Topical delivery of acetazolamide for psoriasis.
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Acetazolamide↗
Biomedical subjects
T Loftsson
Publications and source records attributed to T Loftsson.
Stabilizing effect of tris(hydroxymethyl)aminomethane on N-nitrosoureas in aqueous solutions.
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Drug Stability↗
Improved delivery through biological membranes. XLV. Synthesis, physical-chemical evaluation, and brain uptake studies of 2-chloroethyl nitrosourea delivery systems.
The dihydropyridine in equilibrium with pyridinium redox chemical delivery system (CDS) was supplied to two 2-chloroethylnitrosoureas, i.e., HECNU and CCNUOH, and the physicochemical properties of the delivery systems were studied to assess their potential as improved delivery forms to the CNS. Detailed physicochemical evaluation and brain uptake studies were performed on one of the delivery systems (CCNUOH-CDS) derived from trans-4-hydroxy-CCNU, an active metabolite of CCNU. Two aqueous-based formulations derived from hydroxypropyl-beta-cyclodextrin (HP beta CD) and Tween 80:ethanol:water system were developed for CCNUOH-CDS to overcome the poor aqueous solubility conferred upon it by its high lipophilicity. The formulations enabled a 200- to 400-fold improvement in the water solubility of CCNUOH-CDS. Dose- and vehicle-dependent comparative tissue distribution studies in rats indicated improved brain-to-organ ratios of the delivery system at lower doses.
Animals↗
Metabolism, distribution, and transdermal permeation of a soft corticosteroid, loteprednol etabonate.
The soft corticosteroid, loteprednol etabonate (chloromethyl 17 alpha-ethoxycarbonyloxy-11 beta-hydroxy-3-oxoandrosta-1,4-diene-17 beta-carboxylate), I, was designed based on the "inactive metabolite approach." Accordingly, I should be metabolized by hydrolysis to the corresponding inactive cortienic acid derivative, II. The in vitro and in vivo metabolism of I indeed yielded mainly this inactive metabolite, which is more hydrophilic and thus readily eliminated from the body. Relatively high levels of I were found in tissues after intravenous administration of the drug in rats. The permeability of I through hairless mouse skin was comparable to what has been found for related "hard" steroids, without significant metabolism taking place in the skin.
Androstadienes↗
Degradation of tauromustine (TCNU) in aqueous solutions.
The stability of tauromustine in buffered aqueous solutions was investigated over the pH range 0.9-7.5. The pH rate profile at zero buffer concentration has a specific acid catalytic region at pH below 2, a plateau of pH-independent degradation between pH 2 and 4, and shows a sharp increase in the degradation rate at pH above 4. The activation parameters, the solvent isotope effect and the effect of the dielectric constant on the degradation rate were determined, and possible degradation mechanisms were discussed. The effects of six cyclodextrin (CD) derivatives on the stability of tauromustine in aqueous buffer solutions were investigated. All the CDs tested had some stabilizing effect on the drug at pH 1.98 and 4.06 but they had little or no effect at pH 6.38. Hydroxypropyl-alpha-cyclodextrin (HP alpha CD) had the largest stabilizing effect. Tauromustine degraded about 25 to 50% slower in aqueous buffer solutions containing 2% HP alpha CD compared to buffer solutions containing no CD.
Antineoplastic Agents↗
Solubilization and stabilization of a benzylpenicillin chemical delivery system by 2-hydroxypropyl-beta-cyclodextrin.
A dihydropyridine----pyridinium salt redox carrier-based chemical delivery system for benzylpenicillin (1) was complexed with 2-hydroxypropyl-beta-cyclodextrin (HPCD). The solubility of the lipophilic 1, which is incompatible with aqueous formulations, was dramatically increased and showed a linear dependency on the HPCD concentration. The degree of incorporation was 20 mg of 1 per g of complex. The stability study of 1 in various pH buffers indicated the base-catalyzed hydrolysis of the acyloxyalkyl linkage and the hydration of the 5,6 double bond of the dihydropyridine as the main degradation processes. The overall loss of 1, which follows first-order kinetics, was not influenced by changes in ionic strength and elimination of oxygen from the reaction medium. The HPCD complex of 1, which has a stability constant of 720-940 M-1, stabilized the chemical delivery system. The influence of the temperature on the stability of 1 is also discussed.
2-Hydroxypropyl-beta-cyclodextrin↗
Novel central nervous system targeted semisynthetic penicillins.
A novel series of semisynthetic penicillins was designed and synthesized. The compounds have as an integral part of the molecule a pyridinium <--> dihydropyridine redox system as a substituent at the 6-position. Esters of the dihydropyridine (pro-prodrug) forms of the drugs were expected, because of their pronounced lipophilic character, to easily penetrate biological membranes, including the blood-brain barrier, and to give rise to esters of polar pyridinium ions (prodrug) (via enzymic oxidation of the dihydropyridine moiety). The resulting ions were expected to be rapidly excreted from the periphery, but to be "locked" in the central nervous system; subsequent enzymic cleavage of the ester function was expected to release the free acid-pyridinium salts (drug) in the central nervous system in a sustained manner. The design approach, synthesis, study of some important physicochemical properties, stability determinations and preliminary in vivo distribution and potency evaluations of the novel drugs are described.
Animals↗
The effect of phosphine oxides on transdermal delivery.
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Administration, Cutaneous↗
Effect of choline esters and oleic acid on the penetration of acyclovir, estradiol, hydrocortisone, nitroglycerin, retinoic acid and trifluorothymidine across hairless mouse skin in vitro.
Five choline esters, lauroylcholine, myristoylcholine, palmitoylcholine, stearoylcholine and oleoylcholine, were evaluated as skin penetration enhancers by testing their effects on the penetration of six drugs, acyclovir, 17 beta-estradiol, hydrocortisone, nitroglycerin, all-trans-retinoic acid and trifluorothymidine, across hairless mouse skin in vitro and comparing the results to those obtained with oleic acid. The results show that the transdermal delivery of the drugs tested from propylene glycol vehicle systems, can be significantly increased by adding small amounts of choline esters and/or oleic acid to the vehicle. Lauroylcholine was a better enhancer than oleic acid for the transdermal delivery of 17 beta-estradiol and, in mixtures, lauroylcholine and oleic acid acted as synergists giving larger enhancement of the transdermal delivery of nitroglycerin and acyclovir than when used separately.
Acyclovir↗
Effects of 2-hydroxypropyl-beta-cyclodextrin on the aqueous solubility of drugs and transdermal delivery of 17 beta-estradiol.
The effect of 2-hydroxypropyl-beta-cyclodextrin (2-HPCD) on the aqueous solubility of 18 drugs possessing different physiochemical properties was investigated. The largest increase in aqueous solubility was obtained with very lipophilic drugs with low aqueous solubility and the enhancement was larger at low temperature than at high temperature. In many cases a linear relationship exists between the drug solubility and the 2-HPCD concentration. Ionization of a drug molecule enhanced the solubility effects of 2-HPCD, resulting in greater aqueous solubility than if either method was used by itself. 2-HPCD was found to be an effective transdermal permeability enhancer.
2-Hydroxypropyl-beta-cyclodextrin↗
Effect of oleic acid on diffusion of drugs through hairless mouse skin.
The effect of oleic acid in propylene glycol or 2-ethyl-1,3-hexanediol vehicle systems on the skin permeability of 17 beta-estradiol, triamcinolone acetonide and trifluorothymidine was studied in vitro. The largest enhancement was obtained from a vehicle containing oleic acid in propylene glycol and the enhancement increased with increasing aqueous solubility of the drug. Oleic acid gave far less enhancement when propylene glycol was replaced by 2-ethyl-1,3-hexanediol.
Animals↗
Improved delivery through biological membranes. XXXL: Solubilization and stabilization of an estradiol chemical delivery system by modified beta-cyclodextrins.
A dihydropyridine in equilibrium pyridinium salt chemical delivery system (CDS) for estradiol (E2CDS) was complexed with various modified beta-cyclodextrins including hydroxyethyl-beta-cyclodextrin (HECD), hydroxypropyl-beta-cyclodextrin (HPCD), and heptakis(2,6-di-O-methyl)-beta-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.
Animals↗
Trifluorothymidine: potential non-invasive diagnosis of herpes simplex infection using 19F nuclear magnetic resonance in a murine hepatitis model.
Trifluorothymidine (TFT) is known to be concentrated in herpes simplex virus (HSV) infected cells in vitro in the form of phosphorylated derivatives. We studied a murine hepatitis model of HSV infection to determine whether this in vitro observation would also be demonstrable in vivo. Following i.v. injection of 100 or 160 mg/kg TFT, TFT was found in significantly higher concentrations in the livers of HSV-2 infected mice than in the livers of uninfected mice, mice infected with murine hepatitis virus (MHV-A59) or mice with hepatitis from carbon tetrachloride treatment. Neither altered renal function, nor altered pharmacokinetics could account for this difference. 19F Nuclear Magnetic Resonance spectroscopy readily detected the 19F from TFT in both liver extracts and whole livers, particularly at higher tissue levels, i.e. greater than 50 micrograms/g tissue. If further studies with living animals support these preliminary observations, clinical application could be pursued.
Animals↗
The effect of vehicle additives on the transdermal delivery of nitroglycerin.
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Administration, Cutaneous↗
The effect of ionization on partition coefficients and topical delivery.
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Administration, Topical↗
Improved delivery through biological membranes VIII: Design, synthesis, and in vivo testing of true prodrugs of aspirin.
Novel activated ester-type prodrugs of aspirin were designed and synthesized. The methylthiomethyl, methylsulfinymethyl, and methylsulfonylmethyl esters of aspirin (acetylsalicylic acid) were cleaved in vitro in plasma to form aspirin rather than the corresponding salicylates. In vitro studies using dogs indicated that at least one aspirin derivative, methylsulfinylmethyl-2-acetoxybenzoate, is a true aspirin prodrug since aspirin was detected in the blood after prodrug administration.
Animals↗
Improved delivery through biological membranes IX: Kinetics and mechanism of hydrolysis of methylsulfinymethyl 2-acetoxybenzoate and related aspirin prodrugs.
The complex kinetics and mechanism of the hydrolysis of the methylthiomethyl, methylsulfinylmethyl, and methylsulfonylmethyl 2-acetoxybenzoates, novel aspirin prodrugs, were studied. The pH profiles for the related salicylates and benzoates also were determined. Based on the activation parameters, isotope effects, and other data, it was established that the methylthiomethyl esters hydrolyze via a unimolecular alkyl-oxygen cleavage. The methylsulfinylmethyl and methylsulfonylmethyl 2-acetoxybenzoates undergo neutral hydrolysis of esters at pH greater than 4 to form aspirin, while water acts as a general base; but at lower pH, a different mechanism takes place and the o-acetyl group cleaves first, releasing the corresponding salicylates.
Aspirin↗
Improved delivery through biological membranes XD: Percutaneous absorption and metabolism of methylsulfinylmethyl 2-acetoxybenzoate and related aspirin prodrugs.
Oxidative-reductive interconversion of the methylthiomethyl ester of aspirin and the corresponding sulfoxide and sulfone derivatives can be detected in rat liver homogenate, in addition to the extremely facile hydrolysis of these esters. The methylthiomethyl and methylsulfinylmethyl 2-acetoxybenzoates penetrate freshly excised hairless mice skin rather easily with the simultaneous hydrolysis of the two ester functions. Contrary to in vivo observations in dogs, where significant amounts of aspirin formed, the prodrugs cleave to salicylic acid and/or salicylate esters rather than aspirin.
Animals↗