Study Of Self-assembled In Situ Organogel For Long Term Drug Delivery Implant

To study the injectable in situ forming organogel, which is solution at room temperature, and immediately translating into hemi-solid of gel at body temperature, the biocompatible and biodegradable amino acid derivatives’gelator were sythensized in this article. This in situ organogel was prepared and its properties were determined, in order to obtain the sustained release drug delivery system which could loaded many types of drugs and large biological molecules such as protein and polypeptide.Eight amino acid derivatives’gelator, which based on L-alanine and L-phenylalanine, and reacted with saturated carbonyl chlorides by different carbon-chain were synthesized. The synthesis products were determined by IR,’H-NMR and MS, in order to verify the products were LAM, LAE, LA, SAM, SAE, SA, SPM, SP, respectively. Minimum gelation concentrations (MGC) of organogelators were determined, in order to find out the correlations between gelation ability with molecular structure. The results indicated that the augment with steric hindrance of chiral carbon atom and esterification degree of carboxylic acid group could generate the decline of gelation ability, and the augment with length of carbon-chain could strengthen the gelation ability.In order to prepare organogel, the MGC and gelation time of gelators in different oils, and the anti-gelling ability, solubility, evaporability and safty of anti-gelling solvents were studied to determine the kinds of oil, kinds and amounts of organogelator and anti-gelling solvents. The best formulation of organogel is injectable soybean oil (10 ml), SAM (1.2 g) and N-methyl pyrrole (NMP) (3.5 ml).The rhology, thermodynamic property, biodegradability and biocompatibility of SAM organogel were determined to insure this system can be subcutaneous injectable. The study of rhology indicated that its rheological curves were entirely consistent with the Herschel-Bulkley equation, which showed the property of thixotropicfluid. The organogel displayed the constant elastic modulus (G’) and viscous modulus (G") and lower phase angles, whose viscosity was increscent with concentration of SAM. The phase transition temperature (Tt) were determined by differential scanning caborimetry (DSC) and rhology method, which proved that it could keep gel state at 37℃with the concentration of SAM above 3%. The degradation in vitro was very slow, with 4.2% at 50 days, which could be effected by degradation area, temperature, pH of solution and kinds of oil. Nevertheless, the biodegradation in mice was relatively fast, with full degradation at six weeks, and the biodegradation rates decreased with the increasing of concentration of SAM. The growth form and cell viability of L-929 cell were not restrained by SAM in-situ organogel, which showed well in vitro biocompatibility. The histotomy of rats indicated that in the six weeks’ healing process it emerged a lower and acceptable inflammatory response, which displayed an excellent in vivo biocompatibility. All above can guarantee this organogel system could be use safely as injectable in situ implant.A novel and convenient electrochemical method was firstly developed to monitor the diffusion of NMP, simulate the gelling procedures and gelling time of organogels, and research the gelling dynamics. Results indicated that structure of gelators and kinds of anti-gelling solvents could observably affect the diffusion rate and diffusion percentage of anti-gelling solvent. The increasing of SAM and decreasing of temperature could lead to the decreasing of diffusion rate and extension of diffusion time. Even so, the gelation process of SAM in-situ organogel could also be completed in only two hours.Four types of model drugs were loaded in organogel and its durg delivering behaviors were determined in vitro and in vivo, in order to find out the long-term drug delivering performance and mechanism. The results indicated that the in vitro delivery of liposoluble drug Flurbiprofene (FP) was fitted as Fick diffusion, which completely released for eight days. Comparing with control groups, the blood drug concentration was prolonged from 3 days to 7 days, MRT, t1/2 and Tmax were increased, and Cmax was decreased. It can be concluded that the FP organogel emerged prominent sustained release abilities, meanwhile, burst release was improved in vivo. Glibenclamide (GLB) and Amlodipine besilate (AMB) also loaded in organogel, comparing with FP, and their diffusion coefficient displayed a downward trend. This verified the different property of drugs led to the difference of existence form and affinity in organogel, resulted in the different release rate and mechanism. Arlacel P135 was acted as the emulsifier to prepare the W/O emulsion organogel loaded hydrosoluble drug Venlafaxine hydrochloride (VH). The results indicated that the drug could be sustained release for 14 days, and the release rates increased with the increasing of amount of SAM, amount of NMP and partical size of emulsion. Comparing with control groups, the blood drug concentration was prolonged from two days to twelve days, MRT, t1/2 and Tmax were increased, and Cmax was decreased, which concluded that VH emulsion organogel emerged prominent sustained release ability as long-term drug delivery system.To further study the in vitro and in vivo release behavior of biological molecular, insulin (INS) was selected as model drugs. Central composite design (CCD)-Response Surface Methodology (RSM) was employed to optimize the formulation of INS freeze-dried complex. INS could be soluble in organogel through this complex, which formed reverse micelle in oil. INS organogel displayed excellent stability at room temperature for six months, and cumulative release was 9.4% for eight days. Subcutaneously injecting INS organogel could observably reduce the blood glucose of diabetic rats, the increasing of SAM concentration led to the slow release rate and prolonged the period of drug release, which could keep the blood glucose at low level for eighteen days.It can be concluded that the in-situ organogel based on amino acid derivatives was biocompatible and biodegradable. SAM organogel system was stale and safe for injectable subcutaneous administration. The advantages of organogel drug storage and mechanism of drug delivery were clarified, which provided reliable scientific basis for stabilized long-term drug delivery of large biological molecules such as protein and polypeptide.