Carvedilol-loaded solid lipid nanoparticles (SLNs) were prepared using solubility parameter () to... more Carvedilol-loaded solid lipid nanoparticles (SLNs) were prepared using solubility parameter () to select the lipid, and hot homogenization to fabricate SLNs. The effect of concentration of Compritol 888 ATO (COMP) and Poloxamer 188 (P-188) on the particle size of blank SLNs was studied using the design of experiments. Further narrow concentration range of COMP and P-188 was selected and carvedilol-loaded SLNs were prepared to obtain an optimized formulation which was lyophilized (L-SLNs), transformed into enteric compression-coated tablet and evaluated for drug release, X-ray diffraction and cellular uptake mechanism. COMP was chosen as lipid due to its least value of D with carvedilol. The optimized formulation (7.5% COMP, 5.0% P-188 and 1.11% carvedilol) had 161 nm particle size and 94.8% entrapment efficiency. The enteric-coated carvedilol-loaded SLNs tablet protected carvedilol from acidic environment and similar prolonged release profiles were obtained from L-SLNs, core tablet and enteric-coated tablet. Absence of crystalline carvedilol XRD peak indicated the presence of amorphous carvedilol in SLNs. Higher carvedilol uptake from SLNs compared to drug solution in the Caco-2 cell line exhibited a potential prolonged drug release. Moreover, upon cellular uptake, SLNs could then enter the lymphatic system which will avoid first pass metabolism and hence higher oral bioavailability.
Keywords: liposomes nanoparticles drug delivery systems transdermal drug delivery permeability pe... more Keywords: liposomes nanoparticles drug delivery systems transdermal drug delivery permeability percutaneous controlled release colloid skin lipids a b s t r a c t In the recent decade, skin delivery (topical and transdermal) has gained an unprecedented popularity, especially due to increased incidences of chronic skin diseases, demand for targeted and patient compliant delivery, and interest in life cycle management strategies among pharmaceutical companies. Literature review of recent publications indicates that among various skin delivery systems, lipid-based delivery systems (vesicular carriers and lipid particulate systems) have been the most successful. Ve-sicular carriers consist of liposomes, ultradeformable liposomes, and ethosomes, while lipid particulate systems consist of lipospheres, solid lipid nanoparticles, and nanostructured lipid carriers. These systems can increase the skin drug transport by improving drug solubilization in the formulation, drug partitioning into the skin, and fluidizing skin lipids. Considering that lipid-based delivery systems are regarded as safe and efficient, they are proving to be an attractive delivery strategy for the pharmaceutical as well as cosmeceutical drug substances. However, development of these delivery systems requires comprehensive understanding of physicochemical characteristics of drug and delivery carriers, formulation and process variables, mechanism of skin delivery, recent technological advancements, specific limitations, and regulatory considerations. Therefore, this review article encompasses recent research advances addressing the aforementioned issues.
Enhanced oral bioavailability of poorly aqueous soluble drugs encapsulated in solid lipid nanopar... more Enhanced oral bioavailability of poorly aqueous soluble drugs encapsulated in solid lipid nanoparticles (SLNs) via lymphatic delivery has been documented. Since no in-vitro lymphoid tissue is currently available, human excised Caco-2 cell monolayer could be alternative tissue for development of an in-vitro model to be used as a screening tool before animal studies are undertaken. Therefore, optimized carvedilol-loaded SLNs (FOPT-SLNs) were prepared, characterized, and evaluated using Caco-2 cell line as an in-vitro model. Physical mixture of components of FOPT-SLNs (FOPT-PM) and carvedilol solution were used as control groups. From the studies of effect of SLNs concentration and cells incubation time, suitable carvedilol concentration and incubation time were selected for the model in which cells were subjected to five pretreatments for 24 h or 1 h of cell incubation and then followed with treatment of FOPT-SLNs, FOPT-PM or 100 mg/mL solution of carvedilol, for additional 24 h of cell incubation. The results obtained in this model suggest that main absorption mechanism of FOPT-SLNs could be endocytosis and, more specifically, clathrin-mediated endocytosis. When Transwell Õ permeable supports were used for the cells, carrier-mediated mechanism for FOPT-SLNs and passive absorption mechanism (transcellular and paracellular) for FOPT-PM and drug solution were concluded.
Aims—The purpose of this study was to determine the cell viability and cytotoxicity of various en... more Aims—The purpose of this study was to determine the cell viability and cytotoxicity of various endocytosis and efflux inhibitors which can be used to determine transport and uptake mechanisms in the BeWo (b30 clone) human placental trophoblast cell line. Ethanol and dimethylsulfoxide (DMSO) were also studied since they are often used as cosolvents for administration of these inhibitors. Methodology—The water-soluble tetrazolium-1 (WST-1) assay was used to quantify cell viability and the lactate dehydrogenase (LDH) assay was used to determine cytotoxicity. Results—By the WST-1 assay, reduced cell viability was observed following 4 hours of exposure to chlorpromazine (10 μg/mL), colchicine (1 mM), filipin (3 μg/mL), gentamicin (2 mM), GF120918 (1 μM), methyl-β-cyclodextrin (5 mM), and verapamil (100 μM). By the LDH assay, however, no cytotoxicity was observed after 4 hours of exposure to the aforementioned compounds. Amiloride (500 μM), ethanol (up to 0.1% v/v), and DMSO (up to 0.1% v/v) did not reduce cell viability nor induce cytotoxicity. Conclusion—This information is valuable when selecting potential inhibitors of endocytosis and efflux and the selection of time points for mechanistic studies.
Assessment of drug transport across the placenta is important in understanding the effect of drug... more Assessment of drug transport across the placenta is important in understanding the effect of drugs on placental and fetal health. These phenomena can be studied in both in vitro cell lines and ex vivo placental perfusions. We have successfully developed a sensitive yet simple high performance liquid chromatography (HPLC) method coupled with fluorescence detection to determine the concentration of doxorubicin (DXR) in cell culture media for transport studies in human trophoblast cells (BeWo, b30 clone) and in fetal media for placental perfusion experiments. The method was developed based on a protein precipitation technique and was validated in both media types for linearity, intra-day, and inter-day precision and accuracy. The relationship of peak area to concentration was linear with R 2 values of 0.99 or greater obtained over the concentration range of 1.5 to 15,000 ng/mL. Despite the high concentrations of albumin in fetal perfusion media (30 mg/mL), the lower limits of detection and quantification for DXR were found to be 1.5 and 5 ng/mL, respectively. This analytical method may be used to study the transport of DXR across BeWo cells and human placenta during placental perfusion studies.
Carvedilol-loaded solid lipid nanoparticles (SLNs) were prepared using solubility parameter () to... more Carvedilol-loaded solid lipid nanoparticles (SLNs) were prepared using solubility parameter () to select the lipid, and hot homogenization to fabricate SLNs. The effect of concentration of Compritol 888 ATO (COMP) and Poloxamer 188 (P-188) on the particle size of blank SLNs was studied using the design of experiments. Further narrow concentration range of COMP and P-188 was selected and carvedilol-loaded SLNs were prepared to obtain an optimized formulation which was lyophilized (L-SLNs), transformed into enteric compression-coated tablet and evaluated for drug release, X-ray diffraction and cellular uptake mechanism. COMP was chosen as lipid due to its least value of D with carvedilol. The optimized formulation (7.5% COMP, 5.0% P-188 and 1.11% carvedilol) had 161 nm particle size and 94.8% entrapment efficiency. The enteric-coated carvedilol-loaded SLNs tablet protected carvedilol from acidic environment and similar prolonged release profiles were obtained from L-SLNs, core tablet and enteric-coated tablet. Absence of crystalline carvedilol XRD peak indicated the presence of amorphous carvedilol in SLNs. Higher carvedilol uptake from SLNs compared to drug solution in the Caco-2 cell line exhibited a potential prolonged drug release. Moreover, upon cellular uptake, SLNs could then enter the lymphatic system which will avoid first pass metabolism and hence higher oral bioavailability.
Keywords: liposomes nanoparticles drug delivery systems transdermal drug delivery permeability pe... more Keywords: liposomes nanoparticles drug delivery systems transdermal drug delivery permeability percutaneous controlled release colloid skin lipids a b s t r a c t In the recent decade, skin delivery (topical and transdermal) has gained an unprecedented popularity, especially due to increased incidences of chronic skin diseases, demand for targeted and patient compliant delivery, and interest in life cycle management strategies among pharmaceutical companies. Literature review of recent publications indicates that among various skin delivery systems, lipid-based delivery systems (vesicular carriers and lipid particulate systems) have been the most successful. Ve-sicular carriers consist of liposomes, ultradeformable liposomes, and ethosomes, while lipid particulate systems consist of lipospheres, solid lipid nanoparticles, and nanostructured lipid carriers. These systems can increase the skin drug transport by improving drug solubilization in the formulation, drug partitioning into the skin, and fluidizing skin lipids. Considering that lipid-based delivery systems are regarded as safe and efficient, they are proving to be an attractive delivery strategy for the pharmaceutical as well as cosmeceutical drug substances. However, development of these delivery systems requires comprehensive understanding of physicochemical characteristics of drug and delivery carriers, formulation and process variables, mechanism of skin delivery, recent technological advancements, specific limitations, and regulatory considerations. Therefore, this review article encompasses recent research advances addressing the aforementioned issues.
Enhanced oral bioavailability of poorly aqueous soluble drugs encapsulated in solid lipid nanopar... more Enhanced oral bioavailability of poorly aqueous soluble drugs encapsulated in solid lipid nanoparticles (SLNs) via lymphatic delivery has been documented. Since no in-vitro lymphoid tissue is currently available, human excised Caco-2 cell monolayer could be alternative tissue for development of an in-vitro model to be used as a screening tool before animal studies are undertaken. Therefore, optimized carvedilol-loaded SLNs (FOPT-SLNs) were prepared, characterized, and evaluated using Caco-2 cell line as an in-vitro model. Physical mixture of components of FOPT-SLNs (FOPT-PM) and carvedilol solution were used as control groups. From the studies of effect of SLNs concentration and cells incubation time, suitable carvedilol concentration and incubation time were selected for the model in which cells were subjected to five pretreatments for 24 h or 1 h of cell incubation and then followed with treatment of FOPT-SLNs, FOPT-PM or 100 mg/mL solution of carvedilol, for additional 24 h of cell incubation. The results obtained in this model suggest that main absorption mechanism of FOPT-SLNs could be endocytosis and, more specifically, clathrin-mediated endocytosis. When Transwell Õ permeable supports were used for the cells, carrier-mediated mechanism for FOPT-SLNs and passive absorption mechanism (transcellular and paracellular) for FOPT-PM and drug solution were concluded.
Aims—The purpose of this study was to determine the cell viability and cytotoxicity of various en... more Aims—The purpose of this study was to determine the cell viability and cytotoxicity of various endocytosis and efflux inhibitors which can be used to determine transport and uptake mechanisms in the BeWo (b30 clone) human placental trophoblast cell line. Ethanol and dimethylsulfoxide (DMSO) were also studied since they are often used as cosolvents for administration of these inhibitors. Methodology—The water-soluble tetrazolium-1 (WST-1) assay was used to quantify cell viability and the lactate dehydrogenase (LDH) assay was used to determine cytotoxicity. Results—By the WST-1 assay, reduced cell viability was observed following 4 hours of exposure to chlorpromazine (10 μg/mL), colchicine (1 mM), filipin (3 μg/mL), gentamicin (2 mM), GF120918 (1 μM), methyl-β-cyclodextrin (5 mM), and verapamil (100 μM). By the LDH assay, however, no cytotoxicity was observed after 4 hours of exposure to the aforementioned compounds. Amiloride (500 μM), ethanol (up to 0.1% v/v), and DMSO (up to 0.1% v/v) did not reduce cell viability nor induce cytotoxicity. Conclusion—This information is valuable when selecting potential inhibitors of endocytosis and efflux and the selection of time points for mechanistic studies.
Assessment of drug transport across the placenta is important in understanding the effect of drug... more Assessment of drug transport across the placenta is important in understanding the effect of drugs on placental and fetal health. These phenomena can be studied in both in vitro cell lines and ex vivo placental perfusions. We have successfully developed a sensitive yet simple high performance liquid chromatography (HPLC) method coupled with fluorescence detection to determine the concentration of doxorubicin (DXR) in cell culture media for transport studies in human trophoblast cells (BeWo, b30 clone) and in fetal media for placental perfusion experiments. The method was developed based on a protein precipitation technique and was validated in both media types for linearity, intra-day, and inter-day precision and accuracy. The relationship of peak area to concentration was linear with R 2 values of 0.99 or greater obtained over the concentration range of 1.5 to 15,000 ng/mL. Despite the high concentrations of albumin in fetal perfusion media (30 mg/mL), the lower limits of detection and quantification for DXR were found to be 1.5 and 5 ng/mL, respectively. This analytical method may be used to study the transport of DXR across BeWo cells and human placenta during placental perfusion studies.
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