DRY POWDER FORMULATION - Preparing to Deliver the Next Generation of Inhaled Therapeutics

INTRODUCTION

The global increase in respiratory diseases, as well as the potential to deliver drugs systemically, has led to increased interest and a shifting landscape within inhaled drug delivery. An alternative to pressurised metered dose inhalers (pMDIs), dry powder inhaler (DPI) formulations have the potential to meet the evolving market trends and deliver the next generation of inhaled therapeutics.

The following outlines the trends and challenges within the inhaled drug delivery market. Specifically, DPI delivery will be explored, including how the challenges with dry powder formulation can be overcome and what the future holds for DPIs.

TRENDS PAVING THE WAY FOR THE EVOLUTION OF THE INHALED DRUG DELIVERY MARKET

Chronic respiratory disorders, including asthma, lung cancer, and chronic obstructive pulmonary diseases (COPDs), have been categorized as a leading cause of global mortality and morbidity by the World Health Organisation (WHO).¹ WHO estimates indicate that approximately 235 million people worldwide suffer from asthma, and more than 3 million people die every year from COPDs.¹

Due to the rapid and targeted delivery of drugs to the air-ways and lungs, inhalation remains the most common approach to the prevention and treatment of chronic respiratory disorders.¹ Although pMDIs have traditionally been the inhaled therapeutic of choice, a shifting market landscape has opened the door for alternative methods, such as DPIs. Dry powder formulations have the potential to deliver the next generation of inhaled therapeutics due to their distinct set of advantages, including:

Sustainable Inhaled Drug Delivery: Propellants used within pMDIs are usually hydrofluorocarbons (HFCs), which have a high global warming potential (GWP). The high-GWP properties of currently used pMDI propellants mean they have become a target for increased sustainability within the pharmaceutical industry, with legislation aiming to reduce the use of HFCs in key pMDI markets. Despite progress in low-GWP propellants, continued regulatory changes make it unclear which sustainable propellants to invest in. The uncertainty in the propellant market has led to increased interest in DPIs, which do not use propellants and offer a sustainable inhalation solution. Stable Biologics Delivery: The development of complex and larger biologics has increased interest in DPIs. The large and complex structures of biologics increase their sensitivity and influence their delivery method. Typically, biologics are injected intravenously, bypassing degradation routes (such as the gastrointestinal tract) and ensuring the active product is delivered. Aqueous biologics formulations can show increased sensitivity, which means that factors such as temperature and pressure need to be controlled to avoid degradation and loss of efficacy. In contrast, biologics are inherently more stable in dry powder formulations, providing an innovative solution for product formulation. Adopting dry powder formulations for biologics therefore increases shelf life and maintains the efficacy of the product.

Deep Lung & Systemic Delivery: Another important property of dry powder formulations is the area of the lungs to which they deliver the drug. Biologics (in particular, vaccines) need to be delivered into the deep regions of the lung, something DPIs can achieve. If the development of more complex biologics continues, DPIs will therefore be relied upon more for their delivery into the lungs. The ability to deliver drugs deeper into the lungs also opens the door for systemic delivery. Getting drugs into the bloodstream via the lungs is a considerable challenge, but it is entirely possible. Systemic delivery via inhalation could then lead to self-administered pulmonary products, replacing therapies that would traditionally be administered via injection.

The lack of propellants, the compatibility with biologics, and the ability to deliver to the deep lung mean DPIs will be relied upon heavily for the next generation of inhaled therapeutics. However, there are several considerations and challenges drug developers and manufacturers need to navigate to unlock the full potential of DPIs.

MEETING THE GROWING DEMAND FOR DRY POWDER INHALER DELIVERY

Several key milestones need to be hit to successfully bring DPI therapeutics to market and to the patients who would benefit from them. The quickest way to meet these demands is to start with the simplest drug formulation possible (small molecule or biologic) and focus on commercially available DPI devices.

Capsule-based delivery devices are promising for fulfilling the growing demand. Dry powder formulations can be packaged into a capsule and then loaded into a commercially available delivery device. Using standard capsules and commercial devices means the pathway to the clinic is going to be quicker and more cost-effective, compared to developing proprietary devices. Well-established techniques for DPI formulation, such as spray drying, also ensure drug particles are the correct size for delivery, simplifying another development step.

NAVIGATING THE HURDLES FACING DRY POWDER FORMULATION

The full potential of DPIs can be de-livered by successfully navigating several hurdles associated with their development. Selection of excipients is one of the main challenges in the delivery of next-generation inhaled therapeutics. Excipients improve aerodynamic properties and the stability of the product and are therefore essential when working with unstable biologics. However, there are very few excipients that are approved for pulmonary use. The commonly used approved excipients also show incompatibility issues with bio-logics, further highlighting the need for novel excipients in DPI delivery.

As pre-approved excipients simplify the regulatory pathway, their current lack makes the process more difficult. Precedent excipients can help overcome the challenges with pulmonary excipients. Even if they have not been specifically ap-proved by the FDA, precedent excipients that have been used before during clinical development can help with regulatory approval.

Delivering the correct dose of the drug product is another challenge with DPIs. Dose issues center around the capacity of DPI capsules, which is typically 20-30 mg of powder. The capacity of DPI capsules therefore dictates the formulation of drugs into dry powders, as there is a finite range of how much drug can be de-livered. A limited capacity affects some therapeutics more than others, but altering spray drying conditions and excipients helps optimize formulations and particle sizes.

Regulatory compliance must also be carefully considered to provide a safe and efficacious therapy to patients. It is critical to demonstrate the stability of the active ingredient through the packaging and delivery process. Reproducibility must be tightly controlled when filling capsules and when the drug is delivered from the DPI device. Finally, it must also be demonstrated that the active ingredient is reaching the target site within the lungs.

Using a battery of analytical techniques to generate efficacy and safety data at an early stage is a key approach to demonstrating regulatory compliance. Light scattering and laser-based approaches can provide information regarding the geometric size of particles. Geometric particle size affects the aerodynamic properties of DPIs and how the product deposits during inhalation.

Using a battery of analytical techniques to generate efficacy and safety data at an early stage is a key approach to demonstrating regulatory compliance. Light scattering and laser-based approaches can provide information regarding the geometric size of particles. Geometric particle size affects the aerodynamic properties of DPIs and how the product deposits during inhalation. The aerodynamic performance of the product needs to be assessed to determine the properties of the product in real-life situations. Analysis with a next-generation impactor is an advanced methodology that can predict how the powder will be delivered and which areas of the lung the product will reach.

The chemical properties of the product are equally as important as the physical properties when determining efficacy and safety. Analytical techniques such as HPLC are used to determine if the drug has been damaged during spray drying or formulation. Dry powder formulations can absorb moisture readily, making thermo-graphic analysis essential to determine moisture content. Microbial testing is also critical to avoid product contamination.

LOOKING TO THE FUTURE OF DRY POWDER INHALERS

Inhaled therapeutics is an area of the pharmaceutical industry that is currently in high demand and is set for continued growth in the future. The global increase in respiratory diseases and uncertainty surrounding pMDIs has increased interest in DPI devices. The compatibility with biologics and the ability to deliver drugs deeper into the lung (which also unlocks the potential for systemic delivery) means DPI de-vices have great potential within the growing inhaled therapeutics market.

Several challenges remain if DPIs are to reach their full potential and deliver the next generation of inhaled therapeutics. The selection of excipients, the dose and formulation of dry powders, and the physical and chemical properties must all be considered in the development of new DPI therapeutics. Partnering with specialists in DPI devices and dry powder formulations can bring the knowledge, expertise, and technologies required to turn the DPI potential into reality. With partnerships, challenges can be addressed, and the development of DPI products can be accelerated, reaching the patients that will benefit from them.

REFERENCE

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499344/.

Dr. Richard Johnson founded Upperton Pharma Solutions in August 1999, and continues to play a key role in the management and strategic development of the company. With over 30 years of experience in the pharmaceutical, biotechnology, and drug delivery fields, he previously held senior management positions at Andaris Group (Vectura) and Delta Biotechnology (now Albumedix, Nottingham, UK). He earned an honors degree in Biology from the University of York (UK), a PhD from the University of Warwick (UK), and has a proven track record in successfully developing innovative pharmaceutical products from early feasibility studies through to commercial products.