Preparation And Properties Of Collagen/dialdehyde Cellulose Nanocrystals Composite Films For Ocular Administration

Worldwide,effective ocular administration is a problem that has to be settled urgently.Eye drops are the most common ophthalmic dosage forms clinically,but their bioavailability is extremely low,requiring multiple doses to maintain efficacy.This work aims to prepare a high-strength degradable film with collagen(Col)and cellulose nanocrystals(CNC),which can slowly release drugs in the eyes and markedly improve the bioavailability and compliance of drugs.CNC was prepared with cotton pulp by acid hydrolysis.The aldehyde groups were introduced into the surface of CNC by oxidation of periodate sodium to obtain different kinds of dialdehyde cellulose nanocrystals(DAC).The size,dispersity,degree of oxidation(DO)and surface charge of CNC and DAC were characterized by TEM,AFM,XRD,DLS and FT-IR.Two types of Col/DAC composite films,mixed C/Dn(x)-DFN films and layered C/Dn-IBP-m films were prepared by vacuum suction filtration.The C/Dn(x)-DFN films were prepared with a mixed solution of Col and DAC,and diclofenac sodium(DFN)was loaded by soaking the films into a DFN solution.Since the Schiff base reaction of the C/Dn(x)films occurred in the mixed solution,the chained Col molecules were twined around the rodlike DAC.During the filtration,the stack of Col molecules drove the DAC to arrange horizontally between the Col molecule,and the dense cross-linking network spread throughout the composite films.The DFN solution was also uniformly distributed in the films.The C/Dn-IBP-m films were prepared by alternately filtering the Col solution and the DAC-Ibuprofen(IBP)solution.In the C/Dn-IBP-m films,the Col layers had a tight and uniform layered structure,while the DAC layers were relatively loose and disordered.The adjacent layers were tightly connected with imine bonds on account of the Schiff base reaction only occurring at the interface between the adjacent Col layers and the DAC layers.After mixed with DAC,IBP was adsorbed on the surface of the DAC by hydrogen bonding,and was mainly stored in the DAC layers.In vitro studies showed that increasing the content of Col in the C/Dn(x)films could significantly improve the water-holding capacity and mechanical properties,and increasing the degree of oxidation(DO)of the DAC was beneficial to the optimization of transparency and mechanical strength.The tensile strength of the best was up to 164.1 MPa,and the elongation at break was up to 40.5%.In addition,increasing the DO of DAC and the uniformity of Col and DAC significantly improved the transparency and mechanical strength of the C/Dn-m films.The layered structure not only retained high mechanical strength(Tensile trength: 54.2 MPa)for C/Dn-m film,but also significantly improved the transparency(>90%)and water holding capacity(>70%).In the case of lowering the concentration of the drug solution,the drug loading of the C/Dn-m films was still 2 times than that of the mixed films.The result of in vitro drug release experiment showed that IBP in C/D3-IBP-6 films reached releasing equilibrium at 24 h,and the cumulative release rate reached up to 90%,while the release of DFN in C/D2(0.5)-DFN films was very slow and the cumulative release rate of DFN on day 6 reached only 66%.In addition,the results of cell experiments showed that the two kinds of films could effectively promote cell adhesion and growth within 24 h.In vivo studies showed that when C/D2(0.5)-DFN films were placed in the subconjunctival as an ocular implant,it had no obvious irritation to the eyes and had superior anti-inflammatory activity.As the drug was totally released,the film gradually degraded.It can be seen that by adjusting the structure of the Col/DAC composite films,anti-inflammatory drugs with different solubility can be slowly released at different release rates.The biodegradable Col/DAC film is a safe,convenient and effective drug carriar for ocular administration.