Ophthalmic pharmaceutical compositions and related uses

Abstract

To provide ophthalmic pharmaceutical compositions comprising pilocarpine or a pharmaceutically acceptable salt thereof.SOLUTION: Aspects of the disclosure further relate to uses and preparations of ophthalmic pharmaceutical compositions comprising pilocarpine or a pharmaceutically acceptable salt, for correcting presbyopia and other ocular conditions in a subject.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 377,154, filed on August 19, 2016, the entire content of which is incorporated herein by reference.

[0002] The present disclosure relates to an ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof. Further, aspects of the present disclosure relate to the preparation and use of an ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof for correcting presbyopia and other eye conditions in a subject.

Background Art

[0003] Presbyopia is an impairment in near vision that typically results from the gradual loss of the lens' ability to accommodate for near and far vision after the age of 40 - 45 years. It is the most common physiological change that occurs in the adult eye and can have a significant impact on quality of life and productivity if not corrected (Frick et al., 2015, Ophthalmology 122(8): 1706 - 1710; Goertz et al., 2014, Acta Ophthalmologica 92(6): 497 - 500; Patel et al., 2007, Community eye health / International Centre for Eye Health 20(63): 40 - 41). The main symptom of this condition is that the visual field gradually blurs when performing near work (such as reading, sewing, working on a computer, etc.). This can occur even without visual symptoms related to distance vision. The prevalence of presbyopia worldwide is estimated to reach 1.4 billion by 2020 (Holden et al., 2008, Archives of Ophthalmology 126(12): 1731 - 1739).

[0004] Methods for correcting presbyopia include fixed-focus and variable-focus lens systems (eyeglasses or contact lenses with monofocal, bifocal, or multifocal designs), as well as surgical procedures that attempt to alter the optics of the cornea, replace the lens with a different fixed optical system, or restore at least partially the active portion (Charman, 2014, Ophthalmic & Physiological Optics: the Journal of the College of Optometrists 34(1): 8-29; Charman, 2014, Ophthalmic & Physiological Optics: the Journal of the College of Optometrists 34(4): 397-426; Gil-Cazorla et al., 2016, British Journal of Ophthalmology 100(1): 62-70). However, corrective lens systems can be cumbersome and potentially inappropriate, while surgical methods are invasive and not without risks. For example, patients may experience problems with night vision after surgical intervention. Currently, there are no clinically effective pharmaceutical formulations available to treat the symptoms of presbyopia.

[0005] Therefore, new methods for improving or correcting presbyopia are still needed to avoid the obvious disadvantages for patients who are forced to wear corrective lenses or undergo risky and undesirable surgery. [Overview of the project]

[0006] This disclosure relates to ophthalmic pharmaceutical compositions comprising pilocarpine or a pharmaceutically acceptable salt thereof. Furthermore, this disclosure provides preparations (e.g., kits or implants) of ophthalmic pharmaceutical compositions comprising pilocarpine or a pharmaceutically acceptable salt thereof. In addition, this disclosure also provides methods useful for correcting presbyopia or other ocular conditions in subjects.

[0007] Specific embodiments of this disclosure are summarized in the following paragraphs. This list is illustrative and does not encompass all embodiments provided by this disclosure.

[0008] Embodiment 1. An ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof in a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v) and a pharmaceutically acceptable carrier.

[0009] Embodiment 2. The ophthalmic pharmaceutical composition according to Embodiment 1, wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

[0010] Embodiment 3. The ophthalmic pharmaceutical composition according to Embodiment 1 further comprises diclofenac or a pharmaceutically acceptable salt thereof in a concentration of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), or ketorolac or a pharmaceutically acceptable salt thereof in a concentration of 0.01% (w / w or w / v) to 0.60% (w / w or w / v).

[0011] Embodiment 4. The ophthalmic pharmaceutical composition according to Embodiment 3, wherein the diclofenac salt is diclofenac sodium, or the ketrolac salt is ketrolactromethamine.

[0012] Embodiment 5. The ophthalmic pharmaceutical composition according to Embodiment 1, further comprising a lubricant.

[0013] Embodiment 6. The ophthalmic pharmaceutical composition according to Embodiment 5, wherein the lubricant is hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose or a derivative thereof, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or a mixture thereof.

[0014] Embodiment 7. The ophthalmic pharmaceutical composition according to Embodiment 6, wherein the lubricant is sodium hyaluronate, hydroxypropyl methylcellulose, or a mixture thereof.

[0015] Embodiment 8. The ophthalmic pharmaceutical composition according to Embodiment 7, wherein the sodium hyaluronate is present at a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), and / or the hydroxypropyl methylcellulose is present at a concentration of 0.1% (w / w or w / v) to 2.0% (w / w or w / v).

[0016] Embodiment 9. The aforementioned ophthalmic pharmaceutical composition is (1) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), diclofenac sodium in concentrations of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), and sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.9% (w / w or w / v); (2) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), diclofenac sodium in concentrations of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), and hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 2.0% (w / w or w / v); (3) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), ketrolactromethamine in concentrations of 0.01% (w / w or w / v) to 0.60% (w / w or w / v), and sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.9% (w / w or w / v); (4) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), ketrolactromethamine in concentrations of 0.01% (w / w or w / v) to 0.60% (w / w or w / v), and hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 2.0% (w / w or w / v); or, (5) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), diclofenac sodium in concentrations of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), and hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 2.0% (w / w or w / v); An ophthalmic pharmaceutical composition according to Embodiment 1, comprising:

[0017] Embodiment 10. The ophthalmic pharmaceutical composition is selected from compositions 1 to 32, each of which comprises pilocarpine hydrochloride or pilocarpine nitrate, diclofenac sodium, and sodium hyaluronate as follows: [ka] , the ophthalmic pharmaceutical composition described in Embodiment 1.

[0018] Embodiment 11. The ophthalmic pharmaceutical composition is selected from Compositions 33 to 64, and each of Compositions 33 to 64 contains pilocarpine hydrochloride or pilocarpine nitrate, diclofenac sodium, and hydroxypropyl methylcellulose as follows: [Chemical formula] , the ophthalmic pharmaceutical composition according to Embodiment 1.

[0019] Embodiment 12. The ophthalmic pharmaceutical composition is selected from Compositions 65 to 96, and each of Compositions 65 to 96 contains pilocarpine hydrochloride or pilocarpine nitrate, ketorolac tromethamine, and sodium hyaluronate as follows: [Chemical formula] , the ophthalmic pharmaceutical composition according to Embodiment 1.

[0020] Embodiment 13. The ophthalmic pharmaceutical composition is selected from Compositions 97 to 128, and each of Compositions 97 to 128 contains pilocarpine hydrochloride or pilocarpine nitrate, ketorolac tromethamine, and hydroxypropyl methylcellulose as follows: ] [Chemical formula] , the ophthalmic pharmaceutical composition according to Embodiment 1.

[0021] Embodiment 14. The ophthalmic pharmaceutical composition is a sustained-release composition, the ophthalmic pharmaceutical composition according to Embodiment 1.

[0022] Embodiment 15. The ophthalmic pharmaceutical composition is in the form of a suspension, gel, ointment, injection solution, spray, or eye drop preparation, the ophthalmic pharmaceutical composition according to Embodiment 1.

[0023] Embodiment 16. The ophthalmic pharmaceutical composition described above is suitable for implantation into or on the surface of the target eye or surrounding tissue, as described in Embodiment 1.

[0024] Embodiment 17. The ophthalmic pharmaceutical composition described above is suitable for implantation into the subconjunctival space, nasolacrimal duct, or vitreous cavity of the target, as described in Embodiment 16.

[0025] Embodiment 18. The ophthalmic pharmaceutical composition described above is suitable for local delivery to the target eye or surrounding tissues of the eye, as described in Embodiment 1.

[0026] Embodiment 19. The ophthalmic pharmaceutical composition according to Embodiment 1, comprising a pharmaceutically acceptable diluent, preservative, and / or solvent.

[0027] Embodiment 20. An ophthalmic pharmaceutical composition according to Embodiment 1, further comprising an isotonic agent, a wetting agent, a buffering agent, a stabilizer, a pH agent, a solubilizer, a thickening agent, and / or a dispersing agent.

[0028] Embodiment 21. The ophthalmic pharmaceutical composition described above is effective in correcting presbyopia for up to 24 hours, as described in Embodiment 1.

[0029] Embodiment 22. The ophthalmic pharmaceutical composition described above corrects presbyopia without adversely affecting night vision, as described in Embodiment 1.

[0030] Embodiment 23. The ophthalmic pharmaceutical composition described above corrects presbyopia without unfavorably narrowing the field of vision, as described in Embodiment 1.

[0031] Embodiment 24. A method for correcting presbyopia in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v).

[0032] Embodiment 25. The method according to Embodiment 24, wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

[0033] Embodiment 26. The method according to Embodiment 24, wherein the ophthalmic pharmaceutical composition further comprises diclofenac or a pharmaceutically acceptable salt thereof in a concentration of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), or ketorolac or a pharmaceutically acceptable salt thereof in a concentration of 0.01% (w / w or w / v) to 0.60% (w / w or w / v).

[0034] Embodiment 27. The method according to Embodiment 26, wherein the diclofenac salt is diclofenac sodium, or the ketrolac salt is ketrolactromethamine.

[0035] Embodiment 28. The method according to Embodiment 24, wherein the ophthalmic pharmaceutical composition further comprises a lubricant.

[0036] Embodiment 29. The method according to Embodiment 28, wherein the lubricant is hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose or a derivative thereof, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or a mixture thereof.

[0037] Embodiment 30. The method according to Embodiment 29, wherein the lubricant is sodium hyaluronate, hydroxypropyl methylcellulose, or a mixture thereof.

[0038] Embodiment 31. The method according to Embodiment 30, wherein the sodium hyaluronate is present at a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), and / or the hydroxypropyl methylcellulose is present at a concentration of 0.1% (w / w or w / v) to 2.0% (w / w or w / v).

[0039] Embodiment 32. The aforementioned ophthalmic pharmaceutical composition is (1) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), diclofenac sodium in concentrations of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), and sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.9% (w / w or w / v); (2) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), diclofenac sodium in concentrations of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), and hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 2.0% (w / w or w / v); (3) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), ketrolactromethamine in concentrations of 0.01% (w / w or w / v) to 0.60% (w / w or w / v), and sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.9% (w / w or w / v); (4) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), ketrolactromethamine in concentrations of 0.01% (w / w or w / v) to 0.60% (w / w or w / v), and hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 2.0% (w / w or w / v); or, (5) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), diclofenac sodium in concentrations of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), and hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 2.0% (w / w or w / v); The method of Embodiment 24, including the method described in Embodiment 24.

[0040] Embodiment 33. The ophthalmic pharmaceutical composition is selected from compositions 1 to 32, each of which comprises pilocarpine hydrochloride or pilocarpine nitrate, diclofenac sodium, and sodium hyaluronate as follows: [ka] The method described in Embodiment 24.

[0041] Embodiment 34. The ophthalmic pharmaceutical composition is selected from compositions 33 to 64, each of which comprises pilocarpine hydrochloride or pilocarpine nitrate, diclofenac sodium, and hydroxypropyl methylcellulose as follows: [ka] The method described in Embodiment 24.

[0042] Embodiment 35. The ophthalmic pharmaceutical composition is selected from compositions 65 to 96, each of which comprises pilocarpine hydrochloride or pilocarpine nitrate, ketrolactromethamine, and sodium hyaluronate as follows: [ka] The method described in Embodiment 24.

[0043] Embodiment 36. The ophthalmic pharmaceutical composition is selected from compositions 97 to 128, each of which comprises pilocarpine hydrochloride or pilocarpine nitrate, ketrolactromethamine, and hydroxypropyl methylcellulose as follows: [ka] The method described in Embodiment 24.

[0044] Embodiment 37. The method according to Embodiment 24, wherein the ophthalmic pharmaceutical composition is a sustained-release composition.

[0045] Embodiment 38. The method according to Embodiment 24, wherein the ophthalmic pharmaceutical composition is in the form of a suspension, gel, ointment, injectable solution, spray, or eye drop formulation.

[0046] Embodiment 39. The ophthalmic pharmaceutical composition described above is suitable for implantation into or on the surface of the target eye or surrounding tissue, as described in Embodiment 24.

[0047] Embodiment 40. The ophthalmic pharmaceutical composition is suitable for implantation into the subconjunctival space, nasolacrimal duct, or vitreous cavity of the target, as described in Embodiment 39.

[0048] Embodiment 41. The ophthalmic pharmaceutical composition is suitable for local delivery to the target eye or surrounding tissues, as described in Embodiment 24.

[0049] Embodiment 42. The method according to Embodiment 24, wherein the ophthalmic pharmaceutical composition comprises a pharmaceutically acceptable diluent, preservative, and / or solvent.

[0050] Embodiment 43. The method according to Embodiment 24, further comprising an isotonic agent, a wetting agent, a buffering agent, a stabilizer, a pH agent, a solubilizer, a thickening agent, and / or a dispersing agent.

[0051] Embodiment 44. The method according to Embodiment 24, wherein the ophthalmic pharmaceutical composition is effective in correcting presbyopia for up to 24 hours.

[0052] Embodiment 45. The ophthalmic pharmaceutical composition is the method according to Embodiment 24, which corrects presbyopia without adversely affecting night vision.

[0053] Embodiment 46. The ophthalmic pharmaceutical composition is the method according to Embodiment 24, which corrects presbyopia without unfavorably narrowing the field of vision.

[0054] Embodiment 47. The aforementioned subject is: a) A person who wears spectacles but cannot or will not use progressive or bifocal lenses in the future; b) Have you had cataract surgery? c) Presbyopia developed after corneal treatment; d) Having a monofocal or multifocal intraocular lens; e) Wears contact lenses and cannot tolerate monocular lenses; f) Wears contact lenses and cannot tolerate multifocal lenses; g) Suffering from higher-order aberrations after corneal surgery; h) Having hyperopia or strabismus; i) Inability to tolerate changes in eyeglass prescription; j) I experienced a sudden change in my eyeglass prescription; k) There is a risk of falling when using progressive or bifocal lenses; and / or l) Suffering from higher-order aberrations at night or under dark conditions; The method according to Embodiment 24.

[0055] Embodiment 48. The method according to embodiment 24, wherein the administration is by local or surgical intervention.

[0056] Embodiment 49. The method according to Embodiment 48, wherein the surgical intervention includes the step of administering the ophthalmic pharmaceutical composition to the inside or surface of the target eye or surrounding tissue.

[0057] Embodiment 50. The ophthalmic pharmaceutical composition is administered into the subconjunctival space, nasolacrimal duct, or vitreous humor of the target, as described in Embodiment 49.

[0058] Embodiment 51. A method for reducing pupil size in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier in a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v).

[0059] Embodiment 52. A method for inducing pupillary constriction in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v).

[0060] Embodiment 53. A method for increasing the depth of field in a subject's eye, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v).

[0061] Embodiment 54. A method for reducing the degree of higher-order aberrations in the eye of a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v).

[0062] Embodiment 55. A method for improving uncorrected near and far visual acuity in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v).

[0063] Embodiment 56. An implant comprising an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof in a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v) and a pharmaceutically acceptable carrier.

[0064] Embodiment 57. A kit comprising an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof in a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v) and a pharmaceutically acceptable carrier.

[0065] Embodiment 58. A method for correcting presbyopia in a subject, The method comprises administering to a subject a therapeutically effective amount of an ophthalmic pharmaceutical composition that reduces the size of the pupil in the subject, The method wherein the ophthalmic pharmaceutical composition comprises pilocarpine or a pharmaceutically acceptable salt thereof in a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v) and a pharmaceutically acceptable carrier.

[0066] Embodiment 59. The method according to any one of embodiments 24-55, 58, 68, and 70, wherein the ophthalmic pharmaceutical composition is administered up to twice per application and up to three times per day.

[0067] Embodiment 60. An ophthalmic pharmaceutical composition according to any one of embodiments 1 to 23, 67, and 69, for use in a method of correcting presbyopia in a subject, comprising administering the ophthalmic pharmaceutical composition to the eye of the subject by local or surgical intervention.

[0068] Embodiment 61. An ophthalmic pharmaceutical composition according to any one of embodiments 1 to 23, 67, and 69, for use in a method of reducing the size of the pupil in a subject, which includes administering the ophthalmic pharmaceutical composition to the eye of the subject by local or surgical intervention.

[0069] Embodiment 62. An ophthalmic pharmaceutical composition according to any one of embodiments 1 to 23, 67, and 69, for use in a method for inducing pupillary constriction in a subject, comprising administering the ophthalmic pharmaceutical composition to the eye of the subject by local or surgical intervention.

[0070] Embodiment 63. An ophthalmic pharmaceutical composition according to any one of embodiments 1 to 23, 67, and 69, for use in a method for increasing the depth of field in a target eye, which includes administering the ophthalmic pharmaceutical composition to the target eye by local or surgical intervention.

[0071] Embodiment 64. An ophthalmic pharmaceutical composition according to any one of embodiments 1 to 23, 67, and 69, for use in a method of reducing the degree of higher-order aberrations in a target eye, which includes administering the ophthalmic pharmaceutical composition to the target eye by local or surgical intervention.

[0072] Embodiment 65. An ophthalmic pharmaceutical composition according to any one of embodiments 1 to 23, 67, and 69, for use in a method to improve uncorrected near and far visual acuity in a subject, comprising administering the ophthalmic pharmaceutical composition to the eye of the subject by local or surgical intervention.

[0073] Embodiment 66. An ophthalmic pharmaceutical composition according to any one of embodiments 1 to 23, 67, and 69, for use in a method of treating the body of a human or animal.

[0074] Embodiment 67. The ophthalmic pharmaceutical composition described above corrects presbyopia without adversely reducing distance visual acuity, as described in Embodiment 1.

[0075] Embodiment 68. The ophthalmic pharmaceutical composition according to Embodiment 24 corrects presbyopia without unfavorably reducing distance visual acuity.

[0076] Embodiment 69. The ophthalmic pharmaceutical composition according to Embodiment 10, wherein the ophthalmic pharmaceutical composition is selected from any one of compositions 1 to 32 and further comprises hydroxypropyl methylcellulose in a concentration of 0.1% (w / w or w / v), 0.8% (w / w or w / v), or 1.2% (w / w or w / v).

[0077] Embodiment 70. The method according to Embodiment 33, wherein the ophthalmic pharmaceutical composition is selected from any one of compositions 1 to 32 and further comprises hydroxypropyl methylcellulose in a concentration of 0.1% (w / w or w / v), 0.8% (w / w or w / v), or 1.2% (w / w or w / v).

[0078] Embodiment 71. An ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof in a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose in a concentration of 0.1% (w / w or w / v) to 2.0% (w / w or w / v), and a pharmaceutically acceptable carrier.

[0079] Embodiment 72. The ophthalmic pharmaceutical composition according to Embodiment 71, wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

[0080] Embodiment 73. The ophthalmic pharmaceutical composition according to Embodiment 72, further comprising sodium hyaluronate in a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v).

[0081] Embodiment 74. The ophthalmic pharmaceutical composition according to Embodiment 73, further comprising diclofenac or a pharmaceutically acceptable salt thereof in a concentration of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), or ketorolac or a pharmaceutically acceptable salt thereof in a concentration of 0.01% (w / w or w / v) to 0.60% (w / w or w / v).

[0082] Embodiment 75. The ophthalmic pharmaceutical composition according to Embodiment 74, wherein the diclofenac salt is diclofenac sodium, or the ketrolac salt is ketrolactromethamine.

[0083] Embodiment 76. The aforementioned ophthalmic pharmaceutical composition is (1) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.1% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 1.2% (w / w or w / v), sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), and diclofenac sodium in concentrations of 0.001% (w / w or w / v) to 0.012% (w / w or w / v); or, (2) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.1% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 1.2% (w / w or w / v), sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), and ketrolactromethamine in concentrations of 0.01% (w / w or w / v) to 0.50% (w / w or w / v); An ophthalmic pharmaceutical composition according to Embodiment 75, comprising:

[0084] Embodiment 77. The aforementioned ophthalmic pharmaceutical composition is (1) 0.2% (w / w or w / v) concentration of pilocarpine hydrochloride or pilocarpine nitrate, 0.8% (w / w or w / v) concentration of hydroxypropyl methylcellulose, 0.1% (w / w or w / v) concentration of sodium hyaluronate, and 0.006% (w / w or w / v) concentration of diclofenac sodium; or, (2) 0.2% (w / w or w / v) pilocarpine hydrochloride or pilocarpine nitrate, 0.8% (w / w or w / v) hydroxypropyl methylcellulose, 0.1% (w / w or w / v) sodium hyaluronate, and 0.50% (w / w or w / v) ketrolactromethamine; An ophthalmic pharmaceutical composition according to Embodiment 76, comprising:

[0085] Embodiment 78. (1) Sodium hyaluronate in a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), or diclofenac sodium in a concentration of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), or a mixture thereof; or, (2) Sodium hyaluronate in a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), or ketrolactromethamine in a concentration of 0.01% (w / w or w / v) to 0.60% (w / w or w / v), or a mixture thereof; An ophthalmic pharmaceutical composition of embodiment 72 further comprising the following.

[0086] Embodiment 79. The aforementioned ophthalmic pharmaceutical composition is (1) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.1% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 1.2% (w / w or w / v), and further sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), or diclofenac sodium in concentrations of 0.001% (w / w or w / v) to 0.012% (w / w or w / v), or mixtures thereof; or, (2) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.1% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 1.2% (w / w or w / v), and further sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), or ketrolactromethamine in concentrations of 0.01% (w / w or w / v) to 0.50% (w / w or w / v), or mixtures thereof; An ophthalmic pharmaceutical composition according to Embodiment 72, comprising:

[0087] Embodiment 80. The aforementioned ophthalmic pharmaceutical composition is (1) 0.2% (w / w or w / v) pilocarpine hydrochloride or pilocarpine nitrate, 0.8% (w / w or w / v) hydroxypropyl methylcellulose, and further 0.1% (w / w or w / v) sodium hyaluronate, or 0.006% (w / w or w / v) diclofenac sodium, or a mixture thereof; or, (2) 0.2% (w / w or w / v) pilocarpine hydrochloride or pilocarpine nitrate, 0.8% (w / w or w / v) hydroxypropyl methylcellulose, and further 0.1% (w / w or w / v) sodium hyaluronate, or 0.50% (w / w or w / v) ketrolactromethamine, or a mixture thereof; An ophthalmic pharmaceutical composition according to Embodiment 79, comprising:

[0088] Embodiment 81. The ophthalmic pharmaceutical composition according to Embodiment 71, wherein the ophthalmic pharmaceutical composition comprises a pharmaceutically acceptable diluent, a preservative, and / or a solvent.

[0089] Embodiment 82. An ophthalmic pharmaceutical composition according to Embodiment 71, further comprising an isotonic agent, a wetting agent, a buffering agent, a stabilizer, a pH agent, a solubilizer, a thickening agent, and / or a dispersing agent.

[0090] Embodiment 83. The ophthalmic pharmaceutical composition described in Embodiment 71 is effective in correcting presbyopia for up to 24 hours.

[0091] Embodiment 84. A method for correcting presbyopia in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof in a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose in a concentration of 0.1% (w / w or w / v) to 2.0% (w / w or w / v), and a pharmaceutically acceptable carrier.

[0092] Embodiment 85. The method according to Embodiment 84, wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

[0093] Embodiment 86. The method according to Embodiment 85, wherein the ophthalmic pharmaceutical composition further comprises sodium hyaluronate in a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v).

[0094] Embodiment 87. The method according to Embodiment 86, wherein the ophthalmic pharmaceutical composition further comprises diclofenac or a pharmaceutically acceptable salt thereof in a concentration of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), or ketorolac or a pharmaceutically acceptable salt thereof in a concentration of 0.01% (w / w or w / v) to 0.60% (w / w or w / v).

[0095] Embodiment 88. The method according to Embodiment 87, wherein the diclofenac salt is diclofenac sodium, or the ketrolac salt is ketrolactromethamine.

[0096] Embodiment 89. The aforementioned ophthalmic pharmaceutical composition is (1) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.1% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 1.2% (w / w or w / v), sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), and diclofenac sodium in concentrations of 0.001% (w / w or w / v) to 0.012% (w / w or w / v); or, (2) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.1% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 1.2% (w / w or w / v), sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), and ketrolactromethamine in concentrations of 0.01% (w / w or w / v) to 0.50% (w / w or w / v); The method of embodiment 88, including the method described in embodiment 88.

[0097] Embodiment 90. The aforementioned ophthalmic pharmaceutical composition is (1) 0.2% (w / w or w / v) concentration of pilocarpine hydrochloride or pilocarpine nitrate, 0.8% (w / w or w / v) concentration of hydroxypropyl methylcellulose, 0.1% (w / w or w / v) concentration of sodium hyaluronate, and 0.006% (w / w or w / v) concentration of diclofenac sodium; or, (2) 0.2% (w / w or w / v) pilocarpine hydrochloride or pilocarpine nitrate, 0.8% (w / w or w / v) hydroxypropyl methylcellulose, 0.1% (w / w or w / v) sodium hyaluronate, and 0.50% (w / w or w / v) ketrolactromethamine; The method according to embodiment 89, including the method described in embodiment 89.

[0098] Embodiment 91. The aforementioned ophthalmic pharmaceutical composition is (1) Sodium hyaluronate in a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), or diclofenac sodium in a concentration of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), or a mixture thereof; or, (2) Sodium hyaluronate in a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), or ketrolactromethamine in a concentration of 0.01% (w / w or w / v) to 0.60% (w / w or w / v), or a mixture thereof; The method according to embodiment 85, further comprising:

[0099] Embodiment 92. The aforementioned ophthalmic pharmaceutical composition is (1) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.1% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 1.2% (w / w or w / v), and further sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), or diclofenac sodium in concentrations of 0.001% (w / w or w / v) to 0.012% (w / w or w / v), or mixtures thereof; or, (2) Pilocarpine hydrochloride or pilocarpine nitrate in concentrations of 0.1% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose in concentrations of 0.1% (w / w or w / v) to 1.2% (w / w or w / v), and further sodium hyaluronate in concentrations of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), or ketrolactromethamine in concentrations of 0.01% (w / w or w / v) to 0.50% (w / w or w / v), or mixtures thereof; The method according to embodiment 85, including the method described in embodiment 85.

[0100] Embodiment 93. The aforementioned ophthalmic pharmaceutical composition is (1) 0.2% (w / w or w / v) pilocarpine hydrochloride or pilocarpine nitrate, 0.8% (w / w or w / v) hydroxypropyl methylcellulose, and further 0.1% (w / w or w / v) sodium hyaluronate, or 0.006% (w / w or w / v) diclofenac sodium, or a mixture thereof; or, (2) 0.2% (w / w or w / v) pilocarpine hydrochloride or pilocarpine nitrate, 0.8% (w / w or w / v) hydroxypropyl methylcellulose, and further 0.1% (w / w or w / v) sodium hyaluronate, or 0.50% (w / w or w / v) ketrolactromethamine, or a mixture thereof; The method of embodiment 92, including the method of embodiment 92.

[0101] Embodiment 94. The method according to Embodiment 85, wherein the ophthalmic pharmaceutical composition comprises a pharmaceutically acceptable diluent, preservative, and / or solvent.

[0102] Embodiment 95. The method according to Embodiment 85, wherein the ophthalmic pharmaceutical composition further comprises an isotonic agent, a wetting agent, a buffering agent, a stabilizer, a pH agent, a solubilizer, a thickening agent, and / or a dispersing agent.

[0103] Embodiment 96. The ophthalmic pharmaceutical composition is effective in correcting presbyopia for up to 24 hours, according to the method of Embodiment 85.

[0104] Embodiment 97. The method according to embodiment 85, wherein the administration is by local or surgical intervention.

[0105] Embodiment 98. The aforementioned subject is: a) A person who wears spectacles but cannot or will not use progressive or bifocal lenses in the future; b) Have you had cataract surgery? c) Presbyopia developed after corneal treatment; d) Having a monofocal or multifocal intraocular lens; e) Wears contact lenses and cannot tolerate monocular lenses; f) Wears contact lenses and cannot tolerate multifocal lenses; g) Suffering from higher-order aberrations after corneal surgery; h) Having hyperopia or strabismus; i) Inability to tolerate changes in eyeglass prescription; j) I experienced a sudden change in my eyeglass prescription; k) There is a risk of falling when using progressive or bifocal lenses; and / or l) Suffering from higher-order aberrations at night or under dark conditions; The method described in Embodiment 85.

[0106] Embodiment 99. A method for reducing pupil size in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof in a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose in a concentration of 0.1% (w / w or w / v) to 2.0% (w / w or w / v), and a pharmaceutically acceptable carrier.

[0107] Embodiment 100. A method for increasing the depth of field in the eye of a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof in a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose in a concentration of 0.1% (w / w or w / v) to 2.0% (w / w or w / v), and a pharmaceutically acceptable carrier.

[0108] Those skilled in the art will understand that the drawings shown below are for illustrative purposes only. The drawings are not intended to limit the scope of this instruction. [Brief explanation of the drawing]

[0109] [Figure 1] Figure 1 shows the relationship between the change in depth of field (ΔDoF) and the change in pupil size (ΔPupil) in the presbyopic group (●) and the relationship between the change in depth of field (ΔDoF) and the change in pupil size (ΔPupil) in the pseudophakic eye group (○) when viewing text at a distance (6m) after instilling the ophthalmic pharmaceutical composition of this disclosure into the eye.

[0110] [Figure 2] Figure 2 shows the relationship (●) between the change in depth of field (ΔDoF) and the change in pupil size (ΔPupil) in the presbyopic group when viewing text at close range (40 cm) after instilling the ophthalmic pharmaceutical composition of this disclosure into the eye. [Modes for carrying out the invention]

[0111] Detailed explanation Those skilled in the art will likely conceive of numerous modifications and other embodiments relating to the matters described herein, which also benefit from the teachings presented in the description and accompanying drawings. Therefore, it should be understood that this disclosure is not limited to the specific embodiments disclosed, and that modifications and other embodiments are also intended to be included within the scope of the accompanying claims. Certain terms are used herein, but they are used in a general and descriptive sense only and are not intended to be limiting.

[0112] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which this disclosure pertains. Unless otherwise noted, the techniques used or intended herein are standard methods well known to those skilled in the art. Unless otherwise indicated, the implementation of this disclosure will utilize prior art relating to ophthalmic pharmaceutical formulations and their use within the scope of the art. Materials, methods and examples are illustrative and not limiting. The following are presented illustratively and are not intended to limit the scope of this disclosure.

[0113] For convenience, the specific terms used throughout this specification (including the specification, examples, and appended claims) are set forth here.

[0114] In this specification, the singular forms ("a," "an," and "the") are intended to include the plural forms unless the context explicitly states otherwise. Furthermore, the terms "including," "includes," "having," "has," "with," or variations thereof, when used in the specification and / or claims, are intended to be as inclusive as the word "comprising."

[0115] As used herein, the term “administering” means placing an ophthalmic pharmaceutical composition on a subject by a method or route that localizes the pharmaceutical composition at least partially to a desired site or tissue (e.g., the patient’s eye or periorocular tissue). For example, the composition may be administered topically to the eye or periorocular tissue of the subject. Alternatively, the composition may be administered internally or to the surface of the eye or periorocular tissue of the subject through surgical intervention. In some embodiments of this disclosure, the ophthalmic pharmaceutical composition may be administered by any suitable route that results in an effective treatment of the subject, i.e., the administration results in delivery to a desired site or tissue of the subject, where at least a portion of pilocarpine or a pharmaceutically acceptable salt thereof is placed in the desired site or tissue. In some embodiments of this disclosure, the ophthalmic pharmaceutical composition may be administered several times in a short period of time, for example, within a few seconds or minutes. For example, in some embodiments, the ophthalmic pharmaceutical composition may be administered twice within 2 seconds, 5 seconds, 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes, 20 minutes, or 30 minutes. In one embodiment, the ophthalmic pharmaceutical composition can be administered three times within 2 seconds, 5 seconds, 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes, 20 minutes, or 30 minutes. In another embodiment, the ophthalmic pharmaceutical composition can be administered four times within 2 seconds, 5 seconds, 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes, 20 minutes, or 30 minutes.

[0116] The term “composition” refers to a mixture containing a therapeutically active ingredient and a conventionally widely used carrier or excipient suitable for administration to a subject for therapeutic purposes, such as a pharmaceutically acceptable carrier or excipient. The therapeutically active ingredient is, for example, pilocarpine or a pharmaceutically acceptable salt thereof as described herein. In some embodiments, the composition may be in the form of a suspension, gel, ointment, injectable solution, spray, or ophthalmic formulation (i.e., a composition suitable for administration as an eye drop). In some embodiments, if the composition is in the form of an ophthalmic formulation, it may have a volume of about 10 microliters (μL) per drop, about 10 μL to about 20 μL, about 20 μL to about 50 μL, about 50 μL to about 100 μL, about 100 μL to about 250 μL, or about 250 μL to about 500 μL.

[0117] The terms “comprise,” “have,” and “include” are open-ended verbs. There are no restrictions on any one or more forms or tenses of these verbs, such as “comprise,” “include,” “have,” “have,” “include,” and “include.” For example, a method that “comprises,” “have,” or “includes” one or more steps is not limited to having only those one or more steps, but may also include other steps not listed. Similarly, any composition that “comprises,” “have,” or “includes” one or more features is not limited to having only those one or more features, but may also include other features not listed. Any and all examples or illustrative language used in reference to any embodiment of this specification (e.g., “such as”) is solely for the purpose of improving the understanding of this disclosure and does not impose any limitation on the scope of this disclosure as otherwise claimed.

[0118] The term "consisting essentially of" allows for the presence of additional materials or processes that "do not substantially affect the basic and novel features(s)" of the present invention.

[0119] The term "consisting of" means that the compositions, methods, and individual components described herein do not include any elements not mentioned in the description of the applicable embodiment.

[0120] As used herein, the terms “correct,” “correcting,” or “correction” refer to a reduction or mitigation of the severity of presbyopia. Mitigation may be complete, such as the complete elimination of presbyopia, or it may be partial, such as the degree of presbyopia being less than it was before exposure to the methods or compositions disclosed herein. The degree of presbyopia can be measured by any method known in the art for ophthalmic examination.

[0121] The term "ophthalmically acceptable" is used to describe compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the eyes and surrounding tissues of humans and animals, within the scope of medical judgment, with a reasonable benefit-to-risk ratio, without excessive toxicity, irritation, allergic reactions, or other problems or complications. Pharmaceutical approval agencies (e.g., EMA, US FDA) provide guidance on approving pharmaceutically acceptable compounds, materials, compositions, and / or dosage forms. Examples can be found in pharmacopeias.

[0122] The term "ophthalmologically acceptable carrier" is used herein to mean solvents, dispersions, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, core-shell nanoparticles, polymers, peptides, proteins, cells, hyaluronidases, and mixtures thereof that are suitable for drug administration. The use of such media and agents for pharmaceutically active substances is well known in the field of ophthalmology. The composition may also contain other active compounds that provide supplemental, additive, or enhanced therapeutic functions.

[0123] The term "ophthalmic pharmaceutical composition" refers to a pharmaceutical composition that is useful in manufacturing drugs administered to the eyes of mammals.

[0124] The term "pharmaceutically acceptable salt" refers to a salt of an acidic or basic group that may be present in the compound used in the composition of the present invention. pharmaceutically acceptable salts are well known in the art. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Other pharmaceutically acceptable salts include sulfates, citrates, malates, acetates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, sulfites, phosphates, superphosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, acidic tartrates, ascorbic acidates, succinates, maleates, gentisinates, fumarates, glucons, glucarates, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates. For example, in one embodiment, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate. On the other hand, certain compounds that are acidic in nature and contained in the composition may form base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. For example, in one embodiment, the ophthalmic pharmaceutical composition contains diclofenac sodium. For example, in one embodiment, the ophthalmic pharmaceutical composition contains ketrolactromethamine.

[0125] The terms "substantially significant" or "significantly significant" refer to statistical significance. These terms indicate statistical evidence that a difference exists. It can be defined as the probability of rejecting the null hypothesis when the null hypothesis is actually true. The decision is often made using p-values. Any other measure of significance well-known in this field may also be used.

[0126] The terms “subject” and “individual” are used interchangeably and refer, for example, to an animal, such as a human, to whom treatment using the methods or compositions described herein is provided. In some embodiments, the subject is a human.

[0127] As used herein, the term “therapeutically effective amount” means an amount of a therapeutic agent (e.g., pilocarpine or a pharmaceutically acceptable salt) or pharmaceutical composition sufficient to alleviate at least one symptom of a disease or disorder, or to provide a desired effect. For example, this could be an amount that temporarily alleviates or eliminates presbyopia, such as temporarily partially or completely restoring near vision in the treated eye. For example, it could be an amount that results in a significant reduction in discomfort or the risk of falls when using progressive or bifocal lenses. For example, it could be an amount that reduces or completely eliminates blurred vision or dizziness after ophthalmic surgery.

[0128] As used herein, the terms “treat,” “treatment,” or “treating” refer to the reduction or elimination of a disease or disorder, or at least one recognizable symptom thereof. In some embodiments, “treat” or “treating” refers to the reduction or elimination of at least one measurable physical parameter, which does not necessarily have to be perceived by the patient. For example, treatment may enable the patient to focus on an object at a near point distance, for example, to focus on an object at a distance close to normal reading distance. In some embodiments, treatment is effective in reducing or eliminating presbyopia for a period of 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour. In one embodiment, the treatment is effective in reducing or eliminating presbyopia for up to 24 hours. The degree of presbyopia can be measured by any method known in the art for ophthalmic examination.

[0129] For example, in one embodiment, treatment is measured by the subject's uncorrected (naked) distance and near visual acuity, which can be measured using a standard, appropriate visual acuity chart, such as the Snellen far-point visual acuity chart and the Jaeger near-point visual acuity chart, or the Early Treatment Diabetic Retinopathy Test (ETDRS) chart. All values ​​can be converted to decimal notation using the Halliday conversion table.

[0130] In another embodiment, the treatment is measured by a clinical assessment of depth of field, which can be obtained using standard wavefront aberration measurement or according to the following instructions: • Far point: The optimal distance for eyeglasses in the refractometer head / test frame. View 6 / 9 (0.6) Snellen letters. Increase the power of the positive spherical lens (+a diopters) until the object reports blurring. Repeat with the negative lens (-b diopters). Remove the negative sign before b. Depth of field at the far point = (a+b) diopters. • Near point: Method for determining the optimal distance for eyeglasses by adding +2.5 diopters in the refractometer head / inspection frame. View J2 typeface at a distance of 40cm. Increase the power of the positive spherical lens (+x diopters) until the object becomes blurry. Repeat using the negative lens (-y diopters). Remove the negative sign before y. Depth of field at the near point = (x+y) diopters.

[0131] In yet another embodiment, treatment is measured by changes in pupil size, which can be evaluated by an infrared imaging system used to check alignment during automated refractive index measurements. Infrared imaging of the pupil, converted to visible light, magnified, and displayed on the observation surface of the device, allows the user to observe the pupil and align the device during normal use. Vertical and horizontal pupil diameters can be measured using a ruler on the screen when the subject is at an infinity target. The average of these two measurements can be recorded and corrected for a magnification (approximately ×7 to ×8) for both vertical and horizontal meridians. Pupil size can also be measured by an aberration meter and a pupil meter.

[0132] In yet another embodiment, treatment can be measured by the appearance of the pupil, for example, by examining the pupil for whether the pupil size is symmetrical (a difference of less than 1 mm is typical), whether the pupil shape is normal, its responsiveness to light, and its direct and empathetic accommodation.

[0133] In yet another embodiment, the treatment is measured by non-invasive evaluation of tertiary, quaternary, and quinary ocular aberrations (e.g., coma aberration, spherical aberration, and trefoil), which can be performed using standard wavefront aberration analysis.

[0134] This disclosure is not limited to the specific methodologies, protocols, and reagents described herein, and it should be understood that such methodologies, protocols, and reagents may vary. The terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the scope of this disclosure, which is limited solely by the claims.

[0135] Pharmacological treatment of presbyopia Presbyopia is an age-related deterioration of the eyes. Generally, presbyopia results in a gradual decrease in the range of accommodation, leading to a decline in the ability to focus on objects at near distances. Presbyopic eyes lose the ability to quickly and easily focus on objects at near distances.

[0136] As background information, when young people with normal vision gaze at close objects, two changes occur in the eye: accommodation and pupillary constriction. Accommodation is a change in the refractive power of the crystalline lens. The lens becomes rounder, thereby increasing its refractive power. Pupil constriction is a reduction in the size of the pupil, which increases the depth of field and reduces higher-order aberrations.

[0137] At the molecular level, pupillary constriction and accommodation occur under the influence of the parasympathetic nervous system. The binding of parasympathetic stimulants to muscarinic receptors induces muscle contraction of the ciliary muscle and pupillary sphincter muscle, increasing the refractive power of the eye. If this situation is strong enough, it can overcome some of the loss of the ability to change the shape and position of the lens, which generally occurs with aging, while the lens remains in its original position.

[0138] Presbyopia has traditionally been corrected with glasses, contact lenses, intraocular implants, corneal detachment, or inlays. Surgical methods proposed to correct presbyopia do not fully restore the eye's natural accommodative function, which has been reduced by natural aging or other means. Pharmacological treatment is proposed to restore the natural loss of accommodative function that leads to presbyopia.

[0139] To date, no clinically effective pharmaceutical formulations have been available to treat the symptoms of presbyopia. This disclosure provides a simple, convenient, and painless composition and method of use for patients suffering from the symptoms of presbyopia.

[0140] Ophthalmic pharmaceutical compositions of the present disclosure According to this disclosure, the ophthalmic pharmaceutical composition comprises a therapeutically effective amount of a parasympathomimetic agent or a pharmaceutically acceptable salt thereof.

[0141] Parasympathetic stimulants are intended to include any cholinergic agent that enhances acetylcholine-mediated effects in the central nervous system, the peripheral nervous system, or both. One example of such a parasympathetic stimulant is pilocarpine. Further examples are disclosed in U.S. Patent No. 8,299,079 and may include acetylcholine, muscarine, nicotine, saxamethonium, betanethyl, metacholine, phenylpropanolamine, amphetamine, ephedrine, carbachol, phentolamine, and fenfluramine. In some embodiments, the parasympathetic stimulant is pilocarpine or carbachol. In preferred embodiments, the parasympathetic stimulant is pilocarpine.

[0142] Pilocarpine, in the form of hydrochloride or nitrate, is a miotic agent that has been used for decades in the form of eye drops to treat glaucoma. Long-term topical application of certain concentrations of pilocarpine is associated with undesirable ocular and systemic adverse effects, such as pigment scattering syndrome, dry eye, uveal inflammation, posterior synechiae, ciliary muscle spasm, blurred vision, miosis, accommodative spasm, frontal headache, monoconstrictive eyelid, conjunctival hyperemia, cataracts, iris cysts, retinal detachment, nausea, vomiting, salivation, lacrimation, sweating, pulmonary edema, and bronchospasm (Havener, 1970, WH Ocular Pharmacology 2). nd(ed. CV Mosby & Co, USA, pp. 207-243; Zimmer and Wheeler, 1982, Ophthalmology 89:76-80; Nuzzi et al., 1998, Int Ophthalmol 22:31-35; Pop et al., 2000, Oftalmologia 52:44-48; Diestelhorst, 2000, Graefes Arch Clin Exp Ophthalmol 238:433-439; Nordmann et al., 2000, Br J Ophthalmol 84:181-185). These side effects are generally associated with the chronic use of pilocarpine at concentrations of 1% or higher, taken regularly several times daily. Furthermore, the effect of pilocarpine on the pupil is influenced by the color and pigment of the iris (Barbee and Smith, 1957, Am J Ophthalmol 44:617-622; Harris and Galpin, 1971, Am J Ophthalmol 72:923-925; Smith et al., 1978, Brit J Ophthalmol 62:314-317).

[0143] In some embodiments, the ophthalmic pharmaceutical composition is a pharmaceutically acceptable salt of a parasympathetic stimulant. Therefore, in some embodiments, the ophthalmic pharmaceutical composition comprises a pharmaceutically acceptable salt of pilocarpine or carbachol. In preferred embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate.

[0144] In some embodiments of the ophthalmic pharmaceutical composition, pilocarpine or a pharmaceutically acceptable salt thereof is present in concentrations of approximately 0.01% to 0.4%, approximately 0.01% to 0.35%, approximately 0.01% to 0.3%, approximately 0.01% to 0.25%, approximately 0.01% to 0.2%, approximately 0.01% to 0.15%, approximately 0.01% to 0.1%, approximately 0.01% to 0. 0.05%, approximately 0.05% to approximately 0.4%, approximately 0.05% to approximately 0.35%, approximately 0.05% to approximately 0.3%, approximately 0.05% to approximately 0.25%, approximately 0.05% to approximately 0.2%, approximately 0.05% to approximately 0.15%, approximately 0.05% to approximately 0.1%, approximately 0.1% to approximately 0.4%, approximately 0.1% to approximately 0.35%, approximately 0.1% to approximately 0.3%, approximately 0.1% to approximately 0.2 5%, approximately 0.1% to approximately 0.2%, approximately 0.1% to approximately 0.15%, approximately 0.15% to approximately 0.4%, approximately 0.15% to approximately 0.35%, approximately 0.15% to approximately 0.3%, approximately 0.15% to approximately 0.25%, approximately 0.15% to approximately 0.2%, approximately 0.2% to approximately 0.4%, approximately 0.2% to approximately 0.35%, approximately 0.2% to approximately 0.3%, approximately 0.2% to approximately 0.25%, approximately 0 It may be present in amounts of approximately 0.25% to 0.4%, approximately 0.25% to 0.35%, approximately 0.25% to 0.3%, approximately 0.3% to 0.4%, approximately 0.3% to 0.35%, approximately 0.35% to 0.4%, or approximately 0.01%, approximately 0.05%, approximately 0.1%, approximately 0.15%, approximately 0.2%, approximately 0.25%, approximately 0.3%, approximately 0.35%, or approximately 0.4%. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0145] In some embodiments, the ophthalmic pharmaceutical composition may further contain a nonsteroidal anti-inflammatory drug (NSAID) or a pharmaceutically acceptable salt thereof. NSAIDs can reduce or eliminate local inflammation that may be caused by irritation induced by parasympathomimetic agents (e.g., pilocarpine).

[0146] NSAIDs are well known in the art. In some embodiments, a suitable NSAID is diclofenac. Further examples of NSAIDs include nepafenac, meloxicam, ketorolac, bromfenac, bendazac, flurbiprofen, suprofen, pranoprofen, oxyfenbutazone, serprofen, and indomethacin. Therefore, in some embodiments, the ophthalmic pharmaceutical composition further comprises diclofenac. In some embodiments, the ophthalmic pharmaceutical composition further comprises ketorolac. Alternatively, the ophthalmic pharmaceutical composition may not contain an NSAID.

[0147] In some embodiments, the ophthalmic pharmaceutical composition may further contain a pharmaceutically acceptable salt of an NSAID. Non-limiting examples of such salts include alkali metal salts or alkaline earth metal salts, particularly salts of calcium, magnesium, sodium, lithium, zinc, potassium, and iron. For example, in some embodiments, the ophthalmic pharmaceutical composition further contains diclofenac sodium. In some embodiments, the ophthalmic pharmaceutical composition further contains ketrolactromethamine. Alternatively, the ophthalmic pharmaceutical composition may not contain a pharmaceutically acceptable salt of an NSAID.

[0148] In some embodiments of the ophthalmic pharmaceutical composition, diclofenac or a pharmaceutically acceptable salt thereof (e.g., diclofenac sodium) is present in concentrations of approximately 0.001% to 0.090%, approximately 0.001% to 0.080%, approximately 0.001% to 0.070%, approximately 0.001% to 0.060%, approximately 0.001% to 0.050%, approximately 0.001% to 0.040%, approximately 0.001% to 0.030%, approximately 0.001% to 0.020%, approximately 0.001% to 0.012%, approximately 0.001% to 0.011%, approximately 0.001% to 0.010%, approximately 0.001% to 0.0 0.9%, approximately 0.001%~0.008%, approximately 0.001%~0.007%, approximately 0.001%~0.006%, approximately 0.001%~0.005%, approximately 0.001%~0.003%, approximately 0.003%~0.090%, approximately 0.003%~0.080%, approximately 0.003%~0.070%, approximately 0.003%~0.060%, approximately 0.003%~0.050%, approximately 0.003%~0.040%, approximately 0.003%~0.030%, approximately 0.003%~0.020%, approximately 0.003%~0.012%, approximately 0.003%~0.011%, approximately 0.003 %~approx. 0.010%, approx. 0.003%~approx. 0.009%, approx. 0.003%~approx. 0.008%, approx. 0.003%~approx. 0.007%, approx. 0.003%~approx. 0.006%, approx. 0.003%~approx. 0.005%, approx. 0.005%~approx. 0.090%, approx. 0.005%~approx. 0.080%, approx. 0.005%~approx. 0.070%, approx. 0.005%~approx. 0.060%, approx. 0.005%~approx. 0.050%, approx. 0.005%~approx. 0.040%, approx. 0.005%~approx. 0.030%, approx. 0.005%~approx. 0.020%, approx. 0.005%~approx. 0.012%, approx. 0.005%~approx. 0.011%, Approximately 0.005% to 0.010%, approximately 0.005% to 0.009%, approximately 0.005% to 0.008%, approximately 0.005% to 0.007%, approximately 0.005% to 0.006%, approximately 0.006% to 0.090%, approximately 0.006% to 0.080%, approximately 0.006% to 0.070%, approximately 0.006% to 0.060%, approximately 0.006% to 0.050%, approximately 0.006% to 0.040%, approximately 0.006% to 0.030%, approximately 0.006% to 0.020%, approximately 0.006% to 0.012%, approximately 0.006% to 0.011%, approximately 0.006% to 0.0.10%, approximately 0.006%~0.009%, approximately 0.006%~0.008%, approximately 0.006%~0.007%, approximately 0.007%~0.090%, approximately 0.007%~0.080%, approximately 0.007%~0.070%, approximately 0.007%~0.060%, approximately 0.007%~0.050%, approximately 0.007%~0.040%, approximately 0.007%~0.030%, approximately 0.007%~0.020%, approximately 0.007%~0.012%, approximately 0.007%~0.011%, approximately 0.007%~0.010%, approximately 0.007%~0.009%, approximately 0.00 7%~approx. 0.008%, approx. 0.008%~approx. 0.090%, approx. 0.008%~approx. 0.080%, approx. 0.008%~approx. 0.070%, approx. 0.008%~approx. 0.060%, approx. 0.008%~approx. 0.050%, approx. 0.008%~approx. 0.040%, approx. 0.008%~approx. 0.030%, approx. 0.008%~approx. 0.020%, approx. 0.008%~approx. 0.012%, approx. 0.008%~approx. 0.011%, approx. 0.008%~approx. 0.010%, approx. 0.008%~approx. 0.009%, approx. 0.009%~approx. 0.090%, approx. 0.009%~approx. 0.080%, approx. 0.009%~approx. 0.070% Approximately 0.009%~0.060%, approximately 0.009%~0.050%, approximately 0.009%~0.040%, approximately 0.009%~0.030%, approximately 0.009%~0.020%, approximately 0.009%~0.012%, approximately 0.009%~0.011%, approximately 0.009%~0.010%, approximately 0.010%~0.090%, approximately 0.010%~0.080%, approximately 0.010%~0.070%, approximately 0.010%~0.060%, approximately 0.010%~0.050%, approximately 0.010%~0.040%, approximately 0.010%~0.030%, approximately 0.010%~ 0.020%, approximately 0.010%~0.012%, approximately 0.010%~0.011%, approximately 0.011%~0.090%, approximately 0.011%~0.080%, approximately 0.011%~0.070%, approximately 0.011%~0.060%, approximately 0.011%~0.050%, approximately 0.011%~0.040%, approximately 0.011%~0.030%, approximately 0.011%~0.020%, approximately 0.011%~0.012%, approximately 0.012%~0.090%, approximately 0.012%~0.080%, approximately 0.012%~0.070%, approximately 0.012%~0.060%, approximately 0.0.012%~approximately 0.050%, approximately 0.012%~approximately 0.040%, approximately 0.012%~approximately 0.030%, approximately 0.012%~approximately 0.020%, approximately 0.020%~approximately 0.090%, approximately 0.020%~approximately 0.080%, approximately 0.020%~approximately 0.070%, approximately 0.020%~approximately 0.060%, approximately 0.020%~approximately 0.050%, approximately 0.020%~approximately 0.040%, approximately 0.020%~approximately 0.030%, approximately 0.030%~approximately 0.090%, approximately 0.030%~approximately 0.080%, approximately 0.030%~approximately 0.070%, approximately 0.030%~approximately 0.060%, approximately 0.030%~approximately 0.050%, approximately 0.030%~approximately 0.040%, approximately 0.040%~approximately 0.090%, approximately 0.040%~approximately 0.080%, approximately 0.040%~approximately 0.070%, approximately 0.040%~approximately 0.060% Approximately 0.040%~0.050%, approximately 0.050%~0.090%, approximately 0.050%~0.080%, approximately 0.050%~0.070%, approximately 0.050%~0.060%, approximately 0.060%~0.090%, approximately 0.060%~0.080%, approximately 0.060%~0.070%, approximately 0.070%~0.090%, approximately 0.070%~0.080%, approximately 0.08 It may be present in amounts ranging from 0% to approximately 0.090%, or approximately 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090%. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0149] In some embodiments of the ophthalmic pharmaceutical composition, ketrolac or a pharmaceutically acceptable salt thereof (e.g., ketrolactromethamine) is present in concentrations of approximately 0.01% to 0.6%, approximately 0.01% to 0.5%, approximately 0.01% to 0.4%, approximately 0.01% to 0.3%, approximately 0.01% to 0.2%, approximately 0.01% to 0.1%, approximately 0.01% to 0.05%, approximately 0.05% to 0.6%, approximately 0.05% to 0.5%, approximately 0.05% to 0.4%, approximately 0.05% to 0.3%, approximately 0.05% to 0.2%, approximately 0.05% to 0.1%, approximately 0.1% It may be present in amounts of approximately 0.6%, approximately 0.1% to approximately 0.5%, approximately 0.1% to approximately 0.4%, approximately 0.1% to approximately 0.3%, approximately 0.1% to approximately 0.2%, approximately 0.2% to approximately 0.6%, approximately 0.2% to approximately 0.5%, approximately 0.2% to approximately 0.4%, approximately 0.2% to approximately 0.3%, approximately 0.3% to approximately 0.6%, approximately 0.3% to approximately 0.5%, approximately 0.3% to approximately 0.4%, approximately 0.4% to approximately 0.6%, approximately 0.4% to approximately 0.5%, approximately 0.5% to approximately 0.6%, or approximately 0.01%, approximately 0.05%, approximately 0.1%, approximately 0.2%, approximately 0.3%, approximately 0.4%, approximately 0.5%, or approximately 0.6%. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by the volume (w / v).

[0150] In some embodiments, the ophthalmic pharmaceutical composition may further contain a lubricant. Generally, lubricants can facilitate the administration of the ophthalmic pharmaceutical composition to a target. Suitable lubricants can be independently selected from hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose or a derivative thereof, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or mixtures thereof. In some embodiments, the ophthalmic pharmaceutical composition further contains sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition further contains hydroxypropylmethylcellulose. In some embodiments, the ophthalmic pharmaceutical composition further contains sodium hyaluronate and hydroxypropylmethylcellulose. Alternatively, the ophthalmic pharmaceutical composition may not contain a lubricant.

[0151] In some embodiments of the ophthalmic pharmaceutical composition, the lubricant is sodium hyaluronate, which is present in concentrations of approximately 0.01% to 0.9%, approximately 0.01% to 0.8%, approximately 0.01% to 0.7%, approximately 0.01% to 0.6%, approximately 0.01% to 0.5%, approximately 0.01% to 0.4%, approximately 0.01% to 0.3%, approximately 0.01% to 0.2%, approximately 0.01% to 0.1%, approximately 0.01% to 0.05%, approximately 0.05% to 0.9%, approximately 0.05% to 0.8%, approximately 0.05%~approximately 0.7%, approximately 0.05%~approximately 0.6%, approximately 0.05%~approximately 0.5%, approximately 0.05%~approximately 0.4%, approximately 0.05%~approximately 0.3%, approximately 0.05%~approximately 0.2%, approximately 0.05%~approximately 0.1%, approximately 0.1%~approximately 0.9%, approximately 0.1%~approximately 0.8%, approximately 0.1%~approximately 0.7%, approximately 0.1%~approximately 0.6%, approximately 0.1%~approximately 0.5%, approximately 0.1%~approximately 0.4%, approximately 0.1%~approximately 0.3%, approximately 0.1%~approximately 0.2%, approximately 0.2%~approximately 0.9%, approximately 0. 2%~approx. 0.8%, approx. 0.2%~approx. 0.7%, approx. 0.2%~approx. 0.6%, approx. 0.2%~approx. 0.5%, approx. 0.2%~approx. 0.4%, approx. 0.2%~approx. 0.3%, approx. 0.3%~approx. 0.9%, approx. 0.3%~approx. 0.8%, approx. 0.3%~approx. 0.7%, approx. 0.3%~approx. 0.6%, approx. 0.3%~approx. 0.5%, approx. 0.3%~approx. 0.4%, approx. 0.4%~approx. 0.9%, approx. 0.4%~approx. 0.8%, approx. 0.4%~approx. 0.7%, approx. 0.4%~approx. 0.6%, approx. 0.4%~approx. 0.5% , may be present in amounts of approximately 0.5% to 0.9%, approximately 0.5% to 0.8%, approximately 0.5% to 0.7%, approximately 0.5% to 0.6%, approximately 0.6% to 0.9%, approximately 0.6% to 0.8%, approximately 0.6% to 0.7%, approximately 0.7% to 0.9%, approximately 0.7% to 0.8%, approximately 0.8% to 0.9%, or approximately 0.01%, approximately 0.05%, approximately 0.1%, approximately 0.2%, approximately 0.3%, approximately 0.4%, approximately 0.5%, approximately 0.6%, approximately 0.7%, approximately 0.8%, and approximately 0.9%. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0152] In some embodiments of the ophthalmic pharmaceutical composition, the lubricant is hydroxypropyl methylcellulose, which is present in concentrations of approximately 0.1% to 2.0%, approximately 0.1% to 1.8%, approximately 0.1% to 1.6%, approximately 0.1% to 1.4%, approximately 0.1% to 1.2%, approximately 0.1% to 1.0%, approximately 0.1% to 0.8%, approximately 0.1% to 0.6%, approximately 0.1% to 0.4%, approximately 0.1% to 0.2%, approximately 0.2% to 2.0%, approximately 0.2% to 1.8%, and approximately 0.2%. %~approx. 1.6%, approx. 0.2%~approx. 1.4%, approx. 0.2%~approx. 1.2%, approx. 0.2%~approx. 1.0%, approx. 0.2%~approx. 0.8%, approx. 0.2%~approx. 0.6%, approx. 0.2%~approx. 0.4%, approx. 0.4%~approx. 2.0%, approx. 0.4%~approx. 1.8%, approx. 0.4%~approx. 1.6%, approx. 0.4%~approx. 1.4%, approx. 0.4%~approx. 1.2%, approx. 0.4%~approx. 1.0%, approx. 0.4%~approx. 0.8%, approx. 0.4%~approx. 0.6%, approx. 0.6%~approx. 2.0%, approx. 0.6%~approx. 1 0.8%, approximately 0.6%~approximately 1.6%, approximately 0.6%~approximately 1.4%, approximately 0.6%~approximately 1.2%, approximately 0.6%~approximately 1.0%, approximately 0.6%~approximately 0.8%, approximately 0.8%~approximately 2.0%, approximately 0.8%~approximately 1.8%, approximately 0.8%~approximately 1.6%, approximately 0.8%~approximately 1.4%, approximately 0.8%~approximately 1.2%, approximately 0.8%~approximately 1.0%, approximately 1.0%~approximately 2.0%, approximately 1.0%~approximately 1.8%, approximately 1.0%~approximately 1.6%, approximately 1.0%~approximately 1.4%, approximately 1%~approximately 1.2%, approximately 1 It may be present in amounts of approximately 0.2% to 2.0%, approximately 1.2% to 1.8%, approximately 1.2% to 1.6%, approximately 1.2% to 1.4%, approximately 1.4% to 2.0%, approximately 1.4% to 1.8%, approximately 1.4% to 1.6%, approximately 1.6% to 2.0%, approximately 1.6% to 1.8%, approximately 1.8% to 2.0%, or approximately 0.1%, approximately 0.2%, approximately 0.4%, approximately 0.6%, approximately 0.8%, approximately 1.0%, approximately 1.2%, approximately 1.4%, approximately 1.6%, approximately 1.8%, and approximately 2.0%. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0153] In some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate in a concentration of 0.01% to 0.4%, diclofenac sodium in a concentration of 0.001% to 0.090%, and sodium hyaluronate in a concentration of 0.01% to 0.9%. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0154] In some embodiments, the ophthalmic pharmaceutical composition comprises 0.01% to 0.4% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.090% diclofenac sodium, and 0.1% to 2.0% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0155] In some embodiments, the ophthalmic pharmaceutical composition comprises 0.01% to 0.4% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.090% diclofenac sodium, 0.01% to 0.9% sodium hyaluronate, and 0.1% to 2.0% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0156] In some embodiments, the ophthalmic pharmaceutical composition comprises 0.01% to 0.4% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.60% ketrolactromethamine, and 0.01% to 0.9% sodium hyaluronate. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0157] In some embodiments, the ophthalmic pharmaceutical composition comprises 0.01% to 0.4% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.60% ketrolactromethamine, and 0.1% to 2.0% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0158] In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% to 0.4%. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0159] In some embodiments, the ophthalmic pharmaceutical composition comprises 0.01% pilocarpine hydrochloride or pilocarpine nitrate. In some embodiments, the ophthalmic pharmaceutical composition comprising 0.01% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium. In some embodiments, an ophthalmic pharmaceutical composition containing 0.01% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine. In some embodiments, an ophthalmic pharmaceutical composition containing 0.01% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.01% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.01% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium, and optionally further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate.In some embodiments, an ophthalmic pharmaceutical composition comprising 0.01% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium, and optionally further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.01% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.01% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0160] In some embodiments, the ophthalmic pharmaceutical composition comprises 0.05% pilocarpine hydrochloride or pilocarpine nitrate. In some embodiments, the ophthalmic pharmaceutical composition comprising 0.05% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.05% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.05% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.05% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.05% pilocarpine hydrochloride or pilocarpine nitrate further comprises diclofenac sodium in concentrations of 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090%, and optionally further comprises sodium hyaluronate in concentrations of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9%.In some embodiments, an ophthalmic pharmaceutical composition comprising 0.05% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium, and optionally further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.05% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.05% pilocarpine hydrochloride or pilocarpine nitrate may further comprise 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0161] In some embodiments, the ophthalmic pharmaceutical composition comprises 0.1% pilocarpine hydrochloride or pilocarpine nitrate. In some embodiments, the ophthalmic pharmaceutical composition comprising 0.1% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.1% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.1% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.1% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.1% pilocarpine hydrochloride or pilocarpine nitrate further comprises diclofenac sodium in concentrations of 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090%, and optionally further comprises sodium hyaluronate in concentrations of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9%.In some embodiments, an ophthalmic pharmaceutical composition comprising 0.1% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium, and optionally further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.1% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.1% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0162] In some embodiments, the ophthalmic pharmaceutical composition comprises 0.15% pilocarpine hydrochloride or pilocarpine nitrate. In some embodiments, the ophthalmic pharmaceutical composition comprising 0.15% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.15% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.15% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.15% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.15% pilocarpine hydrochloride or pilocarpine nitrate further comprises diclofenac sodium in concentrations of 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090%, and optionally further comprises sodium hyaluronate in concentrations of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9%.In some embodiments, an ophthalmic pharmaceutical composition comprising 0.15% pilocarpine hydrochloride or pilocarpine nitrate further comprises diclofenac sodium in concentrations of 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090%, and optionally further comprises hydroxypropyl methylcellulose in concentrations of 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0%. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.15% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.15% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0163] In some embodiments, the ophthalmic pharmaceutical composition comprises 0.2% pilocarpine hydrochloride or pilocarpine nitrate. In some embodiments, the ophthalmic pharmaceutical composition comprising 0.2% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.2% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.2% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.2% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.2% pilocarpine hydrochloride or pilocarpine nitrate further comprises diclofenac sodium in concentrations of 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090%, and optionally further comprises sodium hyaluronate in concentrations of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9%.In some embodiments, an ophthalmic pharmaceutical composition comprising 0.2% pilocarpine hydrochloride or pilocarpine nitrate may further comprise 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium, and optionally 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.2% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.2% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0164] In some embodiments, the ophthalmic pharmaceutical composition comprises 0.25% pilocarpine hydrochloride or pilocarpine nitrate. In some embodiments, the ophthalmic pharmaceutical composition comprising 0.25% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.25% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.25% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.25% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.25% pilocarpine hydrochloride or pilocarpine nitrate further comprises diclofenac sodium in concentrations of 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090%, and optionally further comprises sodium hyaluronate in concentrations of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9%.In some embodiments, an ophthalmic pharmaceutical composition comprising 0.25% pilocarpine hydrochloride or pilocarpine nitrate further comprises diclofenac sodium in concentrations of 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090%, and optionally further comprises hydroxypropyl methylcellulose in concentrations of 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0%. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.25% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.25% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0165] In some embodiments, the ophthalmic pharmaceutical composition comprises 0.3% pilocarpine hydrochloride or pilocarpine nitrate. In some embodiments, the ophthalmic pharmaceutical composition comprising 0.3% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.3% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.3% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.3% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.3% pilocarpine hydrochloride or pilocarpine nitrate further comprises diclofenac sodium in concentrations of 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090%, and optionally further comprises sodium hyaluronate in concentrations of 0.3%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9%.In some embodiments, an ophthalmic pharmaceutical composition comprising 0.3% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium, and optionally further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.3% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.3% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0166] In some embodiments, the ophthalmic pharmaceutical composition comprises 0.35% pilocarpine hydrochloride or pilocarpine nitrate. In some embodiments, the ophthalmic pharmaceutical composition comprising 0.35% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.35% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.35% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.35% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.35% pilocarpine hydrochloride or pilocarpine nitrate further comprises diclofenac sodium in concentrations of 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090%, and optionally further comprises sodium hyaluronate in concentrations of 0.3%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9%.In some embodiments, an ophthalmic pharmaceutical composition comprising 0.35% pilocarpine hydrochloride or pilocarpine nitrate further comprises diclofenac sodium in concentrations of 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090%, and optionally further comprises hydroxypropyl methylcellulose in concentrations of 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0%. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.35% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.35% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0167] In some embodiments, the ophthalmic pharmaceutical composition comprises 0.4% pilocarpine hydrochloride or pilocarpine nitrate. In some embodiments, the ophthalmic pharmaceutical composition comprising 0.4% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.4% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.4% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.4% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.4% pilocarpine hydrochloride or pilocarpine nitrate further comprises diclofenac sodium in concentrations of 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090%, and optionally further comprises sodium hyaluronate in concentrations of 0.3%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9%.In some embodiments, an ophthalmic pharmaceutical composition comprising 0.4% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.001%, 0.003%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.020%, 0.030%, 0.040%, 0.050%, 0.060%, 0.070%, 0.080%, or 0.090% diclofenac sodium, and optionally further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.4% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, or 0.9% sodium hyaluronate. In some embodiments, an ophthalmic pharmaceutical composition comprising 0.4% pilocarpine hydrochloride or pilocarpine nitrate further comprises 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6% ketrolactromethamine, and optionally further comprises 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, or 2.0% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0168] For example, in some embodiments, the ophthalmic pharmaceutical composition comprises 0.01% pilocarpine hydrochloride or pilocarpine nitrate and 0.001% to 0.012% diclofenac sodium. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.01% pilocarpine hydrochloride or pilocarpine nitrate and 0.01% to 0.50% ketrolactromethamine. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0169] For example, in some embodiments, the ophthalmic pharmaceutical composition comprises 0.05% pilocarpine hydrochloride or pilocarpine nitrate and 0.001% to 0.012% diclofenac sodium. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.05% pilocarpine hydrochloride or pilocarpine nitrate and 0.01% to 0.50% ketrolactromethamine. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0170] For example, in some embodiments, the ophthalmic pharmaceutical composition comprises a 0.1% concentration of pilocarpine hydrochloride or pilocarpine nitrate and a 0.001% to 0.012% concentration of diclofenac sodium. In some embodiments, the ophthalmic pharmaceutical composition comprises a 0.1% concentration of pilocarpine hydrochloride or pilocarpine nitrate and a 0.01% to 0.50% concentration of ketrolactromethamine. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0171] For example, in some embodiments, the ophthalmic pharmaceutical composition comprises 0.15% pilocarpine hydrochloride or pilocarpine nitrate and 0.001% to 0.012% diclofenac sodium. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.15% pilocarpine hydrochloride or pilocarpine nitrate and 0.01% to 0.50% ketrolactromethamine. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0172] For example, in some embodiments, the ophthalmic pharmaceutical composition comprises a 0.2% concentration of pilocarpine hydrochloride or pilocarpine nitrate and a 0.001% to 0.012% concentration of diclofenac sodium. In some embodiments, the ophthalmic pharmaceutical composition comprises a 0.2% concentration of pilocarpine hydrochloride or pilocarpine nitrate and a 0.01% to 0.50% concentration of ketrolactromethamine. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0173] For example, in some embodiments, the ophthalmic pharmaceutical composition comprises 0.01% pilocarpine hydrochloride or pilocarpine nitrate and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.01% pilocarpine hydrochloride or pilocarpine nitrate and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.01% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.2% sodium hyaluronate, and 0.1% to 1.2% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0174] For example, in some embodiments, the ophthalmic pharmaceutical composition comprises 0.05% pilocarpine hydrochloride or pilocarpine nitrate and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.05% pilocarpine hydrochloride or pilocarpine nitrate and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.05% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.2% sodium hyaluronate, and 0.1% to 1.2% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0175] For example, in some embodiments, the ophthalmic pharmaceutical composition comprises 0.1% pilocarpine hydrochloride or pilocarpine nitrate and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.1% pilocarpine hydrochloride or pilocarpine nitrate and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.1% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.2% sodium hyaluronate, and 0.1% to 1.2% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0176] For example, in some embodiments, the ophthalmic pharmaceutical composition comprises 0.15% pilocarpine hydrochloride or pilocarpine nitrate and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.15% pilocarpine hydrochloride or pilocarpine nitrate and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.15% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.2% sodium hyaluronate, and 0.1% to 1.2% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0177] For example, in some embodiments, the ophthalmic pharmaceutical composition comprises 0.2% pilocarpine hydrochloride or pilocarpine nitrate and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.2% pilocarpine hydrochloride or pilocarpine nitrate and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.2% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.2% sodium hyaluronate, and 0.1% to 1.2% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0178] For example, in some embodiments, the ophthalmic pharmaceutical composition contains 0.01% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition contains 0.01% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition contains 0.01% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, 0.01% to 0.2% sodium hyaluronate, and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.01% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.50% ketrolactromethamine, and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.01% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.50% ketrolactromethamine, and 0.1% to 1.2% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0179] For example, in some embodiments, the ophthalmic pharmaceutical composition contains 0.05% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition contains 0.05% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition contains 0.05% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, 0.01% to 0.2% sodium hyaluronate, and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.05% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.50% ketrolactromethamine, and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.05% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.50% ketrolactromethamine, and 0.1% to 1.2% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0180] For example, in some embodiments, the ophthalmic pharmaceutical composition contains 0.10% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition contains 0.10% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition contains 0.10% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, 0.01% to 0.2% sodium hyaluronate, and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.10% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.50% ketrolactromethamine, and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.10% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.50% ketrolactromethamine, and 0.1% to 1.2% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0181] For example, in some embodiments, the ophthalmic pharmaceutical composition contains 0.15% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition contains 0.15% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition contains 0.15% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, 0.01% to 0.2% sodium hyaluronate, and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.15% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.50% ketrolactromethamine, and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.15% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.50% ketrolactromethamine, and 0.1% to 1.2% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0182] For example, in some embodiments, the ophthalmic pharmaceutical composition contains 0.2% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition contains 0.2% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition contains 0.2% pilocarpine hydrochloride or pilocarpine nitrate, 0.001% to 0.012% diclofenac sodium, 0.01% to 0.2% sodium hyaluronate, and 0.1% to 1.2% hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.2% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.50% ketrolactromethamine, and 0.01% to 0.2% sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition comprises 0.2% pilocarpine hydrochloride or pilocarpine nitrate, 0.01% to 0.50% ketrolactromethamine, and 0.1% to 1.2% hydroxypropyl methylcellulose. In all of these embodiments, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0183] For example, in some embodiments, the ophthalmic pharmaceutical composition may be any one of a non-limiting example of a composition comprising the components listed in the table below and a pharmaceutically acceptable carrier. In some embodiments, the ophthalmic pharmaceutical composition may be any one of a non-limiting example of a composition further comprising the components listed in the table below and a pharmaceutically acceptable carrier, and hydroxypropyl methylcellulose in a concentration of about 0.1% to about 1.2%. In some embodiments, the ophthalmic pharmaceutical composition may be any one of a non-limiting example of a composition further comprising the components listed in the table below and a pharmaceutically acceptable carrier, and hydroxypropyl methylcellulose in a concentration of about 0.1%, about 0.8%, or about 1.2%. In all of these compositions, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v). [ka]

[0184] For example, in some embodiments, the ophthalmic pharmaceutical composition may be any one of the non-limiting examples of compositions comprising the components listed in the table below and a pharmaceutically acceptable carrier. In all of these compositions, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v). [ka]

[0185] For example, in some embodiments, the ophthalmic pharmaceutical composition may be any one of the non-limiting examples of compositions comprising the components listed in the table below and a pharmaceutically acceptable carrier. In all of these compositions, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v). [ka]

[0186] For example, in some embodiments, the ophthalmic pharmaceutical composition may be any one of the non-limiting examples of compositions comprising the components listed in the table below and a pharmaceutically acceptable carrier. In all of these compositions, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v). [ka]

[0187] In some embodiments, the ophthalmic pharmaceutical composition may comprise a pharmaceutically acceptable carrier and one, two, three, or four compounds selected from (1) pilocarpine hydrochloride or pilocarpine nitrate; (2) diclofenac sodium; (3) sodium hyaluronate; and (4) hydroxypropyl methylcellulose, wherein the pilocarpine hydrochloride or pilocarpine nitrate is present in a concentration of about 0.01% to about 0.4%, the diclofenac sodium in a concentration of about 0.001% to about 0.090%, the sodium hyaluronate in a concentration of about 0.01% to about 0.9%, and / or the hydroxypropyl methylcellulose in a concentration of about 0.1% to about 2.0%. In all of these compositions, the percentile is determined by weight (w / w). Alternatively, in all of these embodiments, the percentile is determined by volume (w / v).

[0188] In some embodiments, the ophthalmic pharmaceutical compositions according to this disclosure may include, but are not limited to, ophthalmologically acceptable carriers as used herein: solvents, dispersions, diluents, dispersants, suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, core-shell nanoparticles, polymers, peptides, proteins, cells, hyaluronidases, and mixtures thereof. The use of such media and drugs suitable for ophthalmic administration is well known in the art. Various carriers for formulating ophthalmic pharmaceutical compositions and techniques for preparing such compositions are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition, Edited by Allen, Loyd V., Jr., Pharmaceutical Press, which is incorporated herein by reference in whole). For example, in some embodiments, the ophthalmic pharmaceutical compositions according to the Disclosure may contain one or more preservatives such as phenol, cresol, p-aminobenzoic acid, BDSA, sorbitate, chlorhexidine, benzalkonium chloride, sorbic acid, Purite® (oxychloride compound), Polyquad® (quaternary ammonium compound), polyhexamethylene biguanide, sodium perborate, etc. In some embodiments, ophthalmic pharmaceutical compositions intended for long-term use under chronic conditions may be formulated and packaged to minimize or eliminate the use of preservatives that may be irritating to the eye. For example, the ophthalmic pharmaceutical compositions may be packaged in single-dose containers or in containers that utilize alternative means (such as membranes, valve mechanisms, or silver) to minimize microbial contamination.

[0189] In some embodiments, the ophthalmic pharmaceutical composition further comprises isotonic agents, humectants, buffers, stabilizers, pH agents, solubilizers, thickeners, and / or dispersants. These agents are well known to those skilled in the field of ophthalmology (see, for example, U.S. Patents 8,299,079 and 8,524,758). For example, the pharmaceutical composition may contain an isotonic agent to adjust the formulation to a desired isotonic range. Examples of isotonic agents include glycerin, mannitol, sorbitol, and sodium chloride. Additionally or alternatively, the pharmaceutical composition may contain a humectant that reduces the surface tension of water or other liquids, thereby allowing the liquid to pass through or easily penetrate a solid surface. Some examples of humectants in ophthalmic pharmaceutical compositions include carboxymethylcellulose, hydroxypropylmethylcellulose, glycerin, mannitol, polyvinyl alcohol, or hydroxyethylcellulose. Additionally or alternatively, the pharmaceutical composition may contain a buffer to maintain the pH within a therapeutically useful range. The buffers used are known to those skilled in the art, and are not intended to limit, but some examples include acetic acid, boric acid, carbonic acid, citric acid, and phosphate buffer. Additionally or alternatively, the pharmaceutical composition may contain one or more stabilizers such as sodium bisulfite, ethylenediaminetetraacetic acid, etc. Additionally or alternatively, the pharmaceutical composition may contain one or more solubilizers such as polysorbate, polyethylene glycol, propylene glycol, macrogol 4000, etc. Additionally or alternatively, the pharmaceutical composition may contain one or more thickeners to give the preparations of this disclosure consistent density or consistency. Suitable thickeners include, for example, nonionic water-soluble polymers, fatty alcohols, fatty acids, anionic polymers, and alkali salts thereof, as well as mixtures thereof. Additionally or alternatively, the pharmaceutical composition may contain one or more dispersants such as poly(ethylene glycol), polyethoxylated castor oil, alcohols having 12 to 20 carbon atoms, and mixtures thereof.

[0190] In some embodiments, ophthalmic pharmaceutical compositions are sustained-release compositions. For example, sustained-release ophthalmic pharmaceutical compositions are known to be efficiently and advantageously delivered by intravitreous microinserts near the fundus (e.g., WO2011 / 079123A1). The advantage of microinserts is that the components are released slowly and remain in the eye, and the fluid introduced onto the surface of the eyeball does not flow out through the natural drainage channels. Microinserts save the patient time and effort by avoiding frequent, repeated intravenous infusions.

[0191] The ophthalmic pharmaceutical composition according to this disclosure may be in the form of an eye drop formulation. It may also be applicable to the eye in other forms. For example, the ophthalmic pharmaceutical according to this disclosure may be in the form of a suspension. In some embodiments, the ophthalmic pharmaceutical according to this disclosure may be in the form of a gel. In some embodiments, the ophthalmic pharmaceutical according to this disclosure may be in the form of an ophthalmic ointment. In some embodiments, the ophthalmic pharmaceutical according to this disclosure may be in the form of an injectable solution. In some embodiments, the ophthalmic pharmaceutical according to this disclosure may be in the form of an ophthalmic spray.

[0192] The ophthalmic pharmaceutical compositions according to this disclosure may be suitable for local delivery to the eye or surrounding tissues of the eye. The ophthalmic pharmaceutical compositions according to this disclosure may be suitable for implantation into or on the surface of the eye or surrounding tissues of the eye. In some embodiments, the ophthalmic pharmaceutical compositions are suitable for implantation into the subconjunctival space, nasolacrimal duct, or vitreous humor of the target.

[0193] In some embodiments, the ophthalmic pharmaceutical compositions according to this disclosure may be surgically implanted into the subconjunctival space by an ophthalmologist after a preliminary experiment with topical eye drops has determined that the patient would benefit from the implantation. The components passively reach the iris and interact with the iris muscle fibers to alter the size of the pupil. This action results in an increase in depth of field and improvement of hyperopia and myopia, as discussed in this disclosure.

[0194] Treatment for patients suffering from presbyopia symptoms The object of this disclosure is to treat subjects suffering from presbyopia by directly administering the ophthalmic pharmaceutical composition of this disclosure in a therapeutically effective amount. Therefore, administration of the ophthalmic pharmaceutical composition can alleviate or eliminate the symptoms of presbyopia and improve the patient's ability to focus on close objects, including objects at or near normal reading distance. Furthermore, administration of the ophthalmic pharmaceutical composition may cause a significant reduction in discomfort or the risk of falls when using progressive or bifocal lenses, and / or reduce or completely eliminate blurring and haze after ophthalmic surgery.

[0195] The degree of presbyopia after using the ophthalmic pharmaceutical compositions of this disclosure may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% lower than the degree of presbyopia without using the compositions of this disclosure. The degree of presbyopia can be determined by any method known in the art with respect to ophthalmic examination. For example, a standard test may be performed to examine the patient's ability to focus on close objects, including objects at or near their normal reading distance, after administration of the ophthalmic pharmaceutical compositions of this disclosure.

[0196] In some embodiments, the treatment may be the correction of presbyopia in a subject over a period of approximately 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour. In some embodiments, the treatment may be the correction of presbyopia in a subject over a period of 24 hours or less.

[0197] In some embodiments, administration of the ophthalmic pharmaceutical composition according to this disclosure corrects presbyopia without adversely affecting night vision. In some embodiments, administration of the ophthalmic pharmaceutical composition according to this disclosure corrects presbyopia without adversely affecting the field of vision.

[0198] In some embodiments, the ophthalmic pharmaceutical compositions according to this disclosure may be used to correct presbyopia in a subject, where the subject is: a) A person who wears spectacles but cannot or will not use progressive or bifocal lenses in the future; b) Have you had cataract surgery? c) Presbyopia developed after corneal treatment; d) Having a monofocal or multifocal intraocular lens; e) Wears contact lenses and cannot tolerate monocular lenses; f) Wears contact lenses and cannot tolerate multifocal lenses; g) Suffering from higher-order aberrations after corneal surgery; h) Having hyperopia or strabismus; i) Inability to tolerate changes in eyeglass prescription; j) I experienced a sudden change in my eyeglass prescription; k) There is a risk of falling when using progressive or bifocal lenses; and / or l) Sufferes from higher-order aberrations at night or under dark conditions.

[0199] Other aspects of the present disclosure relate to delivery systems for administering ophthalmic pharmaceutical compositions according to the present disclosure to subjects requiring such administration. In some embodiments, the composition may be administered topically to the eye or periocular tissue of the subject. In some embodiments, the composition may be administered by surgical intervention to the inside or surface of the eye or periocular tissue of the subject. In some embodiments, the surgical intervention includes the step of implanting (e.g., by intraocular insertion) the ophthalmic pharmaceutical composition to the inside or surface of the eye or periocular tissue of the subject. In some embodiments, the ophthalmic pharmaceutical composition is implanted in the subconjunctival space, nasolacrimal duct, or vitreous humor of the subject. In some embodiments, the ophthalmic pharmaceutical composition is a sustained-release composition.

[0200] In some embodiments, a method for correcting presbyopia in a subject includes administering an ophthalmic pharmaceutical composition in the form of an eye drop formulation. In some embodiments, the ophthalmic pharmaceutical composition for correcting presbyopia may be in the form of an ophthalmic suspension. In some embodiments, the ophthalmic pharmaceutical composition for correcting presbyopia may be in the form of a gel. In some embodiments, the ophthalmic pharmaceutical composition for correcting presbyopia may be in the form of an ointment. In some embodiments, the ophthalmic pharmaceutical composition for correcting presbyopia may be in the form of an injectable solution. In some embodiments, the ophthalmic pharmaceutical composition for correcting presbyopia may be in the form of an eye spray.

[0201] In some embodiments, the ophthalmic pharmaceutical composition is preferably administered to the subject in a single dose to correct presbyopia. In some embodiments, the ophthalmic pharmaceutical composition is preferably administered to the subject in multiple doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more) to correct presbyopia. In each embodiment, the "multiple doses" can be separated from each other by short (1-5 minutes), moderate (6-30 minutes), or long (more than 30 minutes, or even several hours) time intervals.

[0202] Ophthalmic pharmaceutical compositions may be administered to subjects in any dose effective in correcting presbyopia. The exact required dose will vary from subject to subject, depending on the species, age, and / or general condition, the severity of the disease, the specific formulation, the method of administration, and the mode of activity. However, it should be understood that the total daily dose of the composition may be determined by the attending ophthalmologist within reasonable medical judgment. The specific pharmaceutically effective dose level for any particular patient will depend on various factors such as the severity of the patient's presbyopia, the specific composition used, age, weight, general health, sex and diet, time of administration, route of administration, duration of treatment, and similar factors well known in the field of ophthalmology.

[0203] However, this disclosure also includes the delivery of ophthalmic pharmaceutical compositions for correcting presbyopia by any suitable route, taking into account possible advances in the science of drug delivery.

[0204] Further applications of the ophthalmic compositions disclosed herein In some embodiments, the ophthalmic pharmaceutical compositions according to the Disclosure may also be used to treat other health conditions in subjects who have symptoms of presbyopia but no history of ophthalmic surgery. In some embodiments, the ophthalmic pharmaceutical compositions according to the Disclosure may be used in subjects with the following conditions: (a) extreme skin conditions (e.g., trypophobia, ichthyosis), (b) multiple allergic syndromes, and / or (c) diabetes. In some embodiments, the ophthalmic pharmaceutical compositions according to the Disclosure may be used in subjects who have undergone the following types of ophthalmic surgery: (a) intraocular lens implantation for cataracts, (b) laser surgery (laser corneal curvature formation (LASIK), photorefractive keratectomy (PRK), or similar surgery, and / or (c) intraocular lens implantation for phakic lens implantation. In some embodiments, the ophthalmic pharmaceutical compositions according to the Disclosure may be used in cases of children for whom ophthalmic surgery is not recommended (e.g., strabismus in childhood).

[0205] Another aspect of the present disclosure relates to the administration of ophthalmic pharmaceutical compositions according to the present disclosure for modulating certain physiological processes in a subject. In non-limiting examples, the modification of physiological processes may include reducing pupil size, causing miosis, increasing depth of field, reducing the degree of higher-order aberrations, and / or improving uncorrected near and distance visual acuity in a subject.

[0206] In some embodiments, a method for reducing the pupil size in a subject includes administering a therapeutically effective amount of the ophthalmic pharmaceutical composition according to the Disclosure to the subject. In some embodiments, the subject is: a) A person who wears spectacles but cannot or will not use progressive or bifocal lenses in the future; b) Have you had cataract surgery? c) Presbyopia developed after corneal treatment; d) having a single - focus or multi - focus intraocular lens; e) using contact lenses and not tolerating monovision lenses; f) using contact lenses and not tolerating multifocal lenses; g) suffering from high - order aberrations after corneal surgery; h) suffering from myopia or strabismus; i) not tolerating changes in glasses prescription; j) having experienced a rapid change in glasses prescription; k) having a risk of falling when using progressive or bifocal lenses; and / or l) suffering from high - order aberrations under night - time or low - light conditions.

[0207] In some embodiments, a method of reducing the pupil size in a subject comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present disclosure, wherein the ophthalmic pharmaceutical composition is a sustained - release composition. In some embodiments, the composition may be administered locally to the subject's eye or the tissue surrounding the eye. In some embodiments, the composition may be administered surgically into or on the surface of the subject's eye or the tissue surrounding the eye. In some embodiments, the surgical intervention comprises transplanting (e.g., by intraocular insertion) the ophthalmic pharmaceutical composition into or on the surface of the subject's eye or the tissue surrounding the eye. In some embodiments, the ophthalmic pharmaceutical composition is transplanted into the subject's sub - conjunctival space, nasolacrimal duct, or vitreous body. In some embodiments, the ophthalmic pharmaceutical composition is a sustained - release composition. In some embodiments, the composition may be in the form of a suspension, gel, ointment, injection solution, spray, or eye - drop formulation.

[0208] In any embodiment for reducing the pupil size in a subject, the effect of the ophthalmic pharmaceutical composition for reducing the pupil size can be evaluated by methods well - known in the art (e.g., see Example 1 disclosed herein).

[0209] In some embodiments, a method of inducing miosis in a subject comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present disclosure. In some embodiments, the subject is: a) a spectacle wearer who cannot use or will not use progressive or bifocal lenses; b) who has undergone cataract surgery; c) who has developed presbyopia after corneal treatment; d) having a monofocal or multifocal intraocular lens; e) using contact lenses and intolerant to monovision lenses; f) using contact lenses and intolerant to multifocal lenses; g) suffering from higher-order aberrations after corneal surgery; h) suffering from myopia or strabismus; i) intolerant to changes in spectacle prescription; j) having experienced rapid changes in spectacle prescription; k) at risk of falling when using progressive or bifocal lenses; and / or l) suffering from higher-order aberrations under night or low-light conditions.

[0210] In some embodiments, a method of inducing miosis in a subject comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present disclosure, wherein the ophthalmic pharmaceutical composition is a sustained-release composition. In some embodiments, the composition may be administered locally to the subject's eye or the surrounding tissues of the eye. In some embodiments, the composition may be administered surgically into or onto the subject's eye or the surrounding tissues of the eye. In some embodiments, the surgical intervention comprises transplanting (e.g., by intraocular insertion) the ophthalmic pharmaceutical composition into or onto the subject's eye or the surrounding tissues of the eye. In some embodiments, the ophthalmic pharmaceutical composition is transplanted into the subject's subconjunctival space, nasolacrimal duct, or vitreous body. In some embodiments, the ophthalmic pharmaceutical composition is a sustained-release composition. In some embodiments, the composition may be in the form of a suspension, gel, ointment, injection solution, spray, or eye drop preparation.

[0211] In any embodiment for inducing pupillary constriction in a subject, the effect of the pupillary constriction-inducing ophthalmic pharmaceutical composition can be evaluated by methods well known in the art (see, for example, Example 1 disclosed herein).

[0212] In some embodiments, a method for increasing the depth of field in the eye of a subject includes administering to the subject a therapeutically effective amount of the ophthalmic pharmaceutical composition according to the Disclosure, in which case the subject is: a) A person who wears spectacles but cannot or will not use progressive or bifocal lenses in the future; b) Have you had cataract surgery? c) Presbyopia developed after corneal treatment; d) Having a monofocal or multifocal intraocular lens; e) Wears contact lenses and cannot tolerate monocular lenses; f) Wears contact lenses and cannot tolerate multifocal lenses; g) Suffering from higher-order aberrations after corneal surgery; h) Having hyperopia or strabismus; i) Inability to tolerate changes in eyeglass prescription; j) I experienced a sudden change in my eyeglass prescription; k) There is a risk of falling when using progressive or bifocal lenses; and / or l) Sufferes from higher-order aberrations at night or under dark conditions.

[0213] In some embodiments, a method for increasing the depth of field in the eye of a subject comprises administering to the subject a therapeutically effective amount of the ophthalmic pharmaceutical composition according to the Disclosure, wherein the ophthalmic pharmaceutical composition is a sustained-release composition. In some embodiments, the composition may be administered topically to the eye or periocular tissue of the subject. In some embodiments, the composition may be administered surgically to the inside or surface of the eye or periocular tissue of the subject. In some embodiments, the surgical intervention includes the step of implanting the ophthalmic pharmaceutical composition inside or on the inside or surface of the eye or periocular tissue of the subject (e.g., by intraocular implantation). In some embodiments, the ophthalmic pharmaceutical composition is implanted in the subconjunctival space, nasolacrimal duct, or vitreous humor of the subject. The composition may be in the form of a suspension, gel, ointment, injectable solution, spray, or eye drop formulation.

[0214] In any embodiment for increasing the depth of field in the target eye, the effect of the ophthalmic pharmaceutical composition for increasing the depth of field can be evaluated by methods well known in the art (see, for example, Example 1 disclosed herein).

[0215] In some embodiments, a method for reducing the degree of higher-order aberrations in the eye of a subject includes administering the ophthalmic pharmaceutical composition according to this disclosure to the subject in a therapeutically effective amount, in which the subject is: a) A person who wears spectacles but cannot or will not use progressive or bifocal lenses in the future; b) Have you had cataract surgery? c) Presbyopia developed after corneal treatment; d) Having a monofocal or multifocal intraocular lens; e) Wears contact lenses and cannot tolerate monocular lenses; f) Wears contact lenses and cannot tolerate multifocal lenses; g) Suffering from higher-order aberrations after corneal surgery; h) Having hyperopia or strabismus; i) Inability to tolerate changes in eyeglass prescription; j) I experienced a sudden change in my eyeglass prescription; k) There is a risk of falling when using progressive or bifocal lenses; and / or l) Suffering from higher-order aberrations under nighttime or low-light conditions.

[0216] In some embodiments, a method for reducing the degree of higher-order aberrations in a subject's eye comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present disclosure, wherein the ophthalmic pharmaceutical composition is a sustained-release composition. In some embodiments, the composition may be administered locally to the subject's eye or the surrounding tissues of the eye. In some embodiments, the composition may be administered surgically into or onto the subject's eye or the surrounding tissues of the eye. In some embodiments, the surgical intervention comprises transplanting (e.g., by intraocular insertion) the ophthalmic pharmaceutical composition into or onto the subject's eye or the surrounding tissues of the eye. In some embodiments, the ophthalmic pharmaceutical composition is transplanted into the subject's subconjunctival space, nasolacrimal duct, or vitreous body. The composition may be in the form of a suspension, gel, ointment, injection solution, spray, or eye drop formulation.

[0217] In any embodiment for reducing the degree of higher-order aberrations in a subject's eye, the effect of the ophthalmic pharmaceutical composition for reducing the degree of higher-order aberrations can be evaluated by methods well known in the art. For example, using wavefront aberrometry, non-invasive third, fourth, and fifth-order higher-order aberrations (coma aberration, spherical aberration, and trefoil aberration) of the eye can be measured at each visit.

[0218] In some embodiments, a method for improving uncorrected near and far vision in a subject comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present disclosure. In some embodiments, the subject is: a) A spectacle wearer who cannot use or will not use progressive or bifocal lenses; b) Who has undergone cataract surgery; c) Who has developed presbyopia after corneal treatment; d) Having a monofocal or multifocal intraocular lens; e) Using contact lenses and intolerant to monovision lenses; f) Wears contact lenses and cannot tolerate multifocal lenses; g) Suffering from higher-order aberrations after corneal surgery; h) Having hyperopia or strabismus; i) Inability to tolerate changes in eyeglass prescription; j) I experienced a sudden change in my eyeglass prescription; k) There is a risk of falling when using progressive or bifocal lenses; and / or l) Sufferes from higher-order aberrations at night or under dark conditions.

[0219] In some embodiments, a method for improving uncorrected near and distance visual acuity in a subject comprises administering to the subject a therapeutically effective amount of the ophthalmic pharmaceutical composition according to the Disclosure, wherein the ophthalmic pharmaceutical composition is a sustained-release composition. In some embodiments, the composition may be administered topically to the eye or periocular tissue of the subject. In some embodiments, the composition may be administered surgically to the inside or surface of the eye or periocular tissue of the subject. In some embodiments, the surgical intervention includes the step of implanting the ophthalmic pharmaceutical composition inside or to the inside or surface of the eye or periocular tissue of the subject (e.g., by intraocular implantation). In some embodiments, the ophthalmic pharmaceutical composition is implanted in the subconjunctival space, nasolacrimal duct, or vitreous humor of the subject. The composition may be in the form of a suspension, gel, ointment, injectable solution, spray, or eye drop formulation.

[0220] In any embodiment for improving uncorrected near and distance visual acuity in a subject, the effect of an ophthalmic pharmaceutical composition that reduces pupil size can be evaluated by methods well known in the art. For example, visual acuity may be determined at various distances using a standard visual acuity chart at each research visit. The test may be performed on one eye at a time by covering the untested eye, and / or on both eyes. Uncorrected visual acuity may be evaluated at moderate distances (50-80 cm) and / or near distances (40 cm). Visual acuity may be measured by: measuring at distance and moderate distances under normal lighting conditions and recording with a light meter. Near visual acuity is measured in both dark places (room lighting dimmed to half the normal level in the examination room) and bright places (full print lighting from the left shoulder), and both are recorded with a light meter. At distance and moderate distances, the luminance should be approximately 3000 lux. At close range, the brightness should be 750-1,000 lux for low contrast and 3,000 lux for high contrast. All visual acuity measurements can be recorded in decimal or LogMar notation. Decimal notation takes precedence.

[0221] Formulations containing ophthalmic compositions Other aspects of this disclosure relate to different formulations (e.g., implants or kits) that include the ophthalmic pharmaceutical compositions relating to this disclosure.

[0222] Some embodiments relate to implants comprising ophthalmic pharmaceutical compositions according to the present disclosure. In some embodiments, the implant may be introduced surgically into or onto the internal or external surface of the eye or peripheral tissue of the subject. In some embodiments, the surgical intervention includes the step of implanting (e.g., by intraocular insertion) the ophthalmic pharmaceutical composition into or onto the internal or external surface of the eye or peripheral tissue of the subject. In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous humor of the subject. In some embodiments, the ophthalmic pharmaceutical composition is a sustained-release composition.

[0223] Delivery via intravitreous microinserts near the fundus is known to be efficient and advantageous (e.g., WO2011 / 079123A1). The advantages of microinserts are that the components are released slowly and remain in the eye, and the fluid introduced onto the surface of the eyeball does not leak out through the natural drainage channels. Microinserts save the patient time and effort by avoiding frequent, repeated intravenous infusions.

[0224] In some embodiments, the sustained-release implant may be surgically implanted in the subconjunctival space by an ophthalmologist after determining that the patient would benefit from the implant following a preliminary experiment with topical eye drops. The components passively reach the iris and interact with the iris muscle fibers to alter pupil size. This action results in increased depth of field and improvement of hyperopia and myopia, as discussed in this disclosure (see Example 1).

[0225] In some embodiments, the implant may be introduced into the subject by surgical intervention, where the subject is: a) A person who wears spectacles but cannot or will not use progressive or bifocal lenses in the future; b) Have you had cataract surgery? c) Presbyopia developed after corneal treatment; d) Having a monofocal or multifocal intraocular lens; e) Wears contact lenses and cannot tolerate monocular lenses; f) Wears contact lenses and cannot tolerate multifocal lenses; g) Suffering from higher-order aberrations after corneal surgery; h) Having hyperopia or strabismus; i) Inability to tolerate changes in eyeglass prescription; j) I experienced a sudden change in my eyeglass prescription; k) There is a risk of falling when using progressive or bifocal lenses; and / or l) Sufferes from higher-order aberrations at night or under dark conditions.

[0226] In some embodiments, the implant is useful for correcting presbyopia in the subject. In some embodiments, the implant is useful for reducing pupil size in the subject. In some embodiments, the implant is useful for inducing pupillary constriction in the subject. In some embodiments, the implant is useful for increasing the depth of field in the subject's eye. In some embodiments, the implant is useful for reducing the degree of higher-order aberrations in the subject's eye. In some embodiments, the implant is useful for improving uncorrected near and far visual acuity in the subject.

[0227] Some embodiments relate to kits containing ophthalmic pharmaceutical compositions according to the present disclosure. The kit may include: a) a container containing the ophthalmic pharmaceutical composition described herein (e.g., a syringe, tube, vial, or dropper); b) instructions for use (which may include diagrams, drawings, or photographs in addition to text). The instructions may include a description of how to handle the materials (which may include storage conditions such as a temperature range for storage), how often to apply the composition, and the efficacy expected from the use of the composition.

[0228] In some embodiments, the kit may be provided to a subject, where the subject is: a) A person who wears spectacles but cannot or will not use progressive or bifocal lenses in the future; b) Have you had cataract surgery? c) Presbyopia developed after corneal treatment; d) Having a monofocal or multifocal intraocular lens; e) Wears contact lenses and cannot tolerate monocular lenses; f) Wears contact lenses and cannot tolerate multifocal lenses; g) Suffering from higher-order aberrations after corneal surgery; h) Having hyperopia or strabismus; i) Inability to tolerate changes in eyeglass prescription; j) I experienced a sudden change in my eyeglass prescription; k) There is a risk of falling when using progressive or bifocal lenses; and / or l) Sufferes from higher-order aberrations at night or under dark conditions.

[0229] In some embodiments, the kit is useful for correcting presbyopia in the subject. In some embodiments, the kit is useful for reducing pupil size in the subject. In some embodiments, the kit is useful for inducing pupillary constriction in the subject. In some embodiments, the kit is useful for increasing depth of field in the subject's eye. In some embodiments, the kit is useful for reducing the degree of higher-order aberrations in the subject's eye. In some embodiments, the kit is useful for improving uncorrected near and far visual acuity in the subject.

[0230] Methods for evaluating improvement in presbyopia One of the effects of changes in pupil size is changes in depth of field (DoF) and visual acuity. The depth of field of the eye is defined as the distance in diopters that an object can be moved closer to or further away from the eye until the retinal image is no longer clearly visible to the eye, while the eye is in a fixed refractive state (Atchison & Smith, 2000, Optics of the human eye, Edinburgh UK, Butterworths-Heinemann, p. 217). The measured depth of field (DoF) depends on several factors, including pupil size, visual acuity, and ambient test conditions. The main factors related to DoF have been comprehensively reviewed by Wang & Ciufredda (2006, Surv Ophthalmol 51:75-85) and later by Pallikaris et al (2011, J Ophthalmol 284961, doi: 10.1155 / 2011 / 284961).

[0231] Atchison et al (1997, Optom Vis Sci. 74:511-520) used apertures to simulate various pupil sizes and found that shifting pupil size from 4 mm to 2 mm increased the average DoF from 0.59 D to 0.86 D. They found a slight increase of 0.27 D. Similarly, Sergienko and Tutchenko (2007, Eur J Ophthalmol 17:836-840) reported that when visual acuity was 1.5, a 2 mm change in artificial pupil size from 5 mm to 3 mm resulted in a 0.26 D increase in DoF. Marcos et al (1999, Vision Res. 39:2039-2049) reported that DoF was affected by various ranges of composition for the observed targets with respect to changes in artificial pupil size, but the change was small on average, only 0.16 D. The slight change in DoF when pupil size decreases by approximately 50% is not significant. However, these results were obtained in a relatively small group of highly trained subjects with good visual acuity. Some have observed that in older subjects, central fixation and an increase in DoF tend to occur, sometimes as much as ±2.5D (Ronchi & Moleskini, 1975, Ophthalmic Res 7:152-157). This increase is likely related to spontaneous age-related pupillary constriction and changes in contrast sensitivity. Mordi and Ciufredda (1998, Vision Res. 38:1643-1653) predicted that DoF increases by 0.027D / year between ages 21 and 50. This corresponds to an increase of 0.80D over 30 years. The evidence for this continued increase clearly leads to the conclusion that: reducing pupil size increases DoF. Tabanero and Artal (2012, J Cataract Refract Surg 38:270-277) brilliantly demonstrated that when the 1.6 mm diameter opening of the Acufocus Kamra corneal implant simulates an artificial pupil in the corrected position, the depth of field (DoF) can be increased to a maximum of 2.5 D. This artificial pupil was positioned close to the actual pupil, but still approximately 3-4 mm away from the actual pupil's position.Studies investigating the effect of pupil size on DoF have used various artificial pupils placed in front of the eyeball or measured pupil size directly. To understand the actual effect of pupil size changes on DoF, adaptation paralysis is necessary, involving the placement of artificial openings of various sizes to prevent the effects of adaptation stimuli on DoF from influencing the actual DoF-pupil size relationship and to simulate the pupil size changes that occur when the actual pupil dilates (Mordi & Ciuffreda, 1998, Vision Res. 38:1643-1653). It would be useful to update DoF in the actual eye under clinical conditions without paralysis, and to compare pharmacologically induced actual changes in pupil size with changes in DoF measured comparatively under normal clinical conditions in patients who have not received proper training. Miotics, due to their biochemical properties, are likely to act not only on iris receptors but also on receptors located in the ciliary body, potentially leading to changes in accommodation and refractive error. Therefore, miotics that promote sufficient pupillary constriction with little effect on the refractive power of the lens are needed.

[0232] Procedure for estimating depth of field (DoF) at a distance DoF can be estimated after creating a defocus curve (Toto et al., 2007, J Cataract Refract Surg 33:1419-1425; Gupta et al., 2007, Cont Lenses Anterior Eye 30:119-124; Cillino et al., 2008, Ophthalmology 115:1508-1516; Cleary et al., 2010, J Cataract Refract Surg 36:762-770). A defocus curve is a graph plot of measured visual acuity (y-axis) in relation to the power of a series of trial spherical lenses placed in front of the eyeball. This is a stimulus-response curve that can be derived using various psychophysical techniques. In clinical practice, obtaining data to create a defocus curve is time-consuming and prone to several errors, including loss of patient concentration.

[0233] This study employed a long-established, simple, and rapid technique reviewed by Wang and Ciuffreda (2006, Surv Ophthalmol 51:75-85) and used by many researchers (see Example 1). Modifications to the basic technique have also been employed in recent studies (Yao et al., 2010, Vision Res 50:1266-1273; Benard et al., 2011, Vision Res 51:2471-2477). Patients were asked to view rows 20 / 30 of the Snellen target through glasses with the optimal corrective distance. The Plus sphere was increased in 0.25D increments at the head of the refractometer until the patient reported that the target was no longer unacceptably sharp. This was performed monocularly under normal ambient light conditions. Benard et al (2011, Vision Res 51:2471-2477) determined subjective DoF using 20 / 50 high-contrast characters. Yao et al (2010, Vision Res 50:1266-73) used a high-contrast square wave grating incorporated within a Badal lens apparatus. Although these two groups of researchers used different settings, the DoF results they found were very similar.

[0234] All of the claims in the claims are incorporated herein by reference in their entirety as additional embodiments. [Examples]

[0235] Example 1: Improvement of uncorrected distance and near visual acuity and depth of field in presbyopia and pseudophakic eyes by pharmacological changes in actual pupil diameter using a pilocarpine composition. The purpose of this embodiment is to measure the effect of actual changes in pupil size on depth of field (DoF) and visual acuity in presbyopia and monofocal or multifocal IOL implants, accompanying routine eye examinations in a clinical setting. A reduction in pupil size increases DoF and, consequently, improves visual acuity.

[0236] Procedures and methods for reducing pupil size (miosis) The use of pilocarpine carries a risk of irritation and inflammation after topical instillation.

[0237] Mixing NSAIDs and tear film compotes with pilocarpine may act as a preventative measure to address pilocarpine-induced inflammatory responses and dry eye.

[0238] As described later, mixing 0.2% pilocarpine hydrochloride or pilocarpine nitrate with 0.006% diclofenac sodium was found to be well-tolerated for topical application and to induce significant miosis. No evidence of short-term or long-term undesirable complications specifically associated with the topical application of 0.006% diclofenac mixed with sodium hyaluronate at concentrations typically used in combination with tear comfort agents was found. Therefore, it was decided to prepare a mixture of 0.1% sodium hyaluronate, 0.2% pilocarpine hydrochloride or pilocarpine nitrate, and 0.006% diclofenac sodium solely for the purpose of providing miosis with minimal discomfort. In this example, the percentile was determined by weight (w / v). This combination was provided in a special formulation to induce miosis during the planned trial. The results showed that, after topical application of the formulation, uncorrected distance and near visual acuity improved by reducing the spontaneous pupil diameter.

[0239] Methods and materials 1. Measuring pupil size The pupil size was measured using an infrared imaging system, which is used to verify alignment during automated refractive index measurement. The infrared image of the pupil, converted to visible light, magnified, and displayed on the device's observation screen, allows the user to observe the pupil and align the instrument during normal use. The vertical and horizontal pupil diameters were measured on the screen using a ruler when the subject was viewing a target at infinity. The average of the two measurements was recorded and magnification correction (approximately ×7 to ×8) was applied to both the vertical and horizontal meridian magnification.

[0240] 2. Visual acuity measurement All visual acuity measurements were taken using the Snellen visual acuity chart for far distances and the Jaeger visual acuity chart for near distances. All values ​​were converted to decimal notation using Halliday's conversion table.

[0241] 3. Procedure for evaluating depth of field (DoF) at the far point. Patients were asked to view lines 20 / 30 of the Snellen visual acuity chart through glasses with the optimal corrective power. The positive sphere in the refractometer head was increased in 0.25D increments (+a diopters) until the patient reported blurring. This procedure was repeated using a negative lens (-b diopters). DoF at the far point = (a+b) diopters. This procedure was performed monocularly on a monocular basis in both presbyopic and pseudophakic eyes under normal ambient lighting conditions (350 lux).

[0242] 4. Procedure for evaluating the depth of field (DOF) at the periphery point. The optimal corrective distance for eyeglasses was increased in +2.50D increments on the refractometer head, and the patient was asked to view a line of J2 typeface at a distance of 0.40m. The positive power of the refractometer head was increased in 0.25D increments (+x diopters) until the patient reported blurring. This procedure was repeated using a negative lens (-y diopters). DoF at the near point = (x+y) diopters. This procedure was performed monocularly on a presbyopic basis under normal peripheral lighting conditions (350 lux).

[0243] 5. Research Design The study was a sequential, prospective, non-randomized interventional trial in accordance with the principles of the Declaration of Helsinki. All presbyopia subjects were recruited from patients participating in routine eye examinations. Exclusion criteria included a history of amblyopia, eye disease or surgery, cataracts, macular degeneration, irregular pupils, or any systemic condition known to affect pupillary dynamics or visual quality. Pseudophakic eye patients were also recruited from those participating in routine eye examinations. Exclusion criteria included a history of amblyopia, ocular complications, implantation with a tolubilic or multifocal IOL, signs of macular degeneration, theca thickening, irregular pupils, or any systemic condition known to affect pupillary dynamics or visual quality. Where appropriate, measurements were taken from both eyes. All subjects were fully informed of the nature and purpose of this study.

[0244] Data was collected before topical application of 1-2 drops of the formulation per eye and 1 hour after application. Any symptoms reported by the subjects (e.g., dryness, nausea, gritty feeling in the eye, etc.) were also recorded.

[0245] 6. Measurement and statistical analysis of the reaction The data was analyzed for the following purposes: 1) Investigate whether uncorrected distance visual acuity was affected by intravenous infusion into presbyopic and pseudophakic eyes (Wilcoxon signed-rank test); 2) Investigate whether uncorrected near vision was affected by intravenous infusion into presbyopic and pseudophakic eyes (Wilcoxon signed-rank test); 3) To compare DoF measurements of the distance between presbyopic and pseudophakic eyes (t-test); 4) Investigate whether there was any relationship between the measured pupil size, age, and DoF measurement at near point distance (Pearson's correlation coefficient); 5) Investigate whether there was any relationship between the measured pupil size, age, and DoF measurement at the far point (Pearson's correlation coefficient); and 6) Investigate whether any changes in DoF at the far point distance were related to changes in pupil size (Pearson correlation coefficient).

[0246] When measurements were obtained from both eyes, appropriate data from the right and left eyes were stored separately to avoid Type I statistical errors. The significance level was set to a p-value of less than 0.05. Bonferroni correction was applied to the data for multiple comparison analysis.

[0247] result Twenty-seven subjects (27) were administered one drop per eye, and 18 subjects (18) were administered two drops of the ophthalmic pharmaceutical composition per eye. In the case of subjects receiving two drops per eye, the second instillation was administered a few seconds after the first instillation.

[0248] The presbyopia group consisted of 18 women and 11 men. A total of 5 people reported side effects including nausea (n=1), dryness (n=1), burning sensation (n=1), blurred vision (n=1), and a stinging sensation (n=1). The pseudophakic eye group consisted of 10 women and 6 men. In this group, 2 people reported a stinging sensation, and the other 2 experienced a burning sensation after instillation. The reported reactions were short-lived and did not cause serious problems.

[0249] In both groups, uncorrected visual acuity at both near and far distances significantly improved after administration of eye drops having the composition disclosed in this embodiment. A simultaneous and significant increase in mean depth of field and a reduction in pupil size were observed. The main results are shown in Tables 1 and 2. [Table 1] [Table 2]

[0250] Compared to the pseudophakic eye group, the average pupil diameter was significantly larger in the presbyopic group both before and after eye drop administration (p<0.001). There was no significant difference in average depth of field between the groups before eye drop administration. However, there was a significant difference between the groups after eye drop administration (p<0.001) (Tables 1 and 2).

[0251] In the presbyopia group, there was no significant association between i) pupil size and age, ii) age and depth of field at far or near distances, and iii) pupil size and depth of field at far or near distances.

[0252] In the pseudophakic eye group, no significant associations were found between i) pupil size and age, ii) age and depth of field at far distances, and iii) pupil size and depth of field.

[0253] Within each group, no significant difference was observed between the results obtained from the right eye and the left eye in bilateral cases. Because there was no clear bias in either the right or left eye, data from both eyes could be pooled for specific types of analysis. For example, in Figures 1 and 2, when examining the possible relationship between changes in depth of field (ΔDoF) and changes in pupil size (ΔPupil) in individual cases, data from the right and left eyes were pooled for specific types of analysis.

[0254] A significant correlation was observed between ΔDoF and ΔPupil diameter in the presbyopia group. These results are shown in Figure 1 (far point) and Figure 2 (near point). The least-squares regression line that equates ΔDoF (y, diopters) and ΔPupil diameter (x, mm) at the far point had the following form: y=0.409-0.289x(r=-0.437,n=53,p<0.001) [Equation 1]. Similarly, the least-squares regression line that equates ΔDoF(y, diopters) and Δpupil diameter(x, mm) at the peripole had the following form: y=0.352-0.253x(r=-0.429,n=53,p<0.001) [Equation 2].

[0255] Within the pseudophakic eye group, no significant correlation was found between ΔDoF and Δpupillary diameter. No significant correlation was found even after combining all data from both groups. The least-squares regression line that equates ΔDoF of the far point distance with Δpupillary diameter for the combined data was of the following form: y = 0.526 - 0.299 x (r = -0.395, n = 81, p < 0.001) [Equation 3].

[0256] Consideration Forty-five subjects participated in this pilot study, of whom 29 had presbyopia and 16 had pseudophakic eyes (subjects with implanted monofocal IOLs). A total of nine subjects (20%) reported mild irritation after intravenous administration of the eye drops. One subject reported dryness, one experienced blurred vision, one felt nausea and headache, three reported a stinging sensation, and three others described a burning sensation after instillation of the eye drops. No subjects reported overall dissatisfaction after administering the eye drops.

[0257] In both groups, uncorrected near and far visual acuity improved after topical application of the formulation. Converting the data in Tables 1 and 2 to Snellen and Jaegar notation, it can be seen that in presbyopia, typical uncorrected distance visual acuity improved from 20 / 20 to 20 / 15, and uncorrected near visual acuity improved from approximately J8 to J6. Referring to the results in Table 1, a 0.72 mm reduction in pupil diameter was associated with improvements in both uncorrected near and far visual acuity in presbyopia. In the pseudophakic eye group, typical uncorrected distance visual acuity improved from 20 / 30 to 20 / 25, and uncorrected near visual acuity improved from J8 to J3. The results in Tables 1 and 2 show that, compared to the presbyopia group, a 1.01 mm reduction in pupil diameter was associated with a significant improvement in uncorrected near visual acuity and a small improvement in uncorrected distance visual acuity in the pseudophakic eye cohort.

[0258] This anomaly may be related to the fact that the pupil is smaller from the start in pseudophakic eyes. Pupil size tends to be smaller in older subjects compared to younger subjects (Birren et al., 1950, J Gerontol 5:216-221; Winn et al., 1994, Investigative Opthalmology & Visual Science 35:1132-1137). No correlation was found between age and pupil size in either of our two groups. However, the mean (±sd) pupil diameter and age in the presbyopia group were 3.89 mm (0.74, right eye), 3.84 mm (0.81, left eye), and 48.7 years (4.20). In the pseudophakic eye group, the corresponding values ​​were 2.92 mm (0.36), 2.97 mm (0.43), and 67.2 years (±7.5). The aberrations between the two groups were significant for both pupil size and age. The smaller pupil size in the pseudophakic eye group was likely more related to the age of the subjects in this cohort than to the patients who had undergone cataract surgery. This, coupled with the differences in optical properties between phakic presbyopia and pseudophakic eyes, is probably the main factor behind the slight differences in response to eye drops.

[0259] The mean DoF values ​​in both groups before the application of eye drops were remarkably similar to those reported previously. Table 1 shows the mean (±sd) DoF values ​​at the far point in presbyopia: 1.31D (0.42) and 1.41D (0.45). These values ​​fall within the limit of up to 1.8D reported in the topic review by Wang and Ciuffreda (2006, Surv Ophthalmol 51:75-85). Table 2 shows the mean DoF values ​​at the far point in pseudophakic eyes: 1.61D (0.51) and 1.65D (0.52). These values ​​fall within the reported limits of 0.80D–1.65D after monofocal IOL implantation (Kamlesh & Kaushik, 2001, Can J Ophthalmol 36:197-201; Macsai et al, 2006, J Cataract Refract Surg. 32:628-633; Nishi et al., 2013, Clin Ophthalmol 7:2159-2164).

[0260] In both the presbyopic and pseudophakic eye groups, the mean Depth of Field (DF) increased after eye drop injection. In the pseudophakic eye group, a mean increase in DoF of 1.03D was accompanied by a mean decrease in pupil size of 1.05mm. Depth of field measured at the far point remained unchanged in 5 of the 53 presbyopic patients. However, in the same 5 patients, pupil size decreased, and the depth of field measured at the near point increased by up to 1D. By pooling all data in our disposal, a significant relationship was revealed between changes in pupil size (Δpupillary diameter) and changes in DoF (ΔDoF). The exponent of the linear regression equation predicts that a 1mm reduction in pupil diameter will result in a simultaneous increase of 0.83D in DoF at the far point and 0.61D in DoF at the near point.

[0261] As described above, uncorrected far and near visual acuity improved after topical application of this formulation.

[0262] Of the 45 subjects, nine reported side effects, but none expressed overall dissatisfaction with the formulation. The formulation was well tolerable, with one subject even inquiring whether it could be used permanently.

[0263] Example 2: Safety, tolerability, and efficacy of CSF-1 in presbyopia CSF-1 is a topical ophthalmic eye drop containing 0.2% pilocarpine hydrochloride or pilocarpine nitrate, 0.006% diclofenac sodium, 0.1% sodium hyaluronate, and 0.8% hydroxypropyl methylcellulose. In this example, the percentile is determined by weight (w / w). The formulation is designed to provide pupillary constriction and increase depth of field for temporary correction of presbyopia. The placebo contains the same components as the investigational drug, excluding the active ingredient.

[0264] subject This example was a double-blind, randomized, placebo-controlled, bidirectional crossover repeated-dose trial conducted in subjects with presbyopia. After signing informed consent and undergoing screening evaluations, subjects were randomly assigned in a 1:1 ratio to one of two treatment sequences as follows: [ka] Each treatment, CSF-1 or placebo, was self-administered by the subjects over two weeks (one drop each morning into each eye), with a 24-hour washout period between treatments. The acceptable interval between treatment visits was 11–17 days. All subjects received the same evaluation regardless of their treatment group assignment. Each subject was followed up for two weeks after the end of the treatment period. The maximum duration for individual patients was 64 days (~9 weeks), including the following periods: Screening period: Up to 21 days (comprehensive); Treatment period: 29 days; and Observation period: 14 days.

[0265] The purpose of this examination was as follows: 1) To establish the safety and tolerability of repeated administration of CSF-1 in patients with presbyopia; and 2) Determine the effectiveness of repeated administration of CSF-1 in patients with presbyopia.

[0266] Methods and materials 1. Measuring pupil size The pupil size was measured using an infrared imaging system, which is used to verify alignment during automated refractive index measurement. The infrared image of the pupil, converted to visible light, magnified, and displayed on the device's observation screen, allows the user to observe the pupil and align the instrument during normal use. The vertical and horizontal pupil diameters were measured on the screen using a ruler when the subject was viewing a target at infinity. The average of the two measurements was recorded, and magnification correction (approximately ×7 to ×8) was applied to both the vertical and horizontal meridian magnification.

[0267] 2. Visual acuity measurement All visual acuity measurements were taken using FDA-approved standard EDTRS visual acuity charts at both far and near distances. EDTRS visual acuity charts provide visual acuity measurements in Snellen, decimal, and logMAR notation. The design of these charts features a simple column of letter-sized 0.1 units on a logMAR scale, moving from one line of text to the next, and a scale for conversion to other notations such as Snellen or decimal. For example, if a subject can only identify the letter at the top of the 11th line of an EDTRS visual acuity chart at a distance of 4M, designated as a 20 / 20 Snellen visual acuity, the subject's visual acuity can be expressed as 0.0 logMAR or 1.0 decimal alongside the 20 / 20 notation. Visual acuity that allows the subject to identify the letter at the top of the next line, i.e., the 12th line, would indicate a visual acuity of -0.1 logMAR, 1.25 decimal, or 20 / 16 Snellen. The logMAR notation provides a more accurate and valid statistical comparison. Distance visual acuity was measured in both eyes under standard high ambient illumination (~3,000 lux) during the visual acuity test, using monocular vision (right eye followed by left eye) and binocular vision. Near visual acuity was measured in both eyes under standard high ambient illumination (~3,000 lux) using monocular vision (right eye followed by left eye) and binocular vision, and then repeated under lower illumination (20-1,000 lux).

[0268] 3. Procedures for evaluating peripheral vision Visual field was evaluated using a standard clinical trial, commonly referred to as a face-to-face test, known in the industry. This test checks for any visual field loss or abnormalities in the superior, inferior, nasal, and temporal regions of each eye's visual field.

[0269] 4. Procedure for evaluating depth of field (DoF) at the far point. The patient was asked to view the 0.1 logMAR row of the eye chart through glasses with the best corrective power. The positive sphere in the refractometer head was increased in 0.25D increments (+a diopters) until the patient reported blurring. This procedure was repeated using a negative lens (-b diopters). DoF at the far point = (a+b) diopters. This operation was performed monocularly under normal ambient light conditions (~3000 lux).

[0270] 5. Procedure for evaluating depth of field (DoF) at the periphery point. The patient was asked to view the 0.1 logMAR row of the visual acuity chart through glasses with the optimal corrective power. The positive sphere in the refractometer head was increased in 0.25D increments (+a diopters) until the patient reported blurring. This procedure was repeated with a negative lens (-y diopters). DoF at the near point = (a+b) diopters. This procedure was performed monocularly under normal ambient light conditions (~3000 lux).

[0271] 6. Procedure for evaluating the effects The initial effect endpoint was defined as a 0.2 or 0.3 improvement in uncorrected near visual acuity (UNVA) according to logMAR notation. This was equivalent to a 2 or 3-line improvement in visual acuity using a standard EDTRS visual acuity chart for near visual acuity (40 cm).

[0272] 7. Research Design The study was a double-blind, bicentered, randomized, placebo-controlled, repeated-dose, crossover trial to establish the safety, tolerability, and efficacy of CSF-1 in presbyopia, in accordance with the principles of the Declaration of Helsinki. All presbyopia subjects were recruited from patients participating in routine eye examinations. All subjects had a best-corrected visual acuity of at least 20 / 20 equal to 0.0 on the logMAR scale, and all relied on reading glasses or bifocals with myopia correction >+1.00 diopters. In addition, all subjects required no or minimal optical distance correction, such that spherical parts were ±0.75 diopters or less and / or cylindrical parts were ±0.75 DC or less, and refraction along any principal meridian was 1.00 diopter or less. Exclusion criteria included cases with amblyopia, eye disease or surgery, cataracts, macular degeneration, irregular pupils, a natural pupil diameter of less than 2.5 mm per eye under ambient illumination of 8–15 lux, and a history of any systemic condition known to affect pupillary dynamics or visual quality. Measurements were taken from both eyes where appropriate. All participants were fully informed of the nature and purpose of this study.

[0273] Data was collected before administration and during daily self-administration of either CSF-1 or placebo to both eyes, at the time of the patient's visit to the clinic. Any symptoms reported by the patient (e.g., dryness, nausea, gritty feeling in the eyes, etc.) were also recorded.

[0274] 8. Measurement and statistical analysis of the reaction The data was analyzed for the following purposes: 1) Check whether uncorrected distance visual acuity was affected by the eye drops; 2) Check whether uncorrected near vision was affected by the eye drops; 3) Check whether the pupil size was affected by the eye drops; 4) Investigate whether the depth of field at distance and near is affected by the eye drops.

[0275] To analyze quantitative changes, appropriate statistical tests were applied, such as McNemar's test and paired t-test for paired samples, or signed-rank tests (paired observations) for two means. All tests were two-tailed, and p-values ​​less than 5% were considered statistically significant.

[0276] result Thirty-six participants (21 women and 15 men, mean age 51.5 years [sd=±4.43], range 44.5–62.5 years) completed the study.

[0277] In both eyes and the right eye, there was no overall difference in uncorrected distance visual acuity between the CSF-1 and placebo groups. In the left eye, CSF-1 significantly improved uncorrected visual acuity. In the left eye, the difference between CSF-1 and placebo was statistically significant. Important information is listed in Table 3.

[0278] [Table 3]

[0279] A significant change in mean uncorrected near visual acuity was observed after CSF-1 treatment compared to any change observed after placebo. The change after CSF-1 treatment was substantially greater than any change observed with placebo. Important information is presented in Tables 4-6.

[0280] [Table 4] [Table 5] [Table 6] Compared to any changes after using a placebo, a significant change was observed in the average depth of field at both far and near distances after using CSF-1. Important information is presented in Table 7.

[0281] [Table 7] Compared to the changes observed after using a placebo, a significant change in the average depth of field at both the far and near points was observed after using CSF-1. Important information is presented in Table 8.

[0282] [Table 8] No significant changes were observed in tear film stability after using either CSF-1 or placebo. Important information is presented in Table 9.

[0283] [Table 9]

[0284] Consideration uncorrected distance vision A certain concentration of pilocarpine stimulates the ciliary muscle, leading to accommodation and reducing distance visual acuity (see, for example, Emsley, 1972, Optics of Vision, 5th edition, Visual Optics Vol. 1, London UK, Butterworths, p. 88; Williams, 1976, J Am Optom Assoc 47:761-764; Mazor et al., 1979, Br J Ophthalmol 63:48-51; Edgar et al., 1999, Graefes Arch Clin Opthalmol 237:117-124). CSF-1 improved uncorrected near visual acuity but did not reduce uncorrected distance visual acuity. Since distance visual acuity was not impaired (Table 3), the data indicate that CSF-1 did not stimulate accommodation at all. More specifically, unexpectedly, 91.7% of eyes treated with CSF-1 showed no change in uncorrected distance visual acuity. When a placebo was used, only 86.2% of eyes showed no change in uncorrected distance visual acuity.

[0285] uncorrected near vision Only pilocarpine concentrations of 0.5% or higher are effective in improving near visual acuity (U.S. Patent No. 9,579,308). However, the results of this study show that, unexpectedly, uncorrected binocular near visual acuity at 40 cm improved by more than two rows in 41.7% of patients using CSF-1 and 22.2% of patients using placebo under high ambient light conditions (p=0.0348) (Table 4). Under low ambient light conditions, 41.7% of patients were recorded as showing such a clear increase in uncorrected binocular near visual acuity, whereas only 16.7% of patients using placebo were recorded as showing such an increase (p=0.0067) (Table 5).

[0286] Moving on to results obtained from individual eyes, under low ambient light conditions, CSF-1 administration resulted in an improvement of three or more rows in uncorrected near visual acuity at 40 cm in 27.8% of left eyes and 22.2% of right eyes (Table 5). However, in the placebo group, improvement of three or more rows was observed in only 2.8% of left eyes and 5.6% of right eyes (p<0.0143 right eye & p<0.0027 left eye) (Table 5). These findings were unexpected, as pilocarpine is expected to reduce retinal brightness and visual acuity under low ambient light conditions by decreasing pupil size and limiting the amount of light entering the eye.

[0287] pupil At low concentrations of pilocarpine (less than 1%), it will likely have little effect on pupil size (Mazor et al., 1979, Br J Opthalmol 63:48-51; Edgar et al., 1999, Graefes Arch Clin Exp Opthalmol 237:117-124). However, this study revealed an unexpected and significant result: the average pupil size was 4.29 mm before CSF-1 administration, but it constricted to an average of 3.10 mm after CSF-1 instillation (Table 7). While not bound by mechanistic theories, these results suggest that CSF-1 acts through miosis rather than accommodation.

[0288] depth of field Depth of field is inversely proportional to pupil size. As pupil size decreases, depth of field increases. Low concentrations of pilocarpine (less than 1%) will have little effect on pupil size (Mazor et al., 1979, Br J Opthalmol 63:48-51; Edgar et al., 1999, Graefes Arch Clin Exp Opthalmol 237:117-124). Therefore, it is not expected that the increase in DoF is due to the administration of pilocarpine at less than 1%. However, this study revealed an unexpectedly significant increase in depth of field after CSF-1 administration compared to the changes observed after placebo administration, at both far and near distances (Table 8).

[0289] Tear film Topical eye drops containing pilocarpine salts can induce dry eye due to both decreased tear production and reduced stability of the tear film (Nuzzi et al., 1998, Int Opthalmol 22:31-35; Baffa et al., 2008, Arq Bras Opthalmol 71:18-21). Unexpectedly, this study showed no significant change, either decrease or increase, in tear film stability after the use of either CSF-1 or placebo (Table 9).

[0290] Field of view under low light conditions The miosis caused by pilocarpine can affect visual field and visual acuity when ambient light levels are low. Therefore, patients may notice partial vision loss or a reduced ability to perform important tasks when good vision is required at night. Unexpectedly, no reduction or shrinkage of overall visual field size was reported in patients using either CSF-1 or placebo. The study results showed that all 23 patients whose visual fields were tested in both the drug and placebo groups had normal visual fields and showed no reduction at all. At the start of the study, 75% of participants reported being able to drive at night without glasses. After using CSF-1 or placebo, this percentage increased to 83% and 86%, respectively.

Claims

1. An ophthalmic pharmaceutical composition comprising one therapeutic active ingredient, pilocarpine or a pharmaceutically acceptable salt thereof, in a concentration of 0.2% to 0.4% (w / w or w / v); at least one pharmaceutically acceptable carrier; and at least one component selected from hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, and povidone.

2. The ophthalmic pharmaceutical composition according to claim 1, wherein the aforementioned component comprises a mixture of sodium hyaluronate and hydroxypropyl methylcellulose.

3. The ophthalmic pharmaceutical composition according to claim 1 or 2, wherein the sodium hyaluronate is present at a concentration of 0.01% to 0.9% (w / w or w / v), and the hydroxypropyl methylcellulose is present at a concentration of 0.1% to 2.0% (w / w or w / v).

4. The ophthalmic pharmaceutical composition according to any one of claims 1 to 3, wherein the at least one pharmaceutically acceptable carrier comprises a solvent.

5. The ophthalmic pharmaceutical composition according to any one of claims 1 to 4, wherein the at least one pharmaceutically acceptable carrier comprises an isotonic agent.

6. The ophthalmic pharmaceutical composition according to claim 5, wherein the isotonic agent comprises sodium chloride.

7. The ophthalmic pharmaceutical composition according to any one of claims 1 to 6, wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

8. The ophthalmic pharmaceutical composition according to any one of claims 1 to 7, wherein the ophthalmic pharmaceutical composition is a sustained-release composition.

9. The ophthalmic pharmaceutical composition according to any one of claims 1 to 8, wherein the ophthalmic pharmaceutical composition is in the form of a suspension, gel, ointment, injectable solution, spray, or eye drop formulation.

10. The ophthalmic pharmaceutical composition according to any one of claims 1 to 9, wherein the ophthalmic pharmaceutical composition is suitable for implantation into or on the surface of the target eye or surrounding tissue; or the ophthalmic pharmaceutical composition is suitable for implantation into the subconjunctival space, nasolacrimal duct, or vitreous cavity of the target; or the ophthalmic pharmaceutical composition is suitable for local delivery to the target eye or surrounding tissue.

11. An ophthalmic pharmaceutical composition according to any one of claims 1 to 10 for correcting presbyopia for up to 24 hours.

12. An ophthalmic pharmaceutical composition according to any one of claims 1 to 11, for correcting presbyopia without adversely affecting night vision or unfavorably narrowing the field of vision.

13. An ophthalmic pharmaceutical composition comprising one therapeutic active ingredient, pilocarpine or a pharmaceutically acceptable salt thereof, in a concentration of 0.2% to 0.4% (w / w or w / v), at least one pharmaceutically acceptable carrier, and at least one component from among hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, and povidone, for correcting presbyopia in a subject.

14. The ophthalmic pharmaceutical composition according to claim 13, wherein the aforementioned component comprises a mixture of sodium hyaluronate and hydroxypropyl methylcellulose.

15. The ophthalmic pharmaceutical composition according to claim 13 or 14, wherein the sodium hyaluronate is present at a concentration of 0.01% to 0.9% (w / w or w / v), and the hydroxypropyl methylcellulose is present at a concentration of 0.1% to 2.0% (w / w or w / v).

16. The ophthalmic pharmaceutical composition according to any one of claims 13 to 15, wherein the at least one pharmaceutically acceptable carrier comprises a solvent.

17. The ophthalmic pharmaceutical composition according to any one of claims 13 to 16, wherein the at least one pharmaceutically acceptable carrier comprises an isotonic agent.

18. The ophthalmic pharmaceutical composition according to claim 17, wherein the isotonic agent comprises sodium chloride.

19. The ophthalmic pharmaceutical composition according to any one of claims 13 to 18, wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

20. The ophthalmic pharmaceutical composition according to any one of claims 13 to 19, wherein the ophthalmic pharmaceutical composition is a sustained-release composition.

21. The ophthalmic pharmaceutical composition according to any one of claims 13 to 20, wherein the ophthalmic pharmaceutical composition is in the form of a suspension, gel, ointment, injectable solution, spray, or eye drop formulation.

22. The ophthalmic pharmaceutical composition according to any one of claims 13 to 21, wherein the ophthalmic pharmaceutical composition is suitable for implantation into or on the surface of the target eye or surrounding tissue; or, the ophthalmic pharmaceutical composition is suitable for implantation into the subconjunctival space, nasolacrimal duct, or vitreous cavity of the target; or, the ophthalmic pharmaceutical composition is suitable for local delivery to the target eye or surrounding tissue.

23. An ophthalmic pharmaceutical composition according to any one of claims 13 to 22 for correcting presbyopia for up to 24 hours.

24. An ophthalmic pharmaceutical composition according to any one of claims 13 to 23, for correcting presbyopia without adversely affecting night vision or significantly narrowing the field of vision.

25. The aforementioned object has at least one of the following characteristics: a) A person who wears eyeglasses and is unable to use or will not use progressive or bifocal lenses in the future; b) I have had cataract surgery; c) Presbyopia developed after corneal treatment; d) Having a monofocal or multifocal intraocular lens; e) Wears contact lenses and cannot tolerate monocular lenses; f) Wears contact lenses and cannot tolerate multifocal lenses; g) Suffering from higher-order aberrations after corneal surgery; h) Having hyperopia or strabismus; i) Inability to tolerate changes in eyeglass prescription; j) I experienced a sudden change in my eyeglass prescription; k) There is a risk of falling when using progressive or bifocal lenses; and / or l) Suffering from higher-order aberrations at night or under dark conditions , the ophthalmic pharmaceutical composition according to any one of claims 13 to 24.

26. An ophthalmic pharmaceutical composition comprising one therapeutic active ingredient, pilocarpine or a pharmaceutically acceptable salt thereof, in a concentration of 0.2% to 0.4% (w / w or w / v), at least one pharmaceutically acceptable carrier, and at least one component from among hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, and povidone, for the purpose of reducing the size of the pupil in a subject.

27. An ophthalmic pharmaceutical composition comprising one therapeutic active ingredient, pilocarpine or a pharmaceutically acceptable salt thereof, in a concentration of 0.2% to 0.4% (w / w or w / v), at least one pharmaceutically acceptable carrier, and at least one component from among hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, and povidone, for inducing pupillary constriction in a subject.

28. An ophthalmic pharmaceutical composition comprising one therapeutic active ingredient, pilocarpine or a pharmaceutically acceptable salt thereof, in a concentration of 0.2% to 0.4% (w / w or w / v), at least one pharmaceutically acceptable carrier, and at least one component from among hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, and povidone, for increasing the depth of field in the target eye.

29. An ophthalmic pharmaceutical composition comprising one therapeutic active ingredient, pilocarpine or a pharmaceutically acceptable salt thereof, in a concentration of 0.2% to 0.4% (w / w or w / v), at least one pharmaceutically acceptable carrier, and at least one component from among hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, and povidone, for reducing the degree of higher-order aberrations in the target eye.

30. An ophthalmic pharmaceutical composition comprising one therapeutic active ingredient, pilocarpine or a pharmaceutically acceptable salt thereof, in a concentration of 0.2% to 0.4% (w / w or w / v), at least one pharmaceutically acceptable carrier, and at least one component from among hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, and povidone, for improving uncorrected near and far visual acuity in a subject.

31. An implant comprising an ophthalmic pharmaceutical composition containing one therapeutic active ingredient, pilocarpine or a pharmaceutically acceptable salt thereof, in a concentration of 0.2% to 0.4% (w / w or w / v), at least one pharmaceutically acceptable carrier, and at least one component from among hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, and povidone.

32. A kit comprising an ophthalmic pharmaceutical composition containing one therapeutic active ingredient, pilocarpine or a pharmaceutically acceptable salt thereof, in a concentration of 0.2% to 0.4% (w / w or w / v); at least one pharmaceutically acceptable carrier; and at least one component from among hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, and povidone.

33. The ophthalmic pharmaceutical composition according to any one of claims 26 to 31, wherein the aforementioned component comprises a mixture of sodium hyaluronate and hydroxypropyl methylcellulose.

34. The ophthalmic pharmaceutical composition according to any one of claims 26 to 31 and 33, wherein the sodium hyaluronate is present at a concentration of 0.01% to 0.9% (w / w or w / v), and the hydroxypropyl methylcellulose is present at a concentration of 0.1% to 2.0% (w / w or w / v).

35. The ophthalmic pharmaceutical composition according to any one of claims 26 to 31, 33, and 34, wherein the at least one pharmaceutically acceptable carrier comprises a solvent.

36. The ophthalmic pharmaceutical composition according to any one of claims 26 to 31 and 33 to 35, wherein the at least one pharmaceutically acceptable carrier comprises an isotonic agent.

37. The ophthalmic pharmaceutical composition according to claim 36, wherein the isotonic agent comprises sodium chloride.

38. An ophthalmic pharmaceutical composition comprising one therapeutic active ingredient, pilocarpine or a pharmaceutically acceptable salt thereof, in a concentration of 0.2% to 0.4% (w / w or w / v); at least one pharmaceutically acceptable carrier; and one or more components selected from hydroxypropyl methylcellulose, sodium hyaluronate, one or more pH agents, one or more stabilizers, one or more solvents, and one or more isotonic agents.

39. The ophthalmic pharmaceutical composition according to claim 38, wherein the salt of pilocarpine is pilocarpine hydrochloride.

40. The ophthalmic pharmaceutical composition according to claim 38 or 39, wherein the pilocarpine hydrochloride is present at a concentration of 0.4% (w / w or w / v).

41. The ophthalmic pharmaceutical composition according to any one of claims 38 to 40, wherein the hydroxypropyl methylcellulose is present at a concentration of 0.8% (w / w or w / v).

42. The ophthalmic pharmaceutical composition according to any one of claims 38 to 41, wherein the sodium hyaluronate is present at a concentration of 0.1% (w / w or w / v).

43. An ophthalmic pharmaceutical composition according to any one of claims 38 to 42, comprising: 0.4% (w / w or w / v) concentration of pilocarpine or a pharmaceutically acceptable salt thereof; at least one pharmaceutically acceptable carrier; 0.8% (w / w or w / v) concentration of hydroxypropyl methylcellulose; 0.1% (w / w or w / v) concentration of sodium hyaluronate, sodium chloride, one or more pH agents, one or more solvents, and one or more stabilizers.

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