No description available.

Percutaneous delivery of drugs promises many advantages over oral or intravenous administration, such as a better control of blood levels, a reduced incidence of systemic toxicity, an absence of hepatic first-pass metabolism, better patient compliance, etc. However, the dermal drug transport is limited by the unsuitable physicochemical properties of most drugs and the efficient barrier function of the skin. Thus, numerous attempts have been reported to improve topical absorption of drugs, concentrating mainly on the barrier function of the stratum corneum by use of penetration enhancers and/or skin warming. An alternative and interesting possibility for improved dermal permeability is the synthesis of derivatives or analogues with the aim of changing the physicochemical properties in favour of skin permeation, efficacy and therapeutic value. Cyclizine (I) is an anti-emetic drug primarily indicated for the prophylaxis and treatment of nausea and vomiting associated with motion sickness, post operation and Meniere's disease. It acts both on the emetic trigger zone and by damping the labyrinthine sensitivity. Pharmacologically it has anti-histaminic, antiserotonergic, local anaesthetic and vagolytic actions. It is widely used and also suitable for children from six year of age. Percutaneous absorption of (I) can, among others, avoid the "first-pass" effect and the discomfort of injection. The main objective of this study was to explore the feasibility of percutaneous absorption of (I) and its alkyl analogues via physicochemical characterization and assessment of their permeation parameters. The intent was also to establish a correlation between the physicochemical properties of these compounds and their percutaneous rate of absorption. To achieve these objectives, the study was undertaken by synthesizing the alkyl analogues and determining the physicochemical parameters relevant to skin transport. Identification and level of purity for the prepared analogues were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectrometry and infrared (IR) spectrometry. Experimental aqueous solubility (25 °c & 32 °C) and partition coefficient for each compound were determined. In vitro permeation studies were performed at pH 7.4, using Franz diffusion cells with human epidermal membranes. Diffusion experiments were conducted over a period of 24 hours maintaining a constant temperature (37 DC) by means of water bath. All samples were analysed by high pressure liquid chromatography (HPLC). Cyclizine (I) has a methyl group at N-4. Increasing the alkyl chain length on N-4 of the piperazine ring resulted' in compounds with lower melting points and higher water solubility than (I). (II) exhibited 3-fold increase in water solubility, followed by (IV) with about 2.5 fold increase. The water solubility of (III) was almost the same as that of (I). Log partition coefficients increased linearly with increasing alkyl chain length. The analogues therefore, possessed more favourable physicochemical properties to be delivered percutaneously. Indeed, the in vitro skin permeation data proved that these analogues could be delivered more easily than (I) itself. The flux of (I) was 0.132 ug/cm2/h in a saturated aqueous solution. Compound (II) resulted in a 53-fold (6.952 ug/cm2/h) increase in permeation compared to (I). (III) and (IV) resulted in a 2- and 5fold enhancement of permeation respectively. Based on the results of the study, it seems that increased aqueous solubility and low level of crystallinity play a vital role in optimizing percutaneous absorption of (I) and its alkyl analogues. But the importance of the effect of increased lipophilicity cannot be ignored. The low percutaneous• absorption of (I) might be attributed to its low aqueous solubility and increased crystallinity, as is evident from the higher melting point than the analogues. From all the permeability data using aqueous solutions, it is clear that compound (II) is the best permeant of this series and in addition it is known that this compound antagonizes the effects of histamine. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.

Percutaneous delivery of drugs promises many advantages over oral or intravenous administration, such as a better control of blood levels, a reduced incidence of systemic toxicity, an absence of hepatic first-pass metabolism, better patient compliance, etc. However, the dermal drug transport is limited by the unsuitable physicochemical properties of most drugs and the efficient barrier function of the skin. Thus, numerous attempts have been reported to improve topical absorption of drugs, concentrating mainly on the barrier function of the stratum corneum by use of penetration enhancers and/or skin warming. An alternative and interesting possibility for improved dermal permeability is the synthesis of derivatives or analogues with the aim of changing the physicochemical properties in favour of skin permeation, efficacy and therapeutic value. Cyclizine (I) is an anti-emetic drug primarily indicated for the prophylaxis and treatment of nausea and vomiting associated with motion sickness, post operation and Meniere's disease. It acts both on the emetic trigger zone and by damping the labyrinthine sensitivity. Pharmacologically it has anti-histaminic, antiserotonergic, local anaesthetic and vagolytic actions. It is widely used and also suitable for children from six year of age. Percutaneous absorption of (I) can, among others, avoid the "first-pass" effect and the discomfort of injection. The main objective of this study was to explore the feasibility of percutaneous absorption of (I) and its alkyl analogues via physicochemical characterization and assessment of their permeation parameters. The intent was also to establish a correlation between the physicochemical properties of these compounds and their percutaneous rate of absorption. To achieve these objectives, the study was undertaken by synthesizing the alkyl analogues and determining the physicochemical parameters relevant to skin transport. Identification and level of purity for the prepared analogues were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectrometry and infrared (IR) spectrometry. Experimental aqueous solubility (25 °c & 32 °C) and partition coefficient for each compound were determined. In vitro permeation studies were performed at pH 7.4, using Franz diffusion cells with human epidermal membranes. Diffusion experiments were conducted over a period of 24 hours maintaining a constant temperature (37 DC) by means of water bath. All samples were analysed by high pressure liquid chromatography (HPLC). Cyclizine (I) has a methyl group at N-4. Increasing the alkyl chain length on N-4 of the piperazine ring resulted' in compounds with lower melting points and higher water solubility than (I). (II) exhibited 3-fold increase in water solubility, followed by (IV) with about 2.5 fold increase. The water solubility of (III) was almost the same as that of (I). Log partition coefficients increased linearly with increasing alkyl chain length. The analogues therefore, possessed more favourable physicochemical properties to be delivered percutaneously. Indeed, the in vitro skin permeation data proved that these analogues could be delivered more easily than (I) itself. The flux of (I) was 0.132 ug/cm2/h in a saturated aqueous solution. Compound (II) resulted in a 53-fold (6.952 ug/cm2/h) increase in permeation compared to (I). (III) and (IV) resulted in a 2- and 5fold enhancement of permeation respectively. Based on the results of the study, it seems that increased aqueous solubility and low level of crystallinity play a vital role in optimizing percutaneous absorption of (I) and its alkyl analogues. But the importance of the effect of increased lipophilicity cannot be ignored. The low percutaneous• absorption of (I) might be attributed to its low aqueous solubility and increased crystallinity, as is evident from the higher melting point than the analogues. From all the permeability data using aqueous solutions, it is clear that compound (II) is the best permeant of this series and in addition it is known that this compound antagonizes the effects of histamine. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.

The proposed human intestinal absorption prediction model is applied to over 900 pharmaceuticals and has about 82.5% true prediction power. This study will provide a screening tool that can differentiate well absorbed and poorly absorbed drugs in the early stage of drug discovery and development. This model is based on fundamental physicochemical properties and can be applied to virtual compounds. The maximum well-absorbed dose (i.e., the maximum dose that will be more than 50 percent absorbed) calculated using this model can be utilized as a guideline for drug design, synthesis, and pre-clinical studies.

In this project, we have designed and synthesized a new series of long-chain, water-soluble, dendritic, anionic amphiphiles [3CAmn, RCONHC(CH₂CH₂COOH)₃, R= CnH2n+1] to alleviate the low aqueous solubility of fatty acids. The dendritictricarboxlyato headgroup improves aqueous solubility and allows us to measure the intrinsic biological activity of our amphiphiles without the potential hindrance of low aqueous solubility. The aqueous solubilities of the anionic amphiphiles have been measured and were vastly higher than that of fatty acids. For example, 3CAm17 (1700 μM at pH 7.2) has much better aqueous solubility than the C₁₈ fatty acid analog (<<1 micromol at pH 7.4). Following the determination of aqueous solubility, both anionic and nonionic amphiphiles were tested against a wide variety of microorganisms. The anionic amphiphiles were mostly active against Candida albicans (4.4 microgram/mL), Saccharomyces cerevisiae (4.4 μg/mL), and Mycobacterium smegmatis (18 microgram/mL) and exhibited modest activity against both Gram-negative (71–280 microgram/mL) and Gram-positive bacteria (36– >6300 microgram/mL). With the exception of Neisseria gonorrhoeae (9.8 microgram/mL), the nonionic amphiphiles were mostly minimally active or inactive against Gram-negative bacteria (630–5000 microgram/mL). The nonionic amphiphiles were similarly inactive against fungi (625–5000 microgram/mL). However, the nonionic amphiphiles exhibited good activity against M. smegmatis (20 microgram/mL) and exhibited the best activity against Grampositive bacteria, such as MRSA (22 microgram/mL), Staphylococcus aureus (20 microgram/mL), and Micrococcus luteus (20 microgram/mL). The anionic and nonionic amphiphiles were also tested for possible spermicidal and anti-human immunodefiency virus (HIV) activity. The anionic amphiphiles exhibited anti-HIV activity (EC₅₀, 73–340 microgram/mL), but lacked spermicidal activity. The series had comparable anti-HIV activity to the commercial product N-9 (80 microgram/mL). Except 3CAm13, all anionic amphiphiles (1.4–4) had better selectivity indices than that of N-9 (0.9). The nonionic amphiphiles exhibited both anti-HIV (44–67 microgram/mL) and spermicidal activity (226–2000 microgram/mL). The nonionic amphiphile were more spermicidal and antiviral than Nonoxynol-9. In addition to biological activity, we determined whether the anionic amphiphiles could be utilized as corrosion inhibitors or ore flotation enhancers. The anionic amphiphiles formed stable thin films on silver oxide that were resistant to ethanol washings. We also measured the water contact angles of the anionic amphiphiles on mineral surfaces [apatite (95°), calcite (92°)]. / Ph. D.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第18221号 / 薬科博第25号 / 新制||薬科||4(附属図書館) / 31079 / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 掛谷 秀昭, 教授 高須 清誠, 准教授 大野 浩章 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第19958号 / 理博第4225号 / 新制||理||1607(附属図書館) / 33054 / 京都大学大学院理学研究科化学専攻 / (主査)教授 杉山 弘, 教授 三木 邦夫, 教授 秋山 芳展 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

No description available.

no / The increasing prevalence of poorly soluble drugs in development provides notable risk of new products demonstrating low and erratic bioavailabilty with consequences for safety and efficacy, particularly for drugs delivered by the oral route of administration. Although numerous strategies exist for enhancing the bioavailability of drugs with low aqueous solubility, the success of these approaches is not yet able to be guaranteed and is greatly dependent on the physical and chemical nature of the molecules being developed. Crystal engineering offers a number of routes to improved solubility and dissolution rate, which can be adopted through an in-depth knowledge of crystallisation processes and the molecular properties of active pharmaceutical ingredients. This article covers the concept and theory of crystal engineering and discusses the potential benefits, disadvantages and methods of preparation of co-crystals, metastable polymorphs, high-energy amorphous forms and ultrafine particles. Also considered within this review is the influence of crystallisation conditions on crystal habit and particle morphology with potential implications for dissolution and oral absorption.

yes / Ibuprofen (IBF) is an outstanding non-steroidal drug for analgesic and anti-inflammatory therapies but it exhibits poor solubility in water [1, 2]. Increased dosage administration has been linked to gastrointestinal and cardiovascular complications [3]. Many techniques have been employed to improve the solubility of NSAIDs [4]. In this study, the anti-solvent precipitation method was used to make Ibuprofen nanoparticles (IBF NPs). Optimised preparation parameters such as solvent (ethanol), raw drug concentration (400 mg), solvent/anti-solvent ratio (1:50) and surfactant concentration (0.25 mg/ml) have been studied to yield nanoparticles with a mean size of 58.8 nm, which is confirmed by dynamic light scattering and transmission electron microscopy. These IBF NPs posess increased aqueous solubility compared to the micro counterpart and maintain with chemical integrity indicated by high performance liquid chromatography and Fourier transform infrared spectroscopy. In addition, in vitro cytotoxicity of IBF NPs has been studied on A549 and HaCat cell lines using MTT and LDH assays. Both cells were obtained from ATCC. The A549 cells were grown in a modification of Ham’s F-12, containing L-glutamine, called F-12K. The HaCaT cells were grown in DMEM containing sodium pyruvate (110 mg/l). Normal cell culture and sub-culture were applied and the cells were used after around 45 passages [5]. The cell culture media containing 105cells/ml were placed in a 96-well plate with addition of IBF NPs and Micro form at concentrations in the range of between 6 and 500 ug/ml by diluting them with DMEM and F-12K for use with the HaCaT and A549 cells respectively. After 24, 48 and 72h exposure, the MTT and LDH cytotoxicity assay were performed in triplicates and on three separate experiment cultures and the absorbance was recorded at 570 nm and 492nm respectively with Elisa micro plate reader. The cell viability (%) related to control (cells in culture medium without NPs) was calculated. A very good cytotoxicity profile was observed, indicating an in vitro cytocompatibility of the IBF NPs in these cell culture systems and no significant changes in cytotoxicity compared with Micro IBF. We conclude that our IBF NPs have increased solubility, same chemical integrity and unchanged cytotoxicity compared to IBF Micro drug. Further work will concentrate on optimising more rigorous parameter to produce excellent quality NPs. More detailed characterisation of IBF NPs is to be tested, such as using PXRD and SEM to further corroborate particle shape and size. The range of no toxic in vitro concentrations is also to be further confirmed. Eventually scaled up preparation of IBF NPs will be developed without relinquishing NPs quality. This would improve the potential for in vitro/ in vivo applications and clinical use of IBF NPs and NSAIDs in general.