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1.
AAPS PharmSciTech ; 21(2): 39, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31897724

RESUMO

The development of orodispersible tablets (ODTs) for poorly soluble and poorly flowable drugs via direct compression is still a challenge. This work aimed to develop ODTs of poorly soluble drugs by combining cyclodextrins that form inclusion complexes to improve wetting and release properties, and directly compressible co-processed excipients able to promote rapid disintegration and solve the poor flowability typical of inclusion complexes. Carbamazepine (CBZ) and hydroxypropyl-ß-cyclodextrin (HPßCD) were used, respectively, as a model of a poorly soluble drug with poor flowability and as a solubilizing agent. Specifically, CBZ-an antiepileptic and anticonvulsant drug-may benefit from the studied formulation approach, since some patients have swallowing difficulties or fear of choking and are non-cooperative. Prosolv® ODT G2 and F-Melt® type C were the studied five-in-one co-processed excipients. The complex was prepared by kneading. Flow properties of all materials and main properties of the tablets were characterized. The obtained results showed that ODTs containing CBZ/HPßCD complex can be prepared by direct compression through the addition of co-processed excipients. The simultaneous use of co-processing and cyclodextrin technologies rendered ODTs with an in vitro disintegration time in accordance with the European Pharmacopoeia requirement and with a fast and complete drug dissolution. In conclusion, the combination of five-in-one co-processed excipients and hydrophilic cyclodextrins may help addressing the ODT formulation of poorly soluble drugs with poor flowability, by direct compression and with desired release properties.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/química , Carbamazepina/administração & dosagem , Carbamazepina/química , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Liberação Controlada de Fármacos , Excipientes , Comprimidos , Difração de Raios X
2.
Food Chem ; 303: 125419, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470276

RESUMO

ß-Cyclodextrin- and 2-hydroxypropyl-ß-cyclodextrin/Danube common nase (Chondrostoma nasus L.) oil complexes (ß-CD- and HP-ß-CD/CNO) have been obtained for the first time. The fatty acid (FA) profile of the CNO indicates an important content of polyunsaturated fatty acids, the most important being eicosapentaenoic acid (EPA, 6.3%) and docosahexaenoic acid (DHA, 1.6%), both ω-3 FAs. The complexes have been obtained by kneading method. The moisture content and successful of molecular encapsulation have been evaluated by thermal and spectroscopic techniques. Thermogravimetry and differential scanning calorimetry analyses reveals that the moisture content of CD/CNO complexes significantly decreased, compared to starting CDs. On the other hand, the crystallinity index was for the first time determined for such type of complexes, the ß-CD/CNO complex having values of 43.9(±18.3)%, according to X-ray diffractometry. FA profile and CD/CNO characteristics sustain the use of these ω-3 based complexes for food supplements or functional food products, but further studies are needed.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Óleos de Peixe/química , beta-Ciclodextrinas/química , Animais , Varredura Diferencial de Calorimetria , Cyprinidae , Solubilidade , Difração de Raios X
3.
Planta Med ; 85(16): 1233-1241, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31610603

RESUMO

The chroman-like chalcone Xanthohumol C, originally found in hops, was demonstrated to be a potent neuroregenerative and neuroprotective natural product and therefore constitutes a strong candidate for further pharmaceutical research. The bottleneck for in vivo experiments is the low water solubility of this chalcone. Consequently, we developed and validated a suitable formulation enabling in vivo administration. Cyclodextrins were used as water-soluble and nontoxic complexing agents, and the complex of Xanthohumol C and 2-hydroxypropyl-ß-cyclodextrin was characterized using HPLC, HPLC-MS, NMR, and differential scanning calorimetry. The water solubility of Xanthohumol C increases with increasing concentrations of cyclodextrin. Using 50 mM 2-hydroxypropyl-ß-cyclodextrin, solubility was increased 650-fold. Furthermore, in vitro bioactivity of Xanthohumol C in free and complexed form did not significantly differ, suggesting the release of Xanthohumol C from 2-hydroxypropyl-ß-cyclodextrin. Finally, a small-scaled in vivo experiment in a rat model showed that after i. p. administration of the complex, Xanthohumol C can be detected in serum, the brain, and the cerebrospinal fluid at 1 and 6 h post-administration. Mean (± SD) Xanthohumol C serum concentrations after 1, 6, and 12 h were determined as 463.5 (± 120.9), 61.9 (± 13.4), and 9.3 (± 0.8) ng/mL upon i. v., and 294.3 (± 22.4), 45.5 (± 0.7), and 13 (± 1.0) ng/mL after i. p. application, respectively. Accordingly, the formulation of Xanthohumol C/2-hydroxypropyl-ß-cyclodextrin is suitable for further in vivo experiments and further pharmaceutical research aiming for the determination of its neuroregenerative potential in animal disease models.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/administração & dosagem , Benzopiranos/administração & dosagem , 2-Hidroxipropil-beta-Ciclodextrina/química , 2-Hidroxipropil-beta-Ciclodextrina/farmacocinética , Animais , Benzopiranos/química , Benzopiranos/farmacocinética , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Espectroscopia de Ressonância Magnética , Ratos , Solubilidade
4.
Int J Nanomedicine ; 14: 8221-8234, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632029

RESUMO

Background: Phenamil (PH) is a small molecule that induces bone formation through upregulation of the TRB3 gene in the bone-regeneration process. ß-Cyclodextrins (ßCDs) with hydrophilic surfaces and a relatively hydrophobic cavity can form inclusion complexes with primarily hydrophobic small molecules such as PH, and increase their apparent solubility and dissolution rate. The hydrophilic surface of ßCDs prevents their interaction with the hydrophobic lipids of the cell membrane for penetration. Therefore, binding of penetrative groups, such as lysine, arginine, and histidine (His), to ßCDs for cell penetration is required. Aim: The aim of this study was to investigate the effect of His-conjugated ßCD on cellular uptake of PH for bone differentiation. Methods: In this study, His-ßCDs were synthesized and used to prepare an inclusion complex of His-ßCD-PH. A hydroxypropyl-ßCD-PH (HP-ßCD-PH) inclusion complex for increasing PH solubility without a penetrative group was prepared for comparison. 3-D geometry of ßCD derivatives and PH-inclusion complexes was investigated by Fourier-transform infrared spectroscopy and molecular docking. Alizarin red staining and real-time PCR were performed to compare bone differentiation of His-ßCD-PH and HP-ßCD-PH. Results: The results suggested that the benzene ring of PH was inserted into the wide side of both His-ßCD and HP-ßCD. Alizarin red staining at 14 days postculture in the presence of His-ßCD-PH at total concentration of 50 µM for PH showed that bone-matrix mineralization increased significantly compared with free PH and HP-ßCD-PH. Real-time PCR confirmed this result, and showed gene expression increased significantly (OPN 1.84-fold, OCN 1.69-fold) when stem cells were cultured with His-ßCD-PH. Conclusion: The overall results indicated that His-ßCD-PH is a promising carrier for osteoinductive PH with possible penetration ability and sustained release that reduces BMP2 consumption for differentiation of mesenchymal stem cells to bone tissue.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Amilorida/análogos & derivados , Endocitose , Histidina/química , Osseointegração , Células-Tronco/metabolismo , 2-Hidroxipropil-beta-Ciclodextrina/síntese química , Tecido Adiposo/citologia , Amilorida/farmacologia , Calcificação Fisiológica/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Osseointegração/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Tamanho da Partícula , Espectroscopia de Prótons por Ressonância Magnética , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática
5.
Int J Pharm ; 570: 118652, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31472219

RESUMO

The aim of this work was to optimize the preparative process of quercetin loaded casein nanoparticles as well as to evaluate the pharmacokinetics of this flavonoid when administered orally in Wistar rats. Nanoparticles were obtained by coacervation after the incubation of casein, 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and quercetin in an aqueous environment. Then, nanoparticles were purified and dried. The resulting nanoparticles displayed a size of 200 nm with a negative zeta potential and a payload of about 32 µg/mg. Release studies showed a zero-order kinetic, suggesting a mechanism based on erosion of the nanoparticle matrix. For the pharmacokinetic study, quercetin was orally administered to rats as a single dose of 25 mg/kg. Animals treated with quercetin-loaded casein nanoparticles displayed higher plasma levels than those observed in animals receiving the solution of the flavonoid (control). Thus, the relative oral bioavailability of quercetin when administered as casein nanoparticles (close to 37%) was found to be about 9-times higher than the oral solution of the flavonoid in a mixture of PEG 400 and water. In summary, the combination of casein and 2-hydroxypropyl-ß-cyclodextrin produces nanoparticles that may be a good option to load quercetin for both nutraceutical and pharmaceutical purposes.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Caseínas/química , Nanopartículas/química , Quercetina/química , Quercetina/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Portadores de Fármacos/química , Flavonoides/química , Masculino , Polietilenoglicóis/química , Ratos , Ratos Wistar
6.
Food Chem Toxicol ; 133: 110795, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31472225

RESUMO

Lactobacillus fermentum is commonly responsible for fruit juice fermentation and spoilage. The aim of this study was to investigate the potential use of nerolidol to control the spoilage of fresh orange juice by L. fermentum. Nerolidol was incorporated into hydroxypropyl-ß-cyclodextrin inclusion complex, conventional liposome, and drug-in-cyclodextrin-in liposome systems. The systems were lyophilized and characterized with respect to their nerolidol content, size, and morphology. The effects of the acidity and cold storage of orange juice on the survival of L. fermentum were evaluated. Subsequently, the antibacterial activity of nerolidol in refrigerated orange juice was assessed at pH 3.3. Nerolidol showed a faster antibacterial activity at 4 000 µM (5 days) compared to 2 000 µM (8 days). Under the same conditions, the inclusion complex completely killed bacteria within 6 days of incubation at 4 000 µM, suggesting its potential application in fruit juices. Nerolidol-loaded liposomes did not exhibit an antibacterial activity and altered the appearance of juice.


Assuntos
Antibacterianos/farmacologia , Citrus sinensis/microbiologia , Sucos de Frutas e Vegetais/microbiologia , Lactobacillus fermentum/efeitos dos fármacos , Sesquiterpenos/farmacologia , 2-Hidroxipropil-beta-Ciclodextrina/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Temperatura Baixa , Portadores de Fármacos/química , Conservação de Alimentos/métodos , Lipossomos/química , Refrigeração
7.
Eur J Pharm Sci ; 139: 105056, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31446076

RESUMO

Topical application of aluminum-chloride phthalocyanine (AlClPc) is a challenge because of the drug's extremely low solubility, which prevents its absorption into deeper skin layers and causes molecule aggregation, reducing the photophysical effect. The goal of this study was to obtain a formulation applied in a certain condition that would allow homogeneous accumulation of AlClPc in cutaneous tissues, meaning a safer and non-invasive topical treatment for skin tumors based on photodynamic therapy. We first prepared and characterized AlClPc complexes with cyclodextrin to increase the photosensitizing agent solubility. The inclusion complex of AlClPc with hydroxypropyl-ß-cyclodextrin (HP-ßCD) amplified its loading dose in aqueous medium and maintained its photosensitizing properties in terms of reactive oxygen species production. Assays to determine the complex's in vitro cytotoxicity against murine melanoma skin cancer cells showed that when irradiated, the complex significantly reduced cell viability, whereas the absence of irradiation did not affect cell viability. Three physical techniques for permeation enhancement (i.e., tape-stripping abrasion, microneedle pretreatment and iontophoresis) were then evaluated. When applied in impaired skin, the complex could not increase drug penetration. The skin penetration of AlClPc, however, increased 2.3-fold following iontophoresis application in a shorter period compared to passive permeation. Therefore, these results suggest the administration of complexed AlClPc mediated by iontophoresis, followed by application of photodynamic therapy, might be an effective and non-invasive alternative for topical treatment of cutaneous tumors.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/administração & dosagem , Cloreto de Alumínio/administração & dosagem , Indóis/administração & dosagem , Melanoma Experimental/tratamento farmacológico , Compostos Organometálicos/administração & dosagem , Fármacos Fotossensibilizantes/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , 2-Hidroxipropil-beta-Ciclodextrina/química , Administração Cutânea , Cloreto de Alumínio/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Indóis/química , Iontoforese , Camundongos , Compostos Organometálicos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/química , Pele/metabolismo , Absorção Cutânea , Suínos
8.
Biochimie ; 165: 196-205, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408673

RESUMO

Chemical chaperones are a class of small molecules which enhance folding and prevent aggregation of proteins. Investigation of their effects on the processes of protein aggregation is of importance for further understanding of implication of protein aggregation in neurodegenerative diseases, as well as for solving biotechnological tasks. The effects of chemical chaperones trehalose and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) on the kinetics of aggregation of UV-irradiated muscle glycogen phosphorylase b (UV-Phb) at 37 °C have been studied. The process of thermal aggregation of UV-Phb includes a slow stage of structural reorganization of the UV-Phb molecule, nucleation stage and fast attachment of structurally reorganized UV-Phb molecules to nuclei formed during the nucleation stage. It was shown that both trehalose and HP-ß-CD increased the duration of the nucleation phase and slowed down the rate of structural reorganization of the UV-Phb molecule. This conclusion has been confirmed by the circular dichroism data. In the absence of chaperones, 82% UV-Phb aggregates, whereas in the presence of HP-ß-CD or trehalose the portion of aggregated protein decreases to 70 and 66%, respectively. The data on analytical ultracentrifugation demonstrated that in the presence of these additives the size of protein aggregates decreased. Analysis of the combined effect of trehalose and HP-ß-CD on UV-Phb aggregation showed that protein aggregation was independently affected by trehalose and HP-ß-CD.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Glicogênio Fosforilase Muscular/química , Agregados Proteicos , Trealose/química , 2-Hidroxipropil-beta-Ciclodextrina/farmacologia
9.
AAPS PharmSciTech ; 20(6): 244, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286296

RESUMO

Cyclodextrin (CD) inclusions are generally used to increase the solubility of poorly soluble drugs. In this study, magnolol (MAG) was used as a model drug for exploring the effects of CD on the degradation of pharmaceutical drugs by intestinal microflora. MAG/ß-cyclodextrin (ß-CD) and MAG/hydroxypropyl-ß-CD (HP-ß-CD) inclusion complexes were successfully prepared by the saturated aqueous solution and freeze-drying methods, respectively. Structural characterisation along with analyses of solubility, residual water content and drug content of the inclusion complexes was performed. The intestinal microflora of male rats was used to study MAG degradation in vitro. At three concentrations, the degradation of both the inclusion complexes was slower than that of the MAG monomer, MAG and CD mixtures and the MAG-poloxamer 188 micelle. There were no statistically significant differences in the degradation of the MAG/ß-CD and MAG/HP-ß-CD inclusion complexes. A simulation first-order equation of the degradation parameters revealed that the degradation of the inclusion complexes was slower and pronounced, judging by slope. The experimental findings were verified by molecular docking for predicting the stable molecular structure of the inclusion complexes. In conclusion, the inclusion complexes partially protected MAG from degradation by the intestinal bacteria.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Bactérias/metabolismo , Compostos de Bifenilo/metabolismo , Intestinos/microbiologia , Lignanas/metabolismo , beta-Ciclodextrinas/química , Animais , Liofilização , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Solubilidade
10.
J Chromatogr A ; 1603: 269-277, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31279475

RESUMO

In this study, a hydroxypropyl-ß-cyclodextrin (HP-ß-CD) functionalized monolithic capillary column was prepared by one-pot sequential reaction for the first time. The preparation of the HP-ß-CD functionalized monolithic column involves two sequential reactions in one pot: (1) the ring opening reaction between HP-ß-CD and glycidyl methacrylate (GMA) catalyzed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); (2) the copolymerization of GMA-HP-ß-CD, ethylene dimethacrylate (EDMA) and 2-acrylamido-2-methyl propane sulfonic acid (AMPS). A series of monolithic columns were successfully prepared by varying the temperature of the ring opening reaction or several copolymerization parameters (the type and composition of porogenic solvents, ratio of GMA-HP-ß-CD to EDMA and polymerization temperature). Then, the morphologies and structures of the resulting monolithic stationary phases were characterized by optical microscopy, scanning electron microscopy (SEM) and nitrogen adsorption analysis. Raman spectroscopy clearly indicated the successful bonding of HP-ß-CD onto the monolith. When the prepared chiral stationary phase (CSP) was applied for the separation of a set of racemic compounds by capillary electrochromatography (CEC), including racemic anticholinergic drugs, ß-adrenergic drugs, meptazinol and its intermediates, satisfactory separation selectivities were obtained. Additionally, the column also showed excellent separation abilities towards four flavanone glycosides epimers. Furthermore, the prepared monolithic columns exhibited satisfactory stability and reproducibilities of retention time, resolution and column efficiency. These results demonstrated the potential and usefulness of the developed one-pot sequential strategy in the preparation of other derivatized CD functionalized monolithic columns.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Eletrocromatografia Capilar/métodos , Adsorção , Compostos de Epóxi/química , Metacrilatos/química , Nitrogênio/química , Permeabilidade , Polimerização , Polímeros/química , Espectroscopia de Prótons por Ressonância Magnética , Reprodutibilidade dos Testes , Análise Espectral Raman , Estereoisomerismo , Temperatura Ambiente
11.
J Chromatogr A ; 1607: 460375, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31353071

RESUMO

Four amino acid chiral ionic liquids were evaluated in dual systems with hydroxypropyl-ß-cyclodextrin to investigate the enantioseparation by CE of a group of seven drugs as model compounds (duloxetine, verapamil, terbutaline, econazole, sulconazole, metoprolol, and nadolol). The use of two of these chiral ionic liquids (tetramethylammonium L-Lysine ([TMA][L-Lys]) and tetramethylammonium L-glutamic acid ([TMA][L-Glu])) as modifiers in CE is reported for the first time in this work whereas tetrabutylammonium L-lysine ([TBA][L-Lys]) and tetrabutylammonium L-glutamic acid ([TBA][L-Glu]) were employed previously in CE although very scarcely. The effect of the nature and the concentration of each ionic liquid added to the separation buffer containing the neutral cyclodextrin on the enantiomeric resolution and the migration time obtained for each drug, was investigated. A synergistic effect was observed when combining each chiral ionic liquid with hydroxypropyl-ß-cyclodextrin in the case of the five compounds for which the cyclodextrin showed enantiomeric discrimination power when used as sole chiral selector (duloxetine, verapamil, terbutaline, econazole, sulconazole). Buffer concentration and pH, temperature and separation voltage were varied in order to optimize the enantiomeric separation of these five compounds using dual systems giving rise to resolutions ranging from 1.1 to 6.6.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Aminoácidos/química , Eletroforese Capilar/métodos , Líquidos Iônicos/química , Preparações Farmacêuticas/isolamento & purificação , Tampões (Química) , Ácido Glutâmico/química , Concentração de Íons de Hidrogênio , Estereoisomerismo , Temperatura Ambiente
12.
Spectrochim Acta A Mol Biomol Spectrosc ; 223: 117278, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31234019

RESUMO

Fluorescence spectra, 1H NMR, thermoanalysis and molecular modeling were used to investigate the host-guest inclusion system of hydroxypropyl-ß-cyclodextrin (HPßCD) with capsaicin. Job's plot was employed to confirm a 1:2 host-guest stoichiometry. Phase solubility study indicated that the apparent stability constant was 3.76 × 106 M-2. With the enhancing fluorescence of capsaicin complexation with HPßCD, a spectrofluorimetric method approach to determine the capsaicin in bulk aqueous solution was developed. Linearity was achieved wide ranges (0.05-60 µg/mL), with low detection limit of 0.04 µg/mL, and the relative standard deviation was 1.30%. Application to the analysis of chili powder samples obtained a satisfactory recovery of 99.5-105.6%.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Capsaicina/análise , Capsaicina/química , Concentração de Íons de Hidrogênio , Simulação de Dinâmica Molecular , Espectroscopia de Prótons por Ressonância Magnética , Solubilidade , Espectrometria de Fluorescência , Termogravimetria , Fatores de Tempo
13.
Biomolecules ; 9(6)2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234312

RESUMO

α, ß amyrin (ABAM) is a natural mixture of pentacyclic triterpenes that has a wide range of biological activities. ABAM is isolated from the species of the Burseraceae family, in which the species Protium is commonly found in the Amazon region of Brazil. The aim of this work was to develop inclusion complexes (ICs) of ABAM and ß-cyclodextrin (ßCD) and hydroxypropyl-ß-cyclodextrin (HPßCD) by physical mixing (PM) and kneading (KN) methods. Interactions between ABAM and the CD's as well as the formation of ICs were confirmed by physicochemical characterization in the solid state by Fourier transform infrared (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), thermogravimetry (TG) and differential scanning calorimetry (DSC). Physicochemical characterization indicated the formation of ICs with both ßCD and HPßCD. Such ICs were able to induce changes in the physicochemical properties of ABAM. In addition, the formation of ICs with cyclodextrins showed to be an effective and promising alternative to enhance the anti-inflammatory activity and safety of ABAM.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , 2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Ácido Oleanólico/análogos & derivados , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Ácido Oleanólico/química , Solubilidade
14.
Biomed Chromatogr ; 33(10): e4616, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31166607

RESUMO

The established analytical method for determining the concentration of dantrolene sodium (Da) in rat tissues by HPLC/MS/MS technique was successfully applied to tissue distribution studies of Da in rats. Tissue homogenate samples were pretreated by protein precipitation with pre-cooled methanol. Chromatographic separation was achieved on an Acquity HPLC column (Kromat Universil XB-C18 , 2.1 × 150 mm, 3 µm). Mass spectrometry was conducted with an electrospray ionization interface in negative ionization mode and multiple reaction monitoring was used for quantitative analysis. The results showed that Da was rapidly and widely distributed in tissues and reached the maximum concentration within 0.5 h in all tissues after oral administration of Da-hydroxypropyl-ß-cyclodextrin (DHC). It was then metabolized by liver and finally excreted from kidney,which indicated that DHC inclusion complex has better absorption and higher oral bioavailability than Da. The results also provided evidence for the safety and effectiveness of drug clinical application.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Cromatografia Líquida de Alta Pressão/métodos , Dantroleno , Espectrometria de Massas em Tandem/métodos , Animais , Dantroleno/análise , Dantroleno/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Distribuição Tecidual
15.
Carbohydr Polym ; 221: 55-62, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31227167

RESUMO

This work aimed to explore for the first time the use of cyclodextrins to prepare printlets of poorly soluble drugs, such as carbamazepine, which require fine dose adjustment and rapid release. Orodispersible (flash) and immediate release formulations were 3D printed via semisolid extrusion of wet masses of hydroxypropyl-ß-cyclodextrin (HPßCD) and cellulose ethers and regulating tablet porosity. Rheology of the wet masses allowed identifying printable compositions. Printing robustness was assessed evaluating weight, dimensions, hardness, drug content, and microstructure. Drug crystallinity, printlet disintegration and dissolution profiles were also characterized. The results highlight the feasibility of using HPßCD as excipient in printlets of poorly soluble drugs, and the possibilities of tuning drug release profiles through small changes in cellulose ethers nature and ratio. Semisolid extrusion-based 3D printing is revealed as a feasible approach to in situ form carbamazepine-HPßCD complexes and to produce printlets with suitable physical and drug release properties for oral delivery.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Anticonvulsivantes/química , Carbamazepina/química , Excipientes/química , Impressão Tridimensional , Carboximetilcelulose Sódica/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Reologia
16.
Ultrason Sonochem ; 56: 84-93, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31101292

RESUMO

Ultrasound is an energy saving, simple, high efficiency and eco-friend physical technology. In this study, the inclusion complex of cuminaldehyde (CUM), a major constituent of cumin essential oil, with 2-hydroxypropyl-ß-cyclodextrin (HPßCD) was synthesised with the aid of ultrasound. The solid CUM/HPßCD-IC was characterized using Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC) techniques. The stability constants were evaluated by phase solubility, absorption and fluorimetry methods, and were found to be 168, 122 and 256 M-1, respectively. FT-IR and molecular modeling studies indicated that the phenyl ring with the aldehyde group of CUM was inserted into the hydrophobic HPßCD cavity. Further, the efficacy of CUM/HPßCD-IC for inactivation of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) was investigated through plate colony counting method. According to the results, the inactivation was 100 ±â€¯0.06% for both E. coli and S. aureus bacteria. The results demonstrated the inclusion of CUM within the harmless HPßCD cavity assisted by ultrasound technology, contributing the improvements of water solubility, thermal stability and antibacterial activities.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , 2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Benzaldeídos/química , Ondas Ultrassônicas , Configuração de Carboidratos , Escherichia coli/efeitos dos fármacos , Modelos Moleculares , Solubilidade , Staphylococcus aureus/efeitos dos fármacos , Temperatura Ambiente , Água/química
17.
Electrophoresis ; 40(14): 1787-1794, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31141181

RESUMO

In the past decade, more than 100 different cathinone derivatives slopped over entire Europe due to their enormous popularity. Generally, these novel psychoactive substances are easily available via the internet. This fact leads to various social problems, since cathinones are substances with consciousness-changing effects and are mainly misused for recreational matters by their consumers. Cathinones possess a chiral center including two enantiomeric forms with potentially different pharmacological behavior. This fact makes analytical method development regarding their chiral separation indispensable. In this study, a chiral capillary zone electrophoresis method for the enantioseparation of 61 cathinone and pyrovalerone derivatives was developed by means of four different ß-cyclodextrin derivatives. As chiral selectors, native ß-cyclodextrin as well as three of its derivatives namely acetyl-ß-cyclodextrin, 2-hydroxypropyl-ß-cyclodextrin, and carboxymethyl-ß-cyclodextrin were used. The cathinone and pyrovalerone derivatives were either purchased in internet stores or seized by police. As a result, overall 58 of 61 studied substances were partially or baseline separated by at least one of the four chiral selectors using 10 mM of ß-cyclodextrin derivative in a 10 mM sodium phosphate buffer (pH 2.5). Furthermore, the method was found to be suitable for simultaneous enantioseparations, for enantiomeric purity checks and to differentiate between positional isomers. Moreover, an intra- and an interday validation was performed successfully for each chiral selector to prove the robustness of the method.


Assuntos
Alcaloides/isolamento & purificação , Eletroforese Capilar , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina/química , Pirrolidinas/isolamento & purificação , Estereoisomerismo
18.
J Chromatogr A ; 1601: 340-349, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31060783

RESUMO

In this study, three functionalized chiral ionic liquids (CILs) derived from l-valinol, l-prolinol and l-phenylalaninol, namely N,N,N-trimethyl-l-valinol-bis(trifluoromethanesulfon)imide ([TMLV]+[Tf2N]-, CIL1), N,N-dimethyl-l-prolinol-bis(trifluoromethanesulfon)imide ([DMLP]+[Tf2N]-, CIL2) and N,N,N-trimethyl-l-phenylalaninol-bis(trifluoromethanesulfon)imide ([TMLP]+[Tf2N]-, CIL3), were synthesized and subsequently utilized for enantiomeric separation in capillary electrophoresis (CE) with 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) as chiral selector for the first time. Compared with traditional single HP-ß-CD separation system, the synergistic system exhibited substantially improved separations of six tested drugs. Using the CIL1/HP-ß-CD as a model system, the influence of crucial parameters including the type and proportion of organic modifier, CILs concentration, HP-ß-CD concentration and buffer pH was investigated in detail. Additionally, molecular modeling with AutoDock was applied to elucidate the enhanced enantioselectivity in the presence of CILs, which has certain guiding value in predicting the migration order of the enantiomers and studying the interactions important for the chiral recognition.


Assuntos
Amino Álcoois/química , Eletroforese Capilar/métodos , Líquidos Iônicos/síntese química , 2-Hidroxipropil-beta-Ciclodextrina/química , Concentração de Íons de Hidrogênio , Líquidos Iônicos/química , Estereoisomerismo
19.
Carbohydr Polym ; 216: 129-139, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047049

RESUMO

A novel biotin and arginine modified hydroxypropyl-ß-cyclodextrin (biotin-Arg(pbf)-HP-ß-CD) was successfully synthesized. The hydroxyl groups of HP-ß-CD on the primary faces were coupled with carboxyl groups of biotin using arginine as the functional spacer. Using biotin-Arg(pbf)-HP-ß-CD as the carrier, paclitaxel (PTX)-loaded nanoparticles were developed by modified emulsion solvent evaporation method. The optimized PTX-loaded biotin-Arg(pbf)-HP-ß-CD nanoparticles had a mean diameter of 121.9 nm and zeta potential of -57.7 mV. Transmission electron microscopy (TEM) observation revealed that the nanoparticles were spherical in shape. XRD spectra confirmed the successful encapsulation of PTX. Moreover, in vitro and in vivo evaluations were performed to demonstrate the superior antitumor activity of the PTX-loaded nanoparticles. The cellular uptake study demonstrated the biotin receptor-mediated endocytosis of biotin-Arg(pbf)-HP-ß-CD nanoparticles and the increase of cellular uptake by introduction of biotin and arginine. It can be concluded that the biotin-Arg(pbf)-HP-ß-CD nanoparticles are efficient tumor-targeting drug delivery systems for PTX.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Antineoplásicos/uso terapêutico , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/uso terapêutico , 2-Hidroxipropil-beta-Ciclodextrina/síntese química , 2-Hidroxipropil-beta-Ciclodextrina/toxicidade , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Arginina/análogos & derivados , Arginina/síntese química , Arginina/toxicidade , Biotina/análogos & derivados , Biotina/síntese química , Biotina/toxicidade , Carcinoma/tratamento farmacológico , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Feminino , Humanos , Células MCF-7 , Camundongos , Nanopartículas/toxicidade , Paclitaxel/química , Paclitaxel/farmacologia , Tamanho da Partícula , Neoplasias do Colo do Útero/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Methods Mol Biol ; 1985: 321-337, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31069742

RESUMO

Chiral separations by countercurrent chromatography are mainly divided into two types: homogeneous chiral selector addition and interfacial chiral ligand exchange. In this chapter, we describe two methods for the enantioseparation of phenylsuccinic acid and α-hydroxy acids by high-speed countercurrent chromatography using hydroxypropyl-ß-cyclodextrin and N-n-dodecyl-L-proline as chiral selectors for both above mentioned modes.


Assuntos
Distribuição Contracorrente/métodos , 2-Hidroxipropil-beta-Ciclodextrina/química , Cromatografia Líquida de Alta Pressão , Hidroxiácidos/química , Ligantes , Estereoisomerismo , Ácido Succínico/química
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