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1.
AAPS PharmSciTech ; 21(4): 131, 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32405869

RESUMO

5-Fluorouracil is a member of cytotoxic drugs with poor selectivity to cancer cells. Currently, systemic administration of this anti-cancer drug (oral or injection) exposes normal tissues to the drug-induced toxicity. Nowadays, attention has been greatly directed towards in situ gel-forming systems that can be injected into the affected tissues in its sol form with a minimally invasive technique. More specifically, chitosan hydrogel systems were in focus due to their antibacterial effect as well as their biodegradable, biocompatible, and mucoadhesive properties. In the present work, 5-fluorouracil was loaded on various thermosensitive chitosan hydrogel systems cross linked with different linking agents like ß-glycerophosphate, pluronic F127, and hydroxyapatite. Also, methotrexate was added to 5-fluorouracil in order to gain its previously reported synergistic effects. Firstly, a compatibility study was performed using UV-spectrophotometric, infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) techniques to exclude the possibility of any physical or chemical interactions between the selected drugs and excipients. The prepared hydrogel systems were characterized for their physicochemical properties including organoleptic, pH, syringeability and injectability, viscosity, and gelation temperature (Tgel) by various analysis techniques. Moreover, the in vitro release behavior of 5-fluorouracil and methotrexate was determined with a modified analytical method. The results indicated that chitosan hydrogel system cross-linked with a combination of ß- glycerophosphate, and 10 % pluronicF127 (F4) showed the most suitable physicochemical properties and release profile. Accordingly, this formula can be considered as a missionary system for localized sustained delivery of cytotoxic drugs.


Assuntos
Quitosana/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Fluoruracila/metabolismo , Hidrogéis/metabolismo , Metotrexato/metabolismo , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/metabolismo , Varredura Diferencial de Calorimetria/métodos , Quitosana/química , Hidrogéis/química , Temperatura
2.
AAPS PharmSciTech ; 21(4): 125, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350635

RESUMO

Sunlight is important to health, but higher exposure to radiation causes early aging of the skin and skin damage that can lead to skin cancers. This study aimed at producing a stable octyl p-methoxycinnamate (OMC)-loaded nanostructured lipid carrier (NLC) sunscreen, which can help in the photoprotective effect. NLC was produced by emulsification-sonication method and these systems were composed of myristyl myristate (MM), caprylic capric triglyceride (CCT), Tween® 80 (TW), and soybean phosphatidylcholine (SP) and characterized by dynamic light scattering (DLS), zeta potential (ZP) measurement, atomic force microscopy (AFM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and in vitro release studies. Pre-formulation studies were performed changing TW concentrations and no differences were found at concentrations of 1.0 and 2.0%. Two selected formulations were designed and showed an average size of 91.5-131.7, polydispersity index > 0.2, and a negative value of ZP. AFM presented a sphere-like morphology and SEM showed ability to form a thin film. DSC exhibited that the incorporation of OMC promoted reduction of enthalpy due to formation of a more amorphous structure. Drug release shows up to 55.74% and 30.57%, and this difference could be related to the presence of SP in this formulation that promoted a more amorphous structure; the release mechanism study indicated Fickian diffusion and relaxation. Sun protection factor (SPF) evaluation was performed using NLC and presented values around 40, considerably higher than those observed in the literature. The developed formulations provide a beneficial alternative to conventional sunscreen formulations.


Assuntos
Cinamatos/síntese química , Portadores de Fármacos/síntese química , Lipídeos/síntese química , Nanoestruturas/química , Fator de Proteção Solar/métodos , Protetores Solares/síntese química , Varredura Diferencial de Calorimetria/métodos , Cinamatos/farmacocinética , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Lipídeos/farmacocinética , Microscopia de Força Atômica/métodos , Microscopia Eletrônica de Varredura/métodos , Tamanho da Partícula , Protetores Solares/farmacocinética
3.
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
4.
Biochim Biophys Acta Biomembr ; 1862(5): 183201, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972164

RESUMO

Alkanes are known to promote the fluid lamellar (Lα)-to-inverted hexagonal (HII) phase transition of different phospholipids. In this work, we studied the interaction of decane and tetradecane with self-assemblies formed of 1-palmitoyl-2-oleoyl-sn-glycero-phosphoethanolamine (POPE), using sequential 2H and 31P solid-state NMR spectroscopy. This technique allowed calculating the partitioning constant of the alkanes between the Lα and HII phases of POPE. Our results show that both alkanes are preferentially distributed in the HII phase compared to the Lα phase. In the HII phase, both alkanes display a very high conformational disorder, consistent with their location in the intercylinder voids. This preferential partitioning in the HII phase is more pronounced for tetradecane than for decane. This finding is proposed to be associated with a less energetically favored insertion (limited solubility) of tetradecane in the lamellar phase. This proposition is supported by the observation that tetradecane experiences more conformational freedom than its shorter analog in POPE bilayers, suggesting that it is located, on average, closer to the middle of the bilayers. It is also established that the increase in size of the intercylinder voids, by the addition of 1-palmitoyl-2-oleoyl-sn-glycero-phosphocholine (POPC) in the HII cylinders, enhances the partitioning of decane in the HII phase compared to the Lα phase. These findings propose handles to modulate the balance of the relative Lα/HII phase stability.


Assuntos
Alcanos/química , Bicamadas Lipídicas/química , Fosfatidiletanolaminas/química , Varredura Diferencial de Calorimetria/métodos , Espectroscopia de Ressonância Magnética/métodos , Conformação Molecular , Transição de Fase , Temperatura
5.
Biochim Biophys Acta Biomembr ; 1862(3): 183173, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31883997

RESUMO

Micro Exon Gene (MEG) proteins are thought to play major roles in the infection and survival of parasitic Schistosoma mansoni worms in host organisms. Here, the physical chemical properties of two small MEG proteins found in the genome of S. mansoni, named MEG-24 and MEG-27, were examined by a combination of biophysical techniques such as differential scanning calorimetry, tensiometry, circular dichroism, fluorescence, and electron spin resonance spectroscopies. The proteins are surface active and structurally arranged as cationic amphipathic α-helices that can associate with lipid membranes and cause their disruption. Upon adsorption to lipid membranes, MEG-27 strongly affects the fluidity of erythrocyte ghost membranes, whereas MEG-24 forms pores in erythrocytes without modifying the ghost membrane fluidity. Whole-mount in situ hybridization experiments indicates that MEG-27 and MEG-24 transcripts are located in the parasite esophagus and subtegumental cells, respectively, suggesting a relevant role of these proteins in the host-parasite interface. Taken together, these characteristics lead us to propose that these MEG proteins may interact with host cell membranes and potentially modulate the immune process using a similar mechanism as that described for α-helical membrane-active peptides.


Assuntos
Éxons/genética , Membranas/química , Schistosoma mansoni/genética , Sequência de Aminoácidos , Animais , Varredura Diferencial de Calorimetria/métodos , Dicroísmo Circular/métodos , Peptídeos/química , Conformação Proteica em alfa-Hélice , Schistosoma mansoni/metabolismo , Esquistossomose mansoni/genética , Esquistossomose mansoni/metabolismo
6.
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
7.
Ultrason Sonochem ; 61: 104831, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31669847

RESUMO

The objective of the study is to elucidate the effect of ultrasound treated salt solution on curing of pork meat. The interactions of salt (NaCl) solutions of 3 and 25% with the proteins of pork meat are studied. High intensity ultrasound operating at 20 kHz was used. The differential scanning calorimetry (DSC), NMR spin-spin relaxation time, unfrozen water and water diffusion coefficient measurements were carried out in meat cured with ultrasound treated and untreated salt solutions. The effect of ultrasonication was most evident from measured spin-spin relaxation times T21, the rate of chemical exchange of water protons k and the amount of unfrozen water Wunf in the meat. The measured diffusion coefficient of water Dw in meat cured with ultrasound treated and control salt solution did not show significant difference. The nuclear magnetic resonance (NMR) relaxation data, differential scanning calorimetry (DSC) and the diffusion coefficient data reliably show that the possible action of ultrasound to salt solution was manifested on the first 2 days of the experiment with a 3% salt solution.


Assuntos
Proteínas de Carne/química , Sais/química , Sonicação , Animais , Varredura Diferencial de Calorimetria/métodos , Conservação de Alimentos , Suínos
8.
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
9.
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
10.
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
11.
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
12.
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
13.
Drug Deliv ; 26(1): 1058-1067, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31735064

RESUMO

Realgar and (-)-Epigallocatechin-3-gallate (EGCG) are natural medicines that inhibit cancer cell growth, resulting in inhibition of formation and development of tumors. The anticancer effects of realgar and EGCG were greatly improved following formulation as nanoparticles. EGCG has received increased attention as a drug carrier. The aim of this study was to prepare a new nanomedicine, (EGCG-RNPs), in which encapsulated nano-realgar. EGCG-RNPs were prepared by coprecipitation and characterized by transmission electron microscopy (TEM), differential scanning calorimetry (DSC), particle size and zeta potential, X-ray diffraction, Fourier transform infrared spectroscopy (FTIR) and in vitro release. Furthermore, we evaluated the antiproliferative effects of EGCG-RNPs on HL-60 cells in vitro, antitumor effect by intratumoral injection of EGCG-RNPs into solid tumors derived from APL HL-60 cells in vivo. Possible mechanisms were evaluated using uptake and efflux experiments in HL-60 cells. The results showed that the average particle size and zeta potentials of EGCG-RNPs was 200.3 ± 1.23 nm and -46.8 ± 1.31 mV. Controlled release of EGCG-RNPs was sustained and continued up to 72 h in vitro. Compared with nano-realgar and EGCG + RNPs (EGCG and nano-realgar physical mixing), EGCG-RNPs significantly inhibited growth of HL-60 cells. In a solid tumor model, EGCG-RNPs decreased tumor volumes, with an inhibitory rate of 60.18% at a dose of 70 mg · kg-1. The mechanisms of antitumor improvement may correlate with the increased uptake of realgar and prolonged the retention time of realgar in HL-60 cells due to EGCG as a carrier. EGCG-RNPs could enhance anticancer therapeutic efficacy for acute promyelocytic leukemia.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Catequina/análogos & derivados , Leucemia Promielocítica Aguda/tratamento farmacológico , Nanopartículas/química , Varredura Diferencial de Calorimetria/métodos , Catequina/química , Catequina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Células HL-60 , Humanos , Nanomedicina/métodos , Tamanho da Partícula
14.
Molecules ; 24(22)2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31717559

RESUMO

In this study, we prepared complex nanoparticles from a combination of two proteins and one polysaccharide for the encapsulation and delivery of lipophilic bioactive compounds. Two proteins, zein and sodium caseinate (NaCas), provided a hydrophobic core for the encapsulation of a lipophilic compound (curcumin), while a polysaccharide dialdehyde, oxidized dextran, served as the coating material and macromolecular crosslinker to create covalent linkage with two proteins for stabilization purposes. The heating time and crosslinker concentration were optimized to achieve the desirable colloidal stability in simulated gastric and intestinal fluids. Our results suggested that heating time played a more important role than the concentration of oxidized dextran. The optimized complex nanoparticles had a particle size of around 150 nm with a PDI < 0.1 and negative surface charge. Morphological observation by transmission electron microscopy revealed a spherical shape and uniform size distribution. Fourier transform infrared and fluorescence spectroscopies evidenced the formation of Schiff base complex, confirming the validity of covalent crosslinking. Furthermore, the complex nanoparticles demonstrated superior encapsulation properties for curcumin, showing an efficiency of >90% at 10% loading. A rather slow kinetic release profile of curcumin from complex nanoparticles was observed under simulated gastrointestinal conditions. The complex nanoparticles prepared from zein, NaCas, and oxidized dextran hold promising potential for the oral delivery of lipophilic bioactive compounds.


Assuntos
Caseínas/química , Curcumina/química , Dextranos/química , Nanopartículas/química , Zeína/química , Varredura Diferencial de Calorimetria/métodos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Microscopia Eletrônica de Transmissão/métodos , Tamanho da Partícula
15.
Eur J Pharm Biopharm ; 145: 98-112, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31698042

RESUMO

The present study evaluates the physical stability and intermolecular interactions of Rivaroxaban (RXB) amorphous solid dispersions (ASDs) in polymeric carriers via thermodynamic modelling and molecular simulations. Specifically, the Flory-Huggins (FH) lattice solution theory was used to construct thermodynamic phase diagrams of RXB ASDs in four commonly used polymeric carriers (i.e. copovidone, coPVP, povidone, PVP, Soluplus, SOL and hypromellose acetate succinate, HPMCAS), which were stored under 0%, 60% and 75% relative humidity (RH) conditions. In order to verify the phase boundaries predicted by FH modelling (i.e. truly amorphous zone, amorphous-amorphous demixing zones and amorphous-API recrystallization zones), samples of ASDs were examined via polarized light microscopy after storage for up to six months at various RH conditions. Results showed a good agreement between the theoretical and the experimental approaches (i.e. coPVP and PVP resulted in less physically-stable ASDs compared to SOL and HPMCAS) indicating that the proposed FH-based modelling may be a useful tool in predicting long-term physical stability in high humidity conditions. In addition, molecular dynamics (MD) simulations were employed in order to interpret the observed differences in physical stability. Results, which were verified via differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR), suggested the formation of similar intermolecular interactions in all cases, indicating that the interaction with moisture water plays a more crucial role in ASD physical stability compared to the formation of intermolecular interactions between ASD components.


Assuntos
Polímeros/química , Rivaroxabana/química , Varredura Diferencial de Calorimetria/métodos , Cristalização/métodos , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Umidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Termodinâmica
16.
Drug Deliv ; 26(1): 1049-1057, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31691602

RESUMO

Doxorubicin (DOX) is widely used in the chemotherapy of a wide range of cancers. However, intravenous administration of DOX causes toxicity to most major organs which limits its clinical application. DOX-loaded drug delivery system could provide a continuous sustained-release of drugs and enables high drug concentrations at the target site, while reducing systemic toxicity. Additionally, local chemotherapy with DOX may be a promising approach for lowering post-surgical recurrence of cancer. In this study, the sustained-release DOX-loaded implants were prepared by melt-molding method. The implants were characterized with regards to drug content uniformity, micromorphology and drug release profiles. Furthermore, differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) analyses were carried out to investigate the drug-excipient compatibility. To determine the local penetration of DOX in liver, the minipigs received intrahepatic implantation of DOX-loaded implants by abdominal surgery. UPLC-MS/MS method was used to detect the concentration of DOX in liver tissues. Our results suggested that DOX-loaded implants delivered high doses of drug at the implantation site for a prolonged period and provided valuable information for the future clinical applications of the DOX-loaded implants.


Assuntos
Doxorrubicina/administração & dosagem , Doxorrubicina/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Varredura Diferencial de Calorimetria/métodos , Cromatografia Líquida de Alta Pressão/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Excipientes/química , Feminino , Fígado/efeitos dos fármacos , Masculino , Próteses e Implantes , Ratos , Ratos Wistar , Suínos , Porco Miniatura , Espectrometria de Massas em Tandem/métodos
17.
Eur J Pharm Biopharm ; 145: 113-120, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31682903

RESUMO

Lipid-based drug delivery systems (LBDDS) are highly relevant as pharmaceutical formulations significantly enhancing the bioavailability of active pharmaceutical ingredients (APIs). These formulations often are complex mixtures of APIs, various lipids, and other excipients (e.g. surfactants). In their simplest form, LBDDS contain one API being dissolved in a pure lipid, which often is a triglyceride (TG). In this work, solubilities of the APIs indomethacin, ibuprofen, and fenofibrate in pure TGs of different chain lengths (C chain 8-18) and degree of saturation were investigated. Solubilities of APIs in TGs were measured via differential scanning calorimetry, hot-stage microscopy, high-performance liquid chromatography, and Raman spectroscopy. The influence of fatty-acid chain length and degree of saturation on the API solubility in the TGs was investigated. APIs showed a higher solubility in saturated (wIBU = 10.5 wt% at 25 °C in tricaprylin) TGs compared to unsaturated ones (wIBU = 4.0 wt% at 25 °C in triolein). The fatty-acid chain length of TGs only slightly affects the solubility of ibuprofen and fenofibrate, but strongly influences the eutectic temperature of the API/TG mixtures. API solubilities in TGs and TG mixtures (mixtures of tricaprylin and tricaprin) were successfully modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) accounting for the intermolecular API/TG interactions providing a deep understanding of the energetic and structural impact of the TGs on API solubility.


Assuntos
Preparações Farmacêuticas/química , Solubilidade/efeitos dos fármacos , Triglicerídeos/química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Excipientes/química , Fenofibrato/química , Ibuprofeno/química , Indometacina/química , Lipídeos/química
18.
AAPS PharmSciTech ; 20(8): 327, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659590

RESUMO

Freeze-dried immunoglobulin G (IgG) incorporating trehalose and human serum albumin (HSA) was statistically evaluated regarding the existence of synergism between additives on the stability profile. The levels of HSA (X1) and trehalose (X2) were independent variables. Aggregation following the process (Y1), after 2 and 3 months at 40°C (Y2) and (Y3), respectively, along with the rate constant of aggregation (Y4) were dependent variables. Aggregation and beta-sheet conformation were quantified through size-exclusion chromatography (SEC-HPLC) and Fourier transform infrared spectroscopy (FTIR). Central composite design (CCD) suggested the best formulation. The integrity and thermodynamic stability of optimized formulation were investigated through sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and differential scanning calorimetry (DSC). The calculated responses were Y1, 0-0.90%; Y2, 0.4-4.3%; Y3, 2.10-13.46%; and Y4, 0.16-0.69 1/month. The optimized formulation had 10 mg IgG, 86 mg trehalose, and 1 mg HSA with observed responses of Y1, 0.01%; Y2, 0.51%; Y3, 3.08%; and Y4, 0.33 1/month. The models were statistically well-fitted. The optimized formulation was amorphous during freeze-drying (FD), and no fragmentation was observed. Trehalose and HSA demonstrated statistical synergism. CCD was successfully employed to recommend the best ratio of stabilizers and achieve the maximum stabilization of IgG as a model freeze-dried antibody.


Assuntos
Desenho de Fármacos , Imunoglobulina G/química , Albumina Sérica Humana/síntese química , Trealose/síntese química , Varredura Diferencial de Calorimetria/métodos , Combinação de Medicamentos , Estabilidade de Medicamentos , Liofilização/métodos , Humanos , Imunoglobulina G/administração & dosagem , Albumina Sérica Humana/administração & dosagem , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Trealose/administração & dosagem
19.
Mater Sci Eng C Mater Biol Appl ; 104: 109890, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31500018

RESUMO

A protein-polymer blend system based on silkworm silk fibroin (SF) and polylactic acid (PLA) was systematically investigated to understand the interaction and miscibility of proteins and synthetic biocompatible polymers in the macro- and micro-meter scales, which can dramatically control the cell responses and enzyme biodegradation on the biomaterial interface. Silk fibroin, a semicrystalline protein with beta-sheet crystals, provides controllable crystal content and biodegradability; while noncrystallizable PDLLA provides hydrophobicity and thermal stability in the system. Differential scanning calorimetry (DSC) combined with scanning electron microscope (SEM) showed that the morphology of the blend films was uniform on a macroscopic scale, yet with tunable micro-phase patterns at different mixing ratios. Fourier transform infrared analysis (FTIR) revealed that structures of the blend system, such as beta-sheet crystal content, gradually changed with the mixing ratios. All blended samples have better stability than pure SF and PLA samples as evidenced by thermogravimetric analysis. Protease XIV enzymatic study showed that the biodegradability of the blend samples varied with their blending ratios and microscale morphologies. Significantly, the topology of the micro-phase patterns on the blends can promote cell attachment and manipulate the cell growth and proliferation. This study provided a useful platform for understanding the fabrication strategies of protein-synthetic polymer composites that have direct biomedical and green chemistry applications.


Assuntos
Fibroínas/química , Poliésteres/química , Polímeros/química , Seda/química , Animais , Materiais Biocompatíveis/química , Bombyx/química , Varredura Diferencial de Calorimetria/métodos , Microscopia Eletrônica de Varredura/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos
20.
Mater Sci Eng C Mater Biol Appl ; 104: 109882, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31500041

RESUMO

Topical sunscreen products are universally applied by numerous individuals to protect their skin from the detrimental effects of UV radiation. However, lately, studies have revealed the risks associated with percutaneous absorption of UV filters leading to undesirable systemic side effects such as hormonal disturbances and allergies. In this study, an innovative sunscreen formulation was developed based on starch microsponges as a key carrier encapsulating an organic sunscreen benzophenone­3. The developed starch microsponges were characterized by scanning electron microscopy and nitrogen adsorption/desorption analysis. The results showed that starch microsponges possessed a high BET surface area (85.45 m2/g) with spherical porous morphology with pore size <200 nm. Benzophenone­3 was loaded into the starch microsponges by immersion/solvent evaporation and benzophenone­3 loaded starch microsponges were characterized by scanning electron microscopy, differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy, and nitrogen adsorption-desorption measurements. Results corroborated that benzophenone­3 was successfully entrapped within the nanopores of starch microsponges. A starch microsponge based sunscreen cream was formulated, characterized and clinically tested. Rheological, texture and sensorial assessment showed that starch microsponges based sunscreen product showed good spreadability, non-sticky, rich texture favorable for consumer usage. In vitro and ex-vivo studies demonstrated benzophenone­3 loaded starch microsponges gave improved photoprotection, higher SPF and reduced cutaneous penetration compared to raw benzophenone­3 cream. Clinically, patch study confirmed that the developed starch microsponges based sunscreen cream was skin safe and biocompatible. Thus, the amalgamation of sunscreen molecule benzophenone­3 into starch microsponges produced a safe, effective innovative sunscreen product.


Assuntos
Absorção Cutânea/efeitos dos fármacos , Pele/efeitos dos fármacos , Amido/química , Protetores Solares/química , Protetores Solares/farmacologia , Varredura Diferencial de Calorimetria/métodos , Sistemas de Liberação de Medicamentos/métodos , Humanos , Porosidade , Difração de Raios X/métodos
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