Thesis (M.A.)--University of North Carolina at Chapel Hill, 2002. / Includes bibliographical references (leaves 57-59).

Two possible variables of the McKenzie/Stoughton blanching assay, namely amount applied to the test site and occlusion time have been investigated. Subsequently, two topical steroid preparations, Synalar cream (0,025% fluocinolone acetonide) and Betnovate cream (0,1% betamethasone 17-valer ate) were extemporaneously diluted with five and six placebo bases respectively. Taking cognizance of the two possible variables, these diluted preparations were assessed in vivo using a modified version of the McKenzie/Stoughton blanching assay for blanching activity over a 14 month period. It was found that the base E45, which is slightly alkali, had the greatest effect on both preparations. In the case of betamethasone 17-valerate this base c aused the conversion to the less active isomer, betamethasone 21-valerate whereas at the end of the 14 month test period it was found that the Synalar/E45 dilution contained no fluocinolone acetonide. Quantitative analysis of all the diluted preparations by high performance liquid chromatography using a reverse-phase system was performed. The data obtained f r om the systematic stUdies of the effects of varying concentrations and occlusion times were presented at the Eleventh National Congress of the South African Pharmacological Society. / KMBT_363 / Adobe Acrobat 9.53 Paper Capture Plug-in

M.Tech. / Purpose: This study aims to compare the effects of spinal manipulative therapy to the lumbar spine and/or pelvis, and spinal manipulative therapy to the lumbar spine and/or pelvis in conjunction with the application of transcutaneous flurbiprofen patches in the treatment of sub-acute/chronic mechanical low back pain with regards to pain, disability and lumbar spine and pelvic range of motion. These effects were based on a questionnaire consisting of a Numerical Pain Rating Scale, and an Oswestry Low Back Pain and Disability Questionnaire, and on lumbar spine range of motion (ROM) readings taken using a digital inclinometer. The questionnaire was completed and the ROM readings taken prior to treatment on the first, fourth and seventh consultations.

Opioid addiction is a serious national crisis impacting public health. Naloxone is a potent opioid antagonist administered to reverse the effects of opioid overdose. It is currently administered as an intravenous, intramuscular, subcutaneous injection and intranasal spray. The short duration of action of naloxone results in requirement of frequent re-dosing, especially in cases of larger overdoses, which may impact successful outcomes, especially when drug administration is provided by non-medical personnel as in case of intranasal sprays. These weaknesses necessitate the development of a non-injectable dosage form that has a rapid onset and extended duration of action. Delivery of drugs via skin is an attractive alternative that provides these benefits. Our study aimed to assess the effect of microneedles on the amount and lag time of permeation of naloxone across skin. In vitro permeation studies were performed to assess the delivery of naloxone through dermatomed porcine ear skin using Franz Diffusion cells. The donor and receptor chamber of the cells contained the drug solution and phosphate buffered saline, respectively. The receptor was sampled until 6 h and analyzed using HPLC. The permeation of naloxone across intact (passive) and microneedle-treated (Dr. Pen™ Ultima A6) skin was evaluated. Two microporation conditions with donor concentration of 10 mg/mL were investigated: needle lengths (500 µm and 250 µm) for 1 minute and 500 µm needle length for different durations (1 and 2 minutes). Further, the effect of application of different naloxone concentrations (10 and 20 mg/mL) on skin treated with 500 µm microneedles for 2 minutes was also tested. One-way ANOVA was applied to ascertain statistical difference between the different test groups. The amount of passive permeation after 6 h and lag time for naloxone was observed to be 8.251.06 µg/cm2 and88.58 ± 3.05 min, respectively. One minute treatment with 500 µm needles significantly enhanced the permeation to 463.24 ± 30.21 µg/cm2 and reduced the lag time to 15.90 ± 1.63 min (p0.05). Microneedles were found to enhance the permeation of naloxone across skin. The observation of quick onset of drug permeation in the in vitro settings is very encouraging and future studies would focus on developing a microneedle patch for quick onset and extended drug release.

Transdermal iontophoretic delivery of ketoprofen in cadaver skin and healthy volunteers was examined. In vitro anodic and cathodic iontophoresis (0.5 mA/cm2, 3 h) of ketoprofen (75 mg/ml) resulted in equivalent intracutaneous ketoprofen permeation (232.1 ± 27.1 vs. 275.0 ± 141.0 μg/cm2, respectively), which in turn was higher than passive intracutaneous uptake of ketoprofen (40.7 ± 42.1 μg/cm2). In contrast, only cathodic iontophoresis resulted in transcutaneous ketoprofen permeation across cadaver skin, under these conditions. The in vitro study was then repeated to achieve transcutaneous permeation of ketoprofen at clinical iontophoretic parameters (0.28 mA/cm2, 40 min) by increasing drug concentration to 300 mg/ml. No stereo-selective permeation of R- and S-ketoprofen enantiomers was observed in vitro. In humans, cathodic iontophoresis of 300 mg/ml ketoprofen (0.28 mA/cm2, 40 min) was performed at the wrist. Ketoprofen was detected at 40 min (0.88 ± 0.42 μg/ml) from the forearm veins of the ipsilateral arm. Urinary excretion of ketoprofen totaled 790 ± 170 μg at 16 h post iontophoresis. This investigation is the first to clearly demonstrate transcutaneous iontophoresis of an antiinflammatory agent in humans utilizing a commercially cleared iontophoretic device. The investigation also adds to the very limited number of publications in the area of iontophoretic delivery of drugs to humans.

Background and Purpose. Iontophoresis is a process that uses bipolar electric fields to propel molecules across intact skin and into underlying tissue. The purpose of this study was to describe and experimentally examine an iontophoresis drug delivery model. Subjects and Methods. A mechanistic model describing delivery was studied in vitro using agarose gels and was further tested in vivo by evaluation of cutaneous vasoconstriction following iontophoresis in human volunteers. Results. In vitro cathodic iontophoresis at 4 mA and 0.1 mA each delivered dexamethasone/dexamethasone phosphate (DEX/DEX-P) from a 4-mg/mL donor solution to a depth of 12 mm following a 40 mA·minute stimulation dosage. Delivery of DEX/DEX-P to at least the depths of the vasculature in humans was confirmed by observation of cutaneous vasoconstriction. This cutaneous vasoconstriction was longer lasting and greater in magnitude when using low-current, long-duration (∼0.1 mA) iontophoresis compared with equivalent dosages delivered by higher-current, shorter-duration (1.5-4.0 mA) iontophoresis. Discussion and Conclusion. From data gathered with the gel model, the authors developed a model of a potential mechanism of drug depot formation following iontophoresis. The authors believe this drug depot formation to be due to exchange of drug ions for chloride ions as the ionic current carriers. Furthermore, diffusion, not magnitude of current, appears to govern the depth of drug penetration. Although the authors did not address the efficacy of the drug delivered, the results of human experiments suggest that current magnitude and duration should be considered as factors in treating musculoskeletal dysfunctions with iontophoresis using DEX/DEX-P at a concentration of 4 mg/mL. [Anderson CR, Morris RL, Boeh SD, et al. Effects of iontophoresis current magnitude and duration on dexamethasone deposition and localized drug retention.

Naloxone (NAL) is administered parenterally or intranasally for treating opioid overdose. The short duration of action of NAL calls for frequent re-dosing which may be eliminated by the development of a transdermal system. This study aimed to assess the effect of microneedles on improving the skin permeation of NAL hydrochloride. In vitro permeation of NAL across intact and microneedle-treated (Dr. Pen™ Ultima A6) porcine skin was evaluated. The effect of microneedle length and application duration, and donor concentration on NAL permeation were investigated. In-vitro in-vivo correlation of the permeation results was done to predict the plasma concentration kinetics of NAL in patients. In vitro passive permeation of NAL after 6 h was observed to be 8.25±1.06 µg/cm2. A 56- and 37-fold enhancement was observed with 500 and 250 µm needles applied for 1 min, respectively. Application of 500 µm MNs for 2 min significantly reduced the lag time to ~ 8 min and increasing the donor concentration for the same treatment group doubled the permeation (p < 0.05). Modeling simulations demonstrated the attainment of pharmacokinetic profile of NAL comparable to those obtained with the FDA-approved intramuscular and intranasal devices. Microneedle-mediated transdermal delivery holds potential for rapid and sustained NAL delivery for opioid overdose treatment.

The high rise in the population suffering from depression depicts the need for improved and highly effective treatment options for this condition. Efforts to develop existing drugs into user-friendly dosage forms with a number of advantages in major depressive states, including but not limited to: sustained drug release, reduced drug dosing frequency, improved tolerance and adherence, suitability for use in diverse populations and different treatment scenarios, as well as less central nervous system side effects are required. One such non-invasive drug delivery route that could provide the aforementioned benefits in the treatment of depression is the transdermal route. A number of conventional and emerging transdermal delivery strategies have been investigated for some potent antidepressants and results depict the potential of this route as a viable means for systemic delivery of therapeutically relevant doses of the tested agents, with Emsam®, the commercially available patch of selegiline, being an evidence for the same. The investigated approaches include the formulation of transdermal patches, use of vesicular drug carriers, pro-drug approach, microemulsification, chemical as well as physical enhancement technologies. This review provides a comprehensive account of the rationale, developments made till date, scope and future prospects of delivering antidepressants via the transdermal1 route of administration.

Adequate evidence exists in the literature indicating a relatively positive shift with regards to the legal acceptance of cannabis and cannabis-derived products for medicinal purposes in some countries. Concomitantly, scientists are showing renewed interest in cannabis-related research work. Over the years, clinical and preclinical studies have demonstrated the therapeutic significance of cannabinoids for diverse indications. Additionally, efforts are being made to develop cannabis-related products into acceptable prescription products. FDA authorization for the commercial use of four cannabinoid-derived products, available as oral dosage forms is a significant progress already. However, there are certain drawbacks associated with the conventional delivery forms of cannabinoids. These include low oral bioavailability due to hepatic degradation, gastric instability, poor water solubility, and the side effects experienced upon the use of high doses of psychotropic cannabinoids associated with heightened plasma concentrations of the drug. These are however, limitable with the aid of transcutaneous drug delivery. Emerging topical and transdermal strategies could be exploited for the successful development of highly effective delivery systems for cannabinoids. This review discusses the feasibility of delivering therapeutic cannabinoids via skin and provides a comprehensive account of the supporting research studies that have been reported in the literature till date.

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