- Improved delivery through biological membranes XXXI: Solubilization and stabilization of an estradiol chemical delivery system by modified β-cyclodextrins
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A dihydropyridine ? pyridinium salt chemical delivery system (CDS) for estradiol (E2CDS) was complexed with various modified β-cyclodextrins including hydroxyethyl-β-cyclodextrin (HECD), hydroxypropyl-β-cyclodextrin (HPCD), and heptakis(2,6-di-O-methyl)-β-cyclodextrin (DMCD). Complex formation with all of these cyclodextrins resulted in dramatic increases in the water solubility of E2CDS. Studies on the complex of E2CDS and HPCD (E2CDS-CD) indicated that the encapsulated estrogen was approximately four times more stable than the unmanipulated CDS, producing an estimated half-life of degradation of 4 years compared with 1.2 years for the uncomplexed drug at room temperature. The complexation of E2CDS and HPCD also stabilized the dihydronicotinate in solutions containing potassium ferricyanide. This formulation was shown to be equivalent to E2CDS in dimethyl sulfoxide in delivering the oxidized, estradiol precursor (E2Q+) to the brain, and also produced similar biological responses; these included decreased luteinizing hormone (LH) secretion and a decrease in the rate of weight gain in castrated female rats.
- Brewster,Estes,Loftsson,Perchalski,Derendorf,Mullersman,Bodor
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- Determination of estredox, a compound with sustained estradiol function, and its impurity profile by HPLC
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The HPLC methods described here for the assay and purity test of Estredox (E2CDS), a molecule with a redox-based, brain-targeted chemical delivery system for estradiol, allow reliable conclusions to be made on the potency and purity of API and E2CDS/HPCD complex samples. Extensive work was done to isolate and characterize the major, potential contaminants, and ensure the required stability of solutions of E2CDS, an inherently labile compound by design. Both the sample solvent and the eluent were thoroughly tested to avoid unwanted changes in sample solutions during analyses. The 12 minute isocratic assay method at 220 or 360 nm is simple, well-founded, highly precise and accurate. Purity profiling of E2CDS raised several problems in detection, stability and accuracy, owing to the fact that the pattern of the UV spectra and the stability of the compound and those of the potential contaminants often differed greatly. As a result of meticulous analysis of the UV spectra and the factors influencing the behaviour, in solution, of the compounds concerned, the 20 minute gradient method developed for the purity test, at 220 nm, of E2CDS and E2CDS/HPCD complex samples has proved to be a reliable means of adequately resolving 15-20 peaks of known and unknown compounds, and establishing the purity of various E2CDS samples. Sample impurity can be expressed as area % at 220 nm, and/or as approximate w/w % (if needed), since the relative response factors, at 220 nm, of the 6 major, potential contaminants have also been determined.
- Patthy,Seres,Toth-Sarudy,Hazai,Pallagi,Simay, Antal,Bodor
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experimental part
p. 210 - 216
(2009/04/05)
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- Method for treating male sexual dysfunction
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The invention provides a method for treating sexual dysfunction in male mammals using a compound of the formula[E--DHC] (I)or a non-toxic pharmaceutically acceptable salt thereof, wherein [E] is an estrogen and [DHC] is the reduced, biooxidizable, blood-brain barrier-penetrating, lipoidal form of a dihydropridine pyridinium salt redox carrier. Compositions for use in the subject method are also disclosed. A preferred compound for use in the method and compositions is an estradiol derivative, namely, 17β-[(1-methyl-1,4-dihydro-3-pyridinyl)carbonyloxy]estra-1,3,5(10)-trien-3-ol.
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- Brain-specific drug delivery
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The subject compounds, which are adapted for the site-specific/sustained delivery of centrally acting drug species to the brain, are: (a) compounds of the formula wherein [D] is a centrally acting drug species, and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine pyridinium salt redox carrier, with the proviso that when [DHC] is STR1 wherein R is lower alkyl or benzyl and [D] is a drug species containing a single NH2 or OH functional group, the single OH group when present being a primary or secondary OH group, said drug species being linked directly through said NH2 or OH function group to the carbonyl function of [DHC], then [D] must be other than a sympathetic stimulant, steroid sex hormone or long chain alkanol; and (b) non-toxic pharmaceutically acceptable salts of compounds of formula (I) wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine pyridinium salt redox carrier. The corresponding ionic pyridinium salt type drug/carrier entitles [D--QC]+ X- are also disclosed.
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- Improved delivery through biological membranes. 32. Synthesis and biological activity of brain-targeted delivery systems for various estradiol derivatives
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Brain-targeted delivery systems based on the dihydropyridine ? pyridinium salt redox interconversion were synthesized for estradiol, estradiol 3-benzoate, and ethynylestradiol. Initial biological evaluation indicated that while all four compounds synthesi
- Brewster,Estes,Bodor
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p. 244 - 249
(2007/10/02)
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- Method and compositions for weight control
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The invention provides a method for controlling mammalian body weight using a compound of the formula or a non-toxic pharmaceutically acceptable salt thereof, wherein [E] is an estrogen and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal form of a dihydropyridine pyridinium salt redox carrier. Novel compositions for weight control comprising a compound of formula (I) or its salt are also disclosed. A preferred compound for use in the subject method and compositions is an estradiol derivative, namely, 17 β-[(1-methyl-1,4-dihydro-3-pyridinyl)carbonyloxy]estra-1,3,5(10)-trien-3-ol.
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