Effect of dosing regimen and microneedle pretreatment on in vitro skin retention of topically applied beta-blockers

Abstract

Topical beta-blocker formulations are commonly used to treat infantile hemangiomas (IHs); however, the skin concentrations and drug permeation through the skin have not been quantified. Microneedles (MNs) may increase local skin concentrations, which could further enhance lesion clearance and improve dosing regimens. The objective of this study was to quantify skin concentrations and drug permeation of two beta-blockers, propranolol and timolol, in vitro after application to intact skin and skin pretreated with solid MNs of two lengths. Propranolol skin concentrations and drug permeation were significantly higher than timolol skin concentrations for all study conditions, which is likely due to the lipophilic nature of propranolol compared to the hydrophilicity of timolol. Propranolol skin concentrations were significantly influenced by dosing regimen, as skin concentrations increased with increasing drug application. Pretreatment of the skin with solid 250 μm and 500 μm length MNs increased local skin concentrations of timolol; propranolol skin concentrations did not significantly increase after MN pretreatment. Propranolol and timolol permeation through the skin increased after MN pretreatment with both MN lengths for both compounds. Taken together, solid MN pretreatment prior to application of topical timolol may be beneficial for deep or mixed IHs upon further optimization of the MN treatment paradigm.

Microneedle delivery system with rapid dissolution and sustained release of bleomycin for the treatment of hemangiomas

“…Meanwhile, timolol maleate has also been widely studied for topical application for IH treatment due to the commercial availability of timolol ophthalmic drops. For both propranolol and timolol, topical treatment is typically applied multiple times a day, which can reduce adherence to therapy [ 14 , 15 ].…”

“…Meanwhile, timolol maleate has also been widely studied for topical application for IH treatment due to the commercial availability of timolol ophthalmic drops. For both propranolol and timolol, topical treatment is typically applied multiple times a day, which can reduce adherence to therapy [14,15]. Bleomycin (BLM), a chemotherapy agent that inhibits DNA synthesis, is gaining increased prominence in sclerotherapy for patients with vascular anomalies [16].…”

Using Esterase Selectivity to Determine the In Vivo Duration of Systemic Availability and Abolish Systemic Side Effects of Topical β-Blockers

“…Furthermore, there is concern over the CNS development and growth impairment with systemic medications given to neonates for prolonged periods, although two recent studies have suggested no impairment of psychomotor development or growth impairment (at age three years , ). Other β-blockers have also been shown to be beneficial in infantile hemeangioma (e.g., timolol and atenolol − ), and there is increasing interest in using topical β-blockers, and developing improved topical delivery methods, in order to avoid the significant systemic problems associated with oral propranolol. − β-Blocker treatment for retinopathy of prematurity has been shown effective (although 20% of infants had serious adverse systemic side effects , ). β-Blocker treatment for other topical vascular tumors are now being investigated and used successfully, for example, pyogenic granuloma , and Kaposi’s sarcoma, , and in reducing epistaxis in hereditary hemorrhagic telangiectasia …”