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Pharmaceutical Services

Part 1: Viscosity Enhancers

Excipients for Ophthalmic Drug Delivery:

Existing & Emerging Technologies to Tackle the Unique Challenges of Drug Delivery to the Eye

Part 1 of 4: Viscosity Enhancers

Excipients are the often-overlooked inactive ingredients included in a pharmaceutical formulation along with the active drug (known as the active pharmaceutical ingredient, API). APIs may attract the spotlight, but excipients are vital to a successful drug formulation. This is especially true for ophthalmic drug formulations, where the eye’s natural defensive barriers increase the difficulty in delivering a drug to the target.

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 1, we’ll discuss Viscosity Enhancers.

Part 1: Viscosity Enhancers

The tear film barrier is the first line of defense for the eyes. Only 20% of a topically delivered ophthalmic drug physically remains due to precorneal loss. Tears are comprised of a complex mixture of proteins, enzymes, oils, and electrolytes which interact and wash away the drug. Bioavailability is even lower, with estimated values of 1–5% resulting from the combination of poor permeation of the corneal epithelium and rapid drainage from the surface of the eye

One strategy to overcome the bioavailability challenges of topical ophthalmic drug delivery is to increase the viscosity (thickness) of the formulation. Increasing the viscosity extends precorneal residence time, and potential the bioavailability. This is achieved via two main strategies: inherent viscosity and triggered viscosity:

  1. Intrinsic Viscosity – for this strategy, excipients are added to increase the viscosity of the formulation in its dosage form. For liquid eye drops, excipients added include:
    1. Polysaccharides: cellulose derivatives, including carboxymethylcellulose (CMC), hydroxyethyl cellulose (HEC) are commonly used along with hyaluronate, and gums such as xanthan and guar gum.
    2. Synthetic Polymers: this category of excipients are primary added for other benefits but also increase viscosity. Examples include povidone (PVP), polyvinyl alcohol (PVA), and carbomers (e.g., Carbopol 940).
    3. Hydrocarbons: these are the predominant excipient in ointment-type ophthalmic drug formulations. Mineral oil and petrolatum (petroleum jelly) are the quintessential members of this category.
  2. Triggered Viscosity – the second approach is to administer a low viscosity liquid to the eye, after which an environmental cue initiates (triggers) a change the viscosity. This in situ process can be:
    1. pH Triggered – these formulations undergo gelation at pH values above the pKa values of their weakly acidic groups of the excipient used—carboxylic acids for example. Carbopol is a polyacrylic acid-based excipient that forms a gel at pH ~7.
    2. Temperature Triggered – these remain as free-flowing, low viscosity liquids at ambient temperatures (~25°C), but transition to hydrogels at elevated, physiological temperatures (~37°C). Examples of these excipients include the poloxamers (188 and 407), polyethylene-poly(lactic-co-glycolic acid) block polymers (e.g., PLGA-PEG-PLGA), and polysaccharides such as xyloglucan.

Ion Triggered – these formulations undergo solution-gelation transition upon changes in ionic concentration. The cations (e.g., Na+ and Ca2+) in tears serve as the initiator for the transition—typically a cross-linking or aggregation event. Examples include the polysaccharides pectin and alginate, as well as gellan gum.

Emerging Technologies: Thiolated Chitosan Nanoparticle Viscosity Enhancers

A growing area of research is the use of thiolated chitosan nanoparticles as viscosity enhancers in ophthalmic drug formulations. These technologies chemically modify chitosan with thiol groups. Upon administration to the ocular surface, the mildly oxidative environment of the tear film triggers the formation of disulfide bonds that cross-link the chitosan nanoparticles. The cross-linking significantly increases viscosity and forms a bioadhesive gel on the ocular surface. Although clinical success has not been achieved, academics have found applications, including the delivery of the antibiotic tobramycin (see. Javed, S., et al. Heliyon 9(9), 2023).