Preparation Of Debranched Starch Used As Sustained-release Gel-forming Excipients And Evaluation Of Its Drug Release Behavior

Sustained-release tablets can extend drug release and decrease the frequency of administration resulting in a stable drug plasma concentration instead of obvious fluctuation which is not favored in treating chronic diseases.Starch and its derivatives are cheap,safe,biocompatible and biodegradable.They have been widely used in tablets as disintegrants,fillers and binders.However,native starch can not be used as excipients in sustained-release tablets due to its low low compactibility and elastic compression behaviors.In this work,starch was enzymatically modified by pullulanase which can selectively hydrolyze?-1,6glycosidic bonds,leading to the formation of linear short amylose with low molecular weights.The aim of this work was to prepare and evaluate debranched starch?DBS?used in sustained-release tablets with perfect digestibility and hydrogel-forming ability.The optimized DBS sample performed most similarly to hydroxypropyl methylcellulose?HPMC?was obtained by investigating the correlation between DBS components contents and hydrogel properties,digestibility,as well as sustained-release properties.The main research contents are as follows:?1?Sustained-release properties of DBS-based tablets from different botanical sources.The results revealed that DBSs from maize starch?MS?,wheat starch?WS?,potato starch?PoS?and pea starch?PeS?were all V type starches with low crystallinity.They were able to form hydrogels and resist the hydrolysis of amylase.The in vitro drug release properties of these DBS-based tablets were similar and can successfully control drug release over 12 h.The n values of DBMS,DBWS,DBPoS,DBPeS by fitting Peppas equation were0.5272,0.5609,0.4697,0.5289,respectively,indicating the drug release profiles were case II anomalous transport and the drug release was controlled by the combination of Fick diffusion and matrix erosion.?2?Drug release behaviours of DBS-based tablets.Hydrolysis conditions including hydrolysis time and enzyme dosage can affect the physicochemical properties of DBS and drug release behaviours of its tablets.The results indicated partially debranched starch hydrolyzed for 4 h with 30 U/g pullulanase possessed the best sustained-release property,and its in vitro drug release profile was most similar to that of HPMC-based tablets with a similar factor?f₂?of 60.75.DBS-based tablet with a lower debranching degree tended to form soft hydrogel which was easy to be eroded by amylase,while more cracks tended to form on the surface of DBS-based tablet with a higher debranching degree.The drug release profile from DBS-based tablets with a medium debranching degree was a zero-order release,and the n value was 0.5354 indicating the drug release was case II anomalous transport controlled by the combination of Fick diffusion and matrix erosion.?3?Resistance to amylase of DBS.Starch molecules in DBS tend to aggragate and form gel network in medium which was resistant to the hydrolysis of amylase and decrease the content of rapidly digestible starch?RDS?.This property was essential for the DBS tablets to resist the erosion of medium and control drug release.When the debranching time increased from 0 h to 4 h,the content of RDS of debranched native starch?DBNS?,debranched high amylose starch?DBHAS?and debranched waxy starch?DBWS?significantly decreased,and the resistant ability to amylase was strengthened.When the debranching time extended 4 h,the digestibility of DBS was independent with debranching time.The slowly digestible starch?SDS?content of DBHAS and resistant starch?RS?content of DBWS were not significantly influenced by debranching time.Debranching modification can endow starch with the ability to resist the hydrolysis of amylase.?4?Hydrogel properties of DBS.The results revealed that amylopectin molecules possess poor mobility and can not entangled duo to their high molecular weight.Debranching modification can increase the molecule mobility and entanglement of starch.The strength of DBS gels was obviously changed when the debranching time increased from 0 h to 4 h.When the debranching time was longer than 4 h,this influence became weaker.The strength of DBNS gels were highest followed by DBHAS and DBWS gels.Debranching modification can strengthen the DBNS and DBWS gels,while DBHAS gels showed an opposite trend.The mobility of mobile water in DBNS and DBWS gels was decreased,while that in DBHAS gels was increased after debranching modification.And the mobility and content of free water in DBHAS gels was decreased.?5?Controllability and in vitro-in vivo correlation?IVIVC?of DBS-based tablets.The drug release can be accelerated by reducing compression force,increasing drug loading and adding magnesium stearate.DBS was a good candidate to prepare sustained-release tablet with high drug loading.The results of pharmacokinetics in New Zealand white rabbit revealed that propranolol hydrochloride?PH?in immediate-release commercial products?IR?can be rapidly absorbed with a peak plasma concentration(C_max)of 118.14 ug/L and time of its occurrence(T_max)was 1 h.Compared to IR tablets,HPMC-based and DBS-based tablets can reduce C_max and prolong T_max with values of 59.38 ug/L,36.89 ug/L and 4.89 h,4.11 h,respectively.The biological half-life(t_1/2)of IR,HPMC and DBS tablets was 1.99 h,5.90 h and 3.94 h,respectively.The IVIVC of DBS tablet with a correlation coefficient?R²?of0.9163 indicated that there was a good correlation between in vitro drug release and in vivo drug absorbed.DBS can form hydrogel and resist the erosion of amylase.It possessed good compactibility and its tablets can achieve a zero-order drug release.The drug release from DBS-based tablets was case II anomalous transport controlled by the combination of Fick diffusion and matrix erosion.The in vitro drug release from DBS-based tablet was predictive to the in vivo drug absorbed.