RESUMEN
The purposes of this project are to enhance the trans-membrane penetration of Δ8-Tetrahydrocannabinol (Δ8-THC) and to study the effect of various lipid based systems in delivering the compound, non-invasively, to anterior and posterior ocular chambers. Solid lipid nanoparticles (SLNs), fast gelling films were manufactured using high pressure homogenization and melt cast techniques, respectively. The formulations were characterized for drug content, entrapment efficiency, particle size and subsequently evaluated in vitro for trans-corneal permeation. In vivo, the drug disposition was tested via topical administration in albino rabbits. The eye globes were enucleated at the end of experiment and tissues were analyzed for drug content. All formulations showed favorable physicochemical characteristics in terms of particle size, entrapment efficiency, and drug content. In vitro, the formulations exhibited a transcorneal flux that depended on the formulation's drug load. An increase in drug load from 0.1 to 0.75% resulted in 12- to16-folds increase in permeation. In vivo, the film was able to deliver THC to all the tissues with high accumulations in cornea and sclera. The SLNs showed a greater ability in delivering THC to all the tissues, at a significantly lower drug load, due to their colloidal size range, which in turn enhanced corneal epithelial membrane penetration. The topical formulations evaluated in the present study were able to successfully deliver Δ8-THC in therapeutically meaningful concentrations (EC50 values for CB1: 6 nM and CB2: 0.4 nM) to all ocular tissues except the vitreous humor, with pronounced tissue penetration achieved using SLNs as a Δ8-THC delivery vehicle.
Asunto(s)
Córnea/efectos de los fármacos , Córnea/metabolismo , Dronabinol/administración & dosificación , Dronabinol/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Administración Oftálmica , Administración Tópica , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/metabolismo , Animales , Composición de Medicamentos , Masculino , Nanopartículas/química , Tamaño de la Partícula , ConejosRESUMEN
Cannabinoids are increasingly being used in the treatment of chemotherapy-induced nausea and vomiting (CINV) because of their action on the cannabinoid receptors, CB1 and CB2. The currently marketed capsule formulations (sesame oil based and crystalline powder) are required to be administered frequently to maintain therapeutic levels, which leads to non-compliance. In the present study, oral controlled release tablet formulations of Δ(9)-tetrahydrocannabinol (THC) were prepared using the lipids Precirol® and Compritol®. Release profiles using THC-lipid matrices and/or with the lipids in the external phase (blend) were evaluated. The effect of directly compressible diluents lactose mixture (Ludipress®), dicalcium phosphate anhydrous (Emcompress®) and microcrystalline cellulose (Avicel® 102) on tablet characteristics and in vitro drug release was also investigated. Further, in vitro THC release in the presence of a lipase inhibitor, Pluronic® F68, was also studied. A 24 h zero-order THC release profile was obtained with a combination of Precirol® and Compritol® in the compression blend. Addition of Pluronic® F68 did not alter THC release in vitro. These optimized tablets were chemically and physically stable for 3 months, the last time point tested, at 25 °C/60% RH. The overall results demonstrate the feasibility of preparing oral THC tablets for once a day administration which can improve CINV management.