Study On Novel Thermosensitive In Situ Gel System Of Penciclovir For Ophthalmic Use

Penciclovir (PCV) was an antiviral drug that can be used to treat herpes simplex virus (HSV-1, HSV-2) and varicella-zoster virus (VZV) infections. PCV was often used in the formulations of creams or intravenous solutions. Traditional dosage forms for delivery of drugs in the eye have been formulated in eye drops. A large proportion of the topically applied drug is immediately diluted in the tear film. This leads to a short corneal contact time and poor ocular bioavailability that is commonly. Therefore, many ophthalmic drugs are applied in high concentrations which in turn cause both ocular and systemic side-effects. These are obstacle to the development of PCV for ophthalmic use.Object:Preparing thermosensitive in situ gel of PCV for ophthalmic use aim to prolong drug release, increase bioavailability and reduce adverse effect. Furthermore, we should ensure this in situ gel with controllable quality, safety and effectiveness.Method:①The pre-formulation experiments was carried out to study solubility and oil-water partition coefficients. The effects of various excipient on the gelation temperature, osmotic pressure, and viscosity were investigated, thereby optimized formulations. Preparation process was also improved.②Quality study of the optimized formulations was carried out, which includes the determination of PCV and its related substances, microstructure feature, texture behavior, characteristic of drug release and cornea permeation and so on.③Stability of thermosensitive in situ gel of PCV was studied by influencing factors and accelerated test.④Bioavailability of PCV was studied on rabbits, using pharmacokinetic methods. PCV concentration in the aqueous humour and plasma was analyzed by HPLC, and then the area under curve (AUC) was calculated.⑤Eye irritation test was carried out to evaluate the safety of in situ gels.Result:①The optimum formulations were18%F127+0.1%HPMC+0.1%PCV+0.01%BC;19%F127+0.3%F68+0.1%PCV+0.01%BC;20%F127+1.0%F68+0.1%PCV+0.01%BC.Adding other expedients after PCV dissolved was the optimum technique.②Quality study showed that the content of PCV in situ gels was 95.55%, while geletion temperature was at about 34℃and osmotic pressure met the isotonic conditions. The viscosity was low at room temperature while extremely increased at temperature of the ocular surface. Drug release from in situ gels was delayed compared to eye drops.③Study on influencing factors showed that drug was stable under high temperature and humidity, intensive light or low temperature. pH, osmotic pressure and content were almost unchanged in accelerate experiment while viscosity was decreased.④Pharmacokinetics study results showed that in situ gel can increase the bioavailability of PCV for ophthalmic use.⑤Eye irritation test showed that PCV in situ gel had no irritation on eyes.Conclusion:PCV thermosensitive in situ gels were quality controlled with high safety and stability, the AUC and Cmax of which were increased contrasted PCV eye drops.