RESUMEN
Lipid-based drug delivery systems hold immense promise in addressing critical medical needs, from cancer and neurodegenerative diseases to infectious diseases. By encapsulating active pharmaceutical ingredients - ranging from small molecule drugs to proteins and nucleic acids - these nanocarriers enhance treatment efficacy and safety. However, their commercial success faces hurdles, such as the lack of a systematic design approach and the issues related to scalability and reproducibility. This work aims to provide insights into the drug-phospholipid interaction by combining molecular dynamic simulations and thermodynamic modelling techniques. In particular, we have made a connection between the structural properties of the drug-phospholipid system and the physicochemical performance of the drug-loaded liposomal nanoformulations. We have considered two prototypical drugs, felodipine (FEL) and naproxen (NPX), and one model hydrogenated soy phosphatidylcholine (HSPC) bilayer membrane. Molecular dynamic simulations revealed which regions within the phospholipid bilayers are most and least favoured by the drug molecules. NPX tends to reside at the water-phospholipid interface and is characterized by a lower free energy barrier for bilayer membrane permeation. Meanwhile, FEL prefers to sit within the hydrophobic tails of the phospholipids and is characterized by a higher free energy barrier for membrane permeation. Flory-Huggins thermodynamic modelling, small angle X-ray scattering, dynamic light scattering, TEM, and drug release studies of these liposomal nanoformulations confirmed this drug-phospholipid structural difference. The naproxen-phospholipid system has a lower free energy barrier for permeation, higher drug miscibility with the bilayer, larger liposomal nanoparticle size, and faster drug release in the aqueous medium than felodipine. We suggest that this combination of molecular dynamics and thermodynamics approach may offer a new tool for designing and developing lipid-based nanocarriers for unmet medical applications.
Asunto(s)
Membrana Dobles de Lípidos , Liposomas , Simulación de Dinámica Molecular , Naproxeno , Termodinámica , Liposomas/química , Membrana Dobles de Lípidos/química , Naproxeno/química , Naproxeno/administración & dosificación , Felodipino/química , Felodipino/administración & dosificación , Fosfatidilcolinas/química , Fosfolípidos/química , Sistemas de Liberación de MedicamentosRESUMEN
Nanodrugs offer promising alternatives to conventionally used over the counter drugs. Compared to its free form, therapeutic benefits, and gastric tissue safety of naproxen sodium nanoformulation (NpNF) were recently demonstrated. Essential regulatory safety data for this formulation are, however, not available. To address this, male and female BALB/c mice were subjected to acute and 14-day repeated-oral dose assessments. Our data indicate that NpNF was well tolerated up to 2000 mg/kg b.w. A 14-day subacute toxicity testing revealed that the oral administration of low dose (30 mg/kg) NpNF did not produce any adverse effects on blood profile and serum biochemical parameters. Levels of oxidative stress markers and antioxidant enzymes neared normal. Histology of selected tissues also showed no evidence of toxicity. In contrast, a ten-fold increase in NpNF dosage (300 mg/kg), demonstrated, irrespective of gender, mild to moderate toxicity (p < 0.05) in the brain, stomach, and heart tissues, while ROS, LPO, CAT, SOD, POD, and GSH levels remained unaffected in the liver, kidney, spleen, testis, and seminal vesicles. No effect on serum biochemical parameters, overall indicated a no-observed-adverse-effect level (NOAEL) is 300 mg/kg. Further increase in dosage (1000 mg/kg) significantly altered all parameters demonstrating that high dose is toxic.
Asunto(s)
Ratones Endogámicos BALB C , Naproxeno , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad Subaguda , Animales , Femenino , Naproxeno/toxicidad , Naproxeno/administración & dosificación , Masculino , Antiinflamatorios no Esteroideos/toxicidad , Antiinflamatorios no Esteroideos/administración & dosificación , Ratones , Administración Oral , Estrés Oxidativo/efectos de los fármacos , Nanopartículas/toxicidad , Relación Dosis-Respuesta a Droga , Nivel sin Efectos Adversos ObservadosRESUMEN
OBJECTIVE: Tension-type headache is the most common type of primary headache and results in a huge socioeconomic burden. This network meta-analysis (NMA) aimed to compare the efficacy and safety of simple analgesics for the treatment of episodic tension-type headache (ETTH) in adults. METHODS: We searched the Cochrane Library, PubMed, Web of Science, Embase, Chinese BioMedical Literature database and International Clinical Trials Registry Platform databases for eligible randomized clinical trials reporting the efficacy and/or safety of simple analgesics. A Bayesian NMA was performed to compare relative efficacy and safety. The surface under the cumulative ranking curve (SUCRA) was calculated to rank interventions. PROSPERO registration number: CRD42018090554. RESULTS: We highlighted six studies including 3507 patients. For the 2 h pain-free rate, the SUCRA ranking was ibuprofen > diclofenac-K > ketoprofen > acetaminophen > naproxen > placebo. All drugs except naproxen reported a higher 2 h pain-free rate than placebo, with a risk ratio (RR) of 2.86 (95% credible interval, CrI: 1.62-5.42) for ibuprofen and 2.61 (1.53-4.88) for diclofenac-K. For adverse events rate, the SUCRA ranking was: metamizol > diclofenac-K > ibuprofen > lumiracoxib > placebo > aspirin > acetaminophen > naproxen > ketoprofen. The adverse event rates of all analgesics were no higher than those of placebo, except for ketoprofen. Moreover, all drugs were superior to placebo in the global assessment of efficacy. In particular, the RR of lumiracoxib was 2.47 (1.57-4.57). Global heterogeneity I2 between the studies was low. CONCLUSIONS: Simple analgesics are considered more effective and safe as a placebo for ETTH in adults. Our results suggest that ibuprofen and diclofenac-K may be the two best treatment options for patients with ETTH from a comprehensive point of view (both high-quality evidence).
To our knowledge, this is the first network meta-analysis comparing the available data on adult patients with episodic tension-type headache (ETTH) treated with different simple analgesics recommended by the current guidelines.Ibuprofen (400 mg) and diclofenac-K (12.5 mg, 25 mg) are potentially the most effective and safe treatment options, supported by high-quality evidence.
Asunto(s)
Analgésicos , Ibuprofeno , Metaanálisis en Red , Cefalea de Tipo Tensional , Humanos , Cefalea de Tipo Tensional/tratamiento farmacológico , Analgésicos/efectos adversos , Analgésicos/uso terapéutico , Analgésicos/administración & dosificación , Adulto , Ibuprofeno/efectos adversos , Ibuprofeno/administración & dosificación , Ibuprofeno/uso terapéutico , Acetaminofén/uso terapéutico , Acetaminofén/efectos adversos , Acetaminofén/administración & dosificación , Teorema de Bayes , Resultado del Tratamiento , Diclofenaco/efectos adversos , Diclofenaco/uso terapéutico , Diclofenaco/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Naproxeno/uso terapéutico , Naproxeno/efectos adversos , Naproxeno/administración & dosificación , Cetoprofeno/efectos adversos , Cetoprofeno/uso terapéutico , Cetoprofeno/administración & dosificación , Cetoprofeno/análogos & derivados , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/uso terapéutico , Antiinflamatorios no Esteroideos/administración & dosificación , Femenino , MasculinoRESUMEN
Fexuprazan, a novel potassium-competitive acid blocker, is expected to be used for the prevention of nonsteroidal anti-inflammatory drugs (NSAIDs) induced ulcer. This study aimed to evaluate pharmacokinetic (PK) interactions between fexuprazan and NSAIDs in healthy subjects. A randomized, open-label, multicenter, six-sequence, one-way crossover study was conducted in healthy male subjects. Subjects randomly received one of the study drugs (fexuprazan 40 mg BID, celecoxib 200 mg BID, naproxen 500 mg BID, or meloxicam 15 mg QD) for 5 or 7 days in the first period followed by the combination of fexuprazan and one of NSAIDs for the same days and the perpetrator additionally administered for 1-2 days in the second period. Serial blood samples for PK analysis were collected until 48- or 72-h post-dose at steady state. PK parameters including maximum plasma concentration at steady state (Cmax,ss) and area under plasma concentration-time curve over dosing interval at steady state (AUCτ,ss) were compared between monotherapy and combination therapy. The PKs of NSAIDs were not significantly altered by fexuprazan. For fexuprazan, differences in PK parameters (22% in Cmax, 19% in AUCτ,ss) were observed when co-administered with naproxen, but not clinically significant. The geometric mean ratio (90% confidence interval) of combination therapy to monotherapy for Cmax,ss and AUCτ,ss was 1.22 (1.02-1.46) and 1.19 (1.00-1.43), respectively. There were no significant changes in the systemic exposure of fexuprazan by celecoxib and meloxicam. Fexuprazan and NSAIDs did not show clinically meaningful PK interactions.
Asunto(s)
Antiinflamatorios no Esteroideos , Estudios Cruzados , Interacciones Farmacológicas , Humanos , Masculino , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/administración & dosificación , Adulto , Adulto Joven , Voluntarios Sanos , Área Bajo la Curva , Meloxicam/farmacocinética , Meloxicam/administración & dosificación , Naproxeno/farmacocinética , Naproxeno/administración & dosificación , Celecoxib/farmacocinética , Celecoxib/administración & dosificación , Persona de Mediana EdadRESUMEN
The toxicity for the human body of non-steroidal anti-inflammatory drugs (NSAIDs) overdoses is a consequence of their low water solubility, high doses, and facile accessibility to the population. New drug delivery systems (DDS) are necessary to overcome the bioavailability and toxicity related to NSAIDs. In this context, UiO-66(Zr) metal-organic framework (MOF) shows high porosity, stability, and load capacity, thus being a promising DDS. However, the adsorption and release capability for different NSAIDs is scarcely described. In this work, the biocompatible UiO-66(Zr) MOF was used to study the adsorption and release conditions of ibuprofen, naproxen, and diclofenac using a theoretical and experimental approximation. DFT results showed that the MOF-drug interaction was due to an intermolecular hydrogen bond between protons of the groups in the defect sites, (µ3 - OH, and - OH2) and a lone pair of oxygen carboxyl functional group of the NSAIDs. Also, the experimental results suggest that the solvent where the drug is dissolved affects the adsorption process. The adsorption kinetics are similar between the drugs, but the maximum load capacity differs for each drug. The release kinetics assay showed a solvent dependence kinetics whose maximum liberation capacity is affected by the interaction between the drug and the material. Finally, the biological assays show that none of the systems studied are cytotoxic for HMVEC. Additionally, the wound healing assay suggests that the UiO-66(Zr) material has potential application on the wound healing process. However, further studies should be done.
Asunto(s)
Antiinflamatorios no Esteroideos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Estructuras Metalorgánicas , Naproxeno , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/química , Estructuras Metalorgánicas/química , Naproxeno/administración & dosificación , Naproxeno/química , Naproxeno/farmacocinética , Ibuprofeno/administración & dosificación , Ibuprofeno/química , Ibuprofeno/farmacocinética , Humanos , Adsorción , Portadores de Fármacos/química , Diclofenaco/administración & dosificación , Diclofenaco/química , Diclofenaco/farmacocinética , Supervivencia Celular/efectos de los fármacos , Ácidos FtálicosRESUMEN
As the monotherapy of available analgesics is usually accompanied by serious side effects or limited efficacy in the management of chronic pain, multimodal analgesia is widely used to achieve improved benefit-to-risk ratios in clinic. Drug-drug salts are extensively researched to optimize the physicochemical properties of active pharmaceutical ingredients (APIs) and achieve clinical benefits compared with individual APIs or their combination. New drug-drug salt crystals metformin-ibuprofen (MET-IBU) and metformin-naproxen (MET-NAP) were prepared from metformin (MET) and two poorly water-soluble anti-inflammatory drugs (IBU and NAP) by the solvent evaporation method. The structures of these crystals were confirmed by single crystal and powder X-ray diffraction, Hirshfeld surface, Fourier transform infrared spectroscopy and thermal analysis. Both MET-IBU and MET-NAP showed significantly improved solubility and intrinsic dissolution rate than the pure IBU or NAP. The stability test indicated that MET-IBU and MET-NAP have excellent physical stability under stressing test (10 days) and accelerated conditions (3 months). Moreover, isobolographic analysis suggested that MET-IBU and MET-NAP exerted potent and synergistic antinociceptive effects in λ-Carrageenan-induced inflammatory pain in mice, and both of them had an advantage in rapid pain relief. These results demonstrated the potential of MET-IBU and MET-NAP to achieve synergistic antinociceptive effects by developing drug-drug salt crystals.
Asunto(s)
Analgésicos , Cristalización , Sinergismo Farmacológico , Ibuprofeno , Metformina , Naproxeno , Solubilidad , Metformina/química , Metformina/administración & dosificación , Metformina/farmacología , Animales , Naproxeno/química , Naproxeno/administración & dosificación , Ibuprofeno/química , Ibuprofeno/administración & dosificación , Ibuprofeno/farmacología , Analgésicos/química , Analgésicos/administración & dosificación , Analgésicos/farmacología , Ratones , Masculino , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Dolor/tratamiento farmacológico , Estabilidad de Medicamentos , Carragenina , Liberación de Fármacos , Sales (Química)/químicaRESUMEN
Hydrogen sulfide (H2S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H2S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H2S levels has a potential therapeutic value. Consequently, synthetic H2S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H2S donors; furthermore, herein we discuss their preparation, the H2S-releasing mechanisms, and their -biological applications.
Asunto(s)
Descubrimiento de Drogas , Gasotransmisores/farmacología , Sulfuro de Hidrógeno/farmacología , Animales , Bencenosulfonatos/administración & dosificación , Bencenosulfonatos/metabolismo , Bencenosulfonatos/farmacología , Bencenosulfonatos/uso terapéutico , Química Farmacéutica , Gasotransmisores/administración & dosificación , Gasotransmisores/metabolismo , Gasotransmisores/uso terapéutico , Humanos , Sulfuro de Hidrógeno/administración & dosificación , Sulfuro de Hidrógeno/metabolismo , Sulfuro de Hidrógeno/uso terapéutico , Morfolinas/administración & dosificación , Morfolinas/metabolismo , Morfolinas/farmacología , Morfolinas/uso terapéutico , Naproxeno/administración & dosificación , Naproxeno/análogos & derivados , Naproxeno/metabolismo , Naproxeno/farmacología , Naproxeno/uso terapéutico , Compuestos Organotiofosforados/administración & dosificación , Compuestos Organotiofosforados/metabolismo , Compuestos Organotiofosforados/farmacología , Compuestos Organotiofosforados/uso terapéuticoRESUMEN
A drug delivery system based on mesoporous particles MCM-41 was post-synthetically modified by photo-sensitive ligand, methyl-(2E)-3-(4-(triethoxysilyl)-propoxyphenyl)-2-propenoate (CA) and the pores of MCM-41 particles were loaded with Naproxen sodium salt (NAP). The CA was used as a photoactive molecule that can undergo a reversible photo-dimerization by [2π + 2π] cycloaddition when irradiated with UV light of specific wavelengths. Thus, it has a function of gate-keeper that is responsible for opening/closing the pores and minimizing premature release of NAP. The physicochemical properties of the prepared system were studied by infrared spectroscopy (IR), nitrogen adsorption measurements, thermogravimetric analysis (TGA), scanning transmission electron microscopy (STEM) and energy dispersive X-ray spectroscopy (EDX). The mechanism of the opening/closing pores was confirmed by UV measurements. In vitro and in vivo drug release experiments and the concentration of released NAP was determined by UV spectroscopy and high-performance liquid chromatography (HPLC). In vivo drug release in the blood circulatory system of rats has demonstrated the effective photo-cleavage reaction of CA molecules after UV-light stimulation. The localization and morphological changes of the particles were studied in the blood and liver of rats at different time intervals. The particles in the blood have been shown to retain their original rod-like shape, and the particles in the liver have been hydrolysed, which has resulted in spherical shape with a reduced size.
Asunto(s)
Portadores de Fármacos/química , Naproxeno , Dióxido de Silicio/química , Animales , Liberación de Fármacos , Masculino , Naproxeno/administración & dosificación , Naproxeno/farmacocinética , Ratas , Ratas Wistar , SolubilidadRESUMEN
Aim of this study was to evaluate and compare the efficacy of anti-arthritic drugs (naproxen, prednisolone, and hydroxychloroquine) alone and in combination. The in vitro anti-arthritic activity was evaluated by stabilization of human erythrocytes (HRBCs) membrane assays. In vivo activity was carried out using Complete Freund's Adjuvant (CFA) induced arthritic model in Wistar rat. Individual and combination drugs were administered for 21 days in rats 8 days post inoculation with CFA (0.15 ml injected in right hind paw). Body weight and paw edema were measured at different intervals. Combination treatments exhibited more HRBC stabilization than individual treatments. All individual and combination treatments reduced the level of C-reactive protein (CRP), liver function enzymes, malondialdehyde, white blood cells and platelets, with the most pronounced activity exhibited by the combination of three drugs. The level of oxidative stress biomarkers (reduced glutathione, catalase, and superoxide dismutase), red blood cells, and hemoglobin were notably increased in all treatment groups in contrasts to diseased control rats. Histopathological evaluation of the paw showed that all the treatments had reduced (p < 0.05-0.001) the arthritic indices in contrasts to diseased control rats. The serum concentrations of TNF-α and PGE2 were provoked in diseased control rats but had been notably (p < 0.0001) restored by treatments with individual and combination drugs. It was also found that combination treatments, more precisely triple drug was remarkably effective in treating arthritis. It can be concluded that naproxen, prednisolone, and hydroxychloroquine effectively ameliorated the CFA-induced arthritis and were more effective in combination as compared to individual drug therapy probably due to reduction in oxidative stress and inflammatory markers. Moreover, two lower doses (half NPH/2 and one-third NPH/3) of triple combination therapy naproxen, prednisolone, and hydroxychloroquine (NPH) showed no significant difference in anti-arthritic effect as compared to the highest dose level of NPH.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Hidroxicloroquina/farmacología , Naproxeno/farmacología , Prednisolona/farmacología , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Antirreumáticos/administración & dosificación , Antirreumáticos/farmacología , Artritis Experimental/patología , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Femenino , Adyuvante de Freund , Humanos , Hidroxicloroquina/administración & dosificación , Inflamación/tratamiento farmacológico , Inflamación/patología , Masculino , Naproxeno/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Prednisolona/administración & dosificación , Ratas , Ratas WistarRESUMEN
BACKGROUND AND OBJECTIVE: Bioequivalence tests are fundamental step in assessing the equivalence in bioavailability between a test and reference product. In practice, two separate linear mixed models (LMMs) with random subject effects, which have an area under the concentration-time curve (AUC) and the peak concentration (Cmax) as the responses, have become the gold standard for evaluating bioequivalence. Recently, Lee et al developed a multivariate hierarchical generalized linear model (HGLM) for several responses that modeled correlations among multivariate responses via correlated random effects. The objective of this study was to apply this multivariate analysis to the bioequivalence test in practice and to compare the performance of multivariate HGLM and separate LMMs. METHODS: Three pharmacokinetic datasets, fixed-dose combination (naproxen and esomeprazole), tramadol and fimasartan data were analyzed. We compared the 90% confidence interval (CI) for the geometric mean ratio (GMR) of a test product to a reference product using the multivariate HGLM and two conventional separate LMMs. RESULTS: We found that the 90% CIs for the GMRs of both AUC and Cmax from the multivariate HGLM were narrower than those from the separate LMMs: (0.843, 1.152) vs (0.825, 1.177) for Cmax of esomeprazole in fixed-dose combination data; (0.805, 0.931) vs (0.797, 0.941) for Cmax in tramadol data; (0.801, 1.501) vs (0.762, 1.578) for Cmax and (1.163, 1.332) vs (1.009, 1.341) for AUC in fimasartan data, consistent with the random subject effects from two separate LMMs being highly correlated in the three datasets (correlation coefficient r = 0.883; r = 0.966; r = 0.832). CONCLUSION: This multivariate HGLM had good performance in the bioequivalence test with multiple endpoints. This method would provide a more reasonable option to reduce the 90% CI by adding correlation parameters and thus an advantage especially in evaluating the bioequivalence of highly variable drugs with broad 90% CIs.
Asunto(s)
Compuestos de Bifenilo/farmacocinética , Esomeprazol/farmacocinética , Modelos Estadísticos , Pirimidinas/farmacocinética , Tetrazoles/farmacocinética , Tramadol/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Compuestos de Bifenilo/administración & dosificación , Conjuntos de Datos como Asunto , Combinación de Medicamentos , Esomeprazol/administración & dosificación , Humanos , Modelos Lineales , Masculino , Análisis Multivariante , Naproxeno/administración & dosificación , Naproxeno/farmacocinética , Pirimidinas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Tetrazoles/administración & dosificación , Equivalencia Terapéutica , Tramadol/administración & dosificaciónRESUMEN
Layered rare-earth hydroxides have begun to gather increasing attention as potential theranostic platforms owing to their extensive intercalation chemistry combined with magnetic and fluorescent properties. In this work, the potential of layered terbium hydroxide (LTbH) as a platform for simultaneous drug delivery and fluorescence imaging was evaluated. LTbH-Cl ([Tb2(OH)5]Cl·yH2O) was loaded with three nonsteroidal anti-inflammatory drugs (diclofenac, ibuprofen, and naproxen) via ion-exchange. Drug release studies in phosphate buffered saline (pH = 7.4) revealed all three formulations release their drug cargo rapidly over the course of approximately 5 hours. In addition, solid state fluorescence studies indicated that fluorescence intensity is strongly dependent on the identity of the guest anion. It was postulated that this feature may be used to track the extent of drug release from the formulation, which was subsequently successfully demonstrated for the ibuprofen loaded LTbH. Overall, LTbH exhibits good biocompatibility, high drug loading, and a strong, guest-dependent fluorescence signal, all of which are desirable qualities for theranostic applications.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Diclofenaco/administración & dosificación , Sistemas de Liberación de Medicamentos , Hidróxidos/administración & dosificación , Ibuprofeno/administración & dosificación , Naproxeno/administración & dosificación , Terbio/administración & dosificación , Animales , Antiinflamatorios no Esteroideos/química , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Diclofenaco/química , Liberación de Fármacos , Estabilidad de Medicamentos , Eritrocitos/efectos de los fármacos , Femenino , Células HEK293 , Hemólisis/efectos de los fármacos , Humanos , Hidróxidos/química , Ibuprofeno/química , Intercambio Iónico , Naproxeno/química , Imagen Óptica , Ratas Wistar , Terbio/químicaRESUMEN
In this study, an attempt was made to produce Liqui-Tablets for the first time. This was carried out through the compaction of naproxen Liqui-Pellets. The incentive to convert the novel Liqui-Pellet into Liqui-Tablet was due to the array of inherent advantages of the popular and preferred tablet dosage form. The study showed that naproxen Liqui-Tablet could be successfully produced and the rapid drug release rate (100% drug release ~ 20 min) could be achieved under pH 1.2, where naproxen is insoluble. It was observed that the different pH of the dissolution medium affected the trend of drug release from formulations with varying amounts of liquid vehicle. The order of the fastest drug-releasing formulations was different depending on the pH used. The presence of Neusilin US2 showed considerable enhancement in the drug release rate as well as improving Liqui-Tablet robustness and hardness. Furthermore, images from X-ray micro-tomography displayed a uniform distribution of components in the Liqui-Tablet. The accelerated stability studies showed acceptable stability in terms of dissolution profile.
Asunto(s)
Composición de Medicamentos/métodos , Naproxeno/administración & dosificación , Naproxeno/síntesis química , Tecnología Farmacéutica/métodos , Administración Oral , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacocinética , Formas de Dosificación , Liberación de Fármacos , Excipientes/administración & dosificación , Excipientes/síntesis química , Excipientes/farmacocinética , Naproxeno/farmacocinética , ComprimidosRESUMEN
In this study, the aerogel technology was used to prepare pulmonary drug carriers consisting of alginate and alginate-hyaluronic acid by an emulsion gelation technique and supercritical CO2 drying. During the preparation process, the emulsification rate and inner phase viscosity were varied to control the diameter of aerogel microspheres. Results showed that the aerogel microspheres were highly porous (porosity > 98%) with low densities in the range between 0.0087 and 0.0634 g/cm3 as well as high surface areas between 354 and 759 m2/g. The obtained microspheres showed aerodynamic diameter below 5 µm making them suitable for pulmonary drug delivery. An in vitro drug release study with the model drug sodium naproxen was conducted and a non-Fickian drug release mechanism was observed, with no significant difference between the release profiles of alginate and alginate-hyaluronic acid microspheres. During the emulsion gelation step, the feasibility of using the capillary number to estimate the largest stable droplet size in the emulsions was also studied and it was found that using this number, the droplet size in the emulsions may well be predicted.
Asunto(s)
Alginatos/química , Sistemas de Liberación de Medicamentos , Ácido Hialurónico/química , Naproxeno/administración & dosificación , Química Farmacéutica , Portadores de Fármacos/química , Liberación de Fármacos , Emulsiones , Geles , Pulmón/metabolismo , Microesferas , Naproxeno/farmacocinética , Tamaño de la Partícula , Porosidad , Tecnología Farmacéutica , Distribución Tisular , ViscosidadRESUMEN
Alaska Native people are under-represented in genetic research but have unique gene variation that may critically impact their response to pharmacotherapy. Full resequencing of CYP2C9 in a cross-section of this population identified CYP2C9 Met1Leu (M1L), a novel, relatively common single nucleotide polymorphism hypothesized to confer CYP2C9 poor metabolizer phenotype by disrupting the start codon. M1L is present at a minor allele frequency of 6.3% in Yup'ik Alaska Native people and thus can contribute to the risk of an adverse drug response from narrow-therapeutic-index CYP2C9 substrates such as (S)-warfarin. This study's objective was to characterize the catalytic efficiency of the Leu1 variant enzyme in vivo by evaluating the pharmacokinetic behavior of naproxen, a probe substrate for CYP2C9 activity, in genotyped Yup'ik participants. We first confirmed the selectivity of (S)-naproxen O-demethylation by CYP2C9 using activity-phenotyped human liver microsomes and selective cytochrome P450 inhibitors and then developed and validated a novel liquid chromatography mass spectrometry method for simultaneous quantification of (S)-naproxen, (S)-O-desmethylnaproxen, and naproxen acyl glucuronide in human urine. The average ratio of (S)-O-desmethylnaproxen to unchanged (S)-naproxen in urine was 18.0 ± 8.0 (n = 11) for the homozygous CYP2C9 Met1 reference group and 10.3 ± 6.6 (n = 11) for the Leu1 variant carrier group (P = 0.011). The effect of M1L variation on CYP2C9 function and its potential to alter the pharmacokinetics of drugs metabolized by the enzyme has clinical implications and should be included in a variant screening panel when pharmacogenetic testing in the Alaska Native population is warranted. SIGNIFICANCE STATEMENT: The novel CYP2C9 Met1Leu variant in Alaska Native people was recently identified. This study validated (S)-naproxen as a CYP2C9 probe substrate to characterize the in vivo functional activity of the CYP2C9 Leu1 variant. The results of this pharmacogenetic-pharmacokinetic study suggest that the CYP2C9 Leu1 variant exhibits loss of enzyme activity. This finding may be important to consider when administering narrow-therapeutic-index medications metabolized by CYP2C9 and also compels further investigation to characterize novel genetic variation in understudied populations.
Asunto(s)
/genética , Antiinflamatorios no Esteroideos/orina , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Variación Genética/genética , Naproxeno/orina , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Estudios Transversales , Femenino , Humanos , Leucina/genética , Masculino , Metionina/genética , Naproxeno/administración & dosificación , Adulto JovenRESUMEN
Though pharmaceutical polymers were widely used in inhibiting drug recrystallization via strong intermolecular hydrogen and ionic bonds, the improved drug stability was achieved at the cost of the drug release rate or amount in the drug-in-adhesive transdermal patch. To overcame the difficulty, this study aimed to increase drug loading utilizing a novel drug-ionic liquid (drug-IL) strategy and illustrate the underlying molecular mechanism. Here, naproxen (NPX) and triamylamine (TAA) were chosen as the model drug and corresponding counterion, respectively. In addiiton, carboxylic pressure-sensitive adhesive (PSA) was chosen as the model polymer. The drug-IL (NPX-TAA) was synthesized and characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and proton nuclear magnetic resonance. The miscibility between NPX-TAA and PSA was assessed using microscopy study, X-ray diffraction, fluorescence spectroscopy, and solubility parameter calculation. In addition, molecular mechanisms of crystallization inhibition were revealed by FT-IR, Raman spectroscopy, DSC, X-ray photoelectron spectroscopy (XPS), and molecular docking. Finally, the release pattern of the high load patch of NPX-TAA was evaluated using in vitro drug release and verified by a skin permeation experiment. The results showed that drug loading in PSA was increased by 5.0 times, which was caused by the synergistic effect of strong ionic hydrogen bonding (the decreased intensity and blue shift of the O-H peak of COOH in PSA) formed between NPX-TAA and PSA-COO- and normal hydrogen bonding (red shift of the CâO peak in PSA) formed between NPX-TAA and the carbonyl group of PSA. In addition, -NH+ of TAA was confirmed as the molecular basis of ionic hydrogen bonding through new peak appearance (binding energy: 400.0 eV) in XPS spectra. Moreover, high drug release percent (80.8 ± 1.8%) was achieved even at high drug loading compared with the control group (72.4 ± 2.2%). Thus, this study introduced an effective drug-IL method to enhance drug loading capacity and illustrated the brand-new action mechanism, which provided a powerful instrument for the development of a high drug loading-high release patch.
Asunto(s)
Adhesivos/química , Hidrógeno/química , Líquidos Iónicos/química , Compuestos Macrocíclicos/química , Adhesivos/administración & dosificación , Animales , Rastreo Diferencial de Calorimetría/métodos , Cristalización/métodos , Liberación de Fármacos/efectos de los fármacos , Enlace de Hidrógeno/efectos de los fármacos , Compuestos Macrocíclicos/administración & dosificación , Simulación del Acoplamiento Molecular/métodos , Naproxeno/administración & dosificación , Naproxeno/química , Espectroscopía de Fotoelectrones/métodos , Polímeros/química , Conejos , Piel/efectos de los fármacos , Absorción Cutánea/efectos de los fármacos , Solubilidad/efectos de los fármacos , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Espectrometría Raman/métodos , Parche Transdérmico , Difracción de Rayos X/métodosRESUMEN
OBJECTIVE: Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS. DESIGN: We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs). RESULTS: Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control. CONCLUSIONS: Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. TRIAL REGISTRATION NUMBER: gov Identifier: NCT02052908.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Quimioprevención , Neoplasias Colorrectales Hereditarias sin Poliposis/tratamiento farmacológico , Neoplasias Colorrectales Hereditarias sin Poliposis/inmunología , Naproxeno/farmacología , Adulto , Anciano , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Naproxeno/administración & dosificaciónRESUMEN
In this work, the tabletability and dissolution of spray-dried forms of naproxen and its sodium salt were compared with those of unprocessed drugs. Solutions of naproxen or naproxen sodium alone or with HPMC (5% w/w of drug content) were spray dried. Scanning electron micrographs showed that naproxen sodium spray-dried particles were spherical, whereas those of naproxen were non-spherical but isodiametric. Powder x-ray diffraction and thermal analysis indicated that co-spray drying with HPMC resulted in reduced crystallinity of naproxen and higher naproxen sodium dihydrate content. FTIR and Raman analysis showed shifting, merging or elimination of bands in the spectra of the co-spray dried products signifying solid-state alterations. When mixed with suitable processing aids (7% w/w), all co-spray dried powders produced satisfactory tablets in the pressure range 73-295 MPa. Conversely, physical mixtures of naproxen compressed with the same aids failed tableting, whereas naproxen sodium produced weak tablets. Dissolution tests showed significant improvement for co-spray dried drugs tablets. Therefore, since the large therapeutic doses of naproxen and sodium naproxen limit the use of tableting aids, the improved compaction and dissolution performance of the spray-dried forms may be a formulation alternative.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Química Farmacéutica , Derivados de la Hipromelosa/química , Naproxeno/administración & dosificación , Antiinflamatorios no Esteroideos/química , Cristalización , Composición de Medicamentos/métodos , Liberación de Fármacos , Excipientes/química , Naproxeno/química , Solubilidad , Secado por Pulverización , ComprimidosRESUMEN
Naproxen is a widely used non-steroidal anti-inflammatory drug for the control of postoperative inflammatory signs and symptoms in dentistry. Its association with esomeprazole has been widely studied and has yielded good results for the control of acute pain, even with the delayed absorption of naproxen owing to the presence of esomeprazole. To further understand the absorption, distribution, and metabolism of this drug alone and in combination with esomeprazole, we will analyze the pharmacokinetic parameters of naproxen and its major metabolite, 6-O-desmethylnaproxen, in saliva samples. A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometric method for the simultaneous determination of naproxen and 6-O-desmethylnaproxen in saliva will be developed and validated. Sequential saliva samples from six patients will be analyzed before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6 8, 11, 24, 48, 72, and 96 h after the ingestion of one naproxen tablet (500 mg) and esomeprazole-associated naproxen tablets (500 + 20 mg), at two different times. After liquid-liquid extraction with ethyl acetate and HCl, the samples will be analyzed using an 8040 Triple Quadrupole Mass Spectrometer (Shimadzu, Kyoto, Japan). Separation of naproxen and its major metabolic products will be performed using a Shim-Pack XR-ODS 75Lx2.0 column and C18 pre-column (Shimadzu, Kyoto, Japan) at 40°C using a mixture of methanol and 10 mM ammonium acetate (70:30, v/v) with an injection flow of 0.3 mL/min. The total analytical run time will be 5 min. The detection and quantification of naproxen and its metabolite will be validated, which elucidate the pharmacokinetics of this drug, thereby contributing to its proper prescription for the medical and dental interventions that cause acute pain.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Monitoreo de Drogas/métodos , Esomeprazol/farmacocinética , Naproxeno/análogos & derivados , Saliva/química , Administración Oral , Adolescente , Adulto , Antiinflamatorios no Esteroideos/aislamiento & purificación , Cromatografía Líquida de Alta Presión/métodos , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Esomeprazol/administración & dosificación , Esomeprazol/aislamiento & purificación , Femenino , Absorción Gastrointestinal , Humanos , Masculino , Metanol/química , Persona de Mediana Edad , Naproxeno/administración & dosificación , Naproxeno/aislamiento & purificación , Naproxeno/farmacocinética , Dolor Asociado a Procedimientos Médicos/tratamiento farmacológico , Reproducibilidad de los Resultados , Comprimidos , Espectrometría de Masas en Tándem/métodos , Adulto JovenRESUMEN
BACKGROUND: The present work aimed to develop an ethosomal gel of naproxen sodium for the amelioration of rheumatoid arthritis. OBJECTIVE: In the present work, we have explored the potential of ethosomes to deliver naproxen into deeper skin strata. Further, the anti-inflammatory efficacy of naproxen ethosomal formulation was assessed using the carrageenan-induced rat paw edema model. METHODS: Naproxen sodium nanoethosomes were prepared using different proportions of lipoid S100 (50mg-200mg), ethanol (20-50%) and water, and were further characterized on the basis of vesicle morphology, entrapment efficiency, zeta potential, in-vitro drug release and ex-vivo permeation studies. RESULTS: The optimized ethosomal formulation was found to have 129 ± 0.01 nm particle size, 0.295 Polydispersity Index (PDI), -3.29 mV zeta potential, 88% entrapment efficiency and 96.573% drug release in 24 hours. TEM and SEM analysis of the optimized formulation showed slightly smooth spherical structures. The Confocal laser scanning microscopy showed that ethosomes could easily infiltrate into deeper dermal layers (upto 104.9µm) whereas the hydroalcoholic solution of the drug could penetrate up to 74.9µm. Further, the optimized ethosomal formulation was incorporated into 1% carbopol 934 gel base and optimized wherein the transdermal flux was found to be approximately 10 times more than the hydroethanolic solution. Also, the in-vivo pharmacodynamic study of the optimized ethosomal gel exhibited a higher percentage inhibition of swelling paw edema than marketed diclofenac gel. CONCLUSION: The ethosomal gel was successfully developed and has shown the potential to be a good option for the replacement of conventional therapies of rheumatoid arthritis.