Ophthalmic pharmaceutical compositions and uses relating thereto

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 August 19, 2016, the entire contents of which are incorporated herein by reference.

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

[0003] Presbyopia is a near vision impairment resulting from the gradual loss of lens accommodation, usually after the age of 40–45. It is the most common physiological change occurring in the adult eye and, if uncorrected, can significantly impact quality of life and productivity (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 primary symptom of this condition is a gradual blurring of vision when performing near tasks (e.g., reading, sewing, working at a computer). This can occur in the absence of visual symptoms related to distance vision. It is estimated that the global prevalence of presbyopia will reach 1.4 billion people 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 modify the optics of the cornea, replace the crystalline lens with a different fixed optic, or attempt to at least partially restore the active area (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 have problems with night vision after surgical intervention. Currently, no clinically effective pharmaceutical preparations are available to treat the symptoms of presbyopia.

[0005] Therefore, new methods of improving or correcting presbyopia remain needed to avoid the obvious disadvantages for patients who are forced to wear corrective lenses or undergo risky and unwanted surgery. Summary of the Invention

[0006] The present disclosure relates to ophthalmic pharmaceutical compositions containing pilocarpine or a pharmaceutically acceptable salt thereof. The present disclosure also provides preparations (e.g., kits or implants) of ophthalmic pharmaceutical compositions containing pilocarpine or a pharmaceutically acceptable salt thereof. Furthermore, the present disclosure also provides methods useful for correcting presbyopia and other ocular conditions in a subject.

[0007] Certain embodiments of the present disclosure are summarized in the following paragraphs. This list is illustrative only and is not intended to be an exhaustive list of all embodiments provided by the present disclosure.

[0008] Embodiment 1. An ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof at 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. 2. The ophthalmic pharmaceutical composition of embodiment 1, wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

[0010] Embodiment 3. The ophthalmic pharmaceutical composition of embodiment 1, further comprising diclofenac or a pharmaceutically acceptable salt thereof at 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 at a concentration of 0.01% (w / w or w / v) to 0.60% (w / w or w / v).

[0011] Embodiment 4. 4. The ophthalmic pharmaceutical composition of embodiment 3, wherein the diclofenac salt is diclofenac sodium or the ketorolac salt is ketorolac tromethamine.

[0012] Embodiment 5. 2. The ophthalmic pharmaceutical composition of embodiment 1, wherein the ophthalmic pharmaceutical composition further comprises a lubricant.

[0013] Embodiment 6. 6. The ophthalmic pharmaceutical composition of 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, a polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or a mixture thereof.

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

[0015] Embodiment 8. 8. The ophthalmic pharmaceutical composition of 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 ophthalmic pharmaceutical composition comprises: (1) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), diclofenac sodium at a concentration of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), and sodium hyaluronate at a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v); (2) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), diclofenac sodium at a concentration of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), and hydroxypropyl methylcellulose at a concentration of 0.1% (w / w or w / v) to 2.0% (w / w or w / v); (3) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), ketorolac tromethamine at a concentration of 0.01% (w / w or w / v) to 0.60% (w / w or w / v), and sodium hyaluronate at a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v); (4) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), ketorolac tromethamine at a concentration of 0.01% (w / w or w / v) to 0.60% (w / w or w / v), and hydroxypropyl methylcellulose at a concentration of 0.1% (w / w or w / v) to 2.0% (w / w or w / v); or (5) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), diclofenac sodium at a concentration of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), sodium hyaluronate at a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), and hydroxypropyl methylcellulose at a concentration of 0.1% (w / w or w / v) to 2.0% (w / w or w / v); 2. The ophthalmic pharmaceutical composition of embodiment 1, comprising:

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

[0018] Embodiment 11. The ophthalmic pharmaceutical composition is selected from compositions 33 to 64, each of which contains pilocarpine hydrochloride or pilocarpine nitrate, diclofenac sodium, and hydroxypropyl methylcellulose as follows: [ka] ,An ophthalmic pharmaceutical composition described in embodiment 1.

[0019] Embodiment 12. The ophthalmic pharmaceutical composition is selected from compositions 65 to 96, each of which contains pilocarpine hydrochloride or pilocarpine nitrate, ketorolac tromethamine, and sodium hyaluronate as follows: [ka] ,An ophthalmic pharmaceutical composition described in embodiment 1.

[0020] Embodiment 13. The ophthalmic pharmaceutical composition is selected from compositions 97 to 128, each of which contains pilocarpine hydrochloride or pilocarpine nitrate, ketorolac tromethamine, and hydroxypropyl methylcellulose as follows: [ka] ,An ophthalmic pharmaceutical composition described in embodiment 1.

[0021] Embodiment 14. The ophthalmic pharmaceutical composition of embodiment 1, wherein the ophthalmic pharmaceutical composition is a sustained release composition.

[0022] Embodiment 15. 2. The ophthalmic pharmaceutical composition of embodiment 1, wherein the ophthalmic pharmaceutical composition is in the form of a suspension, gel, ointment, injectable solution, spray, or eye drop formulation.

[0023] Embodiment 16. 2. The ophthalmic pharmaceutical composition of embodiment 1, wherein the ophthalmic pharmaceutical composition is suitable for implantation into or on the surface of a subject's eye or surrounding tissue.

[0024] Embodiment 17. 17. The ophthalmic pharmaceutical composition of embodiment 16, wherein the ophthalmic pharmaceutical composition is suitable for implantation into the subconjunctival space, nasolacrimal duct, or vitreous cavity of a subject.

[0025] Embodiment 18. 2. The ophthalmic pharmaceutical composition of embodiment 1, wherein the ophthalmic pharmaceutical composition is suitable for local delivery to the eye or tissue surrounding the eye of a subject.

[0026] Embodiment 19. 2. The ophthalmic pharmaceutical composition of embodiment 1, wherein the ophthalmic pharmaceutical composition comprises a pharmaceutically acceptable diluent, preservative, and / or solvent.

[0027] Embodiment 20. 10. The ophthalmic pharmaceutical composition of embodiment 1, further comprising a tonicity agent, a wetting agent, a buffering agent, a stabilizer, a pH agent, a solubilizing agent, a viscosity increasing agent, and / or a dispersing agent.

[0028] Embodiment 21. 2. The ophthalmic pharmaceutical composition of embodiment 1, wherein the ophthalmic pharmaceutical composition is effective in correcting presbyopia for up to 24 hours.

[0029] Embodiment 22. 2. The ophthalmic pharmaceutical composition of embodiment 1, wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely affecting night vision.

[0030] Embodiment 23. 2. The ophthalmic pharmaceutical composition of embodiment 1, wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely narrowing the visual field.

[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 comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v) and a pharmaceutically acceptable carrier.

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

[0033] Embodiment 26. 25. The method of 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. 27. The method of embodiment 26, wherein the diclofenac salt is diclofenac sodium or the ketorolac salt is ketorolac tromethamine.

[0035] Embodiment 28. 25. The method of embodiment 24, wherein the ophthalmic pharmaceutical composition further comprises a lubricant.

[0036] Embodiment 29. 29. The method of 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, a polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or a mixture thereof.

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

[0038] Embodiment 31. 31. The method of embodiment 30, wherein the sodium hyaluronate is present in 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 in a concentration of 0.1% (w / w or w / v) to 2.0% (w / w or w / v).

[0039] Embodiment 32. The ophthalmic pharmaceutical composition comprises: (1) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), diclofenac sodium at a concentration of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), and sodium hyaluronate at a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v); (2) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), diclofenac sodium at a concentration of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), and hydroxypropyl methylcellulose at a concentration of 0.1% (w / w or w / v) to 2.0% (w / w or w / v); (3) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), ketorolac tromethamine at a concentration of 0.01% (w / w or w / v) to 0.60% (w / w or w / v), and sodium hyaluronate at a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v); (4) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), ketorolac tromethamine at a concentration of 0.01% (w / w or w / v) to 0.60% (w / w or w / v), and hydroxypropyl methylcellulose at a concentration of 0.1% (w / w or w / v) to 2.0% (w / w or w / v); or (5) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), diclofenac sodium at a concentration of 0.001% (w / w or w / v) to 0.090% (w / w or w / v), sodium hyaluronate at a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), and hydroxypropyl methylcellulose at a concentration of 0.1% (w / w or w / v) to 2.0% (w / w or w / v); 25. The method of embodiment 24, comprising:

[0040] Embodiment 33. The ophthalmic pharmaceutical composition is selected from compositions 1 to 32, each of which contains 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 contains 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 contains pilocarpine hydrochloride or pilocarpine nitrate, ketorolac tromethamine, 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 contains pilocarpine hydrochloride or pilocarpine nitrate, ketorolac tromethamine, and hydroxypropyl methylcellulose as follows: [ka] ,The method described in embodiment 24.

[0044] Embodiment 37. The method of embodiment 24, wherein the ophthalmic pharmaceutical composition is a sustained release composition.

[0045] Embodiment 38. 25. The method of 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. 25. The method of embodiment 24, wherein the ophthalmic pharmaceutical composition is suitable for implantation into or on the surface of the subject's eye or surrounding tissue.

[0047] Embodiment 40. 40. The method of embodiment 39, wherein the ophthalmic pharmaceutical composition is suitable for implantation into the subconjunctival space, nasolacrimal duct, or vitreous cavity of a subject.

[0048] Embodiment 41. 25. The method of embodiment 24, wherein the ophthalmic pharmaceutical composition is suitable for local delivery to the eye or tissue surrounding the eye of a subject.

[0049] Embodiment 42. 25. The method of embodiment 24, wherein the ophthalmic pharmaceutical composition comprises a pharmaceutically acceptable diluent, preservative, and / or solvent.

[0050] Embodiment 43. 25. The method of embodiment 24, further comprising a tonicity agent, a wetting agent, a buffering agent, a stabilizer, a pH agent, a solubilizing agent, a thickening agent, and / or a dispersing agent.

[0051] Embodiment 44. 25. The method of embodiment 24, wherein the ophthalmic pharmaceutical composition is effective in correcting presbyopia for up to 24 hours.

[0052] Embodiment 45. 25. The method of embodiment 24, wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely affecting night vision.

[0053] Embodiment 46. 25. The method of embodiment 24, wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely narrowing the visual field.

[0054] Embodiment 47. The subject is: a) Spectacle wearers who cannot use or will not use progressive or bifocal lenses; b) have had cataract surgery; c) developed presbyopia after corneal procedures; d) have monofocal or multifocal intraocular lenses; e) contact lens wearers and intolerant of monocular lenses; f) contact lens wearers and intolerant of multifocal lenses; g) suffer from high-order aberrations after corneal surgery; h) suffer from hyperopia or strabismus; i) Not tolerating changes in eyeglass prescription; j) experienced a sudden change in eyeglass prescription; k) The use of progressive or bifocal lenses poses a risk of falls; and / or l) suffer from high-order aberrations at night or under low light conditions; 25. The method of embodiment 24.

[0055] Embodiment 48. 25. The method of embodiment 24, wherein said administering is by topical or surgical intervention.

[0056] Embodiment 49. The method of embodiment 48, wherein the surgical intervention comprises administering the ophthalmic pharmaceutical composition to within or on the surface of the subject's eye or surrounding tissue.

[0057] Embodiment 50. The method of embodiment 49, wherein the ophthalmic pharmaceutical composition is administered into the subconjunctival space, nasolacrimal duct, or vitreous cavity of the subject.

[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 comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v) and a pharmaceutically acceptable carrier.

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

[0060] Embodiment 53. 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 comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v) and a pharmaceutically acceptable carrier.

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

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

[0063] Embodiment 56. An implant comprising an ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof at 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 at 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. 1. A method of correcting presbyopia in a subject, comprising: The method includes administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition that reduces pupil size in the subject; The above method, wherein the ophthalmic pharmaceutical composition comprises pilocarpine or a pharmaceutically acceptable salt thereof at 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 of any one of embodiments 24-55, 58, 68, and 70, wherein the ophthalmic pharmaceutical composition is administered up to two times per application, up to three applications 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 for correcting presbyopia in a subject, comprising administering the ophthalmic pharmaceutical composition to the eye of the subject either topically or by 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 for reducing pupil size in a subject, comprising administering the ophthalmic pharmaceutical composition to the eye of the subject either topically or by surgical intervention.

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

[0070] Embodiment 63. An ophthalmic pharmaceutical composition described in any one of embodiments 1 to 23, 67 and 69 for use in a method for increasing the depth of field in a subject's eye, comprising administering the ophthalmic pharmaceutical composition to the subject's eye locally or by surgical intervention.

[0071] Embodiment 64. An ophthalmic pharmaceutical composition described in any one of embodiments 1 to 23, 67 and 69 for use in a method for reducing the degree of high-order aberrations in a subject's eye, comprising administering the ophthalmic pharmaceutical composition to the subject's eye locally or by surgical intervention.

[0072] Embodiment 65. An ophthalmic pharmaceutical composition described in any one of embodiments 1 to 23, 67 and 69 for use in a method for improving uncorrected near and distance vision in a subject, comprising administering the ophthalmic pharmaceutical composition to the subject's eye either topically or by surgical intervention.

[0073] Embodiment 66. 70. An ophthalmic pharmaceutical composition according to any one of embodiments 1 to 23, 67 and 69 for use in a method of treating the human or animal body.

[0074] Embodiment 67. 2. The ophthalmic pharmaceutical composition of embodiment 1, wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely reducing distance vision.

[0075] Embodiment 68. 25. The method of embodiment 24, wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely reducing distance vision.

[0076] Embodiment 69. 11. The ophthalmic pharmaceutical composition of embodiment 10, wherein the ophthalmic pharmaceutical composition is selected from any one of compositions 1 to 32 and further comprises hydroxypropyl methylcellulose at 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. 34. The method of embodiment 33, wherein the ophthalmic pharmaceutical composition is selected from any one of compositions 1 to 32 and further comprises hydroxypropyl methylcellulose at 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 at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose at 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 of embodiment 71, wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

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

[0081] Embodiment 74. 74. The ophthalmic pharmaceutical composition of 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 of embodiment 74, wherein the diclofenac salt is diclofenac sodium or the ketorolac salt is ketorolac tromethamine.

[0083] Embodiment 76. The ophthalmic pharmaceutical composition comprises: (1) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose at a concentration of 0.1% (w / w or w / v) to 1.2% (w / w or w / v), sodium hyaluronate at a concentration of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), and diclofenac sodium at a concentration of 0.001% (w / w or w / v) to 0.012% (w / w or w / v); or (2) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose at a concentration of 0.1% (w / w or w / v) to 1.2% (w / w or w / v), sodium hyaluronate at a concentration of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), and ketorolac tromethamine at a concentration of 0.01% (w / w or w / v) to 0.50% (w / w or w / v); 76. The ophthalmic pharmaceutical composition of embodiment 75, comprising:

[0084] Embodiment 77. The ophthalmic pharmaceutical composition comprises: (1) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% (w / w or w / v), hydroxypropyl methylcellulose at a concentration of 0.8% (w / w or w / v), sodium hyaluronate at a concentration of 0.1% (w / w or w / v), and diclofenac sodium at a concentration of 0.006% (w / w or w / v); or (2) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% (w / w or w / v), hydroxypropyl methylcellulose at a concentration of 0.8% (w / w or w / v), sodium hyaluronate at a concentration of 0.1% (w / w or w / v), and ketorolac tromethamine at a concentration of 0.50% (w / w or w / v); 77. The ophthalmic pharmaceutical composition of embodiment 76, comprising:

[0085] Embodiment 78. (1) Sodium hyaluronate at a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), or diclofenac sodium at 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 at a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), or ketorolac tromethamine at a concentration of 0.01% (w / w or w / v) to 0.60% (w / w or w / v), or a mixture thereof; The ophthalmic pharmaceutical composition of embodiment 72, further comprising:

[0086] Embodiment 79. The ophthalmic pharmaceutical composition comprises: (1) Pilocarpine hydrochloride or pilocarpine nitrate in a concentration of 0.1% (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 1.2% (w / w or w / v), and further sodium hyaluronate in a concentration of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), or diclofenac sodium in a concentration of 0.001% (w / w or w / v) to 0.012% (w / w or w / v), or a mixture thereof; or (2) Pilocarpine hydrochloride or pilocarpine nitrate in a concentration of 0.1% (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 1.2% (w / w or w / v), and further sodium hyaluronate in a concentration of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), or ketorolac tromethamine in a concentration of 0.01% (w / w or w / v) to 0.50% (w / w or w / v), or mixtures thereof; 73. The ophthalmic pharmaceutical composition of embodiment 72, comprising:

[0087] Embodiment 80. The ophthalmic pharmaceutical composition comprises: (1) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% (w / w or w / v), hydroxypropyl methylcellulose at a concentration of 0.8% (w / w or w / v), and further sodium hyaluronate at a concentration of 0.1% (w / w or w / v), or diclofenac sodium at a concentration of 0.006% (w / w or w / v), or a mixture thereof; or (2) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% (w / w or w / v), hydroxypropyl methylcellulose at a concentration of 0.8% (w / w or w / v), and further sodium hyaluronate at a concentration of 0.1% (w / w or w / v), or ketorolac tromethamine at a concentration of 0.50% (w / w or w / v), or a mixture thereof; 80. The ophthalmic pharmaceutical composition of embodiment 79, comprising:

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

[0089] Embodiment 82. The ophthalmic pharmaceutical composition of embodiment 71, further comprising an isotonicity agent, a wetting agent, a buffering agent, a stabilizer, a pH agent, a solubilizing agent, a thickening agent, and / or a dispersing agent.

[0090] Embodiment 83. The ophthalmic pharmaceutical composition of embodiment 71, wherein the ophthalmic pharmaceutical composition 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 comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose at 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. 85. The method of embodiment 84, wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

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

[0094] Embodiment 87. 87. The method of 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 of embodiment 87, wherein the diclofenac salt is diclofenac sodium or the ketorolac salt is ketorolac tromethamine.

[0096] Embodiment 89. The ophthalmic pharmaceutical composition comprises: (1) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose at a concentration of 0.1% (w / w or w / v) to 1.2% (w / w or w / v), sodium hyaluronate at a concentration of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), and diclofenac sodium at a concentration of 0.001% (w / w or w / v) to 0.012% (w / w or w / v); or (2) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose at a concentration of 0.1% (w / w or w / v) to 1.2% (w / w or w / v), sodium hyaluronate at a concentration of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), and ketorolac tromethamine at a concentration of 0.01% (w / w or w / v) to 0.50% (w / w or w / v); The method of embodiment 88, comprising:

[0097] Embodiment 90. The ophthalmic pharmaceutical composition comprises: (1) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% (w / w or w / v), hydroxypropyl methylcellulose at a concentration of 0.8% (w / w or w / v), sodium hyaluronate at a concentration of 0.1% (w / w or w / v), and diclofenac sodium at a concentration of 0.006% (w / w or w / v); or (2) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% (w / w or w / v), hydroxypropyl methylcellulose at a concentration of 0.8% (w / w or w / v), sodium hyaluronate at a concentration of 0.1% (w / w or w / v), and ketorolac tromethamine at a concentration of 0.50% (w / w or w / v); The method of embodiment 89, comprising:

[0098] Embodiment 91. The ophthalmic pharmaceutical composition comprises: (1) Sodium hyaluronate at a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), or diclofenac sodium at 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 at a concentration of 0.01% (w / w or w / v) to 0.9% (w / w or w / v), or ketorolac tromethamine at a concentration of 0.01% (w / w or w / v) to 0.60% (w / w or w / v), or a mixture thereof; 86. The method of embodiment 85, further comprising:

[0099] Embodiment 92. The ophthalmic pharmaceutical composition comprises: (1) Pilocarpine hydrochloride or pilocarpine nitrate in a concentration of 0.1% (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 1.2% (w / w or w / v), and further sodium hyaluronate in a concentration of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), or diclofenac sodium in a concentration of 0.001% (w / w or w / v) to 0.012% (w / w or w / v), or a mixture thereof; or (2) Pilocarpine hydrochloride or pilocarpine nitrate in a concentration of 0.1% (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 1.2% (w / w or w / v), and further sodium hyaluronate in a concentration of 0.01% (w / w or w / v) to 0.2% (w / w or w / v), or ketorolac tromethamine in a concentration of 0.01% (w / w or w / v) to 0.50% (w / w or w / v), or mixtures thereof; The method of embodiment 85, comprising:

[0100] Embodiment 93. The ophthalmic pharmaceutical composition comprises: (1) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% (w / w or w / v), hydroxypropyl methylcellulose at a concentration of 0.8% (w / w or w / v), and further sodium hyaluronate at a concentration of 0.1% (w / w or w / v), or diclofenac sodium at a concentration of 0.006% (w / w or w / v), or a mixture thereof; or (2) Pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% (w / w or w / v), hydroxypropyl methylcellulose at a concentration of 0.8% (w / w or w / v), and further sodium hyaluronate at a concentration of 0.1% (w / w or w / v), or ketorolac tromethamine at a concentration of 0.50% (w / w or w / v), or a mixture thereof; The method of embodiment 92, comprising:

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

[0102] 95. The method of embodiment 85, wherein the ophthalmic pharmaceutical composition further comprises a tonicity agent, a wetting agent, a buffering agent, a stabilizer, a pH agent, a solubilizing agent, a viscosity increasing agent, and / or a dispersing agent.

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

[0104] 97. The method of embodiment 85, wherein said administration is by local or surgical intervention.

[0105] Embodiment 98. The subject is: a) Spectacle wearers who cannot use or will not use progressive or bifocal lenses; b) have had cataract surgery; c) developed presbyopia after corneal procedures; d) have monofocal or multifocal intraocular lenses; e) contact lens wearers and intolerant of monocular lenses; f) contact lens wearers and intolerant of multifocal lenses; g) suffer from high-order aberrations after corneal surgery; h) suffer from hyperopia or strabismus; i) Not tolerating changes in eyeglass prescription; j) experienced a sudden change in eyeglass prescription; k) The use of progressive or bifocal lenses poses a risk of falls; and / or l) suffer from high-order aberrations at night or under low light conditions; The method of 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 comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose at 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 comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w / w or w / v) to 0.4% (w / w or w / v), hydroxypropyl methylcellulose at 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, described below, are for illustrative purposes only and are not intended to limit the scope of the present teachings. [Brief explanation of the drawings]

[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 group (○) when looking at letters at a distance (6 m) after instilling the ophthalmic pharmaceutical composition of the present disclosure.

[0110] [Figure 2] Figure 2 shows the relationship (●) between the change in depth of field (ΔDoF) and the change in pupil size (ΔPupillary Diameter) in the presbyopic group when viewing letters at close range (40 cm) after instilling the ophthalmic pharmaceutical composition of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0111] Detailed Description Many modifications and other embodiments of the subject matter described herein will come to mind to one skilled in the art having the benefit of the teachings presented in the description and accompanying drawings. It is to be understood, therefore, that the disclosure is not intended to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0112] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Unless otherwise noted, the techniques used or contemplated herein are standard methods well known to those of ordinary skill in the art. The practice of this disclosure will employ conventional techniques for ophthalmic pharmaceutical formulation and use that are within the skill of the art, unless otherwise indicated. The materials, methods, and examples are illustrative only and not limiting. The following are offered by way of illustration and are not intended to limit the scope of this disclosure.

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

[0114] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise. Furthermore, the words "including," "includes," "having," "has," "with," or variations thereof, when used in either the specification and / or claims, are intended to be inclusive in the same manner as the word "comprising."

[0115] As used herein, the term "administering" refers to placing an ophthalmic pharmaceutical composition in a subject by a method or route that at least partially localizes the pharmaceutical composition at a desired location or tissue site (e.g., a patient's eye or surrounding tissues). For example, the composition may be administered topically to the subject's eye or surrounding tissues. Alternatively, the composition may be administered into or onto the subject's eye or surrounding tissues through surgical intervention. In some embodiments of the present disclosure, the ophthalmic pharmaceutical composition can be administered by any suitable route that results in an effective treatment for the subject, i.e., administration results in delivery to the desired site or tissue of the subject, where at least a portion of the pilocarpine or pharmaceutically acceptable salt thereof is deposited at the desired site or tissue location. In some embodiments of the present disclosure, the ophthalmic pharmaceutical composition can be administered several times within a short period of time, for example, within a few seconds or minutes. For example, in some embodiments, the ophthalmic pharmaceutical composition can be administered twice within 2 seconds, 5 seconds, 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes, 20 minutes, or 30 minutes. In some embodiments, 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 some embodiments, 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 carrier or excipient, such as a pharmaceutically acceptable carrier or excipient, that is conventionally used and suitable for administration to a subject for therapeutic purposes. The therapeutically active ingredient may be, for example, pilocarpine or a pharmaceutically acceptable salt thereof disclosed 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 eye drops). In some embodiments, when the composition is in the form of an ophthalmic formulation, each drop may have a volume of about 10 microliters (μL), 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. Any form or tense of one or more of these verbs, such as "comprise," "including," "having," "having," "comprises," or "including," is open-ended. For example, a method that "comprises," "has," or "includes" one or more steps is not limited to having only those one or more steps, but may also include other unrecited steps. Similarly, any composition that "comprises," "has," or "includes" one or more features is not limited to having only those one or more features, but may also include other unrecited features. The use of any and all examples or exemplary language (e.g., "such as") used in connection with certain embodiments herein is solely for the purpose of facilitating understanding of the disclosure and does not impose limitations on the scope of the disclosure as otherwise claimed.

[0118] The term "consisting essentially of" permits the presence of additional materials or steps that "do not materially affect the basic and novel characteristic(s)" of the invention.

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

[0120] As used herein, the terms "correct," "correcting," or "correction" refer to a reduction or alleviation of the severity of presbyopia. The reduction may be complete, e.g., complete elimination of presbyopia. The reduction may also be partial, such that the amount of presbyopia is less than would be present in the absence of exposure to the disclosed methods and compositions. The amount of presbyopia can be measured by any method known in the art for ophthalmic examination.

[0121] The phrase "ophthalmically acceptable" is used to refer to compounds, materials, compositions and / or dosage forms that, within the scope of medical judgment, are suitable for use in contact with the eye and surrounding tissues of humans and animals without excessive toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit / risk ratio. Drug approval agencies (e.g., EMA, US FDA) provide guidance on what compounds, materials, compositions, and / or dosage forms are approved as pharmaceutically acceptable. Examples can be found in Pharmacopeias.

[0122] The phrase "ophthalmically acceptable carrier" is used herein to refer to solvents, dispersion media, diluents, dispersants, suspending agents, surfactants, tonicity agents, thickeners or emulsifiers, preservatives, core-shell nanoparticles, polymers, peptides, proteins, cells, hyaluronidase, and mixtures thereof that are suitable for pharmaceutical administration. The use of such media and agents for pharmaceutical active substances is well known in the ophthalmic field. The compositions may also contain other active compounds that provide complementary, additive, or enhanced therapeutic functions.

[0123] The phrase "ophthalmic pharmaceutical composition" refers to a pharmaceutical composition useful for preparing a medicament for administration to the mammalian eye.

[0124] The term "pharmaceutically acceptable salt" refers to a salt of an acidic or basic group that may be present in a compound used in the present compositions. 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 sulfate, citrate, malate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, sulfite, phosphate, superphosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, acid tartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucarate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate salts. For example, in some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate. On the other hand, certain compounds contained in the composition that are acidic in nature may form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. For example, in one embodiment, the ophthalmic pharmaceutical composition comprises diclofenac sodium. For example, in one embodiment, the ophthalmic pharmaceutical composition comprises ketorolac tromethamine.

[0125] The term "substantially significant" or "significantly" refers to statistical significance. The term indicates statistical evidence that there is a difference. It can be defined as the probability of deciding to reject the null hypothesis when the null hypothesis is in fact true. The decision is often made using a p-value. Any other measure of significance known in the art may also be used.

[0126] The terms "subject" and "individual" are used interchangeably and refer to an animal, e.g., a human, to which treatment using the methods and compositions described herein may be provided. In some embodiments, the subject is a human.

[0127] As used herein, the term "therapeutically effective amount" refers to 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, it may be an amount that temporarily reduces or eliminates presbyopia, such that near vision in the treated eye is temporarily partially or completely restored. For example, it may be an amount that results in a significant reduction in discomfort or risk of falls when using progressive or bifocal lenses. For example, it may be an amount that reduces or completely eliminates blurred vision or dimness after eye surgery.

[0128] As used herein, the terms "treat," "treatment," or "treating" refer to the reduction or elimination of a disease or disorder, or of at least one discernible symptom thereof. In certain embodiments, "treat" or "treating" refers to the reduction or elimination of at least one measurable physical parameter, which may not necessarily be discernible by the patient. For example, treatment may enable a patient to focus on objects at a near distance, e.g., to focus on objects at a distance close to normal reading distance. In certain embodiments, treatment is effective to reduce or eliminate presbyopia for 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 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 (uncorrected) distance and near visual acuity, which can be measured using a standard appropriate eye chart, such as the Snellen far-distance chart and the Jaeger near-distance chart, or the Early Treatment Diabetic Retinopathy Screening System (ETDRS) chart. All values ​​can be converted to decimal notation using a Halliday conversion table.

[0130] In another embodiment, treatment is measured by clinical assessment of depth of field, which can be obtained using standard wavefront aberrometry or according to the following instructions: Far point: Best distance glasses power in refractor head / examination frame. Look at 6 / 9 (0.6) Snellen character. Increase power of plus spherical lens (+a diopters) until subject reports blur. Repeat with minus lens (-b diopters). Remove minus sign before b. Depth of field at far point = (a+b) diopters. Near point: Best distance spectacle power with +2.5 diopter addition in refractor head / test frame. Look at J2 type at a distance of 40 cm. Increase power of plus spherical lens (+x diopters) until object reports blur. Repeat with minus lens (-y diopters). Remove the minus sign before y. Depth of field at near point = (x+y) diopters.

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

[0132] In yet another embodiment, treatment may be measured by pupil appearance, for example, by examining the pupils for equal pupil size (less than 1 mm difference would be normal), normal pupil shape, reactivity to light, and direct and consonant accommodation.

[0133] In yet another embodiment, treatment is measured by non-invasive objective assessment of third, fourth, and fifth order ocular higher order aberrations (e.g., coma, spherical aberration, and trefoil), which can be performed using standard wavefront aberration analysis techniques.

[0134] It is to be understood that the present disclosure is not limited to the particular methodology, protocols, and reagents, etc. described herein, as these may vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present disclosure, which is limited only by the claims.

[0135] Pharmacological treatment of presbyopia Presbyopia is an age-related deterioration of the eye. Presbyopia generally results in a decreased ability to focus objects at near distances due to a gradual decrease in the amplitude of accommodation. The presbyopic eye loses its ability to focus objects at near distances quickly and easily.

[0136] By way of background, when young emmetropes fixate on a nearby object, two changes occur in the eye: accommodation and miosis. Accommodation is a change in the refractive power of the crystalline lens; the lens becomes rounder, thereby increasing its refractive power. Miosis is a reduction in pupil size, thereby increasing depth of field and reducing high-order aberrations.

[0137] At the molecular level, pupil constriction and accommodation occur under parasympathetic influence. Binding of parasympathomimetics to muscarinic receptors induces muscle contraction of the ciliary and pupillary sphincter muscles, increasing the refractive power of the eye. If this effect is strong enough, it can overcome some of the loss of the lens's ability to change shape and position, while remaining in place, that typically occurs with aging.

[0138] Presbyopia is traditionally corrected by the use of glasses, contact lenses, or intraocular implants, corneal abrasions, or inlays. Surgical procedures proposed to correct presbyopia do not fully restore the eye's natural accommodative function, which has been diminished by natural aging (aging) or by other means. Pharmacological treatments have been proposed to restore the eye's 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. The present disclosure provides compositions and methods of use that are simple, convenient, and painless for patients suffering from the symptoms of presbyopia.

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

[0141] Parasympathomimetics are intended to include any cholinergic agonist that potentiates acetylcholine-mediated effects in the central nervous system, the peripheral nervous system, or both. One example of such a parasympathomimetic is pilocarpine. Further examples are disclosed in U.S. Pat. No. 8,299,079 and may include acetylcholine, muscarine, nicotine, saxamethonium, bethanechol, methacholine, phenylpropanolamine, amphetamine, ephedrine, carbachol, phentolamine, and fenfluramine. In some embodiments, the parasympathomimetic is pilocarpine or carbachol. In a preferred embodiment, the parasympathomimetic is pilocarpine.

[0142] Pilocarpine in the form of hydrochloride or nitrate is a miotic agent that has been used in the form of eye drops for decades to treat glaucoma. Long-term topical application of certain concentrations of pilocarpine is associated with undesirable ocular and systemic adverse side effects, such as pigment scattering syndrome, dry eye, uveal inflammation, posterior synechiae, ciliary muscle spasm, blurred vision, miosis, accommodative spasm, frontal headache, twitching eyelids, conjunctival injection, 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, regularly administered 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 parasympathomimetic. Thus, 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 an amount of about 0.01% to about 0.4%, about 0.01% to about 0.35%, about 0.01% to about 0.3%, about 0.01% to about 0.25%, about 0.01% to about 0.2%, about 0.01% to about 0.15%, about 0.01% to about 0.1%, or about 0.01% to about 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 an amount of about 0.25% to about 0.4%, about 0.25% to about 0.35%, about 0.25% to about 0.3%, about 0.3% to about 0.4%, about 0.3% to about 0.35%, about 0.35% to about 0.4%, or about 0.01%, about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, or about 0.4%. In all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0145] In some embodiments, the ophthalmic pharmaceutical composition may further comprise a nonsteroidal anti-inflammatory drug (NSAID) or a pharmaceutically acceptable salt thereof, which can reduce or eliminate local inflammation that may occur due to irritation caused by parasympathomimetics (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, oxyphenbutazone, serprofen, and indomethacin. Thus, 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 comprise an NSAID.

[0147] In some embodiments, the ophthalmic pharmaceutical composition may further comprise a pharmaceutically acceptable salt of the NSAID. Non-limiting 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 some embodiments, the ophthalmic pharmaceutical composition further comprises diclofenac sodium. In some embodiments, the ophthalmic pharmaceutical composition further comprises ketorolac tromethamine. Alternatively, the ophthalmic pharmaceutical composition may not comprise a pharmaceutically acceptable salt of the NSAID.

[0148] In some embodiments of the ophthalmic pharmaceutical composition, diclofenac or a pharmaceutically acceptable salt thereof (e.g., diclofenac sodium) is present in an amount of from about 0.001% to about 0.090%, from about 0.001% to about 0.080%, from about 0.001% to about 0.070%, from about 0.001% to about 0.060%, from about 0.001% to about 0.050%, from about 0.001% to about 0.040%, from about 0.001% to about 0.030%, from about 0.001% to about 0.020%, from about 0.001% to about 0.012%, from about 0.001% to about 0.011%, from about 0.001% to about 0.010%, from about 0.001% to about 0.0 09%, approximately 0.001% to approximately 0.008%, approximately 0.001% to approximately 0.007%, approximately 0.001% to approximately 0.006%, approximately 0.001% to approximately 0.005%, approximately 0.001% to approximately 0.003%, approximately 0.003% to approximately 0.090%, approximately 0.003% to approximately 0.080%, approximately 0.003% to approximately 0.070%, approximately 0.003% to approximately 0.060%, approximately 0.003% to approximately 0.050%, approximately 0.003% to approximately 0.040%, approximately 0.003% to approximately 0.030%, approximately 0.003% to approximately 0.020%, approximately 0.003% to approximately 0.012%, approximately 0.003% to approximately 0.011%, approximately 0.003 % to approximately 0.010%, approximately 0.003% to approximately 0.009%, approximately 0.003% to approximately 0.008%, approximately 0.003% to approximately 0.007%, approximately 0.003% to approximately 0.006%, approximately 0.003% to approximately 0.005%, approximately 0.005% to approximately 0.090%, approximately 0.005% to approximately 0.080%, approximately 0.005% to approximately 0.070%, approximately 0.005% to approximately 0.060%, approximately 0.005% to approximately 0.050%, approximately 0.005% to approximately 0.040%, approximately 0.005% to approximately 0.030%, approximately 0.005% to approximately 0.020%, approximately 0.005% to approximately 0.012%, approximately 0.005% to approximately 0.011%, Approximately 0.005% to approximately 0.010%, approximately 0.005% to approximately 0.009%, approximately 0.005% to approximately 0.008%, approximately 0.005% to approximately 0.007%, approximately 0.005% to approximately 0.006%, approximately 0.006% to approximately 0.090%, approximately 0.006% to approximately 0.080%, approximately 0.006% to approximately 0.070%, approximately 0.006% to approximately 0.060%, approximately 0.006% to approximately 0.050%, approximately 0.006% to approximately 0.040%, approximately 0.006% to approximately 0.030%, approximately 0.006% to approximately 0.020%, approximately 0.006% to approximately 0.012%, approximately 0.006% to approximately 0.011%, approximately 0.006% to approximately 0.010%, approximately 0.006% to approximately 0.009%, approximately 0.006% to approximately 0.008%, approximately 0.006% to approximately 0.007%, approximately 0.007% to approximately 0.090%, approximately 0.007% to approximately 0.080%, approximately 0.007% to approximately 0.070%, approximately 0.007% to approximately 0.060%, approximately 0.007% to approximately 0.050%, approximately 0.007% to approximately 0.040%, approximately 0.007% to approximately 0.030%, approximately 0.007% to approximately 0.020%, approximately 0.007% to approximately 0.012%, approximately 0.007% to approximately 0.011%, approximately 0.007% to approximately 0.010%, approximately 0.007% to approximately 0.009%, approximately 0.00 7% to approximately 0.008%, approximately 0.008% to approximately 0.090%, approximately 0.008% to approximately 0.080%, approximately 0.008% to approximately 0.070%, approximately 0.008% to approximately 0.060%, approximately 0.008% to approximately 0.050%, approximately 0.008% to approximately 0.040%, approximately 0.008% to approximately 0.030%, approximately 0.008% to approximately 0.020%, approximately 0.008% to approximately 0.012%, approximately 0.008% to approximately 0.011%, approximately 0.008% to approximately 0.010%, approximately 0.008% to approximately 0.009%, approximately 0.009% to approximately 0.090%, approximately 0.009% to approximately 0.080%, approximately 0.009% to approximately 0.070 , about 0.009% to about 0.060%, about 0.009% to about 0.050%, about 0.009% to about 0.040%, about 0.009% to about 0.030%, about 0.009% to about 0.020%, about 0.009% to about 0.012%, about 0.009% to about 0.011%, about 0.009% to about 0.010%, about 0.010% to about 0.090%, about 0.010% to about 0.080%, about 0.010% to about 0.070%, about 0.010% to about 0.060%, about 0.010% to about 0.050%, about 0.010% to about 0.040%, about 0.010% to about 0.030%, about 0.010% to about 0.020%, approximately 0.010% to approximately 0.012%, approximately 0.010% to approximately 0.011%, approximately 0.011% to approximately 0.090%, approximately 0.011% to approximately 0.080%, approximately 0.011% to approximately 0.070%, approximately 0.011% to approximately 0.060%, approximately 0.011% to approximately 0.050%, approximately 0.011% to approximately 0.040%, approximately 0.011% to approximately 0.030%, approximately 0.011% to approximately 0.020%, approximately 0.011% to approximately 0.012%, approximately 0.012% to approximately 0.090%, approximately 0.012% to approximately 0.080%, approximately 0.012% to approximately 0.070%, approximately 0.012% to approximately 0.060%, approximately 0.0.012% to approximately 0.050%, approximately 0.012% to approximately 0.040%, approximately 0.012% to approximately 0.030%, approximately 0.012% to approximately 0.020%, approximately 0.020% to approximately 0.090%, approximately 0.020% to approximately 0.080%, approximately 0.020% to approximately 0.070%, approximately 0.020% to approximately 0.060%, approximately 0.020% to approximately 0.050%, approximately 0.020% to approximately 0.040%, approximately 0.020% to approximately 0.030%, approximately 0.030% to approximately 0.090%, approximately 0.030% to approximately 0.080%, approximately 0.030% to approximately 0.070%, approximately 0.030% to approximately 0.060%, approximately 0.030% to approximately 0.050%, approximately 0.030% to approximately 0.040%, approximately 0.040% to approximately 0.090%, approximately 0.040% to approximately 0.080%, approximately 0.040% to approximately 0.070%, approximately 0.040% to approximately 0.060% ,approx. 0.040% to approx. 0.050%,approx. 0.050% to approx. 0.090%,approx. 0.050% to approx. 0.080%,approx. 0.050% to approx. 0.070%,approx. 0.050% to approx. 0.060%,approx. 0.060% to approx. 0.090%,approx. 0.060% to approx. 0.080%,approx. 0.060% to approx. 0.070%,approx. 0.070% to approx. 0.090%,approx. 0.070% to approx. 0.080%,approx. 0.08 It may be present in an amount of 0% to about 0.090%, or about 0.001%, about 0.003%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.010%, about 0.011%, about 0.012%, about 0.020%, about 0.030%, about 0.040%, about 0.050%, about 0.060%, about 0.070%, about 0.080%, or about 0.090%. In all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0149] In some embodiments of the ophthalmic pharmaceutical composition, ketorolac or a pharmaceutically acceptable salt thereof (e.g., ketorolac tromethamine) is present in an amount of about 0.01% to about 0.6%, about 0.01% to about 0.5%, about 0.01% to about 0.4%, about 0.01% to about 0.3%, about 0.01% to about 0.2%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 0.6%, about 0.05% to about 0.5%, about 0.05% to about 0.4%, about 0.05% to about 0.3%, about 0.05% to about 0.2%, about 0.05% to about 0.1%, about 0.1% to about 0.1% It may be present in an amount of about 0.6%, about 0.1% to about 0.5%, about 0.1% to about 0.4%, about 0.1% to about 0.3%, about 0.1% to about 0.2%, about 0.2% to about 0.6%, about 0.2% to about 0.5%, about 0.2% to about 0.4%, about 0.2% to about 0.3%, about 0.3% to about 0.6%, about 0.3% to about 0.5%, about 0.3% to about 0.4%, about 0.4% to about 0.6%, about 0.4% to about 0.5%, about 0.5% to about 0.6%, or about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, or about 0.6%. In all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0150] In some embodiments, the ophthalmic pharmaceutical composition may further comprise a lubricant. Generally, a lubricant can facilitate administration of the ophthalmic pharmaceutical composition to a subject. 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 comprises sodium hyaluronate. In some embodiments, the ophthalmic pharmaceutical composition further comprises hydroxypropylmethylcellulose. In some embodiments, the ophthalmic pharmaceutical composition further comprises sodium hyaluronate and hydroxypropylmethylcellulose. Alternatively, the ophthalmic pharmaceutical composition may be free of a lubricant.

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

[0152] In some embodiments of the ophthalmic pharmaceutical composition, the lubricant is hydroxypropyl methylcellulose, which is about 0.1% to about 2.0%, about 0.1% to about 1.8%, about 0.1% to about 1.6%, about 0.1% to about 1.4%, about 0.1% to about 1.2%, about 0.1% to about 1.0%, about 0.1% to about 0.8%, about 0.1% to about 0.6%, about 0.1% to about 0.4%, about 0.1% to about 0.2%, about 0.2% to about 2.0%, about 0.2% to about 1.8%, about 0.2% to about 1.2%. % to about 1.6%, about 0.2% to about 1.4%, about 0.2% to about 1.2%, about 0.2% to about 1.0%, about 0.2% to about 0.8%, about 0.2% to about 0.6%, about 0.2% to about 0.4%, about 0.4% to about 2.0%, about 0.4% to about 1.8%, about 0.4% to about 1.6%, about 0.4% to about 1.4%, about 0.4% to about 1.2%, about 0.4% to about 1.0%, about 0.4% to about 0.8%, about 0.4% to about 0.6%, about 0.6% to about 2.0%, about 0.6% to about 1 .8%, approximately 0.6% to approximately 1.6%, approximately 0.6% to approximately 1.4%, approximately 0.6% to approximately 1.2%, approximately 0.6% to approximately 1.0%, approximately 0.6% to approximately 0.8%, approximately 0.8% to approximately 2.0%, approximately 0.8% to approximately 1.8%, approximately 0.8% to approximately 1.6%, approximately 0.8% to approximately 1.4%, approximately 0.8% to approximately 1.2%, approximately 0.8% to approximately 1.0%, approximately 1.0% to approximately 2.0%, approximately 1.0% to approximately 1.8%, approximately 1.0% to approximately 1.6%, approximately 1.0% to approximately 1.4%, approximately 1% to approximately 1.2%, approximately 1 It may be present in an amount of about 0.2% to about 2.0%, about 1.2% to about 1.8%, about 1.2% to about 1.6%, about 1.2% to about 1.4%, about 1.4% to about 2.0%, about 1.4% to about 1.8%, about 1.4% to about 1.6%, about 1.6% to about 2.0%, about 1.6% to about 1.8%, about 1.8% to about 2.0%, or about 0.1%, about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1.0%, about 1.2%, about 1.4%, about 1.6%, about 1.8%, or about 2.0%. In all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are 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, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0154] 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 hydroxypropyl methylcellulose in a concentration of 0.1% to 2.0%. In all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0155] 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%, sodium hyaluronate in a concentration of 0.01% to 0.9%, and hydroxypropyl methylcellulose in a concentration of 0.1% to 2.0%. In all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

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

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

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

[0159] In some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% further comprises diclofenac sodium at a concentration 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%. In some embodiments, ophthalmic pharmaceutical compositions comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%. In some embodiments, ophthalmic pharmaceutical compositions comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% further comprise sodium hyaluronate at a concentration 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, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% further comprises hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and optionally may further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0160] In some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05% further comprises diclofenac sodium at a concentration 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%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05% further comprises ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05% further comprises sodium hyaluronate at a concentration 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, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05% further comprises hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and optionally may further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and optionally hydroxypropyl methylcellulose at a concentration 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 all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0161] In some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% further comprises diclofenac sodium at a concentration 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%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% further comprises ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% further comprises sodium hyaluronate at a concentration 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, the ophthalmic pharmaceutical composition comprising a 0.1% concentration of pilocarpine hydrochloride or pilocarpine nitrate further comprises hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and optionally may further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0162] In some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15% further comprises diclofenac sodium at a concentration 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%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15% further comprises ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15% further comprises sodium hyaluronate at a concentration 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, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15% further comprises hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and optionally may further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0163] In some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% further comprises diclofenac sodium at a concentration 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%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% further comprises ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% further comprises sodium hyaluronate at a concentration 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, the ophthalmic pharmaceutical composition comprising a 0.2% concentration of pilocarpine hydrochloride or pilocarpine nitrate further comprises hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% may further comprise diclofenac sodium at a concentration 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 hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and optionally may further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0164] In some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.25%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.25% further comprises diclofenac sodium at a concentration 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%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.25% further comprises ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.25% further comprises sodium hyaluronate at a concentration 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, the ophthalmic pharmaceutical composition comprising a 0.25% concentration of pilocarpine hydrochloride or pilocarpine nitrate further comprises hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.25% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.25% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.25% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and optionally may further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.25% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0165] In some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.3%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.3% further comprises diclofenac sodium at a concentration 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%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.3% further comprises ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.3% further comprises sodium hyaluronate at a concentration 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, the ophthalmic pharmaceutical composition comprising a 0.3% concentration of pilocarpine hydrochloride or pilocarpine nitrate further comprises hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.3% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.3% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.3% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and optionally may further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.3% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0166] In some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.35%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.35% further comprises diclofenac sodium at a concentration 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%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.35% further comprises ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.35% further comprises sodium hyaluronate at a concentration 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, the ophthalmic pharmaceutical composition comprising a 0.35% concentration of pilocarpine hydrochloride or pilocarpine nitrate further comprises hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.35% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.35% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.35% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and optionally may further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.35% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0167] In some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.4%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.4% further comprises diclofenac sodium at a concentration 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%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.4% further comprises ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%. In some embodiments, the ophthalmic pharmaceutical composition comprising pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.4% further comprises sodium hyaluronate at a concentration 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, the ophthalmic pharmaceutical composition comprising a 0.4% concentration of pilocarpine hydrochloride or pilocarpine nitrate further comprises hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.4% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.4% may further comprise diclofenac sodium at a concentration 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 may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.4% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and optionally may further comprise sodium hyaluronate at a concentration 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 pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.4% may further comprise ketorolac tromethamine at a concentration of 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or 0.6%, and may optionally further comprise hydroxypropyl methylcellulose at a concentration 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 all of these embodiments, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0187] In some embodiments, an ophthalmic pharmaceutical composition can include 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; or (4) hydroxypropyl methylcellulose, wherein the pilocarpine hydrochloride or pilocarpine nitrate is at a concentration of about 0.01% to about 0.4%, the diclofenac sodium is at a concentration of about 0.001% to about 0.090%, the sodium hyaluronate is at a concentration of about 0.01% to about 0.9%, and / or the hydroxypropyl methylcellulose is at a concentration of about 0.1% to about 2.0%. In all of these compositions, percentiles are determined by weight (w / w). Alternatively, in all of these embodiments, percentiles are determined by volume (w / v).

[0188] In some embodiments, the ophthalmic pharmaceutical compositions of the present disclosure may comprise an ophthalmologically acceptable carrier, which, as used herein, includes, but is not limited to, solvents, dispersion media, diluents, dispersants, suspending aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, core-shell nanoparticles, polymers, peptides, proteins, cells, hyaluronidase, and mixtures thereof. The use of such vehicles and agents 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, e.g., Remington: The Science and Practice of Pharmacy, 22nd Edition, Edited by Allen, Loyd V., Jr., Pharmaceutical Press, incorporated herein by reference in its entirety). For example, in some embodiments, ophthalmic pharmaceutical compositions according to the present disclosure may include one or more preservatives, such as phenol, cresol, p-aminobenzoic acid, BDSA, sorbitrate, chlorhexidine, benzalkonium chloride, sorbic acid, Purite® (oxychloride compounds), Polyquad® (quaternary ammonium), polyhexamethylene biguanide, sodium perborate, etc. In some embodiments, ophthalmic pharmaceutical compositions intended for long-term use in chronic conditions can be formulated and packaged to minimize or eliminate the use of preservatives that may be irritating to the eye. For example, ophthalmic pharmaceutical compositions can be packaged in single-dose containers or containers that utilize alternative means to minimize microbial contamination (such as membranes, valve mechanisms, or silver).

[0189] In some embodiments, the ophthalmic pharmaceutical composition further comprises a tonicity agent, a humectant, a buffer, a stabilizer, a pH agent, a solubilizer, a thickener, and / or a dispersant. These agents are well known to those skilled in the art of ophthalmology (see, e.g., U.S. Patent Nos. 8,299,079 and 8,524,758). For example, the pharmaceutical composition may contain a tonicity agent to adjust the formulation to a desired isotonic range. Examples of tonicity 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, allowing the liquid to pass through or penetrate easily through solid surfaces. 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 buffering agents used are known to those skilled in the art, and some examples are, but are not limited to, acetate, borate, carbonate, citrate, and phosphate buffers. Additionally or alternatively, the pharmaceutical composition may include one or more stabilizers, such as sodium bisulfite, ethylenediaminetetraacetic acid, etc. Additionally or alternatively, the pharmaceutical composition may contain one or more solubilizing agents, such as polysorbates, polyethylene glycol, propylene glycol, macrogol 4000, etc. Additionally or alternatively, the pharmaceutical composition may contain one or more thickening agents to provide consistency in density or consistency to the preparations of the present disclosure. Suitable thickening agents 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 dispersing agents, such as poly(ethylene glycol), polyethoxylated castor oil, alcohols having 12 to 20 carbon atoms, and mixtures thereof.

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

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

[0192] The ophthalmic pharmaceutical compositions of the present disclosure may be suitable for topical delivery to a subject's eye or surrounding ocular tissues. The ophthalmic pharmaceutical compositions of the present disclosure may be suitable for implantation into or on a subject's eye or surrounding ocular tissues. In some embodiments, the ophthalmic pharmaceutical compositions are suitable for implantation into the subconjunctival space, nasolacrimal duct, or vitreous body of a subject.

[0193] In some embodiments, the ophthalmic pharmaceutical compositions of the present disclosure may be surgically implanted into the subconjunctival space after an ophthalmologist determines that the patient will benefit from the implantation after preliminary testing with topical eye drops. The components passively reach the iris and interact with iris muscle fibers to alter pupil size. This action results in increased depth of field and improvement in farsightedness and nearsightedness, as discussed in the present disclosure.

[0194] Treating subjects suffering from symptoms of presbyopia It is an object of the present disclosure to treat a subject suffering from symptoms of presbyopia by directly administering a therapeutically effective amount of the disclosed ophthalmic pharmaceutical composition. Thus, administration of the ophthalmic pharmaceutical composition can reduce or eliminate the symptoms of presbyopia and improve a patient's ability to focus on near-distance objects, including objects near normal reading distances. Administration of the ophthalmic pharmaceutical composition can also significantly reduce discomfort or the risk of falls when using progressive or bifocal lenses, and / or reduce or completely eliminate blur and haze after ophthalmic surgery.

[0195] The degree of presbyopia after use of an ophthalmic pharmaceutical composition of the present 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 use of the composition of the present disclosure. The degree of presbyopia can be determined by any method known in the art for ophthalmic examination. For example, a standard test may be performed to examine a patient's ability to focus on near-distance objects, including objects near their normal reading distance, after administration of an ophthalmic pharmaceutical composition of the present disclosure.

[0196] In some embodiments, the treatment may be to correct presbyopia in a subject over about 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 to correct presbyopia in a subject within 24 hours.

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

[0198] In some embodiments, the ophthalmic pharmaceutical compositions of the present disclosure may be used to correct presbyopia in a subject, wherein the subject is: a) Spectacle wearers who cannot use or will not use progressive or bifocal lenses; b) have had cataract surgery; c) developed presbyopia after corneal procedures; d) have monofocal or multifocal intraocular lenses; e) contact lens wearers and intolerant of monocular lenses; f) contact lens wearers and intolerant of multifocal lenses; g) suffer from high-order aberrations after corneal surgery; h) suffer from hyperopia or strabismus; i) Not tolerating changes in eyeglass prescription; j) experienced a sudden change in eyeglass prescription; k) The use of progressive or bifocal lenses poses a risk of falls; and / or l) Suffer from high order aberrations at night or under low light conditions.

[0199] Another aspect of the present disclosure relates to a delivery system for administering an ophthalmic pharmaceutical composition according to the present disclosure to a subject in need thereof. In some embodiments, the composition may be administered topically to the subject's eye or surrounding ocular tissue. In some embodiments, the composition may be administered via surgical intervention into or on the subject's eye or surrounding ocular tissue. In some embodiments, the surgical intervention comprises implanting the ophthalmic pharmaceutical composition into or on the subject's eye or surrounding ocular tissue (e.g., via intraocular insertion). In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous 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 comprises 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 a subject in a single dose to correct presbyopia. In some embodiments, the ophthalmic pharmaceutical composition is preferably administered to a 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 one another by short (1-5 minutes), medium (6-30 minutes), or long (more than 30 minutes, or even several hours) time intervals.

[0202] The ophthalmic pharmaceutical composition may be administered to a subject using any dosage effective to correct presbyopia. The exact dosage required will vary from subject to subject, depending on the subject's species, age, and / or general condition, the severity of the disease, the particular formulation, its method of administration, its mode of activity, and the like. However, it will be understood that the total daily usage of the composition may be determined by the attending ophthalmologist within the scope of sound medical judgment. The specific pharmaceutically effective dosage level for any particular patient will depend on a variety of factors, including the severity of the patient's presbyopia, the particular composition used, age, weight, general health, sex, and diet, the time of administration, the route of administration, the duration of treatment, and similar factors well known in the art of ophthalmology.

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

[0204] Further uses of the ophthalmic compositions of the present disclosure In some embodiments, the ophthalmic pharmaceutical compositions of the present disclosure may also be used to treat other health conditions, for example, in subjects who have not had ophthalmic surgery and who have symptoms of presbyopia. In some embodiments, the ophthalmic pharmaceutical compositions of the present disclosure may be used in subjects who have the following conditions: (a) extreme skin conditions (e.g., trypophobia, ichthyosis), (b) multiple allergy syndrome, and / or (c) diabetes. In some embodiments, the ophthalmic pharmaceutical compositions of the present 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-assisted keratomileusis (LASIK), photorefractive keratectomy (PRK), or similar procedures, and / or (c) phakic intraocular lens implantation. In some embodiments, the ophthalmic pharmaceutical compositions of the present disclosure may be used in pediatric cases where ophthalmic surgery is not recommended (e.g., childhood strabismus).

[0205] Another aspect of the present disclosure relates to the administration of an ophthalmic pharmaceutical composition according to the present disclosure to modulate some physiological process in a subject. By way of non-limiting example, the modulation of the physiological process may include reducing pupil size, causing miosis, increasing the depth of field, reducing the amount of high-order aberrations, and / or improving uncorrected near and distance visual acuity in a subject.

[0206] In some embodiments, a method for reducing pupil size in a subject comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present disclosure. a) Spectacle wearers who cannot use or will not use progressive or bifocal lenses; b) have had cataract surgery; c) developed presbyopia after corneal procedures; d) have monofocal or multifocal intraocular lenses; e) contact lens wearers and intolerant of monocular lenses; f) contact lens wearers and intolerant of multifocal lenses; g) suffer from high-order aberrations after corneal surgery; h) suffer from hyperopia or strabismus; i) Not tolerating changes in eyeglass prescription; j) experienced a sudden change in eyeglass prescription; k) The use of progressive or bifocal lenses poses a risk of falls; and / or l) Suffer from high order aberrations at night or under low light conditions.

[0207] In some embodiments, a method for reducing 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 topically to the subject's eye or surrounding ocular tissue. In some embodiments, the composition may be administered via surgical intervention into or on the subject's eye or surrounding ocular tissue. In some embodiments, the surgical intervention comprises implanting the ophthalmic pharmaceutical composition into or on the subject's eye or surrounding ocular tissue (e.g., via intraocular insertion). In some embodiments, the ophthalmic pharmaceutical composition is implanted in the subconjunctival space, nasolacrimal duct, or vitreous body of the subject. 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, injectable solution, spray, or eye drop formulation.

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

[0209] In some embodiments, a method for inducing miosis in a subject comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present disclosure. a) Spectacle wearers who cannot use or will not use progressive or bifocal lenses; b) have had cataract surgery; c) developed presbyopia after corneal procedures; d) have monofocal or multifocal intraocular lenses; e) contact lens wearers and intolerant of monocular lenses; f) contact lens wearers and intolerant of multifocal lenses; g) suffer from high-order aberrations after corneal surgery; h) suffer from hyperopia or strabismus; i) Not tolerating changes in eyeglass prescription; j) experienced a sudden change in eyeglass prescription; k) The use of progressive or bifocal lenses poses a risk of falls; and / or l) Suffer from high order aberrations at night or under low light conditions.

[0210] In some embodiments, a method for 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 topically to the subject's eye or surrounding ocular tissue. In some embodiments, the composition may be administered via surgical intervention into or on the subject's eye or surrounding ocular tissue. In some embodiments, the surgical intervention comprises implanting the ophthalmic pharmaceutical composition into or on the subject's eye or surrounding ocular tissue (e.g., via intraocular insertion). In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous body of the subject. 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, injectable solution, spray, or eye drop formulation.

[0211] In any embodiment for inducing miosis in a subject, the effect of the ophthalmic pharmaceutical composition in inducing miosis can be assessed by methods well known in the art (see, e.g., Example 1 disclosed herein).

[0212] In some embodiments, a method for increasing depth of field in an eye of 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: a) Spectacle wearers who cannot use or will not use progressive or bifocal lenses; b) have had cataract surgery; c) developed presbyopia after corneal procedures; d) have monofocal or multifocal intraocular lenses; e) contact lens wearers and intolerant of monocular lenses; f) contact lens wearers and intolerant of multifocal lenses; g) suffer from high-order aberrations after corneal surgery; h) suffer from hyperopia or strabismus; i) Not tolerating changes in eyeglass prescription; j) experienced a sudden change in eyeglass prescription; k) The use of progressive or bifocal lenses poses a risk of falls; and / or l) Suffer from high order aberrations at night or under low light conditions.

[0213] In some embodiments, a method for increasing depth of field in a subject's eye comprises administering to a 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 topically to the subject's eye or surrounding ocular tissue. In some embodiments, the composition may be administered via surgical intervention into or on the subject's eye or surrounding ocular tissue. In some embodiments, the surgical intervention comprises implanting the ophthalmic pharmaceutical composition into or on the subject's eye or surrounding ocular tissue (e.g., via intraocular insertion). In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous body 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 a subject's eye, the effect of the ophthalmic pharmaceutical composition on increasing the depth of field can be assessed by methods well known in the art (see, e.g., Example 1 disclosed herein).

[0215] In some embodiments, a method for reducing the level of high-order aberrations in an eye of 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: a) Spectacle wearers who cannot use or will not use progressive or bifocal lenses; b) have had cataract surgery; c) developed presbyopia after corneal procedures; d) have monofocal or multifocal intraocular lenses; e) contact lens wearers and intolerant of monocular lenses; f) contact lens wearers and intolerant of multifocal lenses; g) suffer from high-order aberrations after corneal surgery; h) suffer from hyperopia or strabismus; i) Not tolerating changes in eyeglass prescription; j) experienced a sudden change in eyeglass prescription; k) The use of progressive or bifocal lenses poses a risk of falls; and / or l) Suffer from high order aberrations at night or under low light conditions.

[0216] In some embodiments, a method for reducing the level of high-order aberrations in a subject's eye comprises administering to a 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 topically to the subject's eye or surrounding ocular tissue. In some embodiments, the composition may be administered via surgical intervention into or on the subject's eye or surrounding ocular tissue. In some embodiments, the surgical intervention comprises implanting the ophthalmic pharmaceutical composition into or on the subject's eye or surrounding ocular tissue (e.g., via intraocular insertion). In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous body of the subject. The composition may be in the form of a suspension, gel, ointment, injectable solution, spray, or eye drop formulation.

[0217] In any embodiment for reducing the degree of high-order aberrations in a subject's eye, the effectiveness of the ophthalmic pharmaceutical composition in reducing the degree of high-order aberrations can be assessed by methods known in the art, for example, wavefront aberrometry can be used to measure non-invasive third, fourth, and fifth order ocular high-order aberrations (coma, spherical aberration, and trefoil aberration) at each visit.

[0218] In some embodiments, a method for improving uncorrected near and distance vision in a subject comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present disclosure. a) Spectacle wearers who cannot use or will not use progressive or bifocal lenses; b) have had cataract surgery; c) developed presbyopia after corneal procedures; d) have monofocal or multifocal intraocular lenses; e) contact lens wearers and intolerant of monocular lenses; f) contact lens wearers and intolerant of multifocal lenses; g) suffer from high-order aberrations after corneal surgery; h) suffer from hyperopia or strabismus; i) Not tolerating changes in eyeglass prescription; j) experienced a sudden change in eyeglass prescription; k) The use of progressive or bifocal lenses poses a risk of falls; and / or l) Suffer from high order aberrations at night or under low light conditions.

[0219] In some embodiments, a method for improving uncorrected near and distance vision 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 topically to the subject's eye or surrounding ocular tissue. In some embodiments, the composition may be administered via surgical intervention into or on the subject's eye or surrounding ocular tissue. In some embodiments, the surgical intervention comprises implanting the ophthalmic pharmaceutical composition into or on the subject's eye or surrounding ocular tissue (e.g., via intraocular insertion). In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous body 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 the ophthalmic pharmaceutical composition on reducing pupil size can be assessed by methods well known in the art. For example, visual acuity may be determined at various distances using a standard eye chart at every study visit. Testing may be performed one eye at a time by covering the untested eye, and / or both eyes. Uncorrected visual acuity may be assessed at intermediate distance (50-80 cm) and / or near distance (40 cm). Photometric measurements of visual acuity may be performed as follows: distance and intermediate distances are measured under normal lighting conditions and recorded with a luminometer. Near visual acuity is measured in both dim light (room lighting dimmed to half the normal visibility in the examination room) and bright light (full-print lighting shining from the left shoulder), both recorded with a luminometer. At distance and intermediate distances, luminance should be approximately 3000 lux. At close range, luminance should be 750-1,000 lux at low contrast and 3,000 lux at high contrast. All visual acuity measurements can be recorded in decimal or LogMar notation. Decimal notation is preferred.

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

[0222] Some embodiments relate to an implant comprising an ophthalmic pharmaceutical composition according to the present disclosure. In some embodiments, the implant may be introduced into or on the surface of a subject's eye or surrounding ocular tissues via surgical intervention. In some embodiments, the surgical intervention comprises implanting the ophthalmic pharmaceutical composition into or on the surface of a subject's eye or surrounding ocular tissues (e.g., by intraocular insertion). In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous of the subject. In some embodiments, the ophthalmic pharmaceutical composition is a sustained-release composition.

[0223] Delivery via intravitreal microinserts near the fundus is known to be efficient and advantageous (e.g., WO2011 / 079123A1). The advantage of microinserts is that the components are slowly released and remain in the eye, and fluid introduced to the ocular surface does not flow out of the natural drainage channels. Microinserts save patients time and effort by avoiding frequent repeated instillation.

[0224] In some embodiments, the sustained-release implant may be surgically implanted into the subconjunctival space after an ophthalmologist determines that the patient will benefit from implantation after preliminary testing with topical eye drops.The component passively reaches the iris and interacts with the iris muscle fibers to change pupil size.This action leads to an increase in depth of field and improvement in farsightedness and nearsightedness, as discussed in the present disclosure (see Example 1).

[0225] In some embodiments, the implant may be introduced into a subject by surgical intervention, wherein the subject: a) Spectacle wearers who cannot use or will not use progressive or bifocal lenses; b) have had cataract surgery; c) developed presbyopia after corneal procedures; d) have monofocal or multifocal intraocular lenses; e) contact lens wearers and intolerant of monocular lenses; f) contact lens wearers and intolerant of multifocal lenses; g) suffer from high-order aberrations after corneal surgery; h) suffer from hyperopia or strabismus; i) Not tolerating changes in eyeglass prescription; j) experienced a sudden change in eyeglass prescription; k) The use of progressive or bifocal lenses poses a risk of falls; and / or l) Suffer from high order aberrations at night or under low light conditions.

[0226] In some embodiments, the implant is useful for correcting presbyopia in a subject. In some embodiments, the implant is useful for reducing pupil size in a subject. In some embodiments, the implant is useful for inducing miosis in a subject. In some embodiments, the implant is useful for increasing the depth of field in an eye of a subject. In some embodiments, the implant is useful for reducing the amount of high-order aberrations in an eye of a subject. In some embodiments, the implant is useful for improving uncorrected near and distance vision in a subject.

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

[0228] In some embodiments, a kit may be provided to a subject, wherein the subject: a) Spectacle wearers who cannot use or will not use progressive or bifocal lenses; b) have had cataract surgery; c) developed presbyopia after corneal procedures; d) have monofocal or multifocal intraocular lenses; e) contact lens wearers and intolerant of monocular lenses; f) contact lens wearers and intolerant of multifocal lenses; g) suffer from high-order aberrations after corneal surgery; h) suffer from hyperopia or strabismus; i) Not tolerating changes in eyeglass prescription; j) experienced a sudden change in eyeglass prescription; k) The use of progressive or bifocal lenses poses a risk of falls; and / or l) Suffer from high order aberrations at night or under low light conditions.

[0229] In some embodiments, the kit is useful for correcting presbyopia in a subject. In some embodiments, the kit is useful for reducing pupil size in a subject. In some embodiments, the kit is useful for inducing miosis in a subject. In some embodiments, the kit is useful for increasing depth of field in an eye of a subject. In some embodiments, the kit is useful for reducing the amount of high-order aberrations in an eye of a subject. In some embodiments, the kit is useful for improving uncorrected near and distance visual acuity in a subject.

[0230] Methods for assessing improvement in presbyopia One of the effects of changing pupil size is a change in depth of field (DoF) and visual acuity. The depth of field of the eye is defined as the distance in diopters that a viewed object can be moved closer to or further from the eye while the eye is in a fixed refractive state until the retinal image is no longer clearly and sharply visible from the object (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 testing 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 mean DoF from 0.59 D to 0.86 D. They found a small increase of 0.27 D. Similarly, Sergienko and Tutchenko (2007, Eur J Ophthalmol 17:836-840) reported that at a visual acuity of 1.5, DoF increased by 0.26 D in response to a 2 mm change in artificial pupil size from 5 mm to 3 mm. Marcos et al. (1999, Vision Res. 39:2039-2049) reported that DoF was affected by a range of compositions for the observed target with varying artificial pupil size, but the change was small, averaging only 0.16 D. The small changes in DoF when pupil size is reduced by approximately 50% are not significant. However, these results were obtained in a relatively small group of trained subjects with high visual acuity. Some have observed that in elderly subjects, with central fixation, DoF tends to increase, sometimes by as much as ±2.5 D (Ronchi & Moleskini, 1975, Ophthalmic Res 7:152-157). This increase is probably related to naturally occurring age-related miosis and changes in contrast sensitivity. Mordi and Ciufredda (1998, Vision Res. 38:1643-1653) predicted that between ages 21 and 50, DoF increases at 0.027 D / year, corresponding to an increase of 0.80 D over a 30-year period. Growing evidence clearly points to the following conclusion: Reducing pupil size increases DoF. Tabanero and Artal (2012, J Cataract Refract Surg 38:270-277) elegantly demonstrated that a 1.6 mm diameter opening in the Acufocus Kamra corneal implant, when placed in a corrective position to simulate an artificial pupil, could increase DoF by up to 2.5 D. This artificial pupil was placed close to the actual pupil, but still approximately 3-4 mm away from the pupil's actual location.Studies investigating the effect of pupil size on DoF have used various artificial pupils placed in front of the eye or directly measured pupil size. The actual effect of changes in pupil size on DoF requires accommodation paralysis, in which artificial openings of various sizes are placed to prevent the effect of accommodation stimuli on DoF from affecting the actual DoF-pupil size relationship and to simulate changes in pupil size when the actual pupil dilates (Mordi & Ciuffreda, 1998, Vision Res. 38:1643-1653). It would be useful to update DoF in real eyes under clinical conditions without paralysis and to compare pharmacologically induced changes in actual pupil size with changes in contrasting measurements of DoF under normal clinical conditions in normal, untrained patients. Miotics, due to their biochemical properties, likely act not only on iris receptors but also on receptors located in the ciliary body, resulting in changes in accommodation and refraction. Therefore, miotics that promote sufficient pupil constriction with little effect on the refractive power of the lens are needed.

[0232] A procedure for estimating depth of field (DoF) with distance DoF can be estimated after constructing 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 graphical plot of measured visual acuity (y-axis) in relation to the power of a series of trial spherical lenses placed in front of the eye. It is a stimulus-response curve that can be derived using various psychophysical methods. In clinical practice, obtaining data to construct a defocus curve is time-consuming and prone to several sources of error, including patient loss of concentration.

[0233] A long-established, simple, and rapid technique reviewed by Wang and Ciuffreda (2006, Surv Ophthalmol 51:75-85) and used by many researchers was employed in this study (see Example 1). Modifications of 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 the 20 / 30 line of a Snellen target through glasses with the best corrective distance. The Plus sphere was increased in 0.25D increments on the refractor head until the patient reported that the target was no longer acceptable sharpness. This was performed monocularly under normal ambient light conditions. Benard et al. (2011, Vision Res 51:2471-2477) determined subjective DoF using a 20 / 50 high-contrast letter. Yao et al. (2010, Vision Res 50:1266-73) used a high-contrast square-wave grating incorporated within a Badal lens device. Although these two groups of researchers used different settings, they found very similar DoF results.

[0234] All of the claims below are hereby incorporated by reference in their entirety as additional embodiments. [Example]

[0235] Example 1: Pharmacological alteration of actual pupil diameter with a pilocarpine composition improves unaided distance and near visual acuity and depth of field in presbyopic and pseudophakic eyes The purpose of this study was to determine the effect of actual changes in pupil size on depth of field (DoF) and visual acuity in presbyopia and monofocal or multifocal IOL implants following routine eye examinations in a clinical setting. Reducing pupil size increases DoF and therefore 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 application.

[0237] Combining NSAIDs and tear consolidants with pilocarpine may act as a preventive measure to combat pilocarpine-induced inflammatory reactions and dry eye.

[0238] As described below, mixing 0.2% pilocarpine hydrochloride or pilocarpine nitrate with 0.006% diclofenac sodium was found to be well tolerated upon topical application and to produce significant miosis. There was no evidence of short- or long-term undesirable complications specifically associated with topical application of 0.006% diclofenac mixed with sodium hyaluronate at concentrations typically combined with tear comfort agents. 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 for the sole purpose of providing miosis with minimal, negligible discomfort. In this example, percentiles are determined by weight (w / v). This combination was provided in a custom formulation to induce miosis during the planned study. Results indicated that topical application of the formulation improved unaided distance and near vision by reducing natural pupil diameter.

[0239] Methods and Materials 1. Measuring Pupil Size Pupil size was measured using an infrared imaging system used to verify alignment during automated refraction measurements. An infrared image of the pupil, converted to visible light, magnified, and displayed on the device's viewing screen, allows the user to observe the pupil and align the instrument during normal use. Vertical and horizontal pupil diameters were measured on the screen with a ruler when the subject was looking at a target at infinity. The average of the two measurements was recorded and magnification-corrected (approximately ×7 to ×8) for both vertical and horizontal meridian magnification.

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

[0241] 3. Procedure for assessing depth of field (DoF) at the far point Patients were asked to look at the 20 / 30 line of a Snellen chart through glasses with the power of their best correction distance. 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 (-b diopters). DoF at the far point = (a + b) diopters. This procedure was performed on a monocular basis in both the presbyope and pseudophakic groups under everyday ambient lighting conditions (350 lux).

[0242] 4. Procedure for assessing depth of field (DOF) at the near point The spectacle power at the best corrective distance was increased in +2.50D increments on the refractometer head, and the patient was asked to look at a line of J2 type at a distance of 0.40m. The plus power of the refractometer head was increased in 0.25D increments (+x diopters) until the patient reported blurring. This procedure was repeated with a negative lens (-y diopters). DoF at the near point = (x + y) diopters. This procedure was performed on a monocular basis under everyday peripheral lighting conditions (350 lux) in presbyopes.

[0243] 5. Study Design The study was a prospective, consecutive, non-randomized interventional trial that adhered to the principles of the Declaration of Helsinki. All presbyopic subjects were recruited from patients attending routine eye examinations. Exclusion criteria included a history of amblyopia, ocular disease or surgery, cataracts, macular degeneration, irregular pupils, or any systemic condition known to affect pupil dynamics or visual quality. Pseudophakic patients were also recruited from those attending routine eye examinations. Exclusion criteria included amblyopia, ocular complications, toric or multifocal IOL implantation, signs of macular degeneration, capsular thickening, irregular pupils, or a history of any systemic condition known to affect pupil dynamics or visual quality. When appropriate, measurements were taken from both the left and right eyes. All subjects were fully informed of the nature and purpose of this study.

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

[0245] 6. Response Measurement and Statistical Analysis Data were analyzed to: 1) to examine whether uncorrected distance visual acuity was affected by instillation in presbyopic and pseudophakic eyes (Wilcoxon signed-rank test); 2) to examine whether uncorrected near visual acuity was affected by instillation in presbyopic and pseudophakic eyes (Wilcoxon signed-rank test); 3) to compare DoF measurements of far point distance between presbyopes and pseudophakic eyes ( t -test); 4) To examine whether there was any relationship between measured pupil size, age, and DoF measurements at near point distance (Pearson's correlation coefficient); 5) to examine whether there was any relationship between measured pupil size, age, and DoF measurements at far point distance (Pearson's correlation coefficient); and 6) To examine whether any changes in DoF at far point distance were associated with changes in pupil size (Pearson correlation coefficient).

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

[0247] result Twenty-seven (27) subjects received one drop per eye, and eighteen (18) subjects received two drops per eye of the ophthalmic pharmaceutical composition. For subjects receiving two drops per eye, the second drop was administered several seconds after the first.

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

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

[0250] Compared with the pseudophakic group, the mean pupil diameter was significantly larger in the presbyopic group both before and after instillation (p<0.001). There was no significant difference in the mean depth of field between the groups before instillation. However, the difference between the groups became significant after instillation (p<0.001) (Tables 1 and 2).

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

[0252] In the pseudophakic group, no significant correlation was found between i) pupil size and age, ii) age and depth of field at far point, or iii) pupil size and depth of field.

[0253] Within each group, in binocular cases, no significant differences were found between the results obtained from the right eye compared to the left eye. Because there was no obvious bias toward the right or left eye, data obtained from both eyes can 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 (ΔPupillary) in individual cases, data obtained from the right and left eyes were pooled for specific types of analysis.

[0254] In the presbyopic group, a significant correlation was found between ΔDoF and Δpupillary diameter. These results are shown in Figure 1 (far point) and Figure 2 (near point). The least-squares regression line equating ΔDoF (y, diopters) and Δpupillary 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 equating ΔDoF (y, diopters) and Δpupil diameter (x, mm) at the near point was of the form: y=0.352-0.253x(r=-0.429,n=53,p<0.001) [Equation 2].

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

[0256] Consideration Forty-five subjects participated in this pilot study, including 29 presbyopic subjects and 16 pseudophakic subjects (subjects with an implanted monofocal IOL). A total of 9 of the 45 subjects (20%) reported mild irritation after instillation of the drops. One subject reported dryness, one subject noted blurred vision, one subject experienced nausea and headache, three subjects reported a stinging sensation, and another three subjects described a burning sensation after instillation. No subjects reported overall dissatisfaction after instillation of the drops.

[0257] In both groups, unaided distance and near 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 presbyopes, typical unaided distance visual acuity improved from 20 / 20 to 20 / 15, and unaided 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 an improvement in both unaided distance and near visual acuity in presbyopes. In the pseudophakic group, typical unaided distance visual acuity improved from 20 / 30 to 20 / 25, and unaided near visual acuity improved from J8 to J3. The results in Tables 1 and 2 show that a 1.01 mm reduction in pupil diameter was associated with a greater improvement in unaided near visual acuity and a smaller improvement in unaided distance visual acuity in the pseudophakic cohort when compared to the presbyope group.

[0258] This anomaly may be related to the fact that the pupil is initially smaller in pseudophakic eyes. Pupil size tends to be smaller in older subjects compared with younger subjects (Birren et al., 1950, J Gerontol 5:216-221; Winn et al., 1994, Investigative Ophthalmology & Visual Science 35:1132-1137). No correlation was found between age and pupil size in each of our two groups. However, the mean (±sd) pupil diameter and age in the presbyopic 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 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 pupils in the pseudophakic group were probably related to the age of the subjects in this cohort rather than to the patients who underwent cataract surgery. This, in conjunction with the differences in optical properties between phakic presbyopes and pseudophakic eyes, probably accounts for the slight differences in response to eye drops.

[0259] The mean DoF values ​​for both groups before application of eye drops were remarkably similar to previous reports. Table 1 shows the mean (±sd) DoF values ​​at the far point in presbyopia, 1.31 D (0.42) and 1.41 D (0.45). These values ​​fall within the maximum limit of 1.8 D reported in the review on the topic by Wang and Ciuffreda (2006, Surv Ophthalmol 51:75-85). Table 2 shows the mean DoF values ​​at the far point in pseudophakic eyes, 1.61 D (0.51) and 1.65 D (0.52). These values ​​are within the limits of 0.80D to 1.65D reported 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 presbyope and pseudophakic groups, the mean DoF increased after instillation. In the pseudophakic group, a mean increase in DoF of 1.03 D was accompanied by a mean decrease in pupil size of 1.05 mm. The measured depth of field at the far point remained unchanged in 5 of the 53 presbyopes. However, in the same 5 cases, pupil size decreased and the measured depth of field at the near point increased by up to 1 D. Pooling all data at our disposal revealed a significant relationship between the change in pupil size (Δpupillary diameter) and the change in DoF (ΔDoF). The exponent of the linear regression equation predicts that a 1 mm reduction in pupil diameter would result in a simultaneous increase in DoF of 0.83 D at the far point and 0.61 D at the near point.

[0261] As mentioned above, after topical application of this formulation, the unaided far and near visual acuity improved.

[0262] Of the 45 subjects, 9 reported side effects, but none expressed overall dissatisfaction with the product. The product was well tolerated, with one subject even inquiring about 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, percentiles are determined by weight (w / w). The formulation is designed to provide miosis and increase depth of field for the temporary correction of presbyopia. The placebo contains the same ingredients as the investigational drug, excluding the active ingredient.

[0264] subject This study was a double-blind, randomized, placebo-controlled, two-way crossover, repeated-dose study conducted in subjects with presbyopia. After signing informed consent and undergoing a screening assessment, 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 subject (one drop in each eye each morning) for two weeks, with a 24-hour washout period between treatments. The allowed interval between treatment visits was 11 to 17 days. All subjects underwent the same evaluations regardless of their treatment group assignment. Each subject continued to be followed up for two weeks after the end of the treatment period. The maximum duration for an individual patient was 64 days (~9 weeks) and included the following periods: Screening period: up to 21 days (inclusive); Treatment duration: 29 days; and Follow-up period: 14 days.

[0265] The objectives of this study were to: 1) To establish the safety and tolerability of repeated administration of CSF-1 in presbyopic subjects; and 2) To determine the effectiveness of repeated administration of CSF-1 in presbyopic subjects.

[0266] Methods and Materials 1. Measuring Pupil Size Pupil size was measured using an infrared imaging system used to verify alignment during automated refraction measurements. An infrared image of the pupil, converted to visible light, magnified, and displayed on the device's viewing screen, allows the user to observe the pupil and align the instrument during normal use. Vertical and horizontal pupil diameters were measured on the screen using a ruler when the subject was looking at a target at infinity. The average of the two measurements was recorded and magnification-corrected (approximately ×7 to ×8) for both vertical and horizontal meridian magnification.

[0267] 2. Visual acuity measurement All visual acuity measurements were obtained using FDA-approved standard EDTRS charts at far and near distances. EDTRS charts provide visual acuity measurements in Snellen, decimal, and logMAR notation. These chart designs feature a simple 0.1-increment column of letter-sized characters from one line to the next on the logMAR scale, and a scale for conversion to other notations such as Snellen or decimal notation. For example, when a subject can only distinguish the letters on line 11 of the EDTRS chart at 4M, designated as 20 / 20 Snellen visual acuity, the subject's visual acuity can be expressed as 0.0 logMAR or 1.0 decimal beside the 20 / 20 notation. Being able to distinguish the letters on the next line, i.e., line 12, would indicate -0.1 logMAR or 1.25 decimal, or 20 / 16 Snellen visual acuity. The logMAR notation provides greater precision and valid statistical comparisons. Distance visual acuity was measured in each eye under standard high ambient lighting (~3,000 lux) and binocular vision under standard high ambient lighting (~3,000 lux) during visual acuity testing. Near visual acuity was measured in each eye under standard high ambient lighting (~3,000 lux) and binocular vision under standard high ambient lighting (~3,000 lux) and binocular vision under standard high ambient lighting (~3,000 lux), and measurements were repeated under lower lighting (20-1,000 lux).

[0268] 3. Procedures for Assessing Peripheral Vision Visual fields were assessed using a standard clinical test known in the art, commonly referred to as the en face test, which checks for any visual field loss or abnormalities in the superior, inferior, nasal, and temporal regions of the visual field in each eye.

[0269] 4. Procedure for assessing depth of field (DoF) at the far point The patient was asked to view the 0.1 logMAR line of the eye chart through glasses with the best corrective distance. 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 (-b diopters). DoF at the far point = (a + b) diopters. This procedure was performed monocularly under everyday ambient lighting conditions (~3000 lux).

[0270] 5. Procedure for assessing depth of field (DoF) at the near point Patients were asked to view the 0.1 logMAR line of the eye chart through glasses with the best corrective distance. The plus 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 on a monocular basis under everyday ambient lighting conditions (~3000 lux).

[0271] 6. Procedures for evaluating effectiveness The primary efficacy endpoint was defined as a 0.2 or 0.3 improvement in unaided near (UNVA) visual acuity according to the logMAR notation, which was equivalent to a 2- or 3-line improvement in visual acuity using a standard EDTRS chart for near vision (40 cm).

[0272] 7. Study Design The study was a double-blind, double-centered, randomized, placebo-controlled, repeated-dose, crossover trial to establish the safety, tolerability, and efficacy of CSF-1 in presbyopia, following the principles of the Declaration of Helsinki. All presbyopic subjects were recruited from patients attending routine eye examinations. All subjects had best-corrected visual acuity of at least 20 / 20, equivalent to 0.0 on the logMAR scale, and all relied on reading or bifocal glasses with a myopic addition of >+1.00 diopters. In addition, all subjects required no or low optical distance correction, with a spherical component of ±0.75 diopters or less and / or a cylindrical component of ±0.75 DC or less, and a refraction along any principal meridian of 1.00 diopters or less. Exclusion criteria included amblyopia, ocular disease or surgery, cataract, macular degeneration, irregular pupils, a natural pupil diameter of less than 2.5 mm in one eye under ambient lighting of 8-15 lux, and a history of any systemic condition known to affect pupil dynamics or visual quality. Measurements were taken from both eyes, where appropriate. All subjects were fully informed of the nature and purpose of this study.

[0273] Data were collected before and during clinic visits following self-administration of the formulation (CSF-1 or placebo) topically to both eyes. Any symptoms reported by the subjects (e.g., dryness, nausea, grittiness, etc.) were also recorded.

[0274] 8. Response Measurement and Statistical Analysis Data were analyzed to: 1) Determine whether the eye drops affected uncorrected distance visual acuity; 2) to determine whether uncorrected near vision was affected by the eye drops; 3) to determine whether the eye drops affected pupil size; 4) To determine whether the eye drops affected depth of field for distance and near vision.

[0275] To analyze quantitative changes, appropriate statistical tests were applied, such as the McNemar test and paired t-test for two paired samples, or the signed-rank test for two means (paired observations). All tests were two-tailed, and a p-value of less than 5% was considered statistically significant.

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

[0277] There was no overall difference between the CSF-1 and placebo groups in uncorrected distance visual acuity in both eyes and in the right eye. 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. Key information is listed in Table 3.

[0278] [Table 3]

[0279] There was a significant change in mean uncorrected near visual acuity after CSF-1 compared with any change after placebo. The changes after CSF-1 treatment were substantially greater than any changes observed with placebo. Key information is listed in Tables 4-6.

[0280] [Table 4] [Table 5] [Table 6] There were significant changes in mean depth of field at far and near distances after using CSF-1 compared with any change after using placebo. Key information is listed in Table 7.

[0281] [Table 7] Significant changes in mean depth of field at far and near points were observed after using CSF-1 compared to the changes after using placebo. Key information is listed in Table 8.

[0282] [Table 8] No significant changes in tear film stability were observed after use of either CSF-1 or placebo. Key information is listed in Table 9.

[0283] [Table 9]

[0284] Consideration uncorrected distance vision Certain concentrations of pilocarpine will stimulate the ciliary muscle to induce accommodation, resulting in decreased distance visual acuity (see, e.g., Emsley, 1972, Optics of Vision, 5th ed., 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 decrease uncorrected distance visual acuity. Since distance visual acuity was not impaired (Table 3), the data indicate that no accommodation was stimulated by CSF-1. More specifically, unexpectedly, 91.7% of eyes treated with CSF-1 showed no change in uncorrected distance visual acuity. With placebo, 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 under high ambient lighting, binocular near visual acuity at 40 cm unexpectedly improved by two or more lines in 41.7% of patients receiving CSF-1 and 22.2% of patients receiving placebo (p=0.0348) (Table 4). Under low ambient lighting, 41.7% of patients unexpectedly scored as demonstrating such an increase in uncorrected binocular near visual acuity, compared with only 16.7% receiving placebo (p=0.0067) (Table 5).

[0286] Turning to the results obtained from individual eyes, under low ambient lighting conditions, CSF-1 treatment improved uncorrected near visual acuity at 40 cm by 3 or more lines in 27.8% of left eyes and 22.2% of right eyes (Table 5). However, with placebo, only 2.8% of left eyes and 5.6% of right eyes improved by 3 or more lines (p<0.0143 right eye & p<0.0027 left eye) (Table 5). These findings were unexpected because pilocarpine reduces pupil size and limits the amount of light entering the eye, which would be expected to reduce the brightness of the retinal image and visual acuity under low ambient lighting conditions.

[0287] pupil Low concentrations of pilocarpine (below 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). However, the present study revealed an unexpected and significant result: miosis constricted from a mean of 4.29 mm before CSF-1 administration to a mean of 3.10 mm after instillation of CSF-1 (Table 7). Without being bound by theory regarding the mechanism, the results of this study suggest that CSF-1 acts through miosis rather than accommodation.

[0288] depth of field Depth of field is inversely related to pupil size. Depth of field increases as pupil size decreases. Low concentrations of pilocarpine (below 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, increases in DoF would not be expected with pilocarpine at concentrations below 1%. However, this study revealed an unexpectedly significant increase in depth of field after CSF-1 administration compared with the changes observed after placebo administration, at both far and near distances (Table 8).

[0289] Tear film Topical eye drops containing salts of pilocarpine can induce dry eye due to both decreased tear production and 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 changes, either decreases or increases, in tear film stability after the use of either CSF-1 or placebo (Table 9).

[0290] Vision in low light conditions Pilocarpine-induced miosis can affect visual field and visual acuity when ambient light levels are reduced. Therefore, patients may notice partial loss of visual field and a reduced ability to perform important tasks when good vision is required at night. Unexpectedly, no reduction or decrease in the overall size of the visual field was reported when patients used either CSF-1 or placebo. The study results revealed that all 23 patients whose visual fields were tested, in both the drug and placebo groups, had normal visual fields and no visual field reduction. At the start of the study, 75% of subjects 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 pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.4% (w / w or w / v), hydroxypropylmethylcellulose, and a pharmaceutically acceptable carrier.

2. 2. The ophthalmic pharmaceutical composition according to claim 1, wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

3. The ophthalmic pharmaceutical composition according to claim 1, wherein the ophthalmic pharmaceutical composition is a sustained release composition.

4. The ophthalmic pharmaceutical composition of claim 1, wherein the ophthalmic pharmaceutical composition is in the form of a suspension, gel, ointment, injection solution, spray, or eye drop formulation.

5. The ophthalmic pharmaceutical composition of claim 1, wherein the ophthalmic pharmaceutical composition is suitable for implantation into or on the surface of a subject's eye or surrounding tissues of the eye; or the ophthalmic pharmaceutical composition is suitable for implantation into the subconjunctival space, nasolacrimal duct, or vitreous of a subject; or the ophthalmic pharmaceutical composition is suitable for local delivery to a subject's eye or surrounding tissues of the eye.

6. 10. The ophthalmic pharmaceutical composition according to claim 1 for correcting presbyopia for up to 24 hours.

7. 10. The ophthalmic pharmaceutical composition of claim 1 for correcting presbyopia without adversely affecting night vision or adversely narrowing the visual field.

8. An ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.4% (w / w or w / v), hydroxypropyl methylcellulose, and a pharmaceutically acceptable carrier, for correcting presbyopia in a subject.

9. The ophthalmic pharmaceutical composition according to claim 8, wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

10. The ophthalmic pharmaceutical composition according to claim 8, wherein the ophthalmic pharmaceutical composition is a sustained release composition.

11. The ophthalmic pharmaceutical composition according to claim 8, wherein the ophthalmic pharmaceutical composition is in the form of a suspension, a gel, an ointment, an injectable solution, a spray, or an eye drop formulation.

12. The ophthalmic pharmaceutical composition of claim 8, wherein the ophthalmic pharmaceutical composition is suitable for implantation into or on the surface of a subject's eye or surrounding tissues of the eye; or the ophthalmic pharmaceutical composition is suitable for implantation into the subconjunctival space, nasolacrimal duct, or vitreous of a subject; or the ophthalmic pharmaceutical composition is suitable for local delivery to a subject's eye or surrounding tissues of the eye.

13. 9. The ophthalmic pharmaceutical composition according to claim 8, for correcting presbyopia for up to 24 hours.

14. 9. The ophthalmic pharmaceutical composition according to claim 8, for correcting presbyopia without adversely affecting night vision or significantly narrowing the visual field.

15. The subject has at least one of the following characteristics: a) Spectacle wearers who cannot use or will not use progressive or bifocal lenses; b) have had cataract surgery; c) developed presbyopia after corneal procedures; d) having a monofocal or multifocal intraocular lens; e) Wears contact lenses and cannot tolerate monocular vision lenses; f) contact lens wearers and intolerant of multifocal lenses; g) suffer from high-order aberrations after corneal surgery; h) suffer from hyperopia or strabismus; i) Does not tolerate changes in eyeglass prescription; j) experienced a sudden change in eyeglass prescription; k) the use of progressive or bifocal lenses poses a risk of falling; and / or l) suffer from high-order aberrations at night or under low light conditions The ophthalmic pharmaceutical composition according to claim 8.

16. An ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.4% (w / w or w / v), hydroxypropyl methylcellulose, and a pharmaceutically acceptable carrier, for reducing pupil size in a subject.

17. An ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.4% (w / w or w / v), hydroxypropyl methylcellulose, and a pharmaceutically acceptable carrier, for inducing miosis in a subject.

18. An ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.4% (w / w or w / v), hydroxypropyl methylcellulose, and a pharmaceutically acceptable carrier, for increasing the depth of field in a subject's eye.

19. An ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.4% (w / w or w / v), hydroxypropyl methylcellulose, and a pharmaceutically acceptable carrier, for reducing the degree of high-order aberrations in a subject's eye.

20. An ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.4% (w / w or w / v), hydroxypropyl methylcellulose, and a pharmaceutically acceptable carrier, for improving uncorrected near and distance vision in a subject.

21. An implant comprising an ophthalmic pharmaceutical composition consisting of pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.4% (w / w or w / v), hydroxypropyl methylcellulose, and a pharmaceutically acceptable carrier.

22. A kit comprising an ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.4% (w / w or w / v), hydroxypropylmethylcellulose, and a pharmaceutically acceptable carrier.

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