Preparation method of taste-masking slow-release oral soluble film

Abstract

The invention provides a preparation method of a taste-masking slow-release oral soluble film, which comprises the following steps: adding a first coating material into an organic solvent according to a certain proportion, and dissolving to obtain a first lipid phase; adding a second coating material into the organic solvent according to a certain proportion, and dissolving to obtain a second lipid phase; adding the medicines into a buffer solution, and performing ultrasonic treatment until the medicines are completely dissolved to obtain a water phase; mixing the water phase with the first lipid phase and the second lipid phase in sequence to obtain a suspension, and removing the organic solvent; adding a film-forming agent into water according to a certain proportion, stirring and dissolving to prepare a base film solution; mixing the suspension, a plasticizer and water, and stirring to obtain an API suspension; uniformly mixing the API suspension, the basement membrane liquid, the opacifying agent and the flavoring agent, and standing for defoaming; and coating the defoamed mixed solution, and drying to obtain the taste-masking slow-release oral soluble film. According to the technical scheme, the medicine is encapsulated by two layers of different coating materials, so that the pungent taste is reduced, and the slow release effect is realized.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a method for preparing a taste-masked sustained-release orally dissolving film. Background Art

[0002] Oral rapidly dissolving film is a dosage form of medicine that is lighter in weight, has variable dosages, and uses less excipients, and is a high-demand product in taste-masking technology. There are many technologies for masking the taste of medicine, such as complexation, encapsulation, hot melt extrusion, coating, granulation, mixing with sweeteners, freeze-drying, and printing.

[0003] In the prior art, there are applications in which drugs are encapsulated by coating, such as liposomes or nano-carriers such as soybean phospholipids, to reduce the taste stimulation of the drug to patients. Although these oral rapidly dissolving films can play a taste-masking role to a certain extent.

[0004] For example, Chinese Patent No. 202311588483.7 discloses an ebastine orally dissolving film and its preparation method, which includes liposome materials. The prepared orally dissolving film has a smaller particle size, good taste-masking effect, reduces the dosage of flavoring agents, and still can achieve a better taste.

[0005] However, for some drugs that need to be sustained-release, the release rate of these liposomes in the patient's mouth and gastrointestinal tract is too fast, the drug effect time is short, the condition cannot be continuously controlled, and the sustained-release effect is poor.

[0006] For example, Chinese Patent No. 202411563532.6 discloses an oral dissolving film solution based on nano-carriers and a preparation method of an oral dissolving film. This method uses nano-carrier technology, multi-layer microcapsule coating, low-temperature electrochemical polymerization technology, and ultrasonic dispersion technology to achieve uniform distribution and multi-stage sustained release of drugs in the oral rapidly dissolving film. First, the drug active ingredient is encapsulated by nano-carriers, and then a multi-layer composite coating structure is formed through microcapsule technology to achieve different-stage drug release effects.

[0007] Although these orally dissolving films can achieve taste-masking and sustained-release respectively, for some antipsychotic drugs, patients have poor motivation to take medicine, take medicine less frequently, and are sensitive to the smell of medicine. Therefore, it is necessary to produce an orally dissolving film that can achieve both taste-masking effect and sustained-release effect. Summary of the Invention

[0008] The main object of the present invention is to propose a method for preparing a taste-masked sustained-release orally dissolving film, aiming to solve the technical problems of short drug effect time and poor taste-masking effect of the existing taste-masked oral rapidly dissolving film.

[0009] To achieve the above object, a method for preparing a taste-masked sustained-release orally dissolving film proposed by the present invention includes the following steps: Add the first coating material to an organic solvent in a certain proportion and dissolve to obtain a first lipid phase; Add the second coating material to an organic solvent in a certain proportion and dissolve to obtain a second lipid phase; Add the drug to a buffer solution and ultrasonically dissolve it until completely dissolved to obtain an aqueous phase; Mix the first lipid phase and the second lipid phase with the aqueous phase in sequence to obtain a suspension, and remove the organic solvent; Add the film-forming agent to water in a certain proportion, stir and dissolve to prepare a base film solution; Mix the suspension, plasticizer and water, and stir to obtain an API suspension; Mix the API suspension, base film solution, light-shielding agent and flavoring agent evenly, and let it stand to defoam; Coat the defoamed mixed solution and dry it to obtain a taste-masked sustained-release orally dissolving film.

[0010] Optionally, in the step of adding the first coating material to an organic solvent in a certain proportion and ultrasonically dissolving it until completely dissolved to obtain a first lipid phase, the first coating material is soy lecithin and cholesterol.

[0011] Optionally, the mass ratio of the soy lecithin to the cholesterol is 1:(0.5 - 2).

[0012] Optionally, in the step of adding the second coating material to an organic solvent in a certain proportion and dissolving it to obtain a second lipid phase, the second coating material is one or more of polylactic acid and its copolymers.

[0013] Optionally, the second coating material is polylactic acid, poly(lactic acid - polyethylene glycol - maleimide) copolymer, poly(lactic acid - polyethylene glycol - carboxyl) copolymer.

[0014] Optionally, the mass ratio of the polylactic acid, poly(lactic acid - polyethylene glycol - maleimide) copolymer, and poly(lactic acid - polyethylene glycol - carboxyl) copolymer is 1:(1 - 2):(0.5 - 1).

[0015] Optionally, the weight-average molecular weight of the polylactic acid is 30000 - 60000 Da, the weight-average molecular weight of the poly(lactic acid - polyethylene glycol - maleimide) copolymer is 20000 - 40000 Da, and the weight-average molecular weight of the poly(lactic acid - polyethylene glycol - carboxyl) copolymer is 15000 - 40000 Da.

[0016] Optionally, in the step of adding the drug to a buffer solution and ultrasonically dissolving it until completely dissolved to obtain an aqueous phase, the buffer solution is one of phosphate buffer solution, acetate buffer solution, lactate buffer solution, and citrate buffer solution.

[0017] Optionally, in the step of adding a film-forming agent into water in a certain proportion and stirring to dissolve to obtain a base film solution, the film-forming agent includes one or more of polyvinyl alcohol and hydroxypropyl methylcellulose.

[0018] Optionally, the film-forming agent is polyvinyl alcohol and hydroxypropyl methylcellulose, and the mass ratio of the polyvinyl alcohol to the hydroxypropyl methylcellulose is 1:(1-2).

[0019] In the technical solution of the present invention, the drug is encapsulated by two different coating materials, so that the irritating taste of the drug in the patient's mouth is greatly reduced. At the same time, the double coating material reduces the dissolution rate of the drug in the patient's body, achieving a sustained release effect. Description of the Drawings

[0020] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on the structures shown in these drawings.

[0021] Figure 1 It is a schematic flowchart of an embodiment of the preparation method of the taste-masking and sustained-release orally disintegrating film provided by the present invention; Figure 2 It is the 37°C in vitro cumulative release curve of the taste-masking and sustained-release olanzapine orally disintegrating film prepared in Example 7 and Comparative Example 1 of the present invention.

[0022] The realization, functional features and advantages of the object of the present invention will be further described in conjunction with the embodiments with reference to the drawings. Detailed Embodiments

[0023] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some of the embodiments of the present invention, rather than all of the embodiments.

[0024] It should be noted that for those not specified with specific conditions in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. For reagents or instruments without indicating the manufacturer, they are all conventional products that can be obtained through commercial purchase. In addition, the meaning of "and / or" appearing throughout the text includes three parallel scenarios. Taking "A and / or B" as an example, it includes Scenario A, or Scenario B, or the scenario where both A and B are satisfied simultaneously. In addition, the technical solutions between the various embodiments can be combined with each other, but it must be based on the ability of those of ordinary skill in the art to implement. When the combination of technical solutions results in contradictions or cannot be implemented, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0025] In the prior art, there are applications in which drugs are encapsulated by coating, such as liposomes of resin, soy lecithin, etc., to reduce the taste stimulation of patients to the drugs. Although these orally disintegrating films can play a taste masking role to a certain extent, for some drugs that need to be sustained released, the release rate of these liposomes in the patient's mouth and gastrointestinal tract is too fast, the drug effect time is short, the condition cannot be continuously controlled, and the sustained release effect is poor.

[0026] In view of this, the present invention proposes a preparation method of a taste masking and sustained release orally disintegrating film, combined with Figure 1 Provided is a schematic flow chart of an embodiment of the preparation method of the taste masking and sustained release orally disintegrating film. The preparation method of the taste masking and sustained release orally disintegrating film includes the following steps.

[0027] Step S10: Add the first coating material to an organic solvent in a certain proportion and dissolve to obtain a first lipid phase.

[0028] Specifically, in implementation, the first coating material is a liposome material such as soy lecithin and cholesterol. The mass ratio of soy lecithin to cholesterol is 1:(0.5 - 2), and their proportion in the prescription amount is 5 - 10 wt%. The organic solvent is selected from volatile substances such as ethanol and ether.

[0029] Step S20: Add the second coating material to an organic solvent in a certain proportion and dissolve to obtain a second lipid phase.

[0030] In specific implementation, the second coating material is one or more of polylactic acid and its copolymers. Preferably, the second coating material is polylactic acid, poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer, poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer, and the proportion of the coating material in the prescription amount is 10-20 wt%, and the weight ratio of the first coating material to the second coating material is 1:(1-4). The mass ratio of polylactic acid, poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer, and poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer is 1:(1-2):(0.5-1). Among them, the weight-average molecular weight of polylactic acid is 30,000-60,000 Da, the weight-average molecular weight of poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer is 20,000-40,000 Da, the ratio of lactic acid monomers to ethylene glycol monomers is 75:25, the weight-average molecular weight of poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer is 15,000-40,000 Da, and the ratio of lactic acid monomers to ethylene glycol monomers is 75:25. By using a variety of polymers, the encapsulation efficiency of the drug can be effectively improved, and it has better biocompatibility.

[0031] Step S30: Add the drug to the buffer solution and ultrasonically dissolve it until completely dissolved to obtain an aqueous phase.

[0032] In specific implementation, the buffer solution is one of phosphate buffer solution, acetate buffer solution, lactate buffer solution, and citrate buffer solution. The drug is most commercially available water-soluble drugs, including olanzapine, ondansetron, etc., and the addition amount accounts for 1-5 wt% in the prescription amount.

[0033] Step S40: Mix the first lipid phase and the second lipid phase with the aqueous phase in sequence to obtain a suspension, and remove the organic solvent.

[0034] Step S50: Add the film-forming agent to water in a certain proportion, stir and dissolve it to prepare a base film solution.

[0035] In specific implementation, the film-forming agent includes one or more of polyvinyl alcohol and hydroxypropyl methylcellulose. In this embodiment, polyvinyl alcohol and hydroxypropyl methylcellulose are used simultaneously, and the mass ratio of polyvinyl alcohol to hydroxypropyl methylcellulose is 1:(1-2), and their proportion in the aqueous solution is 5-10 wt%.

[0036] Step S60: Mix the suspension, plasticizer, and water, and stir to obtain an API suspension.

[0037] In specific implementation, the plasticizer is selected from one or more of glycerol, sorbitol, allyl alcohol, and low-molecular-weight polyethylene glycol, and the dosage range is the same as that of commercially available orally disintegrating films.

[0038] Step S70: Mix the API suspension, the base film solution, the light-shielding agent, and the flavoring agent evenly, and let it stand to defoam.

[0039] In specific implementation, titanium dioxide is selected as the light-shielding agent; one or more of aspartame, stevioside, glycyrrhizin, sucralose, fructose, sucrose, and maltose are selected as the sweetening agent.

[0040] Step S80: Coat the defoamed mixed solution and then dry it to obtain the taste-masking sustained-release orally dissolving film.

[0041] In specific implementation, the defoamed mixed solution is scraped into a thin film by a doctor blade of a coater and coated on a base film, and then through the method of freeze-drying or heat-drying, the finished brexpiprazole orally dissolving film agent is obtained.

[0042] In the technical solution of the present invention, the drug is encapsulated by two different coating materials, so that the irritating taste of the drug in the patient's mouth is greatly reduced, and at the same time, the dual coating materials reduce the dissolution rate of the drug in the patient's body, realizing the sustained-release effect.

[0043] The following further details the technical solution of the present invention in conjunction with specific embodiments and the drawings. It should be understood that the following embodiments are only used to explain the present invention and are not used to limit the present invention. Example 1 Prescription 1 and Its Preparation

[0044] Table 1 Prescription 1

[0045] 2.0 g of lecithin and 1.0 g of cholesterol are added to 30 mL of DMSO, and ultrasonicated until completely dissolved to obtain the first lipid phase. 3.0 g of polylactic acid, 3.0 g of polylactic acid-polyethylene glycol-maleimide copolymer, and 1.5 g of polylactic acid-polyethylene glycol-carboxyl copolymer are added to 30 mL of DMSO, and ultrasonicated until completely dissolved to obtain the second lipid phase. The weight-average molecular weight of the polylactic acid is 45000 Da, the weight-average molecular weight of the polylactic acid-polyethylene glycol-maleimide copolymer is 30000 Da, and the weight-average molecular weight of the polylactic acid-polyethylene glycol-carboxyl copolymer is 27500 Da. 0.5 g of olanzapine is ultrasonically dissolved in 50 mL of sodium phosphate buffer solution to form an aqueous phase. After the first lipid phase and the aqueous phase are stirred and mixed, the second lipid phase is added and stirred and mixed to obtain a suspension, and DMSO is removed by heating; 25.0 g of polyvinyl alcohol and 25.0 g of hydroxypropyl methylcellulose are added to 400 mL of water according to a certain ratio, and stirred and dissolved to prepare a base film solution; the suspension after removing DMSO, 3.9 g of polyethylene glycol, and 50 mL of water are mixed and stirred to obtain an API suspension; the API suspension, the base film solution, 1.0 g of titanium dioxide, and 0.1 g of aspartame are mixed evenly and then left to stand for defoaming; the defoamed mixed solution is coated and dried to obtain the taste-masking sustained-release olanzapine orally dissolving film. Example 2 Prescription 2 and Its Preparation

[0046] Table 2 Prescription 2

[0047] 2.0 g of lecithin and 2.0 g of cholesterol were added to 30 mL of DMSO and ultrasonicated until completely dissolved to obtain the first lipid phase. 3.0 g of polylactic acid, 3.0 g of polylactic acid - polyethylene glycol - maleimide copolymer, and 1.5 g of polylactic acid - polyethylene glycol - carboxyl copolymer were added to 30 mL of DMSO and ultrasonicated until completely dissolved to obtain the second lipid phase. The weight - average molecular weight of polylactic acid was 45000 Da, the weight - average molecular weight of polylactic acid - polyethylene glycol - maleimide copolymer was 30000 Da, and the weight - average molecular weight of polylactic acid - polyethylene glycol - carboxyl copolymer was 27500 Da. 0.5 g of olanzapine was ultrasonically dissolved in 50 mL of sodium phosphate buffer solution to form an aqueous phase. After the first lipid phase and the aqueous phase were stirred and mixed, the second lipid phase was added and stirred to obtain a suspension, and DMSO was removed by heating. 25.0 g of polyvinyl alcohol and 25.0 g of hydroxypropyl methylcellulose were added to 400 mL of water in a certain proportion and stirred until dissolved to prepare a base film solution. The suspension after removing DMSO, 3.9 g of polyethylene glycol, and 50 mL of water were mixed and stirred to obtain an API suspension. The API suspension, the base film solution, 1.0 g of titanium dioxide, and 0.1 g of aspartame were mixed evenly and then left to stand for defoaming. The defoamed mixed solution was coated and dried to obtain the taste - masking sustained - release olanzapine orally disintegrating film. Example 3 Prescription 3 and Its Preparation

[0048] Table 3 Prescription 3

[0049] 2.0 g of lecithin and 4.0 g of cholesterol were added to 30 mL of DMSO, and ultrasonicated until completely dissolved to obtain the first lipid phase. 3.0 g of polylactic acid, 3.0 g of poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer, and 1.5 g of poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer were added to 30 mL of DMSO, and ultrasonicated until completely dissolved to obtain the second lipid phase. The weight-average molecular weight of the polylactic acid was 45000 Da, the weight-average molecular weight of the poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer was 30000 Da, and the weight-average molecular weight of the poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer was 27500 Da. 0.5 g of olanzapine was ultrasonically dissolved in 50 mL of sodium phosphate buffer solution to form an aqueous phase. After the first lipid phase and the aqueous phase were stirred and mixed, the second lipid phase was added and stirred and mixed to obtain a suspension, and DMSO was removed by heating; 25.0 g of polyvinyl alcohol and 25.0 g of hydroxypropyl methylcellulose were added to 400 mL of water in a certain proportion, and stirred and dissolved to prepare a base film solution; the suspension after removing DMSO, 3.9 g of polyethylene glycol and 50 mL of water were mixed and stirred to obtain an API suspension; the API suspension, the base film solution, 1.0 g of titanium dioxide and 0.1 g of aspartame were mixed evenly and left to stand for defoaming; the defoamed mixed solution was coated and dried to obtain a taste-masked sustained-release olanzapine orally disintegrating film. Example 4 Prescription 4 and Its Preparation

[0050] Table 4 Prescription 4

[0051] 2.0 g of lecithin and 1.0 g of cholesterol were added to 30 mL of DMSO, and ultrasonicated until completely dissolved to obtain the first lipid phase. 3.0 g of polylactic acid, 4.5 g of poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer, and 2.25 g of poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer were added to 30 mL of DMSO, and ultrasonicated until completely dissolved to obtain the second lipid phase. The weight-average molecular weight of the polylactic acid was 45000 Da, the weight-average molecular weight of the poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer was 30000 Da, and the weight-average molecular weight of the poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer was 27500 Da. 0.5 g of olanzapine was ultrasonically dissolved in 50 mL of sodium phosphate buffer solution to form an aqueous phase. After the first lipid phase and the aqueous phase were stirred and mixed, the second lipid phase was added and stirred and mixed to obtain a suspension, and DMSO was removed by heating; 25.0 g of polyvinyl alcohol and 25.0 g of hydroxypropyl methylcellulose were added to 400 mL of water in a certain proportion, and stirred and dissolved to prepare a base film solution; the suspension after removing DMSO, 3.9 g of polyethylene glycol and 50 mL of water were mixed and stirred to obtain an API suspension; the API suspension, the base film solution, 1.0 g of titanium dioxide and 0.1 g of aspartame were mixed evenly and left to stand for defoaming; the defoamed mixed solution was coated and dried to obtain a taste-masked sustained-release olanzapine orally disintegrating film. Example 5 Prescription 5 and Its Preparation

[0052] Table 5 Prescription 5

[0053] 2.0 g of lecithin and 1.0 g of cholesterol were added to 30 mL of DMSO and ultrasonicated until completely dissolved to obtain the first lipid phase. 3.0 g of polylactic acid, 6.0 g of poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer, and 3.0 g of poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer were added to 30 mL of DMSO and ultrasonicated until completely dissolved to obtain the second lipid phase. The weight-average molecular weight of the polylactic acid was 45000 Da, the weight-average molecular weight of the poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer was 30000 Da, and the weight-average molecular weight of the poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer was 27500 Da. 0.5 g of olanzapine was ultrasonically dissolved in 50 mL of sodium phosphate buffer solution to form an aqueous phase. After the first lipid phase and the aqueous phase were stirred and mixed, the second lipid phase was added and stirred and mixed to obtain a suspension, and DMSO was removed by heating. 25.0 g of polyvinyl alcohol and 25.0 g of hydroxypropyl methylcellulose were added to 400 mL of water in a certain proportion and stirred and dissolved to prepare a base film solution. The suspension after removing DMSO, 3.9 g of polyethylene glycol, and 50 mL of water were mixed and stirred to obtain an API suspension. The API suspension, the base film solution, 1.0 g of titanium dioxide, and 0.1 g of aspartame were mixed evenly and then allowed to stand for defoaming. The defoamed mixed solution was coated and dried to obtain the taste-masked sustained-release olanzapine orally disintegrating film. Example 6 Prescription 6 and Its Preparation

[0054] Table 6 Prescription 6

[0055] 2.0 g of lecithin and 1.0 g of cholesterol were added to 30 mL of DMSO, and ultrasonicated until completely dissolved to obtain the first lipid phase. 3.0 g of polylactic acid, 3.0 g of poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer, and 1.5 g of poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer were added to 30 mL of DMSO, and ultrasonicated until completely dissolved to obtain the second lipid phase. The weight-average molecular weight of the polylactic acid was 45000 Da, the weight-average molecular weight of the poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer was 30000 Da, and the weight-average molecular weight of the poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer was 27500 Da. 0.5 g of olanzapine was ultrasonically dissolved in 50 mL of sodium phosphate buffer solution to form an aqueous phase. The first lipid phase and the aqueous phase were stirred and mixed, and then the second lipid phase was added and stirred and mixed to obtain a suspension, and DMSO was removed by heating; 25.0 g of polyvinyl alcohol and 25.0 g of hydroxypropyl methylcellulose were added to 400 mL of water in a certain proportion, and stirred and dissolved to prepare a base film solution; the suspension after removing DMSO, 3.9 g of polyethylene glycol, and 50 mL of water were mixed and stirred to obtain an API suspension; the API suspension, the base film solution, 1.0 g of titanium dioxide, and 0.1 g of aspartame were mixed evenly and then left to stand for defoaming; the defoamed mixed solution was coated and dried to obtain a taste-masked sustained-release olanzapine orally disintegrating film. Example 7 Prescription 7 and Its Preparation

[0056] Table 7 Prescription 7

[0057] 2.0 g of lecithin and 1.0 g of cholesterol were added to 30 mL of DMSO, and ultrasonicated until completely dissolved to obtain the first lipid phase. 3.0 g of polylactic acid, 3.0 g of poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer, and 1.5 g of poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer were added to 30 mL of DMSO, and ultrasonicated until completely dissolved to obtain the second lipid phase. The weight-average molecular weight of the polylactic acid was 45000 Da, the weight-average molecular weight of the poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer was 30000 Da, and the weight-average molecular weight of the poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer was 27500 Da. 0.5 g of olanzapine was ultrasonically dissolved in 50 mL of sodium phosphate buffer solution to form an aqueous phase. The first lipid phase and the aqueous phase were stirred and mixed, and then the second lipid phase was added and stirred and mixed to obtain a suspension, and DMSO was removed by heating; 25.0 g of polyvinyl alcohol and 25.0 g of hydroxypropyl methylcellulose were added to 400 mL of water in a certain proportion, and stirred and dissolved to prepare a base film solution; the suspension after removing DMSO, 3.9 g of polyethylene glycol, and 50 mL of water were mixed and stirred to obtain an API suspension; the API suspension, the base film solution, 1.0 g of titanium dioxide, and 0.1 g of aspartame were mixed evenly and then left to stand for defoaming; the defoamed mixed solution was coated and dried to obtain a taste-masked sustained-release olanzapine orally disintegrating film. Comparative Example 1 Prescription 1 and Its Preparation

[0058] Table 8 Prescription 8

[0059] Dissolve 0.5 g of olanzapine ultrasonically in 50 mL of sodium phosphate buffer solution to form an aqueous phase; add 25.0 g of polyvinyl alcohol and 25.0 g of hydroxypropyl methylcellulose to 400 mL of water in a certain proportion, stir and dissolve to prepare a base film solution; mix the aqueous phase, 3.9 g of polyethylene glycol and 50 mL of water and stir to obtain an API suspension; mix the API suspension, the base film solution, 1.0 g of titanium dioxide and 0.1 g of aspartame evenly and then let it stand for defoaming; coat the defoamed mixed solution and dry it to obtain an olanzapine orally disintegrating film. Measure the in vitro release of the olanzapine orally disintegrating film

[0060] Select 40 schizophrenia patients from a certain hospital for the experiment. Divide them into 8 groups with 5 people in each group. Take 5 copies of 0.5 g of the 8 samples of the above Examples 1-7 and Comparative Example 1 respectively, corresponding to each group of patients. Put each orally disintegrating film sample into the mouth, and evaluate the taste of the sample in the mouth within 10 s. Take the median of each evaluation result and summarize it.

[0061] Take 50 mg of the orally disintegrating film samples of Examples 1-7 and Comparative Example 1 respectively. Using the sample separation method, disperse each sample in a flask containing a release medium (pH 7.4 PBS, containing 0.5% (w / v) Tween 80 and 0.02% (w / v) sodium azide), incubate in an air bath oscillator (37 °C, 100 rpm), collect an appropriate amount of sample after 2 h, centrifuge to take the supernatant to detect the drug concentration, disperse the precipitate with an equal amount of release medium and wash it back into the flask. The cumulative release data of olanzapine in each sample are as follows.

[0062]

[0063] Conclusion: When the dosage of the first lipid phase composed of lecithin and cholesterol increases, the taste masking effect is enhanced; when the dosage of the second lipid phase composed of poly(lactic acid)-poly(ethylene glycol)-maleimide copolymer, poly(lactic acid)-poly(ethylene glycol)-carboxyl copolymer, and polyvinyl alcohol increases, the sustained-release effect is enhanced, and when the dosage ratio of the drug, the first lipid phase, and the second lipid phase is 1:6:15, the taste masking and sustained-release effects are optimal. According to Figure 2 It can be seen from the release graph in that compared with the orally disintegrating film without coating material, the sustained-release effect of the orally disintegrating film prepared by this scheme is greatly improved.

[0064] The technical features of the above embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope recorded in this specification.

[0065] The above embodiments only represent several implementation manners of the present application. The description thereof is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can still be made, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the appended claims.

Claims

1. A method for preparing a taste-masked sustained-release orally dissolving film, characterized in that: The preparation method comprises the following steps: Adding the first coating material into an organic solvent in a certain proportion to dissolve it into a first lipid phase; Adding the second coating material into the organic solvent in a certain proportion to dissolve it to obtain a second fat phase; The drug is added to the buffer solution and sonicated until completely dissolved to obtain an aqueous phase; The first lipid phase and the second lipid phase are sequentially mixed with the aqueous phase to obtain a suspension, and the organic solvent is removed; Add the film-forming agent into water in a certain proportion, stir and dissolve, and prepare the base film solution; The suspension, plasticizer and water are mixed and stirred to obtain an API suspension; The API suspension, base membrane solution, opacifier and flavoring agent are mixed evenly and allowed to stand for degassing; The degassed mixed solution is applied and then dried to obtain a taste-masked sustained-release orally dissolving film.

2. The method for preparing the taste-masked sustained-release orally dissolving film according to claim 1, characterized in that: In the step of adding the first coating material into the organic solvent in a certain proportion and performing ultrasonic treatment until the first coating material is completely dissolved to obtain the first lipid phase, the first coating material is soybean lecithin and cholesterol.

3. The method for preparing the taste-masked sustained-release orally dissolving film according to claim 2, characterized in that: The mass ratio of the soybean lecithin to the cholesterol is 1:(0.5-2).

4. The method for preparing the taste-masked sustained-release orally dissolving film according to claim 1, characterized in that: In the step of adding the second coating material into the organic solvent in a certain proportion to dissolve it to obtain the second fat phase, the second coating material is one or more of polylactic acid and its copolymers.

5. The method for preparing the taste-masked sustained-release orally dissolving film according to claim 4, characterized in that: The second coating material is polylactic acid, polylactic acid-polyethylene glycol-maleimide copolymer, polylactic acid-polyethylene glycol-carboxyl copolymer.

6. The method for preparing the taste-masked sustained-release orally dissolving film according to claim 5, characterized in that: The mass ratio of the polylactic acid, the polylactic acid-polyethylene glycol-maleimide copolymer, and the polylactic acid-polyethylene glycol-carboxyl copolymer is 1:(1-2):(0.5-1).

7. The method for preparing the taste-masked sustained-release orally dissolving film according to claim 5, characterized in that: The weight average molecular weight of the polylactic acid is 30000-60000Da, the weight average molecular weight of the polylactic acid-polyethylene glycol-maleimide copolymer is 20000-40000Da, and the weight average molecular weight of the polylactic acid-polyethylene glycol-carboxyl copolymer is 15000-40000Da.

8. The method for preparing the taste-masked sustained-release orally dissolving film according to claim 1, characterized in that: In the step of adding the drug to a buffer solution and performing ultrasonication until the drug is completely dissolved to obtain an aqueous phase, the buffer solution is one of a phosphate buffer, an acetate buffer, a lactate buffer, and a citrate buffer.

9. The method for preparing the taste-masked sustained-release orally dissolving film according to claim 1, characterized in that: In the step of adding a film-forming agent into water in a certain proportion and stirring to dissolve to prepare a base film solution, the film-forming agent includes one or more of polyvinyl alcohol and hydroxypropyl methylcellulose.

10. The method for preparing the taste-masked sustained-release orally dissolving film according to claim 9, characterized in that: The film-forming agent is polyvinyl alcohol and hydroxypropyl methylcellulose, and the mass ratio of the polyvinyl alcohol to the hydroxypropyl methylcellulose is 1: (1-2).

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