Understanding Carrier Performance in Low-Dose Dry Powder Inhalation: An In Vitro-In Silico Approach.

Joana T Pinto,Amrit Paudel,João F Pinto,Inês Cachola

doi:10.3390/pharmaceutics13030297

Abstract

The use of physiologically based pharmacokinetic (PBPK) models to support drug product development has become increasingly popular. The in vitro characterization of the materials of the formulation provides valuable descriptors for the in silico prediction of the drug’s pharmacokinetic profile. Thus, the application of an in vitro–in silico framework can be decisive towards the prediction of the in vivo performance of a new medicine. By applying such an approach, this work aimed to derive mechanistic based insights into the potential impact of carrier particles and powder bulk properties on the in vivo performance of a lactose-based dry powder inhaler (DPI). For this, a PBPK model was developed using salbutamol sulphate (SS) as a model drug and the in vitro performance of its low-dose blends (2% w/w) with different types of lactose particles was investigated using different DPI types (capsule versus reservoir) at distinct airflows. Likewise, the influence of various carrier’s particle and bulk properties, device type and airflow were investigated in silico. Results showed that for the capsule-based device, low-dose blends of SS had a better performance, when smaller carrier particles (Dv0.5 ≈ 50 μm) with about 10% of fines were used. This resulted in a better predicted bioavailability of the drug for all the tested airflows. For the reservoir type DPI, the mean particle size (Dv0.5) was identified as the critical parameter impacting performance. Shear cell and air permeability or compressibility measurements, particle size distribution by pressure titration and the tensile strength of the selected lactose carrier powders were found useful to generate descriptors that could anticipate the potential in vivo performance of the tested DPI blends.

Highlights

Dry powder inhalers (DPIs) are dosage forms used to deliver drugs to the lung
Various lactose grades presenting distinct solid-states, particle size distribution, shapes and morphologies were selected as carriers
This lactose showed to be composed of irregular aggregates, resulting in particles with a relatively large SSA, pore volume and shape coefficient

Summary

Introduction

It is generally accepted that the active pharmaceutical ingredient (API) particles must have a size between 1 and 5 μm to enter the respiratory tract and deposit on the bronchio-alveolar epithelium [1] Due to their large specific surface area, inhalable drug particles are very cohesive, present poor flowability and are a challenge to process in order to be efficiently delivered to the lung. To improve their flowability, the inhalable API powders are often blended with larger excipient particles, through a practice known as adhesive mixing [2]. While the API particles are expected to attach strongly enough to the carrier surface to avoid problems such as poor flowability and segregation, the adhesion should not be so strong

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