Pradeep Kumar Karla

Glaucoma therapy aims at lowering intra-ocular pressure (IOP). Brinzolamide, a carbonic anhydrase inhibitor, is utilized as a second-line medication for treating ocular hypertension and primary open-angle glaucoma (POAG). The drug lowers the IOP making it a therapeutic agent against glaucoma, and due to its poor water solubility, is commercially available as Azopt^®, a 1% ophthalmic suspension. Adverse effects such as blurred vision, ocular irritation, discomfort, and bitter taste are associated with the use of the marketed brinzolamide formulation. This study aims to test the feasibility of formulating and in vitro testing of brinzolamide-PLGA nanoparticles for improved toxicity profile. The nanoparticles were prepared by the oil-in-water (O/W) emulsion-solvent evaporation method. Particle size and zeta potential were determined by dynamic light scattering (DLS). The morphology of the nanoparticles was determined by scanning electron microscopy (SEM). Encapsulation of the drug was verified by high-performance liquid chromatography (HPLC) and the compatibility of the polymer and drug was verified by Fourier transform infrared (FTIR) spectroscopy. The in vitro drug release profile was assessed employing the dialysis method. Intracellular localization of the nanoparticles was assessed by confocal microscopy utilizing Rhodamine 123-loaded nanoparticles. Cytotoxicity of the formulation was assessed on Statens Seruminstitut Rabbit Cornea (SIRC) and transfected Human Corneal Epithelial (SV40 HCEC) cell lines. The particle size of the nanoparticle formulations ranged from 202.3 ± 2.9 nm to 483.1 ± 27.9 nm for blank nanoparticles, and 129.6 ± 1.5 nm to 350.9 ± 8.5 nm for drug-loaded nanoparticles. The polydispersity of the formulations ranged from 0.071 ± 0.032 to 0.247 ± 0.043 for blank nanoparticles, and 0.089 ± 0.028 to 0.158 ± 0.004 for drug-loaded nanoparticles. Drug loading and encapsulation efficiencies ranged from 7.42–15.84% and 38.93–74.18%, respectively. The in vitro drug release profile for the optimized formulation was biphasic, with a ~54% burst release for the initial 3 h, followed by a cumulative 85% and 99% released at 24 and 65 h, respectively. Uptake study showed nanoparticles(NPs) localization in the cytoplasm and around the nuclei of the cells. Brinzolamide-PLGA nanoparticles were successfully developed, characterized, and tested in vitro. Preliminary data show intracellular localization of the nanoparticles in the cytoplasm of SIRC and SV40 HCEC cells. The formulations appeared to be relatively non-cytotoxic to the cells. The research data from the study provided preliminary data for successful development and promising in vitro absorption efficacy for brinzolamide-loaded PLGA nanoparticle formulation.

Polymers have always played a critical role in the development of novel drug delivery systems by providing the sustained, controlled and targeted release of both hydrophobic and hydrophilic drugs. Among the different polymers, polyamides or poly(amino acid)s exhibit distinct features such as good biocompatibility, slow degradability and flexible physicochemical modification. The degradation rates of poly(amino acid)s are influenced by the hydrophilicity of the amino acids that make up the polymer. Poly(amino acid)s are extensively used in the formulation of chemotherapeutics to achieve selective delivery for an appropriate duration of time in order to lessen the drug-related side effects and increase the anti-tumor efficacy. This review highlights various poly(amino acid) polymers used in drug delivery along with new developments in their utility. A thorough discussion on anticancer agents incorporated into poly(amino acid) micellar systems that are under clinical evaluation is included.

The primary objective of the research study is to investigate Glucose (GLUT) transporter targeting of the drug (Citalopram-Hbr) for increased permeability across the Blood-Brain Barrier (BBB). The current study reports the development, physicochemical characterization, cytotoxicity analysis and in-vitro BBB permeability assessment of the Citalopram-Hbr liposomal formulations. Rat Primary Brain Microvascular Endothelial Cells (RPBECs) were used for cytotoxicity analysis and drug permeability testing. Five N-Acetyl Glucosamine (NAG) coated PEGylated multilamellar liposomal formulations were prepared and tested. Permeability of the liposomal formulations was evaluated in RPBECs monolayer. The particle size of the formulations ranged from 13 to 4259 nm. Entrapment efficiency was 50-75%. Cytotoxicity analysis indicated viability (>90%) for all five formulations (0.3–1.25 mg/ml). Apparent drug permeability (Papp) of the formulations ranged from 5.01 × 10⁴ to 15 × 10⁴ cm/min. The study demonstrated successful preparation of NAG-coated PEGylated multilamellar liposomal formulations with high drug entrapment efficiency. Cytotoxicity data indicated that the formulations were well tolerated by the cells up to a concentration of 1.25 mg/ml. Transport study data demonstrated that RPBMECs monolayers can be employed as a robust screening tool for future drug transport studies targeting GLUT transporter on the BBB. The drug permeability values provide a promising preliminarily proof that NAG-coated liposomal formulations can be an effective tool for BBB-GLUT transporter targeting.

Ocular drug delivery is challenging due to the presence of anatomical and physiological barriers. These barriers can affect drug entry into the eye following multiple routes of administration (e.g., topical, systemic, and injectable). Topical administration in the form of eye drops is preferred for treating anterior segment diseases, as it is convenient and provides local delivery of drugs. Major concerns with topical delivery include poor drug absorption and low bioavailability. To improve the bioavailability of topically administered drugs, novel drug delivery systems are being investigated. Nanocarrier delivery systems demonstrate enhanced drug permeation and prolonged drug release. This review provides an overview of ocular barriers to anterior segment delivery, along with ways to overcome these barriers using nanocarrier systems. The disposition of nanocarriers following topical administration, their safety, toxicity and clinical trials involving nanocarrier systems are also discussed.

Nanoformulations (NF) are widely explored as potential alternatives for traditional ophthalmic formulation approaches. The effective treatment of ocular diseases using conventional eye drops is often hampered by factors such as: physiological barriers, rapid elimination, protein binding, and enzymatic drug degradation. Combined, these factors are known to contribute to reduced ocular residence time and poor bioavailability. Recent research studies demonstrated that NF can significantly enhance the therapeutic efficacy and bioavailability of ocular drugs, compared to the established ophthalmic drug delivery strategies. The research studies resulted in a number of patent inventions, reporting a significant increase in therapeutic efficacy for various chronic ocular disease states of both the anterior and posterior ocular segments. This article reviews these patent disclosures in detail and emphasizes the therapeutic advantages conferred by the following nanoformulation approaches: Calcium Phosphate (CaP) nanoparticles, Liposomes, Nanoemulsions, Nanomicelles, and Hydrogels. The nanoformulation approaches were shown to enhance the ocular bioavailability by reducing the drugprotein binding, increasing the corneal resident time, enhancing the drug permeability and providing a sustained drug release. Further, the article discusses United States Food and Drug Administration (USFDA) approved ocular drugs employing nanotechnology and future developments. It should be noted that, despite the potential therapeutic promise demonstrated by nanotechnology for ocular drug delivery, the bench to bed transition from patent inventions to marketed drug products has been insignificant. Majority of the discussed technologies are still in development and testing phase for commercial viability. Further, studies are in progress to assess ocular tolerance and nanotoxicity for prolonged use of NF.