The development of siRNA-based gene silencing therapies has significant potential for effectively treating debilitating genetic, hyper-proliferative or malignant skin conditions caused by aberrant gene expression. To be efficacious and widely accepted by physicians and patients, therapeutic siRNAs must access the viable skin layers in a stable and functional form, preferably without painful administration. In this study we explore the use of minimally-invasive steel microneedle devices to effectively deliver siRNA into skin. A simple, yet precise microneedle coating method permitted reproducible loading of siRNA onto individual microneedles. Following recovery from the microneedle surface, lamin A/C siRNA retained full activity, as demonstrated by significant reduction in lamin A/C mRNA levels and reduced lamin A/C protein in HaCaT keratinocyte cells. However, lamin A/C siRNA pre-complexed with a commercial lipid-based transfection reagent (siRNA lipoplex) was less functional following microneedle coating. As Accell-modified “self-delivery” siRNA targeted against CD44 also retained functionality after microneedle coating, this form of siRNA was used in subsequent in vivo studies, where gene silencing was determined in a transgenic reporter mouse skin model. Self-delivery siRNA targeting the reporter (luciferase/GFP) gene was coated onto microneedles and delivered to mouse footpad. Quantification of reporter mRNA and intravital imaging of reporter expression in the outer skin layers confirmed functional in vivo gene silencing following microneedle delivery of siRNA. The use of coated metal microneedles represents a new, simple, minimally-invasive, patient-friendly and potentially self-administrable method for the delivery of therapeutic nucleic acids to the skin.
Pharmaceutical tests for hard shell capsules are designed for orally administered capsules. The use of capsules in dry powder inhalers is widespread and increasing and therefore more appropriate tests are required to ensure quality and determine if these capsules are fit for purpose. This study aims to determine the flexibility, reproducibility and sensitivity of a quantitative method that is designed to evaluate the puncture characteristics of different capsule shell formulations under different climatic conditions. A puncture testing method was used to generate force displacement curves for five capsule formulations that were stored and tested at two different temperatures (5°C and 19°C). Force-displacement puncture profiles were reproducible for individual capsule shell formulations. The methodology was able to discriminate between capsules produced using different primary materials i.e. gelatin versus hypromellose, as well as more minor changes to capsule formulation i.e. different material grades and excipients. Reduced temperature increased the forces required for capsule puncture however further work is required to confirm its significance. Results indicate the method provides a reproducible and sensitive means of evaluating capsule puncture. Future studies should validate the methodology at different test sites, using different operators and with different capsule shell formulations.
Twenty‐seven women who had clomiphene‐resistant anovulation as the only cause of infertility were studied. They were divided into 2 groups on the basis of pre‐treatment endocrine and ultrasound assessment: hypogonadotropic hypogonadism (HH) (N=6) and polycystic ovarian disease (PCOD) (N=21). They were administered pulsatile luteinizing hormone releasing hormone (LHRH) therapy using miniaturized portable infusion pumps at a constant dose 15 ug per pulse every 90 minutes. The patients with HH were treated for a total of 31 cycles and 4 pregnancies were obtained. Twenty‐eight out of 31 cycles of therapy were ovulatory. The patients with PCOD were treated for a total of 65 cycles and, of these, 40 cycles were ovulatory. Ten patients became pregnant. When the patients with PCOD who ovulated were compared with those who failed to ovulate, it was found that the only predictor of successful therapy was the ponderal or body mass index. The mean ponderal index of those who ovulated was 22.20±2.62 (±SD) compared with 26.01±0.81 (±SD) for those who remained anovulatory. We conclude that pulsatile LHRH therapy is efficacious therapy for patients with HH but not as effective for patients with PCOD. In the latter group the ponderal index predicts for the likelihood of successful response to therapy.
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