Category: Formulation and Quality
Purpose: Although the awareness and demand of individualized medicine has increased, some drugs may be suitable for alternative methods of improving drug efficacy and safety for a broader patient population. For example, the dissolution and subsequent intestinal absorption of a weak base drug is heavily dependent on dissolution at gastric pH levels prior to entering the duodenum. Thus, patients with elevated gastric pH (i.e. hypochlorhydria) may have lower systemic exposure upon administration of weak bases. In an attempt to elucidate and overcome this issue, this study investigated the dissolution behavior of three different ketoconazole (KTZ) formulations using a microscale medium/pH-shift gastro-intestinal in vitro model at normal (1.6) and elevated (5.0) gastric pH.
Methods: Three formulations were tested: crystalline KTZ, pure amorphous KTZ stabilized in Sylysia® 550FCP (SYL) at 20% w/w drug load (amorphous KTZ) and co-amorphous KTZ and oxalic acid (OXA) in a 1:1 molar ratio (co-amorphous KTZ:OXA). The amorphous KTX was loaded into SYL by melt quenching a physical mixture of the components at 150 °C followed by rapid cooling and grinding. The co-amrophous KTZ:OXA was prepared by ball milling a physical mixture of the components for 99 minutes at 30 Hz in a Mixer Mill MM 400 from Retsch GmbH (Haan, Germany). The successful amorphization of the two latter formulations was verified using X-ray diffraction. The dissolution behavior of the three KTZ formulations was tested using the µDISS profiler from Pion Inc. (Woburn, MA, USA). To simulate normal and elevated gastric pH conditions, 10 ml fasted state simulated gastric fluid (FaSSGF) adjusted to 1.6 or 5.0, respectively, was used as dissolution media for the first 30 min of the experiment. After 30 min, the dissolution medium was then shifted to a fasted state simulated intestinal fluid (FaSSIF) through addition of 1 ml of concentrated FaSSIF and NaOH to reach a pH of 6.5 for an additional 60 min of the experiment. The concentration of KTZ during the experiment was determined by integrating the second derivative from 280-350 nm using the Au Pro software (v. 5.5.2). Standard curves were prepared at different pH by spiking the FaSSGF/FaSSIF with a solution of KTZ in DMSO. To compensate for the lower volume of the dissolution vial compared to the human stomach after drinking a glass of water (10 vs 260 ml), the dose was lowered accordingly to 1:26 of the normal KTZ dose of 200 mg (i.e. 7.7 mg). To ensure proper wetting of the materials, the formulations were suspended by hand in a small volume of FaSSGF immediately prior to the experiment.
Results: The dissolution profiles for the three different KTZ formulations are shown in Figure 1. As can be seen in Figure 1A, all formulations display similar dissolution behavior and readily dissolve in FaSSGF pH 1.6 to reach the maximum dose of 770 µg/ml. After the medium/pH-shift at 30 minutes, the formulations then precipitate to reach a concentration of around 60 µg/ml as a result of the change in KTZ solubility at pH ≥ pKa. As can be seen in Figure 1B, the formulations do not display similar dissolution behavior in FaSSGF pH 5.0. Crystalline KTZ readily reach the equilibrium solubility of around 40 µg/ml whereas amorphous KTZ initially reach 385 µg/ml after 10 min, but then precipitates to reach a concentration of around 100 µg/ml due the high degree of supersaturation. In contrast, the dissolution behavior of co-amorphous KTZ:OXA in FaSSGF pH 5.0 is almost identical to that in FaSSGF pH 1.6. This is most likely caused by OXA lowering the pH of the FaSSGF to 3.6, and thereby increasing the equilibrium solubility of KTZ. This in vitro dissolution data indicates that co-amorphous KTZ:OXA will have similar systemic exposure in vivo in both healthy individual and patient groups with elevated gastric pH. Even though this was not demonstrated in this study, addition of a precipitation inhibitor such as hydropropyl methylcellulose (HPMC) to the co-amorphous formulation may further improve efficacy and safety compared to the marketed products.
Conclusion: The current study showed that (in contrast to crystalline or amorphous KTZ) a co-amorphous system containing KTZ and OXA display almost identical dissolution behavior at normal (1.6) and elevated (5.0) gastric pH. This finding indicate that co-amorphization of a weak base with an organic acid may negate the lower systemic exposure observed in patient groups with elevated gastric pH compared to healthy individuals.