Development of Inhalable Dry Powder Antibiotics and On-Bead Transcription Strategies

摘要

The global resurgence of tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) bacilli, has been driven by poverty, the development of drug resistance strains of Mtb, imperfect diagnostic assays, limited access to healthcare, poor healthcare infrastructure in the most highly infected areas, limited vaccine efficacy, lack of new drugs, and -- most profoundly -- the spread of HIV. Within this web of limitations dry powder inhalable antibiotics offer an opportunity to potentially reduce the lengthy treatment times associated with TB treatment. Incomplete tuberculosis treatment is the leading factor in the development of antibiotic resistant strains of Mtb. Inhalable antibiotics, by merit of specific aerodynamic diameters, are designed to target secluded populations of Mtb, often associated with extended treatment duration. The single dose, needle-free delivery strategies proposed here are an attractive treatment alternative for avoiding needle stick injuries and the transmission of blood-borne pathogens. Techniques incorporating Carbon-dioxide Assisted Nebulization with a Bubble Dryer® (CAN-BD) were used to develop several inhalable antibiotic formulations with desirable inhalation properties. This particle producing technique is versatile for producing particles from both antibiotic solutions and water-in-oil-in water emulsions. Particle properties such as fine particle fraction, emitted dose, moisture, particle size, and shape were characterized for several antibiotic formulations. Additionally, inhalable antibiotic microparticle formulations were tested in different dry powder inhalers. One of the inhalers was design enhanced, with a new anti-static innovation, to improve emitted dose. Finally a technique for improving In Vitro Selections, a unique evolutionary method for mediating new particle materials and catalyst, is explored.