INTRODUCTION IPAC-RS Dissolution Working Group: Andrew Cooper 1 , Jan Arp 2 , David Christopher 3 , Agnes Colombani 4 , Svetlana Lyapustina 5 , Janet Maas 6 , Jolyon Mitchell 7 , Maria Reiners 8 , Trevor Riley 9 , Nastaran Sigari 10 , Terrence Tougas 11 . ACKNOWLEDGEMENTS B †Corresponding Author Email: [email protected] In-vitro dissolution testing of the respirable fraction of inhaled products is a relatively new area of pharmaceutical science which has received increasing attention in recent years. The IPAC-RS Dissolution Working Group has reviewed publications describing a number of techniques and a variety of applications to commercial and developmental products across a range of active ingredient and formulation properties. These applications provide evidence that dissolution rate can be affected by API properties such as solubility and particle size, and between formulations of the same drug. Dissolution testing may have value as a tool in the development of particles and formulations engineered to achieve modified release. However, there is currently limited evidence that, for more general application, dissolution testing exhibits sensitivity to effects which cannot be predicted theoretically or from simpler measurements. It is also clear from published data that there are particular challenges in terms of practicality, robustness, data handling and in application to low solubility drugs. Dissolution testing of inhaled products should therefore be viewed as a development tool rather than a potential quality control test. Drug dissolution may have an impact on lung retention and pharmacokinetics of inhaled products in-vivo 1,2 . A number of techniques have been described for the in-vitro determination of dissolution of the respirable fraction of inhaled products 3-7. The IPAC-RS Dissolution Working Group has reviewed the available information from number of perspectives, such as: • How is the aerosolised dose collected? • What dissolution apparatus is used? • What assumptions are made in designing the experiment? • What are the advantages and limitations of the method and are these discussed? • What is the underlying purpose of the dissolution experiment? • Is there information linking dissolution to PK or any clinical measure? • Is the statistical analysis robust and appropriate for the purpose? Is any information on reproducibility/repeatability provided? The experimental techniques used for dissolution testing of inhaled products are reviewed elsewhere at this conference 8. This poster focuses on the published applications of dissolution to inhaled products, and reviews the factors shown to affect dissolution rate. The role of dissolution testing in inhaled product development is discussed. The authors would like to thank the IPAC-RS Board of Directors for its support of this project. <section title>. <insert text as needed> DISCUSSION Author Affilations: 1 Pfizer, Sandwich, UK; 2 Teva, Haarlem, Netherlands ; 3 Merck, Kenilworth, NJ, USA ; 4 AstraZeneca, Loughborough, UK; 5 Drinker Biddle &Reath, Washington DC, USA; 6 Novartis, Horsham, West Sussex, UK; 7 Trudell Medical International, London, ON, Canada; 8 Boehringer Ingelheim, Ingelheim am Rhein, Germany; 9 GlaxoSmithKline, Ware UK; 10 Merck, Summit, NJ, USA ; 11 Boehringer Ingelheim, Ridgefield, CT, USA TABLE 1: PUBLISHED APPLICATIONS OF IN-VITRO DISSOLUTION TESTING TO THE RESPIRABLE FRACTION OF INHALED PRODUCTS Drug Aqueous Solubility Product Technique Reference Salbutamol (albuterol) sulfate >100 mg/ml Ventolin HFA MDI Paddle over disk 6 Hydrocortisone 300 µg/ml Development DPI Paddle over disk 5 Development LABA 300 µg/ml Development MDI Flow-through 4 Flunisolide 140 µg/ml Aerobid MDI Diffusion Cell 7 Triamcinolone acetonide 21-26 µg/ml Azmacort MDI Diffusion Cell 7 Triamcinolone acetonide 21-26 µg/ml Azmacort MDI Flow-through 3 Budesonide 14-21 µg/ml Pulmicort Turbuhaler DPI Diffusion Cell 7 Budesonide 14-21 µg/ml Pulmicort Turbuhaler DPI Flow-through 3 Development ICS <5 Development MDI Flow-through 4 Beclomethasone dipropionate 0.1 µg/ml QVAR solution MDI Diffusion Cell 7 Beclomethasone dipropionate 0.1 µg/ml Vanceril MDI Diffusion Cell 7 Fluticasone propionate 0.1 µg/ml Flovent Diskus DPI Diffusion Cell 7 Fluticasone propionate 0.1 µg/ml Flovent HFA MDI Diffusion Cell 7 Fluticasone propionate 0.1 µg/ml Flixotide Accuhaler DPI Flow-through 3 Arora et al 7 made direct comparison of dissolution rate between formulations of fluticasone propionate (FP DPI vs MDI) and beclomethasone dipropionate (BDP suspension vs solution MDI) using a diffusion cell system. BDP exhibited a faster dissolution rate than FP (despite similar solubility of the crystalline APIs), and a difference in initial dissolution rate was observed between the two BDP products. These observations were atttributed to the presence of BDP in a more soluble form than the crystalline solid in the ex-device respirable dose from these products. MODIFIED RELEASE APPLICATIONS Applications of dissolution testing in the development of particles or formulations engineered to achieve modified release have been reported 9-11 . Testing has focused on API or blend powder without separation of the respirable fraction, typically using conventional USP dissolution apparatus. A relationship between in-vitro dissolution and in- vivo performance has been demonstrated in some of these cases 9,11. In addition to a review of the current state of dissolution techniques, the IPAC-RS Dissolution Working Group has considered the purpose of dissolution testing of inhaled products in light of the published work in the area. Dissolution testing appears to be most promising as a tool supporting the development of particles or formulations which have been engineered to achieve modified release to or through the lung. There is some evidence that dissolution testing may be able to distinguish between formulations of the same drug. It may therefore prove to have value as a more general development tool, probing the effect of drug or formulation characteristics. However, the published literature does not demonstrate conclusively that dissolution testing provides insight into such effects that could not be achieved by theoretical considerations or simpler measurements. Fundamental challenges remain in the development of dissolution methodology for inhaled products, exhibited particularly in the published data for the low solubility compounds which are thought most likely to be subject to dissolution rate-limitation in-vivo. These arise from the limited surface area on which the respirable dose is necessarily captured in-vitro, and are manifest as mass-dependent dissolution rates and/or permeation- controlled zero-order kinetics in a number of examples. These effects may impact the discriminating ability of the technique, and make quantitative comparison between batches or products challenging. The methodology remains practically challenging, e.g. in terms of dose collection and in the preparation of biorelevant media preferred by many authors. Considering these challenges, the lack of evidence demonstrating robustness of most published approaches and limited discussion of statistical approaches to data handling, dissolution testing of inhaled products should currently be regarded as a developmental tool which itself requires further development. There is no evidence suggesting that there is a need for dissolution to be considered as a quality control test for inhaled products, and it is clear that current methodology would be incapable of robustly supporting such application. Summary of Techniques for Measuring Dissolution of Orally Inhaled Products: Review of Published Applications EFFECT OF DRUG SOLUBILITY Fig. 1. Dissolution of ICS and LABA of differing solubilities (from ref. 4) A number of authors have shown that dissolution rate increases with increasing drug solubility, as expected from theory (e.g. Noyes-Whitney equation). EFFECT OF PARTICLE SIZE Fig. 2. Dissolution of hydrocortisone aerodynamic particle size fractions collected from NGI stages 2 through 5 (from ref. 5) Son et al 5,6 demonstrated that dissolution rates carrier-free formulations of hydrocortisone and budesonide increased with decreasing aerodynamic particle size by carrying out measurements on size fractions collected from different impactor stages. This is also expected from Noyes-Whitney theory. PRODUCT COMPARISONS Fig.3. Comparison of dissolution rates for 2.1-3.3 µm aerodynamic size fractions of fluticasone propionate and beclomethasone dipropionate products (from ref. 7) Fig. 4. Comparison of dissolution rate of unmodified with poly(lactic acid)-coated budesonide particles (from ref. 9) REFERENCES 1. Dolovich MB, Jordana M, Newhouse MT, Eur J Nucl Med 13 S45-S52 (1987). 2. Hochhaus G, Möllmann H, Derendorf H, Gonzalez-Rothi RJ, J Clin Pharmacol 881- 892 (1997). 3. Davies NM, Feddah MR, Int J Pharmaceutics 255 175-187 (2003). 4. 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