| Objective:In order to optimize the preparation process of glycyrrhetinic acid complex TOGA-X4 microparticles to improve the microparticle-related properties,to reduce the average particle size and PDI,and to improve the rehydration.Using the microparticles prepared by the optimized technology as raw materials to prepare the micrometer-sized freeze-dried orally disintegrating tablets.Through change the administration's way of TOGA-X4 for oral administration to solve the disadvantages of inconvenient to use and low bioavailability.At the same time,providing new research ideas for the development and application of more insoluble drugs.Method:On the basis of the previous preparation process of the research group,the preparation process of glycyrrhetinic acid complex TOGA-X4 microparticles would be optimized.Using stainless steel rapid membrane emulsification method to prepare the microparticles,taking the average particle size(Z-average),polydispersity index(PDI),rehydration,drug content,PVA residue as the evaluation index,several key factors affecting the properties of the particles would be investigated to optimize the microparticles preparation process.Single factor investigation of disintegration time and tablet type were used to determine the preparation process of orally disintegrating tablets prepared by using microparticles as raw materials.The quality of the prepared orally disintegrating tablets was evaluated by investigating the disintegration time limit,weight difference,content uniformity and the release rate and degree in vitro,etc.By analyzing the in vivo pharmacokinetic parameters of beagle dogs administered in different parts of oral mucosa to determined the specific mode of administration of orally disintegrating tablets and the advantages of orally disintegrating tablets.Results:1.After optimization,the microparticles preparation process was partially changed:transmembrane pressure was changed from 0.4 MPa to 0.7 MPa,the curing temperature was reduced from 70?(atmospheric pressure)to 50?(vacuum),and centrifugal conditions were changed to10,000r·min-1,40min,and then washed that sediment with 10000 r·min-1,10min.The average particle size decreased from(944.3±81.3)nm to(640.3±60.75)nm,and the PDI decreased from(0.29±0.06)to(0.173±0.01).The drug content was(64.73±0.68)%,and the average PVA residual amount in the microparticles was(1.34±0.22)%.The moldability and rehydration were significantly improved compared with the previous ones.2.The prescription of orally disintegrating tablets was 20 mg microparticles/tablet,1.5%Pullulan,0.5%Tween-80,and 0.05%xanthan gum;freezing time was 5 min;The following was it's freeze-drying curve:put it in the freeze-drying box at-30?,kept for 60 min,then slowly increasing the tempreature to-5? within 25 min and holding-5? for 60 min,and then slowly increasing the tempreature to 25? within 30 min and maintaining 25? for120 min.The orally disintegrating tablets were white,full,complete,no slump and split,and could be rapidly disintegrated and dispersed in water.The average disintegration time was(1.07±0.20)s,the average tablet weight was(28.82±0.0008)mg,and the average drug content per tablet was(8.817±0.17)mg.The properties of heterogeneity,content uniformity,disintegration time limit and other properties were in line with the requirements of the fourth edition of the Chinese Pharmacopoeia of the 2015 edition.General in vitro release,in 0.5%sodium lauryl sulfate phosphate buffer at pH=6.8,the orally disintegrating tablets could release 50%in 4h and 95.96%in 24h.The fitted in vitro release curve was most consistent with the first-order kinetic equation,Q=93.22806(1-e^(0.0033t)),R2= 0.99014.3.The Beagle's own double-cycle cross-administration demonstrated that TOGA-X4 can be absorbed through the oral mucosa.The pharmacokinetic parameters associated with sublingual mucosal administration(n=6)could be seen:AUC(0-t)was(394.630±172.286)?g L-1·h,AUC(0-?)was(560.712±360.467)?g·L-1·h,MRT(0-t)was(13.805±5.636)h,MRT(0-?)was(16.378±7.461)h,t,/:was(10.473±6.265)h,CL was(53.555±33.957)L·(h·kg)-1,V was(578.497±184.567)L·kg-1,Tmax was(1.583±0.204)h,Cmax was(43.469±32.546)?g L-1,absolute bioavailability was 36.45%.The pharmacokinetic parameters associated with administration on the tongue(n=6)could be seen:AUC(0-t)was(396.019±202.958)?g·L-1·h,AUC(0-?)was(539.246±523.207)?g·L-1·h,MRT(0-t)was(14.833±1.958)h,MRT(0-?)was(30.735±26.399)h,t1/2was(18.582±25.955)h,CL was(57.381±25.896)L·(h·kg)-1,V was(834.115±517.318)L· kg-1,Tmax was(2.028±1.976)h,Cmax was(69.904±30.145)?g·L-1,the absolute bioavailability was 36.58%.The administration on the tongue of API,the dog(n=1)was only absorbed within 1 hour.The absolute bioavailability was about 0%.The administration on the tongue of microparticles,the Beagle dog(n=1)have absorption in the two time periods of 20 min to 4 h and 12 h to 24 h,and the relevant pharmacokinetic parameters could be seen:AUC(0-t)was 158.184 ?g·L-1·h,AUC(0-?)was 158.187?pg· L-1·h,MRT(0-t)was 12.876 h,MRT(0-?)was 17.662 h,t1/2was 1.604 h,CL was 131.237 L·(h·kg)-1,V was 303.679 L·kg-1,Tmax was 1.500 h,Cmax was 31.804 ?g·L-1,absolute bioavailability was 14.61%;The pharmacokinetic parameters of intravenous administration of beagle dogs(n=1)could be seen:AUC(0-t)was1082.655 ?g·L-11· h,AUC(0-?)was 4644.790 ?g· L-1hh,MRT(0-t)was26.157 h,MRT(0-?)was 135.820 h,t1/2 was 83.746 h,CL was 4.470L·(h kg)-1,V was 540.123 L·kg-1,Tmax was 48.000 h,and Cmax was 29.530 ?g·L-1.Conclusion:1.After the process optimization,the average particle size and PDI of the microparticles were reduced,the formability and rehydration were greatly improved,and the particle preparation efficiency was greatly improved.2.The orally disintegrating tablets were looked white and complete,and could be rapidly disintegrated and dispersed in a small amount of water.Each property was in line with the requirements of the fourth edition of the Chinese Pharmacopoeia.It has created possibilities for the clinical application of glycyrrhetinic acid complex TOGA-X4,and also provided new research ideas and methods for the development of poorly soluble drugs.3.Compared with the tongue administration,the sublingual mucosa of beagle orally disintegrating tablet had a higher blood concentration in the first 20 minutes.After 20 minutes,the difference between both of them was small,but the Cmax on the tongue was higher than Cmax under the tongue.There was no statistical difference in the other parameters.After comprehensive consideration,the specific mode of administration of orally disintegrating tablets was based on tongue administration.4.Through comparative experiments,it was found that the absolute bioavailability of the tongue and sublingual mucosa of the orally disintegrating tablets were about 36%,which was about 2.5 times that of the administration on the tongue of microparticles.The API was not absorbed in the body.The orally disintegrating tablets could be absorbed through the oral mucosa after disintegration in the oral cavity.At the same time,according to the pharmacokinetic behavior,it was speculated that the absorbed drug was not only the drug molecule but also the microparticles,and the microparticles were slowly released into the body,while the microparticle orally disintegrating tablet promoted the drug absorption compared with the microparticle,more drug molecules and microparticles were absorbed into the blood.After intravenous administration,greate absorption of drugs was found in all blood samples taken within 48 h,and blood drug concentration was relatively stable,it was speculated that it may be achieved the relative balance of microparticle release and drug metabolism. |
PDF Full Text Request