| Schizophrenia is a common,chronic psychosis with unclear mechanisms,mainly manifested by psychotic symptoms(such as hallucinations,delusions,and confusion),behavioral and cognitive dysfunction.DT-195 is a new compound that is poorly soluble during preclinical development.It has high affinity for 5-HT receptor and DA receptor,and is expected to become an original antischizophrenic drugIn the process of drug development research,we must first conduct a systematic preformulation study of the drug,in order to fully grasp the physical and chemical properties of the drug to provide guidance for the later development of preparations.In this paper,the quality properties of DT-195 are firstly studied,including the appearance characteristics,crystallinity,solubility,melting point,the equilibrium solubility of API at different pH values of high and low ion concentration,the apparent oil-water partition coefficient and other parameters.DT-195 is a kind of off-white crystalline powder,which is a prismatic prism crystal structure without crystal water,and melting point is 228.72?.DT-195 is sparingly soluble in methanol and 1,2-propanediol,slightly soluble in water and ethanol,and very slightly soluble in acetonitrile.The equilibrium solubility decreases with the increase of the solvent pH value and ion concentration,and shows insoluble properties when pH=7.4 and 7.8.The apparent oil-water partition coefficient(LgP)of DT-195 is 0.23.It is necessary to improve the solubility and oral bioavailability through self-emulsification technologyIn addition,the HPLC analysis method for content and related substances determination of DT-195 was established,and systematic methodology validation was conducted for the first time in this article.The determined chromatographic conditions are:Vensuil MP C18(5?m,4.6mm×250mm)as the chromatographic column,methanol:0.020 mol/L potassium dihydrogen phosphate solution(phosphoric acid adjusted to pH3.0)=60:40 isocratic elution as mobile phase,flow rate 1.0 ml/min,detection wavelength 284nm,column temperature 25?,injection volume 20?l.The system suitability,linearity,precision,recovery rate,solution stability,durability,sensitivity,and specificity of the analysis method were mainly validated.The established method is accurate and reliable,and meets the measurement requirementsBased on the above preformulation study,this article conducted a formulation study of DT-195 SMEDDS preparation.By measuring the equilibrium solubility of DT-195 in different oil phases,surfactants and cosurfactants,it was determined that glyceryl monolinoleate(Maisine CC)is the oil phase,polyoxyethylene hydrogenated castor oil(Cremophor(?)RH40)is the surfactant and 1,2-propanediol is the cosurfactant.Based on the determination of the optimal formulation components,according to the pseudo-ternary phase diagram,the range of each component that can form self-emulsification is:Maisine CC 20%-50%,Cremophor(?)RH40 40%-80%,1,2-propanediol 0-40%(w/w).Finally,the optimal formulation is determined by the D-optimal mixture design-response surface method,and the optimal formulation is validated verified.The selected model has ideal predictability and the experimental design is reliableBased on the above DT-195 SMEDDS formulation study,the quality of the DT-195 SMEDDS formulation was evaluated.The main factors affecting drug absorption were evaluated including appearance,particle size,Zeta potential,percent transmittance,dilution stability,drug content,etc The appearance of the prepared DT-195 SMEDDS is a clear slightly viscous liquid with light yellow.After being diluted by distilled water with appropriate multiples,the emulsion is clear and transparent with a slight blue light.transmission electron microscopy observed that the emulsion droplets are round and normal,and the particle size distribution is uniform.The average particle size of the emulsion droplets is 125.45±5.02nm,the Zeta potential is-9.40±0.44mV,and the percent transmittance is 74.40±1.32%.The effects of different dispersion media,temperature and rotation speed on the self-emulsification rate,as well as the influence of different dispersion media and rotation speed on the particle size of emulsion droplets were investigated.The content determination results of 3 batches of DT-195 SMEDDS were in the range of 98%-102%,and the RSD value was less than 2.0%,which met the requirements.The study on the stability of DT-195 SMEDDS after dilution showed that the particle size,content and appearance color of the emulsion did not change significantly within 6 hours,and no drug precipitation,indicating that the diluted emulsion was in distilled water,pH1.2 HCl,ph6.8 PBS can be stable in all three mediaFinally,a preliminary pharmacokinetic evaluation of DT-195 SMEDDS preparation in rats was carried out.The method for determining the content of DT-195 in plasma samples was established.plasma samples were measured within 24 hours after gavage of DT-195 suspension(reference preparation)and DT-195 SMEDDS(experimental preparation)in SD rats.The pharmacokinetic parameters comparison results showed that after oral administration of DT-195 suspension and DT-195 SMEDDS in SD rats,the plasma concentration quickly reached the peak concentration within 1 h.However,AUC0-t,AUC0-? and Cmax of DT-195 SMEDDS were significantly higher than that of DT-195 suspension,which were 2.27 times,2.23 times and 2.32 times of DT-195 suspension,respectively.Compared with the same dose of DT-195 suspension,the Frel of DT-195 SMEDDS was 227.16%.In summary,DT-195 SMEDDS can effectively improve the oral bioavailability of DT-195 in SD ratsIn short,in this study,insoluble antischizophrenia new drug DT-195 was prepared into a well-absorbed SMEDDS preparation with the drug loading of up to 25mg/g.DT-195 SMEDDS can effectively improve the oral bioavailability of DT-195 in SD rats.Provide scientific support for the development of the oral preparation of the drug. |
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