RU2791371C2 - Ophthalmic pharmaceutical formulae and their use - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions is intended for correction of presbyopia and other ophthalmic diseases in a subject. The ophthalmic composition contains one API, such as pilocarpine or a pharmaceutically acceptable salt thereof, at a concentration of 0.01-0.4% (w/w or w/v), a lubricant and a pharmaceutically acceptable carrier. Also provided are a method for correcting presbyopia, a method for reducing pupil size, a method for inducing miosis, a method for increasing the depth of field of the eye, a method for reducing the magnitude of higher order aberrations in the eye, and a method for improving uncorrected near and distance visual acuity, including administration of the said composition to a subject. In addition, a graft and a kit containing the said composition are provided. In another presentation, an ophthalmic composition is provided containing pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01-0.4% (w/w or w/v), hydroxypropyl methylcellulose at a concentration of 0.1-2.0% (w/w or w/v). weight/volume) and a pharmaceutically acceptable carrier. The said composition is used in methods for correcting presbyopia, reducing pupil size and increasing the depth of field of the eye.

EFFECT: use of the group of inventions provides correction of presbyopia, reduction of pupil size, induction of miosis, increase in the depth of field of the eye, decrease in the magnitude of higher-order aberrations in the eye, and improving uncorrected near and distance visual acuity. 66 cl, 2 dwg, 22 tbl, 2 ex

Description

Cross-reference to related applications

This application claims priority based on U.S. Provisional Application No. 62/377154, filed Aug. 19, 2016, the entire contents of which are incorporated herein by reference.

Field of invention

The present invention relates to an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof. Aspects of the invention further relate to formulations and uses of ophthalmic pharmaceutical compositions containing pilocarpine or a pharmaceutically acceptable salt for the correction of presbyopia and other ocular disorders in a subject.

State of the art

Presbyopia is a near vision disorder that occurs as a result of a gradual loss of accommodation of the lens, usually after the age of 40-45. This is the most common physiological change occurring in the adult eye and, if not corrected, can have a significant negative impact on quality of life and performance (Frick et al., 2015, Ophthalmology 122(8): 1706-1710; Goertzetal. , 2014, ActaOphthalmologica 92(6): 497-500; Pateletal., 2007, Community eye health/International Center for Eye Health 20(63): 40-41). The main symptom of this condition is a progressive deterioration of vision when performing tasks at close range (reading, sewing, working at a computer, and so on). This can occur in the absence of any visual symptoms associated with long distance vision. By 2020, 1.4 billion people worldwide are expected to be affected by presbyopia (Holden et al., 2008, Archives of Ophthalmology 126(12): 1731-1739).

Methods for correcting presbyopia can include both fixed and zoom lens systems (spectacles or contact lenses with monofocal, bifocal, or multifocal designs), as well as surgical procedures that change the optics of the cornea, changing the lens to another fixed optic, or trying restore active accommodation at least partially (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 or not provide adequate treatment, and surgical methods can be invasive and come with certain risks. For example, after surgery, the patient may have problems with night vision. There are currently no clinically effective pharmaceuticals to treat the symptoms of presbyopia.

Accordingly, in order to overcome the obvious inconvenience for patients who are forced to wear corrective lenses or undergo unwanted operations that involve certain risks, there remains a need for new ways to reduce the symptoms or correct presbyopia.

The essence of the invention

The present invention relates to an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof. The present invention also relates to formulations (eg kits or implants) containing ophthalmic pharmaceutical compositions containing pilocarpine or a pharmaceutically acceptable salt thereof. Aspects of the invention further provide methods useful for correcting presbyopia and other ocular conditions in a subject.

Some embodiments of the present invention are summarized in the following paragraphs. This list is illustrative only and is not exhaustive for all embodiments presented in the present invention.

Embodiment 1. 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).

Embodiment 2 The ophthalmic pharmaceutical composition of Embodiment 1 wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

Embodiment 3. The ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition further comprises diclofenac or a pharmaceutically acceptable salt thereof at a concentration of 0.001% (w/w or w/v) - 0.090% (w/w or w/v), or ketorolac or its pharmaceutically acceptable salt at a concentration of 0.01% (w/w or w/v) - 0.60% (w/w or w/v).

Embodiment 4 The ophthalmic pharmaceutical composition of Embodiment 3 wherein the diclofenac salt is diclofenac sodium or wherein the ketorolac salt is ketorolac tromethamine.

Embodiment 5 The ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition further comprises a lubricant.

Embodiment 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, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or mixtures thereof.

Embodiment 7 The ophthalmic pharmaceutical composition of Embodiment 6 wherein the lubricant is sodium hyaluronate or hydroxypropyl methylcellulose or mixtures thereof.

Embodiment 8. An ophthalmic pharmaceutical composition of Embodiment 7 wherein sodium hyaluronate is present at a concentration of 0.01% (w/w or w/v) - 0.9% (w/w or w/v), and/or where hydroxypropyl methylcellulose is present at a concentration of 0.1% (w/w or w/v) - 2.0% (w/w or w/v).

Embodiment 9. The ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition contains:

(1) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w or w/v), diclofenac sodium at a concentration of 0.001% (w/w or w/v) /volume) - 0.090% (w/w or w/v) and sodium hyaluronate at a concentration of 0.01% (w/w or w/v) - 0.9% (w/w or w/v);

(2) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w or w/v), diclofenac sodium at a concentration of 0.001% (w/w or w/w) /volume) - 0.090% (w/w or w/v) and hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) - 2.0% (w/w or w/v);

(3) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w or w/v), ketorolac tromethamine at a concentration of 0.01% (w/w) or mass / volume) - 0.60% (mass / mass or mass / volume) and sodium hyaluronate at a concentration of 0.01% (mass / mass or mass / volume) - 0.9% (mass / mass or mass / volume );

(4) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w or w/v), ketorolac tromethamine at a concentration of 0.01% (w/w) or w/v) - 0.60% (w/w or w/v) and hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) - 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) - 0.4% (w/w or w/v), diclofenac sodium at a concentration of 0.001% (w/w or w/w) /volume) - 0.090% (w/w or w/v), sodium hyaluronate at a concentration of 0.01% (w/w or w/v) - 0.9% (w/w or w/v) and hydroxypropyl methylcellulose in concentrations of 0.1% (w/w or w/v) - 2.0% (w/w or w/v).

Embodiment 10 An ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition is selected from Compositions 1-32, and wherein each of Compositions 1-32 contains pilocarpine hydrochloride or pilocarpine nitrate, diclofenac sodium, and sodium hyaluronate as follows:

Composition pilocarpine hydrochloride or pilocarpine nitrate
(mass/mass or mass/volume) diclofenac sodium
(mass/mass or mass/volume) sodium hyaluronate
(mass/mass or mass/volume) 1 0.1% 0% 0% 2 0.1% 0.001% 0% 3 0.1% 0.006% 0% 4 0.1% 0.090% 0% 5 0.1% 0% 0.01% 6 0.1% 0% 0.1% 7 0.1% 0% 0.9% 8 0.1% 0.001% 0.01% 9 0.1% 0.001% 0.1% 10 0.1% 0.001% 0.9% eleven 0.1% 0.006% 0.01% 12 0.1% 0.006% 0.1% 13 0.1% 0.006% 0.9% 14 0.1% 0.090% 0.01% 15 0.1% 0.090% 0.1% 16 0.1% 0.090% 0.9% 17 0.2% 0% 0% 18 0.2% 0.001% 0% 19 0.2% 0.006% 0% 20 0.2% 0.090% 0% 21 0.2% 0% 0.01% 22 0.2% 0% 0.1% 23 0.2% 0% 0.9% 24 0.2% 0.001% 0.01% 25 0.2% 0.001% 0.1% 26 0.2% 0.001% 0.9% 27 0.2% 0.006% 0.01% 28 0.2% 0.006% 0.1% 29 0.2% 0.006% 0.9% thirty 0.2% 0.090% 0.01% 31 0.2% 0.090% 0.1% 32 0.2% 0.090% 0.9%

Embodiment 11 An ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition is selected from Compositions 33-64, and wherein each of Compositions 33-64 contains pilocarpine hydrochloride or pilocarpine nitrate, diclofenac sodium, and hydroxypropyl methylcellulose as follows:

Composition pilocarpine hydrochloride or pilocarpine nitrate
(mass/mass or mass/volume) diclofenac sodium
(mass/mass or mass/volume) hydroxypropyl methylcellulose
(mass/mass or mass/volume) 33 0.1% 0% 0% 34 0.1% 0.001% 0% 35 0.1% 0.006% 0% 36 0.1% 0.090% 0% 37 0.1% 0% 0.1% 38 0.1% 0% 0.8% 39 0.1% 0% 1.2% 40 0.1% 0.001% 0.1% 41 0.1% 0.001% 0.8% 42 0.1% 0.001% 1.2% 43 0.1% 0.006% 0.1% 44 0.1% 0.006% 0.8% 45 0.1% 0.006% 1.2% 46 0.1% 0.090% 0.1% 47 0.1% 0.090% 0.8% 48 0.1% 0.090% 1.2% 49 0.2% 0% 0% 50 0.2% 0.001% 0% 51 0.2% 0.006% 0% 52 0.2% 0.090% 0% 53 0.2% 0% 0.1% 54 0.2% 0% 0.8% 55 0.2% 0% 1.2% 56 0.2% 0.001% 0.1% 57 0.2% 0.001% 0.8% 58 0.2% 0.001% 1.2% 59 0.2% 0.006% 0.1% 60 0.2% 0.006% 0.8% 61 0.2% 0.006% 1.2% 62 0.2% 0.090% 0.1% 63 0.2% 0.090% 0.8% 64 0.2% 0.090% 1.2%

Embodiment 12 An ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition is selected from Compositions 65-96, and wherein each of Compositions 65-96 contains pilocarpine hydrochloride or pilocarpine nitrate, ketorolac tromethamine, and sodium hyaluronate as follows:

Composition pilocarpine hydrochloride or pilocarpine nitrate (w/w or w/v) ketorolac tromethamine (w/w or w/v) sodium hyaluronate (w/w or w/v) 65 0.1% 0% 0% 66 0.1% 0.01% 0% 67 0.1% 0.30% 0% 68 0.1% 0.50% 0% 69 0.1% 0% 0.01% 70 0.1% 0% 0.1% 71 0.1% 0% 0.9% 72 0.1% 0.01% 0.01% 73 0.1% 0.01% 0.1% 74 0.1% 0.01% 0.9% 75 0.1% 0.30% 0.01% 76 0.1% 0.30% 0.1% 77 0.1% 0.30% 0.9% 78 0.1% 0.50% 0.01% 79 0.1% 0.50% 0.1% 80 0.1% 0.50% 0.9% 81 0.2% 0% 0% 82 0.2% 0.01% 0% 83 0.2% 0.30% 0% 84 0.2% 0.50% 0% 85 0.2% 0% 0.01% 86 0.2% 0% 0.1% 87 0.2% 0% 0.9% 88 0.2% 0.01% 0.01% 89 0.2% 0.01% 0.1% 90 0.2% 0.01% 0.9% 91 0.2% 0.30% 0.01% 92 0.2% 0.30% 0.1% 93 0.2% 0.30% 0.9% 94 0.2% 0.50% 0.01% 95 0.2% 0.50% 0.1% 96 0.2% 0.50% 0.9%

Embodiment 13 An ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition is selected from Compositions 97-128, and wherein each of Compositions 97-128 contains pilocarpine hydrochloride or pilocarpine nitrate, ketorolac tromethamine, and hydroxypropyl methylcellulose as follows:

Composition pilocarpine hydrochloride or pilocarpine nitrate (w/w or w/v) ketorolac tromethamine (w/w or w/v) Hydroxypropyl methylcellulose (w/w or w/v) 97 0.1% 0% 0% 98 0.1% 0.01% 0% 99 0.1% 0.30% 0% 100 0.1% 0.50% 0% 101 0.1% 0% 0.1% 102 0.1% 0% 0.8% 103 0.1% 0% 1.2% 104 0.1% 0.01% 0.1% 105 0.1% 0.01% 0.8% 106 0.1% 0.01% 1.2% 107 0.1% 0.30% 0.1% 108 0.1% 0.30% 0.8% 109 0.1% 0.30% 1.2% 110 0.1% 0.50% 0.1% 111 0.1% 0.50% 0.8% 112 0.1% 0.50% 1.2% 113 0.2% 0% 0% 114 0.2% 0.01% 0% 115 0.2% 0.30% 0% 116 0.2% 0.50% 0% 117 0.2% 0% 0.1% 118 0.2% 0% 0.8% 119 0.2% 0% 1.2% 120 0.2% 0.01% 0.1% 121 0.2% 0.01% 0.8% 122 0.2% 0.01% 1.2% 123 0.2% 0.30% 0.1% 124 0.2% 0.30% 0.8% 125 0.2% 0.30% 1.2% 126 0.2% 0.50% 0.1% 127 0.2% 0.50% 0.8% 128 0.2% 0.50% 1.2%

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

Embodiment 15 The ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition is in the form of a suspension, gel, ointment, injection, spray, or eye drops.

Embodiment 16 The ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition is suitable for implantation in or on the subject's eye, or tissue surrounding the subject's eye.

Embodiment 17 An ophthalmic pharmaceutical composition of Embodiment 16, wherein the ophthalmic pharmaceutical composition is suitable for implantation into the subconjunctival space, nasolacrimal duct, or vitreous body of a subject.

Embodiment 18 An ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition is suitable for topical delivery to the eye or tissue surrounding the eye of a subject.

Embodiment 19 An ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition contains a pharmaceutically acceptable diluent, preservative and/or solvent.

Embodiment 20. An ophthalmic pharmaceutical composition of Embodiment 1 further comprising an isotonicizer, a wetting agent, a buffer, a stabilizer, a pH agent, a solubilizer, a thickening agent, and/or a dispersing agent.

Embodiment 21 The ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition is effective for correcting presbyopia for up to 24 hours.

Embodiment 22 The ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely affecting night vision.

Embodiment 23 The ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely reducing the visual field.

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

Embodiment 25. The method of Embodiment 24 wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

Embodiment 26. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition further comprises diclofenac or a pharmaceutically acceptable salt thereof at a concentration of 0.001% (w/w or w/v) - 0.090% (w/w or w/v), or ketorolac or its pharmaceutically acceptable salt at a concentration of 0.01% (w/w or w/v) - 0.60% (w/w or w/v).

Embodiment 27. The method of Embodiment 26 wherein the diclofenac salt is diclofenac sodium or wherein the ketorolac salt is ketorolac tromethamine.

Embodiment 28. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition further comprises a lubricant.

Embodiment 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, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone or mixtures thereof.

Embodiment 30. The method of Embodiment 29 wherein the lubricant is sodium hyaluronate or hydroxypropyl methylcellulose or mixtures thereof.

Embodiment 31. The method of Embodiment 30 wherein sodium hyaluronate is present at a concentration of 0.01% (w/w or w/v) - 0.9% (w/w or w/v) and/or wherein hydroxypropyl methylcellulose is present at a concentration of 0.1% (w/w or w/v) - 2.0% (w/w or w/v).

Embodiment 32. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition comprises:

(1) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w or w/v), diclofenac sodium at a concentration of 0.001% (w/w or w/v) /volume) - 0.090% (w/w or w/v), and sodium hyaluronate at a concentration of 0.01% (w/w or w/v) - 0.9% (w/w or w/v);

(2) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w or w/v), diclofenac sodium at a concentration of 0.001% (w/w or w/w) /volume) - 0.090% (w/w or w/v) and hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) - 2.0% (w/w or w/v);

(3) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w or w/v), ketorolac tromethamine at a concentration of 0.01% (w/w) or mass / volume) - 0.60% (mass / mass or mass / volume), and sodium hyaluronate at a concentration of 0.01% (mass / mass or mass / volume) - 0.9% (mass / mass or mass / volume);

(4) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w or w/v), ketorolac tromethamine at a concentration of 0.01% (w/w) or w/v) - 0.60% (w/w or w/v) and hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) - 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) - 0.4% (w/w or w/v), diclofenac sodium at a concentration of 0.001% (w/w or w/w) /volume) - 0.090% (w/w or w/v), sodium hyaluronate at a concentration of 0.01% (w/w or w/v) - 0.9% (w/w or w/v) and hydroxypropyl methylcellulose in concentrations of 0.1% (w/w or w/v) - 2.0% (w/w or w/v).

Embodiment 33. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition is selected from Compositions 1-32 and wherein each of Compositions 1-32 contains pilocarpine hydrochloride or pilocarpine nitrate, diclofenac sodium and sodium hyaluronate as follows:

Composition pilocarpine hydrochloride or pilocarpine nitrate (w/w or w/v) diclofenac sodium (w/w or w/v) sodium hyaluronate (w/w or w/v) 1 0.1% 0% 0% 2 0.1% 0.001% 0% 3 0.1% 0.006% 0% 4 0.1% 0.090% 0% 5 0.1% 0% 0.01% 6 0.1% 0% 0.1% 7 0.1% 0% 0.9% 8 0.1% 0.001% 0.01% 9 0.1% 0.001% 0.1% 10 0.1% 0.001% 0.9% eleven 0.1% 0.006% 0.01% 12 0.1% 0.006% 0.1% 13 0.1% 0.006% 0.9% 14 0.1% 0.090% 0.01% 15 0.1% 0.090% 0.1% 16 0.1% 0.090% 0.9% 17 0.2% 0% 0% 18 0.2% 0.001% 0% 19 0.2% 0.006% 0% 20 0.2% 0.090% 0% 21 0.2% 0% 0.01% 22 0.2% 0% 0.1% 23 0.2% 0% 0.9% 24 0.2% 0.001% 0.01% 25 0.2% 0.001% 0.1% 26 0.2% 0.001% 0.9% 27 0.2% 0.006% 0.01% 28 0.2% 0.006% 0.1% 29 0.2% 0.006% 0.9% thirty 0.2% 0.090% 0.01% 31 0.2% 0.090% 0.1% 32 0.2% 0.090% 0.9%

Embodiment 34. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition is selected from Compositions 33-64 and wherein each of Compositions 33-64 contains pilocarpine hydrochloride or pilocarpine nitrate, diclofenac sodium and hydroxypropyl methylcellulose as follows:

Composition pilocarpine hydrochloride or pilocarpine nitrate (w/w or w/v) diclofenac sodium (w/w or w/v) Hydroxypropyl methylcellulose (w/w or w/v) 33 0.1% 0% 0% 34 0.1% 0.001% 0% 35 0.1% 0.006% 0% 36 0.1% 0.090% 0% 37 0.1% 0% 0.1% 38 0.1% 0% 0.8% 39 0.1% 0% 1.2% 40 0.1% 0.001% 0.1% 41 0.1% 0.001% 0.8% 42 0.1% 0.001% 1.2% 43 0.1% 0.006% 0.1% 44 0.1% 0.006% 0.8% 45 0.1% 0.006% 1.2% 46 0.1% 0.090% 0.1% 47 0.1% 0.090% 0.8% 48 0.1% 0.090% 1.2% 49 0.2% 0% 0% 50 0.2% 0.001% 0% 51 0.2% 0.006% 0% 52 0.2% 0.090% 0% 53 0.2% 0% 0.1% 54 0.2% 0% 0.8% 55 0.2% 0% 1.2% 56 0.2% 0.001% 0.1% 57 0.2% 0.001% 0.8% 58 0.2% 0.001% 1.2% 59 0.2% 0.006% 0.1% 60 0.2% 0.006% 0.8% 61 0.2% 0.006% 1.2% 62 0.2% 0.090% 0.1% 63 0.2% 0.090% 0.8% 64 0.2% 0.090% 1.2%

Embodiment 35. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition is selected from compositions 65-96 and wherein each of compositions 65-96 contains pilocarpine hydrochloride or pilocarpine nitrate, ketorolac tromethamine, and sodium hyaluronate as follows:

Composition pilocarpine hydrochloride or pilocarpine nitrate (w/w or w/v) ketorolac tromethamine (w/w or w/v) sodium hyaluronate (w/w or w/v) 65 0.1% 0% 0% 66 0.1% 0.01% 0% 67 0.1% 0.30% 0% 68 0.1% 0.50% 0% 69 0.1% 0% 0.01% 70 0.1% 0% 0.1% 71 0.1% 0% 0.9% 72 0.1% 0.01% 0.01% 73 0.1% 0.01% 0.1% 74 0.1% 0.01% 0.9% 75 0.1% 0.30% 0.01% 76 0.1% 0.30% 0.1% 77 0.1% 0.30% 0.9% 78 0.1% 0.50% 0.01% 79 0.1% 0.50% 0.1% 80 0.1% 0.50% 0.9% 81 0.2% 0% 0% 82 0.2% 0.01% 0% 83 0.2% 0.30% 0% 84 0.2% 0.50% 0% 85 0.2% 0% 0.01% 86 0.2% 0% 0.1% 87 0.2% 0% 0.9% 88 0.2% 0.01% 0.01% 89 0.2% 0.01% 0.1% 90 0.2% 0.01% 0.9% 91 0.2% 0.30% 0.01% 92 0.2% 0.30% 0.1% 93 0.2% 0.30% 0.9% 94 0.2% 0.50% 0.01% 95 0.2% 0.50% 0.1% 96 0.2% 0.50% 0.9%

Embodiment 36. The method of Embodiment 24, wherein the ophthalmic pharmaceutical composition is selected from compositions 97-128, and wherein each of compositions 97-128 contains pilocarpine hydrochloride or pilocarpine nitrate, ketorolac tromethamine, and hydroxypropyl methylcellulose as follows:

Composition pilocarpine hydrochloride or pilocarpine nitrate (w/w or w/v) ketorolac tromethamine (w/w or w/v) Hydroxypropyl methylcellulose (w/w or w/v) 97 0.1% 0% 0% 98 0.1% 0.01% 0% 99 0.1% 0.30% 0% 100 0.1% 0.50% 0% 101 0.1% 0% 0.1% 102 0.1% 0% 0.8% 103 0.1% 0% 1.2% 104 0.1% 0.01% 0.1% 105 0.1% 0.01% 0.8% 106 0.1% 0.01% 1.2% 107 0.1% 0.30% 0.1% 108 0.1% 0.30% 0.8% 109 0.1% 0.30% 1.2% 110 0.1% 0.50% 0.1% 111 0.1% 0.50% 0.8% 112 0.1% 0.50% 1.2% 113 0.2% 0% 0% 114 0.2% 0.01% 0% 115 0.2% 0.30% 0% 116 0.2% 0.50% 0% 117 0.2% 0% 0.1% 118 0.2% 0% 0.8% 119 0.2% 0% 1.2% 120 0.2% 0.01% 0.1% 121 0.2% 0.01% 0.8% 122 0.2% 0.01% 1.2% 123 0.2% 0.30% 0.1% 124 0.2% 0.30% 0.8% 125 0.2% 0.30% 1.2% 126 0.2% 0.50% 0.1% 127 0.2% 0.50% 0.8% 128 0.2% 0.50% 1.2%

Embodiment 37. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition is a sustained release composition.

Embodiment 38. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition is in the form of a suspension, gel, ointment, injection, spray or eye drops.

Embodiment 39. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition is suitable for implantation in or on the subject's eye, or tissue surrounding the subject's eye.

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

Embodiment 41. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition is suitable for topical delivery to the eye or tissue surrounding the eye of a subject.

Embodiment 42. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition contains a pharmaceutically acceptable diluent, preservative and/or solvent.

Embodiment 43. The method of Embodiment 24 further comprising an isotonicizer, a wetting agent, a buffer, a stabilizer, a pH agent, a solubilizer, a thickening agent, and/or a dispersing agent.

Embodiment 44. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition is effective in correcting presbyopia for up to 24 hours.

Embodiment 45. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely affecting night vision.

Embodiment 46. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely reducing the visual field.

Embodiment 47. The method of Embodiment 24 wherein the subject:

a) is a spectacle wearer who cannot or will not wear progressive or bifocal lenses;

b) has undergone cataract surgery;

c) who develops presbyopia after a corneal procedure;

d) has monofocal or multifocal intraocular lenses;

e) wears contact lenses and is intolerant of monovisual contact lenses;

f) wears contact lenses and is intolerant of multifocal contact lenses;

g) suffers from a higher order aberration after corneal surgery;

h) suffers from hyperopia or tropia;

i) is intolerant of changes in scoring;

j) is undergoing rapid changes in scoring;

k) is at risk of falling when using progressive or bifocal lenses; and/or

l) suffers from higher order aberration at night or in low light conditions.

Embodiment 48. The method of Embodiment 24 wherein the administration is local or surgical.

Embodiment 49. The method of Embodiment 48 wherein the surgical intervention comprises the step of administering the ophthalmic pharmaceutical composition to or on the subject's eye, or tissue surrounding the subject's eye.

Embodiment 50. The method of Embodiment 49 wherein the ophthalmic pharmaceutical composition is administered to the subconjunctival space, nasolacrimal duct, or vitreous body of the subject.

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

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

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

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

Embodiment 55. A method of improving uncorrected near and far visual acuity in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w/w or w/v) - 0, 4% (w/w or w/v) and a pharmaceutically acceptable carrier.

Embodiment 56. An implant containing an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w or w/v) and is pharmaceutically acceptable carrier.

Embodiment 57. A kit containing an ophthalmic pharmaceutical composition containing pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w or w/v) and is pharmaceutically acceptable carrier.

Embodiment 58. A method of correcting presbyopia in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition that reduces pupil size in the subject, the ophthalmic pharmaceutical composition comprising pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w/w or w /volume) - 0.4% (w/w or w/v) and a pharmaceutically acceptable carrier.

Embodiment 59. The method according to any one of Embodiments 24-55, 58, 68 and 70, wherein the ophthalmic pharmaceutical composition is administered up to two times per application, up to three applications per day.

Embodiment 60. An ophthalmic pharmaceutical composition according to any of Embodiments 1-23, 67 and 69 for use in a method for correcting presbyopia in a subject, comprising administering an ophthalmic pharmaceutical composition to the subject's eye topically or through surgery.

Embodiment 61. An ophthalmic pharmaceutical composition according to any of Embodiments 1-23, 67, and 69 for use in a method for reducing pupil size in a subject, comprising administering an ophthalmic pharmaceutical composition to the subject's eye topically or through surgery.

Embodiment 62. An ophthalmic pharmaceutical composition according to any of Embodiments 1-23, 67 and 69 for use in a method for inducing miosis in a subject, comprising administering an ophthalmic pharmaceutical composition to the subject's eye topically or through surgery.

Embodiment 63. An ophthalmic pharmaceutical composition according to any one of Embodiments 1-23, 67, and 69 for use in a method for increasing depth of field in the eye of a subject, comprising administering an ophthalmic pharmaceutical composition to the eye of a subject topically or through surgery.

Embodiment 64. An ophthalmic pharmaceutical composition according to any of Embodiments 1-23, 67 and 69 for use in a method for reducing the magnitude of higher order aberration in the eye of a subject, comprising administering an ophthalmic pharmaceutical composition to the eye of a subject topically or through surgery.

Embodiment 65. An ophthalmic pharmaceutical composition according to any of Embodiments 1-23, 67, and 69 for use in a method for improving uncorrected near and far visual acuity in a subject, comprising administering an ophthalmic pharmaceutical composition to the subject's eye topically or through surgery.

Embodiment 66 An ophthalmic pharmaceutical composition according to any of Embodiments 1-23, 67 and 69 for use in a method of treating a human or animal body.

Embodiment 67 An ophthalmic pharmaceutical composition of Embodiment 1, wherein the ophthalmic pharmaceutical composition corrects presbyopia without negatively reducing distance visual acuity.

Embodiment 68. The method of Embodiment 24 wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely reducing distance visual acuity.

Embodiment 69 The ophthalmic pharmaceutical composition of Embodiment 10, wherein the ophthalmic pharmaceutical composition is selected from any of Compositions 1-32, further comprising hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v), 0.8% (w/w) /mass or mass/volume) or 1.2% (mass/mass or mass/volume).

Embodiment 70. The method of Embodiment 33 wherein the ophthalmic pharmaceutical composition is selected from any of Compositions 1-32 further comprising 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).

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) - 0.4% (w/w or w/v), hydroxypropyl methylcellulose at a concentration of 0, 1% (w/w or w/v) - 2.0% (w/w or w/v) and a pharmaceutically acceptable carrier.

Embodiment 72 The ophthalmic pharmaceutical composition of Embodiment 71 wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

Embodiment 73 The ophthalmic pharmaceutical composition of Embodiment 72 further comprising sodium hyaluronate at a concentration of 0.01% (w/w or w/v) - 0.9% (w/w or w/v).

Embodiment 74. An ophthalmic pharmaceutical composition of Embodiment 73 further comprising diclofenac or a pharmaceutically acceptable salt thereof at a concentration of 0.001% (w/w or w/v) - 0.090% (w/w or w/v), or ketorolac or a pharmaceutically acceptable salt thereof acceptable salt at a concentration of 0.01% (w/w or w/v) - 0.60% (w/w or w/v).

Embodiment 75. The ophthalmic pharmaceutical composition of Embodiment 74 wherein the diclofenac salt is diclofenac sodium or wherein the ketorolac salt is ketorolac tromethamine.

Embodiment 76. The ophthalmic pharmaceutical composition of Embodiment 75, wherein the ophthalmic pharmaceutical composition contains:

(1) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% (w/w or w/v) - 0.4% (w/w or w/v), hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) mass / volume) - 1.2% (mass / mass or mass / volume), sodium hyaluronate at a concentration of 0.01% (mass / mass or mass / volume) - 0.2% (mass / mass or mass / volume) and diclofenac sodium at a concentration of 0.001% (w/w or w/v) - 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) - 0.4% (w/w or w/v), hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) mass / volume) - 1.2% (mass / mass or mass / volume), sodium hyaluronate at a concentration of 0.01% (mass / mass or mass / volume) - 0.2% (mass / mass or mass / volume) and Ketorolac tromethamine at a concentration of 0.01% (w/w or w/v) - 0.50% (w/w or w/v).

Embodiment 77 An ophthalmic pharmaceutical composition of Embodiment 76, wherein the ophthalmic pharmaceutical composition contains:

(1) Pilocarpine hydrochloride or pilocarpine nitrate 0.2% (w/w or w/v), hydroxypropyl methylcellulose 0.8% (w/w or w/v), sodium hyaluronate 0.1% ( mass/mass or mass/volume) and diclofenac sodium at a concentration of 0.006% (mass/mass or mass/volume); or

(2) Pilocarpine hydrochloride or pilocarpine nitrate 0.2% (w/w or w/v), hydroxypropyl methylcellulose 0.8% (w/w or w/v), sodium hyaluronate 0.1% ( w/w or w/v) and Ketorolac tromethamine at a concentration of 0.50% (w/w or w/v).

Embodiment 78. The ophthalmic pharmaceutical composition of Embodiment 72, further comprising:

(1) sodium hyaluronate 0.01% (w/w or w/v) - 0.9% (w/w or w/v) or diclofenac sodium 0.001% (w/w or w/v) - 0.090% (w/w or w/v) or mixtures thereof; or

(2) sodium hyaluronate at a concentration of 0.01% (w/w or w/v) - 0.9% (w/w or w/v) or ketorolac tromethamine at a concentration of 0.01% (w/w or w/v). volume) - 0.60% (w/w or w/v) or mixtures thereof.

Embodiment 79. The ophthalmic pharmaceutical composition of Embodiment 72, wherein the ophthalmic pharmaceutical composition contains:

(1) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% (w/w or w/v) - 0.4% (w/w or w/v), hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) mass / volume) - 1.2% (mass / mass or mass / volume), and additionally contains sodium hyaluronate at a concentration of 0.01% (mass / mass or mass / volume) - 0.2% (mass / mass or mass /volume) or diclofenac sodium at a concentration of 0.001% (w/w or w/v) - 0.012% (w/w or w/v) or mixtures thereof; or

(2) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% (w/w or w/v) - 0.4% (w/w or w/v), hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) mass / volume) - 1.2% (mass / mass or mass / volume), and additionally contains sodium hyaluronate at a concentration of 0.01% (mass / mass or mass / volume) - 0.2% (mass / mass or mass /volume) or Ketorolac tromethamine at a concentration of 0.01% (w/w or w/v) - 0.50% (w/w or w/v) or mixtures thereof.

Embodiment 80. The ophthalmic pharmaceutical composition of Embodiment 79, wherein the ophthalmic pharmaceutical composition contains:

(1) pilocarpine hydrochloride or pilocarpine nitrate at 0.2% (w/w or w/v), hydroxypropyl methylcellulose at 0.8% (w/w or w/v), and additionally contains sodium hyaluronate at 0, 1% (w/w or w/v) or diclofenac sodium at a concentration of 0.006% (w/w or w/v) or mixtures 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 additionally contains 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 mixtures thereof.

Embodiment 81. The ophthalmic pharmaceutical composition of Embodiment 71, wherein the ophthalmic pharmaceutical composition contains a pharmaceutically acceptable diluent, preservative, and/or solvent.

Embodiment 82. The ophthalmic pharmaceutical composition of Embodiment 71 further comprising an isotonicizer, a wetting agent, a buffer, a stabilizer, a pH agent, a solubilizer, a thickening agent, and/or a dispersing agent.

Embodiment 83. The ophthalmic pharmaceutical composition of claim 71, wherein the ophthalmic pharmaceutical composition is effective for correcting presbyopia for up to 24 hours.

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

Embodiment 85. The method of Embodiment 84 wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate.

Embodiment 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) - 0.9% (w/w or w/v).

Embodiment 87. The method of Embodiment 86 wherein the ophthalmic pharmaceutical composition further comprises diclofenac or a pharmaceutically acceptable salt thereof at a concentration of 0.001% (w/w or w/v) - 0.090% (w/w or w/v) or ketorolac or its pharmaceutically acceptable salt at a concentration of 0.01% (w/w or w/v) - 0.60% (w/w or w/v).

Embodiment 88. The method of Embodiment 87 wherein the diclofenac salt is diclofenac sodium or wherein the ketorolac salt is ketorolac tromethamine.

Embodiment 89. The method of Embodiment 88 wherein the ophthalmic pharmaceutical composition comprises:

(1) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% (w/w or w/v) - 0.4% (w/w or w/v), hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) mass / volume) - 1.2% (mass / mass or mass / volume), sodium hyaluronate at a concentration of 0.01% (mass / mass or mass / volume) - 0.2% (mass / mass or mass / volume) and diclofenac sodium at a concentration of 0.001% (w/w or w/v) - 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) - 0.4% (w/w or w/v), hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) mass / volume) - 1.2% (mass / mass or mass / volume), sodium hyaluronate at a concentration of 0.01% (mass / mass or mass / volume) - 0.2% (mass / mass or mass / volume) and Ketorolac tromethamine at a concentration of 0.01% (w/w or w/v) - 0.50% (w/w or w/v).

Embodiment 90. The method of Embodiment 89 wherein the ophthalmic pharmaceutical composition comprises:

(1) Pilocarpine hydrochloride or pilocarpine nitrate 0.2% (w/w or w/v), hydroxypropyl methylcellulose 0.8% (w/w or w/v), sodium hyaluronate 0.1% ( mass/mass or mass/volume) and diclofenac sodium at a concentration of 0.006% (mass/mass or mass/volume); or

(2) Pilocarpine hydrochloride or pilocarpine nitrate 0.2% (w/w or w/v), hydroxypropyl methylcellulose 0.8% (w/w or w/v), sodium hyaluronate 0.1% ( w/w or w/v) and Ketorolac tromethamine at a concentration of 0.50% (w/w or w/v).

Embodiment 91. The method of Embodiment 85 wherein the ophthalmic pharmaceutical composition further comprises:

(1) sodium hyaluronate 0.01% (w/w or w/v) - 0.9% (w/w or w/v) or diclofenac sodium 0.001% (w/w or w/v) - 0.090% (w/w or w/v) or mixtures thereof; or

(2) sodium hyaluronate at a concentration of 0.01% (w/w or w/v) - 0.9% (w/w or w/v) or ketorolac tromethamine at a concentration of 0.01% (w/w or w/v). volume) - 0.60% (w/w or w/v) or mixtures thereof.

Embodiment 92. The method of Embodiment 85 wherein the ophthalmic pharmaceutical composition comprises:

(1) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% (w/w or w/v) - 0.4% (w/w or w/v), hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) mass / volume) - 1.2% (mass / mass or mass / volume), and additionally contains sodium hyaluronate at a concentration of 0.01% (mass / mass or mass / volume) - 0.2% (mass / mass or mass /volume) or diclofenac sodium at a concentration of 0.001% (w/w or w/v) - 0.012% (w/w or w/v) or mixtures thereof; or

(2) pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% (w/w or w/v) - 0.4% (w/w or w/v), hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) mass / volume) - 1.2% (mass / mass or mass / volume), and additionally contains sodium hyaluronate at a concentration of 0.01% (mass / mass or mass / volume) - 0.2% (mass / mass or mass /volume) or Ketorolac tromethamine at a concentration of 0.01% (w/w or w/v) - 0.50% (w/w or w/v) or mixtures thereof.

Embodiment 93. The method of Embodiment 92 wherein the ophthalmic pharmaceutical composition comprises:

(1) pilocarpine hydrochloride or pilocarpine nitrate at 0.2% (w/w or w/v), hydroxypropyl methylcellulose at 0.8% (w/w or w/v), and additionally contains sodium hyaluronate at 0, 1% (w/w or w/v) or diclofenac sodium at a concentration of 0.006% (w/w or w/v) or mixtures 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 additionally contains 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 mixtures thereof.

Embodiment 94. The method of Embodiment 85 wherein the ophthalmic pharmaceutical composition contains a pharmaceutically acceptable diluent, preservative and/or solvent.

Embodiment 95. The method of Embodiment 85, wherein the ophthalmic pharmaceutical composition further comprises an isotonic agent, a wetting agent, a buffer, a stabilizer, a pH agent, a solubilizer, a thickening agent, and/or a dispersing agent.

Embodiment 96. The method of Embodiment 85 wherein the ophthalmic pharmaceutical composition is effective in correcting presbyopia for up to 24 hours.

Embodiment 97. The method of Embodiment 85 wherein the administration is local or surgical.

Embodiment 98. The method of Embodiment 85 wherein the subject:

a) is a spectacle wearer who cannot or will not wear progressive or bifocal lenses;

b) has undergone cataract surgery;

c) who develops presbyopia after a corneal procedure;

d) has monofocal or multifocal intraocular lenses;

e) wears contact lenses and is intolerant of monovisual contact lenses;

f) wears contact lenses and is intolerant of multifocal contact lenses;

g) suffers from a higher order aberration after corneal surgery;

h) suffers from hyperopia or tropia;

i) is intolerant of changes in scoring;

j) is undergoing rapid changes in scoring;

k) is at risk of falling when using progressive or bifocal lenses; and/or

l) suffers from higher order aberration at night or in low light conditions.

Embodiment 99. A method of 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) - 0.4% (w/w) /mass or mass/volume), hydroxypropyl methylcellulose at a concentration of 0.1% (mass/mass or mass/volume) - 2.0% (mass/mass or mass/volume) and a pharmaceutically acceptable carrier.

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

Description of drawings

Those skilled in the art will appreciate that the drawings below are for illustrative purposes only. The drawings are not intended to limit the scope of the present invention in any way.

Figure 1 shows the relationship between change in depth of field (ΔDoF) and change in pupil size (Δpupil) in the presbyopic group (solid circle) and in the pseudophakic group (solid circle), whose members look at distant symbols (6 m) after instillation ophthalmic pharmaceutical composition of the present invention.

Figure 2 shows the relationship between change in depth of field (ΔDoF) and change in pupil size (Δpupil) in a presbyopic group (solid circle) whose members look at closely spaced symbols (40 cm) after instillation of the ophthalmic pharmaceutical composition of the present invention.

Detailed description

Numerous modifications and other embodiments of the invention presented herein will be considered by a person skilled in the art to which the present invention pertains, taking advantage of the ideas presented in the above descriptions and associated drawings. Accordingly, it is to be understood that the invention is not to be limited to the specific embodiments described, and that modifications and other embodiments are included within the scope of the appended claims. While specific terms are used in this document, they are used in a general and descriptive sense only, and not for purposes of limitation.

Definitions

Unless specifically defined otherwise, all technical and scientific terms used herein have the same meanings as generally understood by those skilled in the art to which the present invention pertains. Unless otherwise indicated, the methods used or described herein are standard methods well known to those skilled in the art. The practice of the present invention will use conventional methods for the preparation and use of ophthalmic pharmaceutical preparations that are known to those skilled in the art, unless otherwise indicated. The materials, methods and examples are illustrative only and are not limiting. The following is presented by way of illustration and is not intended to limit the scope of the present invention.

For convenience, some of the terms used throughout this application (including the description, examples, and the appended claims) are collected here.

As used herein, the singular forms of words also include plural forms, unless the context clearly indicates otherwise. In addition, where the terms "including", "includes", "having", "has", "with", or variations thereof are used in the detailed description and/or claims, such terms mean inclusion in a manner analogous to the term "comprising".

As used herein, the term "administration" refers to the placement of an anophthalmic pharmaceutical composition in a subject in a manner or manner that provides at least partial localization of the pharmaceutical composition to the desired site or tissue site (e.g., the subject's eye or tissues surrounding the eye). For example, the composition can be applied topically to the subject's eye or tissue surrounding the subject's eye. Alternatively, the composition may be administered via surgery to or on the subject's eye or tissue surrounding the subject's eye. In some embodiments, the ophthalmic pharmaceutical composition may be administered by any suitable route that provides effective treatment to the subject, i.e., administration provides delivery to the desired site or tissue of the subject, where at least a portion of the pilocarpine or pharmaceutically acceptable salt thereof is localized to the desired area or section of tissue. In some embodiments of the invention, the ophthalmic pharmaceutical composition may be administered several times over a short period of time, for example, within seconds or minutes. For example, in some embodiments, the ophthalmic pharmaceutical composition may be administered twice over 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 may be administered 3 times over 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 may be administered 4 times over 2 seconds, 5 seconds, 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes, 20 minutes, or 30 minutes.

The term "composition" refers to a mixture that contains the therapeutically active ingredient(s) and a carrier or excipient, such as a pharmaceutically acceptable carrier or excipient, which is conventional in the art and which is suitable for administration to a subject for the intended therapeutic purposes. The therapeutically active ingredient may include, for example, pilocarpine or a pharmaceutically acceptable salt of the invention. In some embodiments, the composition may be in the form of a suspension, gel, ointment, injection, spray, or eye drops (ie, compositions that are suitable for administration as eye drops). In some embodiments, when the composition is in the form of eye drops, each eye drop solution may have a volume of about 5 microliters to about 10 microliters, about 10 microliters to about 20 microliters, about 20 microliters to about 50 microliters, about 50 microliters to about 100 microliters, from about 100 microliters to about 250 microliters, or from about 250 microliters to about 500 microliters.

The terms "contain", "have", and "include" are non-limiting linking verbs. Any forms or tenses of one or more of these verbs, such as "contains", "containing", "has", "having", "includes", and "comprising", are also non-limiting. For example, any method that "comprises", "has", or "comprises" one or more steps is not limited to having only those one or more steps, and may also cover other steps not listed. Similarly, any composition that "comprises", "has", or "includes" one or more features is not limited to having only one or more of these features, and may cover other non-listed features. The use of any and all examples or illustrative language (eg, "such as") provided in relation to certain embodiments herein is only intended to better explain the present invention and does not limit the scope of the present invention as otherwise claimed. No wording in the present description should be construed as indicating any unclaimed element essential to the practice of the present invention.

The term "consisting essentially of" allows for the presence of additional substances or steps that "do not significantly affect the essential(s) and novel(s) feature(s)" of the claimed invention.

The term "consisting of" refers to compositions, methods, and their respective components, as described herein, which exclude any element not specified in this description of the embodiment.

As used herein, the terms "correct", "corrective", or "correction" refer to the reduction or amelioration of the severity of presbyopia. The weakening may be complete, for example, the complete absence of presbyopia. The relief can also be partial, such that the degree of presbyopia is less than the degree that would be without exposure to the methods and compositions of the present invention. The degree of presbyopia can be determined by any method known in the field of ophthalmological research.

The phrase "ophthalmologically acceptable" is used herein to refer to those compounds, substances, compositions and/or dosage forms which, within the limits of sound medical judgment, are suitable for use in contact with the eye and surrounding tissues of humans and animals without causing undue toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit/risk ratio. Drug agencies (eg EMA, US-FDA) provide guidance and approve pharmaceutically acceptable compounds, substances, compositions and/or dosage forms. Examples can be found in Pharmacopoeias.

The phrase "ophthalmologically acceptable carrier" is used herein to refer to a pharmaceutically acceptable substance selected from a solvent, dispersion medium, diluent, dispersion, suspension additive, surfactant, isotonic agent, thickener or emulsifier, preservative, core-shell nanoparticle, polymer, peptide, protein, cell, hyaluronidase and mixtures thereof which are compatible with pharmaceutical use. The use of such media and substances for pharmaceutically active substances is well known in the field of ophthalmology. The compositions may also contain other active compounds that provide adjuvant, additional or enhanced therapeutic functions.

The phrase "ophthalmic pharmaceutical composition" refers to a pharmaceutical composition that is used to manufacture a drug that is administered to the eye of a mammal.

The term "pharmaceutically acceptable salt(s)" refers to salts of acidic or basic groups that may be present in the compounds 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 the amino group formed by 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, bisulfate, phosphate, hydrogen phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, sodium p-toluene sulfate. For example, in some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate. On the other hand, certain compounds included in the present compositions, which are acidic in nature, are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali or alkaline earth metal salts, and in particular calcium, magnesium, sodium, lithium, zinc, potassium and iron salts. For example, in some embodiments, the ophthalmic pharmaceutical composition contains diclofenac sodium. For example, in some embodiments, the ophthalmic pharmaceutical composition contains ketorolac tromethamine.

The term "statistically significant" or "significantly" refers to statistical significance. The term refers to statistical evidence that there is a difference. This can be defined as the probability of deciding to reject the null hypothesis if the null hypothesis is indeed true. The decision is often made using a p-value. Any other measure of significant significance that is well known in the art can be used.

The terms "subject" and "individual" are used interchangeably herein and refer to an animal, such as a human, that is treated by the methods described herein. In some embodiments, the subject is a human.

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 reduce at least one or more symptoms of a disease or disorder, or to provide a desired effect. For example, this may be an amount that temporarily improves or even eliminates presbyopia such that near vision of the treated eye is temporarily restored partially or completely. For example, this may be an amount that causes a significant reduction in discomfort or the risk of falls when using progressive or bifocal lenses. For example, it may be an amount that reduces or completely eliminates distortion and haze after ophthalmic surgery.

As used herein, the terms "treat", "treatment", or "treatment" refer to the amelioration or elimination of a disease or disorder, or at least one overt symptom thereof. In some embodiments, "treatment" or "treatment" refers to the reduction in intensity or elimination of at least one measurable physical parameter, not necessarily perceptible by the patient. For example, the treatment may allow the patient to visually focus on objects at close range, including objects at close to normal reading distance. In some embodiments, the treatment is effective to relieve or eliminate presbyopia within 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 is effective to relieve or eliminate presbyopia for up to 24 hours. The degree of presbyopia can be determined by any method known in the art of ophthalmic examination.

For example, in one embodiment, treatment is determined by the subject's uncorrected near and far visual acuity, which can be determined using a standard acceptable visual acuity chart, such as Snellen distance visual acuity charts and Jaeger near visual acuity charts. or ETDRS (Early Treatment Study for Diabetic Retinopathy) tables. All values can be converted to decimal using the Halliday conversion table.

In another embodiment, the treatment is determined by a clinical assessment of the depth of field, which can be obtained using standard wavefront aberrometry or according to the following instructions:

Far: Distance spectacle fitting with maximum correction using a phoroptor/trial frame. The subject looks at the symbols 6/9 (0.6) on the Snellen chart. Increase the positive power until the subject reports image blur (+D). Repeat the procedure using negative lenses (-b diopters). Remove the negative sign before b. Depth of field in the distance \u003d (a + b) diopters.

Near: Distance spectacle fitting with maximum correction plus +2.5 diopters using a phoroptor/trial frame. The subject looks at image J2 from a distance of 40 cm. Increase the positive power until the subject reports image blur (+x diopters). Repeat the procedure using negative lenses (-y diopters). Remove the negative sign in front of y. Depth of field near=(x+y) diopters.

In yet another embodiment, treatment is determined by pupil size change, which can be assessed using an infrared imaging system used to check alignment in an autorefractometry process. The infrared image of the pupil, converted to visible light, amplified and displayed on the instrument screen for visual inspection, allows the user to observe the pupil and center the instrument during normal operation. Vertical and horizontal pupil diameters can be measured on the screen using a ruler while the subject is observing an object at infinity. The average of two measurements can be recorded and corrected for magnification (approximately x7 to x8) for vertical and horizontal meridians. Pupil size can also be measured with an aberrometer and pipulometer.

In yet another embodiment, treatment is determined by the appearance of the pupil, which may include examining the pupils for uniform size (a difference of 1 mm or less may be normal), correct shape, response to light, and direct and consistent accommodation.

In yet another embodiment, treatment is determined by non-invasive objective assessments of higher order aberrations of the eye (3rd, 4th and 5th) (eg, coma, spherical aberration, and trefoil), which can be performed using standard wavefront aberrometry.

It should be understood that the present invention is not limited to the particular methodology, protocols, reagents, and so forth described herein, and which, as such, are subject to change. The terminology used herein is only intended to describe specific embodiments and is not intended to limit the scope of the present invention, which is solely defined by the claims.

Pharmacological treatment of presbyopia

Presbyopia is usually associated with age-related visual impairment. Presbyopia usually develops a reduced ability to focus on objects at close distances due to a gradual loss of accommodation amplitude. With presbyopia, the eye loses the ability to quickly and easily focus on objects at close distances.

As a reference, when a young emmetrope fixes its gaze on a near object, two major changes occur in the eye: accommodation and miosis. Accommodation is a change in the refractive power of the lens of the eye. The lens becomes more round, which increases its refractive power. Miosis is a decrease in pupil size, in which the depth of field increases and higher-order aberrations decrease.

At the molecular level, both miosis and accommodation occur under the influence of the parasympathetic nervous system. Binding of parasympathomimetic drugs to muscarinic receptors causes muscle contraction of the ciliary muscle and pupillary sphincter and increases the refractive power of the eye. If this stimulation is strong enough, some decrease in the ability of the lens to change shape and position, which usually occurs with age, can be reversed while this stimulation is in effect.

Presbyopia was corrected with glasses, contact lenses or intraocular implants, as well as corneal ablation or implantation. The surgical methods that have been proposed for the correction of presbyopia do not fully restore the natural accommodative function of the eye, which has been reduced either as a result of natural aging or for other reasons. Pharmacological treatment has been proposed to restore the natural loss of accommodative function of the eye that leads to presbyopia.

To date, there are no clinically effective pharmaceuticals to treat the symptoms of presbyopia. The present invention provides simple, convenient and comfortable to use compositions and methods for patients suffering from the symptoms of presbyopia.

Ophthalmic compositions according to the invention

In accordance with the present invention, the ophthalmic pharmaceutical composition contains a therapeutically effective amount of a parasympathomimetic drug or a pharmaceutically acceptable salt thereof.

A parasympathomimetic drug is intended to include any cholinergic drug that enhances acetylcholine-mediated effects in the central nervous system, the peripheral nervous system, or both. One example of such parasympathomimetic drugs is pilocarpine. Additional examples are described in US Pat. No. 8,299,079 and may include acetylcholine, muscarine, nicotine, suxamethonium, bethanechol, methacholine, phenylpropanolamine, amphetamine, ephedrine, carbachol, phentolamine, and fenfluramine. In some embodiments, the parasympathomimetic drug is pilocarpine or carbachol. In preferred embodiments, the parasympathomimetic drug is pilocarpine.

Pilocarpine in the form of hydrochloride or nitrate is a miotic that has been used in the form of drops for the treatment of glaucoma for several decades. Long-term topical use of pilocarpine at certain concentrations has been associated with several undesirable ocular and systemic side effects, such as pigmentary dispersion, dry eyes, uveal tract inflammation, posterior synechia, ciliary muscle spasm, blurred vision, miosis, accommodation spasm, forehead headache , eyelid twitching, conjunctival injection, cataract, iris cyst, 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, IntOphthalmol 22:31- 35; Pop et al., 2000, Oftalmologia 52:44-48; Diestelhorst, 2000, Graefes Arch ClinExpOphthalmol 238:433-439; Nordmann et al., 2000, Br J Ophthalmol 84:181-185). These side effects are usually associated with the constant use of 1% pilocarpine or its higher concentration, constantly in several doses per day. In addition, pilocarpine, acting on the pupil, changes the color and pigmentation 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).

In some embodiments, the ophthalmic pharmaceutical composition comprises a pharmaceutically acceptable salt of a parasympathomimetic drug. Accordingly, in some embodiments, the implementation of the ophthalmic pharmaceutical composition contains a pharmaceutically acceptable salt of pilocarpine or carbachol. In preferred embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate.

In some embodiments of ophthalmic pharmaceutical compositions, pilocarpine or a pharmaceutically acceptable salt thereof may be present in an amount of from about 0.01% to about 0.4%, from about 0.01% to about 0.35%, from about 0.01% up to about 0.3%, from about 0.01% to about 0.25%, from about 0.01% to about 0.2%, from about 0.01% to about 0.15%, from about 0, 01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 0.4%, about 0.05% to about 0.35%, from about 0.05% to about 0.3%, about 0.05% to about 0.25%, about 0.05% to about 0.2%, about 0.05% to about 0.15%, about 0.05% to about 0.1%, about 0.1% to about 0.4%, about 0.1% to about 0.35%, about 0.1% to about 0.3 %, about 0.1% to about 0.25%, about 0.1% to about 0.2%, about 0.1% to about 0.15%, about 0.15% to about 0 .4%, from about 0.15% to about 0.35%, from about 0.15% to about 0.3%, from about 0.15% to about 0.25%, from about 0.15% to about 0.2%, from about 0.2% to about 0.4%, from about 0.2% to about 0.35%, about 0.2% to about 0.3%, about 0.2% to about 0.25%, about 0.25% to about 0.4%, about 0.25 % to about 0.35%, from about 0.25% to about 0.3%, from about 0.3% to about 0.4%, from about 0.3% to about 0.35%, from about 0 .35% to about 0.4% or at about 0.01%, about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0, 3%, about 0.35%, about 0.4%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition may further comprise a non-steroidal anti-inflammatory drug (NSAID) or a pharmaceutically acceptable salt thereof. NSAIDs can reduce or eliminate local inflammation that may result from stimulation caused by a parasympathomimetic drug (such as pilocarpine).

NSAIDs are well known in the art. In some embodiments, a suitable NSAID is diclofenac. Additional examples of NSAIDs include nepafenac, meloxicam, ketorolac, bromfenac, bendazac, flurbiprofen, suprofen, pranoprofen, oxyphenbutazone, surprofen, and indomethacin. Accordingly, in some embodiments, the ophthalmic pharmaceutical composition further comprises diclofenac. In some embodiments, the ophthalmic pharmaceutical composition further comprises ketorolac. Alternatively, the ophthalmic pharmaceutical composition may not contain NSAIDs.

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 or alkaline earth metal salts, and in particular calcium, magnesium, sodium, lithium, zinc, potassium and iron salts. For example, in some embodiments, the ophthalmic pharmaceutical composition further comprises sodium diclofenac. In some embodiments, the ophthalmic pharmaceutical composition further comprises ketorolac tromethamine. Alternatively, the ophthalmic pharmaceutical composition may not contain a pharmaceutically acceptable salt of the NSAID.

In some embodiments of ophthalmic pharmaceutical compositions, diclofenac or a pharmaceutically acceptable salt thereof (e.g., diclofenac sodium) may be 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%, 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 0.009%, from about 0.001% to about 0.006%, about 0.001% to about 0.005%, about 0.001% to about 0.003%, about 0.003% to about 0.090%, about 0.003% to about 0.080%, about 0.003% to about 0.070%, about 0.003% to about 0.060%, about 0.003% to about 0.050%, about 0.003% to about 0.040%, about 0.003% to about 0.030%, from about 0.0 03% to about 0.020%, about 0.003% to about 0.012%, about 0.003% to about 0.011%, about 0.003% to about 0.010%, about 0.003% to about 0.009%, about 0.003% to about 0.008% , from about 0.003% to about 0.007%, from about 0.003% to about 0.006%, from about 0.003% to about 0.005%, from about 0.005% to about 0.090%, from about 0.005% to about 0.080%, from about 0.005% to about 0.070%, from about 0.005% to about 0.060%, from about 0.005% to about 0.050%, from about 0.005% to about 0.040%, from about 0.005% to about 0.030%, from about 0.005% to about 0.020%, about 0.005% to about 0.012%, about 0.005% to about 0.011%, about 0.005% to about 0.010%, about 0.005% to about 0.009%, about 0.005% to about 0.008%, about 0.005% to about 0.007%, about 0.005% to about 0.006%, about 0.006% to about 0.090%, about 0.006% to about 0.080%, about 0.006% to about 0.070%, about 0.006% to about 0.060%, from about 0.006% to about 0.050%, about 0.006% to about 0.040%, about 0.006% to about 0.030%, about t about 0.006% to about 0.020%, about 0.006% to about 0.012%, from about 0.006% to about 0.011%, from about 0.006% to about 0.010%, from about 0.006% to about 0.009%, from about 0.006% to about 0.008%, about 0.006% to about 0.007%, about 0.007% to about 0.090%, about 0.007% to about 0.080%, about 0.007% to about 0.070%, about 0.007% to about 0.060%, from about 0.007% to about 0.050%, about 0.007% to about 0.040%, about 0.007% to about 0.030%, about 0.007% to about 0.020%, about 0.007% to about 0.012%, about 0.007% to about 0.011 %, from about 0.007% to about 0.010%, from about 0.007% to about 0.009%, from about 0.007% to about 0.008%, from about 0.008% to about 0.090%, from about 0.008% to about 0.080%, from about 0.008 % to about 0.070%, from about 0.008% to about 0.060%, from about 0.008% to about 0.050%, from about 0.008% to about 0.040%, from about 0.008% to about 0.030%, from about 0.008% to about 0.020% , from about 0.008% to about 0.012%, from about 0.008% to about 0.011%, from about 0.008% to about 0.010%, from about 0.008% to about 0.009%, from about 0.009% to about 0.090%, from about 0.009% to about 0.080%, from about 0.009% to about 0.070%, from about 0.009% to about 0.060%, from about 0.009% to about 0.050%, from about 0.009% to about 0.040%, from about 0.009% to about 0.030%, from about 0.009% to about 0.020%, from about 0.009% to about 0.012%, from 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%, from about 0.010 % to about 0.050%, from about 0.010% to about 0.040%, from about 0.010% to about 0.030%, from about 0.010% to about 0.020%, from about 0.010 to about 0.012, from about 0.010 to about 0.011, from about 0.011 % to about 0.090%, from about 0.011% to about 0.080%, from about 0.011% to about 0.070%, from about 0.011% to about 0.060%, from about 0.011% to about 0.050%, from about 0.011% to about 0.040% , from about 0.011% to about 0.030%, from about 0.011% to about 0.020% , from about 0.011 to about 0.012, from about 0.012% to about 0.090%, from about 0.012% to about 0.080%, from about 0.012% to about 0.070%, from about 0.012% to about 0.060%, from about 0.012% to about 0.050%, about 0.012% to about 0.040%, about 0.012% to about 0.030%, about 0.012% to about 0.020%, about 0.020% to about 0.090%, about 0.020% to about 0.080%, from about 0.020% to about 0.070%, about 0.020% to about 0.060%, about 0.020% to about 0.050%, about 0.020% to about 0.040%, about 0.020% to about 0.030%, about 0.030% to about 0.090 %, from about 0.030% to about 0.080%, from about 0.030% to about 0.070%, from about 0.030% to about 0.060%, from about 0.030% to about 0.050%, from about 0.030% to about 0.040%, from about 0.040 % to about 0.090%, from about 0.040% to about 0.080%, from about 0.040% to about 0.070%, from about 0.040% to about 0.060%, from about 0.040% to about 0.050%, from about 0.050% to about 0.090% , from about 0.050% to about 0.080%, from about 0.050% to about 0.070%, from about 0 050% to about 0.060%, about 0.060% to about 0.090%, about 0.060% to about 0.080%, about 0.060% to about 0.070%, about 0.070% to about 0.090%, about 0.070% to about 0.080%, about 0.080% to about 0.090% or at 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%, about 0.090%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments of ophthalmic pharmaceutical compositions, ketorolac or a pharmaceutically acceptable salt thereof (e.g., ketorolac tromethamine) may be present in an amount of from about 0.01% to about 0.6%, from 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 0.6%, 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%, from about 0.2% to about 0.6%, from about 0.2% to about 0.5%, from about 0.2% to about 0.4%, from 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%, from about 0.4% to about 0.6%, about 0.4% to about 0.5%, about t about 0.5% to about 0.6% or at about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition may further comprise a lubricant. Typically, a lubricant may facilitate administration of the ophthalmic pharmaceutical composition to a subject. Suitable substances may 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 hydroxypropyl methylcellulose. In some embodiments, the ophthalmic pharmaceutical composition further comprises sodium hyaluronate and hydroxypropyl methylcellulose. Alternatively, the ophthalmic pharmaceutical composition may not contain a lubricant.

In some embodiments of ophthalmic pharmaceutical compositions, the lubricating agent is sodium hyaluronate, which may be present in an amount of from about 0.01% to about 0.9%, from about 0.01% to about 0.8%, from about 0. 01% to about 0.7%, about 0.01% to about 0.6%, about 0.01% to about 0.5%, about 0.01% to about 0.4%, from 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 0.9%, about 0.05% to about 0.8%, about 0.05% to about 0.7%, 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 0.9%, about 0.1% to about 0.8%, about 0.1% to about 0.7%, about 0.1% to about 0.6%, about 0.1% to about 0.5%, about 0.1% to about 0.4%, about 0.1 % to about 0.3%, from about 0.1% to about 0.2%, from about 0.2% to about 0.9%, about 0.2% to about 0.8%, about 0.2% to about 0.7%, about 0.2% to about 0.6%, from 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 0.9%, from about 0.3% to about 0.8%, about 0.3% to about 0.7%, 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 0.9%, about 0.4% to about 0.8%, about 0.4% to about 0.7 %, about 0.4% to about 0.6%, about 0.4% to about 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 at 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%, about 0.9%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments of ophthalmic pharmaceutical compositions, the lubricant is hydroxypropyl methylcellulose, which may be present in an amount of from about 0.1% to about 2.0%, from about 0.1% to about 1.8%, from about 0.1% to about 1.6%, from about 0.1% to about 1.4%, from about 0.1% to about 1.2%, from about 0.1% to about 1.0%, from 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%, from about 0.2% to about 1.8%, from about 0.2% to about 1.6%, from about 0.2% to about 1.4%, from 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%, from about 0.6% to about 1.8%, about 0.6% to about 1.6%, about 0.6% to about 1.4%, about 0.6% to about 1.2% , about 0.6% to about 1.0%, about 0.6% to about 0.8%, about 0.8% to about 2.0%, about 0.8% to about 1, 8%, about 0.8% to about 1.6%, about 0.8% to about 1.4%, about 0.8% to about 1.2%, about 0.8% to about 1.0%, about 1.0% to about 2.0%, about 1.0% to about 1.8%, about 1.0% to about 1.6%, from about 1.0% to about 1.4%, from about 1% to about 1.2%, from about 1.2% to about 2.0%, from about 1.2% to about 1.8%, from about 1.2% to about 1.6%, from about 1.2% to about 1.4%, from about 1.4% to about 2.0%, from about 1.4% to about 1.8%, from 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 at 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%, about 2.0%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% - 0.4%, diclofenac sodium at a concentration of 0.001% - 0.090%, and sodium hyaluronate at a concentration of 0.01% - 0.9%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% - 0.4%, diclofenac sodium at a concentration of 0.001% - 0.090%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 2.0%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition comprises pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% - 0.4%, diclofenac sodium at a concentration of 0.001% - 0.090%, sodium hyaluronate at a concentration of 0.01% - 0.9%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 2.0%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% - 0.4%, ketorolac tromethamine at a concentration of 0.01% - 0.60%, and sodium hyaluronate at a concentration of 0.01% - 0 ,9%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume)

In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% - 0.4%, ketorolac tromethamine at a concentration of 0.01% - 0.60%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 2, 0%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% - 0.4%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01%. In some embodiments, an ophthalmic pharmaceutical composition containing pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% additionally contains 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, an ophthalmic pharmaceutical composition containing pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% 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, an ophthalmic pharmaceutical composition containing pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% additionally contains 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 containing 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% 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%, and may additionally contain 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 containing pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% 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%, and may additionally contain 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, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05%. In some embodiments, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1%. In some embodiments, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15%. In some embodiments, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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 containing 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2%. In some embodiments, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.25%. In some embodiments, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.25% 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.3%. In some embodiments, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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 containing pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.3% 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.35%. In some embodiments, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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 containing pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.35% 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.4%. In some embodiments, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing 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, an ophthalmic pharmaceutical composition containing pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.4% 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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 containing 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%, and may additionally contain 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, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

For example, in some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% and diclofenac sodium at a concentration of 0.001% - 0.012%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% and ketorolac tromethamine at a concentration of 0.01% - 0.50%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

For example, in some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05% and diclofenac sodium at a concentration of 0.001% - 0.012%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05% and ketorolac tromethamine at a concentration of 0.01% - 0.50%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

For example, in some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% and diclofenac sodium at a concentration of 0.001% - 0.012%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% and ketorolac tromethamine at a concentration of 0.01% - 0.50%. In all of these embodiments, percentile amounts are determined by weight (w/w ). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

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% - 0.012%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15% and ketorolac tromethamine at a concentration of 0.01% - 0.50%. In all of these embodiments, percentile amounts are determined by weight (w/w ). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

For example, in some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% and diclofenac sodium at a concentration of 0.001% - 0.012%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% and ketorolac tromethamine at a concentration of 0.01% - 0.50%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

For example, in some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% and sodium hyaluronate at a concentration of 0.01% - 0.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01% and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01%, sodium hyaluronate at a concentration of 0.01% - 0.2%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

For example, in some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05% and sodium hyaluronate at a concentration of 0.01% - 0.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05% and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05%, sodium hyaluronate at a concentration of 0.01% - 0.2%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

For example, in some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% and sodium hyaluronate at a concentration of 0.01% - 0.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1% and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.1%, sodium hyaluronate at a concentration of 0.01% - 0.2%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

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% - 0.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15% and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15%, sodium hyaluronate at a concentration of 0.01% - 0.2%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

For example, in some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% and sodium hyaluronate at a concentration of 0.01% - 0.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2% and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2%, sodium hyaluronate at a concentration of 0.01% - 0.2%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

For example, in some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01%, diclofenac sodium at a concentration of 0.001% - 0.012%, and sodium hyaluronate at a concentration of 0.01% - 0.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01%, diclofenac sodium at a concentration of 0.001% - 0.012%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01%, diclofenac sodium at a concentration of 0.001% - 0.012%, sodium hyaluronate at a concentration of 0.01% - 0.2%, and hydroxypropyl methylcellulose at a concentration of 0, 1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.01%, ketorolac tromethamine at a concentration of 0.01% - 0.50%, and sodium hyaluronate at a concentration of 0.01% - 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% - 0.50%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

For example, in some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05%, diclofenac sodium at a concentration of 0.001% - 0.012%, and sodium hyaluronate at a concentration of 0.01% - 0.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05%, diclofenac sodium at a concentration of 0.001% - 0.012%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05%, diclofenac sodium at a concentration of 0.001% - 0.012%, sodium hyaluronate at a concentration of 0.01% - 0.2%, and hydroxypropyl methylcellulose at a concentration of 0, 1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05%, ketorolac tromethamine at a concentration of 0.01% - 0.50%, and sodium hyaluronate at a concentration of 0.01% - 0.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.05%, ketorolac tromethamine at a concentration of 0.01% - 0.50%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

For example, in some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.10%, diclofenac sodium at a concentration of 0.001% - 0.012%, and sodium hyaluronate at a concentration of 0.01% - 0.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.10%, diclofenac sodium at a concentration of 0.001% - 0.012%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.10%, diclofenac sodium at a concentration of 0.001% - 0.012%, sodium hyaluronate at a concentration of 0.01% - 0.2%, and hydroxypropyl methylcellulose at a concentration of 0. 1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.10%, ketorolac tromethamine at a concentration of 0.01% - 0.50%, and sodium hyaluronate at a concentration of 0.01% - 0.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.10%, ketorolac tromethamine at a concentration of 0.01% - 0.50%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

For example, in some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15%, diclofenac sodium at a concentration of 0.001% - 0.012%, and sodium hyaluronate at a concentration of 0.01% - 0.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15%, diclofenac sodium at a concentration of 0.001% - 0.012%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15%, diclofenac sodium at a concentration of 0.001% - 0.012%, sodium hyaluronate at a concentration of 0.01% - 0.2%, and hydroxypropyl methylcellulose at a concentration of 0. 1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.15%, ketorolac tromethamine at a concentration of 0.01% - 0.50%, and sodium hyaluronate at a concentration of 0.01% - 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% - 0.50%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

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% - 0.012%, and sodium hyaluronate at a concentration of 0.01% - 0.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2%, diclofenac sodium at a concentration of 0.001% - 0.012%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2%, diclofenac sodium at a concentration of 0.001% - 0.012%, sodium hyaluronate at a concentration of 0.01% - 0.2%, and hydroxypropyl methylcellulose at a concentration of 0. 1% - 1.2%. In some embodiments, the ophthalmic pharmaceutical composition contains pilocarpine hydrochloride or pilocarpine nitrate at a concentration of 0.2%, ketorolac tromethamine at a concentration of 0.01% - 0.50%, and sodium hyaluronate at a concentration of 0.01% - 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% - 0.50%, and hydroxypropyl methylcellulose at a concentration of 0.1% - 1.2%. In all of these embodiments, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

For example, in some embodiments, the ophthalmic pharmaceutical composition may be any of the following non-limiting examples of compositions, which include the components listed in the table in this paragraph, and a pharmaceutically acceptable carrier. In some embodiments, the ophthalmic pharmaceutical preparation may be any of the following non-limiting examples of compositions that include the components listed in the table in this paragraph and a pharmaceutically acceptable carrier further containing hydroxypropyl methylcellulose at a concentration of from about 0.1% to about 1.2 %. In some embodiments, the ophthalmic pharmaceutical preparation may be any of the following non-limiting examples of compositions, which include the components listed in the table in this paragraph, and a pharmaceutically acceptable carrier, additionally containing hydroxypropyl methylcellulose at a concentration of about 0.1%, about 0.8% or about 1.2%. In all of these compositions, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

Composition pilocarpine hydrochloride or pilocarpine nitrate diclofenac sodium sodium hyaluronate 1 0.1% 0% 0% 2 0.1% 0.001% 0% 3 0.1% 0.006% 0% 4 0.1% 0.090% 0% 5 0.1% 0% 0.01% 6 0.1% 0% 0.1% 7 0.1% 0% 0.9% 8 0.1% 0.001% 0.01% 9 0.1% 0.001% 0.1% 10 0.1% 0.001% 0.9% eleven 0.1% 0.006% 0.01% 12 0.1% 0.006% 0.1% 13 0.1% 0.006% 0.9% 14 0.1% 0.090% 0.01% 15 0.1% 0.090% 0.1% 16 0.1% 0.090% 0.9% 17 0.2% 0% 0% 18 0.2% 0.001% 0% 19 0.2% 0.006% 0% 20 0.2% 0.090% 0% 21 0.2% 0% 0.01% 22 0.2% 0% 0.1% 23 0.2% 0% 0.9% 24 0.2% 0.001% 0.01% 25 0.2% 0.001% 0.1% 26 0.2% 0.001% 0.9% 27 0.2% 0.006% 0.01% 28 0.2% 0.006% 0.1% 29 0.2% 0.006% 0.9% thirty 0.2% 0.090% 0.01% 31 0.2% 0.090% 0.1% 32 0.2% 0.090% 0.9%

For example, in some embodiments, the ophthalmic pharmaceutical composition may be any of the following non-limiting examples of compositions that contain the components listed in the table in this paragraph and a pharmaceutically acceptable carrier. In all of these compositions, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

Composition pilocarpine hydrochloride or pilocarpine nitrate diclofenac sodium hydroxypropyl methylcellulose 33 0.1% 0% 0% 34 0.1% 0.001% 0% 35 0.1% 0.006% 0% 36 0.1% 0.090% 0% 37 0.1% 0% 0.1% 38 0.1% 0% 0.8% 39 0.1% 0% 1.2% 40 0.1% 0.001% 0.1% 41 0.1% 0.001% 0.8% 42 0.1% 0.001% 1.2% 43 0.1% 0.006% 0.1% 44 0.1% 0.006% 0.8% 45 0.1% 0.006% 1.2% 46 0.1% 0.090% 0.1% 47 0.1% 0.090% 0.8% 48 0.1% 0.090% 1.2% 49 0.2% 0% 0% 50 0.2% 0.001% 0% 51 0.2% 0.006% 0% 52 0.2% 0.090% 0% 53 0.2% 0% 0.1% 54 0.2% 0% 0.8% 55 0.2% 0% 1.2% 56 0.2% 0.001% 0.1% 57 0.2% 0.001% 0.8% 58 0.2% 0.001% 1.2% 59 0.2% 0.006% 0.1% 60 0.2% 0.006% 0.8% 61 0.2% 0.006% 1.2% 62 0.2% 0.090% 0.1% 63 0.2% 0.090% 0.8% 64 0.2% 0.090% 1.2%

For example, in some embodiments, the ophthalmic pharmaceutical composition may be any of the following non-limiting examples of compositions that contain the components listed in the table in this paragraph and a pharmaceutically acceptable carrier. In all of these compositions, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

Composition pilocarpine hydrochloride or pilocarpine nitrate ketorolac tromethamine sodium hyaluronate 65 0.1% 0% 0% 66 0.1% 0.01% 0% 67 0.1% 0.30% 0% 68 0.1% 0.50% 0% 69 0.1% 0% 0.01% 70 0.1% 0% 0.1% 71 0.1% 0% 0.9% 72 0.1% 0.01% 0.01% 73 0.1% 0.01% 0.1% 74 0.1% 0.01% 0.9% 75 0.1% 0.30% 0.01% 76 0.1% 0.30% 0.1% 77 0.1% 0.30% 0.9% 78 0.1% 0.50% 0.01% 79 0.1% 0.50% 0.1% 80 0.1% 0.50% 0.9% 81 0.2% 0% 0% 82 0.2% 0.01% 0% 83 0.2% 0.30% 0% 84 0.2% 0.50% 0% 85 0.2% 0% 0.01% 86 0.2% 0% 0.1% 87 0.2% 0% 0.9% 88 0.2% 0.01% 0.01% 89 0.2% 0.01% 0.1% 90 0.2% 0.01% 0.9% 91 0.2% 0.30% 0.01% 92 0.2% 0.30% 0.1% 93 0.2% 0.30% 0.9% 94 0.2% 0.50% 0.01% 95 0.2% 0.50% 0.1% 96 0.2% 0.50% 0.9%

For example, in some embodiments, the ophthalmic pharmaceutical composition may be any of the following non-limiting examples of compositions that contain the components listed in the table in this paragraph and a pharmaceutically acceptable carrier. In all of these compositions, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

Composition pilocarpine hydrochloride or pilocarpine nitrate ketorolac tromethamine hydroxypropyl methylcellulose 97 0.1% 0% 0% 98 0.1% 0.01% 0% 99 0.1% 0.30% 0% 100 0.1% 0.50% 0% 101 0.1% 0% 0.1% 102 0.1% 0% 0.8% 103 0.1% 0% 1.2% 104 0.1% 0.01% 0.1% 105 0.1% 0.01% 0.8% 106 0.1% 0.01% 1.2% 107 0.1% 0.30% 0.1% 108 0.1% 0.30% 0.8% 109 0.1% 0.30% 1.2% 110 0.1% 0.50% 0.1% 111 0.1% 0.50% 0.8% 112 0.1% 0.50% 1.2% 113 0.2% 0% 0% 114 0.2% 0.01% 0% 115 0.2% 0.30% 0% 116 0.2% 0.50% 0% 117 0.2% 0% 0.1% 118 0.2% 0% 0.8% 119 0.2% 0% 1.2% 120 0.2% 0.01% 0.1% 121 0.2% 0.01% 0.8% 122 0.2% 0.01% 1.2% 123 0.2% 0.30% 0.1% 124 0.2% 0.30% 0.8% 125 0.2% 0.30% 1.2% 126 0.2% 0.50% 0.1% 127 0.2% 0.50% 0.8% 128 0.2% 0.50% 1.2%

In some embodiments, the ophthalmic pharmaceutical composition may contain a pharmaceutically acceptable carrier and one, two, three or four components selected from (1) pilocarpine hydrochloride or pilocarpine nitrate; (2) diclofenac sodium; (3) sodium hyaluronate; and (4) hydroxypropyl methylcellulose, wherein pilocarpine hydrochloride or pilocarpine nitrate is present at a concentration of about 0.01% to about 0.4%, diclofenac sodium is present at a concentration of about 0.001% to about 0.090%, sodium hyaluronate is present at a concentration of about 0 01% to about 0.9%, and/or hydroxypropyl methylcellulose is present at a concentration of from about 0.1% to about 2.0%. In all of these compositions, percentile amounts are determined by weight (w/w). Alternatively, in all of these embodiments, percentile amounts are determined by volume (mass/volume).

In some embodiments, the ophthalmic pharmaceutical composition of the present invention may further comprise an ophthalmologically acceptable carrier, which as used herein includes, but is not limited to, a solvent, a dispersion medium, a diluent, a dispersion, a suspension additive, a surfactant agent, isotonicizer, thickener or emulsifier, preservative, core-shell nanoparticles, polymer, peptide, protein, cell, hyaluronidase, and mixtures thereof. The use of such media and agents that are compatible with ophthalmic administration is well known in the art. Various carriers for formulating ophthalmic pharmaceutical compositions and methods for preparing the composition are well known in the art. (See, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition, Edited by Allen, Loyd V., Jr, Pharmaceutical Press; incorporated herein by reference in its entirety). For example, in some embodiments, an ophthalmic pharmaceutical composition according to the present invention may contain one or more preservatives such as phenol, cresol, p-aminobenzoic acid, BDSA, sorbitrate, chlorhexidine, benzalkonium chloride, sorbic acid, Purite. RTM. (oxychloride compounds), Polyquad. RTM (quaternary ammonium), polyhexamethylene biguanide, sodium perborate and the like. In some cases, ophthalmic pharmaceutical compositions intended for long-term use in chronic conditions may be formulated and packaged to minimize or eliminate the use of preservatives that can irritate the eyes. For example, the ophthalmic pharmaceutical composition may be packaged in single-dose packs or in packs using alternative means to minimize microbial contamination, such as membranes, valve mechanisms, or silver.

In some embodiments, the ophthalmic pharmaceutical composition further comprises an isotonicizer, a wetting agent, a buffer, a stabilizer, a pH agent, a solubilizer, a thickening agent, and/or a dispersing agent. These agents are well known to those skilled in the art of ophthalmology (see, for example, US Pat. Nos. 8,299,079 and 8,524,758). For example, pharmaceutical compositions may contain a tonicity agent to bring the drug into the desired isotonic range. Some examples of a tonicity agent include glycerin, mannitol, sorbitol, and sodium chloride. Additionally or alternatively, pharmaceutical compositions may contain a wetting agent that reduces the surface tension of water or other liquid, causing the liquid to spread or more easily penetrate the surface of a solid. Some examples of wetting agents in ophthalmic compositions include carboxymethylcellulose, hydroxypropylmethylcellulose, glycerin, mannitol, polyvinyl alcohol or hydroxyethylcellulose. Additionally or alternatively, the pharmaceutical compositions may contain a buffering agent to maintain the pH in a therapeutically effective range. The buffering agents used are those known to those skilled in the art and, while not intended to be limiting, some examples are acetate, borate, carbonate, citrate and phosphate buffers. Additionally or alternatively, pharmaceutical compositions may contain one or more stabilizers such as sodium hydrosulfite, ethylenediaminetetraacetic acids, and the like. Additionally or alternatively, the pharmaceutical compositions may contain one or more solubilizers such as polysorbate, polyethylene glycol, propylene glycol, macrogol 4000, and the like. Additionally or alternatively, the pharmaceutical compositions may contain one or more thickeners which make the formulation of the present invention firm or viscous in texture. Suitable thickeners include, for example, non-ionic water-soluble polymers, fatty alcohols, fatty acids, anionic polymers and their alkaline salts, and mixtures thereof. Additionally or alternatively, the pharmaceutical compositions may contain one or more dispersing agents such as poly(ethylene glycol), polyethoxylated castor oil, an alcohol having from 12 to 20 carbon atoms, and mixtures thereof.

In some embodiments, the ophthalmic pharmaceutical composition is a sustained release composition. For example, for a sustained release ophthalmic pharmaceutical composition, delivery via an intravitreal microinsert, near the base of the eye, is known to be effective and preferred (eg WO 2011/079123 A1). The advantage of the micro-insert is that the slow-release ingredients remain in the eye and are not lost through the natural drainage channels associated with fluids applied to the ocular surface. The micro-insert saves patients time and effort by avoiding quite frequent instillations.

The ophthalmic pharmaceutical composition according to the present invention may be in the form of eye drops. Other forms of application to the eye are possible. For example, the ophthalmic preparation according to the present invention may be in the form of a suspension. In some embodiments, the implementation, the ophthalmic preparation in accordance with the present invention may be in the form of a gel. In some embodiments, the ophthalmic preparation of the present invention may be in the form of an ophthalmic ointment. In some embodiments, the ophthalmic preparation of the present invention may be in the form of an injectable solution. In some embodiments, the ophthalmic formulation of the present invention may be in the form of an eye spray.

An ophthalmic pharmaceutical composition according to the present invention may be suitable for topical delivery to a subject's eye or tissue surrounding the eye. An ophthalmic pharmaceutical composition according to the present invention may be suitable for implantation in or on the subject's eye, or tissue surrounding the subject's eye. In some embodiments, the ophthalmic pharmaceutical composition is suitable for implantation into the subconjunctival space, nasolacrimal duct, or vitreous body of a subject.

In some embodiments, an ophthalmic pharmaceutical composition according to the present invention may be surgically implanted into the subconjunctival space by an ophthalmic surgeon after she or he determines that the patient has benefited from the implant after prior testing using topical drops. applications. The components passively reach the iris and interact with the muscle fibers of the iris, changing the size of the pupil. This action provides enhanced depth of field and improved distance and near vision as discussed in the present invention.

Treatment of subjects, Treatment of subjects suffering from symptoms of presbyopia

It is an object of the present invention to treat subjects suffering from symptoms of presbyopia by directly administering a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present invention. Accordingly, the administration of the ophthalmic pharmaceutical composition can alleviate or eliminate the symptoms of presbyopia to improve the patient's ability to focus on objects at close range, including objects at a distance close to the normal reading distance. The use of an ophthalmic pharmaceutical composition may also cause a significant reduction in discomfort or the risk of falls when using progressive or bifocal lenses and/or reduce or completely eliminate blurring and opacities after eye surgery.

The degree of presbyopia, after application of the ophthalmic pharmaceutical compositions of the present invention, 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% less than the degree of presbyopia , which could be without the use of the compositions in the present invention. The degree of presbyopia can be determined by any method known in the field of ophthalmic research. For example, standard tests can be performed to examine a patient's ability to focus on objects at close range, including objects at a distance close to the normal reading distance, after administration of the ophthalmic pharmaceutical compositions of the present invention.

In some embodiments, treatment can correct presbyopia in a subject within 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 correct the subject's presbyopia within up to 24 hours.

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

In some embodiments, the ophthalmic pharmaceutical compositions of the present invention may be used to correct presbyopia in a subject, wherein the subject

a) is a spectacle wearer who cannot or will not wear progressive or bifocal lenses;

b) has undergone cataract surgery;

c) who develops presbyopia after a corneal procedure;

d) has monofocal or multifocal intraocular lenses;

e) wears contact lenses and is intolerant of monovisual contact lenses;

f) wears contact lenses and is intolerant of multifocal contact lenses;

g) suffers from a higher order aberration after corneal surgery;

h) suffers from hyperopia or tropia;

i) is intolerant of changes in scoring;

j) is undergoing rapid changes in scoring;

k) is at risk of falling when using progressive or bifocal lenses; and/or

l) suffers from higher order aberration at night or in low light conditions.

Other aspects of the invention relate to delivery systems for administering an ophthalmic pharmaceutical composition according to the present invention to a subject in need of such administration. In some embodiments, the composition may be administered topically to the subject's eye or tissue surrounding the subject's eye. In some embodiments, the composition may be administered by surgery to or on the subject's eye, or the tissue surrounding the subject's eye. In some embodiments, the surgical intervention includes the step of implanting (eg, with ocular inserts) an ophthalmic pharmaceutical composition into or onto the subject's eye, or tissue surrounding the subject's eye. In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous body of a subject. In some embodiments, the ophthalmic pharmaceutical composition is a slow release composition.

In some embodiments, a method for correcting presbyopia in a subject comprises administering an ophthalmic pharmaceutical composition in the form of eye drops. 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.

In some embodiments, the ophthalmic pharmaceutical composition is administered to a subject to correct presbyopia, preferably in a single administration. In some embodiments, the ophthalmic pharmaceutical composition is administered to the subject to correct presbyopia, preferably several (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more) introductions. In each of the embodiments in this paragraph, "multiple injections" can be separated from each other by short (1-5 minutes), medium (6-30 minutes) or long (more than 30 minutes or even several hours) time intervals.

The ophthalmic pharmaceutical composition may be administered to a subject using any administration dose effective to correct presbyopia. The exact dose required will vary from subject to subject depending on the species, age and general condition of the subject, the severity of the disease, the particular composition, its route of administration, its mode of action, and the like. It is understood, however, that the total daily use of the compositions may be determined by the attending ophthalmologist within sound medical judgment. The specific pharmaceutically effective dosage level for any particular patient will depend on a variety of factors, including the severity of presbyopia, the particular composition used, age, body weight, general health, sex and diet of the patient, time of administration, route of administration, duration of treatment, and the like, well known in the field of ophthalmology.

However, the present invention also encompasses the delivery of an ophthalmic pharmaceutical composition for the correction of presbyopia by any suitable method, taking into account the most likely advances in the field of drug delivery.

Additional Uses for Ophthalmic Compositions of the Invention

In some embodiments, the ophthalmic pharmaceutical compositions of the present invention may also be used to treat other conditions and diseases, for example, in a subject with symptoms of presbyopia without a history of eye surgery. In some embodiments, the ophthalmic pharmaceutical compositions of the present invention may be administered to a subject who suffers from the following conditions: (a) severe skin conditions (e.g., triophobia, ichthyosis), (b) multiple allergy syndrome, and/or (c) diabetes. In some embodiments, the ophthalmic pharmaceutical compositions of the present invention may be used in a subject who has received the following types of eye surgery: (a) intraocular lens implantation after cataract, (b) post-laser eye surgery (laser in situ keratomileusis (LASIK) ), photorefractive keratectomy (PRK) or their analogues) and/or (c) post-implantation of intraocular phakic implants. In some embodiments, the ophthalmic pharmaceutical compositions of the present invention may be used in cases of childhood disorders (eg childhood strabismus) where eye surgery is not recommended.

Another aspect of the present invention relates to the administration of an ophthalmic pharmaceutical composition according to the present invention to modulate several physiological processes in a subject. As non-limiting examples, the modulation of a physiological process may include a reduction in pupil size, induction of miosis, an increase in depth of field, a decrease in the magnitude of higher order aberration, and/or an improvement in uncorrected near and far visual acuity in a subject.

In some embodiments, a method for reducing pupil size in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition in accordance with the present invention. In some embodiments, the subject

a) is a spectacle wearer who cannot or will not wear progressive or bifocal lenses;

b) has undergone cataract surgery;

c) who develops presbyopia after a corneal procedure;

d) has monofocal or multifocal intraocular lenses;

e) wears contact lenses and is intolerant of monovisual contact lenses;

f) wears contact lenses and is intolerant of multifocal contact lenses;

g) suffers from a higher order aberration after corneal surgery;

h) suffers from hyperopia or tropia;

i) is intolerant of changes in scoring;

j) is undergoing rapid changes in scoring;

k) is at risk of falling when using progressive or bifocal lenses; and/or

l) suffers from higher order aberration at night or in low light conditions.

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 invention, wherein the ophthalmic pharmaceutical composition is a slow release composition. In some embodiments, the composition may be administered topically to the subject's eye or tissue surrounding the subject's eye. In some embodiments, the implementation of the composition can be entered through surgical intervention in or on the subject's eye, or tissue surrounding the subject's eye. In some embodiments, surgery includes the step of implanting (eg, with ocular inserts) an ophthalmic pharmaceutical composition into or onto the subject's eye, or tissue surrounding the subject's eye. In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous body of a subject. The compositions may be in the form of a suspension, gel, ointment, injection, spray or eye drops.

In any of the embodiments, to reduce pupil size in a subject, the effect of an ophthalmic pharmaceutical composition on pupil size reduction can be assessed by methods well known in the art (see, for example, Example 1 described herein).

In some embodiments, a method of inducing miosis in a subject comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present invention. In some embodiments, the subject

a) is a spectacle wearer who cannot or will not wear progressive or bifocal lenses;

b) has undergone cataract surgery;

c) who develops presbyopia after a corneal procedure;

d) has monofocal or multifocal intraocular lenses;

e) wears contact lenses and is intolerant of monovisual contact lenses;

f) wears contact lenses and is intolerant of multifocal contact lenses;

g) suffers from a higher order aberration after corneal surgery;

h) suffers from hyperopia or tropia;

i) is intolerant of changes in scoring;

j) is undergoing rapid changes in scoring;

k) is at risk of falling when using progressive or bifocal lenses; and/or

l) suffers from higher order aberration at night or in low light conditions.

In some embodiments, the method of inducing miosis in a subject comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present invention, 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 tissue surrounding the subject's eye. In some embodiments, the composition may be administered via surgery to or on the subject's eye, or the tissue surrounding the subject's eye. In some embodiments, the surgical intervention includes the step of implanting (eg, via ophthalmic inserts) an ophthalmic pharmaceutical composition into or onto the subject's eye, or tissue surrounding the subject's eye. In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous body of a subject. The compositions may be in the form of a suspension, gel, ointment, injection, spray or eye drops.

In any of the embodiments for the induction of miosis in a subject, the effect of the ophthalmic pharmaceutical composition on the induction of miosis can be assessed by methods well known in the art. (See, for example, Example 1 described herein).

In some embodiments, a method for increasing depth of field in a subject's eye comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition in accordance with the present invention. In some embodiments, the subject

a) is a spectacle wearer who cannot or will not wear progressive or bifocal lenses;

b) has undergone cataract surgery;

c) who develops presbyopia after a corneal procedure;

d) has monofocal or multifocal intraocular lenses;

e) wears contact lenses and is intolerant of monovisual contact lenses;

f) wears contact lenses and is intolerant of multifocal contact lenses;

g) suffers from a higher order aberration after corneal surgery;

h) suffers from hyperopia or tropia;

i) is intolerant of changes in scoring;

j) is undergoing rapid changes in scoring;

k) is at risk of falling when using progressive or bifocal lenses; and/or

l) suffers from higher order aberration at night or in low light conditions.

In some embodiments, a method for increasing depth of field in a subject's eye comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present invention, 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 tissue surrounding the subject's eye. In some embodiments, the composition may be administered via surgery to or on the subject's eye, or the tissue surrounding the subject's eye. In some embodiments, the surgical intervention includes the step of implanting (eg, via ophthalmic inserts) an ophthalmic pharmaceutical composition into or onto the subject's eye, or tissue surrounding the subject's eye. In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous body of a subject. The compositions may be in the form of a suspension, gel, ointment, injection, spray or eye drops.

In any of the embodiments for increasing depth of field in a subject's eye, the effect of an ophthalmic pharmaceutical composition on increasing depth of field can be assessed by methods well known in the art (see, for example, Example 1 described herein).

In some embodiments, a method for reducing the amount of higher order aberration in a subject's eye comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition in accordance with the present invention. In some embodiments, the subject

a) is a spectacle wearer who cannot or will not wear progressive or bifocal lenses;

b) has undergone cataract surgery;

c) who develops presbyopia after a corneal procedure;

d) has monofocal or multifocal intraocular lenses;

e) wears contact lenses and is intolerant of monovisual contact lenses;

f) wears contact lenses and is intolerant of multifocal contact lenses;

g) suffers from a higher order aberration after corneal surgery;

h) suffers from hyperopia or tropia;

i) is intolerant of changes in scoring;

j) is undergoing rapid changes in scoring;

k) is at risk of falling when using progressive or bifocal lenses; and/or

l) suffers from higher order aberration at night or in low light conditions.

In some embodiments, the method of reducing the amount of higher order aberration in the eye of a subject comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present invention, wherein the ophthalmic pharmaceutical composition is a sustained release composition. In some embodiments, the composition may be topically administered to the subject's eye or tissue surrounding the subject's eye. In some embodiments, the composition may be administered via surgery to or on the subject's eye, or the tissue surrounding the subject's eye. In some embodiments, the surgical intervention includes the step of implanting (eg, via ophthalmic inserts) an ophthalmic pharmaceutical composition into or onto the subject's eye, or tissue surrounding the subject's eye. In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous body of a subject. The compositions may be in the form of a suspension, gel, ointment, injection, spray or eye drops.

In any of the embodiments, to reduce the magnitude of higher order aberrations in a subject's eye, the effect of the ophthalmic pharmaceutical composition in reducing the magnitude of higher order aberrations can be assessed by methods well known in the art. For example, non-invasive objective measurements of higher order ocular aberration - 3rd, 4th and 5th order (coma, spherical aberration and trefoil) can be taken at each visit by means of wavefront aberrometry.

In some embodiments, a method for improving uncorrected near and far visual acuity in a subject comprises administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition in accordance with the present invention. In some embodiments, the subject

a) is a spectacle wearer who cannot or will not wear progressive or bifocal lenses;

b) has undergone cataract surgery;

c) who develops presbyopia after a corneal procedure;

d) has monofocal or multifocal intraocular lenses;

e) wears contact lenses and is intolerant of monovisual contact lenses;

f) wears contact lenses and is intolerant of multifocal contact lenses;

g) suffers from a higher order aberration after corneal surgery;

h) suffers from hyperopia or tropia;

i) is intolerant of changes in scoring;

j) is undergoing rapid changes in scoring;

k) is at risk of falling when using progressive or bifocal lenses; and/or

l) suffers from higher order aberration at night or in low light conditions.

In some embodiments, a method of improving uncorrected near and far visual acuity in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition according to the present invention, 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 tissue surrounding the subject's eye. In some embodiments, the composition may be administered via surgery to or on the subject's eye, or the tissue surrounding the subject's eye. In some embodiments, the surgical intervention includes the step of implanting (eg, via ophthalmic inserts) an ophthalmic pharmaceutical composition into or onto the subject's eye, or tissue surrounding the subject's eye. In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous body of a subject. The compositions may be in the form of a suspension, gel, ointment, injection, spray or eye drops.

In any of the embodiments for improving uncorrected near and far visual acuity in a subject, the effect of the ophthalmic pharmaceutical composition on improving uncorrected near and far visual acuity can be assessed by methods well known in the art. For example, visual acuity can be assessed at all study visits using a standardized table for determining visual acuity at various distances. The study can be carried out on one eye, while covering the eye that is not being examined, and binocularly. Uncorrected visual acuity can be assessed at far/distant, intermediate (50-80 cm) and near/near (40 cm). Aperture measurements for determining visual acuity can be carried out as follows: far distance and average distance are measured under normal lighting conditions and recorded using a photometer. Far visual acuity can be measured in both low light (room light in the doctor's office reduced to half normal) and bright light (full print lights illuminated over the left shoulder)—both also recorded with a photometer. For long distance and medium distance, the illuminance should be about 3000 lux; for close range, the illumination should be between 750 and 1000 lux for low contrast and 3000 lux for high contrast. All sharpness measurements can be recorded according to the decimal system or the LogMar system. The decimal system is preferred.

Preparations containing ophthalmic compositions

Another aspect of the present invention relates to various formulations (eg, implant or kit) containing an ophthalmic pharmaceutical composition in accordance with the present invention.

Some embodiments relate to an implant containing an ophthalmic pharmaceutical composition in accordance with the present invention. In some embodiments, the implementation, the implant can be introduced through surgery in or on the subject's eye, or tissue surrounding the subject's eye. In some embodiments, the surgical intervention includes the step of implanting (eg, via ophthalmic inserts) an ophthalmic pharmaceutical composition into or onto the subject's eye, or tissue surrounding the subject's eye. In some embodiments, the ophthalmic pharmaceutical composition is implanted into the subconjunctival space, nasolacrimal duct, or vitreous body of a subject. In some embodiments, the ophthalmic pharmaceutical composition The ophthalmic pharmaceutical composition is a slow release composition.

It is well known that delivery via an intravitreal microinsert at the base of the eye is effective and preferred (eg WO 2011/079123 A1). The advantage of the micro-insert is that the slow-release ingredients remain in the eye and are not lost through the natural drainage channels associated with fluids applied to the ocular surface. The micro-insert saves patients time and effort by avoiding quite frequent instillations.

In some embodiments, the slow release implant is surgically inserted into the subconjunctival space by an ophthalmic surgeon after he or she determines that the patient has benefited from the implant after prior testing with topical drops. The components passively reach the iris and interact with the muscle fibers of the iris, changing the size of the pupil. This action provides an increase in the depth of field and improved distance and near vision, as discussed in the present invention (see example 1).

In some embodiments, the implant may be inserted into a subject through surgery, wherein the subject

a) is a spectacle wearer who cannot or will not wear progressive or bifocal lenses;

b) has undergone cataract surgery;

c) who develops presbyopia after a corneal procedure;

d) has monofocal or multifocal intraocular lenses;

e) wears contact lenses and is intolerant of monovisual contact lenses;

f) wears contact lenses and is intolerant of multifocal contact lenses;

g) suffers from a higher order aberration after corneal surgery;

h) suffers from hyperopia or tropia;

i) is intolerant of changes in scoring;

j) is undergoing rapid changes in scoring;

k) is at risk of falling when using progressive or bifocal lenses; and/or

l) suffers from higher order aberration at night or in low light conditions.

In some embodiments, the implant is used to correct presbyopia in a subject. In some embodiments, the implant is used to reduce the pupil size of a subject. In some embodiments, the implant is used to induce miosis in a subject. In some embodiments, the implant is used to increase the depth of field in the subject's eye. In some embodiments, the implant is used to reduce the amount of higher order aberration in the subject's eye. In some embodiments, the implant is used to improve uncorrected near and far visual acuity in a subject.

Some embodiments relate to a kit containing an ophthalmic pharmaceutical composition in accordance with the present invention. Kits may include: a) a container (eg, syringe, tube, vial, dropper) containing an ophthalmic pharmaceutical composition as described herein; and b) instructions for use, which may include diagrams, drawings or photographs, in addition to the text of the instructions. The instructions may include sequences on how to handle the substance (which may include storage conditions, such as storage temperature ranges), how often to apply the composition, and what can be expected from the application of the composition.

In some embodiments, a kit may be provided to a subject, wherein the subject

a) is a spectacle wearer who cannot or will not wear progressive or bifocal lenses;

b) has undergone cataract surgery;

c) who develops presbyopia after a corneal procedure;

d) has monofocal or multifocal intraocular lenses;

e) wears contact lenses and is intolerant of monovisual contact lenses;

f) wears contact lenses and is intolerant of multifocal contact lenses;

g) suffers from a higher order aberration after corneal surgery;

h) suffers from hyperopia or tropia;

i) is intolerant of changes in scoring;

j) is undergoing rapid changes in scoring;

k) is at risk of falling when using progressive or bifocal lenses; and/or

l) suffers from higher order aberration at night or in low light conditions.

In some embodiments, the kit is used to correct presbyopia in a subject. In some embodiments, the kit is used to reduce a subject's pupil size. In some embodiments, the kit is used to induce miosis in a subject. In some embodiments, the kit is used to increase the depth of field in the subject's eye. In some embodiments, the kit is used to reduce the amount of higher order aberration in a subject's eye. In some embodiments, the kit is used to improve uncorrected near and far visual acuity in a subject.

Measures to evaluate the elimination of presbyopia

One of the effects of changes in 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 visible object can move towards or away from the eye until the image on the retina is recognized by the subject as no longer sharp enough, while the eye remains in a fixed state of refraction. (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 environmental conditions. The key factors associated with DoF have been carefully considered by Wang & Ciufredda (2006, SurvOphthalmol 51:75-85) and later by Pallikaris et al. (2011, J Ophthalmol 284961, doi: 10.1155/2011/284961).

Atchison et al. (1997, Optom Vis Sci. 74: 511-520) used apertures to simulate different pupil sizes and found that the mean DoF increased from 0.59D to 0.86D for a pupil size shift from 4 mm to 2 mm. They found only a small increase of 0.27D. Similarly, Sergienko and Tutchenko (2007, Eur. J Ophthalmol 17:836-840) reported an increase in DoF of 0.26D, corresponding to a 2 mm change in artificial pupil size from 5 mm to 3 mm when visual acuity was 1.5 . Marcos et al. (1999, Vision Res. 39: 2039-2049) reported that DoF was also affected by the spectral content of the observed optotype, together with changes in artificial pupil size, but the changes were small, averaging only 0.16D. A small change in DoF when the pupil size is reduced by about 50% is not special. However, these results were obtained in relatively small groups of trained subjects with high visual acuity. In others, it has been observed that, with central fixation, DoF can reach up to ±2.5D with a tendency to increase in the elderly (Ronchi & Moleskini, 1975, Ophthalmic Res 7:152-157). The increase is probably due to natural age-related miosis and changes in contrast sensitivity. Mordi and Ciufredda (1998, Vision Res. 38:1643-1653) predicted an increase in DoF of 0.027D/yr in subjects aged 21 to 50 years. This is equivalent to an increase of 0.80D in 30 years. A growing body of evidence clearly points to the following conclusion: decreasing pupil size will increase DoF. Tabanero and Artal (2012, J Cataract Refract Surg 38:270-277) easily demonstrated that the DoF can be increased to 2.5D when the 1.6 mm AcufocusKamra corneal implant aperture is set correctly to mimic an artificial pupil. This artificial pupil, although close to the actual pupil, is still 3-4 mm away from the true pupil position. Studies looking at the effect of pupil size on DoF have either used various artificial pupils placed in front of the eye or measured pupil size directly. The real effect of changes in pupil size with respect to DoF requires accommodation paralysis to prevent the accommodative stimulus from affecting DoF from being affected by the actual DoF ratio and pupil size, and setting artificial apertures of various sizes to simulate changes in pupil size with real pupil dilation (Mordi & Ciuffreda, 1998, Vision Res 38:1643-1653). It would be reasonable to obtain a DoF update in real eyes in a clinical setting without paralysis. And also to compare pharmacologically induced real changes in real pupil size with any changes in subjective DoF values under normal clinical conditions in normal unprepared patients. Miotics, by their biochemical nature, probably act not only on iris receptors, but also on receptors located in the ciliary body, which leads to changes in the accommodative state and refraction. Accordingly, a miotic is required, which contributes to a sufficient constriction of the pupil, with practically no effect on the optical power of the lens.

Depth of field (DoF) distance estimation procedure

It is possible to estimate the DoF after a defocus curve has been built (Toto et al., 2007, J Cataract Refract Surg 33:1419-1425; Gupta et al., 2007, ContLenses Anterior Eye 30:119-124; Cillino et al., 2008, Ophthalmology 115 :1508-1516; Cleary et al., 2010, J Cataract Refract Surg 36:762-770). The defocus curve is a graphical representation of the measured visual acuity (y-axis) associated with the strength of a number of spherical lenses under study placed in front of the eye. This curve is a stimulus-response curve that can be obtained using various psychophysical methods. In a clinical setting, obtaining data to construct a defocus curve is time consuming and subject to several sources of error, including loss of concentration in the patient.

This study used a simpler, faster, conventional technique used by many researchers, reviewed by Wang and Ciuffreda (2006, SurvOphthalmol 51:75-85) (see example 1). More recent studies have also used a modification of the main method (Yao et al., 2010, Vision Res 50:1266-1273; Bénard et al., 2011, Vision Res 51:2471-2477). The patient was asked to look at the 20/30 row of Snellen optotypes when scoring for distance with maximum correction. The positive power in the phoroptor was increased in increments of 0.25D until the patient reported that the optotypes were no longer acceptably clear. This procedure was performed monocularly under normal natural light conditions. Bénard et al (2011, Vision Res 51:2471-2477) determined subjective DoF using 20/50 high contrast symbols. Yao et al (2010, Vision Res 50:1266-73) used high contrast square wave gratings built into the Badal lens system. Both groups of researchers used different systems, but the DoF data they obtained was very similar.

All claims in the list of claims are incorporated herein by reference in the specification in their entirety as additional embodiments.

EXAMPLES

EXAMPLE 1: Improvement of naked eye far and near visual acuity and eye depth of field in presbyopic and pseudophakic subjects by pharmacologically altering actual pupil size with pilocarpine formulations

The purpose of this example is to measure the effect of actual changes in pupil size on depth of field (DoF) and visual acuity in subjects with presbyopia and subjects with pseudophakia - an implanted monofocal or multifocal IOL attending routine eye examinations in a clinical setting. Reducing pupil size increases DoF, which in turn improves visual acuity.

Procedure and vehicle for pupil size reduction (miosis)

The use of pilocarpine carries the risk of irritation and inflammation after local instillation.

Mixing an NSAID and an eye comfort moisturizer with pilocarpine should serve as a preventive measure to combat the inflammatory response and dry eyes caused by pilocarpine.

As described below, mixing 0.2% pilocarpine hydrochloride or pilocarpine nitrate with 0.006% diclofenac sodium was found to be well tolerated when applied topically and resulted in overt miosis. There were no signs of short-term or long-term adverse events associated, in particular, with the topical application of diclofenac 0.006% mixed with sodium hyaluronate at a concentration usually associated with agents that provide hydration for eye comfort. Therefore, it was decided to prepare a mixture consisting of 0.1% sodium hyaluronate, 0.2% pilocarpine hydrochloride or pilocarpine nitrate and 0.006% diclofenac sodium with the sole purpose of providing miosis with minimal discomfort. In this example, percentile amounts are determined by weight (mass/volume). This combination was given extemporaneously to induce miosis during a scheduled study. The results show that, after topical application of the drug, distance and near visual acuity of the naked eye improves with a decrease in the size of the natural pupil.

Methods and substances

1. Pupil size measurement

The infrared imaging system used to check alignment during the autorefractometry process was used to measure pupil size. An infrared image of the pupil converted to visible light, magnified and displayed on the screen of the instrument for visual control, allows the user to observe the pupil and center the instrument during normal operation. Vertical and horizontal pupil diameters were measured on the screen using a ruler while the subject was observing an infinitely distant object. The average of two measurements was recorded and corrected for magnification (approximately x7 to x8) for vertical and horizontal meridians.

2. Measurement of visual acuity

All measurements of distance visual acuity were performed using the standard Snellen table, as well as near visual acuity using Jaeger tables. All values were converted to decimal using the Halliday conversion table.

3. Procedure for estimating depth of field (DoF) in the distance

The patient was asked to look at a line of 20/30 Snellen optotypes with distance scoring with maximum correction. The positive refractive power in the phoroptor was increased in increments of 0.25D until the patient reported fuzzy images (+a diopters). The procedure was repeated using negative lenses (-b diopters). DoF far = (a+b) diopter. This procedure was performed monocularly under normal natural light conditions (350 lux) in both the presbyopic and pseudophakic groups.

4. The procedure for estimating the depth of field (DoF) near

To select glasses for distance with maximum correction, the optical power was increased by adding +2.50D in the phoroptor and the patient was asked to look at the image line J2 from a distance of 0.40 m. The positive optical power in the phoroptor was increased in increments of 0.25D until the patient did not report blurry images (+x diopters). The procedure was repeated using negative lenses (-y diopters). DoF near=(x+y) diopters This procedure was performed monocularly under normal natural light conditions (350 lux) for presbyopic subjects.

5. Research plan

The study was a prospective, sequential, non-randomized intervention study that followed the principles of the Declaration of Helsinki. All subjects with presbyopia were selected from patients undergoing routine eye examinations. Exclusion criteria included amblyopic eyes, cases with a history of ocular disease or surgery, cataracts, macular degeneration, abnormal pupil, any known systemic condition affecting pupillary dynamics or visual quality. Patients with pseudophakia were also selected from among those who participated in routine eye examinations. Exclusion criteria included amblyopic eyes, cases with a history of ocular complications, implant with toric or multifocal IOLs, evidence of macular degeneration, capsular thickening, abnormal pupil, any systemic disease known to affect pupil dynamics or visual quality. Where appropriate, measurements were taken for both the right and left eyes. All subjects were fully informed of the nature and purpose of this study.

Data were collected before and one hour after topical application of one or two drops of the drug to the eye. Any symptoms noted by the subjects (such as dryness, nausea, gritty sensation in the eyes) were also recorded.

6. Response rates and statistical analysis

The data was analyzed to

1) To determine whether instillation had an effect on uncorrected distance visual acuity in subjects with presbyopia and in subjects with pseudophakism of the eye (Wilcoxon signed rank test);

2) To determine whether instillation had an effect on uncorrected near visual acuity in subjects with presbyopia and in subjects with pseudophakism of the eye (Wilcoxon signed rank test);

3) Comparisons of distance DoF measurements between presbyopic and pseudophakic subjects (t-test);

4) Determine if there was any relationship between measured pupil size, age, and distance DoF measurements for presbyopic subjects and pseudophakic subjects (Pearson's correlation coefficient);

5) Determine if there was any relationship between measured pupil size, age, and near DoF measurements for presbyopic subjects (Pearson's correlation coefficient); And

6) Determine if any change in the distance DoF was associated with any change in pupil size (Pearson's correlation coefficient).

In cases where measurements were taken on both eyes, the corresponding data for the right and left eyes were stored separately to avoid statistical errors of the first kind. The significance level was set corresponding to the p value, less than 0.05. The Bonferonni correction was applied because the data were subjected to multiple comparisons.

results

Twenty-seven (27) subjects received 1 drop per eye and eighteen (18) subjects received 2 drops per eye of the ophthalmic pharmaceutical composition. For those subjects who received two drops per eye, the second drop was administered a few seconds after the first.

The presbyopic group consisted of 18 women and 11 men. A total of 5 people underwent and reported adverse reactions in the form of nausea (n=1), dryness (n=1), burning sensation (n=1), blurred vision (n=1) and a feeling of acute pain (n=1) . Artifakia group consisted of 10 women and 6 men. In this group, 2 people reported a tingling sensation and 2 others experienced a burning sensation after instillation. The reactions reported were of short duration and were not overtly unpleasant.

In both groups, uncorrected visual acuity, both far and near, improved significantly after instillation of a drop having the composition described in this example. There was a simultaneous and significant increase in the average depth of field and a decrease in pupil size. The main results are shown in tables 1 and 2.

Table 1 : Subjects with presbyopia - depth of field, pupil size and naked eye visual acuity.

Measurement Before After Meaning RIGHT EYES (n=29) Depth of field, far (D) 1.31(0.42) 1.97(0.61) <0.001 Pupil diameter (mm) 3.89(0.74) 3.14(0.75) <0.001 Depth of field, near (D) 1.64(0.39) 2.20(0.54) <0.001 UDVA (mean ± standard deviation) 1.10(0.32) 1.33(0.40) <0.001 UDVA (median & range) 1.2(0.5-1.0) 1.5(0.60-2.0) <0.001 UNVA (mean ± standard deviation) 0.33(0.17) 0.45(0.27) <0.001 UDVA (median & range) 0.25(0.10-0.63) 0.40(0.10-0.80) <0.001 LEFT EYES (n=24) Depth of field, far (D) 1.41(0.45) 2.02(0.59) <0.001 Pupil diameter (mm) 3.84(0.81) 3.16(0.76) <0.001 Depth of field, near (D) 1.69(0.36) 2.19(0.52) <0.001 UDVA (mean ± standard deviation) 1.09(0.30) 1.28(0.38) <0.001 UDVA (median & range) 1.0(0.50-1.5) 1.2(0.60-1.50) <0.001 UNVA (mean ± standard deviation) 0.31(0.19) 0.46(0.26) <0.001 UDVA (median & range) 0.25(0.1-0.63) 0.36(0.1-0.80) <0.001

Table 2 : Subjects with pseudophakia - depth of field, pupil size and naked eye visual acuity.

Measurement Before After Meaning RIGHT EYES (n=13) Depth of field, far (D) 1.61(0.51) 2.67(0.52) <0.001 Pupil diameter (mm) 2.92(0.36) 1.97(0.26) <0.001 UDVA (mean ± standard deviation) 0.64(0.18) 0.89(0.16) <0.001 UDVA (median & range) 0.70(0.3-1.0) 0.90(0.7-1.2) <0.001 UNVA (mean ± standard deviation) 0.30(0.16) 0.71(0.15) <0.001 UNVA (median & range) 0.30(0.1-0.55) 0.70(0.5-1.0) <0.001 LEFT EYES (n=15) Depth of field, far (D) 1.65(0.52) 2.72(0.47) <0.001 Pupil diameter (mm) 2.97(0.43) 1.91(0.23) <0.001 UDVA (mean ± standard deviation) 0.69(0.16) 0.91(0.14) <0.001 UDVA (median & range) 0.7(0.40-1.0) 0.9(0.70-1.0) <0.001 UNVA (mean ± standard deviation) 0.34(0.17) 0.76(0.13) <0.001 UNVA (median & range) 0.40(0.1-0.55) 0.80(0.6-1.0) <0.001

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

In the presbyopic group, there was no significant relationship between i) pupil size and age ii) age and far and near depth of field iii) pupil size and far and near depth of field.

In the pseudophakic group, there was no significant relationship between i) pupil size and age ii) age and distance field iii) pupil size and depth of field.

In each group, there were no significant differences between the data obtained for the right eyes compared with the left eyes in cases of binocular examination. Since there was no apparent bias towards the right or left eye, data from the right and left eyes could be combined for specific analyses. For example, in FIG. 1 and 2, when examining the possible relationship between change in depth of field (ΔDoF) and change in pupil size (Δpupil) for individual cases, the data obtained for the right and left eyes were combined for specific types of analysis.

In the presbyopic group, there was a significant correlation between ΔDoF and pupillary Δ. This data is shown in Fig. 1 (distant) and FIG. 2 (side by side). The least squares regression line corresponding to ΔDoF (y, diopters) in the distance and Δpupil (x, mm) had the form:

y=0.409-0.289x (r= -0.437, n=53, p< 0.001) [eq.1]

Similarly, the least squares regression line corresponding to ΔDoF (y, diopters) near and Δpupil (x, mm) was:

y=0.352-0.253x (r= -0.429, n=53, p<0.001) [eq.2]

In the group with pseudophakia, no significant correlation was found between ΔDoF and pupillary Δ. A significant correlation was found after pooling all data from both groups. The least squares regression line, equal to ΔDoF away and Δpupil for the combined data, was:

y=0.526-0.299x (r= -0.395, n=81, p<0.001) [equiv.3]

Data review

This exploratory study included 45 subjects, of which 29 were presbyopic subjects and 16 were pseudophakic subjects (subjects with an implanted monofocal IOL). A total of 9 of 45 subjects (20%) reported a slight sensation after instillation. One complained of dryness, another noticed blurry vision, one felt nausea and headache, three experienced a feeling of sharp pain, and three more described this sensation as a burning sensation after instillation of drops. None of the subjects expressed complete dissatisfaction after instillation of drops.

In both groups, distance and near visual acuity of the naked eye improved after topical application of the drug. Converting the data in Tables 1 and 2 to Snellen and Yeager's notation shows that in subjects with presbyopia, typical naked eye distance visual acuity improved from 20/20 to 20/15, and naked eye near visual acuity improved from about J8 to J6 . Referring to the data in Table 1, a 0.72 mm reduction in pupil size in presbyopic subjects was associated with this improvement in both distance and near visual acuity of the naked eye. In the pseudophakic group, typical naked eye distance visual acuity improved from 20/30 to 20/25, and naked eye near visual acuity improved from J8 to J3. The data in Tables 1 and 2 show that in the pseudophakia group of subjects, a 1.01 mm decrease in pupil size was associated with a greater improvement in naked eye near visual acuity and a smaller improvement in naked eye far visual acuity compared to presbyopic subjects.

This deviation may be due to the fact that the pupil was smaller from the very beginning in subjects with pseudophakia. Pupil size tends to be smaller in older people than in younger people (Birren et al, 1950, J Gerontol 5: 216-221; Winn et al., 1994, Investigative Ophthalmology & Visual Science 35:1132-1137). In each of these two groups, there was no correlation between age and pupil size. However, mean (±SD) pupil size and age in the presbyopic group were 3.89 mm (0.74, right eyes), 3.84 mm (0.81, left eyes), and 48.7 years (4.20 ). In the group with pseudophakia, the corresponding values were 2.92 mm (0.36), 2.97 mm (0.43) and 67.2 years (±7.5). The differences between the two groups were significant, both in terms of pupil size and age. The smaller pupil in the pseudophakia group was likely due to the age of the subjects in this group, and not to the patients who had undergone cataract surgery. This, combined with the difference in optical properties between the phakic eye in presbyopia and pseudophakia, probably explains the slight difference in drop response.

The mean DoF values in both groups before the drops were very similar to previous data. Table 1 shows the mean (±SD) distance DoF values corresponding to 1.31D (0.42) and 1.41D (0.45) in presbyopic subjects. These values are in the range up to 1.8D reported by Wang and Ciuffreda in a detailed review on the subject (2006, SurvOphthalmol 51:75-85). Table 2 shows mean distance DoF values of 1.61D (0.51) and 1.65D (0.52) in subjects with pseudophakia. These values range from 0.80D to 1.65D, which have been reported after implantation of monofocal IOLs. (Kamlesh & Kaushik, 2001, Can J Ophthalmol 36:197-201; Macsai et al, 2006, J Cataract Refract Surg. 32:628-633; Nishi et al., 2013, ClinOphthalmol 7:2159-2164).

In both the presbyopic and pseudophakic groups, mean DOF increased after instillation. In the pseudophakic group, a mean increase in DoF of 1.03D was accompanied by a mean decrease in pupil size of 1.05 mm. And in the presbyopic group, an average increase in DoF of 0.60D was accompanied by an average decrease in pupil size of 0.76 mm. In 5 of 53 eyes with presbyopia, the measured distance depth of field did not change. However, in the same 5 cases, the pupil size decreased and the measured near depth of field increased to almost 1D. Combining all the data at our disposal revealed a significant relationship between pupil size change (Δpupil) and DoF change (ΔDoF). The indices of the linear regression equations give a theoretical prediction that a decrease in pupil size by 1 mm should lead to an increase in the distance DoF of 0.83D and a simultaneous increase of 0.61D near.

As noted earlier, distance and near visual acuity of the naked eye improved after topical application of the drug.

None of the 45 subjects expressed complete dissatisfaction with the drug, although 9 of them reported an adverse reaction. The drug was well tolerated and the subjects requested that the drug be provided to them on a more permanent basis.

EXAMPLE 2 Safety, Tolerability and Efficacy of CSF-1 in Presbyopia

CSF-1 is a topical 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, percentile amounts are determined by weight (mass/mass). This drug is intended to provide miosis and increase depth of field for the temporary correction of presbyopia. The placebo contains the same ingredients as the study product, with the exception of the active ingredients.

Subjects

This example was a randomized, double-blind, placebo-controlled, double-treatment, repeat-treatment cross-over study in presbyopic patients. After signing informed consent and undergoing a screening evaluation, eligible subjects were randomly selected in a 1:1 ratio for one of the two treatment sequences shown below:

Processing sequence 1
(n=18) Processing sequence 2
(n=18) 1 CSF-1 placebo 2 placebo CSF-1

Each treatment, using CSF-1 or placebo, was administered by the subject himself for two weeks (one drop in each eye each morning) with a 24-hour lavage interval between treatments. The allowable interval between treatment visits was 11 to 17 days. All subjects, regardless of their allocation to treatment groups, were evaluated in the same way. Each subject continued to be observed for two weeks after the end of the treatment period. The maximum duration for an individual patient was 64 days (~9 weeks), including:

Screening period: up to 21 days inclusive;

Treatment/treatment period: 29 days; And

Observation period: 14 days.

The objectives of the study were:

1) To determine the safety and tolerability of repeated administration of CSF-1 in subjects with presbyopia; And

2) To determine the effectiveness of repeated administration of CSF-1 to subjects with presbyopia.

Methods and substances

1. Pupil size measurement

An infrared imaging system used to check alignment in the autorefractometry process was used to measure pupil size. An infrared image of the pupil converted to visible light, magnified and displayed on the screen of the instrument for visual control, allows the user to observe the pupil and center the instrument during normal operation. Vertical and horizontal pupil diameters were automatically measured using the firmware of the imaging system when the subject observed an infinitely distant object. The measurement was recorded and corrected for magnification (approximately x7 to x8) for vertical and horizontal meridians.

2. Measurement of visual acuity

All visual acuity measurements were performed using FDA-approved distance and near standard EDTRS charts. The EDTRS tables provide measurements of visual acuity in the Snellen system, decimal system and logMAR system. The structure of these tables is characterized by a simple progression of 0.1 units in character size on the logMAR scale from one character string to the next, and scales for conversion to other systems such as the Snellen system or the decimal system. For example, when a person can only identify the characters, for example, in row 11, which, in the ETDRS table from a distance of 4M (4 meters), is indicated as Snellen sharpness 20/20, then her/his sharpness, in addition to 20/20, can be marked as either 0.0 logMAR or decimal 1.0. The ability to identify characters on the next line, which is line 12, would indicate a sharpness of -0.1 logMAR or 1.25 decimal or 20/16 Snellen. The logMAR system is more sensitive and provides reliable statistical comparisons. Distance visual acuity was measured in each eye both monocularly (right eye then left eye) and binocularly under standard high ambient light (~3000 lux) to test visual acuity. Near acuity was measured at 40 cm for each eye both monocularly (right eye then left eye) and binocularly under standard high (~3000 lux) ambient light and repeated at lower (20-1000 lux) illumination.

3. Procedure for assessing peripheral visual fields

The visual field was assessed using a standard clinical procedure, commonly referred to as the reference visual field method known in the art. With this method, any prolapse or anomaly in the visual field of each eye in the upper, lower, nasal and temporal regions is checked.

4. Procedure for estimating depth of field (DoF) in the distance

The patient was asked to look at the line of 0.1 logMAR optotypes when fitting glasses for distance with the best corrected distance spectacle prescription. The positive refractive power in the phoroptor was increased in increments of 0.25D until the patient reported fuzzy images (+a diopters). The procedure was repeated using negative lenses (-b diopters). DoF far = (a+b) diopter. This procedure was performed monocularly under normal natural light conditions (~3000 lux).

5. Procedure for estimating the depth of field (DoF) near

The patient was asked to look at the 0.1 logMAR line of optotypes when fitting spectacles for best corrected distance spectacle prescription. The positive refractive power in the phoroptor was increased in increments of 0.25D until the patient reported fuzzy images (+a diopters). The procedure was repeated using negative lenses (-b diopters). DoF far = (a+b) diopter. This procedure was performed monocularly under normal natural light conditions (~3000 lux).

6. Performance evaluation procedure

The primary efficacy endpoint was defined as a 0.2 or 0.3 improvement in near naked eye visual acuity (UNVA) according to the logMAR system. This is equivalent to two or three lines of improvement in visual acuity using the standard near (40 cm) EDTRS chart.

7. Study plan

The study was a double-blind, two-centre, randomized, placebo-controlled, repeat-dose, crossover study to establish the safety, tolerability, and efficacy of CSF-1 in presbyopia, which was consistent with the principles of the Declaration of Helsinki. Each subject with presbyopia was selected from patients undergoing routine eye examinations. All subjects had a maximum corrected visual acuity corresponding to at least 20/20, which is equivalent to 0.0 on the logMAR scale, and all subjects were dependent on reading glasses or bifocals in which the addition for near vision is > +1, 00 diopters In addition, all subjects required neither far nor near optical correction, where the spherical component did not exceed ±0.75 D and/or the cylindrical component did not exceed ±0.75 DC, refraction along any prime meridian was not greater than 1, 00 diopters Exclusion criteria included amblyopic eyes, cases with abnormalities related to binocular vision, oculomotor dysfunction, history of ocular disease or surgery, cataracts, macular degeneration, abnormal pupil, natural pupil size less than 2.5 mm in any eye with ambient light 8- 15 lux, and any known systemic condition affecting the dynamics or quality of vision. Where appropriate, measurements were taken for both the right and left eyes. All subjects were fully informed of the nature and purpose of this study.

Data collection was performed before and during follow-up clinic visits after the study subject applied a topical application of the drug (CSF-1 or placebo) to both eyes daily. Any symptoms noted by the subjects (such as dryness, nausea, and a gritty feeling in the eyes) were also recorded.

8. Response rates and statistical analysis

The data was analyzed to

1) Determine if drops will affect uncorrected distance vision;

2) Determine if drops will affect uncorrected near vision;

3) Determine if drops affect pupil size; And

4) Determine if the drops affect the depth of field far and near.

Appropriate statistical tests were used to analyze quantitative changes, such as McNimar's test for related samples and paired t-test or Wilcoxon's signed-rank test for two means (paired observations). All tests were two-sided and a p-value of 5% or less was considered statistically significant.

results

Thirty-six subjects (21 females and 15 males, mean age 51.5 g [SD=±4.43], range 44.5 to 62.5 years) completed the study.

For both the eyes and the right eye, there was no overall difference between CSF-1 and placebo in terms of uncorrected distance visual acuity. In the left eye, CSF-1 significantly improved uncorrected visual acuity. The difference between CSF-1 and placebo in the left eye was statistically significant. The main data are given in table 3.

Table 3 : Uncorrected (4 m) distance visual acuity - frequency of change in standard high illumination. BV=with both eyes; OD=right eye; and OS=left eye.

Change from original values N % P-value (Wilcoxon signed-rank test)* BV Change from CSF-1 -1 3 8.3 0 19 52.8 1 eleven 30.6 2 3 8.3 BV Change from placebo -1 5 13.9 0 24 66.7 0.0933 1 6 16.7 2 1 2.8 OD Change from CSF-1 -2 1 2.8 -1 5 13.9 0 eleven 30.6 1 14 38.9 2 4 11.1 3 1 2.8 OD Change from placebo -1 5 13.9 0 19 52.8 1 9 25.0 0.2295 2 3 8.3 OS Change with CSF-1 -2 1 2.8 -1 2 5.6 0 14 38.9 1 eleven 30.6 2 6 16.7 3 2 5.6 OS Change with placebo -1 7 19.4 0 17 47.2 1 9 25.0 0.0008 2 3 8.3

*P-value derived from the Wilcoxon test indicates the statistical significance of the difference between changes with CSF-1 and placebo.

After CSF-1, a significant change in mean uncorrected near visual acuity was observed compared to any change after placebo. The change after CSF-1 treatment was significantly greater than any change found using placebo. The main data are presented in tables 4-6.

Table 4 : Uncorrected near visual acuity (high light). Positive effect was defined as an improvement of at least 2 or 3 lines from baseline according to the ETDRS table. BV=with both eyes; OD=right eye; and OS=left eye.

Degree of positive effect CSF-1 placebo p-value N % N % McNimar criterion BV Buff/improvement for 2 lines No positive effect (<2) 21 58.3 28 77.8 Positive effect (≥2) 15 41.7 8 22.2 0.0348 Buff/upgrade for 3 lines No positive effect (<3) 27 75.0 34 94.4 Positive effect (≥3) 9 25.0 2 5.6 0.0196 OD Buff/improvement for 2 lines No positive effect (<2) 20 55.6 28 77.8 Positive effect (≥2) 16 44.4 8 22.2 0.0455 Buff/upgrade for 3 lines No positive effect (<3) 27 75.0 31 86.1 Positive effect (≥3) 9 25.0 5 13.9 0.2059 OS Buff/improvement for 2 lines No positive effect (<2) 24 66.7 31 86.1 Positive effect (≥2) 12 33.3 5 13.9 0.0707 Buff/upgrade for 3 lines No positive effect (<3) 31 86.1 35 97.2 Positive effect (≥3) 5 13.9 1 2.8 0.0455

Table 5 : Uncorrected near visual acuity (low light). Positive effect was defined as an improvement of at least 2 or 3 lines from baseline according to the ETDRS table. BV=with both eyes; OD=right eye; and OS=left eye.

Degree of positive effect CSF-1 placebo p-value N % N % McNimar criterion BV Buff/improvement for 2 lines No positive effect (<2) 21 58.3 thirty 83.3 Positive effect (≥2) 15 41.7 6 16.7 0.0067 Buff/upgrade for 3 lines No positive effect (<3) thirty 83.3 34 94.4 Positive effect (≥3) 6 16.7 2 5.6 0.1025 OD Buff/improvement for 2 lines No positive effect (<2) 22 61.1 thirty 83.3 Positive effect (≥2) 14 38.9 6 16.7 0.0209 Buff/improvement for 3 lines No positive effect (<3) 28 77.8 34 94.4 Positive effect (≥3) 8 22.3 2 5.6 0.0143 OS Buff/improvement for 2 lines No positive effect (<2) 20 55.6 32 88.9 Positive effect (≥2) 16 44.4 4 11.1 0.0005 Buff/upgrade for 3 lines No positive effect (<3) 26 72.2 35 97.2 Positive effect (≥3) 10 27.8 1 2.8 0.0027

Table 6 : Uncorrected near visual acuity (high or low light, left, right or both eyes). A positive effect was defined as an improvement of at least 2 or 3 lines from baseline according to the ETDRS table in high or low light in the left, right, or both eyes. BV=with both eyes; OD=right eye; and OS=left eye.

Degree of positive effect CSF-1 placebo p-value N % N % McNimar criterion Buff/improvement for 2 lines No positive effect (<2) eleven 30.6 20 55.6 Positive effect (≥2) 25 69.4 16 44.4 0.0290 Buff/upgrade for 3 lines No positive effect (<3) 19 52.8 thirty 83.3 Positive effect (≥3) 17 47.2 6 16.7 0.0045

After CSF-1, there was a significant change in mean pupil size compared to any change after placebo. The main data are presented in table 7.

Table 7 : Changes in pupil size (mm) after CSF-1 or placebo.

Pupil size N Average Standard Min Median Max P-value (paired t-test) Baseline 72 4.29 0.87 2.50 4.30 6.80 CSF-1 72 3.10 0.93 1.60 2.95 6.00 placebo 70 3.67 1.13 1.50 3.95 6.00 Changes after CSF-1 treatment 72 -1.18 0.92 -3.40 -1.10 1.40 Changes after placebo treatment 70 -0.60 1.32 -3.50 -0.40 3.20 The difference between CSF-1 and placebo 70 0.54 1.51 -3.50 0.80 3.20 0.0037

There was a significant change in mean distance and near depth of field after CSF-1 compared to any change after placebo. The main data are given in table 8.

Table 8 . Changes in depth of field (D) after CSF-1 or placebo.

Depth of field N Average Mill. Min Median Max P-value (paired t-test) 40 cm Preliminary processing 72 3.70 2.70 -5.25 4.38 8.50 Changes after CSF-1 treatment 72 0.98 2.33 -5.25 0.50 12.00 Changes after placebo treatment 70 0.57 2.33 -6.50 0.25 13.00 placebo 70 4.33 2.29 0.25 5.13 7.75 CSF-1 72 4.68 2.57 0.25 5.00 11.00 The difference between CSF-1 and placebo 70 -0.44 1.81 -9.25 -0.25 5.00 0.0462 4 m Preliminary processing 72 1.51 0.65 0.50 1.50 3.25 Changes after CSF-1 treatment 72 0.22 0.86 -2.75 0.25 1.75 Changes after placebo treatment 70 0.01 0.74 -2.00 0.00 2.50 placebo 70 1.54 0.52 0.00 1.50 3.75 CSF-1 72 1.73 0.55 0.00 1.75 2.75 The difference between CSF-1 and placebo 70 -0.21 0.65 -1.50 -0.25 2.25 0.0071

There were no significant changes in tear film stability after either CSF-1 or placebo. The main data are presented in table 9.

Table 9 : Precorneal tear film stability. OD=right eye and OS=left eye.

Tear film (sec.) and changes N Average Standard Min Median Max P-value (Wilcoxon signed rank test) OD Baseline 23 13.8 3.6 9.0 14.0 20.0 With CSF-1 23 14.1 5.8 5.0 14.0 28.0 with placebo 23 15.0 3.6 8.0 15.0 22.0 At follow-up 21 14.5 4.4 6.0 15.0 25.0 Changes after CSF-1 treatment 23 0.3 6.3 -12.0 0.0 15.0 0.7753 Changes after placebo administration 23 1.2 4.6 -10.0 2.0 7.0 0.1473 Baseline 23 13.8 3.1 9.0 14.0 22.0 OS With CSF-1 23 14.5 6.0 3.0 15.0 30.0 with placebo 23 13.9 3.8 5.0 14.0 20.0 At follow-up 21 14.1 4.7 4.0 15.0 25.0 Changes after CSF-1 treatment 23 0.7 6.4 -11.0 0.0 14.0 0.7880 Changes after placebo administration 23 0.1 5.2 -11.0 1.0 7.0 0.8930

Data review

Uncorrected distance visual acuity

Pilocarpine at certain concentrations stimulates the ciliary muscle, resulting in accommodation and reduced distance visual acuity (see, for example, Emsley, 1972, Optics of Vision, ^5th ed., Visual Optics Vol. 1, London UK, Butterworths, p. 88 ; Williams, 1976, J Am OptomAssoc 47:761-764; Mazor et al., 1979, Br J Ophthalmol 63:48-51; Edgar et al., 1999, Graefes Arch ClinExpOphthalmol 237:117-124). CSF-1 improved uncorrected near vision but did not decrease uncorrected distance visual acuity. Since distance vision was not impaired (Table 3), the data indicated that CSF-1 did not cause any accommodation. More specifically, surprisingly, 91.7% of the eyes were presented with no change in uncorrected distance visual acuity after CSF-1 treatment. With placebo, only 86.2% of eyes were presented with no change in uncorrected distance visual acuity.

Uncorrected near visual acuity

Only concentrations of pilocarpine above 0.5% are effective for improving near vision (US Pat. No. 9,579,308). However, study data showed that naked binocular near vision visual acuity at 40 cm unexpectedly improved by 2 or more lines in 41.7% of patients with CSF-1 and in 22.2% of patients with placebo (p = 0.0348) in high ambient light (table 4). Surprisingly, in low light conditions, 41.7% of patients were reported as showing such an increase in their binocular uncorrected near visual acuity, while only 16.7% were reported as having such an increase with placebo (p=0.0067) (Table 5).

Referring to single eye data, uncorrected near visual acuity at 40 cm in low ambient light improved by 3 or more lines in 27.8% of the left eyes and 22.2% of the right eyes with CSF-1 (Table 5 ). However, only 2.8% of the left eyes and 5.6% of the right eyes improved by 3 lines or more after placebo (p<0.0143 right eye and p<0.0027 left eye) (Table 5). These findings were unexpected because pilocarpine is expected to reduce pupil size, limiting the amount of light entering the eye, and which in turn will reduce retinal image brightness and visual acuity in low ambient light.

Pupil

Low (below 1%) concentrations of pilocarpine will have little effect on pupil size (Mazor et al., 1979, Br J Ophthalmol 63:48-51; Edgar et al., 1999, Graefes Arch ClinExpOphthalmol 237:117-124). However, the study revealed unexpected and significant results in pupillary constriction after CSF-1 administration, from an average of 4.29 mm before treatment to an average of 3.10 mm after CSF-1 instillation (Table 7). Without being bound by any mechanistic theory, these studies show that CSF-1 works by pupil contraction rather than by accommodation.

Depth of field

Depth of field is inversely related to pupil size. As the pupil size decreases, the depth of field increases. Compared to placebo, depth of field is not expected to change significantly if pupil size does not change. Low (below 1%) concentrations of pilocarpine have little effect on pupil size (Mazor et al., 1979, Br J Ophthalmol 63:48-51; Edgar et al., 1999, Graefes Arch ClinExpOphthalmol 237:117-124). Thus, no increase in DoF is expected after administration of less than 1% pilocarpine. However, the study revealed an unexpected and significant increase in depth of field after CSF-1 administration compared to any changes observed after placebo administration, both far and near (Table 8).

tear film

Topical drops containing pilocarpine salts can cause dry eyes by reducing both tear production and tear film stability (Nuzzi et al., 1998, IntOphthalmol 22:31-35; Baffa et al., 2008, Arq Bras Oftalmol 71:18-21). Surprisingly, the study did not reveal any significant change, neither decrease nor increase in tear film stability after either CSF-1 or placebo (Table 9).

Fields of view in low light conditions

Pilocarpine-induced miosis may affect visual field and visual acuity when light levels are reduced. Thus, it can be expected that there will be some loss of visual field and reduced ability to perform vital tasks in cases where good vision at night is required. Surprisingly, there were no reports of any loss or reduction in final visual field size when patients used either CSF-1 or placebo. The data showed that all 23 study patients had a normal visual field and did not observe a decrease in its field, both in the drug group and in the placebo group. At the start of the study, 75% of subjects reported being able to drive at night without glasses. This percentage increased to 83% and 86% after using CSF-1 or placebo, respectively.

Claims (90)

1. An ophthalmic pharmaceutical composition containing one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w or w/w) /volume), a lubricant, and a pharmaceutically acceptable carrier, wherein the lubricant is hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose or a derivative thereof, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400 , polysorbate, propylene glycol, polyvinyl alcohol, povidone, or mixtures thereof. 2. The ophthalmic pharmaceutical composition of claim 1 wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate. 3. An ophthalmic pharmaceutical composition according to claim 1, wherein the lubricating agent is sodium hyaluronate, or hydroxypropyl methylcellulose, or mixtures thereof. 4. Ophthalmic pharmaceutical composition according to claim 3, where sodium hyaluronate is present at a concentration of 0.01% (w/w or w/v) - 0.9% (w/w or w/v) and/or where hydroxypropyl methylcellulose is present in concentrations of 0.1% (w/w or w/v) - 2.0% (w/w or w/v). 5. An ophthalmic pharmaceutical composition according to claim 1, wherein the ophthalmic pharmaceutical composition is a sustained release composition. 6. An ophthalmic pharmaceutical composition according to claim 1, wherein the ophthalmic pharmaceutical composition is in the form of a suspension, gel, ointment, injection, spray or eye drops. 7. The ophthalmic pharmaceutical composition of claim 1, wherein the ophthalmic pharmaceutical composition is suitable for implantation in or on the subject's eye or tissue surrounding the subject's eye. 8. An ophthalmic pharmaceutical composition according to claim 7, wherein the ophthalmic pharmaceutical composition is suitable for implantation in the subconjunctival space, nasolacrimal duct, or vitreous body of a subject. 9. The ophthalmic pharmaceutical composition of claim 1, wherein the ophthalmic pharmaceutical composition is suitable for topical delivery to the eye or tissue surrounding the eye of a subject. 10. An ophthalmic pharmaceutical composition according to claim 1, wherein the ophthalmic pharmaceutical composition further comprises a pharmaceutically acceptable diluent, preservative and/or solvent. 11. An ophthalmic pharmaceutical composition according to claim 1, further comprising an isotonic agent, a wetting agent, a buffer, a stabilizer, a pH agent, a solubilizer, a thickening agent and/or a dispersing agent. 12. The ophthalmic pharmaceutical composition of claim 1, wherein the ophthalmic pharmaceutical composition is effective in correcting presbyopia for up to 24 hours. 13. The ophthalmic pharmaceutical composition of claim 1, wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely affecting night vision. 14. The ophthalmic pharmaceutical composition of claim 1, wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely reducing the visual field. 15. A method for correcting presbyopia in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w/w or w/v ) - 0.4% (w/w or w/v), a lubricant and a pharmaceutically acceptable carrier, where the lubricant is hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose or its derivative, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran , gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or mixtures thereof. 16. The method of claim 15 wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate. 17. The method of claim 15 wherein the lubricating agent is sodium hyaluronate or hydroxypropyl methylcellulose or mixtures thereof. 18. The method according to claim 17, where sodium hyaluronate is present at a concentration of 0.01% (w/w or w/v) - 0.9% (w/w or w/v) and/or where hydroxypropyl methylcellulose is present at a concentration of 0 .1% (w/w or w/v) - 2.0% (w/w or w/v). 19. The method of claim 21 wherein the ophthalmic pharmaceutical composition is a sustained release composition. 20. The method of claim 21 wherein the ophthalmic pharmaceutical composition is in the form of a suspension, gel, ointment, injection, spray or eye drops. 21. The method of claim 21 wherein the ophthalmic pharmaceutical composition is suitable for implantation in or on the subject's eye or tissue surrounding the subject's eye. 22. The method of claim 21, wherein the ophthalmic pharmaceutical composition is suitable for implantation into the subconjunctival space, nasolacrimal duct, or vitreous body of a subject. 23. The method of claim 15 wherein the ophthalmic pharmaceutical composition is suitable for topical delivery to the eye or tissue surrounding the eye of a subject. 24. The method of claim 15 wherein the ophthalmic pharmaceutical composition contains a pharmaceutically acceptable diluent, preservative and/or diluent. 25. The method of claim 15 further comprising an isotonicizer, a wetting agent, a buffer, a stabilizer, a pH agent, a solubilizer, a thickening agent, and/or a dispersing agent. 26. The method of claim 15, wherein the ophthalmic pharmaceutical composition is effective for correcting presbyopia for up to 24 hours. 27. The method of claim 15 wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely affecting night vision. 28. The method of claim 15, wherein the ophthalmic pharmaceutical composition corrects presbyopia without significantly reducing the visual field. 29. The method according to claim 15, where the subject: a) is a spectacle wearer who cannot or will not wear progressive or bifocal lenses; b) has undergone cataract surgery; c) who develops presbyopia after a corneal procedure; d) has monofocal or multifocal intraocular lenses; e) wears contact lenses and is intolerant of monovisual contact lenses; f) wears contact lenses and is intolerant of multifocal contact lenses; g) suffers from a higher order aberration after corneal surgery; h) suffers from hyperopia or tropia; i) is intolerant of changes in scoring; j) is undergoing rapid changes in scoring; k) is at risk of falling when using progressive or bifocal lenses; and/or l) suffers from higher order aberration at night or in low light conditions. 30. The method of claim 15, wherein the administration is topical or surgical. 31. The method of claim 30, wherein the surgical intervention comprises the step of administering the ophthalmic pharmaceutical composition to or on the subject's eye or tissue surrounding the subject's eye. 32. The method of claim 31, wherein the ophthalmic pharmaceutical composition is administered to the subconjunctival space, nasolacrimal duct, or vitreous body of the subject. 33. A method for reducing pupil size in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w/w or w/ volume) - 0.4% (w/w or w/v), a lubricant and a pharmaceutically acceptable carrier, where the lubricant is hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose or its derivative, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or mixtures thereof. 34. A method for inducing miosis in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w/w or w/v ) - 0.4% (w/w or w/v), a lubricant and a pharmaceutically acceptable carrier, where the lubricant is hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose or its derivative, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran , gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or mixtures thereof. 35. A method for increasing the depth of field of a subject's eye, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (wt/wt or wt/ volume) - 0.4% (w/w or w/v), a lubricant and a pharmaceutically acceptable carrier, where the lubricant is hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose or its derivative, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or mixtures thereof. 36. A method for reducing the magnitude of higher order aberrations in the eye of a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w or w/v), a lubricant and a pharmaceutically acceptable carrier, where the lubricant is hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose or its derivative, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose , methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or mixtures thereof. 37. A method for improving uncorrected near and far visual acuity in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w/w mass or mass / volume) - 0.4% (mass / mass or mass / volume), a lubricant and a pharmaceutically acceptable carrier, where the lubricant is hyaluronic acid or its pharmaceutically acceptable salt, cellulose or its derivative, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or mixtures thereof. 38. An implant containing an ophthalmic pharmaceutical composition containing one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or its pharmaceutically acceptable salt at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w) mass or mass / volume), a lubricant and a pharmaceutically acceptable carrier, where the lubricant is hyaluronic acid or its pharmaceutically acceptable salt, cellulose or its derivative, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300 , polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or mixtures thereof. 39. A set containing an ophthalmic pharmaceutical composition containing one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or its pharmaceutically acceptable salt at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w) mass or mass / volume), a lubricant and a pharmaceutically acceptable carrier, where the lubricant is hyaluronic acid or its pharmaceutically acceptable salt, cellulose or its derivative, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300 , polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or mixtures thereof. 40. A method for correcting presbyopia in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition that reduces the size of the subject's pupil, wherein the ophthalmic pharmaceutical composition contains one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0 01% (w/w or w/v) - 0.4% (w/w or w/v), a lubricant and a pharmaceutically acceptable carrier, where the lubricant is hyaluronic acid or a pharmaceutically acceptable salt thereof, cellulose or a derivative thereof , sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, gelatin, polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate, propylene glycol, polyvinyl alcohol, povidone, or mixtures thereof. 41. The method according to any one of claims 15-39 and 40, wherein the ophthalmic pharmaceutical composition is administered up to two times per application, up to three applications per day. 42. An ophthalmic pharmaceutical composition according to any one of claims 1 to 14 for use in a method for correcting presbyopia in a subject, comprising administering an ophthalmic pharmaceutical composition to the subject's eye topically or through surgery. 43. An ophthalmic pharmaceutical composition according to any one of claims 1 to 14 for use in a method for reducing pupil size in a subject, comprising administering an ophthalmic pharmaceutical composition to the subject's eye topically or through surgery. 44. An ophthalmic pharmaceutical composition according to any one of claims 1 to 14 for use in a method for inducing miosis in a subject, comprising administering an ophthalmic pharmaceutical composition to the subject's eye topically or through surgery. 45. An ophthalmic pharmaceutical composition according to any one of claims 1 to 14 for use in a method for increasing depth of field in a subject's eye, comprising administering an ophthalmic pharmaceutical composition to the subject's eye topically or through surgery. 46. An ophthalmic pharmaceutical composition according to any one of claims 1 to 14 for use in a method for reducing the magnitude of higher order aberration in the eye of a subject, comprising administering an ophthalmic pharmaceutical composition to the subject's eye topically or through surgery. 47. An ophthalmic pharmaceutical composition according to any one of claims 1 to 14 for use in a method for improving uncorrected near and far visual acuity in a subject, comprising administering an ophthalmic pharmaceutical composition to the subject's eye topically or through surgery. 48. An ophthalmic pharmaceutical composition according to any one of claims 1 to 14 for use in a method of treating a human or animal body. 49. The ophthalmic pharmaceutical composition of claim 1, wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely reducing distance visual acuity. 50. The method of claim 15, wherein the ophthalmic pharmaceutical composition corrects presbyopia without adversely reducing distance visual acuity. 51. An ophthalmic pharmaceutical composition containing one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w/w or w/v) - 0.4% (w/w or w/w) /volume), hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) - 2.0% (w/w or w/v) and a pharmaceutically acceptable carrier. 52. The ophthalmic pharmaceutical composition of claim 51 wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate. 53. An ophthalmic pharmaceutical composition according to claim 52, additionally containing sodium hyaluronate at a concentration of 0.01% (w/w or w/v) - 0.9% (w/w or w/v). 54. An ophthalmic pharmaceutical composition according to claim 51, wherein the ophthalmic pharmaceutical composition further comprises a pharmaceutically acceptable diluent, preservative and/or solvent. 55. An ophthalmic pharmaceutical composition according to claim 51, further comprising an isotonic agent, a wetting agent, a buffer, a stabilizer, a pH agent, a solubilizer, a thickening agent, and/or a dispersing agent. 56. The ophthalmic pharmaceutical composition of claim 51, wherein the ophthalmic pharmaceutical composition is effective in correcting presbyopia for up to 24 hours. 57. A method for correcting presbyopia in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w/w or w/v ) - 0.4% (w/w or w/v), hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) - 2.0% (w/w or w/v) and a pharmaceutically acceptable carrier . 58. The method of claim 57 wherein the pilocarpine salt is pilocarpine hydrochloride or pilocarpine nitrate. 59. The method of claim 58, wherein the ophthalmic pharmaceutical composition further comprises sodium hyaluronate at a concentration of 0.01% (w/w or w/v) - 0.9% (w/w or w/v). 60. The method of claim 58, wherein the ophthalmic pharmaceutical composition further comprises a pharmaceutically acceptable diluent, preservative and/or diluent. 61. The method of claim 58, wherein the ophthalmic pharmaceutical composition further comprises an isotonic agent, a wetting agent, a buffer, a stabilizer, a pH agent, a solubilizer, a thickening agent, and/or a dispersing agent. 62. The method of claim 58, wherein the ophthalmic pharmaceutical composition is effective for correcting presbyopia for up to 24 hours. 63. The method of claim 58, wherein the administration is topical or surgical. 64. The method according to claim 58, where the subject: a) is a spectacle wearer who cannot or will not wear progressive or bifocal lenses; b) has undergone cataract surgery; c) who develops presbyopia after a corneal procedure; d) has monofocal or multifocal intraocular lenses; e) wears contact lenses and is intolerant of monovisual contact lenses; f) wears contact lenses and is intolerant of multifocal contact lenses; g) suffers from a higher order aberration after corneal surgery; h) suffers from hyperopia or tropia; i) is intolerant of changes in scoring; j) is undergoing rapid changes in scoring; k) is at risk of falling when using progressive or bifocal lenses; and/or l) suffers from higher order aberration at night or in low light conditions. 65. A method for reducing pupil size in a subject, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (w/w or w/ volume) - 0.4% (w/w or w/v), hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) - 2.0% (w/w or w/v) and pharmaceutically acceptable carrier. 66. A method for increasing the depth of field of a subject's eye, comprising administering to the subject a therapeutically effective amount of an ophthalmic pharmaceutical composition containing one therapeutically active ingredient, where the therapeutically active ingredient is pilocarpine or a pharmaceutically acceptable salt thereof at a concentration of 0.01% (wt/wt or wt/ volume) - 0.4% (w/w or w/v), hydroxypropyl methylcellulose at a concentration of 0.1% (w/w or w/v) - 2.0% (w/w or w/v) and pharmaceutically acceptable carrier.

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