University of Groningen Inhalable levodopa: from laboratory to the patient Luinstra, Marianne

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University of Groningen

Inhalable levodopa: from laboratory to the patient

Luinstra, Marianne

DOI:

10.33612/diss.113190195

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Luinstra, M. (2020). Inhalable levodopa: from laboratory to the patient. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.113190195

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INHALABLE LEVODOPA:

FROM LABORATORY TO THE PATIENT

Marianne Luinstra

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Colophon

Cover artwork & design: Eva Dambrink

Layout: Douwe Oppewal, oppewal.nl

Printing: Ipskamp Printing

ISBN: 978-94-034-2326-5 ISBN (digital): 978-94-034-2327-2

The research presented in this thesis was carried out at the Department of Pharmaceutical Technology and Biopharmacy of the University of Groningen, and at the Martini Hospital Groningen. Financial support for lay-out and printing the thesis was received from PureIMS, the University Library, the department of Clinical Pharmacy and the Martini Science Fund of the Martini Hospital and the Graduate School of Science and Engineering of the University of Groningen.

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Inhalable levodopa: from

laboratory to the patient

Proefschrift

ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen

op gezag van de

rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College voor Promoties.

De openbare verdediging zal plaatsvinden op vrijdag 28 februari 2020 om 14.30 uur

door

Marianne Luinstra

geboren op 14 augustus 1983

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Promotores

Prof. dr. H.W. Frijlink Prof. dr. T. van Laar

Copromotor

Dr. A.H. de Boer

Beoordelingscommissie

Prof. dr. M. Schmidt

Prof. dr. E.N. van Roon Prof. dr. J.M.A. van Gerven

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Chapter 1 Inhaled drugs for systemic action

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Chapter 2 Can patients with Parkinson’s disease use

29 dry powder inhalers during off periods?

PLoS One. 2015 Jul 14;10(7):e0132714

Chapter 3 A levodopa dry powder inhaler for the treatment

45 of parkinson’s disease patients in off periods.

Eur J Pharm Biopharm. 2015 Nov, 97(PT A):22-9.

Chapter 4 Pharmacokinetics and tolerability of inhaled levodopa

63 from a new dry powder inhaler in Parkinson’s disease patients.

Ther Adv Chronic Dis 2019, Vol. 10: 1-10.

Chapter 5 Learning from Parkinson’s patients:

79 usability of the cyclops dry powder inhaler.

Int J Pharm. Volume 567, August 2019.

Chapter 6 Effectiveness of inhaled levodopa in Parkinson’s disease.

93 A summary of the study design (NTR7054).

Chapter 7 General discussion and practical implications for future use.

105 Appendix A Summary

115 Appendix B Samenvatting

123 Curriculum Vitae

130 List of Publications

131

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PROLOGUE

There is a growing interest in using the pulmonary route for the administration of systemically acting drugs. This route of administration may have certain specific advantages. It may, for example, overcome problems with drugs that have a low or variable bioavailability when given via other routes of administration such as the oral route. Pulmonary administration may also be of advantage with drugs that, due to pylorospasm or gastroparesis, have problems passing from the stomach to the small intestine where the absorption has to take place, as is the case for levodopa in Parkinson’s disease (1). Parkinson’s disease is a progressive degenerative disorder and many patients suffer from off periods at some stage of their disease. During off periods, motor symptoms of the disease are poorly controlled and a rapid onset of effect of the anti-Parkinson drug is wanted. Since levodopa is a small molecule (±197 Da) that can rapidly pass the pulmonary membranes it is an interesting candidate for pulmonary delivery, in case an immediate action of the drug is desired. Moreover, the gastro-intestinal and first-pass metabolism can be circumvented by using the pulmonary route.

However, systemic drug delivery using inhaled aerosols is accompanied by several specific requirements and challenges. Small molecules like levodopa can be absorbed over both the airway and alveolar membranes (2). The major determinant for a successful administration is the lung-dose that can be achieved with inhalation. Whether pulmonary administration is possible and to which extent it will be successful depends on many factors, including the tolerability of the drug, the drug formulation and the inhaler technology as well as on how the inhalers are used by the patients. And even after successful delivery to the lungs, the destiny of the particles after deposition at the site of absorption is often still uncertain. Metabolism and clearance mechanisms in the lungs may be effective in degradation and removal respectively, thereby diminishing the bioavailability of the drug (3). This all makes the entire process from drug aerosolization to systemic therapeutic effect very complex and challenging.

This thesis starts with a detailed review about the requirements and uncertainties regarding the pulmonary delivery of systemically acting drugs in general. Since we are interested in the systemic delivery of levodopa by inhalation, the next chapter discusses the applicability of a levodopa dry powder inhaler during off periods in Parkinson’s disease patients. For effective delivery in the peripheral airways, it is a prerequisite that Parkinson’s patients are able to perform an adequate inhalation manoeuvre. However, such a manoeuvre consists of different steps that have to be performed in the right order. It can be imagined that this may be hard for a Parkinson’s patient, especially in an off period, when the motor function is disturbed and symptoms of the disease are poorly controlled. An easy to perform preparation and inhalation procedure are therefore of paramount importance to achieve successful drug administration. In this thesis chapter 2 investigates whether or not patients with Parkinson’s disease are able to perform an adequate inhalation procedure with the inhaler we developed. As described in chapter 5, the ability of

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9 Parkinson’s patients to prepare the Cyclops inhaler for use was studied, since the disturbed motor function of Parkinson’s disease patients may be of influence. A next step in the development of a good inhalation product would be the development of a suitable powder formulation. In chapter 3, we describe the development of a levodopa formulation that contains only 2% excipient, which is quite unique.

Next, the results of a pharmacokinetic and tolerability study in Parkinson’s patients with the developed inhalation powder and inhaler combination are described in chapter 4. Finally the study protocol of a trial regarding the effect of levodopa inhalation powder on the recovery of off periods is shown. The study is currently ongoing and if the results are positive, this opens the way to further development and upscaling of our levodopa inhalation powder for use in the recovery from off periods.

REFERENCES

(1) Mukherjee A., Biswas A., Das SK. Gut dysfunction in Parkinson’s disease. World J Gastroenterol. 2016-7-07;22(25):5742-52. (2) Patton JS., Fishburn CS., Weers JG. The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc.

2004;1(4):338-44.

(3) Patton JS., Brain JD., Davies LA., et al. The particle has landed--characterizing the fate of inhaled pharmaceuticals. J Aerosol Med Pulm Drug Deliv. 2010-12;23:71-87.

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CHAPTER

1

INHALED DRUGS FOR SYSTEMIC ACTION

M. Luinstra, A.H. de Boer, H.W. Frijlink

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INTRODUCTION

There is a growing interest in using the pulmonary route for the administration of systemically acting drugs as this route may have certain advantages for drugs that have a low or variable bioavailability when given orally. Drugs that show a poor permeation over the intestinal membrane or drugs that are metabolised by the enzymes in the gastrointestinal lumen and the liver into inactive components (first-pass effect) are typical examples. Further, some drugs may have problems passing from the stomach to the small intestine, where the absorption has to take place, due to pylorospasm or gastroparesis, as in Parkinson’s disease (1). Finally, the pulmonary route is attractive for administering those drugs for which a fast onset of action is desired. The ongoing uncertainty about the future of inhaled insulin has reduced the number of completed developments for systemically acting drugs administered by inhalation to only two much smaller molecules so far: levodopa and loxapine. Levodopa has been developed under the name InbrijaTM_{(during the clinical phases referred to as CVT-301) by Acorda Therapeutics Inc.} (formerly Civitas) and the FDA approval decision for the product was announced on December 21, 2018. Self-administration of CVT-301 (35 or 50 mg) during OFF periods by patients with Parkinson’s Disease with > 2 hours per day OFF time provided rapid improvement of motor function and significant reduction of daily OFF time compared to oral levodopa > 4 times per day (2). Plasma levodopa concentrations were found to increase more rapidly and with less variability than after oral levodopa administration to the same patients. However, some adverse events were reported, like dizziness, cough and nausea (3). Luinstra et al (4) developed a levodopa inhalation powder for use with the Cyclops inhaler (5). The Cyclops is a disposable classifier-based dry powder inhaler for high doses (5) (PureIMS, Roden, The Netherlands). In a clinical trial with 8 participants, a rapid and reproducible rise of the levodopa plasma concentrations was seen after inhalation of 30 and 60 mg levodopa and no adverse events were reported so far (6). This absence of adverse events is probably caused by the relatively high inhaler resistance of the Cyclops combined with its efficient powder dispersion principle, which both may lead to a reduction of large particle deposition in the throat. The levodopa inhalation powder administered with the Cyclops is currently in a clinical trial in which efficacy is investigated. Loxapine was developed under the brand name Adasuve® by Alexza Pharmaceuticals Inc. and approved by the FDA in 2012 for acute treatment of agitation associated with schizophrenia and bipolar disorder in adults. Several studies on healthy volunteers have confirmed a rapid absorption via the lung with a T_max reached after 2 minutes for a C_max of 257 + 219 ng/mL from a 10 mg dose (7). Inhaled loxapine was well tolerated in patients with mild to moderate adverse effects like dysgeusia, throat irritation and sedation. These two examples, and insulin, prove that systemic action via the pulmonary route is feasible indeed and they may boost the development of advanced technology needed for further optimization of the therapy via this route.

Systemic drug delivery using inhaled aerosols is accompanied by several specific requirements

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13 and challenges. It starts with defining the target site for deposition of the inhaled aerosol, which may be different for different applications. For instance, the preferred site of deposition for vaccines may depend on the type of vaccine (8) whereas for adequate absorption of the drug into the systemic circulation, delivery to the alveolar region is claimed to be mandatory for proteins having a molecular weight of 1.4-20 kDa (9). Whether, and to what extent the latter is feasible or not depends on the drug formulation, the inhaler technology as well as on how the inhaler is used. Device design and instruction for use are, therefore, of utmost importance to the success of the delivery. And even after successful delivery to the (peripheral) lung, the fate of the particles and dissolved drug molecules after deposition at the site of absorption is often still uncertain (10). Metabolism and clearance mechanisms in the lungs may be effective in decomposition and removal respectively, thereby diminishing the bioavailability of the drug. This all makes the entire process from drug aerosolization to systemic therapeutic effect very complex. It involves many different steps (see Table 1) that are to some extent insufficiently explored and poorly understood. As a consequence, some of these process steps are inadequately controlled and the failure of any of these steps can make the entire process ineffective. The array of subsequent steps comprising the total process from drug aerosolization to the therapeutic effect in the treatment of systemic diseases is shown in Table 1 for the example of dry powder inhalation.

Table 1: array of steps in pulmonary drug delivery for the treatment of systemic diseases with dry powder

inhalers (DPIs).

Steps Phase 1

Technical design, manufacturing and logistics.

1. Aerosol particle design and inhaler design.

2. Formulation and manufacturing into inhalation powder. 3. Powder handling, storage and dose measuring.

Phase 2

The inhalation process. 4. Aerosol generation during inhalation.5. Inhalation profile and breath hold.

6. Aerosol particle transport and deposition in the respiratory tract.

Phase 3

Post-inhalation processes. 7. Particle wetting, dissolution and/or drug release.8. Dose elimination by metabolism and clearance mechanisms. 9. Drug permeation across the epithelial surface.

10. Drug partitioning in lung tissue.

11. Drug distribution via local and systemic circulations.

Since there is already a lot of literature available regarding the requirements for a dry powder inhaler, this is only briefly summarized in this overview. Factors (possibly) influencing drug bioavailability when aiming for systemic drug delivery via inhalation are addressed. This will make clear that aiming for systemic delivery via the airways is very complicated.

Systemic drug delivery using a dry powder inhaler

DPIs seem the most appropriate type of pulmonary delivery system for the administration of drugs for systemic action. DPIs can deliver high doses and the drug is in the dry state. Therefore, stability is not, or at least much less an issue compared to drug in solution. Some systemically acting drugs as levodopa are dosed in the mg- instead of in the mg-range and DPIs can potentially deliver high doses per inhalation cycle. Doses of up to 100 mg or more can be administered in no

INHALED DRUGS FOR SYSTEMIC ACTION

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more than one or a few inhalations (11,12). DPIs can be simple, cheap and yet be highly efficient drug aerosolization devices (5,13). DPIs are (almost) ready for immediate use when a fast onset of action is needed as for instance in Parkinson’s disease (levodopa: (4)) or psychiatric disorders (loxapine: (7)). Also, compared to nebulisation, DPI is more user friendly and less time consuming for the patient, thereby improving therapy adherence. Last, but not least, DPIs can be designed to deliver a finer aerosol and/or a higher fine particle dose when the patient inhales more forcefully, resulting in a higher flow rate through the device. This compensates at least partly for a shift in deposition towards larger airways, including the oropharynx. Consequently, a much more flow rate (i.e. patient) independent central and peripheral lung deposition is obtained compared to devices that generate aerosols with the same properties at all flow rates (14,15).

It is desired that the inhalation manoeuvre for optimal device performance is the same as the manoeuvre for optimal lung deposition of the produced aerosol. To take advantage of this, it is required that the patient acts in accordance with the instructions for correct inhaler use and that the instructor knows well how to achieve optimal lung deposition with the device. Preferably, correct DPI operation is also highly intuitive to minimise the errors in dry powder inhalation. Optimal lung deposition for large molecules requires convective transport into the respiratory bronchioles and the alveoli. To achieve this effectively in a single breath, the patient has to exhale first deeply to residual volume before inhaling a volume of air with the aerosol that equals the vital lung capacity. Furthermore, to make certain that the majority of the inhaled dose is transported to the intended target area indeed, the entire dose has to be released within the first 0.5 to 1.0 L of inhaled air. The flow rate at which the aerosol is inhaled should preferably be lower than 60 L/min. In addition, the aerosol particles should preferably not be larger than 3 μm at that flow rate (16). The requirements on the DPI design for optimal performance depend on the dose weight and the type of powder formulation, which emphasizes the need for inhaler-formulation integrated development. Optimising the inhaler aerodynamics and minimising the contact between drug particles and the inhaler walls contribute to keeping the loss factor by drug retention in the inhaler low. The choice of construction material may be different for different drug formulations and should be taken into consideration as well. However, first priority in inhaler design has to be given to achieving maximal powder dispersion into the desired narrow size distribution needed for deposition in the peripheral airways. This requires a powerful dispersion principle operating effectively at a low flow rate. It has been described before which type of dispersion force is most effective (17). Such forces are for instance generated in air classifier chambers, which also have the advantage of classification upon particle size (18) and delivering more fine particles when the flow rate through the DPI is increased (19). An aspect that needs particular attention when designing a DPI is the losses of drug that occur. Even when dispersion of the powder formulation is complete into particles with the appropriate size distribution for deep lung deposition, only a fraction of the dose really becomes available at the site of absorption. Losses related to inhaler design are the result of incomplete powder entrainment from the dose (measuring) compartment and fine

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15 particle adherence onto the inhaler walls, both contributing to the inhaler retention. Losses also include drug deposition in the oropharynx and upper tract due to the release of particles with high inertia that are either (aerodynamically) too large, and/or travelling too fast. Such particles, although released from the inhaler, do not reach the target area and cannot contribute to the desired action. As such they may be considered lost for the therapy too. Figure 1 shows the drug losses for the current adhesive mixture DPIs and three relatively new DPIs. It makes clear that reducing these losses deserves major attention in optimising pulmonary delivery of (systemically acting) drugs that need to be processed into adhesive mixtures. Preferably, the sum of inhaler losses and oropharyngeal deposition is reduced to no more than 25% of the dose, leaving three quarters of the dose for lung deposition.

Figure 1: Mean drug losses and drug fractions available for lung deposition for three new dry powder

inhaler types, the NEXThaler® (20,21) carrying adhesive mixtures with improved dispersion from adding a force control agent (magnesium stearate) for use in asthma, the Podhaler® carrying PulmoSphere® tobramycin (TOBI®) particles for use in cystic fibrosis (22,23) and the MedTone® carrying self-assembling, inhalable carrier particles with insulin for use in diabetes (24-26).

Reduction of the losses must come from improving the dispersion and reducing the velocity at which the aerosol is released. However, improving dispersion at a low flow rate requires the design of more effective dispersion principles. Additional improvement can be obtained from adding dispersion enhancers (or force control agents: FCAs) to the formulation. These enhancers are compounds (e.g. magnesium or sodium stearate and l-leucine) that are also used in the tabletting process as lubricant. The NEXThaler® (Chiesi) (20,21) makes use of such dispersion enhancers in adhesive mixtures for the drug.

The drug absorption site

In case of systemic drug delivery using inhaled aerosols, a target site for drug deposition has to be defined for the drug and patient population in consideration. Because of the direct relation

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between the available surface for drug absorption and the absorption rate, the large surface area of the respiratory airways (approx. 95% of total lung surface area) and the thin barrier for drug transport seem to make the airway generations 17-23 most appropriate for the deposition of drugs for systemic action. The challenge for inhalation scientists seems therefore to get the inhaled drug as effectively as possible past airway generation 16 of the healthy lung. However, it should be recognised that the requirements for different drugs may vary significantly. For larger molecules (1.4-20 kDa) (9), absorption can occur only via the alveoli. In contrast, for smaller molecules like levodopa (±197 Da) the entire respiratory tract may offer a suitable absorption membrane. Obviously this changes the deposition requirements for these different drugs. Additionally, the drug needs to become available in the desired release mode after deposition.

A fast dissolution or sustained release may be required depending on the type of drug and its desired plasma concentration-time profile. Finally, it may be considered necessary to protect deposited drug particles against the clearance mechanisms being active at the site of deposition. This all requires appropriate particle manufacturing procedures, effective particle aerosolization during inhalation and good patient compliance with well doable instructions for optimal inhaler use. Figure 2 shows the predominant parameters for drug transport from the lungs into the systemic circulation.

Figure 2: Respiratory airways as target area for drug deposition (schematically).

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Epithelial lining fluid as solvent for the drug

The total volume of the lining fluid coating the inner walls of the airways, referred to as the Epithelial Lining Fluid (ELF), equals the dissolution volume for inhaled drugs. For pharmacokinetic studies of inhaled drugs, it is desirable to know the volume of ELF and its distribution over the respiratory tract. In combination with the drug distribution this knowledge allows for the assessment of (mean) drug concentrations in various lung sections. An estimation for the total volume of ELF can be made from morphometry or from using bronchoalveolar lavage (BAL) but both techniques are not very reliable. The distribution of ELF over the entire lung can theoretically be estimated from the lung surface distribution and the thickness of the fluid layer covering the respiratory epithelium (27). Unfortunately, both the surface distribution and the thickness are not precisely known, partly because they are highly variable, locally discontinuous and disease dependent. Further, the precise composition of ELF changes with age and particularly the pro-inflammatory cytokines, surfactant proteins and lipids, and complement components are significantly altered over lifetime (28). It is likely that these changes affect the dissolution (rate) of drug particles in the ELF (29). It is thus clear that it is hardly possible to use just one value for the total volume of ELF, since there are many influencing factors.

Local drug concentration

The mean drug concentration achieved in various regions of the lungs depends on the drug distribution over the entire respiratory tract and the surface area of the region in consideration. As a driving force for permeation through the gas-blood barrier into the systemic circulation, a high concentration is desired in the preferred site of absorption.

Experimental drug deposition studies with radionuclide (usually 99m Technetium) adhering to the drug particles show that the lung distribution of the inhaled drug fraction from DPIs is roughly one third in the central, one third in the intermediate and one third in the peripheral lung (15,23,30-33).

Table 2 shows the regional lung depositions from clinical studies with 6 different marketed DPIs used at approx. 60 L/min. The overall mean values 7.6 (+1.7) in the central lung, 8.6 (+2.7/-2.5) in the intermediate lung and 8.6 (+5.0/-3.8) in the peripheral lung can be calculated (Table 2) (15,23,30-33).

Table 2: Regional lung depositions as percent of the nominal or delivered dose from 6 different DPIs at

approximately 60 L/min.

Inhaler Central lung Intermediate lung Peripheral lung

MAGhaler 7.2 9.2 10.0 Easyhaler 7.3 6.1 5.1 Airmax 6.5 8.6 10.7 Novolizer 7.8 8.9 7.8 Turbuhaler 5.9 8.5 8.5 7.3 7.4 10.1 4.8 5.9 11.2 Podhaler 9.3 11.3 13.6 Mean % of total 7.6 30.7% 8.6 34.7% 8.6 34.7% INHALED DRUGS FOR SYSTEMIC ACTION

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This more or less equal drug distribution over the three lung regions is confirmed with monodisperse aerosols of 3 μm, exhibiting 65.7% deposition (two third of total lung dose) in the central plus intermediate (C+I) airways and 34.3% (one third of total lung dose) in the peripheral airways (33). A particle size of 3 μm corresponds well with the arithmetic mean of the narrow range of the mass median aerodynamic diameters of aerosols from many marketed DPIs (approx. 2 to 4 μm) at a moderate flow rate (e.g. (34-38)). As to be expected, for larger particles (6 μm) the distribution shifts to higher values for C+I (75,4% of total lung deposition), whereas for smaller particles (1.5 μm) C+I deposition is lower (65.1%), to the benefit of peripheral deposition (39).

The more or less equal drug distribution over the entire lung from DPIs at approx. 60 L/min may not be interpreted as obtaining the same drug concentration throughout the lungs. At least two physiological variables interfere with this conception. First of all, the increasing number of airways from the trachea to the alveoli causes the surface area of successive airway generations to increase exponentially. Secondly, the volume of the ELF in which the drug has to dissolve, differs between airway generations as the result of differences in both the surface area and the thickness of the liquid layer. Different estimates for the total inner surface area of the airways can be found in literature, and an average value of 100 (+ 60) m2_{for adults seems quite realistic. To this large total lung surface area,} the airway generations 0-16 (trachea-bronchial tree) contribute only 4 to 5 m2_{and the respiratory} bronchioles and alveoli (airway generations 17-23) approximately 95% and it may be clear that the alveoli represent a large part of that. On the basis of the Weibel A model, their contribution to total inner surface area is nearly 40% and that of the last three airway generations 21-23 together is even 75%. Considering that the number of alveoli is much higher than predicted for a dichotomous branching airway system, a realistic estimation for their contribution could easily by even more than 50%.

Table 3A: Assessment of the volume of ELF on the basis of estimated thickness and lung surface areas in

four different lung regions.

Lung region _generationsAirway Thickness ELF_(m) Surface area (Weibel A)*_(m2₎ Volume ELF_(ml)

Central 0-11 10 x 10-6 _0.7 _7.0

Intermediate 12-16 4 x 10-6 _3.8 _15.2

Peripheral 17-21 1.5 x 10-6 _34.2 _51.3

Alveolar 22+23 0.1 x 10-6 _61.4 _6.1

SUM

100

79.6

*Based on a total lung surface area of 100 m2

The changes in surface area and thickness of the ELF over the respiratory tract partly compensate for each other with respect to the local drug concentrations to be expected. This is shown in Table 3B, as an extension of Table 3A. Assuming a total lung dose of 100 μg, local drug concentrations can be assessed in μg/ml as well as in μg/m2_{from the more or less equal deposition in the central,} intermediate and peripheral lung.

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Table 3B: Assessment of local drug concentrations (see Tables 3A and text).

Lung region _generationsAirway Volume ELF_(ml) μg deposition _{in region**} concentrationDrug

μg/ml ELF Drug concentration* μg/m2 Central 0-11 7.0 33.3 4.76 47.6 Intermediate 12-16 15.2 33.3 2.19 8.8 Peripheral 17-21 51.3 16.65 0.32 0.5 Alveolar 22+23 6.1 16.65 2.72 0.2

*Based on a total lung surface area of 100 m2

**Based on a total lung dose of 100 μg and equal drug deposition (33% of total lung dose) in all three regions

For Table 3B it is assumed that in the peripheral region, with respiratory bronchioles (generation 17-21) and alveolar regions (generation 22+23) each, 50% of the peripheral dose is deposited. The differences in local concentration expressed in μg/ml in Table 2B are relatively small, with an exception for the respiratory bronchioles, whereas the differences expressed in μg/m2_are rather extreme between the central and most peripheral airways. It may be clear that even quite considerable inaccuracies in the assumptions made for the preparation of Table 3B do not significantly increase the drug concentrations in the most distal airway generations in terms of μg/m2_{. A low value in μg/m}2_{may have relevance to locally acting drugs, as relatively few drug} receptors may be reached; for systemically acting drugs high concentrations may very locally still be achieved in the respiratory bronchioles and alveoli, unless rapid dilution occurs. This is in the absence of a mucociliary escalator in the respiratory bronchioles not very likely. Therefore, local spots with high drug concentrations may be present, yielding locally a high driving force for permeation into the blood circulation.

In the alveoli re-distribution after dissolution seems much more likely due to the continuous changes in surface area and surfactant concentration. This may promote rapid sideways diffusion of dissolved drug through the liquid film. Also, re-distribution from one alveolus into adjacent neighbouring alveoli is possible through the pores of Kohn (40).

Structural changes and anomalies of the respiratory tract

Age related changes

There exist plenty examples of intrinsic and external factors affecting various aspects of the lung structure and this may have significant effect on the bioavailability of inhaled drugs. Various anatomical, physiological and immunological changes take place in the respiratory tract of elderly (41). Lungs are mature at the age of 20-25 years and gradually start to decline at the age of 35 years. The respiratory diaphragm gets weaker and lung tissue that helps to keep the airways open can lose elasticity, which causes a reduction in airway diameter. Structural changes are also the result of deformation of the chest wall and the thoracic spine, which reduces the room for the lungs to expand and impairs the total respiratory system compliance. The alveolar dead space increases with poorly perfused and/or completely closed alveoli from which neither gas exchange nor drug permeation into the blood stream can occur. As the residual volume increases, less alveoli can

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be ventilated. Between the age of 20 and 80 years the residual volume can double from 1.2 to 2.4 litres for a lung with a total volume of 6 L. This has great effect on the drug distribution in the lungs and convective drug transport to the alveoli may decline to almost zero. Due to all these age-related differences in lung anatomy, it is expected that the bioavailability of certain inhaled drugs for systemic action may be age dependent. For example drugs that need to be absorbed in the alveoli.

Disease related changes

Next to age related changes, various diseases are known to change the lung structure and lung physiology dramatically. The changes can be complex, they may interact with, or induce each other respectively and are partly the same for different diseases. These changes may affect the inhaled aerosol penetration, particle distribution and drug absorption to the extreme. Typical examples of diseases changing the lung structure are asthma and emphysema. Airway remodelling in asthma leads to bronchial wall thickening and increased airway smooth muscle mass. Advanced emphysema is a lung disease in which alveoli and supporting tissue are destroyed and lost. This leads to reduced gas exchange capacity, which, in combination with changes in the airway dynamics, impairs the expiratory air flow and leads to progressive air trapping in the most peripheral airways. The effects of all these age and disease related changes in lung parameters on aerosol transport; particle deposition and drug absorption have been investigated only scarcely. Understanding these effects may have relevance to the treatment of individual patients (42,43) but drawing general conclusions is often hampered by the extreme inter- and intra-patient variability.

Airway protection and clearance mechanisms

The airway protection system consists of anatomical interception systems, and specialized epithelial barriers and immune responses (44). In addition, a variety of neural reflex responses limit the potential harm of inhaled substances, including particles. Although the defence and clearance mechanisms are indispensable for the protection of the lungs from inhaled particulate matter, they may have a negative effect on the efficacy of inhaled drugs. Inhaled drug particles can be removed from the respiratory tract before dissolution and absorption when dissolution is slow or when they were processed into sustained release particles (e.g. liposomes) carrying a drug depot. The array of components that comprise the entire defence system can be divided into those located in the upper airways and those in the alveoli (45). They can also be divided in mechanisms preventing particle deposition in the alveoli and mechanisms removing particles that do make contact with the inner airway walls, as shown schematically in Figure 3.

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Figure 3: Schematic presentation of the components of the lung’s defence system against invading

particles.

For oral inhalation, inertial deposition in the mouth-throat region is the first interception mechanism. The efficacy of oropharyngeal deposition depends on particle properties, inhalation flow rate and direction, and anatomical factors (airway shape and dimensions) and can to a large extent be predicted with the impaction parameter (IP), being the product of the inhaled particle’s density (r), the square of its diameter (D) and its velocity (U): IP = ρ.D2_{.U (46).The role of} the anatomical factors as well as that of the variables expressed in the impaction parameter have been investigated extensively (e.g. (47-51)).

Deposition studies with monodisperse aerosols have shown that already substantial fractions of particles as small as 6 μm are deposited in the mouth and throat of stable asthmatics at moderate flow rates between 30 (approx. 40%) and 70 L/min (approx. 65%) (39). Also for polydisperse aerosols (e.g. from the Turbuhaler® with a carrier-free drug formulation), having a mass median aerodynamic diameter of only 2.5 μm at 60 L/min (34,37) between 53 and 72% deposition in the oropharynx has been reported (15,52). These data indicate that most particles larger than 3 to 5 μm from commonly marketed DPIs are removed from the inhaled air stream by inertial deposition in the mouth-throat area at flow rates considerably below 60 L/min. Therefore, particles inhaled at 60 L/min, or more, should preferably be smaller than 3 μm.

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Coughing is the immediate removal mechanism for particles deposited in the throat and upper airways area (45). A reflex cough occurs when airway afferent nerves are activated by the particle deposition. Coughing produces violent air expansion that creates turbulence and shear forces to extrude the foreign particles. When a cough reflex is observed as a response to the inhalation of a therapeutic aerosol, this may remove a substantial part of the inhaled dose from the upper respiratory tract.

The mucociliary apparatus or escalator is the second line of defence against intruding particles. It starts at the terminal bronchioles and exists of ciliated epithelium cells and a mucus film covering the epithelium produced by goblet cells. The viscous mucus film entraps inhaled particles and the cilia beat the mucus layer from the terminal bronchioles to the pharynx from where it is swallowed. There is limited consensus about the speed with which the cilia beat the mucus towards the pharynx in healthy subjects. The relevance of this speed reflects on the residence time of particles in the respiratory tract that is available for drug dissolution or release and absorption.

Various diseases and inhaled matter may influence the mucociliary clearance however, thereby changing not only the residence time of the drug in the respiratory tract but in many cases also the thickness and properties of the diffusion layer for the drug. Clearance rate may furthermore depend on the physico-chemical characteristics of the deposited particulate material (53). Finally, cilia movement may temporally be decreased by external factors, like exposure to cold air or industrial gasses associated with smog, like O₃, SO₂, NO₂ and NH₃ (54).

Tracheobronchial clearance may additionally include several slower processes, like (submicron) particle uptake into epithelial cells and phagocytosis by airway macrophages. As a result, significant particle fractions (up to 40%) of the inhaled dose can be retained in the tracheobronchial region after 24 hours (53).

Particles remaining airborne throughout the respiratory tract may end up in respiratory bronchioles, the alveolar ducts and sacs, and ultimately the alveoli where they can deposit by slow sedimentation or diffusion. In the lower tracheobronchial region (starting at generations 14 to 16) the number of ciliated cells and mucin secreting goblet cells gradually decreases and the clearance is taken over by macrophages.

Relatively little is known about the particle clearance rate and efficacy by alveolar macrophage. However, although it is known to depend on the size, shape, density, charge and hydrophilic/ lipophilic nature of the foreign matter (55).

Another factor influencing particle clearance rate is the mechanism that prompts alveolar macrophages to respond to an invasion of foreign particles. This mechanism, named chemotaxis, relies on a concentration gradient of external stimuli relating somehow to the source of infection and is dependent on the chemical composition of the stimuli (56). It is thus clear that the airways have very complex mechanisms to prevent a drug particle entering the systemic circulation.

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DISCUSSION AND CONCLUSIONS

As becomes clear from this overview, there are several uncertainties and difficulties when it comes to systemic delivery of inhaled drugs. Some of these uncertainties and difficulties have long prevented considering the pulmonary route suitable for the administration of systemically acting drugs. There still is poor recognition of the most favourable absorption site for the drug, whereas little is known about the fate of a particle after its deposition in the peripheral airways. Precise lung conditions of the patients using the pulmonary route for drug delivery are often unknown and there may be concerns about the patient’s compliance with the inhalation instruction and adherence to the therapy.

Regarding the choice for the type of delivery device there are good arguments to claim that DPIs offer the best possibilities for delivering drugs to the systemic circulation via the respiratory tract. Nevertheless, the performance of the classic DPI concept is clearly of insufficient quality. DPI improvement and reduction of various losses may be obtained from designing better drug formulations as well as from improving the inhaler concept, and to achieve optimal performance of the combination, simultaneous co-development is needed. In an abundance of studies, it has been shown that formulation technology has great potential for improving dispersion and increasing the delivered fine particle dose, but many of the approaches also have major drawbacks, particularly for high dose drugs. Various particle engineering processes increase the powder mass or volume to be inhaled. This may leave insufficient room for high-dose drugs, unless the number of inhalations for a single dose is increased, which is likely to deteriorate the patient’s motivation to perform successive inhalation manoeuvres correctly, and to adhere to the therapy. Some processes also yield less stable (amorphous) or hygroscopic powders. Spray drying may render further particle processing (e.g. pelletisation) impossible and many excipients, even though being approved by the FDA, should preferably not be inhaled because of the uncertainty of their long-term safety. Therefore, attempts to improve the design of DPI devices must have high priority and the improvements may come particularly from reducing the drug waste due to inhaler retention and oropharyngeal deposition.

The reduction of oropharyngeal deposition comes from delivering finer particles at a lower flow rate. This requires highly effective dispersion at a relatively low energy from the inhaled air stream and this puts high demands on the design of the powder dispersion principle. Assuming that the alveoli and respiratory bronchioles comprise the most important target area for systemically acting drugs, delivering of the entire dose within the first 0.5-1.0 litre of inhaled air is an additional requirement for DPI design. This makes fast and complete emptying of the dose (measuring) compartment necessary. In addition to all that, operating the inhaler correctly is equally important as inhaler design. Improper inhalation technique can cause a cascade of errors, including poor inhaler performance and drug deposition at the wrong site in the lung or even complete absence of lung deposition.

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Regarding the optimal site of deposition for systemically acting drugs, considerably more research is needed. In available literature, drug deposition in the alveoli is often considered mandatory for fast and complete drug permeation to the blood circulation. However, the respiratory bronchioles (approximate generations 16 to 22) have a very thin mucus layer, that is partly even absent. They also have a very thin epithelium and they contain possibly lower numbers of macrophages than the alveoli. Therefore, and because of the low velocity of the mucociliary escalator in the respiratory bronchioles, the clearance rate for deposited particles in this region is possibly low. Furthermore, the respiratory bronchioles, together with the alveoli, receive the entire cardiac output and with that they are the best perfused part of the human body (57). Hence, absorption via the bronchioles may be fast as well and deposition modelling studies show that there is a peak in the deposition probability in these bronchioles (58). From patient point of view, it would be very advantageous to have the respiratory bronchioles as main target area instead of the alveoli because this reduces the required inhalation volume considerably compared to what is needed for drug transport into the alveoli.

Several studies seem to confirm indeed that alveolar deposition may not always be necessary (6,59). In the study of Luinstra et al (6), levodopa peak plasma levels (C_max per mg of inhaled drug) appeared to show no correlation at all with the volume of air inhaled with the drug, whereas for the lowest volumes (< 2-2.5 L) convective drug delivery to the alveoli can be excluded. Neither the amount of drug absorbed (expressed as AUC per mg inhaled drug) showed a relationship with the inhaled air volume in which the aerosol was dispersed. Even the time to reach C_max (T_max) appeared to be independent of the drug penetration depth and be very short between 5 and 15 minutes for all inhaled volumes ranging from 1.1 to 4.2 litres (Fig. 4), showing that the absorption rate must have been independent of the drug distribution over the lungs.

Also inhaled loxapine has shown good systemic absorption via the respiratory tract without targeting specifically the alveoli and this suggests that for drugs of smaller size the deposition area may be less critical. This has a great effect on the required inhalation manoeuvre as it reduces the total volume of air to be inhaled by almost 50%, and this makes inhaling for the patient much easier. A good compliance with the inhalation instructions is more likely when the inhalation manoeuvre does not demand the utmost from the patient.

Targeting a very specific deposition site for many systemically acting drugs may not only appear to be unnecessary, it is impossible as well. Particle deposition in the respiratory tract is largely a random event, depending on how the particle travels through the tract and what position it takes upon entering an airway. Therefore, lung deposition is to a certain extent unpredictable and uncontrollable. This is confirmed by numerous deposition simulation studies (58) as well as by real deposition studies (39) with radiolabelled monodispersed particles. Such studies show that even particles of the same size are distributed over the entire lung. Distribution over a large area is further promoted by the release of the dose in a large volume of inhaled air. This brings some particles deeper in the lungs than others. Hence, targeting exclusively one particular lung region

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25 with classic inhaler technology is impossible. A complicating factor is de intra- and inter-patient variability. Age and disease related lung geometry make each individual patient unique, whereas the lung conditions of patients also vary with the severity of their disease, which may be from time to time. Also, for patients with a high residual volume (higher than the aveleolair volume), it is anyhow impossible to obtain convective aerosol transport to the alveoli. Therefore, designing tailor-made DPIs for individual patients seems rather meaningless.

1

Figure 4:

Cyclops DPI at 43.5 L/min (average flow rate).

Also inhaled loxapine has shown good systemic absorption

without targeting specifically the alveoli and this suggests that for drugs

the deposition area may be less

0 2 4 6 8 10 12 14 0 1 2 3 4 5 Cm ax -(n g/ m L) -p er -m g-del iver ed -do se-(DD) Inhaled-volume-(L) 30-mg-dose-Cmax/DD 60-mg-dose-Cmax/DD 0 100 200 300 400 500 600 700 800 900 0 1 2 3 4 5 AU C-(m in .n g/ m L)-p er --m g-del iver ed -d os e-(DD) Inhaled-volume-(L) 30-mg-dose-AUC/DD 60-mg-dose-AUC/DD 0 2 4 6 8 10 12 14 16 0 1 2 3 4 5 Tma x-( mi n) Inhaled-volume-(L) 30-mg-dose-Tmax 60-mg-dose-Tmax

Figure 4: Peak plasma concentrations (Cmax) (top), areas under the curve (AUC) (middle), both per mg

of delivered drug, and time to reach the peak plasma concentration (Tmax) (bottom) as function of the inhaled volume for levodopa from the Cyclops DPI at 43.5 L/min (average flow rate).

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(59) Hoppentocht M., Akkerman OW., Hagedoorn P., et al. Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Tobramycin Free Base in Non-Cystic Fibrosis Bronchiectasis Patients. PLoS ONE. 2016;11(3).

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29

CHAPTER

2

CAN PATIENTS WITH PARKINSON’S DISEASE USE DRY

POWDER INHALERS DURING OFF PERIODS?

M. Luinstra1,2*_{, A.W.F. Rutgers}3 _{, H. Dijkstra}2 _{, F. Grasmeijer}2 _{, P. Hagedoorn}2 _{, J.M.J. Vogelzang}1 _{, H.W.}

Frijlink2 _{, A.H. de Boer}2 _.

PLoS One. 2015 Jul 14;10(7):e0132714.

1_{Department of Clinical Pharmacy, Martini Hospital, Groningen, The Netherlands.}

2_{Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen,}

The Netherlands.

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ABSTRACT

Because of its rapid onset of action, pulmonary administration of levodopa is an interesting alternative to oral administration for the rescue treatment of Parkinson’s disease patients in an off period. We studied the ability of Parkinson’s disease patients to operate a dry powder inhaler (DPI) correctly during an off period. We used an instrumented test inhaler with three different resistances to air flow to record flow curves and computed various inhalation parameters. We observed that all 13 patients were able to generate pressure drops > 2 kPa over the highest resistance and 10 out of 13 patients achieved at least 4 kPa. Inhaled volumes (all resistances) varied from 1.2 L to 3.5 L. Total inhalation time and the time to peak inspiratory flow rate both decreased with decreasing inhaler resistance. Twelve out of thirteen patients could hold their breath for at least five seconds after inhalation and nine could extend this time to ten seconds. The data from this study indicate that patients with Parkinson’s disease will indeed be able to use a dry powder inhaler during an off period and they provide an adequate starting point for the development of a levodopa powder inhaler to treat this particular patient group.

Keywords

Clinical feasibility study; dry powder inhalation; inhalation manoeuvre; levodopa; off period; Parkinson’s disease; rescue treatment.

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31

INTRODUCTION

Parkinson’s disease is a degenerative disorder of the central nervous system, causing various movement related and psychiatric symptoms. Levodopa and dopamine agonists are effective in alleviating the motor symptoms of the disease, but a high variability in levodopa absorption from the gastrointestinal tract after oral administration causes fluctuations in the plasma concentration of the drug (1). In more advanced Parkinson’s patients, this often results in fluctuations between ‘on periods’, in which the Parkinson’s disease symptoms are well controlled, and ‘off periods’, in which the Parkinson’s disease symptoms are poorly controlled (2). Off periods are characterised by an extensive variety of complaints, such as decreased mobility, bradykinesia, tremor, autonomic symptoms, sensory symptoms and psychiatric disorders (3). A delayed onset of effect of levodopa after oral administration due to irregular gastrointestinal absorption can cause a delayed or even failing return of the motor function after an off period (4), which is a significant burden to patients.

Therefore, an increased, faster and more reproducible absorption for levodopa as that provided by the currently used oral medication is desired. Pulmonary administration may offer an attractive alternative to oral administration, due to its immediate presentation of the drug to the absorption membrane, the large size of the absorption membrane and relatively low metabolic activity in the lungs (5). The pulmonary epithelium can be targeted with inhaled drug aerosols, for instance, from a dry powder inhaler (DPI) (6). Previous studies in rats (7) have already shown a rapid onset of action after pulmonary administration of levodopa. This makes inhalation of the drug particularly interesting for the rescue treatment of Parkinson’s disease patients in an off period. From the storage stability point of view, a dry powder inhalation product is preferable over a nebulised formulation as levodopa in solution has a poor stability (8). However, correct operation of a passive DPI requires that the patient will be able to perform an appropriate inhalation manoeuvre, not only for adequate aerosol generation by the DPI, but also for good deposition of the aerosol in the target area. Therefore, the inspiratory flow manoeuvre performed by the patient is crucial for achieving the desired improvement in bioavailability.

Hardly anything is known about Parkinson’s disease patients’ abilities to operate a DPI. Especially in off periods, bradykinesia and rigidity might diminish the inspiratory muscle strength and, thereby, reduce the ability to use a DPI appropriately (9). This expectation is strengthened by the finding of Guedes et al (10) that the mean maximal inspiratory pressure (MIP) of Parkinson’s disease patients in an off period is lower than the MIP of healthy volunteers. Although the exact implications of this finding regarding the ability to operate DPIs are unclear, it does question the feasibility of rescue treatment by dry powder inhalation for Parkinson’s patients in an off period. For that reason, the aim of our study was to assess the ability of Parkinson’s disease patients to use a DPI suitable for the administration of a high dose of levodopa during an off period. For this study, a test inhaler with three different resistances to air flow around the resistance of the RUG’s Cyclops disposable DPI (11) was used. We monitored how the test inhaler was handled and we recorded the inspiratory flow rates generated by 13 Parkinson’s disease patients while they were in an off period. Flow rate and breath hold recordings were evaluated by comparing them with the requirements for adequate operation of the Cyclops as well as achieving efficient aerosol deposition.

CAN PATIENTS WITH PARKINSON’S DISEASE USE DRY POWDER INHALERS DURING OFF PERIODS?

University of Groningen Inhalable levodopa: from laboratory to the patient Luinstra, Marianne