The Study Of Insoluble New Drug Tecovirimat Solid Dispersion Capsule

Tecovirimat(ST-246) is a low-molecular-weight compound (molecular weight=376.33), Which is active in fighting against multiple orthopoxviruses, including vaccinia, monkeypox, camelpox, ectromelia (mousepox), and especially cowpox, which has been vaccinated. The EC50value is0.01～0.05μmol, and the antitoxic capacity is5～50times than that of others. It can also prevent kinds of cowpoxvirus’ variation and reproduction. The purpose of the project is to find a new dosage-form for ST-246, by investigating tecovirimat’s chemical and physical properties and to prepare general capsule and solid dispersion capsule.It was found that the equilibrium solubility of ST-246in water was (3.35±0.15)mg·L-1at (37±0.5)℃. and the oil/water apparent partition coefficients of ST-246was230.49(LgP=2.36). It had the highest partition coefficients in n-octanol/pH4.0buffer solution system which reached to779(LgP=2.89). The pKa of ST-246was assayed by potentiometric titration. ST-246is hard to be dissolved in water and is almost insoluble in the gastrointestinal tract but with good permeability of the membrane, which shows that it can be prepare a new oral administration preparation of gastro-intestinal tract absorption by solubilization technology.According to the above experimental results, common capsules of ST-246was prepared. On the basis of the stability of pharmaceutical excipients’compatibility, the methods of the thinners, adhesives, drying temperature and time, and the preparation of disintegrating agent addition process were established by single factor investigation. Orthogonal experiment was designed through three main factors (thinner proportion, the amount of the binder and disintegration typese) and the index of45 minute dissolution rate. Then the optimal prescription was determined. And three batches of samples were perpared, and its quality control standard and stability were investigated. At present40%isopropyl alcohol solution is used for the dissolution medium for general capsules, but such a high concentration of organic solvent can’t be applied in current drug quality standards. So the solid dispersions will be prepared to improve its dissolution characteristics.ST-246SD was prepared by solvent and solvent-melting methods, and PVPk30, HPME E6, PVP VA64, PEG6000as carriers, The ratio of carriendrug is2.5:1. And its thermodynamic properties were determined by DSC and X-ray diffraction. The results indicated that ST-246completely dispersed in the carrier as amorphous state. SD dissolution experiment showed that:HPMC E6:ST-246SD was the most superior of them, greatly increasing the proportion and more dissolution. More optimized HPMC E6:ST-246SD capsule prescription and its technology were obtained by single factor investigation on preparation temperature, ratio of carrier:drug and solvent in which drug and carrier with the ratio of2.5:1were put in the beaker respectively before appropriate amount of anhydtous ethanol was added and mixed, followed they were evaporated by reduction vaporization at38℃to remove the solvent, they were sifted through a100mesh and preserved for drying before they were put in vacuum calorstat to be dried for24h at40℃.