Predicting the Fine Particle Fraction of Dry Powder Inhalers Using Artificial Neural Networks.

Dry powder inhalers are increasingly popular for delivering drugs to the lungs for the treatment of respiratory diseases, but are complex products with multivariate performance determinants. Heuristic product development guided by in vitro aerosol performance testing is a costly and time-consuming process. This study investigated the feasibility of using artificial neural networks (ANNs) to predict fine particle fraction (FPF) based on formulation device variables. Thirty-one ANN architectures were evaluated for their ability to predict experimentally determined FPF for a self-consistent dataset containing salmeterol xinafoate and salbutamol sulfate dry powder inhalers (237 experimental observations). Principal component analysis was used to identify inputs that significantly affected FPF. Orthogonal arrays (OAs) were used to design ANN architectures, optimized using the Taguchi method. The primary OA ANN r2 values ranged between 0.46 and 0.90 and the secondary OA increased the r2 values (0.53-0.93). The optimum ANN (9-4-1 architecture, average r2 0.92 ± 0.02) included active pharmaceutical ingredient, formulation, and device inputs identified by principal component analysis, which reflected the recognized importance and interdependency of these factors for orally inhaled product performance. The Taguchi method was effective at identifying successful architecture with the potential for development as a useful generic inhaler ANN model, although this would require much larger datasets and more variable inputs.

Interaction of Formulation and Device Factors Determine the In Vitro Performance of Salbutamol Sulphate Dry Powders for Inhalation.

A variety of capsule-based dry powder inhalers were used to evaluate formulation-device interaction. The in vitro deposition of salbutamol sulphate (SS) was compared directly to published data for salmeterol xinafoate (SX). A 3(2) factorial design was used to assess the effect of SS formulations with three blends of different grade coarse lactose supplemented with different levels of fine lactose. These formulations were tested for homogeneity and evaluated for their in vitro deposition using Aeroliser, Handihaler and Rotahaler devices. The performance of the SS-lactose formulations differed across the grade of lactose and amount of fine lactose used compared to the same powder compositions blended with SX. SX had a greater fine particle fraction than SS for most of the comparable formulations, probably because of the different cohesiveness of the drugs. A head-to-head comparison of 'matched' SX and SS formulations when aerosolised from the same three devices demonstrated that formulation-device interactions are as critical in determining the in vitro deposition of drug-lactose blends as the identity of the active pharmaceutical ingredient. This work has revealed the limitations of the interpretative value of published in vitro performance data generated with a single device (even at equivalent aerosolisation force), when designing formulations for a different device.

Potential of a cyclone prototype spacer to improve in vitro dry powder delivery.

PURPOSE: Low inspiratory force in patients with lung disease is associated with poor deagglomeration and high throat deposition when using dry powder inhalers (DPIs). The potential of two reverse flow cyclone prototypes as spacers for commercial carrier-based DPIs was investigated. METHODS: Cyclohaler®, Accuhaler® and Easyhaler® were tested with and without the spacers between 30 and 60 Lmin−1. Deposition of particles in the next generation impactor and within the devices was determined by high performance liquid chromatography. RESULTS: Reduced induction port deposition of the emitted particles from the cyclones was observed due to the high retention of the drug within the spacers (e.g. salbutamol sulphate (SS): 67.89 ± 6.51% at 30 Lmin−1 in Cheng 1). Fine particle fractions of aerosol as emitted from the cyclones were substantially higher than the DPIs alone. Moreover, the aerodynamic diameters of particles emitted from the cyclones were halved compared to the DPIs alone (e.g. SS from the Cyclohaler® at 4 kPa: 1.08 ± 0.05 µm vs. 3.00 ± 0.12 µm, with and without Cheng 2, respectively) and unaltered with increased flow rates. CONCLUSION: This work has shown the potential of employing a cyclone spacer for commercial carrier-based DPIs to improve inhaled drug delivery.