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1.
Mol Pharm ; 19(2): 532-546, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-34958588

RESUMO

The present study systematically investigates the effect of annealing conditions and the Kolliphor P 407 content on the physicochemical and structural properties of Compritol (glyceryl behenate) and ternary systems prepared via melt cooling (Kolliphor P 407, Compritol, and a hydrophilic API) representing solid-lipid formulations. The physical properties of Compritol and the ternary systems with varying ratios of Compritol and Kolliphor P 407 were characterized using differential scanning calorimetry (DSC), small- and wide-angle X-ray scattering (SWAXS) and infrared (IR) spectroscopy, and hot-stage microscopy (HSM), before and after annealing. The change in the chemical profiles of different Compritol components as a function of annealing was evaluated using 1H NMR spectroscopy. While no change in the polymorphic form of API and Kolliphor P 407 occurred during annealing, a systematic conversion of the α- to ß-form was observed in the case of Compritol. Furthermore, the polymorphic transformation of Compritol was found to be dependent on the Kolliphor P 407 content. As per the Flory-Huggins mixing theory, higher miscibility was observed in the case of monobehenin-Kolliphor P 407, monobehenin-dibehenin, and dibehenin-tribehenin binary mixtures. The miscibility of Kolliphor P 407 with monobehenin and 1,2-dibehenin was confirmed by 1H NMR analysis. The observed higher miscibility of Kolliphor P 407 with monobehenin and 1,2-dibehenin is proposed as the trigger for the physical separation from the 1,3-diglyceride and triglycerides during melt solidification of the formulations. The phase separation is postulated as the mechanism underlying the formation of a stable ß-polymorphic form (a native form of 1,3-diglyceride) of Compritol upon annealing. This finding is expected to have an important implication for developing stable solid-lipid-surfactant-based drug formulations.


Assuntos
Excipientes , Tensoativos , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Excipientes/química , Transição de Fase , Solubilidade , Tensoativos/química
2.
Drug Deliv ; 29(1): 1398-1408, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35532137

RESUMO

Triptolide (TP), a compound isolated from a Chinese medicinal herb, possesses potent anti-tumor, immunosuppressive, and anti-inflammatory properties, but was clinically limited due to its poor solubility, bioavailability, and toxicity. Considering the environment-friendly, low-cost mechanochemical techniques and potential dissolution enhancement ability of Na2GA, an amorphous solid dispersion (Na2GA&TP-BM) consisting of TP and Na2GA were well-prepared to address these issues. The performance of Na2GA&TP-BM was improved through ball milling, such as from crystalline state to an amorphous solid dispersion, suitable nano micelle size and surface potential, and increased solubility. This change had a significant improvement of pharmacokinetic behavior in mice and could be able to extend the blood circulation time of the antitumor drug. Moreover, in vitro and in vivo anti-tumor study showed that Na2GA&TP-BM displayed more potent cytotoxicity to tumor cells. The work illustrated an environment-friendly and safe preparation of the TP formulation, which was promising to enhance the oral bioavailability and antitumor ability of TP, might be considered for efficient anticancer therapy.


Assuntos
Diterpenos , Fenantrenos , Administração Oral , Animais , Disponibilidade Biológica , Diterpenos/farmacologia , Compostos de Epóxi , Camundongos , Micelas , Fenantrenos/farmacologia , Solubilidade
3.
AAPS PharmSciTech ; 23(5): 133, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534652

RESUMO

Sediment delivery model (SeDeM) system is innovative tool to correlate micromeritic properties of powders with compressibility. It involves computation of indices which facilitate direct compressibility of solids and enable corrective measures through particle engineering. Study had multiple objectives, viz, (i) to enhance solubility of BCS class II, nevirapine using solid dispersions; (ii) SeDeM analyses of excipients and solid dispersions to analyze direct compressibility; and (iii) prepare orodispersible tablets (ODT). Solid dispersions were prepared by solvent evaporation. Superdisintegrants and solid dispersions were analyzed for primary indices of dimension, compressibility, flowability, stability, and disgregability derived from micromeritic properties. Radar diagrams were constructed to provide visual clues to deficient properties for direct compressibility. ODTs were prepared using excipients which passed criteria for direct compressibility and evaluated for tablet properties. Solid dispersions with Eudragit S100 revealed 6 to 10 fold increase in solubility in various dissolution media including biorelevant media in comparison with plain drug. Solubility was found to be pH dependent. SeDeM analyses facilitated identification of superdisintegrants and excipients with unfavorable compressibility. Radar diagrams provided a clear pictorial evidence of lacunae in powder properties. Based on SeDeM results, tablets were formulated by direct compression using crosspovidone, croscarmellose sodium, and mannitol. All batches showed 40% release in first minute in simulated salivary fluid.


Assuntos
Excipientes , Sistemas Especialistas , Composição de Medicamentos/métodos , Excipientes/química , Pós/química , Solubilidade , Comprimidos/química
4.
AAPS PharmSciTech ; 23(5): 134, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534702

RESUMO

Nature has been used as therapeutic resources in the treatment of diseases for many years. However, some natural compounds have poor water solubility. Therefore, physicochemical strategies and technologies are necessary for development of systems for carrying these substances. The self-emulsifying drug delivery systems (SEDDS) have been used as carriers of hydrophobic compounds in order to increase the solubility and absorption, improving their bioavailability. SEDDS are constituted with a mixture of oils and surfactants which, when come into contact with an aqueous medium under mild agitation, can form emulsions. In the last years, a wide variety of self-emulsifying formulations containing bioactive compounds from natural origin has been developed. This review provides a comprehensive overview of the main excipients and natural bioactive compounds composing SEDDS. In addition, applications, new technologies and innovation are reviewed as well. Examples of self-emulsifying formulations administered in different sites are also considered for a better understanding of the use of this strategy to modify the delivery of compounds from natural origin.


Assuntos
Sistemas de Liberação de Medicamentos , Excipientes , Administração Oral , Disponibilidade Biológica , Emulsões/química , Excipientes/química , Solubilidade
5.
AAPS PharmSciTech ; 23(5): 138, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534746

RESUMO

Rifampicin (RFP) solutions, intended to reduce incidence of prosthetic graft infection, were prepared as three-dimensional ground mixtures (3DGMs) using ß-cyclodextrin (ßCD) and γ-cyclodextrin (γCD) and characterized for their spectroscopic properties and solubility. Phase solubility diagrams revealed that 3DGMs (RFP/ßCD and RFP/γCD) produced a complex at 1:1 molar ratio. Pulsed field gradient nuclear magnetic resonance experiments indicated that the diffusion coefficients for RFP/ßCD and RFP/γCD were similar to the respective diffusion coefficients for ßCD and γCD. Rotating-frame Overhauser effect spectroscopy NMR spectra revealed the existence of a new exchanger peak for RFP/γCD, suggesting an intermolecular interaction different from that of RFP/ßCD. Differential scanning calorimetry confirmed the presence of endothermic peak at 191 °C indicating the manifestation of RFP in the inclusion complex. Interestingly, molecular interactions from the complexes, RFP/ßCD and RFP/γCD, revealed different patterns of inclusion in the 3DGMs. In RFP/ßCD, nuclear Overhauser effect spectroscopy NMR spectra indicated cross peaks for the protons of the methyl group of RFP and the protons (H-5 and H-6) in the ßCD cavity. The methyl group of RFP interacted with the narrow rim of ßCD. With RFP/γCD, cross peaks were due to the protons of the methyl group of RFP and the protons of the cavity of γCD suggesting multiple inclusion patterns. The observed multiple cross peaks affirm the inclusion of RFP into the CD cavity which enhanced its solubility by 1.6-2.0-fold when prepared as 3DGMs as RFP/ßCD and RFP/γCD, respectively.


Assuntos
beta-Ciclodextrinas , gama-Ciclodextrinas , Espectroscopia de Ressonância Magnética , Prótons , Rifampina , Solubilidade , beta-Ciclodextrinas/química , gama-Ciclodextrinas/química
6.
Sci Rep ; 12(1): 7100, 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35501338

RESUMO

Regulatory testing of hydraulic cements used in dentistry and standard test methods for root-end filling materials do not exist. The aim of this study was to identify a simple, reproducible method for testing the solubility of materials that set with water (hydraulic) used as root-end filling materials in dentistry. Commercial and prototype hydraulic cements were characterized by scanning electron microscopy and X-ray diffraction analyses and their solubilities were determined using ISO 6876; 2012 standard, a modified ISO 6876 method with media alternative to water and a new method measuring the percentage mass loss and volume change of materials (micro-CT method) from a single surface exposed to three solutions. The solubility testing was performed by three operators to enable an intra-laboratory comparison. The solubility data obtained from the two commercial and two prototype materials varied depending on the method used, with the ISO 6876 method identifying differences in solubility of the materials (p < 0.05) but when modified with alternative solutions, no differences were found (p > 0.05). The changes in solution thus effected the solubility of the tested materials. Inter-operator differences were observed with the weight changes determined from the new method indicating this method was not robust. The weight and volume assessments using the new method were not solution-dependent. The advantage of the proposed method compared with the ISO standard is its simplicity, enabling a number of tests to be performed on the same set of samples that also more closely mimics the clinical environment.


Assuntos
Materiais Restauradores do Canal Radicular , Compostos de Cálcio , Silicatos , Solubilidade , Água
7.
AAPS J ; 24(3): 60, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35501614

RESUMO

Traditionally, excipients have been considered in drug development from the perspective of their influence on drug solubility, manufacturability, and ability to control in vitro and in vivo drug release. These effects have been largely evaluated through studies involving in vitro dissolution methods. However, there is a growing awareness that what had previously been considered biologically inert excipients can exert numerous in vivo effects. This includes the potential to change gastrointestinal (GI) transit time, enterocyte passive transcellular or paracellular permeability, active transport activity, or presystemic drug metabolism. In this critical overview of the biological effects of excipients (Part I), we provide a summary of select published studies that explore these various in vivo factors. We also include a table that points readers to published reviews that list a range of excipients known to have biological activity. A subsequent discussion on in vitro, in vivo, and in silico methods that can be used to explore these excipient effects is provided in a separate (Part 2) continuation of this critical overview.


Assuntos
Excipientes , Absorção Intestinal , Permeabilidade , Solubilidade
8.
Eur Rev Med Pharmacol Sci ; 26(8): 3010-3024, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35503601

RESUMO

OBJECTIVE: The aim of the study was to improve the bioavailability of Cinacalcet hydrochloride (CLC) and enhance its efficacy by the nanoemulsion drug delivery system. MATERIALS AND METHODS: First, cinacalcet hydrochloride-nanoemulsion (CLC-NE) was prepared and optimized through the pseudo ternary phase diagram and central composite design response surface methodology (CCD). The release of CLC-NE in vitro was investigated with four different dissolution media, and the bioavailability of CLC-NE in vivo was studied through beagle dogs. Finally, the pharmacodynamics of CLC-NE was evaluated by the rat model of uremia. RESULTS: Oleic acid, op-10, and PEG-200 were selected as oil phase, emulsifier, and co-emulsifier, respectively. The optimum ratio of oleic acid, op-10, PEG-200, and water was 9.87%, 38.33%, 12.78%, and 39.02%. CLC-NE has similar dissolution rates in different pH media, and the relative bioavailability of CLC-NE was 166.5%. The uremia model showed that CLC-NE could enhance renal function and reduce the excessive phosphorus (P), serum creatinine (Scr), and urea nitrogen (Urea) of model rats, as well as the inhibited increase of fibroblast growth factor-23 (FGF23) and parathyroid hormone (PTH). CONCLUSIONS: The solubility, bioavailability, and pharmacodynamics of CLC can be significantly improved through the nanoemulsion drug delivery system.


Assuntos
Nanopartículas , Uremia , Animais , Disponibilidade Biológica , Cinacalcete/farmacologia , Cães , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Feminino , Humanos , Masculino , Nanopartículas/química , Ácido Oleico , Tamanho da Partícula , Ratos , Solubilidade , Ureia
9.
Chem Pharm Bull (Tokyo) ; 70(5): 383-390, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35491195

RESUMO

Numerous efforts have been devoted to improving the solubility of poorly water-soluble drugs. Recently, it was reported that the use of metal-organic frameworks (MOFs), which are a new class of porous materials consisting of metal ions and organic ligands, is effective in improving the solubility of poorly water-soluble drugs. Our previous study demonstrated an improvement in the solubility of indomethacin (IDM) triggered by the zeolitic imidazolate framework-8 (ZIF-8). The present study aimed to elucidate the solubilization mechanism using the ZIF series, namely, ZIF-8, ZIF-67, and ZIF-L. It was confirmed that the solubility of ZIF-trapped IDM and ibuprofen (IBU) was enhanced compared to the raw drugs, regardless of the ZIF type. This study focused on 2-methylimidazole (2-MIM), which is commonly used as a ZIF organic ligand. Both IDM and IBU were easily dissolved by the addition of 2-MIM, suggesting that the presence of 2-MIM enhanced the solubility of the drugs. Inductively coupled plasma measurements also confirmed the presence of metal ions of ZIFs in the supernatant solution after the drug release tests, indicating the decomposition of ZIFs during drug release. The findings of this study demonstrated the solubilization mechanism of poorly water-soluble drugs using ZIF particles. We observed that the drugs loaded on the ZIFs were released simultaneously with the decomposition of some of the ZIFs. The 2-MIM molecules were also released concurrently. The presence of 2-MIM improved the solubility of poorly water-soluble drugs.


Assuntos
Zeolitas , Liberação Controlada de Fármacos , Metais , Solubilidade , Água
10.
Crit Rev Ther Drug Carrier Syst ; 39(2): 79-95, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35378014

RESUMO

In the last few years, the polymeric micelles played a major role as a drug carrier in nano-sized drug delivery system. The polymeric micelles are designed from synthetic block co-polymers and graft copolymers. In the mixed micelles, the bilayer lipid membrane and surfactants are used. Both micelles are in nano-sized and used to enhance the drug delivery to treat different diseases. In this review, we will discuss some examples from the literature included demonstrating the polymeric micelles used as drug-carriers in skin cancer treatment by using different drugs. We also summarized mixed micelles, polymeric micelles in skin drug delivery, various polymers, and techniques of polymeric micelles. These micelles may improve delivery of drug in the skin's targeted sites in specific and dermatological diseases like skin cancer, acne, and fungal infection. In the comparison of surfactant micelles, the polymeric micelles are more stable. Polymeric micelles act as a colloidal carrier for incorporating poorly water-soluble and amphiphilic drugs.


Assuntos
Micelas , Neoplasias Cutâneas , Sistemas de Liberação de Medicamentos , Humanos , Polímeros , Neoplasias Cutâneas/tratamento farmacológico , Solubilidade
11.
AAPS PharmSciTech ; 23(4): 102, 2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35378669

RESUMO

Topical microemulsion (ME) might provide a novel and advanced transdermal delivery system due to the enhances of drug solubility and permeability across the stratum corneum. Foams are topical delivery systems that have excellent patient compliance, acceptability, and preference. Therefore, this study aimed to investigate a foamable microemulsion as an alternative topical and transdermal dosage form for diclofenac sodium (DS). The physicochemical properties (optical clarity, percentage transmittance, homogeneity, consistency of formulation, particle size, zeta potential, conductivity, viscosity, and morphology, etc.) of the DS-loaded ME were investigated. The foam stability of both drug-free ME and DS-loaded ME was measured. The foam quality was evaluated, and the chemical stability over 90 days was determined. Franz diffusion cells were employed to assess the in vitro drug release of a foamed DS-loaded ME and compared with a commercial topical product. A foamable and stable DS-loaded ME that maintained small particle sizes and constant zeta potential and was transparent and translucent in appearance after 90 days was successfully produced. The foam of the DS-loaded ME was physically more stable compared to the drug-free foam. The foam had an increased drug release rate compared to the commercial product. The foamable DS-loaded ME has a great potential to enhance the transdermal delivery of DS after topical administration. Foamed DS-loaded ME is a promising alternative to the current topical formulation of DS.


Assuntos
Diclofenaco , Administração Cutânea , Diclofenaco/química , Liberação Controlada de Fármacos , Emulsões/química , Humanos , Solubilidade
12.
Sci Rep ; 12(1): 5463, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35361835

RESUMO

The solubility of proteins is usually a necessity for their functioning. Recently an emergence of machine learning approaches as trained alternatives to statistical models has been evidenced for empirical modeling and optimization. Here, soluble production of anti-EpCAM extracellular domain (EpEx) single chain variable fragment (scFv) antibody was modeled and optimized as a function of four literature based numerical factors (post-induction temperature, post-induction time, cell density of induction time, and inducer concentration) and one categorical variable using artificial neural network (ANN) and response surface methodology (RSM). Models were established by the CCD experimental data derived from 232 separate experiments. The concentration of soluble scFv reached 112.4 mg/L at the optimum condition and strain (induction at cell density 0.6 with 0.4 mM IPTG for 24 h at 23 °C in Origami). The predicted value obtained by ANN for the response (106.1 mg/L) was closer to the experimental result than that obtained by RSM (97.9 mg/L), which again confirmed a higher accuracy of ANN model. To the author's knowledge this is the first report on comparison of ANN and RSM in statistical optimization of fermentation conditions of E.coli for the soluble production of recombinant scFv.


Assuntos
Escherichia coli , Anticorpos de Cadeia Única , Escherichia coli/genética , Aprendizado de Máquina , Proteínas Recombinantes , Solubilidade
13.
Int J Pharm Compd ; 26(2): 163-174, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35413015

RESUMO

The future of dosage form design is expected to move towards the production of personalized dosage forms tailored to each patient. The 3D printer was introduced to solve that problem but is not easy to use in a pharmacy. Herein, a new 3D mold technology is adopted for tablet manufacturing. Preparation of amlodipine tablets was used as a Biopharmaceutics Classification System Class 1 drug model to study this technology. Different concentrations of either starch or Avicel-based formulations and different concentrations of hydroxypropyl methylcellulose as a binder for mass formation were used. The mass formed for each formula was cast into the mold for tablet preparation. Different non-pharmacopeial and pharmacopeial quality-control tests of the prepared tablets by using the 3D mold were compared to a marketed tablet product of amlodipine. 3D-molded tablets showed compliance properties with the tablet pharmacopeial quality standard. Studying the equivalence of the 3D mold tablets to the brand marketed product under biowaiver conditions was carried out. The difference and similarity factors studies of molded tablets prepared using starch or Avicel as a filler and 2.5% of hydroxypropyl methylcellulose showed acceptable characters to the drug brand name. It is predicted that by using this simple technique, it would be possible to produce tablets with designed disintegration and release profiles, which could potentially allow the tailoring of the drug release and hence personalize the medicine for each patient.


Assuntos
Anlodipino/administração & dosagem , Excipientes , Tecnologia Farmacêutica , Celulose , Composição de Medicamentos , Humanos , Derivados da Hipromelose , Impressão Tridimensional , Solubilidade , Amido , Comprimidos , Tecnologia Farmacêutica/métodos
14.
Protein Sci ; 31(5): e4299, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35481654

RESUMO

When engineering a protein for its biological function, many physicochemical properties are also optimized throughout the engineering process, and the protein's solubility is among the most important properties to consider. Here, we report two novel computational methods to calculate the pH-dependent protein solubility, and to rank the solubility of mutants. The first is an empirical method developed for fast ranking of the solubility of a large number of mutants of a protein. It takes into account electrostatic solvation energy term calculated using Generalized Born approximation, hydrophobic patches, protein charge, and charge asymmetry, as well as the changes of protein stability upon mutation. This method has been tested on over 100 mutations for 17 globular proteins, as well as on 44 variants of five different antibodies. The prediction rate is over 80%. The antibody tests showed a Pearson correlation coefficient, R, with experimental data from .83 to .91. The second method is based on a novel, completely force-field-based approach using CHARMm program modules to calculate the binding energy of the protein to a part of the crystal lattice, generated from X-ray structure. The method predicted with very high accuracy the solubility of Ribonuclease SA and its 3K and 5K mutants as a function of pH without any parameter adjustments of the existing BIOVIA Discovery Studio binding affinity model. Our methods can be used for rapid screening of large numbers of design candidates based on solubility, and to guide the design of solution conditions for antibody formulation.


Assuntos
Física , Proteínas , Concentração de Íons de Hidrogênio , Estabilidade Proteica , Proteínas/química , Proteínas/genética , Solubilidade
16.
Carbohydr Polym ; 289: 119468, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35483865

RESUMO

In the present work, we constructed a methodology to graft starch with special groups, such as alkyl, phenolic, naphthalimide derivatives (ND) and polymer, by a simple reaction under generally mild conditions without catalysts or UV irradiation, based on precursor starch acetoacetate (SAA). The completeness of these reactions has been proved to be ideal. After grafting, the starch derivatives have some common changes, for instance, their solubility is improved in certain solvents. On the other hand, the introduction of different functional groups will also bring some characteristics to the derivatives (e.g. ND brings fluorescence). In addition, part of the derivatives shows excellent machinability, and their hot-pressed samples exhibit great transparency and mechanical strength. Specially, the alkyl grafted starch displays excellent toughness, properties of deformation and self-recovery. In conclusion, this method has good universality and methodological significance, and offers insights into the larger-scale industrial application of starch.


Assuntos
Acetoacetatos , Amido , Polímeros , Solubilidade , Solventes
17.
Int J Nanomedicine ; 17: 1783-1801, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35479768

RESUMO

Introduction: This work was aimed to develop a Curcuma oil-based self-nanoemulsifying drug delivery system (SNEDDS) 3D-printed polypills containing glimepiride (GMD) and rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes as a model for metabolic syndrome (MS). Methods: Compartmentalized 3D printed polypills were prepared and studied in streptozotocin/poloxamer induced diabetic/dyslipidemic rats. The pharmacokinetic parameters of GMD and RSV in the prepared polypills were evaluated. Blood glucose level, lipid profile, antioxidant, and biochemical markers activities were investigated. Also, histopathological examination of the liver and pancreas was carried out. The atherosclerotic index, the area of islets of Langerhans, and liver steatosis lesion scores were calculated. Results: The developed SNEDDS-loaded GMD/RSV polypills showed acceptable quality control characteristics with a high relative bioavailability of 217.16% and 224.28% for GMD and RSV, respectively, when compared with the corresponding non-SNEDDS pills. The prepared polypills showed dramatic lowering in blood glucose levels and substantial improvement in lipid profile and hepatic serum biomarkers as well as remarkable decrease in serum antioxidants in response to Poloxamer 407 intoxication. The prepared polypills decreased the risk of atherosclerosis and coronary disease by boosting the level of high-density lipoprotein and lowering both triglyceride and low-density lipoprotein. Microscopic examination showed normal hepatic sinusoids and high protection level with less detectable steatosis in the examined hepatocytes. Normal size pancreatic islets with apparently normal exocrine acini and pancreatic duct were also noticed. Conclusion: This formulation strategy clearly shows the potential of the developed polypills in personalized medicine for treatment of patients with MS.


Assuntos
Síndrome Metabólica , Nanopartículas , Administração Oral , Animais , Glicemia , Emulsões , Humanos , Lipídeos , Síndrome Metabólica/tratamento farmacológico , Nanotecnologia , Tamanho da Partícula , Impressão Tridimensional , Ratos , Rosuvastatina Cálcica , Solubilidade
18.
Sci Rep ; 12(1): 6547, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35449391

RESUMO

Proteins are prone to aggregate when expressed above their solubility limits. Aggregation may occur rapidly, potentially as early as proteins emerge from the ribosome, or slowly, following synthesis. However, in vivo data on aggregation rates are scarce. Here, we classified the Escherichia coli proteome into rapidly and slowly aggregating proteins using an in vivo image-based screen coupled with machine learning. We find that the majority (70%) of cytosolic proteins that become insoluble upon overexpression have relatively low rates of aggregation and are unlikely to aggregate co-translationally. Remarkably, such proteins exhibit higher folding rates compared to rapidly aggregating proteins, potentially implying that they aggregate after reaching their folded states. Furthermore, we find that a substantial fraction (~ 35%) of the proteome remain soluble at concentrations much higher than those found naturally, indicating a large margin of safety to tolerate gene expression changes. We show that high disorder content and low surface stickiness are major determinants of high solubility and are favored in abundant bacterial proteins. Overall, our study provides a global view of aggregation rates and hence solubility limits of proteins in a bacterial cell.


Assuntos
Dobramento de Proteína , Proteoma , Escherichia coli/genética , Escherichia coli/metabolismo , Proteoma/metabolismo , Ribossomos/metabolismo , Solubilidade
19.
Food Chem ; 387: 132872, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35390604

RESUMO

This study aimed to investigate the effects of standing curing (SC), tumbling curing (TC), vacuum tumbling curing (VTC) and ultrasonic-assisted curing (UAC) on the edible quality of black pork and property of myofibrillar proteins (MPs) extracted from black pork. The results showed that all curing methods could improve the marinating absorptivity and the gel water retention of black pork, the solubility and surface hydrophobicity of myofibrillar proteins, and reduce the cooking loss and shear force of black pork, the hydrogen bond content of myofibrillar proteins and the gel whiteness compared with the control group (SC). The result of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) showed that the concentration of protein bands by VTC treatment was decreased obviously. In addition, the result of the scanning electron microscope (SEM) presented that tumbling and ultrasound treatment would destroy the structure of muscle fibers and make them loose and disordered.


Assuntos
Carne de Porco , Carne Vermelha , Animais , Culinária , Eletroforese em Gel de Poliacrilamida , Proteínas , Solubilidade , Suínos
20.
Mol Pharm ; 19(5): 1604-1618, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35362988

RESUMO

Spray drying is one of the most commonly used manufacturing techniques for amorphous solid dispersions (ASDs). During spray drying, very fast solvent evaporation is enabled by the generation of small droplets and exposure of these droplets to a heated drying gas. This fast solvent evaporation leads to an increased viscosity that enables kinetic trapping of an active pharmaceutical ingredient (API) in a polymer matrix, which is favorable for the formulation of supersaturated, kinetically stabilized ASDs. In this work, the relation between the solvent evaporation rate and the kinetic stabilization of highly drug-loaded ASDs was investigated. Accordingly, thermal gravimetric analysis (TGA) was employed to study the evaporation kinetics of seven organic solvents and the influence of solutes, i.e., poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), fenofibrate (FNB), and naproxen (NAP), on the evaporation behavior. At 10 °C below the boiling point of the respective solvent, methanol (MeOH) had the lowest evaporation rate and dichloromethane (DCM) had the highest. PVPVA decreased the evaporation rate for all solvents, yet this effect was more pronounced for the relatively faster evaporating solvents. The APIs had opposite effects on the evaporation process: FNB increased the evaporation rate, while NAP decreased it. The latter might indicate the presence of interactions between NAP and the solvent or NAP and PVPVA, which was further investigated using Fourier transform-InfraRed (FT-IR) spectroscopy. Based on these findings, spray drying process parameters were adapted to alter the evaporation rate. Increasing the evaporation rate of MeOH and DCM enabled the kinetic stabilization of higher drug loadings of FNB, while the opposite trend was observed for ASDs of NAP. Even when higher drug loadings could be kinetically stabilized by adapting the process parameters, the improvement was limited, demonstrating that the phase behavior of these ASDs of FNB and NAP immediately after preparation was predominantly determined by the API-polymer-solvent combination rather than the process parameters applied.


Assuntos
Química Farmacêutica , Secagem por Atomização , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Cinética , Naproxeno/química , Polímeros/química , Solubilidade , Solventes/química , Espectroscopia de Infravermelho com Transformada de Fourier
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