Process for overcoming drug retention in hard gelatin inhalation capsules.

The quantity and consistency of drug delivery from dry powder inhalation devices that incorporate a pre-measured dose in a hard shell capsule of gelatin or other compatible material can be negatively affected by mold release lubricants used in capsule manufacturing. This paper describes a novel process employing supercritical CO2 for selective extraction of the fraction of lubricant responsible for the observed high and inconsistent drug retention in capsules and the ensuing lack of reproducibility of drug delivery. The process allows for lubricant removal from seemingly inaccessible interior surfaces of assembled capsule shells without altering the structural or chemical properties of the capsules. Diffusion limitations are overcome through repeated pressure increase and decrease to generate significant convective flow of dissolved lubricant out of the capsule. Drug retention is alleviated only if nearly all the retentive fraction of the lubricant is removed. The effect of extraction with supercritical CO2 on the structure of the internal surfaces of the capsules is investigated using scanning electron microscopy. Key performance parameters such as drug and carrier retention and fine particle mass are investigated using simulated inhalation tests. Laboratory and pilot scale extractions yielded similar results.