Methods for treating eye diseases

Abstract

This article describes methods and pharmaceutical preparations for treating eye conditions.

Description

[0001] This application is a divisional application of Chinese patent application No. 201580067940.5, filed on October 19, 2015, entitled "Method for Treating Eye Diseases".

[0002] Cross-references

[0003] This application claims the benefits of U.S. Provisional Application No. 62 / 066,280, filed October 20, 2014, and U.S. Provisional Application No. 62 / 100,844, filed January 7, 2015, both of which are incorporated herein by reference in their entirety. Background of the Invention

[0004] Dry eye disease (“DED”) is a condition affecting millions of people worldwide. In North America, approximately 40 million people suffer from some form of dry eye, and millions more worldwide. DED is caused by the disruption of the natural tear film on the surface of the eye and can lead to eye discomfort, visual impairment, and a decline in vision-related quality of life. Individuals with severe DED are at risk of serious eye health defects such as corneal ulcers and may experience quality of life deficits comparable to moderate to severe angina. Invention Summary

[0005] In some embodiments, a method for increasing tear production is provided herein, comprising topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors. In some embodiments, a method for increasing tear production comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method for increasing tear production comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from α3β4, α4β2, and α7. In some embodiments, a method for increasing tear production comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount not systemically bioavailable. In some embodiments, a method for increasing tear production includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for increasing tear production includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects.

[0006] In some embodiments, a method for increasing tear production is provided herein, comprising topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method for increasing tear production comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from α3β4, α4β2, and α7. In some embodiments, a method for increasing tear production comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount not systemically bioavailable. In some embodiments, a method for increasing tear production includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for increasing tear production includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects.

[0007] In some embodiments, a method for treating dry eye is also provided herein, comprising topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors. In some embodiments, a method for treating dry eye comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method for treating dry eye comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from α3β4, α4β2, and α7. In some embodiments, a method for treating dry eye comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount not systemically bioavailable. In some embodiments, a method for treating dry eye includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for treating dry eye includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects.

[0008] In some embodiments, a method for treating dry eye is also provided herein, comprising topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method for treating dry eye comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from α3β4, α4β2, and α7. In some embodiments, a method for treating dry eye comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount not systemically bioavailable. In some embodiments, a method for treating dry eye includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for treating dry eye includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects.

[0009] In some embodiments, a method for improving ocular discomfort is also provided herein, comprising topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors. In some embodiments, a method for improving ocular discomfort comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method for improving ocular discomfort comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from α3β4, α4β2, and α7. In some embodiments, a method for improving ocular discomfort comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount not systemically bioavailable. In some embodiments, a method for improving eye discomfort includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for improving eye discomfort includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects.

[0010] In some embodiments, a method for improving ocular discomfort is also provided herein, comprising topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method for improving ocular discomfort comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from α3β4, α4β2, and α7. In some embodiments, a method for improving ocular discomfort comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount not systemically bioavailable. In some embodiments, a method for improving eye discomfort includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for improving eye discomfort includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects.

[0011] In some embodiments, a method for improving ocular surface health is also provided herein, comprising topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method for improving ocular surface health comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from α3β4, α4β2, and α7. In some embodiments, a method for improving ocular surface health comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount not systemically bioavailable. In some embodiments, a method for improving ocular surface health includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for improving ocular surface health includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects.

[0012] In some embodiments, a method for protecting the ocular surface during challenging environmental conditions is also provided herein, comprising topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from α3β4, α4β2, and α7. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount not systemically bioavailable. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychiatric side effects. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects.

[0013] In some embodiments, a method for increasing mucin content on the ocular surface is also provided herein, comprising topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method for increasing mucin content on the ocular surface includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from α3β4, α4β2, and α7. In some embodiments, a method for increasing mucin content on the ocular surface includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount not systemically bioavailable. In some embodiments, a method for increasing the mucin content on the ocular surface includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for increasing the mucin content on the ocular surface includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects.

[0014] In some embodiments, a method for increasing the amount or concentration of one or more tear proteins on the ocular surface is also provided herein, comprising topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins on the ocular surface includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from α3β4, α4β2, and α7. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins on the ocular surface includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount that is not systemically bioavailable. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins on the ocular surface includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, the tear protein is epidermal growth factor, lactoferrin, lacrimal protein, prolactin, adrenocorticotropic hormone, leucine enkephalin, ALS2CL, ARHGEF19, KIAA1109, PLXNA1, POLG, WIPI1, ZMIZ2, or other proteins of the tear proteome.

[0015] In some embodiments, a method for improving tear clearance is also provided herein, comprising topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method for improving tear clearance comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from α3β4, α4β2, and α7. In some embodiments, a method for improving tear clearance comprises topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount not systemically bioavailable. In some embodiments, a method for improving tear clearance includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychiatric side effects. In some embodiments, a method for improving tear clearance includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects.

[0016] In another embodiment of any of the above embodiments, the method further includes the topical application of one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. In another embodiment of any of the above embodiments, the method further includes the topical application of one or more substances that prevent or reduce the entry of nicotinic acetylcholine receptors into a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. In some embodiments, the one or more substances are selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase A (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus.

[0017] In another embodiment of any of the above embodiments, the nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, scutellarin, varenclin, tebuclam, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380.

[0018] In another embodiment of any of the above embodiments, the nicotinic acetylcholine receptor agonist is a compound selected from those disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011 or WO 2010 / 028033, each of which is incorporated herein by reference.

[0019] In another embodiment of any of the above embodiments, at least 1 microgram of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments, at least 5 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments, at least 10 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments, at least 25 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments, at least 50 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments, at least 100 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments, at least 250 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments, at least 500 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity.

[0020] In another embodiment of any of the above embodiments, the nicotinic acetylcholine receptor agonist is administered at least once daily. In another embodiment of any of the above embodiments, the nicotinic acetylcholine receptor agonist is administered at least twice daily. In another embodiment of any of the above embodiments, the nicotinic acetylcholine receptor agonist is administered for at least two days.

[0021] In another embodiment of any of the above embodiments, the nicotinic acetylcholine receptor agonist is administered when needed. In another embodiment of any of the above embodiments, the nicotinic acetylcholine receptor agonist is administered in response to symptoms when needed. In another embodiment of any of the above embodiments, the timing or frequency of administration of the nicotinic acetylcholine receptor agonist is designed or adjusted to prevent desensitization of the nicotinic acetylcholine receptors.

[0022] In another embodiment of any of the above embodiments, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. In another embodiment of any of the above embodiments, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity via a syringe, dropper, bottle-type nebulizer, nebulizer pump, inhaler, powder sprayer, vaporizer, patch, applicator stick, pipette, or liquid injector.

[0023] In another embodiment of any of the above embodiments, the trigeminal nerve is activated. In yet another embodiment, the anterior ethmoidal nerve is activated.

[0024] In another embodiment of any of the above embodiments, the nasolacrimal reflex is activated.

[0025] In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity is also provided, comprising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects. In some embodiments, the pharmaceutical formulation further comprises one or more substances selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase A (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, the nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, scutellarin, varencrine, tebuclam, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In some embodiments, the nicotinic acetylcholine receptor agonist is selected from the compounds disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011, or WO2010 / 028033. In some embodiments, the nicotinic acetylcholine receptor agonist selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from α3β4, α4β2, and α7. In some embodiments, the pharmaceutical formulation comprises about 1 mg / mL of the nicotinic acetylcholine receptor agonist. In some embodiments, the pharmaceutical formulation comprises about 10 mg / mL of the nicotinic acetylcholine receptor agonist. In some embodiments, the pharmaceutical formulation comprises at least 1 microgram of the nicotinic acetylcholine receptor agonist per dose. In some embodiments, the pharmaceutical formulation comprises at least 5 micrograms of the nicotinic acetylcholine receptor agonist per dose. In some embodiments, the pharmaceutical formulation comprises at least 10 micrograms of the nicotinic acetylcholine receptor agonist per dose. In some embodiments, the pharmaceutical formulation comprises at least 25 micrograms of the nicotinic acetylcholine receptor agonist per dose. In some embodiments, the pharmaceutical formulation comprises at least 50 micrograms of the nicotinic acetylcholine receptor agonist per dose. In some embodiments, the pharmaceutical formulation comprises at least 100 micrograms of the nicotinic acetylcholine receptor agonist per dose.In some embodiments, the pharmaceutical preparation comprises at least 250 micrograms of the nicotinic acetylcholine receptor agonist per dose. In some embodiments, the pharmaceutical preparation comprises at least 500 micrograms of the nicotinic acetylcholine receptor agonist per dose. In some embodiments, the pharmaceutical preparation comprises between 5 micrograms and 1 gram of the nicotinic acetylcholine receptor agonist per dose. In some embodiments, the pharmaceutical preparation is administered at least once daily. In some embodiments, the pharmaceutical preparation is administered at least twice daily. In some embodiments, the pharmaceutical preparation is administered for at least two days. In some embodiments, the pharmaceutical preparation is applied to the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. In some embodiments, the pharmaceutical preparation is administered to the nasal cavity by a syringe, dropper, bottle nebulizer, nebulizer pump, inhaler, powder sprayer, vaporizer, patch, applicator stick, pipette, or liquid jet injector. Brief description of the attached diagram

[0026] Figure 1 The tear production of patients receiving OC-01 was shown compared with baseline and placebo.

[0027] Figure 2 The study described patient-reported dry eye symptoms in patients receiving OC-01 compared to patients receiving a placebo.

[0028] Figure 3 It is the Visual Analogue Scale (VAS), which also includes the following description: "There are many symptoms of dry eye, including dryness, stickiness, burning, foreign body sensation, itching, blurred vision, light sensitivity, and pain. Please rate the severity of your current 'dryness' symptoms (not others) by drawing a vertical line on the lines below." Invention Details

[0029] Our understanding of the etiology of DED is becoming increasingly clear. DED is inherently progressive and is primarily caused by insufficient tear coverage on the ocular surface. This poor tear coverage hinders healthy gas exchange and nutrient transport on the ocular surface, promotes cell desiccation, and causes poor visual refractive surfaces. Poor tear coverage is typically caused by: 1) insufficient production of aqueous tears by the lacrimal glands (e.g., secondary to postmenopausal hormone deficiency, autoimmune diseases, LASIK surgery, etc.); and / or 2) excessive evaporation of aqueous tears due to meibomian gland dysfunction. Low tear volume creates a high osmotic pressure environment, thereby inducing an inflammatory state on the ocular surface. This inflammatory response induces apoptosis of surface cells, which in turn hinders the proper distribution of the tear film on the ocular surface, making any provided tear volume less effective. This triggers a vicious cycle in which greater inflammation can subsequently lead to greater damage to surface cells, etc. In addition, because sensory neurons on the ocular surface are damaged, the neural control loop that controls the activation of reflexive tears is disrupted. Therefore, less tears are secreted, and a second vicious cycle occurs that leads to further progression of the disease (less tears lead to nerve cell loss, which in turn leads to less tears, etc.).

[0030] Various treatments exist for DED; however, none offer substantial efficacy in treating the aforementioned symptoms. Treatment options include artificial tear substitutes, ointments, gels, warm compresses, environmental modifications, topical cyclosporine, omega-3 fatty acid supplements, lacrimal duct plugs, and moisture chamber lenses. Patients with severe disease may require further treatment with lacrimal duct cauterization, systemic cholinergic agonists, systemic anti-inflammatory agents, mucolytics, autologous serum tears, PROSE scleral contact lenses, and eyelid margin sutures. Despite these treatment options, DED remains one of the worst-treated ophthalmic diseases. Therefore, a more effective dry eye treatment will be needed.

[0031] Nicotinic acetylcholine receptors are cholinergic receptors found in the central nervous system (CNS), peripheral nervous system (PNS), and skeletal muscle. These receptors are ligand-gated ion channels with binding sites for acetylcholine and other molecules. When a nicotinic acetylcholine receptor agonist binds to the receptor, it stabilizes the ion channel's open state, allowing the influx of cations such as potassium, calcium, and sodium ions.

[0032] Systemic nicotinic acetylcholine receptor agonists, acting on the central nervous system, have attracted attention as drug candidates for a variety of conditions, such as Alzheimer's disease, Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder (ADHD), and nicotine addiction. However, systemic exposure to these central nervous system agents is associated with a number of unwanted psychological side effects, including anxiety, depression, and irritability.

[0033] This document describes methods for treating ocular conditions and / or improving ocular surface health, comprising the topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors. In some embodiments, the nicotinic acetylcholine receptor agonist binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, the nicotinic acetylcholine receptor agonist binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations and is administered at an amount that is not systemically bioavailable. In some embodiments, the nicotinic acetylcholine receptor agonist binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations and is administered at an amount that does not cause unwanted psychiatric side effects. In some embodiments, the nicotinic acetylcholine receptor agonist binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations and is administered at an amount that does not cause unwanted systemic side effects.

[0034] Prolonged or repeated exposure to stimuli often leads to a decrease in the responsiveness of the receptors to those stimuli, a phenomenon known as desensitization. It has been reported that prolonged exposure of nicotinic acetylcholine receptors to agonists can cause agonist-induced conformational changes in the receptors, resulting in receptor desensitization.

[0035] This document describes methods for treating ocular conditions and / or improving ocular surface health, comprising topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors, and further comprising topically administering one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. In some embodiments, the one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state are selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase A (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors.

[0036] This article also describes pharmaceutical formulations for topical application to an individual's nasal cavity, comprising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization. This article also describes pharmaceutical formulations for topical application to an individual's nasal cavity, further comprising one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. This article also describes pharmaceutical formulations for topical application to an individual's nasal cavity, further comprising one or more substances that prevent or reduce the entry of nicotinic acetylcholine receptors into a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. This article also describes pharmaceutical formulations for topical application to an individual's nasal cavity, further comprising one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, wherein said one or more substances are selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. This article also describes pharmaceutical formulations for topical application to an individual's nasal cavity, which further comprise one or more substances that prevent or reduce nicotinic acetylcholine receptors from entering a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, wherein said one or more substances are selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors.

[0037] Increase tear production

[0038] In some embodiments, this document provides a method for increasing tear production in a subject. One embodiment of the method for increasing tear production includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. Another embodiment of the method for increasing tear production includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from α3β4, α4β2, and α7. Yet another embodiment of the method for increasing tear production includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to the peripheral nicotinic acetylcholine receptor subtype α3β4. In some embodiments, a method for increasing tear production includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to peripheral nicotinic acetylcholine receptor subtype α4β2. In some embodiments, a method for increasing tear production includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to peripheral nicotinic acetylcholine receptor subtype α7. In some embodiments, a method for increasing tear production includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount that is not systemically bioavailable. In some embodiments, a method for increasing tear production includes topically applying a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for increasing tear production includes topically applying a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects. In some embodiments, a method for increasing tear production further includes topically applying one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state.In some implementations, this is a method for increasing tear production, which also includes the topical application of one or more substances that prevent or reduce nicotinic acetylcholine receptors from entering a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state.

[0039] In some embodiments, a method for increasing tear production further includes the topical application of one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for increasing tear production further includes the topical application of one or more substances that prevent or reduce nicotinic acetylcholine receptor entry into a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for increasing tear production further includes the topical application of protein kinase C (PKC) or factors that upregulate or upregulate PKC. In some embodiments, a method for increasing tear production further includes the topical application of cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA. In some embodiments, a method for increasing tear production further includes the topical application of a calcineurin inhibitor. In some embodiments, a method for increasing tear production further includes the topical application of a calcineurin inhibitor, wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for increasing tear production further includes the topical application of cyclosporine. In some embodiments, a method for increasing tear production further includes the topical application of pimecrolimus. In some embodiments, a method for increasing tear production further includes the topical application of tacrolimus.

[0040] In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, cytisine, varencrine, tebuclam, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is nicotine. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is varencrine. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is tebuconazole. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is DBO-83. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is CC4. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is ABT-418. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is ABT-366833. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is ABT-202. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is ABT-894. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is SIB-1663. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is GTS-21. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is PHA-543613. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is PNU-282987. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is LY-2087101.In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is A85380. In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is 5-I-A85380.

[0041] In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is a compound selected from those disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011 or WO 2010 / 028033.

[0042] In another embodiment of any of the above-described embodiments for increasing tear production, at least 1 microgram of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for increasing tear production, at least 5 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for increasing tear production, at least 10 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for increasing tear production, at least 25 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for increasing tear production, at least 50 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for increasing tear production, at least 100 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for increasing tear production, at least 250 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for increasing tear production, at least 500 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for increasing tear production, at least 750 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for increasing tear production, at least 1000 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for increasing tear production, between 1 microgram and 1000 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for increasing tear production, between 5 micrograms and 100 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 5 and 50 micrograms. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 10 and 50 micrograms. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 25 and 1000 micrograms.In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 50 micrograms and 1000 micrograms. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 100 micrograms and 1000 micrograms. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 100 micrograms and 750 micrograms. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 150 micrograms and 750 micrograms. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 150 micrograms and 600 micrograms.

[0043] In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered once daily. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered at least once daily. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered twice daily. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered at least twice daily. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered three times daily. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered at least three times daily. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered for one day. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered for at least two days. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered for at least three days. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered for at least four days. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered for at least five days. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered for at least seven days. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered for at least ten days. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered for at least fourteen days. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered for at least twenty-one days. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered for at least thirty days.

[0044] In another embodiment of any of the above embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into alternating nostrils.

[0045] In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a suspension. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an aerosol. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a gel. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an ointment. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a dry powder. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a cream. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a paste. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a wash. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a balm.

[0046] In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe, dropper, bottle nebulizer, nebulizer pump, inhaler, powder sprayer, vaporizer, patch, applicator stick, pipette, or liquid jet injector. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a dropper. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a bottle nebulizer. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer pump. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via an inhaler. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a powder spray device. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a vaporizer. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a patch. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nasal cannula. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a pipette. In another embodiment of any of the above-described embodiments for increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a liquid sprayer.

[0047] In another embodiment of any of the above embodiments for increasing tear production, the trigeminal nerve is activated. In another embodiment for increasing tear production, the anterior ethmoidal nerve is activated. In another embodiment of any of the above embodiments for increasing tear production, the nasolacrimal reflex is activated.

[0048] Treatment of dry eye

[0049] In some embodiments, this document provides a method for treating dry eye in a subject. In some embodiments, a method for treating dry eye includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method for treating dry eye includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from α3β4, α4β2, and α7. In some embodiments, a method for treating dry eye includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to the peripheral nicotinic acetylcholine receptor subtype α3β4. In some embodiments, a method for treating dry eye includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to peripheral nicotinic acetylcholine receptor subtype α4β2. In some embodiments, a method for treating dry eye includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to peripheral nicotinic acetylcholine receptor subtype α7. In some embodiments, a method for treating dry eye includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount that is not systemically bioavailable. In some embodiments, a method for treating dry eye includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for treating dry eye includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects. In some embodiments, a method for treating dry eye further includes topically administering one or more substances that prevent or reduce nicotinic acetylcholine receptor entry into a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. In some embodiments, a method for treating dry eye further includes topically administering one or more substances that prevent or reduce nicotinic acetylcholine receptor entry into a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state.In some embodiments, a method for treating dry eye further includes the topical application of one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for treating dry eye further includes the topical application of one or more substances that prevent or reduce nicotinic acetylcholine receptor entry into a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for treating dry eye further includes the topical application of protein kinase C (PKC) or factors that upregulate or upregulate PKC. In some embodiments, a method for treating dry eye further includes the topical application of cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA. In some embodiments, a method for treating dry eye further includes the topical application of a calcineurin inhibitor. In some embodiments, a method for treating dry eye further includes the topical application of a calcineurin inhibitor, wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for treating dry eye further includes the topical application of cyclosporine. In some embodiments, a method for treating dry eye further includes the topical application of pimecrolimus. In some embodiments, a method for treating dry eye further includes the topical application of tacrolimus.

[0050] In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, cytisine, varencrine, tebuclam, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is nicotine. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is varencrine. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is tebuconazole. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is DBO-83. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is CC4. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is ABT-418. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is ABT-366833. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is ABT-202. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is ABT-894. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is SIB-1663. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is GTS-21. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is PHA-543613. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is PNU-282987. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is LY-2087101. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is A85380.In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is 5-I-A85380.

[0051] In another embodiment of any of the above embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is a compound selected from those disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011 or WO 2010 / 028033.

[0052] In another embodiment of any of the above-described embodiments for treating dry eye, at least 1 microgram of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for treating dry eye, at least 5 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for treating dry eye, at least 10 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for treating dry eye, at least 25 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for treating dry eye, at least 50 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for treating dry eye, at least 100 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for treating dry eye, at least 250 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for treating dry eye, at least 500 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for treating dry eye, at least 750 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for treating dry eye, at least 1000 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for treating dry eye, between 1 microgram and 1000 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for treating dry eye, between 5 micrograms and 100 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 5 and 50 micrograms. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 10 and 50 micrograms. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 25 and 1000 micrograms. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 50 and 1000 micrograms.In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 100 micrograms and 1000 micrograms. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 100 micrograms and 750 micrograms. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 150 micrograms and 750 micrograms. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 150 micrograms and 600 micrograms.

[0053] In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered once daily. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered at least once daily. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered twice daily. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered at least twice daily. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered three times daily. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered at least three times daily. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered for one day. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered for at least two days. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered for at least three days. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered for at least four days. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered for at least five days. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered for at least seven days. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered for at least ten days. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered for at least fourteen days. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered for at least twenty-one days. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered for at least thirty days.

[0054] In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into alternating nostrils.

[0055] In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a suspension. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an aerosol. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a gel. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an ointment. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a dry powder. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a cream. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a paste. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a lotion. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a balm.

[0056] In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe, dropper, nebulizer, nebulizer pump, inhaler, powder sprayer, vaporizer, patch, applicator stick, pipette, or liquid jet injector. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a dropper. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer pump. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via an inhaler. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a powder spray device. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a vaporizer. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a patch. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via an applicator. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a pipette. In another embodiment of any of the above-described embodiments for treating dry eye, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a liquid jet injector.

[0057] In another embodiment of any of the above-described embodiments for treating dry eye, the trigeminal nerve is activated. In another embodiment of treating dry eye, the anterior ethmoidal nerve is activated. In another embodiment of any of the above-described embodiments for treating dry eye, the nasolacrimal reflex is activated.

[0058] Improve eye discomfort

[0059] In some embodiments, this document provides a method for improving ocular discomfort in a subject. One embodiment of a method for improving ocular discomfort includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. Another embodiment of a method for improving ocular discomfort includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from α3β4, α4β2, and α7. Yet another embodiment of a method for improving ocular discomfort includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to the peripheral nicotinic acetylcholine receptor subtype α3β4. In some embodiments, methods for improving ocular discomfort include topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to peripheral nicotinic acetylcholine receptor subtype α4β2. In some embodiments, methods for improving ocular discomfort include topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to peripheral nicotinic acetylcholine receptor subtype α7. In some embodiments, methods for improving ocular discomfort include topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount that is not systemically bioavailable. In some embodiments, a method for improving eye discomfort includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for improving eye discomfort includes topically administering one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state.In some embodiments, a method for improving eye discomfort further includes the topical application of one or more substances that prevent or reduce nicotinic acetylcholine receptors from entering a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. In some embodiments, a method for improving eye discomfort further includes the topical application of one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for improving eye discomfort further includes the topical application of one or more substances that prevent or reduce nicotinic acetylcholine receptors from entering a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for improving ocular discomfort further includes topical application of protein kinase C (PKC) or factors that upregulate or upregulate PKC. In some embodiments, a method for improving ocular discomfort further includes topical application of cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA. In some embodiments, a method for improving ocular discomfort further includes topical application of a calcineurin inhibitor. In some embodiments, a method for improving ocular discomfort further includes topical application of a calcineurin inhibitor, wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for improving ocular discomfort further includes topical application of cyclosporine. In some embodiments, a method for improving ocular discomfort further includes topical application of pimecrolimus. In some embodiments, a method for improving ocular discomfort further includes topical application of tacrolimus.

[0060] In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, cytisine, varencrine, tebuclam, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is nicotine. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is varencrine. In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is tebuconazole. In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is DBO-83. In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is CC4. In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is ABT-418. In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is ABT-366833. In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is ABT-202. In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is ABT-894. In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is SIB-1663. In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is GTS-21. In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is PHA-543613. In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is PNU-282987. In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is LY-2087101.In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is A85380. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is 5-I-A85380.

[0061] In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is a compound selected from those disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011 or WO 2010 / 028033.

[0062] In another embodiment of any of the above embodiments for improving eye discomfort, the eye discomfort is associated with dry eye disease. In another embodiment of any of the above embodiments for improving eye discomfort, the eye discomfort is associated with symptoms of dry eye disease. In another embodiment of any of the above embodiments for improving eye discomfort, the eye discomfort is associated with symptoms of dry eye disease; wherein the symptoms are selected from itching, dryness, photophobia, blurred vision, pain, stickiness, burning, stinging, and foreign body sensation.

[0063] In another embodiment of any of the above-described embodiments for improving eye discomfort, the eye discomfort is associated with blepharitis. In another embodiment of any of the above-described embodiments for improving eye discomfort, the eye discomfort is associated with meibomian gland dysfunction. In another embodiment of any of the above-described embodiments for improving eye discomfort, the eye discomfort is associated with allergic conjunctivitis. In another embodiment of any of the above-described embodiments for improving eye discomfort, the eye discomfort is associated with ocular surface poisoning and irritation. In another embodiment of any of the above-described embodiments for improving eye discomfort, the eye discomfort is associated with tear drainage problems. In another embodiment of any of the above-described embodiments for improving eye discomfort, the eye discomfort is associated with eyelid conditions.

[0064] In another embodiment of any of the above-described embodiments for improving eye discomfort, at least 1 microgram of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving eye discomfort, at least 5 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving eye discomfort, at least 10 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving eye discomfort, at least 25 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving eye discomfort, at least 50 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving eye discomfort, at least 100 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving eye discomfort, at least 250 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving eye discomfort, at least 500 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving eye discomfort, at least 750 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving eye discomfort, at least 1000 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving eye discomfort, between 1 microgram and 1000 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving eye discomfort, between 5 micrograms and 100 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 5 and 50 micrograms. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 10 and 50 micrograms. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 25 and 1000 micrograms.In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 50 micrograms and 1000 micrograms. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 100 micrograms and 1000 micrograms. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 100 micrograms and 750 micrograms. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 150 micrograms and 750 micrograms. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 150 micrograms and 600 micrograms.

[0065] In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered once daily. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered at least once daily. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered twice daily. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered at least twice daily. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered three times daily. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered at least three times daily. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered for one day. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered for at least two days. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered for at least three days. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered for at least four days. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered for at least five days. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered for at least seven days. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered for at least ten days. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered for at least fourteen days. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered for at least twenty-one days. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered for at least thirty days.

[0066] In another embodiment of any of the above embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into alternating nostrils.

[0067] In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a suspension. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an aerosol. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a gel. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an ointment. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a dry powder. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a cream. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a paste. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a lotion. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a balm.

[0068] In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe, dropper, bottle nebulizer, nebulizer pump, inhaler, powder sprayer, vaporizer, patch, applicator stick, pipette, or liquid jet injector. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a dropper. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a bottle nebulizer. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer pump. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via an inhaler. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a powder spray device. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a vaporizer. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a patch. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a swab. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a pipette. In another embodiment of any of the above-described embodiments for improving eye discomfort, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a liquid injector.

[0069] In another embodiment of any of the above embodiments for improving eye discomfort, the trigeminal nerve is activated. In another embodiment for improving eye discomfort, the anterior ethmoidal nerve is activated. In another embodiment of any of the above embodiments for improving eye discomfort, the nasolacrimal reflex is activated.

[0070] Improve ocular surface health

[0071] In some embodiments, this document provides a method for improving ocular surface health in a subject. One embodiment of a method for improving ocular surface health includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. Another embodiment of a method for improving ocular surface health includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from α3β4, α4β2, and α7. A third embodiment of a method for improving ocular surface health includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to the peripheral nicotinic acetylcholine receptor subtype α3β4. In some embodiments, methods for improving ocular surface health include the topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to peripheral nicotinic acetylcholine receptor subtype α4β2. In some embodiments, methods for improving ocular surface health include the topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to peripheral nicotinic acetylcholine receptor subtype α7. In some embodiments, methods for improving ocular surface health include the topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount that is not systemically bioavailable. In some embodiments, a method for improving ocular surface health includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for improving ocular surface health includes topically administering one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state.In some embodiments, a method for improving ocular surface health further includes the topical application of one or more substances that prevent or reduce nicotinic acetylcholine receptor entry into a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. In some embodiments, a method for improving ocular surface health further includes the topical application of one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for improving ocular surface health further includes the topical application of one or more substances that prevent or reduce nicotinic acetylcholine receptor entry into a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for improving ocular surface health further includes the topical application of protein kinase C (PKC) or factors that upregulate or upregulate PKC. In some embodiments, a method for improving ocular surface health further includes the topical application of cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA. In some embodiments, a method for improving ocular surface health further includes the topical application of a calcineurin inhibitor. In some embodiments, a method for improving ocular surface health further includes the topical application of a calcineurin inhibitor, wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for improving ocular surface health further includes the topical application of cyclosporine. In some embodiments, a method for improving ocular surface health further includes the topical application of pimecrolimus. In some embodiments, a method for improving ocular surface health further includes the topical application of tacrolimus.

[0072] In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, cytisine, varencrine, tebuclam, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is nicotine. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is varencrine. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is tebuconazole. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is DBO-83. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is CC4. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is ABT-418. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is ABT-366833. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is ABT-202. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is ABT-894. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is SIB-1663. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is GTS-21. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is PHA-543613. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is PNU-282987. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is LY-2087101.In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is A85380. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is 5-I-A85380.

[0073] In another embodiment of any of the above embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is a compound selected from those disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011 or WO 2010 / 028033.

[0074] In another embodiment of any of the above-described embodiments for improving ocular surface health, at least 1 microgram of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving ocular surface health, at least 5 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving ocular surface health, at least 10 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving ocular surface health, at least 25 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving ocular surface health, at least 50 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving ocular surface health, at least 100 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving ocular surface health, at least 250 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving ocular surface health, at least 500 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving ocular surface health, at least 750 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving ocular surface health, at least 1000 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving ocular surface health, between 1 microgram and 1000 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving ocular surface health, between 5 micrograms and 1000 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 5 and 50 micrograms. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 10 and 50 micrograms. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 25 and 1000 micrograms.In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 50 μg and 1000 μg. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 100 μg and 1000 μg. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 100 μg and 750 μg. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 150 μg and 750 μg. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 150 μg and 600 μg.

[0075] In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered once daily. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered at least once daily. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered twice daily. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered at least twice daily. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered three times daily. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered at least three times daily. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered for one day. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered for at least two days. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered for at least three days. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered for at least four days. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered for at least five days. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered for at least seven days. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered for at least ten days. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered for at least fourteen days. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered for at least twenty-one days. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered for at least thirty days.

[0076] In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered into alternating nostrils.

[0077] In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a suspension. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an aerosol. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a gel. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an ointment. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a dry powder. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a cream. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a paste. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a lotion. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a balm.

[0078] In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe, dropper, bottle nebulizer, nebulizer pump, inhaler, powder sprayer, vaporizer, patch, applicator stick, pipette, or liquid injector. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a dropper. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a bottle nebulizer. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer pump. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via an inhaler. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a powder spray device. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a vaporizer. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a patch. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a swab. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a pipette. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a liquid injector.

[0079] In another embodiment of any of the above-described embodiments for improving ocular surface health, the trigeminal nerve is activated. In another embodiment of improving ocular surface health, the anterior ethmoidal nerve is activated. In another embodiment of any of the above-described embodiments for improving ocular surface health, the nasolacrimal reflex is activated.

[0080] Protect the ocular surface during challenging environmental conditions.

[0081] In some embodiments, this document provides a method for protecting the ocular surface of a subject during challenging environmental conditions. One embodiment of this method includes the topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. Another embodiment of this method includes the topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from α3β4, α4β2, and α7. Finally, another embodiment of this method includes the topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to the peripheral nicotinic acetylcholine receptor subtype α3β4. In some embodiments, methods for protecting the ocular surface during challenging environmental conditions include the topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to peripheral nicotinic acetylcholine receptor subtype α4β2. In some embodiments, methods for protecting the ocular surface during challenging environmental conditions include the topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to peripheral nicotinic acetylcholine receptor subtype α7. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions includes the topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount that is not systemically bioavailable. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychiatric side effects. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects.In some embodiments, a method for protecting the ocular surface during challenging environmental conditions is provided, the method further comprising the topical application of one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions is provided, the method further comprising the topical application of one or more substances that prevent or reduce the entry of nicotinic acetylcholine receptors into a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions is provided, further comprising the topical application of one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions further includes the topical application of one or more substances that prevent or reduce nicotinic acetylcholine receptors from entering a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. The substances are selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions further includes the topical application of protein kinase C (PKC) or factors that upregulate or upregulate PKC. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions further includes the topical application of cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions further includes the topical application of calcineurin inhibitors. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions further includes the topical application of a calcineurin inhibitor, wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions further includes the topical application of cyclosporine. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions further includes the topical application of pimecrolimus. In some embodiments, a method for protecting the ocular surface during challenging environmental conditions further includes the topical application of tacrolimus.

[0082] In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, cytisine, varencrine, tebuclam, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is nicotine. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is scutellarin. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is varencrine. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is tebuconazole. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is DBO-83. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is CC4. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is ABT-418. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is ABT-366833. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is ABT-202. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is ABT-894. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is SIB-1663. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is GTS-21. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is PHA-543613.In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is PNU-282987. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is LY-2087101. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is A85380. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is 5-I-A85380.

[0083] In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is a compound selected from those disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011 or WO 2010 / 028033.

[0084] In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, at least 1 microgram of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, at least 5 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, at least 10 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, at least 25 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, at least 50 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, at least 100 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, at least 250 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, at least 500 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, at least 750 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, at least 1000 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, between 1 microgram and 1000 micrograms of the nicotinic acetylcholine receptor agonist are administered into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 5 micrograms and 1000 micrograms. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 5 micrograms and 100 micrograms. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 5 micrograms and 50 micrograms.In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered in amounts between 10 and 50 micrograms into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered in amounts between 25 and 1000 micrograms into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered in amounts between 50 and 1000 micrograms into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered in amounts between 100 and 1000 micrograms into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered in amounts between 100 and 750 micrograms into the nasal cavity. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 150 and 750 micrograms. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered intranasally in amounts between 150 and 600 micrograms.

[0085] In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered once daily. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered at least once daily. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered twice daily. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered at least twice daily. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered three times daily. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered at least three times daily. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered once daily. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered for at least two days. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered for at least three days. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered for at least four days. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered for at least five days. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered for at least seven days. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered for at least ten days. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered for at least fourteen days. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered for at least twenty-one days. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered for at least thirty days.

[0086] In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered into alternating nostrils.

[0087] In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a suspension. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an aerosol. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a gel. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an ointment. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a dry powder. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a cream. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a paste. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a lotion. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a balm.

[0088] In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe, dropper, nebulizer, nebulizer pump, inhaler, powder sprayer, vaporizer, patch, applicator stick, pipette, or liquid injector. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a dropper. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer pump. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via an inhaler. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a powder sprayer. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a vaporizer. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a patch. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nasal applicator. In another embodiment of any of the above-described embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a pipette. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a liquid injector.

[0089] In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the trigeminal nerve is activated. In another embodiment of protecting the ocular surface during challenging environmental conditions, the anterior ethmoidal nerve is activated. In another embodiment of any of the above embodiments for protecting the ocular surface during challenging environmental conditions, the nasolacrimal reflex is activated.

[0090] Increase the amount of mucin on the surface of the eye

[0091] In some embodiments, this document provides a method for increasing the amount of mucin on the ocular surface of a subject. One embodiment of this method involves topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. Another embodiment of this method involves topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from α3β4, α4β2, and α7. A third embodiment of this method involves topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to the peripheral nicotinic acetylcholine receptor subtype α3β4. In some embodiments, a method for increasing mucin content on the ocular surface includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to peripheral nicotinic acetylcholine receptor subtype α4β2. In some embodiments, a method for increasing mucin content on the ocular surface includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to peripheral nicotinic acetylcholine receptor subtype α7. In some embodiments, a method for increasing mucin content on the ocular surface includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount that is not systemically bioavailable. In some embodiments, a method for increasing the mucin content on the ocular surface includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for increasing the mucin content on the ocular surface includes topically administering one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state.In some embodiments, a method for increasing the content of mucin on the ocular surface is included, the method further comprising the topical application of one or more substances that prevent or reduce nicotinic acetylcholine receptors from entering a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. In some embodiments, a method for increasing the content of mucin on the ocular surface is included, further comprising the topical application of one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for increasing the content of mucin on the ocular surface is included, the method further comprising the topical application of one or more substances that prevent or reduce nicotinic acetylcholine receptors from entering a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for increasing the mucin content on the ocular surface further includes the topical application of protein kinase C (PKC) or a factor that upregulates or upregulates PKC. In some embodiments, a method for increasing the mucin content on the ocular surface further includes the topical application of cAMP-dependent protein kinase (PKA) or a factor that upregulates or upregulates PKA. In some embodiments, a method for increasing the mucin content on the ocular surface further includes the topical application of a calcineurin inhibitor. In some embodiments, a method for increasing the mucin content on the ocular surface further includes the topical application of a calcineurin inhibitor, wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for increasing the mucin content on the ocular surface further includes the topical application of cyclosporine. In some embodiments, a method for increasing the mucin content on the ocular surface further includes the topical application of pimecrolimus. In some embodiments, a method for increasing the mucin content on the ocular surface further includes the topical application of tacrolimus.

[0092] In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, cytisine, varencrine, tebuclam, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is nicotine. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is varencrine. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is tebuconazole. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is DBO-83. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is CC4. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is ABT-418. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is ABT-366833. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is ABT-202. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is ABT-894. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is SIB-1663. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is GTS-21. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is PHA-543613.In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is PNU-282987. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is LY-2087101. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is A85380. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is 5-I-A85380.

[0093] In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is a compound selected from those disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011 or WO 2010 / 028033.

[0094] In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, at least 1 microgram of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, at least 5 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, at least 10 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, at least 25 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, at least 50 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, at least 100 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, at least 250 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, at least 500 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, at least 750 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, at least 1000 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, between 1 microgram and 1000 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, between 5 micrograms and 1000 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 5 and 100 micrograms. In another embodiment of any of the above-described embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 5 and 50 micrograms. In another embodiment of any of the above-described embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 10 and 50 micrograms.In another embodiment of any of the above-described embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 25 micrograms and 1000 micrograms. In another embodiment of any of the above-described embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 50 micrograms and 1000 micrograms. In another embodiment of any of the above-described embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 100 micrograms and 1000 micrograms. In another embodiment of any of the above-described embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 100 micrograms and 750 micrograms. In another embodiment of any of the above-described embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 150 micrograms and 750 micrograms. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 150 and 600 micrograms.

[0095] In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered once daily. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered at least once daily. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered twice daily. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered at least twice daily. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered three times daily. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered at least three times daily. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered for one day. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered for at least two days. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered for at least three days. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered for at least four days. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered for at least five days. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered for at least seven days. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered for at least ten days. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered for at least fourteen days. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered for at least twenty-one days. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist has been administered for at least thirty days.

[0096] In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into alternating nostrils.

[0097] In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a suspension. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an aerosol. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a gel. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an ointment. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a dry powder. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a cream. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a paste. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a lotion. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a balm.

[0098] In another embodiment of any of the above-described embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe, dropper, nebulizer, nebulizer pump, inhaler, powder sprayer, vaporizer, patch, applicator stick, pipette, or liquid injector. In another embodiment of any of the above-described embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe. In another embodiment of any of the above-described embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a dropper. In another embodiment of any of the above-described embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer. In another embodiment of any of the above-described embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer pump. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via an inhaler. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a powder sprayer. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a vaporizer. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a patch. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nasal applicator. In another embodiment of any of the above embodiments for increasing mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a pipette. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a liquid injector.

[0099] In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the trigeminal nerve is activated. In another embodiment of increasing the mucin content on the ocular surface, the anterior ethmoidal nerve is activated. In another embodiment of any of the above embodiments for increasing the mucin content on the ocular surface, the nasolacrimal reflex is activated.

[0100] Increase the amount or concentration of one or more tear proteins.

[0101] In some embodiments, this document provides a method for increasing the amount or concentration of one or more tear proteins in a subject. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from α3β4, α4β2, and α7. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to the peripheral nicotinic acetylcholine receptor subtype α3β4. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to peripheral nicotinic acetylcholine receptor subtype α4β2. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to peripheral nicotinic acetylcholine receptor subtype α7. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount that is not systemically bioavailable. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects.In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein said tear proteins are epithelial growth factor, lactoferrin, lacrimal protein, prolactin, adrenocorticotropic hormone (ACTH), leucine enkephalin, ALS2CL, ARHGEF19, KIAA1109, PLXNA1, POLG, WIPI1, ZMIZ2, or other proteins of the tear proteome. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein at least one tear protein is epithelial growth factor. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein at least one tear protein is lactoferrin. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein at least one tear protein is lacrimal protein. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein at least one tear protein is prolactin. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein at least one tear protein is ACTH. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein at least one tear protein is leucine enkephalin. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein at least one tear protein is ALS2CL. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein at least one tear protein is ARHGEF19. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein at least one tear protein is KIAA1109. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein at least one tear protein is PLXNA1. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein at least one tear protein is POLG. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein at least one tear protein is WIPI1. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, wherein at least one tear protein is ZMIZ2. In some embodiments, a method is used to increase the amount or concentration of one or more tear proteins, the method further comprising the topical application of one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. In some embodiments, it is a method of increasing the amount or concentration of one or more tear proteins, the method further comprising the local application of one or more substances that prevent or reduce nicotinic acetylcholine receptors from entering a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state.In some embodiments, a method for increasing the amount or concentration of one or more tear proteins further includes the topical application of one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins further includes the topical application of one or more substances that prevent or reduce nicotinic acetylcholine receptor entry into a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins further includes the topical application of protein kinase C (PKC) or factors that upregulate or upregulate PKC. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins further includes the topical application of a cAMP-dependent protein kinase (PKA) or a factor that upregulates or upregulates PKA. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins further includes the topical application of a calcineurin inhibitor. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins further includes the topical application of a calcineurin inhibitor, wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins further includes the topical application of cyclosporine. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins further includes the topical application of pimecrolimus. In some embodiments, a method for increasing the amount or concentration of one or more tear proteins further includes the topical application of tacrolimus.

[0102] In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, cytisine, varencrine, tebuclam, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is nicotine. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is terbinafine. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is varencrine. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is tebuconazole. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is DBO-83. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is CC4. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is ABT-418. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is ABT-366833. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is ABT-202. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is ABT-894. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is SIB-1663. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is GTS-21. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is PHA-543613.In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is PNU-282987. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is LY-2087101. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is A85380. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is 5-I-A85380.

[0103] In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is a compound selected from those disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011 or WO 2010 / 028033.

[0104] In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, at least 1 microgram of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, at least 5 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, at least 10 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, at least 25 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, at least 50 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, at least 100 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, at least 250 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, at least 500 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, at least 750 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, at least 1000 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, between 1 microgram and 1000 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 5 micrograms and 1000 micrograms. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 5 micrograms and 100 micrograms. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 5 micrograms and 50 micrograms.In another embodiment of any of the above-described embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 10 and 50 micrograms. In another embodiment of any of the above-described embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 25 and 1000 micrograms. In another embodiment of any of the above-described embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 50 and 1000 micrograms. In another embodiment of any of the above-described embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 100 and 1000 micrograms. In another embodiment of any of the above-described embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 100 and 750 micrograms. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 150 micrograms and 750 micrograms. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 150 micrograms and 600 micrograms.

[0105] In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered once daily. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered at least once daily. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered twice daily. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered at least twice daily. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered three times daily. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered at least three times daily. In another embodiment of any of the above embodiments of increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered once daily. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered for at least two days. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered for at least three days. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered for at least four days. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered for at least five days. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered for at least seven days. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered for at least ten days. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered for at least fourteen days. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist has been administered for at least twenty-one days. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist has been administered for at least thirty days.

[0106] In another embodiment of any of the above embodiments that increase the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into alternating nostrils.

[0107] In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a suspension. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an aerosol. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a gel. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an ointment. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a dry powder. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a cream. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a paste. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a lotion. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a balm.

[0108] In another embodiment of any of the above-described embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe, dropper, nebulizer, nebulizer pump, inhaler, powder sprayer, vaporizer, patch, applicator stick, pipette, or liquid jet injector. In another embodiment of any of the above-described embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe. In another embodiment of any of the above-described embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a dropper. In another embodiment of any of the above-described embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer. In another embodiment of any of the above-described embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer pump. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via an inhaler. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a powder spray device. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a vaporizer. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a patch. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nasal applicator. In another embodiment of any of the above embodiments for increasing the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a pipette. In another embodiment of any of the above embodiments that increase the amount or concentration of one or more tear proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a liquid injector.

[0109] In another embodiment of any of the above embodiments that increase the amount or concentration of one or more tear proteins, the trigeminal nerve is activated. In another embodiment of any of the above embodiments that increase the amount or concentration of one or more tear proteins, the anterior ethmoidal nerve is activated. In another embodiment of any of the above embodiments that increase the amount or concentration of one or more tear proteins, the nasolacrimal reflex is activated.

[0110] Improve tear clearance

[0111] In some embodiments, this document provides a method for improving tear clearance in a subject. One embodiment of a method for improving tear clearance includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and does not cross the blood-brain barrier at pharmacologically relevant concentrations. Another embodiment of a method for improving tear clearance includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from α3β4, α4β2, and α7. Yet another embodiment of a method for improving tear clearance includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to the peripheral nicotinic acetylcholine receptor subtype α3β4. In some embodiments, methods for improving tear clearance include topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to peripheral nicotinic acetylcholine receptor subtype α4β2. In some embodiments, methods for improving tear clearance include topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist does not cross the blood-brain barrier at pharmacologically relevant concentrations and selectively binds to peripheral nicotinic acetylcholine receptor subtype α7. In some embodiments, methods for improving tear clearance include topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and is administered in an amount that is not systemically bioavailable. In some embodiments, a method for improving tear clearance includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted psychological side effects. In some embodiments, a method for improving tear clearance includes topically administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the agonist selectively binds to peripheral nicotinic acetylcholine receptors and the amount does not cause unwanted systemic side effects. In some embodiments, a method for improving tear clearance further includes topically administering one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state.In some embodiments, a method for improving tear clearance further includes the topical application of one or more substances that prevent or reduce nicotinic acetylcholine receptors from entering a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state. In some embodiments, a method for improving tear clearance further includes the topical application of one or more substances that prevent or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for improving tear clearance further includes the topical application of one or more substances that prevent or reduce nicotinic acetylcholine receptors from entering a desensitized state or promote the recovery of nicotinic acetylcholine receptors from a desensitized state, said substances being selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a method for improving tear clearance further includes the topical application of protein kinase C (PKC) or a factor that upregulates or upregulates PKC. In some embodiments, a method for improving tear clearance further includes the topical application of cAMP-dependent protein kinase (PKA) or a factor that upregulates or upregulates PKA. In some embodiments, a method for improving tear clearance further includes the topical application of a calcineurin inhibitor. In some embodiments, a method for improving tear clearance further includes the topical application of a calcineurin inhibitor, wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for improving tear clearance further includes the topical application of cyclosporine. In some embodiments, a method for improving tear clearance further includes the topical application of pimecrolimus. In some embodiments, a method for improving tear clearance further includes the topical application of tacrolimus.

[0112] In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, cytisine, varencrine, tebuclam, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is nicotine. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is cytisine. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is varencrine. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is tebuconazole. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is DBO-83. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is CC4. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is ABT-418. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is ABT-366833. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is ABT-202. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is ABT-894. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is SIB-1663. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is GTS-21. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is PHA-543613. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is PNU-282987. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is LY-2087101.In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is A85380. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is 5-I-A85380.

[0113] In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is a compound selected from those disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011 or WO 2010 / 028033.

[0114] In another embodiment of any of the above embodiments for improving tear clearance, at least 1 microgram of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for improving tear clearance, at least 5 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for improving tear clearance, at least 10 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for improving tear clearance, at least 25 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for improving tear clearance, at least 50 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for improving tear clearance, at least 100 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for improving tear clearance, at least 250 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for improving tear clearance, at least 500 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for improving tear clearance, at least 750 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for improving tear clearance, at least 1000 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for improving tear clearance, between 1 microgram and 1000 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above embodiments for improving tear clearance, between 5 micrograms and 1000 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 5 and 100 micrograms. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 5 and 50 micrograms. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 10 and 50 micrograms. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 25 and 1000 micrograms.In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 50 μg and 1000 μg. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 100 μg and 1000 μg. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 100 μg and 750 μg. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 150 μg and 750 μg. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity in amounts between 150 μg and 600 μg.

[0115] In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered once daily. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered at least once daily. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered twice daily. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered at least twice daily. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered three times daily. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered at least three times daily. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered for one day. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered for at least two days. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered for at least three days. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered for at least four days. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered for at least five days. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered for at least seven days. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered for at least ten days. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered for at least fourteen days. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered for at least twenty-one days. In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered for at least thirty days.

[0116] In another embodiment of any of the above embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into alternating nostrils.

[0117] In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a liquid. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a suspension. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an aerosol. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a gel. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an ointment. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a dry powder. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a cream. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a paste. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a wash. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a balm.

[0118] In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe, dropper, nebulizer, nebulizer pump, inhaler, powder sprayer, vaporizer, patch, applicator stick, pipette, or liquid jet injector. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a dropper. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer pump. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via an inhaler. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a powder spray device. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a vaporizer. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a patch. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via an applicator stick. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a pipette. In another embodiment of any of the above-described embodiments for improving tear clearance, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a liquid jet applicator.

[0119] In another embodiment of any of the above embodiments for improving tear clearance, the trigeminal nerve is activated. In another embodiment for improving tear clearance, the anterior ethmoidal nerve is activated. In another embodiment of any of the above embodiments for improving tear clearance, the nasolacrimal reflex is activated.

[0120] certain terms

[0121] Unless otherwise stated, the following terms as used in this application (including the specification and claims) have the definitions given below. It must be noted that, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” as used in this specification and appended claims include a plural of indicators. In this application, unless otherwise stated, the use of “or” or “and” means “and / or”. Furthermore, the use of the term “comprising” and other forms is not restrictive. Some headings used herein are for organizational purposes only and should not be considered as limiting the subject matter described.

[0122] As used herein, the terms “co-administration” and the like are intended to cover the administration of a selected therapeutic agent to a single patient and are intended to include treatment regimens in which the agent is administered via the same or different routes of administration or at the same or different times.

[0123] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an amount of a drug or compound administered that is sufficient to alleviate, to a certain extent, one or more symptoms of a disease or condition being treated. The result may be a reduction and / or relief of disease signs, symptoms, or precipitating factors, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a pharmaceutical preparation containing a nicotinic acetylcholine receptor agonist, as disclosed herein, required to provide a clinically significant reduction in disease symptoms. In any individual case, the appropriate "effective" amount may be determined using techniques such as dose-scaling studies.

[0124] The terms “individual,” “subject,” and “patient” encompass both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans; non-human primates such as chimpanzees and other apes and monkeys; livestock such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0125] A “tissue” comprises two or more types of cells. These two or more types of cells may have similar functions and / or functions. The tissue may be connective tissue, epithelial tissue, muscle tissue, or nerve tissue. Alternatively, the tissue may be bone, tendon (both referred to as musculoskeletal grafts), cornea, skin, heart valves, or veins.

[0126] An "organ" comprises two or more tissues. These two or more tissues may perform a specific function or a set of specific functions. In some cases, the organ is the lung, mouth, nose, parathyroid gland, pineal gland, pituitary gland, carotid body, salivary gland, skin, gallbladder, pancreas, small intestine, stomach, spleen, spinal cord, thymus, thyroid gland, trachea, uterus, or appendix. Alternatively, the organ is the adrenal gland, appendix, brain, bladder, kidney, intestine, large intestine, small intestine, liver, heart, or muscle.

[0127] The term "nicotinic acetylcholine receptor agonist" encompasses both full and partial agonists of the nicotinic acetylcholine receptor.

[0128] As used herein, the term "treatment" includes reducing, alleviating, or improving at least one symptom of a disease or condition; preventing other symptoms; preventing the development of the condition; inhibiting the disease or condition (e.g., halting its development); reducing the disease or condition; resolving the disease or condition; reducing symptoms caused by the disease or condition; or stopping the symptoms of the disease or condition. In one embodiment, treatment is preventive treatment. In another embodiment, treatment refers to therapeutic treatment.

[0129] As used in this article, “will not cross the blood-brain barrier at pharmacologically relevant concentrations” means that the amount of nicotinic acetylcholine receptor agonists disclosed herein is insufficient to cross the blood-brain barrier to produce a pharmacological response.

[0130] As used in this article, the term "unintended psychological side effects" refers to unintended effects in the brain, including but not limited to anxiety, depression, hallucinations, euphoria, addiction, sleep disorders / disorders, insomnia, unusual dreams, and nightmares.

[0131] As used herein, the term "unintended systemic side effects" refers to unintended effects in the body, including but not limited to abdominal pain, vomiting, nausea, constipation, diarrhea, flatulence, indigestion, and dry mouth.

[0132] As used herein, the term "nicotinic acetylcholine receptor agonist formulated to prevent desensitization" refers to a formulation that does not induce tolerance, dependence, withdrawal, or desensitization to the effects of nicotinic acetylcholine receptor agonists.

[0133] As used herein, the term "environmentally challenging conditions" refers to external conditions, including both natural and anthropogenic conditions. Naturally occurring environmentally challenging conditions include, but are not limited to, exposure to smog, wind, and dry climates. Anthropogenic environmentally challenging conditions include, but are not limited to, exposure to pollution from automobiles, factories, and aircraft, as well as homes / offices with low humidity, high airflow, or poor air quality. In some implementations, "environmentally challenging conditions" refers to controlled challenging environments commonly used in dry eye clinical trials.

[0134] The term "eye discomfort" includes, but is not limited to, symptoms of dry eye, such as itching, dryness, photophobia, blurred vision, pain, stickiness, burning, stinging, and a foreign body sensation. In some implementations, eye discomfort is associated with blepharitis, meibomian gland dysfunction, allergic conjunctivitis, ocular surface poisoning and irritation, tear drainage problems, or eyelid conditions.

[0135] As used in this article, the term "soft drug" refers to an active pharmaceutical ingredient that is rapidly metabolized into an inactive form immediately after achieving its therapeutic effect.

[0136] Nicotinic acetylcholine receptor agonists

[0137] The methods described herein involve the local administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is a full agonist. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is a partial agonist. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, hyoscyamine, varencrine, tebuconazole, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is nicotine. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is cytisine. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is hyoscyamine. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is varencrine. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is tebuconazole. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is DBO-83. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is CC4. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is ABT-418. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is ABT-366833. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is ABT-202. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is ABT-894. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is SIB-1663. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is GTS-21. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is PHA-543613. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is PNU-282987. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is LY-2087101. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is A85380.In some embodiments of the method described herein, the nicotinic acetylcholine receptor agonist is 5-I-A85380. In some embodiments of the method described herein, the nicotinic acetylcholine receptor agonist is a compound selected from those disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011, or WO 2010 / 028033.

[0138] In some embodiments of the method described herein, the nicotinic acetylcholine receptor agonist is a soft drug.

[0139] Some embodiments of the method described herein are nicotinic acetylcholine receptor agonists having the following structure:

[0140]

[0141] Or its pharmaceutically acceptable salt.

[0142] Intranasal administration

[0143] The methods described herein include the topical application of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need. In some embodiments, the methods described herein include the topical application of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the nicotinic acetylcholine receptor agonist is applied into the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is applied into the nasal cavity in the form of a liquid. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is applied into the nasal cavity in the form of a suspension. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is applied into the nasal cavity in the form of an aerosol. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is applied into the nasal cavity in the form of a gel. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of an ointment. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a dry powder. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a cream. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a paste. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a lotion. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is applied to the nasal cavity in the form of a balm.

[0144] In some embodiments, the methods described herein include the topical administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need, wherein the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe, dropper, nebulizer, nebulizer pump, inhaler, powder sprayer, vaporizer, patch, applicator stick, pipette, or liquid jet injector. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a syringe. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a dropper. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a nebulizer pump. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via an inhaler. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a powder sprayer. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a vaporizer. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a patch. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a swab. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a pipette. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is administered into the nasal cavity via a liquid injector.

[0145] Drug formulation, administration method and treatment regimen

[0146] This document also provides pharmaceutical formulations of nicotinic acetylcholine receptor agonists for topical application to an individual's nasal cavity. In some embodiments, a pharmaceutical formulation of a nicotinic acetylcholine receptor agonist for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, further comprising one or more substances selected from protein kinase C (PKC) or factors upregulating or upregulating PKC, cAMP-dependent protein kinase (PKA) or factors upregulating or upregulating PKA, and calcineurin inhibitors. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, further comprising protein kinase C (PKC) or factors upregulating or upregulating PKC. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, and further comprises a cAMP-dependent protein kinase (PKA) or a factor that upregulates or upregulates PKA. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, and further comprises a calcineurin inhibitor. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, and further comprises a calcineurin inhibitor, wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, and further comprises a calcineurin inhibitor, wherein the calcineurin inhibitor is cyclosporine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, and further comprises a calcineurin inhibitor, wherein the calcineurin inhibitor is pimecrolimus. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, and further comprises a calcineurin inhibitor, wherein the calcineurin inhibitor is tacrolimus.

[0147] In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, scutellarin, varenclin, tebuclam, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is nicotine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is cytisine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is terbinafine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is varencrine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is tebuclam. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is DBO-83. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is CC4. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is ABT-418.In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is ABT-366833. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is ABT-202. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is ABT-894. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is SIB-1663. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is GTS-21. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is PHA-543613. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is PNU-282987. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is LY-2087101. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is A85380. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is 5-I-A85380.

[0148] In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is a compound selected from those disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011 or WO2010 / 028033.

[0149] In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from α3β4, α4β2, and α7. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist selectively binds to the peripheral nicotinic acetylcholine receptor subtype α3β4. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist selectively binds to the peripheral nicotinic acetylcholine receptor subtype α4β2. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist selectively binds to peripheral nicotinic acetylcholine receptor subtype α7.

[0150] In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is a soft drug.

[0151] In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist has a structure selected from:

[0152]

[0153] Or its pharmaceutically acceptable salt.

[0154] In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity is also described herein, comprising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychological side effects. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychological side effects, further comprising one or more substances selected from protein kinase C (PKC) or factors that upregulate or upregulate PKC, cAMP-dependent protein kinase (PKA) or factors that upregulate or upregulate PKA, and calcineurin inhibitors. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychological side effects, further comprising protein kinase C (PKC) or factors that upregulate or upregulate PKC. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychological side effects, and further comprises a cAMP-dependent protein kinase (PKA) or a factor that upregulates or upregulates PKA. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychological side effects, and further comprises a calcineurin inhibitor. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychological side effects, and further comprises a calcineurin inhibitor, wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychological side effects, and further comprises a calcineurin inhibitor, wherein the calcineurin inhibitor is cyclosporine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychological side effects, and further comprises a calcineurin inhibitor, wherein the calcineurin inhibitor is pimecrolimus. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychological side effects, and further comprises a calcineurin inhibitor, wherein the calcineurin inhibitor is tacrolimus.

[0155] In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects. The nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, scutellarin, varenclin, tebuconazole, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects. The nicotinic acetylcholine receptor agonist is nicotine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychoactive side effects, wherein the nicotinic acetylcholine receptor agonist is cytisine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychoactive side effects, wherein the nicotinic acetylcholine receptor agonist is valencrine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychoactive side effects, wherein the nicotinic acetylcholine receptor agonist is tebuconazole. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is DBO-83. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is CC4. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is ABT-418.In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is ABT-366833. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is ABT-202. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is ABT-894. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is SIB-1663. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is GTS-21. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is PHA-543613. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is PNU-282987. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is LY-2087101. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is A85380. In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is 5-I-A85380.

[0156] In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is a compound selected from those disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011 or WO 2010 / 028033.

[0157] In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in doses that do not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist is a soft drug.

[0158] In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist has a structure selected from:

[0159]

[0160] Or its pharmaceutically acceptable salt.

[0161] In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychological side effects, wherein the nicotinic acetylcholine receptor agonist selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from α3β4, α4β2, and α7. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychological side effects, wherein the nicotinic acetylcholine receptor agonist selectively binds to the peripheral nicotinic acetylcholine receptor subtype α3β4. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted psychological side effects, wherein the nicotinic acetylcholine receptor agonist selectively binds to the peripheral nicotinic acetylcholine receptor subtype α4β2. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in doses that do not cause unwanted psychogenic side effects, wherein the nicotinic acetylcholine receptor agonist selectively binds to peripheral nicotinic acetylcholine receptor subtype α7.

[0162] In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity is also described herein, comprising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, further comprising one or more substances selected from protein kinase C (PKC) or factors upregulating or upregulating PKC, cAMP-dependent protein kinase (PKA) or factors upregulating or upregulating PKA, and calcineurin inhibitors. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, further comprising protein kinase C (PKC) or factors upregulating or upregulating PKC. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, and further comprises a cAMP-dependent protein kinase (PKA) or a factor that upregulates or upregulates PKA. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, and further comprises a calcineurin inhibitor. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, and further comprises a calcineurin inhibitor, wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, and further comprises a calcineurin inhibitor, wherein the calcineurin inhibitor is cyclosporine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, and further comprises a calcineurin inhibitor, wherein the calcineurin inhibitor is pimecrolimus. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, and further comprises a calcineurin inhibitor, wherein the calcineurin inhibitor is tacrolimus.

[0163] In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects. The nicotinic acetylcholine receptor agonist is selected from nicotine, cytisine, scutellarin, varenclin, tebuclam, DBO-83, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I-A85380. In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects. The nicotinic acetylcholine receptor agonist is nicotine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is cytisine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is terbinafine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is valencrine. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is tebuconazole. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is DBO-83. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is CC4. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is ABT-418.In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is ABT-366833. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is ABT-202. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is ABT-894. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is SIB-1663. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is GTS-21. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is PHA-543613. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is PNU-282987. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is LY-2087101. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is A85380. In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in doses that do not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is 5-I-A85380.

[0164] In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is a compound selected from those disclosed in WO 2008 / 057938, WO 2009 / 111550, WO 2010 / 028011 or WO 2010 / 028033.

[0165] In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in doses that do not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist is a soft drug.

[0166] In some embodiments, a pharmaceutical preparation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in doses that do not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist has a structure selected from:

[0167]

[0168] Or its pharmaceutically acceptable salt.

[0169] In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist selectively binds to at least one of peripheral nicotinic acetylcholine receptor subtypes selected from α3β4, α4β2, and α7. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist selectively binds to the peripheral nicotinic acetylcholine receptor subtype α3β4. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dose that does not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist selectively binds to the peripheral nicotinic acetylcholine receptor subtype α4β2. In some embodiments, a pharmaceutical formulation for topical application to an individual's nasal cavity comprises a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in doses that do not cause unwanted systemic side effects, wherein the nicotinic acetylcholine receptor agonist selectively binds to peripheral nicotinic acetylcholine receptor subtype α7.

[0170] In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 0.1 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 0.2 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 0.5 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 1 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 2 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 3 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 4 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 5 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 6 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 7 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 8 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 9 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 10 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 12 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 15 mg / mL of the nicotinic acetylcholine receptor agonist. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises about 20 mg / mL of the nicotinic acetylcholine receptor agonist.

[0171] In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises at least 1 microgram of the nicotinic acetylcholine receptor agonist per dose. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises at least 5 micrograms of the nicotinic acetylcholine receptor agonist per dose. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises at least 10 micrograms of the nicotinic acetylcholine receptor agonist per dose. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises at least 25 micrograms of the nicotinic acetylcholine receptor agonist per dose. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises at least 50 micrograms of the nicotinic acetylcholine receptor agonist per dose. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises at least 100 micrograms of the nicotinic acetylcholine receptor agonist per dose. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises at least 250 micrograms of the nicotinic acetylcholine receptor agonist per dose. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises at least 500 micrograms of the nicotinic acetylcholine receptor agonist per dose. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises at least 750 micrograms of the nicotinic acetylcholine receptor agonist per dose. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises at least 1000 micrograms of the nicotinic acetylcholine receptor agonist per dose. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises between 1 microgram and 1000 micrograms of the nicotinic acetylcholine receptor agonist per dose. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises between 5 micrograms and 1000 micrograms of the nicotinic acetylcholine receptor agonist per dose. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises the nicotinic acetylcholine receptor agonist at a dose between 5 micrograms and 50 micrograms. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises the nicotinic acetylcholine receptor agonist at a dose between 10 micrograms and 50 micrograms. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises the nicotinic acetylcholine receptor agonist at a dose between 25 micrograms and 1000 micrograms.In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises the nicotinic acetylcholine receptor agonist at a dose between 50 micrograms and 1000 micrograms. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises the nicotinic acetylcholine receptor agonist at a dose between 100 micrograms and 1000 micrograms. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises the nicotinic acetylcholine receptor agonist at a dose between 100 micrograms and 750 micrograms. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises the nicotinic acetylcholine receptor agonist at a dose between 150 micrograms and 750 micrograms. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation comprises the nicotinic acetylcholine receptor agonist at a dose between 150 micrograms and 600 micrograms.

[0172] In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation is administered once daily. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation is administered at least once daily. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation is administered twice daily. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation is administered at least twice daily. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation is administered three times daily. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation is administered at least three times daily. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation is administered for one day. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation is administered for at least two days. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation is administered for at least three days. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation is administered for at least four days. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation is administered for at least five days. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation is administered for at least seven days. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation has been administered for at least ten days. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation has been administered for at least fourteen days. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation has been administered for at least twenty-one days. In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation has been administered for at least thirty days.

[0173] In another embodiment of any of the above-described pharmaceutical formulation embodiments, the pharmaceutical formulation is administered into alternating nostrils.

[0174] In some embodiments, the pharmaceutical preparations described herein are administered for preventative and / or therapeutic treatment. In some therapeutic applications, the pharmaceutical preparation is administered to a patient already suffering from the disease or symptom in an amount sufficient to cure or at least partially block at least one symptom of the disease or symptom. The effective amount for this purpose depends on the severity and course of the disease or symptom, prior therapy, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective amount may optionally be determined by a variety of methods, including but not limited to dose-escalation clinical trials.

[0175] In prophylactic use, the pharmaceutical preparations described herein are administered to patients who are susceptible to or at risk of a particular disease, condition, or symptom. Such a quantity is defined as the “preventative effective amount or dose.” In this application, the exact amount also depends on the patient’s health status, weight, etc. When used on a patient, the effective amount for this purpose will depend on the severity and course of the disease, condition, or symptom, prior therapy, the patient’s health status and response to the drug, and the judgment of the treating physician.

[0176] In some implementations, where the patient’s condition does not improve, the physician administers the drug preparation for an extended period of time, including throughout the patient’s life, in order to improve or otherwise control or limit the symptoms of the patient’s disease or condition.

[0177] In some implementations, where the patient's condition does not improve, the dosage of the administered drug preparation may be temporarily reduced or temporarily interrupted for a period of time (i.e., a "drug holiday"). In specific implementations, the length of a drug holiday ranges from 2 days to 1 year, including, for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. For example, during a drug holiday, the dosage is reduced by 10% to 100%, including, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0178] In some embodiments, the dosage of the administered pharmaceutical preparation may be temporarily reduced or temporarily interrupted for a period of time (i.e., a "drug change"). In specific embodiments, the length of the drug change is between 2 days and 1 year, including, for example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. For example only, the dosage is reduced by 10% to 100% during the drug change, including, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. Optionally, the normal dosing schedule is resumed after the appropriate length of time.

[0179] In some implementations, a maintenance dose is administered as needed once the patient's symptoms have improved. Subsequently, in specific implementations, the dose or frequency, or both, are reduced as symptoms change until the improved disease, condition, or symptom is maintained at a level. However, in some implementations, the patient requires long-term intermittent treatment after any recurrence of symptoms.

[0180] The amount of a specified drug corresponding to such a quantity varies depending on many factors, such as the specific drug formulation, the condition and its severity, the characteristics of the subject or host requiring treatment (e.g., weight, sex), but can still be determined based on the specific circumstances of the individual case, including, for example, the specific nicotinic acetylcholine receptor agonist being administered, the condition being treated, and the subject being treated.

[0181] As used herein, a pharmaceutical formulation refers to a mixture of a nicotinic acetylcholine receptor agonist as described herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, fillers, suspending agents, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. In some embodiments, the pharmaceutical formulation described herein is mixed with other active ingredients, as in combination therapies. In some embodiments, the pharmaceutical formulation includes other substances of therapeutic value. In other embodiments, the pharmaceutical formulation includes other medical or pharmaceutical reagents, carriers, adjuvants, preservatives, stabilizers, wetting or emulsifying agents, solution promoters, salts and / or buffers for adjusting osmotic pressure.

[0182] In some embodiments, the pharmaceutical formulation described herein refers to a mixture of a nicotinic acetylcholine receptor agonist and a buffer solution. In some embodiments, the pharmaceutical formulation described herein refers to a mixture of a nicotinic acetylcholine receptor agonist and a phosphate-buffered saline (PBFS). In some embodiments, the pharmaceutical formulation described herein refers to a mixture of a nicotinic acetylcholine receptor agonist and a phosphate-buffered saline (PBFS), wherein the pH of the PBFS is about 7.0. In some embodiments, the pharmaceutical formulation described herein refers to a mixture of a nicotinic acetylcholine receptor agonist and a phosphate-citrate buffer solution. In some embodiments, the pharmaceutical formulation described herein refers to a mixture of a nicotinic acetylcholine receptor agonist and a phosphate-citrate buffer solution, wherein the pH of the phosphate-citrate buffer solution is about 6.0. In some embodiments, the pharmaceutical formulation described herein refers to a mixture of a nicotinic acetylcholine receptor agonist and a phosphate-citrate buffer solution. In some embodiments, the pharmaceutical formulation described herein refers to a mixture of a nicotinic acetylcholine receptor agonist and a phosphate-citrate buffer solution, wherein the pH of the phosphate-citrate buffer solution is about 5.0.

[0183] The pharmaceutical formulation facilitates the administration of the compound to a living organism. In practicing the methods described herein, a therapeutically effective amount of the nicotinic acetylcholine receptor agonist described herein is administered in the pharmaceutical formulation to a mammal suffering from the disease, condition, or symptom to be treated. In some embodiments, the mammal is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The nicotinic acetylcholine receptor agonist can be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0184] The pharmaceutical preparations described herein are administered into the nasal cavity of the subjects. The pharmaceutical preparations described herein include, but are not limited to, liquids, suspensions, aerosols, gels, ointments, dry powders, creams, pastes, lotions, or balms.

[0185] Pharmaceutical formulations comprising nicotinic acetylcholine receptor agonists as described herein are manufactured using conventional methods.

[0186] The pharmaceutical composition will include, as an active ingredient, a nicotinic acetylcholine receptor agonist as described herein, in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. Additionally, the methods and pharmaceutical formulations described herein include N-oxides (where appropriate), crystalline forms, amorphous phases, and active metabolites of the same type of activity using these nicotinic acetylcholine receptor agonists. In some embodiments, the nicotinic acetylcholine receptor agonists described herein may be in a nonsolvent form or in a solvate form with a pharmaceutically acceptable solvent such as water, ethanol, etc. The solvate forms of the nicotinic acetylcholine receptor agonists provided herein are also considered to be disclosed herein. In some embodiments, the compound may be present as a tautomer. All tautomers are included within the scope of the nicotinic acetylcholine receptor agonists provided herein.

[0187] In some embodiments, the nicotinic acetylcholine receptor agonist is present as an enantiomer, diastereomer, or other stereoisomer. The nicotinic acetylcholine receptor agonists disclosed herein include all enantiomers, diastereomers, and epimers, as well as mixtures thereof.

[0188] In some embodiments, the pharmaceutical formulations provided herein include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances, such as phenylmercuric borate and thimerosal; stable chlorine dioxide; and quaternary ammonium compounds, such as benzalkonium chloride, hexadecyltrimethylammonium bromide, and hexadecylpyridine chloride.

[0189] In some embodiments, the pharmaceutical formulations described herein benefit from antioxidants, metal chelators, thiol compounds, and other general stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol; (b) about 0.1% to about 1% w / v methionine; (c) about 0.1% to about 2% w / v monothioglycerol; (d) about 1 mM to about 10 mM EDTA; (e) about 0.01% to about 2% w / v ascorbic acid; (f) 0.003% to about 0.02% w / v polysorbate 80; (g) 0.001% to about 0.05% w / v polysorbate 20; (h) arginine; (i) heparin; (j) dextran sulfate; (k) cyclodextrin; (l) polypentosan sulfate and other heparin-like substances; (m) divalent cations, such as magnesium and zinc; or (n) combinations thereof.

[0190] The pharmaceutical formulations comprising nicotinic acetylcholine receptor agonists described herein are formulated in any suitable dosage form, including but not limited to liquids, suspensions, aerosols, gels, ointments, dry powders, creams, pastes, lotions, or balms. The pharmaceutical formulations comprising nicotinic acetylcholine receptor agonists described herein are formulated in any suitable dosage form for administration into the nasal cavity via syringes, droppers, bottle-type nebulizers, nebulizer pumps, inhalers, powder sprayers, vaporizers, patches, applicators, pipette...

Claims

1. Use of varenclin or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating dry eye, said treatment comprising nasal administration of varenclin at concentrations between 5 and 1000 micrograms to an individual in need, said medicament being a liquid pharmaceutical composition comprising about 0.1 mg / mL, about 0.2 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, or about 5 mg / mL of varenclin, and said liquid pharmaceutical composition being administered to said individual by nasal spray.

2. The use according to claim 1, wherein the treatment comprises valencrine administered nasally in doses between 5 micrograms and 100 micrograms.

3. The use according to claim 1, wherein the treatment comprises valencrine administered nasally in doses between 5 micrograms and 600 micrograms.

4. The use according to claim 1, wherein the liquid pharmaceutical composition contains about 0.5 mg / mL of the varenclin.

5. The use according to claim 1, wherein the liquid pharmaceutical composition contains about 1 mg / mL of the varenclin.

6. The use according to claim 1, wherein the drug comprises about 0.2 mg / mL of varencrine.

7. The use according to claim 1, wherein the drug comprises about 0.1 mg / mL of varencrine.

8. The use according to any one of claims 1 to 5, wherein the varenclin is applied at least once a day.

9. The use according to any one of claims 1 to 5, wherein the varenclin is applied at least twice daily.

10. The use according to any one of claims 1 to 5, wherein the varenclin is applied at least once a week.

11. The use according to claim 1, wherein the treatment comprises valencrine administered nasally at a dose between 5 and 600 micrograms daily.

12. The use according to claim 1, wherein the treatment comprises valencrine administered nasally twice daily at a dose between 5 and 100 micrograms.

13. A pharmaceutical preparation for topical application to the nasal cavity of an individual in need, wherein the pharmaceutical preparation is a liquid pharmaceutical preparation comprising varenclin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable inactive ingredients, wherein the pharmaceutical preparation comprises varenclin at a dose between 5 micrograms and 1000 micrograms, and wherein the concentration of varenclin in the pharmaceutical preparation is about 0.1 mg / mL, about 0.2 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, and wherein the pharmaceutical preparation is used to treat dry eye.

14. The pharmaceutical formulation of claim 13, wherein the pharmaceutical formulation comprises varencrine at doses between 5 micrograms and 100 micrograms.

15. The pharmaceutical formulation of claim 13, wherein the pharmaceutical formulation comprises varencrine at a dose between 5 micrograms and 600 micrograms.

16. The pharmaceutical formulation of claim 13, wherein the pharmaceutical formulation comprises varencrine at a dose between 100 micrograms and 750 micrograms.

17. The pharmaceutical formulation of claim 13, wherein the amount of varencrine in each dose of the pharmaceutical formulation is between 5 micrograms and 50 micrograms.

18. The pharmaceutical preparation according to any one of claims 13 to 17, wherein the pharmaceutical preparation comprises about 0.5 mg / mL of varencrine.

19. The pharmaceutical preparation according to any one of claims 13 to 17, wherein the pharmaceutical preparation comprises about 1 mg / mL of varencrine.

20. The pharmaceutical preparation according to any one of claims 13 to 17, wherein the pharmaceutical preparation comprises about 0.2 mg / mL of varencrine.

21. The pharmaceutical preparation according to any one of claims 13 to 17, wherein the pharmaceutical preparation is administered at least once daily.

22. The pharmaceutical preparation according to any one of claims 13 to 17, wherein the pharmaceutical preparation is administered at least twice daily.

23. The pharmaceutical preparation according to any one of claims 13 to 17, wherein the pharmaceutical preparation is administered at least once a week.

24. The pharmaceutical preparation according to any one of claims 13 to 17, wherein the pharmaceutical preparation is applied to alternating nostrils in the form of a liquid, aerosol, or nasal spray.

25. The pharmaceutical preparation according to any one of claims 13 to 17, wherein the pharmaceutical preparation is administered into alternating nostrils by means of a syringe, dropper, nebulizer, nebulizer pump, inhaler, vaporizer, pipette, liquid injector or nasal spray bottle.

26. The pharmaceutical preparation of claim 13, wherein the pharmaceutical preparation comprises a solution of varenclin or varenclin salt.

27. The pharmaceutical preparation of claim 24, wherein the pharmaceutical preparation is administered as a nasal spray.

28. The pharmaceutical formulation of claim 13, wherein the pharmaceutical formulation comprises a buffer.

29. The pharmaceutical formulation of claim 28, wherein the buffer comprises a phosphate buffer or a phosphate-citrate buffer.

30. The pharmaceutical preparation of claim 29, comprising a buffer having a pH of 5.0, 6.0, 7.0 or 7.

4.

31. A nasal spray comprising a solution of varenclin or a pharmaceutically acceptable varenclin salt and one or more pharmaceutically acceptable inactive ingredients, wherein the nasal spray comprises varenclin at a dose of 5 micrograms to 1000 micrograms, and wherein the concentration of varenclin in the formulation is about 0.1 mg / mL, about 0.2 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, or about 5 mg / mL, wherein the formulation is used to treat dry eye.

32. The nasal spray of the liquid pharmaceutical preparation of claim 31, wherein the nasal spray comprises valenclin at doses ranging from 5 micrograms to 100 micrograms.

33. The nasal spray of the liquid pharmaceutical preparation of claim 31, wherein the nasal spray comprises valencrine at doses ranging from 5 micrograms to 600 micrograms.

34. The nasal spray of the liquid pharmaceutical preparation of claim 31, wherein the nasal spray comprises valenclin at a dose of 5 to 50 micrograms.

35. The nasal spray of the liquid pharmaceutical formulation according to claim 31, wherein the formulation comprises phosphate buffer or phosphate-citrate buffer.

36. The nasal spray of the liquid pharmaceutical formulation of claim 35, wherein the formulation comprises a buffer having a pH of 5.0, 6.0, 7.0 or 7.

4.

37. A nasal spray bottle for topical application to an individual's nasal cavity of a liquid pharmaceutical preparation comprising a solution of varenclin or a pharmaceutically acceptable varenclin salt and one or more pharmaceutically acceptable inactive ingredients, wherein the concentration of varenclin in the preparation is about 0.1 mg / mL, about 0.2 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, or about 5 mg / mL, wherein the preparation is used to treat dry eye.

38. The nasal spray bottle of claim 37, wherein a single spray of the resulting liquid pharmaceutical preparation contains 5 to 100 micrograms of valenclin.

39. The nasal spray bottle of claim 37, wherein the pharmaceutical preparation comprises phosphate buffer or phosphate-citrate buffer.

40. The nasal spray bottle of claim 39, wherein the pharmaceutical preparation comprises a buffer with a pH of 5.0, 6.0, 7.0 or 7.

4.

41. The nasal spray bottle of claim 37, wherein the pharmaceutical preparation comprises a buffer with a pH of 5.0, 6.0, 7.0 or 7.

4.

42. Use of the pharmaceutical preparation according to any one of claims 13-30 in the preparation of a medicament for treating dry eye.

Images