Oral Insulin Study Of Self-micro-emulsifying Drug Delivery Systems

Multiple parenteral injections of Insulin (INS) are currently the standard treatment for insulin-dependent diabetic patients. Although it has specific clinical efficacy and rapid action, poor control of blood glucose level and poor patient compliance are associated with this method. Better ways of insulin administration are being sought, such as oral, nasal, or inhaled routes. There are many ongoing investigations to improve the oral bioavailability of the peptide, including some applications of novel delivery systems, such as nanoparticle (nanocapsule), microemulsion , colon targeted drug delivery systems (CDDS). Despite its imperfect results, the pharmacists still pa}' more and more interests in oral insulin delivery systems.The present dissertation aims to design a delivery system of INS to get across intestinal barrier, according to the characteristics of human gastrointestinal tract and the structure of INS. Using self-microemulsifying drug delivery system (SMEDDS), intermix INS aqueous solution , surfactant, co-surfactant, oil and hydrophihc bio-adhesive excipients to get a homogeneous mixture. A kind of white self-microemulsifying solid powder was obtained after freeze-dried. As soon as the powder touches the liquid (such as intestine liquid), it will become microemulsion which particle size is below 1 OOrrm.The type of this microemulsion is similar to oil in water (o/w) or bi-continuous (B.C.) , it belongs to Winsor I type. In such a system, INS hydrophobic chains are surrounded by oil phase, while hydrophihc chains extend into aqueous phase, result in a structure like micelles. Owing to this "micell structure", its capabilities of hydrophilic and lipophilic are both enhanced, so it can be absorbed into circulation through the cell pathway or lymphatic Payer's patches in small intestine mucosa, and decrease the blood glucose level.Two determined methods of blood glucose have been compared, i.e. Glucose Oxidase method (GOD) and o-Toluidine method (O-T). Both of them are sensitive, good linear and have the same result. But the latter has a little higher value. O-T method carries out simply, no need for composition separation, but will cause hemolysis and make the date lost. In addition, the reagent in O-T method are more toxic and irritative, so GOD method adopted in this paper.The stability of INS in digestive secretion was investigated. The results show that the degradation rate in gastric solution was so fast that any pharmaceuticalmodification and adding enzyme inhibitors could not protect it. The degradation rate of INS in intestinal solution is lower than in gastric solution, and the microemulsifying and chitosan could inhibit the degradation.The absorption site of INS in intestinal tract was studied, and found that INS solution could be minim absorbed in large intestine, but this will lead into blood glucose drop clearly. The absorption and efficacy have no difference between water solution and microemulsion in large intestine. In small intestine, INS solution has no absorption and couldn't make blood glucose decline, while INS microemulsion could be absorbed through the mucosa of small intestine and caused obvious drop of blood glucose. Caco-2 cell model experiments indicates that the excipients using in SMEDDS has no toxicity to cell membrane. INS couldn't get through the membrane by passive diffusion.There is no obvious improvement of the pharmacological bioavailability of INS by adding the surfactant and enzyme inhibitor into the intestinal circulation solution, both in large intestine and small intestine. Surfactant can make the membrane permeation changed, but couldn't increase the passive diffusion of INS. With the formation of microemulsion, interfacial tension of drug solution is reduced. And the adjuvant of chitosan can increase microemulsion Zeta-potential, which make the SMEDDS more stable, and the positive charged microemulsion is readily to spread on intestinal mucosa, that is beneficial to drug absorption.The relative pharmacological bioavailability of insulin in rats through duodenum was...