The Challenge: Glaucoma and the Limits of Conventional Brinzolamide Eye Drops

Glaucoma is one of the leading causes of blindness among the elderly. It is a chronic disease that requires lifelong management, which places a heavy burden on patient adherence over the course of treatment. Brinzolamide, a carbonic anhydrase inhibitor used to lower intraocular pressure, is available commercially as a 1% ophthalmic suspension marketed as Azopt and is indicated as a treatment for glaucoma. It can be used as a first-line medication as well as an adjunct to other therapies for the management of chronic glaucoma.

Conventional brinzolamide suspension dosing carries two practical limitations. First, the commercial suspension requires thrice-daily dosing. Suspensions must dissolve before the drug can absorb, and in the ocular space rapid fluid turnover and loss through the naso-lacrimal duct mean that only about 5% of the applied dose is absorbed. Second, the frequency of dosing leads to missed doses through patient non-compliance, which undermines the steady intraocular pressure control that chronic glaucoma management depends on.

A clinical need therefore exists for a delivery system that offers a more sustained release profile while still delivering bioavailable drug to the target tissue. A formulation that holds brinzolamide on the ocular surface, releases it gradually, and reduces dosing frequency would address both the bioavailability and the adherence limitations of conventional suspension eye drops.

The OcuSurf™ Platform Applied to Brinzolamide

To address the bioavailability and sustained delivery limitations of conventional ophthalmic suspensions, Integral BioSystems developed OcuSurf™, a lipid-based, nanostructured delivery system designed for the ocular surface. OcuSurf™ belongs to the same family as the company’s lipid-based delivery technologies, using ordered nanolipid structures to carry a poorly water-soluble drug in a stable, deliverable ophthalmic form.

OcuSurf™ is a biphasic nano-dispersion built from both hydrophobic and hydrophilic GRAS excipients. The active compound is dissolved in the phase that forms the dispersed nanoscale cores of the system. Those cores are suspended in an aqueous, hydrophilic continuous phase that keeps them dispersed and stable. Within the cores, the lipids organize into liquid-crystalline ordered structures, and that ordered architecture is one of the mechanisms behind the sustained release of the drug. An amphiphilic self-assembled layer interacts with the lipid bilayer of corneal cells, and membrane-interactive permeation enhancers support transport across the cornea.

In this research, OcuSurf™ was used to develop OcuSurf-Brinzolamide, a sustained release nanocore formulation of brinzolamide intended as an alternative to the conventional suspension format. Key platform attributes of the OcuSurf™ system relevant to a sustained release brinzolamide product include:

• Liquid-crystalline, lipid-based ordered structures that entrap the drug and enable sustained release
• A biphasic design that dissolves a hydrophobic compound in stable nanoscale cores within an aqueous continuous phase
• High bioavailability enabled by the presence of dissolved drug in the nanostructure cores
• High permeability enabled by membrane-interactive permeation enhancers
• A formulation that becomes fluid at physiological temperature, releasing drug gradually from the nano-core matrix
• Construction from GRAS excipients, supporting tolerability on the ocular surface, with a scaleable platform suitable for multiple small molecule drugs

Research Design and Methods

The research, presented at the 2018 ARVO Annual Meeting (Poster 5690 – A0409, Session 516), characterized OcuSurf-Brinzolamide across physicochemical properties, nanostructure imaging, in vitro release, and ex vivo corneal permeability, with the commercial Azopt product used as the reference comparator.

OcuSurf-Brinzolamide was prepared as a biphasic nano-dispersion using hydrophobic and hydrophilic GRAS excipients, with the API dissolved in the dispersed core phase. Particle size distribution was measured using a Laser Diffraction Particle Sizer at 25 degrees Celsius. Nanostructure was examined under crossed polarizers on an Olympus BX51P Polarizing Light Microscope, with hot-stage imaging conducted across a temperature range at 5 degrees per minute and images captured every 5 minutes (Triclinic Labs). In vitro release was conducted at 37 degrees Celsius and pH 7.4 using a Spectra/Por Float-A-Lyzer G2 Dialysis Device (50 kDa), placed in a 50 mL tube containing 40 grams of phosphate buffer at pH 7.4, assembled on a Robbins Scientific Model 400 rotating incubator, with 1 mL time-point samples analyzed by HPLC. Ex vivo corneal permeability was assessed using six fresh bovine calf corneas mounted on Franz diffusion cells at 37 degrees Celsius, with donor chambers containing either OcuSurf-Brinzolamide (n=3) or Azopt and the receptor chamber filled with 5 mL of phosphate buffer at pH 7.4, with drug and drug content in the cornea measured by LC/MS/MS (TSQ Quantum Ultra). Differential scanning calorimetry was performed on the drug-containing phase using hermetically sealed pans with a DSC25 (TA Instruments), heating at 5 degrees Celsius per minute to 100 degrees Celsius.

Key Findings from the Research

The following results are relevant for teams evaluating ophthalmic formulation development strategies for sustained release small-molecule glaucoma products:

Nano-Sized Particles with Physical Stability over 30 Days

OcuSurf-Brinzolamide was characterized with a mean particle size of 190 to 200 nm. Particle size distribution measured at T=0, T=7 days, and T=30 days showed minimal change across the study period, with D10 values of approximately 0.086 to 0.089 microns, D50 values of approximately 0.138 to 0.142 microns, and D90 values of approximately 0.209 to 0.215 microns. This consistency indicates physical stability of the nano-dispersion over time, and the nanoscale size supports physical transport through the pores of the ocular mucosa, as illustrated by cryo-SEM imaging of the ocular mucosa included in the research.

Liquid-Crystalline Structure Triggers Release at Physiological Temperature

Hot-stage polarized light microscopy showed that the drug-containing phase maintained a liquid-crystalline ordered structure at lower temperatures and transitioned toward an isotropic, disordered fluid state as temperature increased toward physiological levels. Differential scanning calorimetry data confirmed that drug release is triggered at approximately 37 degrees Celsius. This temperature-responsive phase transition is the mechanism behind the sustained release behavior: the formulation remains structured during storage and becomes a drug-releasing fluid upon contact with the ocular surface.

Brinzolamide Encapsulated Intact into the Nanocores

Chromatographic analysis confirmed that brinzolamide was encapsulated intact within the OcuSurf nanocores. The comparison of the drug-loaded formulation against diluent and placebo controls showed a distinct API peak attributable to brinzolamide, indicating that the encapsulation process carried the drug into the nanostructure cores without degrading it. This supports the feasibility of delivering functional brinzolamide from the system.

Sustained, Near-Linear Brinzolamide Release Relative to Azopt

In vitro release studies at 37 degrees Celsius and pH 7.4 demonstrated that brinzolamide encapsulated in OcuSurf was released in a sustained manner, with near-linear rates of release from the OcuSurf matrix measured across timepoints out to approximately 24 hours. The cumulative release of OcuSurf-Brinzolamide was tracked alongside the commercial Azopt comparator. The sustained, gradual release profile supports the goal of maintaining therapeutic drug levels on the ocular surface over a longer interval than conventional suspension dosing, which is the central design objective for reducing dosing frequency in chronic glaucoma therapy.

Steady Corneal Permeation in the OcuSurf-Brinzolamide Group

In the ex vivo bovine cornea model, the OcuSurf-Brinzolamide group demonstrated a constant rate of brinzolamide permeation through the cornea across the 1 to 5 hour measurement window, measured against the Azopt comparator. A steady, sustained permeation rate is consistent with the gradual release behavior of the liquid-crystalline nano-core matrix and indicates that the formulation can carry brinzolamide across the corneal barrier in a controlled manner rather than as a single early burst.

What This Means for Ophthalmic Development Teams

For R&D and formulation teams working on glaucoma therapeutics or sustained release ophthalmic small molecules, this research highlights several practical considerations:

• A liquid-crystalline nanocore platform can reformulate an established small molecule such as brinzolamide into a sustained release ophthalmic product, addressing the low bioavailability and high dosing frequency of conventional suspensions.
• The temperature-responsive phase transition at 37 degrees Celsius enables sustained release from the nano-core matrix upon contact with the ocular surface, supporting a longer dosing interval.
• The drug was encapsulated intact, and the formulation showed near-linear release and a steady corneal permeation rate relative to the commercial comparator, all consistent with a controlled-release design objective.
• Nano-sized particles in the 190 to 200 nm range support physical transport through the pores of the ocular mucosa, and physical stability over 30 days is an encouraging early signal for shelf life and product development feasibility.
• The same platform approach can be applied to other hydrophobic ocular small molecules where sustained release and improved bioavailability would reduce dosing burden.

Integral BioSystems’ expertise in drug development services for ophthalmic compounds, combined with lipid-based nanostructured delivery platforms, supports programs working with sustained release small molecules from early feasibility through process engineering.

Read the Full Research

This blog post summarizes key findings from the ARVO 2018 poster by Barman K, Li H, Chen Y, Li Y, Ward, and Barman SP (Poster 5690 – A0409). To review the complete research, including detailed materials and methods, characterization data, particle size results, DSC data, encapsulation chromatograms, corneal permeability profiles, and in vitro release curves, download the full poster (PDF).

Explore all Integral BioSystems research on the publications page.

Discuss Your Ophthalmic Formulation Program

Whether you are evaluating nanocore delivery for a sustained release glaucoma product, reformulating an established small molecule for improved ocular bioavailability, or considering a liquid-crystalline platform for your active, Integral BioSystems can support your program from feasibility through process engineering. Request a formulation consult to discuss your molecule and delivery objectives.