The world-wide transdermal drug delivery market is quite large, but only a small number of agents have FDA approval. The primary reason for such limited development is the difficulty in permeating the stratum corneum layer of human skin. In our study, we developed a novel percutaneous delivery enhancing approach. Magainin peptide was previously shown to disrupt vesicles from stratum corneum lipid components and this ability of magainin allows us to propose that magainin can increase skin permeability. Therefore, we tested the hypothesis that magainin, a pore-forming peptide, can increase skin permeability by disrupting stratum corneum lipid structure and that magainin¡¯s enhancement requires co-administration of a surfactant chemical enhancer to increase magainin penetration into the skin. In support of these hypotheses, synergistic enhancement of transdermal permeation can be observed with magainin peptide in combination of N-lauroyl sarcosine (NLS) in 50% ethanol-PBS solution. The exposure to NLS in 50% ethanol solution increased in vitro skin permeability to fluorescein 15 fold and the addition of magainin synergistically increased skin permeability 47 fold. In contrast, skin permeability was unaffected by exposure to magainin without co-enhancement by NLS-ethanol. To elucidate the mechanism of this synergistic effect, several characterization methods such as differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray diffraction were applied. These analyses showed that NLS-ethanol disrupted stratum corneum lipid structure and that the combination of magainin and NLS-ethanol disrupted stratum corneum lipids even further. Furthermore, confocal microscopy showed that magainin in the presence of NLS-ethanol penetrated deeply and extensively into stratum corneum, whereas magainin alone penetrated poorly into the skin. Together, these data suggest that NLS-ethanol increased magainin penetration into stratum corneum, which further increased stratum corneum lipid disruption and skin permeability. Finally, skin permeability was enhanced by changing the charge of magainin peptide via pH change. We modulated pH from 5 to 11 to change the magainin charge from positive to neutral, which decreased skin permeability to a negatively charged fluorescein and increased skin permeability to a positively charged granisetron. This suggests that an attractive interaction between the drug and magainin peptide improves transdermal flux.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammation and pain (Escribano et al., 2003:203). Diclofenac, a classical NSAID, is considerably more effective as an analgesic, antipyretic and anti-inflammatory drug than other traditional NSAIDs, like indomethacin and naproxen (Grosser et al., 2011:986). However, the use of diclofenac is known for its many side effects, such as gastric disorders, while fluid and sodium retention are also commonly observed (Rossiter, 2012:391). Since topical diclofenac offers a more favourable safety profile, it is a valuable substitute for oral NSAID therapy in the treatment of osteoarthritis (Roth & Fuller, 2011:166). The benefits of topically applied NSAIDs, compared to oral administration and systemic delivery, include the easy cessation of treatment, should effects become troublesome (Brown et al., 2006:177), the avoidance of extensive, first-pass metabolism (Cleary, 1993:19; Kornick, 2003:953; Prausnitz & Langer, 2008:1261; Lionberger & Brennan, 2010:225), reduced systemic side effects (Colin Long, 2002:41), convenience of application and improved patient compliance (Cleary, 1993:19; Prausnitz & Langer, 2008:1261). An approach that is often applied in optimising the solubility and dissolution rate of poorly water soluble, weak electrolytes is to prepare a salt of the active pharmaceutical ingredient (API) (Minghetti et al., 2007:815; O’Connor & Corrigan, 2001:281-282). Diclofenac is frequently administered as a salt, due to the high partition coefficient and very low water solubility of this molecule (Fini et al., 1999:164). Formulating for efficacy (FFETM) is a software programme designed by JW Solutions to facilitate the formulation of cosmetic ingredients or solvents into a product that would optimally deliver active ingredients into the skin. The notion is built upon solubility, i.e. solubility of the active ingredient in the formulation and solubility of the formulation in the skin. This programme could also be employed to optimise amounts of predetermined ingredients, to propose formulations that would ensure optimal drug delivery, to calculate the skin delivery gap (SDG) and to demonstrate transdermal permeation of active ingredients and excipients (JW Solutions Software, 2013a). When the SDG is known, it mathematically indicates the optimal active ingredient and topical delivery vehicle to use (JW Solutions, 2013b). In this study, diclofenac sodium (DNa), diclofenac diethylamine (DDEA) and diclofenac N-(2- hydroxyethyl) pyrrolidine (DHEP) were each formulated in the following emulgels: * An emulgel optimised towards the stratum corneum (SC) (enhancing drug delivery into this layer and deeper tissues) (oily phase ~30%), * A more hydrophilic emulgel (oily phase ~15%), and * A more lipophilic emulgel (oily phase ~45%). Components of the oily phase and its respective amounts, as well as the SDG of formulations were determined by utilising the FFETM software of JW Solutions (2013a). The aqueous solubilities of DNa, DDEA and DHEP were determined and their respective values were 11.4 mg/ml, 8.0 mg/ml and 11.9 mg/ml, all indicative of effortless percutaneous delivery (Naik et al., 2000:319). Log D (octanol-buffer distribution coefficient) (pH 7.4) determinations for DNa, DDEA and DHEP were performed and their values established at 1.270 (DNa), 1.291 (DDEA) and 1.285 (DHEP). According to these values, diclofenac, when topically applied as a salt in a suitable vehicle, should permeate transdermally without the aid of radical intervention (Naik et al., 2000:319; Walters, 2007:1312). Membrane release studies were also carried out in order to determine the rate of API release from these new formulations. Results confirmed that diclofenac was indeed released from all nine of the formulated emulgels. The more hydrophilic DNa formulation released the highest average percentage of diclofenac (8.38%) after 6 hours. Subsequent transdermal diffusion studies were performed to determine the diclofenac concentration that permeated the skin. The more hydrophilic DNa emulgel showed the highest average percentage skin diffusion (0.09%) after 12 hours, as well as the highest average flux (1.42 ± 0.20 μg/cm2.h). The concentrations of diclofenac in the SC-epidermis (SCE) and epidermis-dermis (ED) were determined through tape stripping experiments. The more lipophilic DNa emulgel demonstrated the highest average concentration (0.27 μg/ml) in the ED, while the DNa emulgel that had been optimised towards the SC, had the highest concentration in the SCE (0.77 μg/ml). / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammation and pain (Escribano et al., 2003:203). Diclofenac, a classical NSAID, is considerably more effective as an analgesic, antipyretic and anti-inflammatory drug than other traditional NSAIDs, like indomethacin and naproxen (Grosser et al., 2011:986). However, the use of diclofenac is known for its many side effects, such as gastric disorders, while fluid and sodium retention are also commonly observed (Rossiter, 2012:391). Since topical diclofenac offers a more favourable safety profile, it is a valuable substitute for oral NSAID therapy in the treatment of osteoarthritis (Roth & Fuller, 2011:166). The benefits of topically applied NSAIDs, compared to oral administration and systemic delivery, include the easy cessation of treatment, should effects become troublesome (Brown et al., 2006:177), the avoidance of extensive, first-pass metabolism (Cleary, 1993:19; Kornick, 2003:953; Prausnitz & Langer, 2008:1261; Lionberger & Brennan, 2010:225), reduced systemic side effects (Colin Long, 2002:41), convenience of application and improved patient compliance (Cleary, 1993:19; Prausnitz & Langer, 2008:1261). An approach that is often applied in optimising the solubility and dissolution rate of poorly water soluble, weak electrolytes is to prepare a salt of the active pharmaceutical ingredient (API) (Minghetti et al., 2007:815; O’Connor & Corrigan, 2001:281-282). Diclofenac is frequently administered as a salt, due to the high partition coefficient and very low water solubility of this molecule (Fini et al., 1999:164). Formulating for efficacy (FFETM) is a software programme designed by JW Solutions to facilitate the formulation of cosmetic ingredients or solvents into a product that would optimally deliver active ingredients into the skin. The notion is built upon solubility, i.e. solubility of the active ingredient in the formulation and solubility of the formulation in the skin. This programme could also be employed to optimise amounts of predetermined ingredients, to propose formulations that would ensure optimal drug delivery, to calculate the skin delivery gap (SDG) and to demonstrate transdermal permeation of active ingredients and excipients (JW Solutions Software, 2013a). When the SDG is known, it mathematically indicates the optimal active ingredient and topical delivery vehicle to use (JW Solutions, 2013b). In this study, diclofenac sodium (DNa), diclofenac diethylamine (DDEA) and diclofenac N-(2- hydroxyethyl) pyrrolidine (DHEP) were each formulated in the following emulgels: * An emulgel optimised towards the stratum corneum (SC) (enhancing drug delivery into this layer and deeper tissues) (oily phase ~30%), * A more hydrophilic emulgel (oily phase ~15%), and * A more lipophilic emulgel (oily phase ~45%). Components of the oily phase and its respective amounts, as well as the SDG of formulations were determined by utilising the FFETM software of JW Solutions (2013a). The aqueous solubilities of DNa, DDEA and DHEP were determined and their respective values were 11.4 mg/ml, 8.0 mg/ml and 11.9 mg/ml, all indicative of effortless percutaneous delivery (Naik et al., 2000:319). Log D (octanol-buffer distribution coefficient) (pH 7.4) determinations for DNa, DDEA and DHEP were performed and their values established at 1.270 (DNa), 1.291 (DDEA) and 1.285 (DHEP). According to these values, diclofenac, when topically applied as a salt in a suitable vehicle, should permeate transdermally without the aid of radical intervention (Naik et al., 2000:319; Walters, 2007:1312). Membrane release studies were also carried out in order to determine the rate of API release from these new formulations. Results confirmed that diclofenac was indeed released from all nine of the formulated emulgels. The more hydrophilic DNa formulation released the highest average percentage of diclofenac (8.38%) after 6 hours. Subsequent transdermal diffusion studies were performed to determine the diclofenac concentration that permeated the skin. The more hydrophilic DNa emulgel showed the highest average percentage skin diffusion (0.09%) after 12 hours, as well as the highest average flux (1.42 ± 0.20 μg/cm2.h). The concentrations of diclofenac in the SC-epidermis (SCE) and epidermis-dermis (ED) were determined through tape stripping experiments. The more lipophilic DNa emulgel demonstrated the highest average concentration (0.27 μg/ml) in the ED, while the DNa emulgel that had been optimised towards the SC, had the highest concentration in the SCE (0.77 μg/ml). / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Hypoactive sexual desire or low libido in women are collectively referred to as hypoactive sexual desire disorder (HSDD). HSDD is estimated to occur in 10% to 15% of adult women. HSDD is likely the most common female sexual dysfunction (FSD) in menopausal women. The hallmark of the diagnosis is personal distress and interpersonal difficulties resulting from low sex drive. Most women will not seek help for this problem. Studies have suggested that primary care providers and gynecologic healthcare providers report not feeling qualified to treat patients with sexual dysfunction, especially HSDD. Testosterone, specifically transdermal testosterone, has been suggested to play an integral part in the treatment of HSDD in menopause. It is proven to increase the frequency of satisfying sexual activity, sexual desire, and orgasmic response, and to decrease personal distress. Testosterone has a demonstrated a safety history and medication tolerance when prescribed for this purpose. In spite of its proven efficacy in relation to HSDD, the Food and Drug Administration (FDA) has not approved testosterone for this purpose, though its use for HSDD is currently suggested by the Endocrine Society in their Clinical Practice Guidelines (CPGs). The primary purpose of this study was to assess Vermont primary care providers' and gynecologic healthcare providers' perceptions, knowledge, and practices regarding treatment of HSDD in naturally induced menopause with a focus on transdermal testosterone. After respondent inclusion criteria and demographic information about the respondents was collected, the study asked questions and tested knowledge about topics regarding menopause and sexuality, evaluation of FSD, and treatment of low libido and diminished sexual desire with a focus on testosterone. The study was a descriptive cross-sectional online survey that was completed electronically on a secure server through the University of Vermont. The conclusions were that providers believe sexuality and sexual satisfaction are quality of life indicators and perceived that maintaining sexual function is important to naturally occurring menopausal women. The majority of providers would prescribe a pharmaceutical treatment for menopausal women seeking to maintain their sexual function, enhance sexual satisfaction, and/or treat symptoms of HSDD as long as there were no contraindications. However, testosterone, a proven treatment for women with complaints of low libido and/or diminished sexual desire, was reportedly underutilized. This may be related to inconsistent screening for FSD in menopause at each comprehensive visit and lack of provider knowledge about testosterone (including safety and efficacy) impacting confidence to prescribe testosterone for this purpose. Further, providers were divided on whether low libido and/or diminished sexual desire in naturally occurring menopause is a medical condition or disorder or a natural part of aging. It is unclear how the aforementioned divisions impact evaluation and treatment.

Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Patch-based transdermal drug delivery offers a convenient way to administer drugs without the drawbacks of standard hypodermic injections relating to issues such as patient acceptability and injection safety. However, conventional transdermal drug delivery is limited to therapeutics where the drug can diffuse across the skin barrier. By using miniaturized needles, a pathway into the human body can be established which allow transport of macromolecular drugs such as insulins or vaccines. These microneedles only penetrate the outermost skin layers, superficial enough not to reach the nerve receptors of the lower skin. Thus, microneedle insertions are perceived as painless. The thesis presents research in the field of microneedle-based drug delivery with the specific aim of investigating a microneedle-based transdermal patch concept. To enable controllable drug infusion and still maintain an unobtrusive and easy-to-use, patch-like design, the system includes a small active dispenser mechanism. The dispenser is based on a novel thermal actuator consisting of highly expandable microspheres. When actuated, the microspheres expand into a liquid reservoir and, subsequently, dispense stored liquid through outlet holes. The microneedles are fabricated in monocrystalline silicon by Deep Reactive Ion Etching. The needles are organized in arrays situated on a chip. To allow active delivery, the microneedles are hollow with the needle bore-opening located on the side of the needle. This way, the needle can have a sharp and well-defined needle tip. A sharp needle is a further requirement to achieve microneedle insertion into skin by hand. The thesis presents fabrication and evaluation of both the microneedle structure and the transdermal patch as such. Issues such as penetration reliability, liquid delivery into the skin and microneedle packaging are discussed. The microneedle patch was also tested and studied in vivo for insulin delivery. Results show that intradermal administration with microneedles give rise to similar insulin concentration as standard subcutaneous delivery with the same dose rate. / QC 20100623

Microemulsions have gained interest from the pharmaceutical industry due to their ability to co-solubilize hydrophilic and lipophilic drugs, and to provide enhanced drug penetration. In this work, thermosensitive gelatin- and poloxamer 407-stabilized microemulsion-based gels (MBGs) were formulated using alcohol-free, low toxicity and low viscosity lecithin-based linker microemulsions. The addition of gelatin to water-rich bicontinuous microemulsions induced the formation of clear viscoelastic gels containing an oil-rich microemulsion as the gelatin seemed to dehydrate the original microemulsion. The addition of poloxamer 407 to water-continuous microemulsions produced MBGs with different gelation temperatures. High concentrations of lipophilic components in the microemulsion, particularly the oil, reduced sol-gel transition temperature, while hydrophilic components increased sol-gel transition temperature. Gelatin and poloxamer MBGs provided desirable viscoelastic properties for ophthalmic and transdermal applications with minimal impact on the transport properties of the original microemulsions.

Microemulsions have gained interest from the pharmaceutical industry due to their ability to co-solubilize hydrophilic and lipophilic drugs, and to provide enhanced drug penetration. In this work, thermosensitive gelatin- and poloxamer 407-stabilized microemulsion-based gels (MBGs) were formulated using alcohol-free, low toxicity and low viscosity lecithin-based linker microemulsions. The addition of gelatin to water-rich bicontinuous microemulsions induced the formation of clear viscoelastic gels containing an oil-rich microemulsion as the gelatin seemed to dehydrate the original microemulsion. The addition of poloxamer 407 to water-continuous microemulsions produced MBGs with different gelation temperatures. High concentrations of lipophilic components in the microemulsion, particularly the oil, reduced sol-gel transition temperature, while hydrophilic components increased sol-gel transition temperature. Gelatin and poloxamer MBGs provided desirable viscoelastic properties for ophthalmic and transdermal applications with minimal impact on the transport properties of the original microemulsions.

The molecular basis of the potent transdermal enhancement activity of a series of iminosulfuranes, structure provided where X = H, Cl, Br, and I, is being investigated skin models. It has been shown (J. Lipid Res. 46(2005), 2192-2201.) that correlations exist between the activity of the aforementioned transdermal penetration enhancers (TPE) and the extent to which these agents bind to DMPC vesicles and perturb the gel to liquid crystal phase transition measured by calorimetry. The degree to which the perturbation of these compounds extends into the bilayer interior in contrast to surface activity is unclear. To gain insight into this issue, the 31P NMR resonance from DMPC and DMPC-cholesterol unilamellar vesicles have been split by the slowly penetrating paramagnetic metal ion Pr+3. The extent to which this perturbation is attenuated by transdermal penetration enhancers has been investigated as a function of Pr+3 exposure time and iminosulfurane concentration. The effect of these iminosulfuranes on bilayer integrity is also being explored by monitoring the induced release of carboxyfluorescein from DMPC and DMPC- cholesterol unilamellar vesicles.

Graduation date: 1992