Preparation of macromolecule-containing dry powders for pulmonary delivery.

Drug delivery by inhalation is routine for the treatment of local pulmonary conditions like asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Only recently, though, has the inhalation route been considered for administering drugs for systemic diseases. The pulmonary route is attractive for several reasons. It is non-invasive, it avoids first-pass metabolism, and it allows drug absorption from a large, highly vascularized surface area. However, consistent delivery to the deep lung requires drug particles within a very narrow size range. Several particle engineering approaches have been used to produce dry powders that will reach the alveolar space. Some of these methods, such as spray drying from solution, the formation of drug-containing liposomes, and the controlled crystallization of particles, are described here.

A delineation of diketopiperazine self-assembly processes: understanding the molecular events involved in Nepsilon-(fumaroyl)diketopiperazine of L-Lys (FDKP) interactions.

The Nepsilon-fumaroylated diketopiperazine of L-Lys (FDKP, 1) self-assembles into microparticles that can be used for pulmonary drug delivery. When these particles are formulated with insulin, the resultant powder (Technosphere Insulin) provides a novel prandial insulin therapy. To better understand the self-assembly of 1, a series of model compounds were synthesized that allowed for the determination of the preferred intramolecular hydrogen-bonding pattern of FDKP. Variable-temperature NMR (CDCl3) and FTIR studies of acyclic diamides (3-7a) and diketopiperazine models (7b- 9d) revealed the preference of a 10-membered hydrogen bond between one of the diketopiperazine's amido NH and the appended fumaramido-carbonyl (assigned as a "type B" H bond). Molecular modeling studies identified a low energy conformer in the architecture of 1, which contains two Nepsilon-fumaroylated lysine side chains appended to the diketopiperazine core. The lowest energy form involved a "cooperative" hydrogen bond motif which involved only one of the diketopiperazine amides and had one "arm" involved in a type B motif and the other in a "type A" hydrogen bond (i.e., the fumaramidyl NH H-bonding to the diketopiperazine amide carbonyl). This cooperative hydrogen bond scenario orients the appended fumaryl groups into a distinctive 90 degrees arrangement and is likely involved in its self-assembly into microparticles.