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PubMedDate not supplied

Histamine receptor antagonists and lipid stability in total nutrient admixtures.

Drug stability and compatibility studies should be performed for all medications added to total nutrient admixtures (TNAs) before administration to patients. The stability of TNA components will vary depending on product selection and final concentrations. This variability prohibits generalizing published study results generically to TNAs containing untested products or combinations. Histamine receptor antagonists (H2RAs) are commonly administered by continuous infusion via nutrient solutions. When the delivery vehicle is a TNA, comparative stability and compatibility studies performed under similar test conditions are lacking. The stability of marketed parenteral H2RAs and of the investigational H2RA, nizatidine was analyzed in TNA solutions containing either Liposyn II or Intralipid at differing concentrations. All H2RAs remained at more than 90% of initial concentration at 24 hours. After 48 hours, only ranitidine concentrations fell to less than 90% in all study solutions. Each TNA containing an H2RA was within pH stability ranges for lipid products, and no change in particle size was detected during the 48-hour period. This is the first report determining H2RA compatibility and stability in TNA solutions with both 3% and 5% Intralipid and Liposyn II and using similar methodology for all standard H2RA concentrations. Results suggest that these drugs are stable for 24 hours in TNAs containing either lipid product. Beyond this time, administration of ranitidine may be unreliable because of poor stability under the conditions tested.

Drug Stability↗
PubMed2006

Physical and chemical stability of paclitaxel infusions in different container types.

OBJECTIVES: To determine the physicochemical stability of generic (Teva Pharmaceuticals) paclitaxel infusions (0.3 and 1.2 mg/mL) in 0.9% sodium chloride or 5% glucose in polyolefin (Viaflo), low-density polyethylene (Ecoflac), and glass containers at 2-8 and 25 degrees C. METHODS: Paclitaxel infusions of various concentration/diluent/container combinations were prepared. Containers were light-protected and incubated at test temperatures with further analysis at predetermined intervals of 1-3 days for up to 30 days. Infusions were monitored for pH, weight loss, precipitation, colour change, and subvisual particulates as indicators of physical stability, and assayed for drug concentration to determine chemical stability. RESULTS: Precipitation was the limiting factor. Infusions of paclitaxel (0.3 mg/mL) in 0.9% sodium chloride remained stable for 13, 16 and 13 days at 2-8 degrees C in polyolefin, low-density polyethylene and glass containers, respectively; in 5% glucose for 13, 18, and 20 days, respectively. At 25 degrees C, paclitaxel infusions (0.3 mg/mL) remained stable for 3 days in all diluent/container combinations with the exception of 5% glucose in glass, where stability reached 7 days. Paclitaxel infusions (1.2 mg/mL) in 0.9% sodium chloride remained stable for 9, 12, and 8 days at 2-8 degrees C in polyolefin, low-density polyethylene and glass containers, respectively; in 5% glucose for 10, 12, and 10 days, respectively. At 25 degrees C, paclitaxel 1.2 mg/mL remained stable for 3 days in all diluent/container combinations with the exception of glass, where stability reached 5 days in 0.9% sodium chloride diluent, and 7 days in 5% glucose. CONCLUSION: Paclitaxel stability was influenced by storage temperature, with longer shelf-life at 2-8 degrees C, and also by drug concentration, where 0.3 mg/mL infusions were more stable than 1.2 mg/mL for all diluent/container combinations. Physical stability (precipitation) was the limiting parameter in each case.

Antineoplastic Agents, Phytogenic↗
PubMed2005

Development and application of an automated solution stability assay for drug discovery.

Screening of solution stability provides an early alert on potential liabilities of drug candidates so that strategies can be developed to overcome the challenges. A fully automated solution stability assay has been developed to accelerate traditional manual operation. The assay uses the advanced capabilities of a high-performance liquid chromatography instrument that is present in many pharmaceutical research laboratories. The samples are prepared automatically by a temperature-controlled autosampler. The samples are delivered to the stability matrices, mixed, incubated, and injected at selected time points during the reaction time course. This automated process occurs without operator intervention, thus allowing 96 experiments to be run with 0.5 h of a scientist's time compared to 8 h for the same study when performed manually. Automation not only eliminates the manual operation but also improves accuracy and throughput. The assay protocol has been optimized to achieve homogenous mixing and eliminate carryover. The assay is robust, flexible, and high throughput. It can be used to study stability for a large number of samples under multiple incubation conditions and has a wide range of applications in drug discovery and development, such as screening compound stability in biological assay media, obtaining a stability-pH profile, surveying compound stability in physiological fluids, and performing development forced degradation and excipient compatibility.

Automation↗
PubMed2003

Effect of polyols on the conformational stability and biological activity of a model protein lysozyme.

The purpose of this study was to investigate the stabilizing action of polyols against various protein degradation mechanisms (eg, aggregation, deamidation, oxidation), using a model protein lysozyme. Differential scanning calorimeter (DSC) was used to measure the thermodynamic parameters, mid point transition temperature and calorimetric enthalpy, in order to evaluate conformational stability. Enzyme activity assay was used to corroborate the DSC results. Mannitol, sucrose, lactose, glycerol, and propylene glycol were used as polyols to stabilize lysozyme against aggregation, deamidation, and oxidation. Mannitol was found to stabilize lysozyme against aggregation, sucrose against deamidation both at neutral pH and at acidic pH, and lactose against oxidation. Stabilizers that provided greater conformational stability of lysozyme against various degradation mechanisms also protected specific enzyme activity to a greater extent. It was concluded that DSC and bioassay could be valuable tools for screening stabilizers in protein formulations.

Alcohols↗
PubMed2005

Stabilization of somatropin by heparin.

Somatropin, human growth hormone (hGH), is an unstable protein, posing challenging problems for its formulation and long-term stability. Since hGH formed insoluble adducts with heparin our aim was to evaluate heparin as a stabilizing agent for the drug. These adducts were characterized by particle diameter, tertiary structure variations and release studies. Studies were also carried out to determine the stability of hGH in the presence and absence of heparin by an interfacial denaturation method and real-time stability studies by measuring hGH activity and particle diameter. Moreover, biological activity of hGH and hGH/UH (unfractionated heparin) adducts was identified by daily subcutaneous injections to hypophysectomized rats. There was a decrease in mean hydrodynamic particle diameter of hGH/UH adducts with increased pH (54.4 to 12.2 nm from pH 3 to pH 7) indicating that the adducts were either dissociating or dissolving at high pH. Furthermore, second-derivative spectroscopy indicated that complexation of hGH with heparin did not cause a major disruption in the tertiary structure of hGH but decreased the hydrophilic environment around the tyrosine residues. Release of hGH from hGH/UH adducts was pH and ionic strength dependent with the highest release at pH 8 (93%) and lowest release at pH 3 (0%) over the first hour. Interfacial denaturation methods indicated that vortex agitation over 120 s resulted in no change in the optical density of hGH/UH adducts compared with a substantial increase for hGH alone at pH 6.8. Real-time stability studies over 93 days demonstrated that hGH/UH adducts at both pH 3 and 7 with an excess of heparin produced the highest percent of active hGH remaining in the solution at 4 degrees C and 37 degrees C. The higher stability of hGH/UH adducts with excess heparin compared with the stoichiometric ratio was also confirmed by particle size measurements during storage. The biological activity of these adducts was comparable with hGH alone by weight-gain studies in hypophysectomized rats. The findings suggest the value of using hGH/heparin adducts to stabilize the protein.

Animals↗
PubMed2004

Stability of adenosine deaminase during transportation.

STUDY OBJECTIVE: Measurement of pleural fluid adenosine deaminase (ADA) levels is useful in the differential diagnosis of pleural effusions. However, at ambient temperatures, the levels of this enzyme decline with time. The purpose of the present study was to identify, test, and optimize additives that stabilize ADA, consequently eliminating the need for dry ice or other cold specimen transport media. DESIGN: A preliminary screen of historically proven stabilizing agents for specific proteins demonstrated effectiveness of glycerol for maintenance of pleural fluid ADA levels. Systematic studies for exploitation of the glycerol effect included the following: (1) supplements to the glycerol of promising alternate compounds, (2) long-term stability studies at ambient and elevated temperatures, (3) a field test of an effective mixture as a means for reduction of specimen transport costs, (4) thermal stability studies for optimization of the agents for use at otherwise denaturing temperatures, and (5) inclusion of pleural fluids from patients with a variety of etiologies, including tuberculous pleurisy, in order to gauge the effectiveness of the stabilizing agents on both the high and low molecular weight forms of ADA. RESULTS: A mixture of glycerol and ethylene glycol, each at 5% concentration, maintained pleural fluid ADA levels for at least 21 days at both room temperatures and 37 degrees C. A field test of 32 pleural fluids found that ADA levels in specimens containing this mixture, sent to the laboratory by surface mail at ambient temperatures, were nearly identical to those in aliquots of the same fluids shipped over dry ice. The bias in the measurement was 0.49 IU/L, with a precision of 2.49 IU/L. The correlation coefficient between the two measurements was 0.97. Thermal stability studies found that tuberculous pleural fluids containing 10% glycerol and 0.10 mol/L sodium sulfate maintained constant ADA levels for at least 10 days at 45 degrees C, an otherwise denaturing temperature for nonstabilized specimens. CONCLUSION: The addition of stabilizing agents to pleural fluid specimens allows the transport of those specimens to distant laboratories at ambient temperatures without a decline in the ADA levels. Employment of those agents will decrease the cost of the test and facilitate its use in second- and third-world countries.

Adenosine Deaminase↗
PubMed2000

Effect of cyclodextrins on the solubility and stability of a novel soft corticosteroid, loteprednol etabonate.

To increase the aqueous solubility and stability of the soft corticosteroid loteprednol etabonate (LE), drug complexation using various cyclodextrins (CDs), such as gamma-cyclodextrin (gamma-CD), 2-hydroxypropyl-beta-cyclodextrin (HPBCD), maltosyl-beta-cyclodextrin (MBCD), mixture of glucosyl/maltosyl-alpha-, beta-, and gamma-cyclodextrin (GMCD), and heptakis (2,6-di-O-methyl)-beta-cyclodextrin (DMCD), were attempted. The solubilizing and stabilizing effects of CD by itself or combined with various co-solvents were also investigated. Micronized (5 micron) LE was mixed in various aqueous CD or CD with cosolvent solutions. After equilibration and filtration at 23 degrees C, the solubility of LE was determined by HPLC. Subsequently, the stability of LE in the solutions was also determined by following the LE concentration change in the solution for an appropriate period. CD complexation significantly increased the aqueous solubility and stability of LE. The increase in solubility displayed a concentration dependency on CDs (0-50%). Among the five CDs used, DMCD showed the highest effects on the solubility (4.2-18.3 mg/ml in 10-50% DMCD) and stability (t90 > 4 years at 4 degrees C, when LE 0.5 mg/ml was dissolved in 10% DMCD solution) of LE. By adding co-solvents, such as glycerol, propylene glycol (PG), polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP-10), the solubility of LE in DMCD solutions was further increased. Degradation of LE to the corresponding metabolites, delta 1-cortienic acid etabonate (AE) and delta 1-cortienic acid (A), in aqueous CD solutions appeared to be a predicted, two-step kinetics. Differential Scanning Calorimetry (DSC) was used to assist explaining the solubilizing and stabilizing activity differences between CDs. LE/CD mixture or lyophilized LE/CD complex was scanned at a rate of 20 degrees C/min. The exothermic peak found in the DSC diagram with LE/DMCD sample, but not with LE/HPBCD samples, suggests a stronger complex formed between LE and DMCD, resulting in higher solubility and stability of LE in DMCD than in HPBCD.

Androstadienes↗
PubMed2003

Effects of nonionic surfactants on the physical stability of immunoglobulin G in aqueous solution during mechanical agitation.

The objective of this study was to evaluate the influence of nonionic surfactants in the presence of glycine and sodium chloride on the physical stability of immunoglobulin G (IgG) in aqueous solution. Among surfactants suitable for parenteral preparation, Polysorbate 80 (Tween 80) and Polyoxyl 35 Castor Oil (Cremophor EL) were selected. The physical stability of IgG in the absence and in the presence of excipients was investigated in aqueous solution during mechanical agitation (concentration of IgG 15%; pH 7.1; temperature 6 +/- 2 degrees C). Suitable concentrations of Tween 80 and Cremophor EL were experimentally determined by surface tension measurements at 6 +/- 2 degrees C. Glycine and sodium chloride were used in different concentrations. The influence of the excipients on the physical stability of IgG in solution has been examined by surface tension measurements, protein content assay (Kjeldahl and HPLC) and differential scanning calorimetry (DSC). Based on the results of the investigations, it was found that Tween 80 and Cremophor EL, used in experimentally determined critical micelle concentration (cmc), decreased the physical stability of IgG in solution. Tween 80 and Cremophor EL in the presence of glycine (1.5 g/l) could stabilize the IgG in solution during mechanical agitation. The comparison of the effects of Tween 80 and Cremophor EL on the physical stability of IgG, showed that Tween 80 had better stabilization effects on IgG in solution under the experimental conditions selected.

Calorimetry, Differential Scanning↗
PubMed1992

Stabilization of human neutrophil NADPH oxidase activated in a cell-free system by cytosolic proteins and by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide.

The superoxide-generating respiratory burst oxidase (NADPH oxidase) from human neutrophils can be activated in a cell-free system consisting of plasma membrane and cytosol by anionic amphiphiles such as sodium dodecyl sulfate and arachidonate (McPhail, L. C., Shirley, P. S., Clayton, C. C., and Snyderman, R. (1985) J. Clin. Invest. 75, 1735-1739; Curnutte, J. T. (1985) J. Clin. Invest. 75, 1740-1743; Bromberg, Y., and Pick, E. (1984) Cell. Immunol. 88, 213-221). Herein, the activity thus obtained is shown to be very labile at 37 degrees C. The rate of inactivation varied inversely with cytosol concentration. The stabilizing factor(s) was destroyed by heat and trypsin, indicating that it is protein in nature. Whereas cytosol from normal cells and from a chronic granulomatous disease patient lacking p67phox stabilized the oxidase activity, that from a chronic granulomatous disease patient lacking p47phox did not. Also, dialdehyde NADPH-treated cytosol showed no stabilizing effect, indicating that p47phox and a putative NADPH-binding component both participate in stabilization. The mechanism of inactivation was further explored by examining the stabilizing effect of agents that can act as chemical cross-linkers. Of several tested, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) was the most effective, but others that utilize different chemical mechanisms were also partially effective. EDC extended the half-life at 37 degrees C from 2 to 120 min, protected against the inactivating effects of Triton X-100 and high salt, and did not affect the Km for NADPH. Stabilization required prior activation in the presence of both cytosol and membrane; and EDC treatment of cytosol, membrane, or a mixture of the two prior to the addition of sodium dodecyl sulfate failed to induce stabilization. EDC eliminated the requirement for the continuous presence of cytosol and activator. Dialysis did not cause a loss in activity, whereas control activity was diminished with dialysis and was largely restored with added sodium dodecyl sulfate. In the absence of EDC, the separation of cytosol from the membrane fraction resulted in a significant loss of activity, which was largely restored by the addition of cytosol. However, EDC treatment allowed the isolation of a nearly fully active oxidase in the membrane fraction, the activity of which was not influenced by added cytosol. These results support a model in which the active NADPH oxidase consists of a dissociable complex among membrane and cytosolic components and indicate that the longevity of the activated state requires continuous association of these components.

Cell Membrane↗
PubMedDate not supplied

Statistical evaluation of stability data: criteria for change-over-time and data variability.

In a recently issued ICH Q1E guidance on evaluation of stability data of drug substances and products, the need to perform a statistical extrapolation of a shelf-life of a drug product or a retest period for a drug substance is based heavily on whether data exhibit a change-over-time and/or variability. However, this document suggests neither measures nor acceptance criteria of these two parameters. This paper demonstrates a useful application of simple statistical parameters for determining whether sets of stability data from either accelerated or long-term storage programs exhibit a change-over-time and/or variability. These parameters are all derived from a simple linear regression analysis first performed on the stability data. The p-value of the slope of the regression line is taken as a measure for change-over-time, and a value of 0.25 is suggested as a limit to insignificant change of the quantitative stability attributes monitored. The minimal process capability index, Cpk, calculated from the standard deviation of the regression line, is suggested as a measure for variability with a value of 2.5 as a limit for an insignificant variability. The usefulness of the above two parameters, p-value and Cpk, was demonstrated on stability data of a refrigerated drug product and on pooled data of three batches of a drug substance. In both cases, the determined parameters allowed characterization of the data in terms of change-over-time and variability. Consequently, complete evaluation of the stability data could be pursued according to the ICH guidance. It is believed that the application of the above two parameters with their acceptance criteria will allow a more unified evaluation of stability data.

Drug Stability↗
PubMed2004

[Examination of the stability of hydrogen peroxide solutions].

Reliable stabilization of the pharmaceutical preparation and the active ingredient remains one of the most important problems of world pharmacy because pharmaceutical preparations are not systems which are stable without limitation. The patient must receive a quality drug and that is why the question of stability is paid grest attention to not only in research and development, industrial manufacture, but also in distribution. The measure of stability is the expiration period. Diluted solution of hydrogen peroxide (3% solution) still belongs to the most widely used and at the same time the most easily accessible disinfectants. In practice it is common both in Slovakia and abroad. It is used in several concentrations. One of its most important disadvantages is its limited stability, which markedly decreases its expiration period. The present paper investigates the stability of hydrogen peroxide solutions of routinely used concentrations (3%, 6%, and 10%) without and with a stabilizing additive (phenacetin) prepared in the pharmacy and stored under different conditions for the period of their expected usability. The content of hydrogen peroxide was assayed by the pharmacopoeial method in 7-day time intervals. All concentrations of 3%, 6%, and 10% hydrogen peroxide were found to fulfil the conditions for stability in the period of time under study. Their concentration did not fall below the limit od 90% of the content of the active ingredient, and storage under decreased temperature proved to be more suitable. Storage of hydrogen peroxide in the light is inadmissible. When the conditions of storage are observed, the required therapeutic effect of hydrogen peroxide solution can be expected for the period of three months.

Drug Stability↗
PubMedDate not supplied

Long-term stabilization of a new freeze-dried and albumin-free formulation of recombinant human interferon alpha 2b.

In this work, we evaluate the stability of a new freeze-dried and albumin-free formulation of recombinant human IFN alpha 2b (rhIFN-alpha2b) to be used in humans. The freeze-dried, albumin-free formulation was stored at the recommended temperature of 4 degrees C, and under accelerated storage conditions (28 degrees C). The stability of this product was also compared with the stability of a liquid albumin-free formulation of this cytokine. Finally, the stability of the freeze-dried albumin-free formulation was examined after reconstitution and storage at 4 degrees C and room temperature (28 degrees C) for 30 days. Samples were periodically subjected to biological activity assay (antiviral titration), reversed phase high-performance liquid chromatography (RP-HPLC), pyrogens, sterility and enzyme-linked immunosorbent assay (ELISA) testing, abnormal toxicity screening, organoleptic evaluation, and measurement of residual moisture and pH. Accelerated storage (28 degrees C) data for the freeze-dried albumin-free formulation showed biochemical stability of the active ingredient throughout the 6-month study, showing activity between 85 and 125% of its nominal value. RP-HPLC-determined purity showed that rhIFN-alpha2b remained above 95%. Additionally, the formulation was non-pyrogenic, non-toxic, sterile, and organoleptically acceptable. The real-time storage data confirmed the good biochemical long-term (30 months) stability of the freeze-dried formulation of this cytokine. Comparison with the liquid rhIFN-alpha2b albumin-free preparation showed that the freeze-dried albumin-free formulation maintained the stability of the active ingredient better than the liquid preparation. The formulation was also stable after reconstitution and storage at 4 degrees C and 28 degrees C, for 30 days.

Albumins↗
PubMed1991

Enhanced stability of subtilisin by three point mutations.

This study was undertaken to characterize the effect of three point mutations made on aprA-subtilisin on the stability of the protein to both heat- and detergent-induced denaturation. Asparagine residues at positions 109 and 218 were replaced with serine residues to prevent the possible cyclization between these asparagines and the adjacent glycine residues and hence to increase the long-term stability. The effect of these substitutions on conformational stability was examined by thermal denaturation. At high calcium concentrations, the Ser109-substituted analog showed a 3 degrees C higher transition temperature than that of aprA-subtilisin, while the Ser218 substituted analog had a 4 degrees C higher transition temperature. The analog with both changes had a 7 degrees C higher transition temperature than that of the original aprA-subtilisin, indicating that the contributions of the individual mutations were additive. The analog with both mutations also exhibited increased stability in the presence of sodium dodecyl sulfate (SDS) when compared to aprA-subtilisin. In addition to the above two mutations, the asparagine at position 76, located in the high affinity Ca(2+) binding loop of subtilisin, was changed to aspartic acid. The effect of this mutation on the thermal stability of the protein was examined at different calcium concentrations. The analog with all three mutations exhibited little dependence on calcium concentration below 1 mM levels, while the proteins without the mutation at asparagine-76 displayed a strong dependence of melting temperature on Ca(2+) concentration in this range. At much higher calcium concentrations, the analog with three mutations showed an increase in stability similar to that observed with aprA-subtilisin. The analog with three mutations also exhibited greater stability to SDS-induced denaturation than both aprA-subtilisin and the Ser109- and Ser218-substituted analogs. The activation energy barrier for loss of structure in 1% SDS for the analog with all three mutations was increased over that for aprA-subtilisin by 16 kcal/ml. These results suggest that the mutation of asparagine-76 to aspartic acid increases the affinity of the primary Ca(2+) binding site.

Circular Dichroism↗
PubMed1979

[Stability of glucose-6-phosphate dehydrogenase in human cells cultivated in vitro].

It was shown that the thermal stability of glucose-6-phosphate dehydrogenase in human diploid cells is much higher than in human heteroploid cell lines HeLa and T-9. The purified enzymes from human diploid cells and from HeLa and T-9 cells possess similar thermal stabilities. Mixing of T-9 extracts with the purified enzyme preparations revealed that the non-stability factors of the dehydrogenase are present in the T-9 extracts. An addition of NADP- and NADPH-containing buffers and crystalline NADP to the heteroploid cell extracts stabilizes the enzyme. The thermal stability of the enzyme from "in vitro" cultivated human cells depends on the concentration of the coenzyme. It was also demonstrated that glucose-6-phosphate dehydrogenase stability in HeLa and T-9 extracts is the same at low concentrations of the coenzyme and after addition of crystalline NADP. However, at NADP concentration of 10(-3) M the enzyme stability in HeLa and T-9 extracts is different. It is assumed that the destabilizing factors are the enzymes possessing the nucleotidases activity, which is different in various cell lines.

Buffers↗
PubMed1994

[Native, modified, and immobilized chymotrypsin in chaotropic media. Stabilization limits].

To stabilize alpha-chymotrypsin against irreversible thermal inactivation at high temperatures, methods of covalent modification and multi-point immobilization in combination with the addition of salting-in compounds were used. The upper limit of the protein stability proved to be the same for a combination of the modification and salting-in media and for each of these methods separately. The limit of stabilization reached by means of covalent immobilization is higher than the limit of stabilization reached by two other methods. The greatest stabilization of immobilized alpha-chymotrypsin by the salting-in media (a 10000 fold increase in the native enzyme's stability level) takes place only in the case of the protein with the minimum number of bonds with the support. Stabilization of the enzyme by these methods is explained in terms of the suppression of the conformational inactivation processes.

Chymotrypsin↗
PubMed1976

Stability of injection solutions of vitamin B1 Part 1: Influence of chelating agents.

The chelating agents EDTA, DTPA and HEDTA increase the stability of thiamine hydrochloride solutions. The stabilizing efficiency of HEDTA and DTPA is highly superior to that of EDTA. There is an optimum concentration of EDTA at which its stabilizing effect is maximum; beyond this concentration, the stability of the vitamin decreases gradually by increasing EDTA concentration. EDTA at a comparatively high concentration (10 mmole/1) catalyzes thiamine degradation. The stabilizing action of DTPA increases gradually as a function of its concentration. On the other hand, HEDTA in a very low concentration (0.5 mmole/1) affords a definite inhibitory effect on the rate of thiamine cleavage. However, increasing HEDTA concentration from 0.5 up to 3.0 mmole/1 does not increase its stabilizing efficiency. At HEDTA concentrations higher than 3 mmole/1, the stability of the vitamin increases gradually as a function of the chelating agent concentration.

Chelating Agents↗
PubMed1998

Intracellular and serum stability of liposomal 2',3'-dideoxycytidine. Effect of lipid composition.

The serum and intracellular stability of 2',3'-dideoxycytidine (ddC) encapsulated in liposomes having different physicochemical properties have been investigated. Results showed that the presence of cholesterol in the lipid composition of liposomes resulted in an increased leakage of ddC when incubated in 80% serum at 37 degrees C. The length of the hydrocarbon chains of the phosphatidylcholine component in cholesterol-containing liposomes did not induce major modifications in both the efficiency of encapsulation and retention of the antiviral agent. The uptake and intracellular stability of the different liposomal formulations have also been evaluated as a function of drug concentration in RAW 264.7 macrophages. For all liposomal formulations tested, an enhanced uptake of liposome-encapsulated ddC by macrophages was observed when the liposomal drug concentration was increased. In addition, the anionic character of liposomes seemed to be an important factor to obtain a high intracellular uptake of ddC. The drug release from liposomal ddC-loaded macrophages has also been evaluated in serum-free medium. Liposomes having long saturated fatty acyl phospholipids and containing 50% (molar ratio) of cholesterol displayed the best stability in the intramacrophagic compartments at all liposomal ddC concentrations used. On the other hand, although the leakage of ddC from liposomes sterically stabilized with polyethyleneglycol chains was similar to that of other cholesterol-containing liposomes, the antiviral agent was readily released from cells for all concentrations of liposomal ddC tested. In conclusion, these results show that the serum stability does not necessarily reflect the intracellular stability, and suggest that some lipid components such as cholesterol can modulate the liposomal stability of drugs such as ddC in response to the conditions of the environment, the properties of the drug used and the nature of interactions between liposomes and cells.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1998

[Stabilization of 99m Tc-HMPAO with methylene blue: its use in leukocyte labelling)].

A method to stabilize the 99mTc-HMPAO obtained from Ceretec(R) saline fractions using methylene blue is described. The mean radiochemical purity two hours after the stabilized 99mTc-HMPAO preparation was 92.5% (SD 1.8%), the pH ranged from 7.0 to 7.6 and the osmolality ranged from 305 to 309 mOsm/kg. These features made the stabilized 99mTc-HMPAO suitable for leukocyte labelling. In order to evaluate this method, we performed the labelling of two identical leukocyte samples withdrawn from 10 blood donors. The first sample was labeled using 99mTc-HMPAO non-stabilized and the second one was labelled using 99mTc-HMPAO stabilized 2 hours before with methylene blue. The mean labelling efficiencies we obtained were 70.9% (SD 6.9%) and 66.1% (SD 4.2%) respectively. With the conditions described using the 99mTc-HMPAO stabilized with methylene blue, we had no drawbacks from the stabilizing blue colour and we did not found changes in the cellular viability.

Cell Survival↗