Nebivolol Polymeric Nanoparticles-Loaded In Situ Gel for Effective Treatment of Glaucoma: Optimization, Physicochemical Characterization, and Pharmacokinetic and Pharmacodynamic Evaluation

• Published in: Nanomaterials (Basel, Switzerland) Vol. 14; no. 16; p. 1347
• Main Authors: Rawat, Pradeep Singh, Ravi, Punna Rao, Khan, Mohammed Shareef, Mahajan, Radhika Rajiv, Szeleszczuk, Łukasz
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14.08.2024; MDPI
• Subjects: Aqueous humour; Bioavailability; Design of experiments; Drug delivery systems; Drug development; Effectiveness; Glaucoma; Homogenization; in situ gel; In vivo methods and tests; Intraocular pressure; Laboratories; Molecular weight; Nanoparticles; nebivolol hydrochloride; Nitric oxide; Optimization; Particle size; Pharmacodynamics; Pharmacokinetics; physical characterization; Polycaprolactone; polycaprolactone nanoparticles; Polymers; Polyvinyl alcohol; Residence time distribution; Rheological properties; Side effects; Vasodilation; United States > US; Mumbai India; India; in situ gel; ocular pharmacokinetics; physical characterization; optimization; glaucoma; nebivolol hydrochloride; polycaprolactone nanoparticles
• ISSN: 2079-4991; 2079-4991
• DOI: 10.3390/nano14161347

Nebivolol hydrochloride (NEB), a 3rd-generation beta-blocker, was recently explored in managing open-angle glaucoma due to its mechanism of action involving nitric oxide release for the vasodilation. To overcome the issue of low ocular bioavailability and the systemic side effects associated with conventional ocular formulation (aqueous suspension), we designed and optimized polycaprolactone polymeric nanoparticles (NEB-PNPs) by applying design of experiments (DoE). The particle size and drug loading of the optimized NEB-PNPs were 270.9 ± 6.3 nm and 28.8 ± 2.4%, respectively. The optimized NEB-PNPs were suspended in a dual-sensitive in situ gel prepared using a mixture of P407 + P188 (as a thermo-sensitive polymer) and κCRG (as an ion-sensitive polymer), reported previously by our group. The NEB-PNPs-loaded in situ gel (NEB-PNPs-ISG) formulation was characterized for its rheological behavior, physical and chemical stability, in vitro drug release, and in vivo efficacy. The NEB-PNPs-loaded in situ gel, in ocular pharmacokinetic studies, achieved higher aqueous humor exposure (AUC = 329.2 ng × h/mL) and for longer duration (mean residence time = 9.7 h) than compared to the aqueous suspension of plain NEB (AUC = 189 ng × h/mL and mean residence time = 6.1 h) reported from our previous work. The pharmacokinetic performance of NEB-PNPs-loaded in situ gel translated into a pharmacodynamic response with 5-fold increase in the overall percent reduction in intraocular pressure by the formulation compared to the aqueous suspension of plain NEB reported from our previous work. Further, the mean response time of NEB-PNPs-loaded in situ gel (12.4 ± 0.6 h) was three times higher than aqueous suspension of plain NEB (4.06 ± 0.3 h).