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PubMed2003

Determination of polysorbate 80 in parenteral formulations by high-performance liquid chromatography and evaporative light scattering detection.

Drugs that are not very soluble in aqueous formulations are solubilized with surfactants such as polysorbate 80. In order to evaluate the stability of excipient such as polysorbate 80 in drug formulation, a rapid chromatographic methodology is desired; however, polysorbate 80 does not have a strong chromophore for monitoring by absorption spectrometry. A simple and fast method for the analysis of polysorbate 80 in pharmaceutical formulations was developed using high-performance liquid chromatography with evaporative light scattering detection (ELSD). Separation of polysorbate 80 as a single peak was achieved on a C18 column using a methanol/water gradient mobile phase and ELS detection. The method is specific for polysorbate 80 in the formulation as there were no interferences from the drug or other excipients. Precision, recovery, linearity and limit of quantitation/detection experiments gave acceptable results during the evaluation of the method.

Chromatography, High Pressure Liquid↗

PubMed2004

Simultaneous analysis of docetaxel and the formulation vehicle polysorbate 80 in human plasma by liquid chromatography/tandem mass spectrometry.

An analytical procedure for the simultaneous determination of the anticancer agent docetaxel (Taxotere) and its formulation vehicle polysorbate 80 (Tween 80) in human plasma samples is described. Sample pretreatment involved a double liquid-liquid extraction step with a mixture of acetonitrile/n-butyl chloride (1/4, v/v). Separation of the compounds of interest, including the internal standard paclitaxel, was achieved on a reversed-phase Waters X-Terra mass spectrometry (MS) column (50 x 2.1mm internal diameter) packed with a 3.5-microm octadecyl stationary phase, using isocratic elution. Detection of docetaxel and polysorbate 80 was performed using tandem MS detection with electrospray ionization. Validation results indicated that the method is accurate and precise and has lower limits of quantitation of 0.500 nM (approximately 0.4 ng/ml) and 1.00 microg/ml for docetaxel and polysorbate 80, respectively. The method was subsequently used to measure concentrations of docetaxel and polysorbate 80 in plasma samples in support of a project to assess the influence of polysorbate 80 concentrations on the disposition and toxicity profile of docetaxel in cancer patients receiving Taxotere.

Chromatography, High Pressure Liquid↗

PubMed2004

Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture.

Oral bioavailability of a poorly water-soluble drug was greatly enhanced by using its solid dispersion in a surface-active carrier. The weakly basic drug (pK(a) approximately 5.5) had the highest solubility of 0.1mg/ml at pH 1.5, < 1 microg/ml aqueous solubility between pH 3.5 and 5.5 at 24+/-1 degrees C, and no detectable solubility (< 0.02 microg/ml) at pH greater than 5.5. Two solid dispersion formulations of the drug, one in Gelucire 44/14 and another one in a mixture of polyethylene glycol 3350 (PEG 3350) with polysorbate 80, were prepared by dissolving the drug in the molten carrier (65 degrees C) and filling the melt in hard gelatin capsules. From the two solid dispersion formulations, the PEG 3350-polysorbate 80 was selected for further development. The oral bioavailability of this formulation in dogs was compared with that of a capsule containing micronized drug blended with lactose and microcrystalline cellulose and a liquid solution in a mixture of PEG 400, polysorbate 80 and water. For intravenous administration, a solution in a mixture of propylene glycol, polysorbate 80 and water was used. Absolute oral bioavailability values from the capsule containing micronized drug, the capsule containing solid dispersion and the oral liquid were 1.7+/-1.0%, 35.8+/-5.2% and 59.6+/-21.4%, respectively. Thus, the solid dispersion provided a 21-fold increase in bioavailability of the drug as compared to the capsule containing micronized drug. A capsule formulation containing 25 mg of drug with a total fill weight of 600 mg was subsequently selected for further development. The selected solid dispersion formulation was physically and chemically stable under accelerated storage conditions for at least 6 months. It is hypothesized that polysorbate 80 ensures complete release of drug in a metastable finely dispersed state having a large surface area, which facilitates further solubilization by bile acids in the GI tract and the absorption into the enterocytes. Thus, the bioavailability of this poorly water-soluble drug was greatly enhanced by formulation as a solid dispersion in a surface-active carrier.

Administration, Oral↗

PubMed2005

Polysorbate 80 in medical products and nonimmunologic anaphylactoid reactions.

BACKGROUND: Polyoxyethylene-sorbitan-20-monooleate (also known as polysorbate 80 and Tween 80) is a solubilizing agent ubiquitously used in nutritives, creams, ointments, lotions, and multiple medical preparations (e.g., vitamin oils, vaccines, and anticancer agents) and as an additive in tablets. Whereas its relevance as a contact allergen has declined during the past decades, it is of current relevance as a "hidden" inductor of anaphylactoid reactions. OBJECTIVE: To identify polysorbate 80 (generally believed to be an inert vehicle) as an inductor of a severe anaphylactoid reaction. METHODS: Skin prick testing, enzyme-linked immunosorbent assay, IgE immunoblotting, and flow cytometric detection of basophil activation were performed in controls and in a patient with a medical history of anaphylactic shock due to intravenous administration of a multivitamin product during pregnancy. RESULTS: Polysorbate 80 was identified as the causative agent for the anaphylactoid reaction of nonimmunologic origin in the patient. Polysorbate specific IgE antibodies were not identified in enzyme-linked immunosorbent assay and immunoblot examinations, confirming the nonimmunologic nature of the anaphylactoid reaction. CONCLUSIONS: Polysorbate 80 is a ubiquitously used solubilizing agent that can cause severe nonimmunologic anaphylactoid reactions.

Anaphylaxis↗

PubMed2005

Polysorbate-stabilized solid lipid nanoparticles as colloidal carriers for intravenous targeting of drugs to the brain: comparison of plasma protein adsorption patterns.

Plasma proteins enriched on the surface of drug-delivery-purpose nanoparticles are regarded as key factors for determination of in vivo organ distribution after intravenous injection. Polysorbate 80-coated polybutylcyanoacrylate (PBCA) nanoparticles, preferentially adsorbing apolipoprotein E (apoE) on their surface, have previously been considered to deliver various drugs to the brain. In the present study, in vivo well tolerable solid lipid nanoparticles (SLN) using different types of polysorbates as stabilizers were produced. The influence of the different surfactants on in vitro adsorption of human plasma proteins was investigated using two-dimensional polyacrylamide gel electrophoresis (2-DE). Possible correlations of different amounts of adsorbed apoE to the hydrophilic-lipophilic balance (HLB) of the polysorbates are shown and discussed. Apolipoprotein C-II, albumin and immunoglobulin G, which are also decisive plasma proteins with regard to site-specific drug delivery of intravenously injected carriers to the brain, are compared with regard to adsorption. Moreover, certain similarities to the plasma protein adsorption patterns of previously analysed brain-specific PBCA nanoparticles could be detected. Despite some differences in adsorption behavior of proteins on the surface of polysorbate-stabilized SLN and PBCA nanoparticles, we conclude that in both cases polysorbate 80 might have the highest potential to deliver drugs to the brain.

Adsorption↗

PubMed2005

Body distribution of polysorbate-80 and doxorubicin-loaded [14C]poly(butyl cyanoacrylate) nanoparticles after i.v. administration in rats.

Previously it was shown that poly(butyl cyanoacrylate) (PBCA) nanoparticles coated with polysorbate 80 are able to cross the blood-brain barrier (BBB) after i.v. administration. The objective of the present study was to investigate the influence of polysorbate 80 and doxorubicin-loading on the body distribution in rats. The biodistribution profile and brain concentration of (14)C-radiolabeled PBCA nanoparticles, polysorbate 80 coated (14)C-PBCA nanoparticles, and doxorubicin-loaded (14)C-PBCA nanoparticles were determined by radioactivity counting after i.v. administration in rats. The (14)C-PBCA nanoparticles showed a significant accumulation in the organs of the reticuloendothelial system (RES). Polysorbate 80 coating of the (14)C-PBCA nanoparticles decreased this accumulation to about 40% after 1 h post injection. The brain concentration was increased about 2-fold after polysorbate 80-coating at this time point. The presence of doxorubicin in this preparation, however, decreased the brain concentration to levels similar to uncoated particles, probably caused by the positive charge of this compound. After longer time periods after injection the differences between the three preparations decreased.

Animals↗

PubMedDate not supplied

Hypotensive action of commercial intravenous amiodarone and polysorbate 80 in dogs.

Commercial intravenous amiodarone has been reported to have antiarrhythmic actions and to cause only mild hypotension in humans. In the dog, however, amiodarone was observed to cause severe hypotension. Since commercial intravenous amiodarone is amiodarone compound (50 mg/ml) dissolved in water with polysorbate 80 (Tween 80) (100 mg/kg), the effects of amiodarone in ethanol (5 mg/kg) and polysorbate 80 (10 mg/kg) were studied individually, and in combination in anesthetized dogs. Commercial intravenous amiodarone and polysorbate 80 caused at least a 60% drop in mean blood pressure and left ventricular maximum dP/dt for at least 30 min, whereas amiodarone in ethanol did not. The drop in blood pressure was not principally due to peripheral vasodilation. Therefore, in dogs the diluent polysorbate 80 is the major cause of severe hypotension resulting from commercial intravenous amiodarone. These studies show that commercial intravenous amiodarone produces results different in dogs than has been previously reported in humans. Therefore: (a) canine models for studying the antiarrhythmic actions of commercial intravenous amiodarone would produce results complicated by severe hypotension; and (b) polysorbate 80 is not an inert substance, but is a potent cardiac depressant.

Amiodarone↗

PubMed1991

Effects of amiodarone with and without polysorbate 80 on myocardial oxygen consumption and coronary blood flow during treadmill exercise in the dog.

Since amiodarone has been reported to possess antianginal activity, this study examined the effects of amiodarone on coronary blood flow and myocardial oxygen consumption during exercise. Studies were performed in 14 chronically instrumented dogs trained to run on a motor-driven treadmill. Left circumflex coronary artery blood flow was measured with an electromagnetic flowmeter while aortic and coronary sinus catheters allowed measurement of myocardial oxygen extraction. During control conditions, graded exercise resulted in progressive increases in heart rate, aortic pressure, and coronary blood flow. Two preparations of amiodarone, 5 mg/kg, one dissolved in sterile water and the other in 10% polysorbate 80, were given intravenously to separate groups of dogs. Amiodarone in sterile water caused no hemodynamic changes at rest. However, the increase in heart rate during exercise was blunted after amiodarone, so that heart rate during the heaviest level of exercise was significantly less than during control exercise. Coronary blood flow and myocardial oxygen consumption were unchanged. Amiodarone with polysorbate 80 also blunted the increase in heart rate during exercise, but in addition caused a significant decrease in aortic pressure both at rest and during exercise. Myocardial oxygen consumption and coronary blood flow were significantly decreased after administration of amiodarone with polysorbate 80 at rest and during all exercise levels. Amiodarone with or without polysorbate 80 did not change myocardial oxygen extraction. These data demonstrate that amiodarone exerts a negative chronotropic effect during exercise. However, the decreased arterial pressure and myocardial oxygen consumption were not due to amiodarone, but was seen only with the combination of amiodarone dissolved in polysorbate 80.

Amiodarone↗

PubMedDate not supplied

Significant entry of tubocurarine into the brain of rats by adsorption to polysorbate 80-coated polybutylcyanoacrylate nanoparticles: an in situ brain perfusion study.

The possibility of using polysorbate 80-coated polybutylcyanoacrylate nanoparticles to deliver low molecular polar hydrophilic drugs to the CNS has been studied. Tubocurarine (a quaternary ammonium salt) does not penetrate the normal intact blood-brain barrier. However, the injection of this drug directly into the cerebral ventricles of the brain provokes the development of epileptiform seizures as assessed by electroencephalogram (EEG). An in situ perfused rat brain technique was used as an experimental technique together with a simultaneous recording of the EEG. Nanoparticles were prepared by butylcyanoacrylate polymerization in an acidic medium. Fifteen minutes after the introduction of tubocurarine-loaded polysorbate 80-coated nanoparticles into the perfusate, epileptiform spikes in the EEG appeared. Intraventricular injection of tubocurarine caused the appearance of the EEG seizures 5 min after administration. Neither tubocurarine solution nor tubocurarine-loaded nanoparticles without polysorbate 80 or a mixture of polysorbate 80 and tubocurarine were able to influence the EEG. Thus only the loading of tubocurarine onto the polysorbate 80-coated nanoparticles appears to enable the transport of this quaternary ammonium compound through the blood-brain barrier.

Adsorption↗

PubMed1998

Effect of polysorbates on drug release from wax matrices.

The purpose of this study was to investigate the effect of various types and amounts of polysorbates on potassium chloride release. Potassium chloride, which is a highly water-soluble model drug, was embedded into wax (containing surfactants) to produce a sustained-release dosage form. Various kinds of polysorbates were chosen as surfactants to control the dissolution profile. The release of the model drug was tested by rotating paddle method of USP 23 and the dissolution process was characterized by the Weibull distribution. The surface tension of the aqueous solutions of polysorbates was determined by a computer-controlled Sigma 70 tensiometer. The application of polysorbates in more than 2% concentration did not alter either the release rate of the embedded potassium chloride, or the surface tension values of the aqueous solutions. The results of this study allow the determination of the optimal concentration of polysorbates in the case of the potassium chloride release.

Administration, Oral↗

PubMed1985

Histamine-releasing properties of Polysorbate 80 in vitro and in vivo: correlation with its hypotensive action in the dog.

The solvent of commercial amiodarone (Polysorbate 80) has been reported to produce haemodynamic responses in humans and in dogs similar to those produced by histamine infusion. We therefore evaluated the correlation between hypotension induced by the solvent of amiodarone and its histamine-releasing properties in the awake dog. The solvent of amiodarone administered to a dog, over 5 min in a dose of 10 mg/kg of Polysorbate 80, produced severe hypotension after the first administration; the second injection (24 h later) caused fewer hypotensive effects. Histamine release in the peripheral tissues was demonstrated by a marked increase in plasma histamine concentrations, with the maximum value 10 min after the solvent administration. H1- and H2-receptor blockade with mepyramine (5 mg/kg) and cimetidine (10 mg/kg) significantly reduced the cardiovascular effects of the solvent. Isolated peritoneal mast cells from rats also released histamine in response to Polysorbate 80. These studies show that Polysorbate 80 releases histamine both in vitro and in isolated mast cells from rats and in vivo in the dog, and that the plasma concentrations are correlated with the haemodynamic responses.

Amiodarone↗

PubMed1993

Quantitation of hydroperoxides in the aqueous solutions of non-ionic surfactants using polysorbate 80 as the model surfactant.

The application of coupled oxidation of NADPH to peroxide quantitation in non-ionic surfactant solutions is demonstrated using polysorbate 80 as the model surfactant. The linearity, precision, accuracy, and sensitivity of the method are discussed. The method has the following advantages over the traditional iodimetric method: (1) it is not affected by the non-ionic surfactant present in the solution; (2) it is reactive to less reactive hydroperoxides; (3) it is not light sensitive; and (4) it is carried out at near physiological pH in aqueous solutions. The method was employed to monitor the peroxide concentration of polysorbate 80 solutions stored under three different conditions. The effects of light and heat on peroxide concentration are more pronounced in more dilute solutions (0.1 and 1%). The peroxide concentration determined in the freshly prepared polysorbate 80 solution can be converted to the peroxide number of the raw material, which is not available from the supplier of polysorbate 80.

Glutathione Peroxidase↗

PubMed2005

Polysorbate 80 increases the susceptibility to oxidative stress in rat thymocytes.

Effect of simultaneous application of polysorbate 80, a nonionic surfactant widely used in pharmaceutical products, and hydrogen peroxide on rat thymocytes was examined to see if polysorbate 80 increases the susceptibility to oxidative stress because this surfactant decreases the cellular content of glutathione. Polysorbate 80 at clinically-relevant concentrations increases the cytotoxicity of hydrogen peroxide under the in vitro condition. Result suggests that polysorbate 80 may increase the susceptibility of cells to oxidative stress.

Aniline Compounds↗

PubMed2003

High-performance liquid chromatographic determination of polysorbate 80 in pharmaceutical suspensions.

A quick HPLC method is reported for the analysis of polysorbate 80 in pharmaceutical suspensions. A typical pharmaceutical suspension was mixed with dilute potassium hydroxide, and heated at 40 degrees C for 6 h. This procedure resulted in quantitative hydrolysis of polysorbate 80 to release oleic acid. A quick HPLC procedure was used to analyze the hydrolyzed samples without further sample treatment. Polysorbate 80 USP, treated in the same way as the pharmaceutical suspensions, was used as standard. Full validation tests were carried out and the validation studies demonstrated that this method is suitable for accurate and reproducible analysis of polysorbate 80 in pharmaceutical suspensions.

Chromatography, High Pressure Liquid↗

PubMed1997

Delivery of loperamide across the blood-brain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles.

PURPOSE: The possibility of using polysorbate 80-coated nanoparticles for the delivery of the water insoluble opioid agonist loperamide across the blood-brain barrier was investigated. The analgesic effect after i.v. injection of the preparations was used to indicate drug transport through this barrier. METHODS: Loperamide was incorporated into PBCA nanoparticles. Drug-containing nanoparticles were coated with polysorbate 80 and injected intravenously into mice. Analgesia was then measured by the tail-flick test. RESULTS: Intravenous injection of the particulate formulation resulted in a long and significant analgesic effect. A polysorbate 80 loperamide solution induced a much less pronounced and very short analgesia. Uncoated nanoparticles loaded with loperamide were unable to produce analgesia. CONCLUSIONS: Polysorbate 80-coated PBCA nanoparticles loaded with loperamide enabled the transport of loperamide to the brain.

Analgesics↗

PubMed1999

Indirect evidence that drug brain targeting using polysorbate 80-coated polybutylcyanoacrylate nanoparticles is related to toxicity.

PURPOSE: To investigate the mechanism underlying the entry of the analgesic peptide dalargin into brain using biodegradable polybutylcyanoacrylate (PBCA) nanoparticles (NP) overcoated with polysorbate 80. METHODS: The investigations were carried out with PBCA NP and with non biodegradable polystyrene (PS) NP (200 nm diameter). Dalargin adsorption was assessed by HPLC. Its entry into the CNS in mice was evaluated using the tail-flick procedure. Locomotor activity measurements were performed to compare NP toxicities. BBB permeabilization by PBCA NP was studied in vitro using a coculture of bovine brain capillary endothelial cells and rat astrocytes. RESULTS: Dalargin loading was 11.7 microg/mg on PBCA NP and 16.5 microg/ mg on PS NP. Adding polysorbate 80 to NP led to a complete desorption. Nevertheless, dalargin associated with PBCA NP and polysorbate 80 induced a potent and prolonged analgesia, which could not be obtained using PS NP in place of PBCA NP. Locomotor activity dramatically decreased in mice dosed with PBCA NP, but not with PS NP. PBCA NP also caused occasional mortality. In vitro, PBCA NP (10 microg/ml) induced a permeabilization of the BBB model. CONCLUSIONS: A non specific permeabilization of the BBB, probably related to the toxicity of the carrier, may account for the CNS penetration of dalargin associated with PBCA NP and polysorbate 80.

Analgesics↗

PubMed1999

Significant transport of doxorubicin into the brain with polysorbate 80-coated nanoparticles.

PURPOSE: To investigate the possibility of delivering of anticancer drugs into the brain using colloidal carriers (nanoparticles). METHODS: Rats obtained 5 mg/kg of doxorubicin by i.v. injection in form of 4 preparations: 1. a simple solution in saline, 2. a simple solution in polysorbate 80 1% in saline, 3. bound to poly(butyl cyanoacrylate) nanoparticles, and 4. bound to poly(butyl cyanoacrylate) nanoparticles overcoated with 1% polysorbate 80 (Tween 80). After sacrifice of the animals after 10 min, 1, 2, 4, 6, and 8 hours, the doxorubicin concentrations in plasma, liver, spleen, lungs, kidneys, heart and brain were determined after extraction by HPLC. RESULTS: No significant difference in the body distribution was observed between the two solution formulations. The two nanoparticle formulations very significantly decreased the heart concentrations. High brain concentrations of doxorubicin (>6 microg/g) were achieved with the nanoparticles overcoated with polysorbate 80 between 2 and 4 hours. The brain concentrations observed with the other three preparations were always below the detection limit (< 0.1 microg/g). CONCLUSIONS: The present study demonstrates that the brain concentration of systemically administered doxorubicin can be enhanced over 60-fold by binding to biodegradable poly(butyl cyanoacrylate) nanoparticles, overcoated with the nonionic surfactant polysorbate 80. It is highly probable that coated particles reached the brain intact and released the drug after endocytosis by the brain blood vessel endothelial cells.

Animals↗

PubMed2003

Direct evidence that polysorbate-80-coated poly(butylcyanoacrylate) nanoparticles deliver drugs to the CNS via specific mechanisms requiring prior binding of drug to the nanoparticles.

PURPOSE: [corrected] It has recently been suggested that the poly(butylcyanoacrylate) (PBCA) nanoparticle drug delivery system has a generalized toxic effect on the blood-brain barrier (BBB) (8) and that this effect forms the basis of an apparent enhanced drug delivery to the brain. The purpose of this study is to explore more fully the mechanism by which PBCA nanoparticles can deliver drugs to the brain. METHODS: Both in vivo and in vitro methods have been applied to examine the possible toxic effects of PBCA nanoparticles and polysorbate-80 on cerebral endothelial cells. Human, bovine, and rat models have been used in this study. RESULTS: In bovine primary cerebral endothelial cells, nontoxic levels of PBCA particles and polysorbate-80 did not increase paracellular transport of sucrose and inulin in the monolayers. Electron microscopic studies confirm cell viability. In vivo studies using the antinociceptive opioid peptide dalargin showed that both empty PBCA nanoparticles and polysorbate-80 did not allow dalargin to enter the brain in quantities sufficient to cause antinociception. Only dalargin preadsorbed to PBCA nanoparticles was able to induce an antinociceptive effect in the animals. CONCLUSION: At concentrations of PBCA nanoparticles and polysorbate-80 that achieve significant drug delivery to the brain, there is little in vivo or in vitro evidence to suggest that a generalized toxic effect on the BBB is the primary mechanism for drug delivery to the brain. The fact that dalargin has to be preadsorbed onto nanoparticles before it is effective in inducing antinociception suggests specific mechanisms of delivery to the CNS rather than a simple disruption of the BBB allowing a diffusional drug entry.

Analgesics, Opioid↗