(T1230-01-04) Enteric Coating of an Amorphous Solid Dispersion: An Emerging Strategy to Enhance the Dissolution Performance in Stimulated Gastrointestinal Fluids

Purpose: Delamanid (DLM), an antituberculosis compound, is a weakly basic drug with a high tendency to crystallize in the solid state and in aqueous media. Our previous work indicated that salt formation with ethanedisulfonic acid or hydrochloric acid enhanced the physical stability of amorphous formulations. In addition, dissolved enteric polymers including hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP) were found to be effective at maintaining drug supersaturation and inhibiting crystallization. Amorphous solid dispersions (ASDs) of the DLM edisylate or hydrochloride salt with either HPMCP or HPMCAS led to excellent drug release in phosphate buffer solution (PBS, pH 6.5). However, these polymers are un-ionized and insoluble in acidic environments, leading to reduced crystal growth inhibition effectiveness. Thus, we hypothesized that it is important to minimize contact of the formulation with acidic milieux by adding an enteric coat to the ASD tablet. The overall aim of this study was to evaluate the impact of an enteric coating on the drug release profile of a tablet containing a DLM ASD with HPMCP-50 following immersion in an in vitro gastric compartment with differing pH values.

Methods: ASDs of DLM free base or DLM salt were prepared at 25% drug loading with HPMCP-50. DLM-edisylate-P50 ASD was prepared by rotary evaporation using dichloromethane (DCM) and acetone (1:1 v/v) while ASDs of DLM free base and DLM hydrochloride were obtained by spray drying using DCM-methanol (1:1 v/v). Counter ion was added at a 1:1 molar ratio to drug. Drug crystallization on the ASD particle surface was detected by polarized light microscopy (PLM) and scanning electron microscopy (SEM). Tablets of DLM ASD were enteric coated with Acryl EZE II with a 15% weight gain. Dissolution studies were performed with uncoated and coated tablets of the ASD at 37^oC, 150 rpm in a single stage medium (PBS, pH 6.5) or using pH-shift experiments, first dissolution stage at acidic pH (aqueous hydrochloric acid solution, pH 1.6 or PBS at pH 3.0 or pH 5.0) for 60 minutes followed by dissolution in PBS pH 6.5 for an additional 30 minutes. Drug release was determined using an in situ dissolution monitoring system based on fiber optic UV spectroscopy.

Results: Drug release in a higher pH medium was more than 80% for both DLM free base and DLM salt ASDs (Figure 1). However, delamanid is a weakly basic drug which has higher solubility at low pH value. Thus, even though the ASDs were prepared with acid insoluble enteric polymers, the leaching of drug in the gastric fluid was notable, especially at pH 1.6. Furthermore, the acidic incubation resulted in an incomplete release when transferred to a higher pH solution, which is likely due to drug crystallization on the surface of ASDs during immersion in the gastric stage. Figure 2 indicated that delamanid has a higher tendency to crystallize in solutions of intermediate acidity, where the pH of dissolution medium (pH 3.0) was closed to the drug pKa (pKa 4.3). Enteric coating with Acryl EZE II minimized drug release into simulated gastric fluids at pH 1.6; pH 3.0 or pH 5.0 (Figure 3). Dissolution of enteric coated tablets in higher pH medium after initial acidic immersion was similar single stage dissolution in higher pH dissolution medium. This suggests that minimizing the contact between the ASDs and acidic environments is important to maintain the robust release profiles.

Conclusion: ASDs formulated with an enteric polymer achieved good release in media with a pH corresponding to intestinal media. However, drug crystallization was observed during immersion in simulated gastric fluids of intermediate acidity, leading to incomplete release after pH shift to intestinal pH conditions. Applying an enteric coating to an ASD tablet formulation was found to be effective at maintaining a good release profile following immersion in acidic fluids of various pH levels. This protective coating might be important to reduce absorption variability due to the variations in gastric pH.

Acknowledgements: The Bill and Melinda Gates Foundation is acknowledged for funding this study through award number OPP1159809.


Figure 1: Drug release profile of uncoated tablets of DLM free base ASD and DLM salt ASDs with HPMCP-50 at 25% drug loading. Dashed lines indicate pH shifting from acidic to high pH


Figure 2: Crystallization on ASD surface after immersion in PBS pH 3.0 for 1h confirmed by (A) SEM and (B) PLM


Figure 3: Dissolution of enteric-coated tablets of DLM free base or DLM salt ASDs