A method for preparing taste-masking capsule skin based on molecular simulation and its application

Abstract

This invention belongs to the fields of computational pharmacy and pharmaceutical preparation technology, specifically relating to a method for preparing taste-masking capsules based on molecular simulation and its application. Specifically, this invention employs molecular simulation to prepare taste-masking capsules, focusing on screening highly effective taste-masking agents that match the target bitter-tasting drug. Molecular simulation can reveal the interaction between bitter-tasting drugs and taste-masking agents from a microscopic molecular perspective, exploring the dispersion of bitter-tasting drugs on the surface of the taste-masking agent. It can simulate multiple matching scenarios in a short time, allowing for the selection of the most effective taste-masking scheme from numerous combinations of bitter-tasting drugs and taste-masking agents. Experiments have demonstrated that this invention can prepare taste-masking capsules for bitter-tasting drugs as needed, thereby improving medication compliance and meeting the needs of bitter-tasting drug use, thus possessing significant practical application value.

Description

Technical Field

[0001] This invention belongs to the field of computational pharmacy and pharmaceutical preparation technology, specifically relating to a method for preparing taste-masking capsules based on molecular simulation and its application. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] As one of the most acceptable methods of drug administration for patients, oral administration offers advantages in clinical practice, including safety and ease of use. According to incomplete statistics, nearly half of the drugs on the market are currently administered orally. Common oral preparations such as tablets, pills, and capsules require the masking of bitter tastes when loading bitter-tasting drugs. To overcome the shortcomings of traditional capsule shell materials in masking bitterness, novel capsule shell materials with masking properties have gradually become a research focus in current pharmaceutical formulation development, and the market demand for taste-masking capsule shell materials is growing daily.

[0004] Currently, the masking of bitter drugs is mainly done through experimental methods. The inventors discovered that because there are many possible combinations between masking agents and bitter drugs, traditional experimental methods bring a series of problems, such as long experimental time, high economic cost, high operational difficulty of the entire experimental process, and environmental pollution. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method, system, and application for preparing taste-masking capsules based on molecular simulation. This invention provides a method for preparing taste-masking capsules using molecular simulation, focusing on screening for highly effective taste-masking agents that match a target bitter-tasting drug. Molecular simulation can reveal the interaction between bitter-tasting drugs and taste-masking agents from a microscopic molecular perspective, exploring the dispersion of bitter-tasting drugs on the surface of the taste-masking agent. It can simulate multiple matching scenarios in a short time, allowing for the selection of the most effective taste-masking scheme from numerous combinations of bitter-tasting drugs and taste-masking agents. Based on the above research results, this invention is thus completed.

[0006] This invention is achieved through the following technical solution:

[0007] A first aspect of the present invention provides a method for preparing a taste-masking capsule based on molecular simulation, comprising:

[0008] S1. Establish molecular models for the target bitter-tasting drugs and taste masking agents respectively;

[0009] S2. Perform energy optimization and structure optimization settings on the molecular model constructed in step S1;

[0010] S3. Freeze all atoms in the XYZ directions of the masking agent molecule model to keep them fixed, and calculate the molecular force field parameters;

[0011] S4. Control the molecular simulation parameters and analyze the interaction between bitter drugs and / or masking agents.

[0012] Through experimental verification, this invention successfully prepared a taste-masking capsule skin for the drug oseltamivir phosphate, wherein the taste-masking agent is mesoporous silica, and the formula is oseltamivir phosphate:mesoporous silica:cyclodextrin:glycerol:water in a mass ratio of 1:1:1.8:0.25:1.5. This invention also successfully prepared a taste-masking capsule skin for the drug berberine hydrochloride, wherein the taste-masking agent is mesoporous silica, and the formula is berberine hydrochloride:mesoporous silica:cyclodextrin:glycerol:water in a mass ratio of 1:0.7:1.7:0.3:1.7.

[0013] In a second aspect, the present invention provides a computer-readable storage medium for storing computer instructions, which, when executed by a processor, perform the steps of the above-described method for preparing the flavor-masking capsule skin based on molecular simulation.

[0014] A third aspect of the present invention provides an electronic device, including a memory, a processor, and a computer program stored in the memory and executable on the processor, wherein the processor executes the program to perform the steps of the above-described method for preparing the odor-masking capsule skin based on molecular simulation.

[0015] A fourth aspect of the present invention provides the application of the above-described preparation method in the field of masking bitter drugs.

[0016] The beneficial technical effects of one or more of the above technical solutions are as follows:

[0017] The above-mentioned technical solution effectively overcomes the shortcomings of traditional experimental methods in preparing taste-masking capsules, such as being time-consuming, labor-intensive, costly, and polluting. It provides a scientific basis and research foundation for the targeted screening of taste-masking agents for bitter drugs. At the same time, it can quickly, conveniently, and efficiently provide the taste-masking mechanism of capsules, thus having good practical application value. Attached Figure Description

[0018] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0019] Figure 1Example 1: The trajectory of the center of mass of a bitter medicine, wherein MPS is silicon dioxide and OP is oseltamivir phosphate;

[0020] Figure 2 Example 1: Normalized atomic number density distribution of bitter drug molecules and masking agents, wherein MPS is silicon dioxide and OP is oseltamivir phosphate;

[0021] Figure 3 Example 1: Hydrogen bonding situation, where MPS is silicon dioxide and OP is oseltamivir phosphate;

[0022] Figure 4 Example 1: Total interaction energy curve, where MPS is silicon dioxide and OP is oseltamivir phosphate;

[0023] Figure 5 Example 1: Simulation of the one-dimensional density distribution (A) and two-dimensional density distribution (B) of bitter herbs in the system;

[0024] Figure 6 Example 1: Evaluation results of human taste perception of oseltamivir phosphate taste-masking capsule skin;

[0025] Figure 7 Example 2: Evaluation results of human taste perception of berberine hydrochloride masking sac skin. Detailed Implementation

[0026] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, 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.

[0027] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the present invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof. It should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of the present invention is for the purpose of describing specific embodiments and not for limiting the scope of protection of the present invention.

[0028] This invention discloses components that can be used to perform the disclosed methods and systems. These and other components are disclosed herein, and it should be understood that while specific references to each of the various individual and collective combinations and arrangements of these components may not be explicitly disclosed when disclosing combinations, subgroups, interactions, groups, etc., of these components, each is specifically conceived and described herein for all methods and systems. This applies to all aspects of this application, including but not limited to the steps in the disclosed methods. Therefore, if various additional steps are possible, it should be understood that each of these additional steps can be performed using any particular embodiment or combination of embodiments of the disclosed methods.

[0029] In a typical embodiment of the present invention, a method for preparing a taste-masking capsule based on molecular simulation is provided, comprising the following steps: constructing models of a bitter drug and a taste-masking agent; placing the taste-masking agent model at the bottom center of a simulation box, with the normal of its plane parallel to the Z-axis of the simulation box; then randomly adding bitter drug molecular models to the simulation box; analyzing the model drug's trajectory, atomic number density distribution, hydrogen bond number changes, interaction energy, one-dimensional density distribution, and two-dimensional density distribution. The taste-masking agent and its dosage are determined based on the molecular simulation results. This method allows for the preparation of taste-masking capsules for bitter drugs as needed, thereby improving medication compliance and meeting the medication requirements for bitter drugs.

[0030] More specifically, the preparation method includes:

[0031] S1. Establish molecular models for the target bitter-tasting drugs and taste masking agents respectively;

[0032] S2. Perform energy optimization and structure optimization settings on the molecular model constructed in step S1;

[0033] S3. Freeze all atoms in the XYZ directions of the masking agent molecular model to keep them fixed, add the bitter drug molecular model, and calculate the molecular force field parameters.

[0034] S4. Control the molecular simulation parameters and analyze the interaction between bitter drugs and / or masking agents.

[0035] In step S1, the bitter medicine includes, but is not limited to, one or a combination of several of atomoxetine hydrochloride, oseltamivir phosphate, azithromycin, and berberine hydrochloride.

[0036] The masking agents include, but are not limited to, one or more of silicon dioxide, magnesium aluminum silicate, calcium silicate, sucralose, and aspartame.

[0037] The matching scheme of the masking agent and bitter drug described in this invention is one or more of the following: one bitter drug matched with one masking agent, one bitter drug matched with multiple masking agents, multiple bitter drugs matched with one masking agent, and multiple bitter drugs matched with multiple masking agents.

[0038] The mass ratio of bitter medicine and flavor masking agent in this invention is 1:0.2-5.

[0039] The taste-masking capsule skin of this invention contains one or more of cyclodextrin, glycerol, water, and chitosan.

[0040] In step S2, the energy optimization and structure optimization settings for the molecular model constructed in step S1 can be specifically performed in the simulation software under the Gaussview or Forcite module.

[0041] In step S3, specifically, the optimized masking agent molecule model is added to a simulation box (with a volume of 4.2 × 4.2 × 4.2 nm) using molecular simulation software. 3 In the simulation, the normal of the plane is parallel to the Z-axis of the simulation box; according to the mass ratio of bitter drug to masking agent, the density of the simulation box is set to 1.0 to adjust the volume of the remaining box; all atoms of the masking agent are frozen in the XYZ directions to keep them fixed; then, bitter drug molecule models are randomly added to the simulation box.

[0042] In step S4, the controlled molecular simulation parameters include: a simulation time step of 0.2fs-2fs, a system equilibrium duration of 40-150ps, and a periodic boundary condition (PBC) applied to the entire system. The cutoff distance for van der Waals (vdW) interactions is set to 1nm-1.2nm, and long-range electrostatic interactions are calculated using the particle mesh Ewald (PME) method. Bond lengths are constrained using the LINCS algorithm. All molecular (MD) simulations are performed under NVT conditions, with the temperature maintained at 300K-350K.

[0043] The analysis of the relationship between bitter drugs and / or masking agents specifically includes:

[0044] Analyze the trajectory of the center of mass of bitter drugs and the distribution of bitter drugs on the masking agent;

[0045] Analyze the normalized atomic number density distribution of bitter drugs and masking agents; analyze the adsorption of bitter drugs on masking agents;

[0046] Analyze the hydrogen bonding between bitter drugs, between flavor maskers, and between bitter drugs and flavor maskers; analyze the adsorption of bitter drugs on flavor maskers;

[0047] The total interaction energy between bitter drugs and taste masking agents was analyzed.

[0048] It should be noted that the matching method between the masking agent and the bitter drug in this invention can be one or more of the following: one bitter drug matched with one masking agent, one bitter drug matched with multiple masking agents, multiple bitter drugs matched with one masking agent, and multiple bitter drugs matched with multiple masking agents.

[0049] The molecular simulation software and modules used in this invention include, but are not limited to, Material Studio, Gaussian View, ORCA, GROMACS, PACKMOL, AmberTool, and Lammps.

[0050] Through experimental verification, this invention successfully prepared a taste-masking capsule skin for the drug oseltamivir phosphate, wherein the taste-masking agent is mesoporous silica, and the formula is oseltamivir phosphate:mesoporous silica:cyclodextrin:glycerol:water in a mass ratio of 1:1:1.8:0.25:1.5. This invention also successfully prepared a taste-masking capsule skin for the drug berberine hydrochloride, wherein the taste-masking agent is mesoporous silica, and the formula is berberine hydrochloride:mesoporous silica:cyclodextrin:glycerol:water in a mass ratio of 1:0.7:1.7:0.3:1.7.

[0051] In another specific embodiment of the present invention, a computer-readable storage medium is provided for storing computer instructions, which, when executed by a processor, complete the steps of the above-described method for preparing the taste-masking capsule skin based on molecular simulation.

[0052] In another specific embodiment of the present invention, an electronic device is provided, including a memory, a processor, and a computer program stored in the memory and executable on the processor. When the processor executes the program, it performs the steps of the above-described method for preparing the odor-masking capsule skin based on molecular simulation.

[0053] In another specific embodiment of the present invention, the application of the above preparation method in the field of bitter drug masking treatment is provided.

[0054] The following examples further illustrate the present invention, but do not constitute a limitation thereof. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[0055] Example 1

[0056] The bitter-tasting drug was oseltamivir phosphate, and the taste masking agent was mesoporous silica (MPS). Energy and structure optimization settings for all models were performed in Gaussview simulation software. The optimized mesoporous silica (MPS) molecules were then added to a volume of 4.2 × 4.2 × 4.2 nm using PACKMOL software. 3 In the simulated box, the box density was set to 1.0 to adjust the remaining box volume. A masking agent mesoporous silica (MPS) material was placed at the bottom center of the simulated box, with its plane normal parallel to the Z-axis of the simulated box. All atoms of the masking agent silica (MPS) were frozen in the X, Y, and Z directions to keep them fixed, forming a frozen silica box.

[0057] The OP molecule was structurally optimized and vibrationally analyzed using ORCA software at the B3LYP method and def2-TZVP basis set levels, respectively. Its molecular force field parameters were then calculated using AmberTool. During the molecular dynamics (MD) simulation, all atoms in the MPS were frozen in the X / Y / Z directions to maintain their position.

[0058] Then, the small molecule drug oseltamivir phosphate (OP) was randomly added to the simulated frozen silica box to construct an ideal model of the small molecule drug OP entering the mesoporous silica channels before adsorption equilibrium.

[0059] An ideal model was constructed to simulate the entry of small molecule drug OP into mesoporous silica channels before adsorption equilibrium, with a drug-to-masking agent mass ratio of 1:1. The simulation time step was 2 fs, and a periodic boundary condition (PBC) was applied to the entire system. The cutoff distance for Van der Waals (vdW) interactions was set to 1.2 nm, and long-range electrostatic interactions were calculated using the particle mesh Ewald (PME) method. Bond lengths were constrained using the LINCS algorithm. All molecular dynamics (MD) simulations were performed in the NVT ensemble at a temperature maintained at 300 K.

[0060] The microstructure of oseltamivir phosphate on a frozen silica substrate was investigated at the atomic level using classical molecular dynamics simulations. The initial configuration of the simulation box contained 50 oseltamivir phosphate molecules, and the initial configuration system was constructed using PACKMOL software. After initially constructing the closed system, a 3 nm vacuum was added to the Z-dimensional dimension of the simulation box to eliminate artifacts caused by periodicity. The silica surface was set to rigid to ensure that the atoms on the substrate remained fixed during the simulation. The behavior of the molecules was described using an OPL-AA force field. An interfacial force field was used to describe the silica. The molecular force field consisted of non-bonded and bonded interactions. Non-bonded interactions included van der Waals (VdW) and electrostatic interactions, described by Equations 1 and 2, respectively.

[0061]

[0062]

[0063] For different types of atoms, the van der Waals interactions follow the Lorentz-Berthelot mixing principle, according to Equation 3. The intercept of the van der Waals forces and electrostatic interactions is set to 1.2 nm, and the Particle Mesh Ewald (PME) algorithm is used to calculate long-range electrostatic interactions.

[0064]

[0065] In the initial stages of the simulation, an energy minimization method was used to relax the simulation box. Then, a canonical system (NVT, N-number of particles, V-volume, T-temperature) with a time step of 1.0 fs was used to optimize the simulation box, with the temperature set to 298.15 K. Temperature was maintained using Nose-Hoover temperature control. The optimization time was set to 20.0 ns. After optimization, another canonical system with a time step of 2.0 ns was used to further investigate the behavior of oseltamivir phosphate. Molecular trajectory coordinates were collected and stored at a frequency of 10,000 steps. In all molecular dynamics simulations, the atomic motions were described using classical Newton's equations and solved using the velocity-Verlet algorithm.

[0066] Figure 1The image shows the trajectory of the OP's center of mass. Initially, the OP's center of mass is located at z = 4.6 nm. The inset shows the OP trajectory from time 0 to 100 ps. The adsorption diagram shows the instantaneous conformation at 100 ns, where MPS and OP correspond to the respective z-coordinate values. Molecular dynamics simulations over 100 ns were performed to analyze the changes in the OP's center of mass trajectory. Within the 0–100 ps range, the OP's center of mass gradually approaches the MPS surface, and the curve eventually flattens out within 100 ns. Combined with instantaneous conformational analysis, it was found that the OP molecules gradually aggregate and distribute on the MPS surface from an initial random distribution. Figure 2 As shown, by calculating the atomic number density distribution of OP molecules and MPS, it can be seen that the z-coordinates of the peak atomic number density of OP / MPS are ZOP = 3.4 nm and ZMPS = 2.6 nm, respectively. At the same time, the z-coordinate of the contact surface between MPS and OP is ZMPS' = 3.0 nm. The difference between these two, ZOP-ZMPS', is only 0.4 nm, which indicates that there is a very strong adsorption effect between the inner wall of the pores of MPS and OP. Figure 3 Hydrogen bond analysis indicates that, compared to the HbondOP-MPS relationship between OP molecules and MPS, there are numerous HbondOP-OP hydrogen bonds between OP molecules. This HbondOP-OP relationship may be a key factor promoting the adsorption of a large number of OP molecules after some OP is adsorbed onto the inner wall of the MPS pores. The total interaction energy between OP molecules and MPS was calculated using energy decomposition. Figure 4 As shown, within a simulated scale of 100 ns, after adsorption equilibrium, the total interaction energy between OP molecules and MPS is negative, -1650, meaning that the total interaction between the two promotes the adsorption process. Figure 5 To simulate the one-dimensional density distribution of oseltamivir phosphate along the direction perpendicular to SiO2 (Z-axis) and the two-dimensional density distribution along the directions perpendicular to the X and Z axes in the system, the results show that above the silica surface... The density of oseltamivir phosphate is highest near the location, which is the main distribution area for oseltamivir phosphate.

[0067] Based on the above analysis, mesoporous silica and oseltamivir phosphate exhibit strong binding ability, and the masking agent forms a strong interaction with the bitter-tasting drug. Building upon this, a cyclodextrin film-forming material was added, and a oseltamivir phosphate masking capsule shell material was prepared using a formulation with a mass ratio of oseltamivir phosphate:mesoporous silica:cyclodextrin:glycerol:water of 1:1:1.8:0.25:1.5.

[0068] A taste-masking sac material was used to conduct a human taste evaluation experiment. Volunteers were recruited and selected based on bitterness sensitivity, health status, and age. Twenty-one healthy volunteers (10 men and 11 women, aged 20-36) were selected to participate in the oral tasting experiment. While informing them of the significance of the experiment, detailed information about the sample was not disclosed. Bitterness was graded into five levels: 0, 1, 2, 3, and 4, with the bitterness level increasing as the number increases; level 4 was the most bitter. 5.5 mg of oseltamivir phosphate and the equivalent of 5.5 mg of oseltamivir phosphate were thoroughly dispersed in 15 mL of distilled water at room temperature for 2 minutes. 5 mL of the dispersion was dropped onto the volunteer's tongue, and the volunteer held it in their mouth for 45 seconds. The taste was recorded. Volunteers strictly adhered to a 1-hour interval between each oral tasting experiment, allowing for oral cleaning and taste recovery. Based on the volunteers' ratings, the human taste evaluation results were obtained, such as... Figure 6 As shown, the oseltamivir phosphate capsule has a significant odor-masking effect.

[0069] Example 2

[0070] The bittering agent was berberine hydrochloride, and the masking agent was mesoporous silica. Using PACKMOL software, the mesoporous silica (MPS) material was placed at the bottom center of the simulation chamber, with its plane normal parallel to the Z-axis of the simulation chamber. Then, the small molecule drug berberine hydrochloride (referred to as the drug in this example) was randomly added to the simulation chamber; the simulation steps were as described in Example 1. An ideal model of the small molecule drug berberine hydrochloride entering the mesoporous silica pores before adsorption equilibrium was constructed, with the specific dosage based on a drug-to-silica mass ratio of 1:0.7 for molecular simulation. The simulation time step was 0.2 fs, and the periodic boundary condition (PBC) was applied to the entire system. The cutoff distance for Van der Waals (vdW) interactions was set to 1.1 nm, and long-range electrostatic interactions were calculated using the particle mesh Ewald (PME) method. Bond lengths were constrained using the LINCS algorithm. All MD simulations were performed under the NVT ensemble at a temperature maintained at 350 K. Initially, the drug's center of mass was located at z = 3.5 nm. After a 100 ns molecular dynamics simulation, the change in the drug's center of mass coordinate trajectory was analyzed. It can be seen that within 0–100 ps, ​​the drug's center of mass gradually approached the MPS surface, and the curve eventually flattened out within 100 ns. Combined with transient conformational analysis, it was found that the drug molecules gradually aggregated and distributed on the MPS surface from an initial random distribution conformation. By calculating the atomic number density distribution of the drug molecules and MPS, the z-coordinates of the peak atomic number density for both the drug and the masking agent were Zdrug = 4.3 nm and ZMPS = 4.1 nm, respectively. Simultaneously, the z-coordinate of the contact surface between MPS and the drug was ZMPS' = 4.0 nm. The difference between these two, Zdrug - ZMPS', was only 0.3 nm, indicating a very strong adsorption effect between the MPS pore walls and the drug. Hydrogen bond analysis revealed a significant presence of Hbond drug-MPS bonds between drug molecules and MPS, compared to the Hbond drug-MPS bond. This Hbond drug-MPS bond likely represents a key factor promoting further adsorption of a large number of drug molecules after some drug adsorption adheres to the inner walls of the MPS pores. The total interaction energy between drug molecules and MPS was calculated using energy decomposition. At a simulated scale of 100 ns, after adsorption equilibrium, the total interaction energy between drug molecules and MPS was negative -1700, indicating that the overall interaction promoted the adsorption process. The simulation showed a one-dimensional density distribution of the drug along the direction perpendicular to SiO2 (Z-axis) and a two-dimensional density distribution along the directions perpendicular to the X and Z axes. The results indicate that above the silica surface... The drug density is highest near the location, which is the main distribution area of ​​the drug. Based on the above analysis, mesoporous silica has a strong binding ability with the drug, and the masking agent forms a strong interaction with the bitter drug. Based on this, a cyclodextrin film-forming material was added, and a masking capsule material for berberine hydrochloride was prepared using a formulation with a mass ratio of berberine hydrochloride:mesoporous silica:cyclodextrin:glycerol:water of 1:0.7:1.7:0.3:1.7.

[0071] A taste-masking sac material was used in a human taste evaluation experiment. Similar to the previous example, the same group of volunteers was recruited, and selection was based on bitterness sensitivity, physical health, and age. Twenty-one healthy volunteers (10 men and 11 women, aged 20-36) were selected to participate in the oral tasting experiment. While informing them of the significance of the experiment, detailed information about the sample was not disclosed. Bitterness was divided into five levels: 0, 1, 2, 3, and 4, with bitterness increasing as the number increases; level 4 was the most bitter. 7.0 mg of berberine hydrochloride and an equivalent amount of berberine hydrochloride sac material were thoroughly dispersed in 15 mL of distilled water at room temperature for 2 minutes. 5 mL of the dispersion was dropped onto the volunteer's tongue, and the volunteer held it in their mouth for 45 seconds. The taste was recorded. Volunteers strictly adhered to a 1-hour interval between each oral tasting experiment, allowing for oral hygiene and taste recovery. Based on the volunteers' ratings, the human taste evaluation results were obtained, such as... Figure 7 As shown, the berberine hydrochloride sac membrane has a significant taste-masking effect.

[0072] Example 3

[0073] An electronic device includes a memory and a processor, as well as computer instructions stored in the memory and running on the processor. When the processor executes the computer instructions, it performs various operations in the methods described in Embodiment 1 or Embodiment 2. For the sake of brevity, these will not be described in detail here.

[0074] The electronic device can be a mobile terminal or a non-mobile terminal. Non-mobile terminals include desktop computers, while mobile terminals include smartphones (such as Android phones, iOS phones, etc.), smart glasses, smartwatches, smart bracelets, tablets, laptops, personal digital assistants, and other mobile internet devices capable of wireless communication.

[0075] It should be understood that in this embodiment, the processor can be a central processing unit (CPU), or it can be other general-purpose processors, digital signal processors (DSPs), application-specific integrated circuits (ASICs), programmable gate arrays (FPGAs), or other programmable logic devices, discrete gate or transistor logic devices, discrete hardware components, etc. The general-purpose processor can be a microprocessor or any conventional processor.

[0076] The memory may include read-only memory and random access memory, and provides instructions and data to the processor. A portion of the memory may also include non-volatile random access memory. For example, the memory may also store information about the device type.

[0077] In implementation, each step of the above method can be completed by integrated logic circuits in the processor hardware or by instructions in software. The steps of the method disclosed in this embodiment can be directly implemented by a hardware processor, or by a combination of hardware and software modules in the processor. The software modules can reside in mature storage media in the art, such as random access memory, flash memory, read-only memory, programmable read-only memory, electrically erasable programmable memory, or registers. This storage medium is located in memory; the processor reads information from the memory and, in conjunction with its hardware, completes the steps of the above method. To avoid repetition, detailed descriptions are omitted here. Those skilled in the art will recognize that the units, i.e., algorithm steps, of the various examples described in conjunction with the embodiments disclosed herein can be implemented in electronic hardware or a combination of computer software and electronic hardware. Whether these functions are implemented in hardware or software depends on the specific application and design constraints of the technical solution. Those skilled in the art can use different methods to implement the described functions for each specific application, but such implementation should not be considered beyond the scope of this application.

[0078] Those skilled in the art will understand that, for the sake of convenience and brevity, the specific working processes of the systems, devices, and units described above can be referred to the corresponding processes in the foregoing method embodiments, and will not be repeated here.

[0079] In the embodiments provided in this application, it should be understood that the disclosed systems, apparatuses, and methods can be implemented in other ways. For example, the apparatus embodiments described above are merely illustrative; for instance, the division of units is only a logical functional division, and in actual implementation, there may be other division methods. For example, multiple units or components may be combined or integrated into another system, or some features may be ignored or not executed. Furthermore, the coupling or direct coupling or communication connection shown or discussed may be through some interfaces; the indirect coupling or communication connection of apparatuses or units may be electrical, mechanical, or other forms.

[0080] If the aforementioned functions are implemented as software functional units and sold or used as independent products, they can be stored in a computer-readable storage medium. Based on this understanding, the technical solution of this application, in essence, or the part that contributes to the prior art, or a portion of the technical solution, can be embodied in the form of a software product. This computer software product is stored in a storage medium and includes several instructions to cause a computer device to execute all or part of the steps of the methods described in the various embodiments of this application. The aforementioned storage medium includes various media capable of storing program code, such as USB flash drives, portable hard drives, read-only memory, random access memory, magnetic disks, or optical disks.

[0081] It should be noted that the above examples are only used to illustrate the technical solutions of this embodiment and are not intended to limit it. Although this embodiment has been described in detail with reference to the given examples, those skilled in the art can modify or make equivalent substitutions to the technical solutions of this embodiment as needed, without departing from the spirit and scope of the technical solutions of this embodiment.

Claims

1. A method for the preparation of taste-masking capsule skin based on molecular simulation, characterized by, The method comprises the following steps: S1, establishing a molecular model for each of the target bitter drug and the taste masking agent; S2, performing energy optimization and structure optimization setting on the molecular model constructed in step S1; S3, freezing all atoms in the molecular model of the taste masking agent in the XYZ three directions to keep them fixed, adding the molecular model of the bitter drug, and calculating the molecular force field parameters; In step S3, the optimized molecular model of the taste masking agent is added to a simulation box, the remaining box volume is adjusted according to the mass ratio of the bitter drug to the taste masking agent, the density of the simulation box is set to 1.0, all atoms in the molecular model of the taste masking agent are frozen in the XYZ three directions to keep them fixed, and then the molecular model of the bitter drug is randomly added to the simulation box; S4, controlling the molecular simulation parameter conditions and analyzing the action relationship of the bitter drug and / or the taste masking agent; In step S4, the control of the molecular simulation parameter conditions includes: the step length of the simulation time is 0.2 fs-2 fs, the balance system lasts for 40-150 ps, the periodic boundary condition is suitable for the whole system, the cutoff distance of Van der Waals interaction is set to 1 nm-1.2 nm, the long-range electrostatic interaction is calculated by the particle mesh Ewald method, the LINCS algorithm is used to limit the bond length, and all molecular simulations are performed under NVT, and the temperature is kept at 300K-350K; In step S4, the analysis of the action relationship of the bitter drug and / or the taste masking agent specifically includes: analyzing the center of mass trajectory of the bitter drug and analyzing the distribution of the bitter drug on the taste masking agent; analyzing the normalized atomic number density distribution of the bitter drug and the taste masking agent; analyzing the adsorption of the bitter drug on the taste masking agent; analyzing the hydrogen bond between the bitter drugs, analyzing the hydrogen bond between the taste masking agents, analyzing the hydrogen bond between the bitter drugs and the taste masking agents; analyzing the adsorption of the bitter drug on the taste masking agent; analyzing the total interaction energy between the bitter drug and the taste masking agent.

2. The production method according to claim 1, wherein In step S1, the bitter drug includes one or more of hydrochloric acid tomoxetine, oseltamivir phosphate, azithromycin, and berberine hydrochloride; The taste masking agent includes one or more of silicon dioxide, magnesium aluminum silicate, calcium silicate, sucralose, and aspartame; The mass ratio of the bitter drug to the taste masking agent is 1:0.2-5; The taste masking capsule skin contains one or more of cyclodextrin, glycerol, water, and chitosan.

3. The production method according to claim 1, wherein The matching mode of the taste masking agent and the bitter drug includes one or more of the following: one bitter drug matches one taste masking agent, one bitter drug matches multiple taste masking agents, multiple bitter drugs match one taste masking agent, and multiple bitter drugs match multiple taste masking agents.

4. The production method according to claim 1, wherein The molecular simulation simulation software and modules used include one or more of Material Studio, Gaussian View, ORCA, GROMACS, PACKMOL, AmberTool, and Lammps.

5. A computer readable storage medium storing computer instructions, characterized in that, When the computer instructions are executed by the processor, the steps of the preparation method of the taste masking capsule skin based on molecular simulation in any one of claims 1-4 are completed.

6. An electronic device comprising a memory, a processor, and a computer program stored on the memory and executable on the processor, characterized in that, The processor, when executing the program, implements the steps performed by the method for preparing a taste-masked capsule based on molecular simulation according to any one of claims 1-4.

7. Use of the method for preparing according to any one of claims 1-4 in the field of taste-masking of bitter drugs.

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