Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 925
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Pharm Res ; 36(12): 175, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31677137

RESUMO

PURPOSE: Traditional methods for estimating drug-polymer solubility either require fast dissolution in the polymeric matrix, rapid re-crystallization kinetics from supersaturated states or derive from regular solution theories. In this work, we present a new method for determining drug solubility, purely based on thermodynamic considerations, that uses only experimental data from DSC for calculations. METHODS: The new thermodynamic model presented combines DSC analysis and application of Hess's law to determine free energies of conversion of binary mixtures to amorphous solid dispersions, free energies of mixing as well as solubility as a function of temperature. The model drug indomethacin and polymers HPMCAS LF, PVP K29/32 and Eudragit EPO were used in these studies. RESULTS: Free energies were calculated as a function of temperature, for different drug-polymer compositions and the results show that HPMCAS LF solid dispersion with high drug content are less thermodynamically favorable compared to other polymer systems. Solubility of indomethacin in HPMCAS LF, PVP K29/32 and Eudragit EPO was 24, 55 and 56% w/w, respectively, at 25°C. CONCLUSIONS: The thermodynamic model presented has great advantages over traditional methods. It does not require estimation of any interaction parameters, it is almost assumption-free and uses only thermal data for calculations.


Assuntos
Composição de Medicamentos/métodos , Indometacina/química , Modelos Moleculares , Polímeros/química , Cristalização , Estabilidade de Medicamentos , Cinética , Metilcelulose/análogos & derivados , Metilcelulose/química , Ácidos Polimetacrílicos/química , Povidona/química , Solubilidade , Termodinâmica , Temperatura de Transição
2.
Eur J Pharm Biopharm ; 145: 113-120, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31682903

RESUMO

Lipid-based drug delivery systems (LBDDS) are highly relevant as pharmaceutical formulations significantly enhancing the bioavailability of active pharmaceutical ingredients (APIs). These formulations often are complex mixtures of APIs, various lipids, and other excipients (e.g. surfactants). In their simplest form, LBDDS contain one API being dissolved in a pure lipid, which often is a triglyceride (TG). In this work, solubilities of the APIs indomethacin, ibuprofen, and fenofibrate in pure TGs of different chain lengths (C chain 8-18) and degree of saturation were investigated. Solubilities of APIs in TGs were measured via differential scanning calorimetry, hot-stage microscopy, high-performance liquid chromatography, and Raman spectroscopy. The influence of fatty-acid chain length and degree of saturation on the API solubility in the TGs was investigated. APIs showed a higher solubility in saturated (wIBU = 10.5 wt% at 25 °C in tricaprylin) TGs compared to unsaturated ones (wIBU = 4.0 wt% at 25 °C in triolein). The fatty-acid chain length of TGs only slightly affects the solubility of ibuprofen and fenofibrate, but strongly influences the eutectic temperature of the API/TG mixtures. API solubilities in TGs and TG mixtures (mixtures of tricaprylin and tricaprin) were successfully modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) accounting for the intermolecular API/TG interactions providing a deep understanding of the energetic and structural impact of the TGs on API solubility.


Assuntos
Preparações Farmacêuticas/química , Solubilidade/efeitos dos fármacos , Triglicerídeos/química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Excipientes/química , Fenofibrato/química , Ibuprofeno/química , Indometacina/química , Lipídeos/química
3.
Chem Pharm Bull (Tokyo) ; 67(10): 1050-1060, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582625

RESUMO

Universal nanocrystal formulation which can be applied to water-insoluble compounds was proposed and the criteria of its physicochemical properties as an active pharmaceutical ingredients (API) were investigated. Nanocrystal suspension was prepared by a wet-beads milling method. An acceptable Critical Quality Attributes (CQA) of nanocrystal suspension was defined by Z-average less than 500 nm and Polydispersity index (PDI) less than 0.3. Screening studies of dispersing and wetting agents were conducted using three model compounds in different pKa, melting points, etc., to find universal nanocrystal formulation. The effect of four structurally different polymer species (hydroxypropyl cellulose (HPC), hydoroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA)) and their different grades or five different surfactants (docusate sodium (DOSS), sodium lauryl sulfate (SLS), cetyl trimethyl ammonium bromide (CTAB), polysolbate80 (PS80), and polyoxyethylene castor oil (CO-35)) were studied on the re-dispersion stability. It was found that the combination of 4% (w/v) HPC-SSL and 0.2% (w/v) DOSS was the most robust nanocrystal formulation owing to Z-average less than 200 nm and good re-dispersion stability without aggregates at pH 1.2 and pH 6.8. API physicochemical properties were also identified using ten water-insoluble compounds. Consequently, it was found that solubility (water, pH 1.2 and pH 6.8), molecular weight, hydrogen bonding acceptor and the ratio of log D7.4 to C Log P were critical factors.


Assuntos
Composição de Medicamentos , Fenofibrato/química , Indometacina/química , Nanopartículas/química , Nifedipino/química , Química Física , Concentração de Íons de Hidrogênio , Tamanho da Partícula , Polímeros/química , Solubilidade , Propriedades de Superfície , Tensoativos/química
4.
Pharm Res ; 36(11): 159, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515697

RESUMO

PURPOSE: Amorphous indomethacin (IMC) forms gel with a decreased dissolution behavior compared to crystalline IMC during dissolution. The current study aims to explore gelation mechanism and attempt to eliminate gelling effect by formulation development. METHODS: Amorphous IMC was prepared by melt-quenching method. Dissolution tests of amorphous IMC were performed at various temperatures under sink condition. The formed gels were characterized by PLM, SEM, DSC and XRPD. RESULTS: Amorphous IMC exhibited an initial higher dissolution followed by a decreased dissolution lower than its crystalline counterpart at 32 and 37°C, and even a much lower dissolution during the whole dissolution period at 45°C. Meanwhile, a viscous soft mass ("gel") was observed to adhere upon the paddle or wall of the vessel. The formed gel could be characterized as a three-dimensional dense micro-fiber structure under SEM. The gel formation was proposed to be related to the decreased Tg of amorphous IMC when contacting aqueous medium, resulting in entering into supercooled liquid state with high viscosity. The addition of hydrophilic silica accelerated gel formation, while mixing with hydrophobic silica was able to weaken and even eliminate the gelation, and hence significantly enhancing dissolution. CONCLUSIONS: The present study recommends that gel formation should be included in the investigation of amorphous materials in order to find ways for resolving defects of amorphous materials while keeping their advantages in pharmaceutics.


Assuntos
Indometacina/química , Cristalização , Géis/química , Interações Hidrofóbicas e Hidrofílicas , Transição de Fase , Dióxido de Silício/química , Solubilidade , Temperatura Ambiente
5.
Chem Pharm Bull (Tokyo) ; 67(9): 921-928, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474730

RESUMO

We studied the possibility of using ursodeoxycholic acid (UDCA) as an excipient to create an amorphous composite that can be administered to animals in preclinical studies of experimental drugs. Three UDCA-based amorphous samples composed of nifedipine (NIF), indomethacin (IND), and naproxen (NAP) were found by screening. The UDCA-based formulations were adjudged amorphous by solid-state analysis using X-ray powder diffraction and differential scanning calorimetry. In addition, amorphous samples of NIF-UDCA, IND-UDCA, and NAP-UDCA did not crystallize while in 1% methyl cellulose (MC) solution for 120 min, although an amorphous solid dispersion of NIF-poly(vinylpyrrolidone) (PVP) crystallized rapidly. The low hygroscopicity of UDCA helps NIF maintain an amorphous state in 1% MC solution. The UDCA-based amorphous composites can be administered as suspended formulations to animals in preclinical studies.


Assuntos
Composição de Medicamentos , Preparações Farmacêuticas/química , Ácido Ursodesoxicólico/química , Varredura Diferencial de Calorimetria , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Indometacina/química , Naproxeno/química , Nifedipino/química , Solubilidade
6.
Chem Pharm Bull (Tokyo) ; 67(9): 945-952, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474734

RESUMO

Salt and cocrystal formulations are widely used as techniques to improve physicochemical properties of compounds. Some spectrometric techniques to distinguish cocrystals from salts have been reported; however, it has not been possible to adapt these formulations with many compounds, because of limitations, high difficulty, and exceptions. Therefore, we focused on the possibility of UV spectrometry, which had not been reported as a classification technique for salts and cocrystals. The integration values of solid-state UV/visible (Vis) spectra of indomethacin salts were larger than those of physical mixtures of indomethacin and counter molecules, while that of indomethacin cocrystal was not large compared with that of the physical mixture. From these results, differences between a salt and a cocrystal were observed in their solid-state UV/Vis absorption spectra for indomethacin complexes. Therefore, it is suggested that solid-state UV/Vis absorption spectra can be used as a new technique to classify salts and cocrystals.


Assuntos
Indometacina/química , Espectrofotometria Ultravioleta/métodos , Arginina/química , Cristalização , Espectroscopia de Ressonância Magnética , Meglumina/química , Sacarina/química , Sais/química , Difração de Raios X
7.
Pharm Res ; 36(10): 150, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31428879

RESUMO

PURPOSE: The unconventional tabletability of the indomethacin polymorphs - α and γ - are investigated from a topological and mechanical perspective using powder Brillouin light scattering (p-BLS) to identify the specific structure-performance relationship in these materials. METHOD: Indomethacin (γ-form) was purchased and used to prepare the α polymorph. Powder X-ray diffraction was used to confirm phase identity, while p-BLS was used to obtain the mechanical properties. Energy frameworks were determined with Crystal Explorer to visualize the interaction topologies. Using a Carver press and a stress-strain analyzer, the tableting performance of each polymorph was determined. RESULTS: Polymorph-specific acoustic frequency distributions were observed with distinct, zero-porosity, aggregate elastic moduli determined. The p-BLS spectra for α-indomethacin display a population of low-velocity shear modes, indicating a direction of facilitated shear. This improves slip-mediated plasticity and tabletability. Our p-BLS spectra experimentally indicates that a low-energy slip system is available to α-indomethacin which supports ours and previous energy framework calculations. Despite a 2d-layered crystal motif favorable for shear deformation, the γ-form displays a higher shear modulus that is supported by our hydrogen-bonding analysis of γ-indomethacin. CONCLUSION: Our experimental, mechanical data is consistent with the predicted interaction topologies and these two inputs combined permit a comprehensive, molecular understanding of polymorph-specific tabletability.


Assuntos
Indometacina/química , Cristalização , Dimerização , Composição de Medicamentos , Ligações de Hidrogênio , Luz , Fenômenos Mecânicos , Porosidade , Pós , Espalhamento de Radiação , Comprimidos , Termodinâmica
8.
Int J Mol Sci ; 20(15)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349657

RESUMO

This study designed the transdermal formulations containing indomethacin (IMC)-1% IMC was crushed with 0.5% methylcellulose and 5% 2-hydroxypropyl-ß-cyclodextrin by the bead mill method, and the milled IMC was gelled with or without 2% l-menthol (a permeation enhancer) by Carbopol® 934 (without menthol, N-IMC gel; with menthol, N-IMC/MT gel). In addition, the drug release, skin penetration and percutaneous absorption of the N-IMC/MT gel were investigated. The particle sizes of N-IMC gel were approximately 50-200 nm, and the combination with l-menthol did not affect the particle characterization of the transdermal formulations. In an in vitro experiment using a Franz diffusion cell, the skin penetration in N-IMC/MT gel was enhanced than the N-IMC gel, and the percutaneous absorption (AUC) from the N-IMC/MT gel was 2-fold higher than the N-IMC gel. On the other hand, the skin penetration from the N-IMC/MT gel was remarkably attenuated at a 4 °C condition, a temperature that inhibits all energy-dependent endocytosis. In conclusion, this study designed transdermal formulations containing IMC solid nanoparticles and l-menthol, and found that the combination with l-menthol enhanced the skin penetration of the IMC solid nanoparticles. In addition, the energy-dependency of the skin penetration of IMC solid nanoparticles was demonstrated. These findings suggest the utility of a transdermal drug delivery system to provide the easy application of solid nanoparticles (SNPs).


Assuntos
Indometacina/administração & dosagem , Indometacina/farmacocinética , Mentol/administração & dosagem , Mentol/farmacocinética , Nanopartículas , Administração Cutânea , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Portadores de Fármacos/química , Combinação de Medicamentos , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Indometacina/química , Mentol/química , Microscopia de Força Atômica , Nanopartículas/química , Ratos , Absorção Cutânea , Análise Espectral
9.
ACS Appl Mater Interfaces ; 11(32): 28597-28609, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31314480

RESUMO

An ortho-ester-linked indomethacin (IND) dimer-based nanodrug delivery system was prepared to improve the therapeutic effect of doxorubicin (DOX) by reversing the multidrug resistance. The synthesized dimer (IND-OE) could form stable nanoparticles (IND-OE/DOX) loaded with DOX via the single-emulsion method. Compare to insensitive nanoparticles (IND-C12/DOX), IND-OE/DOX showed a rapid degradation behavior and accelerated drug release at mildly acidic environments. In vitro cell experiments verified that IND-OE nanoparticles could increase DOX concentration due to the efficient intracellular drug release by the degradation of the ortho ester as well as reduced DOX efflux by IND-mediated P-gp downregulation. In vivo studies further demonstrated that IND-OE/DOX displayed the maximized synergetic antitumor efficacy than free DOX or IND-C12/DOX, and the tumor inhibition rates versus saline were 46.78% (free DOX), 60.23% (IND-C12/DOX), and 80.62% (IND-OE/DOX). Overall, this strategy of combination with chemosensitizers and ortho ester linkage has great potential to serve as an amplifying chemotherapy platform against various drug-resistant tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Portadores de Fármacos , Nanopartículas , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Feminino , Humanos , Indometacina/química , Indometacina/farmacocinética , Indometacina/farmacologia , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Drug Dev Ind Pharm ; 45(10): 1599-1609, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31271320

RESUMO

We recently reported lowly hydrolyzed polyvinyl alcohol (L-PVA, 70-74% hydrolyzed, about 580 polymerized, JR-05) as a promising matrix for hot-melt extrusion (HME) due to its unique micelle formation ability compared to the most commonly used PVA (87-89% hydrolyzed, about 580 polymerized). In the present study, we focused on the effect of composition [indomethacin (IND), L-PVA, sorbitol] and process parameters (temperature and screw speed) on each response, i.e. processing torque, and physicochemical properties such as residual crystallinity, residual ratio, and area under the dissolution curve (AUDC) in supersaturated solution using a HME by applying the design of experiment (DoE) approach. To overcome the poor processability of L-PVA, given its semicrystalline nature, we applied sorbitol as a plasticizer and systematically and simultaneously evaluated its influence on the outputs based on the mixture design combined with process factors. Few studies have focused on comprehensive evaluation of the composition and HME process conditions because obtaining a design space requires numerous experiments. We found that incorporating sorbitol into the L-PVA greatly improved the processing torque. However, sorbitol negatively influenced the degree of residual crystallinity and the AUDC of IND. Lastly, we established a laboratory-scale design space that could achieve high supersaturation and ensure adequate miscibility between each component, using an acceptable processing torque for HME, by applying the minimum amount of sorbitol. These fundamental results suggest that sorbitol maximizes the potency of L-PVA as a carrier in HME.


Assuntos
Indometacina/química , Álcool de Polivinil/química , Química Farmacêutica/métodos , Cristalização/métodos , Composição de Medicamentos/métodos , Hidrólise , Micelas , Plastificantes/química , Solubilidade/efeitos dos fármacos , Sorbitol/química , Temperatura Ambiente
11.
Chem Pharm Bull (Tokyo) ; 67(6): 580-586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155564

RESUMO

The aim of this study was to demonstrate the usefulness of T2 measurements conducted with a time-domain NMR (TD-NMR) for the characterization of active pharmaceutical ingredients (APIs) containing solid dosage forms. A solid dispersion (SD) and a physical mixture (PM) consisting of indomethacin (IMC) and polyvinylpyrrolidone (PVP) were prepared at different weight ratios as test samples, and then their T2 relaxation curves were measured by TD-NMR. The T2 relaxation curve of IMC was quite different from that of PVP by nature. T2 values of the SD and PM samples became gradually shortened with increasing IMC content. No difference in T2 relaxation curves was observed between SD and PM. By analyzing the T2 relaxation curves in detail, we succeeded in precisely quantifying the IMC contents incorporated in the samples. Next, this study evaluated the T2 relaxation curves of amorphous and crystalline states of powdered IMC. T2 relaxation rate of crystalline IMC was slightly but significantly higher than that of amorphous IMC, proving that the T2 measurement was sensitive enough to detect these differences. Finally, a thermal stress was imposed on SD and PM samples at 60°C for 7 d, and then an amorphous-to-crystalline transformation occurred in IMC in the PM sample and was successfully monitored by T2 measurement. We believe that T2 measurement by TD-NMR is a promising analysis for the characterization of APIs in solid dosage forms, including SD-based pharmaceuticals.


Assuntos
Anti-Inflamatórios não Esteroides/química , Indometacina/química , Espectroscopia de Ressonância Magnética , Cristalização , Formas de Dosagem , Composição de Medicamentos , Temperatura Ambiente , Difração de Raios X
12.
Eur J Pharm Sci ; 136: 104955, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199980

RESUMO

Amorphous solid dispersions (ASDs) can phase separate in the gel phase during dissolution, lowering the chemical potential and thus the driving force for drug release. The purpose of this study is to explore the connection between amorphous phase separation in the hydrated ASD and its resulting release rate. Poorly soluble model compounds - indomethacin (IND) and ritonavir (RTV) - were formulated as ASDs using PVP as carrier. Rotating disk dissolution studies with varying drug loading levels of IND-PVP and RTV-PVP showed that the drug release was fastest at an intermediate drug loading level. This was in part due to faster erosion of the ASD at lower drug loading levels. More interestingly, at low drug loading levels, PVP and the drug co-eroded, while at high drug loading levels, PVP was released preferentially. In the case of RTV-PVP, the loading level corresponding to this transition was correlated with the change in phase separation morphology as probed by confocal fluorescence imaging studies. At low drug loading levels, the hydrophobic domains were discrete domains while at high drug loading levels, hydrophobic domains were continuous. Our results suggest that at low drug loadings, release is mediated by erosion of the polymer along with embedded drug rich droplets, whereas at high drug loadings, formation of a drug-rich domain continuous morphology leads to preferential release of the polymer-rich domains. The transition from hydrophobic discrete to hydrophobic continuous morphology occurs at the percolation threshold. We discuss the two mechanisms of phase separation and its impact on the drug release from ASDs in the context of the ternary phase diagram.


Assuntos
Indometacina/química , Ritonavir/química , Liberação Controlada de Fármacos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Transição de Fase , Polímeros/química , Polivinil/química , Pirrolidinas/química , Solubilidade/efeitos dos fármacos
13.
Int J Pharm ; 566: 77-88, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31103819

RESUMO

Amorphous solid dispersions are nowadays typically made up of a drug compound and a water-soluble polymer. However, recently it has been demonstrated that amorphous solid dispersions based on insoluble polymers have a different and more delayed drug release profile, resulting in a prolonged duration of supersaturation. In this paper, binary and ternary amorphous solid dispersions based on poly(2-hydroxyethyl methacrylate) were prepared through spray drying to further investigate the potential of this type of carrier. As drug release from this matrix system was expected to be dictated by a diffusion-driven process, porosity of the formulation was adjusted by the inclusion of a water-soluble polymer. The solid state of the formulations was characterized with modulated differential scanning calorimetry, X-ray powder diffraction and thermogravimetric analysis. The release of drug and of the porosity increasing agent was measured in acidic and neutral conditions. In addition, the release performance of the spray dried product was compared with the drug release from poly(2-hydroxyethyl methacrylate) beads, which had already been reported in literature. It appeared that in the case of the spray dried poly(2-hydroxyethyl methacrylate), drug and porosity increasing agent could only be released to a certain extent due to entrapment of both compounds in the poly(2-hydroxyethyl methacrylate) network. While the chemical crosslinks of poly(2-hydroxyethyl methacrylate) beads ensured a more rigid structure with sufficient free space for drug diffusion, the spray dried product was susceptible to intense physical crosslinking upon contact with the dissolution medium.


Assuntos
Carbamazepina/química , Portadores de Fármacos/química , Indometacina/química , Poli-Hidroxietil Metacrilato/química , Povidona/química , Liberação Controlada de Fármacos , Interações Hidrofóbicas e Hidrofílicas , Porosidade , Solubilidade
14.
Eur J Pharm Biopharm ; 140: 60-66, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31055064

RESUMO

There is a trend in pharmaceutical research and development to develop depot formulations with dosing once weekly, once monthly, or even less frequently. A novel approach to achieve long acting injectable suspensions is to produce dense inorganic nanoshells with atomic layer deposition (ALD) on active pharmaceutical ingredients. Such particles can be suspended in an aqueous vehicle and administered subcutaneously. The purpose of this work was to study the release of a model drug, indomethacin, coated with aluminium oxide nanoshells. Indomethacin was ball-milled to a median particle size of 6 µm. The nanoshells were produced with a proprietary ALD process that is trademarked as PharmaShell® by Nanexa AB. The drug load was determined with HPLC-UV to 82 wt%. The test materials were administered subcutaneously in rats (1, 10, and 100 mg/kg) from which blood samples were collected during 12 weeks. Plasma was generated and analyzed with regards to indomethacin using UPLC-MS/MS. The release rate was dramatically slower for the nanoshell coated indomethacin compared with uncoated indomethacin. Drug was released in vivo during more than 12 weeks for the 10 and 100 mg/kg doses, and during 10 weeks for the 1 mg/kg dose, while uncoated indomethacin was eliminated with a half-life of 15 h, as calculated from the release data by fitting a one phase decay function. The exposure levels were similar as earlier reported for therapeutic indomethacin doses, but significantly sustained in the present study using coated drug particles in rats. In conclusion, this is the first long-term in vivo evaluation of nanoshell depot formulations. The stable plasma concentrations for more than 12 weeks demonstrate that nanoshells can enable long-term depot injections with high drug load.


Assuntos
Cromatografia Líquida de Alta Pressão , Preparações de Ação Retardada/química , Indometacina/química , Nanoconchas/química , Animais , Cromatografia Líquida de Alta Pressão/métodos , Composição de Medicamentos/métodos , Excipientes/química , Meia-Vida , Masculino , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley
15.
AAPS PharmSciTech ; 20(5): 204, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31140011

RESUMO

Deep eutectic solvents (DESs) have recently been getting a great deal of attention in many fields of science and technology. The objective of this study was to peruse the solubility of indomethacin (IMC) as sparingly soluble drug in some tetrabutylammonium bromide (TBAB)-based DESs (TBAB/ethylene glycol and TBAB/glycerol). The shake flask method has been employed in this study at temperature ranges T = (298.15-313.15) K and atmospheric pressure (pP = 86.6 kPa). The results showed that the solubility of IMC in TBAB/ethylene glycol system was obtained approximately 17,000-fold more than its solubility in water. The solubility data were accurately correlated by the famous local composition activity coefficient models including e-NRTL and UNIQUAC. It was also our aim to evaluate Hansen solubility parameters in IMC solubility prediction. These parameters can help to predict the solvent performance during the manufacturing processes and will be useful in guessing solvent behavior in many other fields of effort. The experimental and the Hansen solubility parameters results are very well matched. In addition, the apparent thermodynamic properties of dissolution and mixing were studied in these solutions based on Van't Hoff and Gibbs equations.


Assuntos
Anti-Inflamatórios não Esteroides/química , Indometacina/química , Modelos Químicos , Compostos de Amônio Quaternário/química , Temperatura Ambiente , Água/química , Anti-Inflamatórios não Esteroides/farmacocinética , Previsões , Indometacina/farmacocinética , Compostos de Amônio Quaternário/farmacocinética , Solubilidade , Solventes , Termodinâmica
16.
Pharm Dev Technol ; 24(8): 992-1001, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31107609

RESUMO

Novel microparticles coated with poly-γ-glutamic acid (PGA) were developed to improve the oral absorption of indomethacin (IM), a poorly water-soluble drug. Microparticles containing γ-IM (IMbulk-PGA) or crystal polymorph α-IM (IMpolymorph-PGA) were prepared. Additionally, microparticles were prepared containing α-IM without PGA (IMpolymorph without PGA). IMbulk-PGA and IMpolymorph-PGA exhibited better drug retention properties on mucin disks. Drug release rates from IMpolymorph-PGA and IMpolymorph without PGA were higher than from IM bulk powder, and drug release from IMbulk-PGA was also improved. Drug release from IMbulk-PGA could be improved with the use of Tween 80. In addition, PGA may influence the ionization of IM or affect specific molecular interactions. After the microparticles were administered orally to mice, IMbulk-PGA and IMpolymorph-PGA increased the plasma drug concentration more rapidly compared with IM bulk powder, but IMpolymorph without PGA did not increase the plasma drug concentration. It was considered that IMbulk-PGA and IMpolymorph-PGA rapidly reached the intestinal membrane through the mucus layer and IM was absorbed quickly. Because IMbulk-PGA and IMpolymorph-PGA showed a rapid increase in plasma drug concentration, IMbulk-PGA and IMpolymorph-PGA could be useful preparations to improve the gastrointestinal absorption of IM. Furthermore, IMbulk-PGA may maintain higher plasma drug concentrations than IMpolymorph-PGA.


Assuntos
Indometacina/química , Indometacina/metabolismo , Absorção Intestinal/efeitos dos fármacos , Ácido Poliglutâmico/análogos & derivados , Água/química , Administração Oral , Animais , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ácido Poliglutâmico/química , Solubilidade/efeitos dos fármacos
17.
Eur J Pharm Biopharm ; 139: 132-141, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30910731

RESUMO

The current study proposes an original oral delivery system for the bioavailability enhancement of indomethacin (IND), a BCS class II drug, with the aim to overcome the common limitations of amorphous solid dispersion. In fact, the potential risk of drug re-crystallization is a serious concern for the stability of amorphous systems and represents, despite the great bioavailability, one of the primary causes of their limited clinical applications. IND-loaded microparticles (MPs) were prepared by spray congealing using oral-approved excipients (Gelucire 50/13 and the recently marketed Gelucire 48/16). MPs were characterized regarding particle size, morphology, drug content and IND solid state; moreover, they were tested in vitro for IND solubility and dissolution rate. Solid state characterization indicated that IND was present into the MPs in the amorphous form. The best formulation showed a considerable enhancement in drug dissolution rate and 31-fold higher drug solubility than pure γ-IND. The oral administration of MPs showed 2.5-times increased bioavailability in vivo compared to either pure γ-IND or its physical mixture with unloaded MPs. Notably, the formulation was stable after 18 months with no changes in IND solid state and dissolution performance. This study offers a valid approach to enhance IND oral bioavailability by conversion into the amorphous form by spray congealed MPs, which have great potential for industrial application due to their characteristics of high encapsulation efficiency, no-toxicity, low-cost, prolonged stability and the use of a simple and easily scaled-up manufacturing technology.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Composição de Medicamentos/métodos , Excipientes/química , Indometacina/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Disponibilidade Biológica , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Gorduras/química , Indometacina/administração & dosagem , Indometacina/química , Masculino , Modelos Animais , Óleos/química , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Solubilidade , Difração de Raios X
18.
Chem Commun (Camb) ; 55(30): 4411-4414, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30916078

RESUMO

Conjugation of indomethacin with a self-assembling peptide moiety affords co-assembled supramolecular nanostructures of doxorubicin and peptide derivatives for tunable release of two drugs and synergistic effects against cancer cells, which illustrates a simple and effective approach to utilize co-assembled nanostructures for co-delivery of self-complementary drug pairs.


Assuntos
Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Hidrogéis/química , Indometacina/química , Indometacina/farmacologia , Peptídeos/química , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Humanos
19.
Int J Biol Macromol ; 132: 534-540, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30926501

RESUMO

Polysaccharide nanoparticles with potential to stabilize Pickering emulsions have been recently object of many research. Acetylated cashew gum with different degrees of substitution has been used in this work, in the pursuit of obtaining stable Pickering emulsions. Acetylated cashew gum was characterized by infrared and nuclear resonance spectroscopy. Effects of cashew gum derivative acetyl content, droplet size, ionic strength, zeta potential on emulsion properties were investigated. As a proof of concept, indomethacin was encapsulated in droplets and its release profile determined. Data obtained revealed droplet sizes in the range 269-312 nm, with unimodal size distribution and zeta potential values from -46 Mv to -48 Mv. Encapsulation efficiencies were in the range 26-52%, a steady release profile reached in 3 h, releasing maximal 75% IND.


Assuntos
Anacardium/química , Portadores de Fármacos/química , Indometacina/química , Nanopartículas/química , Gomas Vegetais/química , Acetilação , Liberação Controlada de Fármacos , Emulsões , Tamanho da Partícula
20.
Eur J Pharm Biopharm ; 137: 148-163, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30836178

RESUMO

This work explores the use of UV imaging in solid dispersion systems. Solid dispersions are one of the common strategies used in improving the dissolution of poorly soluble drugs. Three manufacturing techniques (spray drying (SD), freeze drying (FD) and homogenising (HG)) are investigated. Differential Scanning Calorimetry (DSC) and X-Ray Powder Diffraction (XRPD) was used in characterising the solid dispersions. Advanced imaging was implemented to give an insight into how these solid dispersions performed. The DSC and XRPD results showed that all three methods and the various ratios studied produced amorphous solid dispersions. Ultra-Violet (UV) imaging of the pseudo Intrinsic Dissolution Rate (IDR) deduced only two samples to have superior pseudo IDR values to the IDR of the parent drug indomethacin (INDO). The whole dose imaging of the capsule formulation however showed all the samples (SD, FD and HG) to have superior dissolution to that of INDO which was in contrast to the IDR results. The UV images obtained from the determination of the pseudo IDR also showed a phenomenon the authors are reporting for the first time where increased polymer (Soluplus) content produced "web-like" strands that migrated to the top of the quartz cell which may have been responsible for the low pseudo IDR values. The authors also report for the first time using this UV imaging technique, the tip of a capsule coming off for drug to go into solution. The area under the curve suggested the best five samples dissolution wise to be 1:3 SD > 1:1 HG > 1:1 SD > 1:3 FD > 1:3 HG meaning a ratio of INDO to SOL in these dispersion of up to 1:3 being sufficient to produce significant dissolution increases. The developed interfacial (surface) area ratio (Sdr) highlighted how the surface area of the IDR compacts varied between the batches, in particular highlighting larger surface area gains for the FD and HG compacts. A choice of instrumentation/techniques to use in making solid dispersions may well come down to cost or instrument availability for a formulator as all three techniques were successful in improving the dissolution of indomethacin. This work thus highlights the importance of having both complimentary IDR and whole dosage imaging techniques in giving a better understanding of solid dispersion systems.


Assuntos
Química Farmacêutica/métodos , Indometacina/química , Espectrofotometria Ultravioleta/métodos , Tecnologia Farmacêutica/métodos , Varredura Diferencial de Calorimetria/métodos , Dessecação , Liberação Controlada de Fármacos , Liofilização , Polietilenoglicóis/química , Polímeros/química , Polivinil/química , Solubilidade , Propriedades de Superfície , Difração de Raios X/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA