Preparation And Characterization Of Indomethacin Supersaturating Drug Delivery Systems

With the application of combinatorial chemistry and high-throughput screening in drug discovery,an increase of poorly water-soluble drug candidates has emerged.Especially for the drug of BCS II with low solubility and high permeability,it is the key to improving the solubility and dissolution rate to increase the bioavailability of the drug.Supersaturating drug delivery systems(SDDS)are one of the strategies to solubilize the poorly water-soluble drug,where the concentration of dissolved drugs in systems can be much higher than the equilibrium solubility of the stable crystal form.However,due to its thermodynamic instability,the drug molecular probably precipitates in vivo before being absorbed,resulting in compromised bioavailability.Among them,amorphous solid dispersions(ASD)have been increasingly utilized as an effective SDDS,and their dissolution and stability are related to carrier materials.In this study,indomethacin(IND)was selected as the model drug.From the perspective of the functional characteristics of the carrier material,the carrier of solubilization function was combined reasonably with the material as inhibitor of precipitation to prepare the ternary ASD by the hot melt extrusion(HME)based on the evaluation of the functional properties,in order to improve the drug dissolution and the solution stability and give full play to the solubility advantages of SDDS.Firstly,in the preformulation research,the simple and feasible ultraviolet and visible spectrophotometry cuvette method and fiber optic probe method were established to determine the drug content and dissolution in vitro.The methodological verification was carried out separately,and the recovery rate and precision met the requirements,indicating the feasibility of the method.Secondly,based on dissolution tests,six carrier materials such as Eudragit EPO,PVP K30,Kollidon VA64,Soluplus,HPMC E5 and Poloxamer 188 were evaluated with solubilization function on IND.The results showed that Eudragit EPO could dramatically increase the drug dissolution.And the binary IND-EPO ASD with a mass ratio of 1:2 released more than 80% drugs within 5 minute.However,as the dissolved drug crystallized,the drug concentration gradually decreased thereafter.In order to maintain the drug supersaturation,the carrier with precipitation inhibition effect should be introduced to the binary IND-EPO ASD system.The results of the solution transfer method and the dissolution in vitro showed that although PVP K30,Kollidon VA64 and HPMC E5 had little effect on drug solubilization,they could effectively inhibit the drug crystallization and precipitation.The ternary IND-EPO-PVP K30 ASD,IND-EPO-VA64 ASD and IND-EPO-HPMC E5 ASD supersaturated system with a mass ratio of 1:2:0.3 could maintain the drug dissolution more than 90% within 1 h,eliminating the drug precipitation during the dissolution process.Through the differential scanning calorimetry(DSC)and the power X-ray diffractometer(PXRD)analysis,the drug existed in an amorphous form in the ternary system.The stability test proved that the drug could maintain the amorphous form within 6 month and the physical stability was well in ternary ASD.Morever,the solubilization mechanism of the ternary IND ASD supersaturation system was discussed from the aspects of solubility promotion and precipitation inhibition.It was found that Eudragit EPO could increase the wettability and improve the solubility of IND.With Eudragit EPO increasing,the proportion of amorphous drugs in the system raised.Under the condition that the mass ratio of drug to Eudragit EPO was 1:2,the drug could exist in completely amorphous form,which promoted the system to produce high supersaturation and greatly improve the drug dissolution.In addition,it was proved that PVP K30,Kollidon VA64 and HPMC E5 had capability to inhibit the nucleation and/or the crystal growth involved in the drug precipitation process with different degrees.In the absent of polymers,the induction time of IND was 3.40 min.In the pre-dissolved PVP K30,Kollidon VA64 and HPMC E5 in the solution,the induction time of IND was 70.69 min,80.89 min and 31.37 min,respectively.Finally,the solubilization effect and the precipitation inhibition effect of the carrier material were comprehensively considered.The combined impact on the drug dissolution and precipitation were explored,that was,the dissolution behavior of the IND SDDS.Taken precipitation inhibitors PVP K30 for example,the influence of the carrier with precipitation inhibition effect on the dissolution behavior of SDDS was investigated.It was found that PVP K30 had the opposed effects on drug dissolution and precipitation for IND SDDS in the low supersaturation system IND-EPO 4:1 ASD or the high supersaturation system IND-EPO 1:2 ASD.A small amount of PVP K30 could effectively control the drug precipitation,but the addition of excessive precipitation inhibitors might negatively impact the dissolution of IND.This opposed effect of PVP K30 was strengthen in ternary co-extrution prepared by HME of IND,Eudragit EPO and PVP K30,which provided theoretical basis for the rational design and development of SDDS for poorly water-soluble drugs.Furthermore,decreased the dissolution medium,the dissolution behavior of IND-EPO-PVP K30 ASD,IND-EPO-VA64 ASD and IND-EPO-HPMC E5 ASD were compared.It was showed that reducing the volume of the medium would cause the system to reach a higher degree of supersaturation and followed precipitation.However,due to the single dissolution medium,the dynamic dissolution behavior of SDDS in vivo could not be predicted.An artificial stomach-duodenum model was built to simulate the dynamic dissolution process in vivo.The results showed that the area under curve(AUC)of the IND,binary IND-EPO ASD,ternary IND-EPO-PVP K30 ASD,IND-EPO-VA64 ASD and IND-EPO-HPMC E5 ASD in the artificial stomach chamber were 0.51,1.57,2.47,2.75 and 2.70 mg?min/m L,respectively and in the artificial duodenal chamber were 0.45,1.27,1.66,1.77 and 1.58 mg?min/m L,respectively.This indicated that the ternary supersaturated IND ASD system increases the gastrointestinal absorption of drugs compared to the IND and binary IND ASD systems.