International journal of pharmaceutics
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The natural gamma-cyclodextrin (gammaCD) is like linear water-soluble dextrins, and unlike the natural alpha- and beta-cyclodextrins (alphaCD and betaCD), digested by salivary and pancreatic amylase. This gives gammaCD a very favorable toxicological profile. However, its usage is hampered by its relatively low solubilizing effect and tendency to form turbid solutions. ⋯ For example, 80:20 mixture of gammaCD and HPgammaCD is up to 50% more effective solubilizer for dexamethasone and hydrocortisone than expected based on the solubilizing effects of the individual cyclodextrins. Mixing alphaCD or betaCD with their more water-soluble derivatives only resulted in additive effects. Mixing gammaCD with HPgammaCD resulted in synergistic effect.
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The absorption-enhancing effects of three different polyamines, spermine (SPM), spermidine (SPD) and putrescine (PUT) on the intestinal absorption of water-soluble macromolecules were examined in rats. Fluorescein isothiocyanate-labeled dextrans (FDs) with different average molecular weights were chosen as models of water-soluble macromolecules and intestinal absorption of FDs with or without these polyamines was examined by an in situ closed loop method. The intestinal absorption of fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4400 (FD4) was relatively low in the absence of these polyamines. ⋯ SPM decreased the TEER values in a concentration dependent manner and 10mM SPM had almost the same effect to decrease the TEER value compared with 10mM EDTA as a positive control. These findings suggest that SPM may loosen the tight junction of the epithelium, thereby increasing the intestinal absorption of drugs via a paracellular route. In summary, polyamines, especially SPM would be one of the suitable absorption enhancers with high effectiveness and low intestinal membrane toxicity.
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Cremophor-free intravenous microemulsions for paclitaxel I: formulation, cytotoxicity and hemolysis.
Two cremophor-free microemulsions, lecithin:butanol:myvacet oil:water (LBMW) and capmul:myvacet oil:water (CMW) for paclitaxel (PAC) were developed for intravenous (i.v.) administration. Six surfactants and four oils were screened with various combinations for maximal water incorporation and PAC solubility. Microemulsion regions were subsequently determined in ternary phase diagrams. ⋯ Promising microemulsions, LBMW and CMW were developed that can incorporate approximately 12 mg/g of PAC, substantially higher than its aqueous solubility (10.8 microg/ml) and that in the Taxol vehicle (6 mg/ml). PAC retained its cytotoxicity in the LBMW and CMW and was less likely to cause hemolysis compared to Taxol. This higher drug loading results in a smaller vehicle volume in required doses of these formulations and potentially less vehicle-related side effects are anticipated.
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The aim of this study was to assess the feasibility of radiosterilization of drugs aqueous solutions and to evaluate the effects of some additives, such as mannitol, nicotinamide and pyridoxine, which might protect the drug from degradation. Metoclopramide was selected as a model drug. The structures of the degradation products were determined to gain insight on the radiolysis mechanisms in aqueous solution in order to design strategies to lower the drug degradation. ⋯ Metoclopramide recovery for gamma and electron beam-irradiated solutions containing either mannitol, pyridoxine or nicotinamide meets the pharmacopoeial specifications for metoclopramide content up to a 15 kGy irradiation so that metoclopramide solutions containing these excipients might be radiosterilized at 15 kGy either with gamma rays or high-energy electrons. Structures are proposed for the majority of radiolysis products. Similar radiolysis products were detected for gamma and electron beam irradiations but the chromatographic profiles were different (differences in the distribution of radiolysis products).
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Two cremophor-free microemulsion systems LBMW (lecithin:butanol:myvacet:water) and CMW (capmul:myvacet:water), for intravenous (IV) administration of paclitaxel (PAC) were previously developed and characterized. Their chemical stability, in vitro release and pharmacokinetics of PAC were assessed using Taxol (cremophor:ethanol 1:1, 6 mg/ml) as a reference. The shelf-lives of PAC at 25 degrees C in Taxol, LBMW and CMW, in an accelerated stability study, were 71, 57 and 31 days, respectively. ⋯ The extents of release of PAC from LBMW and CMW were 25 and 50% of that from Taxol. In vivo pharmacokinetic studies in male Sprague-Dawley rats after IV administration revealed that PAC in LBMW and CMW remained in the systemic circulation five and two times longer and was eight and three times more widely distributed than PAC from Taxol. LBMW and CMW offer a significant clinical advantage in terms of the prolonged half-life and wide tissue distribution, indicating that PAC delivered by these systems intravenously may result in prolonged exposure of PAC to the tumor and subsequently an improved clinical efficacy.