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" THE STABILIZATION OF DRUGS IN LIPOSOMES: "
M. J. Habib
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Latin Dissertation
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| Language of Document
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English
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| Record Number
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1112403
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| Doc. No
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TLpq251787403
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| Main Entry
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M. J. Habib
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| Title & Author
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THE STABILIZATION OF DRUGS IN LIPOSOMES:\ M. J. Habib
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| College
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University of Alberta (Canada)
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| Date
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1987
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| student score
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1987
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| Degree
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Ph.D.
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| Page No
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1
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| Abstract
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Liposomes have been investigated for their potential to stabilize drugs with which they become associated. Acetylsalicylic acid, local anesthetics, and cefotaxime sodium were selected as model compounds for this evaluation. The kinetics of hydrolysis in liposomes were studied as a function of liposome composition, method of preparation, drug:lipid ratio, temperature, pH, and ionic strength of the medium. When ASA was incorporated initially in the lipid phase, a 25% increase in stability was obtained in neutral dimyristoyl lecithin (DMPC) liposomes at pH 4.0 and 30. Increasing the liposome concentration provided a proportional increase in the stabilization of ASA. The addition of stearylamine (STEAR) to the organic solvent mixture caused a rapid initial hydrolysis of ASA but once liposomes were formed the remaining ASA was stabilized at substantially higher levels. The evidence suggests that anionic ASA complexes electrostatically to the phospholipid polar group (to the positively-charged choline groups) and is subsequently protected against hydrolytic attack. The liposome stabilities of several local anesthetics were also measured at pH 12.2 at 30. Increases in stability correlated with their partition coefficients and ranged from 17% and 84% but the addition of 50 mole% of CHOL reduced the increase to about one-third of what it was in lecithin liposomes alone whereas negatively-charged liposomes yielded markedly increased stabilization of the local anesthetics. Cefotaxime sodium (CFX) was not stabilized in liposomes. However, unionized CFX rapidly solubilized liposomes, the rate of solubilization rapidly decreasing with an increase in pH. After solubilization, the solutions gradually returned to a turbid state and large crystals were observed microscopically. The solubilization effect is probably due to mixed micelle formation of phospholipid and CFX initiated by the surface activity of the drug. In conclusion, the potential of liposomes to stabilize drugs in solution is dependent on both the fraction of drug associated with the liposomes and the protection of drug in the phospholipid bilayers. The partition coefficient plays an important role in the stabilization of nonionic drugs whereas electrostatic association of anionic drug, such as ASA, with phospholipid plays a major role. Overall, levels of stabilization in liposomes of 20%-80% were achieved.
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| Subject
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Health and environmental sciences
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Pharmaceuticals
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