Adverse Reactions to Sunscreens.

Adverse reactions to sunscreens are uncommon in relation to their widespread use [Loden et al. Br J Dermatol. 2011;165(2):255-62; Jansen et al. J Am Acad Dermatol. 2013;69(6):867 e861-814; quiz 881-862] and can be related to both active and inactive ingredients in sunscreen products [DiNardo et al. J Cosmet Dermatol. 2018;17(1):15-19; Barrientos et al. Contact Dermatitis. 2019;81(2):151-52]. Pathogenetically, the main cutaneous adverse reaction patterns to sunscreens can be divided into allergic and irritant contact dermatitis, phototoxic and photoallergic contact dermatitis, contact urticaria, and, in solitary cases, anaphylactic reactions [Lautenschlager et al. Lancet. 2007;370(9586):528-37]. A summary is provided in Table 1. Nearly all adverse effects due to active sunscreen ingredients reported to date are related to the organic UV filters, which are sometimes also referred to as "chemical UV filters." This imbalance is attributable to the lipophilic character and small molecular size of the organic UV filters that allow skin penetration, which is the basic requirement to initiate the sensitization [Stiefel et al. Int J Cosmet Sci. 2015;37(1):2-30]. In contrast, cutaneous adverse reactions to inorganic UV filters, initially termed "physical UV filters" owing to their firstly known "physical" mechanism of action through reflection and scattering [Stiefel et al. Int J Cosmet Sci. 2015;37(1):2-30], are only reported by case reports. Neither zinc oxide nor titanium dioxide possesses relevant skin-irritating properties or sensitization potential [Lau-tenschlager et al. Lancet. 2007;370(9586):528-37]. Adverse reactions to UV filters currently approved in the European Union as listed in the Annex VI (updated November 7, 2019) are summarized in Table 2.

Challenges in Formulating Sunscreen Products.

Developing efficient sunscreen products with an acceptable sensory feel after application on skin, that meet current regulatory market and consumer requirements, is a major challenge, exacerbated by new restrictions limiting the use of certain ingredients previously considered crucial. This paper outlines a development strategy for -formulating sunscreens along a generic professional development pathway. Each galenic system will be different and must be customized. Development starts with benchmarking, followed by UVA/UVB filter platform selection and in silico calculation/optimization of photoprotection performance for the desired SPF, UVA-PF, and other requested endpoints. Next comes the selection of the emulsifier system and other key formulation ingredients, such as oil components, triplet quenchers, and antioxidants, with sensory, rheological, and film formation functions. Preliminary cost estimation is then performed to -complete the conceptual process before the start of the practical galenic development. The successful development of modern sunscreen products is based on -comprehensive expertise in chemistry, galenic methodology, regulation, and patenting, as well as specific -market and consumer requirements. The selection of the UV filters is the first key decision and constrains later choices. Other properties, such as water resistance and preservation or active ingredients, may need to be considered. The 4 basic requirements of efficacy, safety, registration, and patent freedom become checklist items to ensure that after development, a sunscreen product has a chance of success.

Topical corticosteroid vehicle composition and implications for clinical practice.

This narrative review highlights the therapeutic significance of topical corticosteroid (TCS) vehicles and provides subsequent guidance to improve clinical and research outcomes. A greater understanding of the relationship between the topical vehicle, corticosteroid and skin is needed to ensure safer, more effective treatment for patients. Topical vehicles are not inert and can affect TCS bioavailability, due to the ability of their composition to positively or negatively influence skin status and change the physiochemical characteristics of an inherent corticosteroid. However, this principle is not commonly understood, and has contributed to inconsistencies in potency classification systems. This review provides an insight into the research methods and standardization needed to determine TCS product bioavailability. It identifies formulation components responsible for vehicle composition that underpin the quality, stability, compounding and functionalities of vehicle ingredients. This helps to contextualize how topical vehicles can be responsible for clinically significant effects, and how their composition gives products unique properties. In turn, this facilitates a more in-depth understanding of which resources offer information to inform the best selection of TCS products and why products should be prescribed by brand or manufacturer. This review will better equip clinicians and formulary teams to appraise products. It will also inform prescribing of Specials and why products should not be manipulated. The recommendations, accompanied by patient perspectives on using TCS products, assist clinical decision-making. They also identify the need for research into concomitant application of TCS products with other topical therapies.

Expanding Patch Testing Beyond the Baseline Series: Usefulness of Customized Antimicrobials, Vehicles, and Cosmetics Series.

BACKGROUND: Testing cosmetics and their ingredients is essential to avoid missing relevant allergens and to monitor fluctuating incidence of hypersensitivity. OBJECTIVE: The aim of this study was to review the usefulness of patch testing with a customized antimicrobials, vehicles, and cosmetics (AVC) series over 15 years at a single Canadian site. METHODS: Between January 1, 2005, and December 31, 2019, patients suspected of having cosmetics allergy were patch tested with a 40-allergen AVC series in addition to the North American Contact Dermatitis Group standard screening series. We reviewed the patch test results of 2868 patients. RESULTS: We consecutively patch tested with the baseline series 6103 patients, of which 2868 (47%) were also tested with the AVC series. Of 53 different allergens that were tested at some point, 26 remained in the series throughout the 15-year span. The most common positive allergens were thimerosal (4.52%), polyvidone-iodine (2.25%), propolis (2.06%), sodium metabisulfite (1.94%), dodecyl gallate (1.53%), carmine (1.10%), lauryl glucoside (1.01%), sandalwood oil (0.7%), and tert-butylhydroquinone (0.7%). CONCLUSIONS: Although the expansion of the North American Contact Dermatitis Group standard screening series has decreased the yield from the AVC series from 21.1% to 13.9%, it still remains a useful adjunct for patients suspected of having cosmetics or disinfectants allergy.

Potential cross-reactivity of polysorbate 80 and cremophor: A case report.

INTRODUCTION: Anaphylactic and hypersensitivity reactions are known adverse effects of many drug products and may be due to the inactive ingredients of the drug formulation. Specifically for paclitaxel and docetaxel, it is their excipients (cremophor and polysorbate 80, respectively) that have been identified as being most likely responsible for these reactions. CASE REPORT: The patient is a 39-year-old female, with a history of breast cancer and no known allergies, who was scheduled to start chemotherapy. While being administered fosaprepitant, she reported shortness of breath and was noted to be hypotensive and flushed. Two months later, the patient returned to clinic to start weekly paclitaxel. During the administration of the paclitxel test dose, the patient reported difficulty breathing, flushing, and chest tightness. Management and outcome: Both medication reactions were managed with epinephrine and other supportive medications. Fosaprepitant was taken out of the patient's antiemetic regimen for future cycles and paclitaxel was switched to nab-paclitaxel. DISCUSSION: It is well documented that paclitaxel and fosaprepitant have the potential to cause hypersensitivity reactions due to their excipients. While it is likely that each reaction was a unique event, it is difficult to ignore the possibility of cross-reactivity due to the presence of oleic acid in both excipients.

Delayed hypersensitivity reactions caused by drug excipients: a literature review

The European Medicines Agency (EMA) defines excipients as the constituents of a pharmaceutical form apart from the active substance. Delayed hypersensitivity reactions (DHRs) caused by excipients contained in the formulation of medications have been described. However, there are no data on the prevalence of DHRs due to drug excipients. Clinical manifestations of allergy to excipients can range from skin disorders to life-threatening systemic reactions. The aim of this study was to perform a literature review on allergy to pharmaceutical excipients and to record the DHRs described with various types of medications, specifically due to the excipients contained in their formulations. The cases reported were sorted alphabetically by type of medication and excipient, in order to obtain a list of the excipients most frequently involved for each type of medication

La Agencia Europea de Medicamentos define los excipientes como los componentes de una forma farmacéutica diferenciados del principio activo. Se han descrito reacciones de hipersensibilidad retardada causadas por los excipientes contenidos en la formulación de medicamentos. Sin embargo, no hay datos sobre la prevalencia de dichas reacciones. Las manifestaciones clínicas de la alergia a los excipientes pueden ir desde trastornos de la piel hasta reacciones sistémicas que ponen en peligro la vida. El objetivo de este estudio fue realizar una revisión de la literatura sobre la alergia a los excipientes farmacéuticos y recopilar las reacciones de hipersensibilidad retardada descritas con diferentes tipos de medicamento, debido solo a excipientes contenidos en sus formulaciones. Los casos se clasificaron alfabéticamente por tipo de medicamento y excipiente, con el fin de obtener una lista de los excipientes más frecuentemente implicados con cada tipo de medicamento

A Review of Topical Corticosteroid Foams

BACKGROUND: Topical corticosteroids are efficacious treatment options for multiple dermatoses. However, ointments and cream corticosteroid vehicles can be cumbersome to patients and may act as a barrier to adherence. Foam vehicles may be preferred by some patients. OBJECTIVE: To evaluate the efficacy and safety of topical corticosteroid foams. METHODS: A literature review was conducted using the keywords "clobetasol," "betamethasone," "propionate," "valerate," "topical," "foam," "vehicles," "desonide," and "clinical trial." Thirty-seven articles were chosen. RESULTS: For moderate plaque-type psoriasis, 68% of subjects using clobetasol propionate foam achieved a Physician Static Global Assessment score of 0 or 1 at week 2 compared with 21% in the control group (P<0.0001). For betamethasone valerate (BMV) foam, a 12-week regimen for alopecia areata yielded a mean Investigator Global Assessment score of 2.9 compared with placebo (4.6; P<0.001) and achieved ≥75% hair regrowth in 42.86% of subjects. Furthermore, BMV foam cleared or almost cleared 72% of scalp psoriasis subjects compared with BMV lotion (P≤0.005%). For calcipotriol plus betamethasone dipropionate foam, 38.3% of psoriasis subjects achieved treatment success compared with placebo (22.5%; P<0.001). Desonide 0.05% foam was superior to vehicle foam in pediatric atopic dermatitis subjects. CONCLUSION: Topical corticosteroid foams can be used for a variety of corticosteroid-responsive dermatoses. Topical corticosteroid foams are generally easy to apply and may improve patient adherence and, therefore, clinical outcome in patients who prefer a convenient and less messy topical therapy.

Two Multicenter, Randomized, Double-Blind, Parallel Group Comparison Studies of a Novel Foam Formulation of Halobetasol Propionate, 0.05% vs Its Vehicle in Adult Subjects With Plaque Psoriasis

BACKGROUND: A novel foam formulation of halobetasol propionate, 0.05% (HBP-Foam) has been developed to treat plaque psoriasis in patients who prefer a thermostable topical foam with low application shear that allows for easier coverage over large and/or hirsute areas than existing formulations. OBJECTIVE: To determine the safety and effectiveness of HBP-Foam in subjects with plaque psoriasis. METHODS: Two randomized, double-blind, vehicle-controlled clinical studies were conducted in 560 adult subjects with moderate to severe plaque psoriasis. Subjects applied the assigned test article to all psoriatic plaques twice daily for 14 days. The key efficacy measures were the proportion of subjects with "treatment success," defined as those subjects that achieved a score of 0 (clear) or 1 (almost clear) and at least a two-grade improvement compared to baseline for the Investigator's Global Assessment (IGA) and for the clinical signs of psoriasis (plaque elevation, scaling, and erythema) as well as pruritus. Safety measurements included adverse events and local skin reactions in the treatment area. RESULTS: HBP-Foam was statistically superior to vehicle in achieving "Treatment Success" in 25.3% and 30.7% vs 3.9% and 7.4% (P<0.001) in Studies 1 and 2, respectively. Pruritus scores statistically improved by over 30% in HBP-Foam treated subjects. In addition, these subjects experienced a significant reduction in the clinical signs of psoriasis (plaque elevation, scaling, and erythema). In contrast, in the vehicle groups the decrease in psoriasis-related signs was generally not observed. Safety outcomes were unremarkable and similar in both the HBP-Foam and vehicle treatment groups. CONCLUSIONS: These results demonstrate the safety and effectiveness of HBP-Foam in the treatment of plaque psoriasis. Furthermore, this novel foam formulation has demonstrable for its ease of application over large and/or hairy treatment areas. ClinicalTrials.gov Registration: NCT02742441 NCT02368210

Carrier oils in dermatology.

Wounds are a common medical infliction. With the increase in microbial resistance and a shift of interest towards complementary medicines, essential oils have been shown to be beneficial in suppressing microbial growth. However, in practice, essential oils are more often diluted into a base due to the risk of topical adverse effects, such as dermatitis. There is a lack of collated evidence-based information on toxicity and efficacy of carrier oils. The current information on the subject matter is restricted to generic, aroma-therapeutic books and pamphlets, based on anecdotal evidence rather than an experimental approach. Therefore, this review aimed at identifying the recommended carrier oils used in dermatology and thereafter collating the scientific evidence to support the use of carrier oils together with essential oils recommended for dermatological use. Aloe vera gel had multiple studies demonstrating the ability to enhance wound healing; however, several other carrier oils have been largely neglected. It was observed that the extracts for certain plant species had been used to justify the use of the carrier oils of the same plant species. This is an inaccurate cross assumption due to the difference in chemical composition and biological activities. Lastly, despite these carrier oils being recommended as a base for essential oils, very little data was found on the interactive profile of the carrier oil with the essential oil. This review provides a platform for further studies, especially if essential oils are to receive credence in the scientific field.

Validation of Botanical Treatment Efficiency for Adults and Children Suffering from Mild to Moderate Atopic Dermatitis

Objective: The study was conducted to determine the efficiency of the botanicals combination incorporated in the Kamedis Eczema Therapy Cream (the tested product) for adults and children suffering from mild to moderate Atopic Dermatitis. Design: The study designed as an interventional, multi-center, double-blind, randomized, controlled study. Setting: Subjects were evenly randomly divided into three treatment groups: tested product, vehicle, and comparator. The vehicle used was the identical tested product without the botanical combination while the comparator was a leading OTC brand in the US market. All three above groups used a similar Kamedis wash for the body and face following by one of the three randomized treatment creams for the affected areas on the face and body. Participants: One hundred and eight (108) subjects with uncomplicated, stable, mild to moderate atopic dermatitis recruited and qualified for the study; 71 females and 37 males, age 3 to 73. Measurements: The investigator assessed the severity of each subject using the Investigator Global Assessment (IGA) and affected body surface area (BSA) at each of the visit days 0, 7, 14, and 28. Results: The tested product demonstrated an improvement in IGA and BSA over the vehicle at every visit across treatment time, proving the validation that the botanical product is much more effective and beneficial than the same product without the botanicals. The tested product as well as the comparator reached exactly the same percentage, 34%, of 'clear' IGA subjects of the enrolled subjects, presenting advantage over the vehicle. The BSA improvement comparison analysis of the tested product over the vehicle yielded statistically significant P value of 0.0369. Conclusion: The study results approve and validate that the botanical combination is the key factor for the efficacy and improvement of the AD symptoms within this study population. J Drugs Dermatol. 2019;18(6):557-561.

A Phase 2b, Randomized, Double-Blind Vehicle Controlled, Dose Escalation Study Evaluating Clascoterone 0.1%, 0.5%, and 1% Topical Cream in Subjects With Facial Acne

Androgens play a key role in acne pathogenesis in both males and females. Clascoterone (CB-03-01, Cortexolone 17α propionate) cream is a topical anti-androgen under investigation for the treatment of acne. The results from a phase 2b dose escalating study are discussed. Methods: Primary objective: to compare the safety and efficacy of topical creams containing clascoterone 0.1% (twice daily [BID]), 0.5% (BID), or 1% (daily [QD] or BID) versus vehicle (QD or BID) in male and female subjects ≥12 years with facial acne vulgaris. Efficacy was assessed by: Investigator's Global Assessment (IGA)--the overall severity of acne using a five-point scale (from 0=clear to 4=severe); inflammatory and non-inflammatory acne lesion counts (ALC); and subject satisfaction with treatment--subjects assessed overall treatment satisfaction using a 4-point scale. Safety assessments: local and systemic adverse events (AEs), physical examination/vital signs, laboratory tests, local skin reactions (LSRs), and electrocardiograms (ECGs). Treatment success required a score of "clear" or "almost clear" (IGA score of 0 or 1) and a two or more-grade improvement from baseline. Results: 363 subjects (N=72, 0.1% BID; N=76, 0.5% BID; N=70, 1% QD; N=70, 1% BID; and N=75, vehicle QD or BID) enrolled. 304 subjects (83.7%) completed the study. Intention to Treat (ITT) population: 196/363 (54.0%) females; 167/363 46.0%) males; (257/363 (70.2%) were white; average age=19.7 years. Demographic and baseline characteristics were similar across all groups. Treatment success at week 12 were highest for the 1% BID (6/70, 8.6%) and 0.1% BID (6/72, 8.3%) groups versus vehicle (2/75, 2.7%). Absolute change in inflammatory (P=0.0431) and non-inflammatory (P=0.0303) lesions was statistically significant among the treatment groups. The median change from baseline at week 12 in inflammatory and non-inflammatory lesions was greatest in the 1% BID group -13.5 and -17.5, respectively. Similar results were observed for the secondary efficacy endpoints whereby the highest success rate and greatest reduction in lesion counts from baseline to week 12 occurred with 1% BID. 93/363 subjects (25.6%) reported ≥1 AEs; total number of AEs=123 with 2 probably/possibly related to treatment (N=1, 1% QD group). Subjects with ≥1AEs: 0.1% BID=25.0%, 0.5% BID=38.2%, 1% QD=22.9%, 1% BID=18.6%, and vehicle=22.7%. AEs were mostly mild in severity and similar across all groups. Most AEs (93/121 76.8%) resolved by the end of the study. Erythema was the most prevalent LSR; 36.8% had at least minimal erythema at some point during the study. Conclusions: All clascoterone cream concentrations were well tolerated with no clinically relevant safety issues noted. Clascoterone 1% BID treatment had the most favorable results and was selected as the best candidate for further clinical study and development. Two Phase 3 investigations of clascoterone topical cream, 1% for the treatment of moderate-to-severe acne vulgaris in individuals ≥9 years recently concluded. J Drugs Dermatol. 2019;18(6):570-575.

Brinzolamide-loaded nanoemulsions: ex vivo transcorneal permeation, cell viability and ocular irritation tests.

The aim of this study was to investigate the corneal penetration of brinzolamide (BZ) nanoemulsions (NEs) and evaluate their in vitro and ex vivo irritancy potential. Twelve BZ NEs were prepared by the spontaneous emulsification method and ex vivo permeability studies were conducted using excised bovine corneas fixed onto Franz diffusion cells. To confirm the safety of the formulations for ophthalmic use, preparations were examined for potential ocular irritancy using a cell viability assay on retinal cells, the Hen's Egg Test-Chorio-Allantoic Membrane (HET-CAM) and the bovine corneal opacity-permeability (BCOP) test. Seven BZ NEs exhibited superior penetration across isolated bovine cornea compared to the marketed BZ suspension. The half maximal inhibitory concentration (IC50) values of various surfactants and oils determined using the sulforhodamine B cell viability assay on retinal cells showed that Transcutol P, Cremophor RH40 and Triacetin were the least toxic excipients and may be safely used in the eye at various concentrations. HET-CAM and BCOP tests revealed that NE6B and NE4C did not result in any irritation and were thus considered safe for ocular use. Our finding suggests that optimized NEs can be a safe and effective vehicle for ocular delivery of BZ.

Well-tolerated oral cyclosporine in a case of hypersensitivity to parenteral cyclosporine in postallogeneic bone marrow transplantation.

Cyclosporine is one of the main drugs used for the prophylaxis of graft versus host disease in bone marrow transplanted patients. Hypersensitivity reaction to intravenous cyclosporine is rare and might be due to its vehicle polyoxyethylated castor oil, Cremophor EL. The exact mechanism is unknown, but IgE and IgG antibodies, complement, and histamine release have been considered to play a role in the development of this reaction. Here, we describe a case of anaphylaxis to intravenous cyclosporine, which was developed in a 19-year-old Iranian female with acute myeloid leukemia who underwent allogeneic bone marrow transplantation from her sister. The corn oil-based soft gelatin capsule (Sandimmune®) was substituted with no reaction. Our observation along with the previous reports confirms the role of Cremophor EL in hypersensitivity reaction to cyclosporine, according to which, modifying the formulation of the intravenous (IV) form could be the solution for this problem.

Patch Testing to Propylene Glycol: The Mayo Clinic Experience.

BACKGROUND: Propylene glycol (PG) is a solvent, vehicle, and humectant being used increasingly in a wide array of personal care products, cosmetics, and topical medicaments. Propylene glycol is a recognized source of both allergic and irritant contact dermatitis. OBJECTIVE: The aim of the study was to report incidence of positive patch tests to PG at Mayo Clinic. METHODS: We retrospectively reviewed records of all patients patch tested to PG from January 1997 to December 2016. RESULTS: A total of 11,738 patients underwent patch testing to 5%, 10%, or 20% PG. Of these, 100 (0.85%) tested positive and 41 (0.35%) had irritant reactions. Patients also tested to a mean of 5.6 concomitant positive allergens. The positive reaction rates were 0%, 0.26%, and 1.86% for 5%, 10%, and 20% PG, respectively, increasing with each concentration increase. The irritant reaction rates were 0.95%, 0.24%, and 0.5% for 5%, 10%, and 20% PG, respectively. CONCLUSIONS: Propylene glycol is common in skin care products and is associated with both allergic and irritant patch test reactions. Increased concentrations were associated with increased reactions.

S2k guidelines for the use of topical preparations on the skin.

The present guidelines are aimed at dermatology residents and board-certified dermatologists as well as policymakers and insurance companies. Developed by dermatologists in collaboration with pharmacists using a formal consensus process (S2k), they include general aspects with respect to pharmacokinetics and regulatory terminology. Recommendations are provided on the various indications for extemporaneous preparations and their quality assurance. The importance of pharmaceutical vehicles and problems associated with substituting one vehicle for another are discussed. The guidelines include criteria for choosing a suitable pharmaceutical vehicle and for specific aspects in terms of treatment planning. In addition, recommendations are given for managing allergic reactions to vehicles or additives.

Potential Interference of Oil Vehicles on Genital Tubercle Development during the Fetal Period in ICR Mice.

Corn oil, sesame oil, and 10% ethanol in corn oil are commonly used as dosing vehicles in toxicology studies. Since these vegetable oils contain bioactive compounds, it is important for toxicology studies to characterize the toxicities of the dosing vehicles themselves. It has been recently proposed that the width of the genital tubercle (GT), the dorsal-ventral length (D-V length) of the GT, and urethral tube closure in mouse fetuses can be used as novel markers for monitoring sexual development in mice. However, how these parameters are influenced by the dosing vehicles themselves remains unclear. Therefore, we evaluated the effects of corn oil, sesame oil, and 10% ethanol in corn oil on GT width, D-V length, and GT morphology in ICR mice. Our results showed that all three vehicles influenced GT width and D-V length, but not GT morphology, suggesting that the effects of dosing vehicles themselves might need to be considered when GT width or D-V length is used as a parameter to evaluate the effects of chemicals on GT development.

Hyperosmolar metabolic acidosis in burn patients exposed to glycol based topical antimicrobials-A systematic review.

BACKGROUND: The well documented susceptibility of burn patients to acquired infections via damaged skin mandates application of antimicrobial agents. These agents are dissolved in various vehicles that augment skin absorption thus allowing greater efficacy. Polyethylene glycol (PEG) and Propylene glycol (PropG) are among the most commonly used vehicles, and both have been used in numerous medications and cosmetic products over the past few decades. Rarely, burn patients treated with agents containing these glycols present with a life threatening systemic toxidrome of hyperosmolar metabolic acidosis. We present a systematic review of outcomes in burn patients treated with similar agents. METHODS: Relevant studies were identified through systematic searches conducted in MEDLINE (Ovid), Embase (Ovid), CENTRAL (Ovid), and Web of Science (Thomson Reuters), from database inception to August 4th, 2016. All publications of clinical burn patient studies included at least one arm receiving a glycol based topical therapy. RESULTS: A total of 61 studies involving 10,282 patients and 4 different antimicrobial medications fulfilled the inclusion criteria. Nine burn patients (0.09%) were documented to present with hyperosmolar metabolic acidosis during topical silver sulfadiazine treatment. Propylene glycol isolated from their blood accounted for the high osmole gap. CONCLUSION: This first systematic review found very few cases of documented hyperosmolar metabolic acidosis, all within one study that had set to specifically explore this toxidrome. High index of suspicion with frequent osmolar gap monitoring may help identify future toxicities in a timely manner.