In Vitro Testing of Sunscreens for Dermal Absorption: Method Comparison and Rank Order Correlation with In Vivo Absorption.

Evaluating the dermal absorption of sunscreen UV filters requires the development of a bio-predictable in vitro permeation test (IVPT). This work describes the comparison of two IVPT methods and rank order correlations of in vitro absorption (skin permeation and retention) with the in vivo absorption (AUC and skin retention) of sunscreens. The IVPT was compared regarding the following elements: (1) application of a single finite dose vs. an infinite dose and (2) the use of heat-separated human epidermis vs. dermatomed skin models. The IVPT was used to evaluate dermal absorption of six UV filters (avobenzone, homosalate, octinoxate, octisalate, octocrylene, and oxybenzone) in commercial sunscreens. Both the in vivo and in vitro permeation studies demonstrated that all UV filters were absorbed following a single-dose application. Sunscreens were rank ordered by the amount of the UV filters absorbed. Data obtained from the IVPT method using a single finite dose and heat-separated human epidermis was found to correlate with the clinical data. Rank orders of the cumulative in vitro skin permeation and the in vivo AUC were found comparable for oxybenzone, homosalate, octisalate, and octinoxate. Rank orders of the in vitro and in vivo skin retention of oxybenzone and octinoxate were also comparable. Additional IVPT parameters may be optimized to enhance the discriminatory power for UV filters with low skin permeation potential (e.g., avobenzone and octocrylene).

In Vitro Testing of Sunscreens for Dermal Absorption: A Platform for Product Selection for Maximal Usage Clinical Trials.

Sunscreen products contain UV filters as active ingredients for the protection of the skin against UVR. The US Food and Drug Administration (FDA) issued a new proposed rule in 2019 (84.FR.6204) for sunscreens and identified the need for additional safety data for certain UV filters including their dermal absorption data. Dermal absorption data reveal systemic exposure of UV filters in humans, which can be obtained from clinical maximal usage trials. FDA guidance recommends conducting in vitro skin permeation tests (IVPTs) to help select formulations for maximal usage clinical trials as IVPT results may be indicative of in vivo absorption. This case study reports in vitro methodologies used for the selection of sunscreen products for an FDA-sponsored proof-of-concept maximal usage clinical trial. An IVPT method was developed using human cadaver skin. Commercially available sunscreen products were tested to determine the skin absorption potential of common UV filters using the IVPT. All the studied sunscreen products demonstrated a certain degree of skin absorption of UV filters using IVPT, and a formulation rank order was obtained. These sunscreen products were also characterized for several formulation properties including the globule size in emulsions, which was found to be an indicator for the rank order.

Analysis of benzonatate overdoses among adults and children from 1969-2010 by the United States Food and Drug Administration.

STUDY OBJECTIVE: To augment the December 2010 United States Food and Drug Administration (FDA) Drug Safety Communication on accidental ingestion of benzonatate in children less than 10 years old by summarizing data on emergency department visits, benzonatate exposure, and reports of benzonatate overdoses from several data sources. DESIGN: Retrospective review of adverse-event reports and drug utilization data of benzonatate. DATA SOURCES: The FDA Adverse Event Reporting System (AERS) database (1969-2010), the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance Project (NEISS-CADES, 2004-2009), and the IMS commercial data vendor (2004-2009). PATIENTS: Any patient who reported an adverse event with benzonatate captured in the AERS or NEISS-CADES database or received a prescription for benzonatate according to the IMS commercial data vendor. MEASUREMENTS AND MAIN RESULTS: Postmarketing adverse events with benzonatate were collected from the AERS database, emergency department visits due to adverse events with benzonatate were collected from the NEISS-CADES database, and outpatient drug utilization data were collected from the IMS commercial data vendor. Of 31 overdose cases involving benzonatate reported in the AERS database, 20 had a fatal outcome, and five of these fatalities occurred from accidental ingestions in children 2 years of age and younger. The NEISS-CADES database captured emergency department visits involving 12 cases of overdose from accidental benzonatate ingestions in children aged 1-3 years. Signs and symptoms of overdose included seizures, cardiac arrest, coma, brain edema or anoxic encephalopathy, apnea, tachycardia, and respiratory arrest and occurred in some patients within 15 minutes of ingestion. Dispensed benzonatate prescriptions increased by approximately 52% from 2004 to 2009. CONCLUSION: Although benzonatate has a long history of safe use, accumulating cases of fatal overdose, especially in children, prompted the FDA to notify health care professionals about the risks of benzonatate overdose. Pharmacists may have a role in preventing benzonatate overdoses by counseling patients on signs and symptoms of benzonatate overdose, the need for immediate medical care, and safe storage and disposal of benzonatate.

Safety of chewable tablets for children.

New emphasis on pediatric drug development makes the availability of safe, easy-to-use dosage formulations imperative for clinical practice. Chewable tablets are a widely used pediatric dosage form; however, a literature review on the safety of this formulation has not been published. We have, therefore, determined the safety of chewable tablets in the pediatric age group based on the published literature. A search of safety information on chewable tablets was performed from the published literature dating from January 1966 to January 1999. Search terms included tablet, chewable tablet, drug formulation, aspiration, choking, asphyxia, airway obstruction, and foreign body. Additional information was obtained from the Physician's Desk Reference, by purchasing products at a local drug store, from calls to manufacturers, and from the IMS Health National Prescription Audit Plus 7. Human, English-language studies of two types were included, clinical articles with any mention of chewable tablets, and aspiration case series. The results of this review showed that more than 60 chewable tablet formulations are approved for use in the United States. Medical issues, including foreign-body injuries, related to the chewable-tablet formulation were extremely rare. The advantages of chewable tablets include palatability, stability, precise dosing, portability, and ease of delivery. It is concluded that the available literature suggests that chewable tablets provide a safe, well-tolerated alternative to traditional pediatric drug formulations and offer significant advantages in children 2 years of age and older.