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PubMed2002

Formulation development of a filter-sterilizable lipid emulsion for lipophilic KW-3902, a newly synthesized adenosine A1-receptor antagonist.

KW-3902 (a newly synthesized adenosine A1-receptor antagonist) has potent diuretic and renal protective activities. The objective of the present study was to develop an injectable formulation of KW-3902, that was water-insoluble and less than 1 microg/ml, and so lipid emulsion was selected as a favorable formulation. Changing the mixing ratio of oil to lecithin, the particle size of the lipid emulsion was controlled, and by adjusting the mixing ratio of oil/lecithin=1:1, the weight ratio, a lipid emulsion with a mean particle size of 130 nm was prepared. This small particle size makes this emulsion filter-sterilizable, which is a favorable feature for heat labile products. The stability of the KW-3902 lipid emulsion was assessed from the viewpoint of the electrostatic repulsion, and by including the oleic acid a stable lipid emulsion was developed, which was stable for at least 12 months at 10 and 25 degrees C and for 3 months at 40 degrees C. The feature of this small particle size emulsion was also characterized by comparing it with a conventional emulsion (oil/lecithin=1:0.12, the weight ratio, particle size is 220 nm). The release of KW-3902 from the oil particles was measured and the apparent permeability of KW-3902 was calculated from the equation according to Fick's theory. The apparent permeability, P, of KW-3902 was not affected by the particle size of the emulsion (1.78x10(-11) cm/s for the small emulsion and 1.76x10(-11)cm/s for the conventional emulsion). The distribution mode of KW-3902 in the lipid emulsion was also discussed by considering the findings of the permeability and solubility of KW-3902.

Drug Carriers↗
PubMed2003

Cardiopulmonary effects of lipid emulsions in patients with ARDS.

STUDY OBJECTIVES: Lipid emulsions have been suspected of inducing certain modifications in gas exchange and pulmonary hemodynamics. The aim of this prospective study was to evaluate the hemodynamic and pulmonary effects of two lipid emulsions. DESIGN: Prospective, randomized, double-blind, crossover study. SETTING: Medical and surgical ICU in a French university hospital. PATIENTS: Eighteen patients presenting ARDS. INTERVENTIONS: Each patient received a 6-h infusion of a 20% fat emulsion containing 100% long-chain triglycerides (LCTs) and a 6-h infusion of 50% LCTs/50% medium-chain triglycerides (MCTs) 20% lipid emulsion at the rate of 1.0 mL/kg/h. An 18-h period with no lipids separated the two periods. An additional 18-h period after the end of the second lipid emulsion administration was observed prior to the final measurements. MEASUREMENTS AND RESULTS: The MCT/LCT emulsion increased the PaO(2)/fraction of inspired oxygen (FIO(2)) ratio (p = 0.005) compared with LCT emulsion alone. The mean (+/- SD) PaO(2)/FIO(2) ratio increased from 165 +/- 55 to 191 +/- 64 mm Hg after 1 h of LCT/MCT administration (p < 0.03), and to 175 +/- 46 mm Hg after 6 h. Moreover, there was an increase in oxygen delivery after 6 h of LCT/MCT administration (p < 0.001 vs baseline). While a time-related increase in mean pulmonary artery pressure (p = 0.012) during lipid administration was found, no effect of the kind of lipid emulsion was observed. The time-related increase in cardiac index (p = 0.002) was more marked when the patients received the LCT/MCT emulsion (p = 0.002). Pulmonary vascular resistances were not affected by the kind of lipid emulsion. CONCLUSIONS: The present work showed that while the LCT emulsion induced no deleterious effects on oxygenation in ARDS patients, the LCT/MCT emulsion improved the PaO(2)/FIO(2) ratio and had a further beneficial effect on oxygen delivery.

Cross-Over Studies↗
PubMed2006

[Preparation and evaluation of clarithromycin emulsion for injection].

AIM: To prepare clarithromycin emulsion and investigate its pharmacokinetics in rats. And to do irritation test of the emulsion. METHODS: High pressure homogenization method was used to prepare clarithromycin emulsion, and the Nicomp380 machine was used to test the mean particle size and zeta-potential of clarithromycin emulsion. Irritation of emulsion was also evaluated compared with the positive control of clarithromycin solution using rat paw lick test and rabbit ear vein irritation test. Microbiological assay method was used for determining the drug concentration in plasma. Pharmacokinetics of two dosage forms in rats was also studied. RESULTS: The mean particle size and zeta potential of clarithromycin emulsion were 156 nm and -31.8 mV, respectively. The emulsion was stable during the storage time at 4 degrees C for 6 month. The pain caused by emulsion reduced significantly compared with that of clarithromycin solution based on the results of rat paw lick test and rabbit ear vein test. The drug concentration-time curves of clarithromycin emulsion and clarithromycin solution were similar and could be described by two compartment model. AUC(0-1) of clarithromycin emulsion and clarithromycin solution were (66.76 +/- 16.34) and (59.00 +/- 11.20) microg x h x mL(-1), respectively. CONCLUSION: Stable emulsion could be prepared using high pressure homogenization method, and irritation caused by i.v. injection could be reduced significantly by using clarithromycin emulsion.

Animals↗
PubMed2004

Degradation of kinetically-stable o/w emulsions.

This article summarizes the studies on the degradation of the thermodynamically unstable o/w (nano)emulsion--a dispersion of one liquid in another, where each liquid is immiscible, or poorly miscible in the other. Emulsions are unstable exhibiting flocculation, coalescence, creaming and degradation. The physical degradation of emulsions is due to the spontaneous trend toward a minimal interfacial area between the dispersed phase and the dispersion medium. Minimizing the interfacial area is mainly achieved by two mechanisms: first coagulation possibly followed by coalescence and second by Ostwald ripening. Coalescence is often considered as the most important destabilization mechanism leading to coursing of dispersions and can be prevented by a careful choice of stabilizers. The molecular diffusion of solubilizate (Ostwald ripening), however, will continuously occur as soon as curved interfaces are present. Mass transfers in emulsion may be driven not only by differences in droplet curvatures, but also by differences in their compositions. This is observed when two or more chemically different oils are emulsified separately and the resulting emulsions are mixed. Compositional ripening involves the exchange of oil molecules between emulsion droplets with different compositions. The stability of the electrostatically- and sterically-stabilized dispersions can be controlled by the charge of the electrical double layer and the thickness of the droplet surface layer formed by non-ionic emulsifier. In spite of the similarities between electrostatically- and sterically-stabilized emulsions, there are large differences in the partitioning of molecules of ionic and non-ionic emulsifiers between the oil and water phases and the thickness of the interfacial layers at the droplet surface. The thin interfacial layer (the electrical double layer) at the surface of electrostatically stabilized droplets does not create any steric barrier for mass transfer. This may not be true for the thick interfacial layer formed by non-ionic emulsifier. The interactive sterically-stabilized oil droplets, however, can favor the transfer of materials within the intermediate agglomerates. The stability of electrosterically-stabilized emulsion is controlled by the ratio of the thickness of the non-ionic emulsifier adsorption layer (delta) to the thickness of the electrical double layer (kappa(-1)) around the oil droplets (delta/(kappa(-1))) = (deltakappa). The monomer droplet degradation can be somewhat depressed by transformation of coarse emulsions to nano-emulsion (miniemulsion) by intensive homogenization and by the addition of a surface active agent (coemulsifier) or/and a water-insoluble compound (hydrophobe). The addition of hydrophobe (hexadecane) to the dispersed phase significantly retards the rate of ripening. A long chain alcohol (coemulsifier) resulted in a marked improvement in stability, as well, which was attributed to a specific interaction between alcohol and emulsifier and to the alcohols tendency to concentrate at the o/w interface to form stronger interfacial film. The rate of ripening, according to the Lifshitz-Slyozov-Wagner (LSW) model, is directly proportional to the solubility of the dispersed phase in the dispersion medium. The increased polarity of the dispersed phase (oil) decreases the stability of the emulsion. The molar volume of solubilizate is a further parameter, which influences the stability of emulsion or the transfer of materials through the aqueous phase. The interparticle interaction is expected to favor the transfer of solubilizate located at the interfacial layer. The kinetics of solubilization of non-polar oils by ionic micelles is strongly related to the aqueous solubility of the oil phase (the diffusion approach), whilst their solubilization into non-ionic micelles can be contributed by interparticle collisions.

Journal Article↗
PubMed2001

Physico-chemical characteristics of oil-in-water emulsions based on whey protein-phospholipid mixtures.

Emulsions prepared with whey proteins, phospholipids and 10% of vegetable oil were used for a model typifying dressings, coffee whitener and balanced diets. For the present study, two whey proteins (partial heat-denatured whey protein concentrate (WPC) and undenatured whey protein isolate (WPI)) in combination with different phospholipids (hydrolysed and unmodified deoiled lecithin) were chosen to investigate the interactions between proteins, phospholipids and salt (sodium chloride) in such emulsion systems. Oil-in-water (o/w) emulsions (10 wt.% sunflower oil) containing various concentrations of commercial whey proteins (1-2%), phospholipids (0.39-0.78%) and salt (0.5-1.5%) were prepared using a laboratory high pressure homogeniser under various preparation conditions. Each emulsion was characterised by droplet size, creaming rate, flow behaviour and protein load. The dynamic surface activity of the whey proteins and lecithins at the oil-water interface was determined using the drop volume method. The properties of emulsions were significantly influenced by the content of whey protein. Higher protein levels improved the emulsion behaviour (smaller oil droplets and increased stability) independent of the protein or lecithin samples used. An increase of the protein content resulted in a lower tendency for oil droplet aggregation of emulsions with WPC to occur and emulsions tending towards a Newtonian flow behaviour. The emulsification temperature was especially important using the partial heat-denatured WPC in combination with the deoiled lecithin. A higher emulsification temperature (60 degrees C) promoted oil droplet aggregation, as well as an increased emulsion consistency. Emulsions with the WPC were significantly influenced by the NaCl content, as well as the protein-salt ratio. Increasing the NaCl content led to an increase of the droplet size, higher oil droplet aggregation, as well as to a higher creaming rate of the emulsions. An increase of the lecithin content from 0.39 to 0.78% in the emulsion system resulted in a small reduction of the single droplet size. This effect was more pronounced when using the hydrolysed lecithins.

Journal Article↗
PubMed1997

Toxicity and efficacy of conventional amphotericin B deoxycholate versus escalating doses of amphotericin B deoxycholate---fat emulsion in HIV-infected patients with oral candidosis.

BACKGROUND: Amphotericin B deoxycholate remains the treatment of choice for most systemic fungal infections; however, its clinical use can be limited by infusion-related side effects and nephrotoxicity. New formulations of amphotericin in lipid compounds have been shown to decrease toxicity. We previously showed that a lipid emulsion preparation of amphotericin B deoxycholate was better tolerated than the conventional preparation in dextrose. Therefore, we have now studied the clinical tolerance, renal toxicity and efficacy of higher doses of amphotericin B deoxycholate prepared and infused in a fat emulsion (Intralipid 20%). Thus, this report adds information to the previous publication. METHODS: Forty-two patients infected with HIV and suffering oral candidosis entered the study. The patients received either amphotericin B deoxycholate---glucose 1 mg/kg/day or amphotericin B deoxycholate---lipid emulsion 1 mg/kg/day for 4 days (randomized phase), or amphotericin B deoxycholate---lipid emulsion 2 mg/kg/day or 3 mg/kg/day (escalating-dose phase) for 5 days. Clinical (immediate) side effects and renal (creatinine) tolerance were assessed daily; efficacy against oral candidosis was measured by using a simple clinical score. Serum levels of amphotericin B were also measured. RESULTS: None of the patients receiving amphotericin B deoxycholate---lipid emulsion had treatment interrupted, as compared to four (36%) in the amphotericin B deoxycholate---glucose group (pless-than-or-equal0.01); chills during or after the infusions were significantly less frequent in the amphotericin B deoxycholate---lipid emulsion groups than in the amphotericin B deoxycholate-glucose group (p=0.03). The increase of creatininemia during treatment was significantly higher for patients receiving amphotericin B deoxycholate---glucose than for those receiving amphotericin B deoxycholate---lipid emulsion (p=0.001). The number of patients who had a creatininemia greater-than-or-equal18 mg/L during treatment was significantly higher in both the amphotericin B deoxycholate---glucose group (36%) and in the group receiving the highest dose of amphotericin B deoxycholate---lipid emulsion than in other groups (pless-than-or-equal0.06). The serum concentrations of amphotericin B were lower for the amphotericin B deoxycholate---lipid emulsion regimen than for the amphotericin B deoxycholate---glucose regimen at the same dose of 1 mg/kg/day, but increased with the dose. The change of the oral candidosis score was similar for the same dose of 1 mg/kg/day of amphotericin B deoxycholate infused in either glucose or lipid emulsion; higher doses of amphotericin B deoxycholate---lipid emulsion were more efficacious (p=0.009) and this efficacy seemed to increase with the dose (p=0.06). CONCLUSIONS: The clinical and renal tolerance of amphotericin B deoxycholate are improved when the drug is directly prepared and infused in lipid emulsion (Intrapid) and this preparation allows for greater dosage, up to 3 mg/kg/day, with resultant greater efficacy. This preparation is simple and cost-effective (approximately 7 US $ per 50 mg of amphotercin B) and could be clinically compared to other formulations of amphotericin B.

Journal Article↗
PubMed1991

A comparison of lipoprotein secretion, bile production and hepatic morphology in isolated rat livers perfused with a perfluorocarbon emulsion or rat erythrocytes.

Isolated rat livers were perfused with an oxygenated perfluorocarbon emulsion, FC-43 emulsion for 1 to 4 hr. FC-43 emulsion contained 20% FC-43 (wt/vol) perfluorotributylamine (the fluorocarbon component for the transport of oxygen and carbon dioxide) emulsified with 2.56% Pluronic F-68 (a nonionic surfactant) in Krebs-Ringer bicarbonate buffer. FC-43 emulsion also contained 3% hydroxyethyl starch as an oncotic agent and 1.8 mg/ml glucose. The viability (oxygen consumption), bile secretion, structural integrity and secretion of nascent lipoproteins by FC-43-perfused rat livers was compared with livers perfused with Krebs-Henseleit bicarbonate buffer that contained rat erythrocytes (25% hematocrit) and 1.5 mg/ml glucose (red blood cell medium). Oxygen consumption was somewhat higher in livers perfused with FC-43 emulsion. Bile secretion of livers perfused with FC-43 emulsion for 4 hr was reduced significantly to 40% of that by red blood cell medium. The structural integrity of livers perfused with FC-43 emulsion varied from normal to marked cellular damage. Light-microscopical examination of rat livers perfused with FC-43 emulsion showed ballooning of sinusoids, presence of vacuoles in sinusoidal lining cells in some hepatocytes and detachment of endothelium in sinusoids. The number of vacuoles progressively increased in longer perfusions. Electron-microscopical studies showed the presence of small (60 to 100 nm) vesicles of varying electron density, presumably fluorocarbon particles inside the vacuoles in sinusoidal lining cells (Kupffer and endothelial) and hepatocytes. After 4 hr of perfusion with FC-43 emulsion, most of the sinusoidal endothelia were denuded, and the microvilli of the hepatocytes all but disappeared. In contrast, the ultrastructure of rat livers perfused with red blood cell medium for 4 hr was unaltered. The accumulation of nascent lipoproteins in perfusates of FC-43-perfused livers was markedly reduced, and no normal very-low-density lipoprotein, low-density lipoprotein or high-density lipoprotein were isolated. Chemical analysis showed the presence of Pluronic F-68 in all lipoprotein fractions. Our data strongly suggest that, during recirculating liver perfusions with FC-43 emulsion (between 1 and 4 hr), the nonionic surfactant detergent Pluronic F-68 dissociated from the emulsion and markedly affected hepatic structure, lipoprotein secretion and the composition of lipoproteins isolated from perfusate. Therefore FC-43 emulsion is not a suitable liver-perfusion medium for studies of lipoprotein metabolism.

Animals↗
PubMedDate not supplied

The effects on beagles of long-term administration of 20% Travamulsion fat emulsion.

The tolerance of 20% Travamulsion intravenous fat emulsion (Travenol Laboratories, Inc., Deerfield, IL) was studied using male beagle dogs. Physiologic (0.9%) saline, USP, was used as the control, and 10% Travamulsion Intravenous fat emulsion (Travenol Laboratories) as the reference article. The 20 and 10% emulsions were administered intravenously to each of eight animals for 91 days at 20 and 40 ml/kg/day, respectively. These dosages were administered over 4 hr and they correspond to approximately 4 g of lipid as soybean oil per kilogram of body weight. The saline was administered to eight animals at 40 ml/kg/day. On day 92, one-half of the animals in each group were necropsied. The remaining dogs were observed and necropsied on day 122. Toxicity was assessed on animal survival; changes in body weight, urinalysis, and hematologic, and serum biochemical analyses; ophthalmologic examination; gross pathology; and histopathology. The results obtained for the 20% Travamulsion fat emulsion correlated well with those for the 10% Travamulsion fat emulsion. The emulsions were well tolerated and all animals survived and gained weight. The 20% Travamulsion fat emulsion administered provided about 45% of the total caloric requirement of the dog, which is equal to an often used clinical dose. However, caloric administration in the form of lipid emulsion in relation to total energy required was performed at three to six times the indicated clinical rate. In addition to demonstrating that it is safe for prolonged administration, the 20% Travamulsion fat emulsion offers an advantage over the 10% Travamulsion fat emulsion in providing the same amount of calories because it produces lower serum levels of phospholipid, cholesterol, and triglyceride, and the volume of emulsion required is reduced.

Animals↗
PubMedDate not supplied

Effect of two perfluorocarbon emulsions on reperfusion injury after coronary artery occlusion in rabbits.

Because of their high oxygen-carrying capability and small particle size, it has been suggested that perfluorochemical emulsions may be useful to reduce reperfusion injury after coronary artery occlusion and reperfusion. We tested the ability of Fluosol and a more concentrated perfluorochemical emulsion (perflubron) to decrease infarct size in anesthetized rabbits undergoing 30 min of coronary occlusion and 4 h of reperfusion. All rabbits were ventilated with 100% oxygen. Treatment was begun at 25 min of coronary occlusion, 5 min before reperfusion. Rabbits were randomized to receive saline (10 ml/kg, n = 15), Fluosol (30 ml/kg, n = 15), or a perflubron emulsion (10 ml/kg, n = 16), or the perflubron emulsion vehicle (10 ml/kg, n = 15). Collateral blood flow during occlusion was measured with radioactive microspheres. The size of the ischemic region at risk was determined by in vivo injection of blue dye and infarct size by in vitro tetrazolium staining. We found that all groups were equally ischemic during occlusion, and that risk zone sizes were comparable. Heart rate and systemic arterial pressure were also similar among groups. Infarct size expressed as a percentage of the risk zone was 30 +/- 4% in saline-treated rabbits, 27 +/- 4% in Fluosol-treated rabbits, and 21 +/- 4% and 21 +/- 3% in perflubron emulsion and perflubron emulsion vehicle treated rabbits, respectively. There was a trend for both perflubron emulsion and perflubron emulsion vehicle groups to have smaller infarcts; however, neither perfluorocarbon emulsion nor the emulsion vehicle significantly reduced infarct size compared with saline treatment. Thus, at the doses used in this study neither Fluosol nor perflubron emulsion, when given just before reperfusion, significantly reduced infarct size in this rabbit model.

Animals↗
PubMed1993

Propofol emulsion reduces proliferative responses of lymphocytes from intensive care patients.

OBJECTIVE: To test propofol lipid emulsion formulation for its immunosuppressive effects. DESIGN: Propofol lipid emulsion and the emulsion alone were tested at increasing concentrations and compared to initial values and between each other. Propofol alone could not be tested due to its insolubility into the culture medium. PATIENTS AND PARTICIPANTS: Lymphocytes from 12 surgical intensive care (ICU) patients (median APACHE score 16 and median TISS score 28) and 12 healthy volunteers. MEASUREMENTS: Phytohaemagglutinin-, concanavalin A- and pokeweed mitogen-induced lymphocyte proliferative responses were measured in the presence of increasing concentrations of propofol lipid emulsion formulation or the lipid emulsion. RESULTS: Lymphocyte proliferative responses from ICU patients were in general on a lower level than in the volunteers. The propofol lipid emulsion formulation (Diprivan) decreased pokeweed mitogen-induced proliferative responses of lymphocytes from ICU patients at propofol concentrations found in the circulation (1-10 micrograms/ml) and the lipid emulsion alon at 100 micrograms/ml triglyceride concentrations while the other mitogen-induced responses were not affected. No changes were observed in the mitogen-induced responses of lymphocytes from healthy volunteers. CONCLUSIONS: Propofol emulsion formulation decreased in surgical intensive care patients pokeweed mitogen-induced lymphocytic responses in vitro at clinically found concentrations, indicating the need for further studies to test B-lymphocyte functions and T-B-lymphocyte co-operation during propofol lipid emulsion administration. (ICU) patients is widespread because of its good control of sedation. Propofol is currently administered in fat emulsion which is considered immunosuppressive during bolus injection or rapid infusion. Therefore, effects of a propofol fat emulsion formulation on proliferative responses of lymphocytes were studied in blood samples obtained from healthy volunteers and ICU patients known to be immunosuppressed.

Adolescent↗
PubMed2005

Effects of droplet size on the oxidative stability of oil-in-water emulsions.

The effects of droplet size and emulsifiers on oxidative stability of polyunsaturated TAG in oil-in-water (o/w) emulsions with droplet sizes of 0.806 +/- 0.0690, 3.28 +/- 0.0660, or 10.7 +/- 0.106 microm (mean +/- SD) were investigated. Hydroperoxide contents in the emulsion with a mean droplet size of 0.831 microm were significantly lower than those in the emulsion with a mean droplet size of 12.8 microm for up to 120 h of oxidation time. Residual oxygen contents in the headspace air of the vials containing an o/w emulsion with a mean droplet size of 0.831 microm were lower compared with those of the emulsion with a mean droplet size of 12.8 microm. Hexanal developed from soybean oil TAG o/w emulsions with smaller droplet size showed significantly lower residual oxygen contents than those of the larger droplet size emulsions. Consequently, oxidative stability of TAG in o/w emulsions could be controlled by the size of oil droplet even though the origins of TAG were different. Spin-spin relaxation time of protons of acyl residues on TAG in o/w emulsions measured by H NMR suggested that motional frequency of some acyl residues was shorter in o/w emulsions with a smaller droplet size. The effect of the wedge associated with hydrophobic acyl residues of emulsifiers was proposed as a possible mechanism to explain differences in oxidative stability between o/w emulsions with different droplet sizes.

Cod Liver Oil↗
PubMed1985

Stable oil-in-water emulsions: preparation and use as vaccine vehicles for lipophilic adjuvants.

Many of the most potent immunoadjuvants for inclusion in vaccines are extremely hydrophobic surfactants. Lipophilic vehicles are needed as carriers for these water-insoluble adjuvants and to provide the hydrophilic-hydrophobic interfacial surface at which they act. We used emulsifiers comprised of fatty acid esters of polyoxyethylene sorbitan (Tweens) or sorbitan (Spans) to prepare oil-in-water (O/W) emulsions of hexadecane. Emulsion stability could be predicted from a ratio of spectrophotometric absorbance readings at 800 and 400 nm but not from published hydrophilelipophile balance (HLB) values. Emulsions that were stable even after heating or freezing resulted when equal volumes of hexadecane and a 70:30 blend of Tween 80/Span 80(T80/S80) were mixed and then diluted with normal saline solution to the desired hexadecane concentration. This blend of monooleate esters has an HLB value of 11.8. Other Tween-Span formulations were mixed to yield emulsifiers with the same HLB value, but only those that contained either T80 or S80 were effective stabilizers. Instability resulted when both esters were derived from saturated fatty acids. Addition of bovine serum albumin (BSA) antigen to the oil phase of 5% hexadecane emulsions tended to destabilize the emulsions, especially at higher protein concentrations. The surface active adjuvant, hexadecylamine, increased emulsion stability. Highest antibody responses in mice were seen when BSA was added to the internal phase of emulsions, i.e., the oil phase of O/W emulsions and the aqueous phase of W/O (Freund's) emulsions. Addition of the hydrophilic T80 to the aqueous phase of O/W emulsions was detrimental to antibody production. In general, stability, oil concentration, and T80/S80 concentration of emulsions had little effect on IgG levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗
PubMed2005

In vitro adsorption of plasma proteins onto the surface (charges) modified-submicron emulsions for intravenous administration.

Surface (charge) modified submicron emulsions (cationic and anionic) were prepared following the well established combined emulsification techniques and characterized for their droplet size distribution and surface charge. The effect of these emulsions on in vitro adsorption of plasma proteins was investigated by means of two dimensional polyacrylamide gel electrophoresis (2D PAGE). The presence of poloxamer 188 in tested emulsions effectively eliminated the adsorption of the larger proteins like immunoglobulins, fibrinogen, etc. However, depending on the type of surface charges, the smaller proteins such as apolipoproteins and albumin were almost completely adsorbed onto the submicron emulsions. Indeed, when compared to marketed lipofundin MCT 10%-and deoxycholic acid-based anionic emulsions, the adsorption of apolipoprotein, especially apoA-1, was approximately three times more on stearylamine-and oleylamine-based cationic emulsions and oleic acid-based anionic emulsions. In addition, the ratio between the apoA-1 and apoA-IV was found to be 1 for lipofundin MCT 10% whereas it was about 0.26 for deoxycholic acid-based anionic emulsion and above 5 for oleic acid-based anionic emulsions and cationic emulsions. This indicates that emulsions having similar surface/interfacial charge imparted by different anion-forming stabilizers (oleic or deoxycholic acids) exhibited markedly different protein adsorption patterns.

Adsorption↗
PubMed2005

Gadolinium incorporated reconstituted chylomicron emulsion for potential application in tumor neutron capture therapy.

Gadolinium (Gd) neutron capture therapy (NCT) is currently under development as a potential approach for tumor therapy. Nanoparticles have been suggested as a potential delivery system to carry or target Gd to tumors for thermal or epithermal neutron irradiation. The reconstituted chylomicron emulsion is an artificial chylomicron remnant prepared using commercially available natural and biocompatible lipids. We proposed to use this nanometer-scale emulsion to deliver Gd to solid tumors by modifying the surface of the emulsion. A lipophilic Gd compound, gadolinium acetylacetonate (GdAcAc), was incorporated into the emulsion, resulting in a final pure Gd concentration of more than 1 mg/mL. The apparent solubility of GdAcAc was enhanced by about 6000-fold by this incorporation. The emulsion particles were shown to be stable in a two-week short-term stability study when stored at 4 degrees C. In addition, no extensive particle aggregation was observed when the emulsion particles were incubated in simulated biological media such as serum. Also, GdAcAc does not significantly 'leak' out from the emulsion particles. Only approximately 5% was released in 20 h in a SDS (0.5% w/v) in phosphate buffered saline (pH 7.4, 10 mM) medium. Finally, the emulsion particles were coated with polyethylene glycol (PEG), and injected into Balb/C mice via the tail vein. A significant proportion (71.6 +/- 18.4%) of the PEG-coated, GdAcAc-incorporated emulsion remained circulating in the blood 5 h after the injection, while the PEG-free emulsion was mainly accumulated inside the liver. This chylomicron emulsion may be used to deliver Gd into solid tumors for NCT.

Animals↗
PubMed2005

Effect of molecular weight and degree of deacetylation of chitosan on the formation of oil-in-water emulsions stabilized by surfactant-chitosan membranes.

The objective of this study was to establish the influence of polyelectrolyte characteristics (molecular weight and charge density) on the properties of oil-in-water emulsions containing oil droplets surrounded by surfactant-polyelectrolyte layers. A surfactant-stabilized emulsion containing small droplets (d32 approximately 0.3 microm) was prepared by homogenizing 20 wt% corn oil with 80 wt% emulsifier solution (20 mM SDS or 2.5 wt% Tween 20, 100 mM acetate buffer, pH 3) using a high-pressure valve homogenizer. This primary emulsion was then diluted with various chitosan solutions to produce secondary emulsions with a range of chitosan concentrations (3 wt% corn oil, 0-1 wt% chitosan). The influence of the molecular characteristics of chitosan on the properties of these emulsions was examined by using chitosan ingredients with different molecular weights (MW approximately 15, 145, and 200 kDa) and degree of deacetylation (DDA approximately 40, 77, and 92%). The electrical charge and particle size of the secondary emulsions were then measured. Extensive droplet aggregation occurred when the chitosan concentration was below the amount required to saturate the droplet surfaces, but stable emulsions could be formed at higher chitosan concentrations. The zeta-potential and mean diameter (d32) of the particles in the secondary emulsions was not strongly influenced by chitosan MW, however the chitosan with the lowest DDA (40%) produced droplets with smaller mean diameters and zeta-potentials than the other two DDA samples examined. Interestingly, we found that stable multilayer emulsions could be formed by mixing medium or high MW chitosan with an emulsion stabilized by a non-ionic surfactant (Tween 20) due to the fact the initial droplets had some negative charge. The information obtained from this study is useful for preparing emulsions stabilized by multilayer interfacial layers.

Chitosan↗
PubMed2006

Preparation of highly monodisperse W/O emulsions with hydrophobically modified SPG membranes.

Experimental investigations on the hydrophobic modification of SPG membranes and the preparation of monodisperse W/O (water-in-oil) emulsions using the modified membranes were carried out. Effects of the osmotic pressure of disperse phase, the average pore size of membranes, emulsifier concentrations in continuous phase and the transmembrane pressure on the average size, size distribution and size dispersion coefficient of emulsions were systematically studied. The stability of W/O emulsions was also investigated. The results showed that SPG membranes took on excellent hydrophobicity through the modification by silane coupler reagent (octyltriethoxysilane) or by silicone resin (polymethylsilsesquioxane). Monodisperse W/O emulsions with size dispersion coefficient of about 0.25, which meant high monodispersity, were successfully prepared by using the hydrophobically modified SPG membranes with average pore sizes of 1.8, 2.0, 2.5, 4.8 and 11.1 microm. When the osmotic pressure was lower than 0.855 MPa, the average size of emulsions was gradually increased while the size dispersion coefficient delta gradually decreased with the osmotic pressure; when the osmotic pressure was higher than 0.855 MPa, both the coefficients kept unvarying. When kerosene was saturated with disperse phase in advance, the average size of emulsions became larger and the monodispersity of emulsions was slightly better than that prepared using unsaturated kerosene. The smaller the pore size of SPG membranes was, the better the monodispersity of the W/O emulsions. The average size and size dispersion coefficient delta were nearly independent on the emulsifier concentrations when the PGPR concentration was in the range from 0.5 to 5.0 wt%, whereas both of them slightly increased as the PGPR concentration was below 0.5 wt%. The effect of the transmembrane pressure on size distributions was slight. Both the average size and size dispersion coefficient delta slightly increased to some extent with the increase of the transmembrane pressure in the experimental range. The stability of the W/O emulsions was dependent on the storage time. The mean size of W/O emulsions decreased gradually with the increase of storage time at the first 35 days, and then kept constant; while the size dispersion coefficient of W/O emulsions was nearly not changed.

Capsules↗
PubMed2006

Submicron lipid emulsion as a drug delivery system for nalbuphine and its prodrugs.

This study investigates the submicron lipid emulsion as a potential parenteral drug delivery system for nalbuphine and its ester prodrugs. Submicron emulsions were prepared using egg phospholipid as the main emulsifier, various co-emulsifiers were also incorporated, including Brij 30, Brij 98, and stearylamine. Squalene as the oil phase formed stable emulsions with small particles. Drug release was affected by incorporating various co-emulsifiers and drugs with various lipophilicity. The loading of nalbuphine into lipid emulsions resulted in the slower and sustained release of nalbuphine. Lipid emulsions containing Brij 98 could further enhance the release of prodrugs as compared to the aqueous solution (control) especially for nalbuphine enanthate (NAE). Hemolysis caused by the interaction between erythrocytes and lipid emulsions was investigated. Brij 30 and Brij 98 could shield the hemolytic activity of phospholipids in the oil/water interface, decreasing the acute toxicological potential of the emulsions. The in vivo analgesic activity of various emulsions was examined by a cold ethanol tail-flick test. The analgesic duration and potency were significantly increased by incorporating nalbuphine and NAE into Brij 98-containing emulsions. There was no need for nalbuphine benzoate (NAB) to show a controlled delivery manner by encapsulating into emulsions, since NAB itself could prolong the analgesic duration of nalbuphine due to the slow enzyme degradation. The in vivo analgesic activity correlated well to the profiles of in vivo pharmacokinetic profiles. The study demonstrates the feasibility of using submicron lipid emulsion as the parenteral drug delivery system for nalbuphine and its prodrugs.

Animals↗
PubMed1996

Calorimetry of apolipoprotein-A1 binding to phosphatidylcholine-triolein-cholesterol emulsions.

The thermotropic properties of triolein-rich, low-cholesterol dipalmitoyl phosphatidylcholine (DPPC) emulsion particles with well-defined chemical compositions (approximately 88% triolein, 1% cholesterol, 11% diacyl phosphatidylcholine) and particle size distributions (mean diameter, approximately 1000-1100 A) were studied in the absence and presence of apolipoprotein-A1 by a combination of differential scanning and titration calorimetry. The results are compared to egg yolk PC emulsions of similar composition and size. Isothermal titration calorimetry at 30 degrees C was used to saturate the emulsion surface with apo-A1 and rapidly quantitate the binding constants (affinity Ka = 11.1 +/- 3.5 x 10(6) M-1 and capacity N = 1.0 +/- 0.09 apo-A1 per 1000 DPPC) and heats of binding (enthalpy H = -940 +/- 35 kcal mol-1 apo-A1 or -0.92 +/- 0.12 kcal mol-1 DPPC). The entropy of association is -3070 cal deg-1 mol-1 protein or -3 cal deg-1 mol-1 DPPC. Without protein on the surface, the differential scanning calorimetry heating curve of the emulsion showed three endothermic transitions at 24.3 degrees C, 33.0 degrees C, and 40.0 degrees C with a combined enthalpy of 1.53 +/- 0.2 kcal mol-1 DPPC. With apo-A1 on the surface, the heating curve showed the three transitions more clearly, in particular, the second transition became more prominent by significant increases in both the calorimetric and Van't Hoff enthalpies. The combined enthalpy was 2.70 +/- 0.12 kcal mol-1 DPPC and remained constant upon repeated heating and cooling. Indicating that the newly formed DPPC emulsion-Apo-A1 complex is thermally reversible during calorimetry. Thus there is an increase in delta H of 1.17 kcal mol-1 DPPC after apo-A1 is bound, which is roughly balanced by the heat released during binding (-0.92 kcal) of apo-A1. The melting entropy increase, +3.8 cal deg-1 mol-1 DPPC of the three transitions after apo-A1 binds, also roughly balances the entropy (-3 cal deg-1 mol-1 DPPC) of association of apo-A1. These changes indicate that apo-A1 increases the amount of ordered gel-like phase on the surface of DPPC emulsions when added at 30 degrees C. From the stoichiometry of the emulsions we calculate that the mean area of DPPC at the triolein/DPPC interface is 54.5 A2 at 41 degrees C and 54.2 A2 at 30 degrees C. The binding of apo-A1 at 30 degrees C to the emulsion reduces the surface area per DPPC molecule from 54.2 A2 to 50.8 A2. At 30 degrees apo-A1 binds with high affinity and low capacity to the surface of DPPC emulsions and increases the packing density of the lipid domain to which it binds. Apo-A1 was also titrated onto DPPC emulsions at 45 degrees C. This temperature is above the gel liquid crystal transition. No heat was released or adsorbed. Furthermore, egg yolk phosphatidylcholine emulsions of nearly identical composition were also titrated at 30 degrees C with apo-A1 and were euthermic. Association constants were previously measured using a classical centrifugation assay and were used to calculate the entropy of apo-A1 binding (+28 cal deg-1 mol-1 apo-A1). This value indicates that apo-A1 binding to a fluid surface like egg yolk phosphatidylcholine or probably DPPC at 45 degrees C is hydrophobic and is consistent with hydrocarbon lipid or protein moities coming together and excluding water. Thus the binding of apo-A1 to partly crystalline surfaces is entropically negative and increases the order of the already partly ordered phases, whereas binding to liquid surfaces is mainly an entropically driven hydrophobic process.

1,2-Dipalmitoylphosphatidylcholine↗