Abstract
The purpose of this study was to design, for the first time, a co-loaded liposomal formulation (CLL) for treatment of glaucoma including timolol maleate (TM) in the lipid bilayer and acetazolamide (Acz)-(2-hydroxy)propyl β-cyclodextrin (HPβCD) complexes (AczHP) solubilized in the aqueous core of liposomes. Formulations with TM (TM-L) and AczHP (AczHP-L), separately, were also prepared and characterized. A preliminary study comprising the Acz/HPβCD complexes and their interaction with cholesterol (a component of the lipid bilayer) was realized. Then, a screening study on formulation factors affecting the quality of the product was carried out following the design of the experiment methodology. In addition, in vitro release and permeation studies and in vivo lowering intraocular pressure (IOP) studies were performed. The results of the inclusion complexation behavior, characterization, and binding ability of Acz with HPβCD showed that HPβCD could enhance the water solubility of Acz despite the weak binding ability of the complex. Ch disturbed the stability and solubility parameters of Acz due to the fact of its competence by CD; thus, Chems (steroid derivative) was selected for further liposome formulation studies. The optimization of the lipid bilayer composition (DDAB, 0.0173 mmol and no double loading) and the extrusion as methods to reduce vesicle size were crucial for improving the physico-chemical properties and encapsulation efficiency of both drugs. In vitro release and permeation studies demonstrated that the CLL formulation showed improvement in in vitro drug release and permeation compared to the liposomal formulations with a single drug (TM-L and AczHP-L) and the standard solutions (TM-S and AczHP-S). CLL showed high efficacy in reducing and prolonging IOP, suggesting that the synergistic effect of TM and Acz on aqueous humor retention and the presence of this cyclodextrin and liposomes as permeation enhancers are responsible for the success of this strategy of co-loading for glaucoma therapy.
Highlights
IntroductionProgressive, and irreversible optic neuropathy characterized by the progressive loss of retinal ganglion cells
Introduction conditions of the Creative CommonsGlaucoma is a chronic, progressive, and irreversible optic neuropathy characterized by the progressive loss of retinal ganglion cells
Based on previous results with liposomes and in literature related to instability when a complexing agent was incorporated into the formulation, we analyzed the influence that the inclusion complex Acz–HPβCD complexes (AczHP) may have had on some components of the liposomal formulation such as Ch
Summary
Progressive, and irreversible optic neuropathy characterized by the progressive loss of retinal ganglion cells. There is a decrease in the number of axons derived from these cells with the consequent atrophy of the optic nerve [1]. Increased intraocular pressure (IOP) is the major clinically modifiable risk factor for glaucoma progression (vision loss) caused by the imbalance of aqueous humor production and outflow. Topical administration continues to be the most common therapeutic strategy for reducing IOP. The pharmacological treatment includes molecules, such as beta-blockers, alpha-2 adrenergic agonists, carbonic anhydrase inhibitors, muscarinic agonists, prostaglandins, nitric oxide donating agents [2], neuroprotective agents [3], and rho-kinase inhibitors [4]
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