Compatible stability of methylprednisolone sodium succinate and tropisetron in 0.9% sodium chloride injection.

Background: A combination of methylprednisolone sodium succinate and tropisetron hydrochloride is commonly used to treat the nausea and vomiting associated with antineoplastic therapy. The objective of this study was to investigate the stability of tropisetron hydrochloride and methylprednisolone sodium succinate in 0.9% sodium chloride injection for up to 48 hours. Methods: Commercial solutions of methylprednisolone sodium succinate and tropisetron hydrochloride were obtained and further diluted with 0.9% sodium chloride injection to final concentrations of either 0.4 or 0.8 mg/mL (methylprednisolone sodium succinate) and 0.05 mg/mL (tropisetron). The admixtures were assessed for periods of up to 48 hours after storage at 4°C with protection from light and at 25°C without protection from light. Physical compatibility was determined visually, and the chemical compatibility was measured with high-performance liquid chromatography (HPLC) and by measurement of pH values. Results: HPLC analysis demonstrated that methylprednisolone sodium succinate and tropisetron hydrochloride in the various solutions were maintained at 97% of the initial concentrations or higher during the testing period. There were no changes observed by physical precipitation or pH in any of the prepared solutions. Conclusions: Tropisetron hydrochloride injection and methylprednisolone sodium succinate injection in 0.9% sodium chloride injection are stable for up to 48 hours at 4°C and 25°C.

Therapeutic Effect of a Novel Nano-Drug Delivery System on Membranous Glomerulonephritis Rat Model Induced by Cationic Bovine Serum.

In order to explore a novel high efficacy drug delivery system for membranous glomerulonephritis (MGN), a complex chronic inflammation, methylprednisolone bovine serum albumin nanoparticles (ME BSA NPs) were designed. The nanoparticles were prepared by desolvation-chemical crosslinking method and its physicochemical characterizations were conducted. The experimental MGN rat models induced by cationic bovine serum albumin were established by a modified Border's method and applied in the pharmacodynamics study of ME BSA NPs. The results showed that the particle size, particle dispersion index, and entrapment efficiency of ME BSA NPs were 131.1 ± 3.4 nm, 0.159 ± 0.036, and 71.51 ± 1.74%, respectively. In addition, the image of transmission electron microscopy showed that the ME BSA NPs were the relatively uniform spherical particles. In the in vivo pharmacodynamics study, compared with saline group and SOLU-MEDROL® group, that the ME BSA NPs group was significantly reduced the levels of 24 h urinary protein (P < 0.01) and serum creatinine (P < 0.05). Consequently, these outcomes indicated that the nanoparticles we studied were a promising drug delivery system for the MGN disease, and it may be also useful for other complex chronic inflammations.

Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases.

The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS), mice experimental autoimmune encephalomyelitis (EAE). The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity (due to high and repeated dosage). We designed two different liposomal nano-drugs, i.e., nano sterically stabilized liposomes (NSSL), remote loaded with: (a) a "water-soluble" amphipathic weak acid glucocorticosteroid prodrug, methylprednisolone hemisuccinate (MPS) or (b) the amphipathic weak base nitroxide, Tempamine (TMN). For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of ß-amyloid. Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting. For the NSSL-MPS and the NSSL-TMN it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE. We have further investigated the MPS nano-drug's therapeutic efficacy and its mechanism of action in both the acute and the adoptive transfer EAE models, as well as optimizing the perfomance of the TMN nano-drug. The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.

Compatibility of intravenous fosaprepitant with intravenous 5-HT3 antagonists and corticosteroids.

PURPOSE: Fosaprepitant dimeglumine for injection is the water-soluble phosphorylated prodrug of the neurokinin-1 receptor antagonist aprepitant. Both agents are approved (in combination with a 5-HT3 antagonist and a corticosteroid) for prevention of chemotherapy-induced nausea and vomiting. Because fosaprepitant is likely to be combined and stored in the same intravenous (IV) bag with 5-HT3 antagonists and corticosteroids, the in vitro compatibility of fosaprepitant with these agents and other IV diluents was assessed. METHODS: Fosaprepitant (1 mg/mL in 0.9 % sodium chloride injection solution) was combined in binary or tertiary fashion with therapeutic-dose preparations of a 5-HT3 antagonist (ondansetron, granisetron, palonosetron, or tropisetron) and/or a corticosteroid (dexamethasone sodium phosphate or methylprednisolone sodium succinate). For diluent compatibility assessment, fosaprepitant was also prepared 1 mg/mL in 0.9 % sodium chloride injection solution, water for injection, or 5 % dextrose injection solution. After 24-h storage under ambient conditions, samples were assayed for degradation. RESULTS: Fosaprepitant demonstrated compatibility when combined in the same IV infusion bag with common 5-HT3 antagonists and corticosteroids for storage and IV coadministration, with the exception of palonosetron (incompatible under all experimental conditions) and tropisetron (incompatible unless combined with a corticosteroid). No incompatibility was observed between fosaprepitant and any of the 3 diluents tested. CONCLUSIONS: Use of fosaprepitant in combination with other antiemetics may provide a flexible option for administration of antiemetics to patients receiving moderately or highly emetogenic chemotherapy.

Doxofylline and methylprednisolone sodium succinate are stable and compatible under normal injection conditions.

To assess the physical compatibility and chemical stability of doxofylline with methylprednisolone sodium succinate in 0.9% sodium chloride or 5% dextrose injection for intravenous infusion. Twenty mL doxofylline solution (0.74 mg/mL) and 1 mL methylprednisolone sodium succinate solution (0.15 mg/mL) were added into 250 mL polyolefin bags containing 5% dextrose injection or 0.9% sodium chloride injection, and stored for 24 h at 20-25(°)C. Chemical compatibility was measured with high-performance liquid chromatography (HPLC), and physical compatibility was determined visually. The results showed that samples were clear and colorless when viewed in normal fluorescent room light. The pH value exhibited little change. The particulate content of > 25 µm was low and within the specification limit. The particulate content of > 10 µm decreased over time and was similar to the control solution. Analysis of chemical stability revealed that doxofylline is stable with methylprednisolone sodium succinate for up to 24 h, and the degradation of methylprednisolone sodium succinate is unrelated to doxofylline, but is closely related to the pH value of the solution. Doxofylline and methylprednisolone sodium succinate did not affect the stability of each other.

Fabrication principles and their contribution to the superior in vivo therapeutic efficacy of nano-liposomes remote loaded with glucocorticoids.

We report here the design, development and performance of a novel formulation of liposome- encapsulated glucocorticoids (GCs). A highly efficient (>90%) and stable GC encapsulation was obtained based on a transmembrane calcium acetate gradient driving the active accumulation of an amphipathic weak acid GC pro-drug into the intraliposome aqueous compartment, where it forms a GC-calcium precipitate. We demonstrate fabrication principles that derive from the physicochemical properties of the GC and the liposomal lipids, which play a crucial role in GC release rate and kinetics. These principles allow fabrication of formulations that exhibit either a fast, second-order (t(1/2) ~1 h), or a slow, zero-order release rate (t(1/2) ~ 50 h) kinetics. A high therapeutic efficacy was found in murine models of experimental autoimmune encephalomyelitis (EAE) and hematological malignancies.

An injectable thiol-acrylate poly(ethylene glycol) hydrogel for sustained release of methylprednisolone sodium succinate.

Clinically available injectable hydrogels face technical challenges associated with swelling after injection and toxicity from unreacted constituents that impede their performance as surgical biomaterials. To overcome these challenges, we developed a system where chemical gelation was controlled by a conjugate Michael addition between thiol and acrylate in aqueous media, with 97% monomer conversion and 6 wt.% sol fraction. The hydrogel exhibited syneresis on equilibration, reducing to 59.7% of its initial volume. It had mechanical properties similar to soft human tissue with an elastic modulus of 189.8 kPa. Furthermore, a mesh size of 6.9 nm resulted in sustained release of methylprednisolone sodium succinate with a loading efficiency of 2 mg/mL. Functionalization with 50 µg/mL of an oligolysine peptide resulted in attachment of freshly isolated murine mesenchymal stem cells. The rational design of the physical, chemical and biological properties of the hydrogel makes it a potentially promising candidate for injectable applications.

Synthesis and in vitro characterization of novel dextran-methylprednisolone conjugates with peptide linkers: effects of linker length on hydrolytic and enzymatic release of methylprednisolone and its peptidyl intermediates.

To control the rate of release of methylprednisolone (MP) in lysosomes, new dextran-MP conjugates with peptide linkers were synthesized and characterized. Methylprednisolone succinate (MPS) was attached to dextran 25 kDa using linkers with 1-5 Gly residues. The release characteristics of the conjugates in pH 4.0 and 7.4 buffers, blood, liver lysosomes, and various lysosomal proteinases were determined using a size-exclusion and/or a newly developed reversed-phase HPLC method capable of simultaneous quantitation of MP, MPS, and all five possible MPS-peptidyl intermediates. We synthesized conjugates with >or=90% purity and 6.9-9.5% (w/w) degree of MP substitution. The conjugates were stable at pH 4.0, but released MP and intact MPS-peptidyl intermediates in the pH 7.4 buffer and rat blood, with faster degradation rates for longer linkers. Rat lysosomal fractions degraded the conjugates to MP and all the possible intermediates also at a rate directly proportional to the length of the peptide. Whereas the degradation of the conjugates by cysteine peptidases (papain or cathepsin B) was relatively substantial, no degradation was observed in the presence of aspartic (cathepsin D) or serine (trypsin) proteinases, which do not cleave peptide bonds with Gly. These newly developed dextran conjugates of MP show promise for controlled delivery of MP in lysosomes.

Controlling liposomal drug release with low frequency ultrasound: mechanism and feasibility.

The ability of low-frequency ultrasound (LFUS) to release encapsulated drugs from sterically stabilized liposomes in a controlled manner was demonstrated. Three liposomal formulations having identical lipid bilayer compositions and a similar size ( approximately 100 nm) but differing in their encapsulated drugs and methods of drug loading have been tested. Two of the drugs, doxorubicin and methylpredinisolone hemisuccinate, were remote loaded by transmembrane gradients (ammonium sulfate and calcium acetate, respectively). The third drug, cisplatin, was loaded passively into the liposomes. For all three formulations, a short exposure to LFUS (<3 min) released nearly 80% of the drug. The magnitude of drug release was a function of LFUS amplitude and actual exposure time, irrespective of whether irradiation was pulsed or continuous. Furthermore, no change in liposome size distribution or in the chemical properties of the lipids or of the released drugs occurred due to exposure to LFUS. Based on our results, we propose that the mechanism of release is a transient introduction of porelike defects in the liposome membrane, which occurs only during exposure to LFUS, after which the membrane reseals. This explains the observed uptake of the membrane-impermeable fluorophore pyranine from the extraliposomal medium during exposure to LFUS. The implications of these findings for clinical applications of controlled drug release from liposomes are discussed.

Co-solubilization of poorly soluble drugs by micellization and complexation.

The use of combined approach of surfactants and cyclodextrins in solubilization of poorly soluble drugs has been described in literature. In this report, a mathematical model has been developed to provide the quantitative basis for this approach. First, by way of hypothetical examples and simulations, the influence of various interaction parameters on the phase solubility profile is presented. Additionally, the model results are compared with (a) results reported by Yang et al., with NSC-639829, sodium lauryl sulfate (SLS) and sulfobutyl-ether-beta-cyclodextrin ((SBE)(7M)-beta-CD) and (b) solubility of methylprednisolone, a model poorly soluble drug, in the presence of its water-soluble 'surfactant-like' prodrug, methylprednisolone 21-hemisuccinate, and (SBE)(7M)-beta-CD. The model shows good agreement with experimental data. Furthermore, theoretical simulations show that the combined solubility is less than the sum of the individual solubility values in cyclodextrins and surfactants. Based on the hypothetical case and the two examples, the factors affecting the phase solubility profile in mixed solutions of surfactants and cyclodextrins are presented. Finally, the limitations of the model to explain co-solubilization by surfactants and cyclodextrins are discussed.

Stability of methylprednisolone sodium succinate in autodose infusion system bags.

OBJECTIVE: To evaluate the physical and chemical stabilities of methylprednisolone sodium succinate solutions packaged in sterile AutoDose Infusion System bags. SETTING: Laboratory. INTERVENTIONS: The test samples were prepared by reconstituting the methylprednisolone sodium succinate, adding the required amount of drug to the AutoDose Infusion System bags, and diluting to the target concentrations of 100 mg/100 mL and 1 gram/100 mL with 0.9% Sodium Chloride Injection. MAIN OUTCOME MEASURES: Physical stability and chemical stability based on drug concentrations initially and at appropriate intervals over periods up to 3 days at 23 degrees C and 30 days at 4 degrees C. RESULTS: The admixtures initially were clear when viewed in normal fluorescent room light and with a Tyndall beam. Measured turbidity and particulate content were low initially and exhibited little change. All samples were essentially colorless throughout the study. High-performance liquid chromatography analysis revealed some decomposition in the samples. Methylprednisolone sodium succinate exhibited about 8% loss after 2 days and about 13% loss after 3 days at 23 degrees C. In the samples stored at 4 degrees C, methylprednisolone sodium succinate exhibited acceptable stability through 21 days of storage, but losses exceeded 10% after 30 days. CONCLUSION: Methylprednisolone sodium succinate exhibited physical and chemical stabilities consistent with those found in previous studies. The AutoDose Infusion System bags did not adversely affect the physical or chemical stability of this drug.

Dextran-methylprednisolone succinate as a prodrug of methylprednisolone: plasma and tissue disposition.

Plasma and tissue disposition of a macromolecular prodrug of methylprednisolone (MP), dextran (70 kDa)-methylprednisolone succinate (DMP), was studied in rats. Single 5-mg/kg doses of DMP or unconjugated MP were administered into the tail veins of different groups of rats (n = 4/group/time point). Blood (cardiac puncture) and tissues (liver, spleen, kidney, heart, lung, thymus, and brain) were collected at various times after DMP (0-96 h) or MP (0-2 h) injections. Concentrations of DMP and MP in samples were analyzed by size-exclusion chromatography (SEC) and reversed-phase high-performance liquid chromatography (HPLC), respectively. Conjugation of MP with 70-kDa dextran resulted in 22-, 300-, and 30-fold decreases in the steady-state volume of distribution, clearance, and terminal plasma rate constant of the steroid, respectively. As for tissue distribution, the conjugate delivered the steroid primarily to the spleen and liver as indicated by 19- and 3-fold increases, respectively, in the tissue/plasma area under the curve (AUC) ratios of the steroid. On the other hand, the tissue/plasma AUC ratios of the prodrug in other organs were negligible. Active MP was released from DMP slowly in the spleen and liver, and AUCs of the regenerated MP in these tissues were 55- and 4.8-fold, respectively, higher than those after the administration of the parent drug. In contrast, no parent drug was detected in the plasma of DMP-injected rats. These results indicate that DMP may be useful for the targeted delivery of MP to the spleen and liver where the active drug is slowly released.

The effect of bulking agent on the solid-state stability of freeze-dried methylprednisolone sodium succinate.

The rate of hydrolysis of methylprednisolone sodium succinate in the freeze dried solid state at 40 degrees C was determined in the presence of two common bulking agents--mannitol and lactose--at two different ratios of drug to excipient. Residual moisture levels were less than 1% in all samples tested, with no significant difference in residual moisture among different formulations. Rate of hydrolysis was significantly higher in mannitol-containing formulations versus lactose-containing formulations, and the rate of hydrolysis increases with increasing ratio of mannitol to drug. Thermal analysis and x-ray diffraction data are consistent with a composition-dependent rate of crystallization of mannitol in the formulation and its subsequent effect on distribution of water in the freeze-dried matrix. Increased water in the microenvironment of the drug decreases the glass transition temperature of the amorphous phase, resulting in an increased rate of reaction. The physical state of lactose remained constant throughout the duration of the study, and the rate of hydrolysis was not significantly different from the control formulation containing no excipient. Thermal analysis and x-ray diffraction data are consistent with formation of a liquid crystal phase in freeze-concentrated solutions of methylprednisolone sodium succinate containing no excipient.

Stability and compatibility of methylprednisolone sodium succinate and cimetidine hydrochloride in 5% dextrose injection.

The stability and compatibility of methylprednisolone sodium succinate in admixtures with cimetidine hydrochloride in 5% dextrose injection were determined. Admixtures containing methylprednisolone sodium succinate, in concentrations equivalent to methylprednisolone 0.4 or 1.25 mg/mL, and cimetidine 3 mg/mL (as the hydrochloride salt) were prepared in 5% dextrose injection 100 mL. Control solutions containing each drug alone at the same concentrations were also prepared. The admixtures were prepared in triplicate and were kept in polyvinyl chloride infusion containers at controlled room temperature (24 degrees C). Immediately after mixing and at 2, 4, 8, 12, and 24 hours, samples were removed and visually inspected, measured for pH, and assayed by stability-indicating high-performance liquid chromatography to determine the concentrations of methylprednisolone 21-succinate ester and cimetidine. No visual evidence of incompatibility was noted either with the unaided eye or a microscope. No substantial changes in pH occurred over the study period. The addition of cimetidine decreased the pH of the methylprednisolone sodium succinate control solutions from about 7.3 to about 5.6. The concentrations of methylprednisolone 21-succinate ester and cimetidine in both test and control solutions did not change significantly over the 24-hour study period. Methylprednisolone sodium succinate, in concentrations equivalent to methylprednisolone 0.4 and 1.25 mg/mL, was chemically stable and visually compatible in admixtures with cimetidine 3 mg/mL (as the hydrochloride salt) in 5% dextrose injection 100 mL at 24 degrees C for 24 hours.