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Considerations in selecting a dosage form for drug delivery to the lungs.
Inhalation drug products are some of the most complex dosage forms on the market and, as such, can present a number of challenges to manufacturers. Setting these challenges aside, the inherent advantages of inhalation drug delivery compared to oral administration of medications include a faster onset of pharmacological action because the drug is being delivered to the site requiring therapeutic effect, and a lower systemic bioavailability, which reduces the occurrence of adverse effects.
The development of an inhalation product involves a combination of both formulation and device selection. As a result, choosing an appropriate dosage form for a development program necessitates a comprehensive decision-making process. When deciding between metered dose inhaler (MDI), dry powder inhaler (DPI), and nebulized dosage forms, multiple technical, business, and regulatory factors need to be given appropriate evaluation. This article looks at some of the key considerations for today’s developers.
MDIs, DPIs, and nebulized solutions and suspensions each present their own advantages, disadvantages, and challenges. The dosage forms differ considerably in the availability of off-the-shelf-devices, while they also accommodate varying dosage ranges. In addition, they have very different types of formulations, which means the selection of a drug form, or salt form if applicable, should be considered in tandem with selection of the dosage form. This is a key factor because the physiochemical properties of the drug may play a leading role in dosage form feasibility.
One of the most important steps in the selection of an inhalation dosage form is salt form screening. Today, approximately 50% of active pharmaceutical ingredients (APIs) in approved products are salt forms (1), with the proportion for APIs in approved inhalation products being slightly higher at 60%. Some salt forms are better suited than others for different formulations or dosage forms. As with all pharmaceutical development, understanding the unique physical and chemical properties of the API will be crucial in defining the dosage-form design space.
Based on the inhalation formulation and dosage form being considered, API characterization studies may be warranted, including polymorph screening, amorphous content, hygroscopicity, moisture content, surface properties, solubility in the formulation matrix, morphology and size, density, flowability, and chemical/physical stability (including excipient and device compatibility).
MDIs and nebulized products can be formulated as solutions or suspensions. For a solution formulation, the API should be completely soluble in the formulation, with a safety margin to prevent precipitation during cold temperature excursions. Fine particle generation by micronization for example can be explored as a means to increase the solubility of a given API. For a suspension formulation, the API should be essentially insoluble in the formulation (e.g., < 0.1 ppm solubility), otherwise particle growth (i.e., Ostwald ripening) may occur (2). Such particle growth may adversely affect the aerosol performance of these products, thereby, decreasing the efficacy of the drug product.
Today, most marketed MDIs are formulated as suspensions, primarily because of the challenges associated with solubilizing APIs in hydrofluoroalkane (HFA) formulations. In cases where APIs are solubilized using a cosolvent such as ethanol, chemical stability can be a significant issue. Early in the MDI formulation feasibility process, the solubility of the API, as well as chemical stability, should be evaluated in HFA formulations. In contrast to MDIs, most nebulized products are solution formulations. The chemical and physical stability considerations for solutions and suspensions remain the same as those outlined for MDIs.
For DPIs, salt selection should be made with a focus on carrier compatibility, ease of processing and dispersion (e.g., flowability), minimizing hygroscopicity, and ensuring stability. The feasibility of micronization is another factor to consider for APIs used in DPI formulations.
A plan can be developed to conduct dosage form feasibility studies based on the limitations of a particular API. In some cases, preformulation data can suggest that more than one dosage form may be feasible, and a parallel path of formulation development and stability characterization may be warranted for those dosage forms. These paths may converge on one dosage form to promote to preclinical toxicology or first-in-man studies. Getting these early studies off to the right start can be crucial to the timeliness and, ultimately, the success of an inhalation drug product development program.
Another factor that plays a significant role in the selection of an inhalation dosage form is the required dose. MDIs, DPIs, and nebulizers can each perform well in delivering small doses in a consistent fashion; however, delivering high doses is significantly different. MDI suspension formulations can deliver 1 to 5 mg of drug per actuation. Doses greater than this range may result in clogging or malfunctioning of the metering valves. The delivery capacity for MDI solution formulations is, therefore, dictated by the solubility of the drug in the formulation and the valve metering chamber volume, which is normally in the range of 25 to 100 µL.
In contrast, DPIs can deliver much higher drug payloads, up to several hundred milligrams. The limiting factor is patient tolerability. Typically, dry powder formulations are comprised mostly of carrier particles; however, neat drugs can sometimes be delivered effectively with the aid of particle or device engineering. Nebulized products are also capable of delivering high doses, in some instances, up to 300 mg of drug.
MDIs have been shown to be suitable for a wide range of patient populations. Children under the age of four and some elderly patients, however, may have difficulty coordinating their breath with the actuation of the device. In these cases, a spacer or valved holding chamber may be used to remove the need for breath coordination. Young children or patients with compromised lung function may also not be able to generate the inspiratory flow required for operation of passive DPIs.
Nebulizers, on the other hand, can be successfully used by most populations, although they are most commonly used with hospitalized or critical care patients. These devices tend to be large, difficult to transport, and treatment times are generally much longer than those for MDIs and DPIs. Cystic fibrosis patients are perhaps the most accustomed to nebulized treatments, though many would welcome more convenient options (3).
In comparing MDIs, DPIs, and nebulized dosage forms, nebulized products have typically been shown to be the least expensive and quickest to develop. One reason is that nebulized formulations are usually aqueous solutions or suspensions and tend to be less complex than MDI and DPI formulations. Another reason for the difference in relative costs is that MDIs and DPIs are regulated as combination products covering both formulation and device.
A significant portion of the total development costs for MDIs and DPIs can be the extensive product characterization studies required for the formulation with a selected device, including priming, re-priming, temperature cycling, device cleaning, effect of orientation, and profiling of doses near device exhaustion. Because most nebulized products are regulated separately from the device, less product characterization is required. The regulatory trend for nebulized products, however, may be toward regulation of combination products in the future (4–6).
Relative costs and timelines for development should also be key factors in device considerations. For MDIs and nebulized products, off-the-shelf devices are readily available. Few off-the-shelf options currently exist for DPIs. Developing a new DPI device or licensing a device that is still under development can add significant time and cost to a program; however, the upside can be the creation of a higher barrier to entry for generic competition.
The most desirable approach is that a drug development program can be started using the dosage form that is intended to be marketed. Nonetheless, there have been situations when developers have deemed it faster and more cost-effective to reach a Phase I clinical study with a nebulized dosage form, even when the final product is expected to be an MDI or DPI. Manufacturers may, however, find this overall program approach to be longer and more expensive due to reformulation and cross-over studies that may be required at a later phase of development. Despite this, there can be sound business reasons to take the cross-over approach, such as in cases where reaching the clinic quickly with a nebulized formulation could secure the next round of funding or a strategic partnership.
The complexity of evaluating dosage forms for inhalation drug products should not be underestimated. The physicochemical properties of the API, the dose, the target patient population, timeline, and budget are all important considerations. In addition, factors such as biopharmaceutics, intellectual property, marketing, and competitive landscape, may be relevant and should also be carefully evaluated. Working through these considerations will provide the first step in matching an API’s unique characteristics and target profile with the most appropriate inhalation dosage form.
1. C.G. Wermuth and P.H. Stahl, “Introduction,” in Handbook of Pharmaceutical Salts: Properties, Selection and Use, P.H. Stahl and C.G. Wermuth, Eds. (Wiley–VCH, Weinheim, Germany, 2002), pp. 1–7.
2. P. Rogueda, Expert Opin. Drug Delivery 2(4) 625-638 (2005).
3. G.S. Sawicki, D.E. Sellers, and W.M. Robinson, J. Cyst. Fibros. 8(2) 91-96 (2009).
4. M. Copley, “Nebulizer Testing: Exploring the Implications of New Regulatory Guidance for Testing Nebulizers,” Inhalation, October 2008.
5. D.A. Morton et al., RDD Europe 2009, Vol 1, 129-148 (2009).
6. T.G. O’Riordan, Respiratory Care 47 (11) 1305-1313 (2002).
Volume 41, Number 9
When referring to this article, please cite it as M.T. Marmura and P. Sheth, “Targeting the Lungs,” Pharmaceutical Technology 41 (9) 2017.