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- Volume 15, Issue 9, 2018
Current Drug Delivery - Volume 15, Issue 9, 2018
Volume 15, Issue 9, 2018
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Nanocrystals Technology for Transdermal Delivery of Water-Insoluble Drugs
Authors: Yangyang Liu, Juan Zhao, Lulu Wang, Beibei Yan, Yu Gu, Ping Chang and Yancai WangThe poor penetration and low bioavailability are the main challenges for transdermal drug delivery. Nanocrystals technology is an attractive method for water-insoluble drug transdermal delivery, as the literature demonstrated that the penetration and bioavailability of the transdermal delivered water-insoluble drugs significantly enhanced and improved by the nanocrystals technology. Currently, the nanocrystals technology has been applied in transdermal delivery of cosmeceutical and for therapy of skin diseases, such as diclofenac acid, tretinoin and rutin. This review focused on the advantages of the nanocrystals technology for transdermal delivery. The special features of nanocrystals for the transdermal delivery of poorly soluble drugs are reviewed (skin disease treatment, safety and compliance, applying to cosmeceutical). Furthermore, the factors of influencing the nanocrystals penetration and the approaches of improving nanocrystals transdermal delivery are also discussed in detail.
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Box-Behnken Design of Experiment Assisted Development and Optimization of Bendamustine HCl loaded Hydroxyapatite Nanoparticles
Authors: Shindu C. Thomas, Tushar Madaan, Zeenat Iqbal and Sushama TalegaonkarBackground: Bendamustine HCl, an antineoplastic drug, has a very short life of about 40 minutes which necessitates administration of large doses which leads to increased side effects as well as costs. Objective: The present work describes the fabrication, optimization, and evaluation of bioactive hydroxyapatite nanoparticles to achieve sustained delivery of bendamustine HCl. Methods: Hydroxyapatite nanoparticles (NPs) were prepared by the wet chemical precipitation method by reacting a calcium and phosphate precursor and the reaction was optimized via Box-Behnken DOE. The drug was loaded on particles by physical adsorption. Various analytical studies were performed on the fabricated nanoparticles in addition to biodistribution studies to establish the physicochemical and biological characteristics of the designed formulation. Results: pH of the reactant solution was found to have a more profound effect on the particle size and size distribution in comparison to reactant concentration. The particles were found to have a spherical morphology by SEM. Size of the blank and drug-loaded nanoparticles was found to be 130±20 nm by TEM. Energy Dispersive X-ray Spectroscopy (EDS) studies confirmed the presence of hydroxyapatite as the dominant phase while DSC studies indicated the presence of the drug in its amorphous form after its adsorption on NPs. Tissue distribution studies further suggested that the majority of drug concentration was released in blood rather than the other organs implying low organ toxicity. Conclusion: Bendamustine loaded hydroxyapatite nanoparticles were successfully optimized and fabricated. Favorable results were obtained in in vitro, in vivo, and analytical studies.
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Improvement of Anti-Hyperlipidemic Activity and Oral Bioavailability of Fluvastatin Via Solid Self-Microemulsifying Systems and Comparative with Liquisolid Formulation
Authors: Katla V. Madhav and Veerabrahma KishanBackground: FR scientists continuously try to increase the in vivo performance of low soluble and bioavailable drugs. Solid SMEDDS and liquisolid formulations are relatively simple to develop and fall within the novel drug delivery approaches. Here, a comparison is made to know relative superiority. Objective: The study aimed to conduct comparative pharmacokinetic (PK) and pharmacodynamic (PD) studies of developed Fluvastatin (FLU) solid SMEDDS (SSMED) and liquisolid formulation (LS) for their relative in vivo efficacy. Method: FLU liquid SMEDDS were optimized by central composite design (CCD). Components, oil, surfactant and co-surfactant were selected as variables; particle size, self-emulsifying time and % drug release in 15min were selected as responses. L-SMEDDS with positive charge inducer were adsorbed on to porous carriers and characterized. Liquisolid formulations were prepared with Avicel PH-102 and Neusilin US2 as carriers. Results: Optimized L-SMEDDS contained 24.92 mg of oil, 45.18 mg of surfactant and 34.28 mg of cosurfactant. SSMEDs containing Syloid XDP (SSMED-XDP) as carrier was selected based on flow properties and liquid retention potential. The average particle size of SSMED-XDP was 154.30±1.10 nm, PDI was 0.311±0.03 and ZP was +19.57±1.34 mV after dilution. The drug release from SSMEDXDP and LS formulations was higher than FLU powder. The bioavailability of SSMEDs was increased by 3.00 fold and that of LS by 1.49 fold more than FLU-suspension. SSMEDs showed 12 h, while LS and suspension showed only 6 h lipid-lowering effect. Conclusion: The development of solid SMEDDS resulted in superior performance in both PK and PD effects over the LS formulation.
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Optimizing Antitumor Efficacy and Adverse Effects of Pegylated Liposomal Doxorubicin by Scheduled Plasmapheresis: Impact of Timing and Dosing
Background: Nanoscale drug delivery systems accumulate in solid tumors preferentially by the enhanced permeation and retention effect (EPR-effect). Nevertheless, only a miniscule fraction of a given dosage reaches the tumor, while >90% of the given drug ends up in otherwise healthy tissues, leading to the severe toxic reactions observed during chemotherapy. Once accumulation in the tumor has reached its maximum, extracorporeal elimination of circulating nanoparticles by plasmapheresis can diminish toxicities. Objective: In this study, we investigated the effect of dosing and plasmapheresis timing on adverse events and antitumor efficacy in a syngeneic rat tumor model. Methods: MAT-B-III cells transfected with a luciferase reporter plasmid were inoculated into female Fisher rats, and pegylated liposomal doxorubicin (PLD) was used for treatment. Plasmapheresis was performed in a discontinuous manner via centrifugation and subsequent filtration of isolated plasma. Results: Bioluminescence measurements of tumor growth could not substitute caliper measurements of tumor size. In the control group, raising the dosage above 9 mg PLD/kg body weight did not increase therapeutic efficacy in our fully immunocompetent animal model. Plasmapheresis was best done 36 h after injecting PLD, leading to similar antitumor efficacy with significantly less toxicity. Plasmapheresis 24 h after injection interfered with therapeutic efficacy, while plasmapheresis after 48 h led to fewer side effects but also to increased weight loss. Conclusion: Long-circulating nanoparticles offer the unique possibility to eliminate the excess of circulating particles after successful accumulation in tumors by EPR, thereby reducing toxicities and likely toxicity-related therapeutic limitations.
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Development of Curcumin-Loaded Solid Lipid Nanoparticles Utilizing Glyceryl Monostearate as Single Lipid Using QbD Approach: Characterization and Evaluation of Anticancer Activity Against Human Breast Cancer Cell Line
Background: Solid lipid nanoparticles (SLNs) represent an affordable, easily scalable, stable and biocompatible drug delivery system with a high drug to lipid ratio which also improves solubility of poorly soluble drugs. Objective: SLNs were developed by using glyceryl monostearate as the single lipid in the presence of surfactant Poloxamer 188 and evaluated the efficiency of SLNs to load the therapeutic cargo, curcumin (CUR). Method: The nano-formulation was optimized by Quality by Design approach to understand the effect of various process parameters on various quality attributes, including drug loadability, particle size and polydispersity. The nanoparticles were characterized using Differential scanning calorimetry (DSC), Fourier Transform Infra-red Spectroscopy (FT-IR) and X-Ray Diffraction (XRD) analysis. These novel SLNs were evaluated for in-vitro anticancer activity using breast adenocarcinoma cells (MDA-MB-231). Results: The optimized formulation had a particle size of 226.802±3.92 nm with low polydispersity index of 0.244±0.018. The % encapsulation of CUR into SLNs was found to be 67.88±2.08 %. DSC, FT-IR and XRD confirmed that the CUR was encapsulated stably into the lipid matrix, thereby improving the solubility of the drug. CUR-SLN showed sustained drug release in comparison to the free CUR solution. CUR-SLNs exhibited higher cellular uptake in human breast adenocarcinoma cells compared to free CUR at both 1 and 4 h time points. CUR-SLNs demonstrated decreased cell viability (43.97±1.53%) compared to free CUR (59.33±0.95%) at a concentration of 50 μg/mL after 24 h treatment. Furthermore, the treatment of MDA-MB-231 cells with CUR-SLNs for 24 h induced significantly higher apoptosis (37.28±5.3%) in cells compared to the free CUR (21.06±0.97%). Conclusion: The results provide a strong rationale for further exploration of the newly developed CUR-SLN to be utilized as a potent chemotherapeutic agent in cancer therapy.
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Lipid Based Aqueous Core Nanocapsules (ACNs) for Encapsulating Hydrophillic Vinorelbine Bitartrate: Preparation, Optimization, Characterization and In vitro Safety Assessment for Intravenous Administration
Authors: Lakshmi, Sanjay Singh, Mahalingam R. Vijayakumar and Hitesh Kumar DewanganBackground: Vinorelbine bitartrate (VRL) is an antimitotic agent approved by FDA for breast cancer and non-small cell lung cancer (NSCLC) in many countries. However, high aqueous solubility and thermo degradable nature of VRL limited the availability of marketed dosage forms. Objectives: The current work is focused on the development of lipid based aqueous core nanocapsules which can encapsulate the hydrophilic VRL in the aqueous core of nanocapsules protected with a lipidic shell which will further provide a sustained release. Methods: The ACNs were prepared by double emulsification technique followed by solvent evaporation. Box Behnken Design was utilized to optimize the formulation and process variables. Thirteen batches were generated utilizing lipid concentration, surfactant concentration and homogenizer speed as dependent variables (at three levels) and particle size and encapsulation efficiency as critical quality attributes. The ACNs were characterized for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, morphology by Transmission Electron Microscopy (TEM) and in vitro release. The ACNs were further evaluated for safety against intravenous administration by haemocompatibility studies. Results: Results demonstrated that lipidic nanocapsules enhanced the entrapment efficiency of VRL up to 78%. Transmission Electron Microscopy revealed spherical shape of ACNs with core-shell structure. The GMS-VRL-ACNs showed that release followed Korsemeyer peppas kinetics suggesting Fickian diffusion. Moreover, the compliance towards haemocompatibility studies depicted the safety of prepared nanocapsules against intravenous administration. Conclusion: ACNs were found to be promising in encapsulating high aqueous soluble anticancer drugs with enhanced entrapment and safety towards intravenous administration.
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Development and Evaluation of an Anti-Epileptic Oral Fast-Dissolving Film with Enhanced Dissolution and In vivo Permeation
Authors: Arezou Soroushnai, Fariba Ganji, Ebrahim Vasheghani-Farahani and Hamid MobediObjectives: The main objective of this novel study was to develop midazolam hydrochloride fast dissolving oral films (FDFs) using solvent casting method and to evaluate the characteristics of the optimum formulation through in vitro and in vivo analysis. The FDFs are new favorable solid dosage forms that deliver drugs rapidly to the blood circulation system and have great advantages in the emergent control of severe neuropathic attacks in children. Methods: Midazolam nanosuspensions were prepared using the ultrasonic method and then incorporated in the hydroxypropyl methyl cellulose (HPMC)/pullulan polymeric matrix with other excipients like glycerol and cellulose nanofiber as a softener and a compatibilizer, respectively. The prepared films were evaluated for mechanical properties, morphology study, disintegration time, and dissolution time. Results: SEM images of FDFs showed the uniform distribution of spherical nanoparticles in the polymeric matrix. A film with 36% HPMC, 64% pullulan, and 21% glycerin was selected as the optimum formulation by the Design Expert 7 software. The optimum film was stable for three months. Conclusion: The pharmacokinetic parameters of midazolam oral film in comparison to coarse midazolam suspension exhibited significant increase in AUC, Cmax, and a good decrease in Tmax. The overall results showed the enhanced in vivo orotransmucosal absorption of poorly water-soluble drugs via the insertion of drugs nanosuspension in buccal films.
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Alpha-lactalbumin Effect on Myo-inositol Intestinal Absorption: In vivo and In vitro
Authors: Giovanni Monastra, Yula Sambuy, Simonetta Ferruzza, Daniela Ferrari and Giulia RanaldiBackground: Myo-inositol is a natural molecule with important therapeutic applications and an impaired oral absorption may result in a reduced clinical effect. Aim of this study was to determine if the combined oral administration of α-lactalbumin and myo-inositol in healthy subjects, could increase the plasma level of myo-inositol administered alone. In vitro studies on human differentiated intestinal Caco-2 cells were also conducted to identify the mechanisms involved in myo-inositol absorption. Objective: The in vivo study was conducted on healthy volunteers in two phases. Subjects received a single oral myo-inositol dose. After 7 days washout, the same subjects were administered a single dose of myo-inositol and α-lactalbumin. Cmax, Tmax and AUC for myo-inositol in plasma were calculated from samples collected at different times. Transepithelial myo-inositol passage, with or without addition of digested α-lactalbumin, was measured in vitro in differentiated Caco-2 cells and compared to transepithelial electrical resistance and phenol red passage. Results: The bioavailability of myo-inositol was modified by the concomitant administration of α- lactalbumin. Although peak concentration of myo-inositol at 180 min (Tmax) was similar for both treatments, administration of α-lactalbumin with myo-inositol in a single dose, significantly increased the plasma concentrations of myo-inositol compared to when administered alone. In vitro, myo-inositol absorption in Caco-2 cells was improved in the presence of digested α-lactalbumin, and this change was associated with an increase in tight junction permeability. Conclusion: Better myo-inositol absorption when orally administered with α-lactalbumin can be beneficial in non-responder patients. Preliminary in vitro findings suggest that peptides deriving from α- lactalbumin digestion may modulate tight junction permeability allowing increased absorption of myoinositol.
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Preparation, Optimization, In vitro Evaluation and Ex vivo Permeation Studies of Finasteride loaded gel Formulations Prepared by using Response Surface Methodology
Authors: Muhammad Z. U. Khan, Petre Makreski and Ghulam MurtazaObjectives: The aim of the present explorative study was to prepare and optimize finasteride loaded topical gel formulations by using three factor [propylene glycol (PG), Tween® 80, and sodium lauryl sulphate (SLS)], five level central composite design. Results: Optimized finasteride topical gel formulation (F4), containing PG, Tween® 80, and SLS in a concentration of 0.8 mg, 0.4 mg and 0.2 mg, respectively, showed 6-fold higher values of cumulative drug release, flux, partition coefficient, input rate, lag time, and diffusion coefficient, when compared to control formulation without permeation enhancer. Conclusion: Finally, it can be concluded that finasteride permeation was enhanced by PG, tween® 80 and SLS individually, while in combination only PG along with tween® 80 had synergistic and more pronounced effect on flux, permeability coefficient and input rate while antagonistic effect on lag time and diffusion coefficient was observed.
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Cell Surface Nucleolin as a Promising Receptor for Effective AS1411 Aptamer-Mediated Targeted Drug Delivery into Cancer Cells
Authors: Jafar Mosafer and Ahad MokhtarzadehBackground: One of the major abundant proteins in the nucleous is nucleolin that overexpressed on the cytoplasmic membrane of malignant and endothelial cells and makes it as a promising condidate for targeted drug delivery. Objectives: In this study, doxorubicin (Dox) as a chemotherapy drug was entrapped into the Poly lacticco- glycolic acid (PLGA)-based nanoparticles (NPs). Then, the targeting ability of anti nucleolin AS1411 aptamer-targeted Dox-encapsulated PLGA-based NPs (AS1411-NPs) was investigated in high nucleolin-expressing C26 colon carcinoma and rat C6 glioma cell lines compared with low nucleolinexpressing mouse L929 cell line. Methods: We recently first assessed the existence of cell surface nucleolin of these three different cell lines by immunocytochemistry method. We found that a large amount of nucleolin was localized in the cytoplasmic membrane of C26 and C6 cell lines, with a very smaller amount on the surface of L929 cell line. Results: As a result, more rapidly internalization of AS1411-NPs into the C26 and C6 cells compared with L929 cells was verified. Conclusion: We think that AS1411-NPs, as a ligand, first bind to nucleolin, as a receptor, and then the receptor-ligand complex is more efficiently incorporated into the high nucleolin-expressing cell lines through receptor-mediated endocytosis pathway.
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Implementing Central Composite Design for Developing Transdermal Diacerein-Loaded Niosomes: Ex vivo Permeation and In vivo Deposition
Authors: Diana E. Aziz, Aly Ahmed Abdelbary and Abdelhalim Ibrahim ElassasyBackground: Niosomes are surfactant-based vesicular nanosystems that proved their efficiency in transdermal delivery by overcoming skin inherent anatomic barrier; startum corneum. Central composite design is an efficient tool for developing and optimizing niosomal formulations using fewer experiments. Objective: The objective of this study was to prepare niosomes as a transdermal delivery system of diacerein using film hydration technique, employing central composite design, for avoiding its oral gastrointestinal problems. Methods: Three-level three-factor central composite design was employed for attaining optimal niosomes formulation with the desired characteristics. Three formulation variables were assessed: amount of salt in hydration medium (X1), lipid amount (X2) and number of surfactant parts (X3). DCNloaded niosomes were evaluated for entrapment efficiency percent (Y1), particle size (Y2), polydispersity index (Y3) and zeta potential (Y4). The suggested optimal niosomes were subjected to further characterization and utilized as a nucleus for developing elastic vesicles for comparative ex vivo and in vivo studies. Results: The values of the independent variables (X1, X2 and X3) in the optimal niosomes formulation were 0 g, 150 mg and 5 parts, respectively. It showed entrapment efficiency percentage of 95.63%, particle size of 436.65 nm, polydispersity index of 0.47 and zeta potential of -38.80 mV. Results of ex vivo permeation and skin deposition studies showed enhanced skin permeation and retention capacity of the prepared vesicles than drug suspension. Conclusion: Results revealed that a transdermal niosomal system was successfully prepared and evaluated using central composite design which will result in delivering diacerein efficiently, avoiding its oral problems.
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Synthesis and Characterization of pH-Sensitive Genipin Cross-Linked Chitosan/Eudragit® L100 Hydrogel for Metformin Release Study Using Response Surface Methodology
Authors: Muhammad Ubaid, Syed N. H. Shah, Shujaat A. Khan and Ghulam MurtazaBackground: In this study, central composite design was utilized for the optimization of genipin cross-linked chitosan/Eudragit®-L 100 interpenetrating hydrogel network films fabricated through solvent evaporation technique. Methods: Hydrogel formulations were studied using response surface methodology; regression analysis and the surface plots were used to evaluate the effect of variables on T50% (the time for 50% of drug release) and dynamic swelling with optimum formulation selection. Initial burst release of drug was observed from the formulated hydrogels during the first 2 hours of dissolution at simulated gastric pH 1.2 and then slow release during the next 10 hours in the simulated intestinal fluid at pH 7.4. Different polymer ratios in formulation showed significant influence on T50% and dynamic swelling of hydrogel. The highest T50% was observed at 9.89 hour and dynamic swelling at 7.86 h. Result: It was observed that by changing the polymer ratio with cross-linker, release rate of metformin could be modified. Cross-linker also affects drug release rate, i.e. the release rate is decreased with the increase in its concentration. The physical state of hydrogel was investigated by scanning electron microscope. Conclusion: It indicated the uniform distribution of drug in hydrogel matrix system. Moreover, the presence of hydrogen and ionic bonds between polymers and crosslinking agent formed interpenetrating hydrogel network, likely responsible for increased value of T50%, as confirmed by FTIR. Acute oral toxicity study was performed to investigate the toxic effect of crosslinking agent and polymer used in formulations.
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Volumes & issues
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Volume 21 (2024)
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Volume 20 (2023)
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Volume 19 (2022)
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Volume 18 (2021)
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Volume 17 (2020)
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Volume 16 (2019)
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Volume 15 (2018)
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Volume 14 (2017)
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Volume 13 (2016)
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Volume 12 (2015)
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Volume 11 (2014)
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Volume 10 (2013)
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Volume 9 (2012)
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Volume 8 (2011)
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Volume 7 (2010)
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Volume 6 (2009)
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Volume 5 (2008)
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Volume 4 (2007)
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Volume 3 (2006)
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Volume 2 (2005)
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Volume 1 (2004)