Topically Applied Therapies for the Treatment of Skin Disease: Past, Present, and Future.

The purpose of this review is to summarize essential biological, pharmaceutical, and clinical aspects in the field of topically applied medicines that may help scientists when trying to develop new topical medicines. After a brief history of topical drug delivery, a review of the structure and function of the skin and routes of drug absorption and their limitations is provided. The most prevalent diseases and current topical treatment approaches are then detailed, the organization of which reflects the key disease categories of autoimmune and inflammatory diseases, microbial infections, skin cancers, and genetic skin diseases. The complexity of topical product development through to large-scale manufacturing along with recommended risk mitigation approaches are then highlighted. As such topical treatments are applied externally, patient preferences along with the challenges they invoke are then described, and finally the future of this field of drug delivery is discussed, with an emphasis on areas that are more likely to yield significant improvements over the topical medicines in current use or would expand the range of medicines and diseases treatable by this route of administration. SIGNIFICANCE STATEMENT: This review of the key aspects of the skin and its associated diseases and current treatments along with the intricacies of topical formulation development should be helpful in making judicious decisions about the development of new or improved topical medicines. These aspects include the choices of the active ingredients, formulations, the target patient population's preferences, limitations, and the future with regard to new skin diseases and topical medicine approaches.

In vitro studies into establishing therapeutic bioequivalence of complex topical products: Weight of evidence.

Over the past decade, topically applied drug products have experienced extraordinary price increases, due to the shortage of multisource generic drug products. This occurrence is mainly related to the underlying challenges evolved in topical bioequivalence documentation. Although there has been continuing regulatory efforts to present surrogate in vitro methods to clinical endpoint studies, there is still a continued need for cost- and time-efficient alternatives that account for product specificities. Hence, this work intended to expose bioequivalence assessment issues for complex topical formulations, and more specifically those related with product efficacy guidance. As a model drug and product, a bifonazole 10 mg/g cream formulation was selected and two different batches of the commercially available Reference Product (RP) were used: RP1 that displayed lower viscosity and RP4 which presented high, but not the highest, viscosity. In vitro human skin permeation testing (IVPT) was carried out and the results were evaluated by means of the traditional bioequivalence assessment approach proposed by the EMA, as well as by the Scaled Average Bioequivalence assessment approach proposed by the FDA. Based on previous experience, there was an expectation of a high level of variability in the results, thus alternative methods to evaluate local drug skin availability were developed. More specifically, an infected skin disease model, where ex vivo human skin was infected and ATP levels were used as a biological marker for monitoring antifungal activity after product application. The results showed that permeation equivalence could not be supported between the different RP batches. In contrast, this statistical difference between the formulation batches was not indicated in the disease model. Nevertheless, in pivotal IVPT studies, the lowest permeant formulation (RP4) evidenced a higher antifungal in vitro activity as reported by the lower levels of ATP. A critical appraisal of the results is likewise presented, focusing on an outlook of the real applicability of the regulatory guidances on this subject.

A Comprehensive Assessment of Radial Scars on Core Needle Biopsy in Patients with or without Breast Cancer: Upgrade Rate and Implications on Management.

BACKGROUND: Radial scars/radial sclerosing lesions (RS) are benign breast lesions identified on core needle biopsy (CNB) which can upgrade to malignancy at excision. There is limited data on RS detection and upgrade rates with more sensitive imaging such as magnetic resonance imaging (MRI) and none during their detection for breast cancer workup and its implication on patient treatment decisions. METHODS: A retrospective institutional study of RS diagnosed on CNB between January 2008 and December 2017 was conducted. Clinicopathologic and radiologic features of RS, patient treatment decisions, upgrade rates and long-term follow-up were examined. RESULTS: We identified 133 patients with RS on CNB, of whom 106 opted for surgery for an upgrade rate to malignancy of 1.9%, 2 patients. Radial scar was diagnosed on mammogram in 60%, MRI in 25% and ultrasound in 15% of patients. In this cohort, 32 patients had their RS detected during breast cancer workup (coexistent group) and they were more likely to have their radial scar detected by MRI (60% vs. 14%, P < .001) and undergo more extensive surgery (94% vs. 75%, P = .02). Among the 27 patients electing observation of their RS, only one (3.7%) developed breast cancer. CONCLUSIONS: Our results show an extremely low upgrade rate to malignancy of RS, regardless if there is coexisting breast cancer elsewhere. Despite this, RS still prompted more extensive surgical excisions. The findings do not support excision of RS even among breast cancer patients when identified at a separate site from their cancer.