Studies On Azithromycin Sustained-Release For Oral Suspension

Azithromycin（AZI）is one of the new macrolides which has been widely used clinically to treat respiratory tract infection, skin and soft tissue infections, urogenifal infection. Due to its gastro-intestinal side effects, the further development of its oral preparation and clinical application was restricted greatly.The aim of this study was to prepare an AZI sustained release for oral suspension in order to mask its unpleasant taste, control the release rate and decrease its side effects. The novel preparation can help to increase the patients’ compliance, who have difficulties in swallowing, and combines the advantages of easy to package, good absorption character and small gastric irritation.The AZI content in microspheres, micropaticle and suspension was determined by an HPLC method. In the preformulation, the stability of AZI in several media, the solubility of AZI and the octanol/water partition coefficients were determined.In pharmaceutical research, firstly, the AZI sustained release microspheres were prepared by quasi-emulsion solvent diffusion method. The influence of preparation methods and formulation factors on the appearance, D₅₀, recovery, drug loading, incorporation efficiency, the release profiles in pH6.0 PBS of the microspheres was investigated to pick out the best formulation. The results showed that the sustained release microspheres made by it were spherical and smooth. D₅₀ was about 175μm, recovery＞90％, drug loading＞50％, incorporation efficiency＞80％, the release profiles in pH6.0 PBS of the microspheres can meet the requirement. The DSC scanning showed that drug is amorphous state in microspheres.The emulsion solvent diffusion method was with good reproducibility, however, considering using organic solvent of dichlormethane and acetoacetate in this method, which was costly and not suitable for application in industry, the spray drying method was studied to prepare the AZI sustained release microparticle afterwards. The influence of preparation methods and formulation factors on the appearance, tap density, D_mean, recovery, drug loading, incorporation efficiency, the release profiles in pH6.0 PBS of the microparticle was investigated to pick out the best formulation. The results showed that the bulk density of the sustained release microparticle was 0.680 g·mL^-1, D_mean was about 61.9μm, recovery＞20％, drug loading＞19.54％, incorporation efficiency＞90％, the release profiles in pH6.0 PBS of the microparticle is qualified. DSC scanning showed that drug is amorphous state in microparticle. The drug release kinetics was conform to the combination of diffusion and erosion mechanics. Results show that the method was with good reproducibility,high efficiency,low cost, convenience, and feasibility, and was suitable for industrial production.The suspending effects on several kinds of suspending agents were explored. According to the results, Xanthan Gum was chosen to be the suspending agents to prepare the AZI sustained release for oral suspension. Based on the formulation screening using sustained release microparticle as materials and sedimentation rate and redispersibility as indexes, the propotions of suspending agent, wetting agent and sweetening agent were confirmed as 0.3％, 0.7％and 0.5％respectively. The optimal formulation fits the requirement of suspension formulation design with a sedimentation rate of 0.98 and a good redispersibility.The results of the stability tests showed that the AZI sustained release for oral suspension were no any significant changes in stress testing, accelerated testing and long-time testing.Finally, an HPLC-MS method was established to determine the drug plasma concentration in dogs. The behavior in vivo of the oral suspension was evaluated in six dogs after an oral administration of single dose of the oral suspension（test formulation）or tablets（reference formulation）. AZI sustained release for oral suspension exhibits two-compartment distribution using compartment modeling in pharmacokinetic studies. The pharmacokinetic parameters of the test formulation were as below: C_max were 3.82μg·mL^-1, T_max were 6.67 h, MRT were 46 h. The T_max was delayed 4.34 h compared to the common tablets. The relative bioavailability was 141.73％. The results in single-dose studies revealed that the tow formulation is not bioequivalent.