Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 41
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Glycoconj J ; 40(5): 565-573, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37402017

RESUMEN

Streptococcus pneumoniae is a highly invasive bacterial pathogen that can cause a range of illnesses. Pneumococcal capsular polysaccharides (CPS) are the main virulence factors that causes invasive pneumococcal disease (IPD). Pneumococcal CPS serotype 7F along with a few other serotypes is more invasive and likely to cause IPD. Therefore, 7F is a target for pneumococcal vaccine development, and is included in the two recently approved multi-valent pneumococcal conjugated vaccines, i.e. VAXNEUVANCE and PREVNAR 20.To support process and development of our 15-valent pneumococcal conjugated vaccine (PCV15), chromatographic methods have been developed for 7F polysaccharide and conjugate characterization. A size-exclusion chromatography (SEC) method with UV, light scattering and refractive index detections was employed for concentration, size and conformation analysis. A reversed-phase ultra-performance liquid chromatography (RP-UPLC) method was used for analysis of conjugate monosaccharide composition and degree of conjugation. The collective information obtained by these chromatographic analysis provided insights into the pneumococcal conjugate and conjugation process.


Asunto(s)
Infecciones Neumocócicas , Humanos , Serogrupo , Serotipificación , Infecciones Neumocócicas/prevención & control , Infecciones Neumocócicas/microbiología , Streptococcus pneumoniae , Vacunas Neumococicas , Vacunas Conjugadas , Antígenos Bacterianos
2.
Mol Breed ; 41(10): 60, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37309315

RESUMEN

Synthetic hexaploid wheat offers breeders ready access to potentially novel genetic variation in wild ancestral species. In this study, we crossed MY3478 (2n = 4x = 28, AABB) as the maternal parent with the stripe rust-resistant SY41 (2n = 2x = 14, DD) as the paternal parent to construct the new hexaploid wheat line NA0928 through natural allopolyploidization. Agronomic traits and the cytology of the S8-S9 generations of NA0928 were analyzed. Abundant variation in agronomic traits was observed among each strain of NA0928 in the S8 generation. Agronomic traits were superior in strains resistant to stripe rust compared with those of highly susceptible strains. The rank order of the coefficients of variation were tiller number (55.3%) > spike length (15.3%) > number of spikelets (13.9%) > plant height (8.7). Number of tillers and spike length are important traits in wheat breeding to improve yield. Cytological observation and fluorescence in situ hybridization showed that the chromosome number and configuration showed rich variation among NA0928 strains in the S9 generation. Chromosome number ranged from 36 to 44. Variation in chromosome karyotype was detected in the A and B subgenomes. Meiotic chromosome behavior in pollen mother cells and multicolor genomic in situ hybridization revealed that two new synthetic hexaploid wheat strains showed genetic stability; one strain was resistant to stripe rust and developed multiple tillers, and the other strain was susceptible to stripe rust, but both showed improved thousand-kernel weight (TKW) weight and produced multiple tillers. The two strains will be valuable germplasm resources for use in wheat breeding.

3.
Anal Bioanal Chem ; 412(2): 377-388, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31773226

RESUMEN

Insulin oligosaccharide conjugates hold promise as potential glucose-responsive insulins (GRIs), which can improve the therapeutic index of insulins and mitigate the risk of hypoglycemia. A key challenge for the analytical development of such molecules is finding an efficient method to characterize the purity and impurities of conjugated insulins. Using the S-Matrix Fusion QbD-ultrahigh performance liquid chromatography (UHPLC) integrated system, we were able to quickly screen and develop two short UHPLC methods. These methods were used to support process development, clinical batch drug substance (DS) release, and stability studies of MK-2640, an insulin oligosaccharide conjugate. Both methods used a Waters CSH C18 column, with a shallow gradient of acetonitrile to aqueous mobile phase containing 25 mM sodium perchlorate and 0.05% perchloric acid. The 10-min run time method was well suited for process development and monitoring as it was able to separate the main product, MK-2640, six oligosaccharide-substituted recombinant human insulin (RHI) impurities, A21 deamidated MK-2640, and the starting material RHI. The 13-min run time method provided improved separation of the major impurities and demonstrated good chromatographic reproducibility on different instruments or using columns from different lots of stationary phase, which made it ideal for the final DS release. Validation of the 13-min method demonstrated great linearity for both the MK-2640 main peak and its related impurities, low limit of detection (0.02%), and limit of quantitation (0.05%). The high specificity of the method allowed the separation of the degradation products from main peak, thus makes it suitable for stability monitoring. The major impurities in the DS were characterized by two-dimensional liquid chromatography-mass spectrometry (2D-LC-MS).


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Glucosa/metabolismo , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Humanos , Límite de Detección , Espectrometría de Masas/métodos , Reproducibilidad de los Resultados
4.
J Cell Biochem ; 120(12): 19422-19431, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31452264

RESUMEN

Osteoporosis (OP), a common metabolic bone disease, is accompanied by reduced bone mass, bone mineral density (BMD), as well as microstructure destruction of bone. Previously, microRNA-196a-2 (miR-196a-2) and miR-196a-3p were reported for its involvement in BMD. Herein, this study set out to identify the functional relevance of miR-196a in osteogenic differentiation in osteoporotic mice and explore the associated mechanism by establishing an OP mouse model. Guanine nucleotide binding protein, alpha stimulating (GNAS) was verified as a target gene of miR-196a, which was decreased in OP mice. Furthermore, the bone marrow stromal cells (BMSCs) were then extracted from OP mice and treated with miR-196 mimic/inhibitor or small interfering RNA against GNAS to investigate miR-196a interaction with GNAS and the Hedgehog signaling pathway. BMSCs in OP mice transfected with miR-196a mimic or si-GNAS displayed the elevated expression of Smo, ALP, Runx2, and OPN, as well as bone gla protein and tartrate-resistant acid phosphatase, elevated ALP vitality and bone formation ability as well as reduced expression of GNAS and PTCH. Taken conjointly, overexpression of miR-196a repressed GNAS expression by activating the Hedgehog signaling pathway, thus promoting osteogenic differentiation in mice with OP.


Asunto(s)
Diferenciación Celular/fisiología , Proteínas Hedgehog/metabolismo , MicroARNs/metabolismo , Osteogénesis/fisiología , Osteoporosis/metabolismo , Animales , Diferenciación Celular/genética , Ensayo de Inmunoadsorción Enzimática , Femenino , Proteínas Hedgehog/genética , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Osteogénesis/genética , Osteoporosis/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Transducción de Señal/fisiología
5.
CMAJ ; 195(22): E799, 2023 06 05.
Artículo en Francés | MEDLINE | ID: mdl-37277125

Asunto(s)
Emolientes , Antebrazo , Humanos
6.
CMAJ ; 195(8): E304, 2023 02 27.
Artículo en Inglés | MEDLINE | ID: mdl-36849173

Asunto(s)
Emolientes , Antebrazo , Humanos
7.
Biochem Biophys Res Commun ; 490(2): 217-224, 2017 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-28602700

RESUMEN

Cancer cells usually utilize glucose as a carbon source for aerobic glycolysis, a phenomenon known as the Warburg effect. Increasing studies have shown that PVT1 (a long non-coding RNA, lncRNA) functions as critical regulator of multiple cancers. However, it remains totally unknown whether and how PVT1 regulates glucose metabolism in OS cells. In this study, we found that the expression of PVT1 were specifically increased in OS cells and tissues, and the upregulated PVT1 indicated poor prognosis. Glucose uptake, lactate production, and the expression of HK2 in OS cells were increased by overexpression of PVT1, while decreased by PVT1 knockdown. We further fund that PVT1 acted as molecular sponge to repress miR-497. Inhibition of miR-497 promoted glucose consumption and lactate production, phenomenon could be reversed by PVT1 silencing. Moreover, HK2 was a direct target of miR-497 and overexpression of HK2 attenuated the suppressive effect of miR-497 on glycolysis. Functionally, knockdown of PVT1 exerted tumor-suppressive effect by suppressing cell proliferation, cell cycle progression, and invasion in vitro, whereas miR-497 inhibitor partially abolished the inhibition effect of si-PVT1. Overexpression of HK2 attenuated the miR-497 induced inhibition of cell growth and motility. Taken together, these findings suggested that PVT1 contributes to OS cell glucose metabolism, cell proliferation, and motility through the miR-497/HK2 pathway, and revealed a novel relation between lncRNA and the alteration of glycolysis in OS cells.


Asunto(s)
Progresión de la Enfermedad , Glucólisis , Hexoquinasa/metabolismo , MicroARNs/metabolismo , Osteosarcoma/metabolismo , ARN Largo no Codificante/metabolismo , Línea Celular Tumoral , Hexoquinasa/genética , Humanos , MicroARNs/antagonistas & inhibidores , Osteosarcoma/enzimología , Osteosarcoma/genética
8.
BMC Complement Altern Med ; 17(1): 310, 2017 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-28610566

RESUMEN

BACKGROUND: Apoptosis plays a critical role in the progression of diabetic cardiomyopathy (DC). Astragalus polysaccharides (APS), an extract of astragalus membranaceus (AM), is an effective cardioprotectant. Currently, little is known about the detailed mechanisms underlying cardioprotective effects of APS. The aims of this study were to investigate the potential effects and mechanisms of APS on apoptosis employing a model of high glucose induction of apoptosis in H9C2 cells. METHODS: A model of high glucose induction of H9C2 cell apoptosis was adopted in this research. The cell viabilities were analyzed by MTT assay, and the apoptotic response was quantified by flow cytometry. The expression levels of the apoptosis related proteins were determined by Real-time PCR and western blotting. RESULTS: Incubation of H9C2 cells with various concentrations of glucose (i.e., 5.5, 12.5, 25, 33 and 44 mmol/L) for 24 h revealed that cell viability was reduced by high glucose dose-dependently. Pretreatment of cells with APS could inhibit high glucose-induced H9C2 cell apoptosis by decreasing the expressions of caspases and the release of cytochrome C from mitochondria to cytoplasm. Further experiments also showed that APS could modulate the ratio of Bcl-2 to Bax in mitochondria. CONCLUSIONS: APS decreases high glucose-induced H9C2 cell apoptosis by inhibiting the expression of pro-apoptotic proteins of both the extrinsic and intrinsic pathways and modulating the ratio of Bcl-2 to Bax in mitochondria.


Asunto(s)
Planta del Astrágalo/química , Cardiomiopatías Diabéticas/fisiopatología , Extractos Vegetales/farmacología , Polisacáridos/farmacología , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Línea Celular , Citocromos c/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/metabolismo , Glucosa/metabolismo , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal/efectos de los fármacos
9.
Lipids Health Dis ; 14: 22, 2015 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-25889773

RESUMEN

BACKGROUND: Low serum cholesterol levels are related to an increased risk of depression and its serious consequences. However, the effect of central cholesterol on depressive disorder and its potential regulatory mechanism is poorly understood. Therefore, brain cholesterol in patients with depression may not only decrease the risk for developing this disease but also increase the beneficial effects of treatment for depression. METHODS: In current study, rats were exposed to chronic mild stress (CMS) for consecutive 28 days, and the depressive-like behavior was tested by sucrose preference test, immobility in the forced swim test, locomotor activity in the open field test, decreased bodyweight and food intake. Additionally, the total cholesterol levels in the medial prefrontal cortex (mPFC) and the hippocampus of rats were measured by gas chromatograph mass spectrometer. Finally, 5-HT1A receptor antagonist WAY100635 was used to determine the potential role of serotonin system in the interaction between central cholesterol and depression. RESULTS: CMS significantly reduced total cholesterol levels in the mPFC but not in the hippocampus and resulted in depressive-like behavior. Chronic supplementation of cholesterol by food reversed the depressive-like behavior induced by CMS. Furthermore, pre-injection of 5-HT1A receptor antagonist WAY100635 into the mPFC blocked the treatment effects of cholesterol on the reversal of behavioral response. CONCLUSION: This finding suggested that cholesterol in the mPFC may have an impact on the sensitivity of the 5-HT1A receptor in the development and treatment of depression. The treatment benefits of cholesterol could be through modulation of the brain 5-HT1A receptor.


Asunto(s)
Colesterol/análisis , Depresión/metabolismo , Hipocampo/química , Corteza Prefrontal/química , Receptor de Serotonina 5-HT1A/fisiología , Animales , Modelos Animales de Enfermedad , Cromatografía de Gases y Espectrometría de Masas , Masculino , Piperazinas/farmacología , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Antagonistas del Receptor de Serotonina 5-HT1/farmacología , Estrés Psicológico/complicaciones
10.
Front Immunol ; 15: 1398222, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38650926

RESUMEN

[This corrects the article DOI: 10.3389/fimmu.2023.1188253.].

11.
Front Immunol ; 14: 1188253, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37377955

RESUMEN

IκBζ (encoded by NFKBIZ) is the most recently identified IkappaB family protein. As an atypical member of the IkappaB protein family, NFKBIZ has been the focus of recent studies because of its role in inflammation. Specifically, it is a key gene in the regulation of a variety of inflammatory factors in the NF-KB pathway, thereby affecting the progression of related diseases. In recent years, investigations into NFKBIZ have led to greater understanding of this gene. In this review, we summarize the induction of NFKBIZ and then elucidate its transcription, translation, molecular mechanism and physiological function. Finally, the roles played by NFKBIZ in psoriasis, cancer, kidney injury, autoimmune diseases and other diseases are described. NFKBIZ functions are universal and bidirectional, and therefore, this gene may exert a great influence on the regulation of inflammation and inflammation-related diseases.


Asunto(s)
FN-kappa B , Psoriasis , Humanos , FN-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Inflamación
12.
Int J Biol Macromol ; 246: 125706, 2023 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-37414316

RESUMEN

In this study, a highly branched polysaccharide (GPF, 112.0 kDa) was isolated and purified from Gomphus clavatus Gray fruiting bodies. GPF was primarily composed of mannose, galactose, arabinose, xylose, and glucose at a molar ratio of 3.2:1.9:1.6:1.2:1.0. GPF was a highly branched heteropolysaccharide composed of 13 glucosidic bonds, with a degree of branching (DB) of 48.85 %. GPF exhibited anti-aging activity in vivo, significantly increased antioxidant enzymes activities (SOD, CAT and GSH-Px), improved total antioxidant capability (T-AOC) and decreased MDA level in the serum and brain of d-Gal induced aging mice. Behavioral experiments showed that GPF effectively improved learning and memory deficits in d-Gal induced aging mice. Mechanistic studies indicated that GPF could activate AMPK by increasing AMPK phosphorylation and upregulating SIRT1 and PGC-1α expression. These findings suggest that GPF has significant potential as a natural candidate to slow down aging and prevent aging-related diseases.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Antioxidantes , Ratones , Animales , Antioxidantes/química , Proteínas Quinasas Activadas por AMP/metabolismo , Envejecimiento , Polisacáridos/farmacología , Polisacáridos/química , Galactosa/farmacología , Estrés Oxidativo
13.
Clin Cosmet Investig Dermatol ; 15: 1029-1036, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35677222

RESUMEN

Background: The biomarker to predict the depression in patients with rosacea was absent. Objective: We aimed to explore the potential association between BDNF and depression in patients with rosacea, and also to determine whether serum BDNF level is a potential biomarker for identifying depression in patients with rosacea. Methods: The patients with rosacea, rosacea with depression and healthy control were included, clinical evaluation (DLQI, RSSs, BDI-II) and serum BDNF levels detection were performed on subjects, the comparisons and correlation analysis of the obtained data were performed. Results: In clinical evaluation, whether DLQI or RSSs, rosacea with depression group was significantly higher compared to rosacea group. Besides, we found the serum BDNF levels were lower in patients with rosacea and rosacea with depression compared to healthy controls, also in the rosacea with depression group, serum BDNF levels were lower than in rosacea patients. Whatever in rosacea or rosacea with depression group, the statistical significance of serum BDNF levels between the different subtypes like the ETR and PPR was not found. In further correlation analysis, we found no correlation between serum BDNF and RSSs in patients with rosacea whatever the subtype of ETR or PPR. Interestingly, we found a negative correlation between serum BDNF levels and BDI-II in rosacea with depression group, the decreased serum BDNF levels were associated with the increased BDI-II, also the ROC confirmed it can evaluate the depression in patients with rosacea. Conclusion: Serum BDNF level is a potential biomarker for identifying depression in patients with rosacea.

14.
Clin Cosmet Investig Dermatol ; 15: 1309-1312, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35847419

RESUMEN

Facial flushing is one of the common conditions in dermatology, which affects the aesthetic of patients to a great extent, and even leads to psychological and economic burdens. The most common causes of facial flushing are often inflammatory skin diseases such as rosacea, contact dermatitis, and others, but the facial flushing as a sign can also be the cutaneous manifestation of systemic disease. Telangiectasia macularis eruptiva perstans (TMEP) is a rare disease associated with mast cells. Here, we describe an unusual clinical finding with persistent facial flushing in a patient with TMEP.

15.
Science ; 376(6599): 1321-1327, 2022 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-35709255

RESUMEN

The emergence of new therapeutic modalities requires complementary tools for their efficient syntheses. Availability of methodologies for site-selective modification of biomolecules remains a long-standing challenge, given the inherent complexity and the presence of repeating residues that bear functional groups with similar reactivity profiles. We describe a bioconjugation strategy for modification of native peptides relying on high site selectivity conveyed by enzymes. We engineered penicillin G acylases to distinguish among free amino moieties of insulin (two at amino termini and an internal lysine) and manipulate cleavable phenylacetamide groups in a programmable manner to form protected insulin derivatives. This enables selective and specific chemical ligation to synthesize homogeneous bioconjugates, improving yield and purity compared to the existing methods, and generally opens avenues in the functionalization of native proteins to access biological probes or drugs.


Asunto(s)
Insulina , Penicilina Amidasa , Péptidos , Ingeniería de Proteínas , Secuencia de Aminoácidos , Humanos , Insulina/análogos & derivados , Insulina/biosíntesis , Lisina/química , Penicilina Amidasa/química , Penicilina Amidasa/genética , Péptidos/química , Péptidos/genética , Ingeniería de Proteínas/métodos
16.
J Med Chem ; 65(7): 5593-5605, 2022 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-35298158

RESUMEN

We have identified a series of novel insulin receptor partial agonists (IRPAs) with a potential to mitigate the risk of hypoglycemia associated with the use of insulin as an antidiabetic treatment. These molecules were designed as dimers of native insulin connected via chemical linkers of variable lengths with optional capping groups at the N-terminals of insulin chains. Depending on the structure, the maximal activation level (%Max) varied in the range of ∼20-70% of native insulin, and EC50 values remained in sub-nM range. Studies in minipig and dog demonstrated that IRPAs had sufficient efficacy to normalize plasma glucose levels in diabetes, while providing reduction of hypoglycemia risk. IRPAs had a prolonged duration of action, potentially making them suitable for once-daily dosing. Two lead compounds with %Max values of 30 and 40% relative to native insulin were selected for follow up studies in the clinic.


Asunto(s)
Diabetes Mellitus Tipo 2 , Hipoglucemia , Animales , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Perros , Hipoglucemia/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Receptor de Insulina , Porcinos , Porcinos Enanos , Índice Terapéutico
17.
J Comput Chem ; 32(6): 987-97, 2011 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-20949511

RESUMEN

The mechanisms and kinetics studies of the OH radical with alkyl hydroperoxides CH(3)OOH and CH(3)CH(2)OOH reactions have been carried out theoretically. The geometries and frequencies of all the stationary points are calculated at the UBHandHLYP/6-311G(d,p) level, and the energy profiles are further refined by interpolated single-point energies method at the MC-QCISD level of theory. For two reactions, five H-abstraction channels are found and five products (CH(3)OO, CH(2)OOH, CH(3)CH(2)OO, CH(2)CH(2)OOH, and CH(3)CHOOH) are produced during the above processes. The rate constants for the CH(3)OOH/CH(3)CH(2)OOH + OH reactions are corrected by canonical variational transition state theory within 250-1500 K, and the small-curvature tunneling is included. The total rate constants are evaluated from the sum of the individual rate constants and the branching ratios are in good agreement with the experimental data. The Arrhenius expressions for the reactions are obtained.


Asunto(s)
Peróxido de Hidrógeno/química , Radical Hidroxilo/química , Teoría Cuántica , Cinética
18.
Int J Anal Chem ; 2021: 9986793, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34306088

RESUMEN

A method using UPLC-HRMS has been developed for a rapid, simultaneous qualitative and quantitative analysis of twenty-five ginsenosides. Chromatographic separation was achieved on a C18 analytical column with an elution gradient comprising 0.1% aqueous formate/acetonitrile as the mobile phase. HRMS detection acquired full mass data for quantification and fullms-ddms2 (i.e., data-dependent scan mode) yielded product ion spectra for identification. Furthermore, quantitative analysis of multiginsenosides by single marker (QAMS) was developed and validated using a relative correction factor. Under optimal conditions, we could simultaneously separate eight groups of isomers of the 25 ginsenosides. Good linearity was observed over the validated concentration range for each analyte (r 2 > 0.9924), showing excellent sensitivity (LODs, 0.003-0.349 ng/mL) and lower limit quantification (LOQs, 0.015-1.163 ng/mL). The LC-MS external standard method (ESM) and QAMS were compared and successfully applied to analyze the ginsenoside content from Panax ginseng roots. Overall, our UPLC-HRMS/QAMS approach provides high precision, stability, and reproducibility and can be used for high-throughput analysis of complex ginsenosides and quantitative analysis of multiple components and quality control of traditional Chinese medicines (TCM).

19.
Artículo en Inglés | MEDLINE | ID: mdl-34741934

RESUMEN

The potential of lipid nanoparticles (LNPs) as nucleic acid delivery vehicles has been demonstrated in recent years, culminating in the emergency use approval of LNP-based mRNA SARS-CoV-2 vaccines in late 2020. The determination of RNA content relative to LNP size can be important to the understanding of efficacy and adverse effects. This work presents the first description of a facile and rapid analytical method for online, size-dependent RNA payload distribution measurement using data from multi-angle light scattering, ultraviolet and refractive index detectors following separation of the LNPs by size-exclusion chromatography. The analysis was validated by size-based fractionation of the LNPs with subsequent offline analysis of the fractions. Four LNPs formulated with different PEG-lipids and different lipid compositions were tested. Good agreement was observed between the online and offline size-based RNA distributions among all four LNPs, demonstrating the utility of the online method for LNP-encapsulated RNA in general, and suggesting a means for simplified biophysical quantitation of a dosing-related critical quality attribute.


Asunto(s)
Vacunas contra la COVID-19/química , Cromatografía en Gel/métodos , Portadores de Fármacos/química , Nanopartículas/química , ARN Mensajero/química , ARN Viral/química , SARS-CoV-2/genética , COVID-19/virología , Vacunas contra la COVID-19/inmunología , Sistemas de Liberación de Medicamentos , Humanos , Lípidos/química , Tamaño de la Partícula , ARN Mensajero/inmunología , ARN Viral/inmunología , SARS-CoV-2/química , SARS-CoV-2/inmunología
20.
J Pharm Sci ; 110(9): 3238-3245, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34089710

RESUMEN

The physical properties of active pharmaceutical ingredients (API) are critical to both drug substance (DS) isolation and drying operations, as well as streamlined drug product (DP) processing and the quality of final dosage units. High aspect ratio, low bulk density, API 'needles' in particular are a hindrance to efficient processing, with a low probability that conventional crystallization routes can modify the challenging morphology. The compound evaluated in this manuscript demonstrated this non-ideal morphology, with the added complexity of shear sensitivity. Modest shear exposure resulted in conversion of the thermodynamically stable crystalline phase to the amorphous phase, with the amorphous phase then undergoing accelerated chemical degradation. Slow filtration during DS isolation resulted in uncontrolled and elevated amorphous levels, while subsequent DP operations including blending, densification and compression increased amorphous content still further. A chemically stable final dosage unit would ideally involve a high bulk density, free flowing API that did not require densification in order to be commercialized as an oral dosage form with direct encapsulation of a single dosage unit. Despite every effort to modify the crystallization process, the physical properties of the API could not be improved. Here, an innovative isolation strategy using a thin film evaporation (TFE) process in the presence of a water soluble polymer alleviated filtration and drying risks and consistently achieved a high bulk density, free flowing co-processed API amenable to direct encapsulation. Characterization of the engineered materials suggested the lower amorphous levels and reduced shear sensitivity were achieved by coating surfaces of the API at relatively low polymer loads. This particle engineering route blurred conventional DS/DP boundaries that not only achieved improved chemical stability but also resulted in a optimized material, with simplified and more robust processing operations for both drug substance and drug product.


Asunto(s)
Química Farmacéutica , Preparaciones Farmacéuticas , Cristalización , Composición de Medicamentos , Estabilidad de Medicamentos , Polímeros , Agua
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA