Effect Of Precipitation Inhibitors On PH-Induecd Phase Behavior And Pharmacokinetics Of Dl-Tetrahydropalmatine

dl-Tetrahydropalmatine（dl-THP）is a class of poorly water-soluble weakly basic compounds,and its solubility decreases with increasing p H.In the process of gastrointestinal transportation,dl-THP has high solubility in Fa SSGF.After it is transferred to Fa SSIF,the solubility decreases and reaches supersaturation instantly.Supersaturation is unstable and easy to precipitate,which reduces the drug concentration in the absorption site（small intestine）and affects its absorption,eventually leading to low bioavailability.Studies have shown that the polymer precipitation inhibitors（PPIs）has the effect similar to"parachute",which can delay the supersaturation precipitation process,thus improving their absorption and bioavailability.In recent years,PPIs have been widely used in supersaturated drug delivery systems to delay precipitation and maintain supersaturation,and different types of PPIs have different effects.At present,there is no report on the effect of PPIs on the p H-induced supersaturated phase behavior of dl-THP.Therefore,this topic has launched a series of studies on the effect of PPIs on p H-induced dl-THP phase behavior and its pharmacokinetics.This topic comprehensively studied the effects of PPIs on p H-induced dl-THP phase behavior and pharmacokinetics from three aspects:types of PPIs,treatment methods of PPIs,and the effects of pharmacokinetics.The specific research content is divided into the following 4 parts:1.The effect of HPMC K4M,HPMC AS MG,Soluplus on the p H-induced phase behavior of dl-THPTo study the effects of PPIs such as HPMC K4M,HPMC AS MG,Soluplus on p H-induced phase behavior of dl-THP in clinical oral administration,and to elucidate the possible mechanisms of PPIs.The p H solubility phase diagram was drawn by measuring and calculating the crystal solubility and amorphous solubility under different p H conditions.The p H solubility phase diagram was used to explain the p H-induced phase behavior of dl-THP in clinical oral administration.The effects of PPIs,such as HPMC K4M,HPMC AS MG,Soluplus on the phase behavior of dl-THP induced by p H at low,medium and high doses were analyzed by p H-shift dissolution experiments with the area under the concentration time curve and supersaturation as indexes.The mechanism of PPIs was analyzed by PLM,DSC,FTIR,and system viscosity determination.The results showed that p H induced dl-THP at a p H of 6.5 at the clinical oral administration dose,the supersaturation of dl-THP reached 3.93 instantaneously,and the supersaturation decreased to about 1 with the passage of time.HPMC K4M,HPMC AS MG,and Soluplus can maintain supersaturation at 200 min in the p H conversion dissolution test:the supersaturation was maintained to 1.19,1.89 at low dose（5%）,to 1.36,1.30,2.35,1.86 at medium dose（20%）,and to1.30,2.60,2.07 at high dose（50%）.In the p H-shift dissolution,the dl-THP precipitate exists in a crystalline state;the addition of PPIs had almost no effect on the viscosity;the FTIR spectrum of the precipitate after adding and not adding PPIs was shifted.In summary,dl-THP has a supersaturated crystal precipitation phase behavior under oral clinical administration doses.HPMC K4M,HPMC AS MG and Soluplus can all exert precipitation inhibition with different strengths through the formation of hydrogen bonds,and HPMC AS MG has an effect optimal.2.The effect of dl-THP/HPMC AS MG treatment on the p H-induced phase behavior of dl-THPTo explore the effect of PPIs/dl-THP treatment on p H-induced phase behavior of dl-THP.Direct mixing method,spray drying method,melting method,rotary evaporation method were used to prepareand other dl-THP/HPMC AS MG mixed samples（PM,SD,SSD,MSD,SSD-P）,XRD analyzed the existence of dl-THP,SEM was used to observe the microstructure;p H-shift dissolution was used to study p H-induced dl-THP phase behavior of dl-THP/HPMC AS MG mixed samples（PM,SD,SSD,MSD,SSD-P）.The results show that the dl-THP in the sample SSD prepared by the XRD spray drying method and the sample MSD prepared by the melting method existed in an amorphous state,and a small amount of dl-THP existed in the crystalline state in the SD sample prepared by the rotary evaporation method.dl-THP existed in a crystalline state in PM.The SSD-P and MSD samples had dense structures.In the p H-shift dissolution,different treatments had different effects on the p H-induced phase behavior of dl-THP The AUC_0-200minof each sample of PM,SD,SSD,MSD,and SSD-P is the value of dl-THP without HPMC AS MG.134.96%,123.44%,119.29%,115.53%,108.51%.In summary,different treatments had different effects on p H-induced phase behavior of dl-THP Various samples prepared by spray drying,melting,and rotary evaporation methods could not inhibit the dissolution of dl-THP in Fa SSGF,so they could not shows a stronger precipitation inhibition effect in Fa SSIF,and the direct mixing method is better than other treat ment methods.3.The effect of PPIs on the p H-induced phase behavior of dl-THP tabletsTo study the effect of HPMC AS MG on the p H-induced phase behavior of dl-THP tablets.This paper refered to the prescription composition of commercially available tablets（dl-THP,corn starch,dextrin,magnesium stearate）,and used HPMC AS MG as tablet excipients on the basis of the commercially available dl-THP tablet prescription.Parameters such as wetting agent type,drying time,lubricant dosage was determined through single factor investigation.Under the premise of maintaining the same drug-adjuvant ratio,the ratio of corn starch and dextrin was investigated,the prescription composition and preparation process of dl-THP were determined,and the quality of the prepared tablets was checked.Finally,the p H-shift dissolution was used to study the effect of HPMC AS MG.The final tablet prescription is dl-THP:HPMC AS MG:corn starch:dextrin:magnesium stearate=60:30:56:14:0.8.The tablets were prepared by wet granulation with water as wetting agent,dried at 37°C for 4 hours,and then granulated and compressed.The prepared tablets had a smooth appearance and a hardness of（43.08±1.93）N.The quality inspections were all in line with the requirements（tablet weight difference,Fragility,disintegration time limit and dissolution rate）.The addition of HPMC AS MG inhibited the supersaturation precipitation of dl-THP tablets.The supersaturation time of dl-THP was extended from 45min to 200min.The degree of supersaturation was 1.43 times that of commercially available dl-THP tablets,and the AUC_0-200minincreased 36.95%.In summary,HPMC AS MG improved the p H-induced phase behavior of dl-THP tablets,increased the degree of dl-THP supersaturation and extended the duration of supersaturation.4.Effect of PPIs on pharmacokinetics of dl-THP in rabbitsTo study the effect of HPMC AS MG on the pharmacokinetics of dl-THP rabbits.According to the dosage of dl-THP（5.6mg/kg）,rabbits were given tablets containing HPMC AS MG and tablets without HPMC AS MG（commercially available dl-THP tablets）by gavage to study their pharmacokinetics difference.The results show that,compared with tablets without HPMC AS MG,tablets containing HPMC AS MG have higher C_maxand AUC_0-t.The C_maxand AUC_0-tof the tablets containing HPMC AS MG were 122.29%and 126.02%,respectively.In summary,HPMC AS MG can increase its bioavailability by affecting p H-induced phase behavior of dl-THP,increasing its absorption in vivo.