Track: Formulation and Delivery - Chemical - Formulation - Bioavailability Enhancement
Category: Poster Abstract
Rapid Development and Pharmacokinetic Evaluation of Amorphous Solid Dispersion with Minimal Material Use
Purpose: The purpose of this study was to utilize the miniaturized amorphous solid dispersion screening tools for identification of lead spray drying matrices and evaluation of their pharmacokinetic performance with PO mouse PK studies for a poorly soluble API. The lead matrix was then manufactured on a larger scale spray drier and evaluated in a mouse PK study. Methods: A visual solubility screening was conducted to find a suitable solvent system for the API. A UV standard curve of the API was determined in a Tetrahydrofuran:Water solution; standard solutions of the proprietary API ranging from concentration of 3.9 µg/mL to 125 µg/mL were measured for absorbance using UV Spectrophotometer (Molecular Devices, SpectraMAX Plus). MicroEvaporative (MicroVap) screening mixtures were prepared by adding appropriate amounts of polymer and API organic solutions to give 75:25 polymer:API and 65:35 polymer:API ratio into 1.5 mL microcentrifuge tubes. The solvent was removed in a Thermo Scientific Savant to give API-Polymer films. The solids in the microcentrifuge tubes were vortexed with pH 6.8 phosphate buffer for 4, 10 and 30 min, and API concentration was measured on the UV Plate Reader. The lead matrix systems were identified, and a dosing vehicle was designed to achieve 3mg/mL solubility from the lead MicroVap matrix tubes. This was done by preparing API-Polymer films of the leading matrices generated through a miniaturized screening tool and the films in the microcentrifuge tubes were vortexed with various dosing vehicles for 4, 10 and 30 min, and API concentration was measured on the UV Plate Reader. The dosing vehicle that showed concentration of 3mg/ml from amorphous matrices in tubes was selected. The matrix systems showing the best API in-vitro dissolution behavior in tubes were dosed in mice via oral gavage and AUCs were determined. 35:55:10 - API:Kollidon VA64:SLS matrix was picked as the lead and a prototype SDD was prepared with a Buchi B-290 spray dryer and characterized by PXRD and mDSC to ascertain API conversion from crystalline form to amorphous state. The Spray Dried Dispersion prepared at larger scale using a Buchi B290 spray dryer and the API alone as control were dosed in mice via oral gavage and bioavailability was compared to determine improvement in PK performance. Results: A total of twelve API-polymer systems were screened. The 35:55:10 - API:Kollidon VA64:SLS system showed a ~35 fold improvement and 35:65- API:Eudragit EPO system showed a ~31 fold improvement in API redissolution behavior. The vehicle system of 5% Captisol in 50:50 Water:Labrasol was found to achieve a 3mg/mL API redissolution from MicroVap matrices. API dissolved in neat PEG300 showed 100% dissolution and showed a bioavailability of 15.2%. Micro-evaporative tubes with 35:55:10- API:Kollidon VA64:SLS showed a slightly higher bioavailability of 12.5% compared to Micro-evaporative tubes with 35:65 API:Eudragit EPO that show a 11.8% bioavailability. The bioavailability of both MicroVap matrices were comparable to the bioavailability of neat API dissolved in PEG300. The protype SDD 35:55:10 - API:Kollidon VA64:SLS presented a bioavailability of 18.7%. The SDD did significantly better than API in 0.5% (w/v) Methylcellulose with a bioavailability of 0.538%. The bioavailability for SDD was found to be higher than the bioavailability of API in PEG300 in female mice. Conclusion: SDDs were successfully prepared based on results of the Micro-Evaporative screening study coupled with in house animal PK study. Kinetic dissolution successfully predicted the lead matrix systems of Eudragit EPO and Kollidon VA64-SLS polymer systems which enhanced API bioavailability. This Micro-evaporative screening study provides a rapid cost-effective means to rank order polymer matrices for amorphous dispersion development. The matrices prepared via solution engine can be used not only to rank order matrices during formulation development but also as a preclinical formulation with a predefined reconstitution vehicle for rapid PK analyses. The data obtained from solution engine correlates with SDD PK data which shows that solution engine is a highly effective technique that can be leveraged for rapid development of amorphous dispersions, thereby, reducing the development time for enabled formulations.