Business need

Asthma is a chronic inflammatory disorder of the airways. At least 300 million people globally have the disease and many more are likely undiagnosed.

The most common form of therapy is the inhalation of active drug substances into the mid-airway. It is important that the particles or droplets being inhaled are of the right size to deposit in the correct part of the lung. If the size is too big then the drug will deposit in the throat and upper airway, and if the size is too small then the drug will simply be exhaled. Broadly, the desired size range is 1 to 5 microns. The drug is commonly administered in one of three ways: as a dry powder; as particles in liquid drops; and aqueous solutions. Most patients use one of two inhaler delivery systems: pressurized metered-dose inhalers (MDIs) and dry powder inhalers (DPIs). The latter may be unit dose (e.g., blister packs or capsules) or metered from a bulk reservoir of powder.

Both types of delivery system require significant coordination of inhalation and device operation and/or sufficiently high inspiratory flow rate. There are many patients for whom this is difficult or who may need greater doses of drug for effective therapy than can be delivered with the more common – and portable – devices. In these cases, an air jet nebulizer can be used.

The principle of operation is simple. A solution or suspension of drug is placed in a reservoir that is connected via a narrow tube to an air compressor. Air is forced into the liquid causing the formation of droplets (nebulization). Careful design of the reservoir allows droplets below a certain size to be entrained in air flowing across the top of the reservoir. This is the air being inhaled by the patient. Sometimes the outlet of the nebulizer is placed in the patient's mouth (similar to a vaping pen) or indirectly via a face mask.

Liquid formulations for nebulizers may come in the form of a bulk solution/suspension or unit-dose packs (often called nebules).

Albuterol (salbutamol) is the most common drug used for asthma therapy and has been used since the late 1960s. It is readily soluble in water and poses few problems from a formulation physical stability perspective. In contrast, subsequent generations and classes of drugs are poorly adsorbed and have low solubility. Therefore, suspension formulations must be developed for use in a nebulizer.

Most particles for pulmonary delivery are generated as micronized powders. Typically, dissolved drug is precipitated from a solution by addition of an antisolvent. After drying, the particle size is commonly a few tens of microns. This is reduced by subjecting the powder to considerable air pressure in a fluid air jet mill (micronizer). The operating conditions must be carefully defined and controlled to meet the required distribution of drug deposited in the lung. The electron micrograph below shows the typical appearance of a micronized drug used for inhaled delivery.

An ideal powder would comprise spherical particles with a very narrow size distribution. Micronized powders are different in a number of important ways:

• Very broad size distibrution (100nm to 5μm)
• Highly irregular shape
• Plate-like surfaces
• Cohesive
• Changes in crystal habit at surface due to attrition

Because the mass of powder delivered to a target location is the important requirement of the material, it is the volume-weighted size distribution that needs to be controlled. Consequently, a volume-weighted mean particle size is usually quoted. The required value is highly dependent on the device used to deliver the drug. It was a requirement for this study that micronized drug used for existing MDI products be used. Such materials had a volume-weighted mean particle diameter of 1 to 2μm, depending on the drug.

In contrast, the mean particle diameter based on the number of particles is much smaller as seen in the micrograph. On a number-weighted basis, the mean effective diameter may be a few hundred nanometers.

The usual treatment program for asthma includes two classes of drug administered together: bronchodilators (such as albuterol and its chemical analogs), and anti-inflammatories (usually corticosteroids). Traditionally, one drug is administered followed by the other from two separate devices. In the early 1990s, it was discovered that if the two drugs were formulated together in a single device then the efficacy of both increased. Since then, many companies have developed and manufacture such dual-combination (or even triple-combination) products in both MDI and DPI devices. Examples include Advair (Seretide) and Symbicort. Although nebules do exist with suspension formulations, they are monotherapies, such as Pulmicort nebules. At the time of this work, the corporate strategy was to develop combination therapy nebules with an anti-inflammatory and a bronchodilator as the two active ingredients and, potentially, a third.

Combination aqueous suspension formulations pose significant challenges that are central to the objective of this case study. In particular, the formulation of the liquid vehicle (i.e., the water and excipients) had to be able to work with all of the drug substances of interest to the company at the time.

It was likely that the greatest challenge to developing a successful formulation would be the ability to redisperse sedimented particles follow prolonged undisturbed storage (e.g., a pharmacy's shelf). The particles must not remain in an aggregated state otherwise they would most likely not deposit in the correct region of the lung, resulting in reduced therapeutic efficacy.

Case study objective

The objective can be stated succinctly:

Develop a universal vehicle that will redisperse one or more micronized drug substances with minor manual effort to give primary particles

Surfactants play a vital role in controlling the aggregation behavior of the particles in a colloidal product. Without surfactants, many of the colloidal forms of matter that are used in many industries would not exist. Surfactants promote stability against aggregation, can control the sedimentation behavior, aid wetting and strongly influence the colloidal dynamics of the suspension. If the overall physicochemical properties of suspension formulations are to be controlled successfully, a working knowledge of the key colloid science is essential. The following lists a typical existing formulation, the target for the new formulation, the criteria to successfully meet the target, and the possible barriers to meeting the target.

Existing suspension formulation (for nasal delivery):

• Micronized drug
• Phosphate buffer (for isotonicity)
• Surfactant (e.g., polysorbate 20, soy lecithin, oleic acid)
• Water for injection

Note that for existing suspension formulations, they are intended for nasal delivery only. The droplet size generated by the nebulizer is too large for pulmonary delivery due to the high viscosity of the formulation.

New formulation target:

• Micronized drug
• Universal stabilizer
• Water for injection

Criteria for success:

• Wet the drug particles
• Prevent the drug particles from aggregating in suspension
• Prevent the drug particles from aggregating once sedimented
• Allow full redispersion of the drug particles using minor manual effort
• Be effective at less than 10% of the drug weight

Possible barriers to success:

• Poor knowledge of the behavior of the drugs in water
• Large size and high density of particles result in strong sedimentation, leading to difficulties in redispersing the particles
• Likely significant electrostatic effects that will influence the physical behavior of the formulation

Just a few rudimentary concepts of colloid science need to be applied to this work. The above description of the case study objective allowed those concepts to be identified and used to design an efficient experimental study that would meet the objective with much less resource than a more typical trial-and-error approach would require.

The next section discusses the relevant concepts of colloid science used in this study.