The effect of mixing on the dispersibility of adhesive mixtures for inhalation. Comparison of high shear and Turbula mixers.

This study investigates the effect of different mixers and the applicability of the mixing energy (ME) concept to dry powder formulations for inhalation. With the aim to step-wise build and expand this concept, adhesive mixtures of 2 % budesonide and lactose carrier were investigated, both with 1 % magnesium stearate (MgSt) added in a 'coating' step, and without, the latter referred to as 'naked' formulations. For high shear mixed formulations, the fine particle fraction (FPF) was found to increase with increasing ME up to 60 % and thereafter decreased, using the Novolizer device. The data could be well fitted to the modeling equation, thus confirming the validity of the ME concept. The naked formulations displayed a linear decrease in FPF with increasing ME, again showing the validity of the ME concept. For Turbula mixed formulations, FPF increased with increased mixing time (and mixing energy) for all batches. The naked (binary) composition reached to higher FPF values than for high shear mixing and the formulation with MgSt reached to FPF values around 60 %, demonstrating that it is possible to achieve the same high drug dispersibility with the Turbula mixer as for high shear mixer. An equation for calculation of mixing energy in Turbula mixing was set up in an analogous way to the equation for high shear mixing, which enabled direct comparison between the two mixers.

The match between adhesive mixture powder formulations for inhalation and the inhaler device.

The device or the formulation? Which one governs drug dispersibility from the inhaler? To address this question, three budesonide-containing reservoir DPIs: Novopulmon Novolizer®, Giona Easyhaler® and DuoResp Spiromax®, were analyzed using the Next Generation Impactor, NGI. Thereafter, the devices were carefully opened, emptied, and formulations were switched between devices. Finally, three 'prototype' formulations with carriers of different particle size were produced and tested in the Novolizer and Easyhaler devices. Among the DPI products, the two devices which have a flow path with a cyclone-type geometry, i.e., the Novolizer and the Spiromax, yielded a fine particle fraction, FPF, above 40%. The Easyhaler, which has a straight mouthpiece outlet, produced an FPF of 18%. When the Novopulmon and the DuoResp formulations were assayed in the Easyhaler device, poor fine particle fractions were obtained. To the contrary, the Giona formulation produced a high FPF when tested in the Novolizer device. The results clearly show that the device is the dominating factor to dispersibility for the investigated products. Along the same lines, all three 'prototype' formulations produced high fine particle fractions in the Novolizer device, with the formulation with the largest carrier giving the best performance. Tested in the Easyhaler device, the prototype formulations produced low fine particle fractions, but interestingly, the formulation with the smallest carrier particle size yielded the highest FPF. It can be concluded that there is a link between inhaler design and the effect of carrier particle size, where larger carriers provide better dispersion in cyclone-type devices while smaller carriers seem to be more beneficial for inhalers which has a straight flow path for the powder formulation.

Systematic Evaluation of the Effect of Formulation Variables on In Vitro Performance of Mometasone Furoate Suspension-Metered Dose Inhalers.

The therapeutic benefits of metered dose inhalers (MDIs) in pulmonary disorders are mainly driven by aerosol performance, which depends on formulation variables (drug and excipients), device design, and patient interactions. The present study provides a comprehensive investigation to better understand the effect of formulation variables on mometasone furoate (MF) suspension-based MDI product performance. The effects of MF particle size (volume median diameter; X50) and excipient concentration (ethanol and oleic acid, cosolvent, and surfactant, respectively) on selected critical quality attributes (delivered dose (DD), fine particle dose of particles lesser than 5 µm (FPD < 5), ex-throat dose and median dissolution time (MDT)) were studied. Eight MF-MDI formulations (one per batch) were manufactured based on a reduced factorial design of experiment (DOE) approach, which included relevant formulation levels with varying X50 (1.1 and 2 µm), concentration of ethanol (0.45, 0.9, 1.8, and 3.6%w/w), and oleic acid (0.001 and 0.025%w/w). The in vitro evaluation of these MF-MDI formulations indicated the importance of drug particle's X50, oleic acid, and ethanol canister concentration as critical formulation variables governing the performance of MF suspension-based MDI products. The effect of these formulation variables on DD, FPD < 5, ex-throat dose, and MDT was subsequently utilized to develop empirical relationships linking formulation factors with effects on in vitro performance measures. The developed strategy could be useful for predicting MF-MDI product performance during MDI product development and manufacturing. The systematic DOE approach utilized in this study may provide insights into the understanding of the formulation variables governing the MF-MDI product performance.

Laboratory Study Comparing Pharmacopeial Testing of Nebulizers with Evaluation Based on Nephele Mixing Inlet Methodology.

Determination of fine droplet dose with preparations for nebulization, currently deemed to be the metric most indicative of lung deposition and thus in vivo responses, involves combining two procedures following practice as described in the United States Pharmacopeia and the European Pharmacopeia. Delivered dose (DD) is established by simulating tidal breathing at the nebulizer, collecting the medication on a filter downstream of the nebulizer mouthpiece/facemask. Fine droplet fraction (FDF

Orally inhaled drug performance testing for product development, registration, and quality control.

A DPI can be split into three different modules; device, formulation, process. These are developed in parallel, and together with the user they provide the performance of an inhalation product. During product development, these modules are evolving and changing, whereas the requirements on an inhalation product are always expressed in terms of the performance of the final commercial product. To do performance testing during development when the product is not finished presents many challenges and can be confusing and misleading. During development, the performance of the final product is typically being predicted by testing ever changing prototypes. This article describes methods and approaches to manage such development and to, during development, provide relevant predictions of the in vitro and in vivo performances of the final product.

Validation of a general in vitro approach for prediction of total lung deposition in healthy adults for pharmaceutical inhalation products.

BACKGROUND: A validated method to predict lung deposition for inhaled medication from in vitro data is lacking in spite of many attempts to correlate in vitro and in vivo outcomes. By using an in vivo-like in vitro setup and analyzing inhalers from the same batches, both in vitro and in vivo, we wanted to create a situation where information from the in vitro and in vivo outcomes could be analyzed at the same time. METHOD: Nine inhalation products containing either budesonide or AZD4818 were evaluated. These comprised two pressurized metered dose inhalers (pMDIs), a pMDI plus a spacer, four dry powder inhalers, and two dosimetric nebulizers. In vitro, an in vivo-like setup consisting of anatomically correct inlet throats were linked to a flow system that could replay actual inhalation flow profiles through the throat to a filter or to an impactor. In vivo, total lung deposition was measured in healthy adults by pharmacokinetic methods. RESULTS AND CONCLUSION: We could show that the amount of drug escaping filtration in a realistic throat model under realistic delivery conditions predicts the typical total lung deposition in trained healthy adult subjects in the absence of significant exhaled mass. We could further show that by using combinations of throat models and flow profiles that represent realistic deviations from the typical case, variations in ex-cast deposition reflect between-subject variation in lung deposition. Further, we have demonstrated that ex-cast deposition collected either by a simple filter or by a cascade impactor operated at a fixed flow rate using a mixing inlet, to accommodate a variable flow profile through the inhaler, predicts equally well the lung deposited dose. Additionally, the ex-cast particle size distribution measured by this method may be relevant for predicting exhaled fraction and regional lung deposition by computational models.

Dose delivery late in the breath can increase dry powder aerosol penetration into the lungs.

In addition to aerosol particle size and mode of inhalation, the time-point of dose delivery during inhalation may be an important factor governing the intrapulmonary distribution of aerosolized drug. To generate different intrapulmonary deposition patterns of a drug model aerosol, a device with the capability of delivering small amounts of technetium-99m-labeled lactose dry powder at pre-set time-points during inhalation was developed. A single dose of the radioaerosol was delivered after inhalation of 20% (A) or 70% (B) of the vital capacity inhaled through the device. Twelve healthy subjects were studied in a randomized crossover fashion. Planar gamma scintigraphy was carried out, and the penetration index, PI, defined as the ratio of peripheral to central lung zone deposition of radioactivity, was estimated. A significant increase in PI from 3.0 (A) to 3.7 (B) was observed with the change from early to late delivery of the dose (p < 0.01). No difference in the total amount of radioactivity within the lungs could be detected. In conclusion, independent of total pulmonary deposition, deeper dry powder aerosol penetration into the lungs was found for the dose delivered at near end instead of at the beginning of inhalation. By computational modeling of the aerosol transport and deposition, that finding was mechanistically explained by differences in airway caliber as a consequence of the level of lung inflation at the time-point of dose delivery.

Mensuration and cleaning of the jets in Andersen cascade impactors.

PURPOSE: Fifty-three Andersen Cascade Impactors (404 stages) have been investigated using an automated visual stage mensuration technique. A cleaning method was suggested for stages with jets smaller than nominal diameters. The impact of nonapproved jet diameters on result parameters from particle size analysis was evaluated theoretically. METHODS: The jet diameters were measured using the Andersen Visual Inspection Device. A stepwise cleaning procedure was performed to recover the jets of noncompliant stages, and after each step a new stage mensuration was performed. RESULTS: The result of this extensive investigation, including measurements of each jet, is compared to other studies, to tolerance limits applied at AstraZeneca Lund and also to limits used by the manufacturer. Sixteen of the investigated stages were outside applied tolerance limits due to too small average diameters. Insertion of a go gauge into every jet of the stages was the only technique of those tested that increased the jet diameters toward nominal dimensions. Moreover, the relative standard deviation of the jet diameters decreased considerably after use of go gauges. CONCLUSIONS: Stage mensuration is a valuable technique for detection of improper jet dimensions of the Andersen Cascade Impactor, and use of go gauges is an effective cleaning method especially for jets with small diameters. However, use of stop/go gauges as a periodical quality control test on a small number of randomly selected jets was a poorly discriminating test, as both compliant and noncompliant stages would most probably pass such a test.