Inhalation drug products
Treating lung ailments such as asthma and chronic obstructive pulmonary disease often involves doses containing a combination
of APIs such as long-acting beta-2 agonists, short-acting derivatives, and steroids to open the airway and reduce inflammation.
Examples of already marketed multiple-API inhalation products include AstraZeneca's (London) Symbicort (budesonide and formoterol
fumarate dehydrate) and GlaxoSmithKline's (London) Seretide (fluticasone propionate and salmeterol xinafoate). Optimal efficacy
of multiple-API inhalation products requires precise control of drug release, the correct drug ratio in each dose, and effective
and reproducible delivery.
Nanoparticle structures may be desired for poorly water-soluble pulmonary formulations because they facilitate dissolution.
Strategies to achieve the 1–5-µm particle size for aerosol formulations include jet milling, precipitation, and supercritical-fluid
processes. These particles are then blended with several excipients to facilitate handling, filling containers, and aerosolization.
To control dissolution, formulators may select low-solubility salt forms of the drug or different modifications of the drug
that have low solubility. Excipients such as lecithin also can be used to modify dissolution rate and control release.
Nonetheless, when used in suspensions in nebulizers, solid nanoparticles may present problems such as agglomeration or Ostwald
ripening. To help alleviate these problems, bottom-up approaches for producing combination API nanoparticles for inhalation
have been developed (3).
One novel strategy involves the assembly of nanoparticles of API into clusters for oral or nasal inhalation. Savara Pharmaceuticals (Austin, TX) develops respiratory therapeutics using its NanoCluster dry powder aerosol technology. The dry powder is composed
nearly entirely of API and comprises discrete nanostructured microparticles of low density and irregular shape (see Figure
3). According to Cory Berkland, cofounder and chief scientific officer of Savara and associate professor at the University
of Kansas, the company uses existing methods to make the nanoparticles, but the new composition of matter is embodied in the
assemblies or agglomerates. Under controlled conditions and at room temperature, a stable colloid nanosuspension is made and
usually consists of the nanosized API particles in a water-based system. Small amounts of generally regarded as safe additives
(e.g. lecithin or leucine) are then introduced that cause the particles to assemble into clusters. Driving forces to assemble
the particles include charge interaction and hydrophobic interaction. The clusters are then filtered off and dried to obtain
a fine powder.
Figure 3: A cluster of nanosized particles of two active pharmaceutical ingredients. (IMAGE IS COURTESY OF SAVARA PHARMACEUTICALS)
"We have a lot of flexibility to make the agglomerates," says Berkland. "We've made several formulations of diverse active
ingredients ranging from steroids to insulin that do not include any excipients. For example, insulin nanoparticles were obtained
by changing the pH of insulin to render it less soluble in water. You can then assemble the nanoparticles in suspension. NanoCluster
technology seems to be equally amenable to water-soluble and water-insoluble compounds."
"Instead of using 1- to 3-µm solid drug microparticles, the method uses drug nanoparticles to rebuild the microparticles.
The result is drug microparticles with many spaces and cracks and with low density. When breathed in, the low-density particles
are captured into the air flow field (aerosolized) and 'fly' better than solid particles, thereby enabling the particle to
travel deeper in the lung," explains Berkland. "Poorly water-soluble drugs can be processed into nanoparticles using water
as a continuous phase, and we can assemble the materials in water. When we work with water-soluble drugs, we tend to precipitate
into another material to form the nanoparticle suspension," he adds.
Multiple-API drug products can be developed in various ways. One method is to have two discrete nanoparticles of the two different
types of drugs created and then assembled together. Another way is to assemble a nanoparticle suspension of a poorly water-soluble
drug (e.g., a steroid) into an agglomerate or cluster and have the other ingredient in solution with the NanoCluster. When
the solution is dried, the water-soluble compound that was in solution deposits on the cluster.
The amount of each drug in each cluster can be controlled by modifying the relative amount or relative concentration of the
two drugs in suspension. This approach allows assembly into various ratios, even high ratios such as 50:1 or 100:1 for high-potency
drugs. "There are even cases where you might want to have two different NanoClusters, for example one that has drug A and
deposits in the upper airways and another that contains drug B and deposits in the peripheral airways or the aveolar region
of the lung," says Berkland. In such cases, the process would produce two different NanoClusters with different flight characteristics.
The clusters would be blended together to get a homogenous mixture of the two for delivery.
Multidrug dosage forms will likely become more popular among patients, partly because they are convenient and facilitate compliance.
Producing these drugs is challenging for formulators and manufacturers alike, even when controlled release is not a consideration.
Yet, as drugmakers gain experience with these sophisticated therapies, they better understand how to surmount the particular
difficulties they present. Patient demand and patent issues, among other factors, could prompt future improvements to the
formulation and manufacturing methods—and production equipment—that these medicines require.
For information on this topic, see the online exclusive, "A Tale of Two Techniques"
1. Glossary, Nature,
http://www.nature.com/nrmicro/journal/v2/n2/glossary/nrmicro821_glossary.html, accessed June 5, 2009.
2. S. Koutsopoulos et al., "Controlled Release of Functional Proteins through Designer Self-Assembling Peptide Nanofiber Hydrogel
Scaffold," Proc. Natl. Acad. Sci. USA
106 (12), 4623–4628 (2009).
3. G. Ruecroft and D. Parikh, "Power Ultrasound and the Production of Mesoscopic Particles and Aqueous Dispersions," Pharm. Technol.
32 (9), s28–s35 (
http://www.prosonix.co.uk/combination-therapy.html, accessed June 11, 2009.