Publications by authors named "Paul Hagedoorn"

41 Publications

The pharmacokinetics of antibiotics in cystic fibrosis.

Expert Opin Drug Metab Toxicol 2021 Jan 29;17(1):53-68. Epub 2020 Dec 29.

Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen , Groningen, The Netherlands.

Introduction: Dosing of antibiotics in people with cystic fibrosis (CF) is challenging, due to altered pharmacokinetics, difficulty of lung tissue penetration, and increasing presence of antimicrobial resistance.

Areas Covered: The purpose of this work is to critically review original data as well as previous reviews and guidelines on pharmacokinetics of systemic and inhaled antibiotics in CF, with the aim to propose strategies for optimization of antibacterial therapy in both children and adults with CF.

Expert Opinion: For systemic antibiotics, absorption is comparable in CF patients and non-CF controls. The volume of distribution (Vd) of most antibiotics is similar between people with CF with normal body composition and healthy individuals. However, there are a few exceptions, like cefotiam and tobramycin. Many antibiotic class-dependent changes in drug metabolism and excretion are reported, with an increased total body clearance for ß-lactam antibiotics, aminoglycosides, fluoroquinolones, and trimethoprim. We, therefore, recommend following class-specific guidelines for CF, mostly resulting in higher dosages per kg bodyweight in CF compared to non-CF controls. Higher local antibiotic concentrations in the airways can be obtained by inhalation therapy, with which eradication of bacteria may be achieved while minimizing systemic exposure and risk of toxicity.
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http://dx.doi.org/10.1080/17425255.2021.1836157DOI Listing
January 2021

Automated Filling Equipment Allows Increase in the Maximum Dose to Be Filled in the Cyclops High Dose Dry Powder Inhalation Device While Maintaining Dispersibility.

Pharmaceutics 2020 Jul 9;12(7). Epub 2020 Jul 9.

Department of Pharmaceutical Technology and Biopharmacy, Faculty of Science and Engineering, University of Groningen, 9700 AB Groningen, The Netherlands.

In recent years there has been increasing interest in the pulmonary delivery of high dose dry powder drugs, such as antibiotics. Drugs in this class need to be dosed in doses far over 2.5 mg, and the use of excipients should therefore be minimized. To our knowledge, the effect of the automatic filling of high dose drug formulations on the maximum dose that can be filled in powder inhalers, and on the dispersion behavior of the powder, have not been described so far. In this study, we aimed to investigate these effects after filling with an Omnidose, a vacuum drum filler. Furthermore, the precision and accuracy of the filling process were investigated. Two formulations were used-an isoniazid formulation we reported previously and an amikacin formulation. Both formulations could be precisely and accurately dosed in a vacuum pressure range of 200 to 600 mbar. No change in dispersion was seen after automatic filling. Retention was decreased, with an optimum vacuum pressure range found from 400 to 600 mbar. The nominal dose for amikacin was 57 mg, which resulted in a fine particle dose of 47.26 ± 1.72 mg. The nominal dose for isoniazid could be increased to 150 mg, resulting in a fine particle dose of 107.35 ± 13.52 mg. These findings may contribute to the understanding of the upscaling of high dose dry powder inhalation products.
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http://dx.doi.org/10.3390/pharmaceutics12070645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407802PMC
July 2020

Reply.

J Allergy Clin Immunol Pract 2020 03;8(3):1166-1167

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, the Netherlands; PureIMS B.V., Roden, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2019.11.023DOI Listing
March 2020

Copper-Heparin Inhalation Therapy To Repair Emphysema: A Scientific Rationale.

Int J Chron Obstruct Pulmon Dis 2019 25;14:2587-2602. Epub 2019 Nov 25.

Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, Groningen, University of Groningen, Groningen, The Netherlands.

Current pharmacotherapy of chronic obstructive pulmonary disease (COPD) aims at reducing respiratory symptoms and exacerbation frequency. Effective therapies to reduce disease progression, however, are still lacking. Furthermore, COPD medications showed less favorable effects in emphysema than in other COPD phenotypes. Elastin fibers are reduced and disrupted, whereas collagen levels are increased in emphysematous lungs. Protease/antiprotease imbalance has historically been regarded as the sole cause of emphysema. However, it is nowadays appreciated that emphysema may also be provoked by perturbations in the sequential repair steps following elastolysis. Essentiality of fibulin-5 and lysyl oxidase-like 1 in the elastin restoration process is discussed, and it is argued that copper deficiency is a plausible reason for failing elastin repair in emphysema patients. Since copper-dependent lysyl oxidases crosslink elastin as well as collagen fibers, copper supplementation stimulates accumulation of both proteins in the extracellular matrix. Restoration of abnormal elastin fibers in emphysematous lungs is favorable, whereas stimulating pulmonary fibrosis formation by further increasing collagen concentrations and organization is detrimental. Heparin inhibits collagen crosslinking while stimulating elastin repair and might therefore be the ideal companion of copper for emphysema patients. Efficacy and safety considerations may lead to a preference of pulmonary administration of copper-heparin over systemic administration.
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http://dx.doi.org/10.2147/COPD.S228411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884741PMC
August 2020

Dispersibility and Storage Stability Optimization of High Dose Isoniazid Dry Powder Inhalation Formulations with L-Leucine or Trileucine.

Pharmaceutics 2019 Dec 25;12(1). Epub 2019 Dec 25.

Department of Pharmaceutical Technology and Biopharmacy, Faculty of Science and Engineering, University of Groningen, 9700 AB Groningen, The Netherlands.

Tuberculosis is the leading cause of death from a single infectious pathogen worldwide. Lately, the targeted delivery of antibiotics to the lungs via inhalation has received increasing interest. In a previous article, we reported on the development of a spray-dried dry powder isoniazid formulation containing an L-leucine coating. It dispersed well but had poor physical stability. In this study, we aimed to improve the stability by improving the leucine coating. To this end, we optimized the spray-drying conditions, the excipient content, and the excipient itself. Using L-leucine, the tested excipient contents (up to 5%) did not result in a stable powder. Contrary to L-leucine, the stability attained with trileucine was satisfactory. Even when exposed to 75% relative humidity, the formulation was stable for at least three months. The optimal formulation contained 3% trileucine /. This formulation resulted in a maximum fine particle dose of 58.00 ± 2.56 mg when a nominal dose of 80 mg was dispersed from the Cyclops dry powder inhaler. The improved moisture protection and dispersibility obtained with trileucine are explained by its amorphous nature and a higher surface enrichment during drying. Dispersion efficiency of the device decreases at higher nominal doses.
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http://dx.doi.org/10.3390/pharmaceutics12010024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022271PMC
December 2019

Pulmonary immunization: deposition site is of minor relevance for influenza vaccination but deep lung deposition is crucial for hepatitis B vaccination.

Acta Pharm Sin B 2019 Nov 28;9(6):1231-1240. Epub 2019 May 28.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen 9713 AV, the Netherlands.

Vaccination the pulmonary route could be an attractive alternative to parenteral administration. Research towards the best site of antigen deposition within the lungs to induce optimal immune responses has conflicting results which might be dependent on the type of vaccine and/or its physical state. Therefore, in this study, we explored whether deep lung deposition is crucial for two different vaccines, .., influenza and hepatitis B vaccine. In view of this, influenza subunit vaccine and hepatitis B surface antigen were labeled with a fluorescent dye and then spray-dried. Imaging data showed that after pulmonary administration to mice the powders were deposited in the trachea/central airways when a commercially available insufflator was used while deep lung deposition was achieved when an in-house built aerosol generator was used. Immunogenicity studies revealed that comparable immune responses were induced upon trachea/central airways or deep lung targeting of dry influenza vaccine formulations. However, for hepatitis B vaccine, no immune responses were induced by trachea/central airways deposition whereas they were considerable after deep lung deposition. Thus, we conclude that deep lung targeting is not a critical parameter for the efficacy of pulmonary administered influenza vaccine whereas for hepatitis B vaccine it is.
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http://dx.doi.org/10.1016/j.apsb.2019.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900555PMC
November 2019

A comparative analysis of changes in pMDI drug dose delivery before and after detergent coating using five antistatic valved holding chambers.

J Allergy Clin Immunol Pract 2020 Mar 5;8(3):1124-1125.e4. Epub 2019 Oct 5.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, the Netherlands; PureIMS B.V., Roden, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2019.09.021DOI Listing
March 2020

Pharmacokinetics and tolerability of inhaled levodopa from a new dry-powder inhaler in patients with Parkinson's disease.

Ther Adv Chronic Dis 2019 21;10:2040622319857617. Epub 2019 Jun 21.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.

Background: Inhaled levodopa may quickly resolve off periods in Parkinson's disease. Our aim was to determine the pharmacokinetics and tolerability of a new levodopa dry-powder inhaler.

Methods: A single-centre, single-ascending, single-dose-response study was performed. Over three visits, eight Parkinson's disease patients (not in the 'off state') received by inhalation 30 mg or 60 mg levodopa, or their regular oral levodopa. Maximum levodopa plasma concentration ( ), time to maximum plasma concentration (T) and area under the concentration time curve 0-180 min were determined. Spirometry was performed three times at each visit.

Results: After inhalation, levodopa occurred within 15 min in all participants, whereas after oral administration, ranged from 20 min to 90 min. The bioavailability of inhaled levodopa without carboxylase inhibitor was 53% relative to oral levodopa with carboxylase inhibitor. No change in lung-function parameters was observed and none of the patients experienced cough or dyspnoea. No correlation was observed between inhalation parameters and levodopa pharmacokinetic parameters.

Conclusion: Inhaled levodopa is well tolerated, absorbed faster than oral levodopa, and can be robustly administered over a range of inhalation flow profiles. It therefore appears suitable for the treatment of off periods in Parkinson's disease.
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http://dx.doi.org/10.1177/2040622319857617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589987PMC
June 2019

Characterization and Formulation of Isoniazid for High-Dose Dry Powder Inhalation.

Pharmaceutics 2019 May 13;11(5). Epub 2019 May 13.

Department of Pharmaceutical Technology and Biopharmacy, Faculty of Science and Engineering, University of Groningen, 9700 AB Groningen, The Netherlands.

Tuberculosis is a major health problem and remains one of the main causes of mortality. In recent years, there has been an increased interest in the pulmonary delivery of antibiotics to treat tuberculosis. Isoniazid is one of these antibiotics. In this study, we aimed to characterize isoniazid and formulate it into a dry powder for pulmonary administration with little or no excipient, and for use in the disposable Twincer inhaler. Isoniazid was jet milled and spray dried with and without the excipient l-leucine. Physiochemical characterization showed that isoniazid has a low Tg of -3.99 ± 0.18 °C and starts to sublimate around 80 °C. Milling isoniazid with and without excipients did not result in a suitable formulation, as it resulted in a low and highly variable fine particle fraction. Spray drying pure isoniazid resulted in particles too large for pulmonary administration. The addition of 5% l-leucine resulted in a fraction <5 µm = 89.61% ± 1.77% from spray drying, which dispersed well from the Twincer. However, storage stability was poor at higher relative humidity, which likely results from dissolution-crystallization. Therefore, follow up research is needed to further optimize this spray dried formulation.
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http://dx.doi.org/10.3390/pharmaceutics11050233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572553PMC
May 2019

Associations of AMP and adenosine induced dyspnea sensation to large and small airways dysfunction in asthma.

BMC Pulm Med 2019 Jan 28;19(1):23. Epub 2019 Jan 28.

Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, PO box 30.0001, 9700, RB, Groningen, The Netherlands.

Background: Bronchial provocation is often used to confirm asthma. Dyspnea sensation, however, associates poorly with the evoked drop in FEV. Provocation tests only use the large airways parameter FEV, although dyspnea is associated with both large- and small airways dysfunction. Aim of this study was to explore if adenosine 5'-monophosphate (AMP) and adenosine evoke an equal dyspnea sensation and if dyspnea associates better with large or small airways dysfunction.

Methods: We targeted large airways with AMP and small airways with dry powder adenosine in 59 asthmatic (ex)-smokers with ≥5 packyears, 14 ± 7 days apart. All subjects performed spirometry, impulse oscillometry (IOS), and Borg dyspnea score. In 36 subjects multiple breath nitrogen washout (MBNW) was additionally performed. We analyzed the association of the change (Δ) in Borg score with the change in large and small airways parameters, using univariate and multivariate linear regression analyses. MBNW was analyzed separately.

Results: Provocation with AMP and adenosine evoked similar levels of dyspnea. ΔFEV was not significantly associated with ΔBorg after either AMP or adenosine provocation, in both univariate and multivariate analyses. In multivariate linear regression, a decrease in FEF during adenosine provocation was independently associated with an increase in Borg. In the multivariate analyses for AMP provocation, no significant associations were found between ΔBorg and any large or small airways parameters.

Conclusion: AMP and adenosine induce equally severe dyspnea sensations. Our results suggest that dyspnea induced with dry powder adenosine is related to small airways involvement, while neither large nor small airways dysfunction was associated with AMP-induced dyspnea.

Trail Registration: NCT01741285 at www.clinicaltrials.gov , first registered Dec 4th, 2012.
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http://dx.doi.org/10.1186/s12890-019-0783-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348600PMC
January 2019

Predictors of clinical response to extrafine and non-extrafine particle inhaled corticosteroids in smokers and ex-smokers with asthma.

Respir Res 2018 Dec 18;19(1):256. Epub 2018 Dec 18.

Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, PO Box 30.0001, 9700, RB, Groningen, The Netherlands.

We performed a post-hoc analysis of the OLiVIA-study investigating whether current and ex-smoking asthmatics with small airways dysfunction (SAD) show a better response in airway hyperresponsiveness (AHR) to small particle adenosine after treatment with extrafine compared to non-extrafine particle inhaled corticosteroids (ICS), and to investigate which clinical parameters predict a favorable response to both treatments. We show that smoking and ex-smoking asthmatics with and without SAD have a similar treatment response with either extrafine or non-extrafine particle ICS. We also found that lower blood neutrophils are associated with a smaller ICS-response in smokers and ex-smokers with asthma, independent from the level of blood eosinophils.
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http://dx.doi.org/10.1186/s12931-018-0961-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299530PMC
December 2018

Challenges for pulmonary delivery of high powder doses.

Int J Pharm 2018 Sep 2;548(1):325-336. Epub 2018 Jul 2.

Department of Pharmaceutical Technology and Biopharmacy, Faculty of Science and Engineering, University of Groningen, Groningen, The Netherlands.

In recent years there is an increasing interest in the pulmonary delivery of large cohesive powder doses, i.e. drugs with a low potency such as antibiotics or drugs with a high potency that need a substantial fraction of excipient(s) such as vaccines stabilized in sugar glasses. The pulmonary delivery of high powder doses comes with unique challenges. For low potency drugs, the use of excipients should be minimized to limit the powder mass to be inhaled as much as possible. To achieve this objective the inhaler design should be adapted to the properties of the API in order to achieve a compatible combination of the drug formulation and inhaler device. The inhaler should have an appropriate powder dosing principle for which prefilled compartments seem most appropriate. The drug formulation should not only allow for accurate filling of these compartments but also enable efficient compartment emptying during inhalation. The dispersion principle must have the capacity to disperse considerable amounts of powder in a short time frame that allows the powder to reach the deep lung. Last, but not least, the inhaler should be simple and intuitive in use, be cost-effective and exhibit accurate and consistent, preferably patient independent, pulmonary delivery performance.
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http://dx.doi.org/10.1016/j.ijpharm.2018.07.008DOI Listing
September 2018

Extrafine compared to non-extrafine particle inhaled corticosteroids in smokers and ex-smokers with asthma.

Respir Med 2017 Sep 8;130:35-42. Epub 2017 Jul 8.

University of Groningen, University Medical Centre Groningen, Department of Pulmonary Diseases, PO Box 30.0001, 9700 RB Groningen, The Netherlands; University of Groningen, University Medical Centre Groningen, Groningen Research Institute for Asthma and COPD, PO Box 30.0001, 9700 RB Groningen, The Netherlands. Electronic address:

Background: Smoking is as prevalent in asthmatics as in the general population. Asthmatic smokers benefit less from inhaled corticosteroids (ICS) than non-smoking asthmatics, possibly due to more smoking-induced small airways disease. Thus targeting small airways may be important in treating asthmatic (ex-)smokers. We hypothesized that extrafine particle ICS improve small airways function more than non-extrafine particle ICS in asthmatic (ex-)smokers.

Methods: We performed an open-label, randomized, three-way cross-over study comparing extrafine beclomethasone (HFA-QVAR) to non-extrafine beclomethasone (HFA-Clenil) and fluticasone (HFA-Flixotide) in 22 smokers and 21 ex-smokers with asthma (?5 packyears).

Results: Improvement from baseline in PD adenosine after using QVAR, Clenil or Flixotide was 1.04 ± 1.71, 1.09 ± 2.12 and 0.94 ± 1.97 doubling doses, mean ± standard deviation (SD), respectively. The change from baseline in R-R at PD adenosine after using QVAR, Clenil or Flixotide was ?0.02 ± 0.27, 0.02 ± 0.21, and ?0.02 ± 0.31 kPa sL, mean ± SD, respectively. The change in PD adenosine and R-R at PD adenosine were neither statistically significant different between QVAR and Clenil (p = 0.86 and p = 0.82) nor between QVAR and Flixotide (p = 0.50 and p = 0.96).

Conclusion: Similar effectiveness in improving small airways function was found for extrafine and non-extrafine particle ICS treatment for asthmatic smokers and ex-smokers.
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http://dx.doi.org/10.1016/j.rmed.2017.07.005DOI Listing
September 2017

Targeting the small airways with dry powder adenosine: a challenging concept.

Eur Clin Respir J 2017 6;4(1):1369328. Epub 2017 Sep 6.

Department of Pulmonary Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

: Small-particle inhaled corticosteroids (ICS) provide a higher small airway deposition than large-particle ICS. However, we are still not able to identify asthma patients who will profit most from small-particle treatment. : We aimed to identify these patients by selectively challenging the small and large airways. We hypothesized that the airways could be challenged selectively using small- and large-particle adenosine, both inhaled at a high and a low flow rate. : In this cross-over study 11 asthma subjects performed four dry powder adenosine tests, with either small (MMAD 2.7 µm) or large (MMAD 6.0 µm) particles, inhaled once with a low flow rate (30 l min) and once with a high flow rate (60 l min). Spirometry and impulse oscillometry were performed after every bronchoprovocation step. We assumed that FEV reflects the large airways, and FEF, R5-R20 and X5 reflect the small airways. : The four adenosine tests were not significantly different with respect to the threshold values of FEV ( = 0.12), FEF ( = 0.37), R5-R20 ( = 0.60) or X5 ( = 0.46). Both small- and large-particle adenosine induced a response in the small airways in the majority of the tests. : In contrast to our hypothesis, all four adenosine tests provoked a response in the small airways and we could not identify different large- or small-airway responders. Interestingly, even the test with large particles and a high flow rate induced a small-airway response, suggesting that selective challenging of the small airways is not necessary. Future studies should investigate the relation between particle deposition and the site of an airway response.
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http://dx.doi.org/10.1080/20018525.2017.1369328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642194PMC
September 2017

Prerequisites for a dry powder inhaler for children with cystic fibrosis.

PLoS One 2017 11;12(8):e0183130. Epub 2017 Aug 11.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.

Correct inhalation technique is essential for effective use of dry powder inhalers (DPIs), as their effectiveness largely depends on the patient's inhalation manoeuvre. Children are an especially challenging target population for DPI development due to the large variability in understanding and inspiratory capacities. We previously performed a study in which we determined the prerequisites for a paediatric DPI in a mostly healthy paediatric population, for which we used an empty test inhaler with variable internal airflow resistance and mouthpiece. In the current study we investigated what specifications are required for a DPI for children with cystic fibrosis (CF), for which we expanded on our previous findings. We recorded flow profiles of 35 children with CF (aged 4.7-14.7 years) at three airflow resistances (0.031-0.045 kPa0.5.min.L-1) from which various inspiratory parameters were computed. Obstructions in the mouth during inhalation were recorded with a sinuscope. All children were able to perform a correct inhalation manoeuvre, although video analysis showed that children did not place the inhaler correctly in the mouth in 17% of the cases. No effect was found of medium to high airflow resistance on total inhaled volume, which implies that the whole resistance range tested is suitable for children with CF aged 4-14 years. No effect could be established of either mouthpiece design or airflow resistance on the occurrence of obstructions in the mouth cavity. This study confirms our previous conclusion that the development of DPIs specifically for children is highly desired. Such a paediatric DPI should function well at 0.5 L inhaled volume and a peak inspiratory flow rate of 20 to 30 L/min, depending on the internal airflow resistance. This resistance can be increased up to 0.045 kPa0.5.min.L-1 (medium-high) to reduce oropharyngeal deposition. A higher resistance may be less favourable due to its compromising effect on PIF and thereby on the energy available for powder dispersion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183130PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553717PMC
October 2017

Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Tobramycin Free Base in Non-Cystic Fibrosis Bronchiectasis Patients.

PLoS One 2016 9;11(3):e0149768. Epub 2016 Mar 9.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, the Netherlands.

Rationale: Bronchiectasis is a condition characterised by dilated and thick-walled bronchi. The presence of Pseudomonas aeruginosa in bronchiectasis is associated with a higher hospitalisation frequency and a reduced quality of life, requiring frequent and adequate treatment with antibiotics.

Objectives: To assess local tolerability and the pharmacokinetic parameters of inhaled excipient free dry powder tobramycin as free base administered with the Cyclops dry powder inhaler to participants with non-cystic fibrosis bronchiectasis. The free base and absence of excipients reduces the inhaled powder dose.

Methods: Eight participants in the study were trained in handling the device and inhaling correctly. During drug administration the inspiratory flow curve was recorded. Local tolerability was assessed by spirometry and recording adverse events. Serum samples were collected before, and 15, 30, 45, 60, 75, 90, 105, 120 min; 4, 8 and 12 h after inhalation.

Results And Discussion: Dry powder tobramycin base was well tolerated and mild tobramycin-related cough was reported only once. A good drug dose-serum concentration correlation was obtained. Relatively small inhaled volumes were computed from the recorded flow curves, resulting in presumably substantial deposition in the central airways-i.e., at the site of infection.

Conclusions: In this first study of inhaled dry powder tobramycin free base in non-cystic fibrosis bronchiectasis patients, the free base of tobramycin and the administration with the Cyclops dry powder device were well tolerated. Our data support further clinical studies to evaluate safety and efficacy of this compound in this population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149768PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784940PMC
August 2016

A levodopa dry powder inhaler for the treatment of Parkinson's disease patients in off periods.

Eur J Pharm Biopharm 2015 Nov 13;97(Pt A):22-9. Epub 2015 Oct 13.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Ant. Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Adequate treatment of Parkinson's patients in off periods with orally administered levodopa is hindered by a poor bioavailability and a slow onset of action. Hence, there is a need for a fast and reliable alternative as for instance via pulmonary administration of the drug. We developed a levodopa containing powder formulation for pulmonary delivery by a recently presented high dose dry powder inhaler (Cyclops). The objective was to produce the drug formulation by means of simple techniques such as micronization, either as pure active substance or with a minimum amount of excipients. After an initial screening on dispersion behaviour, the most promising formulation in the Cyclops was characterized in vitro over a range of pressure drops (2-6 kPa) and doses (20, 30 and 40 mg), representative of those to be expected in practice. A co-micronized levodopa formulation with 2% L-leucine appeared to yield the best aerosol properties for inhalation and highest delivered dose reproducibility. The combination of this particular formulation and the Cyclops inhaler seems to meet the basic requirements for satisfactory deposition in the airways. This formulation is therefore expected to be a promising candidate for the treatment of Parkinson's patients in an off period.
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http://dx.doi.org/10.1016/j.ejpb.2015.10.003DOI Listing
November 2015

Recent advances in the fundamental understanding of adhesive mixtures for inhalation.

Curr Pharm Des 2015 ;21(40):5900-14

University of Groningen, Department of Pharmaceutical Technology and Biopharmacy, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Adhesive mixtures for inhalation are the most widely used type of formulation in dry powder inhalation products. Although they have been the subject of active research, the relationships between properties of the starting materials, the mixing and dispersion processes, and the dispersion performance of this type of formulation are generally poorly understood. Interactions between relevant variables have been mentioned as an important cause. By reviewing the effects on mixture dispersion performance of the most widely studied formulation variables we try to find out whether or not the understanding of adhesive mixtures has improved in recent years. We furthermore propose an approach that may potentially accelerate the process of understanding. General conclusions concerning the effects of the variables considered cannot be drawn, because inconsistent findings are reported throughout the literature for all of them. These inconsistencies are indeed largely the result of interactions between variables of the formulation and dispersion processes. Mechanisms for most of the observed effects and interactions have been proposed, but they often remain unproven and, therefore, speculative. We have attempted to condense the knowledge from the literature into a theoretical framework that is intended to help explain the interplay between variables. According to this framework, only few mixture properties are key to understanding the effects of and interactions between formulation variables. Therefore, we suggest that the development or optimisation of techniques to accurately characterise these mixture properties could be an effective approach to further the fundamental understanding of adhesive mixtures for inhalation and enable their rational engineering.
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http://dx.doi.org/10.2174/1381612821666151008124622DOI Listing
September 2016

Can 'extrafine' dry powder aerosols improve lung deposition?

Eur J Pharm Biopharm 2015 Oct 26;96:143-51. Epub 2015 Jul 26.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Ant. Deusinglaan 1, Groningen, The Netherlands.

There is increasing interest in the use of so-called 'extrafine' aerosols to target the small airways in the management of asthma and COPD. Using previously presented deposition data, we assessed whether submicron (<1μm) particles can improve central and deep lung deposition. Our data show instead that particles in the range 1-3μm are much more relevant in this respect. Based on this finding the Symbicort Turbuhaler, Seretide Diskus, Rolenium Elpenhaler and Foster (Fostair) NEXThaler ICS/LABA combination DPIs were tested in vitro as a function of the pressure drop (2, 4 and 6kPa) across the inhaler. Obtained fine particle fractions (FPFs) <5μm (as percent of label claim) were divided into subfractions <1, 1-3 and 3-5μm. Differences of up to a factor of 4 were found between the best (Turbuhaler) and worst performing DPI (Elpenhaler), particularly for the FPF in the size range 1-3μm. The NEXThaler, described as delivering 'extrafine' particles, did not appear to be superior in this size range. The marked differences in amount and size distribution of the aerosols between the devices in this study must cause significant differences in the total lung dose and drug distribution over the airways.
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http://dx.doi.org/10.1016/j.ejpb.2015.07.016DOI Listing
October 2015

The role of disposable inhalers in pulmonary drug delivery.

Expert Opin Drug Deliv 2015 Jan 6;12(1):143-57. Epub 2014 Nov 6.

University of Groningen, Department of Pharmaceutical Technology and Biopharmacy , Ant. Deusinglaan 1, 9713 AV Groningen , The Netherlands

Introduction: There is increasing interest in the pulmonary route for both local and systemically acting drugs, vaccines and diagnostics and new applications may require new inhaler technology to obtain the most therapeutically and/or cost-effective administration. Some of these new applications can benefit from the use of disposable inhalers.

Areas Covered: Current trends in pulmonary drug delivery are presented in this review as well as the possible contribution of disposable inhalers to the improvement of pulmonary administration therein. Arguments in favour of disposable inhalers and the starting points for development of devices and their formulations are discussed. Also, a brief review of the state of the art regarding current disposable inhaler development is given.

Expert Opinion: Prerequisites for the use of disposable inhalers, particularly dry powder inhalers, in applications such as childhood vaccination and for preventing or stopping pandemic outbreaks of highly infectious diseases (like influenza, bird flu, SARS) are that they are simple, cheap and effective. Not only do the devices have to be simple in design, but the drug formulations should also be cheap. This may require a different approach as the formulation may not need to be adapted to improve the inhaler must be designed to enhance formulation dispersion.
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http://dx.doi.org/10.1517/17425247.2014.952626DOI Listing
January 2015

The clinical relevance of dry powder inhaler performance for drug delivery.

Respir Med 2014 Aug 24;108(8):1195-203. Epub 2014 May 24.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Ant. Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Background: Although understanding of the scientific basis of aerosol therapy with dry powder inhalers (DPIs) has increased, some misconceptions still persist. These include the beliefs that high resistance inhalers are unsuitable for some patients, that extra fine (<1.0 μm) particles improve peripheral lung deposition and that inhalers with flow rate-independent fine particle fractions (FPFs) produce a more consistent delivered dose to the lungs.

Objectives: This article aims to clarify the complex inter-relationships between inhaler design and resistance, inspiratory flow rate (IFR), FPF, lung deposition and clinical outcomes, as a better understanding may result in a better choice of DPI for individual patients.

Methods: The various factors that determine the delivery of drug particles into the lungs are reviewed. These include aerodynamic particle size distribution, the inspiratory manoeuvre, airway geometry and the three basic principles that determine the site and extent of deposition: inertial impaction, sedimentation and diffusion. DPIs are classed as either dependent or independent of inspiratory flow rate and vary in their internal resistance to inspiration. The effects of these characteristics on drug deposition in the airways are described using data from studies directly comparing currently available inhaler devices.

Results: Clinical experience shows that most patients can use a high resistance DPI effectively, even during exacerbations. Particles in the aerodynamic size range from 1.5-5 μm are shown to be optimal, as particles <1.0 μm are very likely to be exhaled again while those >5 μm may impact on the oropharynx. For DPIs with a constant FPF at all flow rates, less of the delivered dose reaches the central and peripheral lung when the flow rate increases, risking under-dosing of the required medication. In contrast, flow rate-dependent inhalers increase their FPF output at higher flow rates, which compensates for the greater impaction on the upper airways as flow rate increases.

Conclusions: The technical characteristics of different inhalers and the delivery and deposition of the fine particle dose to the lungs may be important additional considerations to help the physician to select the most appropriate device for the individual patient to optimise their treatment.
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http://dx.doi.org/10.1016/j.rmed.2014.05.009DOI Listing
August 2014

Effect of inhaler design variables on paediatric use of dry powder inhalers.

PLoS One 2014 5;9(6):e99304. Epub 2014 Jun 5.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.

Age appropriateness is a major concern of pulmonary delivery devices, in particular of dry powder inhalers (DPIs), since their performance strongly depends on the inspiratory flow manoeuvre of the patient. Previous research on the use of DPIs by children focused mostly on specific DPIs or single inspiratory parameters. In this study, we investigated the requirements for a paediatric DPI more broadly using an instrumented test inhaler. Our primary aim was to assess the impact of airflow resistance on children's inspiratory flow profiles. Additionally, we investigated children's preferences for airflow resistance and mouthpiece design and how these relate to what may be most suitable for them. We tested 98 children (aged 4.7-12.6 years), of whom 91 were able to perform one or more correct inhalations through the test inhaler. We recorded flow profiles at five airflow resistances ranging from 0.025 to 0.055 kPa0.5.min.L-1 and computed various inspiratory flow parameters from these recordings. A sinuscope was used to observe any obstructions in the oral cavity during inhalation. 256 flow profiles were included for analysis. We found that both airflow resistance and the children's characteristics affect the inspiratory parameters. Our data suggest that a medium-high resistance is both suitable for and well appreciated by children aged 5-12 years. High incidences (up to 90%) of obstructions were found, which may restrict the use of DPIs by children. However, an oblong mouthpiece that was preferred the most appeared to positively affect the passageway through the oral cavity. To accommodate children from the age of 5 years onwards, a DPI should deliver a sufficiently high fine particle dose within an inhaled volume of 0.5 L and at a peak inspiratory flow rate of 25-40 L.min-1. We recommend taking these requirements into account for future paediatric inhaler development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099304PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047113PMC
October 2015

Adenosine dry powder inhalation for bronchial challenge testing, part 2: proof of concept in asthmatic subjects.

Eur J Pharm Biopharm 2014 Sep 26;88(1):148-52. Epub 2014 Apr 26.

University of Groningen, Department of Pharmaceutical Technology and Biopharmacy, Groningen, The Netherlands. Electronic address:

Adenosine is an indirect stimulus to assess bronchial hyperresponsiveness (BHR(2)) in asthma. Bronchial challenge tests are usually performed with nebulised solutions of adenosine 5'-monophosphate (AMP(3)). The nebulised AMP test has several disadvantages, like long administration times and a restrictive maximum concentration that does not result in BHR in all patients. In this study, we investigated the applicability of dry powder adenosine for assessment of BHR in comparison to nebulised AMP. Dry powder adenosine was prepared in doubling doses (0.01-80 mg) derived from the nebulised AMP test with addition of two higher doses. Five asthmatic subjects performed two bronchial challenge tests, one with nebulised AMP following the 2-min tidal breathing method; the second with dry powder adenosine administered with an investigational inhaler and single slow inhalations (inspiratory flow rate 30-40 L/min). All subjects reached a 20% fall in FEV₁(4) with the new adenosine test (PD20(5)) compared to four subjects with the AMP test (PC₂₀(6)). Dry powder adenosine was well tolerated by all subjects and better appreciated than nebulised AMP. In conclusion, this new bronchial challenge test appears to be a safe and convenient alternative to the nebulised AMP test to assess BHR in asthmatic subjects.
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http://dx.doi.org/10.1016/j.ejpb.2014.04.008DOI Listing
September 2014

New mechanisms to explain the effects of added lactose fines on the dispersion performance of adhesive mixtures for inhalation.

PLoS One 2014 28;9(1):e87825. Epub 2014 Jan 28.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.

Fine excipient particles or 'fines' have been shown to improve the dispersion performance of carrier-based formulations for dry powder inhalation. Mechanistic formulation studies have focussed mainly on explaining this positive effect. Previous studies have shown that higher drug contents may cause a decrease in dispersion performance, and there is no reason why this should not be true for fines with a similar shape, size and cohesiveness as drug particles. Therefore, the effects on drug detachment of 'fine lactose fines' (FLF, X50 = 1.95 µm) with a similar size and shape as micronised budesonide were studied and compared to those of 'coarse lactose fines' (CLF, X50 = 3.94 µm). Furthermore, interactions with the inhalation flow rate, the drug content and the mixing order were taken into account. The observed effects of FLF are comparable to drug content effects in that the detached drug fraction was decreased at low drug content and low flow rates but increased at higher flow rates. At high drug content the effects of added FLF were negligible. In contrast, CLF resulted in higher detached drug fractions at all flow rates and drug contents. The results from this study suggest that the effects of fines may be explained by two new mechanisms in addition to those previously proposed. Firstly, fines below a certain size may increase the effectiveness of press-on forces or cause the formation of strongly coherent fine particle networks on the carrier surface containing the drug particles. Secondly, when coarse enough, fines may prevent the formation of, or disrupt such fine particle networks, possibly through a lowering of their tensile strength. It is recommended that future mechanistic studies are based on the recognition that added fines may have any effect on dispersion performance, which is determined by the formulation and dispersion conditions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087825PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905031PMC
November 2014

Adenosine dry powder inhalation for bronchial challenge testing, part 1: inhaler and formulation development and in vitro performance testing.

Eur J Pharm Biopharm 2014 Jan 17;86(1):105-14. Epub 2013 Oct 17.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands. Electronic address:

Dry powder administration of adenosine by use of an effective inhaler may be an interesting alternative to nebulisation of adenosine 5'-monophosphate in bronchial challenge testing, because of a shorter administration time and more consistent delivered fine particle dose over the entire dose range. In this study, we tested various powder formulations and classifier based dispersion principles and investigated the in vitro performance of the most promising formulation/classifier combination in a new test inhaler system. Spray-dried formulations of either pure adenosine (100%) or adenosine and lactose as diluent (1% and 10% adenosine) were prepared to cover the entire expected dose range for adenosine (0.01-20mg). All three powders, in all 12 suggested doses, dispersed well with the newly developed test inhaler with a multiple air jet classifier disperser, into aerosols with an average volume median diameter of 3.1μm (3.0-3.3μm). For eleven out of 12 dose steps, the fine particle fractions<5μm as percent of the loaded dose varied within the range of 67-80% (mean: 74%). The new test concept allows for more consistent aerosol delivery over the entire dose range with narrower size distributions than nebulisation and thus may improve adenosine administration in bronchial challenge testing.
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http://dx.doi.org/10.1016/j.ejpb.2013.06.027DOI Listing
January 2014

Drug content effects on the dispersion performance of adhesive mixtures for inhalation.

PLoS One 2013 14;8(8):e71339. Epub 2013 Aug 14.

Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.

The drug content in adhesive mixtures for inhalation is known to influence their dispersion performance, but the direction and magnitude of this influence depends on other variables. In the past decades several mechanisms have been postulated to explain this finding and a number of possible interacting variables have been identified. Still, the role of drug content in the formulation of adhesive mixtures for inhalation, which includes its significance as an interacting variable to other parameters, is poorly understood. Therefore, the results from a series of drug detachment experiments are presented in which the effect of drug content and its dependence on flow rate, the mixing time and the type of drug is studied. Furthermore, it is investigated whether the effect depends on the range within which the drug content is changed. Quantitative and qualitative multiple order interactions are observed between these variables, which may be explained by a shifting balance between three different mechanisms. The results therefore demonstrate that accounting for (multiple order) interactions between variables has to be part of quality by design activities and the rational design of future experiments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071339PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743805PMC
March 2014
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