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1.
Int J Pharm ; 605: 120800, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34133972

RESUMO

The method of 1H Nuclear Magnetic Resonance (NMR) relaxometry is applied to investigate the kinetics of the recrystallization of an active pharmaceutical ingredient (felodipine) from the amorphous phase of its physical mixture with a polymer (polyvinylpyrrolidone, PVP). Comparison of the recrystallization results obtained for amorphous felodipine and its mixtures with PVP shows that the recrystallization process of API is faster in the mixtures and depends on the content of water in the system. The free induction decay (FID) for protons that were detected are composed of three components, and the loss of water from PVP strongly influences the part characterized by the longest spin-spin lattice relaxation time. Analysis of the FID of the physical mixture indicates that the content of water does not change during the recrystalization process. The study shows that the T11H NMR relaxometry method is very useful for analysing the composition of a three-phase mixture and the recrystallization process.


Assuntos
Felodipino , Povidona , Cristalização , Cinética , Espectroscopia de Ressonância Magnética , Solubilidade
2.
Int J Pharm ; 602: 120625, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33892062

RESUMO

Multidrug dosage forms (aka combination dosage forms, polypills, etc.) create value for patients through reduced pill burdens and simplified administration to improve adherence to therapy. Enhanced flexibility of multidrug dosage forms would provide further opportunities to better match emerging needs for individualized therapy. Through modular dosage form concepts, one approach to satisfy these needs is to adapt multidrug dosage forms to a wider variety of drugs, each with a variety of doses and release profiles. This study investigates and technically explores design requirements for extending the capability of modular multidrug dosage form concepts towards individualization. This builds on our recent demonstration of independent tailoring of dose and drug release, which is here extended towards poorly water-soluble drugs. The challenging design requirement of carrying higher drug loads in smaller volumes to accommodate multiple drugs at their clinical dose is here met regarding dose and release performance. With a modular concept, we demonstrate high precision (<5% RSD) in dose and release performance of individual modules containing felodipine or naproxen in Kollidon VA64 at both a wide drug loading range (5% w/w and 50% w/w drug) and a small module size (3.6 mg). In a forward-looking design-based discussion, further requirements are addressed, emphasizing that reproducible individual module performance is predictive of dosage form performance, provided the modules are designed to act independently. Therefore, efforts to incorporate progressively higher drug loads within progressively smaller module volumes will be crucial to extend the design window further towards full flexibility of future dosage forms for individualized multidrug therapy.


Assuntos
Preparações Farmacêuticas , Composição de Medicamentos , Quimioterapia Combinada , Felodipino , Humanos , Hansenostáticos , Solubilidade , Água
3.
Biochem Biophys Res Commun ; 555: 1-6, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33812052

RESUMO

Cigarette smoke (CS) contains many toxins that collectively harm nearly every organ in the body, and smoking is a key risk factor for many chronic diseases. Aside from its toxic actions, CS may alter expression of the drug- and steroid-binding pregnane X receptor (PXR), which when activated upregulates expression of cytochrome P450 (CYP) enzymes, glutathione transferases (GSTs), and multidrug resistance protein 1 (MDR1), an adaptive metabolic array that mediates clearance of CS component toxins. We sought to identify new PXR agonists that may be useful for restoring PXR activity in conditions wherein it is suppressed, and their mechanisms of PXR binding and activation. PXR has a uniquely larger, hydrophobic, and highly flexible ligand-binding domain (LBD) vs. other nuclear receptors, enabling it to interact with structurally diverse molecules. We tested certain calcium channel blockers (CCBs) as a pharmacological subset of potential PXR ligands, analyzing by molecular docking methods, and identified a putative active site in the PXR LBD, along with the relevant bonds and bonding energies. We analyzed felodipine binding and agonist activity in detail, as it showed the lowest binding energy among CCBs tested. We found felodipine was a potent PXR agonist as measured by luciferase reporter assay, whereas CCBs with higher binding energies were less potent (amlodipine) or nearly inactive (manidipine), and it induced CYP3A4 expression in HepG2 cells, a known target of PXR agonism. Felodipine also both induced PXR mRNA in HepG2 hepatocytes and reduced CS extract-induced diminution of PXR levels, indicating it modulates PXR expression. The results illuminate mechanisms of ligand-induced PXR activation and identify felodipine as a novel PXR agonist.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Fumar Cigarros/efeitos adversos , Felodipino/farmacologia , Receptor de Pregnano X/agonistas , Receptor de Pregnano X/metabolismo , Sítios de Ligação , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/metabolismo , Simulação por Computador , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Indutores do Citocromo P-450 CYP3A/farmacologia , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Felodipino/química , Felodipino/metabolismo , Células Hep G2 , Humanos , Ligantes , Simulação de Acoplamento Molecular , Receptor de Pregnano X/química
4.
Int J Pharm ; 596: 120202, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33493600

RESUMO

Felodipine is a calcium channel blocker, which shows low oral bioavailability (<15%) owing to poor water solubility and high first pass metabolism. The aim of the present investigation was to study the surface science (dynamic surface tension) and characteristics of microemulsion (Capmul MCM, Tween 20 and polyethylene glycol) to enhance the oral bioavailability of felodipine by improving permeability of the drug in the intestine. The paper is the first attempt to study the stability of oil-water interface of microemulsion using bubble tensiometer. The Smix at 2:1 ratio showed the maximum microemulsion area which did not alter in the presence of drug. The microemulsion batch coded Fe-O5-Smix45 (5% Capmul MCM and 45% Smix) was selected based on transmittance (>99%), dilution (stable after 100 times dilution with water), size (15.1 nm), dispersibility (grade A) and thermodynamic stability studies. The dynamic surface tension at newly created surface indicate the stability of surfactant film at the oil/water interface. The microemulsion was also stable in the presence of drug and in different buffer phases. The ex vivo intestinal permeability studies showed significant increase in the microemulsion permeation (74.1% after 1 h) in comparison to the felodipine suspension (16.9% after 1 h). The in vivo pharmacokinetic parameters in the rat model confirmed the improvement in oral bioavailability with microemulsion (relative bioavailability = 21.9) in comparison to the felodipine suspension, due to high surface area of oil droplets and its lymphatic uptake via transcellular route. In conclusion, the stable microemulsion offers a promising approach to improve the oral bioavailability of felodipine which can help to reduce the dose and its associated side effects.


Assuntos
Felodipino , Tensoativos , Administração Oral , Animais , Disponibilidade Biológica , Emulsões , Tamanho da Partícula , Ratos , Solubilidade
5.
J Pharm Sci ; 110(4): 1457-1469, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33359813

RESUMO

The objective of this study was to investigate thermodynamic and kinetic miscibility for two structurally similar model compounds nifedipine (NIF) and felodipine (FEL) when formulated as amorphous solid dispersions (ASDs) with an amphiphilic polymer Soluplus®. Thermodynamic miscibility was studied via melting point depression approach for the two systems. The Flory Huggins theory was used to calculate the interaction parameter and generate the phase diagrams. It was shown that NIF was more miscible in Soluplus® than FEL. The nature of drug polymer interactions was studied by fourier transform infra-red spectroscopy (FTIR) and solid-state nuclear magnetic resonance spectroscopy (ssNMR). The data from spectroscopic analyses showed that both the drugs interacted with Soluplus® through hydrogen bonding interactions. Furthermore, 13C ssNMR data was used to get quantitative estimate of the extent of hydrogen bonding for ASDs samples. Proton relaxation measurements were carried out on ASDs in order to evaluate phase heterogeneity on two different length scales of mixing. The data suggested that better phase homogeneity in NIF:SOL systems especially for lower Soluplus® content ASDs on smaller domains. This could be explained by understanding the extent of hydrogen bonding interactions for these two systems. This study highlights the need to consider thermodynamic and kinetic mixing, when formulating ASDs with the goal of understanding phase mixing between drug and polymer.


Assuntos
Felodipino , Preparações Farmacêuticas , Varredura Diferencial de Calorimetria , Nifedipino , Polietilenoglicóis , Polímeros , Polivinil , Solubilidade
6.
J AOAC Int ; 103(4): 966-971, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33241342

RESUMO

BACKGROUND: Felodipine is a calcium channel blocker used together with metoprolol succinate for treatment of hypertension. OBJECTIVE: Two chromatographic methods were developed for simultaneous determination of felodipine (FEL) and metoprolol succinate (MET), and their major metabolites, dehydrofelodipine and metoprolol acid, respectively. METHODS: The first method was RP-HPLC which comprised separation of the studied components by gradient elution using a Phenomenex C8 column and a mobile phase composed of water (adjusted to pH 3.5 with o-phosphoric acid)-acetonitrile - methanol (45:40:15, by volume) for the first 6 min and (30:60:10, by volume) for the next 4 min at a flow rate of 1 mL/min followed by UV detection of the eluted peaks at 225 nm. The second method was an HPTLC method where separation was achieved using a mobile phase consisting of toluene-ethyl acetate-methanol-ammonia-formic acid (10:5:2.5:0.3:0.1, by volume) and scanning of the separated bands at 225 nm. RESULTS: Validation of the developed methods was done according to ICH guidelines. Successful application of the developed methods was carried out for determination of the studied drugs in human spiked plasma and in Logimax® tablets. CONCLUSIONS: The developed RP-HPLC and HPTLC methods can be further applied for quality control testing of the studied drugs. HIGHLIGHTS: RP-HPLC and HPTLC methods for determination of FEL, MET and their major metabolites. The developed methods were successfully applied for determination of FEL and MET in Logimax® tablets.


Assuntos
Felodipino , Metoprolol , Cromatografia Líquida de Alta Pressão , Humanos , Reprodutibilidade dos Testes , Comprimidos
7.
Chem Pharm Bull (Tokyo) ; 68(10): 946-953, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32999146

RESUMO

In the present study, a novel cocrystal of felodipine (FEL) and ß-resorcylic acid (ßRA) was developed. We specially focused on the change of binding pattern with bovine serum albumin (BSA) induced by cocrystallization of FEL with ßRA. The solid characterizations and density functional theory (DFT) simulation verified that FEL-ßRA cocrystal formed in equimolar ratio (1 : 1 M ratio) through C=O…H-O hydrogen bond between C=O group in FEL and O-H group in ßRA. The binding interactions between FEL-ßRA system and BSA were studied using fluorescence spectral and molecular docking methods. Two guest molecule systems, including a physical mixture of FEL and ßRA and FEL-ßRA cocrystal were performed binding to BSA in molecular docking. According to the Kb and binding energy, the supramolecular form of FEL-ßRA system was retained during binding to BSA. Molecular docking simulation suggested that FEL and its cocrystal inserted into the subdomain IIIA (site II') of BSA. The interactions between FEL and BSA including hydrogen bonding with ASN390 residue and intermolecular hydrophobic interactions with LEU429 and LEU452 residues. However, the size of supramolecular FEL-ßRA better matched that of active cavity of BSA; the cocrystal is closely bound to BSA through hydrogen bonding with ASN390 residue and intermolecular hydrophobic interactions with LEU429, VAL432, LEU452 and ILE387 residues. This change on binding affinity of FEL to BSA induced by cocrystallization with ßRA provided theoretical basis to evaluate the transportation, distribution and metabolism of cocrystal drug.


Assuntos
Felodipino/química , Hidroxibenzoatos/química , Soroalbumina Bovina/química , Sequência de Aminoácidos , Sítios de Ligação , Cristalização , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Ligação Proteica , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier , Termodinâmica
8.
Mol Pharm ; 17(11): 4401-4406, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32975418

RESUMO

Amorphous solid dispersions (ASDs), in which polymers are admixed with a drug, retard or inhibit crystallization of the drug, increasing the drug's apparent solubility and oral bioavailability. To date, there are no guidelines regarding how much polymer should be added to stabilize the amorphous form of the drug. We hypothesized that only drug that is not within a "sphere of influence" of a polymer chain is able to nucleate and form crystals and that the degree of crystallization should depend primarily on the ratio C/C*, where C is the polymer concentration and C* is the overlap concentration. We tested this hypothesis by quenching dispersions of polyvinylpyrrolidone (PVP) dissolved in molten felodipine (FEL) or indomethacin (IMC) at four molecular weights of PVP. For each molecular weight of PVP, C* in the drug (as solvent) was determined by dynamic light scattering and intrinsic viscosity. The enthalpy of fusion (ΔHf), determined by DSC, was used to measure the fraction of drug that crystallized in an ASD. It was found, roughly, that ΔHf/ΔHf,C=0 = f(C/C*) and that no crystallization occurred when C > C*. XRD also showed that crystallization was completely inhibited up to ∼Tg + 75 °C when the polymer concentration was above C*. Our results suggest that stabilization of amorphous drugs can be achieved by incorporating a polymer just above C*, which is much lower than polymer concentrations customarily used in ASDs. This work reveals the importance of C* in selecting polymer concentrations when formulating drugs as ASDs.


Assuntos
Composição de Medicamentos/métodos , Felodipino/química , Indometacina/química , Povidona/química , Solventes/química , Cristalização , Estabilidade de Medicamentos , Difusão Dinâmica da Luz/métodos , Temperatura Alta , Peso Molecular , Solubilidade , Viscosidade
9.
Mol Pharm ; 17(10): 4018-4028, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-32870692

RESUMO

Using fixed dose combinations of drugs instead of administering drugs separately can be beneficial for both patients and the health care system, but the current understanding of how multidrug formulations work at the molecular level is still in its infancy. Here, we explore dissolution, solubility, and supersaturation of various drug combinations in amorphous formulations. The effect of chemical structural similarity on combination behavior was investigated by using structurally related compounds of both drugs. The effect of polymer type on solution behavior was also evaluated using chemically diverse polymers. Indapamide (IPM) concentration decreased when combined with felodipine (FDN) or its analogues, which occurred even when the IPM solution was undersaturated. The extent of solubility decrease of FDN was less than that of IPM from the dissolution of an equimolar formulation of the drugs. No significant solubility decrease was observed for FDN at low contents of IPM which was also observed for other dihydropyridines, whereas FDN decreases at high contents of IPM. This was explained by the complex nature of the colloidal precipitates of the combinations which impacts the chemical potential of the drugs in solution at different levels. The maximum achievable concentration of FDN and IPM during dissolution of the polyvinylpyrrolidone-based amorphous solid dispersion was higher than the value measured with the hydroxypropyl methylcellulose acetate succinate-based formulation. This emphasizes the significance of molecular properties and chemical diversity of drugs and polymers on solution chemistry and solubility profiles. These findings may apply to drugs administered as a single dosage form or in separate dosage forms and hence need to be well controlled to assure effective treatments and patient safety.


Assuntos
Anti-Hipertensivos/farmacocinética , Química Farmacêutica , Composição de Medicamentos/métodos , Anti-Hipertensivos/química , Anti-Hipertensivos/uso terapêutico , Cristalização , Combinação de Medicamentos , Interações Medicamentosas , Liberação Controlada de Fármacos , Felodipino/química , Felodipino/farmacocinética , Felodipino/uso terapêutico , Humanos , Hipertensão/tratamento farmacológico , Indapamida/química , Indapamida/farmacocinética , Indapamida/uso terapêutico , Metilcelulose/análogos & derivados , Metilcelulose/química , Segurança do Paciente , Povidona/química , Solubilidade , Soluções/química
10.
Pharm Dev Technol ; 25(10): 1226-1237, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32787680

RESUMO

ABSTRCT Felodipine has been widely used as a poorly water-soluble model drug for various studies to improve its oral bioavailability and in vivo efficacy. In this study, we developed amorphous solid dispersions (ASDs) via spray drying to enhance the bioavailability of felodipine through using natural zein protein as a novel polymeric excipient. The solid state characterization results demonstrated a single glass transition temperature (Tg ) around 128.6 °C and good physical stability post 3 months accelerated study under the condition of 40 °C and 75% relative humidity (RH), which is possibly accounted for the molecular immobilization and hydrogen bonding interactions between felodipine and zein. By combining the in vitro dissolution study with TIM-1 gastrointestinal simulation investigation, it is indicated that felodipine was rapidly released from the ASD in 30 mins, and the supersaturation of felodipine was well maintained over 6 h, which resulted in a significant enhancement of felodipine bioavailability during simulated digestive processes in the upper GI tract. This study suggests that spray drying combined with natural excipient zein is an efficient formulation strategy for the development of ASDs with enhanced aqueous solubility and bioavailability.


Assuntos
Bloqueadores dos Canais de Cálcio/administração & dosagem , Excipientes/química , Felodipino/administração & dosagem , Zeína/química , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Química Farmacêutica/métodos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Felodipino/química , Felodipino/farmacocinética , Trato Gastrointestinal/metabolismo , Umidade , Ligação de Hidrogênio , Técnicas In Vitro , Solubilidade , Temperatura , Temperatura de Transição
11.
Pharm Res ; 37(9): 169, 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32794010

RESUMO

PURPOSE: Penetration enhancers (PEs) enhancing efficacy depends on two processes: PEs release from patches and action on skin. Compared with their action on skin, PEs release process was poorly understood. Therefore, the purpose of this study was to make a mechanistic understanding of PEs release from acrylic pressure-sensitive adhesive of patches and propose an unconventional enhancement of PEs efficacy. METHODS: PEs efficacy was evaluated both in drug permeation study and drug pharmacokinetic study. Confocal Raman spectroscopy was employed to observe PEs release behavior by mapping PEs dynamic distribution in skin. The mechanism of PEs release behavior was provided from molecular interaction and rheology using FT-IR, molecular docking, molecular dynamic simulation and rheometer, separately. RESULTS: The release behavior of PEs themselves greatly restricted their efficacy. By using PEG 400, an improvement of oleic acid (OA) release behavior was achieved, and the efficacy of OA was significantly enhanced with enhancing ratio (ER) from 2.69 to 4.10 and AUClast from 1574 ± 87 to 2664 ± 249 ng·h/mL, separately. The improvement of OA release behavior was primarily resulted from reduction of the interaction between OA and adhesive, which was caused by other small molecules with a strong ability in forming hydrogen bonds with adhesive. Also, the rigidity of adhesive was a factor in affecting PEs release behavior. CONCLUSIONS: An unconventional passive enhancement of transdermal drug delivery was achieved via improving PEs themselves releasing from acrylic pressure-sensitive adhesive. Graphical abstract Influence of PEs release behavior on drug permeation through skin and molecular mechanism.


Assuntos
Liberação Controlada de Fármacos/fisiologia , Absorção Cutânea/fisiologia , Adesivos/química , Administração Cutânea , Animais , Química Farmacêutica , Sistemas de Liberação de Medicamentos , Ácidos Graxos/química , Felodipino/administração & dosagem , Felodipino/farmacocinética , Masculino , Modelos Moleculares , Simulação de Acoplamento Molecular , Preparações Farmacêuticas/metabolismo , Ratos , Pele/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Adesivo Transdérmico
12.
AAPS PharmSciTech ; 21(5): 170, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32529303

RESUMO

Felodipine (FLD), a dihydropyridine calcium channel blocker with excellent antihypertensive effect, is poorly soluble and undergoes extensive hepatic metabolism, which lead to poor oral bioavailability (about 15%) and limit its clinic application. The goal of this study was to develop solid lipid nanoparticles (SLNs) loading FLD to improve the oral bioavailability. The FLD loaded solid lipid nanoparticles (FLD-SLNs) were prepared by the effervescent dispersion technique developed by our laboratory, which might have some advantages over traditional methods. The FLD-SLNs showed desired particle characteristics with particle size (198.15 ± 1.82 nm), poly dispersity index (0.26 ± 0.02), zeta-potential (- 25.53 ± 0.60 mV), entrapment efficiency (95.65 ± 0.70%), drug loading (2.33 ± 0.10%), and a spherical appearance. Pharmacokinetic results showed that the FLD-SLNs presented 3.17-fold increase in area under the curve (AUC(0-t)) compared with free FLD after oral administration in beagle dogs, which indicated that SLNs prepared using the effervescent dispersion technique can improve the bioavailability of lipophilic drugs like felodipine by enhancement of absorption and reduction first-pass metabolism.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacocinética , Química Farmacêutica/métodos , Felodipino/farmacocinética , Nanopartículas/metabolismo , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/síntese química , Estudos Cross-Over , Cães , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Felodipino/administração & dosagem , Felodipino/síntese química , Lipídeos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Tamanho da Partícula , Distribuição Aleatória
13.
Mol Pharm ; 17(7): 2499-2507, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32369379

RESUMO

Natural edible oils (NEOs) are common excipients for lipid-based formulations. Many of them are complex mixtures comprising hundreds of different triglycerides (TGs). One major challenge in developing lipid-based formulations is the variety in NEO compositions affecting the solubility of active pharmaceutical ingredients. In this work, solubilities of indomethacin (IND), ibuprofen (IBU), and fenofibrate (FFB) in soybean oil and in coconut oil were measured via differential scanning calorimetry, high-performance liquid chromatography, and Raman spectroscopy. Furthermore, this work proposes an approach that mimics NEOs using one key TG and models the API solubilities in these NEOs based on perturbed-chain statistical associating fluid theory (PC-SAFT). Key TGs were determined using the 1,2,3-random hypothesis, and PC-SAFT parameters were estimated via a group-contribution method. Using the proposed approach, the solubility of IBU and FFB was modeled in soybean oil and coconut oil. Furthermore, the solubilities of five more APIs (IND, cinnarizine, naproxen, griseofulvin, and felodipine) were modeled in soybean oil. All modeling results were found in very good agreement with the experimental data. The influence of different NEO kinds on API solubility was examined by comparing FFB and IBU solubilities in soybean oil and refined coconut oil. PC-SAFT was thus found to allow assessing the batch-to-batch consistency of NEO batches in silico.


Assuntos
Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Excipientes/química , Fenofibrato/química , Ibuprofeno/química , Óleos Vegetais/química , Varredura Diferencial de Calorimetria , Cromatografia Líquida de Alta Pressão , Cinarizina/química , Cinarizina/farmacologia , Óleo de Coco/química , Sistemas de Liberação de Medicamentos , Felodipino/química , Felodipino/farmacologia , Fenofibrato/farmacologia , Griseofulvina/química , Griseofulvina/farmacologia , Ibuprofeno/farmacologia , Indometacina/química , Modelos Moleculares , Naproxeno/química , Naproxeno/farmacologia , Óleos Vegetais/farmacologia , Solubilidade , Óleo de Soja/química , Análise Espectral Raman , Termodinâmica , Temperatura de Transição , Triglicerídeos/química
15.
Int J Pharm ; 581: 119300, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32268185

RESUMO

The potential for inhibiting recrystallization with Eudragit® L (EUD-L), hypromellose acetate succinate (HPMC-AS), and polyvinylpyrrolidone-co-vinylacetate (PVP-VA) on amorphous felodipine (FLD) at low polymer loading was investigated in this study. The physical stabilities of the FLD/polymer amorphous solid dispersions (ASDs) were investigated through storage at 40 °C. The HPMC-AS and PVP-VA strongly inhibited FLD recrystallization, although EUD-L did not effectively inhibit the FLD recrystallization. The rotating frame 1H spin-lattice relaxation time (1H-T1ρ) measurement clarified that EUD-L was not well mixed with FLD in the ASD, which resulted in weak inhibition of recrystallization by EUD-L. In contrast, the HPMC-AS and PVP-VA were well mixed with the FLD in the ASDs. Solid-state 13C spin-lattice relaxation time (13C-T1) measurements at 40 °C showed that the molecular mobility of the FLD was strongly suppressed when mixed with polymer. The reduction in the molecular mobility of FLD was in the following order, starting with the least impact: FLD/EUD-L ASD, FLD/HPMC-AS ASD, and FLD/PVP-VA ASD. FLD mobility at the storage temperature, evaluated by 13C-T1, showed a good correlation with the physical stability of the amorphous FLD. The direct investigation of the molecular mobility of amorphous drugs at the storage temperature by solid-state NMR relaxation time measurement can be a useful tool in selecting the most effective crystallization inhibitor at low polymer loading.


Assuntos
Isótopos de Carbono/química , Química Farmacêutica/métodos , Força Compressiva , Cristalização/métodos , Felodipino/química , Polímeros/química , Antiarrítmicos/análise , Antiarrítmicos/química , Isótopos de Carbono/análise , Portadores de Fármacos/análise , Portadores de Fármacos/química , Felodipino/análise , Previsões , Polímeros/análise
16.
Int J Clin Pharmacol Ther ; 58(7): 375-386, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32301702

RESUMO

OBJECTIVE: This study evaluated different influences of 14 single nucleotide polymorphisms (SNPs) and demographic factors leading to individual differences in the antihypertensive efficacy of felodipine in healthy Chinese subjects. MATERIALS AND METHODS: 24 subjects were sequenced for candidate SNPs. Plasma samples were obtained as clinical trial protocol, and were determined by a HPLC-MS/MS method. Pharmacokinetic parameters were calculated by WinNonlin 6.0. Statistical analysis was mainly performed by SPSS 22.0. A multiple linear regression model provided different weight coefficients of different demographic and genetic factors. RESULTS: The trend of Cmax is almost consistent with AUCss increase, but tmax of individuals is different; the antihypertensive effect of felodipine is individually different. A significant association was observed between systolic blood pressure decrease (ΔSBP) and SNPs of CACNA1C, CACNA1D, GNB3 respectively, while CACNA1C and CACNA1 were associated with diastolic blood pressure decrease (ΔDBP). CYP3A5 rs766746 and CYP3A4 rs2242480 were linked with Cmax and AUCss, and ABCB1 rs1045642 was associated with T1/2. Significant relationships were shown between AUCss and ΔSBP (p = 0.022) as well as Cmax and ΔSBP (p = 0.015). CONCLUSION: The efficacy of felodipine is individually different, influenced especially by CACNA1C rs1051375 and ABCB1 rs1045642. ΔDBP is associated with ΔSBP in multiple-dosing of felodipine in healthy Chinese subjects.


Assuntos
Anti-Hipertensivos , Felodipino , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Anti-Hipertensivos/farmacologia , Grupo com Ancestrais do Continente Asiático/genética , Canais de Cálcio Tipo L/genética , Citocromo P-450 CYP3A , Felodipino/farmacologia , Humanos , Espectrometria de Massas em Tandem
17.
BMJ Open ; 10(3): e034086, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-32139488

RESUMO

OBJECTIVE: Severity of coeliac disease depends in part on the extent of small intestinal mucosa injury. Patients with the most abnormal pathology have loss of duodenal villi CYP3A4, a drug-metabolising enzyme that inactivates many drugs. These patients are hypothesised to have greater systemic concentrations of felodipine, a drug which normally has low oral bioavailability secondary to intestinal CYP3A4-mediated metabolism. It serves as a representative for a class containing many medications. DESIGN: A phase I, open-label, single-dose, pharmacokinetic study. SETTING: London, Ontario, Canada. PARTICIPANTS: Patients with coeliac disease (n=47) with positive serology and healthy individuals (n=68). MAIN OUTCOME MEASURES: Patients with coeliac disease-upper gastrointestinal endoscopy and oral felodipine pharmacokinetics study within a 3-week period. Healthy individuals-oral felodipine pharmacokinetics study with water and grapefruit juice. RESULTS: Coeliac stratification categories: Group A (n=15, normal), B+C (n=16, intraepithelial lymphocytosis with/without mild villous blunting) and D (n=16, moderate/severe villous blunting). Groups A, B+C and D had linear trends of increasing felodipine AUC0-8; mean±SEM, 14.4±2.1, 17.6±2.8, 25.7±5.0; p<0.05) and Cmax (3.5±0.5, 4.0±0.6, 6.4±1.1; p<0.02), respectively. Healthy subjects receiving water had lower felodipine AUC0 - 8 (11.9±0.9 vs 26.9±0.9, p=0.0001) and Cmax (2.9±0.2 vs 7.7±0.2, p=0.0001) relative to those receiving grapefruit juice. CONCLUSIONS: Increased felodipine concentrations in patients with coeliac disease were most probably secondary to decreased small intestinal CYP3A4 expression. Patients with severe coeliac disease and healthy individuals with grapefruit juice had equivalently enhanced effect. Thus, patients with severe coeliac disease would probably experience similarly altered drug response, including overdose toxicity, from many important medications known to be metabolised by CYP3A4. Patients with coeliac disease with severe disease should be considered for other clinical drug management, particularly when there is the potential for serious drug toxicity.


Assuntos
Doença Celíaca/tratamento farmacológico , Felodipino/farmacocinética , Adulto , Idoso , Doença Celíaca/metabolismo , Citrus paradisi/efeitos adversos , Estudos Cross-Over , Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Felodipino/administração & dosagem , Felodipino/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
18.
Sud Med Ekspert ; 63(1): 47-52, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32040088

RESUMO

The objective of the work was to study felodipine distribution in warm-blooded animals (rats). The methods of TLC, GC-MS, and UV spectrophotometry were used in the experiments. A lethal dose of felodipine (1.05 g/kg) preliminary suspended in water was introduced intragastric into test animals (male rats of the Wistar line). The analyzed compound was isolated from solid tissues and blood of the animals with acetone, purified by the solvent replacement, and by macrocolumn chromatography with the Silasorb S-18 sorbent of 30 µm and polar eluent, acetonitrile-water (7:3). The analyte was identified by chromatographic behavior in a thin sorbent layer, retention time, and a set of positive ions in its mass spectrum, as well as by the UV spectrum. The analyte was quantitatively detected in biological matrices using UV spectrophotometry. The method was validated by the criteria of linearity, selectivity, accuracy, precision, limits of detection, and quantitative determination. The predominant content of felodipine was detected in tissues of the stomach (312.303±25.980 µg/g), small intestine with its contents (93.235±12.310 µg/g), stomach contents (80.072±8.510 µg/g), and in the spleen (26.083±1.758 µg/g).


Assuntos
Anti-Hipertensivos , Felodipino , Animais , Anti-Hipertensivos/farmacocinética , Cromatografia em Camada Delgada , Felodipino/farmacocinética , Toxicologia Forense , Masculino , Ratos , Ratos Wistar , Distribuição Tecidual
19.
J Heart Lung Transplant ; 39(6): 541-550, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32061508

RESUMO

BACKGROUND: Calcium channel blockers may ameliorate the decline in renal function caused by calcineurin inhibitors in lung transplantation (LTX) recipients. We hypothesized that pre-operative and 12-week post-operative treatment with the calcium channel blocker felodipine would reduce the decline in glomerular filtration rate (GFR). METHODS: In this prospective, randomized, double-blind trial, 39 LTX recipients were transplanted and received placebo (n = 19; GFR, 102 ml/min/1.73 m2 [range, 91-113 ml/min/1.73 m2]) or felodipine (n = 20, GFR, 96 ml/min/1.73 m2 [range, 88-104 ml/min/1.73 m2]). Pre-operative treatment was titrated post-operatively to 10 mg or the maximum tolerable dose. The primary end-point was the change in GFR using Cr-51-labeled EDTA from LTX to 12 weeks thereafter, and follow-up was 52 weeks. RESULTS: The treatment group showed an absolute mean decline in GFR of 31 ml/min/1.73 m2 (95% CI: -40 to 22 ml/min/1.73 m2), whereas that of the placebo group was 48 ml/min/1.73 m2 (95% confidence interval [CI]: -56 to 40 ml/min/1.73 m2). Thus, the difference between groups at 12 weeks was 17 ml/min/1.73 m2 (95% CI: 4-29 ml/min/1.73 m2; p = 0.01). Half of the patients were unable to complete the 3-month primary follow-up, and the analysis includes these patients by intention-to-treat. After 52 weeks (40 weeks after termination of treatment), the treatment effect was maintained at 12 ml/min/1.73 m2 (95% CI: 0-24 ml/min/1.73 m2, p = 0.05). The number of days with registered hypotension was significantly higher in the felodipine group than in the placebo group (39 days vs 13 days, rate ratio: 2.9 [95% CI: 1.5-5.3]). CONCLUSIONS: Use of felodipine in select patients was associated with greater preservation in renal function early (90 days) after LTX. The observed benefits were attenuated by 1 year, although trends in better renal function were noted.


Assuntos
Pressão Sanguínea/fisiologia , Felodipino/administração & dosagem , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/fisiopatologia , Transplante de Pulmão , Bloqueadores dos Canais de Cálcio/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
20.
Int J Pharm ; 579: 119120, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32035254

RESUMO

The nano-particulate system for oral delivery faces a big challenge across the gastrointestinal bio-barriers. The aim was to explore the potential applications of bile acid transporter mediated the self-assembled hybrid nanoparticles (SHNPs) of sodium taurocholate (STC) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus) for augmenting the oral delivery of poorly water-soluble drugs. Felodipine (FLDP) was chosen as a model drug. The self-assembly of STC with Soluplus to load FLDP and the microstructure of the SHNPs were confirmed using molecular simulation, STC determination by high performance liquid chromatography (HPLC) and transmission electron microscope. Results showed that STC was integrated with Soluplus on the surface of nanoparticles by hydrophobic interactions. The permeability of FLDP loaded STC/Soluplus SHNPs was STC dependent in the ileum, which was inhibited by the higher concentrations of STC and the inhibitor of apical sodium-dependent bile acid transporter (ASBT). STC/Soluplus (1:9) SHNPs significantly improved the drug loading of FLDP, achieved the highest permeability of FLDP and realized 1.6-fold of the area under the curve (AUC) of Soluplus self-assembled nanoparticles (SNPs). A water-quenching fluorescent probe P4 was loaded into the STC/Soluplus SHNPs, which verified that the SHNPs were transferred intactly across the ileum. In conclusion, STC/Soluplus SHNPs via ASBT are a potential strategy for enhancing the oral bioavailability of poorly water-soluble drugs.


Assuntos
Portadores de Fármacos/química , Felodipino/administração & dosagem , Nanopartículas/química , Transportadores de Ânions Orgânicos Dependentes de Sódio/química , Simportadores/química , Ácido Taurocólico/química , Administração Oral , Animais , Área Sob a Curva , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Felodipino/farmacocinética , Interações Hidrofóbicas e Hidrofílicas , Masculino , Camundongos , Permeabilidade , Polietilenoglicóis/química , Polivinil/química , Ratos
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