Preclinical Evaluation of a Pilocarpine-(R)-Lipoic Acid Eye Drop for Presbyopia

Abstract

Purpose: Presbyopia is a progressive, age-related loss of near vision. Although current therapies offer symptomatic relief, they fail to target the underlying pathology. These studies investigated a novel dual-mechanism eye drop, CLX-162 (pilocarpine lipoate salt), focusing on three key characteristics: (1) tolerability, (2) pharmacokinetics and ocular tissue penetration, and (3) chemical stability within a dual-chamber delivery system.

Methods: Tolerability and pharmacokinetic studies involved administering CLX-162 and lipoic acid choline ester (LACE) ophthalmic formulations to New Zealand White rabbits. Investigators assessed ocular tolerability using the Draize scoring system and evaluated pharmacokinetics by collecting and analyzing ocular tissues. A third study evaluated CLX-162 stability by storing it in a dual-chamber system under varying conditions and analyzing the drug substance and reconstituted product.

Results: CLX-162 demonstrated superior ocular tolerability compared to LACE, with no corneal, iridial, or conjunctival effects observed. It induced transient pupillary constriction, whereas LACE caused mild redness and discharge. Pharmacokinetic analysis showed that CLX-162 achieved significantly higher and longer lasting (R)-lipoic acid levels in the aqueous humor and lens than LACE. Pilocarpine remained detectable for up to 8 hours. Stability studies confirmed that CLX-162 retained potency for 6 months in the dual-chamber container, with pilocarpine and (R)-lipoic acid levels within 95% to 100%. After reconstitution, it remained stable for 21 days.

Conclusions: These preclinical studies demonstrated the stability, penetrability, and safety of CLX-162 dispensed in a dual-chamber, supporting progression to clinical trials.

Translational relevance: The dual-mechanism design of CLX-162 addresses the oxidative stress-driven lens changes underlying presbyopia, bridging preclinical findings to future patient care.

Figure 1.

Dual-chamber bottle for CLX-162. The upper chamber houses the CLX-162 salt, and the lower chamber contains the sterile reconstitution buffer. A tamper-evident cap ensures sterility and stability of the product prior to activation. Upon reconstitution, the system facilitates accurate dosing and minimizes handling steps, thereby reducing the risk of contamination and improving ease of use in clinical settings. (Adapted from https://tekni-plex.com.)

Figure 2.

(R)-lipoic acid concentration in the rabbit aqueous humor following treatment with CLX-162 and LACE formulations. (A) (R)-lipoic concentration in the aqueous humor at different time points. Data are presented as mean ± SD (n = 3 rabbits/time point). (B) C_max of (R)-lipoic acid. (C) AUC of (R)-lipoic acid.

Figure 3.

(R)-lipoic acid concentration in the rabbit lens following treatment with CLX-162 and LACE formulations. (A) (R)-lipoic acid concentration in the lens at different time points. Data are presented as mean ± SD (n = 3 rabbits/time point). (B) C_max of (R)-lipoic acid. (C) AUC of (R)-lipoic acid.

Figure 4.

(A, B) Pilocarpine concentrations in the aqueous humor (A) and iris (B) from rabbits treated with CLX-162 formulation.

Figure 5.

Stability testing of CLX-162 at 1, 2, 3, and 6 months. The upper chamber of the dual-chamber container stored CLX-162 while the container was kept under different conditions at various time points. (A) The percentage of pilocarpine compared to the control under different conditions. (B) The percentage of (R)-lipoic acid compared to the control at various time points.

Figure 6.

Stability testing of CLX-162 reconstituted in the buffer on Day 1 and Day 21 after reconstitution at various time points. The percentage of pilocarpine is compared to control CLX-162. (A–D) Investigators reconstituted CLX-162 stored in the upper chamber of the dual-chamber container under various conditions at 1 month (A), 2 months (B), 3 months (C), and 6 months (D) and determined the percentage of pilocarpine compared to the control.

Figure 7.

Stability testing of CLX-162 reconstituted in the buffer on Day 1 and Day 21 after reconstitution at various time points. The percentage of (R)-lipoic acid is compared to control CLX-162. (A–D) Investigators reconstituted CLX-162 stored in the upper chamber of the dual-chamber container under various conditions at 1 month (A), 2 months (B), 3 months (C), and 6 months (D) and determined the percentage of (R)-lipoic acid compared to the control.