RESUMEN
The aim of this contribution is to summarize recent findings on the potential use of cyclodextrins and their derivatives as carriers for oligonucleotide agents. Their peculiar properties could be exploited in such an emerging therapeutic area by virtue of their capability of interacting with cellular membranes, thus giving rise to improved cellular uptake. In particular, some specific derivatives could be considered as promising future excipients for the delivery of "naked" antisense and/or decoy oligonucleotides which are difficult to formulate with existing pharmaceutical excipients.
Asunto(s)
Ciclodextrinas , Oligonucleótidos/administración & dosificación , Animales , Ciclodextrinas/química , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , HumanosRESUMEN
The objective of this mini-review is to summarize the findings concerning the physicochemical properties and the pharmaceutical applications of acidic drugs whose performances have been modified by simultaneous complexation with cyclodextrins and salt formation. Particular attention is paid to the approaches undertaken for increasing the solubility of the drugs by proper choice of the type of counterion analogously to what has been reported for complexes of basic drugs in the presence of hydroxy acids.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Ácidos y Sales Biliares/química , Ciclodextrinas/química , Hipoglucemiantes/química , beta-Ciclodextrinas , Ácidos/química , Antiinflamatorios no Esteroideos/farmacología , Ácidos y Sales Biliares/farmacología , Hipoglucemiantes/farmacología , Estructura Molecular , Sales (Química)/química , TermodinámicaRESUMEN
The polymorphism of rac-5,6-diisobutyryloxy-2-methylamino-1,2,3,4-tetrahydro-naphthalene hydrochloride (CHF 1035) was investigated. Three different crystal forms (Form I, Form II, and Form III) were obtained by recrystallization procedures from common organic solvents. The polymorphs were characterized by Raman and carbon-13 nuclear magnetic resonance ((13)C NMR) spectroscopy, in solution and in solid state (cross polarization-magic angle spinning), powder X-ray diffractometry, and thermal methods (differential scanning calorimetry, hot stage microscopy, and thermogravimetry). Moreover, the diffraction patterns of Form I, collected at controlled temperatures, gave evidence of the presence of two reversible structural rearrangements at approximately 60 and approximately 75 degrees C. These structural variations were confirmed by the results obtained by differential scanning calorimetry and hot stage microscopy techniques. The analysis of the Raman spectra allowed the identification of peculiar absorption bands for each polymorph. Form III was the stable crystal form at room temperature as determined by the basis of slurry conversion method.
Asunto(s)
Ésteres , Naftalenos/química , Tetrahidronaftalenos , Rastreo Diferencial de Calorimetría , Cristalización , Espectroscopía de Resonancia Magnética , Espectrometría Raman , Difracción de Rayos XRESUMEN
The objective of this mini-review is to summarize the findings concerning the properties and the pharmaceutical applications of multicomponent complexes made of a sparingly water-soluble amino-type drug, a cyclodextrin, and a hydroxy carboxylic acid. Simultaneous complexation and salt formation with these acids significantly increase the solubilizing power, allowing us to reduce the amount of cyclodextrin necessary for making the targeted formulation. In many cases, the aqueous solubility of the hydrophobic drug can be enhanced by several orders of magnitude, while that of CD can be enhanced more than 10-fold. The mechanism through which these complexes elicit their synergetic effects on the drug solubility is also discussed. Finally, some general observations are made concerning the structural requirements of the drug necessary for exploiting the aforementioned effect.
Asunto(s)
Ciclodextrinas/química , Hidroxiácidos/química , Excipientes Farmacéuticos/química , Animales , Ciclodextrinas/farmacocinética , Sinergismo Farmacológico , Excipientes/química , Excipientes/farmacocinética , Humanos , Hidroxiácidos/farmacocinética , Excipientes Farmacéuticos/farmacocinética , SolubilidadRESUMEN
The results of a Raman and solid state 13C-NMR spectroscopic investigation aimed at studying the conformation of piroxicam (P) and its interaction with beta-cyclodextrin (betaCD) in 1 : 1 amorphous PbetaCD inclusion compound are reported. The 1700-1200 cm(-1) FT-Raman and the 13C CP/MAS NMR spectra of 1 : 1 PbetaCD inclusion compound are discussed and assigned in comparison with those of the three main modifications of piroxicam (alpha, beta, and monohydrate). The FT-Raman and 13C-NMR results show that in 1 : 1 PbetaCD inclusion compound piroxicam mainly assumes the zwitterionic structure typical of monohydrate, even if the presence of a different structure, that is, beta form, is not excluded. Piroxicam monohydrate, differently from alpha and beta forms, is characterized by a zwitterionic structure with an internal proton transfer and an increased charge delocalization, as shown by our spectroscopic results. The charge delocalization characteristic of this zwitterionic structure gives rise to the interaction with betaCD via electrostatic and hydrogen bonds. The possibility of a host-guest interaction between piroxicam and betaCD is not excluded; the guest molecule can be accommodated in betaCD cavity by interaction via hydrophobic bonds.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Ciclodextrinas/química , Piroxicam/química , beta-Ciclodextrinas , Isótopos de Carbono , Espectroscopía de Resonancia Magnética , Espectrometría RamanRESUMEN
1H NMR spectroscopy was used for determining the optical purity of cis-ketoconazole enantiomers obtained by fractional crystallization. The chiral analysis was carried out using beta-cyclodextrin in the presence of (+)-L-tartaric acid. The mechanism of the chiral discrimination process, the stability of the complexes formed, and their structure in aqueous solution were also investigated by 1H and 13C chemical shift analysis, two-dimensional NOE experiments, relaxation time measurements, and mass spectrometry experiments. Theoretical models of the three-component interaction were built up on the basis of the available NMR data, by performing a conformational analysis on the relevant fragments on ketoconazole and docking studies on the components of the complex. The model derived from a folded conformation of ketoconazole turned out to be fully consistent with the molecular assembly found in aqueous solution, as inferred from NOE experiments. An explanation of the different association constants for the complexes of the two enantiomers is also provided on the basis of the interaction energies.
Asunto(s)
Antifúngicos/química , Ciclodextrinas/química , Cetoconazol/química , Tartratos/química , beta-Ciclodextrinas , Antifúngicos/aislamiento & purificación , Interacciones Farmacológicas , Estabilidad de Medicamentos , Cetoconazol/aislamiento & purificación , Espectrometría de Masas , Modelos Moleculares , Conformación Molecular , Resonancia Magnética Nuclear Biomolecular , Protones , Soluciones/química , Estereoisomerismo , Termodinámica , Agua/químicaRESUMEN
A new chiral derivatization procedure for the HPLC resolution of chiral catecholamines and structurally related compounds is described. The homochiral reagent, (+)-(R)-1-phenylethyl isocyanate (RPEIC), was added to separate and quantitate the enantiomers of rac-5,6-dihydroxy-2-methyl-aminotetralin, the main metabolite of rac-5, 6-diisobutyryl-2-methyl-aminotetralin, a potent dopamine agonist, by reversed-phase HPLC analysis. To avoid catecholamine degradation in the basic reaction medium and to obtain the selective and quantitative derivatization of the amino group of the compound, the reversible complex formation between diphenylborinic acid (DPBA) and the catechol group, in alkaline medium, was performed before homochiral isocyanate addition. The RPEIC derivatization was completed in 30 min and then the DPBA complex was dissociated by adding dilute acid. The structure of intermediates and urea derivatives was confirmed by mass spectometry. The use of an electrochemical detector, operating in redox mode, allowed HPLC quantitation of enantiomers at the nanogram level in plasma and urine. The derivatization procedure is also suitable for other catecholamine-related compounds.
Asunto(s)
Líquidos Corporales/química , Tetrahidronaftalenos/química , Animales , Compuestos de Boro , Cromatografía Líquida de Alta Presión , Indicadores y Reactivos , Ratas , Estereoisomerismo , Tetrahidronaftalenos/aislamiento & purificación , Tetrahidronaftalenos/farmacocinéticaRESUMEN
The solid state structures of the (-)-n-heptylcarbamate of geneseroline and its hydrochloride salt were determined by single crystal X-ray diffraction analysis. Both compounds gave crystals belonging to the orthorombic P2(1)2(1)2(1) space group with a = 27.597(7) A, b = 8.899(2) A, c = 9.290(2) A, V = 2281.5(9) A3, Z = 4, and R = 0.0682 for the base and a = 11.300(1) A, b = 8.3485(5) A, c = 24.141(2) A, V = 2277.3(3) A3, Z = 4, and R = 0.0482 for the salt. X-ray and 1H NMR analysis revealed that the base is a 1,2-oxazine derivative. The six-membered ring adopts a 4C1 chair conformation in the solid-state, whereas, in CDCl3 solution, it exists as a mixture of two possible chair conformers, 4C1 and 1C4, with the N-methyl group in the equatorial position (ratio approximately 75:25). The salt is an N-oxide derivative; the five-membered ring adopts different envelope conformations in the solid-state and in CDCl3 solution, suggesting a certain flexibility. In more polar solvents, the salt partially undergoes fast inversion at the tetrahedral nitrogen, giving rise to the corresponding epimer.
Asunto(s)
Alcaloides/síntesis química , Alcaloides/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Conformación Molecular , Soluciones , Difracción de Rayos XRESUMEN
The phospholipidic classes of the natural pulmonary surfactant Curosurf were separated by bidimensional TLC and isolated. Quantitative analysis of each class was made by colorimetric determination of phosphorus. FD/MS and NH3-CI/MS were used to identify individual components. GC was used for qualitative/quantitative analysis of fatty acid moieties as methyl esters, using internal standards, by comparison with authentic samples.
Asunto(s)
Productos Biológicos , Fosfolípidos/química , Surfactantes Pulmonares/química , Animales , Cromatografía en Capa Delgada , Colorimetría , Ácidos Grasos/análisis , Espectrometría de Masas , Fosfatidilcolinas/análisis , Espectrofotometría Ultravioleta , PorcinosRESUMEN
A high-performance liquid chromatographic method is described for the quantitation in plasma of the four stereoisomers of a new aminotetralin, (SRR, RSS)(SRS, RSR)-5,6-dimethoxy-2-[3'-(p-hydroxyphenyl)-3'-hydroxy-2'- propyl]aminotetralin (CHF 1255, internal code). After liquid-liquid extraction of the drug, separation was obtained after chiral derivatization with R-(+)-alpha-methylbenzyl isocyanate. The selective derivatization of the amino group was obtained by controlling the pH of the reaction medium at 7.5. The reaction was quantitative after a period of 16 h. The structures of the urea derivatives were confirmed by proton nuclear magnetic resonance spectroscopy and high-performance liquid chromatography with mass spectrometric detection. The use of an electrochemical detector, operating in the oxidative mode, allows the quantitation in plasma of all four urea derivatives at the nanogram level. The method was demonstrated to be precise, reproducible and applicable to pharmacokinetics studies after administration of the two epimeric racemates.
Asunto(s)
Fenoles/sangre , Tetrahidronaftalenos/sangre , Cromatografía Líquida de Alta Presión , Electroquímica , Humanos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Fenoles/farmacocinética , Análisis de Regresión , Estereoisomerismo , Tetrahidronaftalenos/farmacocinética , Urea/análisisRESUMEN
Proton nuclear magnetic resonance spectroscopy showed that piroxicam sodium salt forms an inclusion complex with beta-cyclodextrin in aqueous solution. The 1:1 stoichiometry of the complex was determined by the continuous variation method. Significant nuclear Overhauser effects were observed between the inner protons of beta-cyclodextrin and protons of both the aromatic rings of piroxicam sodium salt, a result indicating that two isomeric 1:1 complexes must be present in solution within the range of concentrations investigated. The overall association constant was 113 M at 298 K. At concentrations less than 1.0 x 10(-3) M, the complex is completely dissociated.