Ophthalmic pharmaceutical compositions and uses thereof
Provided herein are ophthalmic pharmaceutical compositions comprising (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide (WS-12) for effectively treating dry eye in a subject in need thereof, effectively reducing dry eye in a subject in need thereof, effectively reducing the likelihood of dry eye in a subject in need thereof, or for treating, preventing, or ameliorating signs or symptoms of dry eye in a subject in need thereof.
1. An ophthalmic pharmaceutical composition, comprising:
about 0.0005% w/v to about 0.01% w/v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide or a pharmaceutically acceptable salt thereof;
about 0.1% w/v to about 5 w/v of a solubilizing agent selected from polyethylene glycol 400, castor oil, polyoxyethylene (20) sorbitan mono-oleate, or polyoxyl 35 castor oil;
about 0.1% w/v to about 0.5% w/v of a viscosity modifier;
a buffer; and
about 0.1% w/v to about 1.0% w/v of a tonicity agent.
2. The ophthalmic pharmaceutical composition of claim 1 , having a pH of about 5.0 to about 8.5.
3. The ophthalmic pharmaceutical composition of claim 1 , having a pH of about 6.7 to about 7.3.
4. The ophthalmic pharmaceutical composition of claim 1 , further comprising a pH adjuster.
5. The ophthalmic pharmaceutical composition of claim 4 , wherein the pH adjuster is 1N sodium hydroxide and the pH is adjusted to about 7.
6. An ophthalmic pharmaceutical composition, consisting of:
about 0.0005% w/v to about 0.01% w/v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide or a pharmaceutically acceptable salt thereof;
about 0.1% w/v to about 5 w/v of a solubilizing agent selected from polyethylene glycol 400, castor oil, polyoxyethylene (20) sorbitan mono-oleate, or polyoxyl 35 castor oil;
about 0.1% w/v to about 0.5% w/v of a viscosity modifier;
a buffer;
about 0.1% w/v to about 1.0% w/v of a tonicity agent;
water; and
a pH of about 5.0 to about 8.5.
7. The ophthalmic pharmaceutical composition of claim 1 , wherein the solubilizing agent is polyoxyl 35 castor oil.
8. The ophthalmic pharmaceutical composition of claim 1 , wherein the viscosity modifier is selected from a cellulose derivative, a clay, a natural gum, a synthetic polymer, colloidal silicon dioxide, or any combination thereof.
9. The ophthalmic pharmaceutical composition of claim 8 , wherein:
the cellulose derivative is selected from methylcellulose, microcrystalline cellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, or hydroxypropyl methylcellulose;
the clay is selected from hectorite, bentonite, aluminum silicate, magnesium silicate, kaolin, or a combination thereof; and
the natural gum is selected from acacia, guar gum, tragacanth, xanthan gum, alginate, carrageenan, or locust bean gum.
10. The ophthalmic pharmaceutical composition of claim 1 , wherein the viscosity modifier comprises hydroxypropyl methylcellulose.
11. The ophthalmic pharmaceutical composition of claim 1 , wherein the tonicity agent is selected from dextrose, glycerin, mannitol, potassium chloride, or sodium chloride.
12. The ophthalmic pharmaceutical composition of claim 1 , wherein the tonicity agent is sodium chloride.
13. The ophthalmic pharmaceutical composition of claim 1 , wherein the buffer is selected from a phosphate buffer, a citrate buffer, TRIS Base, TRIS HCl, PBS, HEPES, MES, PIPES, or TES.
14. The ophthalmic pharmaceutical composition of claim 1 , wherein the buffer is a phosphate buffer.
15. The ophthalmic pharmaceutical composition of claim 1 , further comprising purified water.
16. The ophthalmic pharmaceutical composition of claim 1 , comprising:
about 0.003% w/v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide;
about 0.14% w/v hypromellose;
about 3.0% w/v polyoxyl 35 castor oil;
about 0.78% w/v sodium dihydrogen phosphate dihydrate buffer;
about 0.55% w/v NaCl;
a sufficient amount of NaOH to provide the ophthalmic pharmaceutical composition with a pH of about 7; and
purified water.
17. The ophthalmic pharmaceutical composition of claim 1 , comprising:
about 0.0014% w/v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide;
about 0.14% w/v hypromellose;
about 3.0% w/v polyoxyl 35 castor oil;
about 0.78% w/v sodium dihydrogen phosphate dihydrate buffer;
about 0.55% w/v NaCl;
a sufficient amount of NaOH in order to provide the ophthalmic pharmaceutical composition with a pH of about 7; and
purified water.
18. The ophthalmic pharmaceutical composition of claim 1 , comprising:
about 0.003% w/v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide;
about 0.14% w/v hypromellose;
about 3.0% w/v polyoxyl 35 castor oil;
about 0.78% w/v sodium dihydrogen phosphate dihydrate buffer;
about 0.55% w/v NaCl;
a sufficient amount of NaOH to provide the ophthalmic pharmaceutical composition with a pH of about 7.0; and
purified water q.s to about 1.0 mL.
19. The ophthalmic pharmaceutical composition of claim 1 , comprising:
about 0.0014% w/v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide;
about 0.14% w/v hypromellose;
about 3.0% w/v polyoxyl 35 castor oil;
about 0.78% w/v sodium dihydrogen phosphate dihydrate buffer;
about 0.55% w/v NaCl;
a sufficient amount of NaOH to provide the ophthalmic pharmaceutical composition with a pH of about 7.0; and
purified water q.s to about 1.0 mL.
20. A method of treating dry eye or reducing the likelihood of dry eye in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the ophthalmic pharmaceutical composition of claim 1 .
21. A method of treating an ophthalmic disease or disorder that involves tear production or reducing the signs or symptoms of the ophthalmic disease or disorder that involves tear production in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the ophthalmic pharmaceutical composition of claim 1 .
22. The method of claim 21 , wherein the ophthalmic disease or disorder is dry eye.
23. A method of treating ocular irritation involving tear production or reducing ocular irritation involving tear production in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the ophthalmic pharmaceutical composition of claim 1 .
24. The method of claim 20 , wherein the ophthalmic pharmaceutical composition comprises:
about 0.003% w/v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide;
about 0.14% w/v hypromellose;
about 3.0% w/v polyoxyl 35 castor oil;
about 0.78% w/v sodium dihydrogen phosphate dihydrate buffer;
about 0.55% w/v NaCl;
a sufficient amount of NaOH to provide the ophthalmic pharmaceutical composition with a pH of about 7; and
purified water.
25. The method of claim 20 , wherein the ophthalmic pharmaceutical composition comprises:
about 0.0014% w/v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide;
about 0.14% w/v hypromellose;
about 3.0% w/v polyoxyl 35 castor oil;
about 0.78% w/v sodium dihydrogen phosphate dihydrate buffer;
about 0.55% w/v NaCl;
a sufficient amount of NaOH to provide the ophthalmic pharmaceutical composition with a pH of about 7; and
purified water.
26. The method of claim 21 , wherein the ophthalmic pharmaceutical composition comprises:
about 0.003% w/v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide;
about 0.14% w/v hypromellose;
about 3.0% w/v polyoxyl 35 castor oil;
about 0.78% w/v sodium dihydrogen phosphate dihydrate buffer;
about 0.55% w/v NaCl;
a sufficient amount of NaOH to provide the ophthalmic pharmaceutical composition with a pH of about 7; and
purified water.
27. The method of claim 21 , wherein the ophthalmic pharmaceutical composition comprises:
about 0.0014% w/v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide;
about 0.14% w/v hypromellose;
about 3.0% w/v polyoxyl 35 castor oil;
about 0.78% w/v sodium dihydrogen phosphate dihydrate buffer;
about 0.55% w/v NaCl;
a sufficient amount of NaOH to provide the ophthalmic pharmaceutical composition with a pH of about 7; and
purified water.
28. The method of claim 26 , wherein the ophthalmic disease or disorder is dry eye.
29. The method of claim 23 , wherein the ophthalmic pharmaceutical composition comprises:
about 0.003% w/v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide;
about 0.14% w/v hypromellose;
about 3.0% w/v polyoxyl 35 castor oil;
about 0.78% w/v sodium dihydrogen phosphate dihydrate buffer;
about 0.55% w/v NaCl;
a sufficient amount of NaOH to provide the ophthalmic pharmaceutical composition with a pH of about 7; and
purified water.
30. The method of claim 23 , wherein the ophthalmic pharmaceutical composition comprises:
about 0.0014% w/v (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide;
about 0.14% w/v hypromellose;
about 3.0% w/v polyoxyl 35 castor oil;
about 0.78% w/v sodium dihydrogen phosphate dihydrate buffer;
about 0.55% w/v NaCl;
a sufficient amount of NaOH to provide the ophthalmic pharmaceutical composition with a pH of about 7; and
purified water.
31. The method of claim 20 , wherein the ophthalmic pharmaceutical composition is administered topically to the subject.
32. The ophthalmic pharmaceutical composition of claim 1 , wherein the ophthalmic pharmaceutical composition is stored in a polyolefin container.