The Development Of A01-bile Salt Phosphatidycholine-mixed Micelles Injection

Objective:Poorly soluble drug is difficult to prepare the injection due to its insolubility in water.A01,a novel drug candidate,is expectedly to be used for the treatment of pulmonary hypertension.In this study,a Bile salt-Phosphatidylcholine-Mixed Micelles system was developed for preparing the A01 injection,aiming to emergency treatment and new indications.Methods:single-factor experiment is applied to optimize the formulation and its preparation process.A sensitive and specific HPLC method was developed for the determination of A01 assay and its impurities.To characterize the mixed micelle,in terms of size distribution,zeta potential and shape,DLS and TEM were used.The stability of the final formulation was investigated both in accelerated and long term conditions.For the in vivo study,beagle dogs were used as model animals,the experimental group of dogs were injected the mixed micelle formulation at a constant speed and the control group were orally administrated capsules of Aol at the same of,a HPLC method was established for the determination of plasma eoncentration of AO l,and the pharmacokinetic parameters were obtained by Winnolin software.Results:sodium deoxycholate and soybean phospholipid were ultimately chose to prepare mixed micelle.DLS results showed that the size distribution and zeta potential were 11.53 nm and-33 mv respectively.TEM images showed a spherical shape of the mixed micelle.Results form Stress testing indicated that the formulation should be stored in dark place and at 4-8 degrees centigrade and the formulation showed a good stability in.Accelerated condition.In the in vivo experiment,the Cmax and AUCo·t of the mixed micelle injection were 10898.210±481.604 μg·L-1 and 3825.643±231.230 μg·L-1·h respectively in comparison with that the corresponding values for the oral administration group were 364.325±98.146 μg·L-1 and 641.449±78.834 μg·L-1·h,respectively.The injection showed 16.61-fold increase of relative bioavailability over that of capsule.Conclusion:An A01·Bile salt-Phosphatidylcholine-Mixed Micelles injection was successfully prepared after formulation and manufacture process optimization.It showed a very good long term stability and significant enhancement of bioavailability in vivo,suggesting that this formulation is very promising for the further development for the treatment of pulmonary hypertension stroke.