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At least 487 records · Page 27Linked to original sources
PubMed1977

Rectal absorption of nitrofurantoin.

The adsorption in humans of nitrofurantoin from seven suppository bases was studied using urinary excretion measurements. Rectal absorption was poorer than GI absorption. The administration of 400 mg of nitrofurantoin in a polyethylene glycol-polysorbate 80 suppository base and in a polyethylene glycol-silica suppository based provided an adequate urinary concentration of nitrofurantoin. Persons who cannot tolerate orally administered nitrofurantoin due to gastric upset could receive nitrofurantoin therapy rectally.

Administration, Oral↗
PubMed1977

Kinetics of indomethacin degradation II: Presence of alkali plus surfactant.

The kinetics of indomethacin were studied in the presence of the surfactants ethoxylated lanolin, polysorbate 80, and cetrimonium bromide under alkaline conditions at 30.3 degrees. The degradation followed apparent first-order kinetics. Plots of kobs versus surfactants; concentrations were curved with negative slopes for nonionic surfactants; but with the ionic surfactant, the plots showed a marked positive change in kobs as the surfactant concentration passed through the critical micelle concentration. Literature model systems adequately explained the data for nonionic surfactants but not for the ionic surfactant. A new set of equations was derived for each case using electrochemical potentials. The experimental data for all three surfactants fit the derived equations quite well.

Alkalies↗
PubMed1978

Effect of formulation factors on penetration of hydrocortisone through mouse skin.

The effect of formulation factors on the steady-state flux of hydrocortisone through mouse skin was evaluated. The flux of hydrocortisone from solutions containing propylene glycol as a cosolvent varied inversely with the propylene glycol concentration. Solutions containing 2-propanol gave flux values higher than those obtained from propylene glycol solutions and independent of the 2-propanol concentration. Addition of polysorbate 80 to 2-propanol-water solutions produced an increase in flux at low surfactant concentrations that reached an apparent limiting value at higher concentrations. The penetration flux was the same from solutions and gels. The role of vehicle-skin interactions in penetration is emphasized.

Administration, Topical↗
PubMed1978

Simultaneous solubilization of steroid hormones I: estrogens and C21 steroids.

The simultaneous solubilization of some estrogens and C21 steroids in aqueous polysorbate 40, tetradecyltrimethylammonium bromide, and sodium lauryl sulfate was studied. The less soluble estrogen estradiol was solubilized independently of the C21 steroids. The micellar solubilities of ethinyl estradiol and both corticosterone and hydrocortisone were independnet of the presence of each other while the solubility of 11alpha-hydroxyprogesterone was enhanced by ethinyl estradiol. The solubilizations of ethinyl estradiol and the two C21 steroids, progesterone and 21-hydroxyprogesterone, were dependent on each other so that a varying amount of the steroid solubilized first was precipitated by an excess of the second steroid. If saturated solutions of the two steroids were mixed, no precipitation occurred. A possible mechanism for the simultaneous solubilization of steroids and its relation to structure are discussed.

Chemistry, Pharmaceutical↗
PubMed1979

Percutaneous absorption of butylparaben through guinea pig skin in vitro.

Percutaneous absorption of aqueous butylparaben through guinea pig dorsal skin was studied using a diffusion chamber. Polysorbate 80 increased the solubilized concentration but decreased penetration of the preservative. Polyethylene glycol 400 also reduced the amount of penetration. Propylene glycol was less effective than polyethylene glycol 400. Preservative activities of these systems on several microorganisms were evaluated on agar plates. The relationship between the butylparaben penetration and preservative activity is discussed.

Animals↗
PubMed1981

Micellar solubilization of cetaben sodium in surfactant and lipid solutions.

Cetaben sodium solubilities were evaluated by micellar solubilization in various surfactants and lipid solvents. At pH 8, the relationship between cetaben sodium solubility and surfactant concentration delineated apparent saturable kinetics; at pH 4.9, the relationship between the two parameters was linear. In the presence of 0.5% sodium taurocholate and polysorbate 80, cetaben sodium solubility increased as the medium pH was increased; however, in the presence of 0.5% poloxamer 188, cetaben sodium solubility revealed a hyperbola when the pH was changed from 4.9 to 8.0. Cetaben sodium solubility was enhanced greatly by mixed physiological surfactants, full-strength caprylic-capric monodiglycerides or monodiglycerides, when compared to a single surfactant system. Cetaben sodium solubility is influenced by pH, surfactant type, surfactant concentration, lipid solvent type, and the simultaneous presence of surfactants or phospholipids.

4-Aminobenzoic Acid↗
PubMed1982

Viscosity change after dilution with solutions of water--oil--water emulsions and solute permeability through the oil layer.

A water-in-oil-water (W/O/W) multiple phase emulsion was prepared by a two-step emulsification procedure. The oil phase consisted of paraffin oil and sorbitan monooleate. The inner aqueous phase and the outer aqueous phase were 0.5% glucose solution and 3% polysorbate 80 solution, respectively. Viscosity measurements were carried out on the W/O/W emulsion after diluting it with a number of solutions. A given sequence for the solutes that would increase the emulsion viscosity after dilution was determined. This sequence was identical with that obtained with the solutes in an independent permeability experiment using a planar membrane composed of sorbitan monooleate alone. As a result, it was suggested that solutes as well as water can permeate the oil layer of vesicles of the emulsion to change the vesicle volume, thereby causing a change in the emulsion viscosity.

Emulsions↗
PubMed1985

Liquid chromatographic analysis of enviradene, a new antiviral agent, in plasma and its application in bioavailability studies in the dog.

A rapid and specific high-performance liquid chromatographic (HPLC) assay has been developed for the determination of enviradene, 1, at concentrations of 2-5 ng/mL in plasma. The drug was extracted from the samples using benzene. The benzene extract was evaporated and the residue dissolved in the mobile phase. The HPLC system consisted of a reversed-phase column and a 75% methanol:25% 0.2 M sodium acetate mobile phase. Either a UV detector set at 268 nm or an electrochemical (EC) detector set at a potential of +0.9 V (versus Ag/AgCl/3 M NaCl) was used to monitor the drug. A column-switching system was used to remove late-eluting plasma constituents that interfered in subsequent chromatograms. The limit of sensitivity was 2 ng/mL for the HPLC-EC procedure and 5 ng/mL for the HPLC-UV procedure. Recovery from plasma was approximately 97%; the procedure had a relative error of approximately 3% and a relative standard deviation of 4.5% over the range of 20-200 ng of 1/mL of plasma. Following intravenous administration of 1 or 2 mg/kg of 1 to dogs, the parent drug was quantitated in plasma for 24 h using this procedure. The terminal phase half-life in plasma was calculated to be 10 h. Oral administration to dogs of single 8 mg/kg doses of 1, formulated with povidone-30 or polysorbate 80 and microcrystalline cellulose, produced high and persistent plasma concentrations of drug. At doses below 2 mg/kg, plasma concentrations were found to be nonlinearly related to the amount of the dose administered. The bioavailability of the drug in dogs was found to be increased by the concomitant administration of food.

Administration, Oral↗
PubMed1986

Solubilization of water by hydrotropic salts.

The effect of some electrolytes, nonelectrolytes, surfactants, and hydrotropic salts on the solubility of water in 1-butanol and 1-hexanol was investigated. While sodium chloride and sodium acetate decrease the solubility of water in 1-butanol, urea has no significant effect. The ionic surfactants, sodium lauryl sulfate and cetrimide, cause an initial decrease in the solubility of water in 1-butanol followed by an increase at high surfactant concentrations. The nonionic surfactant, polysorbate 20, does not show the initial decrease in water solubility. On the other hand, the hydrotropic salts, sodium benzoate, sodium salicylate, and sodium gentisate, are shown to be the best water solubilizers in 1-butanol. Sodium salicylate showed the maximum solubilizing power. The effect of sodium benzoate, sodium salicylate, and sodium lauryl sulfate on the solubility of water in 1-hexanol was also investigated. Similar results were obtained.

Chemical Phenomena↗
PubMed1988

Physicochemical basis of increased bioavailability of a poorly water-soluble drug following oral administration as organic solutions.

The physicochemical basis of improvement of the bioavailability of a poorly water-soluble drug [REV 5901; alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; 1] after oral administration as organic solutions was investigated. The drug, which exists in solid and metastable liquid forms, had a pKa value of 3.7 and a solubility of approximately 0.002 mg/mL in water (pH approximately 6) at 37 degrees C. It had appreciable aqueous solubility only at pH values less than 2. The dissolution rate of 1 at pH values greater than 3 was practically zero. On dilution of the water-miscible organic solutions (polyethylene glycol 400 and polysorbate 80) of 1 with aqueous media, the drug instantaneously formed saturated solutions and the excess drug separated as emulsified oily globules. The dispersibility of the globules improved in the presence of surfactants. The average globule size of the oily form of 1 was 1.6 micron or less, as compared with a particle size of 5-10 microns for the solids. Thus, a high surface area of 1 was obtained after oral intake of water-miscible organic solutions. Although 1 was practically insoluble under intestinal pH conditions, its solubility was greatly increased in the presence of bile salts, lecithin, and lipid-digestion mixtures. The high surface area of 1 separating from organic solutions would facilitate its dissolution rate in the presence of biological surfactants and lipids and, therefore, would increase its bioavailability.

Administration, Oral↗
PubMed1989

Effects of hydrotropic agents on the solubility, precipitation, and protein binding of etoposide.

Etoposide, a commonly used anticancer agent, has an aqueous solubility of 0.2 mg/mL. It is formulated for intravenous use as a more concentrated solution (Vepesid; 20 mg/mL) with polysorbate 80 and with cosolvents. In this work, hydrotropic agents such as sodium benzoate, sodium o-hydroxybenzoate (sodium salicylate), sodium 2,5-dihydroxybenzoate (sodium gentisate), and the sodium salts of 2,4-dihydroxy- and 2,6-dihydroxybenzoic acid and of 2,4,6-trihydroxybenzoic acid have been used as alternative solubilizers of etoposide. The weakest and strongest interactants with etoposide were, respectively, sodium benzoate and sodium 2,4,6-trihydroxybenzoate. The effect of mono- and dihydroxybenzoates on etoposide solubility was intermediate. Although sodium 2,4,6-trihydroxybenzoate is the most efficient solubilizer, its use is limited by its own low aqueous solubility. The effect of sodium salicylate and other formulation ingredients on the in vitro protein binding and precipitation of etoposide upon dilution with normal saline and human plasma has been studied. Etoposide binds to the extent of 94% to human serum albumin (HSA) and human plasma, but only 24% to bovine serum albumin (BSA) in vitro. Sodium salicylate significantly decreased the binding of the drug to both HSA and human plasma, whereas the components of Vepesid did not. Dilution of Vepesid (1:2 and 1:3) with plasma in vitro resulted in immediate precipitation, while the corresponding dilutions of etoposide aqueous solution (20 mg/mL in 2 M sodium salicylate) produced no precipitate for the first hour.

Chemistry, Pharmaceutical↗
PubMed1992

Rate-limiting steps in oral absorption of a leucotriene D4 antagonist in the beagle dog.

Oral administration of a leucotriene D4 antagonist drug (1) in the Beagle dog at doses of 2, 20, 100, 300, and 800 mg/kg resulted in dose-dependent bioavailability values (4-50%). To understand the dose dependence of the absorption of 1 in the dog, initial rates of absorption of 1, which were estimated from Loo-Riegelman analysis of the concentration in blood data, were analyzed in terms of dissolution and absorption rates. From the Loo-Riegelman plots, the initial rates of absorption of 1 were estimated as 8.2, 41.9, 41.1, 76.1, and 72.8 micrograms.mL-1.h-1, respectively, for the doses given earlier. These data, which indicate leveling of the initial absorption rates at high doses, were consistent with an absorption model in which the dissolution rate is the rate-controlling step in the intestinal absorption of 1 at doses less than 100 mg/kg. The powder dissolution rate of 1 in 17 mM bile salt solution was estimated as 14 and 700 micrograms.mL-1.h-1 for amounts of 1 equivalent to the amounts given to dogs at 2- and 100-mg/kg doses, respectively. After consideration of the volume of distribution and the volume of intestinal fluid in the dog, the value of the initial dissolution rate was much lower than the initial absorption rates at the 2-mg/kg dose. Oral administration of 1 at 2 mg/kg in a 3% polysorbate 80 solution enhanced both the rate and the extent of absorption of the compound. These results confirm the validity of the conclusion that the intestinal absorption of 1 is limited by dissolution rate at low doses.

Administration, Oral↗
PubMed1992

Epithelial transport of drugs in cell culture. VII: Effects of pharmaceutical surfactant excipients and bile acids on transepithelial permeability in monolayers of human intestinal epithelial (Caco-2) cells.

The effects of anionic (sodium dodecyl sulfate and sodium dioctyl sufosuccinate) and nonionic (polysorbate 80 and polyoxyl 40 hydrogenated castor oil) synthetic surfactants and bile acids (sodium taurocholate, sodium taurodeoxycholate, and sodium taurodihydrofusidate) on epithelial integrity were studied in monolayers of human intestinal epithelial (Caco-2) cells grown on microporous polycarbonate filters. The effects of the surfactants on intracellular enzyme activity, cell monolayer permeability, and morphology were studied. The effects on permeability were studied by two methods: measurements of transport of marker molecules (mannitol and polyethylene glycol) and measurements of transepithelial electrical resistance. All surfactants demonstrated concentration-dependent effects on intracellular enzyme activities, permeability, and morphology. The effects of the anionic surfactants were more pronounced than those of the nonionic surfactants. The effects on transepithelial electrical resistance correlated with intracellular dehydrogenase activity. Fluxes of marker molecules were the most sensitive measure of epithelial integrity. The results indicate that the hydrophilic marker molecules permeate the epithelial monolayers through different pathways at different concentrations of the surfactants. The effects of the surfactants were reversible at intermediate concentrations, even though the morphology of the monolayers had changed. The results agree with published data obtained with experimental animals and indicate that Caco-2 cells can be used to study the concentration-dependent effects of surfactants and other pharmaceutical additives on intestinal epithelial permeability.

Bile Acids and Salts↗
PubMed1995

Antitumor efficacy of taxane liposomes on a human ovarian tumor xenograft in nude athymic mice.

Taxanes such as paclitaxel (Taxol) and docetaxel (Taxotere) are promising agents for use against ovarian cancer and other malignancies. Recently, SB-T-1011, a semisynthetic taxane, has been prepared from 14-hydroxy-10-deacetylbaccatin III. SB-T-1011 shows similar or greater in vitro cytostatic activity than paclitaxel, depending on the tumor cell line. The administration of taxanes is problematic due to their low solubility in most pharmaceutically acceptable solvents; formulations used clinically contain Cremophor/ethanol (diluent 12) or polysorbate 80/ethanol, excipients which may cause serious adverse effects. To eliminate these vehicles, we have prepared paclitaxel liposome formulations. The objective of the present work was to evaluate the antitumor activity of paclitaxel and two semisynthetic analogs in Cremophor-based and liposomal formulations. Antitumor activity was evaluated against A121a, a taxane-sensitive human ovarian tumor, growing as subcutaneous xenografts in athymic nude mice. Free and liposomal formulations of each taxane showed similar antitumor effect. The antitumor activity of paclitaxel and SB-T-1011 was similar, and docetaxel was more potent than either paclitaxel or SB-T-1011. Overall, taxane liposomes were better tolerated and more easily administered iv than taxane formulated in Cremophor/ethanol.

Animals↗
PubMed1984

Novel accessory skull bone in fetal rats after exposure to aspirin.

Aspirin was administered by oral gavage to 25 gravid Sprague-Dawley rats on gestation day 10, as a single dose of 500 mg/kg, in a concentration of 50 mg/ml. The aspirin was suspended in a mixture of 0.5% w/v hydroxypropylmethylcellulose (Methocel E-4M) and 0.1% w/v polysorbate 80 (Tween 80). A control group of 25 gravid rats was given 10 ml/kg/day of the suspending vehicle alone, by oral gavage, on gestation days 6 through 15. C-sections were performed on gestation day 20. Approximately two-thirds of the fetuses were processed for skeletal examination with Alizarin Red S; the remaining fetuses were placed in Bouin's solution. Examination of the fetal skeletal specimens from the aspirin-treated group revealed a 20% fetal (43% litter) incidence of an accessory skull bone, located between the nasal and frontal bones. This structure ranged in size from a small, barely discernible, circular ossification site (less than 0.5 mm) to a relatively large, bilobate bone (approximately 2 mm). This anomaly has not been previously reported in fetal rats.

Abnormalities, Drug-Induced↗
PubMed1994

Comparative study of the holding strength of slipknots using absorbable and nonabsorbable ligature materials.

The holding and tensile characteristics of five extracorporeal slipknots in relation to absorbable and nonabsorbable ligature materials have been evaluated in a standardized in vitro test rig. The knots studied: Tayside, Roeder, Melzer (modified Roeder), Cross square, and Blood knots were tied with the following materials: silk, polyamide, Dacron, polydioxanone (PDS), and lactomer (Polysorb). Following construction and slippage (run down) to a fixed-diameter loop around a cylinder, the knots were locked (tightened) using a standardized force after which they were removed from the test rig and subjected to holding strength (force required to induce reverse slippage) and other tensile characteristics (stress, strain, elasticity) by a tensiometer. Analysis of the data has demonstrated the following: (1) The safest slip knots (resist slippage) are the Tayside, Melzer, and Roeder knots tied with lactomer and Dacron. (2) The holding strengths of the Cross square and Blood knots are weak with all ligature materials tested. (3) Polydioxanone is a safe ligature material for the Melzer and Tayside but not the Roeder knot. (4) Extracorporeal slipknots tied with silk and polyamide are less secure than the equivalent knots tied with Dacron, lactomer, and polydioxanone.

Insect Proteins↗
PubMed1994

Clinical and pharmacokinetic overview of parenteral etoposide phosphate.

Etoposide phosphate (Etopophos, BMY-40481) is a water-soluble derivative of the widely used podophyllotoxin etoposide (VP-16). The phosphate ester renders the compound water-soluble, eliminating the need for formulation in polysorbate (Tween) 80, ethanol, and polyethylene glycol. As a result the compound can be given at high concentrations and as a bolus. In animals and in vitro, etoposide phosphate (EP) is rapidly and completely converted to VP-16. Clinical development of the i.v. formulation has focused on the identification of the maximum tolerated dose (MTD) and pharmacokinetic characteristics of the drug using a 5 daily dose schedule and a days 1, 3, and 5 schedule, with the drug being given over 30 or 5 (bolus) min. Myelosuppression was dose-limiting. Data from these trials show the rapid and complete conversion of EP to VP-16, a pharmacokinetic/pharmacodynamic relationship for myelosuppression and exposure to VP-16, and an MTD of 100 and 150 mg/m2 (molar equivalent to VP-16) when EP is given daily for 5 days and on days 1, 3, and 5, respectively. A formal randomized trial has been conducted to show the pharmacokinetic comparability of EP and VP-16. In this trial, exposure to VP-16 was the same after the parenteral administration of equimolar doses of EP or VP-16. The feasibility of bolus dosing and treatment at high concentrations has been demonstrated, with no effects on the cardiovascular system being noted. Parenteral EP is pharmacokinetically and biologically equivalent to VP-16 and has the advantages of the elimination of potentially toxic excipients; more convenient administration; and ability to be given as a bolus, at high concentrations, and as a continuous infusion.

Animals↗