Design And Evaluation On Intelligence Drug Delivery System Of The Genus Of Grafted Polymer Of Guar Gum And Acrylamide

Intelligence drug delivery system which was named respond drug delivery system, was a new kind of drug delivery system. Intelligence drug delivery system can adjust the drug release with the condition changing of the body and the environment. In this study, thermo-/ pH-sensitive polymer GG-g-PNIAAm-AAm ( GPNA ) and pH-sensitive polymer GG-PAAm-AAc, (GPAA) were synthesized using the method of chain initiation ,at the presence of Ce⁶⁺ as the initiator. N-isopropylacrylamide(NIAAm) and acrylacide (AAc) or acrylamide(AAm) and the acrylacid (AAc) were used as the monomers. Guar gum (GG) was conjugated with the polymer during the chain transfer step. The implant hydrogel and the impulse controlled- release tablet were prepared with the two kind of new intelligent polymers. To characterize the two kinds of new intelligent polymers, FTIR, DSC, TGA, ¹³CNMR and Element-analysis were used. To inspect the security, acute toxicity experiment and biocompatibility experiment were made. The properties of the polymer hydrogels such as the elasticity, swelling degree, permeation and release behavior of drugs from the hydrogels and the pharmakinetics of the implant hydrogel and the impulse controlled- release tablet were investigated.Element-analysis indicated that the content of the C, N and H in the GPNA were 40.51%, 3.85% and 6.735%, and the content of NIAAm in the GPNA was 31.625%. Viscosity was used to determine the lower critical solution temperature (LCST) of the GPNA which was about 37.5℃. Both the ratio of the monomers and the ion strength have effect on the LCST of GPNA. The LCST increased with the increasing of the content of AAm and with the decreasing of ion strength. In the biodegradability study of GPNA, DSC was used to determine the thermal properties of GPNA. The local crystallization was observed in the degraded GPNA.The amount of -OH in the chain of GPNA decreased with the increase of crosslinker, so the tounch spot between the chain of polymer and the water molecule decreased. So the elasticity and equilibrium swelling ratio of GPNA hydrogel increased with decrease in the crosslinker concentation. With the increase in the amount of NaC1, the chain of GPNA changed from unfold to fold. The tenacity of the polymer chain increased, the rigidity decreased. So the elasticity GPNA hydrogel increased and equilibrium swelling ratio decreased with increase in the NaCI concentation.The shrinking behaviours of GPNA hydrogel were obvious different at the temperatures that higher of lower then the LCST. As it was lower than the LCST, the release mass of water in the GPNA hydrogel increased with the time^1/2; when the temperature was higher than the LCST, the shrinking of the GPNA hydrogel was slow at the beginning and then quick increased with the destroy of the structure of the hydrogel. With the increase of NaCl, the losing water rate of GPNA hydrogel increased, the shrinking ability strengthened. The permeance of vapor and model drug (SM) was estimated using the first diffuse law of Fick's. The permeance of thermo- sensitive film was faster as the temperature was above LCST than it was below the LCST. GA can compact the chain of the polymer. So the permeance of vapour and SM of thermo-sensitive film decreased with the increasing of GA. The state and amount of water of GPNA hydrogel were studied by differential scanning calorimetry (DSC). The results indicated the existence of freezing bond water and free water when the water content of hydrogel was more than 98.4ï¼…. The melting enthalpy of freezing bound water was higher than it of free water, but the melting temperature was lower. The content of freezing water was more than it of non-freezing water.The diffusion coefficients were calculated using the equation of Higuchi. The concentration of polymer (GPNA) and the ion strength of medium had no significant effect on diffusion of SM, while the temperature, pH and the content of GA had significant effect on it. With the increasing of ion strength of medium, content of GA and concentration of polymer, the release of model drug(SM) from the hydrogel decreased. The drug release was faster in acidic media (0.1mol/LHCl) than it in neutral and basic environment (0.1mol/L pH6.8 PBS). When the temperature was lower than LCST, the diffusion coefficient had no prominent difference. When the temperature increases, the surface of the gel may shrink. The dense surface structure will then limit more drug release. When the temperature was lower or higher than LCST, the flow of hydrogel was pseudoplastic flow or dilatant flow. With the increase of GA content, the flow of hydrogel changed from dilatant flow to pseudoplastic.In comparison male rates implanting insulin (30 IU/kg) hydrogel with male rates subcutaneously injecting insulinl IU/kg, the area of over curve (AOC) calculated by the blood glucose level versus time profiles was 4433.96 and 5978.111 respectively, the bioavailability calculated by the blood glucose level versus time profiles was 2,472ï¼…. The blood glucose level versus time profiles of the rats between the groups had obvious difference, had no difference with in group. The blood glucose of the rats reduced obviously, when the temperature of rat was reduced physically. The blood glucose of the rats with normal temperature rose. The GPNA hydrogel loaded insulin had obvious temperature sensitivity. It can be realized that the rate of drug release changed with the temperature changing.The content of the C, N and H in the GPAA were 44.93ï¼…, 7.188ï¼…and 5.507ï¼…. The content of AAm and AAc in the GPNA was 36.45ï¼…and 24.67ï¼…. In the biodegradability study of GPAA, it was identified that the crystals occur in GPAA before and after degradation. But the degree of crystallization was very low.The properties of swelling and the drug release from GPAA hydrogel were studied with the model drug KP.The courses of hydrogel swelling were analyzed by fitting the experimental dates with mathematical models, such as Vergnaud model. The rate of swelling was caculated in terms of the second swelling dynamics equation of Schotto The equilibrium swelling ratio of GPAA impulse control release tablets increased with increasing pH of medium. At pH 3.0 and pH6.8 the equilibrium-swelling ratio had obvious change. The accumulated drug release of 2 h in 0.1mol/L HC1 was fewer than 10ï¼…, and of 24 h was not more than 40ï¼…; But the drug accumulated release of 12 h in PBS with pH6.8 was more 80ï¼…; which were consonant with the law of pharmacopoeia for enteric preparation. With the content of AAc in the polyer increased from 50ï¼…to70ï¼…, the equilibrium-swelling ratio of hydrogel in pH 6.8 PBS increased, the diffusion coefficient of KP increased from 0.6260 to 0.8274. It took 9.5 h for the hydrogel to swell completely in medium with ion strength of 0.1, but it only took 7.5 h for hydrogel to swell completely in medium with ion strength of 1.0. The equilibrium-swelling ratio of hydrogel let up from6.8819 to3.0962, the sopping ability of hydrogel took off, the KP release rate took off. With the increase of water-soluble additive (lactose), the sopping rate of hydrogel increased, the drug release rate improved. With the increase of rotate speed, the sopping rate of hydrogel slightly increased. The content of GPAA had significant influence on the drug release. Fitting the experimental dates with the Ritger-Peppas equation, the diffusion coefficient decreased from 0.9034 to 0.7592, with the content of GPAA increasing from 35ï¼…to 60ï¼…. The drug release followed Caseâ…¡mechanism and then followed Fickian and Caseâ…¡mechanism. The inital erosion rate of the tablet was faster. The water- soluble additive can increase the erosion rate of the tablets.The Gamma-scintigraphic trace evaluation demonstrated that the release of KP impulse controlled- released tablets in stomach was very less, and KP release in intestine faster and release completely after 7 h. The plasma concentration of KP in dogs was determined by HPLC using enteric capsules as the reference. The C_max, and T_max of the impulse controlled- release tablets were5.00 h andl 5.40μg/ml. The release of drug from the impulse controlled- released tablets of KP was shown to be in pulsed way in vivo. Its relative bioavailability was 108.71ï¼…. A good correlation existed between absorption percentage in vivo and release rate in vitro. The absorption degree of KP impulse controlled- released tablets and KP enteric capsules was equal.