| Ocular surface mucous layer consists of mucins and tears,ocular mucus has a dual effect for drugs on the ocular bioavailability,ocular mucus could act as barrier and retention site for cationic drug delivery system in the ocular surface after topical administration.The bioavailability of drug in the ocular depends on the extent of the mucin behavior.Therefore,the study comparing these two different mechanisms of leading role has important significance to improve the ocular bioavailability.In this study,cyclosporine A（Cs A）,a treatment drug for dry eye diseased,was selected as a model drug.Four Cs A nanosuspensions were successfully prepared by antisolvent precipitation and they had positive charge and mucus penetration properties,respectively.The results of mucin binding experiments showed that the cationic nanosuspension F1（+14m V）and F3（+37m V）could bond with negatively charged mucin quickly throug electrostatic force,which resulted high adhesion and could increase the drug in the ocular surface retention time.Transwell chamber diffusion was used to study the permeability and the results showed that the apparent permeability coefficient（Papp）of F3(0.43×10-6cm.s-1)<F1(1.01×10-6cm.s-1)<F2(3.44×10-6cm.s-1)<F4(4.94×10-6cm.s-1),F4 had stronger mucus permeability,which could overcome the mucus barrier and avoided drug rapidly removal from the surface of eye to increase the drug in the ocular surface retention time.Finally,Cs A concentration in rabbit cornea was detected by LC-MS after topical administration.the results showed that the drug concentartion in cornea of F3（13641.10ng/g）>F1（11912.58ng/g）>F4（11436.073ng/g）>F2（8471.47ng/g）,all formulation were able to deliver Cs A to anterior ocular tissues in effective therapeutic concentrations（10～20μg/g）with topical drop instillation,except F2.In conclusion,the nanosuspension with mucus penetration or mucus adhesion could improve the drug bioavailability in cornea and the cationic nanosuspension had a relatively enhanced ocular bioavailability.It is clearly indicated that the mucoadhesive properties for electrostatic interaction with mucin layer would play the main role on bioavailability of Cs A in ocular delivery and these cationic nanosuspension might be a more promising candidate for a topical ocular drug delivery system. |
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