(M1330-09-50) Bioequivalence Prediction with Dissolution-Permeation Set Up and tinyTim for Amorphous Solid Dispersion Manufactured by a Novel Co-precipitation Process and Spray Drying

Purpose: Enabling formulation are often needed to ensure sufficient in-vivo bioavailability of poorly water-soluble drugs. Amorphous solid dispersion (ASD) is one of the promising strategy for enhancing oral bioavailability by increasing solubility and/or dissolution rate, improving the driving force for oral absorption. However, the drug release behavior, the impact of supersaturation, precipitation and drug speciation along the gastrointestinal tract on oral absorption is not well understood and make it difficult to predict the in-vivo performance of supersaturating formulation. In this study, we propose the use of in-vitro biopredictive tools; dissolution-permeation assays (µFLUX, BioFLUX) and a multi compartment gastrointestinal model (tinyTIM) to assess the performance of crystalline drug, ASDs intermediate manufactured using a novel co-precipitation process or a spray-drying process and formulated ASDs.

Methods: ASDs of a BCS class II drug and polymer A were manufactured using a spray-dried and a novel co-precipitate based process. Formulated immediate release tablets containing spray-dried (SDD) or co-precipitated intermediate with filler and disintegrants were directly compressed before testing. In-vitro dissolution-permeation studies were carried out using µFLUX or BioFLUX apparatus (Pion Inc., Billerica MA, USA) which consist of a donor and a receiver chamber separated by an artificial membrane (polyvinylidenfluoride filter impregnated with GIT Lipid, Pion Inc. solution). Measurements were performed using canine fasted state simulated intestinal fluid (FaSSIFc) in the donor side and Acceptor Sink Buffer (ASB pH 7.4) in the receiver compartments. Unformulated ASDs powder or formulated tablets were added into the donor compartments of the µFLUX or BioFLUX respectively and concentration was monitored for 2-3 hours in both chambers using in-situ monitoring technique implemented with Rainbow fiber optic UV-Vis spectrometer (Rainbow R2D8, Pion Inc). In-vitro release profiles from tinyTIM, a multi compartmental model that simulates gastrointestinal tract luminal condition, were collected in the fed state using the protocol specific procedure provided by TIM company. Samples were collected up to 6 hours and analyzed by HPLC.

Results: In-situ concentration time profiles from donor and receiver chambers for crystalline API and ASDs powder were collected in µFLUX for initial screening of ASDs intermediate performance. In-situ concentration time profiles from donor and receiver chambers of formulated tablets were collected in the BioFLUX to assess formulation performance. Intermediate powder and formulated ASDs showed similar dissolution profiles with a faster initial release seen for co-precipitated material. Overall, dissolution of ASDs were significantly greater ( >15 fold) than dissolution of crystalline API. The flux across the membrane representing the amount of drug substance crossing a unit area of the membrane per unit time, was calculated from the concentration-time profiles in the receiver compartments using AuPro software in a range that capture the initial rate as the drug enter the receiver compartment. Flux values for SDD and co-precipitated in FaSSIFc were similar with slightly higher Flux seen for co-precipitated tablets: Flux ratio (co-precipitate/SDD): 1.1. In-vitro release profiles from tinyTIM were collected for both formulated ASDs in the fed state. Tablets from co-precipitate have similar bioaccessible fraction and maximum bioaccessibility when compared to SDD for the 6 hr run (14.3 mg and 13.3 mg respectively). Co-precipitate material did have a faster onset in the fed state compared to SDD. In-vivo PK studies were performed in 4 male beagle dogs pre-treated with Famotidine to increase their stomach up to pH 6-7. The plasma concentration profiles after single oral administration for both ASD formulations are similar with comparable pharmacokinetic parameters (Cmax, Tmax and AUC). C(max) and AUC were approximately 1.5 fold higher for co-precipitate tablets compared to the SDD tablets while time to reach the maximum plasma concentration was comparable for both formulations.

Conclusion: A quantitative correlation of Flux, tiny TIM and animal exposure shows that the flux-based approach was able to predict bioequivalence of ASDs formulation. This study shows that the small-scale in-vitro dissolution-permeation setup could be used as a screening tool to assess the impact of process parameters, drug loading on the bioperformance of ASDs using a small amount of unformulated intermediate under biorelevant condition. the larger dissolution-permeation setup could be used to establish bioequivalence of formulated ASD tablets using different processes under biorelevant condition. Overall, the flux-based approach, could guide formulation development of supersaturating formulations.