(M1130-12-83) A Data Based Approach to Selection of Bioavailability Enhancement Strategy Using New Simultaneous Dissolution-Flow Through Permeability for Formulation Development

Purpose: To investigate a strategy for screening and estimation of bioavailability enhancement (BAE) for BCS class II, III, and IV drugs. The process uses in-vitro flux of formulated products through biomimetic membranes in conjunction with early phase pharmacokinetic (pk) data from the drug substance to predict relative changes to bioavailability and estimate the area under the curve (AUC) for proposed enhancing formulation(s).

Methods: Materials: FaSSIF/FeSSIF (Biorelevant.com), Sodium Lauryl Sulfate-reagent grade (VWR), Poloxamer 407 (Sigma Aldrich), Vit. E TPGS (Parchem), SilSol 6035 (Grace), Kleptose Oral HP (Roquette), Polyvinylpyrrolidone (Alfa Aesar). Donor media: 20 mL FaSSIF, acceptor media 1% SLS. mFlux (Pion) and Permetro (Logan) combined dissolution and flow through side-by-side diffusion cell apparatus. Diffusion barriers: PVDF membrane, GIT-0 Lipid solution (small scale) or Permeapad Barrier (full scale). Detection with in sitsu fiber optic probes with PDA (200-720 nm) with 2 mm stainless steel probes (Pion, Billerica MA). Flux Testing: donor media-FaSSIF, acceptor media-1%SLS, temperature-37°C. Analysis: Minitab® statistical processing software. Excipient screening samples were prepared as micro-blends. Sample Preparation: The silica dispersion was prepared by dissolving the API in acetone and then loading/drying onto the base in repeated intervals. All samples were dosed at 4 mg for the small scale studies. Prototype formulation samples were prepared on the lab scale and dosed at 20 mg in HMPC capsules. Spray dried dispersion A (SDD) was prepared in acetone and methanol with HPMC-AS. SDD B was spray dried with HPMC. The micronized oral suspension was prepared using jet milled API dispersed in xanthan gum and poloxamer.

Results: The small scale screening (Table 1) indicated a linear correlation between the steady state solubility (saturation) and in-vitro flux. These data also trended with the expected linear regression model for the free dissolved fraction of drug (Figure 1) which was developed during earlier studies. The results also suggested that the amorphous silica dispersion showed the best improvement. Based on this, two small scale spray dried dispersions were prepared for the drug product trial as this process is more scalable compared to the silica dispersion. A micronized suspension was also selected to investigate a more traditional/pediatric acceptable dosage form. The flow through in-vitro flux results for the 3 drug product formulations (Table 2) indicated that both of the SDD’s improved the permeability of the drug ~170-220% compared to the native API used in the phase one pk study. The suspension formulation also demonstrated a relative increase in permeability of ~ 133%. From these data it was hypothesized that SDD formulation A would likely result in the highest increase in bioavailability, but both SDD formulations were expected to be similar. Using the results from the regression model, and previous in-vivo pk data for the native API (Table 2), estimated AUC/ranges for the new formulations were calculated. The span of the range was given by the 90% CI of the variance observed during the in-vitro testing. The in-vivo pk results (Table 2) confirmed that SDD A yielded the greatest increase in AUC compared to the native API ( >200%), and formulation B was only slightly less. The suspension also demonstrated an increased AUC of ~183%. The relative proportionality of the flux in the flow through cell was found to be similar to the relative AUC; and the percent agreement between the predicted and measured AUC for all three formulations was between 70%-100%.

Conclusion: The proposed approach to in-vitro screening and formulation selection demonstrated both discrimination and selectivity based on the formulation changes. In-vitro modeling of the flux data with existing in-vivo pk data for the drug substance demonstrated the potential for accurate prediction/estimation of changes to the AUC and potential utility as a tool for formulation development and de-risking early stage failures due to bioavailability problems.

References: Sironi D, Christensen M, Rosenberg J, Bauer-Brandl A, Brandl M. Evaluation of a dynamic dissolution/permeation model: Mutual influence of dissolution and barrier-flux under non-steady state conditions. Int J Pharm. 2017 Apr 30;522(1-2):50-57. doi: 10.1016/j.ijpharm.2017.03.002. Epub 2017 Mar 2. PMID: 28263834.
Cagno M, Bibi HA, Bauer-Brandl A. New biomimetic barrier Permeapad™ for efficient investigation of passive permeability of drugs. Eur J Pharm Sci. 2015 Jun 20;73:29-34. doi: 10.1016/j.ejps.2015.03.019. Epub 2015 Mar 31. PMID: 25840123.
Stewart A, Grass M, Mudie D, Morgen M, Dwayne F Vodak D. (2017). Development of a Biorelevant, Material-Sparing Membrane Flux Test for Rapid Screening of Bioavailability-Enhancing Drug Product Formulations. Molecular Pharmaceutics. 14. 0.1021/acs.molpharmaceut.7b00121.

Table 1: Small scale In-vitro solubility and flux screening for bioavailability enhancement.

Table 2: IVIVC Comparison for Selected Drug Product Formulations - Permetro® In-Vitro Flux and AUC Predictions with In-Vivo AUC Results

Figure 1: µFlux Comparison of small scale in-vitro flux results to the flux regression model for the API