Ophthalmic Pharmaceutical Compositions and Uses Thereof Formulating a TRPM8 Agonist to Treat Dry Eye

This patent covers stable ophthalmic formulations of WS-12, a potent activator of the cold-sensing TRPM8 ion channel in corneal nerve endings, designed to stimulate natural tear production in patients with dry eye disease.

The Problem

Dry eye affects over 30 million people in the United States alone, yet fewer than 10% receive pharmaceutical treatment. The condition arises when tear production is insufficient or tear film quality is compromised, leading to ocular surface inflammation, discomfort, and in severe cases, corneal damage. Existing treatments include artificial tear drops (which lubricate but do not address the underlying failure of tear production), anti-inflammatory agents such as cyclosporine (which take weeks to work and may cause initial burning), and pilocarpine (a non-selective secretagogue with systemic side effects). There is a significant unmet need for a therapy that directly stimulates the neural circuit responsible for basal tear secretion. The corneal surface is densely innervated with sensory nerve endings including TRPM8-expressing cold-sensitive neurons. TRPM8 is the ion channel activated by menthol and cooling compounds; its stimulation in corneal nerves is known to trigger reflex tearing. However, natural menthol is poorly selective and short-acting. Developing a stable, preservative-free ophthalmic formulation of a more potent and selective TRPM8 agonist that is itself water-insoluble presents a significant pharmaceutical chemistry challenge.

What This Invention Does

Alcon’s invention provides ophthalmic pharmaceutical compositions containing WS-12, chemically (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide, a synthetic TRPM8 agonist substantially more potent than menthol. WS-12 is practically insoluble in water, requiring a solubilizing excipient system to achieve stable aqueous formulation. The patent discloses that polyoxyl 35 castor oil (KOLLIPHOR EL), polyethylene glycol 400, castor oil, and polysorbate 80 (TWEEN 80) satisfactorily solubilize WS-12, while polyvinylpyrrolidone, propylene glycol, and Tyloxapol do not. A representative preferred formulation comprises approximately 0.003% w/v WS-12, approximately 3.0% w/v polyoxyl 35 castor oil as solubilizer, approximately 0.14% w/v hypromellose as viscosity modifier, a sodium phosphate buffer, and sodium chloride as tonicity agent, at a pH of approximately 7, without a preservative. The composition treats or reduces dry eye and its signs and symptoms in a subject by stimulating tear production through the TRPM8 pathway.

Key Features

• Novel mechanism via TRPM8 activation. WS-12 triggers tear secretion by activating cold-sensitive TRPM8 channels in corneal sensory neurons, engaging the endogenous neural pathway for basal tear production rather than simply lubricating the ocular surface or suppressing inflammation.
• Solubilization of a water-insoluble active. Identifying excipients that successfully solubilize WS-12 in an aqueous ophthalmic formulation was a non-obvious challenge. The patent specifies which solubilizers work and which fail, providing a clear differentiation from prior attempts.
• Preservative-free formulation. Preservatives commonly used in eye drops, such as benzalkonium chloride, can damage the ocular surface and worsen dry eye over time. The absence of a preservative in the claimed compositions addresses this concern and improves suitability for chronic, daily use.
• Defined excipient ranges with a worked example. Quantified ranges for each component (WS-12 from 0.0005% to 0.01% w/v; solubilizer from 0.1% to 5% w/v; viscosity modifier from 0.1% to 0.5% w/v; buffer from 0.3% to 1% w/v; tonicity agent from 0.1% to 1.0% w/v) are paired with a specific preferred embodiment, giving the patent strong definiteness alongside broad coverage.
• Stability considerations. The patent addresses the need to maintain WS-12 stability against temperature, humidity, and light exposure, including UV, which is relevant to packaging requirements for marketed ophthalmic products.

Who Is Behind It?

The applicant is Alcon Inc., a Swiss-American multinational and one of the world’s largest eye care companies, with major franchises in surgical devices and pharmaceutical eye care. The sole named inventor is Anjali Joshi. The application is a divisional of AU 2022409839 and claims priority from US Provisional Application 63/290,781 filed 17 December 2021. The Australian patent attorney is K&L Gates in Melbourne.

Why It Matters

Dry eye disease is one of the most common reasons for ophthalmology and optometry visits in Australia, driven by an ageing population, high screen time, and the prevalence of contact lens wear. A drug that stimulates natural tear production via a novel neural mechanism would represent a meaningful therapeutic advance over existing options. Alcon’s development of a stable, preservative-free WS-12 formulation positions the company at the frontier of this approach. If the product reaches the Australian market, it would be relevant to the millions of Australians managing chronic dry eye, and to the optometrists, ophthalmologists, and pharmacies serving them. The patent protects the specific formulation chemistry that makes a pharmacologically active but poorly soluble compound deliverable as a safe and stable eye drop.

Related Concepts

This patent engages two interrelated fields: ophthalmic drug formulation and TRP channel pharmacology. The TRPM8 channel, activated by menthol and cooling compounds, is the primary molecular target, and its stimulation in corneal sensory neurons triggers the reflex tearing pathway – offering a fundamentally different mode of action from lubricating drops or anti-inflammatory therapies.

A persistent challenge in ophthalmic formulation is solubilising hydrophobic actives in aqueous media while avoiding preservatives such as benzalkonium chloride that can exacerbate dry eye with chronic use. Identifying excipients that achieve stable solubilisation of WS-12 is the core pharmaceutical chemistry contribution of this work.

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AU 2026201834 was published in the Australian Official Journal of Patents on 2 April 2026 and is open for public inspection. Patent applications represent inventions that are sought to be protected and do not necessarily reflect commercially available products.