Research On The Method Of Gel Formulation Design Based On Molecular Dynamics Simulation

Gels use polymer materials as drug carriers,and have the advantages of good biocompatibility,convenient use,and low irritation,which have a wide application in tissue engineering,sustained-release drug delivery systems and biosensors.It is one of the commonly used dosage forms of transdermal preparations.Based on many factors,the conventional gel prescription design process chooses different evaluation indexes and uses various experimental designs to carry out experiments to obtain the optimal prescription.Due to the limitation of research methods,this process often requires a large number of exploratory experiments,causing problems such as heavy workload,long cycle time and high cost of the prescription design process.Molecular dynamics simulation is a cost-effective research method derived from the rapid increase of computing power.In the field of prescription research,by studying the interaction between the drug and the carrier with simulation technology,the existence form and release process of the drug in the formulation can be presented at the micro and mesoscopic levels,and the influence of the factors can be explored to further guide the drug delivery system,which can reduce the blindness of routine experiments and save resources.Therefore,taking gels as the research object,this paper intended to use molecular dynamics simulation to investigate the compatibility of drugs and different matrices,conduct preliminary screening of matrix types,and then examined the formulation factors such as the degree of matrix polymerization,drug concentration,and additives to the gel.Through the screening and optimization of prescriptions,a research method of gel formulations based on computer simulation was constructed,which can provide a new method for the development of gels,and at the same time provide a reference for the development of other transdermal drug preparations based on polymer materials.This work is organized as follows:1.Study on compatibility of gel matrix and drugIn this section,commonly used gel matrices(carbopol,hydroxypropyl methylcellulose,carboxymethyl chitosan,etc.)and model drug molecules(capsaicin)were used as research carriers.The molecular dynamics simulation method was used to investigate the compatibility of different matrices and capsaicin.The solubility parameter and mixed energy parameter were used as evaluation indicators to optimize the matrix.Differential scanning calorimetry experiments and microscope experiments were then used to verify the simulation results.The results obtained were consistent with the simulation results,which proved that the solubility parameter and the mixed energy parameter as evaluation indexes are feasible to screen the gel matrix.Compared with conventional methods,molecular dynamics simulation technology is simple and easy to operate,with fast calculation and good repeatability,and can be used as a new method for gel matrix screening.2.Molecular dynamics simulation of the effects of different prescription factors on the quality of gelThis section introduced coarse-grained molecular dynamics simulation methods into the research of screening and optimization of gel formulations.Through computer simulation,a gel model and its evaluation parameter system are established to dynamically and deeply explain drugs and matrices from the mesoscopic level providing a theoretical basis for accelerating the development of gels.First,in this paper,Martini force field was used to coarsely granulate the selected matrix,model drug,solvent and other molecules,and compared with the results of the full-atom model.The bond distribution and solvation free energy results were consistent,which proved the accuracy of coarse-grained models.Then,the coarse-grained model drug,matrix,and solvent were jointly constructed into a gel model.Based on this,with capsaicin as the model drug,the gyration radius and root mean square deviation of the matrix chain,the root mean square displacement of the drug and its diffusion constant were used as indicators.Single factor test design methods were used to investigate the effects of prescription factors such as the degree of matrix polymerization,drug concentration,matrix concentration,and additives on the matrix structure and drug diffusion behavior to evaluate the quality of the gel and optimize its formulation.The results showed that all the factors examined had no significant effect on the matrix structure but had a certain effect on the distribution of the matrix and drug.The diffusion rate of capsaici1 was the best(0.46×10-7 cm2·s-1)when the matrix polymerization degree was 40,the drug concentration was 42.86%,the matrix concentration was 24.14%,and no 1,2-propylene glycol was added.In addition,using pogostone as a verification drug,the gel system containing pogostone and capsaicin was studied under the same conditions,and the diffusion rate of pogostone was 0.38x10-7 cm2·s-1,which was lower than that of capsaicin.The reason was that the root mean square deviation of the matrix chain in the pogostone system was smaller,and the position of the matrix chain changed slowly,resulting in a low drug diffusion rate.This result verified the accuracy of the constructed simulation method and evaluation parameters.3.Experimental study on the effect of different prescription factors on the quality of gelIn order to complement and verify the accuracy of the simulation parameters for the screening and optimization of prescriptions,and to further improve the establishment of a prescription research method system based on molecular dynamics simulations,this section took the in vitro release rate as an indicator and used the dialysis bag method for different drug concentrations and matrix concentration and additives(1,2-propylene glycol concentration)for drug diffusion effect experiments.The results showed that the trends of the experimental phenomena of these three factors were consistent with the simulation results,and thus the feasibility of molecular dynamics simulation to evaluate the factors of the gel formulation was preliminary verified.In summary,the prescription research method of gel based on molecular dynamics simulations constructed in this paper can dynamically explain the interaction between drugs and matrices from the mesoscopic level,and provide a theoretical basis for accelerating the development of gels.This method has the advantages of high efficiency,greenness and economy,and it can provide a new method for the development of gels and also provide a reference for the research of other transdermal drug formulations.