Development of a UV-Stabilized Topical Formulation of Nifedipine for the Treatment of Raynaud Phenomenon and Chilblains

Abstract

Raynaud’s Phenomenon is a vascular affliction resulting in pain and blanching of the skin caused by excessive and prolonged constriction of arterioles, usually due to cold exposure. Nifedipine is a vasodilatory calcium channel antagonist, which is used orally as the first-line pharmacological treatment to reduce the incidence and severity of attacks when other interventions fail to alleviate the condition and there is danger of tissue injury. Oral administration of nifedipine, however, is associated with systemic adverse effects, and thus topical administration with nifedipine locally to the extremities would be advantageous. However, nifedipine is subject to rapid photodegradation, which is problematic for exposed skin such as the hands. The goal of this project was to analyze the photostability of a novel topical nifedipine cream to UVA light. The effect of incorporating the photoprotectants rutin, quercetin, and/or avobenzone (BMDBM) into the nifedipine cream on the stability of nifedipine to UVA light exposure and the appearance of degradation products of nifedipine was determined. Rutin and quercetin are flavonoids with antioxidant activity. Both have the potential to improve the photostability of nifedipine by a number of mechanisms that either quench the intermolecular electron transfer of the singlet excited dihydropyridine to the nitrobenzene group or by preventing photoexcitation of nifedipine. Rutin at either 0.1% or 0.5% (w/w) did not improve the stability of nifedipine 2% (w/w) in the cream after UVA exposure up to 3 h. Incorporation of quercetin at 0.5% (w/w) did improve nifedipine stability from 40% (no quercetin) to 77% (with quercetin) of original drug concentration after 3 h UVA exposure. A combination of BMDBM and quercetin was the most effective photoprotectant for maintaining nifedipine concentration following up to 8 h UVA exposure.

Raynaud's phenomenon and digital ulcers: advances in evaluation and management

“…Although the use of topical glyceryl trinitrate for Raynaud's phenomenon was suggested as far back as 1951 [56], progress with topical therapies has been very slow. It is hoped that recent systematic reviews on topical nitrates [57,58] herald a wave of new interest, with several publications on topical therapies over the last 3 years [59–61,62 ▪ ,63–65,66 ▪ ]. Wasan et al [62 ▪ ] reported a preclinical study investigating the formulation of a novel nifedipine cream stable to ultraviolet light.…”

“…It is hoped that recent systematic reviews on topical nitrates [57,58] herald a wave of new interest, with several publications on topical therapies over the last 3 years [59–61,62 ▪ ,63–65,66 ▪ ]. Wasan et al [62 ▪ ] reported a preclinical study investigating the formulation of a novel nifedipine cream stable to ultraviolet light. Topical PDE5 inhibitors are also being researched [63,64] and topical econazole nitrate, an antagonist of Transient Receptor Potential Melastatin 8 has been studied in vitro [61,66 ▪ ].…”

Raynaud's phenomenon

“…18 Topical approaches to treatment also merit revisiting, as such, a 'local' approach to treatment could be better tolerated compared with systemic therapies for RP (and also digital ischaemic complications). [65][66][67]…”

Complex Spectroscopy Studies of Nifedipine Photodegradation

“…After 136 min UV irradiation, the ratio between the absorbances of bands at 224 nm, 276 nm and 310 nm is equal to 2.4:1.6:1. Recently, a band at 310 nm was reported in the case of NIF in methanol, which was exposure to UVA light for 2 h [31]. According to Ref.…”