DOI

10.17077/etd.wv5kg3q0

Document Type

Dissertation

Date of Degree

Summer 2018

Access Restrictions

Access restricted until 08/31/2020

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmacy

First Advisor

Brogden, Nicole K.

First Committee Member

Brogden, Nicole K.

Second Committee Member

An, Guohua

Third Committee Member

Fairley, Janet

Fourth Committee Member

Milavetz, Gary

Fifth Committee Member

Salem, Aliasger K.

Abstract

Infantile hemangiomas (IHs), benign vascular lesions present on the surface of the skin of children, are treated with systemic or topical beta-adrenergic antagonists (known as “beta-blockers”). However, systemic beta-blocker therapy is associated with serious adverse events in pediatric patients, and there are currently no topical formulations optimized for the skin. The objectives of this work were to 1) evaluate the local skin concentrations and drug permeation through the skin using novel beta-blocker formulations, and 2) characterize the epidermal properties and skin surface inflammatory mediators of IH skin.

Skin concentrations and drug permeation through the skin from current topical treatment options were quantified in vitro; these data served as benchmarks to which other treatment paradigms in later studies were compared. Microneedle (MN)-mediated delivery of two beta-blockers, propranolol and timolol, was evaluated in vitro using solid MNs and two dissolving MN array formulations. Solid MNs increased skin concentrations of timolol compared to intact skin, while producing similar skin concentrations of propranolol. Drug permeation through the skin was increased for both drugs after MN pretreatment. Both formulations of dissolving MN arrays were ineffective at increasing local skin concentrations compared to intact skin. This was likely due to the small loading capacity of drug into the array.

Drug-loaded microemulsions (ME) of varying composition were formulated and characterized. All ME formulations had solubilization properties, and water rich MEs had the greatest cumulative release through a homogenous membrane compared to surfactant rich MEs. Drug-loaded MEs did not increase local skin concentrations in vitro compared to a drug solution; however, water rich ME formulations produced greater skin-to-receiver ratio of drug concentration, indicating their potential for skin accumulation. MN pretreatment increased the skin-to-receiver ratios for surfactant rich formulations but not for water rich formulations, indicating this enhancement in skin retention after MN pretreatment is formulation dependent. These results demonstrate the potential for topical treatment of IHs upon further optimization of delivery and formulation parameters.

The epidermal properties and skin surface mediators of IH skin were compared to normal, unaffected skin. Significant differences in barrier function and color, as well as chemokine and growth factor concentrations, were observed between the two sites. These results provide a greater understanding of the IH properties that have previously not been quantified. Similar changes in lesion color, which correlate to efficacy, were observed after beginning treatment with oral propranolol or topical timolol, while changes in barrier function were similar between the two treatment groups. These results indicate topical timolol may be a safe alternative for systemic treatment for superficial IHs without a loss of efficacy.

Keywords

beta-blockers, infantile hemangioma, microemulsion, microneedle, topical

Pages

xx, 165 pages

Bibliography

Includes bibliographical references (pages 157-165).

Copyright

Copyright © 2018 Megan N. Kelchen

Available for download on Monday, August 31, 2020

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