RESUMEN

Juvenile dermatomyositis (JDM) is a rare immune-mediated disease of childhood with putative links to microbial exposures. In this multi-center, prospective, observational cohort study, we evaluated whether JDM is associated with discrete oral and gut microbiome signatures. We generated 16S rRNA sequencing data from fecal, saliva, supragingival, and subgingival plaque samples from JDM probands (n = 28). To control for genetic and environmental determinants of microbiome community structure, we also profiled microbiomes of unaffected family members (n = 27 siblings, n = 26 mothers, and n = 17 fathers). Sample type (oral-vs-fecal) and nuclear family unit were the predominant variables explaining variance in microbiome diversity, more so than having a diagnosis of JDM. The oral and gut microbiomes of JDM probands were more similar to their own unaffected siblings than they were to the microbiomes of other JDM probands. In a sibling-paired within-family analysis, several potentially immunomodulatory bacterial taxa were differentially abundant in the microbiomes of JDM probands compared to their unaffected siblings, including Faecalibacterium (gut) and Streptococcus (oral cavity). While microbiome features of JDM are often shared by unaffected family members, the loss or gain of specific fecal and oral bacteria may play a role in disease pathogenesis or be secondary to immune dysfunction in susceptible individuals.

Asunto(s)

Dermatomiositis , Heces , Microbioma Gastrointestinal , Boca , ARN Ribosómico 16S , Humanos , Heces/microbiología , Dermatomiositis/microbiología , Dermatomiositis/genética , Femenino , Masculino , Niño , Boca/microbiología , ARN Ribosómico 16S/genética , Microbioma Gastrointestinal/genética , Estudios Prospectivos , Disbiosis/microbiología , Microbiota/genética , Preescolar , Adolescente , Saliva/microbiología , Adulto

RESUMEN

OBJECTIVE: The objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: The Biologics Workgroup of the Childhood Arthritis and Rheumatology Research Alliance JDM Research Committee used case-based surveys, consensus framework, and nominal group technique to produce bDMARD CTPs for patients with refractory moderately severe JDM. RESULTS: Four bDMARD CTPs were proposed: tumor necrosis factor α (TNFα) inhibitor (adalimumab or infliximab), abatacept, rituximab, and tocilizumab. Each CTP has different options for dosing and/or route. Among 76 respondents, consensus was achieved for the proposed CTPs (93% [67 of 72]) as well as for patient characteristics, assessments, outcome measures, and follow-up. By weighted average, respondents indicated that they would most likely administer rituximab, followed by abatacept, TNFα inhibitor, and tocilizumab. CONCLUSION: CTPs for the administration of bDMARDs in refractory moderately severe JDM were developed using consensus methodology. The implementation of the bDMARD CTPs will lay the groundwork for registry-based prospective comparative effectiveness studies.

RESUMEN

Ibuprofen (IBP), a common non-steroidal anti-inflammatory drug (NSAID) with a log P of 3.51, has been shown to possess potential benefit in the treatment of Alzheimer's disease. However, the bioavailability of IBP to the brain is poor, which can be linked to its extensive binding to plasma proteins in the blood. This study aimed to evaluate the nanoparticle production of IBP by flash nanoprecipitation (FNP) technology, and to determine whether the nanoparticles prepared by FNP could enhance the delivery of IBP into the brain. Polymeric IBP nanoparticles were prepared with poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) diblock copolymer as stabilizer under optimized conditions using a four-stream multi-inlet vortex mixer (MIVM). The optimized nanoparticles displayed a mean particle size of around 50 nm, polydispersity index of around 0.2, drug loading of up to 30% and physical stability of up to 34 days. In-depth surface characterization using zeta potential measurement, atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS) showed that the surfaces of these nanoparticles were covered with the hydrophilic PEG groups from the diblock copolymer. In vivo brain uptake study of the IBP nanoparticles indicated that the particles, when coated with polysorbate 80, displayed an enhanced brain uptake. However, the extent of brain uptake enhancement appeared limited, possibly due to a rapid release of IBP from the nanoparticles into the blood stream following intravenous administration.

Asunto(s)

Ibuprofeno , Nanopartículas , Encéfalo , Tamaño de la Partícula , Polietilenglicoles , Polímeros

RESUMEN

OBJECTIVES: Pneumocystis jirovecii pneumonia (PJP) is associated with significant morbidity and mortality in adult myositis patients; however, there are few studies examining PJP in juvenile myositis [juvenile idiopathic inflammatory myopathy (JIIM)]. The purpose of this study was to determine the risk factors and clinical phenotypes associated with PJP in JIIM. METHODS: An research electronic data capture (REDCap) questionnaire regarding myositis features, disease course, medications and PJP infection characteristics was completed by treating physicians for 13 JIIM patients who developed PJP (PJP+) from the USA and Canada. Myositis features and medications were compared with 147 JIIM patients without PJP (PJP-) from similar geographic regions who enrolled in National Institutes of Health natural history studies. RESULTS: PJP+ patients were more often of Asian ancestry than PJP- patients [odds ratio (OR) 8.7; 95% CI 1.3, 57.9]. Anti- melanoma differentiation associated protein 5 (MDA5) autoantibodies (OR 12.5; 95% CI 3.0, 52.4), digital infarcts (OR 43.8; 95% CI 4.2, 460.2), skin ulcerations (OR 12.0; 95% CI 3.5, 41.2) and interstitial lung disease (OR 10.6; 95% CI 2.1, 53.9) were more frequent in PJP+ patients. Before PJP diagnosis, patients more frequently received pulse steroids, rituximab and more immunosuppressive therapy compared with PJP- patients. Seven PJP+ patients were admitted to the intensive care unit and four patients died due to PJP or its complications. CONCLUSIONS: PJP is a severe infection in JIIM that can be associated with mortality. Having PJP was associated with more immunosuppressive therapy, anti-MDA5 autoantibodies, Asian race and certain clinical features, including digital infarcts, cutaneous ulcerations and interstitial lung disease. Prophylaxis for PJP should be considered in juvenile myositis patients with these features.

Asunto(s)

Pueblo Asiatico/estadística & datos numéricos , Dermatomiositis , Inmunosupresores/uso terapéutico , Helicasa Inducida por Interferón IFIH1/inmunología , Enfermedades Pulmonares Intersticiales , Neumonía por Pneumocystis , Úlcera Cutánea , Autoanticuerpos/sangre , Niño , Dermatomiositis/sangre , Dermatomiositis/epidemiología , Dermatomiositis/fisiopatología , Dermatomiositis/terapia , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Masculino , América del Norte/epidemiología , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/mortalidad , Neumonía por Pneumocystis/diagnóstico , Neumonía por Pneumocystis/inmunología , Neumonía por Pneumocystis/mortalidad , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Úlcera Cutánea/diagnóstico , Úlcera Cutánea/etiología

RESUMEN

While nanoparticulate drugs for deep lung delivery hold promise for particular disease treatments, their size-related physical instability and tendency of being exhaled during breathing remain major challenges to their inhaled formulation development. Here we report a viable method for converting drug nanosuspensions into inhalable, stable and redispersible nano-agglomerates through combined in-situ thermal gelation and spray drying. Itraconazole (ITZ) nanosuspensions were prepared by flash nanoprecipitation, and co-spray dried with two different grades of the gel-forming polymer, methylcellulose (MC M20 and MC M450) as protectants. MC M20 was found superior in protecting ITZ nanoparticles against thermal stress (through nanoparticle entrapment within its gel network structure) during spray drying. In terms of redispersibility, an Sf/Si ratio (i.e., ratio of nanoparticle sizes after and before spray drying) of unity (1.02 ± 0.03), reflecting full particle size preservation, was achieved by optimizing the suspending medium content and spray drying parameters. Formulation components, nanosuspension concentration and spray drying parameters all showed a significant impact on the aerosol performance of the resulting agglomerates, but an absence of defined trends or correlations. Overall, the MC-protected nano-agglomerates displayed excellent in-vitro aerosol performance with fine particle fractions higher than 50% and mass median aerodynamic diameters within the 2-3 µm range, which are ideal for deep lung delivery.

Asunto(s)

Antifúngicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Itraconazol/administración & dosificación , Nanopartículas , Administración por Inhalación , Aerosoles , Antifúngicos/química , Geles , Itraconazol/química , Pulmón/metabolismo , Metilcelulosa/química , Tamaño de la Partícula , Suspensiones , Tecnología Farmacéutica

RESUMEN

While flash nanoprecipitation (FNP) has proven to be an extremely rapid and highly efficient nanoparticle fabrication process for hydrophobic drugs, physical instability associated with nonequilibrium molecular orientation of amphiphilic stabilizers (ASs) in nanoparticles remains a major snag in the general application of this nanotechnology, particularly for a drug with ACDLog P in the range of ∼2-9. This study was aimed at elucidating the costabilizing role of cholesterol (CLT) in the FNP of AS-stabilized nanoparticles of itraconazole (ITZ), a model drug with an ACDLog P of 4.35 ± 1.22 and log P of 5.66. The presence of CLT was shown to reduce the initial particle size and markedly improve the short-term storage stability of ITZ nanoparticles. The stability-enhancement by CLT can be linked to its higher miscibility or stronger interaction with the AS hydrophobic moiety than with ITZ (as reflected by the absolute differences of their solubility parameter values). Surface analyses employing X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) suggest that, through the coprecipitation of CLT with ITZ to form a mixed hydrophobic drug core, the CLT molecules that are exposed on the core surface serve to afford a stronger and more timely surface anchorage of the AS hydrophobic moieties, thereby facilitating the rearrangement of AS molecules toward the stable micelle-like structure. The present findings offer a mechanistic insight into the interplay between amphiphilic stabilizer and costabilizer in enhancing the physical stability of drug nanoparticles and may carry important implications for the development of more stable and efficacious nanoparticle therapeutics.

Asunto(s)

Colesterol/química , Itraconazol/química , Nanopartículas/química , Interacciones Hidrofóbicas e Hidrofílicas , Microscopía de Fuerza Atómica , Espectroscopía de Fotoelectrones , Solubilidad

RESUMEN

Two pharmaceutical polymers with high glass transition temperatures (Tg > 100 °C), polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), have been assessed for their impact on the storage stability of itraconazole (ITZ) amorphous solid dispersions (ASDs). The results showed that the inhibitory effect of PVPVA on the recrystallization of amorphous ITZ was highly sensitive to surrounding relative humidity (RH), especially at RH above 60%. In contrast, amorphous ITZ in HPMCAS matrix exhibited much stronger resistance to recrystallization even under high RH conditions, reflecting the superior crystallization-inhibitory effect of HPMCAS. While the ITZ loads in the two polymers far exceeded the respective thermodynamic solubility limits, both ASD systems remained physically stable over an extended storage period at RH ≤ 60%. Kinetics rather than thermodynamics dictate the physical stability of ITZ ASDs. Crystallization of ITZ in ASDs appears to involve a complex interplay of multiple factors, including polymer type, glass transition temperatures (Tgs) of drug and polymer, crystallization tendency of amorphous drug, and storage conditions. Specifically, with respect to the impact of polymer type, HPMCAS is particularly effective for maintaining the storage stability of ITZ ASDs, which can be attributed to its higher Tg and lower hydrophilicity.

Asunto(s)

Excipientes/química , Itraconazol/administración & dosificación , Metilcelulosa/análogos & derivados , Pirrolidinas/química , Compuestos de Vinilo/química , Antifúngicos/administración & dosificación , Antifúngicos/química , Química Farmacéutica/métodos , Cristalización , Portadores de Fármacos/química , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Humedad , Interacciones Hidrofóbicas e Hidrofílicas , Itraconazol/química , Metilcelulosa/química , Polímeros/química , Termodinámica , Temperatura de Transición

RESUMEN

Flash nanoprecipitation (FNP) is a controlled antisolvent precipitation process that has proven effective for consistent production of drug nanoparticles with a defined mean particle size and narrow particle size distribution. However, physical instability of the generated nanoparticles remains a major challenge in the application of this technology in pharmaceutical formulation. Aimed at resolving this problem, the present study has investigated the FNP process and associated stabilization mechanism of itraconazole (ITZ) nanoparticles through in-depth nanoparticle characterization. Results showed that ITZ nanoparticles could be reproducibly produced with a mean particle size <100 nm and a polydispersity index <0.2 in the presence of amphiphilic stabilizers (ASs). Surface analysis of freshly formed nanoparticles by X-ray photoelectron spectroscopy (XPS) revealed initially a disordered packing structure and subsequently a time-dependent molecular rearrangement of incorporated AS towards a micelle-like structure. The faster the molecular rearrangement of AS, the more stable the nanoparticles, as monitored by the change in particle size with time. These findings may have important implications for the selection of effective ASs for formulating stable drug nanoparticles. The present study is the first of its kind to demonstrate the utility of XPS to track the molecular transport of stabilizers in rapidly generated nanoparticles.

Asunto(s)

Antifúngicos/química , Itraconazol/química , Nanopartículas/química , Precipitación Química , Composición de Medicamentos , Estabilidad de Medicamentos , Microscopía de Fuerza Atómica , Espectroscopía de Fotoelectrones , Polietilenglicoles/química , Vitamina E/química

RESUMEN

This study aimed to investigate the particle size effect on bioactivity, cellular internalization and bioavailability of curcumin (CUR) nanosuspension (CUR-NS). CUR-NSs of different particle sizes were prepared by two different anti-solvent precipitation methods. CUR-NS with the smallest size showed similar in vitro anticancer activity and bioavailability to the CUR solution, whereas nanosuspensions of larger particle sizes displayed higher in vitro cellular internalization and cytotoxicity, as well as higher in vivo AUC and slower clearance rate after i.v. administration in rats. CUR solution and different sized CUR-NSs reached the highest concentrations in the lung, followed by liver and spleen while the lowest concentration was observed in the brain after i.v. administration in mice. Specifically, CUR-NS of 70nm accumulated more in the brain, whereas CUR-NS of 200nm accrued more in liver and spleen. CUR-NS of 20nm displayed no significant biodistribution difference compared with CUR solution in all tissues.

Asunto(s)

Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Curcumina/administración & dosificación , Curcumina/farmacocinética , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Curcumina/farmacología , Humanos , Masculino , Ratones Endogámicos C57BL , Nanopartículas/administración & dosificación , Nanopartículas/análisis , Neoplasias/tratamiento farmacológico , Tamaño de la Partícula , Ratas Sprague-Dawley , Distribución Tisular

RESUMEN

Over-expression of ATP-binding cassette transporters is one of the most important mechanisms responsible for multidrug resistance. Here, we aimed to develop a stable polymeric nanoparticle system by flash nanoprecipitation (FNP) for enhanced anticancer drug delivery into drug resistant cancer cells. As an antisolvent precipitation process, FNP works best for highly lipophilic solutes (logP>6). Thus we also aimed to evaluate the applicability of FNP to drugs with relatively low lipophilicity (logP=1-2). To this end, doxorubicin (DOX), an anthracycline anticancer agent and a P-gp substrate with a logP of 1.3, was selected as a model drug for the assessment. DOX was successfully incorporated into the amphiphilic diblock copolymer, polyethylene glycol-b-polylactic acid (PEG-b-PLA), by FNP using a four-stream multi-inlet vortex mixer. Optimization of key processing parameters and co-formulation with the co-stabilizer, polyvinylpyrrolidone, yielded highly stable, roughly spherical DOX-loaded PEG-b-PLA nanoparticles (DOX.NP) with mean particle size below 100nm, drug loading up to 14%, and drug encapsulation efficiency up to 49%. DOX.NP exhibited a pH-dependent drug release profile with higher cumulative release rate at acidic pHs. Surface analysis of DOX.NP by XPS revealed an absence of DOX on the particle surface, indicative of complete drug encapsulation. While there were no significant differences in cytotoxic effect on P-gp over-expressing LCC6/MDR cell line between DOX.NP and free DOX in buffered aqueous media, DOX.NP exhibited a considerably higher cellular uptake and intracellular retention after efflux. The apparent lack of cytotoxicity enhancement with DOX.NP may be attributable to its slow DOX release inside the cells.

Asunto(s)

Antibióticos Antineoplásicos/farmacología , Precipitación Química , Doxorrubicina/farmacología , Portadores de Fármacos/química , Nanopartículas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Composición de Medicamentos , Liberación de Fármacos , Resistencia a Antineoplásicos/genética , Expresión Génica , Humanos , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Cinética , Lactatos/química , Nanopartículas/metabolismo , Nanopartículas/ultraestructura , Tamaño de la Partícula , Polietilenglicoles/química , Povidona/química

RESUMEN

The present study was aimed at tailoring the particle size of ursolic acid (UA) nanosuspension for improved anticancer activity. UA nanosuspensions were prepared by antisolvent precipitation using a four-stream multi-inlet vortex mixer (MIVM) under defined conditions of varying solvent composition, drug feeding concentration or stream flow rate. The resulting products were characterized for particle size and polydispersity. Two of the UA nanosuspensions with mean particle sizes of 100 and 300 nm were further assessed for their in-vitro activity against MCF-7 breast cancer cells using fluorescence microscopy with 4',6-diamidino-2-phenylindole (DAPI) staining, as well as flow cytometry with propidium (PI) staining and with double staining by fluorescein isothiocyanate. It was revealed that the solvent composition, drug feeding concentration and stream flow rate were critical parameters for particle size control of the UA nanosuspensions generated with the MIVM. Specifically, decreasing the UA feeding concentration or increasing the stream flow rate or ethanol content resulted in a reduction of particle size. Excellent reproducibility for nanosuspension production was demonstrated for the 100 and 300 nm UA preparations with a deviation of not more than 5% in particle size from the mean value of three independent batches. Fluorescence microscopy and flow cytometry revealed that these two different sized UA nanosuspensions, particularly the 300 nm sample, exhibited a higher anti-proliferation activity against the MCF-7 cells and afforded a larger population of these cells in both early and late apoptotic phases. In conclusion, MIVM is a robust and pragmatic tool for tailoring the particle size of the UA nanosuspension. Particle size appears to be a critical determinant of the anticancer activity of the UA nanoparticles.

Asunto(s)

Antineoplásicos/química , Precipitación Química , Nanopartículas/química , Tamaño de la Partícula , Suspensiones/química , Triterpenos/química , Triterpenos/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Estabilidad de Medicamentos , Femenino , Humanos , Células MCF-7 , Microscopía Electrónica de Transmisión , Reproducibilidad de los Resultados , Solubilidad , Solventes/química , Propiedades de Superficie , Suspensiones/farmacología , Ácido Ursólico

RESUMEN

The influence of critical operating parameters on the Flash Nanoprecipitation (FNP) and resulting material properties of curcumin (CUR) nanoparticles has been evaluated using a confined impinging jets-with-dilution mixer (CIJ-D-M). It has been shown that the mixing rate, molecular weight of polymeric stabilizer (i.e., polyethylene glycol-b-poly(dl-lactide) di-block copolymer; PEG-PLA) and drug-to-copolymer mass ratio all exert a significant impact on the particle size and stability of the generated nanosuspensions. The attainable mean particle size and span of the nanoparticles through optimization of these process parameters were approximately 70nm and 0.85 respectively. However, the optimized nanosuspension was only stable for about two hours after preparation. Co-formulation with polyvinylpyrrolidone (PVP) substantially extended the product lifespan to 5days at ambient conditions and two weeks at 4°C. Results from zeta potential measurement and X-ray photoelectron spectroscopy (XPS) suggested that the enhanced stability is probably due to the formation of an additional protective barrier by PVP around the particle surface, thereby suppressing the dissociation of PEG-PLA from the particles and preventing CUR leakage from inside. Long-term storage stability (>1year) could be achieved by lyophilization of the optimized nanosuspension with Kleptose (hydroxypropyl-ß-cyclodextrin), which was shown to be the only effective lyoprotectant among all the ones tested for the CUR nanoparticles. At an optimal concentration of Kleptose (1.25% w/v), the redispersibility (Sf/Si; ratio of the final and initial particle sizes) and encapsulation efficiency of lyophilized CUR nanoparticles were about 1.22% and 94%, respectively.

Asunto(s)

Curcumina/química , Nanopartículas/química , Nanotecnología/métodos , Tecnología Farmacéutica/métodos , Precipitación Química , Química Farmacéutica , Estabilidad de Medicamentos , Diseño de Equipo , Liofilización , Nanotecnología/instrumentación , Tamaño de la Partícula , Polietilenglicoles/química , Propiedades de Superficie , Tecnología Farmacéutica/instrumentación

RESUMEN

Diagnosis of Alzheimer's disease (AD) can be performed with the assistance of amyloid imaging. The current method relies on positron emission tomography (PET), which is expensive and exposes people to radiation, undesirable features for a population screening method. Magnetic resonance imaging (MRI) is cheaper and is not radioactive. Our approach uses magnetic nanoparticles (MNPs) made of superparamagnetic iron oxide (SPIO) conjugated with curcumin, a natural compound that specifically binds to amyloid plaques. Coating of curcumin-conjugated MNPs with polyethylene glycol-polylactic acid block copolymer and polyvinylpyrrolidone by antisolvent precipitation in a multi-inlet vortex mixer produces stable and biocompatible curcumin magnetic nanoparticles (Cur-MNPs) with mean diameter <100 nm. These nanoparticles were visualized by transmission electron microscopy and atomic force microscopy, and their structure and chemistry were further characterized by X-ray diffraction, thermogravimetric analysis, X-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectrometry, and Fourier transform infrared spectroscopy. Cur-MNPs exhibited no cytotoxicity in either Madin-Darby canine kidney (MDCK) or differentiated human neuroblastoma cells (SH-SY5Y). The Papp of Cur-MNPs was 1.03 × 10(-6) cm/s in an in vitro blood-brain barrier (BBB) model. Amyloid plaques could be visualized in ex vivo T2*-weighted magnetic resonance imaging (MRI) of Tg2576 mouse brains after injection of Cur-MNPs, and no plaques could be found in non-transgenic mice. Immunohistochemical examination of the mouse brains revealed that Cur-MNPs were co-localized with amyloid plaques. Thus, Cur-MNPs have the potential for non-invasive diagnosis of AD using MRI.

Asunto(s)

Enfermedad de Alzheimer/diagnóstico , Curcumina , Imagen por Resonancia Magnética , Nanopartículas de Magnetita , Placa Amiloide/diagnóstico , Adsorción , Enfermedad de Alzheimer/complicaciones , Animales , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Curcumina/química , Modelos Animales de Enfermedad , Perros , Humanos , Inmunohistoquímica , Células de Riñón Canino Madin Darby , Nanopartículas de Magnetita/ultraestructura , Ratones Transgénicos , Tamaño de la Partícula , Espectroscopía de Fotoelectrones , Placa Amiloide/complicaciones , Polietilenglicoles/química , Espectrometría de Masa de Ion Secundario , Espectroscopía Infrarroja por Transformada de Fourier , Termogravimetría , Difracción de Rayos X

RESUMEN

The relative performance of two specially designed mixers for nanoparticle production, namely, two-stream confined impinging jets with dilution mixer (CIJ-D-M) and four-stream multi-inlet vortex mixer (MIVM), was evaluated using the model compound, curcumin (CUR), under defined conditions of varying mixing rate and organic solvent. In the absence of turbulent fluctuations, higher mixing rate tended to generate finer particles. Among the three water-miscible organic solvents tested, acetone afforded the smallest particle size and the narrowest particle size distribution. Both mixers were capable of reproducibly fabricating CUR nanoparticles with particle size below 100 nm and high encapsulation efficiency (>99.9%). Specifically, CIJ-D-M yielded nanoparticles with smaller size and polydispersity index while the particles obtained by the MIVM displayed better short-term stability. In addition, CIJ-D-M tended to produce a mixture of irregular nanoaggregates and primary nanoparticles while roughly spherical nanoparticles were generated with the MIVM. The observed particle size and morphological differences could be attributed to the differences in the configuration of the mixing chamber and the related mixing order.

Asunto(s)

Curcumina/química , Nanopartículas , Cromatografía Líquida de Alta Presión , Luz , Microscopía Electrónica de Rastreo , Dispersión de Radiación

RESUMEN

Solid state manipulation by amorphous solid dispersion has been the subject of intensive research for decades due to their excellent potential for dissolution and bioavailability enhancement. The present review aims to highlight the latest advancement in this area, with focus on the fundamentals, characterization, formulation development and manufacturing of amorphous solid dispersions as well as the new generation amorphization technologies. Additionally, specific applications of amorphous solid dispersion in the formulation of herbal drugs or bioactive natural products are reviewed to reflect the growing interest in this relatively neglected area.

Asunto(s)

Portadores de Fármacos/química , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/química , Preparaciones de Plantas/administración & dosificación , Preparaciones de Plantas/química , Disponibilidad Biológica , Química Farmacéutica , Química Física , Estabilidad de Medicamentos , Tamaño de la Partícula , Preparaciones Farmacéuticas/metabolismo , Preparaciones de Plantas/farmacocinética , Solubilidad , Soluciones , Termodinámica

RESUMEN

The complexes (BDI)MgX(THF), where X = Bu(n), NEt2, and OBu(t), are shown to undergo THF exchange at low added concentrations of THF by a dissociative mechanism: X = Bu(n), ΔH(#) (kcal mol(-1)) = 13.4 ± 0.4 and ΔS(#) (cal mol(-1) K(-1)) = 6.3 ± 1.6; X = NEt2, ΔH(#) (kcal mol(-1)) = 15.2 ± 0.5 and ΔS(#) (cal mol(-1) K(-1)) = 11.4 ± 2.3; X = OBu(t), ΔH(#) (kcal mol(-1)) = 16.4 ± 0.3 and ΔS(#) (cal mol(-1) K(-1)) = 9.5 ± 1.3. The apparent aryl group rotations involving the BDI ligands have, within experimental error, the same activation parameters as the THF dissociation, which suggests that the two are correlated involving a three coordinate reactive intermediate akin to what is well-known for related (BDI)ZnR compounds involving three-coordinate trigonal planar Zn(2+). At higher concentrations of THF for X = Bu(n) and OBu(t), but not for X = NEt2, the coalescence temperatures for apparent aryl group rotation are depressed from those of the pure compounds in toluene-d8, and evidence is presented that this correlates with an associative interchange process which becomes dominant in neat THF. We estimate the Ia mechanism to have activation parameters: ΔH(#) (kcal mol(-1)) = 5.4 ± 0.1 and ΔS(#) (cal mol(-1) K(-1)) = -20.9 ± 0.3 for X = Bu(n) and ΔH(#) (kcal mol(-1)) = 8.3 ± 0.8 and ΔS(#) (cal mol(-1) K(-1)) = -19.8 ± 3.0 for X = OBu(t). For the complex (BDI)MgBu(n)(2-MeTHF), the dissociative exchange with added 2-MeTHF occurs more readily than for its THF analogue, as expected for the more sterically demanding Lewis base O-donor: ΔH(#) (kcal mol(-1)) = 12.8 ± 0.5 and ΔS(#) (cal mol(-1) K(-1)) = 8.6 ± 1.8. At very low temperatures in toluene-d8, restricted rotation about the Mg-O(THF) bond is observed for the complexes where X = NEt2 and OBu(t) but not for the complex where X = Bu(n). These observations, which have been determined from dynamic NMR studies, are correlated with the reactivities of these complexes in solution.

RESUMEN

X-ray crystallographic NMR and calculational modeling studies using B3LYP/6-311G* of selected dilithium derivatives of the 1,3-butadiene dianion including cis-dilithio-1,4-bis(TMS)-2-butene·(TMEDA)(2)2, internally solvated cis-dilithio-1,4-bis[bis(2-methoxyethyl)aminomethyldimethylsilyl]-2-butene 5, and using only modeling, 1,4-dilithio-2-butene·(TMEDA)(2)9 reveal remarkably similar structural and NMR parameters. In the solid, 5 consists of unusual "T" shaped dynamic clusters. In all three bridging lithiums are sited between 1.8 and 1.9 Å normal to the centroids of opposite faces of the near coplanar of the 2-butene component. Typical bond lengths of the latter are 1.458 ± 0.004, 1.385 ± 0.006, and 1.459 ± 0.003 Å, for C1-C2, C2-C3, and C3-C4, respectively. The (13)C chemical shifts lie within the ranges δ 21 ± 0.5, 99 ± 0.7, 99 ± 0.7 and 21 ± 0.5 for C1, C2 and C3 together, and C4, respectively. Dynamic (13)C NMR provides activation parameters for nitrogen inversion in 2 and 5, overall molecular inversion of 5, and conformational interconversion of 2.

RESUMEN

The therapeutic effects of curcumin in treating Alzheimer's disease (AD) depend on the ability to penetrate the blood-brain barrier. The latest nanoparticle technology can help to improve the bioavailability of curcumin, which is affected by the final particle size and stability. We developed a stable curcumin nanoparticle formulation to test in vitro and in AD model Tg2576 mice. Flash nanoprecipitation of curcumin, polyethylene glycol-polylactic acid co-block polymer, and polyvinylpyrrolidone in a multi-inlet vortex mixer, followed by freeze drying with ß-cyclodextrin, produced dry nanocurcumin with mean particle size <80 nm. Nanocurcumin powder, unformulated curcumin, or placebo was orally administered to Tg2576 mice for 3 months. Before and after treatment, memory was measured by radial arm maze and contextual fear conditioning tests. Nanocurcumin produced significantly (p=0.04) better cue memory in the contextual fear conditioning test than placebo and tendencies toward better working memory in the radial arm maze test than ordinary curcumin (p=0.14) or placebo (p=0.12). Amyloid plaque density, pharmacokinetics, and Madin-Darby canine kidney cell monolayer penetration were measured to further understand in vivo and in vitro mechanisms. Nanocurcumin produced significantly higher curcumin concentration in plasma and six times higher area under the curve and mean residence time in brain than ordinary curcumin. The P(app) of curcumin and tetrahydrocurcumin were 1.8×10(-6) and 1.6×10(-5)cm/s, respectively, for nanocurcumin. Our novel nanocurcumin formulation produced highly stabilized nanoparticles with positive treatment effects in Tg2576 mice.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Barrera Hematoencefálica/metabolismo , Curcumina/administración & dosificación , Nanopartículas , Nootrópicos/administración & dosificación , Administración Oral , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Química Farmacéutica , Condicionamiento Psicológico/efectos de los fármacos , Curcumina/química , Curcumina/farmacocinética , Modelos Animales de Enfermedad , Perros , Estabilidad de Medicamentos , Miedo , Femenino , Lactatos/química , Células de Riñón Canino Madin Darby , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones , Ratones Transgénicos , Nanotecnología , Nootrópicos/sangre , Nootrópicos/química , Nootrópicos/farmacocinética , Tamaño de la Partícula , Permeabilidad , Placa Amiloide , Polietilenglicoles/química , Povidona/química , Tecnología Farmacéutica/métodos , beta-Ciclodextrinas/química

RESUMEN

PURPOSE: To be fully exploitable in both formulation and manufacturing, a drug cocrystal needs to demonstrate simultaneous improvement of multiple key pharmaceutical properties over the pure drug crystal. The present work was aimed at investigating such feasibility with two model profen-nicotinamide cocrystals. METHODS: Phase pure 1:1 ibuprofen-nicotinamide and flurbiprofen-nicotinamide cocrystals were prepared from solutions through rapid solvent removal using rotary evaporation,and characterized by DSC, PXRD, FTIR, phase solubility measurements, equilibrium moisture sorption analysis, dissolution testing and tabletability analysis. RESULTS: Temperature-composition phase diagrams constructed from DSC data for each profen and nicotinamide crystal revealed the characteristic melting point of the 1:1 cocrystal as well as the eutectic temperatures and compositions. Both cocrystals exhibited higher intrinsic dissolution rates than the corresponding profens. The cocrystals also sorbed less moisture and displayed considerably better tabletability than the individual profens and nicotinamide. CONCLUSIONS: Phase behaviors of 1:1 profen-nicotinamide cocrystal systems were delineated by constructing their temperature-composition phase diagrams. Cocrystallization with nicotinamide can simultaneously improve tableting behavior, hygroscopicity, and dissolution performance of ibuprofen and flurbiprofen. This could pave the way for further development of such cocrystal systems into consistent, stable, efficacious and readily manufacturable drug products.

Asunto(s)

Analgésicos/química , Flurbiprofeno/química , Ibuprofeno/química , Niacinamida/química , Complejo Vitamínico B/química , Rastreo Diferencial de Calorimetría , Cristalización/métodos , Modelos Moleculares , Difracción de Polvo , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Comprimidos , Humectabilidad , Difracción de Rayos X