Preparation Of Oral Insulin Nanoparticles Based On Degradable Polymer

The incidence of diabetes in developing countries is increasing.And diabetes is also everywhere in our daily life.The treatment of diabetes can not be separated from insulin,which has a variety of ways of administration.Among them,insulin is mainly administered by injection,and other methods of administration play only a subsidiary role.However,injection administration is not only easy to cause discomfort,pain,trauma,incompatibility,local infection,etc.,but also the injection of exogenous insulin takes effect in peripheral tissues without metabolism in the liver.Oral administration of insulin improves patient compliance,comfort,and acceptability.In deeper levels,oral insulin is absorbed through the stomach into the intestine and then delivered via the portal venous circulation to the liver,where it directly inhibits hepatic glucose,the whole process simulates normal human sugar regulation.These advantages make oral administration stand out in various ways of administration.Insulin is usually delivered in the form of nanoparticles,however,the limitations include its instability in the acidic pH environment,susceptibility to digestive enzyme degradation,and low nanoparticle bioavailability due to poor diffusion across the mucus layer and inadequate permeation through the GI tract epithelium.In this paper,the surface of nanoparticles with oligo(polyethylene glycol)is constructed,which facilitates the passage of nanoparticles in the mucosal layer and improves the utilization rate of insulin.In this paper,biodegradable polylactide was selected as the main chain material,which was obtained by ring-opening polymerization.Branch chain of mOEG was obtained by 1,3-dipolar cycloaddition with no metal ion-catalyzed,and the aminated branch was prepared by thiol-ene click reaction which had the advantage of short reaction time and high efficiency.We used a simple configuration method,combined with no need to add an organic solvent,electrostatic bonding with insulin to form a polyelectrolyte complex in pure aqueous solution.Then,we obtained the P/mOEG/NH2-INS nanoparticles.Average diameter 67.6±4.1 nm of nanoparticles were obtained by adjusting the block ratio of the polymer and mixing insulin and polymer with different ratios.The polydispersity index was 0.18±0.03.And the particle size did not change significantly within 30 h.The entrapment efficiency was 94.3%,and the drug loading was 35.6%.Protein gel electrophoresis confirmed that insulin did not cause denaturation by this way of preparation.In vitro release studies demonstrated that the nanoparticles had a sustained release effect.In addition,in this paper,by changing the above-mentioned reaction material in the last step,mercaptopropionic acid was used for the optical click reaction to obtain a carrier polymer containing both polyethylene glycol side groups and carboxyl side groups.A chitosan having a cell permeability and capable of reversibly opening tight junction of the epithelial cell was introduced into the system as a positive charge carrier.The P/mOEG/COOH-CS-INS nanoparticles were obtained by electrostatic binding.Appropriate nanoparticles could be obtained by adjusting the block ratio of the polymer and mixing the polymer,chitosan and insulin in different proportions.The average particle size was 59.1±4.7 nm,PDI was 0.22±0.01,The stability of the particles was greatly increased compared to the previous system,and the particles were stable within 7 days.The entrapment efficiency was 92.1%and the drug loading was 18.7%.Protein gel electrophoresis verified that insulin did not cause denaturation by this way of preparation.In vitro release studies showed that nanoparticles had a certain pH sensitivity and could partially resist the low pH environment.