Transdermal drug delivery system is in the centre of attention in recent years. For efficient dermal drug delivery the drug has to overcome the barrier of the outermost layer of the skin, the stratum corneum. For facilitating dermal drug transport, the barrier properties of the stratum corneum can be varied by applying chemical penetration enhancers. The aim of this work was to characterize various penetration enhancers and investigate their mechanism of action. We combined well established techniques like differential scanning calorimetry (DSC) and infrared spectroscopy (IR) with confocal Raman microscopy (CRM) as an upcoming technique in skin research. CRM offers the possibility of label-free and non- destructive, chemically selective analysis of stratum corneum lipids and proteins. We used isolated human stratum corneum for incubation with the penetration enhancers. As a novel approach, the samples of treated stratum corneum were freeze dried to avoid any discrepancies which might come up with differences in the hydratation state of stratum corneum (SC). Furthermore, the structure of lipids and proteins in the stratum corneum was analyzed. In our study, stratum corneum was treated with dimethyle sulphoxide, propylene glycol, ethylene glycol, ethylene glycol-d4 and oleic acid. We observed that...

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Onychomycosis is fungal infection of toe nails or fingernails caused by a fungal microbe that invades the nail bed. It is the most common disease of the nails and constitutes about a half of all nail abnormalities and may affect toenails or fingernails, but toenail infections are particularly common. It occurs in about 10 percent of the adult population. The most common symptoms of fungal nail infection are thickening and discoloration of the nail. Treatment of onychomycosis is challenging because the infection is embedded in the nail making it difficult for the drug to diffuse to the site of infection. Onychomycosis is an opportunistic infection in people with compromised immune function and in those with diabetes, psoriasis, HIV/AIDS etc. Onychomycosis affects patients’ physical and psychological health and has a negative impact on overall quality of life. Oral administration of antifungal agents has been the mainstay in treatment of onychomycosis such as griseofulvin, terbinafine and itraconazole, but has limitations of systemic adverse events and drug interactions, whereas several drugs have been approved for topical administration but their efficacy is limited by the low permeability of the nail plate. This study evaluated the preformulation transungual permeability of econazole nitrate and formulation development of a transungual topical patch utilizing penetration enhancers in combination with econazole nitrate to optimize the delivery and penetration through the nail. The objectives of this project were to: 1) determine the critical factors for the in vitro transungual delivery of econazole nitrate, 2) design and develop a transungual formulation containing econazole nitrate and selection of the penetration enhancers, and 3) characterize the physical characteristics and functional properties of a novel transungual formulation. There were ten penetration enhancers being screened in this project according to the enhancement for saturation solubility, in vitro nail penetration and in vitro skin permeation and penetration of the antifungal drug econazole nitrate. Unlike transdermal drug delivery, the selection requirements for skin penetration enhancer were to increase drug accumulation in the epidermis and decrease the amount in the dermis to avoid unnecessary systermic absorption (Palliyil, et al. 2013). Thiourea (TU) improved the solubility and nail penetration of econazole nitrate. It also produced enhancement in the transungual diffusion of the drug. It was selected as the nail permeation enhancer and skin penetration enhancer for econazole nitrate. In the pH study, pH 5 ammonium phosphate buffer was the most effective pH for both enhancing the amount of drug in the nail and decreasing keratin binding. This resulted in increased accumulated of free drug in the target nail. In the formulation screening study, pressure sensitive adhesives (PSA), polyisobutylene, polysiloxane and polyacrylate classes of adhesives, were screened to develop a monolithic drug-in-adhesive type nail patch. Increasing the concentration of TU from 1% to 2.5% resulted in drug crystallization in the dry patch, therefore the concentration of 1% (w/w) TU was selected for all further screening. The concentration of econazole nitrate, propylene glycol and triethyl citrate were screened at 2.5%, 10% and 10% accordingly to ensure high drug release rate with no drug crystallization. The in vitro drug release rate of EN from the patch was improved with propylene glycol and hydrophobic plasticizer triethyl citrate. Polyvinylpyrrolidone was added to the patch formulation to lower the pH of the patch. This resulted in a greater concentration of ionized EN. The nail permeation and penetration of EN were studied in vitro using human cadaver toenails mounted in Franz diffusion cells. Thiourea, when formulated in the novel nail patch, was shown to deliver higher amount of EN into target tissues with a shorter permeation lag time compared to formulations which did not utilize thiourea. / Pharmaceutical Sciences

Onychomycosis is the most common disease of nails and constitutes about a half of all nail abnormalities. The thickness of the nails become the major challenge in developing a topical formulation for treatment on OM. In this study, penetration enhancers are used to enhance the solubility and permeability of the drug enconazole nitrate into the nail and the skin. It turns out of all the penetration enhancers, thiourea is the best choice because it can improve the solubility and nail penetration of econazole nitrate at the same time. / Pharmaceutical Sciences

The skin, by weight, is the largest organ of the body. Human skin serves to provide several important functions that may be classified. in a general context, as protective, maintaining homeostasis and sensing. The outermost layer of the skin, the stratum corneum, has an essential role as a barrier against the transport of water and of chemical and biological agents. In this study acyclovir (ACV), an antiviral used for treating the varicella zoster virus, was used. It is sensible to say that a hydrophilic drug like acyclovir needs a delivery vehicle or penetration enhancer to permeate the skin with more ease. In an attempt to enhance the permeation of acyclovir, it was formulated in a delivery vehicle with the same formulation as for a micro-emulsion. Increasing percentages of the surfactant, Brij 97, were incorporated in the formulation to determine which of the four formulations is indeed a micro-emulsion. A gelating agent. carrageenan, was used to make the emulsion transdermally more applicable; the influence of this component on the transdermal delivery of acyclovir was also determined. Therefore the aim of this study was to determine: -The effect of a drug delivery vehicle on the transdermal delivery of acyclovir; -The specific formulation of a micro-emulsion and -The influence of a gelating agent on the transdermal delivery of acyclovir. Diffusion studies were performed in vertically mounted glass Franz diffusion cells. The epidermis of female abdominal skin, obtained after abdomeoplasty, was heat separated from the dermis. One millilitre of emulsion (0.1%: 1mg/ml ACV) was added to the skin sample in the donor side of the diffusion cell. The control solution had an equivalent amount of active in water and was added to the donor compartment in a separate experiment. The receptor phase was PBS (phosphate buffered solution). The entire receptor phase of the cells was removed every second hour and was replaced with fresh receptor phase at 37°C. The amount of acyclovir in the receptor phase was determined by HPLC analysis. The cumulative amounts of the active that permeated the skin over the 24 hour period were plotted with the slope of the graphs representing the flux in ng/cm²/h. The average flux values of the experimental cells and control cells were compared. Results of the diffusion studies without carrageenan showed that increasing the concentration of the surfactant increased the diffusion of acyclovir. Permeation studies with carrageenan had a totally different outcome. The enhancement ratio of the experimental cells was much lower than that of the control cells. However the experimental cells showed a small increase as the concentration of the surfactant increased. From VanKel dissolution studies it could be seen that release of acyclovir from the emulsion was not a problem and that the active was available for absorption. Confocal studies were done to determine whether there were any vesicles in the emulsions. Vesicles were expected in the 25% Brij 97 emulsion because it was the same formulation as a micro-emulsion, but vesicles could only be found in the 4% and 8% Brij 97 emulsion. A previous study with acyclovir and three different delivery vehicles gave enhancement ratios between 0.32 to 2.92. Values obtained in this study of the 4% and 8% Brij 97 emulsion without carrageenan were more or less the same but the 15% and 25% Brij 97 emulsion had a much higher enhancement ratio. For the emulsions with carrageenan not one exceeded an enhancement ratio of 0.57. More studies still have to be done on micro-emulsions to determine which specific concentration of surfactant forms a micro-emulsion. The active itself and its physicochemical properties also play an important role in the diffusion studies with the specific delivery vehicle and further research has to be done with different model drugs. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2006.

The skin, by weight, is the largest organ of the body. Human skin serves to provide several important functions that may be classified. in a general context, as protective, maintaining homeostasis and sensing. The outermost layer of the skin, the stratum corneum, has an essential role as a barrier against the transport of water and of chemical and biological agents. In this study acyclovir (ACV), an antiviral used for treating the varicella zoster virus, was used. It is sensible to say that a hydrophilic drug like acyclovir needs a delivery vehicle or penetration enhancer to permeate the skin with more ease. In an attempt to enhance the permeation of acyclovir, it was formulated in a delivery vehicle with the same formulation as for a micro-emulsion. Increasing percentages of the surfactant, Brij 97, were incorporated in the formulation to determine which of the four formulations is indeed a micro-emulsion. A gelating agent. carrageenan, was used to make the emulsion transdermally more applicable; the influence of this component on the transdermal delivery of acyclovir was also determined. Therefore the aim of this study was to determine: -The effect of a drug delivery vehicle on the transdermal delivery of acyclovir; -The specific formulation of a micro-emulsion and -The influence of a gelating agent on the transdermal delivery of acyclovir. Diffusion studies were performed in vertically mounted glass Franz diffusion cells. The epidermis of female abdominal skin, obtained after abdomeoplasty, was heat separated from the dermis. One millilitre of emulsion (0.1%: 1mg/ml ACV) was added to the skin sample in the donor side of the diffusion cell. The control solution had an equivalent amount of active in water and was added to the donor compartment in a separate experiment. The receptor phase was PBS (phosphate buffered solution). The entire receptor phase of the cells was removed every second hour and was replaced with fresh receptor phase at 37°C. The amount of acyclovir in the receptor phase was determined by HPLC analysis. The cumulative amounts of the active that permeated the skin over the 24 hour period were plotted with the slope of the graphs representing the flux in ng/cm²/h. The average flux values of the experimental cells and control cells were compared. Results of the diffusion studies without carrageenan showed that increasing the concentration of the surfactant increased the diffusion of acyclovir. Permeation studies with carrageenan had a totally different outcome. The enhancement ratio of the experimental cells was much lower than that of the control cells. However the experimental cells showed a small increase as the concentration of the surfactant increased. From VanKel dissolution studies it could be seen that release of acyclovir from the emulsion was not a problem and that the active was available for absorption. Confocal studies were done to determine whether there were any vesicles in the emulsions. Vesicles were expected in the 25% Brij 97 emulsion because it was the same formulation as a micro-emulsion, but vesicles could only be found in the 4% and 8% Brij 97 emulsion. A previous study with acyclovir and three different delivery vehicles gave enhancement ratios between 0.32 to 2.92. Values obtained in this study of the 4% and 8% Brij 97 emulsion without carrageenan were more or less the same but the 15% and 25% Brij 97 emulsion had a much higher enhancement ratio. For the emulsions with carrageenan not one exceeded an enhancement ratio of 0.57. More studies still have to be done on micro-emulsions to determine which specific concentration of surfactant forms a micro-emulsion. The active itself and its physicochemical properties also play an important role in the diffusion studies with the specific delivery vehicle and further research has to be done with different model drugs. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2006.

Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-01-16T14:44:15Z No. of bitstreams: 1 rodrigojoselupatininogueira.pdf: 2876267 bytes, checksum: bdc1dc017b1978a2518a09845b329662 (MD5) / Rejected by Adriana Oliveira (adriana.oliveira@ufjf.edu.br), reason: Favor corrigir: Silva Filho, Ademar Alves da on 2018-01-22T16:16:44Z (GMT) / Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-01-22T16:24:05Z No. of bitstreams: 1 rodrigojoselupatininogueira.pdf: 2876267 bytes, checksum: bdc1dc017b1978a2518a09845b329662 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-01-24T12:06:25Z (GMT) No. of bitstreams: 1 rodrigojoselupatininogueira.pdf: 2876267 bytes, checksum: bdc1dc017b1978a2518a09845b329662 (MD5) / Made available in DSpace on 2018-01-24T12:06:25Z (GMT). No. of bitstreams: 1 rodrigojoselupatininogueira.pdf: 2876267 bytes, checksum: bdc1dc017b1978a2518a09845b329662 (MD5) Previous issue date: 2014-08-22 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A administração de medicamentos na pele através da via transcutânea é uma prática que tem sido utilizada pela humanidade ao longo de milênios. Os anti-inflamatórios não esteroidais (AINEs) apresentam-se como uma classe de fármacos de interesse para o desenvolvimento de formulações transcutâneas já que apresentam efeitos gastrointestinais graves ao serem utilizados para o tratamento crônico de doenças, como por exemplo artrite reumatóide. Entre os fármacos desta classe, o ibuprofeno (IBU) representa um bom candidato para a permeação cutânea, já que apresenta baixo peso molecular (206,28), coeficiente de partição (log P) inferior a 4 e curta meia vida plasmática. Uma estratégia efetiva para facilitar a passagem de fármacos pela pele é o emprego de promotores de permeação na pele. Recentemente, alguns trabalhos vem relacionando o uso de terpenos e óleos naturais ricos em terpenos na promoção de permeação cutânea de fármacos. O óleo de copaíba, devido ao seu rico conteúdo em terpenos, apresenta-se como uma ótima escolha de promotor de permeação de fármacos administrados na pele. Neste trabalho foram desenvolvidas duas formulações em creme contendo IBU 5% com duas concentrações diferentes de óleo de copaíba: IBOC5, contendo 5% de óleo de copaíba e IBOC10, com 10% do mesmo óleo. Os ensaios de permeação e penetração in vitro do IBU foram realizados utilizando-se pele de orelha suína como membrana biológica no aparelho de células de difusão vertical do tipo Franz. Já a avaliação da permeação in vivo foi realizada através do teste de atividade anti-inflamatória induzida pelo óleo de cróton em orelhas de camundongos. O fluxo de permeação (J) do IBU nas amostras IBOC5 (35,72 ± 6,35) e IBOC10 (29,78 ±2,41) foram superiores (p < 0,01 e p < 0,05, respectivamente) ao creme controle, sem óleo de copaíba (10,32 ± 1,52) e produto comercial (14,44 ± 2,39). Na análise de penetração, a quantidade de IBU nas amostras IBOC5 e IBOC10 foi maior (p < 0,01 e p < 0,05, respectivamente) na derme quando comparada à epiderme. No ensaio in vivo, as amostras IBOC5 e IBOC10 reduziram (p < 0,05 e p < 0,001, respectivamente) o processo inflamatório quando comparadas ao controle negativo, entretanto, não foram diferentes (p > 0,05) do controle positivo. Face aos resultados, pode-se concluir que a adição do óleo de copaíba apresentou capacidade de promoção de permeação e penetração cutânea do ibuprofeno nas amostras em creme para o teste de células de difusão in vitro. Já o modelo in vivo de edema de orelha em camundongos, sugere-se que este não foi o teste mais adequado para avaliação da permeação do ibuprofeno nas amostras analisadas. / The administration of medications on the skin through transcutaneous routeis a practice that has been used by mankind for millennia. The non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to be a class of drugs of interest for transcutaneous formulation development, since they present severe gastro-intestinal effects when used for treatment of chronic diseases such as rheumatoid arthritis. Among drugs of this class, Ibuprofen (IBU) is considered a good candidate for skin permeation, since it has a low molecular weight (206.28), partition coefficient (log P) lower than 4 and short plasma half-life. Therefore, an effective strategy to facilitate the drug diffusion through the skin is the use of permeation enhancers. Recently, some studies have been reporting the use of terpenes and natural oils rich in terpenes and their roles in promoting cutaneous drug penetration. Copaiba oil, due to its rich content of terpenes, presents itself as a great choice of penetration enhancer for drugs administered on the skin. In this study, two cream formulations containing 5% of IBU were developed: IBOC5 with 5% of Copaiba oil and IBOC10 with 10% of the same oil. In vitro cutaneous penetration/permeation studies of IBU were performed using pig ear skin as biological membrane in the Franz-type diffusion cells. In vivo permeation tests were also performed through anti-inflammatory activity evaluation using Croton oil-induced mouse ear edema test. The permeation flux (J) of IBU samples, IBOC5 (35.72 + 6.35) and IBOC10 (29.78 + 2.41) were significantly higher (p < 0.01 and p < 0.05, respectively) when compared to control cream, without Copaiba oil (10.32 + 1.52) and to commercial product (14.44 + 2.39). In the penetration analysis, the amount of IBU found in the samples IBOC5 and IBOC10 was higher (p < 0.01 and p < 0.05, respectively) in dermis than epidermis. In vivo tests showed that samples IBOC5 and IBOC10 decreased (p < 0.05 e p < 0,001, respectively) inflammatory process when it was compared to the negative control, however they weren’t considered statistically different (p > 0.05) of positive control. Concluding, Copaiba oil showed a significant capability to promote skin penetration and permeation of ibuprofen when it was added into the cream samples, according to the in vitro diffusion cells test results. On the other hand, the results obtained from the in vivo method weren’t enough satisfactory considering the analyzed samples.

No / Incorporating edge activators (surfactants) into liposomes was shown previously to improve estradiol vesicular skin delivery; this phenomenon was concentration dependent with low or high concentrations being less effective. Replacing surfactants with limonene produced similar behaviour, but oleic acid effects were linear with concentration up to 16% (w/w), beyond which it was incompatible with the phospholipid. This present study thus employed high sensitivity differential scanning calorimetry to probe interactions of additives with dipalmitoylphosphatidylcholine (DPPC) membranes to explain such results. Cholesterol was included as an example of a membrane stabiliser that removed the DPPC pre-transition and produced vesicles with a higher transition temperature (Tm). Surfactants also removed the lipid pre-transition but reduced Tm and co-operativity of the main peak. At higher concentrations, surfactants also formed new species, possibly mixed micelles with a lower Tm. The formation of mixed micelles may explain reduced skin delivery from liposomes containing high concentrations of surfactants. Limonene did not remove the pre-transition but reduced Tm and co-operativity of the main peak, apparently forming new species at high concentrations, again correlating with vesicular delivery of estradiol. Oleic acid obliterated the pre-transition. The Tm and the co-operativity of the main peak were reduced with oleic acid concentrations up to 33.2 mol%, above which there was no further change. At higher concentrations, phase separation was evident, confirming previous skin transport findings.

No / Piperacillin, a potent ß-lactam antibiotic, is effective in a large variety of Gram+ and Gram¿ bacterial infections but its administration is limited to the parenteral route as it is not absorbed when given orally. In an attempt to overcome this problem, we have synthesized a novel series of charged liposaccharide complexes of piperacillin comprising a sugar moiety derived from d-glucose conjugated to a lipoamino acid residue with varying side-chain length (cationic entity) and the piperacillin anion. A complete multiple reaction monitoring LC¿MS/MS method was developed to detect and characterize the synthesized complexes. The same method was then successfully applied to assess the in vitro apparent permeability values of the charged liposaccharide complexes in Caco-2 monolayers. / BBSRC

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