Studies On The Ophthalmic Drug Delivery System Of Puerarin And Its Complex

Owing to the complex structure and many barrier in the eye,traditional ophthalmic preparation have a lot of problems in patient compliance,healing effect et al. In order to make therapeutic drugs exert better curative effect on intraocular, novel ophthalmic drug delivery system gradually become the hot spot in pharmaceutics researches.It has been a long history to treat ocular diseases by using chinese herbal medicine.TCM has obvious characteristic advantage especially in the treatment of interna eye diseases such as glaucoma,cataracts,vitreous hemorrhage,retinopathy caused by diabetes,retinal vein occlusion and retinal artery occlusion.Among the commonly used chinese herbal medicine, By pharmacological research and clinical use,puerarin and Salvia miltiorrhiza are proved that they can expand capillaries and improve microcirculation,have good curative effect in retina,ocular trauma,chronica inflammatory disease.The main administration form of chinese herbal medicine was oral,but ophthamic drug administrtion had more advantages and feasibility to enter in the target areas of eye.In order to better reflect and develop the advantage of preventing ocular disease by TCM,it is necessary to combine the theory of modern pharmaceutical technology and drug delivery system for research and development of TCM ophthamic delivery system.Non-ionic surfactant vesicles,for short niosomes, is a new drug delivery system similar with liposomes.As ophthalmic drug carrier,its advantage lies in:prolong the drug retention time in cornea and vitreous body as drug storage library, protect the drug molecules from destroy by metabolic enzymes in tears or corneal epithelium, and exert the drug effect in corneal surface slowly; it also has a strong affinity with eyes organization,conjunctiva and sclera, and can disperse rapidly in the eye after droping, hence to enhance the cornea penetrability. In situ forming eye gel is another kind of ophthalmic drug delivery system well-studied recently, in physiological condition it is free flow liquid, in physiological conditions it will form a gel.This can prolong drug residence time in the eye, so as to improve the drug bioavailability.The aim of this study is to improve low bioavailability and potential risk of clinical pue eyedrops through pue niosomes, and then we study the feasibility of its application in the eye. Meanwhile we choose poloxamer407 and poloxamer188 as temperature sensitive gel matrix, to study pueraria lobata and salvia miltiorrhiza compound in situ forming eye gel, in order to lay foundation for new herbal ophthalmic preparations in the future.In this study,the main investigation focused on four parts as follows:The first part, the extraction and Pueification of Puerarin and Salvia miltiorrhiza. through the literature material and prediction of preparation,we extract and Pueify pueraria lobata and salvia miltiorrhiza respectively. Among them pueraria lobata with pue for index, the 70% ethanol refluxing extraction and then dissolved n-buoh extraction method of recrystallization glacial acetic acid, get the Pueity of 89% pue; Salvia miltiorrhiza are divided into the extraction and Pueification of total ketone and total phenolic acid two parts, respectively by ketoneâ…¡A,total and phenolic acids B, total phenolic acids for effective component index to the dan-shen root ethanol-extraction and water extraction, get more than 50% effective parts Pueity of salvia miltiorrhiza total ketone and total phenolic acids extract.The second part, Puerarin nonionic surfactant vesicles preparation research. After the comparison of the centrifugation, dialysis and glucan gel column chromatography method, we determine glucan gel column chromatography as the effective separation methods. Then the preparation of puerarin niosome and its characterizition is studied, experiment contrast found Injection method formed into law vesicles appearance dispersivity is good, small and is relatively concentrated particle. But the content determination results showed that the puerarin entrapment rate is very low, this is one of the main problems need to be solved.The third part, the research on prescription and preparation of Dange mingmu in situ forming eye gel. The phase transition temperature before and after diluted by STF is observed as index, we use the uniform design method to optimum the temperature sensitive type ophthalmic gel matrix prescription, established fitting equation between poloxamer concentration and phase-change temperatures, the results showed that the gel phase-change temperatures with concentrations of P407 decreases; And in a certain range P188 can improve the phase-change temperatures. Then we choose three prescription in the results, the viscosity of them before and after diluted by STF are conducted, finally we determine the lower concentration:19% P407 and 1% P188 as temperature sensitive ophthalmic gel matrix. On this basis, the other additional agents in prescription of Dange mingmu in situ eye-gel is screened, including help solvent (tween 20), preservative (benzene pierced ammonium chloride) and pH regulator (NaOH), etc, and then after accession of drug and accessories, gelation temperature and viscosity was investigated, to meet the requirements,we make corresponding adjustment to get Dange mingmu temperature sensitive in situ forming eye gel.The last part, the preliminary evaluation research on Dange mingmu in situ forming eye gel. Established the content determination methods of Dange mingmu in situ forming eye gel:using HPLC to analyse pue and Salvianolic acid B (preparation index component). According to the in vivo characteristic of ocular administration,a memebraneless model was used to study the gel erosion and drug release simultaneously.Correlation analysis demonstrated that drug release,which followed zero-order kinetics,from poloxamer vehicle was completely controlled by gel erosion.The retention time of rabbit eye experiment shows that in situ eye-gel significantly prolong drug retention time in the eye. The rabbit eye single dose and many times experiment demonstrate that Dange mingmu in situ forming eye gel have no irritant reaction to rabbit eyes. There was also no allergic reaction after spraying on the skin of guinea pigs many times.The novelty in our studies lies in we attemp to use new technology, new method on ophthalmic drug delivery system of TCM,in order to make the drugs and carrier achieve an complementary effection,there are no essays established about relative researches on pue niosomes and Dange mingmu in situ forming eye gel.The study results can provide certain reference and ideas to solve some of the TCM technical issues in common, which is benefit to promote further development on ophthalmic new preparations of TCM and its compounds.