University of Groningen Technology in practice Lexmond, Anne · 2016. 3. 8. · with deviating lung...

University of Groningen

Technology in practiceLexmond, Anne

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CHAPTER 1

GENERAL INTRODUCTION AND SYNTHESIS

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Chapter 1

“In those who have not established a tolerance of tobacco, its use is soon followed by a well-known condition of collapse, much resembling sea-sickness – vertigo, loss of power in the limbs, a sense of deadly faintness, cold sweat, inability to speak or think, nausea, vomiting. The moment this condition can be induced the asthma ceases, as if stopped by a charm.”

Henry H. Salter. Asthma: Its pathology and treatment, 1864.

Smoking tobacco was a rigorous but well-established anti-asthmatic therapy in the late 19th and early 20th century. As a depressant, it was claimed to counteract the spasm of the airway musculature – quite extremely – by inducing collapse (1). Smok-ing tobacco fell out of grace in the second half of the 20th century due to its obvious negative effects on the respiratory tract, pre-eminently the induction of lung cancer and chronic obstructive pulmonary disease (COPD). Still, over the years it has con-tinued to be advocated as obscure reliever of breathlessness for asthmatic patients.

In essence, tobacco may offer a treatment for asthma, as it has been shown that ben-eficial effects can be attributed to nicotine’s suppression of various inflammatory and allergic parameters (2). However, the cigarette constitutes what may be the worst example of a delivery device required for administering the nicotine to the lungs as, in fact, the administration method does more harm than good.

Pulmonary delivery of aerosols presents an elegant and effective approach to get-ting active agents into the body, when the delivery method is properly designed to meet the requirements of the administration. Inhalation technology is the research discipline that focuses on the products, i.e. the formulations and devices needed to deliver active agents to or through the respiratory tract. Following an adequate de-sign, further development and optimisation of these products can greatly enhance the patient’s therapy and experience.

In the following sections, particle dynamics and the mechanisms of particle deposi-tion in the lungs are discussed as a foundation to pulmonary aerosol delivery. Subse-quently, by taking into account three determinants – the purpose, patient, and prod-uct – a strategy is proposed for choosing the most suitable approach for optimisation of inhaled drugs and diagnostics.

13

Introduction and synthesis

PULMONARY AEROSOL DELIVERY

The respiratory system offers a unique route for the delivery of pharmacologically ac-tive substances to the body. Traditionally, this route has been used for the delivery of locally acting substances for the treatment of respiratory conditions, such as asthma, COPD, and airway infections. Targeted delivery of substances to the lungs has some key advantages over systemic administration by other routes, including a more rapid onset of action, an increased therapeutic effect, and reduced systemic side effects, since the required local concentration can be obtained with a lower dose (3,4).

The particular architecture of the lower respiratory tract, with its vast absorptive sur-face area of approximately 100 m2 (5), also allows for more applications than just local therapy. Consequently, the lungs can function as a non-invasive systemic delivery route, for example when a rapid effect is desired like for pain relievers (6–11), or for substances with low (or no) bioavailability after administration via the gastrointes-tinal tract (12,13). Examples of such substances are therapeutic proteins, which are prone to degradation by metabolic enzymes (pepsin) in the gastric lumen (14–18), or substances that are metabolised extensively upon first passage through the gastroin-testinal wall and the liver (the first-pass effect) (19).

However, the lungs’ architecture also comprises the main challenge for pulmonary aerosol1 delivery, as it has evolved to prevent foreign matter from reaching the pe-ripheral parts of the lungs. Therefore, aerosols must meet a strict set of physicochem-ical and physical requirements for pulmonary administration to be successful. More-over, a device is needed for aerosol generation and facilitation of its delivery to the lungs. This makes pulmonary delivery of any kind of substance much more complex than oral or parenteral administration.

Aerosol deposition in the respiratory tract

Aerosolised particles (or droplets)2 can only exert their pharmacologic effect or reach the systemic circulation when they first pass the oropharynx and subsequently come

1 An aerosol is defined as a colloidal suspension of particles dispersed in air or gas (Oxford Dictionary of English). In pulmonary delivery in general, and in this thesis in particular, this term is applied more broadly, as it also includes dispersed droplets (liquid) as well as non-colloidal (unstable) systems. 2 Aerosols consist of particles or droplets, depending on the device that is used for aerosol generation. For the convenience of both the reader and the writer, I will refer to particles only, except for when explicit distinction between the two is required.

14

Chapter 1

in contact with the airway surface following inhalation into the respiratory tract. Transport of the particles towards these surfaces, i.e. their deposition, results from a balance between the forces that act on the inhaled particles. Four types of forces are involved in particle deposition in the respiratory tract: inertial, gravitational, and diffusional forces, as well as the drag force of the moving air that counteracts depo-sition (20,21).3

Impaction as a result of high particle inertia is the predominant deposition mecha-nism in the upper airways, where the air velocity is high and the airflow turbulent. Particles of a sufficient mass (sufficiently high inertia) cannot follow the changes of airflow direction at the bifurcations fast enough and collide with the opposing airway surface. The probability of impaction increases with the square of the particle diam-eter, particle density, and particle velocity. Generally, particles with an aerodynamic diameter larger than 5–10 μm (at particle velocities above 30–50 L/min) have the highest probability of depositing in the throat by inertial impaction.

The second deposition mechanism is sedimentation, the settling of particles under the influence of gravity. The gravitational force increases with the mass (cubic particle diameter) and the stationary settling velocity (counteracted by the drag force) with the square of the particle diameter. Furthermore, sedimentation is a time-dependent process, which implies that the longer a particle resides in an airway duct, the high-er the probability that it will deposit by sedimentation. Therefore, this mechanism prevails when both the air velocity is low and of the same order of magnitude as the settling velocity, and the residence time is high, which is the case in the peripheral airways.

The third mechanism, diffusion or Brownian motion, is the random movement of particles through a gas resulting from collisions with gas molecules. Diffusion in-creases with decreasing particle diameter and only very fine particles (smaller than 0.5 μm) have a chance of being deposited by diffusion. Like sedimentation, diffusion is a time-dependent process. Hence, deposition by diffusion occurs mainly in the peripheral airways, although the relatively limited residence time of particles in the respiratory tract in combination with their random movements results in a very low deposition probability. Therefore, particles with diameters below 0.5 µm are more likely to be exhaled instead.

3 Deposition mechanisms based on electrostatic forces and interception are ignored in this thesis as there is insufficient evidence for their occurrence.

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In the descriptions above, four parameters have been identified that determine whether a particle deposits in the respiratory tract and by which mechanism: the particle diameter,4 the particle density, the particle velocity, and the residence time in the airways. The particle diameter and density are characteristics of the aerosol, whereas the particle velocity and residence time are resultants of the patient’s inha-lation manoeuvre. A fifth important determinant is the geometry of the respiratory tract. With decreasing airway diameter, the deposition probability of all three mech-anisms increases.5 This implies that deposition patterns are different in populations with deviating lung anatomy, such as children (smaller airways), asthma and COPD patients (narrowed and obstructed airways), or patients with bronchiectasis (dilated airways filled with sputum). Therefore, the optimal particle size in the aerosol may not only depend on the desired site of deposition, but also on the intended patient population. In general, particles with a diameter of 1–5 μm, especially when inhaled with a slow to moderate flow rate (30–90 L/min), are regarded suitable for inhalation.

The aerodynamic particle diameter and particle size distribution

Small, spherical particles with high density can exhibit the same aerodynamic be-haviour as much larger spheres with a lower density. Hence, expressing the size of such particles in their geometric diameter is not useful for predicting their fate after inhalation based on stopping distance (impaction) and settling velocity (sedimen-tation). For irregular particles, a complicating factor is their shape, which makes it impossible to express their size in a simple diameter. For these reasons, the concept aerodynamic diameter has been introduced, which standardises for shape and den-sity (20). By definition, the aerodynamic diameter of a particle is the diameter of a sphere of unit density that settles with the same velocity in still air (thus under the influence of gravity) as the particle in question. Particles with the same aerodynamic diameter also exhibit the same inertial behaviour.

In addition to variations in shape and density, aerosol particles are usually not of the same size either. Some experimental aerosol generators (developed for research purposes) are capable of producing near-monodisperse aerosols (22), which in the-ory means that all particles have similar sizes, and thus that the geometric standard deviation (GSD) of the aerosol is 1 (in practice, this value is set to 1.2). Aerosols from marketed inhalation devices are polydisperse; they consist of particles with different

4 Up to here, only spherical particles have been accounted for when referring to particles (and particle di-ameter). The shape of the particle is also important, which will be touched upon in the following paragraph.5 In addition to differences between patient populations, there are of course also significant species differen-ces in airways anatomy that require consideration when extrapolating data from animals to humans.

16

Chapter 1

sizes. Specifically for dry powder inhalers, the aerosol also contains agglomerates due to incomplete break-up of the powder, which adds to the diversity of particle properties in the aerosol with shape and density distributions. For characterisation of these polydisperse aerosols for pulmonary delivery, the mass median aerodynamic diameter (MMAD: the aerodynamic diameter below which 50% of the emitted mass is contained) is commonly used, in combination with the GSD as measure for the size distribution. Yet this parameter provides no information on how much of the dose is converted into an aerosol. More meaningful parameters are the fine particle fraction (FPF) and fine particle dose (FPD), which express the portion of the dose (in percentage and mass respectively) with an aerodynamic diameter below a specified size, usually below 5 µm.

The target area for aerosol deposition

For optimal efficacy of a pharmacologically active agent, maximal delivery to and deposition in the target area in the respiratory tract is desired. Where the target area is, depends on the purpose of the administration, or – more specifically – on the agent and the intended effect. For locally acting substances, target areas are those regions that contain the target cells and/or receptors. The target site for substances intended for systemic absorption depends on the physicochemical properties of the substance. Small molecules, both hydrophobic and hydrophilic, are rapidly absorbed throughout the whole lung, whereas for most macromolecules deep-lung deposition is required (12).

Once the target area has been established, the optimal particle size can be determined in relation to the inspiratory flow rate by which the aerosol is delivered. The further the aerosol has to travel through the respiratory tract to reach the target area, the smaller the desired particle size (up to the lower limit of 1 µm), the lower the inspira-tory flow rate, and the longer the residence time in the lungs.

Patient-related factors that influence aerosol deposition

Aerosol deposition patterns are not solely determined by the aerodynamic size dis-tribution of the particles. Particle velocity, residence time, and airway diameter have already been mentioned as parameters that affect deposition. These parameters are largely dependent on the patient inhaling the aerosol.

17


Inhalation is the result of expansion of the chest, which creates a pressure difference between the lungs and the atmosphere, in response to which air flows into the lungs. The flow rate with which the air is inhaled and the total inhaled volume depend on the inhalation manoeuvre of the patient.

Particles travel into the respiratory tract with initially the same velocity as the air inhaled. At higher velocities, particle deposition shifts more towards inertial impac-tion, as more (finer) particles cannot follow the changes in airflow direction at the bifurcations.

The inhaled air functions as medium for aerosol transport into the lungs. To reach the alveolar region, the inhaled volume has to be sufficiently large. This can be ac-complished by either exhaling maximally prior to deeply inhaling once, or by tidally breathing in the aerosol over a prolonged period of time. In the latter case, mixing of the freshly inhaled air containing the aerosol with the air that is already present in the lungs is required to enable deposition of the aerosol particles in the peripheral parts of the respiratory tract (23,24).

Patients can be instructed to inhale in the most appropriate way. However, not all patients have the capacities – either cognitive or physical, or both – to follow these instructions. When an inhalation device is not used properly, device performance is negatively affected, which inevitably results in altered aerosol deposition, and thus in less active substance in the target area, and possibly in increased chances of develop-ing unwanted side effects too. Moreover, (patho)physiological aspects can also affect deposition, such as the shape of the oropharynx, and the degree and nature of lung disease. For all these reasons, deposition of any aerosol in any individual patient, is hard, if not impossible, to predict based on aerosol properties alone.

Optimisation of pulmonary aerosol delivery

There is no such thing as one optimal strategy in pulmonary aerosol delivery. Many variables are involved, which restrict the possibilities in a specific situation. In any situation, three key determinants can be distinguished: the purpose of the adminis-tration, the patient for whom the administration is intended, and the product – con-sisting of the device that is used for generation and administration of the aerosol and the formulation of the active agent. All these determinants should be addressed, in the right order, to obtain the most suitable approach.

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Chapter 1

THE PURPOSE

“‘Cheshire Puss, would you tell me, please, which way I ought to go from here?’‘That depends a good deal on where you want to get to,’ said the Cat. ‘I don’t much care where –’ said Alice. ‘Then it doesn’t matter which way you go,’ said the Cat.”

Lewis Caroll. Alice’s Adventures in Wonderland, 1865.

Choosing the best approach for delivering a pharmacologically active agent to the respiratory tract starts with the purpose of the administration, since this determinant defines the desired deposition site in the respiratory tract and the dose of the active agent to be given. The respiratory tract provides a versatile administration route for various kinds of substances and purposes, some of which have been studied and used for ages, while others are relatively new and still undeveloped. The following para-graphs discuss some of the main applications of pulmonary aerosol delivery.

Treatment of Asthma and COPD

“The treatment of asthma, like that of all paroxysmal diseases, naturally divides itself into the treatment of the paroxysm and the treatment in the intervals of the paroxysms, and although the last is the real treatment of the disease, while the treatment of the paroxysm is merely the treatment of a symptom, yet the paroxysm being in asthma, potentially though not essentially, the disease (for it is its sole manifestation, the only source of suffer-ing, and the cause of those organic changes in the heart and lungs by which alone asthma threatens life), its treatment holds the first place in the therapeutics of the affection.”


Asthma and COPD are both chronic diseases of the respiratory tract that are charac-terised by airflow limitation, inflammation, and airway remodelling.6 Despite these

6 In 2007, approximately 541,000 patients were diagnosed with asthma in the Netherlands, of whom approx-imately 119,000 (22%) were younger than 15 years. Asthma is more prevalent under adult women than men, whereas the opposite applies to girls and boys under the age of 15 years. Asthma has a very low mortality. In 2011, only 69 patients died primarily from asthma, the majority of them being older than 70 years. The year prevalence of diagnosed COPD in the Netherlands was 323,600 in 2007, of whom less than 18,000 were

19


similarities, asthma and COPD are two distinctly different diseases.

Asthma usually manifests in childhood and distinguishes itself from COPD by the reversible nature of the airflow limitation and a mostly normal lung function in be-tween exacerbations (25). One of the key characteristics of asthma is bronchial hy-perresponsiveness (BHR) to various nonspecific (i.e. non-allergic) as well as allergic stimuli (26,27). In reaction to these stimuli, a diffuse and reversible obstruction of the airways arises, in which different types of inflammatory cells are involved.

In COPD, the incompletely reversible airflow limitation is accompanied by an abnor-mal inflammatory response to harmful particles, microorganisms, or gases, resulting in a progressive decline in lung function. The airflow limitation is mainly due to an increased mucus production, a cellular inflammatory infiltrate, and swelling of the mucous membrane. Characteristic of this disease is that it develops later in life, gen-erally after the fortieth year of age, often as a result of long-term smoking (25,28).

For both diseases, inhalation therapy is used for symptom relief – i.e. dilation of the airways and reduction of the mucous production – and reduction of the inflamma-tion. The target site in the lungs depends on the mechanism of action of the various therapeutic agents used against asthma and COPD. Bronchodilators (β2-agonists and anticholinergic therapeutics) principally target the smooth muscle cells, and maxi-mal therapeutic effect can be achieved by maximising deposition in the conducting airways (22). Consequently, both mild asthmatics and patients with severe airflow obstruction have been shown to benefit most from β2-agonist or anticholinergic aero-sols of approximately 3 µm (22,29–31). Inflammation occurs diffusely throughout the airways, thus optimal treatment requires drug deposition in the entire bronchial tree. By targeting the peripheral airways with a fine, polydisperse aerosol, inevitably a part of the dose will deposit in the upper airways, thereby reaching a distribution over the whole lung (32).

Bronchial challenge testing

“In what, then, does the peculiarity of the asthmatic essentially consist? Manifestly, it is a morbid proclivity of the musculo-ner-vous system of his bronchial tubes to be thrown into a state of activity; the stimulus may be either immediately or remotely applied, but in either case would not normally be attended by

younger than 40 years of age. In stark contrast with asthma, COPD is in the top five of lethal diseases; 4.7% of all deaths in the Netherlands in 2011 were attributed to COPD (350).

20

Chapter 1

any such result. There is no peculiarity in the stimulus, the air breathed is the same to the asthmatic and the non-asthmatic, the ipecacuan powder, the hay effluvium, is the same in both; nor, probably, is there any peculiarity in the irritability of the bron-chial muscle; the peculiarity is confined to the link that connects these two – the nervous system, and consists in its perverted sensibility, in its receiving and transmitting on to the muscle, as a stimulus to contraction, that of which it should take no cogni-zance. [...] it is clear that the vice in asthma consists, not in the production of any special irritant, but in the irritability of the part irritated.”


Inhaled aerosols can be used not only to treat asthma, but also to diagnose BHR; a symptom pivotal to asthma, although many COPD patients demonstrate increased bronchial responsiveness too (33). BHR refers to exaggerated narrowing of the air-ways in response to exposure to various stimuli (27), and it can be measured by means of a bronchial challenge test, in which the sensitivity of the airways to a stimulus is evaluated (26). Both pharmacologic and physical stimuli can be used, which have either a direct effect on effector cells (e.g. airway smooth muscle cells) or an indirect effect through stimulation of inflammatory or neuronal cells (34). In bronchial challenge tests with pharmacologic agents, increasing doses of the agent are administered. The test is positive when the forced expiratory volume in one second (FEV1) is reduced by more than a predefined percentage compared to base-line (usually 20%) (26,35). The dose to which the patient’s response falls below this threshold percentage is a measure of the sensitivity of the airways to that agent. The test is negative when the last dose is administered without provoking the predefined reduction in FEV1.

The diagnostic agent commonly used for quantifying BHR is methacholine, a syn-thetic analogue of acetylcholine that acts directly on muscarinic receptors on the smooth muscle cells (36). Similar to the bronchodilators, it is fair to assume that methacholine should be targeted towards the conducting airways, in this case for the greatest bronchoconstrictive effect.Methacholine challenge testing is highly sensitive, but its positive predictive power is limited (36). In this respect, indirect stimuli may be more specific than direct stimuli, since they better reflect certain aspects of the disease pathology. One of these indirect stimuli is adenosine, a purine nucleoside that is expressed in all cells in the body and is involved in a wide range of physiological processes. Exogenous inhaled adenosine causes a concentration-related bronchoconstriction in asthmatic subjects (37–46),

21


especially through mediator release from primed mast cells, although there is some evidence for activation of neural pathways too (47). Therefore, the response to ad-enosine is considered more relevant to airway inflammation than the response to methacholine (43,44,48,49). On this basis it has been argued that adenosine bronchi-al challenge testing provides a more reliable non-invasive tool for monitoring disease activity and an improved method for assessing the response to anti-inflammatory treatments (48). Moreover, recent findings suggest that challenging with adenosine may improve diagnostic discrimination between asthma and COPD (50).

Another indirect stimulus is mannitol, which provokes airflow limitation by increas-ing the osmolarity of the epithelial fluid, thereby initiating the release of mast cell mediators (51,52). Mannitol may be especially useful to diagnose exercise-induced BHR, which is thought to be caused by a transient increase in osmolarity in the epi-thelial fluid as a result from evaporative water loss from the airway mucosa (53,54).

Increased susceptibility to adenosine and mannitol challenge results from inflam-matory processes that can be present throughout the whole lung. Whether or not it is possible to challenge distinct regions of the airways is still subject of research. It has been suggested that adenosine of different particle sizes can be used as marker of small and large airway involvement in asthma (55). However, the involvement of neural pathways or distal inflammatory mediator transport after indirect challenge may give rise to a total response of the airways, thereby inducing BHR in affected airways regardless of the exact deposition site of the particles (Chapter 5).

Treatment of respiratory tract infections

The respiratory tract is a port of entry to the body for airborne material, and it is therefore subjected to invading microorganisms. Improper removal or eradication of these microorganisms by mucociliary clearance or the immune system may result in respiratory tract infections. Infections of the respiratory tract can be the disease entity, like in tuberculosis, or they can occur as a consequence of other diseases. Ex-amples of the latter are the chronic colonisation of the airways of patients with cystic fibrosis, whose viscous mucus serves as ideal matrix for microorganisms to replicate, or opportunistic infections in immunocompromised subjects.

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Chapter 1

Tuberculosis

“Tuberculosis is a constitutional disease, dependent largely on the evils of civilization and governed by the following law: The death rate from tuberculosis is in direct ratio to suspension of atmospheric influence. [...] Our interpretation of this law is as follows: Suspension of atmospheric influence or imperfect aer-ation of the blood creates in the individual a soil or condition of tissue that allows a natural entrance or growth of the plant tu-bercle bacillus. The first stage of the disease, then, is the creation of the soil. The plant organism or germ tubercle bacillus then en-ters and commences to grow, or take root, in this prepared soil. The entrance or growth of this plant or germ is the second stage of tuberculosis. This growth is now a factor in the disease. What does it do? Hastens the third stage – breaking down of tissue or death of patient.”

Henry H. Spiers. Tuberculosis or Consumption, 1902.

Tuberculosis (TB) is a highly contagious disease caused by Mycobacterium tubercu-losis with a high morbidity and mortality.7 The disease can manifest in almost all organs, but as the major port of entry, the lungs are most often affected. The my-cobacteria are intracellular pathogens that reside in macrophages (and monocytes). Migration of macrophages and other immune cells to the site of infection result in formation of granulomas (tubercles), in which the mycobacteria are contained, but which also allow them to survive in a dormant state for years (56).

TB is treatable and in principle curable, but it requires long-term treatment with multiple antibiotics to attain complete eradication of the mycobacteria. Poor penetra-tion of the antibiotics into the granulomas in combination with poor patient compli-ance to the strict treatment regimes have led to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains (57). MDR strains are resistant to isoniazid and rifampicin, the two most powerful first-line agents used against TB, whereas XDR strains are also unresponsive to the most effective second-line antibiot-ics (58). The rapid spread of MDR-TB and XDR-TB has impelled the search for both new anti-TB agents and new delivery strategies to enhance the efficacy of currently used agents.

7 In 2012, 8.6 million cases of illness and 1.3 million deaths by TB were reported. One in three persons worldwide has the latent form of TB with a lifetime risk of 10% of falling ill, a percentage that increases in immunocompromised subjects (58).

23


One of these strategies is the pulmonary delivery of antibiotics, which can be es-pecially interesting in the early phase of the disease, when high doses of locally ad-ministered antibiotics may avert the spread of the disease to other organs (57). In addition, (add-on) therapy with aerosolised antibiotics in patients with active TB may prevent dissemination of the disease (59). To this end, targeting to the upper airways is desired, where the droplets that cause the transmission are formed (32). The required dose for this application can be strongly reduced compared to oral or parenteral administration, as the required high local doses are easily obtained on the limited surface area of the upper airways (32). A third possible application of aero-solised antibiotics is specific targeting of alveolar macrophages. In contrast to tar-geting the upper airways, targeting the macrophages puts strict requirements on the particle size and demands for the development of formulations that are recognised and phagocytised by the infected macrophages (60).

Cystic fibrosis

“Lungs: In every case of the series there was infection of the lungs; this was apparently primary in the bronchi. In the cases which I have been able to study at first hand, these changes were remarkably uniform and consisted of (1) mild tubular dilatation of the small bronchi and bronchioles; (2) plugging of the lumens of most if not all of the bronchi with tenacious, greenish gray mucopurulent material; (3) multiple small abscesses arising in the smaller bronchi and sometimes spreading to form multiloc-ular abscesses; (4) fresh lobular pneumonia in the intervening parenchyma; (5) perforation of the abscesses through the pleura to produce fibrinous or suppurative pleurisy. The larger bronchi and trachea also contained mucopurulent material, with some congestion of the underlying mucosa. In Huet’s case, in which the pulmonary infection was especially prolonged, there was some fibrosis of the lung.”

Dorothy H. Andersen: Cystic fibrosis of the pancreas and its relation to celiac disease. 1930, American Journal of Diseases in Childhood.

The first recognition of cystic fibrosis (CF) dates back to 1930, when it was described as underlying disease entity to the clinical picture of coeliac disease (61). CF is the most common chronic, life shortening, genetic disease in the Caucasian population.8

8 In the Netherlands, one in 32 persons carries one of the defective gene types and approximately 1,400 patients have been diagnosed with CF. Every year approximately 40 children are born with CF in the Neth-erlands, which corresponds to an incidence of one in 4,750 newborns. In the Anglo-Saxon countries, inci-dences are one in 2,500, one in 15,000, and one in 31,000 newborns for the Caucasian, African-American, and Asian populations respectively (350).

24

Chapter 1

It is a multi-system condition characterised by a disturbed chloride transport across epithelia in the body, resulting in dehydration of the mucus in the respiratory, gastro-intestinal and reproductive tract. In the lungs, the increased viscosity of the mucus hinders the clearance of microorganisms. This leads to chronic bacterial infections that cause inflammation of lung tissue, ending in lung tissue damage and fibrosis of the airways, especially in the peripheral parts of the lungs (62,63).

The early death of CF patients is most often due to the consequences of these chronic infections. Once chronic infection of the lungs has been established, cornerstone in the treatment is the twice-daily use of aerosolised antibiotics to stabilise the infection, thereby improving lung function, and slowing down lung deterioration (64). Ade-quate treatment is only possible when the aerosolised antibiotics deposit to sufficient extent in the whole lung, including the peripheral airways (65). Improper deposition would not result in the desired minimal inhibitory concentration in all pulmonary regions and therefore, present a risk for developing bacterial resistance. To achieve the most homogeneous antibiotic concentration throughout the whole lung possible, the peripheral airways have to be targeted, although even then local concentrations in the upper and central airways are much higher as a consequence of the exponen-tial increase in surface area towards the lung periphery. For effective peripheral lung penetration and deposition an aerodynamic particle size range of 1–3 µm at a low to intermediary flow rate (30–60 L/min) seems most appropriate (22).

Vaccination

“Vaccine Inoculation, effectually prevents the small pox, is never dangerous, requires no particular diet nor medicine, and may be practised at all ages and at every season of the year.”

Edward Jenner. Instructions for Vaccine Inoculation, commonly called Vac-cination, 1807.

In addition to eradication of already established infections, the pulmonary route can also be used to prevent infectious diseases. As port of entry to the body, the respirato-ry tract hosts an array of immune mechanisms, which can be utilised to induce pro-tection against invading pathogens by means of pulmonary vaccination. It has been hypothesised and shown for influenza that following the natural route of infection (for airborne pathogens) may best achieve the induction of immunity in the respi-ratory tract against these pathogens and may possibly lead to more general systemic immunity as well (66–68).

25


Moreover, pulmonary vaccination is a non-invasive, needle-free delivery method, which could overcome some of the disadvantages specifically related to parenteral administration, such as needle fear, needle stick injuries, and – in developing coun-tries – the risk of transmission of blood borne pathogens like HIV by re-use of nee-dles (Chapter 8). For these reasons, the pulmonary route may also be interesting for vaccination against diseases that are not airborne, provided that a qualitatively appropriate and quantitatively sufficient immune response can be obtained.

A critical note to the feasibility of using the pulmonary route for vaccination is the robustness of the administration method. Vaccination generally consists of a single administration, followed up by one or a few booster doses over a prolonged period of time at most. Additionally, there is no direct read-out whether or not the administra-tion has been successful, since vaccination is intended to prevent a new disease rather than treat an existing one. Therefore, it is of utmost importance that the administra-tion is effective, reliable, and preferably patient-independent, the latter meaning that the aerosol is formed regardless of the patient’s inspiratory effort. These requirements render pulmonary vaccination highly challenging.

Some pulmonary vaccines have been investigated in clinical studies, especially against measles and influenza (69–78), but none are commercially available yet. One aspect that has been left relatively unexplored in clinical pulmonary vaccination re-search is the optimal deposition site for vaccines. Preclinical studies with the measles and influenza vaccines suggest that targeting the peripheral lung may be optimal for vaccination, but all methods that delivered the vaccine past the nasal or oral cavi-ty gave a sufficient (local) immune response (79,80). If it can be shown – for other vaccines and in humans – that the exact deposition site is not critical for pulmonary vaccination, the feasibility of this alternative administration route would be greatly enhanced (Chapter 8).

Systemic delivery of proteins and peptides

Pulmonary aerosol delivery is foremost interesting for various local applications, but it has also gained interest as alternative delivery route for substances intended for systemic effect. Especially when oral delivery is not possible, e.g. due to enzymat-ic breakdown of a substance in the gastrointestinal tract, the lungs may provide an attractive alternative to injection for reaching the systemic circulation. Moreover, particularly the alveolar region of the lung has a favourable architecture for rapid systemic absorption, with its vast absorptive area, thin and permeable epithelium,

26

Chapter 1

rich blood supply, the large interstitial spaces between the type I alveolar cells (4 nm), and relatively low enzymatic activity compared to other routes of administra-tion (13,81,82).

For macromolecules, such as proteins and peptides, the bioavailability via the pul-monary route is generally higher than via any other non-invasive delivery route (12). However, diffuse absorption has been shown to be kinetically restricted for peptides and proteins, especially for those larger than 1–10 kDa (83–85). The prolonged res-idence time allows for various alveolar defence mechanisms to remove the macro-molecules before absorption has occurred, often resulting in a bioavailability below 20% and transient therapeutic effects (85). Examples of such defence mechanisms are the uptake by macrophages and enzymatic degradation by peptidases and proteases (13,82,84,86).

Various formulation strategies have been developed to enhance the bioavailability of peptides and proteins after pulmonary administration. These strategies range from relatively simple solutions, such as the addition of an enzyme inhibitor or absorption enhancer, to complex particle engineering methods (13,87). Toxicity is a key issue for all formulation strategies and may limit some currently under investigation. Safety considerations should be addressed for every excipient used in specific formulations (12,13).

Inhaled insulin

The best-known example of an inhaled macromolecule intended for systemic delivery is insulin, a 5.8 kDa polypeptide used to treat diabetes mellitus. Inhaled insulin has been investigated extensively as alternative to subcutaneous injection for postpran-dial glycemic control as it can take away some typical disadvantages of the parenteral administration route, such as the necessity of cold chain storage and needle waste.

Following inhalation, the tmax or time to reach the highest serum concentration is favourably shorter than following subcutaneous injection, being 15–90 min and 60–240 min respectively (17,85,88–92). However, bioavailability is only around 10–15% relative to subcutaneous injection (17,88–91), due to slow absorption from the lungs via paracellular diffusion through the alveolar tight junctions (85). These on first sight contradictory findings are explained by the “flip-flop” pharmacokinetic profile of in-haled insulin, in which the terminal phase slope of the serum concentration profile is not determined by the systemic elimination rate, but by the lungs’ emptying rate instead (85,93). Smoking, which increases the permeability of the alveolar-capillary

27


barrier, has been shown to enhance absorption of insulin from the lungs, resulting in a shorter tmax and a higher bioavailability (94).

In spite of successful clinical development, the first marketed insulin inhaler (Ex-ubera, Pfizer 2006) was withdrawn from the market after just over a year, for the official reason that the drug had failed to gain market share (95), due to poor patient acceptance and high costs. Among the reasons for poor patient acceptance was the inhaler itself, a large device that required a rather complex sequence of preparatory actions to be carried out before a dose could be inhaled (96). Another key role in the withdrawal of the product was attributed to indications of a potentially increased bronchial tumour rate, even though these findings were only reported for (ex) smok-ers (92). Nevertheless, the lung cancer stigma resulted in termination of all other inhaled insulin developments, except the Technosphere technology (Mannkind). The findings of an increased lung cancer rate have not been substantiated since, and recently, the FDA has approved the second inhaled insulin product based on this technology (Afrezza, Mannkind).

THE PATIENT

“‘Speak English!’ said the Eaglet, ‘I don’t know the meaning of half those long words, and, what’s more, I don’t believe you do either!’”


Pulmonary aerosol delivery starts with a specific therapeutic or diagnostic purpose. This purpose cannot be addressed as an isolated determinant, but should always be considered in relation to the patient for whom the administration is intended. The patient can be as challenging as the purpose, since he9 is of utmost importance as to whether pulmonary administration is likely to succeed.

Patient-related factors like the size and morphology of the oropharynx and bronchial tree, as well as the type and severity of lung disease can influence the deposition pat-tern of the aerosol. These factors can be markedly different for distinct target popula-tions, but may also vary extensively within one defined population.

9 The use of personal pronouns, when referring to a human being in general, coerces the writer to choose between awkward sentences (involving “he/she”-like structures) and systematic exclusion of (usually the feminine) half of the population. For readability, I choose the latter.

28

Chapter 1

However, most crucial is the interaction between the patient and the inhalation de-vice. Inhalation devices are not generally suitable for all patients, since most require specific inhalation skills to be operated properly. Whether or not a patient is able to acquire these skills is dependent on both his cognition and physique.

Severe lung disease

In the major lung diseases of asthma, COPD, and CF, airway narrowing occurs due to several pathophysiological phenomena like bronchoconstriction, oedema, and mucus plugging. These phenomena have been shown to cause a shift of deposition towards the upper and central airways, at the expense of deposition in the peripheral parts of the lungs (97–102). The reduction in peripheral deposition may have seri-ous implications for the efficacy of specific therapies, for example with antibiotics or corticosteroids.

During severe exacerbations in asthma or COPD patients, an additional complica-tion to aerosol administration may be the reduced consciousness (or state of panic) of the patient (103). If this is the case, an inhalation device is required that produces the aerosol independently of the patient, which subsequently can be inhaled in an involuntary manner.

Children

Asthma is the most common noncommunicable disease in children and inhalation is the preferred route of administration for asthma therapeutics. Therefore, especially in the management of asthma symptoms, much experience has been gained over the last decades with inhalation therapy in children. However, more paediatric indica-tions exist, for which pulmonary treatment options are often not well studied (104), mainly due to low numbers of patients and ethical limitations for clinical studies in children.

Children constitute a special and highly challenging target population for pulmonary aerosol delivery. Significant developmental changes in lung physiology and cognitive abilities occur over the years and even within an age group large variability exists between children. This variability makes it impossible to develop a “one-fits-all” in-halation system for the different age groups.

29


In their reflection paper on formulations of choice for the paediatric population, the EMA’s Committee for Medicinal Products for Human use (CHMP) state that inhalation is a suitable way to administer actives substances to the lungs of children, especially for local applications, such as asthma and respiratory tract infections in CF (105). Based on the experience with locally administered asthma therapeutics, a summary is given of the appropriate delivery devices in relation to the age of the child. An important recognition in this paper is that the applicability of a specific dosage form largely depends on the paediatric patients themselves. Children, also those of the same age, behave and feel differently and they have different abilities re-garding the handling of a dosage form. A generalised judgement of applicability and acceptability might not be applicable to an individual paediatric patient – or to any adult patient for that matter.

The age or developmental stage of a child thus largely determines the feasibility of pulmonary aerosol delivery (Table 8.4; Chapter 7). Very young children cannot be taught how to inhale, so only devices that function independently of the patient are suitable for this patient group. Children older than 4 to 6 years may be able to under-stand specific inhalation instructions, allowing the use of inhalation devices that are operated by the breath of the patient too, although their smaller lung volumes com-pared to adults may be insufficient for complete dose release from specific devices (Chapter 7).

In general, facemasks are required to facilitate pulmonary administration to young children, but even then success is not guaranteed. The facemask has to fit tightly over nose and mouth, or pulmonary deposition is greatly reduced (106). More problems arise when the child does not cooperate during administration and a good seal of the facemask cannot be accomplished. Resistance of toddlers during pulmonary admin-istration has been shown to result in a very low (below 10%) and highly variable lung deposition (107). Comforting the child and thereby maximising his cooperation, is therefore essential to good inhalation therapy in young children (103).

Elderly patients

The treatment of elderly patients can also be restricted by characteristics specific to this patient group. Special attention should be paid to elderly patients suffering from cognitive decline, as they may be unable to perform complex inhalation manoeuvres (103).

30

Chapter 1

Moreover, ageing of the lungs induces inevitable physiological changes, such as a de-crease of the tissue elasticity and muscle strength (108). These changes result in a re-duced vital capacity, which is the largest volume of air that can be exhaled after taking the deepest possible inhalation, even for otherwise healthy people. In patients with respiratory diseases, a more rapid decline is to be expected (109). Like the smaller vi-tal capacity of children, the reduced vital capacity of the elderly can have implications concerning proper use of certain inhalation devices too. In addition, reduced dexter-ity (i.e. due to arthritis) may further limit the number of suitable devices (103).

THE PRODUCT

“‘What a funny watch!’ she remarked. ‘It tells the day of the month and doesn’t tell what o’clock it is!’‘Why should it?’ muttered the Hatter. ‘Does your watch tell you what year it is?’‘Of course not,’ Alice replied very readily: ‘but that’s because it stays the same year for such a long time together.’‘Which is just the case with mine,’ said the Hatter.”


Inhalation products are complex drug delivery systems consisting of a formulation of the active agent and a delivery device that converts the formulation into an inhalable aerosol. The choice for a device is determined by the therapeutic or diagnostic pur-pose of the administration, but more importantly by the patient to whom the agent is administered. Different patients have different skills, expectancies, and needs with regard to the devices they use.

Device choice may be restricted further by the available formulation options. Al-though the physicochemical properties and dose of the active agent determine to a large extent the formulation strategy for pulmonary delivery of that agent, some freedom of choice may exist in this respect. In the ideal situation, this freedom al-lows for optimally matching the product (device-formulation combination) with the patient and his specific needs. More realistically, the device preferences and formula-tion options – ranging from very simple aqueous solutions or powders in the correct aerodynamic size distribution, to highly complex engineered particulate systems – should be considered carefully in relation to each other to reach what is maximally achievable for a specific administration.

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Inhalation devices

Devices for pulmonary aerosol delivery have three basic functions, namely dose metering, aerosol formation, and facilitation of aerosol transport into the lungs. A distinction is made between passive and active devices. A passive device derives the energy required for aerosol formation from the inhaled air stream, hence from the patient, while active devices create the aerosol independently of the patient’s inhala-tion. Inhalation devices can be further categorised in various ways, like single-dose versus multi-dose, or disposable versus reusable. Multi-dose devices may (but do not necessarily) exhibit some great conveniences for chronic therapy, such as cost reduc-tion, portability, and increased ease of use. For irregular administrations and one-time applications like vaccination, disposable devices may be more suitable (Chapter 8). Furthermore, aspects like the risk of device contamination or antibiotic resistance building may affect the choice for a multi- or single-dose device.

Traditionally, three types of inhalation devices can be distinguished, which have mostly been developed for administration of locally acting substances. These three types are nebulisers, pressurised metered dose inhalers (pMDIs), and dry powder inhalers (DPIs). More recently, new types of devices have emerged, such as the Soft Mist Inhaler (Boehringer Ingelheim), which combine functional characteristics of the traditional types.

Nebulisers

In general, nebulisers generate aerosols from aqueous solutions or suspensions of the active substance. Their use is mainly confined to situations that do not allow for the use of a pMDI or DPI, for example when the patient is unconscious or for therapeutic agents for which no pMDI or DPI formulation is available (yet) (110). Also for highly dosed therapeutics, such as antibiotics, nebulisation was the only available delivery option until recently.

Three different nebuliser types exist: jet, ultrasonic, and vibrating mesh nebulisers. Jet nebulisers produce aerosols with a two-fluid nozzle. The relatively wide size distri-bution of the droplets from such nozzles is adjusted to the desired range by removal of the largest droplets, which occurs through impaction against a flow body in the aerosol stream (baffle). Many variables can influence the droplet size distribution, including the physicochemical properties of the solution (111–114; Figure 5-3), the

32

Chapter 1

jet pressure adjusted for the nozzle (115–117; Figure 5-2), and the breathing manoeu-vre of the patient, or when tested in vitro, the suction flow rate (114,115). The lung deposition efficiency of jet nebulisers is low, resulting in long administration times (110). Other major drawbacks of jet nebulisers are the long preparation and cleaning times as well as the large residual volumes in the nebuliser cups, which may result in considerable waste of the formulation.

Ultrasonic nebulisers produce droplets by applying high-frequency pulses from an oscillating piezo-element to the solution, thereby creating standing waves on the liq-uid surface from which droplets are released. The droplet size distribution depends largely on the oscillation frequency, which is mostly in the order of magnitude be-tween 1.3 and 2.4 kHz. Unlike jet nebulisers, ultrasonic nebulisers do not require rather bulky compressors or other pressurised air systems.

In the more recently developed vibrating mesh nebulisers, the piezo technology is combined with a perforated membrane (mesh), which is in contact with the formu-lation of the active compound. Two different principles are available; those in which the oscillation is applied to the membrane itself and those in which the oscillation comes from a horn transducer that vibrates in the liquid reservoir. Vibrating mesh nebulisers deliver more condense aerosols than jet nebulisers, which increases the output rate and reduces the administration time. They are often equipped with chip technology to adjust the nebulisation procedure to the solution to be administered and to the breathing manoeuvre of the patient (adaptive aerosol delivery), or to mon-itor patient adherence and compliance (24,118–121). This makes such devices expen-sive and therefore, their use is mainly confined to therapies against diseases like CF.

Nebulisers generally are reusable devices. Consequently, they have to be cleaned and disinfected on a regular basis. Improper cleaning can lead to deterioration of nebu-liser performance (122). Moreover, good hygiene is paramount because nebuliser formulations consist of water mostly, and are thus highly sensitive to microbiological contamination.

Formulations for nebulisation

Most formulations for nebulisation consist of aqueous solutions of the active agent and only a few requirements exist for their composition. The only pharmacopoeial requirement for these formulations is that the pH should be between 3 and 8.5 (123). In addition, sterility and isotonicity are preferred, since hypotonic and hypertonic solutions may provoke bronchoconstriction in susceptible patients (124,125).

33


Formulations for nebulisation form a continuous phase and are converted into aero-sols by the nebuliser. The formulation’s properties may strongly affect the nebuliser performance, in terms of output rate and droplet size distribution. Example of such properties are the concentration (114; Figure 2-3), viscosity (111,126,127; Figure 2-3), surface tension (111–113,126), and conductivity (127), which are in their turn determined by the solvent as well as the amount (concentration) and type of solute. The effects of the solution’s properties are not straightforward and depend on the nebuliser type (126). To add up to the complexity, the nebulisation process also af-fects the solution’s properties. As nebulisation progresses, the concentration in the nebuliser cup increases due to evaporation (126,128; Table 2-3), while changes of the solution’s temperature induce changes of properties like surface tension and viscosity, and subsequently the nebuliser output (126).

Other solvents than water (or co-solvents) can be used as well in formulations for nebulisation. Exemplary are the formulation efforts for the immunosuppressive com-pound cyclosporine, which has a very low aqueous solubility but can be administered successfully by nebulisation when dissolved in ethanol or propylene glycol (129–132). An important risk of using a different solvent is enhanced irritation of the airways, as has been shown for ethanol (129,131). Additionally, all available nebulisers have been developed for nebulisation of aqueous formulations, and the different physicochemi-cal properties of other solvents in comparison to water inevitably influence nebuliser performance (133).

Instead of using a different solvent, an aqueous suspension may be preferred when the active agent poorly dissolves in water. Prerequisite is that the suspended particles are small enough to be aerosolised by the nebuliser (and of course within the respi-rable size range) (134). Whether or not the particles affect nebuliser performance has been shown to be dependent on nebuliser design (135), and thus it should be checked whether a nebuliser is compatible with suspensions. Nebulisers can also be used to administer aqueous suspensions of engineered particles, such as liposomes (136–140) and nanoparticles (127,141–144).

One of the main concerns of formulations for nebulisation is the stability of the for-mulation. Chemical stability issues arise when the active substance is sensitive to degradation reactions (e.g. oxidation, hydrolysis), as these occur faster in aqueous conditions than in the dry state. Specifically for suspensions, also physical stability is-sues should be addressed, such as the risk on flocculation of the suspended particles. Such typical storage stability issues may be overcome by providing the formulation as a powder for reconstitution. Additionally, stability can be at stake when the stresses

34

Chapter 1

induced by the nebulisation process itself may damage the formulation, which can be the case for large molecules or complex particulate systems (117,145–152).

Preparing a formulation for nebulisation can be very straightforward, which is the main reason why nebulisers are often used in the early stages of clinical development, as for example seen in studies on pulmonary vaccination (Chapter 8) and lung can-cer therapy (153,154). Also for individualised medicine or off-label purposes, pul-monary administration of the therapeutic can be accomplished by nebulisation of a simple solution of the compound (155). It should be stressed though that in such cases, one cannot simply assume compatibility of the formulation and the nebuliser. Controls of the droplet size distribution and nebuliser output rate can be essential for the application to be successful (114; Chapter 2).

The Soft Mist Inhaler

Like the vibrating mesh nebulisers, the Soft Mist Inhaler (SMI) is a more recent de-velopment in inhalation devices. The SMI is a nebuliser, as it disperses a solution of the active agent into fine droplets. It differs from the traditional nebulisers in that it is a hand-held, portable device that does not require an external power source, but is actuated by a mechanical spring. The instantaneous formation of the aerosol is comparable to a pMDI; thus, proper actuation-inhalation coordination is necessary (156). However, it takes longer before the entire aerosol is generated (1.5 s versus 0.21–0.36 s for an HFA-pMDI) and the aerosol is emitted as a slow-moving mist, allowing for a relatively high lung deposition (157).

Pressurised metered dose inhalers

Pressurised metered dose inhalers (pMDIs) are the most often-prescribed inhalation devices (103), which are especially used for the delivery of therapeutics for symp-tom management in asthma and COPD. PMDIs were introduced in the 1950s as the first portable, multi-dose pulmonary delivery system. Their basic design consists of a canister that is closed off by a metering valve, an actuation mechanism, and a mouth-piece. The canister holds a propellant under pressure, in which the active agent and any excipients are dissolved or suspended (158).

Pressing the canister down actuates the metering valve of the pMDI. Subsequently, a fixed amount of the contents is released that disperses into small particles by rapid expansion of the propellant in the nozzle region, which largely determines the size

35


distribution in the aerosol. Despite the inherent advantage of flow rate independence of aerosol formation and delivery, the requirement of patient coordination may be a disadvantage. Dose release and inhalation should be synchronic, or the entire dose deposits in the back of the patient’s throat. Therefore, good actuation-inhalation (“hand-lung”) coordination is required, which cannot be taught to all patients.

To allow for more generalised use of pMDIs, two alternatives have been intro-duced: the breath-actuated pMDI and the use of a valved holding chamber (VHC). Breath-actuated pMDIs still require for the patient to comprehend how to perform the desired inhalation manoeuvre. When no comprehension is to be expected at all, for example in very young children, a VHC can be used.

VHCs are extension devices10 with a one-way valve incorporated into the mouth-piece, allowing for the patient to inhale a static aerosol instead of a plume. The patient can keep the device in his mouth while breathing in and out, as the exhalation into the VHC is directed away from the aerosol-holding chamber via the one-way valve. This way, the aerosol can be inhaled in multiple breaths. Even though less mouth deposition can be expected when using a VHC, the final lung deposition is still low due to losses in the VHC by various mechanisms, including impaction and sedimen-tation of the aerosol (159).

PMDI formulations

The principal excipient present in all pMDI formulations is the propellant, which is required for aerosolisation of the active agent, but which also acts as solvent or suspension medium. In addition, co-solvents, solubilisers, and stabilisers may be present. The first generation pMDIs contained chlorofluorocarbons (CFCs) as pro-pellants, which have been phased out from use since the 1987 Montreal Protocol on Substances that Deplete the Ozone Layer,11 due to their ozone depleting properties (160). The Montreal protocol has led to replacement of CFCs by hydrofluoroalkanes (HFAs) in pMDIs. As HFAs are more polar than CFCs, the solubility of (often hydro-phobic) active agents is different for these propellants (158). Therefore, reformulation is usually required when replacing a CFC by an HFA, for example the addition of ethanol as co-solvent to retain the agent in solution or of stabilising excipients when

10 Also simpler types of extension devices – spacers – are available, which have no valve and function solely by increasing the distance between the pMDI and the throat of the patient. This lack of a valve strongly di-minishes the spacer’s applicability in patients who cannot follow inhalation instructions, as it bears the risk of the patient exhaling into the device and thereby ruining the aerosol. Therefore, I consider spacers inept and do not discuss them here. 11 http://ozone.unep.org/new_site/en/montreal_protocol.php.

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Chapter 1

switching to a suspension.

Some important differences exist between CFC-pMDIs and HFA-pMDIs. On aver-age, the plumes from HFA-pMDIs have a lower velocity and higher temperature than CFC-pMDI plumes (161), which may affect patient experience, especially in com-bination with altered taste when ethanol is added (103). In addition, the particles generated with HFA-pMDIs can be smaller, which has led to the development of so-called extra-fine particle products. By virtue of the lower plume velocity and smaller aerosol particle size, HFA-pMDIs show an enhanced lung deposition (162–165).

The active agent in a pMDI formulation should either be suspended or dissolved. Partial solubility can lead to crystal growth through Ostwald ripening, resulting in a change in particle size distribution and emitted dose (158). Suspensions are pre-ferred over solutions in terms of the chemical stability of the active substance, but the reduced physical stability of the system may require the use of stabilising excipients, such as surfactants (166). Moreover, suspension pMDIs should be shaken before use, an action that is often forgotten by patients and caretakers, which results in incorrect and inconsistent dosing due to particle sedimentation in the canister.

PMDI formulation properties strongly interact with the performance of the pMDI. Physicochemical properties, such as lipophilicity and molecular weight, but also the concentration of the active substance may affect pMDI function (158). In low con-centration suspension systems (up to 0.1% v/v), emitted droplets generally contain no more than one particle and the resulting particle size approximates the suspended particle size (167). With increasing concentration, the number of particles per drop-let increases. Thus, the resulting particle size increases too. High concentrations of non-volatile surfactant or co-solvent will lead to an increased droplet size in the aero-sol, as they do not evaporate from the suspended particles surface (166). In solution systems, the particle size is dependent on the emitted droplet size, the concentration of non-volatile components, and the ambient conditions (158,166).

PMDIs are predominantly used for bronchodilators and inhaled corticosteroids, which are given in relatively low doses (6–200 µg per actuation). The described con-centration effects limit the use of pMDIs for highly dosed therapeutics such as an-tibiotics. For protein-based agents, maintaining protein integrity and stability in the propellant is the main concern during formulation (168,169). The hostile non-polar environment created by the propellant poses an important constraint on the applica-bility of pMDIs for delivery of biotherapeutics.

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Dry powder inhalers

Dry powder inhalers (DPIs) are the only inhalation devices that contain the pharma-cologically active agent in the dry state. DPIs typically consist of a powder formula-tion, a dose metering mechanism that either contains or measures a single dose of the therapeutic, a powder de-agglomeration principle, and a mouthpiece (21). Most DPIs are passive (breath-actuated)12 devices, so actuation and inhalation do not have to be coordinated as with pMDIs. Being operated by the breath of the patient implies that a certain minimal inspiratory effort from the patient is required for proper dose release from the DPI.

Various DPIs containing different therapeutics are commercially available. These de-vices can be classified into three types. The first are multi-dose DPIs, which contain the powder formulation in bulk in a reservoir, from which a dose is metered upon use by the patient. The second category includes devices that contain multiple pre-me-tered (sealed) doses within the device, which are called multiple unit-dose devices. Lastly, single-dose DPIs exist that are loaded with a single dose of the powder for-mulation, which is done either by the manufacturer (disposable devices) or by the patient immediately before use (capsule-based devices).

Delivery of the powder formulation to the lungs occurs through consecutive pro-cesses within the DPI, which are (typically) initiated by the inhalation manoeuvre of the patient. After entrainment of the powder formulation from the dose metering system, de-agglomeration or dispersion takes place, eventually resulting in an aerosol of small, inhalable particles of the active agent (and any excipients). The effectiveness of these processes, and hence the effectiveness of aerosol formation, is dependent on the powder formulation, the DPI (especially the de-agglomeration principle), and the patient’s inspiratory effort (inspiratory flow rate and inhaled volume).

The inhalation manoeuvre is particularly important for DPIs and depends on the working principle of the inhaler and the desired deposition site in the lungs (21). Whether a patient is able to perform the inhalation manoeuvre required for a specific DPI depends on patient characteristics like age and clinical condition (i.e. type and severity of disease), which may present physical limitations or insufficient under-standing of how to handle the device (170–173; Chapter 7).

12 Despite a few examples of active DPIs – most of which are still in (pre)clinical stages of research – the vast majority of all (commercialised) DPIs are passive devices. Further considerations only address devices that are operated by the breath of the patient, unless stated differently.

38

Chapter 1

DPIs are versatile and applicable to a wide array of purposes, by virtue of the large dose range that can be covered, the dry state of the formulation, and the various for-mulation approaches that are available. DPIs are also very complex delivery systems, consisting of an inextricable combination of device and formulation. For that reason, the development of DPI products is often a next-level approach, to be explored once the potential of the pulmonary delivery route has been established by nebulisation.

DPI formulations

The main characteristic of DPI formulations is – as their name implies – that they are in the solid state. Dry formulations have some important advantages compared to wet formulations, mainly concerned with the chemical, physical, and microbiological stability of the active agent and formulation.

The starting point for designing a DPI formulation is that the aerosolised particle size should be within the earlier defined aerodynamic range of 1–5 µm for effective lung deposition. The aerosolised particle size does not necessarily have to be the pri-mary particle size, since agglomerates of submicron-sized particles can exhibit the desired aerodynamic behaviour too. Such small particles can be obtained by various techniques, which are either top-down (e.g. milling) or bottom-up (e.g. spray drying or controlled crystallisation). Regardless of the production method, small particles have a large specific surface area, resulting in a high degree of cohesiveness and adhe-siveness by Van der Waals forces (21). Consequently, powders of respirable particles often exhibit poor flow properties and have a tendency to agglomerate and stick to surfaces with which contact is made.

In addition to particle size, physicochemical properties of the active substance, par-ticle morphology, crystalline habit, and moisture content of the powder contribute to DPI formulation performance (174); by themselves, but also in relation to DPI design.

DPIs can be used for the administration of doses ranging from a few micrograms of a potent bronchodilator (e.g. formoterol) up to several tens of milligrams of an antibiotic (e.g. colistin or tobramycin). Especially for doses up to 1 mg, excipients are required to provide bulk for accurate dose metering and dose reproducibility. Most marketed low dosed formulations contain an excipient (usually α-lactose monohy-drate) that functions as carrier for the drug particles. Such formulations are called adhesive mixtures, named after the adhesive Van der Waals forces between the mi-cron-sized particles of the active agent and the surface of the coarse carrier crystals.

39


The adhesion forces between carrier and active particles have to be balanced carefully between two opposing requirements. They must be strong enough to ensure a mix-ture that is stable during preparation and storage, but weak enough to be overcome by the dispersion forces during the inhalation manoeuvre (21). Many variables in-fluence the adhesion forces in an adhesive mixture, such as drug content (175), mix-ing time (176), humidity (177–179), carrier surface characteristics (180–183), and carrier size (182,184). Ternary compounds like magnesium stearate, leucine, or fine lactose particles (185) can also be added to control the adhesion forces between drug and carrier particles.

Spherical pellets are another type of DPI formulation, which are agglomerates con-sisting of either pure micronised active agent or a mixture of micronised active agent and micronised excipient, and can be up to 200–2000 µm in diameter (21). The large size and round shape of the pellets improve the flowability of the powder, and thus dose reproducibility during manufacturing and metering (in multi-dose devices). The pellets have a high porosity and low mechanical stability, which means they are easily dispersed upon inhalation (186), and they can be used for both low and highly dosed agents.

A third formulation approach to improve aerosolisation behaviour comprises various particle engineering strategies, such as spray drying, spray-freeze drying, and super-critical fluid precipitation, which produce respirable particles in a one-step process. These bottom-up methods, in which the particles are formed out of solution, offer quite some flexibility with regard to particle size and morphology (174). By con-trolling the surface properties, particles can be obtained that readily disperse with-out the need for a carrier, which is especially interesting for highly dosed agents. A concern of these methods is that they often yield amorphous material, which may have implications for the reproducibility and stability of the product. The engineered particles can consist of pure or diluted active agent (67,187–192; Chapter 3), but may also be more complex particulate systems, for example nanoparticles incorporated in a matrix (193–196).

Large or hollow porous particles are a particular type of engineered particles (197,198). These particles, generally prepared by spray drying of surfactant-containing formu-lations or by spray-freeze drying, have a relatively large geometric diameter but ex-hibit favourable aerodynamic behaviour by virtue of their low density. The porous appearance of the particle surface decreases the contact area between the particles. In addition, their larger size of up to 20 µm reduces their tendency to agglomerate and enhances their responsiveness to various de-agglomeration forces, thereby improv-

40

Chapter 1

ing their dispersion properties (174). However, the porous, low-density nature of the particles restricts the dose that can be delivered with this type of formulation (32).

DPI formulations can be highly interesting for biotherapeutics and vaccines for in-creasing their storage stability compared to liquid formulations, though it should be emphasised that stresses during the formulation process may limit the possibilities and generally require the use of protective excipients, such as sugars (67,190,191,199).

Excipients

Pulmonary formulations frequently require excipients to increase the ease of ad-ministration. Additionally, excipients can be added to pulmonary formulations for a variety of reasons, e.g. to enable or control bioavailability of the active agent or to improve the stability of the product. The lungs’ epithelial lining fluid has a limited buffering capacity, making them sensitive to irritation or injury by exogenous sub-stances. Therefore, only compounds that are biocompatible with the epithelium of the airways and that are easily metabolised or cleared are suitable for pulmonary formulations (174,200).

A limited number of excipients have been approved for pulmonary administration (201), since specific tests are required to evaluate local toxicity concerns for the respi-ratory tract (202). In essence, the only approved excipients are those that are used in marketed inhalation products, which poses quite some limitations on the translation of new pulmonary formulations from lab to clinic, especially for the more complex engineered formulations.

THE INTERPLAY OF THE DETERMINANTS

When developing or prescribing an inhaled application (usually as therapy), the purpose of the administration, the patient (population), and the inhalation product should all be acknowledged. Since the patient and purpose are beyond control, the product has to be adapted accordingly. It is only when the three are considered in concert that maximal benefits can be gained from the administration.

In this respect, the starting points for prescribing an inhaled compound and for de-veloping a new inhaled drug or diagnostic are entirely different. A limited array of

41


therapeutic options is usually available, and from these the most suitable one should be chosen for a specific individual patient and his specific needs, wishes, and abili-ties. When developing a new inhaled application, the optimal product design should be based primarily on the question which device would best suit the capacities and needs of the patient – by virtue of the purpose – rather than which formulation is easiest to realise. In very specific situations, such as highly specialised or immediate-ly required individualised medical treatments (often antibiotics), the fastest feasible solution can have the preference.

Product meets patient

In search of the optimal approach five basic yet crucial questions should be answered first: why, who, when, where, and what. The “why” and the “who” have been dis-cussed extensively, being the purpose and patient respectively. The “when” accounts for the dose regimen, which can range from one-time administration or on-demand therapy to life-long daily treatment. The “where” can refer to the setting in which the administration takes place, either at home or in the clinic, but also to the part of the world for which the application is intended. Although extremely sad, it is obvious that many more possibilities and funds exist for “first-world products” than for those intended for developing countries. Lastly, the “what” is the optimal product, i.e. de-vice-formulation combination, which follows from answering the other questions, accounting for any formulation constraints, or – in case of prescribing therapy – the available products.

When and where

When and where an orally inhaled application is intended to be used are perhaps less crucial questions to ask in terms of feasibility. Still, when striving for optimisation, taking them into consideration will increase the probability of choosing the most successful approach.

Convenience and administration time are factors that become more important with increasing dosing frequency and duration of the therapy, especially with regard to compliance. Single-use applications or applications where hygiene is at stake may be better served with a disposable device. Disposable devices that are cheap to produce are furthermore suitable for use in developing countries, where they can be used for large-scale vaccination campaigns (Chapter 8). If the device itself cannot be used as a disposable item, a disposable extension piece may provide a solution, as for ex-

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Chapter 1

ample has been included in the design of two active DPIs intended for pulmonary vaccination (Solovent, BD Technologies and Puffhaler, Aktiv-Dry). If the disposable extension piece is not part of the original device design, a critical (in vitro) evaluation of the effects on device performance is strongly recommended (Chapter 6).

At home the patient or caretaker is in charge of the administration, while in the clin-ic a healthcare professional is responsible. Additionally, clinical therapies are usual-ly confined to a limited number of administrations, or administered under special circumstances, for example to mechanically ventilated patients. For these reasons, clinical therapies can be much more complex than those intended for use at home.

Prescribing the best therapy

The interaction between patient and device is the most important interaction to ac-knowledge when prescribing an inhalation product, since the device has to be pre-pared and used correctly to achieve sufficient pulmonary deposition required for the desired therapeutic effect. In other words, an inhalation product is only as good as the patient’s ability to use it, or his motivation to use and maintain it correctly. The options are of course limited by the therapies that are available. Asthma (and COPD) medication is the best-established inhaled therapeutic purpose, for which numerous options are available – not only in number of active substances, but also in num-ber of devices. Exemplary is the short-acting β2-agonist salbutamol, of which in the Netherlands at least four nebuliser solutions are available (two with and two without conservative), three HFA-pMDIs, one breath-actuated pMDI, and five DPIs, most of these in various dosages.13

When there is ample choice, the prescriber should opt for the therapy that has the highest chance of success. This chance is not only dependent on the patient’s ability to use a specific device, but also on his preferences, cooperativeness and willingness, and possibly familiarity with the device. If a patient has used a specific device correct-ly for years, his therapy may not by definition be improved by switching to a device that by itself is better than the one he has been using, because he has to learn and adopt new handling instructions and possibly also a new inhalation manoeuvre. Still, a patient who is competent and willing may very well benefit from putting effort into learning a new technique and switching to the new device.

13 College ter Beoordeling van Geneesmiddelen (Medicines Evaluation Board): http://www.cbg-meb.nl/CBG/nl/humane-geneesmiddelen/geneesmiddeleninformatiebank/default.htm.

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For all types of devices, large numbers of patients have been reported to use their de-vice incorrectly, resulting in suboptimal therapy (172,203,204). These proportions in-crease when patients use multiple devices, especially when different types of devices are combined (205,206). Therefore, it is advised to limit the number of (different) de-vices per patient, if possible. Fixed dose combination products may have therapeutic benefits in this respect, provided that the combination is rational – i.e. the combined drugs have a synergistic effect and comparable dosing frequency, and preferably the same target area in the respiratory tract. In addition to a few combination products that are already available (e.g. the inhaled corticosteroid/long-acting β2-agonist com-binations budesonide/formoterol, fluticasone/salmeterol, beclometason/formoterol against asthma, and the muscarinic antagonist/long-acting β2-agonist combination glycopyrronium/indacaterol against COPD), various more combination products are currently in late stage development, especially for COPD treatment (e.g. the musca-rinic antagonist/long-acting β2-agonist combinations umeclidinium/vilanterol, acli-dinium/formoterol).

Further to increasing the chance of successful therapy, choice also allows a rationale based on costs. From the national healthcare authorities’ perspective, mitigating costs is a very – one might wonder if not the most – important motive in healthcare.14 This generally implies that the moment a cheaper alternative product becomes available, patients must switch to this product. However, because of the precarious balance be-tween patient use and device performance, switching may not be in the best interest of the patient at all. If the effectiveness of the therapy would drastically be reduced due to the switch, costs may even increase on the long term. The better strategy in this respect would be maximising cost-effectiveness rather than minimising the direct costs of the medication.

When the choice is limited or there is none at all, it is the physician’s – and pharma-cist’s – duty to enable maximal therapeutic benefit for the patient. Training and reg-ularly checking the patient’s (or his caretaker’s) technique are essential in this respect (207,208). Enabling maximal therapeutic benefit includes prescribing appropriate ac-cessories for specific age groups or devices, such as facemasks for infants and toddlers or VHCs for pMDIs respectively.

14 Total healthcare expenses in 2000 in the Netherlands were 47 billion euros. In 12 years time, these ex-penses almost doubled to more than 92 billion euros in 2012. Medicinal products account for only a modest fraction of these costs: 8.5% (4 billion euros) in 2000 and 6.4% (5.9 billion euros) in 2012. Although in itself an increase of almost 50%, it is clear from these figures that reducing expenses on medicinal products will not be the solution to containing healthcare expenditure. Centraal Bureau voor de Statistiek (Statistics Netherlands): http://statline.cbs.nl/StatWeb/publication/?DM=SLNL&PA=71914ned&D1=0-23&D2=a&HDR=G1&STB=T&VW=T.

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Effectiveness, effect of training, and compliance

Key to effective inhalation therapy is correct inhaler and inhalation technique, which comprise both correct handling of the device and the performance of a correct in-halation manoeuvre. What makes this so hard is that practically each single device has its own mode of operation. Overall, the same procedures apply to the different types of inhalation devices, but the steps can vary significantly among these types, especially for DPIs. Therefore, general guidelines on the use of a type of inhaler lack practicality and usefulness and should be avoided.

Correct inhaler and inhalation technique can only be expected when the patient is properly trained in using his device. Training is a joint effort of the healthcare provid-er and the patient, which starts with teaching and learning the manoeuvre, followed by repeated demonstration by the patient and, if necessary, adjusting of the tech-nique by the healthcare provider (172,208). Needless to say, the healthcare provider must completely understand and master the technique for every specific inhalation device that he deals with. Unfortunately, this is often not the case (209), which can be attributed at least partly to poor apprehension of inhaler technology. Initiatives15 that increase knowledge of the mechanisms of inhalation devices among healthcare providers are therefore very welcome, as well as appointing physician assistants and nurse practitioners specialised in pulmonary diseases and inhalation therapies.

Besides correct technique, patient compliance is just as important for effective in-halation therapy (210). Compliance is expressed as the level at which the patient’s behaviour complies with the prescribed therapy. Indeed, flawless inhaler technique is useless when the patient does not take his medication. Noncompliance is not nec-essarily deliberate (forgetting to take medication) and it is not necessarily harmful either. Still, if a patient has good reasons not to adhere to his prescribed therapy, for example side effects, discussing alternatives with his physician is better than altering the dose or dose regimen himself. Taking t

University of Groningen Technology in practice Lexmond, Anne · 2016. 3. 8. · with deviating lung...

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