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Introduction: The manufacture of modern dry powder inhalers (DPIs), starting with the Spinhaler (Fisons) in 1967, was only possible thanks to a series of technological developments in the 20th century, of which many started first around 1950. Not until then, it became possible to design and develop effective, cheap and mass-produced DPIs. The link between these technological developments and DPI development has never been presented and discussed before in reviews about the past and present of DPI technology. Areas covered: The diversity of currently used DPIs with single dose, multiple-unit dose and multi-dose DPIs is discussed, including the benefits and drawbacks of this diversity for correct use and the efficacy of the therapy. No specific databases or search engines otherwise than PubMed and Google have been used. Expert opinion: Considering the relatively poor efficacy regarding lung deposition of currently used DPIs, the high rates of incorrect inhaler use and inhalation errors and the poor adherence to the therapy with inhalers, much effort must be put in improving these shortcomings for future DPI designs. Delivered fine particle doses must be increased, correct inhaler handling must become more intuitive and simpler to perform, and the use of multiple inhalers must be avoided.

Introduction: Inhalation of herbs and other compounds has a long history but habits for medical treatment are intertwined with rituals to obtain hallucinatory effects and pleasurable sensations. Several examples of inhaled herbs, and the diseases they were used for, based on early translations of ancient manuscripts related to inhalation were found to be speculative and inconsistent with each other in literature. They needed to be reconsidered and verified with the original sources of information. Areas covered: Examples of ancient inhalation and the development of early dry powder inhalers up to and including the first half of the twentieth century. Databases used for literature about historic events, ancient habits, and ancient science, included SmartCat, JSTOR, and ANDAT; various facts were verified via personal communication with historians and custodians of historic manuscripts and artifacts. Expert opinion: Inhalation does not necessarily require active creation of inhalable aerosols, smokes or fumes. Inhaling ‘healthy air’ with volatile and gaseous components, or fine aerosols in pine forests, on volcano slopes and at the seaside must be considered as inhalation therapy too. From this viewpoint, inhalation therapy may have been much more common and widespread and have a longer history than is currently known from written evidence.

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.

RationaleInhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing for higher and therefore more effective pulmonary concentrations without dose limiting toxic effects.ObjectivesTo assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler.Methods12healthy volunteers were trained in inhaling HCQ correctly. Local tolerability and safety were assessed by pulmonary function tests, ECG and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation.Results and discussionDry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1post inhalation. The serum HCQ concentration remained below 10 µg/L in all samples.ConclusionInhaled dry powder HCQ is safe and well tolerated. Our data support further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy is warranted.

BACKGROUND: Nebulization of antimicrobial drugs such as tobramycin and colistin is a cornerstone in the treatment of patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa. However, nebulization has a high treatment burden. The Twincer™ is a dry powder inhaler specifically developed for the inhalation of antibiotics such as colistin. The aim of this study was to compare patient outcomes and experience with colistin dry powder by the Twincer with nebulization of colistin or tobramycin in adult CF patients in a real-life setting.METHODS: This was a retrospective study from 01-01-2015 until 01-07-2018. Effectiveness was evaluated by comparing FEV1 decline and exacerbation rate during a mean of 4.1 years of nebulization therapy prior to the initiation of the Twincer against the same values during a mean of 1.7 years of treatment with the Twincer.RESULTS: Twenty-one patients were evaluated, of whom twelve could be included in the effectiveness analysis, with a total of twenty patient years. Of all patients 71.4% preferred therapy with the Twincer over nebulization. Twincer use resulted in high treatment adherence with an average adherence rate of 92.5%. There was no significant difference in annual decline in FEV1%pred prior to and after start changing from nebulization to the use of the Twincer powder inhaler (median decline -1.56 [-5.57-5.31] and 1.35 [-8.45-6.36]) respectively, p = 0.45 (linear mixed effect model)). No significant difference was found in the number of intravenous or combined total intravenous and oral antibiotic courses during Twincer therapy compared to when using nebulization (1.68 and 2.49 courses during Twincer therapy versus 1.51 and 2.94 courses during nebulization, p = 0.88 and p = 0.63).CONCLUSION: Colistin dry powder inhalation with the Twincer is a more patient friendly alternative to nebulization, and we did not observe significant differences in the clinical outcome, regarding lung function and exacerbation rates.

Background: valved holding chambers are known to be non-interchangeable, but their antistatic counterparts are generally regarded as equally antistatic. Methods: in this study we test this supposition by measuring the in vitro delivered doses of salbutamol (Ventolin®) and beclomethasone (Qvar®) from five antistatic valved holding chambers (Aerochamber PlusTM Flow-VuTM, Compact Space Chamber PlusTM, InspiraChamberTM, OptiChamber DiamondTM and VortexTM) used without (i.e. ‘rinsed’) and with a detergent coating (i.e. ‘drip dried’). Results: delivered doses of salbutamol and beclomethasone from the Compact Space Chamber PlusTM and InspiraChamberTM are improved by up to a factor two by drip drying, indicating that the antistatic properties of these antistatic valved holding chambers are suboptimal. Drip drying of the Aerochamber PlusTM Flow-VuTM, OptiChamber DiamondTM and VortexTM on the other hand did not significantly affect the delivered doses of both drugs from these devices, indicating that their antistatic properties are optimal. Of the latter three, the delivered doses from the OptiChamber DiamondTM were consistently lower, which therefore must be caused by differences in its shape or size, or a different functioning of its valve. Conclusions: some ‘antistatic’ valved holding chambers are only poorly antistatic. As a result, antistatic valved holding chambers are non-interchangeable, which means that switching between them should be discouraged.

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.

Pulmonary drug delivery can have several advantages over other administration routes, in particular when using dry powder formulations. Such dry powder inhalation formulations generally include natural and bio-inspired excipients, which, among other purposes, are used to improve dosing reproducibility and aerosolization performance. Amino acids can enhance powder dispersibility and provide protection against moisture uptake. Sugars are used as drug-carrying diluents, stabilizers for biopharmaceuticals, and surface enrichers. Lipids and lipid-like excipients can reduce interparticle adhesive forces and are also used as constituents of liposomal drug delivery systems. Finally, biodegradable polymers are used to facilitate sustained release and targeted drug delivery. Despite their promise, pulmonary toxicity of many of the discussed excipients remains largely unknown and requires attention in future research.

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 w/w. This formulation resulted in a maximum fine particle dose of 58.00 &plusmn, 2.56 mg when a nominal dose of 80 mg was dispersed from the Cyclops&reg, 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.

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&reg, 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 &minus, 3.99 &plusmn, 0.18 &deg, C and starts to sublimate around 80 &deg, 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 &lt, 5 &micro, m = 89.61% &plusmn, 1.77% from spray drying, which dispersed well from the Twincer&reg, 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.

Recent history of dry powder inhalation dates back to the sixties of the previous century. The design and development of dry powder inhalers (DPIs) in this period was driven by patient dissatisfaction with metered dose inhaler (MDI) use and the imminent ban of chlorofluorocarbon propellants in these MDIs. For their design, the 1960s state of the art in powder formulation for low dose drugs (adhesive mixtures) was used and powder masses with single drug doses were measured into hard gelatin capsules. Adhesive mixtures and capsule inhalers are not the most optimal combination, however, because of the high flow rates needed to empty the capsule completely. Capsule DPIs also lack an efficient powder dispersion principle and as a result relatively coarse aerosols are delivered to the respiratory tract at high velocities. This causes considerable drug deposition in the mouth and throat region. This unsatisfactory performance has given dry powder inhalation science a boost, resulting in the development of multi-dose DPIs and an excess of studies into the mechanisms and variables involved in adhesive mixture preparation and dispersion. Also, various particle engineering techniques have been explored and are currently used to improve drug aerosolisation by controlling the interparticulate forces in the powders for inhalation. Thus, increased understanding of powder dispersion and particle deposition in the respiratory tract and improved technology for drug formulation and aerosol delivery have opened the way to new, mostly high dose applications for dry powder inhalation, like vaccines, inhaled antibiotics, and systemically acting drugs.

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 ( Cmax), time to maximum plasma concentration (Tmax) and area under the concentration time curve 0–180 min were determined. Spirometry was performed three times at each visit. Results: After inhalation, levodopa Tmax occurred within 15 min in all participants, whereas after oral administration, Tmax 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.

Extensively drug-resistant (XDR) tuberculosis (TB) is defined by resistance to isoniazid, rifampicin, any fluoroquinolone and at least one of the three second line injectable drugs, such as amikacin. Drug toxicity and duration impair adherence to treatment and outcome is rather poor [1]. We report on a particularly challenging XDR-TB patient with persistent non-adherence to treatment and an exceptionally complex drug susceptibility pattern., Crossing borders by treating a patient with difficult to treat XDR-TB; highly individualised but holistic approach http://ow.ly/JyjK30ielsD

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 (2–6kPa) and doses (20, 30 and 40mg), 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.

Drug particles can be produced in the proper aerodynamic particle size distribution (PSD) for inhalation by techniques such as micronisation or spray drying (1–5 µm). However, mixing with coarse carrier particles may change the PSD by agglomeration. Furthermore, the spatial distribution of the drug particles on the carrier particles in adhesive mixtures is highly relevant to the dispersion performance of inhalation powders. Coherent anti-Stokes Raman scattering (CARS) microscopy is capable of chemically selective imaging, allowing the distribution of drug particles on the surface of carrier particles to be visualised. We used CARS microscopy to image the drug distribution for budesonide and salmeterol on the surface of lactose carrier particles. Image analysis was performed to determine the drug PSD that was then compared with the PSD obtained from laser diffraction. Additionally, comparative CARS and scanning electron microscopy (SEM) images were recorded to allow a direct comparison of the images obtained from CARS microscopy and from SEM. CARS microscopy revealed the drug to be in clusters on the surface of the carrier particles, while the image analysis identified 68% of the particles to have a median area of 0.4 µm2. Image analysis resulted in measurement of larger particles than laser diffraction, which may be caused by agglomeration during mixing. The combined chemical and morphological information from comparative CARS and SEM analysis resulted in unambiguous identification of the spatial drug distribution over the carrier surface. Our results indicate that CARS microscopy is a useful tool to study adhesive mixtures for inhalation

The dispersion performances of inhalation powders are often tested at only one inhalation flow rate in mechanistic formulation studies. This limited approach is challenged by studies showing that interactions exist between inhalation flow rate and the effects on dispersion performance of several formulation variables. In this note we explain that such interactions with inhalation flow rate are, in fact, always to be expected. Because these interactions may greatly affect conclusions concerning the effects of formulation variables and their underlying mechanisms, the utility of future dry powder inhalation formulation studies may benefit from an approach in which dispersion performance is by default tested over a range of inhalation flow rates. (C) 2014 Elsevier B.V. All rights reserved.

Background: patients prefer dry powder inhalation to nebulisation but the Colobreathe dry powder inhaler for colistimethate sodium (CMS) is not well appreciated in the Netherlands for a number of different reasons, including serious cough problems by some patients after inhalation of the drug. Aim: to assess the suitability of the Twincer as alternative to the Colobreathe for patients having problems with this capsule based inhaler. Methods: in vitro evaluation of the Twincer (55 mg) and Colobreathe (125 mg) was performed using the Next Generation Impactor and a laser diffraction apparatus (Sympatec HELOS) operated at 4 kPa (inhalation volume: 4L; n = 3). Results: laser diffraction analyses shows a finer aerosol from the Twincer than from the Colobreathe. Delivered CMS doses and fine particle doses (FPFs 1-5 µm) from Colobreathe were 126 mg (+14.7/-31.9 mg) and 25.5 mg (+2.8/-3.5 mg) respectively versus 48.5 mg (+2.9/-3.3 mg) and 26.4 mg (+1.4/-1.2 mg) from Twincer. Capsule fragmentation and emission of capsule fragments was observed during evaluation of the Colobreathe but not for the Twincer (having the drug in an aluminum blister). Conclusions: The higher dispersion efficiency of the Twincer (FPF is 54.4% of delivered dose versus 20.2% for Colobreathe) enables to inhale a much lower dose (at lower flow rate) without capsule fragments in the aerosol. As a consequence, the Twincer is expected to be better tolerated by patients and, therefore, provides a suitable alternative to the Colobreathe. This expectation is corroborated by positive feedback from the first patients suffering from CF or non-CF bronchiectasis who received the Twincer on the basis of 9medical need9.

Developments in high dose dry powder aerosol delivery will increasingly challenge the applicability of currently used aerosol characterisation techniques. With cascade impaction analysis bounce effects can negatively influence stage collection efficiency, especially with increasing impactor loads. In this study the suitability of the multi stage liquid impinger (MSLI) and the Next Generation Impactor (NGI) for the characterisation of dry powder aerosols containing up to 50mg of drug is evaluated. The occurrence of bounce effects is quantitatively assessed by comparison with data obtained from laser diffraction analysis. The liquid based impaction surfaces of the MSLI largely prevent bounce effects, but the low number of cut-off values associated with this impactor hinders accurate data interpretation. With the NGI, a standard high viscosity plate coating insufficiently reduces bounce effects, causing the fraction1 μm to be higher than what can maximally be expected based on the primary particle size distribution (PSD) obtained from RODOS dispersion. With this type of impactor, the use of solvent soaked filters as impaction surface is necessary to eliminate bounce effects.

A new definition of the activity of surface sites on lactose carriers for dry powder inhalation is proposed which relates to drug detachment during dispersion. The new definition is expected to improve the understanding of 'carrier surface site activity', which stimulates the unambiguous communication about this subject and may aid in the rational design and interpretation of future formulation studies. In contrast to the currently prevailing view on carrier surface site activity, it follows from the newly proposed definition that carrier surface site activity depends on more variables than just the physicochemical properties of the carrier surface. Because the term 'active sites' is ambiguous, it is recommended to use the term 'highly active sites' instead to denote carrier surface sites with a relatively high activity. © 2014 Elsevier B.V. All rights reserved.

Objective: To assess the ability of Parkinson9s patients to perform an inhalation manoeuvre correctly during an off period. Background: Due to the expected faster onset of effect compared to oral levodopa, administration of levodopa via a dry powder inhaler is an interesting alternative to oral levodopa in Parkinson9s patients in an off period. During an off period, the motor function is impaired and the patient is suffering from symptoms like bradykinesia, tremor and rigidity. Little is known about the ability to use dry powder inhalers during an off period. We studied the inspiratory flow manoeuvre performed by Parkinson9s patients in an off period. Methods: After informed consent was obtained, 13 Parkinson9s patients in an off period simulated inhalation manoeuvres through a testinhaler, with 3 different resistances to air flow. These resistances to air flow are considered medium/high to high, according to the ERS/ISAM task force consensus statement. With the obtained flow curves, we calculated various inhalation parameters. Results: The mean PIF and its ranges were found to increase with decreasing resistance to air flow. The average inhaled volume was > 2 L, for all three resistances to air flow. The total inhalation time and time to PIF were found to decrease with decreasing resistance to air flow. Twelve out of thirteen patients were able to hold their breath for at least 5 seconds after inhalation. Nine of them were able to extend the breath hold time to 10 seconds. Conclusions: Most Parkinson9s patients demonstrated the ability to perform an inhalation manoeuvre that is expected to be sufficient for the successful use of a dry powder inhaler by this particular patient group.

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.

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.

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 mm) with a similar size and shape as micronised budesonide were studied and compared to those of 'coarse lactose fines' (CLF, X50= 3.94 mm). 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. © 2014 Grasmeijer et al.

In Table 2, the data in row "600 min" shifted four columns to the left and the data in row "780 min" shifted six columns to the left. Please see the corrected Table 2 here: http://plosone.org/corrections/pone.0069263.t002.cn.tif

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.

Background: In a previous study it was hypothesised that the effect of mixing time on drug agglomeration and detachment for a coarse lactose carrier is dependent on the presence of large carrier surface discontinuities. To test this hypothesis, experiments were repeated with a fine lactose carrier that contains smaller surface discontinuities. Methods: Mixtures of lactose (63-90 μm) and salmeterol xinafoate or fluticasone propionate were prepared using a Turbula mixer at 90 rpm for 0.5 to 780 minutes. Laser diffraction analysis of undissolved drug clusters in an aqueous suspension after dissolution of the carrier was performed to follow drug agglomeration behaviour in the blends. A classifier based test inhaler was used to determine drug detachment at 20 and 60 L/min. Mixtures were imaged by SEM. Results: Decreasing drug detachment was observed for both drugs at both flow rates with increased mixing time. Until 60-120 minutes of mixing this was accompanied by a decrease in agglomerate size, whereas with prolonged mixing increased dissolution of salmeterol and a gradual film formation by submicron fluticasone particles on the carrier surface were observed. Conclusions: Mechanical forces have a more pronounced negative effect on drug detachment with increased mixing time for a fine lactose carrier of 63-90 μm than for a coarse carrier of 250-315 μm. In addition to drug deagglomeration, continued low shear blending can cause enhanced solubility of salmeterol and film formation by fluticasone. These findings stress the importance of reducing mechanical stress on drug particles during the mixing process, for example, by using carriers with increased macro surface roughness.