Solid Dispersions Preparation And Pharmacokinetics’ Study On High Melting-Point Insoluble Drug

ObjectiveImproving the solubility of insoluble drugs with high melting point is a difficult point for pharmacy.High melting point hydrophobic compound has a higher lattice energy,resulting in a lower bioavailability of the drug.Solid dispersions are a common method for improving the solubility of insoluble drugs by Hot Melt Extrusion(HME)or Spray Drying(SD)process.In this study,the BCS II drug tadalafil(melting point:302℃,water solubility:3.2μg/mL)was selected as the model drug of the insoluble drug with highmelting point。Four kinds of tadalafil solid dispersions were prepared by HME and SD technology.The main objective is to compare the physical and chemical properties of these four kinds of solid dispersion prepared by the four methods,in vitro dissolution,in vivo bioavailability and accelerate stability,in order to evaluate the advantages and disadvantages of these four methods and select the optimized method for preparation of the insoluble drug with high melting point solid dispersion.MethodTadalafil/mannitol HME solid dispersion,tadalafil/Soluplus SD solid dispersion,amorphous tadalafil/Soluplus HME solid dispersion and tadalafil/Soluplus SD-HME solid dispersion were prepared respectively.The four solid dispersions drug loading are in a range of 10%,20%,30%and 40%.The physical and chemical properties and microcosmic surface characterization of four kinds of solid dispersions was investigated by XRPD,DSC,SEM and AFM.Determination of the four solid dispersions drug content,apparent solubility,in vitro dissolution and in vivo SD rats and Beagle pharmacokenectics study were performed.ResultTadalafil dissolution speed was improved due to drug particle size d(0.9)of tadalafil/mannitol HME solid dispersion was decreased from 42μm to about 10μm.Mannitol shows no improvement for tadalafil apparent solubiliy.SD rats’pharmacokinetics study shows that tadalafil/mannitol HME solid dispersion relative bioavailability was 170.1%compared to API.XRPD shows that crystalline tadalafil was changed to amorphous and highly dispered in Tadalafil/Soluplus SD solid dispersion.Due to the drug water concentration increased to 28μg/mL within 5min,which is 8-fold compared to API,indicated that Soluplus can improve tadalafil apparent solubility.In SD rats’in vivo pharmacokinetic study,Tmax was 50%shorter than other preparations,SD rats’ relative bioavailability was 167.5%compared to API.Because of the large surface area and strong hygroscopicity,the powder aggregates and inhibits the release of the drug in the accelerated stability experiment.XRPD showed tadalafil partial crystallization in amorphous tadalafil/Soluplus HME solid dispersion.Dissolution rate and apparent solubility were lower than other formulations.SD rats’ pharmacokinetics study shows that tadalafil/mannitol HME solid dispersion relative bioavailability was 151.2%compared to API.Drug partial crystallization in this preparation,which is causing by extrusion and high temperature,affected the release of the in vitro dissolution.Powder aggregates and inhibits the release of the drug in the accelerated stability experiment.The appearance of tadalafil/Soluplus SD-HME solid dispersion was obviously different from other preparations and showed a transparent state which is suggested that the drug was highly dispersed in the carrier to became a single-phase solid solution.XRPD showed crystalline tadalafil was changed to amorphous in tadalafil/Soluplus HME solid dispersion at a range of 10～20%drug loading.SD rats’ relative bioavailability was 361.3%compared to API while Beagle dogs’ relative bioavailability was 169.5%compared to Cialis tablet.Powder aggregates and inhibits the release of the drug in the accelerated stability experiment.All XRPD spectrum shows no change compared to the solid dispersion initial states in one month accelerate stability test.ConclusionTadalafil/Mannitol HME,tadalafil/Soluplus SD,amorphous tadalafil/Soluplus HME and tadalafil/Soluplus SD-HME solid dispersion were characterized as microcrystal solid suspension,amorphous glass solustion,microcrystal glass suspension and amorphous glass solution,respectively.All of them can improve tadalafil bioavailability in SD rats.Tadalafil/Mannitol solid dispersion prepared by HME without organic solvent shows a good stablility,which is a suitable preparation for tadalafil solid dispersion.Tadalafil/Soluplus SD can be use for immediate release preparation based on its fast dissolution rate highest Cmax and shortest T0.5.Tadalafil/Soluplus SD-HME is the most significant preparation for the tadalafil bioavailability improvement.Drug/Soluplus Spray drying conbining with HME,is a novel method to prepare high melting point insoluble drug amorphous solid dispersion.HME amorphous glass solution is an interesting preparation to improve bioavailability.