The Challenge: Treating Meibomian Gland Dysfunction in Dry Eye Disease
Dry eye disease is a multi-parametric disorder of the tear fluid and ocular surface that produces discomfort and tear film instability. Its pathogenesis has been linked to dysfunction of both the meibomian glands, which synthesize the lipid layer, and the lacrimal gland, which produces the aqueous layer. The tear film depends on its lipid, aqueous, and mucin layers working together to keep the ocular surface in compositional balance, so dysfunction in either gland disrupts that balance.
Inflammation plays a central role. In dry eye, a self-reinforcing cycle of inflammation can develop on the ocular surface, contributing to ocular surface damage. Inflammatory cytokines, including interleukin IL-6, IL-1, and TNF-alpha, are elevated in the tear fluid of dry eye patients and upregulated in the corneal epithelium and conjunctiva. An effective therapy needs to address both the lipid deficiency driven by meibomian gland dysfunction and the underlying inflammatory component.
There is a further formulation barrier. A drug capable of normalizing meibomian lipid production and calming inflammation must also reach its target. Many candidate compounds are hydrophobic small molecules with low water solubility, which makes them difficult to formulate as a stable, well-tolerated eye drop and difficult to deliver in therapeutic concentrations across the ocular surface.
A Nanolipid Approach: The OcuSurf Delivery System
To address the delivery of hydrophobic compounds to the ocular surface, Integral BioSystems developed OcuSurf, a lipid-based, nanostructured delivery system. 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 eye drop 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, viscous 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.
Key functional attributes of the OcuSurf system 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
- Membrane-interactive permeation enhancers that support effective transport across the cornea
- A formulation that becomes fluid at physiological temperature, releasing drug gradually from the nano-core matrix
- Construction entirely from GRAS excipients, supporting tolerability on the ocular surface
In the research described here, OcuSurf was used to formulate OS300, a potent PPAR-gamma agonist. PPAR-gamma is a ligand-activated nuclear receptor with established anti-inflammatory activity, and OS300 has been shown to downregulate inflammatory cytokines involved in dry eye and to target the meibomian gland to help normalize lipid production. The eye drop dose form was designed to contain between 0.05 and 0.1 percent OS300 encapsulated in the OcuSurf system.
Research Design and Methods
The research presented at the 2019 ARVO Annual Meeting (Poster B0421) characterized the OcuSurf formulation of OS300 across physicochemical properties, nanostructure imaging, in vitro release, and ex vivo corneal permeability.
OS300 was prepared as a biphasic nano-dispersion using hydrophobic and hydrophilic GRAS excipients, with the drug dissolved in the dispersed core phase. Particle size distribution was measured by laser diffraction at 25 degrees Celsius. The liquid-crystalline ordered structure was examined under crossed polarizers on an Olympus BX51P polarizing light microscope, including hot-stage imaging across a temperature range to observe the transition to a fluid state. In vitro release was conducted at 37 degrees Celsius and pH 7.4 using a Float-A-Lyzer dialysis device suspended in phosphate buffer on a rotating incubator, with timed 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 drug permeation and corneal drug content measured by LC/MS/MS.
Key Findings from the Research
The following results are relevant for teams evaluating ophthalmic formulation development strategies for hydrophobic compounds and dry eye therapeutics:
Physicochemical Characterization
The OS300 eye drop was characterized at an API concentration of 0.05 percent weight by weight, with an osmolality of 290 to 300 mOsm per kilogram, a pH of 7.4, and a viscosity of approximately 200 centipoise. Particle size distribution placed the D10 at roughly 0.050 to 0.090 microns, the D50 at 0.100 to 0.120 microns, and the D90 at 0.150 to 0.180 microns. These values are consistent with a physically stable, nanosized dispersion suitable for ocular surface administration.
Intact Encapsulation in the Nanocores
Analysis confirmed that OS300 was encapsulated intact within the OcuSurf nanocores. The drug was carried in the dispersed lipid core phase rather than being degraded or destabilized by the formulation process, supporting the feasibility of delivering a functional hydrophobic compound from the system.
Stable Liquid-Crystalline Structure
Particle size distribution measured at day zero, day seven, and day twenty-two showed minimal change across the study period, indicating physical stability of the nano-dispersion over time. Hot-stage polarized light microscopy showed the liquid-crystalline structure becoming fluid as temperature increased toward physiological levels, the transition that underlies gradual drug release from the nano-core matrix.
Effective Corneal Permeation
In the ex vivo bovine cornea model, OS300 permeated corneal membranes effectively, with cumulative drug permeation increasing over the 1 to 24 hour measurement window. This indicates that the OcuSurf system, supported by membrane-interactive permeation enhancers, can carry a hydrophobic compound across the corneal barrier.
Sustained Release over a Full Day
In vitro release studies at 37 degrees Celsius and pH 7.4 demonstrated that the OS300 dry eye product released drug in a sustained manner over the course of a day. Gradual release from the liquid-crystalline nano-core matrix supports the goal of maintaining therapeutic drug levels on the ocular surface without the frequent dosing that conventional eye drops require.
What This Means for Ophthalmic Development Teams
For R&D and formulation teams working on dry eye therapeutics or hydrophobic ophthalmic compounds, this research highlights several practical considerations:
- A lipid-based, liquid-crystalline nanostructure can dissolve and stabilize a poorly water-soluble drug in an eye drop form, addressing one of the central formulation barriers for hydrophobic ophthalmic compounds.
- Sustained release from the nano-core matrix supports therapeutic drug levels over a full day, reducing reliance on frequent dosing.
- Membrane-interactive permeation enhancers can improve transport of a hydrophobic compound across the cornea, as shown in the ex vivo permeability data.
- Physical stability of the nano-dispersion over several weeks is an encouraging early signal for shelf life and product development feasibility.
- A formulation built entirely from GRAS excipients supports ocular surface tolerability, an important consideration for a chronic-use dry eye product.
Integral BioSystems’ expertise in drug development services for ophthalmic compounds, combined with lipid-based nanostructured delivery platforms, supports programs working with hydrophobic actives from early feasibility through process engineering.
Read the Full Research
This blog post summarizes key findings from the ARVO 2019 poster by Barman, Amere, Ward, and Barman (Poster B0421). To review the complete research, including detailed materials and methods, characterization data, particle size results, corneal permeability data, and in vitro release profiles, download the full poster (PDF).
Explore all Integral BioSystems research on the publications page.
Discuss Your Ophthalmic Formulation Program
Whether you are evaluating nanolipid delivery for a hydrophobic ophthalmic compound, exploring sustained release strategies for a dry eye therapeutic, 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.