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At least 325 records · Page 18Linked to original sources
PubMed2003

O/W microemulsions for oral drug delivery.

Quaternary microemulsion compositions for oral administration using isopropyl myristate, polysorbate 80 and ethanol 96 degrees were developed and three ratio of polysorbate to ethanol were selected. Isotropic single-phase compositions were considered as microemulsions and were registered on a Pseudo-Ternary Phase Diagram. The objective was to formulate a therapeutic dose for lorazepam and loperamide in a drop liquid form. Another aim was to obtain a liquid oral formula for nifedipine taking advantage of its insured fast absorption to be used in hypertensive crises. The physical stability of the compositions was evaluated by normal aging, centrifugal resistance time and by cycling as well. The selected formulation characterization included density, pH and conductivity measurements. The particle size distribution was determined by a light scattering method and, finally the carried drugs concentration was valued. The versatility showed by this type of systems allows both to carry drugs of different physico-chemical properties and to deal with a number of pharmacotherapeutic objectives.

Administration, Oral↗
PubMed1983

Influenza vaccines in children. Comparison of new cetrimonium bromide and standard ether-treated vaccines.

We compared a new cetrimonium bromide (CTAB) subunit vaccine with a conventional polysorbate (Tween)-ether split-product vaccine in 63 children and young adults. The vaccines each contained influenza A/Bangkok/79, A/Brazil/78, B/Singapore/79; two doses were given one month apart. Among persons initially seronegative for A/Bangkok/79, the geometric mean antibody titer rose to more than 100 following one dose of vaccine, while those initially seropositive had titers of greater than 200 after one dose of either vaccine. Neither vaccine was able to induce comparable antibody titers to A/Brazil/78 or B/Singapore/79 after one dose in initially seronegative persons. After two doses the titers were greater than 100 for A/Brazil but not for B/Singapore. An A/Bangkok epidemic struck the New York City metropolitan area. The attack rate in the unvaccinated matched sibling control group was 35% (15/43). Only two of the 27 recipients of cetrimonium bromide vaccine and none of the 36 polysorbate-ether vaccines had a fourfold or greater increase in antibody titer during the epidemic.

Adult↗
PubMedDate not supplied

Polymorphic changes of mannitol during freeze-drying: effect of surface-active agents.

The effect of polysorbate 80 on the crystalline properties of mannitol during freeze-drying was studied. Crystallinity and polymorphism play an important role in, e.g., the solubility and stability of freeze-dried products. Polysorbate 80 had an effect on both the polymorphism and the crystallinity of freeze-dried mannitol.

Crystallization↗
PubMed2006

Characterization of a novel polymorphic form of celecoxib.

A new solid form (Form IV) of celecoxib was prepared in the presence of Polysorbate 80 and HPMC. A celecoxib suspension containing the Form IV had significantly higher bioavailability (>4 times) in dogs than the marketed capsules and the suspension containing bulk drug powders (Form III). The new form was characterized using differential scanning calorimetry, powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), infrared spectroscopy, and Raman spectroscopy. The solids separated from the suspension containing the new form showed a melt onset at 145-148 degrees C, which was about 12-15 degrees less than known melting points of Form I, II ,and III of celecoxib. The PXRD pattern of the separated solids was not consistent with any of the known celecoxib crystal forms or the known excipients in the suspension. The formation of the new solid form (Form IV) was dependent upon the concentration and ratio of HPMC and Polysorbate 80. A faster dissolution rate (>2 times) of Form IV was observed compared to the thermodynamically stable form of celecoxib (Form III). There were no measurable changes in the solid state of Form IV either in dried solids or in the suspension for at least 6 months at 40 degrees C and 16 months at 25 degrees C.

Animals↗
PubMed1975

Succinylsulfathiazole crystal forms. III: Crystal growth studies.

Crystal growth accompanying the transformation of succinylsulfathiazole crystal forms in aqueous suspensions was studied using a projecting microscope. The effects of increase of temperature, agitation, inclusion of seeds of Form II (the water-stable dihydrate), sulfathiazole, methylcellulose, and polysorbate 80 on the particle-size distribution of anhydrous succinylsulfathiazole Form I were examined. Rates of crystal growth, calculated as increase of diameter per unit time, were given under different experimental conditions. Increase of temperature, agitation, and seeding with nuclei of Form II had significant growth-accelerating effects. Sulfathiazole and polysorbate 80 had growth-retarding effects. Methylcellulose inhibited the crystal growth of Form I for over a year. Aqueous suspensions of Form II did not show any change in particle-size distribution. The crystal growth was shown to be a direct consequence of the transformation of the crystal form. Physical conditions and additives which had accelerating or retarding effects on the rate of succinylsulfathiazole in aqueous suspensions.

Chemical Phenomena↗
PubMed1979

Simultaneous solubilization of steroid hormones II: androgens and estrogens.

The simultaneous solubilization of some androgens and estrogens in aqueous polysorbate 40, tetradecyltrimethylammonium bromide, and sodium lauryl sulfate was studied. The solubilizations of estradiol and testosterone were independent of each other in all three association colloids. However, if the estrogen component was ethinyl estradiol, the solubilization was dependent on the addition order. The estrogen precipitates more readily than testosterone in polysorbate 40 and tetradecyltrimethylammonium bromide, but the opposite is true in sodium lauryl sulfate. The simultaneous solubilizations of methyltestosterone or ethisterone with the estrogens tested were different from those of testosterone. The solubilization behavior of the steroids is discussed, starting with the pseudophase model and different solubilization loci. Results indicated that the free energy change of micellar binding, delta Gb, decreases with increased steroid polarity. The simultaneous solubilization cannot be predicted by delta Gb but may be explained by differences in the solubilization mechanism.

Androgens↗
PubMed1994

Preparation of drug-carrier emulsions stabilized with phosphatidylcholine-surfactant mixtures.

A method has been developed to produce lipid emulsion particles for parenteral use as drug carriers. The technique uses a mixture of a triacylglycerol oil and purified egg yolk phosphatidylcholine (EPC) as the basic system and sonication under mild conditions to produce the emulsion. A large number of mild "biological" surfactants were tested for their ability to improve the dispersing and stability properties of the basic system. The results showed a preference for polysorbate 80, and a suitable combination of oil and emulsifiers was found to be castor oil:EPC:polysorbate 80 (1:0.4:0.12, weight ratios). Repeated preparation of this emulsion system in phosphate-buffered saline (PBS) gave particles with a mean diameter near 50 nm, in a reproducible way and with a low polydispersity. The stability of the emulsion was very good (> 3 months), both in PBS and in 2.5% glycerol. The method was also tested with two lipophilic anticancer drugs, which were solubilized in castor oil, with satisfactory results. The lipid emulsion particles described in this study also have a potential use as targetable carriers for site-specific drug delivery.

Drug Carriers↗
PubMed2006

Characterization of itraconazole semisolid dosage forms prepared by hot melt technique.

The objective of this study was to formulate itraconazole semisolid dosage forms and characterize their physicochemical properties. Itraconazole and excipients such as polysorbate 80, fatty acids, fatty alcohols, oils and organic acids were melted at 160 degrees C. The fused solution was then cooled immediately at -10 degrees C to make wax-like semisolid preparations. Their physicochemical attributes were first characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy and nuclear magnetic resonance spectrometry. The solubility of itraconazole in semisolid preparations and their dispersability in the simulated gastric fluid were also determined. Our semisolid preparations did not show any distinct endothermic peak of a crystalline form of itraconazole around 160-163 degrees C. This suggested that it was changed into amorphous one, when it was formulated into semisolid preparations. In addition, the distinctive functional peaks and chemical shifts of itraconazole were well retained after processing into semisolid preparations. It could be inferred from the data that itraconazole was stable during incorporation into semisolid preparations by the hot melt technique. In particular, itraconazole semisolid preparations composed of polysorbate 80, fatty acids and organic acids showed good solubility and dissolution when dispersed in an aqueous medium. It was anticipated that the semisolid dosage forms would be industrially applicable to improving the bioavailability of poorly water-soluble drugs.

Calorimetry, Differential Scanning↗
PubMed2003

A preclinical study comparing approaches for augmenting the immunogenicity of a heptavalent KLH-conjugate vaccine against epithelial cancers.

Previously using a series of monovalent vaccines, we demonstrated that the optimal method for inducing an antibody response against cancer cell-surface antigens is covalent conjugation of the antigens to keyhole limpet hemocyanin (KLH) and the use of a saponin adjuvant. We have prepared a heptavalent-KLH conjugate vaccine containing the seven epithelial cancer antigens GM2, Globo H, Lewis(y), TF(c), Tn(c), STn(c), and glycosylated MUC1. In preparation for testing this vaccine in the clinic, we tested the impact on antibody induction of administering the individual conjugates plus adjuvant compared with a mixture of the seven conjugates plus adjuvant, and of several variables thought to augment immunogenicity. These include approaches for decreasing suppressor cell activity or increasing helper T-lymphocyte activity (low dose cyclophosphamide or anti-CTLA-4 MAb), different saponin adjuvants at various doses (QS-21 and GPI-0100), and different methods of formulation (lyophilization and use of polysorbate 80). We find that: (1). Immunization with the heptavalent-KLH conjugate plus GPI-0100 vaccine induces antibodies against the seven antigens of comparable titer to those induced by the individual-KLH conjugate vaccines, high titers of antibodies against Tn (median ELISA titer IgM/IgG 320/10240), STn (640/5120), TF (320/10240), MUC1 (80/20480), and globo H (640/40); while lower titers of antibodies against Lewis(y)()(160/0) and only occasional antibodies against GM2 are induced. (2). These antibodies reacted with the purified synthetic antigens by ELISA, and with naturally expressed antigens on the cancer cell surface by FACS. (3). None of the approaches for further altering the suppressor cell/helper T-cell balance nor changes to the standard formulation by lyophilization or use of polysorbate 80 had any impact on antibody titers. (4). An optimal dose of saponin adjuvant, QS-21 (50 microg) or GPI-0100 (1000 microg), is required for optimal antibody titers. This heptavalent vaccine is sufficiently optimized for testing in the clinic.

Animals↗
PubMed1988

Prostaglandin F2 alpha-1-isopropylester lowers intraocular pressure without decreasing aqueous humor flow.

Using fluorophotometry, we performed a randomized, dose-response study of the effects of a prostaglandin derivative on aqueous humor flow. Prostaglandin F2 alpha 1-isopropylester, 0.224 micrograms, 0.448 micrograms, and 1.120 micrograms, in saline with polysorbate 80 was instilled into one eye of 20 subjects in three separate dose studies. Polysorbate 80 in saline was instilled in the fellow eye as a control. The drug had no measurable effect on aqueous humor flow or corneal endothelial permeability. Intraocular pressure measured eight hours after administration of the highest dose, 1.120 micrograms, was 20% lower in the treated eye as compared to the fellow eye (P less than .001).

Adult↗
PubMed1990

Dissolution of calcium bilirubinate and calcium carbonate debris remaining after methyl tert-butyl ether dissolution of cholesterol gallstones.

Methyl tert-butyl ether rapidly dissolves cholesterol gallstones, although insoluble debris may remain. Total gallstone dissolution could be achieved if safe solvents for these noncholesterol components can be developed. We evaluated the in vitro ability of ethylenediaminetetraacetic acid, citrate, dimethyl sulfoxide, and ionic or nonionic detergents to dissolve the predominantly calcium bilirubinate and calcium carbonate debris remaining after methyl tert-butyl ether gallstone dissolution. Ethylenediaminetetraacetic acid 1% or 2% at pH 9.5 was the most effective of the solvents studied for dissolving calcium and bile pigment. The addition of cholate (25-200 mM) or polysorbate (1%-10%) to ethylenediaminetetraacetic acid 1% at pH 9.5 enhanced pigment dissolution compared to ethylenediaminetetraacetic acid alone. Dissolution of pellets prepared from human gallstones and composed predominantly of either calcium bilirubinate or calcium carbonate was 80% and 85% at 4 h using ethylenediaminetetraacetic acid 1% plus polysorbate-20 1% at pH 9.5. We conclude that ethylenediaminetetraacetic acid, either alone or with a detergent, is an effective solvent for methyl tert-butyl ether-insoluble gallstone debris and deserves assessment in vivo.

Bilirubin↗
PubMed1991

Effect of 'Pan Masala' on the germ cells of male mice.

Cytogenetic analyses of meiotic metaphase I germ cells and abnormalities of head morphology of caudal sperms were conducted in male mice following oral feeding of Pan Masala. The substance was ground to a fine powder, dispersed in polysorbate solution and administered via gavage to the animals at 84, 420 and 840 mg/kg body weight at the rate of 10 ml/kg body weight. Polysorbate and cyclophosphamide served as the vehicle control and positive control respectively. The two higher doses, 420 and 840 mg, gave a significant increase in the frequency of X-Y univalents and breaks over those of the vehicle control. Frequency of sperm head abnormalities were significantly high for all the doses tested. The results indicate that Pan Masala is a potent clastogen, reaches the testes and affects the germinal cells.

Administration, Oral↗
PubMed2005

Relationship of systemic exposure to unbound docetaxel and neutropenia.

OBJECTIVE: Our objective was to evaluate the association between exposure to unbound docetaxel and neutropenia in patients with cancer and to identify factors influencing unbound docetaxel clearance. METHODS: Docetaxel was administered once every 3 weeks at a dose of 75 mg/m 2 to 49 patients with normal liver function (n = 40, group 1) or mild elevations in liver function test results (n = 9, group 2) or at a dose of 50 mg/m2 to patients with moderate elevations in liver function test results (n = 6, group 3). Pharmacokinetic studies and toxicity assessments were performed during the first cycle of therapy. Total docetaxel concentrations were determined by HPLC and tandem mass spectrometry, and unbound docetaxel fraction was determined by equilibrium dialysis. RESULTS: In patients with normal liver function, unbound docetaxel disposition was characterized by mean (+/-SD) maximum plasma concentration (C max), area under the curve (AUC), and clearance values of 233 +/- 101 ng/mL, 32 +/- 143 ng/mL . h, and 565 +/- 329 L/h, respectively. Unbound clearance varied 8.5-fold; polysorbate 80 exhibited mean (+/-SD) C max , AUC, and clearance values of 451 +/- 221 microg/mL, 528 +/- 217 microg/mL . h, and 8.18 +/- 3.66 L/h, respectively; and clearance varied 6.7-fold. Unbound docetaxel clearance was reduced in patients with moderate liver impairment (groups 1 and 2 versus group 3, P = .020). From multiple linear regression analysis, only polysorbate 80 AUC and liver impairment were significantly associated with unbound docetaxel clearance. Both unbound docetaxel AUC and total AUC were correlated with the percentage decrements in absolute neutrophil count (P = .002 and P = .029, respectively), as well as the worst grade of neutropenia (P = .013 and P = .220, respectively), where higher exposure was associated with worse hematologic toxicity. CONCLUSIONS: Exposure to unbound docetaxel is closely related to drug-induced hematologic toxicity and should be considered in future pharmacologic investigations.

Adult↗
PubMed2004

Assessment and modulation of acamprosate intestinal absorption: comparative studies using in situ, in vitro (CACO-2 cell monolayers) and in vivo models.

The purpose of this study was to explore the intestinal absorption mechanism of acamprosate and to attempt to improve the bioavailability (BA) of the drug through modulation of its intestinal absorption using two enhancers (polysorbate 80 and sodium caprate) based on in situ, in vitro and in vivo models and comparing the results obtained. Intestinal transport of the drug, in the absence and in presence of polysorbate 80 (0.06, 0.28 and 9.6 mM) or sodium caprate (13 and 16 mM) was measured by using an in situ rat gut technique and Caco-2 cell monolayers. Additionally, the effect of sodium caprate on drug oral bioavailability, measured as urinary recovery, was quantified by performing in vivo experiments with the rat as animal model. Only sodium caprate was able to increase the absorption rate constant (ka) of acamprosate in the mid-intestine of the rats from 0.29 +/- 0.07 h-1 in the absence of the promoter to 0.51 +/- 0.19 h-1 in the presence of C10 16 mM, along with the apparent permeability (Papp) obtained in Caco-2 cells (around two-fold). However, the drug bioavailability in rats (around 20%) did not improve in the presence of any of the concentrations tested (13, 16 and 50 mM). It is concluded that acamprosate absorption likely occurs via paracellular pathway and can be enhanced by sodium caprate in situ and in vitro but not in vivo-thus suggesting that although in situ and in vitro studies could be useful in early screening to select a potential promoter, in vivo studies in animal models are necessary to confirm the utility of the enhancer and to determine the influence of physiological variables.

Acamprosate↗
PubMed2004

Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo.

The efflux transporter, P-glycoprotein (P-gp), located in the apical membranes of intestinal absorptive cells, can reduce the bioavailability of a wide range of orally administered drugs. A number of surfactants/excipients have been shown to inhibit P-gp, and thus potentially enhance drug absorption. In this study, the improved everted gut sac technique was used to screen excipients for their ability to enhance the absorption of digoxin and celiprolol in vitro. The most effective excipients with digoxin were (at 0.5%, w/v): Labrasol > Imwitor 742 > Acconon E = Softigen 767 > Cremophor EL > Miglyol > Solutol HS 15 > Sucrose monolaurate > Polysorbate 20 > TPGS > Polysorbate 80. With celiprolol, Cremophor EL and Acconon E had no effect, but transport was enhanced by Softigen 767 > TPGS > Imwitor 742. In vivo, the excipients changed the pharmacokinetic profile of orally administered digoxin or celiprolol, but without increasing the overall AUC. The most consistent change was an early peak of absorption, probably due to the higher concentration of excipient in the proximal intestine where the expression of P-gp is lower. These studies show that many excipients/surfactants can modify the pharmacokinetics of orally administered drugs that are P-gp substrates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Stabilizer choice for rapid dissolving high potency itraconazole particles formed by evaporative precipitation into aqueous solution.

The objective of this study was to investigate the influence of stabilizer type on the physicochemical properties, including dissolution, of ultra-high potency powders containing itraconazole (ITZ) formed by evaporative precipitation into aqueous solution (EPAS). ITZ was dissolved in dichloromethane, which was then atomized through a heated coil at 80 degrees C into an aqueous solution over precise periods of time. Stabilizers were present in either the aqueous, organic or both phases. The dispersions were centrifuged and the supernatant was removed. Three hydrophilic stabilizers were investigated, including polysorbate 80, polyvinyl pyrrolidone and poloxamer 407. Rapid dissolving ultra-high potency of ITZ powders was successfully produced. Greater than 80% of ITZ was dissolved in 5 min compared to only 13% of ITZ bulk powders. The resulting stabilizer-coated drug particles had high drug-to-stabilizer ratios greater than 12, corresponding to potencies (wt drug/wt drug+wt surfactant) as high as 93%. An increase in dissolution rate was correlated with the amount of stabilizer adsorbed and the wettability. The combination of polysorbate 80 and poloxamer 407 present in the aqueous and organic phases, respectively, was superior in achieving high wetting and rapid dissolving ITZ powders. The ability to control the adsorption behavior of stabilizers by using synergistic combinations affords the opportunity to achieve high dissolution rates with higher potencies compared to previously reported values.

Adsorption↗
PubMed2004

Analysis by liquid chromatography and infrared spectrometry of di(2-ethylhexyl)phthalate released by multilayer infusion tubing.

Di(2-ethylhexyl)phthalate (DEHP), a plasticiser present in infusion equipment, is known to be harmful to human health. Various studies have shown that DEHP is released into drug solutions from polyvinyl chloride (PVC) infusion lines. New multi-layer tubing has therefore been marketed to overcome this problem. We assessed the inertness of this tubing when placed in contact with a solution of CELLTOP. Chromatographic assay of DEHP showed no significant difference in DEHP levels in the solution when placed in contact with PVC and with multi-layer tubing. Analysis by infrared spectrometry showed that DEHP was initially present in the polyethylene layer of the multi-layer tubing even before contact with the drug solution. Contact with the solution results in release of DEHP from the container into the contents. The substance responsible for this release is in fact an excipient of CELLTOP, polysorbate. This release of DEHP further proves to depend on parameters such as temperature, time of contact between solution and tubing, and the concentration of polysorbate in the infused drug solution.

Chromatography, Liquid↗
PubMed2006

Development of a sensitive size exclusion HPLC method with fluorescence detection for the quantitation of recombinant human erythropoietin (r-HuEPO) aggregates.

Human erythropoietin produced by recombinant DNA technology, is now marketed worldwide for the treatment of anemias associated with chronic renal failure and chemotherapy. No sensitive methods, which can determine r-HuEPO dimer or oligomer aggregate content in formulated products, have been published to date. This report describes the development and validation of a sensitive size exclusion high performance liquid chromatography (HPLC) method for the quantitation of r-HuEPO aggregates in formulations containing 0.03% polysorbate 80. A Waters Alliance 2690 HPLC system connected to a TosoHaas TSKgel G3000 SWxl (7.8 mm x 30 cm, 250 A pore size, 5 microm particle size) column and a Waters 474 fluorescence detector was used. The mobile phase for the SEC-HPLC method consists of isopropyl alcohol-potassium phosphate (0.1 M)/potassium chloride buffer (pH 6.8+/-0.1, 0.2 M) (25:75, v/v). The flow rate was 0.3 mL/min and the method run time was 60 min. The SEC-HPLC method presented here was shown to be specific for r-HuEPO total aggregates (dimer and oligomers) and allows for their quantitation at 80 ng/mL or 4 ngs/injection, in the presence of r-HuEPO monomer and the pharmaceutical excipients, glycine (5 mg/mL), sodium chloride (4.3 mg/mL), and 0.03% polysorbate 80. The finalized method is stability-indicating and is suitable for determining r-HuEPO aggregates between 0.2 and 0.5% levels in the formulated product of r-HuEPO. This method offers a robust way to measure total aggregates on a routine basis with a high sensitivity for use in product quality control.

2-Propanol↗