Optimisation of an isoniazid dry powder formulation for pulmonary administration



The aim of this study was to improve the storage stability by optimizing the L-leucine coating of our previously described isoniazid formulation for pulmonary administration with the Twincer® or Cyclops® DPI. Time-of-Flight secondary ion mass spectrometry (TOF-SIMS) showed that trileucine results in higher leucine:isoniazid ratios of 29 and 38 at the surface of the particles, compared to the previously described L-leucine formulation, which has surface ratios of 11 and 28. The trileucine coating improves the stability considerably. All L-leucine formulations are stable for less than a day with the exception for the 3% and 5% formulations spray dried at 120 °C and stored at 0% relative humidity (RH), which are stable for at least a month. The trileucine formulations are stable longer. The optimum formulation contains 3% trileucine and is spray dried at 40 °C. It is stable for at least three months, even when exposed to 75% RH. This formulation is best dispersed with the Cyclops®. While the Twincer® results in a higher fine particle fraction (FPF), retention is considerably higher. As a result, the Cyclops® results in a higher fine particle dose. The Cyclops® can disperse 100 mg, which results in a fine particle dose of 61.9 ± 1.8 mg. However, 100 mg was the maximum that fit in the inhaler. Further research is needed to study whether a higher dose can be dispersed by increasing the size of the dose compartment, and if this increases the fine particle dose further.

Key Message

Isoniazid spray dried with 3% trileucine results in a powder suitable for inhalation which is delivered consistently from the Twincer® and Cyclops® inhalers. It is stable for at least three months, even when stored at 75% RH. This formulation might provide an improvement in tuberculosis therapy compared to standard treatment.

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