Method and device for screening auxiliary materials for solid dispersion

Abstract

The present application relates to a method and device for screening excipients for solid dispersions. The screening method includes: obtaining target drug molecule information and candidate excipient information; wherein the target drug molecule information includes the corresponding first molecule quantity and protonated three-dimensional structure, and the candidate excipient information includes the corresponding second molecule quantity and excipient three-dimensional structure; constructing multiple simulation boxes for molecular dynamics simulation according to the target drug molecule information and the candidate excipient information; performing molecular dynamics simulation on each simulation box to obtain the corresponding molecular simulation results; obtaining the calculation results of preset parameters according to the molecular simulation results, so as to screen out the target excipient from the candidate excipients according to each calculation result. The scheme provided by the present application, based on the calculation results of preset parameters obtained by molecular dynamics simulation, can efficiently and reliably evaluate candidate excipients, screen out better target excipients for forming solid dispersions, effectively improve R&D efficiency, and reduce R&D costs.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and in particular to a method and device for screening auxiliary materials for solid dispersions. Background Art

[0002] Solid dispersion technology is a drug preparation technology, which usually refers to highly dispersing drugs in excipients (also called carriers) to form a dispersed system, namely solid dispersion. Solid dispersion can destroy the drug crystal lattice, reduce the energy barrier of drug release, and achieve the effect of increasing drug loading, enhancing drug dissolution and in vivo bioavailability.

[0003] In solid dispersions, the compatibility and interaction between drugs and excipients are crucial. Traditional methods can only rely on phase diagrams to make some empirical judgments or a large number of experimental attempts to select appropriate excipients and proportions, thereby completing the formulation development and optimization of drug preparations. However, this development method makes drug development inefficient and consumes a long development cycle and experimental costs. Summary of the invention

[0004] In order to solve or partially solve the problems existing in the related art, the present application provides a method and device for screening excipients for solid dispersions, which can efficiently and reliably screen out excipients suitable for target drug molecules, improve research and development efficiency, and save research and development costs.

[0005] The first aspect of the present application provides a method for screening excipients for solid dispersions, comprising:

[0006] Obtaining target drug molecule information and candidate excipient information; wherein the target drug molecule information includes the corresponding first molecule quantity and protonated three-dimensional structure, and the candidate excipient information includes the corresponding second molecule quantity and excipient three-dimensional structure;

[0007] Constructing a plurality of simulation boxes for molecular dynamics simulation according to the target drug molecule information and the candidate excipient information;

[0008] Performing molecular dynamics simulation on each of the simulation boxes to obtain corresponding molecular simulation results;

[0009] According to the molecular simulation results, calculation results of preset parameters are obtained, so as to screen out target excipients from candidate excipients according to the calculation results.

[0010] In some implementations, the simulation box includes a first simulation box, a second simulation box, and a third simulation box; wherein:

[0011] The first simulation box includes the first number of molecules of protonated three-dimensional structures;

[0012] The second simulation box includes the second molecular amount of the three-dimensional structure of the excipient;

[0013] The third simulation box includes the protonated three-dimensional structure of the first molecular quantity and the auxiliary material three-dimensional structure of the second molecular quantity.

[0014] In some embodiments, the preset parameters include at least one of a FH parameter and an atomic fluctuation rate;

[0015] Wherein, the FH parameters are calculated based on the molecular simulation results of the first simulation box, the second simulation box and the third simulation box;

[0016] The atomic fluctuation rate is calculated based on the molecular simulation results of the third simulation box.

[0017] In some embodiments, the preset parameters further include an average number of hydrogen bonds and / or a solvent accessible surface area; wherein:

[0018] The average number of hydrogen bonds is obtained according to the molecular simulation result of the third simulation box;

[0019] The solvent accessible surface area is obtained according to the molecular simulation results of the first simulation box and the third simulation box.

[0020] In some embodiments, the simulation box further includes a fourth simulation box; wherein the fourth simulation box includes the protonated three-dimensional structure of the first molecular quantity, the auxiliary material three-dimensional structure of the second molecular quantity, and water molecules accounting for 1% by mass;

[0021] The preset parameters include an enthalpy change caused by adding water molecules with a mass percentage of 1% into the fourth simulation box; the enthalpy change is calculated based on the molecular simulation results of the third simulation box and the fourth simulation box.

[0022] In some embodiments, the method further comprises:

[0023] According to the preset drug loading amount and the preset total relative molecular mass, the first molecular quantity of the target drug molecule and the second molecular quantity of the candidate excipient are determined respectively.

[0024] In some embodiments, the molecular dynamics simulation of each simulation box is performed to obtain a corresponding molecular simulation result, including:

[0025] According to the preset temperature and the preset time, the molecules in each simulation box are allowed to reach a state of motion equilibrium;

[0026] According to preset conditions, the simulation box is annealed to obtain corresponding molecular simulation results.

[0027] The second aspect of the present application provides an auxiliary material screening device for solid dispersion, comprising:

[0028] An information acquisition module, used to acquire target drug molecule information and candidate excipient information; wherein the target drug molecule information includes the corresponding first molecule quantity and protonated three-dimensional structure, and the candidate excipient information includes the corresponding second molecule quantity and excipient three-dimensional structure;

[0029] A data generation module, used to construct a plurality of simulation boxes for molecular dynamics simulation according to the target drug molecule information and the candidate excipient information;

[0030] A simulation motion module is used to perform molecular dynamics simulation motion on each of the simulation boxes to obtain corresponding molecular simulation results;

[0031] The parameter calculation module is used to obtain calculation results of preset parameters according to the molecular simulation results, so as to screen out target excipients from candidate excipients according to the calculation results.

[0032] A third aspect of the present application provides an electronic device, including:

[0033] Processor; and

[0034] A memory having executable codes stored thereon, which, when executed by the processor, causes the processor to execute the training method as described in the first aspect or the prediction method as described in the second aspect.

[0035] In a fourth aspect, the present application provides a computer-readable storage medium having executable code stored thereon. When the executable code is executed by a processor of an electronic device, the processor executes the training method described in the first aspect or the prediction method described in the second aspect.

[0036] The fifth aspect of the present application provides a computer program product, including a computer program, characterized in that the computer program is used to execute computer program code instructions corresponding to the training method described in the first aspect or the prediction method described in the second aspect.

[0037] The technical solution provided by this application may have the following beneficial effects:

[0038] The excipient screening method for solid dispersions of the present application can obtain the calculation results of preset parameters based on molecular dynamics simulation, and then evaluate and screen the candidate excipients of the target drug molecule based on the intuitive calculation results, so as to quickly screen out the target excipient, and then conduct experimental tests based on the target excipient, which can greatly improve R&D efficiency and reduce R&D costs.

[0039] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the present application. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The above and other objects, features and advantages of the present application will become more apparent by describing in more detail the exemplary embodiments of the present application in conjunction with the accompanying drawings, wherein the same reference numerals generally represent the same components in the exemplary embodiments of the present application.

[0041] Figure 1 It is a schematic diagram of the process of the excipient screening method for solid dispersions shown in the present application;

[0042] Figure 2 is another schematic flow chart of the method for screening excipients for solid dispersions shown in the present application;

[0043] Figure 3 is a schematic diagram of the structure of the solid dispersion in the third simulation box shown in the present application after being evenly dispersed;

[0044] Figure 4 It is a schematic structural diagram of an auxiliary material screening device for solid dispersions shown in the present application;

[0045] Figure 5 is another structural schematic diagram of the auxiliary material screening device for solid dispersion shown in the present application;

[0046] Figure 6 It is a schematic diagram of the structure of the electronic device shown in this application. DETAILED DESCRIPTION

[0047] The embodiments of the present application will be described in more detail below with reference to the accompanying drawings. Although the embodiments of the present application are shown in the accompanying drawings, it should be understood that the present application can be implemented in various forms and should not be limited by the embodiments described herein. On the contrary, these embodiments are provided to make the present application more thorough and complete, and to fully convey the scope of the present application to those skilled in the art.

[0048] The terms used in this application are for the purpose of describing specific embodiments only and are not intended to limit this application. The singular forms of "a", "said" and "the" used in this application and the appended claims are also intended to include plural forms unless the context clearly indicates other meanings. It should also be understood that the term "and / or" used herein refers to and includes any or all possible combinations of one or more associated listed items.

[0049] It should be understood that although the terms "first", "second", "third", etc. may be used in this application to describe various information, this information should not be limited to these terms. These terms are only used to distinguish the same type of information from each other. For example, without departing from the scope of this application, the first information may also be referred to as the second information, and similarly, the second information may also be referred to as the first information. Thus, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. In the description of this application, the meaning of "multiple" is two or more, unless otherwise clearly and specifically defined.

[0050] In the related art, for each drug molecule, it is necessary to select suitable excipients to form a solid dispersion. However, the screening of excipients based on the experience of researchers and a large number of experiments consumes a long development cycle and experimental costs.

[0051] In response to the above problems, the present application provides a method for screening excipients for solid dispersions, which can efficiently and reliably screen out excipients suitable for target drug molecules, improve research and development efficiency, and save research and development costs.

[0052] The technical solution of the present application is described in detail below with reference to the accompanying drawings.

[0053] See also Figure 1 , an embodiment of the present application provides a method for screening excipients for solid dispersions, which comprises:

[0054] S110, obtaining target drug molecule information and candidate excipient information; wherein the target drug molecule information includes the corresponding first molecule quantity and protonated three-dimensional structure, and the candidate excipient information includes the corresponding second molecule quantity and excipient three-dimensional structure.

[0055] In the present application, the target drug molecule may be an active pharmaceutical ingredient (API) with low solubility. Herein, low solubility means that the water solubility of the API is less than 0.1 mg / mL or less than 0.05 mg / mL or less than 0.02 mg / mL, or even less than 0.01 mg / mL. Herein, the value of water solubility (mg / mL) refers to the minimum value observed for the API in any physiologically relevant aqueous solution (e.g., an aqueous solution with a pH value of 1 to 8). Physiologically relevant aqueous solutions may include, for example, simulated gastric fluid (USP) and intestinal buffer, etc., which are only used as examples and are not intended to be limiting.

[0056] In the present application, candidate excipients refer to carriers for dispersing and mixing with target drug molecules to form solid dispersions. Candidate excipients can be known existing excipient molecules or novel molecules developed independently. In the present embodiment, in a single solid dispersion, the target drug molecule is mixed with one candidate excipient. Alternatively, in other embodiments, the target drug molecule can be mixed with a plurality of candidate excipients to form a solid dispersion.

[0057] In some embodiments, the excipient can be a high molecular polymer, such as but not limited to polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, methylcellulose (MC), hydroxyethyl cellulose, cyclodextrin, hydroxypropyl cellulose (HPC), pectin, galactomannan, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), acrylic resin (such as Eudragit L, Eudragit S, Eudragit RL, Eudragit RS, Eudragit NE, Eudragit FS, Eudragit E PO or Eudragit E, preferably Eudragit L100, Eudragit L100-55 or Eudragit E100), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), cellulose acetate phthalate, cellulose acetate propionate (CAP), cellulose acetate butyrate, cellulose acetate, ethyl cellulose, polyvinyl alcohol, copovidone (PVP VA), polyvinyl pyrrolidone (PVP), polyethylene oxide (PEO), poly(styrene sulfonic acid), polymethacrylate or polyacrylic acid.

[0058] In other embodiments, the excipient may also be a substance such as a sugar, an acid or a surfactant. For example, when the excipient is a sugar, it includes but is not limited to glucose, sucrose, galactose, sorbitol, xylitol, mannitol or lactose. When the excipient is an acid, the acid includes but is not limited to citric acid, succinic acid or acetic acid. When the excipient is a surfactant, the surfactant includes but is not limited to polyoxyethylene stearate, deoxycholic acid, polysorbate, polyethylene glycol glycerol, poloxamer (such as poloxamer 188), vitamin E, TPGS, sodium lauryl sulfate, polyethylene glycol (15) hydroxystearate or dehydrated sorbitan ester) or others (such as pentaerythritol, pentaerythritol tetraacetate, urea, ethyl carbamate or hydroxyalkyl xanthine).

[0059] In this step, after selecting the target drug molecule and the corresponding candidate excipient molecule, the corresponding three-dimensional molecular structure can be obtained by using relevant technologies. Among them, the three-dimensional molecular structure of the target drug molecule is protonated according to the relevant technology to obtain the corresponding protonated three-dimensional structure. The three-dimensional molecular structure of the excipient molecule is the excipient three-dimensional structure.

[0060] Further, it can be understood that the solid dispersion includes a certain number of drug molecules and excipient molecules, and the solid dispersion has a corresponding drug loading. The drug loading refers to the ratio of the drug molecule mass in the solid dispersion to the total molecular mass of the system. When the drug loading is preset, based on the preset total relative molecular mass of the solid dispersion, the molecular number of the target drug molecule (i.e., the first molecular number) and the molecular number of the candidate excipient (i.e., the second molecular number) can be calculated.

[0061] S120, constructing a plurality of simulation boxes for molecular dynamics simulation according to the target drug molecule information and the candidate excipient information.

[0062] In molecular dynamics simulation related software such as GROMACS, OPENMM, and NAMD, a simulation box needs to be constructed before molecular dynamics simulation is carried out. The simulation box refers to a virtual container for loading molecules to be simulated, which has a preset size range in a preset three-dimensional coordinate system, thereby limiting the activity boundaries of each molecule in the container.

[0063] In the present application, a plurality of simulation boxes loaded with different contents are pre-constructed, and each simulation box performs molecular dynamics simulation motion independently of each other. In some specific embodiments, the simulation box includes a first simulation box, a second simulation box, and a third simulation box; wherein:

[0064] The first simulation box includes a first number of protonated three-dimensional structures, the second simulation box includes a second number of auxiliary three-dimensional structures, and the third simulation box includes a first number of protonated three-dimensional structures and a second number of auxiliary three-dimensional structures.

[0065] That is to say, the types and quantities of molecules in each simulation box are different. The molecules in the first simulation box are target drug molecules, which have a corresponding first molecular quantity, and are placed in the corresponding box with a protonated three-dimensional structure. The molecules in the second simulation box are candidate excipient molecules, which have a corresponding second molecular quantity, and are placed in the corresponding box with an excipient three-dimensional structure. The molecules in the third simulation box contain both the first molecular quantity of target drug molecules and the second molecular quantity of candidate excipient molecules, and are placed in the corresponding protonated three-dimensional structure and excipient three-dimensional structure, respectively.

[0066] S130, performing molecular dynamics simulation motion on each simulation box to obtain corresponding molecular simulation results.

[0067] In each simulation box, the protonated three-dimensional structure of the target drug molecule is subjected to molecular dynamics simulation according to the corresponding molecular force field file and atomic charge information, and the three-dimensional structure of the candidate excipient molecule is subjected to molecular dynamics simulation according to the corresponding molecular force field file and atomic charge information. Among them, the molecular force field file and atomic charge information can be automatically generated according to relevant software such as acpype, OpenFF, sobtop, etc., which will not be described in detail here.

[0068] Furthermore, each simulation box can carry out molecular dynamics simulation according to the same or different simulation parameters to obtain independent molecular simulation results. The simulation parameters include one or more of simulation time, system temperature, pressure, simulation step, temperature control method and pressure control method.

[0069] S140, obtaining calculation results of preset parameters according to the molecular simulation results, so as to evaluate the candidate excipients according to the calculation results and screen out the target excipients.

[0070] It is understood that different simulation boxes have independent molecular simulation results. In the present application, relevant parameters can be extracted from each molecular simulation result to participate in the calculation of preset parameters and obtain corresponding calculation results.

[0071] In some embodiments, the preset parameters include at least one of the FH parameter, atomic volatility, and solvent. Specifically, when the calculation result of the FH parameter (i.e., the Flory-Huggins interaction parameter) is a negative number, it means that the target drug molecule and the candidate excipient molecule have good compatibility; conversely, when the calculation result is a positive number, it means that the target drug molecule and the candidate excipient molecule have poor compatibility. When the atomic volatility is smaller, the stability of the formed solid dispersion is better; conversely, when the calculation result of the atomic volatility is larger, the stability of the formed solid dispersion is better.

[0072] In some specific implementations, the FH parameter is calculated based on the molecular simulation results of the first simulation box, the second simulation box, and the third simulation box. Specifically, the FH parameter is based on the mixing enthalpy Calculate the mixing enthalpy. The calculation needs to obtain the simulated properties corresponding to the single-component drug molecule, the simulated properties corresponding to the single-component excipient molecule, and the simulated properties corresponding to the mixed component of the drug molecule and the candidate excipient molecule.

[0073]

[0074] In formula (1), represents the FH parameter, represents the molar reference volume, R represents the ideal gas constant, T represents the thermodynamic temperature, Vseg , R and T are preset constants.

[0075] In formula (2), A represents the target drug molecule, B represents the candidate excipient molecule, and mix represents the mixed component of the drug molecule and the candidate excipient molecule. represents the volume fraction of the corresponding molecule in the solid dispersion, E is the total energy of the components in the corresponding simulation box, and V is the volume of the components in the corresponding simulation box. Accordingly, the parameter value of the first item in formula (2) is extracted based on the molecular simulation results of the third simulation box, the parameter value of the second item is extracted based on the molecular simulation results of the first simulation box, and the parameter value of the third item is extracted based on the molecular simulation results of the second simulation box.

[0076] In some specific embodiments, the atomic volatility is calculated based on the molecular simulation results of the third simulation box. Specifically, based on the molecular simulation results of the third simulation box, the atomic volatility is averaged by the time average results of the RMSF (Root Mean Square Fluctation) average values ​​of all atoms of the target drug molecule. For ease of understanding, for example, the RMSF average value of all atoms based on the current simulation progress is calculated once every 1ns during the simulation process, and finally all the obtained RMSF average values ​​are averaged.

[0077] In summary, for the same target drug molecule, a variety of different candidate excipient molecules can be selected and combined one by one, and processed according to the above S110 to S140 respectively to obtain the calculation results of the preset parameters corresponding to each combination. In some embodiments, by comparing each group of calculation results with each other, a better candidate excipient can be screened out as the target excipient corresponding to the target drug molecule for forming a solid dispersion. In other embodiments, a screening threshold of a preset parameter can be set, and when the corresponding calculation result reaches the screening threshold, it indicates that the candidate excipient is the target excipient.

[0078] From this example, it can be seen that the excipient screening method for solid dispersions of the present application can obtain the calculation results of preset parameters based on molecular dynamics simulation, and then evaluate and screen the candidate excipients of the target drug molecule based on the intuitive calculation results, so as to quickly screen out the target excipient, and then conduct experimental tests based on the target excipient, which can greatly improve R&D efficiency and reduce R&D costs.

[0079] See also Figure 2 Another embodiment of the present application provides a method for screening excipients for solid dispersions, which comprises:

[0080] S210, obtaining molecular input information of target drug molecules.

[0081] The method of the present application can screen target excipients that are compatible with multiple target drug molecules at high throughput to form corresponding solid dispersions. Based on this, the molecular input information can be the SMILES (Simplified Molecular Input Linear System) of the target drug molecule for computer reading and differentiation.

[0082] When there are multiple target drug molecules, each target drug molecule performs the following steps respectively to obtain the corresponding target excipients for forming the corresponding solid dispersion.

[0083] S220, obtaining a corresponding protonated three-dimensional structure according to the molecular input information of the target drug molecule.

[0084] In some embodiments, a corresponding initial three-dimensional conformation is generated based on the SMILES formula of the target drug molecule; and the atoms in the initial three-dimensional conformation are protonated to generate a corresponding protonated three-dimensional structure.

[0085] Specifically, the SMILES formula of the target drug molecule can be read through relevant software such as RDKit, openbabel, Avogadro, etc., and then the corresponding initial three-dimensional conformation can be generated. Then, based on the initial three-dimensional conformation, relevant software such as xtb, Schrodinger, Marvin, etc. are used to calculate the candidate atoms that can be protonated in the target drug molecule in a neutral pH environment (pH value is generally 6.5-7.5), and then protons are added within the preset range of a single candidate atom to generate the corresponding candidate protonated structures; finally, the candidate protonated structures are screened to obtain the protonated three-dimensional structure.

[0086] For ease of understanding, specifically, among the non-hydrogen atoms of the target drug molecule, use relevant software to find all candidate atoms to be protonated. By traversing, protons are added around each candidate atom, and the protons can be hydrogen atoms. Accordingly, according to the number of candidate atoms, for example 10, 10 corresponding candidate protonated structures can be generated. Among them, the preset range where the proton is located can be a position with an equal distance to other atoms connected to the candidate atom. For example, when the candidate atom is a nitrogen atom, the nitrogen atom is connected to 3 carbon atoms respectively. By calculation, a position with an equal distance to the three carbon atoms can be found, which is the placement position of the proton.

[0087] Further, in a specific embodiment, each candidate protonation structure is optimized to obtain a corresponding optimized candidate protonation structure; the optimized candidate protonation structure with the smallest molecular energy value is selected as the protonated three-dimensional structure of the target drug molecule. In other words, the structure can be optimized for each candidate protonation structure according to relevant software such as ORCA, Gaussian, xtb, etc., to obtain the corresponding optimized candidate protonation structure; then the molecular energy values ​​of each optimized candidate protonation structure are compared, and the optimized candidate protonation structure with the smallest value is selected as the protonated three-dimensional structure.

[0088] Furthermore, based on the protonated three-dimensional structure corresponding to the target drug molecule, the corresponding molecular force field file and atomic charge information are generated, which will not be elaborated here.

[0089] S230, determining a first molecular quantity of the target drug molecule and a second molecular quantity of the candidate excipient respectively according to a preset drug loading amount and a preset total relative molecular mass of the solid dispersion.

[0090] Among them, for the same target drug molecule, multiple candidate excipient molecules can be pre-stored for selection and combination to form a candidate combination of solid dispersions. For example, in a candidate combination, it is composed of 1 target drug molecule and 1 candidate excipient molecule. When the drug loading and the total relative molecular mass are both preset and fixed, since the relative molecular masses of the target drug molecule and the candidate excipient molecule are also known, the first molecular quantity of the target drug molecule and the second molecular quantity of the candidate excipient molecule can be determined respectively.

[0091] In some embodiments, the preset drug loading can be 10% to 60%. The preset total relative molecular mass can be 200,000 to 300,000. Assuming that the relative molecular mass of a target drug molecule is 177, the relative molecular mass of a candidate excipient molecule is 888, the preset drug loading is 60%, and the total relative molecular mass is preset to 250,000, the first number of molecules corresponding to the target drug molecule is (60% × 250,000) / 177 = 847, and the second number of molecules corresponding to the candidate excipient molecule is ((1-60%) × 250,000) / 888 = 113.

[0092] S240, constructing a plurality of simulation boxes for molecular dynamics simulation according to the target drug molecule information and the candidate excipient information.

[0093] It can be understood that the target drug molecule information includes the protonated three-dimensional structure and the corresponding first molecular quantity. The candidate excipient information includes the excipient three-dimensional structure and the corresponding second molecular quantity. Among them, the first molecular quantity and the second molecular quantity can be obtained according to step S230. The protonated three-dimensional structure can be obtained by step S220. The excipient three-dimensional structure can be pre-generated and stored in the excipient database for rapid extraction. In other words, an excipient database can be pre-constructed to store all kinds of excipient information, and the excipient information of the excipient database includes the excipient three-dimensional structure corresponding to each candidate excipient, the corresponding molecular force field parameters and the corresponding relative molecular mass.

[0094] Further, the simulation box includes a first simulation box, a second simulation box and a third simulation box, and the details can be referred to the introduction of step S130, which will not be repeated here. Preferably, in some embodiments, the simulation box also includes a fourth simulation box; wherein the fourth simulation box includes a protonated three-dimensional structure of a first molecular quantity, a three-dimensional structure of an excipient of a second molecular quantity, and water molecules with a mass proportion of 1%. It should be noted that the mass proportion refers to the mass proportion relative to the total mass of the target drug molecule and the candidate excipient.

[0095] S250, performing molecular dynamics simulation motion on each simulation box according to the simulation parameters to obtain corresponding molecular simulation results.

[0096] In this step, the first simulation box, the second simulation box, the third simulation box, and the fourth simulation box each independently carry out molecular dynamics simulation motions, for example, based on all the same simulation parameters.

[0097] Specifically, in some embodiments, the molecules in each simulation box are allowed to reach a state of motion equilibrium according to a preset temperature and a preset time; each simulation box is annealed according to preset conditions to obtain a corresponding molecular simulation result. That is, after each simulation box initially reaches a state of motion equilibrium, annealing simulation is performed to ensure that all target drug molecules are evenly dispersed in the candidate excipient molecules.

[0098] In some embodiments, the preset temperature is 600K~800K, and the preset time is 4ns~15ns. For example, when the preset temperature is 800K and the preset time is 4ns, each simulation box is subjected to a high temperature equilibrium simulation for a period of 4ns, and after the state of each molecule in each simulation box tends to be stationary, that is, the motion equilibrium state is reached, and then at least one annealing treatment is performed based on the state obtained by equilibrium at 800K. That is, each simulation box performs molecular simulation motion under the preset conditions of annealing treatment to obtain the final molecular simulation result.

[0099] In some embodiments, each simulation box is subjected to two annealing treatments. The preset conditions for each annealing treatment may be different. For example, the first annealing treatment may reduce the annealing temperature of the simulation box from 800K to 300K. For example, the second annealing treatment may first increase the temperature of the simulation box from 300K to 400K within 5ns, and then return it to 300K between 5ns and 15ns. It is understood that the temperature of each annealing treatment can be customized, and this is only an example.

[0100] Furthermore, when the annealing treatment is performed multiple times, the simulation duration and simulation step size of each annealing treatment may be the same or different. For example, the simulation duration of each annealing treatment is 15 ns, the simulation step size is 1 fs, and the pressure in the simulation may be the standard atmospheric pressure of 1 bar. Figure 3 The solid dispersion structure in the third simulation box shown is annealed to fully mix the target drug molecules and the candidate excipient molecules to form a uniformly dispersed solid dispersion structure. It can be understood that the above parameters can be customized and are only used as examples and are not limited.

[0101] Preferably, after the last annealing is completed, a molecular dynamics simulation can be performed for a period of time, for example, 25 ns, at a temperature, for example, 300 K, after the last annealing is completed, so that the motion state in each simulation box tends to be static, that is, a motion equilibrium state is reached, and a more stable molecular simulation result is obtained for subsequent data analysis.

[0102] S260, according to the molecular simulation results corresponding to different simulation boxes, respectively obtain the calculation results of each preset parameter, so as to screen out the target excipient from the candidate excipients according to each calculation result.

[0103] The preset parameters include at least one of the FH parameters and the atomic volatility. The FH parameters are calculated based on the molecular simulation results of the first simulation box, the second simulation box, and the third simulation box; the atomic volatility is calculated based on the molecular simulation results of the third simulation box. The specific calculation method refers to the above step S140 and will not be repeated here.

[0104] Furthermore, in some embodiments, the preset parameters also include the average number of hydrogen bonds and / or the solvent accessible surface area. When the average number of hydrogen bonds is greater, it means that it is more conducive to the formation of the stability of the solid dispersion; conversely, when the average number of hydrogen bonds is smaller, it means that it is not conducive to the formation of the stability of the solid dispersion. When the value of the solvent accessible surface area is larger, it means that the release performance of the target drug molecule in the system is better; conversely, when the value of the solvent accessible surface area is smaller, it means that the release performance of the target drug molecule in the system is worse.

[0105] Furthermore, the average number of hydrogen bonds can be obtained based on the molecular simulation results of the third simulation box, that is, the number of hydrogen bonds formed between the target drug molecule and the candidate excipient molecule is extracted from the molecular simulation results and divided by the first molecule of the target drug molecule.

[0106] Furthermore, the solvent-accessibility surface area (SASA) can be calculated according to the following formula (3). The normalized calculation of the SASA value is as follows:

[0107]

[0108] in, is the SASA value of the target drug molecule in the third simulation box, is the SASA value of a single drug molecule in the first simulation box, is the number of first molecules corresponding to the target drug molecules in the third simulation box. The normalized SASA value is calculated by the above formula (3) to represent the solvent accessible surface area corresponding to this system combination.

[0109] In some embodiments, when the plurality of simulation boxes also include a fourth simulation box, the preset parameters also include an enthalpy change caused by adding 1% by mass of water molecules into the fourth simulation box; the enthalpy change is calculated based on the molecular simulation results of the third simulation box and the fourth simulation box.

[0110] Among them, the enthalpy change caused by adding 1% by mass of water is used to illustrate the hygroscopicity of the drug preparation; the lower the enthalpy change value, the easier it is to absorb water and become damp; the higher the enthalpy change value, the better the long-term stability of the drug preparation.

[0111] Furthermore, the enthalpy change caused by adding 1% water by mass is , is the difference between the total enthalpy of the solid dispersion system and the total enthalpy of the water system with 1% of the total mass of the solid dispersion added. It can be understood that the total enthalpy of the former is taken from the molecular simulation results of the fourth simulation box, and the total enthalpy of the latter is taken from the molecular simulation results of the third simulation box.

[0112] In summary, based on the molecular simulation results obtained from different simulation boxes, the required parameters can be extracted respectively to calculate the calculation results corresponding to each preset parameter, so as to obtain multi-dimensional evaluation data for evaluating the various properties of the current solid dispersion. At the same time, the advantages and disadvantages of solid dispersions composed of different candidate excipient molecules can be compared with each other, and then better target excipients can be screened out.

[0113] In order to further improve the reliability of the target excipient screening results, multiple parallel simulations can be performed for the same solid dispersion. For example, the above steps S240 to S260 are repeated 3 times to obtain the corresponding evaluation results each time. Specifically, different random seeds can be used to construct a simulation box each time S240 is executed, and then S250 and S260 are continued to be executed with the currently constructed simulation box to screen out the corresponding target excipient. When the screening results are the same or mostly the same each time, it means that the excipient screening method of the present application has a high degree of credibility.

[0114] The auxiliary material screening method of the present application is described below in conjunction with specific examples.

[0115] Taking the target drug molecule neratinib as an example, the candidate excipient molecules are shown in Table 1 below, which respectively form corresponding multiple candidate combinations of solid dispersions. Among them, the preset drug loading is 40%, and the preset total relative molecular mass is 250,000. The calculation results of the five preset parameters are calculated according to the above method.

[0116]

[0117] Note: as-h is high-substituted hydroxypropyl methylcellulose acetate succinate, as-l is low-substituted hydroxypropyl methylcellulose acetate succinate, as-m is medium-substituted hydroxypropyl methylcellulose acetate succinate, HPMC E is hydroxypropyl methylcellulose E, PEG 1000 is PEG with an average molecular weight of 1000, and PVP 40 is PVP with an average molecular weight of 40,000.

[0118] Among them, when the FH parameter is a negative number, it means that the target drug molecule has good compatibility with the corresponding candidate excipient molecule. Both the atomic volatility and the average number of hydrogen bonds can help explain the stability of the solid dispersion formed by the target drug molecule and the candidate excipient molecule. The lower the atomic volatility, the better the stability of the solid dispersion. The more average hydrogen bonds, the more conducive to the stability of the solid dispersion. The SASA value can help predict the release ability of the target drug molecule in the solid dispersion. The larger the SASA value, the better the release performance of the drug. The higher the value, the better the long-term stability of the preparation.

[0119] From the data in Table 1 above, we can see that the FH parameter of the candidate excipient E100 is negative and the atomic volatility is relatively low. These two excellent calculation results show that E100 can be recommended as the target excipient for neratinib. Similarly, the candidate excipients PEG1000, PVP 40, and Soluplus can all be recommended as the target excipients for the target drug molecule. Based on the selected target excipients, further experiments can be conducted to verify the results, thereby reducing the amount of experiments, reducing R&D costs, and improving R&D efficiency.

[0120] Corresponding to the aforementioned application function realization method embodiment, the present application also provides a molecular property prediction device for lipid molecules and corresponding embodiments.

[0121] Figure 4 It is a schematic structural diagram of an auxiliary material screening device for solid dispersions shown in the present application.

[0122] See also Figure 4 The auxiliary material screening device for solid dispersion shown in the present application includes an information acquisition module 410, a data generation module 420, a simulation motion module 430 and a parameter calculation module 440. Among them:

[0123] The information acquisition module 410 is used to acquire target drug molecule information and candidate excipient information; wherein the target drug molecule information includes the corresponding first molecule quantity and protonated three-dimensional structure, and the candidate excipient information includes the corresponding second molecule quantity and excipient three-dimensional structure.

[0124] The data generation module 420 is used to construct multiple simulation boxes for molecular dynamics simulation according to the target drug molecule information and candidate excipient information.

[0125] The simulation motion module 430 is used to perform molecular dynamics simulation motion on each simulation box to obtain corresponding molecular simulation results.

[0126] The parameter calculation module 440 is used to obtain calculation results of preset parameters according to the molecular simulation results, so as to screen out target excipients from candidate excipients according to the calculation results.

[0127] See also Figure 5 In a specific embodiment, the information acquisition module 410 includes a structure acquisition module 411 and a quantity acquisition module 412. The structure acquisition module 411 is used to obtain the corresponding protonated three-dimensional structure according to the input information of the target drug molecule. The structure acquisition module 411 is also used to obtain the three-dimensional structure of the candidate excipients in the excipient database. The quantity acquisition module 412 is used to determine the first molecular quantity of the target drug molecule and the second molecular quantity of the candidate excipient according to the preset drug loading and the preset total relative molecular mass.

[0128] The data generation module 420 includes a first generation module 421, a second generation module 422, a third generation module 423, and a fourth generation module 424. The first generation module 421 is used to construct a first simulation box; the second generation module 422 is used to construct a second simulation box; the third generation module 423 is used to construct a third simulation box; and the fourth generation module 4214 is used to construct a fourth simulation box.

[0129] The parameter calculation module 430 is used to calculate the FH parameters according to the molecular simulation results of the first simulation box, the second simulation box and the third simulation box; to calculate the atomic volatility according to the molecular simulation results of the third simulation box; to obtain the average number of hydrogen bonds and the solvent accessible surface area according to the molecular simulation results of the third simulation box; and to calculate the enthalpy change caused by the addition of 1% of water molecules by mass according to the molecular simulation results of the third simulation box and the fourth simulation box.

[0130] The simulation motion module 440 is used to make the molecules in each simulation box reach a motion equilibrium state according to a preset temperature and a preset time; according to preset conditions, the simulation box is annealed to obtain corresponding molecular simulation results.

[0131] In summary, the excipient screening device for solid dispersions of the present application reduces the tedious simulation preparation process and post-processing analysis and data collation in an automated manner, and selects high-quality target excipients for solid dispersions through designed preset parameters.

[0132] Regarding the device in the above embodiment, the specific manner in which each module performs operations has been described in detail in the embodiment of the method, and will not be elaborated again here.

[0133] Figure 6 It is a schematic diagram of the structure of the electronic device shown in this application.

[0134] See also Figure 6 , the electronic device 1000 includes a memory 1010 and a processor 1020 .

[0135] The processor 1020 may be a central processing unit (CPU), or other general-purpose processors, digital signal processors (DSP), application-specific integrated circuits (ASIC), field-programmable gate arrays (FPGA) or other programmable logic devices, discrete gate or transistor logic devices, discrete hardware components, etc. A general-purpose processor may be a microprocessor or the processor may be any conventional processor, etc.

[0136] The memory 1010 may include various types of storage units, such as system memory, read-only memory (ROM), and permanent storage devices. Among them, ROM can store static data or instructions required by the processor 1020 or other modules of the computer. The permanent storage device may be a readable and writable storage device. The permanent storage device may be a non-volatile storage device that does not lose the stored instructions and data even after the computer is powered off. In some embodiments, the permanent storage device uses a large-capacity storage device (such as a magnetic or optical disk, flash memory) as a permanent storage device. In some other embodiments, the permanent storage device may be a removable storage device (such as a floppy disk, optical drive). The system memory may be a readable and writable storage device or a volatile readable and writable storage device, such as a dynamic random access memory. The system memory may store some or all instructions and data required by the processor at run time. In addition, the memory 1010 may include any combination of computer-readable storage media, including various types of semiconductor storage chips (such as DRAM, SRAM, SDRAM, flash memory, programmable read-only memory), and disks and / or optical disks may also be used. In some embodiments, the memory 1010 may include a readable and / or writable removable storage device, such as a laser disc (CD), a read-only digital versatile disc (such as a DVD-ROM, a double-layer DVD-ROM), a read-only Blu-ray disc, an ultra-density optical disc, a flash memory card (such as an SD card, a mini SD card, a Micro-SD card, etc.), a magnetic floppy disk, etc. The computer-readable storage medium does not include carrier waves and transient electronic signals transmitted wirelessly or wired.

[0137] The memory 1010 stores executable codes, and when the executable codes are processed by the processor 1020 , the processor 1020 can execute part or all of the methods described above.

[0138] In addition, the method according to the present application may also be implemented as a computer program or a computer program product, which includes computer program code instructions for executing some or all of the steps in the above method of the present application.

[0139] Alternatively, the present application can also be implemented as a computer-readable storage medium (or non-transitory machine-readable storage medium or machine-readable storage medium) on which executable code (or computer program or computer instruction code) is stored. When the executable code (or computer program or computer instruction code) is executed by a processor of an electronic device (or server, etc.), the processor executes part or all of the steps of the above-mentioned method according to the present application.

[0140] The embodiments of the present application have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and changes will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The selection of terms used herein is intended to best explain the principles of the embodiments, practical applications, or improvements to the technology in the market, or to enable other persons of ordinary skill in the art to understand the embodiments disclosed herein.

Claims

1. A method for screening excipients for solid dispersions, characterized in that: include: Determining a first molecular quantity of the target drug molecule and a second molecular quantity of the candidate excipient respectively according to a preset drug loading amount and a preset total relative molecular mass of the solid dispersion; Obtaining target drug molecule information and candidate excipient information; wherein the target drug molecule information includes the corresponding first molecule quantity and protonated three-dimensional structure, and the candidate excipient information includes the corresponding second molecule quantity and excipient three-dimensional structure; According to the target drug molecule information and the candidate excipient information, a plurality of simulation boxes for molecular dynamics simulation are constructed; the simulation boxes include a first simulation box, a second simulation box and a third simulation box; wherein: the first simulation box includes the protonated three-dimensional structure of the first number of molecules; the second simulation box includes the excipient three-dimensional structure of the second number of molecules; the third simulation box includes the protonated three-dimensional structure of the first number of molecules and the excipient three-dimensional structure of the second number of molecules; Performing molecular dynamics simulation on each simulation box to obtain corresponding molecular simulation results; wherein, according to a preset temperature and a preset time, the molecules in each simulation box are allowed to reach a motion equilibrium state; according to preset conditions, each simulation box is annealed to obtain corresponding molecular simulation results; According to the molecular simulation results, calculation results of preset parameters are obtained to screen out target excipients from candidate excipients according to each of the calculation results; wherein the preset parameters include at least one of FH parameters and atomic volatility; wherein the FH parameters are calculated based on the molecular simulation results of the first simulation box, the second simulation box and the third simulation box; and the atomic volatility is calculated based on the molecular simulation results of the third simulation box.

2. The auxiliary material screening method according to claim 1, characterized in that: The method further comprises: According to the SMILES formula of the target drug molecule, a corresponding initial three-dimensional conformation is generated; The atoms in the initial three-dimensional conformation are protonated to generate a corresponding protonated three-dimensional structure.

3. The auxiliary material screening method according to claim 2, characterized in that: The preset drug loading is 10% to 60%; The preset total relative molecular mass is 200,000 to 300,000.

4. The auxiliary material screening method according to claim 3, characterized in that: The preset parameters also include the average number of hydrogen bonds and / or the solvent accessible surface area; wherein: The average number of hydrogen bonds is obtained according to the molecular simulation result of the third simulation box; The solvent accessible surface area is obtained according to the molecular simulation results of the first simulation box and the third simulation box.

5. The auxiliary material screening method according to claim 2, characterized in that: The simulation box further includes a fourth simulation box; wherein the fourth simulation box includes the protonated three-dimensional structure of the first molecular quantity, the auxiliary material three-dimensional structure of the second molecular quantity, and water molecules accounting for 1% by mass; The preset parameters include an enthalpy change caused by adding water molecules with a mass percentage of 1% into the fourth simulation box; the enthalpy change is calculated based on the molecular simulation results of the third simulation box and the fourth simulation box.

6. The auxiliary material screening method according to claim 1, characterized in that: The preset temperature is 600K~800K, and the preset time is 4ns~15ns; Each of the simulation boxes was subjected to two annealing treatments.

7. A device for screening auxiliary materials for solid dispersions, characterized in that: include: An information acquisition module, for determining the first molecular quantity of the target drug molecule and the second molecular quantity of the candidate excipient according to the preset drug loading amount and the preset total relative molecular mass of the solid dispersion, and acquiring the target drug molecule information and the candidate excipient information; wherein the target drug molecule information includes the corresponding first molecular quantity and the protonated three-dimensional structure, and the candidate excipient information includes the corresponding second molecular quantity and the excipient three-dimensional structure; A data generation module, for constructing a plurality of simulation boxes for molecular dynamics simulation according to the target drug molecule information and the candidate excipient information; the simulation boxes include a first simulation box, a second simulation box and a third simulation box; wherein: the first simulation box includes the protonated three-dimensional structure of the first number of molecules; the second simulation box includes the three-dimensional structure of the excipient of the second number of molecules; the third simulation box includes the protonated three-dimensional structure of the first number of molecules and the three-dimensional structure of the excipient of the second number of molecules; A simulation motion module is used to perform molecular dynamics simulation motion on each of the simulation boxes to obtain corresponding molecular simulation results; wherein, according to a preset temperature and a preset time, the molecules in each of the simulation boxes are made to reach a motion equilibrium state; according to preset conditions, each of the simulation boxes is annealed to obtain corresponding molecular simulation results; A parameter calculation module is used to obtain calculation results of preset parameters according to the molecular simulation results, so as to screen out target excipients from candidate excipients according to each of the calculation results; wherein the preset parameters include at least one of FH parameters and atomic volatility; wherein the FH parameters are calculated based on the molecular simulation results of the first simulation box, the second simulation box and the third simulation box; and the atomic volatility is calculated based on the molecular simulation results of the third simulation box.

8. A computer-readable storage medium having executable codes stored thereon, which, when executed by a processor of an electronic device, causes the processor to execute the method according to any one of claims 1 to 6.

9. A computer program product, comprising a computer program, characterized in that The computer program is used to execute computer program code instructions corresponding to the method according to any one of claims 1 to 6.

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