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Achieving Optimal Particle Size Distribution Is Crucial For The Manufacture Of Efficacious Inhalation Therapies

Inhalation therapy has been used to deliver various pharmaceutical preparations directly to the lungs for more than a century. Primarily targeting lung-related conditions such as asthma, cystic fibrosis or chronic obstructive pulmonary disease (COPD), these aerosol-based treatments delivered medications deep into the lungs and alveoli, providing rapid onset of action.

More recently, inhalation therapy has been developed as an effective drug delivery technology that has benefited from advances in particle size reduction technology. The technology has been modified and refined to capitalize on advantages such as rapid onset of action, while avoiding some of the challenges inherent in oral drug delivery.

Inhalation Therapy Benefits

For instance, inhaled drugs bypass first-pass metabolism, which, of course, vastly improves bioavailability in most cases. Needless to say, by avoiding the gastrointestinal tract, it is unlikely that a given medication will trigger GI side effects. Such side effects are associated with many common oral drugs; they can significantly impact patient compliance.

In addition to more rapid onset of action and potentially fewer side effects compared to orally ingested medications, inhalable drugs offer enhanced convenience for patients. In some instances — such as the development of inhalable insulin — the condition to be treated is not necessarily related to the lungs themselves. Rather, insulin is a systemic drug that works throughout the entire body to help regulate blood glucose levels.

Such systemically active drugs rely on precisely controlled particle sizes to guarantee their efficacy. The ultimate destination of a given drug plays an important role in determining its optimal particle size. Drugs intended for systemic absorption and circulation must reach deep within the peripheral alveoli. Particle size determines the degree to which particles are deposited throughout the peripheral alveoli (and not exhaled). The other key factor is the velocity of inspiratory flow.

Neither Too Large, Nor Too Small

Particles that are too large (5 – 10 μm) may fail to disseminate deep within the lungs. In fact, they may deposit in the mouth, throat or upper airways, where they will do little good, at best, or trigger undesirable local or systemic side effects, at worst. Intermediate size particles (3 – 5 μm) will certainly travel farther, while small particles of 3 μm or less will reach deep within the peripheral alveoli.

Particles that are smaller still (<0.5 μm) may actually fail to deposit on the alveoli membranes at all. Thus, these minuscule particles are inappropriate candidates for this delivery method. As you can see, there is a sweet spot for inhalable drug particle sizes: 3 – 5 μm. Note that this ideal particle size range is relatively narrow. To be successful, then, it is crucial that active ingredient particles undergo careful and precise size reduction during the drug manufacturing process.

The particle size of some drugs may be a function of the inhaler device itself. This applies to liquid formulations of soluble drugs that are nebulized or “atomized” during activation of the delivery device. Other drugs may need to be delivered in powder form, or as insoluble drugs dispersed in emulsions. In these instances, particle size is a crucial parameter that determines efficacy.

The Right Equipment for the Job

Actual optimal particle sizes will depend on factors such as the dispersal system to be used. Examples include suspensions, emulsions, liposomes or colloidal systems. In these scenarios, drug particle sizes must be smaller than the final droplets that will reach the lungs. Although the Goldilocks range may be 3 – 5 μm, the actual active ingredient may need to consist of particles not larger than 1.0 μm.

While various methods exist for achieving these precise particle size reductions, only high shear fluid processing offers the flexibility to scale up from laboratory and pilot-scale runs to full-scale production runs with relative ease. High shear homogenizer technology is capable of producing extremely small particles of essentially uniform size, while ensuring scale-up is predictable and linear.

This methodology allows for extremely high-process pressures and high-velocity product streams, which in turn delivers much higher shear rates than are achievable using more conventional methods. The bottom line is tighter particle size distribution curves, precisely controlled particle size reductions, and the assurance that every milliliter of product encounters identical processing conditions.

For more information about how a Microfluidics™ Microfluidizer® processor can be used to enable or enhance your inhalable drug manufacturing and processing, call us at 1-800-370-5452 — or contact us here.