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Inhalation formulations are complex, and empirical data are essential for realizing optimal solutions.
Inhaled drug formulation involves consideration of multiple factors, including the properties of the API, the needs of the target patient population, the delivery requirements, and the choice of device. Predicting the performance of a specific API is, consequently, quite challenging. While some computational approaches can help, physical experiments provide the greatest insights.
Historically, the inhaled route has been preferred for the local administration of drugs to treat pulmonary diseases. “Inhaled delivery has clear advantages because delivering the API directly to the intended target allows for more efficient delivery of less overall dose with maximized efficacy and minimized dose-related side effects when compared to simpler systemic dosing,” explains Mark Parry, technical director with Intertek Melbourn.
Inhaled delivery also provides an alternative route for systemic dosing with different pharmacokinetics when compared to traditional routes such as solid oral dose and is of increasing interest where rapid delivery and onset of action is the objective, Parry adds. APIs that have stability issues upon contact with gastrointestinal fluids or decreased bioavailability because of first-pass metabolism can also be considered for inhaled delivery, notes William Wei Lim Chin, manager of global scientific affairs at Catalent.
Today, this route of administration can also be used to deliver systemic drugs for indications such as diabetes, Parkinson’s disease, and for pain management, according to Chin. “The large surface area in the lungs and the thin-walled pulmonary vasculature allow transport of drugs into the bloodstream,” he explains.
Even large molecules such as peptides, antibodies, and various types of engineered proteins can now be delivered via the lungs, Chin observes. These molecules present considerable challenges for delivery via the traditional oral route. “As we see increasing importance of new modalities in the biopharmaceutical space coming through the drug development pipelines, inhalation provides an alternative to parenteral delivery of these active substances that may provide advantages both in terms of the pharmacokinetic behavior and the patient experience,” Parry states.
Indeed, one of the primary factors in determining if formulation for inhaled delivery is the right approach—and the specific type of inhalation device—for any given API is the needs of the target patient population. “If the device does not meet the needs of the patient population, the utility of the product will be severely limited,” observes Jennifer Wylie, director of analytical research and development at Merck.
For instance, while there is evidence that patients prefer inhaled products to injectable ones (1), inhaled devices are usually more complicated to use than oral or injectable dosage forms, Chin notes. “Strategies that include patient education or training can help to address these limitations, as can careful design or selection of the delivery device,” he says.
In another example. Wylie points to the fact that dry-powder inhalers (DPIs) cannot be used by children younger than five to six years of age. “If the indication being addressed has a significant pediatric population, it may therefore be necessary to select an alternate device that is more appropriate, such as a nebulizer,” she comments.
Parry adds that a nebulizer formulation for a soluble API could be the simplest route to develop and, if only used in a hospital setting for short-term treatment, may be well tolerated by the patient and make the most sense commercially. When looking at the management of chronic diseases such as asthma and chronic obstructive pulmonary disease (COPD), however, he comments that the benefits of multidose DPI and pressurized metered-dose inhaler (pMDI) products become more important. Furthermore, engaging in more complex development programs can make commercial sense when considering large patient populations.
In addition to considering the needs of the patient population, Chin points out that whether or not inhalation delivery is the correct choice depends on the desired site of action (local versus systemic), whether there is a need for rapid absorption, and the drug class, all of which must be balanced against the development costs associated with these relatively complex products.
Specific attributes of an API that can affect its suitability for inhalation delivery include its physicochemical and interfacial properties, the ease and robustness of its manufacturing process, its inherent stability and potential routes of degradation, the level to which it interacts with its biological target and how long it is retained in the lung, its local and systemic bioavailability, and its toxicity, according to Charles Evans, senior vice president of pharmaceutical development for MedPharm.
Other factors that are typically considered when selecting inhalation delivery as outlined by Marc Brown, co-founder of MedPharm and chair of the company’s scientific committee, include the intellectual property status; the funds available for formulation development; the main objective of the project (i.e., proof of concept or full commercial development); the delivery device; and the potential processing/production needs of the API, such as micronization, spray drying, freeze drying, coacervation, etc.
Because there are so many diverse classes of APIs considered for inhalation delivery, defining an ideal set of API properties is difficult. “With various platforms and production technologies available, almost any API candidate can be formulated for inhalation,” Chin observes. He does note, however, that certain overarching molecular properties will enable more successful delivery to the lung, such as the nature of the solid state, the level of permeability, and the specific surface area.
In fact, the ideal properties of an API do depend on the specific delivery device, according to Wylie. “Usually, a solution formulation is desired for a nebulizer, and therefore a stable molecule with adequate solubility is desired.For a dry powder inhaler, the ability to reduce its particle size to the appropriate size range is important,” she adds.
One of the first properties to consider for an API when deciding on a type of delivery, Parry agrees, is how soluble the material is, including related salt forms. Equally important is how practical particle engineering such as micronization or spray drying might be, which can be impacted by properties such as the melting point and any characteristic polymorphism. “These considerations will guide the feasibility and likely complexity of the different delivery options,” he says.
Brown adds that APIs with higher aqueous solubilities can be more applicable to nebulizer systems, including both portable and hospital units. “Nebulizer formulations can quite often be a faster route to clinical studies for proof of concept as they leverage the simplest approach,” he adds.
APIs that are soluble in more polar solvents such as alcohols, meanwhile, are often more suitable for MDIs, Brown says. Those with attractive interfacial properties, particularly post-micronization, can be appropriate for DPIs and suspension formulations. He also emphasizes that crystalline materials with good chemical and physical stability are preferred. A thorough understanding of the particle size and its aerodynamics is required for small-molecule APIs delivered via carrier-based or carrier-free DPIs, Chin adds. When an excipient carrier is involved, he stresses that particle-to-particle interactions, particularly the API morphology/shape and surface characteristics, are critically important.
The requirements for small and large molecules intended for inhalation formulations do differ somewhat. For small molecules, Chin notes that properties centered on the solid state of the drug (crystalline for stability purposes versus amorphous for solubility improvement), permeability, and particle size are critical drivers in influencing the drug absorption process in the lung. He adds that it has been reported that small-molecule inhalable drugs generally meet Lipinski’s Rule of Five, with a tendency to have slightly higher molecular weights, high polar surface areas, and lower lipophilicities (2).
For large molecules such as peptides, proteins, and antibodies, Chin observes that particle surface properties are probably more critical criteria for the disposition and retention of these molecules in the lung. Because of the structure of these large molecules, they are more amenable to formulation using a spray-drying process for dry-powder formulations.
“Most important,” Chin contends, “regardless of the type of API and delivery platform, is the ability to repeatedly and consistently deliver the drug molecules as an aerosol.”
Inhaled drug delivery is inherently complex requiring identification of compounds with an appropriate balance of lung retention, toxicity, and bioavailability according to Evans. Several studies have correlated an API’s physicochemical properties with the absorption of inhaled drugs, but Chin notes the current consensus is that there is a lack of reliability of in vitro methods to establish absorption and permeability at the lung level.
“For dry powder inhalers, the particle size of the API must be of a respirable size (usually considered below 5 microns).For any solution formulation (for example, a nebulized solution), the API must have adequate solubility in the proposed formulation. Other than that, it is difficult to predict the performance without any experimental data,” Wylie says.
The pulmonary biopharmaceutics classification system (pBCS), introduced in 2010 and inspired by the oral biopharmaceutics classification system (BCS), attempted to establish a framework by considering the physiology of the lung, drug physicochemical properties, and drug absorption (3). The pBCS, Chin explains, suggested that molecular size, lipophilicity, solubility, acid dissociation constant (pKa), protein binding, polar surface area, and number of rotatable bonds predict an API’s permeability across the lung epithelium.
“From the developability perspective, this was a turning point that generated considerable interest from academia, industry, and regulatory stakeholders,” Chin says, pointing to a workshop on the topic (4). Unfortunately, he observes that 12 years on, the predictive utility of the pBCS framework remains uncertain as there are still many factors other than physicochemical properties that affect drug disposition in the lung, including the variability in patient breathing patterns and compliance to treatment regimens.
On a positive note, MedPharm has found that some cell- and tissue-based models developed in-house at the company can be used to provide a means of comparing performance between APIs and devices, according to Evans.
Parry also points to significant research into better models for understanding the way APIs are deposited in the lungs and then dissolve, which could help improve in-vitro/in-vivo correlation. “While much of this work has been driven by a need to better support the development of generics, we now have an increasingly broad toolbox to understand and study the delivery of poorly soluble APIs that can aid the particle engineering and formulation development work in optimizing their performance,” he remarks.
Computational approaches for aiding inhalation formulation development are being investigated, but developing effective models is not easy. “Development of inhalation products relies heavily on the packaging and delivery device, not only the formulation, so understanding the behavior using computational methods can be very complex,” Brown observes.
Mathematical/computational models for predicting airflow and respiratory aerosol deposition have been reported in the literature, but Brown believes, like many such models, they have significant limitations due to the gross assumptions they require. He does expect the value of these models to increase over time, however, especially for large pharmaceutical companies with libraries comprising thousands of APIs and drug formulations available for screening.
One example is Cohesive Adhesive Balance (CAB), a screening tool for investigating the surface interfacial properties of secondary processed micronized APIs and their influence on blending dynamics, stability, and in vitro performance. “CAB directly quantifies the relative magnitudes of the cohesive and adhesive forces that govern formulation structure and ultimately product functionality,” Brown explains. It can be used throughout API process development, early-phase DPI formulation development, and scale-up.
Chin points to thermodynamic modeling approaches for predicting process parameters that affect the properties of spray-dried particles and computational fluid dynamics (CFD) simulations for understanding the complexity of device and formulation interactions, which he says are being used to improve the performance of DPIs. CFD has more recently been used to study air flow within devices and patients, while discrete element methods are used to simulate dispersion and aerosolization of particles, according to Brown.
Inhaled delivery development is primarily focused on getting efficient dosing of drug to the right area of the lung. “Particles larger than 5 microns may not travel very far into the lung, particles in the 3-5-micron range will tend to deposit in the larger airways, while sub-3-micron particles will reach the deeper lung; the desired target will depend on the API and the condition being treated,” Parry says.
Ultimately, therefore, developing effective inhalation formulations requires extensive physical evaluation and experimentation, Wylie agrees. “The API and its physicochemical characteristics can directly impact the performance of an inhaled product.It is very important to gain understanding of these properties throughout development,” she states.
In general, optimizing for the right particle size may have trade-offs in overall dose amounts delivered to the lung, so optimization for the overall product performance can be complex, observes Parry. “When dealing with solid APIs (DPI or suspension-based products), therefore, understanding the physical properties and behaviors will greatly inform the development objectives,” he says. Having early empirical data from well-designed feasibility and scoping studies is essential.
Typical experiments include solubility and stability studies, as well as extensive analysis to determine particle size, shape, and density; crystallinity, surface morphology, and polymorph content; and the molecule fingerprint of the API, according to Evans. Using these data, the best delivery routes are determined and preliminary formulations and devices are developed simultaneously.
“The specific approach for any given API and project depends on the data that [are] available,” Evans adds. For example, if particle-size data are available, then it is possible to assess whether the distribution will be suitable for an inhalation formulation or if micronization is required. However, he also notes that the potential for successful micronization is more difficult to predict without an understanding of the interfacial properties, which relate to the likelihood of agglomeration at smaller particle sizes. Solubility and stability data, meanwhile, can indicate whether a solution nebulizer system or MDI would be a more viable delivery platform.
Even though gathering experimental data is challenging, it is essential to the development of inhaled delivery formulations. Fortunately, evidence-based models do show promise for improving the development process, including proprietary in-house solutions as well as solutions accessible by the wider stakeholder community.
1. K.D. Stewart, et al., Patient Prefer Adherence 10:1385-1399. (July 27, 2016).
2. T.J. Ritchie, C.N. Luscombe, and S.J.F., J Chem Inf Model, 49 pp. 1025-103 (2009).
3. H. Eixarch et al., J Epithelial Biology & Pharmacology 3:1–14(2010).
4. Hastedt, et al. “Scope and Relevance of a Pulmonary Biopharmaceutical Classification System,” AAPS/FDA/USP Workshop March 16-17th, 2015 in Baltimore, MD. AAPS Open 2, 1 (2016).
Cynthia A. Challener, PhD, is contributing editor to Pharmaceutical Technology.
Volume 46, Number 5
When referring to this article, please cite it as C. Challener, “Inhalation Formulation Development: Predicting API Behavior,” Pharmaceutical Technology 46 (5) 2022.