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PubMedDate not supplied

Radiometric studies of Mycobacterium lepraemurium.

The radiometric method has been applied for studying the metabolism of M. lepraemurium and the conditions which might force or inhibit its metabolic activity in vitro. These organisms assimilate and oxidize (U-14C) glycerol, and (U-14C) acetate, but are unable to oxidize (U-14C) glucose, (U-14C) pyruvate, (U-14C) glycine and 14C-formate. When incubated at 30 degrees C M. lepraemurium oxidizes (U-14C) acetate to 14CO2 faster than 37 degrees C. The smae effect was observed with increasing concentrations of polysorbate 80 (Tween 80), or the 14C-substrate. No change in metabolic rate was observed when the organisms were kept at -20 degrees C for 12 days. Although tried several times, it was not possible to demonstrate any "inhibitors" of bacterial metabolism in the reaction system. The radiometric method seems to be an important tool for studying metabolic pathways and the influence of physical and biochemical factors on the metabolism of M. lepraemurium in vitro.

Acetates↗
PubMed1993

Studies on the reliability of a novel absorption-lipophilicity approach to interpret the effects of the synthetic surfactants on drug and xenobiotic absorption.

Some theoretical principles of the absorption/lipophilicity approach, which attempts to explain the effects of the synthetic surfactants on xenobiotic and drug intestinal absorption, are reviewed and experimentally checked by examining the correlations obtained between "in situ" absorption constants, ka, found in rat colon, and "in vitro" lipophilicity indexes, K', for two compound series (secondary aliphatic amines and phenylalkylamines) in the absence and in the presence of the nonionic surfactant Polysorbate 80, in the intestinal perfusion fluid. Evidence is given for the following actions of the synthetic surfactant: at its critical micelle concentration (CMC), it increases the polarity of the absorbing membrane and, at the same time, it disrupts the aqueous stagnant diffusion layer adjacent to the mucosal barrier. When a supramicellar concentration (SMC) is used, the above actions are almost totally masked by the micellar solubilization of the tested amines, which decreases their absorption constants relative to those found at CMC, as markedly as solute lipophilicity increases. As a consequence of these actions, the correlations between ka and K', which are clearly hyperbolic in free solution, become potential in the presence of the surfactant at its CMC, whereas at SMC a bilinear correlation is obtained. Absorption via lipophilic ionized species seems to take place for both compound series. Mathematical and physicochemical interpretations of this behaviour are outlined, and biopharmaceutical implications of these phenomena are discussed.

Amines↗
PubMed1993

Permeation mechanisms through artificial lipoidal membranes and effects of synthetic surfactants on xenobiotic permeability.

Through the use of permeation/lipophilicity correlations, the mechanisms of permeation of selected test compounds across artificial lipoidal membranes of the polysiloxane type, in the absence and in the presence of a nonionic surfactant (Polysorbate 80), are investigated, in order to design "in vitro" conditions and features suitable for reproducing "in vivo" intestinal absorption tests, as well as to validate some conclusions arising from "in situ" rat gut experiments about the effects of the synthetic surfactants on drug and xenobiotic absorption processes. Six 4-alkylanilines showing a perfect homology were used as test compounds. The reported results clearly show that the in situ biophysical absorption (diffusion) models are completely reproduced by in vitro tests, provided that perfect sink conditions are achieved. Further selection of artificial membrane polarity should be necessary, however, in order to exactly equalize in vitro and in situ permeation rates. As far as the synthetic surfactant action on permeability is concerned, our conclusions are similar to those drawn from in situ studies, except that the effect of the surfactant on membrane polarity is much smaller and the micelle-solubilizing effect somewhat larger. The disruption of the aqueous stagnant diffusion layers adjacent to the membranes by the surfactant has been conclusively demonstrated. A clear first-element deviation for aniline, which prevents its inclusion as a term of the tested series, has been observed; this feature should be borne in mind whenever any in vivo/in vitro correlation has to be established.

Absorption↗
PubMed1979

Evaluation of pseudorabies viral antigens in the agar gel immunodiffusion test.

Procedures designed to extract pseudorabies viral (PRV) antigens from PRV-infected tissue cultures were investigated to determine whether differences in extraction method had an effect upon the final concentrated antigenic product. All four of the preparations made from PRV-infected tissue culture cells (trypsin extract and disrupted cells) or entire PRV-infected cultures (polysorbate 80 extract and (NH4)2SO4 precipitate) contained relatively large amounts of the same antigen, whereas cell-free PRV-infected tissue culture fluids did not contain significant amounts of this antigen. Specific antibody directed against this antigen was present in all PRV antisera tested. Two other antigens were observed in some of the preparations, but PRV antisera varied in their ability to precipitate with these antigens. Therefore, the number of precipitation lines observed in agar gel immunodiffusion between PRV preparations and PRV-positive antisera depended both upon the extraction method used to obtain the antigen and upon the specificity of the selected antiserum.

Ammonium Sulfate↗
PubMed1980

Inhibition of prostaglandin-induced iritis. Topical indoxole vs indomethacin therapy.

Rat eyes pretreated with 10 microL of topically applied indoxole or 14C-indomethacin, both drugs as 0.5%, 1.0%, and 2.0% solutions in polysorbate 80, were subjected 60 minutes later to an intravitreal injection of 5 microL of 5.0% sodium arachidonate. Following a 30-minute interval, the iris vascular pattern was photographed under the same standardized conditions as in the preinjection control photographs. Comparison of the average diameters of preselected vessels showed indoxole to be more effective than indomethacin in inhibition of iris vascular dilation at all concentrations tested. Intracameral unbound indomethacin concentration was a whole order higher than that of indoxole after comparable doses. The difference in relative effect of the two drugs is neither a function of aqueous concentration nor of aqueous protein binding.

Animals↗
PubMed1997

Effects of various chemical sterilization methods on the crosslinking and enzymatic degradation characteristics of an epoxy-fixed biological tissue.

Due to the nature of bioprostheses, which are mainly biological tissues that cannot be sterilized with heat or irradiation, the sterilization method by choice is generally liquid chemicals. It is known that a number of liquid chemicals can have rapid germicidal effect and can be used to sterilize bioprostheses. The study was to evaluate the effects of various chemical sterilization methods on the crosslinking and enzymatic degradation characteristics of an epoxy-fixed biological tissue. The chemical sterilants employed were: a 70% ethanol solution (EtOH), a 2% epoxy compound + 20% ethanol solution (EX-810), a 2% propylene oxide + 20% ethanol solution (PO), and a 0.625% glutaraldehyde + 20% ethanol + 0.2% polysorbate solution (GA). Both masking and crosslinking of the free amino groups within the epoxy-fixed tissue were observed subsequent to sterilization with GA or EX-810. This improved the resistance of the GA or EX-810 sterilized tissues against collagenase degradation as compared to its nonsterilized counterpart. However, subsequent to sterilization with PO, only masking of the free amino groups within the epoxy-fixed tissue was noted. The inhibition of the collagenase degradation by masking of the free amino groups was traded off by the more random molecular packing of the PO sterilized sample due to the introduction of the side branches. Sterilization of the epoxy-fixed tissue with EtOH may increase its denaturation temperature and tensile strength, while neither masking nor crosslinking of free amino groups within the tissue took place. The resistance to degradation of the EtOH sterilized tissue, however, did not improve as compared to its nonsterilized counterpart.

Bioprosthesis↗
PubMed1998

Influence of surfactants on oral bioavailability of albendazole based on the formation of the sulphoxide metabolites in rats.

The influence of two surfactants, sodium taurocholate (STC) and polysorbate 80 (P80), on the bioavailability of albendazole (ABZ), orally administered to rats, has been studied. To assess the effect of the surfactants, they were administered at critical micellar and supramicellar concentrations, 5 and 10 mM for STC and 0.0022 and 0.22% for P80, along with a subclinical dose of 5 mg kg-1 of ABZ. Doses of 5 and 10.6 mg kg-1 ABZ were also administered as controls. The results show an increase in the sulphoxide AUC values: 55% in the STC 5 mM and 88% in the STC 10 mM and P80 0.0022% treatments when compared to the control ABZ 5 mg kg-1 dose. MRT values also show longer-lasting plasma albendazole sulphoxide concentration following these three treatments, particularly for the P80 0.0022% treatment. While there was no change in the apparent rate of formation of ABZSO, the amount of ABZSO formed was increased significantly by the addition of surfactants (STC 10 mM and P80 0.0022%).

Albendazole↗
PubMed2000

Identification of a yellow impurity in aged samples of aqueous butamben suspension: evidence for the oxidative degradation of poly(ethylene glycol).

Butamben (butyl p-aminobenzoate) has been formulated to provide long-acting treatment for chronic pain. The suspension, which contains poly(ethylene glycol) and polysorbate 80, was found to yellow under ambient conditions if not adequately protected from oxygen. The impurity responsible for the color was isolated and identified on the basis of nuclear magnetic resonance spectroscopy and mass spectrometry. The compound is an oxalamidine, which is formally the condensation product of oxalic acid with four equivalents of butamben, and may be formed by the reaction of butamben with an oxidation product of poly(ethylene glycol).

Benzocaine↗
PubMed1995

Docetaxel (Taxotere) associated scleroderma-like changes of the lower extremities. A report of three cases.

BACKGROUND: Docetaxel (Taxotere) is a microtubule-stabilizing agent that is potentially important in chemotherapy for a variety of malignancies. METHODS: A clinical study of the cutaneous reactions experienced by a group of patients receiving docetaxel chemotherapy was undertaken. Patients were examined before initiation of therapy, before and after each cycle of therapy, and were followed subsequent to the completion of docetaxel chemotherapy. RESULTS: Three patients developed diffuse lower extremity edema (3-18 kg) and subsequent scleroderma-like changes after receiving multiple cycles of docetaxel therapy. These patients had different underlying malignancies and dissimilar prior therapy. Rheumatoid factor, antinuclear antibodies, anticentromere, and topoisomerase antibodies were not present in any patient. The diffuse lower extremity edema did not resolve with diuretic therapy. Cutaneous biopsies in two patients revealed diffuse sclerosis. One patient had a normal lymphangiogram during the edematous phase. Discontinuation of docetaxel correlated with resolution of edema and softening of the skin. CONCLUSION: The etiology of the scleroderma-like skin changes is unclear but appears to be either a toxic effect of docetaxel or an effect of polysorbate 80 (Tween 80), the vehicle for docetaxel.

Aged↗
PubMed1985

Suppression of hyaluronic acid synthesis in synovial organ cultures by corticosteroid suspensions.

The effects of sparingly soluble corticosteroid suspensions prepared for intraarticular therapy, of their vehicles, and of hydrocortisone on synovial hyaluronic acid (HA) synthesis were compared in organ cultures of normal canine villous synovium. Both hydrocortisone and the corticosteroid suspensions suppressed HA synthesis, as did 2 vehicle components, polysorbate 80 and myristyl-gamma-picrolinium chloride. Cultures of synovium from joints of dogs which, 1 day previously, had been injected with methylprednisolone acetate suspension synthesized less HA than did control cultures from noninjected joints of the same animals. The results indicate that suppression of HA synthesis is a mechanism by which these drugs can act to reduce joint HA content and promote resolution of synovial effusions.

Animals↗
PubMed2000

Comparative pharmacokinetics, safety, and tolerability after subcutaneous administration of recombinant human erythropoietin formulated with different stabilizers.

This report summarizes the results of two double-blind, single-center, randomized studies that used a two-period crossover design. The objective of these two studies was to compare the safety, tolerability, pharmacokinetics, and pain score at the subcutaneous (sc) injection site of a phosphate-buffered recombinant human erythropoietin (EPREX, epoetin alfa, r-HuEPO) formulated with a new stabilizer (glycine and Polysorbate 80) with the commercially available EPREX formulations, which uses human serum albumin (HSA) as the stabilizer. Twenty-four healthy male volunteers were enrolled in each of the two studies. In the first study, subjects received a single 150 IU/kg sc dose of r-HuEPO using the 2000 IU/mL (2K) phosphate-buffered formulation with or without the new stabilizer (12 subjects/group). In the second study, subjects received a single 750 IU/kg sc dose of r-HuEPO using the 40 000 IU/mL (40K) phosphate-buffered formulation with or without the new stabilizer (12 subjects/group). In each study, r-HuEPO was administered over two separate dosing periods, each separated with a 28-day washout period. There were no significant differences in AUC and C(max) for either strength of r-HuEPO formulated with or without the new stabilizer, indicating that the absorption and disposition characteristics of the two formulations were similar after sc administration. Both r-HuEPO strengths with and without the new stabilizer were safe and well tolerated; the safety and tolerability profiles of both formulations for each r-HuEPO concentration were comparable. There were no statistically significant differences in pain score for either strength of r-HuEPO with and without the new stabilizer. It was concluded that the two phosphate-buffered r-HuEPO concentrations formulated with and without the new stabilizer are pharmacokinetically equivalent.

Adolescent↗
PubMed2003

Large-scale propagation of a replication-defective adenovirus vector in stirred-tank bioreactor PER.C6 cell culture under sparging conditions.

Large-scale propagation of replication-defective adenovirus vectors has not been well studied to date. One of the challenges for efficient propagation at large scale is to overcome the sensitivity of virus infected cells to gas sparging required for oxygenation and CO(2) removal. In our initial experiments, it was observed that productivity of an adenovirus vector was significantly reduced under sparging conditions as compared to nonsparged, i.e., surface-aerated controls in serum-free cultures. Investigations led to the identification of a buffer containing surfactant (Polysorbate-80, PS-80) that was included in the virus seed stock formulation and introduced through virus infection into the culture at a very low concentration as the cause of the reduced virus productivity. This finding was not obvious and trivial, as neither uninfected sparged nor infected nonsparged PER.C6 trade mark cells in serum-free cultures were affected by the buffer at such a low PS-80 concentration of 0.00025% (v/v), which is a common component of serum-free cell culture media. These results strongly suggest that virus-infected cells behave very differently from uninfected cells under sparging conditions. To mitigate the deleterious effects of sparging, the virus seed stock was prepared in the absence of the buffer containing PS-80. At the same time, the concentration of Pluronic-F68 (PF-68) in the serum-free medium was increased to 1 g/L, at which cell growth and metabolism were unaffected, even though this measure alone did not result in virus productivity improvement. Only by implementing the two measures together was virus productivity loss completely eliminated under sparging conditions. After demonstration of the process robustness in 2-L bioreactors, this adenovirus propagation process was successfully scaled up to 250 L in a 300-L bioreactor under the worst-case sparging conditions projected for 10,000-L scale.

Adenoviridae↗
PubMed2002

Spray-freeze-drying for protein powder preparation: particle characterization and a case study with trypsinogen stability.

This work investigates the use of spray freeze-drying (SFD) to produce protein loaded particles suitable for epidermal delivery. In the first part of the study, the effects of formulation and process conditions on particle properties are examined. Aqueous solutions of trehalose produce SFD particles in the size range 20-80 microm, with a smooth, textured surface, but having high internal porosity. The latter was visualized using SEM and a novel particle embedding and sectioning technique. Use of an annealing step during the freeze-drying cycle caused the particles to shrink, reducing hereby porosity and also the measured rate of moisture uptake into these amorphous particles. SFD pure mannitol was approximately 40% amorphous, but not hygroscopic. Incorporation of dextran 37,500 into a combined amorphous trehalose/mannitol formulation led to increased particle shrinkage and lower particle porosity on annealing. The model protein trypsinogen lost approximately 15% activity during SFD of solutions containing 50 mg/mL protein, but was only marginally aggregated (1.4%). It is suggested that trypsinogen forms an irreversible partially unfolded state or molten globule on SFD/rehydration. The pure protein was also partially inactivated without aggregation during atomization into air. Surprisingly, neither activity loss nor aggregation were detected on atomization of the protein solution into liquid nitrogen. Quench-freezing of small droplets may reverse the partial unfolding of trypsinogen occurring on atomization into air. The origin of the trypsinogen inactivation during SFD must therefore be the subsequent freeze-drying step of this multistep process. Isolated freeze drying of trypsinogen produces strong aggregation and equivalent inactivation. This result suggests that trypsinogen behaves differently during freeze drying from frozen droplets and from bulk solution in a vial. In the former case the protein forms an irreversible partially unfolded state, whereas in the latter case aggregates are formed. Trypsinogen inactivation during SFD could be completely prevented by the presence of trehalose in the formulation. Electron Spectroscopy for Chemical Analysis (ESCA) showed a high surface excess of the protein in the SFD particles, which was reduced on inclusion of Polysorbate 80, but not trehalose. Taken together, these results help to elucidate the complex destabilization behavior of trypsinogen during SFD.

Chromatography, Gel↗
PubMed2003

Lecithin-based oil-in-water microemulsions for parenteral use: pseudoternary phase diagrams, characterization and toxicity studies.

Pseudoternary phase diagrams have been constructed to evaluate the phase behavior of systems containing water/lecithin/polysorbate 80/isopropyl myristate at different polysorbate 80:lecithin weight ratios (K(m)). Oil-in-water microemulsion regions were accurately determined and the influence of the K(m) on the area of existence of such disperse systems was also examined. Viscosity studies as well as particle size analysis by dynamic light scattering were carried out on oil-water microemulsions, and the influence of the oil phase content, the total amount of surfactants and K(m) on the rheological behavior, viscosity, and droplet size of such disperse systems was evaluated. All systems studied showed a water-rich isotrope region (oil-in-water microemulsion area), that was seen to be highly dependent upon the surfactant/cosurfactant weight ratio. Most of the microemulsions analyzed showed a non-Newtonian rheological behavior and both, droplet size, and viscosity of the disperse systems, were found to be much more influenced by the total content of oil phase and surfactants present in the microemulsion than by the K(m). The selected system underwent both stability and in vivo acute toxicity studies, and seemed to be highly stable, even at extreme conditions, and very low toxic according to the results obtained.

Animals↗
PubMed2004

Development of stable liquid formulations for adenovirus-based vaccines.

We have evaluated the stability profiles of adenovirus type-5 (Ad5)-based vaccine formulations to identify liquid formulations that are stable during long-term storage at 4 degrees C. By identifying the major physiochemical inactivation pathway(s) during storage, formulations of Ad5 were designed with specific pharmaceutical excipients leading to greatly enhanced stability. For example, results indicate that Ad5 is stabilized by non-ionic surfactants and cryoprotectants as well as excipients known to inhibit free-radical oxidation. A non-ionic surfactant is necessary to prevent adsorption of adenovirus to glass surfaces during storage, and a cryoprotectant is needed to prevent freeze-thaw-induced virus inactivation. In a base formulation (A105) containing sucrose as the cryoprotectant and polysorbate-80 as the non-ionic surfactant, metal-ion catalyzed free-radical oxidation is an important mechanism of Ad5 inactivation. The free-radical oxidation inhibitors ethanol and histidine, combined with the metal-ion chelator ethylenediaminetetraacetic acid (EDTA), were determined to be effective stabilizers of Ad5. Arrhenius plots of stability data are consistent with a first-order inactivation mechanism with apparent activation energies for virus inactivation of 26.5 +/- 0.9 and 28.7 +/- 0.6 kcal/mol in the absence and presence of free-radical oxidation inhibitors, respectively. Optimization of formulation pH, as well as the EDTA and ethanol concentrations, allowed for the identification of formulations that further enhanced long-term storage stability. For example, Ad5 in an optimized liquid formulation (A195) lost <0.1 logs of infectivity after 24 months of storage at 4 degrees C. The immunogenicity of a recombinant Ad5-based human immunodeficiency virus (HIV) vaccine candidate expressing HIV-1 gag (MRKAd5gag) formulated in A195, was shown to be equivalent to the same vaccine formulated in A105. Therefore, the use of EDTA, ethanol, and histidine did not significantly alter the immunogenicity of the vaccine in mice. The identification of 4 degrees C stable liquid formulations should significantly enhance the utility of Ad5 as a vector for vaccines and gene therapy.

Adenoviruses, Human↗
PubMed2004

Determination of P-glycoprotein inhibition by excipients and their combinations using an integrated high-throughput process.

Excipients often used in pharmaceutical formulations have been reported to have inhibitory effects on P-glycoprotein, an important membrane-associated transport protein. Because inhibition of efflux transporters can have an effect on drug bioavailability, identification of these excipients and their extent of inhibition are therefore important for pharmaceutical development. We have developed an automated and integrated high-throughput process for identifying these excipients and their combinations. Common excipients containing polyethylene glycol (PEG) in the chemical structure were screened using a cytotoxic cell growth assay, and excipients giving inhibition were further combined to identify synergistic effects. Our screens identified excipients previously reported to inhibit P-glycoprotein, such as PEG stearates, PEG fatty acid esters, polysorbates, and poloxamers. We also found new excipients, such as those in the PEG glyceryl fatty acid family, which were among the best inhibitors identified. Dose-response studies of these compounds and of cyclosporin A indicated that the extent of inhibition depended logarithmically on the concentration. This suggests a similar mechanism by which inhibition is obtained, despite widely varying chemical structures. In the particular set of combinatorial studies performed, which involved >20,000 samples, we found that inhibitory effects in binary combinations followed the single-excipient logarithmic trend, rather than being synergistic. These experiments showcased the potential for integrated high-throughput processes that enable combinatorial screens which would otherwise be difficult to perform manually.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

A factor analysis for complex systems containing nimesulide.

Binary systems containing Nimesulide and PEG 4000 were prepared by the melting method in the concentration range 3-25% w/w of the drug. The systems are homogeneous in the molten state, while, after cooling, two phases were formed of different density. They were manually separated and separately studied. Upper phases are richer in PEG 4000, while the lower ones contain the drug at levels even higher than those of the starting mixtures. The two phases were examined by DSC and UV techniques; high dissolution rates were observed with upper phases, while lower phases did not display improvement with respect to a physical mixture or micronized drug. With the aim to avoid phase separation, a third component was added to the binary system containing 5% w/w drug, during the melting. The ternary systems were prepared containing sodium dodecyl sulfate, triethanolamine, polysorbate 80, poloxamer, and cetomacrogol: a homogeneous phase was obtained only in two cases (with the addition of sodium dodecyl sulfate and triethanolamine), but only in the presence of triethanolamine dissolution rate was improved. Finally, a factor analysis was performed for complex systems containing a combination of the four additives, each one at two concentrations (1.25 and 2.5% w/w), to evaluate the optimum system in terms of both kinetic and composition parameters. Results suggest that additives affect mainly the physical aspect of the formulation rather than the kinetic behavior, which appears little improved only in a few cases.

Drug Synergism↗
PubMed2005

Stabilization of human papillomavirus virus-like particles by non-ionic surfactants.

Human papillomavirus (HPV) virus-like-particles (VLPs) produced by recombinant expression systems are promising vaccine candidates for prevention of cervical cancers as well as genital warts. At high protein concentrations, HPV VLPs, comprised of the viral capsid protein L1 and expressed and purified from yeast, are protected against detectable aggregation during preparation and storage by high concentrations of NaCl. At low protein concentrations, however, high salt concentration alone does not fully protect HPV VLPs from aggregation. Moreover, the analytical analysis of HPV VLPs proved to be a challenge due to surface adsorption of HPV VLPs to storage containers and cuvettes. The introduction of non-ionic surfactants into HPV VLP aqueous solutions provides significantly enhanced stabilization of HPV VLPs against aggregation upon exposure to low salt and protein concentration, as well as protection against surface adsorption and aggregation due to heat stress and physical agitation. The mechanism of non-ionic surfactant stabilization of HPV VLPs was extensively studied using polysorbate 80 (PS80) as a representative non-ionic surfactant. The results suggest that PS80 stabilizes HPV VLPs mainly by competing with the VLPs for various container surfaces and air/water interfaces. No appreciable binding of PS80 to intact HPV VLPs was observed although PS80 does bind to the denatured HPV L1 protein. Even in the presence of stabilizing level of PS80, however, an ionic strength dependence of HPV VLP stabilization against aggregation is observed indicating optimization of both salt and non-ionic surfactant levels is required for effective stabilization of HPV VLPs in solution.

Calorimetry, Differential Scanning↗