Inhalable dosage forms containing difficult-to-formulate drugs : compositions and processing design space

Pulmonary drug delivery has recently gained much importance in the health care research area as it enables to target the drug delivery directly to lung both for local and systemic treatment. Despite extensive studies in the last decade, the development of inhaled formulations is still challenging, especially for difficult-to-formulate drugs such as macromolecule drugs and amorphous small molecule drugs. Due to the fragile nature of macromolecules, they are prone to degrade when exposed to physicochemical stress such as temperatures, pH, storage humidity, formulation component, atomization. The first two studies demonstrate the strategies to overcome the stability challenge of proteins and peptide in order to deliver a drug to the lung by nebulization. By the right selection of nebulizer and formulation optimization, the stability of fibrinolysins can be preserved after lyophilization, reconstitution, and nebulization using vibrating mesh nebulizers. Furthermore, the effect of counterion on the stability of peptide was studied in the second study. The formulation and processing were optimized to preserve volatile counterions, thus minimizing the pH change of reconstituted solutions and maintaining the stability of peptide. In addition to macromolecules, amorphous small molecules drug is another type of difficult-to-formulate drugs since they are thermodynamically unstable and thus tend to undergo crystallization during storage, which can affect the drug aerosolization and drug release upon deposition in the airway. The third study aimed to investigate the feasibility of thin film freezing to prepare dry powder for inhalation containing a high potency of amorphous tacrolimus. We found that using ultra-rapid freezing can increase drug loading up to 95% while maintaining good aerosol performance and stability. Finally, a new strategy to overcome the challenge in developing ordered mixture dry powder for inhalation was developed in the last study. We found that powders made by TFF ordered mixing process exhibited superior aerosol performance and less variation in content uniformity, compared to powders made by conventional powder blending. Throughout these studies, we can conclude that the right design of formulation and process can help to overcome the challenges in developing inhaled formulations of difficult-to-formulate drugs