RESUMEN
Single-crystal X-ray diffraction and theoretical calculations were conducted for insights into the ß-cyclodextrin (ß-CD)-quetiapine inclusion complex structure. ß-CD and quetiapine form a host-guest inclusion complex at a ratio of 2:1 in which the ß-CD molecules form head-to-head dimers with their secondary hydroxyl groups linked by multiple hydrogen bonds. Quetiapine is totally contained within the ß-CD cavity and exhibits two kinds of disorder (parts 1 and 2) in opposite directions in the ß-CD complex. To clarify the mobility of the guest molecule in the ß-CD cavity, theoretical molecular conformational calculations, crystal optimization and crystal energy calculations were conducted using CONFLEX software. The results of theoretical molecular conformation calculations showed that the mobility of quetiapine is restricted because its tricyclic structure is covered by ß-CD. The results of crystal energy calculations indicated that the conformation of disorder part 1, which has high occupancy, was more stable.
Asunto(s)
beta-Ciclodextrinas , Cristalografía por Rayos X , Enlace de Hidrógeno , Conformación Molecular , Fumarato de QuetiapinaRESUMEN
The photostability of three types of furosemide (FUR) cocrystal (FUR-caffeine, FUR-urea, and FUR-nicotinamide cocrystals) was studied under irradiation with a D65 fluorescent lamp. The coloration of the FUR-urea pellets was significantly faster than that of the intact FUR, whereas the coloration of FUR-nicotinamide was suppressed compared with that of intact FUR and the other cocrystals. In the case of FUR-urea, the chemical degradation of FUR increased by approximately 6.6% after irradiation for 90 d. On the other hand, FUR-nicotinamide showed better chemical stability, with only 1.3% of FUR degraded, which was significantly lower than the other cocrystals. The FUR-urea pellets showed a UV-Visible absorption spectrum similar to that of intact FUR, while the absorption range of FUR-nicotinamide shifted to a shorter wavelength. The light sensitivity of FUR-nicotinamide was improved because of the much lower emission of the D65 fluorescent lamp in the absorption range of the cocrystal.
Asunto(s)
Cafeína/química , Furosemida/química , Luz , Niacinamida/química , Urea/química , Cristalización , Estabilidad de Medicamentos , EspectrofotometríaRESUMEN
Clozapine (CLZ) is an atypical antipsychotic medication used in the treatment of schizophrenia and is poorly soluble in water (0.05 mM). In this study, we have investigated the effect of ß-cyclodextrin (CD) and its derivatives on the solubility of CLZ. The solubility of the CLZ was measured to generate a phase solubility diagram, and the interaction between CLZ and sulfobutyl ether-ß-cyclodextrin (SBE-ß-CD) in aqueous solution was observed by 1H- and 2D rotating-frame Overhauser enhancement spectroscopy (ROESY)-NMR methods. Moreover, the synergistic effect of SBE-ß-CD and water-soluble polymers, including polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose sodium salt, polyvinyl alcohol, sodium alginate, and propylene glycol alginate (PGA), on the solubility of CLZ was investigated. The results show that the solubility of CLZ with 1 w/v% PGA was 7.6 mM, which was almost four times greater than that of CLZ without PGA in a 15 mM SBE-ß-CD solution. In contrast, the solubility of CLZ with 1 w/v % PGA in an aqueous solution decreased by one-third relative to that of CLZ in a 15 mM SBE-ß-CD solution. 2D ROESY-NMR indicated that a CLZ/SBE-ß-CD/PGA ternary complex formed. It was found that the combination of PGA and SBE-ß-CD enhanced the solubility of CLZ.
Asunto(s)
Alginatos/química , Clozapina/química , beta-Ciclodextrinas/química , Alginatos/análisis , Clozapina/análisis , Espectroscopía de Resonancia Magnética/métodos , Solubilidad , beta-Ciclodextrinas/análisisRESUMEN
The crystal structure of an inclusion complex of ß-cyclodextrin (ß-CD) with fentanyl was determined by single crystal X-ray diffraction analysis. The crystal belongs to the triclinic space group P1 and the complex comprises one fentanyl, two ß-CD, and several water molecules. ß-CD and fentanyl form a host-guest inclusion complex at a ratio of 2:1 and the asymmetric unit of the complex contains two host molecules (ß-CDs) in a head-to-head arrangement that form dimers through hydrogen bonds between the secondary hydroxyl groups of ß-CD and one guest molecule. Fentanyl is totally contained within the ß-CD cavity and the structure of the phenylethyl part of fentanyl inside the dimeric cavity of the complex is disordered. Furthermore, theoretical molecular conformational calculations were conducted to clarify the mobility of the guest molecule in the ß-CD cavity using CONFLEX software. Crystal optimization and crystal energy calculations were also conducted. The results of the theoretical calculations confirmed that the conformation of disorder part 1, which was high in occupancy by crystal structure analysis, was more stable. The phenylethyl part of fentanyl existed in several stable conformations.
Asunto(s)
Fentanilo/química , beta-Ciclodextrinas/química , Química Farmacéutica , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos MolecularesRESUMEN
Epalrestat (EPL) is a water-insoluble drug (14µM) that inhibits aldose reductase. This study investigated the interactions between ß-cyclodextrin (CD) derivatives and EPL to determine the solubilizing effect on EPL from phase solubility diagrams. We improved the solubility of EPL in water by adding ß-CD derivatives. Moreover, the solubility of EPL mixed with ß-CD derivatives by cogrinding in a ball mill method was about 2-3 times higher than those of EPL with the same CD concentration (5mM) calculated from phase solubility diagrams. In addition, we investigated the effect of ß-CD derivatives on in vitro percutaneous absorption of EPL through hairless mouse skin. Among the coground mixtures of EPL and ß-CD derivatives, the mixture containing methyl (ME)-ß-CD showed the strongest enhancement of EPL skin permeation. Furthermore, adding 10wt% urea as a skin permeation enhancer after cogrinding with ME-ß-CD improved the flux of EPL 300 times compared to the flux of EPL alone. This result indicates the ME-ß-CD ground mixture system with urea has potential as a new transdermal drug delivery system of EPL for diabetic neuropathy.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Portadores de Fármacos/química , Rodanina/análogos & derivados , Tiazolidinas/química , Tiazolidinas/farmacología , beta-Ciclodextrinas/química , Administración Cutánea , Animales , Rastreo Diferencial de Calorimetría/métodos , Cromatografía Líquida de Alta Presión/métodos , Liberación de Fármacos , Masculino , Ratones , Permeabilidad , Rodanina/química , Rodanina/farmacología , Absorción Cutánea , Solubilidad , Propiedades de Superficie , Difracción de Rayos X/métodosRESUMEN
OBJECTIVES: Water-soluble fentanyl citrate salt has been used in sublingual or buccal formulations for the breakthrough pain treatment. However, fentanyl absorption through the lipid mucosal membrane may be improved by enhancing the non-ionic lipophilic fentanyl base solubility. Therefore, the interaction between cyclodextrins (CDs) and fentanyl base has been evaluated to obtain basic information for its application. METHODS: Parent CDs (α-, ß- and γ-CD) as well as α- and ß-CD derivatives were used for solubility studies with fentanyl base. Nuclear magnetic resonance (NMR) studies were applied in a system including ß-CD or glucosyl-ß-CD (G1-ß-CD) with fentanyl base or fentanyl citrate. (1) H- and (13) C-NMR studies and a two-dimensional rotating frame Overhauser effect spectroscopy (ROESY) study were conducted to confirm inclusion complexes formation. KEY FINDINGS: Parent CDs displayed BS type phase solubility diagrams; ß-CD exhibited a strong interaction with fentanyl base. Hydrophilic ß-CD derivatives, such as G1-ß-CD, displayed AL type phase diagrams and higher solubilizing effects compared with parent CDs. ROESY study suggested that fentanyl phenyl groups were included in ß-CD cavity. CONCLUSIONS: This study revealed that hydrophilic ß-CD derivatives, such as G1-ß-CD, could be useful pharmaceutical additives for oral mucosal formulations because of the improved fentanyl base solubility via inclusion complexation.
Asunto(s)
Analgésicos Opioides/química , Ciclodextrinas/química , Excipientes/química , Fentanilo/química , Solventes/química , Agua/química , Administración Bucal , Analgésicos Opioides/administración & dosificación , Espectroscopía de Resonancia Magnética con Carbono-13 , Composición de Medicamentos , Fentanilo/administración & dosificación , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Químicos , Espectroscopía de Protones por Resonancia Magnética , SolubilidadRESUMEN
Sertraline is one of the serotonin-specific reuptake inhibitors that is effective in treating several disorders such as major depression, obsessive-compulsive disorder, panic disorder, and social phobia. It is marketed in the form of its hydrochloride salt, which exhibits better solubility in water than its free base form. However, the absorption of sertraline through biological membranes could be improved by enhancing the solubility of its base because it is more hydrophobic than sertraline hydrochloride. To clarify the mechanism for the interaction of sertraline base with ß-CD, it is important to study the basic interaction between the ß-CD ring and sertraline base. Therefore, in this study, the currently used hydrochloride salt form was converted into the free base and ß-CD was used as a model for ß-CD derivatives to evaluate the interaction between ß-CD and the sertraline base. The solid-state physicochemical characteristics of the sertraline-ß-CD complex were investigated by the phase solubility method, differential scanning calorimetry, Fourier transform IR spectroscopy, FT-Raman spectroscopy, powder X-ray diffraction, and (13)C cross-polarization magic-angle spinning NMR measurements. The results showed that sertraline base and ß-CD form an inclusion complex, and the stoichiometric ratio of the solid-state sertraline base-ß-CD complex is 1:1, which was estimated by the (1)H NMR measurements of the complex dissolved in DMSO-d6.
Asunto(s)
Sertralina/química , beta-Ciclodextrinas/química , Rastreo Diferencial de Calorimetría/métodos , Interacciones Hidrofóbicas e Hidrofílicas , Espectroscopía de Resonancia Magnética/métodos , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier/métodosRESUMEN
PURPOSE: Lomerizine dihydrochloride (LOM) is a Ca2+ channel blocker used as an antimigraine drug, which is currently administered orally in Japan. We therefore investigated the effect of terpenes in propylene glycol (PG) solvent on the percutaneous absorption of LOM by hairless mouse skin. METHODS: Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), confocal laser scanning microscopy (CLSM), and small angle X-ray scattering (SAXS) were carried out to analyze the effects of terpene enhancers on the biophysical properties of the stratum corneum (SC) of the skin. RESULTS: Of the terpenes tested, the highest permeation rate of LOM (28.8 mg/cm2/h) was observed with 1,8-cineole, while nerolidol conferred the lowest enhancement of LOM flux (14.2 mg/cm2/h). ATR-FTIR studies revealed that terpenes/PG induced higher CH2 stretching frequencies of SC lipids than PG alone. The extent of penetration of the lipophilic fluorescence probes Nile Red and DiI was measured by CLSM in in vitro skin permeation studies, using either PG or terpenes/PG as skin permeation enhancers. With PG alone, both fluorescence dyes were undetectable in the skin. In contrast, when co-administered with terpenes/PG, both probes were distributed into the intercellular space between corneocytes and detected in the deeper layers of the skin. SAXS measurements showed that in SC treated with a combination of 1,8-cineole and PG, the scattering peak of the SC was broad and very weak in intensity compared to untreated SC, whereas pretreatment with PG alone did not alter the peak profile. CONCLUSION: A combination of terpenes and PG enhance the skin permeation of LOM. Our findings suggest that the mechanism for this effect involves the ability of terpenes to increase the fluidity of SC lipids, thus enhancing the distribution of LOM into the intercellular region of the SC. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacocinética , Piperazinas/farmacocinética , Propilenglicol/farmacología , Terpenos/farmacología , Animales , Masculino , Ratones , Ratones Pelados , Absorción Cutánea/efectos de los fármacosRESUMEN
Quetiapine, an antipsychotic drug used for schizophrenia treatment, is poorly water soluble, and therefore, administration of the more water-soluble quetiapine fumarate is preferred. Absorption of quetiapine through biological membranes may be improved by enhancing the solubility of the quetiapine base, the non-ionic form. In this study, the currently used salt form was converted into the free base (oily material). We employed cyclodextrins (CDs) as pharmaceutical additives to improve the solubility of the quetiapine base. The formation of quetiapine-ß-cyclodextrin (ß-CD) complexes was studied by phase solubility studies, continuous variation method, NMR spectroscopy, and powder X-ray diffraction. The formation of a poorly water-soluble complex was confirmed by the phase solubility study, and the interaction between quetiapine and ß-CD in water was confirmed by NMR spectroscopy. In addition, the effects of ß-CD derivatives (glucosyl-ß-CD, maltosyl-ß-CD, 2-hydroxypropyl-ß-CD, dimethyl-ß-CD, and trimethyl-ß-CD) on the solubility of the quetiapine base were studied. The findings indicated that the aforementioned hydrophilic ß-CD derivatives could be used as pharmaceutical additives of quetiapine for parenteral formulations as a result of the improved solubility of the quetiapine base because of inclusion complexation. Therefore, converting the currently used salt form into the free base, investigating the free base as a candidate for CD inclusion, and converting the oily material such as the free base into a powder by forming an inclusion complex that is easy to deal with is considered a worthwhile approach that may lead to novel formulations of the drug in question.
Asunto(s)
Antipsicóticos/química , Ciclodextrinas/química , Dibenzotiazepinas/química , Antipsicóticos/administración & dosificación , Dibenzotiazepinas/administración & dosificación , Infusiones Parenterales , Espectroscopía de Resonancia Magnética , Fumarato de Quetiapina , Solubilidad , Difracción de Rayos XRESUMEN
Three new quinazolinobenzodiazepine derivatives, novobenzomalvins A (1), B (2), and C (3), have been isolated as fibronectin expression regulators from Aspergillus novofumigatus CBS117520. The structures of 1 to 3 were established by spectroscopic and physicochemical analysis, and chemical investigation including the total synthesis of 1. Treatment with novo-benzomalvins A (1), B (2), C (3), and N-methylnovobenzomalvin A (5) increased the expression of fibronectin in normal human neonatal dermal fibroblast cells.
RESUMEN
A novel synthetic path to sequosempervirin A was established by employing a samarium diiodide promoted intramolecular Barbier-type reaction of the lactonic iodide, in which the key structural feature, a spiro[4.5]decane ring system, could be constructed by controlling the stereochemistry of the hydroxyl group at the 8-position. The absolute configuration of natural sequosempervirin A was revised to be 4S based on this synthesis.
Asunto(s)
Compuestos de Espiro/síntesis química , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , Compuestos de Espiro/química , EstereoisomerismoRESUMEN
Phase-solubility studies have been used to evaluate the solubilizing effects of cyclodextrins (CDs) on lipophilic, water-insoluble drugs. However, large amounts of CDs and drugs are required to measure solubility by phase-solubility studies. Thus, more efficient approaches to evaluate the interaction of CDs with drugs are needed. Herein we introduce a method that evaluates the interaction between immobilized ß-cyclodextrin and psychotropic drugs by surface plasmon resonance assay with a Biacore(®) system. Association constants and stoichiometries observed were generally consistent with values calculated by traditional methods, such as phase-solubility and continuous variation methods. Results showed that the analytical method using Biacore(®) was suitable to evaluate CD-drug interactions.
Asunto(s)
Química Farmacéutica/métodos , Psicotrópicos/química , Resonancia por Plasmón de Superficie/métodos , beta-Ciclodextrinas/química , Amoxapina/química , Técnicas de Química Analítica , Humanos , Cinética , Modelos Químicos , Unión Proteica , Reproducibilidad de los Resultados , Solubilidad , Resonancia por Plasmón de Superficie/instrumentación , Trazodona/químicaRESUMEN
Fentanyl base and ß-cyclodextrin (ß-CD) were coground at 1:1 and 1:2 molar ratios (fentanyl: ß-CD) and the physicochemical characteristics of the mixtures were studied using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), solid state (13)C nuclear magnetic resonance (NMR) spectroscopy and powder X-ray diffraction (PXRD) measurement. Additionally, portions of the coground samples were exposed to high relative humidity to investigate fentanyl and ß-CD interactions. The results of DSC and PXRD analyses indicate that the ground mixtures are in an amorphous state, and the FTIR measurements show hydrogen bonding interactions between fentanyl and ß-CD. Solid state (13)C NMR indicates that a fentanyl/ß-CD inclusion compound is formed in the humidified mixture. Furthermore, PXRD data from the humidified mixtures are similar to the PXRD patterns from the inclusion complex.
Asunto(s)
Analgésicos Opioides/química , Fentanilo/química , Tecnología Farmacéutica/métodos , beta-Ciclodextrinas/química , Rastreo Diferencial de Calorimetría , Fenómenos Químicos , Formas de Dosificación , Humedad , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética , Estructura Molecular , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Difracción de Rayos XRESUMEN
The effects of eight cyclodextrins (CDs) on the stability of freeze-dried lactate dehydrogenase (LDH) were investigated. Five low-molecular weight saccharides were used as a reference. In the samples without saccharides, LDH activity was decreased by freeze-drying. The LDH activities of the samples with 2-hydroxypropylated CDs (HP-CDs) such as 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) showed only a small decrease and were more effective protein stabilizers than low-molecular weight saccharides. HP-beta-CD more effectively stabilized LDH than trehalose, at a sugar concentration of less than 1.0 w/w% and furthermore, a close relationship existed between the highly stabilizing effect and the degree of substitution of polar substituents.
Asunto(s)
Ciclodextrinas/química , L-Lactato Deshidrogenasa/química , Estabilidad de Enzimas , Liofilización , L-Lactato Deshidrogenasa/metabolismo , Peso Molecular , Polisacáridos/químicaRESUMEN
The crystal structure of the delta-cyclodextrin complex with cycloundecanone shows a channel-type structure consisting of head-to-head dimer units that include four guest molecules.
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Ciclodextrinas/química , Cicloparafinas/química , Cetonas/química , Rastreo Diferencial de Calorimetría , Dimerización , Difracción de Rayos XRESUMEN
An anhydrous polymorphic form of alpha,alpha-trehalose was prepared from trehalose dihydrate by two different drying methods: (1) heating under vacuum; and (2) heating in hot air. Preparation of this anhydrous form by vacuum heating showed good reproducibility. This form was characterized by X-ray powder diffraction analysis and differential scanning calorimetry. This anhydrous form was converted to an amorphous phase at 127 degrees C and was found to be hygroscopic. At 43% relative humidity at 25 degrees C, this form rapidly reverted to dihydrate, while the amorphous phase remained unchanged. When an amorphous phase coexisted with this form, the rate of water adsorption to the amorphous phase was slower than that to the amorphous phase alone. These properties of this anhydrous form of alpha,alpha-trehalose may explain the effects of trehalose in dehydration tolerance of plants and insects in the desert.