Basic Research On Maillard Reaction In Solid Preparations Based On Lysine-lactose Model

Objective: Maillard reaction is a complex chemical reaction between reducing excipients and amino-containing drugs in preparations,which can cause a series of quality problems in preparations and restrict the application of related excipients.Therefore,it is necessary to avoid or reduce the Maillard reaction by means of preparations.Lactose is a common excipient in preparations at present.In view of the advantages of lactose as an excipient and with the implementation of drug consistency evaluation in China,the use amount and attention of lactose in China have been continuously increased in recent years.However,lactose is a reducing sugar which undergoes Maillard reaction with amino-containing drugs,which not only affects the stability of drugs but also restricts the application of lactose in preparations.At present,the research on Maillard reaction in China and abroad is mainly focused on the food field,and the research on Maillard reaction in preparations is rare.The purpose of this study was to study the Maillard reaction in preparations by building a simple Maillard reaction model of drug-lactose solid preparations,to provide a possible scheme for reducing the Maillard reaction between drugs and lactose in preparations,to guide the selection of various process parameters in the preparation production process,and to make the preparations stable in the shelf-life by selecting appropriate parameter conditions or taking feasible evasive measures to control the reaction.Methods: Lysine(the most commonly used substance with high reactivity in Maillard reaction)-lactose(one of the most commonly used excipients)was selected as the model for the Maillard reaction system of a simple solid preparation.First,the evaluation method of the reaction degree of Maillard reaction system in the lysine-lactose model was established.By analyzing the reactants(high performance liquid chromatography)and products(spectroscopy)of the reaction system,the parameters for evaluating the degree of Maillard reaction in the reaction system were finally determined.Then the influence of the process parameters(dosage form,ratio of reactants,type of lactose,addition method of lactose,tablet preparation method,tablet pressure,tablet diameter,and other common excipients)in the preparation production process on the Maillard reaction is compared by the determined method for evaluating the reaction degree,so as to guide the selection of the process parameters in the preparation production process.Finally,in order to avoid Maillard reaction in preparations,porous starch(physical embedding method)and cyclodextrin(molecular embedding method)as excipients were used as examples to avoid Maillard reaction in preparations.Porous starch was synthesized by enzymatic hydrolysis,and lysine was loaded on the porous starch by adsorption method.The related research on Maillard reaction in porous starch avoidance preparations was conducted.The small molecules of lysine were embedded into the large molecules of cyclodextrin by spray drying,to investigate the Maillard reaction in cyclodextrin evading preparations,and the inclusion mechanism was discussed by molecular simulation.Results:(1)The evaluation method of Maillard reaction degree in lysine-lactose model was established.A method for determining the lysine content of reactant in the reaction system was established by high performance liquid chromatography(HPLC),and the established method was verified,and the method for analyzing the change of reactant content before and after the reaction was determined.Maillard reaction products are usually classified into colorless intermediates that strongly absorb near-ultraviolet light,colorless intermediates that emit fluorescence and melanosomes.The spectroscopic characteristics of Maillard reaction system show that the spectral characteristics of the system can reflect the formation of colorless intermediates(substances that strongly absorb near-ultraviolet light and emit fluorescence),and the analysis method of reaction products is determined.Through the analysis of the reactants and products of the reaction system,in view of the complexity of the products and the disunity of the trend,it was finally determined that the content change of the reactant(lysine)before and after the reaction was used as a parameter to characterize the reaction degree of the reaction system.(2)The effect of process parameters on Maillard reaction during the preparation production was evaluated.The results of the study on the effect of process parameters on Maillard reaction in the preparation process showed that the dosage form of the preparation,the proportion of reactants,the type of lactose,the addition of lactose,the preparation method of the tablet,the tablet pressure,the size of the tablet diameter and other common excipients(magnesium stearate and sodium bisulfite)would affect the degree of Maillard reaction in the preparation.By studying the degree of influence of these process parameters on Maillard reaction,we can guide the selection of process parameters in the preparation production to a certain extent.(3)The inhibition effect of porous starch(physical embedding method)on Maillard reaction was studied.The porous starch was successfully synthesized by enzymatic hydrolysis and lysine was successfully adsorbed into the porous structure of the porous starch.The results showed that loading lysine into the porous structure of the porous starch could protect lysine to a certain extent and inhibit the Maillard reaction of lysine and lactose.(4)The inhibitory effect of cyclodextrin(molecular embedding method)on Maillard reaction was studied.Lysine-cyclodextrin inclusion complex was synthesized by spray drying method.The molecular simulation results showed that the inclusion mechanism might be the combination of hydrogen bond,electrostatic attraction and Van der Waals force.The results showed that the inclusion of lysine in cyclodextrin could inhibit the Maillard reaction of lysine.The inclusion of lysine in different kinds of cyclodextrin had different effects on the inhibition of Maillard reaction.The inclusion of lysine in α-CD and HP-β-CD reduced the Maillard reaction to a greater extent,which might be due to the more stable inclusion compound formed by α-CD and HP-β-CD with lysine,which was not conducive to the occurrence of Maillard reaction.Inclusion of lysine by cyclodextrin to avoid Maillard reaction is not that the more the amount of cyclodextrin is,the better.This may be related to the structural stability of the inclusion compound formed by cyclodextrin and lysineConclusion:The Maillard reaction in a drug-lactose solid preparation was studied by constructing a simple Maillard reaction model.Studies have shown that a variety of process parameters in the preparation production process will affect the Maillard reaction.By selecting the appropriate parameters and conditions,the reaction may be controlled to maintain the stability of the preparation within the shelf life.The embedding of drugs with excipients porous starch(physical embedding method)and cyclodextrin(molecular embedding method)could inhibit the occurrence of Maillard reaction to a certain extent,and its mechanism was mainly to reduce the contact area between the drugs and lactose to protect the drugs,thus providing a reference scheme for the avoidance of Maillard reaction in preparations.