| In this paper,biocompatible and biodegradable amino acid derivatives’gelators were taken as the research subject,investigating their gelation ability,release behavior and degradation properties in vitro and in vivo to explore the relationship between the gel characters and gelator structures,in order to obtain the sustained drug delivery system,which could load large amount of drugs and release in step with the organogel depot.Six amino acid derivatives’ gelator,which based on L-alanine,L-valine,L-glutamic acid and L-lysine,and reacted with saturated fatty acid by different carbon-chain were synthesized.The synthesis products were determined by IR,1H-NMR and MS,in order to vertify the products:N-myristoyl-L-alanine methyl ester(MAM),N-palmitoyl-L-alanine methyl ester(PAM),N-arachidonoyl-L-alanine methyl ester(AAM),N-myristoyl-L-valine methyl ester(MVM),N-myristoyl-L-glutamic acid dimethyl ester(MGM)and methyl(S)-2,5ditetradecanamidopentanoate(MDP),respectivelly.The minimum gelation concentration of gelators in seven oils were investigated to determine the relationship between gelation ability and molecular structure.The results showed that the steric hindrance of the chiral carbon atom could generate a decline of gelation ability,and an augment with number of H-bond site and length of carbon-chain would strengthen the gelation ability.To further investigate the effects of solvents natures on gelation behavior,their gelation abilities in 12 kind of organic solvents were examined,which indicated that the polarizability and the H-bond forming ability of the solvents barred the formation of gel.The blank organogels were prepared based on the synthesized gelators and vegetable oils,whose thermodynamic property,rheology behavior,gelation dynamics,biodegradability and biocompatibility of were investigated.Results indicated that the transition temperatures of the organogel(solution-gel and gel-solution)were increscent with the concentration of gelatoes.For MDP,the organogel could stay stable in body when the concentration was higher than 0.5%.The study of rheology showed that the gelators with better gelation ability gained a bigger elastic modulus(G’),viscous modulus(G")and yield stress,indicating a better mechanical strength.With incensement of concentration,the initial gelation time of organogel was decreased,but the gelation time had a shortest time with concentration instead of the higher concentration the better.This may be due to that the exceed gelator hindered the formation to some extent.The stronger the gelation ability,the lower the concentration needed for the shortest gelation time.Compared with the degradation behavior in vivo,the degradation rates of organogels was slower in vitro,which could be effected by the concentration of gelator,pH of solution and kinds of oils.When lipase was added into the degradation solution,the degradation rates were accelerated obviously.A novel method based on HPLC and ELSD was established to quantify oil and gelator respectively and could investigate the key factors influenced the degradation process deeply.The results showed that the degradation rates of oil was always faster than that of the gelator,both of which were slowed down with the increase of gelator concentration.After reaching certain concentration,the difference between gelator and oil was constant,indicating the oil degraded with gelator.The action sites of pH and lipase to degradation rates were determined by comparing the degradation rates of oil and gelators.Their degradation behaviors in vivo were also investigated via subcutaneous implantation and found that it was closely related with the kind and concentration of gelators,which could be adjusted through these aspects.The histological evaluation of the mouse showed that in the six week’s healing process,it emerged a lower and acceptable inflammatory response,which displayed an excellent in vivo biocompatibility.All above can gurantee that this organogel system could be used safely as injectable in situ impalt.The self-assembly properties of the organogel have been utilized for preparing a formulation with a model lipophilic ibuprofen,flurbiprofen and keprofen,in order to find out their influences on the properties of the organogels and the release mechanism.The results indicated that the drugs containing H bond sites had deep influence to the properties of organogels,such as the a bigger MGC values,a lower amount of gelation inhibitor,the thermal stability decreased with a lower transition temperature and the mechanism of organgoel was also weakened as the values of G’ and G" were much small.At the same time,these influences were strengthed with the ability of H bond and the amount of drugs,thus ketoprofen gained the most significant impacts and ibuprofen was the least one.The release profiles of these three drugs were fitted as Fick diffusion,which can sustain the release of drug obviously.Intereatingly,the release rates of ketoprofen is not the fastest and ibuprofen was not the least as the interactions between gelator and drug molecules.In all,the influence of drugs should take into consideration when preparing an organogel formulation.The model drugs candesartan cilexetil(CC)was loaded into the organogel,and then studied the in vitro and in vivo behavior and explore the nature of the sustained-release drug delivery and release principle of organogel.The in vitro results showed that CC-ⅡOG prolonged the period of drug release obviously,which could provide a sustained release up to 30 days.Gelator structure,concentration,the amount of drug and gelation inhibitor would influence the release rate.Comparing with the drug oil solution,the blood drug concentration was prolonged from 2 days to 10 days,MRT,t1/2,Tmax and AUC0-t increased significantly,and Cmax decreased,indicating the CC-ⅡOG could sustain the drug release capabilities with improving the burst phenomenon and increasing bioavailability.In addition,the release profile of organogel formulation was fitted to the Ritger-Peppas release model and showed that the release behavior was a combined action of drug diffusion and fame erosion.It can be concluded that the in-situ organogel based on amino acid derivatives was biocompatible and biodegradable.The relationship between gel properties and gelator structures,as well as the factors influenced the degradation and release behaviors of organogels were investigated,which provided a ewliable scientific basis for the design and further optimization of the organgoel formulation. |
