Track: Formulation and Delivery - Chemical - Formulation - Bioavailability Enhancement
Category: Poster Abstract
Using Microevaporative Screening Studies in Development of Amorphous Dispersions for Phase I Clinical Trials
Purpose: The purpose of this study was to generate amorphous solid dispersions (ASD) using spray drying and hot melt extrusion with minimal amount of API. The best approach for generating stable amorphous dispersions was selected for rat and dog pharmacokinetics (PK) studies. The prototype with optimal PK profile was scaled-up, placed on stability and used for phase 1 clinical trials. Methods: Miscibility of API and polymers - polyvinylpyrrolidone-vinyl acetate (Kollidon VA64), hypromellose acetate succinate (HPMCAS), and dimethylaminoethyl methacrylate-copolymer (Eudragit EPO) was evaluated using Modulated Differential Scanning Calorimetry (MDSC). Binary matrices of API and polymers were prepared in microcentrifuge tubes using Thermo Scientific Savant Speed Vac concentrator system. These matrices were analyzed for dissolution. Based on miscibility and solubility results, polymers-API combinations with highest solubility were prepared at larger scale using hot melt extrusion (HME) on a Thermo Scientific Haake Mini CTW extruder and spray dried dispersion (SDD) on a Buchi B90 nano spray dryer technologies. Solubility of these ASDs was evaluated using a Non-Sink Dissolution System in fasted simulated gastric fluid (FasSGF) and fasted simulated intestinal fluid (FasSIF). Based on dissolution results, multiple prototypes were selected for pharmacokinetic (PK) studies in Sprague Dawley male rats and Male Beagle Dogs via oral gavage at 5mg/kg dose. API suspended in 0.5% carboxymethyl cellulose (CMC) solution was used as positive control. A comparison was made based on the AUCs and the final prototype was selected for scale-up to Anhydro MS-35 spray dryer. Results: DSC results showed reduction/ absence of API melting peak in binary mixtures containing API:Kollidon VA64 and API:Eudragit EPO at 25:75 ratio. Micro evaporative screening results showed superior solubility enhancement in mixtures containing API:HPMCAS and API:Eudragit EPO at 25:75 proportion. Therefore, API:Kollidon VA64, API:Eudragit EPO mixtures at 25:75 proportion were selected for hot melt extrusion and API:HPMCAS, API:Eudragit EPO mixtures at 25:75 proportion were selected for spray drying. Non-Sink Dissolution results in both media indicated that API:EudragitEPO extrudate and SDD showed superior release compared to API:KollidonVA64 extrudate and API:HPMCAS SDD respectively. Non-Sink Dissolution results in both media confirmed that the SDDs performed better than the hot melt extrudates likely due to higher surface area in SDD enabling higher kinetic solubility. API:HPMCAS SDD, API:Eudragit EPO extrudate and API:Eudragit EPO SDD were selected for PK studies in rats to confirm in-vitro findings. API:Kollidon VA64 extrudate was eliminated for PK studies since it showed no increase in dissolution compared to neat API. Pharmacokinetic results in rats confirmed that SDDs show higher AUCs compared with hot melt extrudates. Contrary to in-vitro results, API:HPMCAS SDD’s showed higher AUCs compared with API:Eudragit EPO SDDs.. The AUCs are tabulated in the table 1. Based on the pharmacokinetics results from rat studies, API:HPMCAS SDD and API:Eudragit EPO SDD were selected for confirmatory pharmacokinetic studies in dogs using different vehicles (citrate buffer, phosphate buffer, 1%HPMC/ 0.1%Tween80 solution). Pharmacokinetic results from dogs confirmed that API:HPMCAS SDD showed superior AUC compared to API:Eudragit EPO SDDs in citrate buffer and phosphate buffer. Though API:Eudragit EPO SDDs shows slightly better AUC compared to API:HPMCAS SDD in 1%HPMCAS/ 0.1%Tween 80 solution, the standard deviation of the AUCs was very high. The AUCs observed in dog pharmacokinetics study are reported in the table 2. Based on the pharmacokinetic results in rats and dogs, API:HPMCAS SDD was selected for further scale-up in MS-35 spray dryer. API:HPMCAS SDD prepared using MS-35 spray dryer were amorphous and showed superior solubility. Spray Drying did not result in an increase in impurities. API:HPMCAS SDD prepared using MS-35 confirmed stability of ASD at accelerated conditions (40°C/ 75%RH) for 6 months. Conclusion: A highly sophisticated miniaturized screening of ASD matrices, solution engine, combining in-vitro and in-vivo animal PK studies lead to the selection of best API:polymer combination for SDD/HME manufacturing. A comparison of ASDs prepared by SDD and HME showed highest plasma AUC levels of the API for SDDs powders compared to extrudates prepared using hot melt extrusion. The spray dried dispersion also was successfully scaled-up to a larger spray dryer and showed good stability at accelerated conditions. The final API:HPMCAS amorphous solid dispersion formulation was then manufactured under GMP conditions and delivered to healthy volunteers in a Phase I clinical trial dosed as an oral suspension.