Assessing the performance of two dry powder inhalers in preschool children using an idealized pediatric upper airway model

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Abstract

High prevalence of pulmonary diseases in childhood requires inhalable medication even for young children. Little is known about the efficiency of aerosol therapy especially in preschool children. One factor which limits the lung dose is the upper airway geometry. Based on clinical data a recently developed idealized pediatric upper airway model (children 4–5 years) was used to investigate the performance of two dry powder inhalers (Easyhaler and Novolizer).

In vitro investigations were first examined using steady flow rates and an inhalation volume of 1 L. Chosen flow rates were 28, 41 and 60 L/min (Easyhaler) and 45, 60 and 75 L/min (Novolizer). Afterwards inhalation profiles simulated by an electronic lung were included.

The investigations showed high amounts of drug particles (up to 80%) which were deposited in the upper airway model. The pulmonary deposition in vitro using the Easyhaler was about 28% (28–60 L/min) and 22% (inhalation profile). Using the Novolizer in vitro pulmonary doses of 8–12% (45–75 L/min) and about 5% (inhalation profile) were observed.

The idealized model shows good performance reproducibility of dry powder inhalers. We have shown that age-dependent models might be appropriate tools for formulation and device development in pediatric age groups.

Introduction

Pharmaceutical aerosols are used for the treatment of respiratory diseases in both children and adults. Cystic fibrosis (CF) is an autosomal recessive multi-organ disease and the most challenging problem in CF is the pulmonary disease (Cohen and Prince, 2012). Respiratory problems like chronic infection and inflammation appear even in early childhood, e.g. prevalence of Pseudomonas aeruginosa is 33% in affected children at 3 years of age (Rosenfeld et al., 2001). Due to this already young children have to use inhaled medications. A further disease in childhood is asthma which proceeds in the first years of life. One-third of preschool children (1–5 years) in the USA and Europe are affected by asthma-like symptoms (cough, wheeze and breathlessness) (Bisgaard and Szefler, 2007). The most prescribed medications in asthma treatment are inhaled ß2-sympathomimetics. Thereby the treatment outcome is clearly unsatisfactory in many cases and asthma-like symptoms are the major cause of morbidity in preschool children (Bisgaard and Szefler, 2007). The major problem is that medications and delivery devices used in preschool children are in most cases developed and designed according to the needs of adult patients and less for children.

For the inhalation therapy of children three different inhalation systems were used: pressurized metered dose inhaler (pMDI), nebulizer and dry powder inhaler (DPI). In dependence of age, physiological condition, mental capacity and manual abilities different devices have been evaluated to be appropriate (Walsh et al., 2011). Whereas pMDIs alone are not appropriate for children under the age of 6 years; pMDIs in combination with spacers/valved holding chambers and facemasks are preferred in children under the age of 4 years of age. A trained breathing pattern (forceful, deep, hold one's breath) is difficult in very young children. Because of this nebulizers (without facemasks) and DPIs are appropriate for children above 4 years of age (Walsh et al., 2011). This paper will focus on passive dry powder inhalers in use of preschool children. Passive DPIs often contain a powder mixture of drug and carrier (e.g. lactose) which can be located in a reservoir (e.g. Novolizer®, Easyhaler®, Turbuhaler®), in gelatin hard capsules (e.g. Aerolizer®, Handihaler®, Breezhaler®) or in blisters (e.g. Diskus®). Despite many available delivery devices only a few medicinal products are labeled for the use in preschool children (in Germany e.g. Serevent® Diskus®, SalbuHexal® Easyhaler®). The majority of information about the suitability and efficacy of various DPIs in children relies on handling studies only to assure that children reach sufficient flow rates through the device (Amirav et al., 2005, Malmstrom et al., 1999, Munzel et al., 2005, Vogelberg et al., 2004, von Berg et al., 2007). Only few scintigraphic studies are available to get information on the in vivo drug deposition in the lung especially in preschool children.

Maturation from childhood to adolescent results in upper airway geometry changes, varying breathing patterns and behavior during an inhalation process (Bennett and Zeman, 2004). Cognitive development plays an important role for the use of inhaled medications, too (Walsh et al., 2011). In comparison to adults children have lower inhalation volumes, lower peak inspiratory flow rates and shorter inhalation times. The motivation to inhale and to handle devices correctly also varies. The upper airway geometry shows a high intra-individual variability in dependence of inhalation maneuver, device and age (Ehtezazi et al., 2005a, Grgic et al., 2004). Tomography data (MRI and CT scans) (Bickmann, 2008, Wachtel, 2010) have shown that the upper airway geometry of children is not a simple scale down of the adult upper airway geometry. Some parts like oral cavity and trachea are smaller but others are even broader. By the age of 5 years most of the changes in upper airway geometry are completed (Allen et al., 2004). Due to the interaction of formulation, device and patient in inhalation therapy the multiple differences between children and adults also influence the drug formulation characteristics. In comparison to general assumptions that particles of 5 μm size have high potential to reach lower airways in vitro investigations have shown that the optimal particle size in infants is 2.4 μm. This result was observed by using a physical model of a 9-month-old child (Schuepp et al., 2005). Investigations in older children especially preschool children are not available.

Differences in inhaler performance with regard to extrathoracic and pulmonary deposition were observed between adults and children in different in vitro studies (Isaacs and Martonen, 2005, Olsson, 1995). In vitro in vivo comparisons have shown that lung deposition is often overestimated by using conventional methods to determine aerodynamic particle size distribution (Newman and Chan, 2008). Because there is a lack of scintigraphic studies in preschool children using DPIs in vitro in vivo correlation is difficult. Correlation between in vitro and in vivo data can be improved by using impactor inlets which simulate the human upper airway geometry more precisely (DeHaan and Finlay, 2004, Ehtezazi et al., 2005b).

Upper airway models which represent the mouth–throat geometry of adults have been published since the 1980s (Cheng et al., 1990, Olsson, 1995, Stapleton et al., 2000). These models have demonstrated good in vitro in vivo correlations and are today appropriate tools for in vitro assessments on device and formulation developments. First throat models which represent children were described 20 years later (Janssens et al., 2001). The poor supply of children with medicines which match their specific needs leads to recent new regulations of EMA and FDA. The focus on pediatric medicinal products has grown by this. For inhaler testing more physical models which represent children were developed.

Various physical upper airway models were described in the literature. Most of them are nose–throat models which represent physiological geometries of infants and premature infants (e.g. SAINT-model, Janssens et al., 2001; PRINT-model, Minocchieri et al., 2008, Cheng et al., 1995, Olsson, 1995, Storey-Bishoff et al., 2008). Further Mitchell et al. (2011) described different face models which represent both nasally and orally breathing infants. Despite the variety of available models there are only three physical models describing older, orally breathing children (Bickmann, 2008, Corcoran et al., 2003, Golshahi and Finlay, 2012). The idealized child throat of Golshahi and Finlay (2012) represent children of 6–14 years. This model based on a scaling by a uniform factor (0.62) of the adult mouth–throat model described by Stapleton et al. (2000). The idealized pediatric models of Bickmann (2008) and Corcoran et al. (2003) represent preschool children and based on MRI data of 5-year-old children.

This paper focuses on the drug deposition of two inhaled products (SalbuHexal® Easyhaler® and Salbu Novolizer®) in preschool children. A physical upper airway model (Bickmann, 2008) which represents 4–5-year-old children was used as impactor inlet to determine the extrathoracic and pulmonary deposition. Deposition measurements were performed using steady conditions (flow rate, volume), but also simulated inhalation profiles.

Section snippets

Physical mouth–throat model

The upper airway geometry of preschool children differs in various dimensions from the adult geometry. Table 1 presents the main geometrical dimensions of the Magnetic Resonance Imaging based physical mouth–throat models. The physical models include the oral cavity, the pharynx, the larynx and the trachea in abraded shape (Bickmann, 2008). Fig. 1 shows the two physical models, the established adult mouth–throat model (“Alberta-throat”) (Stapleton et al., 2000) and the pediatric mouth–throat

Results and discussion

Children from the age of four are supposed to reach peak inspiratory flow rates of 28 L/min and higher through the Easyhaler device (Malmstrom et al., 1999) and 40 L/min through the Novolizer device (Vogelberg et al., 2004). Thereby handling studies gave detailed insight into children's breathing pattern through different inhalation devices. First scope of the study was the product performance at steady flow rates through the particular device. For the Easyhaler flow rates of 28, 41 and 60 L/min

Conclusion

The performance of inhalation products depends on three main factors: formulation, device and patient. Formulations especially for dry powder inhalers were highly heterogeneous. Kind of formulation varies from adhesive mixtures and soft pellets to spray-dried products. The complex interactions between device and formulation were considered in market products with regard to inhalation therapy. The idealized pediatric model is an appropriate tool for in vitro oral inhalable product testing. It

Conflict of interest statement

Deborah Bickmann is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG, but has no further financial interest or conflicts of interest. The Ph.D. project of Antje Below in the research group of Joerg Breitkreutz has been funded by Boehringer Ingelheim Pharma GmbH & Co. KG. The authors declare no additional conflicts of interest.

Acknowledgements

The authors would like to thank A. Schmitz (Heinrich-Heine University, Düsseldorf) for the assistance in HPLC method development. Furthermore we thank Hexal and Astellas for providing the marketed inhalation products.

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