Sunscreens: photostability, formulation and skin penetration

Introduction: Sunscreen products, containing UV-filters, are used worldwide to protect from the deleterious effects of sunlight. However, in order to provide this photoprotective function, they should be photostable and remain on the surface of the skin. The photostability of UVfilters, individually and in combination, using different light sources, light intensities, UV-filter concentrations, solvents and formulations has been extensively investigated. Regulations for sunscreen products in Australia, the USA and Europe do not require photostability testing, as per the International Conference on Harmonisation (ICH) Guideline Q1B for new drug substances and drug products. During UV-irradiation on exposure to sunlight, there is potential for chemical UV-filters to degrade by direct photolysis. Chemical UV-filters are also often used in combination with the physical UV-filter, titanium dioxide (TiO₂), increasing the complexity of the system, due to the ability of TiO₂ to cause photocatalytic reactions. In recent years issues have been raised that TiO₂ nano-particles may penetrate through the skin, but no evidence has been found and the Therapeutic Goods Administration (TGA) regards them as safe. However, whether these TiO₂ nano-particles may have an effect on the photostability of chemical UVfilters has not been investigated. The aim of the study was therefore to determine the photostability and skin penetration of a combination of chemical UV-filters with TiO₂, investigating the effect of particle size on photostability.\ud \ud Methods: Chemical UV-filters, Butyl methoxy dibenzoylmethane (BMDM), Octocrylene (OC) and Benzophenone-3 (B3) were verified for purity by melting point determinations, differential scanning calorimetry (DSC) and high performance liquid chromatography (HPLC). UV-filter identity was confirmed by nuclear magnetic resonance (NMR)-, infrared (IR)- and ultraviolet (UV)-spectroscopy. A reverse-phase HPLC method was developed and validated for the simultaneous determination of BMDM and OC in the presence of their photodegradants. Validation parameters included linearity, accuracy, precision, specificity, sensitivity and robustness. This HPLC method was also employed for the determination of UV-filter B3 during skin penetration studies and to identify photodegradants by liquid chromatography - mass spectroscopy (LC-MS).\ud \ud Photostability studies of BMDM and OC individually and in combination were undertaken in methanol and a microemulsion. The microemulsion was adapted from a formula in the literature, with xanthan gum added to optimise the viscosity for topical application. Photodegradation profiles of chemical UV-filters in methanol were determined in a photoreactor using a medium pressure mercury lamp as light source and a pyrex glass vessel (λ ≥ 300 nm). Incorporated in a microemulsion, UV-filter photostability was determined in a solar simulator (λ ≥ 290 nm), according to ICH Guideline Q1B. The influence of silica coated TiO₂ (~ 119 nm), uncoated micro- (~ 0.6 μm) and nano-TiO₂ (< 25 nm) on the photostability of both chemical UV-filters was investigated. Degradation kinetics of BMDM and OC separately and in combination were studied in methanol in the photoreactor, using a quartz glass vessel (λ ≥ 200 nm).\ud \ud Skin penetration of BMDM and OC, incorporated in the microemulsion, was then studied in vitro using porcine ear skin in Franz diffusion cells. Results were compared to the skin penetration of UV-filter B3, which is known to penetrate the skin and cause photoallergic skin reactions. UV-filter concentrations were determined in the receptor fluid, the skin (stratum corneum and viable epidermis/dermis) and the remaining microemulsion on the skin surface using the validated HPLC method. The stratum corneum was separated from the viable epidermis/dermis using the tape stripping method.\ud \ud Results and Discussion: In methanol, photodegradation of BMDM in the presence of silica coated, micro- and nano-TiO₂ was higher than without TiO₂. In general, OC showed less photodegradation than BMDM. Both, BMDM and OC, followed mixed zero- and first-order degradation kinetics. Photodegradants of both UV-filters were identified by LC-MS and molecular weights were confirmed by Fourier transform - mass spectroscopy (FTMS). Two major photodegradants were found for BMDM. Although in the presence of nano-TiO₂ (pyrex glass), OC recovery was reduced by 38 %, after irradiation through quartz glass, one major photodegradant was identified for OC. The major findings from methanol studies, that nano- TiO₂ causes higher photodegradation than micro-TiO₂ and that BMDM is less photostable than OC, were confirmed in the microemulsion and a reference cream. OC did not degrade in the absence or presence of coated TiO₂ and the lowest OC recovery was determined in the presence of nano-TiO₂ (88 %), while BMDM recovery varied from 0 to 16 %. Irradiated in combination with OC UV-filter BMDM showed a higher recovery (16 %) than irradiated alone (4 %), due to the stabilising effect of UV-filter OC on BMDM via triplet-triplet energy transfer.\ud \ud Although the combination of BMDM and OC influenced their photostability, skin penetration was not affected by their presence in combination. Generally, BMDM, OC and B3 showed low skin penetration. BMDM and OC were not detected in the receptor fluid after 24 hours and only 0.03 % of B3 was detected. To maintain its photoprotective character, a UV-filter should remain on the surface of the skin or in the stratum corneum. Therefore, the presence of these UV-filters in the viable epidermis/dermis is of interest. As expected B3 showed the highest concentration in this skin compartment (1.09 %), followed by BMDM (0.14 %) and OC with the lowest concentration (0.02 %). Percentages were related to the complete UV-filter content in the microemulsion. This penetration is explained in terms of lipophilicity and molecular vi weight of the UV-filters, with B3 being the least lipophilic molecule with the smallest molecular weight, while OC is the most lipophilic molecule with the largest molecular weight.\ud \ud Conclusions: Photostability of BMDM and OC, including TiO₂, has been extensively investigated. UV-filters are often used in combinations in sunscreen products to increase their photoprotective effect and to reduce their individual components to minimise toxicity. Although the inclusion of nano-TiO₂ in sunscreen products is regarded as safe in terms of skin penetration, the effect of this physical UV-filter on the photostability of chemical UV-filters is noteworthy. This research presents the first findings on the effect of particle size of TiO₂ on the photostability of chemical UV-filters and is significant because of the potential for the photoprotection of sunscreen products containing these UV-filters, to be compromised

Photostability of sunscreens

Sunscreens were originally designed to include mainly UVB-filters. Because of the deeper penetration of UVA light, causing photoaging and DNA damage, there has been a shift towards broad spectrum sunscreens. These broad spectrum sunscreens now include both UVA- and UVB-filters and other ingredients which possess antioxidant activity. Although sunscreens are regulated in most countries, photostability testing is not mandatory. Because of the ability of sunscreen ingredients to absorb UV-light and the complexity of most of these formulations, which may include more than one UV-filter, antioxidants and other formulation excipients, it is important that their photostability in combination is determined

Photochemical and photocatalytic degradation of diclofenac and amoxicillin using natural and simulated sunlight

Photochemical and titanium dioxide (TiO2) photocatalysed degradations of diclofenac and amoxicillin in water, under natural and simulated sunlight, were investigated. Direct photolysis of diclofenac resulted in about 80% degradation after exposure to an irradiation level of 400 W/m2 for 4 h, while in the presence of TiO2, 96% of diclofenac was degraded after the same time period. At the irradiation level of 765 W/m2, 99% of the drug was degraded within 1 h exposure. The efficiency of degradation of diclofenac was thus proportional to the level of simulated irradiation. The use of floating solar reactors has resulted in comparable rate of photodegradation by direct natural sunlight to that achieved by the solar simulator. In contrast, amoxicillin remained photostable under direct photolysis, while degrading significantly in the presence of TiO2

Influence of titanium dioxide particle size on the photostability of the chemical UV-Filters butyl methoxy dibenzoylmethane and ctocrylene in a microemulsion

Sunscreen products often contain combinations of ultraviolet (UV)-filters in order to achieve broad spectrum protection from exposure to sunlight. The inclusion of both chemical and physical UV-filters in these products, however, increases the possibility for both photolytic and photocatalytic reactions to occur. This study investigated the effect of titanium dioxide (TiO2) particle size on the photostability of the chemical UV-filters butyl methoxy dibenzoylmethane (BMDM) and octocrylene (OC) formulated in a microemulsion. The International Conference on Harmonisation (ICH) Guideline Q1B for photostability testing of new active substances and medicinal products was applied. BMDM and OC in the microemulsion were irradiated with simulated sunlight in the presence of nano- (<25 nm) and micro-TiO2 (~0.6 μm) and their concentrations determined using a validated high performance liquid chromatography (HPLC) method. For the combination of BMDM and OC, the photodegradation for BMDM was found to be 12% higher in the presence of nano-TiO2 as compared to that of the micro-TiO2. This enhanced photodegradation is attributed to the larger surface area of the nano-TiO2 and the increased generation of reactive oxygen species (ROS). Because of these findings, sunscreen products containing chemical UV-filters and nano-TiO2 should be regarded with caution, due to the potential loss of photoprotection

Common medicines for PRN use: stability considerations in DAAs

[Extract] Dose administration aids (DAAs), also known as multi-compartment compliance aids (MCCA or MCA) or monitored dosage systems (MDS), are designed to assist patients in managing their medicines by organising individual doses according to the prescribed dosing schedule

Stability of paracetamol tablets repackaged in dose administration aids for prn use: implications for practice

[Extract] Paracetamol tablets repackaged into dose administration aids and stored under both ambient and accelerated conditions are stable for 12 months

Repackaged sodium valproate tablets: meeting quality and adherence to ensure seizure control

Purpose: Sodium valproate, which is commonly repacked to assist with adherence to ensure seizure control, is hygroscopic and therefore sensitive to moisture. The aim of this study was thus to determine the stability implications of removing the enteric coated tablets from their original packaging and repackaging into a Dose Administration Aid (DAA) with storage under various environmental conditions. Methods: Physicochemical stability of enteric coated sodium valproate tablets repackaged into a DAA and stored at controlled room temperature, accelerated and refrigerated conditions was evaluated for 28 days. A validated high performance liquid chromatography method was used for the quantitation of the drug content. Results: Although the chemical stability (sodium valproate between 95 and 105% of labelled content) was maintained for 28 days for all storage conditions, for those tablets stored under accelerated conditions the integrity of the enteric coat was compromised after only 8 days. Conclusions: Repackaging of enteric coated sodium valproate should be undertaken with caution and be informed by storage climate. This is particularly relevant for those patients living in hot, humid environments where they should be advised to store their DAA in a refrigerator

Butyl methoxy dibenzoylmethane

This book chapter describes the chemical and physical properties of butyl methoxy dibenzoylmethane, one of the most commonly used topically applied UVA filters in sunscreen products

The precuneus and the insula in self-attributional processes

Attributions are constantly assigned in everyday life. A well-known phenomenon is the self-serving bias: that is, people’s tendency to attribute positive events to internal causes (themselves) and negative events to external causes (other persons/circumstances). Here, we investigated the neural correlates of the cognitive processes implicated in self-serving attributions using social situations that differed in their emotional saliences. We administered an attributional bias task during fMRI scanning in a large sample of healthy subjects (n = 71). Eighty sentences describing positive or negative social situations were presented, and subjects decided via buttonpress whether the situation had been caused by themselves or by the other person involved. Comparing positive with negative sentences revealed activations of the bilateral posterior cingulate cortex (PCC). Self-attribution correlated with activation of the posterior portion of the precuneus. However, self-attributed positive versus negative sentences showed activation of the anterior portion of the precuneus, and self-attributed negative versus positive sentences demonstrated activation of the bilateral insular cortex. All significant activations were reported with a statistical threshold of p ≤ .001, uncorrected. In addition, a comparison of our fMRI task with data from the Internal, Personal and Situational Attributions Questionnaire, Revised German Version, demonstrated convergent validity. Our findings suggest that the precuneus and the PCC are involved in the evaluation of social events with particular regional specificities: The PCC is activated during emotional evaluation, the posterior precuneus during attributional evaluation, and the anterior precuneus during self-serving processes. Furthermore, we assume that insula activation is a correlate of awareness of personal agency in negative situations

HPLC method for the simultaneous determination of the UV-Filters butyl methoxy dibenzoylmethane and octocrylene in the presence of their photodegradants

Butyl methoxy dibenzoylmethane (BMDM) and octocrylene (OC), common UV-filters in sunscreen products are often used in combination. Together they provide broad spectrum photoprotection from exposure to both UVA- and UVB-light. These UV-filters may, however, undergo photodegradation and generate photodegradants, resulting in a potential loss of photoprotection. It is thus a concern that the photostability testing as described by the ICH Guideline Q1B is not a requirement for sunscreen products in Australia, Europe or the USA. UV-filter photodegradants have in addition been shown to be toxic, highlighting the importance of their separation from the parent UV-filters. An HPLC method was developed and validated to quantitatively determine a combination of these UV-filters in the presence of their photodegradants. Reverse-phase chromatography was employed, using a C18 column and an isocratic mobile phase consisting of methanol/water/acetic acid (89/10/1 v/v). Validation according to the ICH guidelines for linearity, accuracy, precision, sensitivity, specificity and robustness was confirmed. The developed and validated method was then successfully applied to the determination of BMDM and OC in an aqueous cream base, typically used in sunscreens, after photostability testing, according to the ICH Guideline Q1B. In addition, the diketo-enol ratio of BMDM in methanol-d 4 was determined by NMR and the two major photodegradants were identified by FTMS and LC–MS