Inhaled Medicines: Optimizing Development through Integration of In Silico, In Vitro and In Vivo Approaches

By Anthony J. J. Hickey

Inhaled medicines are widely used to treat pulmonary and systemic diseases. The efficacy and safety of these medicines can be influenced by the deposited fraction, the regional deposition pattern within the lungs and by post-depositional events such as drug dissolution, absorption and clearance from the lungs. Optimizing performance of treatments thus requires that we understand and are able to quantify these product and drug attributes.

Inhaled Medicines: Optimizing Development through Integration of In Silico, In Vitro and In Vivo Approaches explores the current state of the art with respect to inhalation drug delivery, technologies available to assess product performance, and novel in silico methods now available to link in vitro product performance to clinical performance. Recent developments in the latter field, especially the prospect of integration of three-dimensional Computational Fluid Particle Methods (3D-CFPD) with physiologically based pharmacokinetic (PBPK models), unlocks the potential for in silico population studies that can help inform and optimize treatment and product development strategies. In this highly multidisciplinary field, where progress occurs at the intersection of several disciplines of engineering and science, this work aims to integrate current knowledge and understanding and to articulate a clear vision for future developments.

• Considers the healthcare needs driving the field, and where inhaled drugs could have the maximum impact
• Gives a concise account of the state of the art in key areas and technologies such as device and formulation technologies, clinically relevant in vitro performance assessment, medical imaging, as well as in silico modelling and simulation
• Articulates how the combination of in vitro product performance data, medical imaging and simulations technologies in the framework of large scale in silico pre-clinical trials could revolutionize the field
• Provides systematic and thorough referencing to sources offering a more-in-depth analysis of technical issues

• Language: English
• Publisher: Academic Press
• Release date: Jan 20, 2021
• ISBN: 9780128149751

Book preview

efforts.

Chapter 1

Historical perspective – Disruptive technologies and strategies

Anthony J. Hickey¹ and Joy Conway²,    ¹ RTI International, Research Triangle Park, NC, United States,    ² University of Southampton, Southampton, United Kingdom

Abstract

Inhaled medicines have been used to relieve pulmonary disease throughout recorded history. In modern times, not surprisingly, inhalers have been developed to treat the prominent diseases of asthma and chronic obstructive lung disease. The purpose of this review is not to list the wide range of advances that have occurred over the last century. Others have reviewed this admirably. Rather the focus is on the scientific and technological achievements that have resulted in disruptive change in more recent history. As a result of these advances the efficiency and reproducibility of inhaled drug delivery has improved and the quality, safety and efficacy of drugs used in the treatment of an even wider range of pulmonary and systemic disorders is assured.

Keywords

Aerosols; Drug delivery; Formulation; Inhalers; Pharmaceuticals; Pulmonary; Technology

The evolution of inhaled medicines in recorded history can be traced back to the Indus Valley and China 5000 years ago with inhalation of smokes of stromonium alkaloids and ephedra [1]. There have been some excellent reviews of developments in the intervening period leading to modern developments in the period following since the middle of the 20th century [2,3]. In keeping with the intent of this volume to guide the reader to critical issues in inhaled pharmaceutical research and development, the approach to the topic taken here is to focus on the disruptive technologies and the evolution of modern methods and treatment strategies.

In this regard, the major developments have occurred in dosage forms, aspects of characterization and biopharmaceutical considerations. In addition, the diseases that were primarily the target for therapy, asthma and chronic obstructive pulmonary disease are now expanding to include a wide range of other pulmonary and systemic diseases.

1.1 Dosage forms

1.1.1 Metered dose inhalers

In the mid-1950s metered dose inhaler technology was developed at  3M Pharmaceuticals [4]. The key to the success of this dosage form was the combination of small, metered dose valves and the ability to use the vapor pressure of chlorofluorocarbon propellants (CFCs) as the propulsive force through flash evaporation of small respirable droplets. The discovery in 1973 of the atmospheric ozone depletion resulting from CFC emissions led to the Montreal Protocol, an international agreement, to phase out the CFCs for all applications including medical use [5,6]. Development of hydrofluoroalkane or hydrofluorocarbon (HFA or HFC) alternative propellants was largely driven by the phase out of CFC propellants and resulted in  the first product a corticosteroid (Qvar, beclomethasone dipropionate, 3M Pharmaceuticals) appearing in the late 1990s and the first broncholdilator, albuterol sulfate in 2003 (GSK) [7–9].

As the transition to HFA formulations progressed it became evident that the number of formulation options was even more restricted than had been the case with CFC formulations. Creating a formulation strategy that was generalizable to a variety of drugs was a challenge and the initial approved products required significant formulation optimization. In recent years the development of co-suspension technology (Budesonide, Glycopyrrolate, Bevespi®, AstraZeneca) is a major step towards a solution to the formulation constraints usually experienced [10].

As concerns about global warming potential increase there is some pressure to phase out HFAs and a new series of propellants are under development.

1.1.2 Dry powder inhalers

In the 1960s and 1970s alternative strategies for the delivery of aerosol particles emerged both as a proprietary strategy (Spinhaler, Cromlyn Sodium, Intal®, Pfisons) [11] and as an alternative to metered dose inhalers for those who were for whatever reason reluctant or incapable of using them (Rotahaler, Albuterol Sulfate, Ventolin®, GSK) [12]. These products were not a huge market success but offered a different platform from which to consider aerosol delivery. At the time of CFC phase out discussions, there was a concurrent interest in the delivery of the products of biotechnology, which were not suitable for conventional routes of administration. Consequently, in the early 1990s the focus returned to the potential of dry powder inhaler technology most obviously for insulin products, such as Exubera® (Pfizer/Nektar), which was finally approved in the United States in 2006 [13].

There were a number of dosage form advances as the emphasis was placed on improving the technology. The first step was to move from pre-metered unit dose devices (capsule based) to multidose devices the earliest of which, in the 1980s, was the Turbuhaler originally developed for the delivery of terbutaline (Astrazeneca) [14]. There was significant market uptake for this device particularly for the combination product with budesonide, Pulmocort® [15].

During the early 2000s the advent of new potent drugs and technologies led to dry powder inhalers finally becoming a commercial success led by Advair®/Seretide® Diskus and the first inhaled therapy for Chronic Obstructive Pulmonary Disease, tiotropium (Handihaler, Spiriva®, Boehringer Ingelheim) [16,17].

Throughout the period of new drug and inhaler technology development there had been a significant focus on new formulation approaches. Initial products consisted of micronized (attrition milled) particles that were manipulated to overcome forces of particle interaction by including in carrier particle blends (Intal® and Ventolin®) or through controlled loose aggregates (Turbuhaler) [18]. The focus on stabilizing proteins in dry powders led to exploration of spray drying technology [19,20]. The concept of low-density particles emerged from spray drying engineering with the advantage of producing respirable particles that can be easily dispersed [21]. A similar technology resulted in a dry powder antibiotic form of Tobramycin (PulmoSpheres®, Novartis) [22].

It should be noted that there have been numerous published technologies intended to modify the release rate of drugs or for specific targeting e.g. macrophages, in the lungs. This topic alone would justify an independent review. However, very few of these technologies have resulted in commercial products. Indeed, most modulation of the drug disposition and effect has been achieved through modifying the drug itself during the discovery effort. Therefore, this topic is considered beyond the scope of this historical review, while it is acknowledged it may be important in the future.

1.1.3 Nebulizers

Technology for the delivery of aqueous droplets by Bernoulli, or Venturi, effect from a nebulizer is arguably one of the older technologies for the delivery of solutions of drugs [19,23]. As these devices are uniquely regulated in the United States as separate medical instruments from the drug solution, they exist in a wide variety and are considered a relatively inexpensive commodity item. While the alternative method of ultrasonic aerosol generation has existed for decades, it is a slightly less efficient approach and has generally been less popular the jet nebulizers [23]. The desire to preserve expensive drug, increase the efficiency of delivery and reduce the time of delivery, which would help with patient compliance, was a significant impetus for the development of alternative technologies.

The need to deliver products of biotechnology, potentially expensive potent drugs, initiated the interest in vibrating mesh technologies, which have since been developed to one of the most popular methods of delivering nebulized drugs [24]. The advent of these systems has also allowed for specific nebulizers and drugs to be dispensed together which moves nebulizers closer to regulation as a combined drug product. The delivery of large dose antibiotics, efficiently and over relatively short periods has also benefited from the development of vibrating mesh systems [25].

1.1.4 Soft mist inhalers

Soft mist inhalers represent a unique approach to progressing from metered dose inhalers and dry powder inhalers in terms of metered systems. This product is exemplified by the tiotropium (Spiolto Respimat®, Boehringer Ingelheim®) product, which is based on forcing the drug solution through a silica-based orifice system impinging flows to generate the aerosol [26]. This has been a remarkably successful new technology since its approval in Europe in 2015.

1.1.5 Other considerations

As new technologies related to aerosol delivery and inhaler design are developed there is a growing need to consider components that will assist in patient compliance and adherence. The first step in this direction was the requirement for counters on all metered devices, which began as a universal demand at the turn of the Millennium [27–29]. This has since been followed by a variety of electronic systems that report to both the patient and the clinician. Moreover, these systems can be used for immediate and long-term monitoring of therapy through apps on hand held devices which parallel developments in fitness monitoring [30]. These developments have yet to meet their full potential but the future is clear from the speed of adoption for lifestyle monitoring systems for other aspects of life.

1.2 Characterization

1.2.1 In vitro testing

The performance characteristics of greatest importance for inhalers, as identified by pharmacopoeias and regulatory guidance documents, are delivered dose and aerodynamic particle size distribution (APSD) [31,32]. The latter is a unique characteristic of aerosols and there is only one way to determine practically in a manner that meets the requirements for regulatory approval and this is by a principle known as inertial impaction. Simply stated inertial impaction occurs when the mass of a particle is such that as it approaches a barrier to flow its inertia (mass and linear velocity) propels it toward the object on which it impacts. Particles with smaller mass are more likely to relax into the direction of the airflow on which they are carried and pass around the obstacle. Particles with higher linear velocity, and therefore inertia, tend to impinge on a collection surface and by sequentially increasing the velocity a series of particle sizes can be collected on a device, which is known as a cascade impactor [33,34].

The principle of cascade impaction which is a semi-empirical phenomenon based on Stokes’ law has been known for some time and was originally developed for capturing ambient aerosols following the detonation of conventional and, subsequently, nuclear weapons in the 1940s and 1950s [35]. Their value was soon realized by those studying atmospheric physics, industrial hygiene and inhalation toxicology. Their adoption for characterization of pharmaceutical aerosol was approximately concurrent with the development of the early inhaler technologies. However, by the late 1980s it was evident that there were some important characteristics of inhaled aerosols that differed from atmospheric aerosols. Firstly, atmospheric aerosols were on a short time scale of minutes or hours steady state aerosols that could be sampled at almost any flow rate and through any sampling inlet from atmosphere provided the cascade impactor was calibrated at that flow rate and particles were sufficiently small to pass through the inlet without deposition. Secondly, it was always the case with ambient aerosols that a sample was taken, as collection of the entire aerosol was both physically impossible and given the nature of locational sampling undesirable.

In contrast, pharmaceutical aerosols are not steady state (with the possible exception of nebulized droplets) entitites and it is important that the entire dose is sampled and subjected to chemical analysis. At the end of the 1980s significant attention was given to the flow rate of sampling for relevance to human effort and to the adoption of a standard inlet [32]. Both of these items were central to the ability to compare data from one laboratory to the next and to establish the quality and uniformity of performance. At the turn of the decade from the 1980s to 1990s a standard inlet was adopted by the United States Pharmacopoeia and as the effect of flow rate on performance of dry powder inhalers in particular was noted three flow rates were settled on as relevant for testing of 30, 60 and 90 L/min, representing weak (sedentary), intermediate and strong inhalation effort [31].

The observation that there was a limited correlation between cascade impaction data for particles collected <3 µm in aerodynamic diameter and experimental data on lung deposition for a number of different inhaler devices was encouraging with respect to the prospects of developing predictive models [36].

1.2.1.1 Sampling inlet configuration and airflow rate

The sampling inlet adopted was frequently referred to as the ‘throat’ although there was no evidence that it behaved as an anatomical human oropharynx [37]. However, in time the notion that it should reflect deposition in a human oropharynx gained popularity among those searching for an in vitro predictor or lung deposition. In the 2000s Warren Finlay at the University of Alberta was the first to explore the possibility of a cascade impactor, sampling inlet in which deposition would approximate that of a human throat [38,39].

As inlet considerations were evolving another obvious consideration that would need attention was beginning to be addressed in some laboratories, namely that inspiratory flow is not a step function constant volumetric flow rate as defined by a vacuum pump but is in fact a flow cycle exemplified by acceleration and deceleration or continuous flow variations [40]. The combination of instruments designed to deliver variable inspiratory flow rates with physiological throat casts has been shown to bring our in vitro estimates of lung deposition as close as they have every been to actual predictions [41].

1.2.2 Lung deposition

1.2.2.1 Modeling

As in vitro methods have improved lung deposition modeling has improved dramatically. Extensive analytical modeling appeared between the 1940s and 1990s in the field of atmospheric exposure and industrial hygiene that informed considerations of drug deposition but was not adopted widely by the industry or those in academia focused on pharmaceutical technology [42,43]. At the end of the last Millennium the adoption of computational fluid dynamics both for flow path optimization in devices and for lung deposition modeling linked the two aspects of inhaled medicines in a manner that has promoted its mainstream application [44]. The common approach now seems to be one of combining CFD and analytical approaches to iterate towards greater predictive capacity and to formally link device performance to expectations of biological targeting [45].

1.2.2.2 Imaging

The value of models is gauged by their ability to predict lung deposition and is only as good as our practical knowledge of lung deposition as measured by imaging technologies. Two dimensional planar imaging, using gamma scintigraphy, has been common practice as a diagnostic tool for over a half century [46]. It became the tool of choice for studying the deposition of pharmaceutical aerosols in the 1970s and 1980s and has been used to evaluate all currently marketed products. There are many considerations with respect to the importance of this method [47]. Tissue overlay, attenuation and, ultimately, resolution make this method somewhat insensitive. Nevertheless, qualified researchers in this field are sufficiently well versed in the technology to extract helpful information and have been able, by considering regions of interest, to make broad claims as to measures of deposition site for correlation with subsequent pharmacokinetic and pharmacodynamics interpretation [48]. Three-dimensional methods have been the subject of increasing imagining research since the turn of the Millennium in terms of transitioning to development tools. Single Photon Emitted Computer Tomography (SPECT) and positron emission tomography (PET) have been the subject of extensive development [49]. The approach to interpretation of the data has also expanded to allow for many more regions of interest to be identified, almost to the level of airway branching numbers, through a onion layer approach [50].

1.3 Biopharmaceutics

1.3.1 Pharmacokinetics

Following the disposition of drugs from the lungs has been part of inhaled product development activities for many years. Early product assessments gave little attention to pharmacokinetics as the drugs were delivered in such low doses to the lungs that plasma concentrations were difficult to detect. As analytical methods improved, most notably with the development of high performance liquid chromatography and subsequently with the shift from standard detection methods such as ultra-violet to mass spectrometry detection, sensitivity and limits of detection were reduced dramatically. The ability to follow drug disposition as a function of dose rendered this the most sensitive biological approach to assessing differences in product performance or for generic products differences between innovator and generic alternate products.

As it has been acknowledged that the pharmacokinetics may be the first, and perhaps most important, biological measure of drug performance the approach to studying the data has also evolved [51,52]. It is possible to conduct analysis in a model independent fashion using the raw data, but where complex patterns of disposition are involved this may make data interpretation difficult. Classical pharmacokinetic models call for the overlay of mathematical transformations in which compartments may be inferred for which there may, or may not, be physiological equivalents [53]. In recent years, physiological models are beginning to yield more physically accurate depictions of drug disposition [54]. From a regulatory standpoint, the adoption of population pharmacokinetics in clinical trials now renders interpretation of direct relevance to this important step in establishing the biological performance of an inhaled therapeutic agent [55].

1.3.2 Pharmacodynamics

Clinical endpoints vary from one disease to another. Consequently, there is no general approach to establishing these measures of efficacy that are the desired outcome for the clinician and the patient.

Unfortunately, therapeutic outcomes are rarely good measures of the quality or performance of an aerosol product. The primary commercially available therapeutic categories of drug employed are beta2-adrenergic agonists (BAA), anticholinergics (AC) and corticosteroids (CS) used in the treatment of asthma and chronic obstructive pulmonary disease [56]. BAA and AC drugs are delivered in doses that are so far above their therapeutic dose (along the pharmacological plateau) that the will be effective regardless of a wide disparity in patient pulmonary function due to age, gender or disease state. CS therapy involves stabilizing on daily doses given for a period of time and so any variability in response to an instantaneous dose is averaged over the entire dosing period. Consequently, the challenge is to identify sensitive measures of efficacy that do vary with dose delivered.

Since the majority of the work on inhaled aerosols has focused on asthma and chronic obstructive pulmonary disease, the Forced Expiratory Volume at 1 s (FEV1) has been employed as a measure of pulmonary function in response to drug therapy [57]. However, as interest in the use of therapeutic aerosols has expanded the question has arisen as to whether a broader view of the pulmonary function tests should be taken and whether biomarkers can be identified such as sputum eosinophils, exhaled gas (NO), C-reactive protein or other metrics for infectious disease such as secreted proteins or toxins [58].

1.3.3 Diseases

In modern times asthma was the first disease to be treated with inhaled therapy [59]. The nature of the disease being localized to the airways and its high incidence worldwide made it a clear therapeutic and commercial target. It took almost a half-century for the same approach to be taken to chronic obstructive pulmonary disease despite the localized nature of disease and the severity of disease globally. At this point asthma and COPD are the most significant diseases being treated with aerosol therapy.

As the technology and drug portfolio has evolved many other diseases have become targets for aerosol therapy. Cystic fibrosis is significant among these for the range of treatments that are now available including Mucolytics (sodium chloride and acetylcysteine) DNAse (Dornase®, Genentech), tobramycin (TOBI®, Novartis) and a revival of gene therapy driven by the possibility of gene editing [60,61]. Each of these approaches treats different aspect of disease. Mucolytics hydrate mucus and DNAse clips leukocyte DNA that contributes to thickening of mucus and both make mucus less viscous and more mobile. Tobramycin treat the primary Pseudomonas aeruginosa infection that complicates the disease and causes severe local inflammation. Gene therapy or editing can be employed to correct the Cystic Fibrosis Transmembrane Receptor (CFTR) defects that give rise to a chloride imbalance and result in a thickening of mucus in the lungs [61].

In the late 1980s and early 1990s several organizations began to develop inhaled insulin to treat diabetes by regulating circulating glucose. The first such product, Exubera® (Pfizer/Nektar) was approved in 2006 and voluntarily withdrawn from the market after one year [13]. The second product Afrezza® (Mannkind) was approved in 2014 [62]. There is no question that the drive to develop inhaled insulin had an enormous stimulus particularly on dry powder inhaler development the extent of which would be hard to measure.

Unique inhaler development was required for the delivery of drugs for the treatment of disorders of the brain. One of the first evaporation condensation devices the Staccato® (Alexza Pharmaceuticals) is in development for a number of drugs. Adasuve® (loxapine) for the treatment of schizopherenia and bipolar disorder was approved in 2012 [63]. A supercritical fluid manufacturing method was employed for the preparation of dihydroxyergotamine for inclusion in an HFA metered dose inhaler (Levadex®, MAP Pharma now Allergan) [64]. Approval of this product has been anticipated for over five years.

There are many other diseases for which inhaled therapy may be potentially useful ranging from tuberculosis [65] and non-tuberculous mycobacterial [66] treatment to the delivery of drugs to treat pulmonary arterial hypertension [67] and idiopathic pulmonary fibrosis [68]. There continues to be a bright future for inhaled therapy as technology evolves and new disease applications are identified.

While new developments are occurring there is increasing interest in promoting the development of generic products. The challenge that is being addressed by pharmaceutical scientists is connecting many of the items discussed earlier, in vitro testing, modeling and imaging of lung deposition and pharmacokinetics to allow sufficiently accurate prediction to facilitate product development while meeting regulatory requirements [69–71].

1.4 Conclusion

The history of inhaled therapy is probably as long as man since it is not beyond the realms of possibility to think that inhalation of smokes and vapors has always soothed lung disorders. This can certainly be traced back to the beginning of recorded civilization. In modern times there have been areas in which disruptive technologies and scientific observations have rapidly advanced our ability to treat or evaluate treatment of disease. This chapter has dealt with important developments that have arisen over a period of approximately 60 years. During this time new inhalers have been developed that have advanced in formulation, metering system and aerosol generation. In addition, our understanding and ability to measure in vitro aerosol properties, to predict and measure lung deposition has also improved. We have advanced our ability to understand the disposition of drugs from the lungs and continue to improve our measures of therapeutic outcome. There is no question that with the continued demand for new therapies for diseases that are currently treated with aerosols and for diseases for which aerosol therapy would be beneficial a bright future of inhaled medicines is assured.

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Chapter 2

The API

Britta Bonn¹ and Matthew Perry²,    ¹ Drug Metabolism and Pharmacokinetics, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden,    ² Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

Abstract

In this chapter we discuss the factors that need to be considered in the design of API for inhalation. The objective of an inhaled drug is to achieve an efficacious dose in the lung for a prolonged period whilst minimizing systemic exposure and consequent side-effects. We show that marketed inhaled agents have properties well outside those typical for oral drugs. It is necessary to understand the processes involved in drug action in the lung, the distribution, dissolution and disposition of the inhaled molecule as well as the site of the intended target. The properties of the inhaled agent are typically affected by the type of molecule being administered and we show how four different strategies have been applied to obtain extended duration of action in the lung, that is to say by slow dissolution of the API, modulation of permeability, tissue binding and design of lung-specific prodrugs.

Keywords

Dissolution; Permeability; Pharmacokinetics; Lung retention; Lipophilicity; pKa; Residence time; Prodrug

2.1 Introduction

2.1.1 Inhalation of drugs

The deliberate inhalation of pharmacologically active substances has a long history going back at least as far as the discovery of the effects of tobacco smoke around 1000 years ago [1]. The physiological effects of recreational inhalation arise because the lung provides a highly permeable route enabling molecules to enter the systemic circulation rapidly and without first-pass metabolism, giving an almost immediate effect through interaction with their target proteins.

For pharmaceuticals, inhalation has been used for four categories of drugs:

1. Inhaled gaseous anesthetics.

2. Compounds requiring rapid access to systemic circulation to exert an immediate effect, typically on the CNS.

3. Compounds that are unable to access the systemic circulation through oral administration, this has been used for peptides, nucleotides and related large molecules.

4. Compounds intended to act topically in the lung, often with the intention to minimize systemic exposure and any related side-effects.

In general, absorption of molecules from the lung to the systemic circulation is rapid; even the peptide hormone insulin is absorbed rapidly with a plasma Cmax at only 12–17 minutes post inhalation [2]. In this chapter we will focus discussion on the fourth category of molecules, those intended to exert a local effect in the lung for which rapid absorption is not a benefit but a challenge to overcome.

2.2 Considerations for designing inhaled molecules

Introducing the design of the inhaled active pharmaceutical ingredient (API), we first want to discuss the important considerations and desirable properties of the API followed by describing drivers and compound physico-chemical properties in Section 2.4. We can describe strategies for designing molecules suitable for inhaled route of delivery in terms of physico-chemical properties, but, as described by [3], assessing inhaled pharmacokinetics is accompanied by a list of challenges: (1) dosage form – different material preclinically compared to final product may influence pharmacokinetic profile, (2) lung dose amount – not all of an inhaled dose reaches the lung and this makes for uncertainty over the dose estimate, (3) exposure measurements – lung concentrations can be measured in preclinical species but not in man, (4) Lung retention – lack of understanding of what is really required in terms of concentration over time and how to predict for man, (5) PKPD - requires knowledge of unbound concentrations in lung or even in the relevant compartment of the lung, e.g. epithelium, alveolar region etc., rather than systemically; these are difficult to measure. An additional consideration for inhaled drug programs, in contrast to oral drug delivery, is that the capacity of devices limits the dose (Chapter 5.4.2). This has consequences on the properties of the drug and requires a high potency for the