Excipients for Ophthalmic Drug Delivery:
Existing & Emerging Technologies to Tackle the Unique Challenges of Drug Delivery to the Eye
Part 3 of 4: Penetration Enhancers
The eye certainly doesn’t make it easy. Its complex protective systems create hurdles that must be overcome in order to deliver a drug. It starts with the tear film barrier, a thin liquid layer that coats the ocular surface, which is comprised of a mixture of proteins, enzymes, oils, and electrolytes. This is followed by the corneal barriers, which work in concert to prevent passage of both hydrophilic (water soluble) and hydrophobic (water insoluble) drugs. Navigating these defenses requires a delicate balancing act between the physiochemical properties of the drug and the excipients used in the ophthalmic drug formulation.
Callan Pharma Services specializes in maximizing an excipient’s impact on the safety and efficacy of an API. In this 4-part series we’ll review those excipients already used in approved ophthalmic pharmaceuticals, and discuss emerging technologies being developed to tackle unsolved challenges. In this Part 3, we’ll discuss Penetration Enhancers.
Part 3: Penetration Enhancers
Bioavailability is at the forefront of formulation development for any topical ophthalmic drug. A drug is only as effective as its ability to reach its target tissue. Penetration enhancing excipients are incorporated to enhance the permeability of drugs across the cornea and conjunctiva, where they can elicit their desired effect. Incorporation of penetration enhancing excipients is complicated and is often a balancing act between their desired function and ocular toxicity and irritation.
Those of you following along reading this 4-part series will recognize many penetration enhancers from the other categories of excipients discussed (e.g., viscosity and solubility enhancers). Penetration enhancing excipients can be sub-divided by the mechanism by which they diminish the barrier functions of the eye:
- Tight Junction Disruption – Corneal epithelial cells are adhered to each other by tight junctions, which are critical to maintaining the barrier function of the cornea. The structural integrity of these tight junctions is calcium dependent. One strategy for permeation enhancement is to bind Ca+ and thus disrupt these tight junctions. This strategy is most effective for increasing the permeability of water soluble drugs. Although citrate (a buffer component) has weak calcium binding properties, this category is dominated by ethylenediaminetetraacetic acid (EDTA), which is well tolerated in low (<0.1%) concentrations.
- Membrane Fluidization – this mechanism to enhance drug permeation employs excipients which interact with the lipid bilayers of corneal or conjunctival epithelial cells. This can reduce the packing order of the phospholipids, allowing passage of drugs—particularly lipophilic ones. Almost all ophthalmic excipients with a hydrophobic component can interact with lipid bilayers to some extent. Those generally recognized as permeation enhancers can be categorized as follows:
- Surfactants – when these excipients are incorporated into the lipid bilayer, they can reduce membrane cohesion by forming polar defects. Most commonly used are non-ionic surfactants such as the polysorbates (20 and 80), along with the poloxamers (188 and 407).
- Lipids – this broad category all contain a hydrocarbon component which interacts with structurally similar components of ocular cellular membranes. Either through incorporation or replacement, end result is an increased fluidity and permeability to drugs. Examples include the stearic acid esters polyoxyl 15 hydroxystearate (Kolliphor® HS 15), and polyoxyl 40 stearate (Myrj™ 52). Other lipids include lanolin oil, mineral oil, and petrolatum (petroleum jelly).
- PEGs – this group comes with a caveat; PEGs are most effective in a helper role used together with lipids and surfactants. That said, PEGs can increase water retention at the corneal surface, slightly raising hydration and ultimately relaxing lipid bilayers. PEG 300 and 400 are the most commonly used.
- Mucoadhesion – this strategy relies mainly on electrostatic adhesion of the drug formulation on the ocular surface. By prolonging residence time, the sustained contact allows more time for the drug to permeate—chiefly via passive diffusion—through the corneal or conjunctival epithelium. The excipients in this category are polymeric in nature:
- Synthetic Polymers – The two examples in this category are povidone (PVP), and the polyacrylate carbomers (e.g., Carbopol 940).
- Naturally–Derived Polymers – the majority of the polymers in this category are polysaccharide-based and includes the cellulose derivatives carboxymethylcellulose (CMC) and hydroxyethyl cellulose (HEC). Other members are hyaluronate, and gums (e.g., xanthan and guar gum).
Emerging Technologies: Cell-Penetrating Peptides
Cell-penetrating peptides (CPPs) are short, cationic or amphiphilic peptides (5–30 amino acids) that have an intrinsic ability to translocate across cell membrane via endocytic or non-endocytic mechanisms. This ability has given rise to the hope they can facilitate the intracellular transport of therapeutics, such as small molecules, nucleic acids, and even other peptides and proteins. Two of the most studied CPPs are TAT and penetratin, which can interact with the corneal epithelium, disrupting tight junctions, and facilitating the transport of therapeutic agents. CPPs can be conjugated to a drug or included as an excipient in a complex drug delivery platform, most often a lipid-based one. Fluorescent molecules are typically used to showcase this technology—a straightforward molecule to track in a corneal tissue assay. However, researchers at the University of Birmingham have demonstrated the enhanced permeability of the corticosteroid dexamethasone with this technology (see. Thareja, A., et al. Int. J. Pharm. 660 (2024): 124305).
