Dry powder inhalation, part 1: ancient history and precursors to modern dry powder inhalers.

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.

Dry powder inhalation, part 2: the present and future.

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.

The pharmacokinetics of antibiotics in cystic fibrosis.

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.

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

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.

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

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 ± 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.

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

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 (C max), 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 T max occurred within 15 min in all participants, whereas after oral administration, T max 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.

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

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.

Challenges for pulmonary delivery of high powder doses.

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.

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

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.

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

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.

A proposed definition of the 'activity' of surface sites on lactose carriers for dry powder inhalation.

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.

The dispersion behaviour of dry powder inhalation formulations cannot be assessed at a single inhalation flow rate.

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.

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

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.

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

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.

Mixing time effects on the dispersion performance of adhesive mixtures for inhalation.

This paper deals with the effects of mixing time on the homogeneity and dispersion performance of adhesive mixtures for inhalation. Interactions between these effects and the carrier size fraction, the type of drug and the inhalation flow rate were studied. Furthermore, it was examined whether or not changes in the dispersion performance as a result of prolonged mixing can be explained with a balance of three processes that occur during mixing, knowing drug redistribution over the lactose carrier; (de-) agglomeration of the drug (and fine lactose) particles; and compression of the drug particles onto the carrier surface. For this purpose, mixtures containing salmeterol xinafoate or fluticasone propionate were mixed for different periods of time with a fine or coarse crystalline lactose carrier in a Turbula mixer. Drug detachment experiments were performed using a classifier based inhaler at different flow rates. Scanning electron microscopy and laser diffraction techniques were used to measure drug distribution and agglomeration, whereas changes in the apparent solubility were measured as a means to monitor the degree of mechanical stress imparted on the drug particles. No clear trend between mixing time and content uniformity was observed. Quantitative and qualitative interactions between the effect of mixing time on drug detachment and the type of drug, the carrier size fraction and the flow rate were measured, which could be explained with the three processes mentioned. Generally, prolonged mixing caused drug detachment to decrease, with the strongest decline occurring in the first 120 minutes of mixing. For the most cohesive drug (salmeterol) and the coarse carrier, agglomerate formation seemed to dominate the overall effect of mixing time at a low inhalation flow rate, causing drug detachment to increase with prolonged mixing. The optimal mixing time will thus depend on the formulation purpose and the choice for other, interacting variables.

Characterisation of high dose aerosols from dry powder inhalers.

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 fraction <1 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.