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1.
PLoS One ; 15(8): e0237271, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866161

RESUMO

Molecular separation of pharmaceutical contaminants from water has been recently of great interest to alleviate their detrimental impacts on environment and human well-being. As the novelty, this investigation aims to develop a mechanistic modeling approach and consequently its related CFD-based simulations to evaluate the molecular separation efficiency of ibuprofen (IP) and its metabolite 4-isobutylacetophenone (4-IBAP) from water inside a porous membrane contactor (PMC). For this purpose, octanol has been applied as an organic phase to extract IP and 4-IBAP from the aqueous solution due to high solubility of solutes in octanol. Finite element (FE) technique is used as a promising tool to simultaneously solve continuity and Navier-Stokes equations and their associated boundary conditions in tube, shell and porous membrane compartments of the PMC. The results demonstrated that the application of PMC and liquid-liquid extraction process can be significantly effective due to separating 51 and 54% of inlet IP and 4-IBAP molecules from aqueous solution, respectively. Moreover, the impact of various operational / functional parameters such as packing density, the number of fibrous membrane, the module length, the membrane porosity / tortuosity, and ultimately the aqueous solution flow rate on the molecular separation efficiency of IP and 4-IBAP is studied in more details.


Assuntos
Acetofenonas/isolamento & purificação , Anti-Inflamatórios não Esteroides/isolamento & purificação , Ibuprofeno/isolamento & purificação , Membranas Artificiais , Polímeros/química , Extração Líquido-Líquido/métodos , Octanóis/química , Porosidade , Solubilidade , Soluções
2.
Chemosphere ; 258: 127288, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32947659

RESUMO

The discharge of toxic elements from tailings soils in the aquatic environments occurs chiefly in the presence of indigenous bacteria. The biotic components may interact in the opposite direction, leading to the formation of a passivation layer, which can inhibit the solubility of the elements. In this work, the influence of jarosite on the bio-immobilization of toxic elements was studied by native bacteria. In batch experiments, the bio-immobilization of heavy metals by an inhibitory layer was examined in the different aquatic media using pure cultures of Acidithiobacillus ferrooxidans and Acidithiobacillus thiooxidans. A variety of analyses also investigated the mechanisms of metals bio-immobilization. Among different tests, the highest metal solubility yielded 99% Mn, 91% Cr, 95% Fe, and 78% Cu using A. ferrooxidans in 9KFe medium after ten days. After 22 days, these percentages decreased down to 30% Mn and about 20% Cr, Fe, and Cu, likely due to metal immobilization by biogenic jarosite. The formation of jarosite was confirmed by an electron probe micro-analyzer (EPMA), X-ray diffraction (XRD), and scanning electron microscope (SEM). The mechanisms of metal bio-immobilization by biogenic jarosite from tailings soil confirmed three main steps: 1) the dissolution of metal sulfides in the presence of Acidithiobacillus bacteria; 2) the nucleation of jarosite on the surface of sulfide minerals; 3) the co-precipitation of dissolved elements with jarosite during the bio-immobilization process, demonstrated by a structural study for jarosite. Covering the surface of soils by the jarosite provided a stable compound in the acidic environment of mine-waste.


Assuntos
Compostos Férricos/química , Substâncias Perigosas/análise , Sulfatos/química , Acidithiobacillus , Acidithiobacillus thiooxidans , Bactérias , Substâncias Perigosas/toxicidade , Metais Pesados , Minerais , Solubilidade , Sulfetos/química , Difração de Raios X
3.
Pharm Res ; 37(10): 192, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32914239

RESUMO

PURPOSE: The objective was to characterize hydroxypropyl methylcellulose acetate succinate (HMPCAS) grades L, M, and H to enhance itraconazole (ITZ) release and permeation from spray dried dispersions (SDDs), and to investigate underpinning molecular ITZ-HPMCAS interactions that differentiated grade performance. METHODS: ITZ or its SDDs were subjected to solution stabilization assessment, one-dimensional proton nuclear magnetic resonance (NMR) spectroscopy, saturation transfer difference NMR studies, small volume dissolution, solid state transformation studies, and in vitro dissolution/permeation flux studies. RESULTS: HPMCAS-L was the best performing grade overall and exhibited greatest ITZ supersaturation concentration, small volume dissolution, and in vitro dissolution/permeation flux. Meanwhile, H grade retarded ITZ precipitation to the greatest extent in solution stabilization studies and exhibited greater hydrophobic interaction with ITZ in NMR studies. However, this apparent advantage of H grade through hydrophobic interactions between drug-polymer appeared to limit overall dissolution/permeation performance of SDD. CONCLUSIONS: In vitro SDD studies and drug-polymer interaction studies provided insight into the performance of HPMCAS grades, as well as the relative contributions of various mechanisms that polymer can promote ITZ absorption from SDD.


Assuntos
Itraconazol/química , Metilcelulose/análogos & derivados , Química Farmacêutica , Tecnologia de Fibra Óptica , Cinética , Espectroscopia de Ressonância Magnética , Metilcelulose/química , Solubilidade
4.
Yakugaku Zasshi ; 140(9): 1175-1183, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32879249

RESUMO

The mock patches were prepared with novel acrylic polymers as adhesive layer where biphenyl-4-ylacetic acid (BAA) or 2-(2-fluorobiphenyl-4-yl) propanoic acid (FPA) was used as model active pharmaceutical ingredients (APIs). In addition, the mock patches were formulated with typical ester ingredients for transdermal dosage forms. The molecular state of the model APIs in the adhesive layer was observed by polarized microscope and microscopic Raman spectroscopy, which contains both conventional and low frequency (LF) region. Crystallization behavior would be depended on the interaction between API and polymers in the adhesive layer. In particular, LF Raman measurement was useful to discriminate API polymorphs. The pharmaceutical properties including dissolution and skin permeation of APIs were also evaluated for mock patches. The drug release and transdermal permeation were enhanced with the ester ingredients such as isopropyl myristate and diethyl sebacate due to their diffusion to the test solution or the skin stratum corneum as well as reducing the interaction between API and polymers. Further, the tack strength was not changed, but the peel strength was weakened by the additives. Thus, the adhesive properties were controllable by formulation with the additives. These findings could enable to evaluate the interaction between API and the polymers for adhesive layer and select the appropriate polymer and additives for used APIs when designing the drug products.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Polímeros , Adesivo Transdérmico , Adesividade , Administração Cutânea , Ácidos Decanoicos , Liberação Controlada de Fármacos , Miristatos , Fenilacetatos/administração & dosagem , Fenilacetatos/metabolismo , Propionatos/administração & dosagem , Propionatos/metabolismo , Absorção Cutânea , Solubilidade , Análise Espectral Raman
5.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(6): 843-849, 2020 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895202

RESUMO

OBJECTIVE: To develop a fast, sensitive and cost-effective method based on resonance light scattering (RLS) for characterization of protein solubility to facilitate detection of changes in solubility of mutant proteins. METHODS: We examined the response curve of RLS intensities to the protein concentrations in synchronous scanning mode. The curve intersection points were searched to predict the maximal concentrations of the protein in dispersion state, which defined the solubility of the protein in this given state. Bovine serum albumin (BSA, 0-50 g/L) was used as the model to investigate the influences of pH values (6.5, 7.0, and 7.4) and salt concentrations (0.05, 0.10, 0.15, and 0.20 mol/L) on the determined solubility. The solubility of glutathione S-transferase isoenzymes alpha (GSTA, 0-27.0 g/L) and Mµ (GSTM, 0-20.0 g/L) were estimated for comparison. The RLS-based method was used to determine the solubility of uricase (MGU, 0-0.4 g/L) to provide assistance in improving the solubility of its mutants. RESULTS: We identified two intersection points in the RLS response curves of the tested proteins, among which the lower one represented an approximation of the maximal concentration (or the solubility of the protein) in single molecular dispersion, and the higher one the saturated concentration of the protein in multiple molecular aggregation. In HEPES buffer, the two intersection points of BSA (isoelectric point 4.6) both increased with the increase of pH (6.5-7.4), and their values were ~1.2 g/L and ~33 g/L at pH 7.4, respectively; the latter concentration approached the solubility of commercial BSA in the same buffer at the same pH. The addition of NaCl reduced the values of the two intersection points, and increasing salt ion concentration decreased the values of the lower intersection points. Further characterizations of GSTA and GSTM showed that the low concentration intersection points of the two proteins were ~0.7 g/L and ~0.8 g/L, and their high concentration intersection points were ~10 g/L and ~11 g/L, respectively, both lower than those of BSA, indicating the feasibility of the direct characterization of protein solubility by RLS. The two concentration intersection points of MGU were 0.24 g/L and 0.30 g/L, respectively, and the low concentration intersection point of its selected mutant was increased by 2 times. CONCLUSIONS: RLS allows direct characterization of the solubility of macromolecular proteins. This method, which is simple and sensitive and needs only a small amount of proteins, has a unique advantage for rapid comparison of solubility of low-abundance protein mutants.


Assuntos
Luz , Concentração de Íons de Hidrogênio , Espalhamento de Radiação , Solubilidade , Análise Espectral
6.
Zhongguo Zhong Yao Za Zhi ; 45(15): 3565-3574, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32893545

RESUMO

Quercetin is a kind of typical flavonoid, mainly found in various vegetables, fruits and Chinese herbs that are consumed daily, with the functions of anti-oxidation, anti-tumor, prevention and treatment of cardiovascular and cerebrovascular diseases. Quercetin is a natural compound with defined anti-tumor activity. Due to its low bioavailability and poor water solubility, quercetin has limitations in clinical application. The quercetin derivatives with good solubility, high bioavailability, metabolic stability, and low toxicity have been obtained through modification of quercetin structure. In recent years, a large number of quercetin ethers, esters, complexes, C-4 carbonyloxy substituted derivatives, A,B-ring modified compounds and other derivatives have been synthesized and tested for in vitro anticancer activity. The quercetin derivatives with anti-tumor activity synthesized in the last 5 years were reviewed in this paper.


Assuntos
Neoplasias , Quercetina , Disponibilidade Biológica , Humanos , Oxirredução , Solubilidade
7.
Zhongguo Zhong Yao Za Zhi ; 45(15): 3672-3680, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32893557

RESUMO

In order to improve the supersaturation and maintenance time of drug dispersion in curcumin self-nanoemulsion(CUR-SNEDDS), precipitation inhibitors(PPIs) were introduced to prepare curcumin supersaturated self-emulsion(CUR-SSNEDDS). The composition of CUR-SNEDDS prescriptions was selected through the solubility test, the compatibility of oil phase and surfactant, the investigation of the emulsifying ability of the surfactant and the drawing of the pseudo-ternary phase diagram. Analytic hierarchy process was used in combination with central composite design-response surface method to optimize the prescription. The type and dosage of precipitation inhibitors(PPIs) were selected to maintain the supersaturated concentration and duration of CUR in artificial gastrointestinal fluids. At the same time, polarizing microscope was used to evaluate the crystallization inhibition effect and the quality and in vitro release behavior of CUR-SSNEDDS. The prepared CUR-SSNEDDS prescription was capryol 90-kolliphor RH40-transcutol HP-Soluplus(7.93∶66.71∶25.36∶5), with the drug loading of(65.12±1.25) mg·g~(-1). CUR-SSNEDDS was transparent yellow, and the nanoemulsion droplets were spherical with uniform distribution. The emulsification time was(21.02±0.13) s, the average particle size was(57.03±0.35) nm, the polydispersity index(PDI) was(0.23 ± 0.01), and the Zeta potential was(-18.10±1.30) mV. CUR-SSNEDDS significantly inhibited the generation and growth of crystals after in vitro dilution. The supersaturation could be maintained above 10 within 2 h, and the dissolution rate and degree of CUR in artificial gastrointestinal fluid were significantly increased. Soluplus could effectively maintain the supersaturated state of CUR and enhance CUR dissolution in vitro.


Assuntos
Curcumina , Nanopartículas , Disponibilidade Biológica , Emulsões , Tamanho da Partícula , Solubilidade , Tensoativos
8.
Yonsei Med J ; 61(8): 720-725, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32734736

RESUMO

Lectin-like oxidized low-density lipoprotein (LDL) receptor 1 (LOX1) binds to oxidized LDL, which is associated with inflammation in various vascular disorders. Here, we aimed to investigate the potential of soluble LOX1 (sLOX1) as an indicator of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) activity. Serum levels of sLOX1 in frozen samples from patients with AAV enrolled in a prospective observational cohort study at the Severance Hospital were measured using enzyme-linked immunosorbent assay. Clinical and laboratory data were collected on the date when the blood sampling was performed. The association between sLOX1 and clinical and laboratory data was assessed using Pearson's correlation analysis. The median age of the recruited 79 patients was 62.0 years, and 27 (34.2%) patients were men. The median Birmingham vasculitis activity score (BVAS), five-factor score, vasculitis damage index, and sLOX1 level were 6, 1, 3, and 911.9 pg/mL, respectively. Correlation analysis based on BVAS revealed that sLOX1 and total cholesterol were significantly inversely correlated with BVAS (r=-0.224, p=0.047 and r=-0.424, p<0.001, respectively). No significant correlations were observed between continuous variables and sLOX1 except for BVAS, although total cholesterol tended to correlate with sLOX1 (r=0.190, p=0.093). Additionally, sLOX1 was not influenced by sex, hypertension, diabetes mellitus, or the presence of pulmonary, cardiovascular, and renal involvement of AAV. In summary, sLOX1 was inversely correlated with BVAS in AAV patients, which is different from other vascular diseases or inflammatory diseases.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Lectinas/metabolismo , Receptores Depuradores Classe E/sangue , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Solubilidade
9.
Int J Nanomedicine ; 15: 4877-4898, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32753869

RESUMO

Background: Although dynamics and uses of modified nanoparticles (NPs) as orally administered macromolecular drugs have been researched for many years, measures of molecule stability and aspects related to important transport-related mechanisms which have been assessed in vivo remain as relatively under characterized. Thus, our aim was to develop a novel type of oral-based delivery system for insulin and to overcome barriers to studying the stability, transport mechanisms, and efficacy in vivo of the delivery system. Methods: NPs we developed and tested were composed of insulin (INS), dicyandiamide-modified chitosan (DCDA-CS), cell-penetrating octaarginine (r8), and hydrophilic hyaluronic acid (HA) and were physically constructed by electrostatic self-assembly techniques. Results: Compared to free-insulin, levels of HA-DCDA-CS-r8-INS NPs were retained at more desirable measures of biological activity in our study. Further, our assessments of the mechanisms for NPs suggested that there were high measures of cellular uptake that mainly achieved through active transport via lipid rafts and the macropinocytosis pathway. Furthermore, investigations of NPs indicated their involvement in caveolae-mediated transport and in the DCDA-CS-mediated paracellular pathway, which contributed to increasing the efficiency of sequential transportation from the apical to basolateral areas. Accordingly, high efficiency of absorption of NPs in situ for intestinal loop models was realized. Consequently, there was a strong induction of a hypoglycemic effect in diabetic rats of NPs via orally based administrations when compared with measures related to free insulin. Conclusion: Overall, the dynamics underlying and influenced by HA-DCDA-CS-r8-INS may hold great promise for stability of insulin and could help overcome interference by the epithelial barrier, and thus showing a great potential to improve the efficacy of orally related treatments.


Assuntos
Quitosana/química , Ácido Hialurônico/química , Insulina/administração & dosagem , Nanopartículas Multifuncionais/química , Nanopartículas/química , Administração Oral , Animais , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Morte Celular/efeitos dos fármacos , Quitosana/síntese química , Diabetes Mellitus Experimental/tratamento farmacológico , Impedância Elétrica , Endocitose/efeitos dos fármacos , Guanidinas/síntese química , Guanidinas/química , Humanos , Ácido Hialurônico/síntese química , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Insulina/uso terapêutico , Absorção Intestinal/efeitos dos fármacos , Masculino , Muco/metabolismo , Nanopartículas/ultraestrutura , Ratos , Solubilidade , Suínos
10.
11.
Waste Manag ; 117: 179-187, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32861080

RESUMO

Steel slags are generally alkaline with a high calcium content and are viewed as a potential feedstock for carbon dioxide sequestration and utilization, mostly through aqueous mineral carbonation routes. For recovery of multiple metals such as Ca, Fe, Mg, and Si, and generation of value-added products by dissolution and precipitation reactions in aqueous media, enhancing the metal selectivity and extraction efficiency are important. However, there is limited understanding of independent parameters that influence these important characteristics. In this work, a systematic attempt was made to correlate these key dissolution characteristics of basic oxygen furnace slag in acidic media with its mineralogical and physical characteristics, the changes in aqueous chemistry, and the role of potential secondary precipitates. The findings from this study substantiate that steel slag is a potential feedstock because of the calcium being mainly present as orthosilicates, which were found to leach congruently without forming a leached layer that might hinder calcium extraction. The leaching of Fe(II) from the slag is the main source of impurity and its slow oxidation-precipitation leads to a pH plateau at the end of the dissolution step. Oxidation-precipitation of Fe(II) is controlled by hydroxyl concentration in the aqueous solution, which necessitates a pH-swing step by addition of a base after dissolution. Use of surface complexing agents, such as sodium molybdate, can significantly reduce iron impurity in the leachate and obtain an iron-rich slag residue for recycle to iron and steel industry.


Assuntos
Resíduos Industriais/análise , Aço , Dióxido de Carbono , Metais , Solubilidade
12.
Aquat Toxicol ; 227: 105582, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32823071

RESUMO

While it is likely that ENPs may occur together with other contaminants in nature, the combined effects of exposure to both ENPs and environmental contaminants are not studied sufficiently. In this study, we investigated the acute and sublethal toxicity of PVP coated silver nanoparticles (AgNP) and ionic silver (Ag+; administered as AgNO3) to the marine copepod Calanus finmarchicus. We further studied effects of single exposures to AgNPs (nominal concentrations: low 15 µg L-1 NPL, high 150 µg L-1 NPH) or Ag+ (60 µg L-1), and effects of co-exposure to AgNPs, Ag+ and the water-soluble fraction (WSF; 100 µg L-1) of a crude oil (AgNP + WSF; Ag++WSF). The gene expression and the activity of antioxidant defense enzymes SOD, CAT and GST, as well as the gene expression of HSP90 and CYP330A1 were determined as sublethal endpoints. Results show that Ag+ was more acutely toxic compared to AgNPs, with 96 h LC50 concentrations of 403 µg L-1 for AgNPs, and 147 µg L-1 for Ag+. Organismal uptake of Ag following exposure was similar for AgNP and Ag+, and was not significantly different when co-exposed to WSF. Exposure to AgNPs alone caused increases in gene expressions of GST and SOD, whereas WSF exposure caused an induction in SOD. Responses in enzyme activities were generally low, with significant effects observed only on SOD activity in NPL and WSF exposures and on GST activity in NPL and NPH exposures. Combined AgNP and WSF exposures caused slightly altered responses in expression of SOD, GST and CYP330A1 genes compared to the single exposures of either AgNPs or WSF. However, there was no clear pattern of cumulative effects caused by co-exposures of AgNPs and WSF. The present study indicates that the exposure to AgNPs, Ag+, and to a lesser degree WSF cause an oxidative stress response in C. finmarchicus, which was slightly, but mostly not significantly altered in combined exposures. This indicated that the combined effects between Ag and WSF are relatively limited, at least with regard to oxidative stress.


Assuntos
Copépodes/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Petróleo/toxicidade , Prata/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Antioxidantes/metabolismo , Copépodes/genética , Copépodes/metabolismo , Interações Medicamentosas , Expressão Gênica/efeitos dos fármacos , Íons , Nanopartículas Metálicas/química , Estresse Oxidativo/genética , Água do Mar/química , Prata/química , Solubilidade , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda , Poluentes Químicos da Água/química
13.
Int J Nanomedicine ; 15: 5217-5226, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801687

RESUMO

Aim: Chronic use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) is commonly associated with gastric irritation and gastric ulceration. Therefore, the aim of study was to develop a novel oral drug delivery system with minimum gastric effects and improved dissolution rate for aceclofenac (ACF), a model BCS class-II drug. Methods: Self-emulsifying drug delivery systems (SEDDS) were formulated to increase the solubility and ultimately the oral bioavailability of ACF. Oleic acid was used as an oil phase, Tween 80 (T80) and Kolliphor EL (KEL) were used as surfactants, whereas, polyethylene glycol 400 (PEG 400) and propylene glycol (PG) were employed as co-surfactants. Optimized formulations (F1, F2, F3 and F4) were analyzed for droplet size, poly dispersity index (PDI), cell viability studies, in vitro dissolution in both simulated gastric fluid and simulated intestinal fluid, ex vivo permeation studies and thermodynamic stability. Results: The optimized formulations showed mean droplet sizes in the range of 111.3 ± 3.2 nm and 470.9 ± 12.52 nm, PDI from 244.6 nm to 389.4 ± 6.51 and zeta-potential from -33 ± 4.86 mV to -38.5 ± 5.15 mV. Cell viability studies support the safety profile of all formulations for oral administration. The in vitro dissolution studies and ex vivo permeation analysis revealed significantly improved drug release ranging from 95.68 ± 0.02% to 98.15 ± 0.71% when compared with control. The thermodynamic stability studies confirmed that all formulations remain active and stable for a longer period. Conclusion: In conclusion, development of oral SEDDS might be a promising tool to improve the dissolution of BCS class-II drugs along with significantly reduced exposure to gastric mucosa.


Assuntos
Diclofenaco/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Disponibilidade Biológica , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Diclofenaco/administração & dosagem , Diclofenaco/farmacocinética , Liberação Controlada de Fármacos , Emulsões/administração & dosagem , Excipientes/química , Humanos , Masculino , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Polietilenoglicóis/química , Polissorbatos/química , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacocinética , Ratos Sprague-Dawley , Solubilidade , Tensoativos/química
14.
Int J Nanomedicine ; 15: 5253-5264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801690

RESUMO

Background and Aim: Flibanserin (FLB) is a multifunctional serotonergic agent used for treating hypoactive sexual desire disorder in premenopausal women via oral administration. FLB has a reported limited oral bioavailability of 33% that could be attributed to the drug's first-pass metabolism. In addition, FLB has a pH-dependent solubility that could be a challenging factor for drug dissolution in the body neutral fluid, and consequently, absorption via mucosal barriers. Thus, this work aims at investigating the potential of utilizing nanostructured lipid carriers (NLCs) to overcome the aforementioned drawbacks and to enhance nose-to-brain drug delivery. Methods: Box-Behnken design was applied to explore the impact of solid lipid % (SL%, X 1), liquid lipid % (LL%, X 2), and sonication time (ST, X 3) on particle size. The optimized NLC formulation was characterized and incorporated into gellan gum in situ gel. The prepared gel was subjected to in vitro drug release, in vivo pharmacokinetic performance, and histopathological assessment in rats. Results: Statistical analysis revealed a significant negative effect for both SL% and ST on NLCs size. In contrast, a significant positive effect was observed for the LL%. The optimized formulation showed spherical shape with vesicular size of 114.63 nm. The optimized FLB-NLC in situ gel exhibited adequate stability and enhanced in vitro release compared to raw FLB control gel. The plasma and brain concentrations of the drug after nasal administration in rats increased by more than 3-6-fold, respectively, compared to raw FLB in situ gel. In addition, the histopathological studies revealed the absence of any pathological signs. Conclusion: The aforementioned results highlight the safety of FLB-NLC in situ nasal gel and its potential to improve the drug bioavailability and brain delivery.


Assuntos
Benzimidazóis/administração & dosagem , Encéfalo/efeitos dos fármacos , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Nanoestruturas/administração & dosagem , Administração Intranasal , Animais , Benzimidazóis/farmacocinética , Disponibilidade Biológica , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Géis , Lipídeos/administração & dosagem , Lipídeos/química , Masculino , Nanoestruturas/química , Tamanho da Partícula , Polissacarídeos Bacterianos/química , Ratos Wistar , Solubilidade
15.
Ecotoxicol Environ Saf ; 204: 111088, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32791356

RESUMO

To clarify the role of dissolved organic matter (DOM) in sorption of organic pollutants, batch experiments on effects of two representatives of DOM (dissolved humic acid (HA) and tannic acid (TA)) on sorption of benzotriazole (BTA) to a sandy loam soil were conducted. Both HA and TA promoted BTA sorption to soil. Strong positive correlation between sorbed amount of BTA and DOM confirmed the contribution of cumulative sorption by HA or TA in enhancing BTA binding. TA promoted BTA sorption more obviously than HA by providing more sites. For HA with complex structure composed of heterogeneous fractions, its high molecular weight (>3200 Da) fraction could be preferentially sorbed by soil, and it can enhance BTA sorption more obviously than the low molecular weight fraction. The promoting effect of HA on BTA sorption decreased with pH increasing from 6.5 to 10.5 due to reduced sites and electrostatic repulsion between anionic BTA, HA and soil. Sorption of neutral BTA to soil affected by DOM could be well predicted by a modified Freundlich model with Kd (L kg-1) deviations less than 0.2 log unit.


Assuntos
Substâncias Húmicas/análise , Areia/química , Poluentes do Solo/análise , Solo/química , Taninos/análise , Triazóis/análise , Adsorção , Modelos Teóricos , Solubilidade
16.
AAPS PharmSciTech ; 21(6): 226, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32761293

RESUMO

Approximately 40% of compounds in clinical drug development suffer from solubility and bioavailability challenges. Evidence from literature demonstrates the growing interest to utilize flavonoids as potential compounds owing to their widespread therapeutic utility in various ailments. Nobiletin (NOB), one such dietary polymethoxylated flavonoid found in citrus fruits, has multiple pharmacological effects such as antioxidant, anti-microbial, anti-cancer, and anti-inflammatory. It is useful in cancer, inflammatory bowel diseases, atherosclerosis, obesity, and Alzheimer's disease. Although preclinical studies demonstrate the therapeutic utility of NOB, it suffers from serious biopharmaceutical limitations such as low aqueous solubility (below 1 µg/ml), poor permeability across biological barriers, and low bioavailability. To overcome these biopharmaceutical challenges associated with NOB, the use of advanced formulations and nanotechnology-based strategies appears to be a promising approach to potentiate its therapeutic action. Multiple reviews cover the various therapeutic benefits of NOB in various diseases; however, there is an absence of a comprehensive review that focuses on the formulation development strategies of NOB. The purpose of this review is to provide a concise perspective on NOB as a candidate molecule for formulation development. The manuscript covers various aspects related to NOB, such as its chemistry, physicochemical properties, and pharmacological effects. This is also a thorough review of various formulation development strategies with advances made in the past years to improve the solubility, bioavailability, and therapeutic efficacy of NOB. The review also contains information related to toxicity and patents involving NOB and its formulation.


Assuntos
Antioxidantes/química , Composição de Medicamentos , Flavonas/química , Nanotecnologia , Animais , Antioxidantes/farmacocinética , Disponibilidade Biológica , Flavonas/farmacocinética , Humanos , Solubilidade
17.
PLoS One ; 15(8): e0237255, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764804

RESUMO

In this study, washing tests were performed using samples prepared by contaminating fabrics with hemoglobin, and a kinetic analysis was conducted based the probability density functional method, which expresses the cleaning power using two parameters σrl (related to the cleaning mechanism) and µrl (related to the level of cleaning power). This method allows for the processing of uncertainties specific to protein washing under the assumption that the soil adhesion and detergency are in accordance with a normal distribution. A certain amount of hemoglobin solution was soaked in a cloth, dried, and steam-treated, and then used as a sample for a cleaning test. Two parameters σrl and µrl were calculated based on the detergency (%) after 5 min, 10 min, 15 min, and 20 min of washing with respect to different pH and temperature levels, and different sodium dodecyl sulfate (SDS) concentration and temperature levels. Based on the results, the value of σrl indicated that the hemoglobin was removed by the dissolving action. In addition, µrl increased in accordance with an increase in the pH, SDS concentration, and temperature. With respect to µrl, the relationship of ΔX + ΔY = Δ(X+Y) was observed in several cases, where ΔX represents the effect of the pH or SDS concentration, ΔY is the temperature effect, and Δ(X+Y) is the combined effect. Therefore, there may be an additive relationship between the pH and temperature effects, and the SDS concentration and temperature effects.


Assuntos
Detergentes/química , Hemoglobinas/análise , Dodecilsulfato de Sódio/química , Têxteis/análise , Humanos , Concentração de Íons de Hidrogênio , Cinética , Probabilidade , Solubilidade , Temperatura
18.
AAPS PharmSciTech ; 21(6): 228, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32767034

RESUMO

Rivaroxaban (RXB) is a class II drug, according to the Biopharmaceutics Classification System. Since its bioavailability is low at high doses, dose proportionality is not achieved for pharmacokinetic parameters. However, when taken with food, its bioavailability increases at high doses. In this study, nanocrystal technology was used to increase the solubility and, hence, the bioavailability of RXB. Pluronic F127, pharmacoat 603, and PVP K-30 were used as stabilizers to prepare RXB nanosuspension, combining ball mill and high pressure homogenization methods. Particle sizes of RXB in nanosuspension (formulation A:348 nm; formulation B:403 nm) and nanocrystal formulations (formulation A:1167 nm; formulation B:606 nm) were significantly reduced (p < 0.05) compared to those of bulk RXB. In both formulations, 80% of the drug dissolved in 30 min. For dose proportionality evaluation, 3, 10, and 15 mg/kg of RXB nanosuspensions (formulation B) were administered to rabbits. The dose proportionality for AUC and Cmax of RXB nanocrystals was assessed by the power model, variance analysis of pharmacokinetic parameters, linear regression, and equivalence criterion methods. Dose proportionality for AUC was achieved at doses between 10-15 and 3-15 mg/kg. In conclusion, the preparation of a nanocrystal formulation of RXB improved its dissolution rate and pharmacokinetic profile.


Assuntos
Inibidores do Fator Xa/administração & dosagem , Nanopartículas/química , Rivaroxabana/administração & dosagem , Animais , Área Sob a Curva , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Inibidores do Fator Xa/química , Inibidores do Fator Xa/farmacocinética , Tamanho da Partícula , Coelhos , Rivaroxabana/química , Rivaroxabana/farmacocinética , Solubilidade
19.
AAPS PharmSciTech ; 21(6): 230, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32779033

RESUMO

The vaginal rings research is almost exclusively focused on rings for human medicine, although the dosage form offers improvement of therapeutic effect in other mammals as well. This contribution studied an effect of varying dimension parameters (diameter 20, 30 or 40 mm; height 3, 4 or 5 mm; width of annulus 5, 7.5 or 10 mm) on mechanical properties and dissolution behaviour of silicone vaginal rings with constant drug amount, intended for use in dogs. Results showed that altering dimensions influenced mechanical properties (compressive force, tensile strength and resistance of removal thread), in vitro drug release and water uptake. The removal thread resistance was increasing with increasing height and width. Compression force was higher for the rings with smaller diameter. The total drug release was increasing with decreasing height and rising diameter, surface area and water uptake during dissolution test. The initial dissolution rate was slower for the rings with higher width. As the best candidate for use in model dog subjects, the ring with 30 mm diameter, 3 mm height and 7.5 mm width was found. These drug-free vaginal rings were further tested in in vivo safety study. The results did not show any major deviation from the physiological conditions. Graphical abstract.


Assuntos
Dispositivos Anticoncepcionais Femininos , Animais , Cães , Liberação Controlada de Fármacos , Feminino , Fenômenos Mecânicos , Solubilidade , Resistência à Tração , Testes de Toxicidade
20.
Nature ; 585(7823): 129-134, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32848250

RESUMO

Transmembrane channels and pores have key roles in fundamental biological processes1 and in biotechnological applications such as DNA nanopore sequencing2-4, resulting in considerable interest in the design of pore-containing proteins. Synthetic amphiphilic peptides have been found to form ion channels5,6, and there have been recent advances in de novo membrane protein design7,8 and in redesigning naturally occurring channel-containing proteins9,10. However, the de novo design of stable, well-defined transmembrane protein pores that are capable of conducting ions selectively or are large enough to enable the passage of small-molecule fluorophores remains an outstanding challenge11,12. Here we report the computational design of protein pores formed by two concentric rings of α-helices that are stable and monodisperse in both their water-soluble and their transmembrane forms. Crystal structures of the water-soluble forms of a 12-helical pore and a 16-helical pore closely match the computational design models. Patch-clamp electrophysiology experiments show that, when expressed in insect cells, the transmembrane form of the 12-helix pore enables the passage of ions across the membrane with high selectivity for potassium over sodium; ion passage is blocked by specific chemical modification at the pore entrance. When incorporated into liposomes using in vitro protein synthesis, the transmembrane form of the 16-helix pore-but not the 12-helix pore-enables the passage of biotinylated Alexa Fluor 488. A cryo-electron microscopy structure of the 16-helix transmembrane pore closely matches the design model. The ability to produce structurally and functionally well-defined transmembrane pores opens the door to the creation of designer channels and pores for a wide variety of applications.


Assuntos
Simulação por Computador , Genes Sintéticos/genética , Canais Iônicos/química , Canais Iônicos/genética , Modelos Moleculares , Biologia Sintética , Linhagem Celular , Microscopia Crioeletrônica , Cristalografia por Raios X , Condutividade Elétrica , Escherichia coli/genética , Escherichia coli/metabolismo , Hidrazinas , Canais Iônicos/metabolismo , Transporte de Íons , Lipossomos/metabolismo , Técnicas de Patch-Clamp , Porinas/química , Porinas/genética , Porinas/metabolismo , Engenharia de Proteínas , Estrutura Secundária de Proteína , Solubilidade , Água/química
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