title: Cold flow of estradiol transdermal systems: influence of drug loss on the in vitro flux and drug transfer across human epidermis.
abstract: The objective was to quantify drug loss due to cold flow (CF) in marketed estradiol transdermal drug delivery systems (TDDS), and study its influence on the in vitro flux and drug transfer across contacting skin. TDDS samples (products-A and B) were induced with CF at 25 and 32°C/60% RH by applying 1-kg force for 72h. CF was measured as percent dimensional change and amount of drug loss/migration in CF region. In vitro drug permeation studies were conducted across human epidermis from TDDS excluding CF region, and CF region alone against control (without CF). In both products, significantly higher percentage of CF (dimensional change and drug migration) was observed at 32°C compared to 25°C. In vitro flux from both products excluding CF region either at 25 or 32°C was the same, but significantly lower compared to control. Drug transferred from CF region of product-A after 8h was the same at 25 and 32°C, but significantly higher in product-B. Flux from both products together with CF region at 32°C was significantly lower than that observed at 25°C. Results showed that excessive CF at storage (25°C) and clinical usage (32°C) conditions may have implications on product performance and safety of estradiol TDDS.
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Yellela S R
authors.initials: YS
authors.lastname: Krishnaiah
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hunt
authors.affiliation: Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. Electronic address: krishnaiah.yellela@fda.hhs.gov.
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D003080:Cold Temperature; D016503:Drug Delivery Systems; D004356:Drug Storage; D004817:Epidermis / Q000378:metabolism*; D004958:Estradiol / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008875:Middle Aged; D012869:Skin Absorption; D055815:Young Adult
chemical_list: D004958:Estradiol
keywords: Cold flow; Estradiol; Flux; Human epidermis; In vitro permeation; Transdermal