Engineering the right formulation for enhanced drug delivery

Dry powder inhalers (DPIs) can be used with a wide range of drugs such as small molecules and biologics and offer several advantages for inhaled therapy. Early DPI products were intended to treat asthma and lung chronic inflammatory disease by administering low-dose, high-potency drugs blended with lactose carrier particles. The use of lactose blends is still the most common approach to aid powder flowability and dose metering in DPI products. However, this conventional approach may not meet the high demand for formulation physical stability, aerosolisation performance, and bioavailability.

To overcome these issues, innovative techniques coupled with modification of the traditional methods have been explored to engineer particles for enhanced drug delivery. Different particle engineering techniques have been utilised depending on the types of the active pharmaceutical ingredient (e.g., small molecules, peptides, proteins, cells) and the inhaled dose. This review discusses the challenges of formulating DPI formulations of low-dose and high-dose small molecule drugs, and biologics, followed by recent and emerging particle engineering strategies utilised in developing the right inhalable powder formulations for enhanced drug delivery.

Introduction

Inhaled drug therapy can achieve direct treatment of pulmonary diseases (e.g., asthma, chronic obstructive pulmonary disease (COPD), pneumonia, pulmonary hypertension) by delivering drugs via aerosol inhalation to the site of action in the lungs, thus providing rapid onset and reducing systemic adverse effects. It can also be used for systemic delivery of biologics or other macromolecules which will have poor bioavailability via other routes of administration. In comparison with other inhaled drug delivery systems, dry powder inhalers (DPIs) have distinct advantages for inhaled drug therapy, including improved portability, ease of use, and flexible dosing [1], [2]. Additionally, due to their high chemical stability of solids, dry powders have less need for refrigeration than solution formulations for nebulisation. DPI products are one of the most common delivery systems in the market.

DPI formulations have been increasingly developed for treating both pulmonary and non-pulmonary diseases (Table 1). To successfully deliver drugs in the form of dry powders, the size of particles is most often formulated within the target range of 1–5 µm. However, particles in this size range typically possess high specific area and surface energy, accompanying by reduced dispersive forces such as gravity and aerodynamic forces, leading to poor powder flowability and dispersibility [3]. In addition, important drug-related aspects such as the required dose, the chemical structure of the therapeutic substance, its hygroscopicity and chemical stability, require a holistic consideration. Due to the complex requirements of each drug or drug type, no one-size-fits-all formulation can be applied to all inhaled therapeutics. For example, the dose required to administer to the lungs can vary across orders of magnitude, depending on the drug potency. Potent drugs for asthma and COPD, like inhaled corticosteroids and bronchodilators, generally require a low dose in the microgram range (∼10–500 µg). Drug micronisation followed by physical blending with coarse carriers (hereafter designated as blended formulation) is the most used and conventional platform to formulate low-dose powders. In contrast, drugs for treating lung infection and mucus clearance require a high dose ranging from a few to hundreds of milligrams. The conventional approach of blended formulations is unsuitable for high-dose drugs as the dose containers (e.g., blisters and capsules) in DPIs have a limited space capacity available to contain the formulations [4]. Furthermore, many therapeutic biologics are susceptible to degradation when exposed to various external stresses [5]. This poses another challenge in their powder formulation and delivery. Without the use of suitable formulations, the degradation of biologics can occur and compromise the functional activity.

To overcome challenges for dry powder development of inhaled therapeutics, various sophisticated particle engineering strategies and techniques have been explored to formulate stable powders with improved aerosol performance and bioavailability. Spray drying is the most widely used particle engineering technique, as it possesses the ability to modify various particulate properties via modulating multiple process parameters (e.g., temperature, atomising pressure, air flow and liquid feeds). Other innovative techniques have also been established to fabricate particles with unique functionalities. This review begins with an overview on the particle properties affecting powder dispersion and aerosol deposition. It is followed by a discussion on the current development of particle engineering strategies for low- and high-dose drugs, biologics, and other macromolecules.

Continue reading on DPI formulation

Wei-Ren Ke, Rachel Yoon Kyung Chang, Hak-Kim Chan, Engineering the right formulation for enhanced drug delivery,
Advanced Drug Delivery Reviews, Volume 191, 2022, 114561, ISSN 0169-409X, https://doi.org/10.1016/j.addr.2022.114561.