The formulation of and evaluation of high dose therapies using a novel dry powder inhaler for respiratory delivery

Abstract

The basis of treatment for respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD) is inhalation therapy. These traditional therapies generally require microgram doses, and the devices have thus been developed to deliver small quantities of active pharmaceutical ingredients (API) locally. However, more recently, there has been an increased interest in the delivery of higher dose API to the lung for conditions such as respiratory infections, that require dosages in the milligram range. Inhalable API particles must be small (1-5 μm) and excipients are commonly added to overcome the physical forces, including Van der Waal, electrostatic and capillary forces, which cause cohesion of the small API particles forming agglomerates and adhesion to the inhaler wall. This cohesion of API and adhesion to the inhaler wall decreases the flow and dispersion of the dry powder formulation. These problems hinder powder aerosolisation and decrease API delivery to the lungs, leading to sub-therapeutic concentrations. These drawbacks are much more apparent with increasing concentrations of API. In order to overcome these limitations, to allow greater API delivery to the lungs, this research has investigated how to: (1) Formulate a high dose carrier-based inhalable dry powder: High dose inhaled therapies are inherently cohesive and thus have to be engineered with excipients that enhance flow and agglomerate breakup during inhalation; and (2) Optimise conventional reservoir-type inhaler technology for high dose therapies: This will be achieved through enlargement of the dosing cup size in a manual fed novel dry powder inhaler designed via computer aided design and 3D printing, and subsequent in-vitro testing. XXIV To achieve these outcomes, five different carrier-type formulations of API concentrations of 1-30% (w/w) beclomethasone dipropionate (BDP) were formulated, consisting of coarse granulated α-lactose monohydrate as the carrier particle, with fine lactose and magnesium stearate as excipients. These formulations were tested using a 3D printed, manually fed reservoir-based novel dry powder inhaler with three different sized dosing cups of 16.26 mm3, 55.99 mm3 and 133.04 mm3, respectively. The morphology and efficiency of BDP detachment from the carrier was analysed using scanning electron microscopy and aerosol performance using a British pharmacopeia Apparatus E cascade impactor (Next generation impactor). It was observed that increasing the concentration of BDP from 1-30% w/w of the formulation, decreased the efficiency of BDP dispersion, with significant BDP particles remaining on carrier particles post-aerosolisation. Additionally, it was found that the overall aerosol performance significantly decreased with greater BDP deposition occurring on the USP induction port and the pre-separator. However, when a larger sized dosing cup (133.04 mm3) was utilised, significant increases in the detachment of BDP from the carrier particle occurred, leading to greater dispersion and delivery to the lungs with all concentrations of BDP. The larger sized dosing cup also enabled greater dose loading, leading to greater BDP delivery to the lungs. This research provides a better understanding of the formulation and inhaler device and the complex interaction between the two that is required for high dose therapies for inhalation. This research also provides a foundation for the development and investigation of potential new APIs for the treatment of infection and other diseases requiring delivery of milligram dosages to the lungs.