| Aim:The clinical application of Ketoprofen(KP)is affected by its low solubility,poor stability and adverse effects of gastrointestinal tract during oral administration.And the design and development of drug delivery systems with low toxicity,high stability and high bioavailability is the focus of current research.The hollow tubes inside carbon nanotubes(CNTs)can be full with various small molecules of drugs,and can also form stable covalent bonds to bind drugs,which is a new drug delivery carrier with great potential.Therefore,CNTs are a new drug delivery carrier with great potential.The ethosomes(ES)are elastic and can pass through the stratum corneum to the deeper layers of the skin,increasing drug penetration.Therefore,in this paper,f-CNTs were used to load KP,and ES were used to wrap it,so as to prepare a composite nano-preparation,and solve the defects in the application of KP through percutaneous drug delivery.Methods:In this study,a pre-prescription study was conducted on KP to investigate its equilibrium solubility and oil-water partition coefficient,and establish a content determination analysis method.The raw CNTs were oxidized and their surfaces were modified with water-soluble polymer polyethylene imine(PEI),to obtain functional carbon nanotubes(f-CNTs)with good water dispersion.KP,which is insoluble in water,was loaded onto f-CNTs by ultrasonic method and wrapped by ES to construct a composite nano-preparation.The entrapment efficiency and drug loading of KP were determined by centrifugal method,and the preparation process and prescription were optimized by Box-Behnken effect surface method.The release characteristics of the preparation in vitro were investigated and characterized,including particle size potential determination,differential scanning calorimetry(DSC),X-ray diffraction(XRD),transmission electron microscopy(TEM),and infrared spectroscopy.In this study,carbomer 940 was used as gel matrix to prepare composite nano-preparation gel for convenient drug administration,and Franz diffusion cell method was used to investigate its transdermal properties.The prepared gel is coated on the skin surface of the feed tank and sampled from the receiving tank at a specific time.After the completion of the transdermal process,methanol was used to extract the drug remaining in the skin.The concentration was determined by HPLC,and then the cumulative drug penetration and drug retention on skin were calculated.The preparation was prepared with 0.02%rhodamine B instead of drugs,and the retention of the preparation in the percutaneous osmotic system was observed by fluorescence microscope.A method for determination of KP concentration in rat plasma samples by HPLC was established.The pharmacokinetic experiment was carried out in rats by time-sharing sampling method.The concentration of the samples was determined by HPLC,the drug-time curve was plotted,and the pharmacokinetic process of each preparation gel after percutaneous administration was analyzed according to the two-compartment model.Results:The established HPLC method for the determination of KP content met to the requirements of methodology.The equilibrium solubility of KP in deionized water was 0.291±0.037 mg/m L,and the oil-water partition coefficient in deionized water was 2.13±0.15,indicating that KP was a lipid solubility drug.In this experiment,f-MWCNTs-KP and f-SWCNTs-KP were prepared by optimized formulation and preparation process.The corresponding encapsulation rates were 50.12%and 72.52%,respectively,and the drug loads were 16.41%and 22.49%,respectively.In vitro release experiments showed that the prepared composite nano-preparations had a sustained-release property,and the release was divided into two stages:fast release and slow release,and the release behavior was consistent with the first-order kinetic equation model.The particle size results showed that the particle size of the prepared composite nano-preparations was all less than 400 nm,and there was no multi-peak phenomenon,and the PDI values were all less than 0.3,indicating that the particle size distribution was relatively uniform.The potential results showed that the Zeta potential of the carbon nanotube system was positive,the Zeta potential of ES was negative,and the Zeta potential of the mixed nano preparation f-MWCNTs-KP-ES and f-SWCNTs-KP-ES was close to zero,which indicated that the drug-loaded carbon nanotubes could be effectively combined into the two-layer structure of the ES.The DSC and XRD experiments showed that KP existed in amorphous or molecular state after adsorption and loading into f-CNTs.TEM results show that the structure of carbon nanotubes is still intact after being oxidized and modified by PEI,and the raw carbon nanotubes are truncated,and the dispersion of carbon nanotubes in water is obviously enhanced.The structure of the ES in the composite preparation was clearly visible,with the longer carbon tubes interspersed and surrounded the ES,and the shorter carbon tubes were wrapped into the ES.The results of FTIR experiments showed that PEI was successfully modified to the surface of CNTs-COOH,and KP was successfully loaded to f-CNTs.The results of in vitro percutaneous penetration test in rats showed that f-MWCNTs-KP-ES gel had the fastest percutaneous penetration rate and the cumulative permeability was 602.35±41.06μg/cm~2.In addition,skin retention experiment results showed that both ES and carbon nanotubes could increase drug retention and form drug storage.The transdermal release study showed that the release rules of the prepared preparations were in accordance with the first-order kinetic release model.Fluorescence microscope experiments showed that the fluorescence of f-MWCNTs-RB-ES gel group and f-SWCNTs-RB-ES gel group had basically covered the whole cuticle,active epidermis and dermis after 4 h treatment,and the fluorescence of the former group was stronger than that of the latter group,indicating that the prepared preparation could increase drug retention in the skin of rats.The established HPLC method for the determination of KP concentration in rat plasma samples was consistent with the requirements of biological samples.In vivo pharmacokinetic results showed that,compared with KP commercial gel and KP gel,transdermal delivery of the compound preparation gel has a sustained release effect,which promotes drug absorption and prolongs drug action time in vivo,and improves the bioavailability of the drug KP.Conclusion:The above results indicate that f-CNTs is a promising drug carrier,which can not only improve the stability of drugs but also improve their solubility in water.The composited drug delivery system can promote drug absorption and improve drug bioavailability after transdermal drug delivery,which has a good application prospect. |
