| Azithromycin is a macrolide-type antibiotic with broad-spectrum antibacterial effects.It can cover the major pathogens of bacterial conjunctivitis,with high safety and low drugresistance rate.This drug even shows bactericidal activity on the azithromycin-resistant strains.The clinical trials have shown that Azithromycin Eye Drops could be used in children older than one year without obvious side effects.However,the ocular cornea is usually the main barrier of drug penetration,which prevents drugs from reaching the intraocular target tissues.In addition,the traditional eye drops have a short retention time and low bioavailability.In order to extend the contact time between drug and ocular surface and improve the permeability of drug in the cornea,we chosen azithromycin as the model drug in this study to prepare O/W microemulsion nanodisperse system.The drug was encapsulated in the oil droplet or oil-water interface layer to avoid direct contact with the biological mucosa and reduce the drug irritation on eyes.In this way,the drug stability and bioavailability were enhanced.Moreover,it could lead to sustained drug release and reduce the frequency of medications,which can greatly improve the patients' compliance.In this study,we firstly conducted preformulation study on the Azithromycin Microemulsion Eye Drops,and established a set of accurate,quick and reproducible method to determine azithromycin content in the Azithromycin Microemulsion Eye Drops.Through investigation on the oil-water partition coefficients of azithromycin,the feasibility of azithromycin in making microemulsion was determined.In addition,the solubility of azithromycin in the media at different pH was investigated.We found that the solubility was decreased with the increase of pH.The stabilities of azithromycin raw materials in strong acid,strong alkali,oxidation and high temperature conditions were also investigated.The stability was worst under the strong acid and strong oxidation conditions,followed by high temperature conditions.These stability study laid a foundation for the studies of prescription and preparation process of Azithromycin Microemulsion Eye Drops.We conducted a series of preliminary formulation screening.Five kinds of oil phases(soybean oil,olive oil,ethyl oleate,Miglyol 812,Miglyol 840),five kinds of nonionic emulsifiers(Tween20,Tween80,poloxamer 188,soybean lecithin,Span80),and four kinds of co-emulsifiers(EL-40,glycerol,ethanol and propylene glycol)were compared to determine the types of oil phases,emulsifiers and co-emulsifiers that can form stable microemulsion carriers.Then we drew the pseudo-ternary phase diagram using titration methods to determine the formulation composition system using Miglyol 812 as the oil phase,Tween80 as the emulsifier and EL-40 as the co-emulsifier.In addition,we investigated the factors influencing the formation and stability of O/W microemulsion area.Studies showed that the mass ratio Km of emulsifier and co-emulsifier,temperature,azithromycin dosage,ionic strength and chitosan had different influences on the microemulsion formation.By using encapsulation efficiency and average particle size as evaluation indexes and Box-Behnken Design-Response Surface Methodology,we optimized the dosages of Miglyol 812,Tween80 and EL-40,and achieved the optimal formula finally.In addition,we investigated and determined the compositions and the optimal dosages of other excipients using single factor analysis method.We chose chitosan as the surface positive charge modifier and the bioadhesive polymer cross-linked polymer hydroxypropyl methyl cellulose(HPMC)as the thickening agent to increase cell membrane permeability.We extend the retention time of drugs in the eyes so as to improve the efficacy and the preservation stability at room temperature.In this way,the costs of transport and storage were reduced,the slow release of azithromycin in the eyes was achived and he adverse reaction of drug irritation on eyes was reduced.The process method has been modified on the basis of self-emulsification.In the absence of organic solvents,the modified method can spontaneously form the emulsion droplets to achieve the effect of drug emulsion.After detection,it can form the stable microemulsion eye drops with the encapsulation efficiency of about 70%.The particle size was 21 nm.In addition,we investigated and determined the key processes such as stirring time,preparation temperature,sterilization method,adding method,and pH adjustment method,etc.Then the key process parameters were determined.The preparation process is very simple,reasonable and stable.It is suitable for large-scale production and easy to achieve industrialization.Three batches of samples of Azithromycin Microemulsion Eye Drops were prepared by the above optimized method.According to the characteristics of microemulsion preparation and physiological characteristics of eyes,the quality of Azithromycin Microemulsion Eye Drops was evaluated based on the indexes of appearance,particle size and particle size distribution,Zeta potential,pH value,osmolality,viscosity,encapsulation efficiency and content in vitro release.Results showed that the appearance of Azithromycin Microemulsion Eye Drops,size and distribution of droplets and encapsulation efficiency were conformed to the characteristics of microemulsion.Its pH,osmotic pressure and viscosity were within the physiologically allowable range of eyes.The other indexes were in line with the quality specifications,indicating that the product formulation and process had high reproducibility and the quality of prepared samples was basically stable In order to understand the stability factors,possible degradation pathways of microemulsion and provide basis for the screening of prescription technology,selection of packaging materials and storage conditions,we investigated the effect of high temperature(60?),strong light(4500±500lx)and repeated freezing and thawing on this product using the appearance,pH,particle size,Zeta potential,main drug content and in vitro release as indexes.Results showed that,Azithromycin Microemulsion Eye Drop was not stable under high temperature,but relatively stable under the light and freeze-thaw conditions,indicating that this product should avoid high temperature during storage,but it had excellent light resistance and coagulation stability.Through 40? acceleration test and 25? long-term stability test for 6 months,the active ingredient AzaSite showed no significant changes,suggesting that this product had excellent stability and it was suitable for preservation at room temperature without coagulation. |
PDF Full Text Request