In Vivo-Relevant Transwell Dish-Based Dissolution Testing for Orally Inhaled Corticosteroid Products
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To establish an in vivo-relevant Transwell dish-based dissolution test system for the “respirable” aerosols of inhaled corticosteroids (ICSs) using marketed inhaler products.
“Respirable” ≤ 5.8 or 6.5 μm aerosols of 7 ICSs from 11 inhaler products were collected onto the filter membranes under the modified assembly of the cascade impactor. Their dissolution in 10 ml of the simulated lung lining fluid (sLLF) was determined over time in the Transwell dish at 37°C and ~100% relative humidity in the presence of subsequent diffusive permeation across the Transwell’s supporting membrane.
While three ICSs with high-to-intermediate solubility enabled the first-order “sink” and complete dissolution in 6 h, 4 ICSs with poor solubility including fluticasone propionate (FP) resulted in the pseudo-zero-order “non-sink”, slow and limited dissolution. The aerosol dissolution rate constants (kdiss) were derived, well-correlated with the solubility. For FP, but not for highly-soluble flunisolide (FN), dissolution was kinetically aerosol mass-dependent. However, for a given ICS, dissolution profiles were indistinguishable between the formulations and products upon comparable aerosol mass collection.
The in vivo-relevant Transwell dish-based “respirable” aerosol dissolution test system was developed, kinetically discriminative in accordance with the ICS solubility, but indistinguishable for a given ICS between the marketed products.
KEY WORDSbioequivalence cascade impactor dissolution inhaled corticosteroid transwell
Andersen cascade impactor
Dry powder inhaler
Food and Drug Administration
High performance liquid chromatography method with ultraviolet detection
In vitro and in vivo correlation
Rate constant for dissolution
Observed rate constant for dissolution and permeation
Rate constant for permeation
Lung lining fluid
Metered dose inhaler
Orally inhaled drug product
Simulated lung lining fluid
d-α-tocopheryl polyethylene glycol 1000 succinate
United States Pharmacopeia
- 5.Lionberger RA. New tools for generic orally inhaled drug products to maximize prospects of Food and Drug Administration approval. Respiratory Drug Delivery 2018 (edited by Dalby RN, Byron PR, Hindle M, Peart J, Traini D, Young PM, Farr SJ, Suman JD, Watts A) 2018;1:221–230.Google Scholar
- 7.Sakagami M. Fluticasone pharmacokinetics: meta-analysis and models. Respiratory drug delivery 2014 (edited by Dalby RN, Byron PR, Peart J, Farr SJ, Suman JD, young PM, Traini D) 2014;1:143–154.Google Scholar
- 8.Department of Health and Human Services. Development of in vivo predictive dissolution method for orally inhaled drug products. Posted on April 2013 at https://grants.nih.gov/grants/guide/rfa-files/RFA-FD-13-014.html. Accessed 30 April 2019.
- 12.United States Pharmacopeial Convention, General Chapter <601> Inhalation and nasal drug products: aerosols, sprays, and powders – performance quality tests. 2017. USP40-NF35. Rockville, MD.Google Scholar
- 13.United States Pharmacopeial Convention, General Chapter <1092> The dissolution procedure: development and validation. 2017. USP40-NF35. Rockville, MD.Google Scholar
- 14.Mitchell JP, Nagel MW, Avvakoumova V, MacKay H, Ali R. The abbreviated impactor measurement (AIM) concept: part 1 – influence of particle bounce and re-entrainment – evaluation with a “dry” pressurized metered dose inhaler (pMDI)-based formulation. AAPS PharmSciTech. 2009;10(1):243–51.CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Sakagami M, Arora-Lakhani D. understanding dissolution in the presence of competing cellular uptake and absorption in the airways. Respiratory drug delivery 2012 (edited by Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, Young PM) 2012;1:185–192.Google Scholar
- 20.Gray VA, Hickey AJ, Balmer P, Davies NM, Dunbar C, Foster TS, et al. The inhalation ad hoc advisory panel for the USP performance tests of inhalation dosage forms. Pharmacopeial Forum. 2008;34(4):1068–74.Google Scholar