

[0095] Examples 24-41: Screening of Film-Forming Material Types and Amounts

[0096] Table 8 Prescription Table for Examples 24-29

[0097] Preparation method:

[0098] 1. Weigh the prescribed amount of purified water, add the plasticizer to dissolve and mix well, heat in a water bath to 80°C, and set aside.

[0099] 2. Weigh the prescribed amount of film-forming material, disperse it thoroughly in the mixture prepared in step one, and let it cool to room temperature to obtain the film-forming material solution for later use;

[0100] 3. Add the prescribed amount of sustained-release pellet core intermediate to the adhesive solution and stir for 1 minute until uniform to obtain the coating solution;

[0101] 4. The coating solution is defoamed, coated, dried and cut to obtain a sustained-release oral soluble film formulation.

[0102] Table 9. Appearance of the sustained-release orally dissolving film preparations obtained in Examples 24-29

[0103] As shown in Table 9, Figure 2 (Figures A to F correspond to the sustained-release oral soluble films prepared in Examples 24-29, respectively), and Figure 3, the oral soluble films prepared by using PEO N80 (polyoxyethylene) alone meet the requirements for disintegration time and mechanical properties, but their appearance exhibits edge shrinkage. The sustained-release oral soluble films prepared by using HPMC E5 (hydroxypropyl methylcellulose), HPMC E15, and PVA 17-88 (polyvinyl alcohol) alone as film-forming materials meet the requirements for moldability, demolding, and smoothness. However, HPMC E5 and HPMC E15 alone have low folding endurance, while PVA 17-88 alone has an excessively long disintegration time. Therefore, further consideration is given to using different types of film-forming materials in combination to obtain an oral soluble film formulation with excellent formability and mechanical properties.

[0104] Table 10 Prescription Table for Examples 30-33

[0105] Preparation method:

[0106] 1. Weigh the prescribed amount of purified water, add the plasticizer to dissolve and mix well, heat in a water bath to 80°C, and set aside.

[0107] 2. Weigh the prescribed amount of auxiliary film-forming material, disperse it thoroughly in the mixture obtained in step one, and let it cool to room temperature to obtain the film-forming material solution for later use;

[0108] 3. Weigh out the prescribed amount of PEO N80 and add it to the film-forming material solution. Stir thoroughly until there are no particles to obtain the solution.

[0109] 4. Add the prescribed amount of sustained-release pellet core intermediate to the adhesive solution and stir for 1 minute until uniform to obtain the coating solution;

[0110] 5. The coating solution is defoamed, coated, dried and cut to obtain a sustained-release oral soluble film formulation.

[0111] Table 11. Appearance of the sustained-release orally dissolving film preparations obtained in Examples 30-33

[0112] As shown in Table 11 and Figure 4 (Figures A to D correspond to the sustained-release oral soluble films prepared in Examples 30-33, respectively), the sustained-release oral soluble films prepared by using HPMC E5 and PEO N80 as a compound all meet the requirements for moldability, release properties, and smoothness.

[0113] As shown in Figure 5, the disintegration time and folding endurance of the sustained-release orally soluble film prepared when the ratio of PEO N80 to HPMC E5 is 8:1 to 2:1 both meet the requirements, with the ratio of 8:1 being the optimal one.

[0114] Table 12 Prescription Table for Examples 34-37

[0115] The preparation method is the same as in Examples 30-33.

[0116] Table 13. Appearance of the sustained-release orally dissolving film preparations obtained in Examples 34-37

[0117] As shown in Table 13 and Figure 6 (Figures A to D correspond to the sustained-release oral soluble films prepared in Examples 34-37, respectively), the sustained-release oral soluble films prepared by using HPMC E15 and PEO N80 as a compound all meet the requirements for moldability, release properties, and smoothness.

[0118] As shown in Figure 7, the disintegration time and folding endurance of the sustained-release orally soluble film prepared when the ratio of PEO N80 to HPMC E15 is 8:1 to 2:1 both meet the requirements, with the ratio of 8:1 being the optimal one.

[0119] Table 14 Prescription Table for Examples 38-41

[0120] The preparation method is the same as in Examples 30-33.

[0121] Table 15. Appearance of the sustained-release orally dissolving film preparations obtained in Examples 38-41

[0122] As shown in Table 15 and Figure 8 (Figures A to D correspond to the sustained-release oral soluble films prepared in Examples 38-41, respectively), the moldability and smoothness of the sustained-release oral soluble films prepared when the ratio of PVA 17-88 to PEO N80 is 2:1 to 1:1 do not meet the requirements.

[0123] As shown in Figure 9, when PVA 17-88 and PEO N80 are combined in a ratio of 8:1 to 4:1, the disintegration time and folding endurance of the sustained-release orally soluble film prepared meet the requirements, with a ratio of 8:1 being the optimal one.

[0124] Examples 42-46: Screening of film-forming material formulation dosage

[0125] Table 16 Prescription Table for Examples 42-46

[0126] The preparation method is the same as in Examples 30-33.

[0127] Table 17. Appearance of the sustained-release orally dissolving film preparations obtained in Examples 42-46

[0128] As shown in Table 17 and Figure 10 (Figures A to E correspond to the sustained-release oral soluble films prepared in Examples 42-46, respectively), the sustained-release oral soluble films prepared with a molding material ratio of 45-50% have better molding properties, release properties, and smoothness.

[0129] As shown in Figure 11, when the ratio of PEO N80 to HPMC E15 is 8:1 and the amount of film-forming material in the formulation is 40-60%, the disintegration time and folding endurance of the sustained-release oral soluble film prepared meet the requirements. Among them, the amount of film-forming material in the formulation is 45%, which is the optimal value.

[0130] Examples 47-49: Screening of Plasticizers

[0131] Table 18 Prescription Table for Examples 47-49

[0132] The preparation method is the same as in Examples 30-33.

[0133] As shown in Figure 12 (Figures A to C correspond to the sustained-release oral soluble films prepared in Examples 47-49, respectively), the sustained-release oral soluble films prepared using propylene glycol, glycerol, and PEG 400 as plasticizers all meet the requirements for moldability, release properties, and smoothness.

[0134] As shown in Figure 13, the use of propylene glycol, PEG 400, and glycerin as plasticizers in the sustained-release orally soluble film formulation all meet the requirements for mechanical properties. Among them, propylene glycol has the best plasticizing effect on the prepared sustained-release orally soluble film, and its sustained-release orally soluble film formulation has the best disintegration time, folding endurance, and tensile strength.

[0135] Table 19 Prescription Table for Examples 50-55

[0136] The preparation method is the same as in Examples 30-33.

[0137] As shown in Figure 14, changes in the amount of plasticizer in the formulation have no significant effect on disintegration time. When the amount of propylene glycol in the formulation is 3%, the oral disintegrating film formulation has the highest folding endurance and the lowest tensile strength, indicating that it has the best mechanical properties. Therefore, the optimal formulation ratio of propylene glycol is 3%.

[0138] The present invention will be described in detail below through several specific embodiments, but the present invention is not limited to the embodiments.

[0139] Example 56 Preparation of Topiramate Sustained-Release Oral Dissolving Film

[0140] 1. Preparation of drug-loaded microcapsules

[0141] Preparation process:

[0142] (1) Preparation of the above-mentioned solution: ① Weigh the prescribed amount of purified water, heat it to 80°C in a water bath, slowly add the prescribed amount of HPMC E5, stir thoroughly until completely dissolved, and let it cool to room temperature for later use; ② Weigh the prescribed amount of anhydrous ethanol and place it in a beaker, add the entire prescribed amount of topiramate, completely cover the mouth of the beaker with plastic wrap to prevent ethanol evaporation, and sonicate until the active ingredient is completely dissolved; ③ Mix the solutions in ① and ② to obtain the above-mentioned solution.

[0143] (2) Weigh 300g of blank pellet cores into the bottom-side spray multi-functional fluidized bed. Set the inlet air temperature to 50-55℃, control the material temperature inside the pot to 39-41℃, set the rotating plate speed inside the coating pot to 200rpm, and set the inlet air volume to 0.4m³ / min. 3 The atomization pressure was 0.15 MPa, the atomization airflow was 46 Q / min, and the spray rate was 1.0–2.5 g / min. Drug loading was performed on the core of the pellets, and drug loading was performed on the blank core.

[0144] 2. Preparation of sustained-release pellet cores

[0145] (1) Preparation of coating solution: ① Weigh the prescribed amount of ethyl cellulose, triethyl citrate and talc powder for later use; ② Weigh the prescribed amount of anhydrous ethanol in a beaker of appropriate size, and slowly add the prescribed amount of ethyl cellulose 20pre to it while stirring until dissolved; ③ Weigh the prescribed amount of purified water, add the total prescribed amount of PVP K30, mix well and then add it to the total prescribed amount of triethyl citrate, and stir to mix evenly; ④ While stirring, add the triethyl citrate aqueous solution to the dissolved ethyl cellulose ethanol solution to dissolve and disperse; ⑤ While stirring, add the prescribed amount of talc powder, stir to disperse evenly and obtain the sustained-release coating solution. (2) Weigh 180g of drug-loaded pellet core into a bottom-side spray multifunctional fluidized bed, set the inlet air temperature to 65~70℃, control the internal material temperature to 52~53℃, the rotation speed of the rotating plate in the coating pan to 300rpm, and the inlet air volume to 0.5m 3 The atomization pressure is 0.15 MPa, the atomization airflow is 46 Q / min, and the spray rate is 1.0~1.5 g / min. The core of the pellet is loaded with drug, and the core of the pellet is laminated with drug.

[0146] 3. Preparation of sustained-release oral dissolving film

[0147] ① Weigh the prescribed amount of water, add propylene glycol to dissolve and mix well, and heat to 80℃ in a water bath; ② Add the prescribed amount of HPMC E5, let it cool to room temperature, and then add the prescribed amount of PEO N80 to obtain the gel solution; ③ Add the sustained-release pellet core intermediate to the gel solution to obtain the coating solution; ④ Defoam the coating solution using a vacuum defoamer (parameters: 60s, 2000rpm, 5kPa; 240s, 1800rpm, 0.5kPa), coat (coating thickness: 500μm), dry (oven temperature: 70℃, drying time: 20min), and slit to obtain the oral dissolving film.

[0148] Example 57 Preparation of methylphenidate hydrochloride sustained-release oral dissolving film

[0149] 1. Preparation of drug-loaded microcapsules

[0150] Preparation process:

[0151] (1) Preparation of the above-mentioned solution: ① Weigh the prescribed amount of purified water, heat it to 80°C in a water bath, slowly add the prescribed amount of HPMC E5, stir thoroughly until completely dissolved, and let it cool to room temperature for later use; ② Weigh the prescribed amount of anhydrous ethanol and place it in a beaker, add the entire prescribed amount of methylphenidate hydrochloride, completely cover the mouth of the beaker with plastic wrap to prevent ethanol evaporation, and sonicate until the active ingredient is completely dissolved; ③ Mix the solutions in ① and ② to obtain the above-mentioned solution.

[0152] (2) Weigh 400g of blank pellet cores into a bottom-sprayed multi-functional fluidized bed. Set the inlet air temperature to 53-56℃, control the material temperature inside the bed to 42-43℃, set the rotating plate speed inside the coating pan to 300rpm, and the inlet air volume to 0.5m³ / min. 3 The atomization pressure was 0.15 MPa, the atomization airflow was 50 Q / min, and the spray rate was 1.0–3.0 g / min. Drug loading was performed on the core pellets, and drug loading was performed on the blank core pellets.

[0153] 2. Preparation of sustained-release pellet cores

[0154] (1) Preparation of coating solution: ① Weigh the prescribed amounts of ethyl cellulose, triethyl citrate, and talc powder for later use; ② Weigh the prescribed amount of anhydrous ethanol in a beaker of appropriate size, and slowly add the prescribed amount of ethyl cellulose 20pre to it while stirring until dissolved; ③ Weigh the prescribed amount of purified water, add the total prescribed amount of PVP K30, mix well, and then add it to the total prescribed amount of triethyl citrate, stirring until evenly mixed; ④ While stirring, add the triethyl citrate aqueous solution to the dissolved ethyl cellulose ethanol solution to dissolve and disperse; ⑤ While stirring, add the prescribed amount of talc powder, and stir until evenly dispersed to obtain the sustained-release coating solution. (2) Weigh 180g of drug-loaded pellet cores into a bottom-side spray multifunctional fluidized bed, set the inlet air temperature to 45~55℃, control the internal material temperature to 32~33℃, the rotation speed of the rotating disc in the coating pan to 300rpm, and the inlet air volume to 0.5m³. 3 The atomization pressure was 0.15 MPa, the atomization gas flow rate was 44 Q / min, and the spray rate was 0.5–1.0 g / min for slow-release coating.

[0155] 3. Preparation of sustained-release oral dissolving film

[0156] ① Weigh the prescribed amount of water and add glycerin to dissolve and mix well; ② Add the prescribed amount of PEO N80 to obtain a gel solution; ③ Add the sustained-release pellet core intermediate to the gel solution to obtain a coating solution; ④ Defoam the solution using a vacuum defoaming machine (parameters: 60s, 2000rpm, 5kPa; 240s, 1800rpm, 0.5kPa), coat the solution (coating thickness: 400μm), dry it (oven temperature: 60℃, drying time: 45min), and slit it to obtain an oral dissolving film.

[0157] Example 58 Preparation of Felodipine Sustained-Release Oral Coating

[0158] 1. Preparation of drug-loaded microcapsules

[0159] Preparation process:

[0160] (1) Preparation of the above-mentioned solution: ① Weigh the prescribed amount of purified water, slowly add the prescribed amount of PVPK30 into it, and stir thoroughly until completely dissolved; ② Weigh the prescribed amount of anhydrous ethanol into a beaker, add the entire prescribed amount of felodipine, completely cover the mouth of the beaker with plastic wrap to prevent ethanol evaporation, and sonicate until the active ingredient is completely dissolved; ③ Mix the solutions in ① and ② to obtain the above-mentioned solution.

[0161] (2) Weigh 200g of blank pellet cores into the bottom-side spray multi-functional fluidized bed. Set the inlet air temperature to 45-50℃, control the material temperature inside the bed to 32-33℃, set the rotation speed of the rotating disc inside the coating pan to 200rpm, and the inlet air volume to 0.4m³ / min. 3The atomization pressure was 0.15 MPa, the atomization gas flow rate was 44 Q / min, and the spray rate was 1.0–2.0 g / min for slow-release coating.

[0162] 2. Preparation of sustained-release pellet cores

[0163] (1) Preparation of coating solution: ① Weigh the prescribed amount of ethyl cellulose, triethyl citrate and talc powder for later use; ② Weigh the prescribed amount of anhydrous ethanol in a beaker of appropriate size, and slowly add the prescribed amount of ethyl cellulose 20pre to it while stirring until dissolved; ③ Weigh the prescribed amount of purified water, add the total prescribed amount of PVP K30, mix well and then add it to the total prescribed amount of triethyl citrate, and stir to mix evenly. ④ While stirring, add the triethyl citrate aqueous solution to the dissolved ethyl cellulose ethanol solution to dissolve and disperse; ⑤ While stirring, add the prescribed amount of talc powder, stir to disperse evenly and obtain the sustained-release coating solution. (2) Weigh 180g of drug-loaded pellet core into a bottom-side spray multifunctional fluidized bed, set the inlet air temperature to 55~65℃, control the internal material temperature to 41~42℃, the rotation speed of the rotating plate in the coating pan to 300rpm, and the inlet air volume to 0.5m 3 The atomization pressure was 0.15 MPa, the atomization gas flow rate was 46 Q / min, and the spray rate was 0.5–1.0 g / min for slow-release coating.

[0164] 3. Preparation of sustained-release oral dissolving film

[0165] ① Weigh the prescribed amount of water, add propylene glycol to dissolve and mix well, and heat to 80℃ in a water bath; ② Add the prescribed amount of HPMC E15, let it cool to room temperature, and then add the prescribed amount of PEO N80 to obtain the gel solution; ③ Add the sustained-release microsphere intermediate to the gel solution to obtain the coating solution; ④ Defoam the solution using a vacuum defoamer (parameters: 60s, 2000rpm, 5kPa; 240s, 1800rpm, 0.5kPa), coat the solution (coating thickness: 500μm), dry it (oven temperature: 70℃, drying time: 20min), and slit it to obtain the oral dissolving film.

[0166] Example 59 Preparation of melatonin sustained-release orally dissolving film

[0167] 1. Preparation of drug-loaded microcapsules

[0168] Preparation process:

[0169] (1) Preparation of the above medicine solution: Weigh the prescribed amount of anhydrous ethanol and place it in a beaker. Add the entire prescribed amount of PVPK30 and melatonin. Cover the mouth of the beaker completely with plastic wrap to prevent ethanol evaporation. Sonicate until the active ingredients are completely dissolved to obtain the above medicine solution.

[0170] (2) Weigh 200g of blank pellet cores into the bottom-sprayed multi-functional fluidized bed. Set the inlet air temperature to 50-55℃, control the material temperature inside the pot to 39-41℃, set the rotating plate speed inside the coating pot to 300rpm, and set the inlet air volume to 0.4m³ / min. 3 The atomization pressure was 0.15 MPa, the atomization airflow was 46 Q / min, and the spray rate was 1.0–3.0 g / min. Drug loading was performed on the core pellets, and drug loading was performed on the blank core pellets.

[0171] 2. Preparation of sustained-release pellet cores

[0172] (1) Preparation of coating solution: ① Weigh the prescribed amount of ethyl cellulose, triethyl citrate and talc powder for later use; ② Weigh the prescribed amount of anhydrous ethanol in a beaker of appropriate size, and slowly add the prescribed amount of ethyl cellulose 20pre to it while stirring until dissolved; ③ Weigh the prescribed amount of purified water, add the total prescribed amount of PVP K30, mix well and then add it to the total prescribed amount of triethyl citrate, and stir to mix evenly; ④ While stirring, add the triethyl citrate aqueous solution to the dissolved ethyl cellulose ethanol solution to dissolve and disperse; ⑤ While stirring, add the prescribed amount of talc powder, stir to disperse evenly and obtain the sustained-release coating solution. (2) Weigh 180g of drug-loaded pellet core into a bottom-side spray multifunctional fluidized bed, set the inlet air temperature to 65~70℃, control the internal material temperature to 52~53℃, the rotation speed of the rotating plate in the coating pan to 300rpm, and the inlet air volume to 0.5m 3 The atomization pressure is 0.15 MPa, the atomization airflow is 46 Q / min, and the spray rate is 1.0~1.5 g / min. The core of the pellet is loaded with drug, and the core of the pellet is laminated with drug.

[0173] 3. Preparation of sustained-release oral dissolving film

[0174] ① Weigh the prescribed amount of water, add propylene glycol to dissolve and mix well, and heat to 80℃ in a water bath; ② Add the prescribed amount of HPMC E5, let it cool to room temperature, and then add the prescribed amount of PEO N80 to obtain the gel solution; ③ Add the sustained-release pellet core intermediate to the gel solution to obtain the coating solution; ④ Defoam the coating solution using a vacuum defoamer (parameters: 60s, 2000rpm, 5kPa; 240s, 1800rpm, 0.5kPa), coat (coating thickness: 300μm), dry (oven temperature: 60℃, drying time: 20min), and slit to obtain the oral dissolving film.

[0175] Example 60 Dissolution Investigation

[0176] As shown in Figure 19, the sustained-release orally dissolving films prepared in Examples 56-59 have a slow-release effect and a significant sustained-release effect.

Claims

1. A sustained release mouth dissolving film characterized in that, It includes sustained-release pellet cores, film-forming materials, plasticizers, and flavoring agents.

2. The sustained release oral dissolving film according to claim 1, wherein, The sustained-release pellet core comprises at least three layers, namely, a blank pellet core, an active ingredient layer, and a sustained-release layer.

3. The sustained release fast melt film according to claim 2, wherein, 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.

4. The extended release orally dissolving film according to claim 2, wherein, The particle size of the blank pellet core is 40–150 μm.

5. The extended release orally dissolving film according to claim 2, wherein, The active ingredient layer includes active ingredients, binders, and solvents.

6. The extended release orally dissolving film according to claim 5, wherein, The weight ratio of the active ingredient, binder, and solvent is 1:0:3 to 7:1:

22.

7. The extended release orally dissolving film according to claim 5, wherein, The adhesive includes one or more of HPMC E5, HPMC E6, HPC-ELF, HPC-EF, HPC EXF, HPC-LF, HPC LXF, PVP K25, and PVP K30, and / or the solvent includes one or more of ethanol, acetone, isopropanol, and water.

8. The extended release orally dissolving film according to claim 5, wherein, The active ingredients include one or more of the following: topiramate, methylphenidate hydrochloride, atomoxetine hydrochloride, guanifaxine hydrochloride, risperidone, olanzapine, melatonin, diphenhydramine, baclofen, seclorazine, promethazine, zarostazine, propafenone hydrochloride, captopril, isosorbide mononitrate, felodipine, glipizide, and gliclazide.

9. The extended release orally dissolving film according to claim 2, wherein, The sustained-release layer includes a sustained-release film-forming material, a plasticizer, a pore-forming agent, an anti-adhesion agent, and a solvent.

10. The extended release orally dissolving film according to claim 9, wherein, The sustained-release film-forming material includes one or more of cellulose acetate, ethyl cellulose, and polyacrylic acid resins, and / or the plasticizer includes one or more of triacetin, triethyl citrate, tributyl citrate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, and dibutyl sebacate, and / or the porogen includes one of the active ingredient, sucrose, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyurethane, urea, polyvinylpyrrolidone, and talc, and / or the anti-adhesive includes one or more of talc, micronized silica gel, and magnesium stearate, and / or the solvent includes one or more of ethanol, acetone, isopropanol, and water.

11. The sustained release fast melt film according to claim 1, wherein, The particle size of the sustained-release pellet core is 60–180 μm.

12. The sustained release fast melt film according to claim 1, wherein, The film-forming material includes one or more of chitosan, hyaluronic acid, gelatin, pectin, agar, sodium alginate, amylopectin, pullulan, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyoxyethylene, polyvinyl alcohol, and polyvinyl alcohol-polyethylene glycol copolymer, and / or the plasticizer includes one or more of glycerol, propylene glycol, sorbitol, and polyethylene glycol, and / or the flavoring agent includes one or more of fructose, sucrose, lactose, sucralose, aspartame, and neotame.

13. The extended release orally dissolving film according to any one of claims 1-12, wherein, The sustained-release layer comprises, by weight percentage, the following components: Drug-loaded core: 20-30% blank core, 10-30% active ingredient, 0-3% binder, 47%-70% active ingredient layer solvent; Sustained-release layer: 3-10% sustained-release film-forming material, 0.3%-2.5% plasticizer, 0.5%-1.5% pore-forming agent, 0-2% anti-adhesion agent, 84%-96.2% sustained-release layer solvent; Sustained-release oral dissolving film: 35%-60% sustained-release core intermediate, 40%-60% film-forming material, 0-10% plasticizer, 0-5% flavoring agent; Preferably, the sustained-release oral dissolving film comprises, by weight percentage, the following components: Drug-loaded core: 20-30% blank core, 10-30% active ingredient, 0-3% HPMC E5, 47%-70% 70% ethanol; Sustained-release layer: 20% ethyl cellulose. 3-10%, triethyl citrate 0.3%-2.5%, PVP K30 0.5%-1.5%, talc 0-2%, 95% ethanol 84%-96.2%; sustained-release oral dissolving film: sustained-release microcapsule intermediate 35%-60%, PEO N80 and HPMC E5 40%-60%, propylene glycol 0-10%, sucralose 0-5%.

14. A process for the preparation of the sustained release pellet core according to any one of claims 1 to 13, characterized in that, Includes the following steps: Step 1: Mix the active ingredients, thickener and solvent, spray the drug solution onto the surface of the blank pellet core using a fluidized bed, perform drug deposition, and sieve to obtain the drug-loaded pellet core; Step 2: Mix the sustained-release film-forming material, plasticizer, pore-forming agent, and anti-adhesion agent with the solvent, and use a fluidized bed to spray the coating solution onto the surface of the drug-loaded pellet core. Then, sieve and retain the sustained-release pellet core.

15. A method of preparing the extended release mouth dissolving film according to any one of claims 1 to 14, characterized in that, Includes the following steps: Step 1: Mix the active ingredients, thickener and solvent, spray the drug solution onto the surface of the blank pellet core using a fluidized bed, perform drug deposition, and sieve to obtain the drug-loaded pellet core; Step 2: Mix the sustained-release film-forming material, plasticizer, pore-forming agent, and anti-adhesion agent with the solvent, and use a fluidized bed to spray the coating solution onto the surface of the drug-loaded pellet core. Then, sieve and retain the sustained-release pellet core. Step 3: Mix the film-forming material, plasticizer, flavoring agent and solvent, then add the sustained-release pellet core, stir and disperse evenly to obtain the drug-containing gel solution; Step 4: Take the medicated gel, spread it evenly using a solution coating machine, and cut it after it is completely dried to obtain a sustained-release oral dissolving film formulation.

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