(W0930-09-56) Assessing the Performance of Lipids as Surfactants to Enhance the Release Profile of a Model BCS Class IV Compound from Amorphous Solid Dispersions (ASDs)

Purpose: The aim of this study was to develop amorphous solid dispersions (ASDs) of Anacetrapib, a model lipophilic, BCS IV active, using hot melt extrusion (HME) with lipid-based excipients (LBE) as surfactants to enhance their dissolution performance. A secondary objective was to develop a robust process for the incorporation of solid/ semi-solid excipients into powder blends suitable for hot melt extrusion without the need for specialized feeding ports.

Methods: The saturation solubility of Anacetrapib (API) was determined in LBEs at ambient temperature using hot-stage cross-polarized light microscopy (HSM) and Differential Scanning Calorimetry (DSC). Lipid-based formulations (LBFs) containing 20% w/w API and 80% w/w excipient were prepared and subjected to an in-house dissolution/dispersion testing in water by dispersing 1g formulation in 200 mL deionized water and in vitro lipolysis testing using digestion buffer. For ASDs, 10% surfactant concentrations were considered to be optimal based on the study conducted by Harmon et al., [1]. Hence, the ASDs consisted of 20% drug, 60 - 70% Copovidone, and 10% - 20% surfactant, namely Gelucire^® 44/14, Gelucire^® 59/14, Gelucire^® 48/16, and Labrafil^® M 2130 CS. Gelucire^® 44/14 was incorporated at 10%, 15%, and 20% to evaluate the impact of surfactant at different concentrations. A high shear granulator was used to incorporate molten LBEs, at 10-20% w/w, into the API-Copovidone premix, which was then processed using a twin-screw extruder equipped with a 3 mm die, operated at an approximate temperature of 160 °C. The extrudates were cooled, pelletized, and impact-milled through a 0.033" screen. The milled extrudates were characterized for their performance via dissolution studies in deionized water, in vitro lipolysis in digestion buffer, drug assay, and DSC analysis, all conducted in triplicate to ensure reproducibility. Dissolution testing involved dispersing 50 mg of milled extrudates mixed with 100 mg of Avicel 101 in 100 mL deionized water at ambient temperature, stirred at 150 RPM using a 1” magnetic stir bar. The in vitro lipolysis was conducted by dispersing 1 g of milled extrudates in 36 mL of pH 6.5 lipolysis medium for 10 minutes before and 60 minutes after adding porcine pancreatic lipase, quantifying the solubilized drug at regular intervals. A quantitative drug assay was performed by sampling three discrete regions of the pre-HME and HME processed formulation, followed by dilution and analysis using a validated UPLC method. DSC analysis was performed from 20 °C to 200 °C at a heating rate of 30 °C/min to assess and compare thermal behavior across the neat components, pre-HME blends, and milled extrudates.

Results: Anacetrapib demonstrated excellent solubility in all excipients, enabling incorporation of the target drug load of 200 mg/g in the formulation. LBF with Gelucire^® 44/14 exhibited higher drug solubilization upon dissolution testing. Additionally, upon in vitro lipolysis testing, the LBF with Labrafil^® M 2130 CS exhibited the highest drug solubilization (Figure 1). Dissolution studies conducted on pre-HME (HSG processed) blends demonstrated no solubilization of the drug across all formulations. However, dissolution testing of milled HME extrudates exhibited a substantial enhancement of the dissolution profile, with formulations containing Gelucire^® 44/14 and Gelucire^® 48/16 being able to solubilize the highest amounts of drug. Additionally, varying Gelucire^® 44/14 concentrations did not affect the drug dissolution profile significantly. Lipolysis testing of the milled extrudates showed drug dissolution levels below 10% across all formulations (Figure 2). Assay values for both pre- and post-HME samples suggest a good content uniformity for both samples (Figure 3). DSC thermograms demonstrated a reduction in melting enthalpy for all ASD formulations after undergoing HME processing, indicating their amorphous nature (Figure 3).

Conclusion: The results of this study show that LBEs can be effectively integrated into ASDs prepared by the hot melt extrusion method using with high shear granulator.Formulations using LBEs as surfactants exhibited enhanced drug solubilization in dissolution testing studies, likely due to their ability to facilitate drug diffusion into the test medium. ASDs with Gelucire^® 44/14 and 48/16 were able to enhance the solubility of the drug by 3-5x compared to the traditional ASD without surfactant (reference formulation). Additionally, Kesisoglou, F., et al., study indicates that the improvement of in vivo performance resulting from coadministration with a high-fat meal for Anacetrapib is significantly greater than the in vitro solubilization gains[2] by using a surfactant like Vit E TPGS. Given LBEs’ capability to trigger fed state condition, we hypothesize that the in vivo performance of ASD formulations using LBEs as a surfactant may enhance intestinal dissolution and permeation of Anacetrapib. As a next step, we are considering conducting in vivo studies to further assess the performance of these formulations and demonstrate the potential added benefits of LBEs as surfactants in ASD formulations.

References: 1. Harmon, P., et al., Mechanism of Dissolution-Induced Nanoparticle Formation from a Copovidone-Based Amorphous Solid Dispersion. Molecular Pharmaceutics, 2016. 13(5): p. 1467-1481.
2. Kesisoglou, F., et al., Effect of Amorphous Nanoparticle Size on Bioavailability of Anacetrapib in Dogs. Journal of Pharmaceutical Sciences, 2019. 108(9): p. 2917-2925.

In vitro lipolysis and Dissolution testing profile of Lipid based formulations (LBFs)

In vitro lipolysis and dissolution testing profile of milled hot melt extrudates

DSC thermogram of 10% Gelucire® 44/14 and comparison of assay values of HSG and HME samples