Sponsors frequently ask for our help in selecting an appropriate dosage form for their inhalation product. The decision of metered dose inhaler (MDI) versus dry powder inhaler (DPI) versus nebulized product is sometimes made based on marketing or competitive factors. For example, if there is an interest in a higher barrier-to-entry product, then a DPI may be an appropriate choice. But often the decision is based on the more technical considerations. For example, the expected indication, the target patient population, and the dose of the product are often the first screening questions that can steer us in one direction or another.
To offer the best chance for success, we like to be involved early in the program, at the salt selection and pre-formulation stage. The choice of an appropriate salt form can be critical, and the pre-formulation data, such as solubility, hygroscopicity, and stability, may weigh in favor of one dosage form over another. In other cases, the pre-formulation data suggest that more than one dosage form may be feasible, and a parallel path of formulation development and stability characterization may be warranted, looking at two or three dosage forms at once. These paths may converge on one dosage form to promote to preclinical tox or first-in-man studies. Or, in some scenarios, it may make sense to use a nebulized product for early clinical work and switch to an MDI or DPI at a later stage once toxicity and safety are understood. Setting off on the right foot with these early decisions can be critical to the timeliness and ultimate success of a development program.
Contact me if you would like to discuss your specific dosage form selection plan.
A recent Pharmacopeial Forum (PF) article1 aims to stimulate thinking on the methodologies used to calculate mass median aerodynamic diameter (MMAD). The article presents several MMAD calculation techniques as alternatives to the US Pharmacopeia (USP) method. Because our lab performs this calculation on a routine basis (and I publish a separate website dedicated to the calculation of MMAD), I have a special interest in the topic.
USP <601> calls for plotting, on log probability paper, the percentages of mass less than the stated aerodynamic diameters versus the aerodynamic cut-off diameters. MMAD and geometric standard deviation (GSD) are determined from the plot. In practice, software (e.g. Excel) is often used to automate the determinations. The USP approach makes an underlying assumption that the mass-weighted data are log-normally distributed. The PF article argues that aerosols from many orally inhaled products do no meet this criterion, and thus the MMAD calculation should be performed using techniques that do not log-transform the data.2
Based on a wide range of particle size distributions that I’ve observed in our lab, most deviations from log-normality are due to deviations at the edges of the aerodynamic particle size distribution. As pointed out in the article, the USP method gives equal weighting to these extremes, where there is little drug recovered and assay variability can be high. The practice in our lab has been to use the data points that represent a large proportion of the collected mass (e.g. those points closer to the center of the distribution), to calculate MMAD. One example of this approach, as prescribed by ISO 27427-20103 and used at MMADcalculator.com, is to use two points closest to and on either side of the 50th percentile cumulative distribution, to calculate MMAD from the log-transformed data. Another approach we have employed is to use data from the two or three impactor stages having the largest amount of collected drug (which usually encompass the two points on either side of the 50th percentile cumulative distribution).
Using a range of distributions generated in our lab from MDIs, DPIs, and nebulizers, I calculated MMADs in two ways: 1) a two-point interpolation of log-transformed data, using one point on either side of the 50% mass-weighted cumulative distribution (ISO 27427 approach); and 2) a two-point interpolation of non-log-transformed data using one point on either side of the 50% mass-weighted cumulative distribution (one of the methods recommended in the PF article). The two methods showed close agreement.
I agree with the PF article’s conclusion that the USP methodology for MMAD calculation should be updated. However, I’m not convinced that the deviations from log-normality described above are sufficient cause to scrap the log-normal model. Because single-source aerosols, such as those from orally inhaled products, do tend to approximate log-normal distributions, my personal preference is to modify the current USP approach to use the data points from the distribution that represent the higher drug masses (e.g. ISO 27427 approach). However, I do see the appeal of a simple, two-point interpolation of non-log-transformed data, which gives close agreement to the more mathematically cumbersome two-point log-transformed model. All of this discussion should be kept in perspective: MMAD has less value (for example in the eyes of the regulators) compared to other parameters derived from cascade impactor data, such as the masses of drug on the stages and the fine particle dose.
What is your preference for calculating MMAD?
References and Notes:
1) Christopher JD, Dey M, Lyapustina S, Mitchell JP, Tougas TP, Oort MV, Strickland H, Wyka, B. “Generalized Simplified Approaches for Mass Median Aerodynamic Determination”, Pharmacopeial Forum, Vol 36(3), May-June 2010. This article was published as a part of the USP’s “Stimuli to the Revision Process”.
2) The alternative calculations that do not use log-transformed data do not provide the GSD parameter. However, the PF article suggests that alternative metrics can be used.
3) Anaesthetic and Respiratory Equipment – Nebulizing Systems and Components”, International Standard ISO 27427, 2nd Edition, 2010.
