(T1130-04-23) Development of a Low-Dose Pilocarpine Ophthalmic Formulation that is Stable, Well-Tolerated and Bioavailable at a Near-Neutral pH for the Treatment of Presbyopia

Purpose: To develop a low dose pilocarpine hydrochloride formulation at near-neutral pH of 6 that is sufficiently stable at refrigeration and at room temperature, and is effective, safe and provides comfort for use in individuals with presbyopia.

Methods: 0.4% w/v Pilocarpine HCl ophthalmic solution at pH 6 was filled into single-dose vials under aseptic conditions and placed on stability at 5°C and 25°C (41°F and 77°F). Properties of the solution, including pilocarpine HCl assay, were evaluated during shelf-life period. This formulation was tested in two late-stage Phase 3 clinical studies.

Results: By adjusting the excipients, we designed a formulation at a near-neutral pH that demonstrated a stability profile well within regulatory specification for at least 18 months at 5°C [Fig. 1]. Longer testing demonstrated in-use stability at an additional 3 months at 25°C [Fig. 2] for a total stability of 21 months. The near-neutral 0.4% pilocarpine HCl formulation with pH 6 tested in two identical Phase 3 pivotal studies, demonstrated statistically significant ≥3-line improvement in Distance Corrected Near Visual Acuity (DCNVA) and no loss of 1 line or more in distance visual acuity at all measured time points on Days 1, 8 and 15 with a very favorable tolerability and safety profile. Results demonstrate that pilocarpine HCl assay remained well within standard assay specifications during testing period and are projected to be within specifications for over 4 years at 5°C, [Fig. 1] and 9 months at 25°C, [Fig. 2]. Non-ionized pilocarpine form facilitates transport of the drug through the cornea to the site of action better than the ionized form.^1,2 Since the ratio of the more bioavailable non-ionized form of pilocarpine increases with increasing pH¹, the percent of the non-ionized pilocarpine form at pH 6 is greater than at pH 4.5 and allows an effective dose upon installation. The near-neutral, low dose pilocarpine ophthalmic formulation enables accelerated equilibrium to the tear film pH that increases the pilocarpine rate of absorption, making it bioavailable at a low concentration, as demonstrated in the Phase 3 clinical studies results.^3,4

Conclusion: A low dose, near neutral pilocarpine hydrochloride formulation that is stable at refrigerated storage and room temperature for a total of 21 months was successfully formulated. At a near neutral pH, the bioavailability of the low dose pilocarpine formulation (0.4%) generated statistically significant clinical efficacy, excellent safety and tolerability in late phase clinical studies NEAR-1 and NEAR-2. Continued testing is ongoing to confirm stability at even longer time periods.

References: 1. Anderson RA, Cowle JB. Influence of pH on the effect of pilocarpine on aqueous dynamics. BJO.1968 (52) 607
2. Mitra, A.K. et al. Mechanism of transcorneal permeation of pilocarpine. Jour of Pharm Sci, 1988 (77) 771-775
3. The NEAR-1 Study: Near Eye-Vision Acuity Restoration. Clintrials.gov identifier NCT-04599933. Updated Feb 24, 2022
4. The NEAR-2 Study: Near Eye-Vision Acuity Restoration. Clintrials.gov identifier NCT-04599972. Updated Feb 24, 2022.

Acknowledgments: Sharon Amzel-Sasson and Teresa Ignacio are employees of Orasis Pharmaceuticals. This study was funded by Orasis Pharmaceuticals.

Figure 1. Pilocarpine HCl assay at 5°C, final clinical formulation



Figure 2: Pilocarpine HCl assay at 25°C, towards end of shelf life (after 18 months in 5°C), final clinical formulation