RESUMEN
Lisofylline (LSF) is an anti-inflammatory molecule with high aqueous solubility and rapid metabolic interconversion to its parent drug, pentoxifylline (PTX) resulting in very poor pharmacokinetic (PK) parameters, necessitating high dose and dosing frequency. In the present study, we resolved the physicochemical and pharmacokinetic limitations associated with LSF and designed its oral dosage form as a tablet for effective treatment in type 1 diabetes (T1D). Self-assembling polymeric micelles of LSF (lisofylline-linoleic acid polymeric micelles (LSF-LA PLM)) were optimized for scale-up (6 g batch size) and lyophilized followed by compression into tablets. Powder blend and tablets were evaluated as per USP. LSF-LA PLM tablet so formed was evaluated for in vitro release in simulated biological fluids (with enzymes) and for cell viability in MIN-6 cells. LSF-LA PLM in tablet formulation was further evaluated for intestinal permeability (in situ) along with LSF and LSF-LA self-assembled micelles (SM) as controls in a rat model using single-pass intestinal perfusion (SPIP) study. SPIP studies revealed 1.8-fold higher oral absorption of LSF-LA from LSF-LA PLM as compared to LSF-LA SM and ~5.9-fold higher than LSF (alone) solution. Pharmacokinetic studies of LSF-LA PLM tablet showed greater Cmax than LSF, LSF-LA, and LSF-LA PLM. Designed facile LSF-LA PLM tablet dosage form has potential for an immediate decrease in the postprandial glucose levels in patients of T1D.
Asunto(s)
Diabetes Mellitus Tipo 1/metabolismo , Yeyuno/metabolismo , Ácido Linoleico/farmacocinética , Nanopartículas/metabolismo , Pentoxifilina/análogos & derivados , Perfusión/métodos , Administración Oral , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Formas de Dosificación , Yeyuno/efectos de los fármacos , Ácido Linoleico/administración & dosificación , Ácido Linoleico/síntesis química , Masculino , Ratones , Nanopartículas/administración & dosificación , Nanopartículas/química , Pentoxifilina/administración & dosificación , Pentoxifilina/síntesis química , Pentoxifilina/farmacocinética , Ratas , Ratas Wistar , ComprimidosRESUMEN
Purpose: Methotrexate (MTX) is a first-line drug for rheumatoid arthritis (RA)therapy. However, MTX monotherapy often results in irreversible joint damage due to its slow onset of action and long duration. microRNA-124 (miR-124) has shown direct bone protection activity against RA. A co-delivery system for MTX and microRNA combination may provide therapeutic synergy. Methods: Methotrexate-conjugated polymer hybrid micelles (M-PHMs) were prepared by self-assembly of two functional amphiphilic polymers (MTX-PEI-LA and mPEG-LA) at an optimized weight ratio. Incorporation of microRNA was achieved through electrostatic interactions between microRNA and cationic polymer MTX-PEI-LA. Cellular uptake, endosome escape, biodistribution, and therapeutic efficacy of M-PHMs/miR-124 complexes were investigated and evaluated in RAW264.7 cells and a rat adjuvant-induced arthritis (AIA) model. Results: M-PHMs/miR-124 complexes exhibited folate receptor-mediated uptake in activated RAW264.7 cells. miR-124 was able to escape from the endosome and down-regulate nuclear factor of activated T cells cytoplasmic1 (NFATc1). M-PHMs/miR-124 complexes accumulated in inflamed joints of AIA rats and showed superior therapeutic efficacy through both anti-inflammatory effect and direct bone protective effect. Combination of miR-124 and MTX in these micelles induced disease remission. Conclusions: M-PHMs/miR-124 was highly effective against RA through therapeutic synergy. Additional studies are warranted to further investigate its therapeutic potential and delineate its mechanisms of action.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Metotrexato/uso terapéutico , Micelas , MicroARNs/metabolismo , Polímeros/química , Animales , Artritis Reumatoide/sangre , Muerte Celular/efectos de los fármacos , Citocinas/sangre , Modelos Animales de Enfermedad , Endocitosis/efectos de los fármacos , Endosomas/metabolismo , Receptor 1 de Folato/metabolismo , Hemólisis/efectos de los fármacos , Mediadores de Inflamación/sangre , Articulaciones/patología , Ácido Linoleico/síntesis química , Lipopolisacáridos , Metotrexato/farmacología , Ratones , MicroARNs/genética , Factores de Transcripción NFATC/metabolismo , Polietilenglicoles/síntesis química , Polietileneimina/síntesis química , Espectroscopía de Protones por Resonancia Magnética , Células RAW 264.7 , Ratas , Distribución Tisular/efectos de los fármacosRESUMEN
Totally bio-based thermosetting polymers which are comparable to synthetic polyester thermosets have been prepared from copolymerization of condensed tannin-fatty acid esters with vegetable oils. Oxidative copolymerization of tannin linoleate/acetate mixed esters with linseed oil and tung oil produced polymer films ranging from soft rubbers to rigid thermosets. Tannin incorporation into the formulations was essential for the final product to achieve necessary mechanical strength. Films had ambient modulus values between 0.12 and 1.6 GPa, with glass transition temperatures ranging from 32 to 72 °C and calculated crosslink densities of 1020-57,700 mol m⻳. Film stiffness, T(g) and crosslink density increase with greater tannin linoeate/acetate content due mainly to this tannin component providing rigidity through polyphenolic aromatic rings and unsaturated chains as crosslinking sites.