Polymeric micelle nanocarriers for targeted epidermal delivery of the hedgehog pathway inhibitor vismodegib: formulation development and cutaneous biodistribution in human skin

Background: The aim was to investigate cutaneous delivery and biodistribution of the hedgehog pathway inhibitor, vismodegib (VSD), indicated for basal cell carcinoma (BCC), from polymeric micelle formulations under infinite/finite dose conditions.

Methods: VSD-loaded micelles were characterized for drug content, particle size, and shape; a micelle gel was characterized for its rheological behavior. Cutaneous deposition and biodistribution of VSD were determined using porcine and human skin in vitro with quantification by UHPLC-MS/MS.

Results: The optimal micelle solution (Z_av 20–30 nm) increased the aqueous solubility of VSD by >8000-fold; drug content was stable after 4 weeks at 4°C. Application of micelle solution and micelle gel (0.086% w/v) to human skin for 12 h under infinite dose conditions resulted in statistically equivalent VSD deposition (0.62 ± 0.11 and 0.67 ± 0.14 μg/cm², respectively). Cutaneous biodistribution in human skin under infinite (micelle solution and gel) and finite (micelle gel) dose conditions showed that the VSD concentrations obtained in the basal epidermis, at depths of 120–200 μm, were ?3800- and ?2300-fold greater than the IC₅₀ reported for hedgehog signaling pathway inhibition in vitro.

Conclusion: Cutaneous delivery of VSD from micelle-based formulations might enable targeted, topical treatment of superficial BCC with minimal risk of systemic exposure.     

The antimicrobial effect of Iseganan HCl oral solution in patients receiving stomatotoxic chemotherapy: analysis from a multicenter, double-blind, placebo-controlled, randomized, phase III clinical trial

J Oral Pathol Med (2012) 41 : 229–234 Background: Cytotoxic chemotherapy induces changes in the oral microflora that may cause oral and systemic infections in myelosuppressed cancer patients. These complications prompted us to assess the antimicrobial activity of a topical Iseganan HCl mouthwash vs. placebo on the aerobic and facultatively anaerobic oral flora in these patients. Methods: Two hundred and twenty‐five chemotherapy patients were recruited into a randomized, double‐blind, placebo‐controlled trial, conducted at multiple centers. The study compared the antimicrobial efficacy of Iseganan HCl vs. placebo (95% of the Iseganan and 97% of the control group received myeloablative chemotherapy). Iseganan HCl 9 mg/3 ml was administered as a swish and swallow solution, six times daily for 21–28 days. Microbial cultures were made before and after the daily Iseganan mouth rinse on the first and final days of chemotherapy. Results: The reduction in total microbial load after the first day of treatment was statistically significant (1.59 vs. 0.18 log10 CFU for the Iseganan HCl and placebo groups, respectively, P < 0.0001). Iseganan HCl rinse had a cumulative effect demonstrated by the significant difference between the two groups on the last day of the study (i.e. completion of Iseganan daily treatment) (P < 0.05). The reduction was mainly due to decreased densities of viridans streptococci, non‐hemolytic streptococci, and yeasts. The minimal inhibitory concentration (MIC) of Iseganan HCl remained the same throughout the course of treatment. Conclusions: Topical Iseganan HCl significantly reduces the total oral aerobic bacterial, streptococcal, and yeast load. Its potential as an oral antimicrobial agent in preventing these types of infections is clear.     

复方苯佐卡因凝胶的局部毒性研究

目的评价复方苯佐卡因凝胶的局部刺激性和致敏性。方法依照国家食品药品监督管理局《化学药物刺激性、过敏性和溶血性研究技术指导原则》（以下简称指导原则）,采用大鼠口腔黏膜刺激性实验法、兔眼刺激性实验法以及豚鼠皮肤致敏实验法。结果复方苯佐卡因凝胶给大鼠口腔正常黏膜连续涂药3次,相当于3g·kg-1,均无刺激和毒性反应;一次性按每只0．1g给兔眼结膜涂药,亦未出现刺激性反应;给每只豚鼠皮肤0．2g致敏接触和激发接触,均无过敏反应发生。结论复方苯佐卡因凝胶对口腔黏膜无刺激性,对皮肤也没有致敏性。     

Oral beclomethasone dipropionate in gastrointestinal graft-versus-host disease

Beclomethasone dipropionate is a corticosteroid with topical activity for inflammatory disorders at mucosal surfaces. Oral beclomethasone dipropionate (orBec^®) has demonstrated activity in gastrointestinal acute graft-versus-host disease (aGVHD) associated with hematopoietic cell transplantation. Since the GI tract is the dominant aGVHD target in many patients, oral beclomethasone dipropionate reduces the requirement for systemic immunosuppressive drugs in treating aGVHD. In this patient population, reduced exposure to systemic corticosteroids is associated with fewer infections and, possibly, preserved graft-versus-tumor effects, yielding a statistically significant improvement in survival in a randomized, multicenter clinical trial.     

Insights into future therapeutics for atopic dermatitis

Introduction: Atopic Dermatitis (AD) is a common chronic inflammatory skin disorder with a constellation of symptoms. Currently, there are numerous therapies in various phases of drug development that target the pathogenesis of AD.

Areas covered: Our paper aims to examine small molecule therapies and other novel agents registered for clinical trial in the phase II and mainly phase III stages of development. A literature search using PubMed as well as Clinicaltrials.gov was conducted. Clinical trial evidence of these novel agents was compiled and assessed. Both topical and oral novel therapies with diverse range of mechanistic action are currently being studied, with varying success. These include phosphodiesterase-4 inhibitors, boron molecules, Janus kinase inhibitors, cannabinoid receptors agonists, kappa-opioid receptor agonists. A variety of compounds with yet undisclosed or unknown mechanisms of action are also being studied.

Expert opinion: Further research through extensive clinical trials will allow for more information about these targeted therapies and their potential place in the treatment algorithm of AD. Due to the success of such therapies in treating a spectrum of chronic inflammatory diseases, we remain hopeful that the successful development of targeted therapy for AD lies ahead.     

FDA对皮肤外用药活性成分人体最大用量试验的要求

美国食品药品管理局（FDA）于2018年5月发布了“考虑列入OTC专论的外用药活性成分的最大用量试验：研究要点和考虑的因素供企业用的指导原则”。最大用量试验（MUsT）是评估外用药体内生物利用度的标准方法,该指导原则对MUsT许多研究要点提出了具体的建议。详细介绍该指导原则的主要内容,期待对我国这方面的研究和监管有益。