Carrier-free high-dose dry-powder inhaler formulation of non-steroidal anti-inflammatory drugs

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2016-08

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Abstract

Ibuprofen (IBU) is a non-steroidal anti-inflammatory agent (NSAID) is administered orally as tablets and suspensions. It is indicated for pain, fever, and other inflammatory conditions. More recently, a slower rate of respiratory decline is shown in cystic fibrosis (CF) patients on high, oral doses of IBU in comparison to placebo. The use of this treatment modality has not been well adopted or widespread due to high doses, side effects, contraindications, and black box warnings regarding the use of IBU. Pulmonary delivery may be an attractive alternative to high-dose oral administration in CF since lungs are the desired targets for the anti-inflammatory and antibiotic activities of IBU. Typically with inhaled powders, a binary formulation of a drug with a carrier, such as lactose, significantly improves their performance; however, this strategy is not practical for the delivery of a large drug dose via a dry powder inhaler (DPI). Other inhalation devices such as nebulizers require significantly more time for drug delivery and metered dose inhalers may be incapable of metering sufficiently large drug doses. Therefore, carrier-free DPIs have been explored for large drug dose delivery. IBU exists as the stable polymorph I (in its acicular crystal habit), or as the less stable polymorph II. Low melting point (75.85°C), water solubility, and crystal habit of ibuprofen make its processing challenging. A novel air-jet milled carrier-free formulation of IBU was developed using the design of experiment approach, which possessed superior flowability, in-vitro aerodynamic performance determined by Next Generation Impactor. Furthermore, the developed formulation possessed at least one-year stability at room temperature in the desiccator under vacuum.

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