INTRODUCTION

INTRODUCTION

IPAC-RS Dissolution Working Group: Andrew Cooper1, Jan Arp2, David Christopher3, Agnes Colombani4, Svetlana Lyapustina5, Janet Maas6, Jolyon Mitchell7, Maria Reiners8, Trevor Riley9, Nastaran Sigari10, Terrence Tougas11.

ACKNOWLEDGEMENTS

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†Corresponding Author Email: andrew.d.cooper@pfizer.com

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 productsacross a range of active ingredient and formulation properties. These applications provide evidence that dissolution rate can be affected by API properties such as solubilityand 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 achievemodified release. However, there is currently limited evidence that, for more general application, dissolution testing exhibits sensitivity to effects which cannot be predictedtheoretically or from simpler measurements. It is also clear from published data that there are particular challenges in terms of practicality, robustness, data handling and inapplication 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 andpharmacokinetics of inhaled products in-vivo1,2 . A number of techniqueshave been described for the in-vitro determination of dissolution of therespirable fraction of inhaled products3-7. The IPAC-RS Dissolution WorkingGroup has reviewed the available information from number ofperspectives, 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 thesediscussed?• 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 anyinformation on reproducibility/repeatability provided?

The experimental techniques used for dissolution testing of inhaledproducts are reviewed elsewhere at this conference8. This poster focuseson the published applications of dissolution to inhaled products, andreviews the factors shown to affect dissolution rate. The role of dissolutiontesting in inhaled product development is discussed.

The authors would like to thank the IPAC-RS Board of Directors for its support of thisproject.

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DISCUSSION

Author Affilations: 1Pfizer, Sandwich, UK; 2Teva, Haarlem, Netherlands ; 3Merck, Kenilworth, NJ, USA ; 4AstraZeneca, Loughborough, UK; 5Drinker Biddle &Reath, Washington DC, USA; 6Novartis, Horsham, West Sussex, UK; 7Trudell Medical International, London, ON, Canada; 8 Boehringer Ingelheim, Ingelheim am Rhein, Germany; 9GlaxoSmithKline, Ware UK; 10Merck, Summit, NJ, USA ; 11Boehringer 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 ReferenceSalbutamol (albuterol) sulfate >100 mg/ml Ventolin HFA MDI Paddle over disk 6Hydrocortisone 300 µg/ml Development DPI Paddle over disk 5Development LABA 300 µg/ml Development MDI Flow-through 4Flunisolide 140 µg/ml Aerobid MDI Diffusion Cell 7Triamcinolone acetonide 21-26 µg/ml Azmacort MDI Diffusion Cell 7Triamcinolone acetonide 21-26 µg/ml Azmacort MDI Flow-through 3Budesonide 14-21 µg/ml Pulmicort Turbuhaler DPI Diffusion Cell 7Budesonide 14-21 µg/ml Pulmicort Turbuhaler DPI Flow-through 3Development ICS <5 Development MDI Flow-through 4Beclomethasone dipropionate 0.1 µg/ml QVAR solution MDI Diffusion Cell 7Beclomethasone dipropionate 0.1 µg/ml Vanceril MDI Diffusion Cell 7Fluticasone propionate 0.1 µg/ml Flovent Diskus DPI Diffusion Cell 7Fluticasone propionate 0.1 µg/ml Flovent HFA MDI Diffusion Cell 7Fluticasone propionate 0.1 µg/ml Flixotide Accuhaler DPI Flow-through 3

Arora et al7 made direct comparison of dissolution rate betweenformulations of fluticasone propionate (FP DPI vs MDI) andbeclomethasone dipropionate (BDP suspension vs solution MDI) using adiffusion cell system. BDP exhibited a faster dissolution rate than FP(despite similar solubility of the crystalline APIs), and a difference ininitial dissolution rate was observed between the two BDP products.These observations were atttributed to the presence of BDP in a moresoluble form than the crystalline solid in the ex-device respirable dosefrom these products.

MODIFIED RELEASE APPLICATIONS

Applications of dissolution testing in the development of particles orformulations engineered to achieve modified release have beenreported9-11. Testing has focused on API or blend powder withoutseparation of the respirable fraction, typically using conventional USPdissolution apparatus. A relationship between in-vitro dissolution and in-vivo performance has been demonstrated in some of these cases9,11.

In addition to a review of the current state of dissolution techniques, theIPAC-RS Dissolution Working Group has considered the purpose ofdissolution testing of inhaled products in light of the published work in thearea.

Dissolution testing appears to be most promising as a tool supporting thedevelopment of particles or formulations which have been engineered toachieve modified release to or through the lung.

There is some evidence that dissolution testing may be able to distinguishbetween formulations of the same drug. It may therefore prove to havevalue as a more general development tool, probing the effect of drug orformulation characteristics. However, the published literature does notdemonstrate conclusively that dissolution testing provides insight into sucheffects that could not be achieved by theoretical considerations or simplermeasurements.

Fundamental challenges remain in the development of dissolutionmethodology for inhaled products, exhibited particularly in the publisheddata for the low solubility compounds which are thought most likely to besubject to dissolution rate-limitation in-vivo. These arise from the limitedsurface 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 mayimpact the discriminating ability of the technique, and make quantitativecomparison between batches or products challenging. The methodologyremains practically challenging, e.g. in terms of dose collection and in thepreparation of biorelevant media preferred by many authors.

Considering these challenges, the lack of evidence demonstratingrobustness of most published approaches and limited discussion ofstatistical approaches to data handling, dissolution testing of inhaledproducts should currently be regarded as a developmental tool which itselfrequires further development. There is no evidence suggesting that thereis a need for dissolution to be considered as a quality control test forinhaled products, and it is clear that current methodology would beincapable 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 withincreasing drug solubility, as expected from theory (e.g. Noyes-Whitneyequation).

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 al5,6 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 beclomethasonedipropionateproducts (from ref. 7)

Fig. 4. Comparison of dissolution rate of unmodified with poly(lactic acid)-coated budesonideparticles (from ref. 9)

REFERENCES

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892 (1997).3. Davies NM, Feddah MR, Int J Pharmaceutics 255 175-187 (2003).4. Riley T, Jones AR, Bogalo Huescar M, Roche TC, Respiratory Drug Delivery 2008

p.541.5. Son Y-J, McConville JT, Int J Pharmaceutics 382 15-22 (2009).6. Son Y-J, Horng M, Copley M, McConville JT, Dissolution Technologies May 2010

pp.6-12.7. Arora D, Shah KA, Halquist MS, Sakagami M, Pharm Res 27 786-795 (2010).8. Riley T, Christopher D, presented at IPAC-RS Conference, Mar 28-30 2011,

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9. Coowanitwong I, Arya V, Patel G, Kim W-S, Cracum V, Rocca JR, Singh R, Hochhaus G, J Pharm Pharmacol 59 1473-1484 (2007)

10. Salama R, Traini D, Chan H-K, Young PM, Current Drug Delivery 6 404-41411.Salama R, Traini D, Chan H-K, Young PM, Eur J Pharmaceutics

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