RESUMEN
Microemulsion formulation of repaglinide, a BCS class II hypoglycemic agent with limited oral bioavailability, was developed considering its solubility in various oils, surfactants, and cosurfactants. The pseudo-ternary phase diagrams for microemulsion regions were constructed by water titration method at K m 1:1 and characterized for optical birefringence, percentage transmittance, pH, refractive index, globule size, zeta potential, viscosity, drug content, and thermodynamic stability. To enhance the drug permeation and residence time, the optimized microemulsions having mean globule size of 36.15 ± 9.89 nm was gelled with xanthan gum. The developed microemulsion-based gel was characterized for globule size, zeta potential, pH, and drug content. All evaluation parameters upon gelling were found to be satisfactory. Ex vivo permeability study across rat skin demonstrated higher steady-state flux (P < 0.05) for microemulsion of repaglinide in comparison to the repaglinide microemulsion gel. At the end of 24 h, the cumulative drug permeation from microemulsion and microemulsion gel was found to be 229.19 ± 24.34 and 180.84 ± 17.40 µg/cm2, respectively. The microemulsion formulation showed 12.30-fold increase in flux as compared to drug suspension with highest enhancement ratio (E r ) of 12.36. Whereas microemulsion gel exhibited 10.97-fold increase in flux (with highest E r , 11.78) as compared to repaglinide (RPG) suspension. In vivo efficacy study was performed in normal Sprague-Dawley rats by using oral glucose tolerance test. Results of RPG transdermal microemulsion gel demonstrated remarkable advantage over orally administered RPG by reducing the glucose level in controlled manner. Hence, it could be a new, alternative dosage form for effective therapy of type 2 diabetes mellitus.
Asunto(s)
Carbamatos/administración & dosificación , Hipoglucemiantes/administración & dosificación , Piperidinas/administración & dosificación , Administración Cutánea , Animales , Disponibilidad Biológica , Carbamatos/farmacocinética , Emulsiones , Femenino , Geles , Hipoglucemiantes/farmacocinética , Piperidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Piel/metabolismo , Absorción Cutánea , Solubilidad , Tensoactivos/química , ViscosidadRESUMEN
The use of mucoadhesive biopolymers is one of the best approaches to prolong the drug residence inside the cul-de-sac, consequently increasing the bioavailability. Thus, the focus of this work was to develop mucoadhesive microspheres to overcome the limitations of ocular drug delivery. The chitosan-sodium alginate microspheres of azelastine hydrochloride were fabricated using modified ionotropic gelation technique. The particle size, zeta potential, entrapment efficiency and drug release kinetics were evaluated and characterized by SEM, FT-IR, DSC, in vitro mucoadhesion and in vivo study. The microspheres had average particle size in the range of 3.55 to 6.70 µm and zeta potential +24.55 to +49.56 mV. The fabricated microspheres possess maximum drug entrapment of 73.05% with 65% mucin binding efficiency and revealed a controlled release over the 8-h period following a non-Fickian diffusion. SEM showed that microspheres were distinct solid with irregular shape. FT-IR and DSC results concluded the drug entrapment into microspheres. In vivo studies on ocular rat model revealed that azelastine microspheres had better efficacy. Chitosan sodium alginate microspheres prepared were in particle size range suitable for ocular purpose. In vitro release and in vivo efficacy studies revealed that the microspheres were effective in prolonging the drug's presence in cul de sac with improved therapeutic efficacy.
Asunto(s)
Alginatos/química , Antialérgicos/administración & dosificación , Quitosano/química , Conjuntivitis/tratamiento farmacológico , Preparaciones de Acción Retardada/química , Ftalazinas/administración & dosificación , Animales , Antialérgicos/uso terapéutico , Conjuntivitis/patología , Ojo/efectos de los fármacos , Ojo/patología , Femenino , Ácido Glucurónico/química , Ácidos Hexurónicos/química , Microesferas , Ftalazinas/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
In the present study, potential of polymeric microspheres for treatment of allergic conjunctivitis was investigated. Azelastine hydrochloride loaded Eudragit RL100 microspheres were prepared by solvent evaporation technique. The change in drug-polymer ratio on the particle size, zeta potential, entrapment efficiency and in vitro drug release was investigated. As Eudragit concentration ranged from 40 to 80 mg/ml the size range obtained was 4.18-7.36 µm with positive zeta potential. With the increase in drug polymer ratio, the entrapment efficiency was increased with maximum 14.56%. In vitro release studies demonstrated prolonged release of the drug over the period of 6 hr. Scanning electron micrographs showed that microspheres were spherical with distinct solid dense structure. Fourier transform infrared and differential scanning calorimetry studies concluded slight change in peak intensities of drug in microspheres. In vivo studies in rat model indicated that reduction in eosinophil count number was more pronounced in azelastine hydrochloride microspheres than marketed formulation, Azelast®.
Asunto(s)
Antialérgicos/farmacología , Conjuntivitis Alérgica/tratamiento farmacológico , Microesferas , Ftalazinas/farmacología , Ácidos Polimetacrílicos/farmacología , Administración Oftálmica , Animales , Antialérgicos/química , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacología , Femenino , Tamaño de la Partícula , Ftalazinas/química , Ácidos Polimetacrílicos/química , Ratas , Ratas Sprague-DawleyRESUMEN
Micro and nanoparticulate carriers have been in focus in ophthalmic drug delivery with the objective of improving bioavailability, drug targeting and reducing pulse entry of the drug in ocular cul de sac. Polymeric nanoparticles for ocular purpose have potential in reducing the pulse entry and frequency of dosing, thus improving patient compliance. In the present study, mucoadhesive sodium alginate nanoparticles were developed for Brimonidine Tartrate (BT) as a model antiglaucoma drug by controlled ionic gelation technique. These nanoparticles would not only prolong drugs residence time but also reduce pulse entry in cul de sac. Nanoparticles were evaluated for morphology, surface characteristics, drug polymer interactions, particle size, polydispersibility index, zeta potential, entrapment efficiency, in vitro release profile and in vivo efficacy. The effect of various stabilizers on stabilization of blank and drug loaded nanoparticles was investigated. Irregular shape and loss of crystallinity for BT loaded sodium alginate nanoparticles was observed by TEM and SEM images respectively. IR spectra and DSC thermograms revealed the physicochemical interaction was involved during sodium alginate nanoparticle formation and entrapment of BT. The developed nanoparticles have average particle size of 450nm with PI 0.65, the entrapment efficiency ranged from 4-18 % and zeta potential values ranged from -27.5 mV to -24.1 mV. In vitro release profile showed a gradual drug release over the period of 3 hrs. In-vivo experiments showed that it was possible to prolong the drug release over a period of 8 hr, on topical instillation of BT loaded nanoparticles to albino rabbits, hence reducing the dosage frequency.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/química , Alginatos/química , Tartrato de Brimonidina/química , Portadores de Fármacos , Administración Oftálmica , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Animales , Tartrato de Brimonidina/administración & dosificación , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Preparaciones de Acción Retardada , Estabilidad de Medicamentos , Femenino , Ácido Glucurónico/química , Ácidos Hexurónicos/química , Presión Intraocular/efectos de los fármacos , Cinética , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Nanotecnología , Tamaño de la Partícula , Conejos , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Propiedades de SuperficieRESUMEN
Antisense-mediated exon skipping is a promising therapeutic approach for Duchenne muscular dystrophy (DMD) currently tested in clinical trials. The aim is to reframe dystrophin transcripts using antisense oligonucleotides (AONs). These hide an exon from the splicing machinery to induce exon skipping, restoration of the reading frame and generation of internally deleted, but partially functional proteins. It thus relies on the characteristic of the dystrophin protein, which has essential N- and C-terminal domains, whereas the central rod domain is largely redundant. This approach may also be applicable to limb-girdle muscular dystrophy type 2B (LGMD2B), Myoshi myopathy (MM) and distal myopathy with anterior tibial onset (DMAT), which are caused by mutations in the dysferlin-encoding DYSF gene. Dysferlin has a function in repairing muscle membrane damage. Dysferlin contains calcium-dependent C2 lipid binding (C2) domains and an essential transmembrane domain. However, mildly affected patients in whom one or a large number of DYSF exons were missing have been described, suggesting that internally deleted dysferlin proteins can be functional. Thus, exon skipping might also be applicable as a LGMD2B, MM and DMAT therapy. In this study we have analyzed the dysferlin protein domains and DYSF mutations and have described what exons are promising targets with regard to applicability and feasibility. We also show that DYSF exon skipping seems to be as straightforward as DMD exon skipping, as AONs to induce efficient skipping of four DYSF exons were readily identified.