Micellar Aggregation and Membrane Partitioning of Bile Salts, Fatty Acids, Sodium Dodecyl Sulfate, and Sugar-Conjugated Fatty Acids:  Correlation with Hemolytic Potency and Implications for Drug Delivery

Ross, Benjamin P.; Braddy, April C.; McGeary, Ross P.; Blanchfield, Joanne T.; Prókai, László; Tóth, István

doi:10.1021/mp049964d

Cited by 42 publications

(27 citation statements)

References 64 publications

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“…It is important to do this because numerous papers deal with the toxicity of the excipients used in this study and all come to a similar conclusion, stating that lower level of excipient results in a lower level of toxicity (1,(29)(30)(31). Toxic effects of surfactants are associated with their interaction with biological membranes, and as such are proven to exert hemolytic effect (32). Based on such publications and assessing the benefit/risk ratio of each excipient, it was concluded that the amount of excipient to be reduced first and foremost should be polysorbate 80, followed by the reduction of the concentration of ethanol.…”

Section: Optimizing the Concentration Of Excipientsmentioning

confidence: 76%

Composition Optimization and Stability Testing of a Parenteral Antifungal Solution based on a Ternary Solvent System

et al. 2010

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Abstract. An intravenous solution is a dosage forms intended for administration into the bloodstream. This route is the most rapid and the most bioavailable method of getting drugs into systemic circulation, and therefore it is also the most liable to cause adverse effects. In order to reduce the possibility of side effects and to ensure adequate clinical dosage of the formulation, the primarily formulated composition should be optimized. It is also important that the composition should retain its therapeutic effectiveness and safety throughout the shelf-life of the product. This paper focuses on the optimization and stability testing of a parenteral solution containing miconazole and ketoconazole solubilized with a ternary solvent system as model drugs. Optimization of the solvent system was performed based on assessing the risk/ benefit ratio of the composition and its properties upon dilution. Stability tests were conducted based on the EMEA (European Medicines Agency) "guideline on stability testing: stability testing of existing active substances and related finished products". Experiments show that both the amount of co-solvent and surface active agent of the solvent system could substantially be reduced, while still maintaining adequate solubilizing power. It is also shown that the choice of various containers affects the stability of the compositions. It was concluded that by assessing the risk/benefit ratio of solubilizing power versus toxicity, the concentration of excipients could be considerably decreased while still showing a powerful solubilizing effect. It was also shown that a pharmaceutically acceptable shelf-life could be assigned to the composition, indicating good long-term stability.

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Section: Optimizing the Concentration Of Excipientsmentioning

confidence: 76%

Composition Optimization and Stability Testing of a Parenteral Antifungal Solution based on a Ternary Solvent System

et al. 2010

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“…To test the hypothesis that the antibacterial activities of the acylpolyamines are a consequence of membrane permeabilization due to their cationic amphipathic nature, we sought to correlate the surface activity of these compounds with hemolytic potency (42). Erythrocyte damage was measured using two different techniques.…”

Section: Vol 50 2006 Membrane Permeabilization By Acylhomosperminesmentioning

confidence: 99%

Structural Correlates of Antibacterial and Membrane-Permeabilizing Activities in Acylpolyamines

Balakrishna

Wood

Nguyen

et al. 2006

Antimicrob Agents Chemother

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A homologous series of mono-and bis-acyl polyamines with varying acyl chain lengths originally synthesized for the purpose of sequestering lipopolysaccharide were evaluated for antimicrobial activity to test the hypothesis that these bis-cationic amphipathic compounds may also bind to and permeabilize intact gramnegative bacterial membranes. Some compounds were found to possess significant antimicrobial activity, mediated via permeabilization of bacterial membranes. Structure-activity relationship studies revealed a strong dependence of the acyl chain length on antimicrobial potency and permeabilization activity. Homologated spermine, bis-acylated with C 8 or C 9 chains, was found to profoundly sensitize Escherichia coli to hydrophobic antibiotics such as rifampin. Nonspecific cytotoxicity is a potential drawback of these membranophilic compounds. However, the surface activity of these cationic amphipaths is strongly attenuated under physiological conditions via binding to serum albumin. Significant antibacterial activity is still retained in the presence of physiological concentrations of human serum albumin, suggesting that these compounds may serve as leads in the development of novel adjuncts to conventional antimicrobial chemotherapy.The accelerated emergence of many strains of multidrugresistant bacteria as a result of widespread use and misuse of antibiotics has mandated the urgent need for a renewed search for novel antibacterial agents. The presence of an outer membrane (OM) in gram-negative bacteria provides an effective protective barrier in these organisms (33, 34) to antimicrobial agents that may otherwise be active. For instance, it has been reported that in antibiotics of natural origin that are active against gram-positive bacteria, more than 90% lacked activity at a useful level against Escherichia coli (55). The barrier, formed by a divalent cation-cross-linked matrix (36, 40) of lipopolysaccharide (LPS) molecules on the outer leaflet of the OM (17, 48), can be breached by metal-chelating agents such as EDTA or via displacement of LPS-bound metals by polycations of diverse structural classes (20,36,40,54,57).Polymyxin B (PMB), a cyclic, pentacationic, amphipathic peptide antibiotic isolated from Bacillus polymyxa (49) is a prototype membrane-perturbing agent whose antibacterial action is manifested via its binding to the lipid A moiety of LPS. Perturbation of the OM alone has been thought to result in bacterial killing, since immobilized PMB can disrupt the OM (41); however, alternate hypotheses concerning "self-promoted" uptake of the antibiotic and subsequent perturbation of the inner membrane (IM), culminating in bacterial lysis, have also been suggested (11, 64). The recognition that membrane-active antimicrobials have not yet been exploited adequately in the clinic has spurred the search for noncytolytic, selective bacterial membrane-permeabilizing agents, notable examples of which include cationic peptides (18,19) and smallmolecule PMB mimics (12,13,27,44). The use of cationic peptides as...

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“…It is described that the microdomains contained in the mixed micelles were able to solubilise cholesterol [10][11][12][13][14]. An important aspect in the formation of mixed micelles lies in the fact that the mixed micelle association lowers the monomeric activity of bile salts and thus prevents the solubilisation and thus destruction and membranolytic effect of the apical membrane of the epithelial cells [15,16]. Table 1.…”

Section: Introductionmentioning

confidence: 99%

Membranolytic Activity of Bile Salts: Influence of Biological Membrane Properties and Composition

et al. 2007

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Abstract:The two main steps of the membranolytic activity of detergents: 1) the partitioning of detergent molecules in the membrane and 2) the solubilisation of the membrane are systematically investigated. The interactions of two bile salt molecules, sodium cholate (NaC) and sodium deoxycholate (NaDC) with biological phospholipid model membranes are considered. The membranolytic activity is analysed as a function of the hydrophobicity of the bile salt, ionic strength, temperature, membrane phase properties, membrane surface charge and composition of the acyl chains of the lipids. The results are derived from calorimetric measurements (ITC, isothermal titration calorimetry). A thermodynamic model is described, taking into consideration electrostatic interactions, which is used for the calculation of the partition coefficient as well as to derive the complete thermodynamic parameters describing the interaction of detergents with biological membranes (change in enthalpy, change in free energy, change in entropy etc). The solubilisation properties are described in a so-called vesicle-to-micelle phase transition diagram. The obtained results are supplemented and confirmed by data obtained from other biophysical techniques (DSC differential scanning calorimetry, DLS dynamic light scattering, SANS small angle neutron scattering).

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Micellar Aggregation and Membrane Partitioning of Bile Salts, Fatty Acids, Sodium Dodecyl Sulfate, and Sugar-Conjugated Fatty Acids: Correlation with Hemolytic Potency and Implications for Drug Delivery

Cited by 42 publications

References 64 publications

Composition Optimization and Stability Testing of a Parenteral Antifungal Solution based on a Ternary Solvent System

Composition Optimization and Stability Testing of a Parenteral Antifungal Solution based on a Ternary Solvent System

Structural Correlates of Antibacterial and Membrane-Permeabilizing Activities in Acylpolyamines

Membranolytic Activity of Bile Salts: Influence of Biological Membrane Properties and Composition

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