Study On Debranched Starches Used As Drug Sustained-Release Carrier

Starch and its derivatives are one of the biodegradable natural polymer materials, which possess good biocompatibility. They are a good drug carrier for manipulating the drug dissolution and diffusion through controlling their degradation rate and structure in vivo. Starch contains multiple hydroxyl groups and can be designed functional material after modifications. Such modifications can minimize the stimulating effect of drugs on the gastrointestinal and other digestive organs, and achieve a sustained release of pharmaceutical ingredient in the body. Therefore, developing starch-based material as a sustained-release tablet carrier has great practical significance.This paper used starch, a natural macromolecule, as raw material to perform structural modification through enzymatic method with the aim of altering its digestive property. Starch molecular chain structure and aggregation morphology were studied. Starch based tablets were prepared through direct compression technique and the digestibility of starch at the different parts of human digestive system were regulated. The objective was to increase the stability and effective utilization of active drug, thus to achieve sustained release of active pharmaceutical ingredient. The project established the relationship between the starch molecular structure and aggregation morphology and the drug release profile, and explored releasing mechanism of active pharmaceutical ingredient through the animal experiments. The main contents included the followings:Firstly, The effects of amylose content on the molecular structure of debranched starch carriers were investigated. The results showed that Pullulanase can cleave the α-1,6-glyosidic bonds in both amylose and amylopectin. Waxy maize starch has high amount of amylopectin, thus can produce more linear starch chains after debranching. The interaction between the starch granules was weakened, resulting in more dispersed molecules. The porous structure on the starch surface increased the interaction area with the hydrophilic media. The formation of gel on the starch surface increased the resistance to enzyme digestion. Rheology study showed that stronger frequency dependence was observed for debranched waxy maize starch samples. It is possible that more entanglement occurred in debranched waxy maize starch, enhancing the molecules interaction. GPC results further confirmed that low molecular weight fractions in debranched starch decreased with the increased content of linear starch chains.Secondly, Normal maize starch was used as starting material and was subjected to enzyme debranching with different enzyme amounts and reaction times. The effects of debranching degree on the starch digestion and sustaining release property were studied. The results showed that debranching starch can generate a lot of linear starch chains or oligosaccharides with certain degree of polymerization. With a higher degree of debranching, the linear starch chains have more chances to interact with each other, associate and form double helices, resulting into reduced digestibility and a lower hydrolysis. The sustained release kinetics and sustained release mechanism were found different for the different debranching degrees of starch. The L-DBS based tablets showed that Higuchi equation, M-DBS and H-DBS were suitable for zero-order release and first order release kinetics, respectively. The release mechanism of starch-based tablets was synergies effects of diffusion and erosion.Thirdly, Swelling properties and gel formation were the main factors affecting the sustained release properties of starch-based tablets. The paper examined the molecular structure and drug release profile of debranched starch with prior swelling. The reducing sugar content and molar weight distribution results showed that more linear starch chains could be obtained, and both water binding capability and solubility increased after swelling starch at 80 ℃. Rheology of starch gel showed that more linear starch chains were beneficial for forming the stable starch gel network. The drug sustaining release curves confirmed a better drug release property of debranched starch at 80 ℃.Fourthly, The drug release property of three propranolol hydrochloride tablets containing debranched starch with different linear chains contents was determined using fluorescence spectrometry through an in vivo animal study. The results showed that the peak concentration Cmax, peak time Tmax and half-life T1/ 2 are 114.21 ng/m L, 1.00 h and 1.43 h, respectively for commercial fast-release tablets. For debranched waxy maize starch, debranched normal maize starch, and debranched high amylose maize starch based tablets, the peak concentrations Cmax were 25.37 ng/m L, 25.27 ng/m L and 22.98 ng/m L, respectively; the peak time Tmax was 3.33 h, 3.67 h and 3 h, respectively; and the half-life T1/ 2 was 5.07 h, 7.07 h and 5.33 h, respectively. Compared to the commercial tablets, the debranched starch based tablets had decreased peak concentration Cmax and increased peak time Tmax. It appears that debranched starch based tablets can extend the release of propranolol hydrochloride, stabilize the plasma concentration, impose the sustained release impact and decrease the effects of the plasma concentration changes on the physical treatments. Through correlation analysis, it was found the tablets in vitro drug dissolution and absorption in vivo experiments has good correlation, can be predicted by in vitro experiments ingredient absorption in the body.Finally, Two analytical instruments including SEM and XMT were used to study the inner structure of three starch based tablets. SEM results showed that the normal maize starch based tablets had clear cracks on the surface. The particles were not uniform and were tightly compacted with less flexibility, resulting in a weak porous structure with cracks. In contrast, the debranched starch based tablets did not have cracks. Small particles filled between the large starch particles, indicating a smooth surface and a tight association of molecules. The porosity and hardness of starch 1500 based tablets were apparently lower than the normal maize starch and debranched maize starch based tablets. XMT techniques could clearly show the internal density distribution and porosity of tablets. The XMT results showed that the internal structure of starch based tablets affect the drug diffusion and dissolution. Debranched maize starch based tablets had a lot of small molecule chains, which could form gel structure and inhibit the drug dissolution. Fewer pores were found in debranched maize starch based tablets, which inhibited the diffusion of drug into the media and reduced the rate of drug release.