Time-of-flight resolved light field fluctuations reveal deep human tissue physiology.

Red blood cells (RBCs) transport oxygen to tissues and remove carbon dioxide. Diffuse optical flowmetry (DOF) assesses deep tissue RBC dynamics by measuring coherent fluctuations of multiply scattered near-infrared light intensity. While classical DOF measurements empirically correlate with blood flow, they remain far-removed from light scattering physics and difficult to interpret in layered media. To advance DOF measurements closer to the physics, here we introduce an interferometric technique, surmounting challenges of bulk motion to apply it in awake humans. We reveal two measurement dimensions: optical phase, and time-of-flight (TOF), the latter with 22 picosecond resolution. With this multidimensional data, we directly confirm the unordered, or Brownian, nature of optically probed RBC dynamics typically assumed in classical DOF. We illustrate how incorrect absorption assumptions, anisotropic RBC scattering, and layered tissues may confound classical DOF. By comparison, our direct method enables accurate and comprehensive assessment of blood flow dynamics in humans.

Curcumin-Loaded Nanostructured Lipid Carrier Modified with Partially Hydrolyzed Ginsenoside.

The objective of the present study was to investigate the effect of partially hydrolyzed ginsenoside on the physicochemical properties and in vitro release of curcumin from phospholipid-based nanostructured lipid carrier (NLC). NLC formulas modified with partially hydrolyzed ginsenoside (NLC-PG) were prepared with different amounts of ginsenoside using the conventional hot-melt method. The average particle size of curcumin-loaded NLC-PG ranged from 150 to 200 nm, and polydispersity index was in the range of 0.101-0.177, indicating monodispersed particle size distribution. Optical microscopy showed no sedimentation or recrystallization of curcumin even at 10,000 µg/ml concentration as NLC-PG in distilled water, indicating significantly enhanced solubility. TEM image showed that the nanoparticles were monodispersed with a multilayered core/shell structure. X-ray diffraction and FTIR spectroscopy showed that curcumin was amorphous in the NLC-PG, and there was no interaction between curcumin and the excipients. In vitro release study using simulated gastric/intestinal fluid media revealed that the release rate (Jss) of curcumin from the NLC-PG increased as a function of the ginsenoside content in the lipid carrier. Moreover, the Jss of curcumin kept gradually increasing in the presence of lipase, whereas in the presence of viscozyme, it sharply increased until the ginsenoside content reached 9.09% and subsequently plateaued. Partially hydrolyzed ginsenoside increased the Jss of curcumin from curcumin-loaded NLC-PG and therefore may be useful for improving the bioavailability of curcumin.

In vitro skin penetration of petrolatum and soybean oil and effects of glyceryl monooleate.

OBJECTIVES: Petrolatum and soybean oil are common ingredients incorporated in topical skin formulations for skin protection and moisturization. However, the stratum corneum (SC) penetration kinetics of these two cosmetic ingredients has not been systematically studied. Glyceryl monooleate (GlyMOle) has been shown to enhance skin penetration of various compounds. It was hypothesized that GlyMOle could enhance skin penetration of petrolatum and soybean oil. This study aimed to examine the in vitro skin penetration of petrolatum and soybean oil in the presence or absence of GlyMOle. METHODS: Skin permeation experiments were conducted using the in vitro Franz diffusion cell model with split-thickness human skin and human epidermal membrane (HEM). The effect of permeant dose and the kinetics of permeant penetration were examined with and without GlyMOle in vitro. RESULTS: Petrolatum and soybean oil were found to permeate across HEM, and no effect of GlyMOle on skin permeation into the receptor chamber was observed. GlyMOle enhanced the penetration of petrolatum into the split-thickness skin at 50 µg dose (petrolatum:GlyMOle, 49 : 1, w/w). However, no effect of GlyMOle on petrolatum penetration was observed at 200 µg dose (of the same petrolatum:GlyMOle ratio), indicating a dose-dependent effect. GlyMOle at the level used in the study did not enhance the penetration of soybean oil with 50 and 200 µg doses at any timepoints. CONCLUSION: GlyMOle was a skin penetration enhancer for petrolatum under the in vitro conditions identified in this study.

Chitosan dosage regimen to trap fecal oil excretion after peroral lipase inhibitor administration in mice.

This study was designed to investigate the oil entrapment and systemic oil absorption-reducing activities of chitosan. High-molecular-weight chitosan formed gel aggregates with oil and bile salts in vitro. The oil/chitosan ratio and the molecular weight of chitosan were optimized for the in vivo study, and a molecular weight >100,000 was effective in reducing the oil contamination of mouse fur. The oil/chitosan weight ratio required for effective oil entrapment was less than 13 and 5 in the in vitro and in vivo experiments, respectively. Chitosan administration was most effective during meals, and high-molecular-weight chitosan could trap and facilitate the reduction of systemic absorption of oil droplets separated by orlistat. The activity of the lipase inhibitor was not altered by chitosan as evidenced by thin layer chromatography, and orlistat was not absorbed systemically by the co-administration of chitosan.

Nanometric emulsions encapsulating solid particles as alternative carriers for intracellular delivery.

AIM: Formulate nanometric oil droplets for encapsulating solid nanoparticles and assess their interactions with cells. MATERIALS & METHODS: Soybean oil droplets, stabilized by Pluronic F68 surfactant, incorporating hydrophobically modified fluorescent silica, nanoparticles were obtained. Cytotoxicity over time, internalization, subsequent intracellular localization and internalization pathways were assessed by microscopy (fluoresence and TEM) in vitro with HeLa cells. RESULTS: Oil droplets encapsulating solid nanoparticles are readily internalized by HeLa cells like free nanoparticles but the intracellular localization differs (nanoemulsions less colocalized with lysosomes) as well as internalization pathway is used (nanoemulsions partially internalized by nonendocytic transport). No cytotoxicity could be observed for either particles tested. CONCLUSION: Our results confirm that nanometric emulsions encapsulating solid nanoparticles can be used for alternative and multifunctional intracellular delivery.

The Effect of Lipid Emulsion on Pharmacokinetics of Bupivacaine in Rats: Long-Chain Triglyceride Versus Long- and Medium-Chain Triglyceride.

BACKGROUND: Lipid infusions have been proposed to treat local anesthetic-induced cardiac toxicity. This study compared the effects of long-chain triglyceride (LCT) emulsions with those of long- and medium-chain triglyceride (LCT/MCT) emulsions on the pharmacokinetics of bupivacaine in a rat model. METHODS: After administration of intravenous infusion of bupivacaine at 2 mg·kg·min for 5 minutes in Sprague-Dawley (SD) rats, either Intralipid 20%, an LCT emulsion (LCT group, n = 6), or Lipovenoes 20%, an LCT/MCT emulsion (LCT/MCT group, n = 6), was infused at 2mg·kg·min for 5 minutes. The concentrations of total plasma bupivacaine and bupivacaine that were not bound by lipid (lipid unbound) were measured by a liquid chromatography-tandem mass spectrometric method. A 2-compartmental analysis was performed to calculate the lipid-bound percentage of bupivacaine and its pharmacokinetics. RESULTS: In the LCT group, the clearance (15 ± 2 vs 10 ± 1 mL·min·kg, P = .003) was higher; the volume of distribution (0.57 ± 0.10 vs 0.36 ± 0.11 L·kg, P = .007) and K21 (0.0100 ± 0.0018 vs 0.0070 ± 0.0020 min, P = .021, P' = .032) were larger; and the area under the blood concentration-time curve 0 - t; (605 ± 82 vs 867 ± 110 mgL·min, P =.001) and the area under the blood concentration-time curve (0 - ∞) (697 ± 111 vs 991 ± 121 mgL·min, P =.001) were less, when compared with the LCT/MCT group. CONCLUSIONS: LCT emulsions are more effective than LCT/MCT emulsions in the metabolism of bupivacaine through demonstration of a superior pharmacokinetic profile.

Parenteral lipid emulsions in guinea pigs differentially influence plasma and tissue levels of fatty acids, squalene, cholesterol, and phytosterols.

Lipid emulsions are made by mixing vegetable and/or fish oils with egg yolk and contain different types and amounts of fatty acids and sterols. This study assessed the effects of oral diet, soybean oil (SO)-, fish oil (FO)-, a mixture of olive and soybean oil (OOSO)-, and a mixture of fish, olive, coconut, and soybean oil (FOCS)-based emulsions on plasma triacylglycerols and plasma and tissue fatty acid and sterol content following acute and chronic intravenous administration in the guinea pig. Upon acute administration, peak triacylglycerols were highest with SO and lowest with OOSO. Upon chronic administration, the plasma triglyceride levels did not increase in any group over that of the controls. Fatty acid levels varied greatly between organs of animals on the control diets and organs of animals following acute or chronic lipid administration. Squalene levels increased in plasma following acute administration of OOSO, but plasma squalene levels were similar to control in all emulsion groups following chronic administration. Total plasma phytosterol levels were increased in the SO, OOSO, and FOCS groups following both acute and chronic infusions, whereas phytosterols were not increased following FO infusion. Total phytosterol levels were higher in liver, lung, kidney and adipose tissue following SO and OOSO. Levels were not increased in tissues after FO and FOCS infusion. These results indicate that fatty acid and sterol contents vary greatly among organs and that no one tissue reflects the fatty acid or sterol composition of other tissues, suggesting that different organs regulate these compounds differently.

Determination of in vivo behavior of mitomycin C-loaded o/w soybean oil microemulsion and mitomycin C solution via gamma camera imaging.

In this study, a microemulsion system was evaluated for delivery of mitomycin C (MMC). To track the distribution of the formulated drug after intravenous administration, radiochemical labeling and gamma scintigraphy imaging were used. The aim was to evaluate a microemulsion system for intravenous delivery of MMC and to compare its in vivo behavior with that of the MMC solution. For microemulsion formulation, soybean oil was used as the oil phase. Lecithin and Tween 80 were surfactants and ethanol was the cosurfactant. To understand the whole body localization of MMC-loaded microemulsion, MMC was labeled with radioactive technetium and gamma scintigraphy was applied for visualization of drug distribution. Radioactivity in the bladder 30 minutes after injection of the MMC solution was observed, according to static gamma camera images. This shows that urinary excretion of the latter starts very soon. On the other hand, no radioactivity appeared in the urinary bladder during the 90 minutes following the administration of MMC-loaded microemulsion. The unabated radioactivity in the liver during the experiment shows that the localization of microemulsion formulation in the liver is stable. In the light of the foregoing, it is suggested that this microemulsion formulation may be an appropriate carrier system for anticancer agents by intravenous delivery in hepatic cancer chemotherapy.

Preparation, characterization, and in vitro gastrointestinal digestibility of oil-in-water emulsion-agar gels.

Soybean oil-in-water (O/W) emulsion-agar gel samples were prepared and their digestibility evaluated by using an in vitro gastrointestinal digestion model. Emulsion-agar sols were obtained by mixing the prepared O/W emulsions with a 1.5 wt % agar solution at 60 °C, and their subsequent cooling at 5 °C for 1 h formed emulsion-agar gels. Their gel strength values increased with increasing degree of polymerization of the emulsifiers, and the relative gel strength increased in the case of droplets with an average diameter smaller than 700 nm. Flocculation and coalescence of the released emulsion droplets depended strongly on the emulsifier type; however, the emulsifier type hardly affected the ζ-potential of emulsion droplets released from the emulsion-agar gels during in vitro digestion. The total FFA content released from each emulsion towards the end of the digestion period was nearly twice that released from the emulsion-agar gel, indicating that gelation of the O/W emulsion may have delayed lipid hydrolysis.

Decreased reticuloendothelial system clearance and increased blood half-life and immune cell labeling for nano- and micron-sized superparamagnetic iron-oxide particles upon pre-treatment with Intralipid.

BACKGROUND: Superparamagnetic iron-oxide nanoparticles are useful as contrast agents for anatomical, functional and cellular MRI, drug delivery agents, and diagnostic biosensors. Nanoparticles are generally cleared by the reticuloendothelial system (RES), in particular taken up by Kupffer cells in the liver, limiting particle bioavailability and in-vivo applications. Strategies that decrease the RES clearance and prolong the circulation residence time of particles can improve the in-vivo targeting efficiency. METHODS: Intralipid 20.0%, an FDA approved nutritional supplement, was intravenously administered in rats at the clinical dose (2g/kg) 1h before intravenous injection of ultra-small superparamagnetic iron-oxide (USPIO) or micron-sized paramagnetic iron-oxide (MPIO) particles. Blood half-life, monocyte labeling efficiency, and particle biodistribution were assessed by magnetic resonance relaxometry, flow cytometry, inductively-coupled plasma MS, and histology. RESULTS: Pre-treatment with Intralipid resulted in a 3.1-fold increase in USPIO blood half-life and a 2-fold increase in USPIO-labeled monocytes. A 2.5-fold increase in MPIO blood half-life and a 5-fold increase in MPIO-labeled monocytes were observed following Intralipid pre-treatment, with a 3.2-fold increase in mean iron content up to 2.60pg Fe/monocyte. With Intralipid, there was a 49.2% and 45.1% reduction in liver uptake vs. untreated controls at 48h for USPIO and MPIO, respectively. CONCLUSIONS: Intralipid pre-treatment significantly decreases initial RES uptake and increases in-vivo circulation and blood monocyte labeling efficiency for nano- and micron-sized superparamagnetic iron-oxide particles. GENERAL SIGNIFICANCE: Our findings can have broad applications for imaging and drug delivery applications, increasing the bioavailability of nano- and micron-sized particles for target sites other than the liver.

Soybean oil: a potentially new intravascular perfusate.

BACKGROUND: Given that micelles of lipids are colloids, the hypothesis was generated that the rapid administration of large volumes of soybean oil micelles would be an effective perfusion fluid. We also hypothesized that oxygen loading would be enhanced due to the greater solubility of oxygen in lipids compared to water. METHODS: A 100% lethal mouse model of blood loss was used to compare the ability of soybean oil micelles to that of Ringer's lactate, blood and other fluids, with respect to raising and maintaining the blood pressure for one hour. Oxygen on- and off-loading of various concentrations of soybean oil micelles was determined using mass spectroscopy. Nitric oxide uptake by micelles was also determined in a similar fashion. RESULTS: A 20% soybean oil emulsion was superior to Ringer's lactate in raising and maintaining blood pressure. A 20% soybean oil emulsion with 5% albumin added was superior to shed blood as well as solutions comprised of 5% albumin added to either normal saline or Ringer's lactate. There was a linear relationship between oxygen content and micelle concentration between 10% and 30%. Off-loading of oxygen from the micelles was nearly as fast as off-loading from water. Nitric oxide also loaded preferentially onto soybean oil micelles. CONCLUSIONS: (1) Soybean oil emulsions were superior to other fluids in restoring and maintaining the blood pressure; (2) oxygen-carrying ability of soybean oil micelles exceeds that of water and follows Henry's law between 10% and 30% w/v oil content; (3) nitric oxide was carried by the micelles; (4) animals receiving soybean oil micelles did not exhibit fat embolization; (5) colloids comprised of soybean oil-containing micelles may be used to replace blood loss and may be used to deliver oxygen and other potentially therapeutic gases such as nitric oxide to tissues.

Treatment with a novel topical nanoemulsion (NB-001) speeds time to healing of recurrent cold sores.

BACKGROUND: Current topical therapies for cold sores are only marginally beneficial due to poor skin penetration. We assessed the safety and efficacy of a novel topical antiviral nanoemulsion (NB-001) with high tissue bioavailability. OBJECTIVES: The primary endpoint was the time to lesion healing. METHODS: 482 subjects with recurrent cold sores were randomized to self-initiate treatment with either vehicle or NB-001 (0.1%, 0.3% or 0.5%) at the first signs or symptoms of a cold sore episode. Lotion was applied 5 times per day, approximately 3 to 4 hours apart, for 4 days. Time to lesion healing was correlated with NB-001 bioavailability determined in human cadaver skin. RESULTS: Subjects treated with 0.3% NB-001 showed a 1.3-day improvement in the mean time to healing compared to vehicle (P=0.006). This was consistent with human cadaver skin data indicating that the 0.3% nanoemulsion had the highest bioavailability, compared to 0.1% and 0.5% emulsions. No significant safety or dermal irritation concerns or systemic absorption were noted with any of the doses. CONCLUSIONS: Topical NB-001 (0.3%) was well tolerated and highly efficacious in shortening the time to healing of cold sores. The improvement in time to healing was similar to that reported for oral nucleoside analogues, but without systemic exposure. Topical agents for recurrent herpes labialis (cold sores) reduce healing time by one half day, compared to oral therapies that speed healing by a day or more. A topical antiviral nanoemulsion was well tolerated and improved cold sore healing time by over a day compared to vehicle control. Nanoemulsion (NB-001) could represent a more efficacious topical treatment for recurrent cold sores.

In vitro and in vivo entrapment of bupivacaine by lipid dispersions.

Intravenous lipid emulsion is recommended as treatment for local anesthetic intoxication based on the hypothesis that the lipophilic drug is entrapped by the lipid phase created in plasma. We compared a 15.6 mM 80/20 mol% phosphatidyl choline (PC)/phosphatidyl glycerol (PG)-based liposome dispersion with the commercially available Intralipid® emulsion in a pig model of local anesthetic intoxication. Bupivacaine-lipid interactions were studied by electrokinetic capillary chromatography. Multilamellar vesicles were used in the first in vivo experiment series. This series was interrupted when the liposome dispersion was discovered to cause cardiovascular collapse. The toxicity was decreased by an optimized sonication of the 50% diluted liposome dispersion (7.8 mM). Twenty anesthetized pigs were then infused with either sonicated PC/PG liposome dispersion or Intralipid®, following infusion of a toxic dose of bupivacaine which decreased the mean arterial pressure by 50% from baseline. Bupivacaine concentrations were quantified in blood samples using liquid chromatography/mass spectrometry. No significant difference in the context-sensitive plasma half-life of bupivacaine was detected (p=0.932). After 30 min of lipid infusion, the bupivacaine concentration was 8.2±1.5 mg/L in the PC/PG group and 7.8±1.8 mg/L in the Intralipid® group, with no difference between groups (p=0.591). No difference in hemodynamic recovery was detected between groups (p > 0.05).

Acute hypoxia induces hypertriglyceridemia by decreasing plasma triglyceride clearance in mice.

Obstructive sleep apnea (OSA) induces intermittent hypoxia (IH) during sleep and is associated with elevated triglycerides (TG). We previously demonstrated that mice exposed to chronic IH develop elevated TG. We now hypothesize that a single exposure to acute hypoxia also increases TG due to the stimulation of free fatty acid (FFA) mobilization from white adipose tissue (WAT), resulting in increased hepatic TG synthesis and secretion. Male C57BL6/J mice were exposed to FiO(2) = 0.21, 0.17, 0.14, 0.10, or 0.07 for 6 h followed by assessment of plasma and liver TG, glucose, FFA, ketones, glycerol, and catecholamines. Hypoxia dose-dependently increased plasma TG, with levels peaking at FiO(2) = 0.07. Hepatic TG levels also increased with hypoxia, peaking at FiO(2) = 0.10. Plasma catecholamines also increased inversely with FiO(2). Plasma ketones, glycerol, and FFA levels were more variable, with different degrees of hypoxia inducing WAT lipolysis and ketosis. FiO(2) = 0.10 exposure stimulated WAT lipolysis but decreased the rate of hepatic TG secretion. This degree of hypoxia rapidly and reversibly delayed TG clearance while decreasing [(3)H]triolein-labeled Intralipid uptake in brown adipose tissue and WAT. Hypoxia decreased adipose tissue lipoprotein lipase (LPL) activity in brown adipose tissue and WAT. In addition, hypoxia decreased the transcription of LPL, peroxisome proliferator-activated receptor-γ, and fatty acid transporter CD36. We conclude that acute hypoxia increases plasma TG due to decreased tissue uptake, not increased hepatic TG secretion.

Formulations based on alpha cyclodextrin and soybean oil: an approach to modulate the oral release of lipophilic drugs.

The purpose of this work was to investigate the potential of α-cyclodextrin combined to soybean oil-based formulations to modulate the release of a model drug, indomethacin. Dry emulsion, naked and coated beads were prepared from the same initial formulation using the same manufacturing process. Dry emulsion was selected to accelerate drug release while beads coated with α-cyclodextrin were designed to sustain it. Indomethacin-loaded systems were prepared, characterised and evaluated in vitro. Pharmacokinetic studies were performed in fasted and fed rats. The presence of the α-cyclodextrin coat was confirmed by confocal microscopy, and an increase of the mass and diameter of the beads. The layer of α-cyclodextrin improved their resistance in simulated gastro-intestinal fluids. In vitro, the dissolution of indomethacin was slower with coated beads than with emulsion and naked beads. Lipid-based formulations showed an increase of relative bioavailability of IND versus Indocid®. Whatever the formulation, greater and faster release of indomethacin was noticed in sodium taurocholate-rich medium and in fed rats. Compared to naked beads, an increased Cp(max) with a shorter T(max) was observed with the emulsion while T(max) and MRT were increased and Cp(max) reduced with the coated beads. Interestingly, formulations based on alpha cyclodextrin and soybean oil can modify the release of a lipophilic drug depending on the system formed.

Pharmacokinetic evaluation of pancreatic arterial infusion chemotherapy with lipid emulsion as a drug carrier in an animal model.

The purpose of this study was to investigate the potential pharmacokinetic advantage of pancreatic arterial infusion chemotherapy with lipid emulsion as a drug carrier for pancreatic cancer in a dog model. The 20% Intralipid, as a solvent, was used in the experimental animals with 2 ml/kg (group A) and 1 ml/kg (group B). Normal sodium as a solvent was used as a control with 2 ml/kg (group C) and 1 ml/kg (group D), respectively. Cisplatin (4 mg/kg) was infused into the proximal segment of the splenic artery. The concentrations of cisplatin were measured in plasma of the portal vein and in the liver and pancreas of groups A and C. The area under the concentration-time curve (AUC), the maximum plasma concentration (C(max)), and the elimination half-life (t(1/2)) in plasma were calculated and compared statistically. Compared with group C, the AUC and C(max) of group A were significantly lower (P<0.01 and P<0.01, respectively), the t 1/2 was longer (P<0.05), and the tissue cisplatin concentration of the pancreas was higher (P<0.05). Compared with group D, the AUC and C(max) of group B were significantly lower (P<0.01 and P<0.01, respectively) and the t(1/2) was longer (P<0.01). Pancreatic arterial infusion chemotherapy with lipid emulsion as a drug carrier can increase the local concentration and prolong the retention time of a drug.

Pharmacokinetics, tissue distribution and immunomodulatory effect of intralipid formulation of nystatin in mice.

OBJECTIVES: We developed a novel lipid formulation of nystatin suitable for parenteral administration, nystatin-intralipid (NYT-IL), with antifungal activity and reduced toxicity in mice. We investigated the pharmacokinetics, tissue distribution and immunomodulatory effect of NYT-IL in mice. METHODS: Nystatin levels in serum and organs were determined using HPLC after NYT-IL or nystatin administration in mice. The levels of the pro-inflammatory cytokines tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) and the anti-inflammatory cytokine interleukin 10 (IL-10) produced by splenocytes from mice injected with NYT-IL or nystatin were evaluated by an ELISA assay. RESULTS: Injection of NYT-IL resulted in similar levels and similar kinetics of nystatin in serum, higher concentrations in the liver and lower concentrations in the kidneys, in comparison with nystatin injection. Injection of mice with NYT-IL yielded higher levels of IL-10 than that of nystatin, whereas the levels of TNF-α and IFN-γ induced by NYT-IL were lower than those elicited by nystatin. CONCLUSIONS: Since polyene treatment is associated with nephrotoxicity, lower levels of nystatin in the kidneys following NYT-IL injection suggest the possibility of reduced toxicity. As the acute infusion-related adverse effects associated with polyene treatment are considered to be induced by pro-inflammatory cytokines, a higher level of anti-inflammatory and lower levels of pro-inflammatory cytokines elicited by NYT-IL administration suggest the possibility of amelioration of such effects. In summary, the altered pharmacokinetics, tissue distribution and immune response due to the use of this intralipid formulation of nystatin merit further research towards the development of a therapeutic agent against invasive mycoses.

[Research progress of self-assembled beads drug delivery system prepared from cyclodextrins and oils].

Recently, increasing attention has been paid to beads, an innovative self-assembled drug delivery system prepared from cyclodextrins and oils. Beads are new core-shell minispheres containing poorly water-soluble drugs or lipophilic drugs dissolved in the lipid core without the use of organic solvents and surfactants. Therefore, beads with high drug loading and improved oral bioavailability have great potential for oral delivery of poorly water-soluble drugs and lipophilic drugs. The preparation mechanisms, formulations and methods, the in vitro and in vivo properties of beads were reviewed in order to provide the theoretical basis for further application of beads.

Preparation, characterization and evaluation of breviscapine lipid emulsions coated with monooleate-PEG-COOH.

Series of monooleate-modified PEG with active carboxylic terminus on the other end (MO-PEG-COOH) were used to modify the lipid emulsions surface to prepare a sterically stabilized lipid emulsions for carrying Traditional Chinese Medicine - breviscapine. Based on the research of relationship between polymer structure and prolonged circulation activity, we developed an optimized formulation and a technological method to prepare the sterile and stable MO-PEG(10,000)-COOH (Bre-LE-PEG(10,000)) coated breviscapine lipid emulsions (Bre-LE) for intravenous administration. Follow the optimum preparation, the average particle size, polydispersity index, zeta potential, Ke value and content of final product were determined to be (207.1±8.5)nm, 0.197±0.005, (-33.6±2.0)mV, (21.1±2.3)% and (95.0±1.8)% respectively (n=3). The characteristics, stability and safety of Bre-LE-PEG(10,000) were also studied with Bre-LE as a control. Increased plasma concentration by surface modification of the lipid emulsions may enhance the pharmacological activity of breviscapine to promote blood circulation.

Permeation enhancer-containing water-in-oil nanoemulsions as carriers for intravesical cisplatin delivery.

PURPOSE: In the present work, we developed water-in-oil (w/o) nanoemulsions for the intravesical administration of cisplatin. METHODS: The nanoemulsions were made up of soybean oil as the oil phase and Span 80, Tween 80, or Brij 98 as the emulsifier system. alpha-Terpineol and oleic acid were incorporated as permeation enhancers. The physicochemical characteristics of droplet size, zeta potential, and viscosity were determined. Nanoemulsions were administered intravesically for 1 approximately 4 h to rats in vivo. Animals were subsequently sacrificed, and the bladders were harvested to examine drug accumulation and histology. RESULTS: Ranges of the mean size and zeta potential were 30 approximately 90 nm and -3.4 to -9.3 mV, respectively. The addition of enhancers further reduced the size of the nanoemulsions. The viscosity of all systems exhibited Newtonian behavior. The cisplatin-loaded nanoemulsions were active against bladder cancer cells. The nanoemulsions with Brij 98 exhibited the complete inhibition of cell proliferation. The encapsulation of cisplatin and carboplatin, another derivative of cisplatin, in nanoemulsions resulted in slower and more-sustained release. The amount of drug which permeated into bladder tissues significantly increased when using carriers containing Brij 98, with the alpha-terpineol-containing formulation showing the best result. The nanoemulsion with alpha-terpineol prolonged the duration of higher drug accumulation to 3 approximately 4 h. At the later stage of administration (3 approximately 4 h), this system increased the bladder wall deposition of cisplatin and carboplatin by 2.4 approximately 3.3-fold compared to the control solution. Histological examination of the urothelium showed near-normal morphology in rats instilled with these nanoemulsions. alpha-Terpineol possibly caused slight desquamation of umbrella cells. CONCLUSIONS: The nanoemulsions are feasible to load cisplatin for intravesical drug delivery.