PULMONARY DELIVERY - Development of Pulmonary Dosage Forms for the Successful Delivery of Complex Molecules

INTRODUCTION

The administration of drugs into the lung is a well-estab­lished delivery route for the treatment of a wide range of pul­monary ailments. The direct delivery of drugs to the respiratory system is ideal for the localized treatment of chronic lung dis­eases, such as asthma, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PA), and a number of drugs used in the treatment of chronic lung conditions associated with Cystic Fibrosis.

These lung treatments traditionally relied on devices, such as metered dose inhalers (MDIs) and nebulizers, to deliver drugs to where they were needed in the lung. In many cases, these devices delivered drugs in the upper airways of the lung as well further down the lung architecture.

Whilst these chronic lung conditions will remain a high pri­ority in pulmonary delivery, there is growing interest in delivering drugs deep into the alveolar space for treatments of diseases within the lung or for subsequent systemic delivery after the drug has crossed the lung epithelium.

Traditional devices, such as MDIs and nebulizers, are less suited for many of these next-generation drug treatments as: (1) both types of devices result in signifi­cant quantities of the delivered dose being deposited in the throat and upper airways of the lung, reducing efficacy and causing side effects and (2) many of these drugs are sensitive biologics or oligonucleotides that have limited stability in water or are not compatible with the propellants used in MDIs.

Because of these challenges, there is growing interest in next-generation pul­monary delivery devices that can over­come either or both of these challenges, ie, delivering drugs more efficiently into the deep lung and also delivering ther­mally sensitive drugs that are unstable in solution. These next-generation delivery devices include soft mist inhalers (SMIs) and dry powder inhalers (DPIs). Some of the advantage/disadvantages of these pulmonary delivery devices are summa­rized in Table 1.

DEVELOPING DRY POWDER & SOFT MIST INHALER DOSAGE FORMS

There is growing interest in delivering drugs into the deep lung for localized treatments or for subsequent systemic up­take.

When developing a DPI or an SMI for­mulation containing the drug of choice, it is important to remember the performance of the pulmonary dosage form will be de­pendent on the properties of the formula­tion itself (powder of liquid) in combination with the device used to deliver the dose.

Clearly, the development pathway for either dosage form differs in many ways as one type of device requires a dry pow­der and the other an aqueous liquid. How­ever, both types of dosage forms have factors in common, namely the need to as­sure accurate dosing, a high degree of deep lung deposition (fine particle frac­tion), and a suitable stability profile.

Developing Dry Powder Inhaler Dosage Forms Containing Biologics
The successful development of DPI dosage forms require the creation of a dry powder formulation of the drug that has the correct aerodynamic size for deep lung delivery. Typically, this requires creating drug/excipient formulations with a particle size of around 1 μm to 3 μm. The best technique for creating or “engineering” these drug/excipient particles is spray dry­ing.

Spray drying is particularly useful as the drying equipment comes in a range of sizes that can produce small batches of powder (milligrams), such as the Buchi B-290 spray dryer (Figure 1) through to much larger GEA-Niro spray dryers that can produce batch sizes of hundreds of kilograms, with established tech transfer models and scale up models.

In early development studies drug/ex­cipient solutions can be prepared and spray dried to create particles with the re­quired aerodynamic size for deep lung de­livery. Typically, when creating dry powder formulations containing complex biologics (such as peptides, proteins, oligonu­cleotides, vaccines), it is necessary to add excipients that perform a range of func­tions. Some of the key excipients and their functions are summarized in Table 2.

A typical development program will involve mixing one or more of these excip­ients in solution with the drug in a ration that can achieve the target loading needed for an efficacious dose. These solutions can then be spray dried using conditions that can typically create fine particles in the size range suitable for deep lung delivery (respirable fraction).

Typical size distributions and particle morphologies that can be produced by spray drying are shown in Figure 2.

Once powders have been produced, it is important to test the powders to see if they have the required physical and chem­ical attributes for successful pulmonary de­livery.

Stability of the drug (especially biolog­ics) is essential, and retaining stability is re­quired during the spray drying process (ie, ensuring activity and structure of the bio­logic remains the same as before spray drying) and on subsequent storage over time.

Developing Soft Mist Inhaler Dosage Forms Containing Biologics
Developing liquid formulations that can be delivered using an SMI is much simpler compared to developing a dry powder version. The biologic in question is typically dissolved in an aqueous buffer solution (typically around neutral pH) at a concentration that will allow the required dose to be delivered.

A typical dose delivered from an SMI is typically between 10 μl to 30 μl, so de­pending on solubility of the biologic, the actual dose delivered in a single actuation is relatively low (typically μg quantities compared to a DPI which can deliver sev­eral milligrams per dose). Examples of typ­ical excipients that can be added are summarized in Table 3.

When pilot formulations have been produced, it is important to test the solu­tions to see if they have the required phys­ical and chemical attributes for successful pulmonary delivery via an SMI. These in­clude stability of the drug in the liquid (bulk) solution and the delivery perform­ance from the device itself.

TESTING DELIVERY PERFORMANCE & STORAGE STABILITY OF DPI & SMI DOSAGE FORMS

Two key steps in the successful devel­opment of a pulmonary drug dosage form (delivered by a DPI or an SMI) are: testing that the required dose can be delivered from the device and that it can reach the deep lung (the fine particle fraction), and ensuring the dosage form remains stable at its intended storage conditions. In many aspects, the testing of these two critical pa­rameters is similar for both devices.

Measuring Aerodynamic Particle/Droplet Size & Determining Fine Particle Fraction in DPI & SMI Dosage Forms
The Fine Particle Fraction (FPF) is often defined as the fraction or percentage of the drug mass contained in an aerosol or powder that is small enough to enter the deep lung and exert a clinical effect.

Geometric sizing can be used to measure the size of the particles or droplets that come out of either device. For example, Figure 2 shows a typical laser particle size distribution from a pulmonary formulation produced by spray drying.

However, the FPF of the dose can only be measured when it has been delivered by the device in question and its aerody­namic deposition pattern has been deter­mined.

To measure the FPF requires the use of a multi-stage cascade impactor, such as the Next Generation Impactor (NGI) man­ufactured by Copley Instruments (Figure 3).

A DPI or an SMI containing the drug dose can be fired into the Copley NGI and the drug deposition at each stage deter­mined, typically using an HPLC method or by simple UV absorbance.

The Copley software can then be used to measure the Fine Particle Mass (or FPF) generated by the formulation/device com­bination. A typical FPF for a spray-dried dosage form delivered by a Plastiape DPI can be seen in Figure 4.

Determining Storage Stability in DPI & SMI Dosage Forms
A critical aspect in the successful development of a DPI or an SMI pulmonary dosage form is that of storage stability, ie, ensuring the formulated drug remains sta­ble when filled into the device at the de­sired storage conditions. Typically, filled devices will be stored at a range of temperatures/humidities, and at predefined time periods, devices will be withdrawn from storage and the dosage form subjected to a range of ana­lytical tests. Typical stability indicating as­says are shown below in Table 4.

SUMMARY

The pulmonary delivery route is of in­creasing interest to those looking to deliver more complex molecules, such as biolog­ics, into the lung for local or potentially systemic delivery.

Whilst there are a number of device options available to deliver drugs into the lung, DPIs and SMIs are the two most widely used device types for the more chal­lenging class of molecules. Each of these devices has advantages and disadvan­tages, so choosing between them should be done on a case-by-case basis.

The subsequent development and testing of DPI and SMI dosage forms can be challenging, but many of the tech­niques used are compatible with either dosage form, and the end result remains the same for both – the successful delivery of a suitable dose into the deep lung from a stable formulation/device combi­nation.

Dr. Richard Johnson is the Founding Director and Chief Scientific Officer of Upperton Pharma Solutions, a UK-based Contract, Development and Manufacturing Organisation. Graduating from Warwick University with a PhD in Biochemistry, he was employed as a Protein Chemist at Delta Biotechnology. In 1994, he was part of a management buy-out team that founded Andaris Ltd, a research and development company exploiting the use of spray-drying technology in the fields of diagnostic imaging and drug delivery. In 1999, he founded Upperton and has overseen significant growth and expansion over the past 25 years.