University College of Pharmaceutical Sciences, Kakatiya University, Warangal, A.P., India 506009.
Etoposide was incorporated in an injectable parenteral emulsion, in an attempt to alter its pharmacokinetics and improve anticancer activity. Parenteral emulsion of etoposide (EPE), which remained stable over 6 months' storage, was prepared (under optimal experimental conditions) using soybean oil and phosphatidylcholine as emulsifier. The particle size distribution and zeta potential were measured using photon correlation spectroscopy. The pharmacokinetics and tissue distribution of EPE and commercial etoposide injectable solution (ETP) were studied in Swiss albino mice. The antitumor activity was performed on BDF1 mice bearing Lewis lung carcinoma. The particle size distribution with polydispersity indices, zeta potential, entrapment efficacy, and assay of EPE were found to be 218.7 +/- 4.7 (0.14 +/- 0.0) nm,-53.5 +/- 0.2 mV, 75 +/- 2.1%, and 0.85 +/- 0.1 mg/mL, respectively. The EPE was stable for >6 months and drug leaching was 5.8 +/- 1.5%. The pharmacokinetics and tissue distribution of EPE was significantly different than that of ETP. The EPE showed high AUC(0-alpha), MRT (mean residence time), and lower clearance than that of ETP. It was found that etoposide concentration was higher in liver, spleen, and lung after ETP administration when compared with EPE; however, in heart and brain, etoposide was more after EPE than that of ETP. The EPE showed lower reticuloendothelial system (liver and spleen) tissue uptake. The anticancer activity of EPE was higher in Lewis lung carcinoma-bearing mice. On the fifteenth day of transplantation, the percentage of tumor growth suppression rate was 63.23% in EPE-treated mice and 33.78% in ETP-treated mice.
Evaluation of docetaxel-loaded intravenous lipid emulsion: pharmacokinetics, tissue distribution, antitumor activity, safety and toxicity.
Department of Pharmaceutics, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016, Liaoning Province, People's Republic of China.
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
The objective of the current study was to evaluate the ability of cell penetrating peptides (CPP) to translocate the lipid payload into the skin layers. Fluorescent dye (DID-oil) encapsulated nano lipid crystal nanoparticles (FNLCN) were prepared using Compritol, Miglyol and DOGS-NTA-Ni lipids by hot melt homogenization technique. The FNLCN surface was coated with TAT peptide (FNLCNT) or control YKA peptide (FNLCNY) and in vitro rat skin permeation studies were performed using Franz diffusion cells. Observation of lateral skin sections obtained using cryotome with a confocal microscope demonstrated that skin permeation of FNLCNT was time dependent and after 24h, fluorescence was observed upto a depth of 120 microm which was localized in the hair follicles and epidermis. In case of FNLCN and FNLCNY formulations fluorescence was mainly observed in the hair follicles. This observation was further supported by confocal Raman spectroscopy where higher fluorescence signal intensity was observed at 80 and 120 microm depth with FNLCNT treated skin and intensity of fluorescence peaks was in the ratio of 2:1:1 and 5:3:1 for FNLCNT, FNLCN, and FNLCNY treated skin sections, respectively. Furthermore, replacement of DID-oil with celecoxib (Cxb), a model lipophilic drug showed similar results and after 24h, the CXBNT formulation increased the Cxb concentration in SC by 3 and 6 fold and in epidermis by 2 and 3 fold as compared to CXBN and CXBNY formulations respectively. Our results strongly suggest that CPP can translocate nanoparticles with their payloads into deeper skin layers.
Formulation, characterization and pulmonary deposition of nebulized celecoxib encapsulated nanostructured lipid carriers.
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
The aim of the current study was to encapsulate celecoxib (Cxb) in the Nanostructured Lipid Carrier (Cxb-NLC) nanoparticles and evaluate the lung disposition of nanoparticles following nebulization in Balb/c mice. Cxb-NLC nanoparticles were prepared with Cxb, Compritol, Miglyol and sodium taurocholate using high-pressure homogenization. Cxb-NLC nanoparticles were characterized for physical and aerosol properties. In-vitro cytotoxicity studies were performed with A549 cells. The lung deposition and pharmacokinetic parameters of Cxb-NLC and Cxb solution (Cxb-Soln) formulations were determined using Inexpose system and Pari LC star jet nebulizer. The particle size and entrapment efficiency of Cxb-NLC formulation were 217+/-20nm and > 90%, respectively. The Cxb-NLC released the drug in controlled fashion, and in vitro aersolization of Cxb-NLC formulation showed FPF of 75.6+/-4.6 %, MMAD of 1.6+/-0.13microm and GSD of 1.2+/-0.21. Cxb-NLC showed dose and time dependent cytotoxicity against A549 cells. Nebulization of Cxb-NLC demonstrated 4 fold higher AUC(t/)D in lung tissues compared to Cxb-Soln. The systemic clearance of Cxb-NLC was slower (0.93L/h) compared to Cxb-Soln (20.03L/h). Cxb encapsulated NLC were found to be stable and aerodynamic properties were within the respirable limits. Aerosolization of Cxb-NLC improved the Cxb pulmonary bioavailability compared to solution formulation which will potentially lead to better patient compliance with minimal dosing intervals.
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
OBJECTIVE To obtain stable positively charged Azithromycin (AZI) emulsions with a mean droplet size of 120 nm for the treatment of eye diseases. METHODS The emulsions were obtained by using a suitable homogenization process. The physical stability was monitored by measuring the particle size, zeta potential, and visible appearance. The drug entrapment efficiency was measured by both ultracentrifugation and ultrafiltration methods. Compared with a phosphate solution of AZI, the stability profiles of AZI in lipid emulsions at various pH values were monitored by high-performance liquid chromatography. A pharmacokinetic study was performed to determine the drug levels in rabbit tear fluid using Ultra-performance liquid Chromatography-mass spectrometry. RESULTS Almost all the AZI in the lipid emulsion was distributed in the oil phase and small unilamellar liposomes without contact with water, thereby avoiding hydrolysis. The elimination of the AZI lipid emulsions in tear fluid was consistent with the basic linear pharmacokinetic characteristics. The AUC(0-t) of the AZI lipid emulsion (1%, w/v) and aqueous solution drops (1%, w/v) was 1873.58 +/- 156.87 and 1082.46 +/- 179.06 mugh/ml respectively. CONCLUSIONS This study clearly describes a new formulation of AZI lipid emulsion for ocular administration, and lipid emulsions are promising vehicles for ophthalmic drug delivery.
Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China. email@example.com
The entrapment efficiency (EE) and release in vitro are very important physicochemical characteristics of puerarin submicron emulsion (SME). In this paper, the performance of ultrafiltration (UF), ultracentrifugation (UC), and microdialysis (MD) for determining the EE of SME were evaluated, respectively. The release study in vitro of puerarin from SME was studied by using MD and pressure UF technology. The EE of SME was 86.5%, 72.8%, and 55.8% as determined by MD, UF, and UC, respectively. MD was not suitable for EE measurements of puerarin submicron oil droplet, which could only determine the total EE of submicron oil droplet and liposomes micelles, but it could be applied to determine the amount of free drug in SMEs. Although UC was the fastest and simplest to use, its results were the least reliable. UF was still the relatively accurate method for EE determination of puerarin SME. The release of puerarin SME could be evaluated by using MD and pressure UF, but MD seemed to be more suitable for the release study of puerarin emulsion. The drug release from puerarin SME at three drug concentrations was initially rapid, but reached a plateau value within 30 min. Drug release of puerarin from the SME occurred via burst release.
High-performance liquid chromatographic and pharmacokinetic analyses of an intravenous submicron emulsion of perillyl alcohol in rats.
Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, 40 Daxue Road, Zhengzhou, Henan Province 450052, PR China. firstname.lastname@example.org
Perillyl alcohol (POH) is currently in phase II clinical trials both as a chemopreventative and chemotherapeutic agent. The present report describes a simple, rapid and sensitive HPLC-UV method to quantify POH in rat plasma. After protein precipitation with acetonitrile, POH was separated using an Agilent Zorbax XDB C(18) column (150 mm x 4.6 mm, 5 microm) with a mobile phase consisting of acetonitrile-water (40:60, v/v) at a flow rate of 1.0 ml min(-1), and detected at 210 nm. The method has been used successfully to determine trace levels of POH in plasma down to 0.015 microg ml(-1). The pharmacokinetics of POH after intravenous administrations in three formulations, i.e. POH solution (POH-SOL), negatively charged submicron emulsions (POH-SE) and positively charged submicron emulsions (POH-CSSE) were investigated. AUC(0-infinity), MRT, t(1/2alpha) and t(1/2beta) of POH-SE and POH-CSSE were significantly higher, while their total body clearance was lower than those of POH-SOL. In addition, AUC(0-infinity), MRT and t(1/2beta) of POH-CSSE were significantly higher than those of POH-SE. The results indicate that the submicron emulsion formulation significantly increases POH blood concentrations and retention within the systemic circulation.
Determination of entrapment efficiency and drug phase distribution of submicron emulsions loaded silybin.
Department of Pharmaceutics, Shenyang Pharmaceutical University, Shen Yang, PR China. email@example.com
This paper compared the performance of ultrafiltration (UF), ultracentrifugation (UC) and microdialysis (MD) for determining the entrapment efficiency (EE) of submicron emulsions (SE) loaded with a model drug, silybin (SB). Also, a novel way was created to evaluate the drug phase distribution of SE. The EE of SEI, SEII and SEIII with a range of particle sizes (109.8, 171.7 and 213.2 nm) and the drug phase distribution of SEII and SEIII were separately determined by the three methods. The EEs of SEI were 99.8%, 91.1%, 84.4% determined by MD, UF, UC, respectively, and the EEs of SEII and SEIII were 99.5%, 86.4%, 72.1% and 99.4%, 84.3%, 66.3%, separately. The accuracy of MD to determine EE of SE is much less than that of UF. Although UC is the fastest and most simple to use, its results are the least reliable. The sequence of the amount of drug in SE is as follows: O/W interface, aqueous phase and oil phase. Over 80% of SB was in the O/W interface of SEII and SEIII individually. The method created is reliable for quantifying the phase distribution of drug in submicron emulsions.
NDDS Laboratory, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Andhra Pradesh, India.
Lipid nanospheres (LN) are simple colloidal drug delivery systems, which are proven to be useful for the systemic delivery of lipophilic anticancer drugs. Our previous work shows that the encapsulation of etoposide in LN improved the anticancer activity and a further inclusion of polyethylene glycol-distearoylphosphatidylethanolamine (DSPE-PEG) increased the circulation time and stability of LN. The present study is focused on the targeting ability of LN using Folate-PEG-DSPE. Folate-targeted (Fol-LNE) and non-targeted (SLNE) etoposide-encapsulated lipid nanospheres were prepared with the help of soybean oil, egg phosphatidylcholine, and PEG-DSPE with and without Folate-PEG-DSPE. The anticancer activity of these formulations was assessed in KB cell line. Cell uptake studies were carried out in KB cell lines using fluorescent-labeled targeted (Fol-LN) and non-targeted (SLN) lipid nanospheres without etoposide. Confocal microscopy and flow cytometry results found that, Fol-LN was selectively taken up by the KB cells and the addition of 1 mM folic acid completely blocked this uptake. Cytotoxicity results support the above finding, the IC50 values of etoposide solution, Fol-LNE, and Fol-LNE-comp (competition with 1 mM folic acid) were 33, 5, and 19 muM, respectively. Tissue distribution of Fol-LNE was compared with that of SLNE and etoposide commercial formulation (ETP) in normal mice. The studies show that in the kidney etoposide concentration was higher following Fol-LNE administration than SLNE and ETP.
Department of Pharmaceutics, Shenyang Pharmaceutical University, Wen Hua Road No.103, Shenyang 110016, China.
Etoposide was incorporated in lipid emulsion to develop an i.v. formulation, and improve its physical and chemical stability without addition of organic solvents, for use as a commercial formulation. High-pressure homogenization was used to prepare the lipid nanospheres and localize the drug at the surfactant layer. The particle size distribution and zeta potential were measured using photon correlation spectroscopy (PCS). Ultrafiltration was used to estimate the relative percentage of etoposide in each phase. The stability profile of etoposide in the lipid emulsion at various temperatures, pH values, and concentrations of drug was monitored by high performance liquid chromatography (HPLC). The degradation pattern of etoposide in lipid emulsion followed pseudo-first-order kinetics. The shelf life (T(90%)) of etoposide in lipid emulsion was estimated to be 47 days at 25 degrees C and it would be stable when stored for 427 days at 4 degrees C, which is a significant improvement compared with a stability of 9.5 days in aqueous solution at 25 degrees C. Etoposide in lipid emulsion and aqueous solution were both most stable at pH 5.0 with a half-life of 54.7 h and 38.6 min at 80 degrees C, respectively. The hydrolysis kinetics of etoposide in lipid emulsion was also shown to be dependent on the drug concentration.
School of Biological Sciences, University of Southampton, Biomedical Sciences Building, Bassett Crescent East, Southampton SO16 7PX, UK.
The topoisomerase enzymes are essential for DNA metabolism, where they act to adjust the number of supercoils in DNA, a key requirement in the cellular processes of transcription and replication. Their enzymatic mechanism creates transient nicks (type I) or breaks (type II) in the double stranded DNA polymer, allowing DNA to be converted between topological isomers. Humans possess both types of topoisomerase enzymes, however the two types utilize very different enzymatic mechanisms. Both type I and type II topoisomerases have been identified as clinically important targets for cancer chemotherapy and their inhibitors are central components in many therapeutic regimes. Over the course of the last 30 years inhibitors with extensive structural diversity have been developed through a combination of drug screening and rational design programs. Simultaneously much emphasis has been placed upon establishing the mechanisms of action of both classes of topoisomerase enzyme. Crucial structural insights have come from the crystal structure of topoisomerase I, while modelling comparisons are beginning to map out a possible framework for topoisomerase II action. This review discusses these recent advances in the fields of enzyme mechanism and inhibitor design. We also address the development of drug resistance and dose-limiting side effects as well as cover alternative methods in drug delivery.
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Pharmazie. 2008 May ;63 (5):352-5 18557418
University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Andhra Pradesh, India. firstname.lastname@example.org
The purpose of this study was to estimate the pharmacokinetic parameters and tissue distribution of positively charged stearylamine (LN-P-SA) and pegylated lipid nanospheres (LN-P-PEG) of piperine in BALB/c mice. Lipid nanospheres of piperine (LN-P), LN-P-PEG and LN-P-SA were prepared by homogenization followed by ultrasonication. The pharmacokinetics and tissue distribution of different lipid nanosphere formulations (piperine, LN-P, LN-P-PEG and LN-P-SA) were studied in male BALB/c mice. The pharmacokinetic parameters of LN-P-PEG and LN-P-SA were: AUC(0-24): 372.1 +/- 71.6 and 162.2 +/- 36.4 microg h(-1) ml(-1), clearance 13 +/- 2.5 and 32 +/- 7.5 ml h(-1), Cmax: 24.7 +/- 1.5 and 22.3 +/- 1.0 microg ml(-1), Vd: 0.45 +/- 0.02 and 0.66 +/- 0.06 l Kg(-1)). Pharmacokinetics of piperine in lipid nanospheres showed a biexponential decline with significantly high AUC, a lower rate of clearance and a smaller volume of distribution than piperine.
University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Andhra Pradesh, India.
Present studies are aimed to find out the utility of oil-in-water emulsions also known as lipid nanospheres (LN) or fat emulsions for delivering piperine for the treatment of visceral leishmaniasis. Lipid nanosphere formulations of piperine were prepared using soybean oil, egg lecithin, cholesterol, stearylamine and phosphatidylethanolamine distearylmethoxypolyethyleneglycol (DSPE-PEG) by homogenization followed by ultrasonication of oil and aqueous phases. Antileishmanial activity of all the formulations was assessed in BALB/c mice infected with Leishmania donovani AG83 for 60 days. A single dose (5 mg/kg) of piperine, or lipid nanospheres of piperine (LN-P), or lipid nanosphere of piperine with stearylamine (LN-P-SA) or pegylated lipid nanospheres of piperine (LN-P-PEG) was injected intravenously. Mice were sacrificed after 15 days of treatment with piperine or formulations and Leishman Donovan Unit (LDU) is counted. Toxicity of formulations and pure piperine was assessed in normal mice. The size distribution of formulations ranged from 200 to 885 nm. Piperine reduced the parasite burden in liver and spleen by 38% and 31% after 15 days post infection respectively. LN-P reduced the parasite burden in liver and spleen by 63% and 52% after 15 days post infection, respectively. LN-P-PEG reduced the parasite burden in liver and spleen by 78% and 75% after 15 days post infection, respectively. LN-P-SA reduced the parasite burden in liver and spleen by 90% and 85% after 15 days post infection, respectively. LN-P, LN-P-PEG, LN-P-SA treated mice did not show any significant changes in the serum levels of SGOT, ALP, creatinine and urea compared to normal mice. Stable and sterile formulations of lipid nanospheres of piperine were developed. A single dose of 5 mg/kg of lipid nanospheres of piperine could significantly reduce the liver and splenic parasite burden.
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kakatiya University, Warangal, India.
A reverse phase HPLC method to determine piperine, a pungent constituent of black pepper, in rabbit serum and various tissues of the rat was developed. A pharmacokinetic study was performed in rabbits and tissue distribution studies were carried out in rats. High reproducibility was achieved in quantitative analysis over the concentration range of 0.2-20 micrograms/ml serum. After bolus intravenous administration of piperine at a dose of 10 mg/kg, the serum concentration--time curve fitted the two-compartment open model. The tissue distribution pattern of piperine in rats also supports the two-compartment open model.
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Drug Deliv. 2012 Sep 18;: 22985261
Tissue distribution of 2-methoxyestradiol nanosuspension in rats and its antitumor activity in C57BL/6 mice bearing lewis lung carcinoma.
School of Chemical Engineering and Energy, Zhengzhou University , Zhengzhou , P.R. China.
The purpose of the present study was to evaluate the tissue distribution and antitumor activity of 2-methoxyestradiol (2-ME) nanosuspension compared with 2-ME solution both in vitro and in vivo. 2-ME nanosuspension was made by nanoprecipitation-high-frequency ultrasonication method with the particle size of 168.4 ± 3.2 nm and the zeta potential of -29.79 ± 1.89 mV. The overall targeting efficiency (TE(Q)) of 2-ME nanosuspension was improved from 28.71 to 51.95% in the lung of rats. MTT assay showed that 2-ME nanosuspension could significantly enhance the in vitro cytotoxicity against lewis lung carcinoma (LLC) cells compared with the 2-ME solution, the IC(50) at 72 h was reduced from 6.35 µM for 2-ME solution to 3.56 µM for 2-ME nanosuspension. The antitumor activity in vivo was investigated in C57BL/6 mice bearing LLC, and the results indicated that 2-ME nanosuspension not only exhibited significant suppression of the tumor growth when compared with that of positive group or cyclophosphamide group at the same dose, but also enhanced the spleen indices. Overall, 2-ME nanosuspension could mainly deliver the drug to lungs and made the drug accumulate in the lungs, so 2-ME nanosuspension has a possible lung cancer therapeutic potential.
J Control Release. 2012 Jun 5;: 22684119
In Vivo Biodistribution and Pharmacokinetics of Silica Nanoparticles as a Function of Geometry, Porosity and Surface Characteristics.
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84108, USA.
The in vivo biodistribution and pharmacokinetics of silica nanoparticles (SiO(2)) with systematically varied geometries, porosities, and surface characteristics were investigated in immune-competent CD-1 mice via the intravenous injection. The nanoparticles were taken up extensively by the liver and spleen. Mesoporous SiO(2) exhibited higher accumulation in the lung than nonporous SiO(2) of similar size. This accumulation was reduced by primary amine modification of the nanoparticles. High aspect ratio, amine-modified mesoporous nanorods showed enhanced lung accumulation compared to amine-modified mesoporous nanospheres. Accumulation of the nanoparticles was mainly caused by passive entrapment in the discontinuous openings in the endothelium of the liver and spleen or in the pulmonary capillaries, and was highly dependent on nanoparticle hydrodynamic size in circulation. The SiO(2) were likely internalized by the reticulo-endothelial system (RES) following physical sequestration in the liver and spleen. The nanoparticles that were transiently associated with the lung were re-distributed out of this organ without significant internalization. Pharmacokinetic analysis showed that all SiO(2) were rapidly cleared from systemic circulation. Amine-modified or nonporous nanoparticles possessed a higher volume of distribution at steady state than their pristine counterparts or mesoporous SiO(2). In all, surface characteristics and porosity played important roles in influencing SiO(2) biodistribution and pharmacokinetics. Increasing the aspect ratio of amine-modified mesoporous SiO(2) from 1 to 8 resulted in increased accumulation in the lung.
In-vivo pharmacokinetics, tissue distribution and anti-tumour effect of hydroxycamptothecin delivered in oil-in-water submicron emulsions.
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
OBJECTIVES The aim of this study was to investigate the pharmacokinetics, tissue distribution and anti-tumour effect of hydroxycamptothecin submicron emulsions (HCPT-SEs). METHODS HCPT-SEs or HCPT injection (HCPT-I) was administered intravenously into the tail vein of rats or S180 tumour-bearing mice. KEY FINDINGS HCPT-SEs increased the plasma concentration of HCPT compared with HCPT-I at all time points. The AUC(0-∞), elimination half-life and mean residence time of anionic submicron emulsions containing HCPT (HCPT-ASEs) and cationic submicron emulsions containing HCPT (HCPT-CSEs) were significantly greater than those of HCPT-I (P <0.01). Especially, a prolonged elimination half-life was found for HCPT-CSEs. HCPT-CSEs and HCPT-ASEs resulted in a 7.9-fold and 3.1-fold increase in AUC(0-6h) of tumour compared with HCPT-I, respectively. The targeting efficiency (T(e)) of HCPT-ASEs and HCPT-CSEs indicated their selectivity to tumour and the T(e) of HCPT-CSEs was significantly higher than that of HCPT-ASEs (P<0.01). The anti-tumour effect studies showed that HCPT-SEs improved the therapeutic efficiency of HCPT compared with HCPT-I. The percentage of tumour growth suppression rate of mice treated with HCPT-CSEs (2.0 mg HCPT eq./kg) increased 2.1 fold compared with that of HCPT-I. CONCLUSIONS Submicron emulsions can alter the pharmacokinetic characteristics and tissue distribution of HCPT, and enhance tumour targeting and anti-tumour activity.
Héloïse Ragelle, Sylvie Crauste-Manciet, Johanne Seguin, Denis Brossard, Daniel Scherman, Philippe Arnaud, Guy G Chabot
Paris Descartes University, Faculty of Pharmacy, INSERM U1022, CNRS UMR8151, Chimie ParisTech, Sorbonne Paris Cité, Chemical, Genetic and Imaging Pharmacology Laboratory, F-75006 Paris, France.
The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) has shown antitumour activity but its administration is complicated by its low water solubility. Our aim was to incorporate fisetin into a nanoemulsion to improve its pharmacokinetics and therapeutic efficacy. Solubility and emulsification tests allowed to develop an optimal nanoemulsion composed of Miglyol 812N/Labrasol/Tween 80/Lipoid E80/water (10%/10%/2.5%/1.2%/76.3%). The nanoemulsion had an oil droplet diameter of 153 ± 2 nm, a negative zeta potential (-28.4 ± 0.6 mV) and a polydispersity index of 0.129. The nanoemulsion was stable at 4 °C for 30 days, but phase separation occurred at 20 °C. Pharmacokinetic studies in mice revealed that the fisetin nanoemulsion injected intravenously (13 mg/kg) showed no significant difference in systemic exposure compared to free fisetin. However, when the fisetin nanoemulsion was administered intraperitoneally, a 24-fold increase in fisetin relative bioavailability was noted, compared to free fisetin. Additionally, the antitumour activity of the fisetin nanoemulsion in Lewis lung carcinoma bearing mice occurred at lower doses (36.6 mg/kg) compared to free fisetin (223 mg/kg). In conclusion, we have developed a stable nanoemulsion of fisetin and have shown that it could improve its relative bioavailability and antitumour activity.
Pharmacokinetics and tissue distribution profile of icariin propylene glycol-liposome intraperitoneal injection in mice.
School of Pharmaceutics Science, Wenzhou Medical College Wenzhou Medical College, Wenzhou City, Zhejiang Province, China.
OBJECTIVES The pharmacokinetics and tissue distribution of icariin propylene glycol-liposome suspension (ICA-PG-liposomes) have been investigated. METHODS ICA-PG-liposomes or ICA-PG-solution were prepared and intraperitoneally injected to mice. Morphology and size distribution of ICA-PG-liposomes were observed by transmission electron microscopy (TEM) and laser particle sizer. Plasma and tissues were collected at different times after intraperitoneal injection and icariin concentrations were determined by HPLC. KEY FINDINGS From TEM, ICA-PG-liposomes showed spherical vesicles with a mean particle size of 182.4 nm. The encapsulation efficiency of ICA-PG-liposomes reached 92.6%. Pharmacokinetics of ICA-PG-liposomes displayed the three open compartments model. ICA-PG-liposomes enhanced icariin absorption from the abdominal cavity, prolonged mean retention time (MRT((0-t))), increased area under curve (AUC((0-t))) and maximum concentration in plasma. Compared with ICA-PG-solution, ICA-PG-liposomes resulted in larger amounts of icariin being distributed into spleen (60.38% total icariin), liver (16.68%), lung (6.21%), kidney (4.64%), heart (1.43%) and brain (1.83%). AUC((0-t)) values in most tissues (except lung) of mice administered ICA-PG-liposomes were higher than those administered ICA-PG-solution, while Clearance in most tissues (except brain and lung) decreased. The MRT((0-t)) values of ICA-PG-liposomes in all tissues and half lives of most tissues (except brain) were prolonged. From Targeted efficiency and relative uptake data, the spleen was the target tissue of the ICA-PG-liposomes. CONCLUSIONS ICA-PG-liposomes changed the pharmacokinetic behaviour and enhanced icariin distribution in tissues. With nanometer size, high encapsulation efficiency and improved pharmacokinetics, ICA-PG-liposomes might be developed as promising carriers for icariin injection.
Docetaxel-loaded-lipid-based-nanosuspensions (DTX-LNS): preparation, pharmacokinetics, tissue distribution and antitumor activity.
School of Pharmaceutical Science, Shandong University, 44 Wenhua Xi Road, Ji'nan 250012, Shandong Province, China.
The purpose of the study was to design lipid-based-nanosuspensions (LNS) for Docetaxel (DTX) without Tween 80 for clinical intravenous administration (i.v.). DTX-LNS were prepared by high pressure homogenization method, and then lyophilization was carried out to improve the stability. The physical-chemical properties in terms of particle size, size distribution, zeta potential and morphology were evaluated, respectively. The in vitro cytotoxic activity was assessed by MTT against SKOV-3 and malignant melanoma B16 cells. The in vivo pharmacokinetics, tissue distribution as well as antitumor efficacy were investigated in B16 melanoma-bearing Kunming mice. The particle size and zeta potential of DTX-LNS were (200.0 ± 3.42)nm and (-11.15 ± 0.99)mV, respectively. Compared with Duopafei, it was shown that DTX-LNS exhibited higher antitumor efficacy by reducing tumor volume (P<0.05) and increasing survival rate in B16 melanoma-bearing mice and strongly reduced the anticancer drug toxicity. The results of biodistribution studies clearly indicated the superiority of DTX-LNS to Duopafei in increasing the accumulation of DTX within tumor and the organs rich in macrophages (liver, lungs and spleen), while, the drug concentration in heart and kidney decreased. Together these results suggested that DTX-LNS could effectively inhibit tumor growth, reduce toxicity during the therapeutic procedure and hold the potential to be an appropriate choice for the clinical administration of DTX.
Characterization of trans-resveratrol-loaded lipid-core nanocapsules and tissue distribution studies in rats.
Rudimar L Frozza, Andressa Bernardi, Karina Paese, Juliana B Hoppe, Thaline da Silva, Ana M O Battastini, Adriana R Pohlmann, Silvia S Guterres, Christianne Salbego
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, 90035-003, RS, Brazil.
Several studies have reported that orally ingested trans-resveratrol is extensively metabolized in the enterocyte before it enters the blood and target organs. Additionally, trans-resveratrol is photosensitive, easily oxidized and presents unfavorable pharmacokinetics. Therefore, it is of great interest to stabilize trans-resveratrol in order to preserve its biological activities and to improve its bioavailability in the brain. Here, trans-resveratrol was loaded into lipid-core nanocapsules and analyzed for particle size, polydispersity and zeta potential. The nanocapsule distribution in brain tissue was evaluated by intraperitoneal (i.p.) and gavage routes in healthy rats. The lipid-core nanocapsules had a mean diameter of 241 nm, a polydispersity index of 0.2, and a zeta potential of -15 mV. No physical changes were observed after 1, 2 and 3 months of storage at 25 degrees C. Lipid-core nanocapsules showed high entrapment of trans-resveratrol and displayed a higher trans-resveratrol concentration in the brain, the liver and the kidney after daily i.p. or gavage administration than that observed for the free trans-resveratrol. Because trans-resveratrol is a potent cyclooxygenase-1 inhibitor, gastrointestinal damage was evaluated. The animals that were administered with trans-resveratrol-loaded lipid-core nanocapsules showed significantly less damage when compared to those administered with free trans-resveratrol. In summary, lipid-core nanocapsules exhibited great trans-resveratrol encapsulation efficiency. trans-Resveratrol-loaded lipid-core nanocapsules increased the concentration of trans-resveratrol in the brain tissue. Gastrointestinal safety was improved when compared with free trans-resveratrol. Thus, trans-resveratrol-loaded lipid-core nanocapsules may be used as an alternative potential therapeutic for several diseases including Alzheimer's disease.
Nanotechnology Laboratory, Department of Pharmaceutics, University College of Pharmaceutical Sciences, Kakatiya University, Vidyaranya Puri, Warangal 506009, Andhra Pradesh, India.
The aim of this study was to develop stable parenteral pegylated indinavir submicron lipid emulsions (SLEs) for improving brain specific delivery. The O/W SLEs were prepared by homogenization and ultra sonication process. The sizes of oil globules varied from 241.5 to 296.4nm and zeta potential from -26.6 to -42.4mV. During in vitro drug release studies the cumulative amount of drug released within 12h from SLE-5, DSP2-3 and DPP5-3 was 71.8±0.76, 66.09±1.45 and 68.33±1.29, respectively. The total drug content and entrapment efficiencies were determined. The optimized formulations were stable for the effect of centrifugal stress, thermal stress, dilution stress and storage. In vivo pharmacokinetic and tissue distribution studies were performed in Swiss albino mice, the therapeutic availability (TA) of DSP2-3 was 3.59 times and 2.36 times in comparison to drug solution and SLE-5 respectively, where as DPP5-3 showed TA 2.8 and 1.84 times the drug solution and SLE-5, respectively. The brain to serum ratio of indinavir from DSP2-3 and DPP5-3 varied between 0.4 and 0.7 at all time points indicated the preferential accumulation of drug in brain. In conclusion, pegylated SLEs improved brain specific delivery of indinavir and will be useful in treating chronic HIV infection.
Curcumin-loaded PLGA-PEG-PLGA triblock copolymeric micelles: Preparation, pharmacokinetics and distribution in vivo.
Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 Wenhua Xilu, Jinan 250012, China.
The aim of this study was to assess the potential of new copolymeric micelles to modify the pharmacokenetics and tissue distribution of Curcumin (CUR), a hydrophobic drug. In the present study, a poly (d,l-lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(d,l-lactide-co-glycolide)(PLGA-PEG-PLGA) copolymer was synthesized and characterized by (1)H NMR, gel permeation chromatography and FTIR analysis. The CUR-loaded PLGA-PEG-PLGA micelles were prepared by dialysis method and the physicochemical parameters of the micelles such as zeta potential, size distribution and drug encapsulation were characterized. The pharmacokinetics and biodistribution of CUR-loaded micelles in vivo were evaluated. The results showed that the zeta potential of CUR-loaded micelles was about -0.71mV and the average size was 26.29nm. CUR was encapsulated into PLGA-PEG-PLGA micelles with loading capacity of 6.4±0.02% and entrapment efficiency of 70±0.34%. The plasma AUC((0-)(∞)), t(1/2α), t(1/2β) and MRT of CUR micelles were increased by 1.31, 2.48, 4.54 and 2.67 fold compared to the CUR solution, respectively. The biodistribution study in mice showed that the micelles decreased drug uptake by liver and spleen and enhanced drug distribution in lung and brain. These results suggested that PLGA-PEG-PLGA micelles would be a potential carrier for CUR.
Nanostructured lipid carriers for parenteral delivery of silybin: Biodistribution and pharmacokinetic studies.
Lejiao Jia, Dianrui Zhang, Zhenyu Li, Cunxian Duan, Yancai Wang, Feifei Feng, Feihu Wang, Yue Liu, Qiang Zhang
Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 Wenhua Xilu, Jinan 250012, PR China.
The objective of the present study was to explore the potential of nanostructured lipid carriers (NLCs) for the intravenous delivery of silybin, a poorly water-soluble antihepatopathy agent. Silybin-NLC was prepared by the method of emulsion evaporation at a high temperature and solidification at a low temperature. The resultant NLC had a mean size 232.1 nm and a zeta potential of -20.7 mV. The differential scanning calorimetry (DSC) analysis indicated that silybin was not in crystalline state in the NLC. In vitro data for release of the drug from silybin-NLC was fitted to a two-stage exponential kinetic model. The pharmacokinetics and tissue distribution of silybin-NLC were studied after intravenous administration using New Zealand rabbits and Kunming mice as experimental animals. A silybin control solution was studied parallelly. Silybin-NLC showed higher AUC (area under tissue concentration-time curve) values and circulated in the blood stream for a longer time compared with silybin solution. The tissue distribution demonstrated a high uptake of silybin-NLC in RES organs particularly in liver. These results indicate that NLC is a potential sustained release and targeting system for silybin.