Aerosolization, Drug Permeation and Cellular Interaction of Dry Powder Pulmonary Formulations of Corticosteroids with Hydroxypropyl-β-Cyclodextrin as a Solubilizer.
The purpose of this study was to assess the feasibility of hydroxypropyl-β-cyclodextrin as a solubilizer for the corticosteroids prednisolone and fludrocortisone acetate in dry powder inhalation formulations.



The dry particles were simultaneously produced and coated with nanosized L-leucine crystals using an aerosol flow reactor method. The aerosolization performances of carrier-free powders were studied using Easyhaler® and Twister™ at 2 and 4 kPa pressure drops over the inhalers. Drug permeation properties of the formulations were tested across a Calu-3 cell monolayer. Toxicity and reactive oxygen species induction were tested against Calu-3 and A549 cell lines.



The hydroxypropyl-β-cyclodextrin in the powders promoted the dissolution of fludrocortisone the most, followed by that of prednisolone. Fine particle fractions were 52-70% from emitted doses which showed good repeatability with a coefficient variation of 0.9-0.17. In addition, hydroxypropyl-β-cyclodextrin enhanced the permeation of the corticosteroids. The powders showed no statistically significant toxicity nor reactive oxygen species induction in the tested cell lines.



This study demonstrated the preparation and function of fine powder formulations which combine improved dissolution of poorly soluble drugs with good aerosolization performance. These results are expected to promote particle engineering as a way to develop new types of therapeutic pulmonary powders.
Faculty of Medicine, University of Helsinki, Clinicum, P.O. Box 22, FI-00014, Helsinki, Finland.
Ville
V
Vartiainen
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5E), FI-00014, Helsinki, Finland. luis.bimbo@helsinki.fi.
Luis M
LM
Bimbo
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5E), FI-00014, Helsinki, Finland.
Jouni
J
Hirvonen
School of Science, Aalto University, P.O. Box 15100, FI-00076, Aalto, Finland.
Esko I
EI
Kauppinen
School of Science, Aalto University, P.O. Box 15100, FI-00076, Aalto, Finland. janne.raula@aalto.fi.
Janne
J
Raula
D000073738:2-Hydroxypropyl-beta-cyclodextrin / Q000737:chemistry*; D000072283:A549 Cells; D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000737:chemistry*; D000336:Aerosols / Q000737:chemistry*; D002460:Cell Line; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004337:Drug Carriers / Q000737:chemistry; D058995:Dry Powder Inhalers / Q000379:methods; D005079:Excipients / Q000737:chemistry; D005438:Fludrocortisone / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D007930:Leucine / Q000737:chemistry; D008168:Lung / Q000378:metabolism*; D010316:Particle Size; D010539:Permeability / Q000187:drug effects*; D011208:Powders / Q000737:chemistry*; D011239:Prednisolone / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000737:chemistry; D012995:Solubility; D013499:Surface Properties / Q000187:drug effects
D000305:Adrenal Cortex Hormones; D000336:Aerosols; D004337:Drug Carriers; D005079:Excipients; D011208:Powders; D017382:Reactive Oxygen Species; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D011239:Prednisolone; D007930:Leucine; D005438:Fludrocortisone; C034635:fludrocortisone acetate
coating; cyclodextrin; permeation; poorly soluble drug; pulmonary