Microparticles for Inhalational Delivery of Antipseudomonal Antibiotics

Abstract

Abstract. Chronic pseudomonal bronchopulmonary infections in cystic fibrosis patients are frequently controlled with inhaled antibiotics. Dry-powder inhalable antibiotics are an attractive alternative to nebulized medications. We produced and evaluated microparticles composed of dipalmitoylphosphatidylcholine, albumin, and lactose as a model system for intrapulmonary delivery of ceftazidime, ciprofloxacin, and several combinations of the two, none of which is presently available for inhalation. Microparticles containing one or both antibiotics were prepared by spray-drying. Their Anderson cascade impactor deposition profiles showed 10-30% fine particle fractions of the nominal dose. Microparticles containing varying amounts of each antibiotic showed statistically different deposition profiles. Aerodynamics and deposition of microparticles co-encapsulating both antibiotics were similar to those of single-drug microparticles with the same proportion of ciprofloxacin alone. The antipseudomonal activities of microparticles co-encapsulating half of the 50% effective concentration (EC 50 ) of both ceftazidime and ciprofloxacin (5 mg of particles containing 5% ceftazidime and 10% ciprofloxacin) were at least additive compared to particles containing the EC 50 of each antibiotic separately (5 mg of particles containing 10% ceftazidime or 5 mg of particles containing 20% ciprofloxacin). Co-encapsulation of the antibiotics in microparticles ensures co-deposition at desired ratios, improves the particles' aerodynamics and fine particle fraction, as compared to microparticles with equivalent amounts of ceftazidime alone, and achieves additive antipseudomonal activity.

Inhalable Antibiotic Delivery Using a Dry Powder Co-delivering Recombinant Deoxyribonuclease and Ciprofloxacin for Treatment of Cystic Fibrosis

“…1, indicating that the particle morphology was dictated by the inactive ingredients (DPPC, lactose, and albumin) and not influenced by the presence of drugs. This result was anticipated, as the total drug content in this study was less than 5.5% w/w of the particles, and even particles with~50% drug content were previously reported to have similar morphology as blank particles (22). They consisted of small toroidal particles (1-3 µm in diameter) and larger spherical ones (~10 µm), which were hollow, as shown in the inset of Fig.…”

Lactose characteristics and the generation of the aerosol

“…These particles allow the incorporation of interface-sensitive peptides and have also yielded high pulmonary bioavailability of drugs [208,209]. A typical ratio of the excipients is DPPC:albumin:lactose at 3:1:1 [210,211]. In fact, lactose might offer the skeletal structure necessary for the formation of solid particles with a weak agglomeration tendency through spray drying [206].…”

Encapsulation of vegetable organogels for controlled delivery applications

“…tetanus toxoid) [9], and antibiotics (e.g. gentamicin) [10,11] get degraded in the stomach while non-steroidal anti-inflammatory drugs (e.g. aspirin) [12,13] cause irritation of the gastric mucosa which might result in the ulceration [14].…”