| Drugs regularly travel throughout the body after being administered inconventional formulations during the cancer treatment and only a small amout of thatcan reach the lesion site. The drugs distributing thoughout the body lead to side effect.Therefore it is a long-term pursuit for the scientists engaged in the field of pharmacyor biomaterials to develop sustained-release delivery systems that could targetchemotherapeutic drugs to specific body sites. Chitosan is naturally a linearmacromolecular polysaccharide thst has non-toxicity, good biocompatibility andbiodegradability. It is widely used in the delivery, control and release of the drug.Although chitosan can have a long-term release, and it can be injected into thesubcutaneous through needles within a certain range of particle sizes, due to thedispersion and sudden release phenomena, they cannot concentrate on the lesion siteand release the drug stably. Hydrogel can carry drugs to the lesion site and release it,but it has sudden release penmenon and does not have a good release effect. In thispaper, chitosan is used as a naturally non-toxic marine biomaterial while methotrexateis used as a stardard drug. Chitosan microspheres loaded with methotrexate andthermo-sensitive hydrogel that posses in situ phase change feature are prepared,respectively. The microspheres are dispersed uniformly in the hydrogel. A newthermosensitive phase change compound for in situ injection is prepared, which isused for the directional release of the chemotherapy drug.In order to prepare the appropriate chitosan microspheres as drug carrier,emulsion-chemical crosslinking method and spray drying method are first selected inpreparation. The microspheres prepared in this study have uniform particle size andgoodt dispersion. The properties of chitosan microspheres are also tested. The results indicated that the chitosan microspheres can be injected through needles and themethotrexate can be encapsulated in chitosan microspheres. The drug-loadingefficiency and encapsulation efficiency of chitosan microspheres are also researched.The drug-loading efficiency and encapsulation efficiency of chitosan microsphereswhich used formaldehyde as a crosslinking agent are10.00%~30.14%and52.17%~57.21%, respectively. The drug-loading efficiency and encapsulationefficiency of chitosan microspheres cross-linked with glutaraldehyde are4.50%~12.98%and31.16%~32.66%, respectively. The chitosan microspheres whichare prepared in spray drying method have the lowest drug-loading efficiency(0.70%~1.81%) and the widest range of encapsulation efficiency (5.50%~91.13%).Vitro drug release experiment improves that, the release property of microspheres isaffected by drug-loading efficiency, water content, crosslinking density, compactnessof structure, etc. In3h, the average release rate of methotrexate in chitosanmicrospheres cross-linked with formaldehyde and glutaraldehyde are73.17%and50.34%, respectively. Meanwhile, the average release rate of chitosan microsphereswhich are prepared under spray drying method is90.12%. Thus the chitosanmicrospheres prepared under emulsion-chemical crosslinking method have a bettersustained release effect. The release time is more than33h.Chitosan thermo-sensitive hydrogel is prepared with chitosan andgycerophosphate using ionic crosslinking method. The phase could change from thesol state to a gel state at37℃in1min, which indicated that the hydrogel prepared inthis paper has a good thermo-sensitivity. The drug-loaded chitosan microspherescross-linked with formaldehyde and glutaraldehyde are respectively dispersed in thehydrogels uniformly. The chitosan thermo-sensitive complexities are prepared and therelease rates of them are studied. In3h, the release rates of chitosan thermo-sensitivecomplexities loaded with formaldehyde and glutaraldehyde cross-linked chitosanmicrospheres are31.86%and27.99%, respectively. The release rates are lower thanthat of the drug-loaded chitosan microspheres themselves(73.17%、53.04%). In10h,the release rates of chitosan thermo-sensitive complexities loaded with formaldehyde and glutaraldehyde cross-linked chitosan microspheres are63.22%and50.00%,respectively. The release rates are also lower than that of the drug-loaded chitosanmicrospheres themselves(80.71%、76.00%). In vitro drug release experiments indicatethat, compared with the drug-loaded microspheres, the chitosan thermo-sensitivecomplexities can not only make up for the dispersion of microspheres but alsoobviously improve the phenomenon of sudden release at the first stage of delivery andhas a better sustained release effect. The release time of chitosan thermo-sensitivecomplexity is more than3days.The purpose of this study is to prepare a sustained release carrier that can be usedin the subcutaneous injection. Therefore, the biocompatibility of chitosanmicrospheres, hydrogel and thermo-sensitive complexity is researched, such asMicronucleus test, Hemolytic test, Tissue compatibility experiment, and Bloodcompatibility experiment. The results indicate that the chitosan microspheres,hydrogel, and the thermo-sensitive complexity have a good biocompatibility and canbe gradually degraded in the body. In vivo drug release is also be researched, theresults indicate that after the drug-loaded chitosan thermo-sensitive complexity isinjected into the rats’ subcutaneous for1h, the drug concentration in rats’ blood is3.08μg/mL. After6h, the drug concentration in rats’ blood is1.67μg/mL. And then itis maintained for a stable period. After48h, the drug concentration in rats’ blood is1.14μg/mL. However, the other groups cannot detect the drug concentration at thesame time. The results of vivo drug release indicate that the drug-loaded chitosanthermo-sensitive complexity has a better release effect, and the release time canremain more than three days.In summary,3kinds of drug-loaded chitosan microspheres are prepared. Thebasic physical property and in vitro drug release behaviors of them are researched.Chitosan thermosensitive hydrogel is prepared using ionic crosslinking method andthe microspheres are dispersed in the hydrogel uniformly. The characterizations and invitro drug release of chitosan thermosensitive complexity are studied, as well. Thebiocompatibility of the chitosan microspheres, chitosan thermo-sensitive hydrogel and chitosan thermosensitive complexity indicate that they have a good biocompatibility.In vivo drug release research of the methotrexate, drug-loaded chitosan microspheresand drug-loaded chitosan thermo-sensitive complexity are also studied. The resultsindicated that the chitosan thermo-sensitive complexity has a better effect of sustainedrelease, and the phenomenon of burst release can be suppressed. The chitosanthermo-sensitive complexity prepared in this paper will extensively apply to prolongthe release of drug, improve the bioavailability and alleviate the toxic effects of somedrugs on our body, thus having an important value in clinical application. |
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