RESUMO
Glaucoma is a degenerative optic neuropathy characterized by increased intraocular pressure that if untreated can result in blindness. Ophthalmological drug therapy is a challenge of great clinical importance due to the diversity of ocular biological barriers which commonly causes limited or no effectiveness for drugs delivered through the eye. In this work, we proposed the development of nanosized cubic liquid crystals (cubosomes) as a new drug carrier system for latanoprost, an anti-glaucoma drug. Latanoprost-loaded phytantriol cubosomes (CubLnp) were prepared using a top-down method. Latanoprost concentration in the formulations ranged from 0.00125% to 0.02% w/v. All cubosomes displayed an average size around 200 nm, a low polydispersity index of 0.1 and zeta potential values around -25 mV, with an encapsulation efficiency of about 90%. Structural studies revealed that cubosomes displayed a double-diamond surface, Pn3m cubic-phase structure, and was not affected by drug loading. Calorimetric studies revealed a fast and exothermic interaction between latanoprost and cubosomes. According to in vitro essays, latanoprost release from cubosomes was slow in time, evidencing a sustained release profile. Based on this behavior, the in vivo hypotensive intraocular effect was evaluated by means of the subconjunctival administration of CubLnp in normotensive rabbits. We obtained promising results in comparison with a marketed latanoprost formulation (0.005% w/v).
Assuntos
Glaucoma , Animais , Portadores de Fármacos/uso terapêutico , Álcoois Graxos , Glaucoma/tratamento farmacológico , Latanoprosta/uso terapêutico , CoelhosRESUMO
HYPOTHESIS: Cellulose nanocrystals (CNCs) undergo precipitation in the presence of high concentrations of cationic surfactants in aqueous solutions. To avoid such behavior and/or to promote redispersion of CNC/surfactant mixtures, the CNC surface was grafted with poly di(ethylene oxide) methyl ether methacrylate, P(MEO2MA). EXPERIMENTS: CNC-g-P(MEO2MA) was characterized using the following techniques 13C solid-state nuclear magnetic resonance (13C SSNMR), Fourier-transform infrared spectroscopy - attenuated total reflection spectroscopy (FTIR-ATR) and thermal gravimetric analysis (TGA). Isothermal titration calorimetry (ITC), electrophoretic mobility, light scattering and high sensitivity differential scanning calorimetry (HSDSC) were used to study the interaction between CNC-g-P(MEO2MA) and ionic surfactants, dodecyltrimethylammonium bromide (C12TAB, cationic) and sodium dodecylsulfate (SDS, anionic) at temperatures below and above the LCST. FINDINGS: CNC-g-P(MEO2MA) underwent phase separation above its lower critical solution temperature (LCSTâ¯â¼â¯25⯰C) and precipitated from solution as seen by HSDSC and transmittance experiments. When C12TAB was added to CNC-g-P(MEO2MA) it induced the precipitation that prevented the redispersion due to strong electrostatic interactions with the negative charges on the CNC surface. With increasing concentrations of SDS, the polymer phase transition temperature was increased, which can be used to redisperse the CNC complexes. By removing SDS from the mixture via dialysis, the CNC-g-P(MEO2MA) underwent subsequent phase transition.
Assuntos
Celulose/química , Metacrilatos/química , Éteres Metílicos/química , Nanopartículas/química , Polietilenoglicóis/química , Temperatura , Estrutura Molecular , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
Phytantriol cubosomes loaded with two palmitoyl peptides (Palpepcubes), namely GHKcube and GQPRcube, were prepared using an ultrasonication protocol. The Palpepcubes dimensions were characterized by dynamic light scattering (DLS) and cryo-transmission electron microscopy (cryo-TEM). Small-angle X-ray scattering (SAXS) analyses revealed that the bicontinuous cubic structure remained even at palmitoyl peptide contents as high as 5wt.%, with an increase in the cell parameter from approximately 6.5 to 7.2nm. Isothermal titration calorimetry (ITC) was used to elucidate the interactions between the blank cubosomes and the palmitoyl peptides, revealing an exothermic process of interaction. Moreover, the in vitro release of the palmitoyl peptides from the Palpepcubes was studied using a dialysis method coupled with liquid chromatography-mass spectrometry (LC/MS) technique, in which a sustained release of up to a few days was observed. Finally, the stability of the aqueous solutions of the palmitoyl peptides and the Palpepcubes kept at room temperature and at low temperature (4°C) was studied by LC/MS method, indicating that incorporation into cubosomes increases the peptide stability significantly.
Assuntos
Liberação Controlada de Fármacos , Álcoois Graxos/metabolismo , Lipopeptídeos/metabolismo , Nanopartículas/metabolismo , 2-Hidroxipropil-beta-Ciclodextrina/química , 2-Hidroxipropil-beta-Ciclodextrina/metabolismo , Interações Medicamentosas , Álcoois Graxos/química , Lipopeptídeos/química , Minoxidil/química , Minoxidil/metabolismo , Nanopartículas/química , Espalhamento a Baixo Ângulo , Difração de Raios X/métodosRESUMO
The formation of significant proportions of liposomes during the preparation of dispersed cubic phase particles presents a problem in trying to understanding cubosome behavior with a view to use in applications such as drug delivery. In this study, the variables impacting on liposome formation during cubosome production were interrogated. Bottom-up (BU) and top-down (TD) approaches were employed to prepare submicron sized liquid crystalline dispersions (cubosomes) of phytantriol in water with varying amounts of Pluronic(®)F127 (F127) as a stabilizer. In the BU approach, ethanol was used as a hydrotrope and was later removed using a rotary evaporator, whereas in the TD approach the bulk liquid gel was dispersed using ultrasonication. We aimed at finding the optimum ratio of phytantriol-to-F127 resulting in stable, liposome-free dispersions, whether this depends on the preparation method and the resulting morphology of the particles. The average particle size and zeta potential of the samples were measured using dynamic light scattering (DLS). Cryogenic transmission electron microscopy (Cryo-TEM) images showed a substantial number of liposomes in addition to cubosomes in the dispersion containing 4-1 (w/w) phytantriol-to-F127 prepared by the BU approach compared to very low liposome content with the TD approach. The effects of the amount of F127 in both approaches, amount of ethanol on the BU method and temperature on the TD method were investigated using small-angle X-ray scattering (SAXS). The cubosomes displayed cubic double-diamond (Pn3m) internal structure with a lattice parameter of approximately 6nm. In summary using the TD approach, with 4:1 phytantriol:F127 provided stable cubosome dispersion with minimal liposome co-existence.