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1.
AAPS PharmSciTech ; 21(4): 123, 2020 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-32337654

RESUMO

The objective of this work was to investigate the capacity of mogroside V (MOG-V), a food additive, as a novel carrier to improve the bioavailability and liver distribution of silybin (SLY). Solid dispersion particles (SDPs) of SLY/MOG-V were prepared utilizing the solvent evaporation method. The physicochemical characterizations of SDPs were evaluated by using dynamic light scattering (DLS), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) measurements. DLS results demonstrated the formation of nanoparticles (206 nm) of SDPs in water. DSC and PXRD analysis revealed that SLY was in amorphous form or molecularly dispersed in SDPs. SDPs also exhibited a major increase in both dissolution rate and saturation solubility, as evidenced by a 1931-fold improvement (2201 µg/mL) in solubility compared with pure SLY (1.14 µg/mL). The pharmacokinetic study in rats showed that oral absorption of SLY/MOG-V SDPs was dramatically increased. The mean value of AUC until 12 h for SLY/MOG-V SDPs (27,481 ng·min/mL) was 24.5-fold higher than that of pure SLY (1122 ng·min/mL). In vivo tissue distribution experiment in mice confirmed that the major distribution tissue was changed from lungs to liver after SLY was loaded into MOG-V. In addition, even orally administrated to mice at a high dose (4.2 g/kg), MOG-V exhibited no undesirable effect on the plasma glucose concentrations. Thus, MOG-V may have the applicability to serve as an ideal excipient for solubilization or as a novel liver targeting carrier for the delivery of SLY.


Assuntos
Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Fígado/metabolismo , Silibina/metabolismo , Triterpenos/metabolismo , Administração Oral , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/metabolismo , Disponibilidade Biológica , Portadores de Fármacos/administração & dosagem , Avaliação Pré-Clínica de Medicamentos/métodos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ratos , Ratos Sprague-Dawley , Silibina/administração & dosagem , Edulcorantes/administração & dosagem , Edulcorantes/metabolismo , Triterpenos/administração & dosagem , Difração de Raios X/métodos
2.
AAPS PharmSciTech ; 21(3): 99, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32133549

RESUMO

The objective of the present investigation was to understand the effect of sucrose acetate isobutyrate (SAIB) on abuse-deterrent properties (ADPs) of abuse-deterrent formulations (ADFs) based on Polyox™. SAIB would enhance ADPs of Polyox™-based formulations due to its glassy liquid and hydrophobic properties. Formulations were prepared by granulation followed by compression and heat curing at 90°C. The formulations were evaluated for surface morphology, hardness, manipulation in coffee grinder, particle size distribution, drug (pseudoephedrine hydrochloride) extraction in water, alcohol, 0.1 N HCl, 0.1 N NaOH at room temperature and elevated temperature using microwave and oven, syringeability and injectability, and dissolution. The heat curing of formulations significantly increased the hardness (> 490 N). Addition of SAIB imparted elasticity to formulations and decreased brittleness as indicated by lower values of work done and gradient compared to control formulations. After grinding, about 7.7-25.6% of the powder remained on the sieve (1 mm pore opening), D90 was 53.1-136.7 µm more, and Q (fraction < 500 µm) was 17.8-40.7% less in SAIB-based formulations compared to control formulations. Drug extraction between control and test intact formulations was similar. However, drug extraction was 23.9-42.5% (water), 20.6-26.1% (0.1 N HCl), and 37.4-50.6% (0.1 N NaOH) less in SAIB-based powder cured and uncured formulations compared to control formulations. Dissolution varied from 65.6 ± 4.2 to 97.6 ± 4.0% in 9 h from the formulations. In conclusion, addition of SAIB to Polyox™-based ADFs has synergistic effect on ADPs. This would further decrease potential of drug abuse/misuse by various routes.


Assuntos
Formulações de Dissuasão de Abuso/métodos , Composição de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Sacarose/análogos & derivados , Formulações de Dissuasão de Abuso/tendências , Composição de Medicamentos/tendências , Desenvolvimento de Medicamentos/tendências , Dureza , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/metabolismo , Tamanho da Partícula , Pós , Sacarose/administração & dosagem , Sacarose/química , Difração de Raios X/métodos , Difração de Raios X/tendências
3.
AAPS PharmSciTech ; 21(3): 94, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32096096

RESUMO

The aim of this study is to investigate the relationship between the structural, molecular, and particulate properties of alginic acid and its functional characteristics in direct compression (tabletability, compressibility, elasticity, deformation mechanism, and disintegration ability). Therefore, accurate characterization of two different batches of alginic acid was executed (X-ray powder diffraction, Fourier-transform infrared spectroscopy, thermogravimetric analysis, scanning electronic microscopy, 1H nuclear magnetic resonance, size exclusion chromatography - multi angle light scattering, viscosimetry, carboxylic acid titration, powder flowability, true density, laser granulometry). Results showed that molecular weight seems to affect tablet properties and that the alginic acid with the lowest molecular weight provides the hardest tablets with the lowest elastic recovery. Furthermore, these results show the potential interest of exploiting alginic acid as filler excipient in tablet formulation. Finally, disintegration properties of tested materials were found to be close to that of commercial superdisintegrants (Glycolys® and Kollidon Cl®) but not correlated to their swelling force. It can be concluded, for the first time, that the determination of alginic acid molecular weight seems key for applications in direct compression and in particular for obtaining tablets with reproducible strength.


Assuntos
Ácido Algínico/análise , Ácido Algínico/química , Avaliação Pré-Clínica de Medicamentos/métodos , Elasticidade , Excipientes/química , Dureza , Fenômenos Mecânicos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Relação Estrutura-Atividade , Comprimidos , Difração de Raios X/métodos
4.
J Appl Oral Sci ; 28: e20190371, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049135

RESUMO

OBJECTIVE: This study aims to evaluate the influence of different air-abrasion pressures and subsequent heat treatment on the flexural strength, surface roughness, and crystallographic phases of highly translucent partially stabilized zirconia (Y-PSZ), and on the tensile bond strength of resin cement to Y-PSZ. METHODOLOGY: Fully sintered zirconia specimens were ground with SiC paper (control) and/or air-abraded with 50 µm particles of alumina at 0.1, 0.15, 0.2, or 0.3 MPa or left as-sintered. After air-abrasion at 0.2 MPa (0.2AB), additional specimens were then heated to 1500°C, and held for one hour at this temperature (0.2AB+HT1h). Flexural strength and surface roughness were evaluated. Crystalline phase identification was also carried out using X-ray diffraction. Bonded zirconia specimens with self-adhesive resin cement were stored in distilled water at 37°C for 24 h, either with or without aging (thermal cycling 4-60°C/20000). Results were analyzed statistically by ANOVA and Tukey-Kramer tests. RESULTS: The flexural strength decreased with the increase in air-abrasion pressure, while in contrast, the surface roughness increased. The lowest flexural strength and the highest roughness value were found for the 0.2AB and 0.3AB groups, respectively. All groups contained cubic-, tetragonal ( t )-, and rhombohedral ( r )-ZrO2 phases with the exception of the as-sintered group. Upon increasing the air-abrasion pressure, the relative amount of the r -ZrO2 phase increased, with a significant amount of r -ZrO2 phase being detected for the 0.2AB and 0.3AB groups. The 0.2AB+HT1h group exhibited a similar flexural strength and t -ZrO2 phase content as the as-sintered group. However, the 0.2AB group showed a significantly higher tensile bond strength (p<0.05) than the 0.2AB+HT1h group before and after aging. CONCLUSION: Micromechanical retention by alumina air-abrasion at 0.2 MPa, in combination with chemical bonding of a resin to highly translucent Y-PSZ using a MDP-containing resin cement may enable durable bonding.


Assuntos
Abrasão Dental por Ar/métodos , Óxido de Alumínio/química , Colagem Dentária/métodos , Cimentos de Resina/química , Zircônio/química , Análise de Variância , Resistência à Flexão , Temperatura Alta , Teste de Materiais , Microscopia Confocal/métodos , Valores de Referência , Reprodutibilidade dos Testes , Propriedades de Superfície , Resistência à Tração , Difração de Raios X/métodos
5.
Chem Biol Interact ; 319: 109019, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32092302

RESUMO

The inhibition of the enzyme acetylcholinesterase (AChE) is a frequently used therapeutic option to treat Alzheimer's disease (AD). By decreasing the levels of acetylcholine degradation in the synaptic space, some cognitive functions of patients suffering from this disease are significantly improved. Rivastigmine is one of the most widely used AChE inhibitors. The objective of this work was to determine the effects of this drug on human erythrocytes, which have a type of AChE in the cell membrane. To that end, human erythrocytes and molecular models of its membrane constituted by dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) were used. They correspond to classes of phospholipids present in the outer and inner monolayers of the human erythrocyte membrane, respectively. The experimental results obtained by X-ray diffraction and differential scanning calorimetry (DSC) indicated that rivastigmine molecules were able to interact with both phospholipids. Fluorescence spectroscopy results showed that rivastigmine produce a slight change in the acyl chain packing order and a weak displacement of the water molecules of the hydrophobic-hydrophilic membrane interface. On the other hand, observations by scanning electron microscopy (SEM) showed that the drug changed the normal biconcave shape of erythrocytes in stomatocytes (cup-shaped cells) and echinocytes (speculated shaped).


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Eritrócitos/efeitos dos fármacos , Rivastigmina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Varredura Diferencial de Calorimetria/métodos , Forma Celular/efeitos dos fármacos , Dimiristoilfosfatidilcolina/metabolismo , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Eritrócitos/metabolismo , Humanos , Microscopia Eletrônica de Varredura/métodos , Modelos Moleculares , Fosfatidiletanolaminas/metabolismo , Fosfolipídeos/metabolismo , Espectrometria de Fluorescência/métodos , Difração de Raios X/métodos
6.
PLoS One ; 15(2): e0228720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32045461

RESUMO

Brain aggregates of ß amyloid (ßA) protein plaques have been widely recognized as associated with many neurodegenerative diseases, and their identification can assist in the early diagnosis of Alzheimer's disease. We investigate the feasibility of using a spectral x-ray coherent scatter system with a silicon strip photon-counting detector for identifying brain ßA protein plaques. This approach is based on differences in the structure of amyloid, white and grey matter in the brain. We simulated an energy- and angular-dispersive X-ray diffraction system with an x-ray pencil beam and Silicon strip sensor, energy-resolving detectors. The polychromatic beam is geometrically focused toward a region of interest in the brain. First, the open-source MC-GPU code for Monte Carlo transport was modified to accommodate the detector model. Second, brain phantoms with and without ßA were simulated to assess the method and determine the radiation dose required to obtain acceptable statistical power. For ßA targets of 3, 4 and 5 mm sizes in a 15-cm brain model, the required incident exposure was about 0.44 mR from a 60 kVp tungsten spectrum and 3.5 mm of added aluminum filtration. The results suggest that the proposed x-ray coherent scatter technique enables the use of high energy x-ray spectra and therefore has the potential to be used for accurate in vivo detection and quantification of ßA in the brain within acceptable radiation dose levels.


Assuntos
Encéfalo/diagnóstico por imagem , Placa Amiloide/diagnóstico , Difração de Raios X/métodos , Humanos , Método de Monte Carlo , Fótons , Difração de Raios X/instrumentação
7.
Acta Crystallogr D Struct Biol ; 76(Pt 2): 102-117, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32038041

RESUMO

Ab initio reconstruction methods have revolutionized the capabilities of small-angle X-ray scattering (SAXS), allowing the data-driven discovery of previously unknown molecular conformations, exploiting optimization heuristics and assumptions behind the composition of globular molecules. While these methods have been successful for the analysis of small particles, their impact on fibrillar assemblies has been more limited. The micrometre-range size of these assemblies and the complex interaction of their periodicities in their scattering profiles indicate that the discovery of fibril structures from SAXS measurements requires novel approaches beyond extending existing tools for molecular discovery. In this work, it is proposed to use SAXS measurements, together with diffraction theory, to infer the electron distribution of the average cross-section of a fiber. This cross-section is modeled as a discrete electron density with continuous support, allowing representations beyond binary distributions. Additional constraints, such as non-negativity or smoothness/connectedness, can also be added to the framework. The proposed approach is tested using simulated SAXS data from amyloid ß fibril models and using measured data of Tobacco mosaic virus from SAXS experiments, recovering the geometry and density of the cross-sections in all cases. The approach is further tested by analyzing SAXS data from different amyloid ß fibril assemblies, with results that are in agreement with previously proposed models from cryo-EM measurements. The limitations of the proposed method, together with an analysis of the robustness of the method and the combination with different experimental sources, are also discussed.


Assuntos
Amiloide/química , Espalhamento a Baixo Ângulo , Vírus do Mosaico do Tabaco/química , Difração de Raios X/métodos , Algoritmos , Microscopia Crioeletrônica , Modelos Moleculares , Software
8.
Biochim Biophys Acta Biomembr ; 1862(5): 183191, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31953232

RESUMO

Protein dynamics at atomic resolution can provide deep insights into the biological activities of proteins and enzymes but they can also make structure and dynamics studies challenging. Despite their well-known biological and pharmaceutical importance, integral membrane protein structure and dynamics studies lag behind those of water-soluble proteins mainly owing to solubility problems that result upon their removal from the membrane. Escherichia coli glycerol facilitator (GF) is a member of the aquaglyceroporin family that allows for the highly selective passive diffusion of its substrate glycerol across the inner membrane of the bacterium. Previous molecular dynamics simulations and hydrogen-deuterium exchange studies suggested that protein dynamics play an important role in the passage of glycerol through the protein pore. With the aim of studying GF dynamics by solution and solid-state nuclear magnetic resonance (NMR) spectroscopy we optimized the expression of isotope-labelled GF and explored various solubilizing agents including detergents, osmolytes, amphipols, random heteropolymers, lipid nanodiscs, bicelles and other buffer additives to optimize the solubility and polydispersity of the protein. The GF protein is most stable and soluble in lauryl maltose neopentyl glycol (LMNG), where it exists in a tetramer-octamer equilibrium. The solution structures of the GF tetramer and octamer were determined by negative-stain transmission electron microscopy (TEM), size-exclusion chromatography small-angle X-ray scattering (SEC-SAXS) and solid-state magic-angle spinning NMR spectroscopy. Although NMR sample preparation still needs optimization for full structure and dynamics studies, negative stain TEM and SEC-SAXS revealed low-resolution structures of the detergent-solubilized tetramer and octamer particles. The non-native octamer appears to form from the association of the cytoplasmic faces of two tetramers, the interaction apparently mediated by their disordered N- and C-termini. This information may be useful in future studies directed at reducing the heterogeneity and self-association of the protein.


Assuntos
Aquaporinas/química , Aquaporinas/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Cromatografia em Gel/métodos , Detergentes/química , Escherichia coli/química , Escherichia coli/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Proteínas de Membrana/química , Micelas , Simulação de Dinâmica Molecular , Espalhamento a Baixo Ângulo , Solubilidade , Difração de Raios X/métodos
9.
AAPS PharmSciTech ; 21(3): 75, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31965388

RESUMO

An aprepitant (APT) cholesteryl hemisuccinate (CHEMS) ion pair complex emulsion (AIPE) with high lecithin content was prepared to improve sterilization stability through the film dispersion homogenization method; therefore, it could be a promising delivery system of APT. Medium-chain triglycerides (MCT) was selected as the oil phase to improve the solubility and stability of APT in oil phase. DSC, XRD, FT-IR, and 1H-NMR spectroscopies confirmed that the APT-CHEMS ion pair (AIP) was formed between CHEMS and APT. The formation of AIP significantly increased the hydrophobicity of APT, allowing it to be completely embedded in the oil phase core to improve chemical stability and decrease hydrolysis of APT in the water phase. Also, CHEMS had a strong affinity with lecithin and could stabilize lipid membranes, forming a stronger and thicker interface membrane to increase the physical stability of AIPE. As a result, AIPE could withstand autoclaving at 120°C for 8 min without any change of particle size or content. Furthermore, AIPE with a potential of - 53.4 mV remained stable through spatial repulsion during sterilization. The encapsulation efficiency of AIPE was over 90% and the particle size was 106.8 ± 65.62 nm(0.286). Pharmacokinetic study in rats was comparable with that of CINVANTI which yielded a relative bioavailability of 114.31% indicating that the AIPE had similar pharmacokinetic processes in vivo with the analog of CINVANTI®. The AUC0-t of the AIPE was 4.31-fold that of the APT solution.


Assuntos
Aprepitanto/administração & dosagem , Aprepitanto/química , Temperatura Alta , Fosfolipídeos/administração & dosagem , Fosfolipídeos/química , Esterilização/métodos , Administração Intravenosa , Animais , Estabilidade de Medicamentos , Emulsões , Masculino , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X/métodos
10.
Biochim Biophys Acta Biomembr ; 1862(2): 183095, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672542

RESUMO

Changes in membrane properties occurring upon protein interaction are key questions in understanding membrane protein function. To report on the occurring size and shape variation we present here a combined NMR-SAXS method performed under physiological conditions using the same samples, enabling determination of a global parameter, the hydration radius (rH) and estimating the bicelle shape. We use zwitterionic (DMPC/DHPC) and negatively charged (DMPC/DHPC/DMPG) bicelles and investigate the interaction with model transmembrane and surface active peptides (KALP23 and melittin). 1H NMR measurements based mostly on the translational diffusion coefficient D determination are used to characterize cmc values of DHPC micelles under the investigated conditions, to describe DHPC distribution with exact determination of the q (long chain/short chain) lipid ratio, to estimate aggregation numbers and effective rH values. The scattering curve is used to fit a lenticular core-shell model enabling us to describe the bicelle shape in terms of ellipsoidal axis length parameters. For all studied systems formation of oblate ellipsoids is found. Even though the rG/rH ratio would be an elegant way to characterize shape variations, we show that changes occurring upon peptide-bicelle interaction in the "effective" size and in the measure on the anisometry - morphology - of the objects can be described by using rH and the simplistic ellipsoidal core-shell model. While the influence of the transmembrane KALP peptide is significant, effects upon addition of surface active melittin peptide seem negligible. This synergy of techniques under controlled conditions can provide information about bicellar shape modulation occurring during peptide-bicelle interactions.


Assuntos
Bicamadas Lipídicas/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Peptídeos/metabolismo , Espalhamento a Baixo Ângulo , Meliteno/metabolismo , Proteínas de Membrana/metabolismo , Micelas , Difração de Raios X/métodos
11.
Biochim Biophys Acta Biomembr ; 1862(3): 183159, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31857070

RESUMO

The past three decades have witnessed fast advances in the use of cationic liposome-DNA complexes (lipoplexes) for gene delivery applications. However, no lipoplex formulation has reached into the clinical practice so far. The primary drawback limiting clinical use of lipoplexes is the lack of mechanistic understanding of their low transfection efficiency (TE) in vivo. In physiological environments, lipoplexes are coated by a protein corona (PC) that mediates the interactions with the cell machinery. Here we show that the formation of PC can change the interactions of multicomponent (MC) lipoplexes with our cell model (i.e., HeLa). At the highest lipoplex concentration, the formation of PC can reduce the TE of MC lipoplexes from 60% to <5%. Combining dynamic light scattering and synchrotron small-angle X-ray scattering (SAXS), we clarify that the formation of PC modifies physical-chemical properties of MC lipoplexes so as to affect their TE. Moreover, we examined single transfection barriers by a combination of fluorescence-activated cell sorting, single-cell real-time fluorescence confocal microscopy, and synchrotron SAXS. We demonstrate that PC formation has the ability to modify the relative contribution of caveolae-mediated endocytosis and macropinocytosis in lipoplexes uptake, in favor of the latter, increasing accumulation of PC-decorated lipoplexes into degradative lysosomal compartments. Finally, we report evidences that PC reduces the structural stability of lipoplexes against solubilization by cellular lipids, likely favoring premature DNA release and cytosolic digestion by DNAase. These combined effects revealed here offer a comprehensive mechanistic explanation on the reason behind reduction in gene expression of MC lipoplexes.


Assuntos
Regulação da Expressão Gênica/fisiologia , Lipossomos/química , Coroa de Proteína/metabolismo , Animais , Fenômenos Bioquímicos , Células CHO , Cátions/química , Cricetulus , Citosol/química , DNA/química , Endocitose/fisiologia , Células HeLa , Humanos , Lipídeos/química , Lipossomos/metabolismo , Coroa de Proteína/química , Espalhamento a Baixo Ângulo , Síncrotrons , Transfecção , Difração de Raios X/métodos
12.
Chemosphere ; 240: 124953, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31574435

RESUMO

Chemical characterization of PM2.5 and PM10 is important to identify potential compounds that induce biological responses that translate into cardio-respiratory health problems. This study shows the reliability of the use of crystalline phases, identified in samples from receptor sites, as source markers, helping researchers to infer the main sources of air pollution, even without the use of receptor models. PM2.5 and PM10 samples were collected at two sites in an urban industrialized region located at southeast of Brazil and analyzed by Synchrotron X-ray Diffraction to identify crystalline compounds. Results show 5 PM10 and PM2.5 species not previously reported in the literature. We propose reaction mechanisms for these species and identify specific sources for each crystalline phase found: BaTiO3 was found in PM10 receptor samples and proved to be a vehicular marker formed during brake action; maghemite (γ-Fe2O3), pyracmonite [(NH4)3Fe(SO4)3], ammonium perchlorate (NH3OHClO4) and potassium ferrate (K2Fe2O4) were found in PM2.5 proved to be markers of industrial activities. The crystalline phases found in PM samples from receptor sites and the mechanisms of reactions showed the reliability of the use of crystalline phases as source markers in the identification of potential sources of air pollution without misinterpretation of the likely source.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/análise , Monitoramento Ambiental/métodos , Material Particulado/análise , Material Particulado/química , Sulfato de Amônio/análise , Compostos de Bário/análise , Brasil , Compostos Férricos/análise , Indústrias , Compostos de Ferro/análise , Tamanho da Partícula , Percloratos/análise , Compostos de Potássio/análise , Compostos de Amônio Quaternário/análise , Reprodutibilidade dos Testes , Síncrotrons , Titânio/análise , Difração de Raios X/métodos
13.
Pharm Dev Technol ; 25(1): 68-75, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31544585

RESUMO

To improve the aqueous solubility and the oral bioavailability of a poorly water-soluble biologically active pentacyclic triterpenoid, ursolic acid (UA), ursolic acid-phospholipid complex (UA-PC) was prepared using solvent-assisted grinding method which is green and simple. The phospholipid complex was characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscope (SEM), and transmission electron microscope (TEM), which confirmed the formation of the phospholipid complex. Specifically, compared with free UA, the formulation demonstrated over 276-fold higher aqueous solubility of UA and exhibited faster dissolution rate and higher cumulative dissolution percentages. Finally, the oral bioavailability of the prepared UA-PC was evaluated using Sprague-Dawley (SD) rats. Compared with free UA, the UA-PC exhibited considerable enhancement in the bioavailability with an increase in Cmax (183.80 vs 68.26 µg/l) and AUC 0-24 h (878.0 vs 212.1 µg·h/l), which was consistent with the in vitro results. This enhancement was attributed to the improvement of solubility and dissolution in vitro. Therefore, the method of solvent-assisted grinding appears to be an efficient approach for the preparation of UA-PC, and the prepared UA-PC showed a promising potential to overcome the limitation of poor oral bioavailability associated with low water solubility.


Assuntos
Fosfolipídeos/química , Solubilidade/efeitos dos fármacos , Solventes/química , Triterpenos/química , Administração Oral , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria/métodos , Masculino , Microscopia Eletrônica de Varredura/métodos , Ratos , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Triterpenos/farmacocinética , Água/química , Difração de Raios X/métodos
14.
J Pharm Biomed Anal ; 178: 112937, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31679845

RESUMO

Amorphous solid dispersions (ASDs) are single-phase amorphous systems, where drug molecules are molecularly dispersed (dissolved) in a polymer matrix. The molecular dispersion of the drug molecules is responsible for their improved dissolution properties. Unambiguously establishing the phase behavior of the ASDs is of utmost importance. In this paper, we focused on the complementary nature of (modulated) differential scanning calorimetry ((m)DSC) and X-ray powder diffraction (XRPD) to elucidate the phase behavior of ASDs as demonstrated by a critical discussion of practical real-life examples observed in our research group. The ASDs were manufactured by either applying a solvent-based technique (spray drying), a heat-based technique (hot melt extrusion) or mechanochemical activation (cryo-milling). The encountered limiting factors of XRPD were the lack of sensitivity for small traces of crystallinity, the impossibility to differentiate between distinct amorphous phases and its impossibility to detect nanocrystals in a polymer matrix. In addition, the limiting factors of (m)DSC were defined as the well-described heat-induced sample alteration upon heating, the interfering of residual solvent evaporation with other thermal events and the coinciding of enthalpy recovery with melting events. In all of these cases, the application of a single analytical technique would have led to erroneous conclusions, whilst the combination of (m)DSC and XRPD elucidated the true phases of the ASD.


Assuntos
Polímeros/química , Pós/química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Cristalização/métodos , Temperatura Alta , Nanopartículas/química , Sensibilidade e Especificidade , Solubilidade/efeitos dos fármacos , Solventes/química , Tecnologia Farmacêutica/métodos , Difração de Raios X/métodos
15.
AAPS PharmSciTech ; 21(1): 16, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31807963

RESUMO

Triclabendazole belongs to the class II/IV of the Biopharmaceuticals Classification System, and its low aqueous solubility represents a major drawback during the development of effective dosage forms. Therefore, the goal of this study was to elucidate whether polymeric solid dispersions would represent a suitable approach to overcome such disadvantage. Due to the lack of information on triclabendazole release, four different dissolution media were evaluated to analyze drug dissolution rate. The polymeric solid dispersions were characterized by X-ray diffraction and Fourier transform infrared spectroscopy. The selected final formulations were further stored for 24 months, and their physical stability was evaluated by means of X-ray diffraction and drug dissolution assays. Drug solubility studies indicated that poloxamer 407 (P407) solubilized a higher amount of drug than polyethylene glycol 6000. Drug-to-carrier ratio, nature of the selected carriers, and the type of dissolution media were important factors for increasing dissolution. By infrared spectroscopy, there were no specific interactions between the drug and polymers. The physicochemical characterization of the systems showed a detectable evidence of drug amorphization by increasing the carrier ratio. Micromeritic studies indicated that raw triclabendazole, physical mixtures, and reference formulation showed poor flow properties, in contrast to the triclabendazole:P407 solid dispersion sample. Both the crystalline properties and dissolution rate of selected samples were very similar after 24 months at room temperature. Thus, considering physical stability and dissolution studies, the development of the solid dispersion is a very suitable methodology to improve triclabendazole dissolution and, potentially, its biopharmaceutical performance.


Assuntos
Antiplatelmínticos/química , Sistemas de Liberação de Medicamentos/métodos , Triclabendazol/química , Administração Oral , Antiplatelmínticos/administração & dosagem , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Cristalização/métodos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Solubilidade , Espectrofotometria Infravermelho/métodos , Triclabendazol/administração & dosagem , Difração de Raios X/métodos
16.
Pak J Pharm Sci ; 32(5): 2139-2147, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31813880

RESUMO

Different polymorphic forms can affect the performance of the drug product. In addition, isomorphic crystals show different chemical and physical properties due to the changes in the crystal habit. However, it is unclear whether the crystal habit results in different pharmacological activity. The aim of this study was to investigate whether the pharmacological effect of ibuprofen could be affected due to the variety of the crystal habit. Solvent change technique and conventional fusion method were carried out to modify the characteristics of ibuprofen. The physicochemical properties of each were investigated using powder X-ray diffraction (PXRD), Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) techniques. Results of scanning electron microscopy (SEM) analysis revealed differences in the surface characteristics of the crystals obtained. Further study revealed that the samples crystallized exhibited the remarkable variation on the dissolution profiles in different dissolution medium. Moreover, in vivo antinociceptive and anti-inflammatory findings demonstrated that the crystal habit modifications resulted in the different therapeutic efficacy. Taken together, these results indicate that the modification of the crystal habit had a great influence on the in vivo pharmacological activity of ibuprofen crystals.


Assuntos
Ibuprofeno/química , Ibuprofeno/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Cristalização/métodos , Camundongos , Camundongos Endogâmicos ICR , Microscopia Eletrônica de Varredura/métodos , Tamanho da Partícula , Pós/química , Pós/farmacologia , Ratos , Ratos Wistar , Solubilidade/efeitos dos fármacos , Solventes/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X/métodos
17.
Soft Matter ; 15(46): 9565-9578, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31724682

RESUMO

The performance of orally administered lipid-based drug formulations is crucially dependent on digestion, and understanding the colloidal structures formed during digestion is necessary for rational formulation design. Previous studies using the established bulk pH-stat approach (Hong et al. 2015), coupled to synchrotron small angle X-ray scattering (SAXS), have begun to shed light on this subject. Such studies of digestion using in situ SAXS measurements are complex and have limitations regarding the resolution of intermediate structures. Using a microfluidic device, the digestion of lipid systems may be monitored with far better control over the mixing of the components and the application of enzyme, thereby elucidating a finer understanding of the structural progression of these lipid systems. This work compares a simple T-junction microcapillary device and a custom-built microfluidic chip featuring hydrodynamic flow focusing, with an equivalent experiment with the full scale pH-stat approach. Both microfluidic devices were found to be suitable for in situ SAXS measurements in tracking the kinetics with improved time and signal sensitivity compared to other microfluidic devices studying similar lipid-based systems, and producing more consistent and controllable structural transformations. Particle sizing of the nanoparticles produced in the microfluidic devices were more consistent than the pH-stat approach.


Assuntos
Lipase/metabolismo , Lipídeos/química , Lipossomos/química , Microfluídica/métodos , Nanopartículas/química , Difração de Raios X/métodos , Composição de Medicamentos/métodos , Microfluídica/instrumentação , Espalhamento a Baixo Ângulo , Difração de Raios X/instrumentação
18.
AAPS PharmSciTech ; 21(1): 6, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754916

RESUMO

The aim of the study is to investigate the feasibility of fabricating FDM 3D-printed gastric floating tablets with low infill percentages and the effect of infill percentage on the properties of gastric floating tablets in vitro. Propranolol hydrochloride was selected as a model drug, and drug-loaded polyvinyl alcohol (PVA) filaments were produced by hot melt extrusion (HME). Ellipsoid-shaped gastric floating tablets with low infill percentage of 15% and 25% (namely E-15 and E-25) were then prepared respectively by feeding the extruded filaments to FDM 3D printer. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and scanning electron microscopy (SEM) were employed to characterize the filaments and 3D-printed tablets, and a series of evaluations were performed to the 3D-printed tablets, including the weight variation, drug content, hardness, in vitro floating behavior, and drug release of the tablets. The SEM results showed that the drug-loaded filaments and 3D-printed tablets appeared intact without defects, and the printed tablets were composed of filaments deposited uniformly layer by layer. The model drug and the excipients were thermally stable under the process temperature of extruding and printing, with a small amount of drug crystals dispersing in the drug-loaded filaments and 3D-printed tablets. Both E-15 and E-25 could float on artificial gastric fluids without any lag time and released in a sustained manner. Compared with E-15, the E-25 presented less weight variation, higher tablet hardness, shorter floating time, and longer drug release time.


Assuntos
Portadores de Fármacos/síntese química , Excipientes/síntese química , Impressão Tridimensional , Comprimidos/síntese química , Tecnologia Farmacêutica/métodos , Varredura Diferencial de Calorimetria/métodos , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Excipientes/farmacocinética , Álcool de Polivinil/síntese química , Álcool de Polivinil/farmacocinética , Propranolol/síntese química , Propranolol/farmacocinética , Comprimidos/farmacocinética , Difração de Raios X/métodos
19.
Molecules ; 24(23)2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31779169

RESUMO

The solid dispersion technique, which is widely used in the medical field, was applied to prepare a pesticide dosage form of emamectin benzoate (EM). The preparation, physicochemical characterization, aqueous solubility, release dynamics, photolytic degradation, bioactivity, and sustained-release effects of the prepared EM solid dispersions were studied by a solvent method, using polymer materials as the carriers. Water-soluble polyvinyl pyrrolidone (PVP) K30 and water-insoluble polyacrylic resin (PR)III were used as the carriers. The influence of various parameters, such as different EM:PVP-K30 and EM:PRIII feed ratios, solvent and container choices, rotational speed and mixing time effects on pesticide loading, and the entrapment rate of the solid dispersions were investigated. The optimal conditions for the preparation of EM-PVP-K30 solid dispersions required the use of methanol and a feed ratio between 1:1 and 1:50, along with a rotational speed and mixing time of 600 rpm and 60 min, respectively. For the preparation of EM-PRIII solid dispersions, the use of methanol and a feed ratio between 1:4 and 1:50 were required, in addition to the use of a porcelain mortar for carrying out the process. Under optimized conditions, the prepared EM-PVP-K30 solid dispersions resembled potato-like, round, and irregular structures with a jagged surface. In contrast, the EM-PRIII solid dispersions were irregular solids with a microporous surface structure. The results of X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), ultraviolet (UV) spectrometry, and infrared (IR) spectrometry showed that the solid dispersions were formed by intermolecular hydrogen bonding. The solid dispersion preparation in PVP-K30 significantly improved the solubility and dissolution rate of EM, particularly the aqueous solubility, which reached a maximum of 37.5-times the EM technical solubility, when the feed ratio of 1:10 was employed to prepare the dispersion. Importantly, the wettable powder of EM-PVP-K30 solid dispersion enhanced the insecticidal activity of EM against the Plutella xylostella larvae. Furthermore, the solid dispersion preparation in PRIII afforded a significant advantage by prolonging the EM technical release in water at a pH below 7.0, especially when the PRIII content in solid dispersions was high. While the amplified toxicity of the wettable powder of EM-PRIII solid dispersions against the P. xylostella larvae showed no significant differences from that of the EM technical, the long-term toxicity under the field condition was much better than that of the commercially available EM 1.5% emulsifiable concentrate. Notably, solid dispersions with both the PVP-K30 and PRIII carriers reduced the effect of UV photolysis.


Assuntos
Preparações de Ação Retardada/química , Ivermectina/análogos & derivados , Tecnologia Farmacêutica/métodos , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Interações Hidrofóbicas e Hidrofílicas , Ivermectina/química , Polímeros/química , Polivinil/química , Pós/química , Pirrolidinas/química , Solubilidade , Solventes/química , Espectrofotometria Infravermelho/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Raios Ultravioleta , Difração de Raios X/métodos
20.
AAPS PharmSciTech ; 20(8): 331, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31677012

RESUMO

Because spray-dried dispersion (SDD) performance depends on polymer selection and drug load, time- and resource-sparing methods to screen drug/polymer combinations before spray drying are desirable. The primary objective was to assess the utility of films to anticipate the effects of drug load and polymer grade on dissolution performance of tablets containing SDDs of itraconazole (ITZ). A secondary objective was to characterize the solid-state attributes of films and SDDs to explain drug load and polymer effects on dissolution performance. SDDs employed three different grades of hypromellose acetate succinate (i.e., either HPMCAS-L, HPMCAS-M, or HPMCAS-H). Solid-state characterization employed differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. Results indicate that films correctly anticipated the effects of drug load and polymer on dissolution performance. The best dissolution profiles were observed under the following conditions: 20% drug loading performed better than 30% for both films and SDDs, and the polymer grade rank order was HPMCAS-L > HPMCAS-M > HPMCAS-H for both films and SDDs. No dissolution was detected from films or SDDs containing HPMCAS-H. Solid-state characterization revealed percent crystallinity and phase miscibility as contributing factors to dissolution, but were not the sole factors. Amorphous content in films varied with drug load (10% > 20% > 30%) and polymer grades (HPMCAS-L > HPMCAS-M > HPMCAS-H), in agreement with dissolution. In conclusion, films anticipated the rank-order effects of drug load and polymer grade on dissolution performance from SDDs of ITZ, in part through percent crystallinity and phase miscibility influences.


Assuntos
Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Itraconazol/síntese química , Itraconazol/metabolismo , Metilcelulose/análogos & derivados , Antifúngicos/síntese química , Antifúngicos/metabolismo , Varredura Diferencial de Calorimetria , Dessecação , Metilcelulose/síntese química , Metilcelulose/metabolismo , Polímeros , Solubilidade , Comprimidos , Difração de Raios X/métodos
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