USO0959.7284B2

(12) United States Patent (10) Patent No.: US 9,597,284 B2 Ackermann, Jr. et al. (45) Date of Patent: *Mar. 21, 2017

(54) DRY EYE TREATMENTS (58) Field of Classification Search USPC ...... 424/400 (71) Applicant: Oyster Point Pharma, Inc., South San See application file for complete search history. Francisco, CA (US) (56) References Cited (72) Inventors: Douglas Michael Ackermann, Jr., San Francisco, CA (US); James Loudin, U.S. PATENT DOCUMENTS Houston, TX (US); Kenneth J. 6,277,855 B1 8, 2001 Yerxa, Mandell, Arlington, MA (US) 2006, OO84656 A1 4/2006 Ziegler et al. 2011 OO86086 A1 4/2011 Johnson et al. (73) Assignee: Oyster Point Pharma, Inc., San 2011 O274628 A1 11/2011 Borschke Francisco, CA (US) 2012,0289572 A1 1 1/2012 Mazurov et al. (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 EP 1214062 B1 11, 2003 U.S.C. 154(b) by 0 days. WO WO-03005998 A2 1, 2003 WO WO-03045394 A1 6, 2003 This patent is Subject to a terminal dis WO WO-2004039366 A1 5, 2004 claimer. WO WO 2006/100075 * 9/2006 WO WO-2008O57938 A1 5, 2008 (21) Appl. No.: 14/887,248 WO WO-2009111550 A1 9, 2009 WO WO-2010O28011 A1 3, 2010 (22) Filed: Oct. 19, 2015 WO WO-2010O28033 A1 3, 2010 (65) Prior Publication Data OTHER PUBLICATIONS US 2016/0106745 A1 Apr. 21, 2016 Mazzanti (Int. J. Devl Neuroscience 25 (2007) 259-264.* Beule (GMS Current Topics in Otorhinolaryngology—Head and Neck Surgery 2010, vol. 9, 1-24).* Related U.S. Application Data Thuerauf (Psychopharmacology (1999) 142 : 236-243).* Albietz (Clinical and Experimental Optometry 84.1 Jan.-Feb. 2001, (60) Provisional application No. 62/066,280, filed on Oct. pp. 4-18).* 20, 2014, provisional application No. 62/100,844, PCT/US2015/56273 International Search Report and Written Opin filed on Jan. 7, 2015. ion dated Jan. 8, 2016. Co-pending U.S. Appl. No. 14/887,243, filed Oct. 19, 2015. Co-pending U.S. Appl. No. 14/887.253, filed Oct. 19, 2015. (51) Int. Cl. Co-pending U.S. Appl. No. 14/887.259, filed Oct. 19, 2015. A6 IK 9/00 (2006.01) U.S. Appl. No. 14/887.243 Office Action dated Mar. 24, 2016. A6 IK 3/439 (2006.01) U.S. Appl. No. 14/887.253 Office Action dated Mar. 23, 2016. A6 IK 3/4439 (2006.01) U.S. Appl. No. 14/887.259 Office Action dated Mar. 21, 2016. A6 IK 3/4427 (2006.01) A6 IK 3/4985 (2006.01) * cited by examiner A6 IK 45/06 (2006.01) A 6LX 3L/21995 (2006.01) Primary Examiner — Devang Thakor (52) U.S. Cl. CPC ...... A61K 9/0043 (2013.01); A61K 9/007 (57) ABSTRACT (2013.01); A61K 31/439 (2013.01); A61 K Described herein are methods and pharmaceutical formula 3 1/4427 (2013.01); A61K 31/4439 (2013.01); tions for treating dry eye disease. A6 IK3I/4985 (2013.01); A61K 31/4995 (2013.01); A61K 45/06 (2013.01) 15 Claims, 2 Drawing Sheets U.S. Patent Mar. 21, 2017 Sheet 1 of 2 US 9,597,284 B2

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US 9,597,284 B2 1. 2 DRY EYE TREATMENTS Provided herein, in some embodiments, is a method of increasing tear production, comprising the local administra CROSS-REFERENCE tion of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an This application claims benefit of U.S. Provisional Appli individual in need thereof, wherein the agonist selectively cation No. 62/066,280, filed on Oct. 20, 2014, and U.S. binds to the peripheral nicotinic acetylcholine receptor and Provisional Application No. 62/100,844, filed on Jan. 7, does not cross the blood-brain barrier in a pharmacologically 2015, both of which are herein incorporated by reference in relevant concentration. In some embodiments is method of their entirety. increasing tear production, comprising the local administra 10 tion of a therapeutically effective amount of a nicotinic BACKGROUND OF THE INVENTION acetylcholine receptor agonist into the nasal cavity of an individual in need thereof, wherein the agonist does not Dry Eye Disease (“DED) is a condition that affects cross the blood-brain barrier in a pharmacologically relevant millions of people worldwide. Approximately 40 million concentration and selectively binds to at least one of the people in North America have some form of dry eye, and 15 peripheral nicotinic acetylcholine receptor Subtypes selected many millions more suffer worldwide. DED results from the from alpha3beta4, alpha-4beta2, and alpha7. In some disruption of the natural tear film on the surface of the eye, embodiments is a method of increasing tear production, and can result in ocular discomfort, visual disturbance and comprising the local administration of a therapeutically a reduction in vision-related quality of life. Patients with effective amount of a nicotinic acetylcholine receptor ago severe cases of DED are at risk for serious ocular health nist into the nasal cavity of an individual in need thereof, deficiencies such as corneal ulceration, and can experience wherein the agonist selectively binds to the peripheral a quality of life deficiency comparable to that of moderate nicotinic acetylcholine receptor and is administered in an Severe angina. amount that is not systemically bioavailable. In some embodiments is a method of increasing tear production, SUMMARY OF THE INVENTION 25 comprising the local administration of a therapeutically effective amount of a nicotinic acetylcholine receptor ago Provided herein, in some embodiments, is a method of nist into the nasal cavity of an individual in need thereof, increasing tear production, comprising the local administra wherein the agonist selectively binds to the peripheral tion of a therapeutically effective amount of a nicotinic nicotinic acetylcholine receptor and in an amount that does acetylcholine receptor agonist into the nasal cavity of an 30 not result in undesired psychoactive side effects. In some individual in need thereof, wherein the agonist selectively embodiments is a method of increasing tear production, binds to the peripheral nicotinic acetylcholine receptor. In comprising the local administration of a therapeutically Some embodiments, is a method of increasing tear produc effective amount of a nicotinic acetylcholine receptor ago tion, comprising the local administration of a therapeutically nist into the nasal cavity of an individual in need thereof, effective amount of a nicotinic acetylcholine receptor ago 35 wherein the agonist selectively binds to the peripheral nist into the nasal cavity of an individual in need thereof, nicotinic acetylcholine receptor and in an amount that does wherein the agonist selectively binds to the peripheral not result in undesired systemic side effects. nicotinic acetylcholine receptor and does not cross the Further provided herein, in some embodiments, is a blood-brain barrier in a pharmacologically relevant concen method of treating dry eye, comprising the local adminis tration. In some embodiments is method of increasing tear 40 tration of a therapeutically effective amount of a nicotinic production, comprising the local administration of a thera acetylcholine receptor agonist into the nasal cavity of an peutically effective amount of a nicotinic acetylcholine individual in need thereof, wherein the agonist selectively receptoragonist into the nasal cavity of an individual in need binds to the peripheral nicotinic acetylcholine receptor. In thereof, wherein the agonist selectively binds to at least one Some embodiments, is a method of treating dry eye, com of the peripheral nicotinic acetylcholine receptor Subtypes 45 prising the local administration of a therapeutically effective selected from alpha3beta4, alpha-4beta2, and alpha7. In amount of a nicotinic acetylcholine receptor agonist into the Some embodiments is a method of increasing tear produc nasal cavity of an individual in need thereof, wherein the tion, comprising the local administration of a therapeutically agonist selectively binds to the peripheral nicotinic acetyl effective amount of a nicotinic acetylcholine receptor ago choline receptor and does not cross the blood-brain barrier nist into the nasal cavity of an individual in need thereof, 50 in a pharmacologically relevant concentration. In some wherein the agonist selectively binds to the peripheral embodiments is method of treating dry eye, comprising the nicotinic acetylcholine receptor and is administered in an local administration of a therapeutically effective amount of amount that is not systemically bioavailable. In some a nicotinic acetylcholine receptor agonist into the nasal embodiments is a method of increasing tear production, cavity of an individual in need thereof, wherein the agonist comprising the local administration of a therapeutically 55 selectively binds to at least one of the peripheral nicotinic effective amount of a nicotinic acetylcholine receptor ago acetylcholine receptor subtypes selected from alpha3beta4, nist into the nasal cavity of an individual in need thereof, alpha-4-beta2, and alpha7. In some embodiments is a method wherein the agonist selectively binds to the peripheral of treating dry eye, comprising the local administration of a nicotinic acetylcholine receptor and in an amount that does therapeutically effective amount of a nicotinic acetylcholine not result in undesired psychoactive side effects. In some 60 receptoragonist into the nasal cavity of an individual in need embodiments is a method of increasing tear production, thereof, wherein the agonist selectively binds to the periph comprising the local administration of a therapeutically eral nicotinic acetylcholine receptor and is administered in effective amount of a nicotinic acetylcholine receptor ago an amount that is not systemically bioavailable. In some nist into the nasal cavity of an individual in need thereof, embodiments is a method of treating dry eye, comprising the wherein the agonist selectively binds to the peripheral 65 local administration of a therapeutically effective amount of nicotinic acetylcholine receptor and in an amount that does a nicotinic acetylcholine receptor agonist into the nasal not result in undesired systemic side effects. cavity of an individual in need thereof, wherein the agonist US 9,597,284 B2 3 4 selectively binds to the peripheral nicotinic acetylcholine agonist into the nasal cavity of an individual in need thereof, receptor and in an amount that does not result in undesired wherein the agonist selectively binds to the peripheral psychoactive side effects. In some embodiments is a method nicotinic acetylcholine receptor and is administered in an of treating dry eye, comprising the local administration of a amount that is not systemically bioavailable. In some therapeutically effective amount of a nicotinic acetylcholine embodiments is a method of improving ocular discomfort, receptoragonist into the nasal cavity of an individual in need comprising the local administration of a therapeutically thereof, wherein the agonist selectively binds to the periph effective amount of a nicotinic acetylcholine receptor ago eral nicotinic acetylcholine receptor and in an amount that nist into the nasal cavity of an individual in need thereof, does not result in undesired systemic side effects. wherein the agonist selectively binds to the peripheral Further provided herein, in some embodiments, is a 10 nicotinic acetylcholine receptor and in an amount that does method of treating dry eye, comprising the local adminis not result in undesired psychoactive side effects. In some tration of a therapeutically effective amount of a nicotinic embodiments is a method of improving ocular discomfort, acetylcholine receptor agonist into the nasal cavity of an comprising the local administration of a therapeutically individual in need thereof, wherein the agonist selectively effective amount of a nicotinic acetylcholine receptor ago binds to the peripheral nicotinic acetylcholine receptor and 15 nist into the nasal cavity of an individual in need thereof, does not cross the blood-brain barrier in a pharmacologically wherein the agonist selectively binds to the peripheral relevant concentration. In some embodiments is a method of nicotinic acetylcholine receptor and in an amount that does treating dry eye, comprising the local administration of a not result in undesired systemic side effects. therapeutically effective amount of a nicotinic acetylcholine Further provided herein, in some embodiments, is a receptoragonist into the nasal cavity of an individual in need method of improving ocular discomfort, comprising the thereof, wherein the agonist does not cross the blood-brain local administration of a therapeutically effective amount of barrier in a pharmacologically relevant concentration and a nicotinic acetylcholine receptor agonist into the nasal selectively binds to at least one of the peripheral nicotinic cavity of an individual in need thereof, wherein the agonist acetylcholine receptor subtypes selected from alpha3beta4, selectively binds to the peripheral nicotinic acetylcholine alpha-4-beta2, and alpha7. In some embodiments is a method 25 receptor and does not cross the blood-brain barrier in a of treating dry eye, comprising the local administration of a pharmacologically relevant concentration. In some embodi therapeutically effective amount of a nicotinic acetylcholine ments is a method of improving ocular discomfort, com receptoragonist into the nasal cavity of an individual in need prising the local administration of a therapeutically effective thereof, wherein the agonist selectively binds to the periph amount of a nicotinic acetylcholine receptor agonist into the eral nicotinic acetylcholine receptor and is administered in 30 nasal cavity of an individual in need thereof, wherein the an amount that is not systemically bioavailable. In some agonist does not cross the blood-brain barrier in a pharma embodiments is a method of treating dry eye, comprising the cologically relevant concentration and selectively binds to at local administration of a therapeutically effective amount of least one of the peripheral nicotinic acetylcholine receptor a nicotinic acetylcholine receptor agonist into the nasal subtypes selected from alpha3beta4, alpha-4beta2, and cavity of an individual in need thereof, wherein the agonist 35 alpha7. In some embodiments is a method of improving selectively binds to the peripheral nicotinic acetylcholine ocular discomfort, comprising the local administration of a receptor and in an amount that does not result in undesired therapeutically effective amount of a nicotinic acetylcholine psychoactive side effects. In some embodiments is a method receptoragonist into the nasal cavity of an individual in need of treating dry eye, comprising the local administration of a thereof, wherein the agonist selectively binds to the periph therapeutically effective amount of a nicotinic acetylcholine 40 eral nicotinic acetylcholine receptor and is administered in receptoragonist into the nasal cavity of an individual in need an amount that is not systemically bioavailable. In some thereof, wherein the agonist selectively binds to the periph embodiments is a method of improving ocular discomfort, eral nicotinic acetylcholine receptor and in an amount that comprising the local administration of a therapeutically does not result in undesired systemic side effects. effective amount of a nicotinic acetylcholine receptor ago Further provided herein, in some embodiments, is a 45 nist into the nasal cavity of an individual in need thereof, method of improving ocular discomfort, comprising the wherein the agonist selectively binds to the peripheral local administration of a therapeutically effective amount of nicotinic acetylcholine receptor and in an amount that does a nicotinic acetylcholine receptor agonist into the nasal not result in undesired psychoactive side effects. In some cavity of an individual in need thereof, wherein the agonist embodiments is a method of improving ocular discomfort, selectively binds to the peripheral nicotinic acetylcholine 50 comprising the local administration of a therapeutically receptor. In some embodiments, is a method of improving effective amount of a nicotinic acetylcholine receptor ago ocular discomfort, comprising the local administration of a nist into the nasal cavity of an individual in need thereof, therapeutically effective amount of a nicotinic acetylcholine wherein the agonist selectively binds to the peripheral receptoragonist into the nasal cavity of an individual in need nicotinic acetylcholine receptor and in an amount that does thereof, wherein the agonist selectively binds to the periph 55 not result in undesired systemic side effects. eral nicotinic acetylcholine receptor and does not cross the Further provided herein, in some embodiments, is a blood-brain barrier in a pharmacologically relevant concen method of improving ocular Surface health, comprising the tration. In some embodiments is method of improving ocular local administration of a therapeutically effective amount of discomfort, comprising the local administration of a thera a nicotinic acetylcholine receptor agonist into the nasal peutically effective amount of a nicotinic acetylcholine 60 cavity of an individual in need thereof, wherein the agonist receptoragonist into the nasal cavity of an individual in need selectively binds to the peripheral nicotinic acetylcholine thereof, wherein the agonist selectively binds to at least one receptor and does not cross the blood-brain barrier in a of the peripheral nicotinic acetylcholine receptor Subtypes pharmacologically relevant concentration. In some embodi selected from alpha3beta4, alpha-4beta2, and alpha7. In ments is a method of improving ocular Surface health, Some embodiments is a method of improving ocular dis 65 comprising the local administration of a therapeutically comfort, comprising the local administration of a therapeu effective amount of a nicotinic acetylcholine receptor ago tically effective amount of a nicotinic acetylcholine receptor nist into the nasal cavity of an individual in need thereof, US 9,597,284 B2 5 6 wherein the agonist does not cross the blood-brain barrier in Further provided herein, in some embodiments, is a a pharmacologically relevant concentration and selectively method of increasing mucin content on the ocular Surface, binds to at least one of the peripheral nicotinic acetylcholine comprising the local administration of a therapeutically receptor subtypes selected from alpha3beta4, alpha-4-beta2. effective amount of a nicotinic acetylcholine receptor ago and alpha7. In some embodiments is a method of improving 5 nist into the nasal cavity of an individual in need thereof, ocular Surface health, comprising the local administration of wherein the agonist selectively binds to the peripheral a therapeutically effective amount of a nicotinic acetylcho nicotinic acetylcholine receptor and does not cross the line receptoragonist into the nasal cavity of an individual in blood-brain barrier in a pharmacologically relevant concen need thereof, wherein the agonist selectively binds to the tration. In some embodiments is a method of increasing 10 mucin content on the ocular Surface, comprising the local peripheral nicotinic acetylcholine receptor and is adminis administration of a therapeutically effective amount of a tered in an amount that is not systemically bioavailable. In nicotinic acetylcholine receptor agonist into the nasal cavity Some embodiments is a method of improving ocular Surface of an individual in need thereof, wherein the agonist does health, comprising the local administration of a therapeuti not cross the blood-brain barrier in a pharmacologically cally effective amount of a nicotinic acetylcholine receptor 15 relevant concentration and selectively binds to at least one of agonist into the nasal cavity of an individual in need thereof, the peripheral nicotinic acetylcholine receptor Subtypes wherein the agonist selectively binds to the peripheral selected from alpha3beta4, alpha-4beta2, and alpha7. In nicotinic acetylcholine receptor and in an amount that does Some embodiments is a method of increasing mucin content not result in undesired psychoactive side effects. In some on the ocular Surface, comprising the local administration of embodiments is a method of improving ocular Surface a therapeutically effective amount of a nicotinic acetylcho health, comprising the local administration of a therapeuti line receptor agonist into the nasal cavity of an individual in cally effective amount of a nicotinic acetylcholine receptor need thereof, wherein the agonist selectively binds to the agonist into the nasal cavity of an individual in need thereof, peripheral nicotinic acetylcholine receptor and is adminis wherein the agonist selectively binds to the peripheral tered in an amount that is not systemically bioavailable. In nicotinic acetylcholine receptor and in an amount that does 25 Some embodiments is a method of increasing mucin content not result in undesired systemic side effects. on the ocular Surface, comprising the local administration of Further provided herein, in some embodiments, is a a therapeutically effective amount of a nicotinic acetylcho method of protecting the ocular surface during environmen line receptor agonist into the nasal cavity of an individual in tally challenging conditions, comprising the local adminis need thereof, wherein the agonist selectively binds to the tration of a therapeutically effective amount of a nicotinic 30 peripheral nicotinic acetylcholine receptor and in an amount acetylcholine receptor agonist into the nasal cavity of an that does not result in undesired psychoactive side effects. In individual in need thereof, wherein the agonist selectively some embodiments is a method of increasing mucin content binds to the peripheral nicotinic acetylcholine receptor and on the ocular Surface, comprising the local administration of does not cross the blood-brain barrier in a pharmacologically a therapeutically effective amount of a nicotinic acetylcho relevant concentration. In some embodiments is a method of 35 line receptor agonist into the nasal cavity of an individual in protecting the ocular Surface during environmentally chal need thereof, wherein the agonist selectively binds to the lenging conditions, comprising the local administration of a peripheral nicotinic acetylcholine receptor and in an amount therapeutically effective amount of a nicotinic acetylcholine that does not result in undesired systemic side effects. receptoragonist into the nasal cavity of an individual in need Further provided herein, in some embodiments, is a thereof, wherein the agonist does not cross the blood-brain 40 method of increasing the amount or concentration of one or barrier in a pharmacologically relevant concentration and more lacrimal proteins on the ocular surface, comprising the selectively binds to at least one of the peripheral nicotinic local administration of a therapeutically effective amount of acetylcholine receptor subtypes selected from alpha3beta4, a nicotinic acetylcholine receptor agonist into the nasal alpha-4-beta2, and alpha7. In some embodiments is a method cavity of an individual in need thereof, wherein the agonist of protecting the ocular Surface during environmentally 45 selectively binds to the peripheral nicotinic acetylcholine challenging conditions, comprising the local administration receptor and does not cross the blood-brain barrier in a of a therapeutically effective amount of a nicotinic acetyl pharmacologically relevant concentration. In some embodi choline receptor agonist into the nasal cavity of an indi ments is a method of increasing the amount or concentration vidual in need thereof, wherein the agonist selectively binds of one or more lacrimal proteins on the ocular Surface, to the peripheral nicotinic acetylcholine receptor and is 50 comprising the local administration of a therapeutically administered in an amount that is not systemically bioavail effective amount of a nicotinic acetylcholine receptor ago able. In some embodiments is a method of protecting the nist into the nasal cavity of an individual in need thereof, ocular Surface during environmentally challenging condi wherein the agonist does not cross the blood-brain barrier in tions, comprising the local administration of a therapeuti a pharmacologically relevant concentration and selectively cally effective amount of a nicotinic acetylcholine receptor 55 binds to at least one of the peripheral nicotinic acetylcholine agonist into the nasal cavity of an individual in need thereof, receptor subtypes selected from alpha3beta4, alpha-4-beta2. wherein the agonist selectively binds to the peripheral and alpha7. In some embodiments is a method of increasing nicotinic acetylcholine receptor and in an amount that does the amount or concentration of one or more lacrimal proteins not result in undesired psychoactive side effects. In some on the ocular Surface, comprising the local administration of embodiments is a method of protecting the ocular Surface 60 a therapeutically effective amount of a nicotinic acetylcho during environmentally challenging conditions, comprising line receptor agonist into the nasal cavity of an individual in the local administration of a therapeutically effective amount need thereof, wherein the agonist selectively binds to the of a nicotinic acetylcholine receptor agonist into the nasal peripheral nicotinic acetylcholine receptor and is adminis cavity of an individual in need thereof, wherein the agonist tered in an amount that is not systemically bioavailable. In selectively binds to the peripheral nicotinic acetylcholine 65 Some embodiments is a method of increasing the amount or receptor and in an amount that does not result in undesired concentration of one or more lacrimal proteins on the ocular systemic side effects. Surface, comprising the local administration of a therapeu US 9,597,284 B2 7 8 tically effective amount of a nicotinic acetylcholine receptor C (PKC) or factors that upregulate or up-modulate PKC. agonist into the nasal cavity of an individual in need thereof, cAMP-dependent protein kinase (PKA) or factors that wherein the agonist selectively binds to the peripheral upregulate or up-modulate PKA, and calcineurin inhibitors. nicotinic acetylcholine receptor and in an amount that does In some embodiments, the calcineurin inhibitor is selected not result in undesired psychoactive side effects. In some 5 from cyclosporine, pimecrolimus, and tacrolimus. embodiments is a method of increasing the amount or In a further embodiment of any of the aforementioned concentration of one or more lacrimal proteins on the ocular embodiments, the nicotinic acetylcholine receptor agonist is Surface, comprising the local administration of a therapeu selected from nicotine, cytisine, epibatidine, Varenicline, tically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need thereof, 10 tebanicline, DBO-83, CC4, ABT-418, ABT-366833, ABT wherein the agonist selectively binds to the peripheral 202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU nicotinic acetylcholine receptor and in an amount that does 282987, LY-2087101, A85380, and 5-I-A85380. not result in undesired systemic side effects. In some In a further embodiment of any of the aforementioned embodiments the lacrimal protein is epithelial growth factor, embodiments, the nicotinic acetylcholine receptor agonist is lactoferin, lacritin, prolactin, adrenocorticotropic, leucine 15 selected from a compound disclosed in WO 2008/057938, enkephalin, ALS2CL, ARHGEF19, KIAA1109, PLXNA1, WO 2009/111550, WO 2010/028011, or WO 2010/028033, POLG, WIPI1, ZMIZ2 or other proteins of the tear pro each of which is incorporated herein by reference. teone. In a further embodiment of any of the aforementioned Further provided herein, in some embodiments, is a embodiments, at least 1 microgram of the nicotinic acetyl method of enhancing tear clearance, comprising the local 20 choline receptoragonist is administered into the nasal cavity. administration of a therapeutically effective amount of a In a further embodiment of any of the aforementioned nicotinic acetylcholine receptor agonist into the nasal cavity embodiments, at least 5 micrograms of the nicotinic acetyl of an individual in need thereof, wherein the agonist selec choline receptoragonist is administered into the nasal cavity. tively binds to the peripheral nicotinic acetylcholine receptor In a further embodiment of any of the aforementioned and does not cross the blood-brain barrier in a pharmaco- 25 embodiments, at least 10 micrograms of the nicotinic ace logically relevant concentration. In some embodiments is a tylcholine receptor agonist is administered into the nasal method of enhancing tear clearance, comprising the local cavity. In another embodiment of any of the aforementioned administration of a therapeutically effective amount of a embodiments, at least 25 micrograms of the nicotinic ace nicotinic acetylcholine receptor agonist into the nasal cavity tylcholine receptor agonist is administered into the nasal of an individual in need thereof, wherein the agonist does 30 cavity. In another embodiment of any of the aforementioned not cross the blood-brain barrier in a pharmacologically embodiments, at least 50 micrograms of the nicotinic ace relevant concentration and selectively binds to at least one of tylcholine receptor agonist is administered into the nasal the peripheral nicotinic acetylcholine receptor Subtypes cavity. In another embodiment of any of the aforementioned selected from alpha3beta4, alpha-4beta2, and alpha7. In embodiments, at least 100 micrograms of the nicotinic Some embodiments is a method of enhancing tear clearance, 35 acetylcholine receptor agonist is administered into the nasal comprising the local administration of a therapeutically cavity. In another embodiment of any of the aforementioned effective amount of a nicotinic acetylcholine receptor ago embodiments, at least 250 micrograms of the nicotinic nist into the nasal cavity of an individual in need thereof, acetylcholine receptor agonist is administered into the nasal wherein the agonist selectively binds to the peripheral cavity. In another embodiment of any of the aforementioned nicotinic acetylcholine receptor and is administered in an 40 embodiments, at least 500 micrograms of the nicotinic amount that is not systemically bioavailable. In some acetylcholine receptor agonist is administered into the nasal embodiments is a method of enhancing tear clearance, cavity. comprising the local administration of a therapeutically In a further embodiment of any of the aforementioned effective amount of a nicotinic acetylcholine receptor ago embodiments, the nicotinic acetylcholine receptor agonist is nist into the nasal cavity of an individual in need thereof, 45 administered at least once daily. In another embodiment of wherein the agonist selectively binds to the peripheral any of the aforementioned embodiments, the nicotinic ace nicotinic acetylcholine receptor and in an amount that does tylcholine receptor agonist is administered at least twice not result in undesired psychoactive side effects. In some daily. In another embodiment of any of the aforementioned embodiments is a method of enhancing tear clearance, embodiments, the nicotinic acetylcholine receptor agonist is comprising the local administration of a therapeutically 50 administered for at least two days. effective amount of a nicotinic acetylcholine receptor ago In a further embodiment of any of the aforementioned nist into the nasal cavity of an individual in need thereof, embodiments, the nicotinic acetylcholine receptor agonist is wherein the agonist selectively binds to the peripheral administered as needed. In another embodiment of any of nicotinic acetylcholine receptor and in an amount that does the aforementioned embodiments, the nicotinic acetylcho not result in undesired systemic side effects. 55 line receptor agonist is administered as needed in response In a further embodiment of any of the aforementioned to symptoms. In another embodiment of any of the afore embodiments, the method further comprises the local mentioned embodiments, the timing or frequency of admin administration of one or more Substances that prevent or istration of the nicotinic acetylcholine receptor agonist is facilitate the recovery of the nicotinic acetylcholine receptor designed or adjusted to prevent desensitization of the nico from the desensitized state. In a further embodiment of any 60 tinic acetylcholine receptors. of the aforementioned embodiments, the method further In a further embodiment of any of the aforementioned comprises the local administration of one or more Sub embodiments, the nicotinic acetylcholine receptor agonist is stances that prevent the entry or reduce the entry of the administered into the nasal cavity as a liquid, Suspension, nicotinic acetylcholine receptor into the desensitized State, aerosol, gel, ointment, dry powder, cream, paste, lotion, or or facilitate the recovery of the nicotinic acetylcholine 65 balm. In a further embodiment of any of the aforementioned receptor from the desensitized State. In some embodiments, embodiments, the nicotinic acetylcholine receptor agonist is the one or more Substances are selected from protein kinase administered into the nasal cavity by a syringe, dropper, US 9,597,284 B2 9 10 bottle nebulizer, atomization pump, inhaler, powder spray maceutical formulation comprises between 5 micrograms device, vaporizer, patch, medicated Stick, pipette, or jet of and 1 gram of the nicotinic acetylcholine receptor agonist liquid. per dose. In some embodiments, the pharmaceutical formu In a further embodiment of any of the aforementioned lation is administered at least once daily. In some embodi embodiments, the trigeminal nerve is activated. In a further 5 ments, the pharmaceutical formulation is administered at embodiment, the anterior ethmoidal nerve is activated. least twice daily. In some embodiments, the pharmaceutical In a further embodiment of any of the aforementioned formulation is administered for at least two days. In some embodiments, the nasolacrimal reflex is activated. embodiments, the pharmaceutical formulation is adminis Further provided herein, in some embodiments, is a tered into the nasal cavity as a liquid, Suspension, aerosol, pharmaceutical formulation for local administration in the 10 gel, ointment, dry powder, cream, paste, lotion, or balm. In nasal cavity of an individual comprising a nicotinic acetyl Some embodiments, the pharmaceutical formulation is choline receptor agonist formulated to prevent desensitiza administered into the nasal cavity by a syringe, dropper, tion and in a dosage amount that is not systemically bio bottle nebulizer, atomization pump, inhaler, powder spray available. In some embodiments is a pharmaceutical device, vaporizer, patch, medicated Stick, pipette, or jet of formulation for local administration in the nasal cavity of an 15 liquid. individual comprising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dos BRIEF DESCRIPTION OF THE DRAWINGS age amount that does not result in undesired psychoactive side effects. In some embodiments is a pharmaceutical FIG. 1 shows tear production in patients receiving OC-01 formulation for local administration in the nasal cavity of an compared to baseline and placebo. individual comprising a nicotinic acetylcholine receptor FIG. 2 depicts patient reported symptoms of dry eye in agonist formulated to prevent desensitization and in a dos patients receiving OC-01 versus placebo. age amount that does not result in undesired systemic side effects. In some embodiments, the pharmaceutical formula DETAILED DESCRIPTION OF THE tion further comprises one or more Substances selected from 25 INVENTION protein kinase C (PKC) or factors that upregulate or up modulate PKC. cAMP-dependent protein kinase (PKA) or The etiology of DED is becoming increasingly well factors that upregulate or up-modulate PKA, and calcineurin understood. DED is progressive in nature, and fundamen inhibitors. In some embodiments, the calcineurin inhibitor is tally results from insufficient tear coverage on the surface of selected from cyclosporine, pimecrolimus, and tacrolimus. 30 the eye. This poor tear coverage prevents healthy gas In some embodiments, the nicotinic acetylcholine receptor exchange and nutrient transport for the ocular Surface, agonist is selected from nicotine, cytisine, epibatidine, promotes cellular desiccation and creates a poor refractive varenicline, tebanicline, DBO-83, CC4, ABT-418, ABT surface for vision. Poor tear coverage typically results from: 366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA 1) insufficient aqueous tear production from the lacrimal 543613, PNU-282987, LY-2087101, A85380, and 5-I- 35 glands (e.g. secondary to post-menopausal hormonal defi A85380. In some embodiments, the nicotinic acetylcholine ciency, auto-immune disease, LASIK surgery, etc.), and/or receptor agonist is selected from a compound disclosed in 2) excessive evaporation of aqueous tear resulting from WO 2008/057938, WO 2009/111550, WO 2010/028011, or dysfunction of the meibomian glands. Low tear Volume WO 2010/028033. In some embodiments, the nicotinic causes a hyperosmolar environment that induces an inflamed acetylcholine receptor agonist selectively binds to at least 40 state of the ocular Surface. This inflammatory response one of the peripheral nicotinic acetylcholine receptor Sub induces apoptosis of the Surface cells which in turn prevents types selected from alpha3beta4, alpha-4beta2, and alpha7. proper distribution of the tear film on the ocular surface so In some embodiments, the pharmaceutical formulation com that any given tear volume is rendered less effective. This prises about 1 mg/mL of the nicotinic acetylcholine receptor initiates a vicious cycle where more inflammation can ensue agonist. In some embodiments, the pharmaceutical formu 45 causing more surface cell damage, etc. Additionally, the lation comprises about 10 mg/mL of the nicotinic acetyl neural control loop, which controls reflex tear activation, is choline receptor agonist. In some embodiments, the phar disrupted because the sensory neurons in the Surface of the maceutical formulation comprises at least 1 microgram of eye are damaged. As a result, fewer tears are secreted and a the nicotinic acetylcholine receptor agonist per dose. In second vicious cycle develops that results in further pro Some embodiments, the pharmaceutical formulation com 50 gression of the disease (fewer tears cause nerve cell loss, prises at least 5 micrograms of the nicotinic acetylcholine which results in fewer tears, etc.). receptor agonist per dose. In some embodiments, the phar There is a wide spectrum of treatments for DED, however, maceutical formulation comprises at least 10 micrograms of none provides substantial efficacy for treatment of the con the nicotinic acetylcholine receptor agonist per dose. In dition. Treatment options include: artificial tear substitutes, Some embodiments, the pharmaceutical formulation com 55 ointments, gels, warm compresses, environmental modifi prises at least 25 micrograms of the nicotinic acetylcholine cation, topical cyclosporine, omega-3 fatty acid Supple receptor agonist per dose. In some embodiments, the phar ments, punctal plugs and moisture chamber goggles. maceutical formulation comprises at least 50 micrograms of Patients with severe disease may further be treated with the nicotinic acetylcholine receptor agonist per dose. In punctal cautery, systemic cholinergic agonists, systemic Some embodiments, the pharmaceutical formulation com 60 anti-inflammatory agents, mucolytic agents, autologous prises at least 100 micrograms of the nicotinic acetylcholine serum tears, PROSE scleral contact lenses and tarsorrhaphy. receptor agonist per dose. In some embodiments, the phar Despite these treatment options, DED continues to be con maceutical formulation comprises at least 250 micrograms sidered one of the most poorly treated diseases in ophthal of the nicotinic acetylcholine receptor agonist per dose. In mology. Accordingly, it would be desirable to have a more Some embodiments, the pharmaceutical formulation com 65 effective treatment for dry eye. prises at least 500 micrograms of the nicotinic acetylcholine Nicotinic acetylcholine receptors are cholinergic recep receptor agonist per dose. In some embodiments, the phar tors found in the central nervous system (CNS), peripheral US 9,597,284 B2 11 12 nervous systems (PNS) and skeletal muscles. These recep embodiments, the one or more Substances that prevent or tors are ligand-gated ion channels with binding sites for facilitate the recovery of the nicotinic acetylcholine receptor acetylcholine and other molecules. When a nicotinic acetyl from the desensitized state are selected from protein kinase choline receptor agonist binds to the receptor, it stabilizes C (PKC) or factors that upregulate or up-modulate PKC. the open State of the ion channel allowing influx of cations cAMP-dependent protein kinase (PKA) or factors that Such as potassium, calcium and Sodium ions. upregulate or up-modulate PKA, and calcineurin inhibitors. Acting on the central nervous system, systemic nicotinic Further described herein are pharmaceutical formulations acetylcholine receptor agonists agonist are gaining attention for local administration into the nasal cavity of an individual as drug candidates for multiple disorders such as Alzheim comprising a nicotinic acetylcholine receptor agonist for er's disease, Parkinson's disease, Schizophrenia, attention 10 mulated to prevent desensitization. Also described herein are deficit hyperactivity disorder (ADHD), and nicotine addic pharmaceutical formulations for local administration into tion. However, systemic exposure of these central nervous the nasal cavity of an individual, further comprising one or system agents has been associated with a variety of unde more substances that prevent or facilitate the recovery of the sired psychoactive side effects including anxiety, depres nicotinic acetylcholine receptor from the desensitized State. sion, and irritability. 15 Also described herein are pharmaceutical formulations for Described herein are methods of treating ocular condi local administration into the nasal cavity of an individual, tions and/or improving ocular Surface health comprising the further comprising one or more Substances that prevent the local administration of a therapeutically effective amount of entry or reduce the entry of the nicotinic acetylcholine a nicotinic acetylcholine receptor agonist into the nasal receptor into the desensitized state, or facilitate the recovery cavity of an individual in need thereof, wherein the agonist of the nicotinic acetylcholine receptor from the desensitized selectively binds to the peripheral nicotinic acetylcholine state. Also described herein are pharmaceutical formulations receptor. In some embodiments the nicotinic acetylcholine for local administration into the nasal cavity of an indi receptor agonist binds to the peripheral nicotinic acetylcho vidual, further comprising one or more substances that line receptor and does not cross the blood-brain barrier in a prevent or facilitate the recovery of the nicotinic acetylcho pharmacologically relevant concentration. In some embodi 25 line receptor from the desensitized state, wherein the one or ments the nicotinic acetylcholine receptor agonist binds to more substances are selected from protein kinase C (PKC) the peripheral nicotinic acetylcholine receptor and does not or factors that upregulate or up-modulate PKC. cAMP cross the blood-brain barrier in a pharmacologically relevant dependent protein kinase (PKA) or factors that upregulate or concentration and is administered in an amount that is not up-modulate PKA, and calcineurin inhibitors. Also systemically bioavailable. In some embodiments the nico 30 described herein are pharmaceutical formulations for local tinic acetylcholine receptor agonist binds to the peripheral administration into the nasal cavity of an individual, further nicotinic acetylcholine receptor and does not cross the comprising one or more substances that prevent the entry or blood-brain barrier in a pharmacologically relevant concen reduce the entry of the nicotinic acetylcholine receptor into tration and is administered in an amount that does not result the desensitized state, or facilitate the recovery of the in undesired psychoactive side effects. In some embodi 35 nicotinic acetylcholine receptor from the desensitized State, ments the nicotinic acetylcholine receptor agonist binds to wherein the one or more substances are selected from the peripheral nicotinic acetylcholine receptor and does not protein kinase C (PKC) or factors that upregulate or up cross the blood-brain barrier in a pharmacologically relevant modulate PKC. cAMP-dependent protein kinase (PKA) or concentration and is administered in an amount that does not factors that upregulate or up-modulate PKA, and calcineurin result in undesired systemic side effects. 40 inhibitors. Prolonged or repeat exposure to a stimulus often results in Increased Tear Production decreased responsiveness of that receptor toward a stimulus, Provided herein, in some embodiments, is a method of termed desensitization. It has been reported that, after pro increasing tear production in a subject. In some embodi longed nicotinic acetylcholine receptor exposure to an ago ments, is a method of increasing tear production, comprising nist, the agonist itself causes an agonist-induced conforma 45 the local administration of a therapeutically effective amount tional change in the receptor, resulting in receptor of a nicotinic acetylcholine receptor agonist into the nasal desensitization. cavity of an individual in need thereof, wherein the agonist Described herein are methods of treating ocular condi selectively binds to the peripheral nicotinic acetylcholine tions and/or improving ocular Surface health comprising the receptor and does not cross the blood-brain barrier in a local administration of a therapeutically effective amount of 50 pharmacologically relevant concentration. In some embodi a nicotinic acetylcholine receptor agonist into the nasal ments is method of increasing tear production, comprising cavity of an individual in need thereof, wherein the agonist the local administration of a therapeutically effective amount selectively binds to the peripheral nicotinic acetylcholine of a nicotinic acetylcholine receptor agonist into the nasal receptor, further comprising the local administration of one cavity of an individual in need thereof, wherein the agonist or more substances that prevent or facilitate the recovery of 55 does not cross the blood-brain barrier in a pharmacologically the nicotinic acetylcholine receptor from the desensitized relevant concentration and selectively binds to at least one of state. Also described herein are methods of treating ocular the peripheral nicotinic acetylcholine receptor Subtypes conditions and/or improving ocular Surface health compris selected from alpha3beta4, alpha-4beta2, and alpha7. In ing the local administration of a therapeutically effective Some embodiments is method of increasing tear production, amount of a nicotinic acetylcholine receptor agonist into the 60 comprising the local administration of a therapeutically nasal cavity of an individual in need thereof, wherein the effective amount of a nicotinic acetylcholine receptor ago agonist selectively binds to the peripheral nicotinic acetyl nist into the nasal cavity of an individual in need thereof, choline receptor, further comprising the local administration wherein the agonist does not cross the blood-brain barrier in of one or more Substances that prevent the entry or reduce a pharmacologically relevant concentration and selectively the entry of the nicotinic acetylcholine receptor into the 65 binds to the peripheral nicotinic acetylcholine receptor sub desensitized state, or facilitate the recovery of the nicotinic type alpha3beta4. In some embodiments is method of acetylcholine receptor from the desensitized state. In some increasing tear production, comprising the local administra US 9,597,284 B2 13 14 tion of a therapeutically effective amount of a nicotinic Some embodiments is a method of increasing tear produc acetylcholine receptor agonist into the nasal cavity of an tion, further comprising the local administration of a cal individual in need thereof, wherein the agonist does not cineurin inhibitor. In some embodiments is a method of cross the blood-brain barrier in a pharmacologically relevant increasing tear production, further comprising the local concentration and selectively binds to the peripheral nico administration of a calcineurin inhibitor, wherein the cal tinic acetylcholine receptor Subtype alpha-4beta2. In some cineurin inhibitor is selected from cyclosporine, pimecroli embodiments is method of increasing tear production, com mus, and tacrolimus. In some embodiments is a method of prising the local administration of a therapeutically effective increasing tear production, further comprising the local amount of a nicotinic acetylcholine receptor agonist into the administration of cyclosporine. In some embodiments is a nasal cavity of an individual in need thereof, wherein the 10 agonist does not cross the blood-brain barrier in a pharma method of increasing tear production, further comprising the cologically relevant concentration and selectively binds to local administration of pimecrolimus. In some embodiments the peripheral nicotinic acetylcholine receptor Subtype is a method of increasing tear production, further comprising alpha7. In some embodiments is a method of increasing tear the local administration of tacrolimus. production, comprising the local administration of a thera 15 In a further embodiment of any of the aforementioned peutically effective amount of a nicotinic acetylcholine embodiments of increasing tear production, the nicotinic receptoragonist into the nasal cavity of an individual in need acetylcholine receptor agonist is selected from nicotine, thereof, wherein the agonist selectively binds to the periph cytisine, epibatidine, Varenicline, tebanicline, DBO-83, eral nicotinic acetylcholine receptor and is administered in CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB an amount that is not systemically bioavailable. In some 1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, embodiments is a method of increasing tear production, A85380, and 5-I-A85380. In another embodiment of any of comprising the local administration of a therapeutically the aforementioned embodiments of increasing tear produc effective amount of a nicotinic acetylcholine receptor ago tion, the nicotinic acetylcholine receptor agonist is nicotine. nist into the nasal cavity of an individual in need thereof, In another embodiment of any of the aforementioned wherein the agonist selectively binds to the peripheral 25 embodiments of increasing tear production, the nicotinic nicotinic acetylcholine receptor and in an amount that does acetylcholine receptor agonist is cytisine. In another not result in undesired psychoactive side effects. In some embodiment of any of the aforementioned embodiments of embodiments is a method of increasing tear production, increasing tear production, the nicotinic acetylcholine recep comprising the local administration of a therapeutically tor agonist is epibatidine. In another embodiment of any of effective amount of a nicotinic acetylcholine receptor ago 30 the aforementioned embodiments of increasing tear produc nist into the nasal cavity of an individual in need thereof, wherein the agonist selectively binds to the peripheral tion, the nicotinic acetylcholine receptor agonist is Vareni nicotinic acetylcholine receptor and in an amount that does cline. In another embodiment of any of the aforementioned not result in undesired systemic side effects. In some embodiments of increasing tear production, the nicotinic embodiments is a method of increasing tear production, 35 acetylcholine receptor agonist is tebanicline. In another further comprising the local administration of one or more embodiment of any of the aforementioned embodiments of substances that prevent or facilitate the recovery of the increasing tear production, the nicotinic acetylcholine recep nicotinic acetylcholine receptor from the desensitized State. toragonist is DBO-83. In another embodiment of any of the In some embodiments is a method of increasing tear pro aforementioned embodiments of increasing tear production, duction, further comprising the local administration of one 40 the nicotinic acetylcholine receptor agonist is CC4. In or more substances that prevent the entry or reduce the entry another embodiment of any of the aforementioned embodi of the nicotinic acetylcholine receptor into the desensitized ments of increasing tear production, the nicotinic acetylcho state, or facilitate the recovery of the nicotinic acetylcholine line receptor agonist is ABT-418. In another embodiment of receptor from the desensitized state. any of the aforementioned embodiments of increasing tear In Some embodiments is a method of increasing tear 45 production, the nicotinic acetylcholine receptor agonist is production, further comprising the local administration of ABT-366833. In another embodiment of any of the afore one or more substances that prevent or facilitate the recovery mentioned embodiments of increasing tear production, the of the nicotinic acetylcholine receptor from the desensitized nicotinic acetylcholine receptor agonist is ABT-202. In state selected from protein kinase C (PKC) or factors that another embodiment of any of the aforementioned embodi upregulate or up-modulate PKC. cAMP-dependent protein 50 ments of increasing tear production, the nicotinic acetylcho kinase (PKA) or factors that upregulate or up-modulate line receptor agonist is ABT-894. In another embodiment of PKA, and calcineurin inhibitors. In some embodiments is a any of the aforementioned embodiments of increasing tear method of increasing tear production, further comprising the production, the nicotinic acetylcholine receptor agonist is local administration of one or more substances that prevent SIB-1663. In another embodiment of any of the aforemen the entry or reduce the entry of the nicotinic acetylcholine 55 tioned embodiments of increasing tear production, the nico receptor into the desensitized state, or facilitate the recovery tinic acetylcholine receptor agonist is GTS-21. In another of the nicotinic acetylcholine receptor from the desensitized embodiment of any of the aforementioned embodiments of state selected from protein kinase C (PKC) or factors that increasing tear production, the nicotinic acetylcholine recep upregulate or up-modulate PKC. cAMP-dependent protein tor agonist is PHA-543,613. In another embodiment of any kinase (PKA) or factors that upregulate or up-modulate 60 of the aforementioned embodiments of increasing tear pro PKA, and calcineurin inhibitors. In some embodiments is a duction, the nicotinic acetylcholine receptoragonist is PNU method of increasing tear production, further comprising the 282987. In another embodiment of any of the aforemen local administration of protein kinase C (PKC) or factors tioned embodiments of increasing tear production, the that upregulate or up-modulate PKC. In some embodiments nicotinic acetylcholine receptor agonist is LY-2087101. In is a method of increasing tear production, further comprising 65 another embodiment of any of the aforementioned embodi the local administration of cAMP-dependent protein kinase ments of increasing tear production, the nicotinic acetylcho (PKA) or factors that upregulate or up-modulate PKA. In line receptor agonist is A85380. In another embodiment of US 9,597,284 B2 15 16 any of the aforementioned embodiments of increasing tear embodiments of increasing tear production, between 50 production, the nicotinic acetylcholine receptor agonist is micrograms and 1000 micrograms of the nicotinic acetyl 5-I-A85380. choline receptoragonist is administered into the nasal cavity. In a further embodiment of any of the aforementioned In another embodiment of any of the aforementioned embodiments of increasing tear production, the nicotinic 5 embodiments of increasing tear production, between 100 acetylcholine receptor agonist is selected from a compound micrograms and 1000 micrograms of the nicotinic acetyl disclosed in WO 2008/057938, WO 2009/111550, WO choline receptoragonist is administered into the nasal cavity. 2010/028011, or WO 2010/028033. In another embodiment of any of the aforementioned In another embodiment of any of the aforementioned embodiments of increasing tear production, between 100 embodiments of increasing tear production, at least 1 micro 10 gram of the nicotinic acetylcholine receptor agonist is micrograms and 750 micrograms of the nicotinic acetylcho administered into the nasal cavity. In another embodiment of line receptor agonist is administered into the nasal cavity. In any of the aforementioned embodiments of increasing tear another embodiment of any of the aforementioned embodi production, at least 5 micrograms of the nicotinic acetyl ments of increasing tear production, between 150 micro choline receptoragonist is administered into the nasal cavity. 15 grams and 750 micrograms of the nicotinic acetylcholine In another embodiment of any of the aforementioned receptor agonist is administered into the nasal cavity. In embodiments of increasing tear production, at least 10 another embodiment of any of the aforementioned embodi micrograms of the nicotinic acetylcholine receptoragonist is ments of increasing tear production, between 150 micro administered into the nasal cavity. In another embodiment of grams and 600 micrograms of the nicotinic acetylcholine any of the aforementioned embodiments of increasing tear receptor agonist is administered into the nasal cavity. production, at least 25 micrograms of the nicotinic acetyl In another embodiment of any of the aforementioned choline receptoragonist is administered into the nasal cavity. embodiments of increasing tear production, the nicotinic In another embodiment of any of the aforementioned acetylcholine receptor agonist is administered once daily. In embodiments of increasing tear production, at least 50 another embodiment of any of the aforementioned embodi micrograms of the nicotinic acetylcholine receptoragonist is 25 ments of increasing tear production, the nicotinic acetylcho administered into the nasal cavity. In another embodiment of line receptor agonist is administered at least once daily. In any of the aforementioned embodiments of increasing tear another embodiment of any of the aforementioned embodi production, at least 100 micrograms of the nicotinic acetyl ments of increasing tear production, the nicotinic acetylcho choline receptoragonist is administered into the nasal cavity. line receptor agonist is administered twice daily. In another In another embodiment of any of the aforementioned 30 embodiments of increasing tear production, at least 250 embodiment of any of the aforementioned embodiments of micrograms of the nicotinic acetylcholine receptor agonist is increasing tear production, the nicotinic acetylcholine recep administered into the nasal cavity. In another embodiment of tor agonist is administered at least twice daily. In another any of the aforementioned embodiments of increasing tear embodiment of any of the aforementioned embodiments of production, at least 500 micrograms of the nicotinic acetyl 35 increasing tear production, the nicotinic acetylcholine recep choline receptoragonist is administered into the nasal cavity. tor agonist is administered three times daily. In another In another embodiment of any of the aforementioned embodiment of any of the aforementioned embodiments of embodiments of increasing tear production, at least 750 increasing tear production, the nicotinic acetylcholine recep micrograms of the nicotinic acetylcholine receptoragonist is tor agonist is administered at least three times daily. In administered into the nasal cavity. In another embodiment of 40 another embodiment of any of the aforementioned embodi any of the aforementioned embodiments of increasing tear ments of increasing tear production, the nicotinic acetylcho production, at least 1000 micrograms of the nicotinic ace line receptor agonist is administered for one day. In another tylcholine receptor agonist is administered into the nasal embodiment of any of the aforementioned embodiments of cavity. In another embodiment of any of the aforementioned increasing tear production, the nicotinic acetylcholine recep embodiments of increasing tear production, between 1 45 tor agonist is administered for at least two days. In another microgram and 1000 micrograms of the nicotinic acetylcho embodiment of any of the aforementioned embodiments of line receptoragonist is administered into the nasal cavity. In increasing tear production, the nicotinic acetylcholine recep another embodiment of any of the aforementioned embodi toragonist is administered for at least three days. In another ments of increasing tear production, between 5 micrograms embodiment of any of the aforementioned embodiments of and 1000 micrograms of the nicotinic acetylcholine receptor 50 increasing tear production, the nicotinic acetylcholine recep agonist is administered into the nasal cavity. In another tor agonist is administered for at least four days. In another embodiment of any of the aforementioned embodiments of embodiment of any of the aforementioned embodiments of increasing tear production, between 5 micrograms and 100 increasing tear production, the nicotinic acetylcholine recep micrograms of the nicotinic acetylcholine receptoragonist is tor agonist is administered for at least five days. In another administered into the nasal cavity. In another embodiment of 55 embodiment of any of the aforementioned embodiments of any of the aforementioned embodiments of increasing tear increasing tear production, the nicotinic acetylcholine recep production, between 5 micrograms and 50 micrograms of toragonist is administered for at least seven days. In another the nicotinic acetylcholine receptor agonist is administered embodiment of any of the aforementioned embodiments of into the nasal cavity. In another embodiment of any of the increasing tear production, the nicotinic acetylcholine recep aforementioned embodiments of increasing tear production, 60 tor agonist is administered for at least ten days. In another between 10 micrograms and 50 micrograms of the nicotinic embodiment of any of the aforementioned embodiments of acetylcholine receptor agonist is administered into the nasal increasing tear production, the nicotinic acetylcholine recep cavity. In another embodiment of any of the aforementioned tor agonist is administered for at least fourteen days. In embodiments of increasing tear production, between 25 another embodiment of any of the aforementioned embodi micrograms and 1000 micrograms of the nicotinic acetyl 65 ments of increasing tear production, the nicotinic acetylcho choline receptoragonist is administered into the nasal cavity. line receptor agonist is administered for at least twenty one In another embodiment of any of the aforementioned days. In another embodiment of any of the aforementioned US 9,597,284 B2 17 18 embodiments of increasing tear production, the nicotinic cavity by an inhaler. In another embodiment of any of the acetylcholine receptor agonist is administered for at least aforementioned embodiments of increasing tear production, thirty days. the nicotinic acetylcholine receptor agonist is administered In another embodiment of any of the aforementioned into the nasal cavity by a powder spray device. In another embodiments of increasing tear production, the nicotinic embodiment of any of the aforementioned embodiments of acetylcholine receptor agonist is administered in alternating increasing tear production, the nicotinic acetylcholine recep nostrils. tor agonist is administered into the nasal cavity by a vapor In another embodiment of any of the aforementioned izer. In another embodiment of any of the aforementioned embodiments of increasing tear production, the nicotinic embodiments of increasing tear production, the nicotinic acetylcholine receptor agonist is administered into the nasal 10 acetylcholine receptor agonist is administered into the nasal cavity as a liquid, Suspension, aerosol, gel, ointment, dry cavity by a patch. In another embodiment of any of the powder, cream, paste, lotion, or balm. In another embodi aforementioned embodiments of increasing tear production, ment of any of the aforementioned embodiments of increas the nicotinic acetylcholine receptor agonist is administered ing tear production, the nicotinic acetylcholine receptor into the nasal cavity by a medicated Stick. In another agonist is administered into the nasal cavity as a liquid. In 15 embodiment of any of the aforementioned embodiments of another embodiment of any of the aforementioned embodi increasing tear production, the nicotinic acetylcholine recep ments of increasing tear production, the nicotinic acetylcho toragonist is administered into the nasal cavity by a pipette. line receptor agonist is administered into the nasal cavity as In another embodiment of any of the aforementioned a Suspension. In another embodiment of any of the afore embodiments of increasing tear production, the nicotinic mentioned embodiments of increasing tear production, the acetylcholine receptor agonist is administered into the nasal nicotinic acetylcholine receptor agonist is administered into cavity by a jet of liquid. the nasal cavity as an aerosol. In another embodiment of any In another embodiment of any of the aforementioned of the aforementioned embodiments of increasing tear pro embodiments of increasing tear production, the trigeminal duction, the nicotinic acetylcholine receptor agonist is nerve is activated. In a further embodiment of increasing tear administered into the nasal cavity as a gel. In another 25 production, the anterior ethmoidal nerve is activated. In embodiment of any of the aforementioned embodiments of another embodiment of any of the aforementioned embodi increasing tear production, the nicotinic acetylcholine recep ments of increasing tear production, the nasolacrimal reflex tor agonist is administered into the nasal cavity as an is activated. ointment. In another embodiment of any of the aforemen Treating Dry Eye tioned embodiments of increasing tear production, the nico 30 Provided herein, in some embodiments, is a method of tinic acetylcholine receptor agonist is administered into the treating dry eye in a Subject. In some embodiments, is a nasal cavity as a dry powder. In another embodiment of any method of treating dry eye, comprising the local adminis of the aforementioned embodiments of increasing tear pro tration of a therapeutically effective amount of a nicotinic duction, the nicotinic acetylcholine receptor agonist is acetylcholine receptor agonist into the nasal cavity of an administered into the nasal cavity as a cream. In another 35 individual in need thereof, wherein the agonist selectively embodiment of any of the aforementioned embodiments of binds to the peripheral nicotinic acetylcholine receptor and increasing tear production, the nicotinic acetylcholine recep does not cross the blood-brain barrier in a pharmacologically tor agonist is administered into the nasal cavity as a paste. relevant concentration. In some embodiments is method of In another embodiment of any of the aforementioned treating dry eye, comprising the local administration of a embodiments of increasing tear production, the nicotinic 40 therapeutically effective amount of a nicotinic acetylcholine acetylcholine receptor agonist is administered into the nasal receptoragonist into the nasal cavity of an individual in need cavity as a lotion. In another embodiment of any of the thereof, wherein the agonist does not cross the blood-brain aforementioned embodiments of increasing tear production, barrier in a pharmacologically relevant concentration and the nicotinic acetylcholine receptor agonist is administered selectively binds to at least one of the peripheral nicotinic into the nasal cavity as a balm. 45 acetylcholine receptor subtypes selected from alpha3beta4, In another embodiment of any of the aforementioned alpha-4beta2, and alpha7. In some embodiments is method of embodiments of increasing tear production, the nicotinic treating dry eye, comprising the local administration of a acetylcholine receptor agonist is administered into the nasal therapeutically effective amount of a nicotinic acetylcholine cavity by a syringe, dropper, bottle nebulizer, atomization receptoragonist into the nasal cavity of an individual in need pump, inhaler, powder spray device, vaporizer, patch, medi 50 thereof, wherein the agonist does not cross the blood-brain cated Stick, pipette, or jet of liquid. In another embodiment barrier in a pharmacologically relevant concentration and of any of the aforementioned embodiments of increasing selectively binds to the peripheral nicotinic acetylcholine tear production, the nicotinic acetylcholine receptor agonist receptor Subtype alpha3beta4. In some embodiments is is administered into the nasal cavity by a Syringe. In another method of treating dry eye, comprising the local adminis embodiment of any of the aforementioned embodiments of 55 tration of a therapeutically effective amount of a nicotinic increasing tear production, the nicotinic acetylcholine recep acetylcholine receptor agonist into the nasal cavity of an toragonist is administered into the nasal cavity by a dropper. individual in need thereof, wherein the agonist does not In another embodiment of any of the aforementioned cross the blood-brain barrier in a pharmacologically relevant embodiments of increasing tear production, the nicotinic concentration and selectively binds to the peripheral nico acetylcholine receptor agonist is administered into the nasal 60 tinic acetylcholine receptor Subtype alpha-4beta2. In some cavity by a bottle nebulizer. In another embodiment of any embodiments is method of treating dry eye, comprising the of the aforementioned embodiments of increasing tear pro local administration of a therapeutically effective amount of duction, the nicotinic acetylcholine receptor agonist is a nicotinic acetylcholine receptor agonist into the nasal administered into the nasal cavity by an atomization pump. cavity of an individual in need thereof, wherein the agonist In another embodiment of any of the aforementioned 65 does not cross the blood-brain barrier in a pharmacologically embodiments of increasing tear production, the nicotinic relevant concentration and selectively binds to the peripheral acetylcholine receptor agonist is administered into the nasal nicotinic acetylcholine receptor Subtype alpha7. In some

US 9,597,284 B2 21 22 embodiments of treating dry eye, at least 50 micrograms of the nicotinic acetylcholine receptor agonist is administered the nicotinic acetylcholine receptor agonist is administered twice daily. In another embodiment of any of the aforemen into the nasal cavity. In another embodiment of any of the tioned embodiments of treating dry eye, the nicotinic ace aforementioned embodiments of treating dry eye, at least tylcholine receptor agonist is administered at least twice 100 micrograms of the nicotinic acetylcholine receptor daily. In another embodiment of any of the aforementioned agonist is administered into the nasal cavity. In another embodiments of treating dry eye, the nicotinic acetylcholine embodiment of any of the aforementioned embodiments of receptor agonist is administered three times daily. In another treating dry eye, at least 250 micrograms of the nicotinic embodiment of any of the aforementioned embodiments of acetylcholine receptor agonist is administered into the nasal treating dry eye, the nicotinic acetylcholine receptor agonist cavity. In another embodiment of any of the aforementioned 10 is administered at least three times daily. In another embodi embodiments of treating dry eye, at least 500 micrograms of ment of any of the aforementioned embodiments of treating the nicotinic acetylcholine receptor agonist is administered dry eye, the nicotinic acetylcholine receptor agonist is into the nasal cavity. In another embodiment of any of the administered for one day. In another embodiment of any of aforementioned embodiments of treating dry eye, at least the aforementioned embodiments of treating dry eye, the 750 micrograms of the nicotinic acetylcholine receptor 15 nicotinic acetylcholine receptor agonist is administered for agonist is administered into the nasal cavity. In another at least two days. In another embodiment of any of the embodiment of any of the aforementioned embodiments of aforementioned embodiments of treating dry eye, the nico treating dry eye, at least 1000 micrograms of the nicotinic tinic acetylcholine receptor agonist is administered for at acetylcholine receptor agonist is administered into the nasal least three days. In another embodiment of any of the cavity. In another embodiment of any of the aforementioned aforementioned embodiments of treating dry eye, the nico embodiments of treating dry eye, between 1 microgram and tinic acetylcholine receptor agonist is administered for at 1000 micrograms of the nicotinic acetylcholine receptor least four days. In another embodiment of any of the agonist is administered into the nasal cavity. In another aforementioned embodiments of treating dry eye, the nico embodiment of any of the aforementioned embodiments of tinic acetylcholine receptor agonist is administered for at treating dry eye, between 5 micrograms and 1000 micro 25 least five days. In another embodiment of any of the afore grams of the nicotinic acetylcholine receptor agonist is mentioned embodiments of treating dry eye, the nicotinic administered into the nasal cavity. In another embodiment of acetylcholine receptor agonist is administered for at least any of the aforementioned embodiments of treating dry eye, seven days. In another embodiment of any of the aforemen between 5 micrograms and 100 micrograms of the nicotinic tioned embodiments of treating dry eye, the nicotinic ace acetylcholine receptor agonist is administered into the nasal 30 tylcholine receptor agonist is administered for at least ten cavity. In another embodiment of any of the aforementioned days. In another embodiment of any of the aforementioned embodiments of treating dry eye, between 5 micrograms and embodiments of treating dry eye, the nicotinic acetylcholine 50 micrograms of the nicotinic acetylcholine receptor ago receptor agonist is administered for at least fourteen days. In nist is administered into the nasal cavity. In another embodi another embodiment of any of the aforementioned embodi ment of any of the aforementioned embodiments of treating 35 ments of treating dry eye, the nicotinic acetylcholine recep dry eye, between 10 micrograms and 50 micrograms of the tor agonist is administered for at least twenty one days. In nicotinic acetylcholine receptor agonist is administered into another embodiment of any of the aforementioned embodi the nasal cavity. In another embodiment of any of the ments of treating dry eye, the nicotinic acetylcholine recep aforementioned embodiments of treating dry eye, between tor agonist is administered for at least thirty days. 25 micrograms and 1000 micrograms of the nicotinic ace 40 In another embodiment of any of the aforementioned tylcholine receptor agonist is administered into the nasal embodiments of treating dry eye, the nicotinic acetylcholine cavity. In another embodiment of any of the aforementioned receptor agonist is administered in alternating nostrils. embodiments of treating dry eye, between 50 micrograms In another embodiment of any of the aforementioned and 1000 micrograms of the nicotinic acetylcholine receptor embodiments of treating dry eye, the nicotinic acetylcholine agonist is administered into the nasal cavity. In another 45 receptor agonist is administered into the nasal cavity as a embodiment of any of the aforementioned embodiments of liquid, Suspension, aerosol, gel, ointment, dry powder, treating dry eye, between 100 micrograms and 1000 micro cream, paste, lotion, or balm. In another embodiment of any grams of the nicotinic acetylcholine receptor agonist is of the aforementioned embodiments of treating dry eye, the administered into the nasal cavity. In another embodiment of nicotinic acetylcholine receptor agonist is administered into any of the aforementioned embodiments of treating dry eye, 50 the nasal cavity as a liquid. In another embodiment of any between 100 micrograms and 750 micrograms of the nico of the aforementioned embodiments of treating dry eye, the tinic acetylcholine receptor agonist is administered into the nicotinic acetylcholine receptor agonist is administered into nasal cavity. In another embodiment of any of the afore the nasal cavity as a suspension. In another embodiment of mentioned embodiments of treating dry eye, between 150 any of the aforementioned embodiments of treating dry eye, micrograms and 750 micrograms of the nicotinic acetylcho 55 the nicotinic acetylcholine receptor agonist is administered line receptoragonist is administered into the nasal cavity. In into the nasal cavity as an aerosol. In another embodiment another embodiment of any of the aforementioned embodi of any of the aforementioned embodiments of treating dry ments of treating dry eye, between 150 micrograms and 600 eye, the nicotinic acetylcholine receptor agonist is admin micrograms of the nicotinic acetylcholine receptoragonist is istered into the nasal cavity as a gel. In another embodiment administered into the nasal cavity. 60 of any of the aforementioned embodiments of treating dry In another embodiment of any of the aforementioned eye, the nicotinic acetylcholine receptor agonist is admin embodiments of treating dry eye, the nicotinic acetylcholine istered into the nasal cavity as an ointment. In another receptor agonist is administered once daily. In another embodiment of any of the aforementioned embodiments of embodiment of any of the aforementioned embodiments of treating dry eye, the nicotinic acetylcholine receptor agonist treating dry eye, the nicotinic acetylcholine receptor agonist 65 is administered into the nasal cavity as a dry powder. In is administered at least once daily. In another embodiment of another embodiment of any of the aforementioned embodi any of the aforementioned embodiments of treating dry eye, ments of treating dry eye, the nicotinic acetylcholine recep US 9,597,284 B2 23 24 tor agonist is administered into the nasal cavity as a cream. in a pharmacologically relevant concentration. In some In another embodiment of any of the aforementioned embodiments is method of improving ocular discomfort, embodiments of treating dry eye, the nicotinic acetylcholine comprising the local administration of a therapeutically receptor agonist is administered into the nasal cavity as a effective amount of a nicotinic acetylcholine receptor ago paste. In another embodiment of any of the aforementioned 5 nist into the nasal cavity of an individual in need thereof, embodiments of treating dry eye, the nicotinic acetylcholine wherein the agonist does not cross the blood-brain barrier in receptor agonist is administered into the nasal cavity as a a pharmacologically relevant concentration and selectively lotion. In another embodiment of any of the aforementioned binds to at least one of the peripheral nicotinic acetylcholine embodiments of treating dry eye, the nicotinic acetylcholine receptor subtypes selected from alpha3beta4, alpha-4-beta2. receptor agonist is administered into the nasal cavity as a 10 and alpha7. In some embodiments is method of improving balm. ocular discomfort, comprising the local administration of a In another embodiment of any of the aforementioned therapeutically effective amount of a nicotinic acetylcholine embodiments of treating dry eye, the nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need receptor agonist is administered into the nasal cavity by a thereof, wherein the agonist does not cross the blood-brain Syringe, dropper, bottle nebulizer, atomization pump, 15 barrier in a pharmacologically relevant concentration and inhaler, powder spray device, vaporizer, patch, medicated selectively binds to the peripheral nicotinic acetylcholine Stick, pipette, or jet of liquid. In another embodiment of any receptor Subtype alpha3beta4. In some embodiments is of the aforementioned embodiments of treating dry eye, the method of improving ocular discomfort, comprising the nicotinic acetylcholine receptor agonist is administered into local administration of a therapeutically effective amount of the nasal cavity by a syringe. In another embodiment of any a nicotinic acetylcholine receptor agonist into the nasal of the aforementioned embodiments of treating dry eye, the cavity of an individual in need thereof, wherein the agonist nicotinic acetylcholine receptor agonist is administered into does not cross the blood-brain barrier in a pharmacologically the nasal cavity by a dropper. In another embodiment of any relevant concentration and selectively binds to the peripheral of the aforementioned embodiments of treating dry eye, the nicotinic acetylcholine receptor Subtype alpha-4beta2. In nicotinic acetylcholine receptor agonist is administered into 25 Some embodiments is method of improving ocular discom the nasal cavity by a bottle nebulizer. In another embodiment fort, comprising the local administration of a therapeutically of any of the aforementioned embodiments of treating dry effective amount of a nicotinic acetylcholine receptor ago eye, the nicotinic acetylcholine receptor agonist is admin nist into the nasal cavity of an individual in need thereof, istered into the nasal cavity by an atomization pump. In wherein the agonist does not cross the blood-brain barrier in another embodiment of any of the aforementioned embodi 30 a pharmacologically relevant concentration and selectively ments of treating dry eye, the nicotinic acetylcholine recep binds to the peripheral nicotinic acetylcholine receptor sub tor agonist is administered into the nasal cavity by an type alpha7. In some embodiments is a method of improving inhaler. In another embodiment of any of the aforemen ocular discomfort, comprising the local administration of a tioned embodiments of treating dry eye, the nicotinic ace therapeutically effective amount of a nicotinic acetylcholine tylcholine receptor agonist is administered into the nasal 35 receptoragonist into the nasal cavity of an individual in need cavity by a powder spray device. In another embodiment of thereof, wherein the agonist selectively binds to the periph any of the aforementioned embodiments of treating dry eye, eral nicotinic acetylcholine receptor and is administered in the nicotinic acetylcholine receptor agonist is administered an amount that is not systemically bioavailable. In some into the nasal cavity by a vaporizer. In another embodiment embodiments is a method of improving ocular discomfort, of any of the aforementioned embodiments of treating dry 40 comprising the local administration of a therapeutically eye, the nicotinic acetylcholine receptor agonist is admin effective amount of a nicotinic acetylcholine receptor ago istered into the nasal cavity by a patch. In another embodi nist into the nasal cavity of an individual in need thereof, ment of any of the aforementioned embodiments of treating wherein the agonist selectively binds to the peripheral dry eye, the nicotinic acetylcholine receptor agonist is nicotinic acetylcholine receptor and in an amount that does administered into the nasal cavity by a medicated Stick. In 45 not result in undesired psychoactive side effects. In some another embodiment of any of the aforementioned embodi embodiments is a method of improving ocular discomfort, ments of treating dry eye, the nicotinic acetylcholine recep comprising the local administration of a therapeutically toragonist is administered into the nasal cavity by a pipette. effective amount of a nicotinic acetylcholine receptor ago In another embodiment of any of the aforementioned nist into the nasal cavity of an individual in need thereof, embodiments of treating dry eye, the nicotinic acetylcholine 50 wherein the agonist selectively binds to the peripheral receptor agonist is administered into the nasal cavity by a jet nicotinic acetylcholine receptor and in an amount that does of liquid. not result in undesired systemic side effects. In some In another embodiment of any of the aforementioned embodiments is a method of improving ocular discomfort, embodiments of treating dry eye, the trigeminal nerve is further comprising the local administration of one or more activated. In a further embodiment of treating dry eye, the 55 substances that prevent or facilitate the recovery of the anterior ethmoidal nerve is activated. In another embodi nicotinic acetylcholine receptor from the desensitized State. ment of any of the aforementioned embodiments of treating In some embodiments is a method of improving ocular dry eye, the nasolacrimal reflex is activated. discomfort, further comprising the local administration of Improved Ocular Discomfort one or more Substances that prevent the entry or reduce the Provided herein, in some embodiments, is a method of 60 entry of the nicotinic acetylcholine receptor into the desen improving ocular discomfort in a subject. In some embodi sitized state, or facilitate the recovery of the nicotinic ments, is a method of improving ocular discomfort, com acetylcholine receptor from the desensitized state. In some prising the local administration of a therapeutically effective embodiments is a method of improving ocular discomfort, amount of a nicotinic acetylcholine receptor agonist into the further comprising the local administration of one or more nasal cavity of an individual in need thereof, wherein the 65 substances that prevent or facilitate the recovery of the agonist selectively binds to the peripheral nicotinic acetyl nicotinic acetylcholine receptor from the desensitized State choline receptor and does not cross the blood-brain barrier selected from protein kinase C(PKC) or factors that upregu US 9,597,284 B2 25 26 late or up-modulate PKC. cAMP-dependent protein kinase ABT-894. In another embodiment of any of the aforemen (PKA) or factors that upregulate or up-modulate PKA, and tioned embodiments of improving ocular discomfort, the calcineurin inhibitors. In some embodiments is a method of nicotinic acetylcholine receptor agonist is SIB-1663. In improving ocular discomfort, further comprising the local another embodiment of any of the aforementioned embodi administration of one or more substances that prevent the 5 ments of improving ocular discomfort, the nicotinic acetyl entry or reduce the entry of the nicotinic acetylcholine choline receptor agonist is GTS-21. In another embodiment receptor into the desensitized state, or facilitate the recovery of any of the aforementioned embodiments of improving of the nicotinic acetylcholine receptor from the desensitized ocular discomfort, the nicotinic acetylcholine receptor ago state selected from protein kinase C (PKC) or factors that nist is PHA-543,613. In another embodiment of any of the upregulate or up-modulate PKC. cAMP-dependent protein 10 aforementioned embodiments of improving ocular discom kinase (PKA) or factors that upregulate or up-modulate fort, the nicotinic acetylcholine receptor agonist is PNU PKA, and calcineurin inhibitors. In some embodiments is a 282987. In another embodiment of any of the aforemen method of improving ocular discomfort, further comprising tioned embodiments of improving ocular discomfort, the the local administration of protein kinase C (PKC) or factors nicotinic acetylcholine receptor agonist is LY-2087101. In that upregulate or up-modulate PKC. In some embodiments 15 another embodiment of any of the aforementioned embodi is a method of improving ocular discomfort, further com ments of improving ocular discomfort, the nicotinic acetyl prising the local administration of cAMP-dependent protein choline receptor agonist is A85380. In another embodiment kinase (PKA) or factors that upregulate or up-modulate of any of the aforementioned embodiments of improving PKA. In some embodiments is a method of improving ocular ocular discomfort, the nicotinic acetylcholine receptor ago discomfort, further comprising the local administration of a nist is 5-I-A85380. calcineurin inhibitor. In some embodiments is a method of In a further embodiment of any of the aforementioned improving ocular discomfort, further comprising the local embodiments of improving ocular discomfort, the nicotinic administration of a calcineurin inhibitor, wherein the cal acetylcholine receptor agonist is selected from a compound cineurin inhibitor is selected from cyclosporine, pimecroli disclosed in WO 2008/057938, WO 2009/111550, WO mus, and tacrolimus. In some embodiments is a method of 25 2010/028011, or WO 2010/028033. improving ocular discomfort, further comprising the local In another embodiment of any of the aforementioned administration of cyclosporine. In some embodiments is a embodiments of improving ocular discomfort, the ocular method of improving ocular discomfort, further comprising discomfort is associated with dry eye disease. In another the local administration of pimecrolimus. In some embodi embodiment of any of the aforementioned embodiments of ments is a method of improving ocular discomfort, further 30 improving ocular discomfort, the ocular discomfort is asso comprising the local administration of tacrolimus. ciated with the symptoms of dry eye disease. In another In a further embodiment of any of the aforementioned embodiment of any of the aforementioned embodiments of embodiments of improving ocular discomfort, the nicotinic improving ocular discomfort, the ocular discomfort is asso acetylcholine receptor agonist is selected from nicotine, ciated with the symptoms of dry eye disease; wherein the cytisine, epibatidine, Varenicline, tebanicline, DBO-83, 35 symptoms are selected from itchiness, dryness, photophobia, CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB blurriness, pain, Sticky feeling, burning, stinging, and for 1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, eign body sensation. A85380, and 5-I-A85380. In another embodiment of any of In another embodiment of any of the aforementioned the aforementioned embodiments of improving ocular dis embodiments of improving ocular discomfort, the ocular comfort, the nicotinic acetylcholine receptor agonist is nico 40 discomfort is associated with blepharitis. In another embodi tine. In another embodiment of any of the aforementioned ment of any of the aforementioned embodiments of improv embodiments of improving ocular discomfort, the nicotinic ing ocular discomfort, the ocular discomfort is associated acetylcholine receptor agonist is cytisine. In another with meibomian gland dysfunction. In another embodiment embodiment of any of the aforementioned embodiments of of any of the aforementioned embodiments of improving improving ocular discomfort, the nicotinic acetylcholine 45 ocular discomfort, the ocular discomfort is associated with receptor agonist is epibatidine. In another embodiment of allergic conjunctivitis. In another embodiment of any of the any of the aforementioned embodiments of improving ocu aforementioned embodiments of improving ocular discom lar discomfort, the nicotinic acetylcholine receptoragonist is fort, the ocular discomfort is associated with ocular surface varenicline. In another embodiment of any of the aforemen toxicity and irritation. In another embodiment of any of the tioned embodiments of improving ocular discomfort, the 50 aforementioned embodiments of improving ocular discom nicotinic acetylcholine receptor agonist is tebanicline. In fort, the ocular discomfort is associated with lacrimal drain another embodiment of any of the aforementioned embodi age problems. In another embodiment of any of the afore ments of improving ocular discomfort, the nicotinic acetyl mentioned embodiments of improving ocular discomfort, choline receptor agonist is DBO-83. In another embodiment the ocular discomfort is associated with eyelid disorders. of any of the aforementioned embodiments of improving 55 In another embodiment of any of the aforementioned ocular discomfort, the nicotinic acetylcholine receptor ago embodiments of improving ocular discomfort, at least 1 nist is CC4. In another embodiment of any of the aforemen microgram of the nicotinic acetylcholine receptor agonist is tioned embodiments of improving ocular discomfort, the administered into the nasal cavity. In another embodiment of nicotinic acetylcholine receptor agonist is ABT-418. In any of the aforementioned embodiments of improving ocu another embodiment of any of the aforementioned embodi 60 lar discomfort, at least 5 micrograms of the nicotinic ace ments of improving ocular discomfort, the nicotinic acetyl tylcholine receptor agonist is administered into the nasal choline receptor agonist is ABT-366833. In another embodi cavity. In another embodiment of any of the aforementioned ment of any of the aforementioned embodiments of embodiments of improving ocular discomfort, at least 10 improving ocular discomfort, the nicotinic acetylcholine micrograms of the nicotinic acetylcholine receptoragonist is receptor agonist is ABT-202. In another embodiment of any 65 administered into the nasal cavity. In another embodiment of of the aforementioned embodiments of improving ocular any of the aforementioned embodiments of improving ocu discomfort, the nicotinic acetylcholine receptor agonist is lar discomfort, at least 25 micrograms of the nicotinic US 9,597,284 B2 27 28 acetylcholine receptor agonist is administered into the nasal In another embodiment of any of the aforementioned cavity. In another embodiment of any of the aforementioned embodiments of improving ocular discomfort, the nicotinic embodiments of improving ocular discomfort, at least 50 acetylcholine receptor agonist is administered once daily. In micrograms of the nicotinic acetylcholine receptoragonist is another embodiment of any of the aforementioned embodi administered into the nasal cavity. In another embodiment of 5 ments of improving ocular discomfort, the nicotinic acetyl any of the aforementioned embodiments of improving ocu choline receptor agonist is administered at least once daily. lar discomfort, at least 100 micrograms of the nicotinic In another embodiment of any of the aforementioned acetylcholine receptor agonist is administered into the nasal embodiments of improving ocular discomfort, the nicotinic cavity. In another embodiment of any of the aforementioned acetylcholine receptoragonist is administered twice daily. In 10 another embodiment of any of the aforementioned embodi embodiments of improving ocular discomfort, at least 250 ments of improving ocular discomfort, the nicotinic acetyl micrograms of the nicotinic acetylcholine receptoragonist is choline receptor agonist is administered at least twice daily. administered into the nasal cavity. In another embodiment of In another embodiment of any of the aforementioned any of the aforementioned embodiments of improving ocu embodiments of improving ocular discomfort, the nicotinic lar discomfort, at least 500 micrograms of the nicotinic 15 acetylcholine receptor agonist is administered three times acetylcholine receptor agonist is administered into the nasal daily. In another embodiment of any of the aforementioned cavity. In another embodiment of any of the aforementioned embodiments of improving ocular discomfort, the nicotinic embodiments of improving ocular discomfort, at least 750 acetylcholine receptor agonist is administered at least three micrograms of the nicotinic acetylcholine receptoragonist is times daily. In another embodiment of any of the aforemen administered into the nasal cavity. In another embodiment of tioned embodiments of improving ocular discomfort, the any of the aforementioned embodiments of improving ocu nicotinic acetylcholine receptor agonist is administered for lar discomfort, at least 1000 micrograms of the nicotinic one day. In another embodiment of any of the aforemen acetylcholine receptor agonist is administered into the nasal tioned embodiments of improving ocular discomfort, the cavity. In another embodiment of any of the aforementioned nicotinic acetylcholine receptor agonist is administered for embodiments of improving ocular discomfort, between 1 25 at least two days. In another embodiment of any of the microgram and 1000 micrograms of the nicotinic acetylcho aforementioned embodiments of improving ocular discom line receptoragonist is administered into the nasal cavity. In fort, the nicotinic acetylcholine receptor agonist is admin another embodiment of any of the aforementioned embodi istered for at least three days. In another embodiment of any ments of improving ocular discomfort, between 5 micro of the aforementioned embodiments of improving ocular grams and 1000 micrograms of the nicotinic acetylcholine 30 discomfort, the nicotinic acetylcholine receptor agonist is receptor agonist is administered into the nasal cavity. In administered for at least four days. In another embodiment another embodiment of any of the aforementioned embodi of any of the aforementioned embodiments of improving ments of improving ocular discomfort, between 5 micro ocular discomfort, the nicotinic acetylcholine receptor ago grams and 100 micrograms of the nicotinic acetylcholine nist is administered for at least five days. In another embodi receptor agonist is administered into the nasal cavity. In 35 ment of any of the aforementioned embodiments of improv another embodiment of any of the aforementioned embodi ing ocular discomfort, the nicotinic acetylcholine receptor ments of improving ocular discomfort, between 5 micro agonist is administered for at least seven days. In another grams and 50 micrograms of the nicotinic acetylcholine embodiment of any of the aforementioned embodiments of receptor agonist is administered into the nasal cavity. In improving ocular discomfort, the nicotinic acetylcholine another embodiment of any of the aforementioned embodi 40 receptor agonist is administered for at least ten days. In ments of improving ocular discomfort, between 10 micro another embodiment of any of the aforementioned embodi grams and 50 micrograms of the nicotinic acetylcholine ments of improving ocular discomfort, the nicotinic acetyl receptor agonist is administered into the nasal cavity. In choline receptor agonist is administered for at least fourteen another embodiment of any of the aforementioned embodi days. In another embodiment of any of the aforementioned ments of improving ocular discomfort, between 25 micro 45 embodiments of improving ocular discomfort, the nicotinic grams and 1000 micrograms of the nicotinic acetylcholine acetylcholine receptor agonist is administered for at least receptor agonist is administered into the nasal cavity. In twenty one days. In another embodiment of any of the another embodiment of any of the aforementioned embodi aforementioned embodiments of improving ocular discom ments of improving ocular discomfort, between 50 micro fort, the nicotinic acetylcholine receptor agonist is admin grams and 1000 micrograms of the nicotinic acetylcholine 50 istered for at least thirty days. receptor agonist is administered into the nasal cavity. In In another embodiment of any of the aforementioned another embodiment of any of the aforementioned embodi embodiments of improving ocular discomfort, the nicotinic ments of improving ocular discomfort, between 100 micro acetylcholine receptor agonist is administered in alternating grams and 1000 micrograms of the nicotinic acetylcholine nostrils. receptor agonist is administered into the nasal cavity. In 55 In another embodiment of any of the aforementioned another embodiment of any of the aforementioned embodi embodiments of improving ocular discomfort, the nicotinic ments of improving ocular discomfort, between 100 micro acetylcholine receptor agonist is administered into the nasal grams and 750 micrograms of the nicotinic acetylcholine cavity as a liquid, Suspension, aerosol, gel, ointment, dry receptor agonist is administered into the nasal cavity. In powder, cream, paste, lotion, or balm. In another embodi another embodiment of any of the aforementioned embodi 60 ment of any of the aforementioned embodiments of improv ments of improving ocular discomfort, between 150 micro ing ocular discomfort, the nicotinic acetylcholine receptor grams and 750 micrograms of the nicotinic acetylcholine agonist is administered into the nasal cavity as a liquid. In receptor agonist is administered into the nasal cavity. In another embodiment of any of the aforementioned embodi another embodiment of any of the aforementioned embodi ments of improving ocular discomfort, the nicotinic acetyl ments of improving ocular discomfort, between 150 micro 65 choline receptoragonist is administered into the nasal cavity grams and 600 micrograms of the nicotinic acetylcholine as a Suspension. In another embodiment of any of the receptor agonist is administered into the nasal cavity. aforementioned embodiments of improving ocular discom US 9,597,284 B2 29 30 fort, the nicotinic acetylcholine receptor agonist is admin improving ocular discomfort, the nicotinic acetylcholine istered into the nasal cavity as an aerosol. In another receptor agonist is administered into the nasal cavity by a jet embodiment of any of the aforementioned embodiments of of liquid. improving ocular discomfort, the nicotinic acetylcholine In another embodiment of any of the aforementioned receptor agonist is administered into the nasal cavity as a embodiments of improving ocular discomfort, the trigeminal gel. In another embodiment of any of the aforementioned nerve is activated. In a further embodiment of improving embodiments of improving ocular discomfort, the nicotinic ocular discomfort, the anterior ethmoidal nerve is activated. acetylcholine receptor agonist is administered into the nasal In another embodiment of any of the aforementioned cavity as an ointment. In another embodiment of any of the embodiments of improving ocular discomfort, the nasolac aforementioned embodiments of improving ocular discom 10 rimal reflex is activated. fort, the nicotinic acetylcholine receptor agonist is admin Improved Ocular Surface Health istered into the nasal cavity as a dry powder. In another Provided herein, in some embodiments, is a method of embodiment of any of the aforementioned embodiments of improving ocular Surface health in a Subject. In some improving ocular discomfort, the nicotinic acetylcholine embodiments, is a method of improving ocular Surface receptor agonist is administered into the nasal cavity as a 15 health, comprising the local administration of a therapeuti cream. In another embodiment of any of the aforementioned cally effective amount of a nicotinic acetylcholine receptor embodiments of improving ocular discomfort, the nicotinic agonist into the nasal cavity of an individual in need thereof, acetylcholine receptor agonist is administered into the nasal wherein the agonist selectively binds to the peripheral cavity as a paste. In another embodiment of any of the nicotinic acetylcholine receptor and does not cross the aforementioned embodiments of improving ocular discom blood-brain barrier in a pharmacologically relevant concen fort, the nicotinic acetylcholine receptor agonist is admin tration. In some embodiments is method of improving ocular istered into the nasal cavity as a lotion. In another embodi Surface health, comprising the local administration of a ment of any of the aforementioned embodiments of therapeutically effective amount of a nicotinic acetylcholine improving ocular discomfort, the nicotinic acetylcholine receptoragonist into the nasal cavity of an individual in need receptor agonist is administered into the nasal cavity as a 25 thereof, wherein the agonist does not cross the blood-brain balm. barrier in a pharmacologically relevant concentration and In another embodiment of any of the aforementioned selectively binds to at least one of the peripheral nicotinic embodiments of improving ocular discomfort, the nicotinic acetylcholine receptor subtypes selected from alpha3beta4, acetylcholine receptor agonist is administered into the nasal alpha-4beta2, and alpha7. In some embodiments is method of cavity by a syringe, dropper, bottle nebulizer, atomization 30 improving ocular Surface health, comprising the local pump, inhaler, powder spray device, vaporizer, patch, medi administration of a therapeutically effective amount of a cated stick, pipette, or jet of liquid. In another embodiment nicotinic acetylcholine receptor agonist into the nasal cavity of any of the aforementioned embodiments of improving of an individual in need thereof, wherein the agonist does ocular discomfort, the nicotinic acetylcholine receptor ago not cross the blood-brain barrier in a pharmacologically nist is administered into the nasal cavity by a syringe. In 35 relevant concentration and selectively binds to the peripheral another embodiment of any of the aforementioned embodi nicotinic acetylcholine receptor subtype alpha3beta4. In ments of improving ocular discomfort, the nicotinic acetyl Some embodiments is method of improving ocular Surface choline receptor agonist is administered into the nasal cavity health, comprising the local administration of a therapeuti by a dropper. In another embodiment of any of the afore cally effective amount of a nicotinic acetylcholine receptor mentioned embodiments of improving ocular discomfort, 40 agonist into the nasal cavity of an individual in need thereof, the nicotinic acetylcholine receptor agonist is administered wherein the agonist does not cross the blood-brain barrier in into the nasal cavity by a bottle nebulizer. In another a pharmacologically relevant concentration and selectively embodiment of any of the aforementioned embodiments of binds to the peripheral nicotinic acetylcholine receptor sub improving ocular discomfort, the nicotinic acetylcholine type alpha-4beta2. In some embodiments is method of receptor agonist is administered into the nasal cavity by an 45 improving ocular Surface health, comprising the local atomization pump. In another embodiment of any of the administration of a therapeutically effective amount of a aforementioned embodiments of improving ocular discom nicotinic acetylcholine receptor agonist into the nasal cavity fort, the nicotinic acetylcholine receptor agonist is admin of an individual in need thereof, wherein the agonist does istered into the nasal cavity by an inhaler. In another not cross the blood-brain barrier in a pharmacologically embodiment of any of the aforementioned embodiments of 50 relevant concentration and selectively binds to the peripheral improving ocular discomfort, the nicotinic acetylcholine nicotinic acetylcholine receptor Subtype alpha7. In some receptor agonist is administered into the nasal cavity by a embodiments is a method of improving ocular Surface powder spray device. In another embodiment of any of the health, comprising the local administration of a therapeuti aforementioned embodiments of improving ocular discom cally effective amount of a nicotinic acetylcholine receptor fort, the nicotinic acetylcholine receptor agonist is admin 55 agonist into the nasal cavity of an individual in need thereof, istered into the nasal cavity by a vaporizer. In another wherein the agonist selectively binds to the peripheral embodiment of any of the aforementioned embodiments of nicotinic acetylcholine receptor and is administered in an improving ocular discomfort, the nicotinic acetylcholine amount that is not systemically bioavailable. In some receptor agonist is administered into the nasal cavity by a embodiments is a method of improving ocular Surface patch. In another embodiment of any of the aforementioned 60 health, comprising the local administration of a therapeuti embodiments of improving ocular discomfort, the nicotinic cally effective amount of a nicotinic acetylcholine receptor acetylcholine receptor agonist is administered into the nasal agonist into the nasal cavity of an individual in need thereof, cavity by a medicated Stick. In another embodiment of any wherein the agonist selectively binds to the peripheral of the aforementioned embodiments of improving ocular nicotinic acetylcholine receptor and in an amount that does discomfort, the nicotinic acetylcholine receptor agonist is 65 not result in undesired psychoactive side effects. In some administered into the nasal cavity by a pipette. In another embodiments is a method of improving ocular Surface embodiment of any of the aforementioned embodiments of health, comprising the local administration of a therapeuti US 9,597,284 B2 31 32 cally effective amount of a nicotinic acetylcholine receptor embodiment of any of the aforementioned embodiments of agonist into the nasal cavity of an individual in need thereof, improving ocular Surface health, the nicotinic acetylcholine wherein the agonist selectively binds to the peripheral receptor agonist is Varenicline. In another embodiment of nicotinic acetylcholine receptor and in an amount that does any of the aforementioned embodiments of improving ocu not result in undesired systemic side effects. In some lar Surface health, the nicotinic acetylcholine receptor ago embodiments is a method of improving ocular Surface nist is tebanicline. In another embodiment of any of the health, further comprising the local administration of one or aforementioned embodiments of improving ocular Surface more substances that prevent or facilitate the recovery of the health, the nicotinic acetylcholine receptor agonist is DBO nicotinic acetylcholine receptor from the desensitized State. 83. In another embodiment of any of the aforementioned In some embodiments is a method of improving ocular 10 embodiments of improving ocular Surface health, the nico Surface health, further comprising the local administration of tinic acetylcholine receptor agonist is CC4. In another one or more Substances that prevent the entry or reduce the embodiment of any of the aforementioned embodiments of entry of the nicotinic acetylcholine receptor into the desen improving ocular Surface health, the nicotinic acetylcholine sitized state, or facilitate the recovery of the nicotinic receptor agonist is ABT-418. In another embodiment of any acetylcholine receptor from the desensitized state. In some 15 of the aforementioned embodiments of improving ocular embodiments is a method of improving ocular Surface Surface health, the nicotinic acetylcholine receptoragonist is health, further comprising the local administration of one or ABT-366833. In another embodiment of any of the afore more substances that prevent or facilitate the recovery of the mentioned embodiments of improving ocular Surface health, nicotinic acetylcholine receptor from the desensitized State the nicotinic acetylcholine receptor agonist is ABT-202. In selected from protein kinase C(PKC) or factors that upregu another embodiment of any of the aforementioned embodi late or up-modulate PKC. cAMP-dependent protein kinase ments of improving ocular Surface health, the nicotinic (PKA) or factors that upregulate or up-modulate PKA, and acetylcholine receptor agonist is ABT-894. In another calcineurin inhibitors. In some embodiments is a method of embodiment of any of the aforementioned embodiments of improving ocular Surface health, further comprising the improving ocular Surface health, the nicotinic acetylcholine local administration of one or more substances that prevent 25 receptor agonist is SIB-1663. In another embodiment of any the entry or reduce the entry of the nicotinic acetylcholine of the aforementioned embodiments of improving ocular receptor into the desensitized state, or facilitate the recovery Surface health, the nicotinic acetylcholine receptoragonist is of the nicotinic acetylcholine receptor from the desensitized GTS-21. In another embodiment of any of the aforemen state selected from protein kinase C (PKC) or factors that tioned embodiments of improving ocular Surface health, the upregulate or up-modulate PKC. cAMP-dependent protein 30 nicotinic acetylcholine receptor agonist is PHA-543,613. In kinase (PKA) or factors that upregulate or up-modulate another embodiment of any of the aforementioned embodi PKA, and calcineurin inhibitors. In some embodiments is a ments of improving ocular surface health, the nicotinic method of improving ocular surface health, further compris acetylcholine receptor agonist is PNU-282987. In another ing the local administration of protein kinase C (PKC) or embodiment of any of the aforementioned embodiments of factors that upregulate or up-modulate PKC. In some 35 improving ocular Surface health, the nicotinic acetylcholine embodiments is a method of improving ocular Surface receptor agonist is LY-2087101. In another embodiment of health, further comprising the local administration of any of the aforementioned embodiments of improving ocu cAMP-dependent protein kinase (PKA) or factors that lar Surface health, the nicotinic acetylcholine receptor ago upregulate or up-modulate PKA. In some embodiments is a nist is A85380. In another embodiment of any of the method of improving ocular surface health, further compris 40 aforementioned embodiments of improving ocular Surface ing the local administration of a calcineurin inhibitor. In health, the nicotinic acetylcholine receptor agonist is 5-I- Some embodiments is a method of improving ocular Surface A8538O. health, further comprising the local administration of a In a further embodiment of any of the aforementioned calcineurin inhibitor, wherein the calcineurin inhibitor is embodiments of improving ocular Surface health, the nico selected from cyclosporine, pimecrolimus, and tacrolimus. 45 tinic acetylcholine receptor agonist is selected from a com In some embodiments is a method of improving ocular pound disclosed in WO 2008/057938, WO 2009/111550, Surface health, further comprising the local administration of WO 2010/028011, or WO 2010/028033. cyclosporine. In some embodiments is a method of improv In another embodiment of any of the aforementioned ing ocular Surface health, further comprising the local embodiments of improving ocular Surface health, at least 1 administration of pimecrolimus. In some embodiments is a 50 microgram of the nicotinic acetylcholine receptor agonist is method of improving ocular surface health, further compris administered into the nasal cavity. In another embodiment of ing the local administration of tacrolimus. any of the aforementioned embodiments of improving ocu In a further embodiment of any of the aforementioned lar Surface health, at least 5 micrograms of the nicotinic embodiments of improving ocular Surface health, the nico acetylcholine receptor agonist is administered into the nasal tinic acetylcholine receptoragonist is selected from nicotine, 55 cavity. In another embodiment of any of the aforementioned cytisine, epibatidine, Varenicline, tebanicline, DBO-83, embodiments of improving ocular surface health, at least 10 CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB micrograms of the nicotinic acetylcholine receptoragonist is 1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, administered into the nasal cavity. In another embodiment of A85380, and 5-I-A85380. In another embodiment of any of any of the aforementioned embodiments of improving ocu the aforementioned embodiments of improving ocular Sur 60 lar Surface health, at least 25 micrograms of the nicotinic face health, the nicotinic acetylcholine receptor agonist is acetylcholine receptor agonist is administered into the nasal nicotine. In another embodiment of any of the aforemen cavity. In another embodiment of any of the aforementioned tioned embodiments of improving ocular Surface health, the embodiments of improving ocular surface health, at least 50 nicotinic acetylcholine receptor agonist is cytisine. In micrograms of the nicotinic acetylcholine receptoragonist is another embodiment of any of the aforementioned embodi 65 administered into the nasal cavity. In another embodiment of ments of improving ocular Surface health, the nicotinic any of the aforementioned embodiments of improving ocu acetylcholine receptor agonist is epibatidine. In another lar surface health, at least 100 micrograms of the nicotinic US 9,597,284 B2 33 34 acetylcholine receptor agonist is administered into the nasal tioned embodiments of improving ocular Surface health, the cavity. In another embodiment of any of the aforementioned nicotinic acetylcholine receptor agonist is administered embodiments of improving ocular Surface health, at least twice daily. In another embodiment of any of the aforemen 250 micrograms of the nicotinic acetylcholine receptor tioned embodiments of improving ocular Surface health, the agonist is administered into the nasal cavity. In another nicotinic acetylcholine receptor agonist is administered at embodiment of any of the aforementioned embodiments of least twice daily. In another embodiment of any of the improving ocular surface health, at least 500 micrograms of aforementioned embodiments of improving ocular Surface the nicotinic acetylcholine receptor agonist is administered health, the nicotinic acetylcholine receptor agonist is admin into the nasal cavity. In another embodiment of any of the istered three times daily. In another embodiment of any of aforementioned embodiments of improving ocular Surface 10 the aforementioned embodiments of improving ocular Sur health, at least 750 micrograms of the nicotinic acetylcho face health, the nicotinic acetylcholine receptor agonist is line receptoragonist is administered into the nasal cavity. In administered at least three times daily. In another embodi another embodiment of any of the aforementioned embodi ment of any of the aforementioned embodiments of improv ments of improving ocular surface health, at least 1000 ing ocular Surface health, the nicotinic acetylcholine recep micrograms of the nicotinic acetylcholine receptoragonist is 15 tor agonist is administered for one day. In another administered into the nasal cavity. In another embodiment of embodiment of any of the aforementioned embodiments of any of the aforementioned embodiments of improving ocu improving ocular Surface health, the nicotinic acetylcholine lar surface health, between 1 microgram and 1000 micro receptor agonist is administered for at least two days. In grams of the nicotinic acetylcholine receptor agonist is another embodiment of any of the aforementioned embodi administered into the nasal cavity. In another embodiment of ments of improving ocular Surface health, the nicotinic any of the aforementioned embodiments of improving ocu acetylcholine receptor agonist is administered for at least lar surface health, between 5 micrograms and 1000 micro three days. In another embodiment of any of the aforemen grams of the nicotinic acetylcholine receptor agonist is tioned embodiments of improving ocular Surface health, the administered into the nasal cavity. In another embodiment of nicotinic acetylcholine receptor agonist is administered for any of the aforementioned embodiments of improving ocu 25 at least four days. In another embodiment of any of the lar surface health, between 5 micrograms and 100 micro aforementioned embodiments of improving ocular Surface grams of the nicotinic acetylcholine receptor agonist is health, the nicotinic acetylcholine receptor agonist is admin administered into the nasal cavity. In another embodiment of istered for at least five days. In another embodiment of any any of the aforementioned embodiments of improving ocu of the aforementioned embodiments of improving ocular lar surface health, between 5 micrograms and 50 micro 30 Surface health, the nicotinic acetylcholine receptoragonist is grams of the nicotinic acetylcholine receptor agonist is administered for at least seven days. In another embodiment administered into the nasal cavity. In another embodiment of of any of the aforementioned embodiments of improving any of the aforementioned embodiments of improving ocu ocular Surface health, the nicotinic acetylcholine receptor lar surface health, between 10 micrograms and 50 micro agonist is administered for at least ten days. In another grams of the nicotinic acetylcholine receptor agonist is 35 embodiment of any of the aforementioned embodiments of administered into the nasal cavity. In another embodiment of improving ocular Surface health, the nicotinic acetylcholine any of the aforementioned embodiments of improving ocu receptor agonist is administered for at least fourteen days. In lar surface health, between 25 micrograms and 1000 micro another embodiment of any of the aforementioned embodi grams of the nicotinic acetylcholine receptor agonist is ments of improving ocular Surface health, the nicotinic administered into the nasal cavity. In another embodiment of 40 acetylcholine receptor agonist is administered for at least any of the aforementioned embodiments of improving ocu twenty one days. In another embodiment of any of the lar surface health, between 50 micrograms and 1000 micro aforementioned embodiments of improving ocular Surface grams of the nicotinic acetylcholine receptor agonist is health, the nicotinic acetylcholine receptor agonist is admin administered into the nasal cavity. In another embodiment of istered for at least thirty days. any of the aforementioned embodiments of improving ocu 45 In another embodiment of any of the aforementioned lar surface health, between 100 micrograms and 1000 micro embodiments of improving ocular Surface health, the nico grams of the nicotinic acetylcholine receptor agonist is tinic acetylcholine receptor agonist is administered in alter administered into the nasal cavity. In another embodiment of nating nostrils. any of the aforementioned embodiments of improving ocu In another embodiment of any of the aforementioned lar surface health, between 100 micrograms and 750 micro 50 embodiments of improving ocular Surface health, the nico grams of the nicotinic acetylcholine receptor agonist is tinic acetylcholine receptor agonist is administered into the administered into the nasal cavity. In another embodiment of nasal cavity as a liquid, Suspension, aerosol, gel, ointment, any of the aforementioned embodiments of improving ocu dry powder, cream, paste, lotion, or balm. In another lar surface health, between 150 micrograms and 750 micro embodiment of any of the aforementioned embodiments of grams of the nicotinic acetylcholine receptor agonist is 55 improving ocular Surface health, the nicotinic acetylcholine administered into the nasal cavity. In another embodiment of receptor agonist is administered into the nasal cavity as a any of the aforementioned embodiments of improving ocu liquid. In another embodiment of any of the aforementioned lar surface health, between 150 micrograms and 600 micro embodiments of improving ocular Surface health, the nico grams of the nicotinic acetylcholine receptor agonist is tinic acetylcholine receptor agonist is administered into the administered into the nasal cavity. 60 nasal cavity as a Suspension. In another embodiment of any In another embodiment of any of the aforementioned of the aforementioned embodiments of improving ocular embodiments of improving ocular Surface health, the nico Surface health, the nicotinic acetylcholine receptoragonist is tinic acetylcholine receptor agonist is administered once administered into the nasal cavity as an aerosol. In another daily. In another embodiment of any of the aforementioned embodiment of any of the aforementioned embodiments of embodiments of improving ocular Surface health, the nico 65 improving ocular Surface health, the nicotinic acetylcholine tinic acetylcholine receptor agonist is administered at least receptor agonist is administered into the nasal cavity as a once daily. In another embodiment of any of the aforemen gel. In another embodiment of any of the aforementioned US 9,597,284 B2 35 36 embodiments of improving ocular Surface health, the nico improving ocular surface health, the anterior ethmoidal tinic acetylcholine receptor agonist is administered into the nerve is activated. In another embodiment of any of the nasal cavity as an ointment. In another embodiment of any aforementioned embodiments of improving ocular Surface of the aforementioned embodiments of improving ocular health, the nasolacrimal reflex is activated. Surface health, the nicotinic acetylcholine receptoragonist is Protecting the Ocular Surface During Environmentally administered into the nasal cavity as a dry powder. In Challenging Conditions another embodiment of any of the aforementioned embodi Provided herein, in some embodiments, is a method of ments of improving ocular Surface health, the nicotinic protecting the ocular Surface during environmentally chal acetylcholine receptor agonist is administered into the nasal lenging conditions in a subject. In some embodiments, is a cavity as a cream. In another embodiment of any of the 10 method of protecting the ocular surface during environmen aforementioned embodiments of improving ocular Surface tally challenging conditions, comprising the local adminis health, the nicotinic acetylcholine receptor agonist is admin tration of a therapeutically effective amount of a nicotinic istered into the nasal cavity as a paste. In another embodi acetylcholine receptor agonist into the nasal cavity of an ment of any of the aforementioned embodiments of improv individual in need thereof, wherein the agonist selectively ing ocular Surface health, the nicotinic acetylcholine 15 binds to the peripheral nicotinic acetylcholine receptor and receptor agonist is administered into the nasal cavity as a does not cross the blood-brain barrier in a pharmacologically lotion. In another embodiment of any of the aforementioned relevant concentration. In some embodiments is method of embodiments of improving ocular Surface health, the nico protecting the ocular Surface during environmentally chal tinic acetylcholine receptor agonist is administered into the lenging conditions, comprising the local administration of a nasal cavity as a balm. therapeutically effective amount of a nicotinic acetylcholine In another embodiment of any of the aforementioned receptoragonist into the nasal cavity of an individual in need embodiments of improving ocular Surface health, the nico thereof, wherein the agonist does not cross the blood-brain tinic acetylcholine receptor agonist is administered into the barrier in a pharmacologically relevant concentration and nasal cavity by a syringe, dropper, bottle nebulizer, atomi selectively binds to at least one of the peripheral nicotinic Zation pump, inhaler, powder spray device, vaporizer, patch, 25 acetylcholine receptor subtypes selected from alpha3beta4, medicated Stick, pipette, or jet of liquid. In another embodi alpha-4beta2, and alpha7. In some embodiments is method of ment of any of the aforementioned embodiments of improv protecting the ocular Surface during environmentally chal ing ocular Surface health, the nicotinic acetylcholine recep lenging conditions, comprising the local administration of a toragonist is administered into the nasal cavity by a Syringe. therapeutically effective amount of a nicotinic acetylcholine In another embodiment of any of the aforementioned 30 receptoragonist into the nasal cavity of an individual in need embodiments of improving ocular Surface health, the nico thereof, wherein the agonist does not cross the blood-brain tinic acetylcholine receptor agonist is administered into the barrier in a pharmacologically relevant concentration and nasal cavity by a dropper. In another embodiment of any of selectively binds to the peripheral nicotinic acetylcholine the aforementioned embodiments of improving ocular Sur receptor Subtype alpha3beta4. In some embodiments is face health, the nicotinic acetylcholine receptor agonist is 35 method of protecting the ocular surface during environmen administered into the nasal cavity by a bottle nebulizer. In tally challenging conditions, comprising the local adminis another embodiment of any of the aforementioned embodi tration of a therapeutically effective amount of a nicotinic ments of improving ocular Surface health, the nicotinic acetylcholine receptor agonist into the nasal cavity of an acetylcholine receptor agonist is administered into the nasal individual in need thereof, wherein the agonist does not cavity by an atomization pump. In another embodiment of 40 cross the blood-brain barrier in a pharmacologically relevant any of the aforementioned embodiments of improving ocu concentration and selectively binds to the peripheral nico lar Surface health, the nicotinic acetylcholine receptor ago tinic acetylcholine receptor Subtype alpha-4beta2. In some nist is administered into the nasal cavity by an inhaler. In embodiments is method of protecting the ocular Surface another embodiment of any of the aforementioned embodi during environmentally challenging conditions, comprising ments of improving ocular Surface health, the nicotinic 45 the local administration of a therapeutically effective amount acetylcholine receptor agonist is administered into the nasal of a nicotinic acetylcholine receptor agonist into the nasal cavity by a powder spray device. In another embodiment of cavity of an individual in need thereof, wherein the agonist any of the aforementioned embodiments of improving ocu does not cross the blood-brain barrier in a pharmacologically lar Surface health, the nicotinic acetylcholine receptor ago relevant concentration and selectively binds to the peripheral nist is administered into the nasal cavity by a vaporizer. In 50 nicotinic acetylcholine receptor Subtype alpha7. In some another embodiment of any of the aforementioned embodi embodiments is a method of protecting the ocular Surface ments of improving ocular Surface health, the nicotinic during environmentally challenging conditions, comprising acetylcholine receptor agonist is administered into the nasal the local administration of a therapeutically effective amount cavity by a patch. In another embodiment of any of the of a nicotinic acetylcholine receptor agonist into the nasal aforementioned embodiments of improving ocular Surface 55 cavity of an individual in need thereof, wherein the agonist health, the nicotinic acetylcholine receptor agonist is admin selectively binds to the peripheral nicotinic acetylcholine istered into the nasal cavity by a medicated Stick. In another receptor and is administered in an amount that is not embodiment of any of the aforementioned embodiments of systemically bioavailable. In some embodiments is a method improving ocular Surface health, the nicotinic acetylcholine of protecting the ocular Surface during environmentally receptor agonist is administered into the nasal cavity by a 60 challenging conditions, comprising the local administration pipette. In another embodiment of any of the aforemen of a therapeutically effective amount of a nicotinic acetyl tioned embodiments of improving ocular Surface health, the choline receptor agonist into the nasal cavity of an indi nicotinic acetylcholine receptor agonist is administered into vidual in need thereof, wherein the agonist selectively binds the nasal cavity by a jet of liquid. to the peripheral nicotinic acetylcholine receptor and in an In another embodiment of any of the aforementioned 65 amount that does not result in undesired psychoactive side embodiments of improving ocular surface health, the effects. In some embodiments is a method of protecting the trigeminal nerve is activated. In a further embodiment of ocular Surface during environmentally challenging condi US 9,597,284 B2 37 38 tions, comprising the local administration of a therapeuti 418, ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, cally effective amount of a nicotinic acetylcholine receptor PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I- agonist into the nasal cavity of an individual in need thereof, A85380. In another embodiment of any of the aforemen wherein the agonist selectively binds to the peripheral tioned embodiments of protecting the ocular Surface during nicotinic acetylcholine receptor and in an amount that does environmentally challenging conditions, the nicotinic ace not result in undesired systemic side effects. In some tylcholine receptor agonist is nicotine. In another embodi embodiments is a method of protecting the ocular Surface ment of any of the aforementioned embodiments of protect during environmentally challenging conditions, further ing the ocular Surface during environmentally challenging comprising the local administration of one or more Sub conditions, the nicotinic acetylcholine receptor agonist is stances that prevent or facilitate the recovery of the nicotinic 10 acetylcholine receptor from the desensitized state. In some cytisine. In another embodiment of any of the aforemen embodiments is a method of protecting the ocular Surface tioned embodiments of protecting the ocular Surface during during environmentally challenging conditions, further environmentally challenging conditions, the nicotinic ace comprising the local administration of one or more Sub tylcholine receptor agonist is epibatidine. In another stances that prevent the entry or reduce the entry of the 15 embodiment of any of the aforementioned embodiments of nicotinic acetylcholine receptor into the desensitized State, protecting the ocular Surface during environmentally chal or facilitate the recovery of the nicotinic acetylcholine lenging conditions, the nicotinic acetylcholine receptor ago receptor from the desensitized state. In some embodiments nist is varenicline. In another embodiment of any of the is a method of protecting the ocular Surface during environ aforementioned embodiments of protecting the ocular Sur mentally challenging conditions, further comprising the face during environmentally challenging conditions, the local administration of one or more substances that prevent nicotinic acetylcholine receptor agonist is tebanicline. In or facilitate the recovery of the nicotinic acetylcholine another embodiment of any of the aforementioned embodi receptor from the desensitized state selected from protein ments of protecting the ocular Surface during environmen kinase C (PKC) or factors that upregulate or up-modulate tally challenging conditions, the nicotinic acetylcholine PKC. cAMP-dependent protein kinase (PKA) or factors that 25 receptor agonist is DBO-83. In another embodiment of any upregulate or up-modulate PKA, and calcineurin inhibitors. of the aforementioned embodiments of protecting the ocular In some embodiments is a method of protecting the ocular Surface during environmentally challenging conditions, the Surface during environmentally challenging conditions, fur nicotinic acetylcholine receptor agonist is CC4. In another ther comprising the local administration of one or more embodiment of any of the aforementioned embodiments of substances that prevent the entry or reduce the entry of the 30 protecting the ocular Surface during environmentally chal nicotinic acetylcholine receptor into the desensitized State, lenging conditions, the nicotinic acetylcholine receptor ago or facilitate the recovery of the nicotinic acetylcholine nist is ABT-418. In another embodiment of any of the receptor from the desensitized state selected from protein aforementioned embodiments of protecting the ocular Sur kinase C (PKC) or factors that upregulate or up-modulate face during environmentally challenging conditions, the PKC. cAMP-dependent protein kinase (PKA) or factors that 35 nicotinic acetylcholine receptor agonist is ABT-366833. In upregulate or up-modulate PKA, and calcineurin inhibitors. another embodiment of any of the aforementioned embodi In some embodiments is a method of protecting the ocular ments of protecting the ocular Surface during environmen Surface during environmentally challenging conditions, fur tally challenging conditions, the nicotinic acetylcholine ther comprising the local administration of protein kinase C receptor agonist is ABT-202. In another embodiment of any (PKC) or factors that upregulate or up-modulate PKC. In 40 of the aforementioned embodiments of protecting the ocular Some embodiments is a method of protecting the ocular Surface during environmentally challenging conditions, the Surface during environmentally challenging conditions, fur nicotinic acetylcholine receptor agonist is ABT-894. In ther comprising the local administration of cAMP-depen another embodiment of any of the aforementioned embodi dent protein kinase (PKA) or factors that upregulate or ments of protecting the ocular Surface during environmen up-modulate PKA. In some embodiments is a method of 45 tally challenging conditions, the nicotinic acetylcholine protecting the ocular Surface during environmentally chal receptor agonist is SIB-1663. In another embodiment of any lenging conditions, further comprising the local administra of the aforementioned embodiments of protecting the ocular tion of a calcineurin inhibitor. In some embodiments is a Surface during environmentally challenging conditions, the method of protecting the ocular surface during environmen nicotinic acetylcholine receptor agonist is GTS-21. In tally challenging conditions, further comprising the local 50 another embodiment of any of the aforementioned embodi administration of a calcineurin inhibitor, wherein the cal ments of protecting the ocular Surface during environmen cineurin inhibitor is selected from cyclosporine, pimecroli tally challenging conditions, the nicotinic acetylcholine mus, and tacrolimus. In some embodiments is a method of receptor agonist is PHA-543,613. In another embodiment of protecting the ocular Surface during environmentally chal any of the aforementioned embodiments of protecting the lenging conditions, further comprising the local administra 55 ocular Surface during environmentally challenging condi tion of cyclosporine. In some embodiments is a method of tions, the nicotinic acetylcholine receptor agonist is PNU protecting the ocular Surface during environmentally chal 282987. In another embodiment of any of the aforemen lenging conditions, further comprising the local administra tioned embodiments of protecting the ocular Surface during tion of pimecrolimus. In some embodiments is a method of environmentally challenging conditions, the nicotinic ace protecting the ocular Surface during environmentally chal 60 tylcholine receptor agonist is LY-2087101. In another lenging conditions, further comprising the local administra embodiment of any of the aforementioned embodiments of tion of tacrolimus. protecting the ocular Surface during environmentally chal In a further embodiment of any of the aforementioned lenging conditions, the nicotinic acetylcholine receptor ago embodiments of protecting the ocular surface during envi nist is A85380. In another embodiment of any of the ronmentally challenging conditions, the nicotinic acetylcho 65 aforementioned embodiments of protecting the ocular Sur line receptor agonist is selected from nicotine, cytisine, face during environmentally challenging conditions, the epibatidine, Varenicline, tebanicline, DBO-83, CC4, ABT nicotinic acetylcholine receptor agonist is 5-I-A85380. US 9,597,284 B2 39 40 In a further embodiment of any of the aforementioned grams of the nicotinic acetylcholine receptor agonist is embodiments of protecting the ocular surface during envi administered into the nasal cavity. In another embodiment of ronmentally challenging conditions, the nicotinic acetylcho any of the aforementioned embodiments of protecting the line receptor agonist is selected from a compound disclosed ocular Surface during environmentally challenging condi in WO 2008/057938, WO 2009/111550, WO 2010/028011, 5 tions, between 10 micrograms and 50 micrograms of the or WO 201OfO28O33. nicotinic acetylcholine receptor agonist is administered into In another embodiment of any of the aforementioned the nasal cavity. In another embodiment of any of the embodiments of protecting the ocular surface during envi aforementioned embodiments of protecting the ocular Sur ronmentally challenging conditions, at least 1 microgram of face during environmentally challenging conditions, the nicotinic acetylcholine receptor agonist is administered 10 between 25 micrograms and 1000 micrograms of the nico into the nasal cavity. In another embodiment of any of the tinic acetylcholine receptor agonist is administered into the aforementioned embodiments of protecting the ocular Sur nasal cavity. In another embodiment of any of the afore face during environmentally challenging conditions, at least mentioned embodiments of protecting the ocular surface 5 micrograms of the nicotinic acetylcholine receptor agonist during environmentally challenging conditions, between 50 is administered into the nasal cavity. In another embodiment 15 micrograms and 1000 micrograms of the nicotinic acetyl of any of the aforementioned embodiments of protecting the choline receptoragonist is administered into the nasal cavity. ocular Surface during environmentally challenging condi In another embodiment of any of the aforementioned tions, at least 10 micrograms of the nicotinic acetylcholine embodiments of protecting the ocular surface during envi receptor agonist is administered into the nasal cavity. In ronmentally challenging conditions, between 100 micro another embodiment of any of the aforementioned embodi grams and 1000 micrograms of the nicotinic acetylcholine ments of protecting the ocular Surface during environmen receptor agonist is administered into the nasal cavity. In tally challenging conditions, at least 25 micrograms of the another embodiment of any of the aforementioned embodi nicotinic acetylcholine receptor agonist is administered into ments of protecting the ocular Surface during environmen the nasal cavity. In another embodiment of any of the tally challenging conditions, between 100 micrograms and aforementioned embodiments of protecting the ocular Sur 25 750 micrograms of the nicotinic acetylcholine receptor face during environmentally challenging conditions, at least agonist is administered into the nasal cavity. In another 50 micrograms of the nicotinic acetylcholine receptor ago embodiment of any of the aforementioned embodiments of nist is administered into the nasal cavity. In another embodi protecting the ocular Surface during environmentally chal ment of any of the aforementioned embodiments of protect lenging conditions, between 150 micrograms and 750 ing the ocular surface during environmentally challenging 30 micrograms of the nicotinic acetylcholine receptoragonist is conditions, at least 100 micrograms of the nicotinic acetyl administered into the nasal cavity. In another embodiment of choline receptor agonist is administered into the nasal cavity. any of the aforementioned embodiments of protecting the In another embodiment of any of the aforementioned ocular Surface during environmentally challenging condi embodiments of protecting the ocular surface during envi tions, between 150 micrograms and 600 micrograms of the ronmentally challenging conditions, at least 250 micrograms 35 nicotinic acetylcholine receptor agonist is administered into of the nicotinic acetylcholine receptor agonist is adminis the nasal cavity. tered into the nasal cavity. In another embodiment of any of In another embodiment of any of the aforementioned the aforementioned embodiments of protecting the ocular embodiments of protecting the ocular surface during envi Surface during environmentally challenging conditions, at ronmentally challenging conditions, the nicotinic acetylcho least 500 micrograms of the nicotinic acetylcholine receptor 40 line receptor agonist is administered once daily. In another agonist is administered into the nasal cavity. In another embodiment of any of the aforementioned embodiments of embodiment of any of the aforementioned embodiments of protecting the ocular Surface during environmentally chal protecting the ocular Surface during environmentally chal lenging conditions, the nicotinic acetylcholine receptor ago lenging conditions, at least 750 micrograms of the nicotinic nist is administered at least once daily. In another embodi acetylcholine receptor agonist is administered into the nasal 45 ment of any of the aforementioned embodiments of cavity. In another embodiment of any of the aforementioned protecting the ocular Surface during environmentally chal embodiments of protecting the ocular surface during envi lenging conditions, the nicotinic acetylcholine receptor ago ronmentally challenging conditions, at least 1000 micro nist is administered twice daily. In another embodiment of grams of the nicotinic acetylcholine receptor agonist is any of the aforementioned embodiments of protecting the administered into the nasal cavity. In another embodiment of 50 ocular Surface during environmentally challenging condi any of the aforementioned embodiments of protecting the tions, the nicotinic acetylcholine receptor agonist is admin ocular Surface during environmentally challenging condi istered at least twice daily. In another embodiment of any of tions, between 1 microgram and 1000 micrograms of the the aforementioned embodiments of protecting the ocular nicotinic acetylcholine receptor agonist is administered into Surface during environmentally challenging conditions, the the nasal cavity. In another embodiment of any of the 55 nicotinic acetylcholine receptor agonist is administered aforementioned embodiments of protecting the ocular Sur three times daily. In another embodiment of any of the face during environmentally challenging conditions, aforementioned embodiments of protecting the ocular Sur between 5 micrograms and 1000 micrograms of the nicotinic face during environmentally challenging conditions, the acetylcholine receptor agonist is administered into the nasal nicotinic acetylcholine receptor agonist is administered at cavity. In another embodiment of any of the aforementioned 60 least three times daily. In another embodiment of any of the embodiments of protecting the ocular surface during envi aforementioned embodiments of protecting the ocular Sur ronmentally challenging conditions, between 5 micrograms face during environmentally challenging conditions, the and 100 micrograms of the nicotinic acetylcholine receptor nicotinic acetylcholine receptor agonist is administered for agonist is administered into the nasal cavity. In another one day. In another embodiment of any of the aforemen embodiment of any of the aforementioned embodiments of 65 tioned embodiments of protecting the ocular Surface during protecting the ocular Surface during environmentally chal environmentally challenging conditions, the nicotinic ace lenging conditions, between 5 micrograms and 50 micro tylcholine receptor agonist is administered for at least two US 9,597,284 B2 41 42 days. In another embodiment of any of the aforementioned tioned embodiments of protecting the ocular Surface during embodiments of protecting the ocular surface during envi environmentally challenging conditions, the nicotinic ace ronmentally challenging conditions, the nicotinic acetylcho tylcholine receptor agonist is administered into the nasal line receptor agonist is administered for at least three days. cavity as a cream. In another embodiment of any of the In another embodiment of any of the aforementioned aforementioned embodiments of protecting the ocular Sur embodiments of protecting the ocular surface during envi face during environmentally challenging conditions, the ronmentally challenging conditions, the nicotinic acetylcho nicotinic acetylcholine receptor agonist is administered into line receptoragonist is administered for at least four days. In the nasal cavity as a paste. In another embodiment of any of another embodiment of any of the aforementioned embodi the aforementioned embodiments of protecting the ocular ments of protecting the ocular Surface during environmen 10 Surface during environmentally challenging conditions, the tally challenging conditions, the nicotinic acetylcholine nicotinic acetylcholine receptor agonist is administered into receptor agonist is administered for at least five days. In the nasal cavity as a lotion. In another embodiment of any another embodiment of any of the aforementioned embodi of the aforementioned embodiments of protecting the ocular ments of protecting the ocular Surface during environmen Surface during environmentally challenging conditions, the tally challenging conditions, the nicotinic acetylcholine 15 nicotinic acetylcholine receptor agonist is administered into receptor agonist is administered for at least seven days. In the nasal cavity as a balm. another embodiment of any of the aforementioned embodi In another embodiment of any of the aforementioned ments of protecting the ocular Surface during environmen embodiments of protecting the ocular surface during envi tally challenging conditions, the nicotinic acetylcholine ronmentally challenging conditions, the nicotinic acetylcho receptor agonist is administered for at least ten days. In line receptor agonist is administered into the nasal cavity by another embodiment of any of the aforementioned embodi a syringe, dropper, bottle nebulizer, atomization pump, ments of protecting the ocular Surface during environmen inhaler, powder spray device, vaporizer, patch, medicated tally challenging conditions, the nicotinic acetylcholine Stick, pipette, or jet of liquid. In another embodiment of any receptor agonist is administered for at least fourteen days. In of the aforementioned embodiments of protecting the ocular another embodiment of any of the aforementioned embodi 25 Surface during environmentally challenging conditions, the ments of protecting the ocular Surface during environmen nicotinic acetylcholine receptor agonist is administered into tally challenging conditions, the nicotinic acetylcholine the nasal cavity by a syringe. In another embodiment of any receptor agonist is administered for at least twenty one days. of the aforementioned embodiments of protecting the ocular In another embodiment of any of the aforementioned Surface during environmentally challenging conditions, the embodiments of protecting the ocular surface during envi 30 nicotinic acetylcholine receptor agonist is administered into ronmentally challenging conditions, the nicotinic acetylcho the nasal cavity by a dropper. In another embodiment of any line receptor agonist is administered for at least thirty days. of the aforementioned embodiments of protecting the ocular In another embodiment of any of the aforementioned Surface during environmentally challenging conditions, the embodiments of protecting the ocular surface during envi nicotinic acetylcholine receptor agonist is administered into ronmentally challenging conditions, the nicotinic acetylcho 35 the nasal cavity by a bottle nebulizer. In another embodiment line receptor agonist is administered in alternating nostrils. of any of the aforementioned embodiments of protecting the In another embodiment of any of the aforementioned ocular Surface during environmentally challenging condi embodiments of protecting the ocular surface during envi tions, the nicotinic acetylcholine receptor agonist is admin ronmentally challenging conditions, the nicotinic acetylcho istered into the nasal cavity by an atomization pump. In line receptor agonist is administered into the nasal cavity as 40 another embodiment of any of the aforementioned embodi a liquid, Suspension, aerosol, gel, ointment, dry powder, ments of protecting the ocular Surface during environmen cream, paste, lotion, or balm. In another embodiment of any tally challenging conditions, the nicotinic acetylcholine of the aforementioned embodiments of protecting the ocular receptor agonist is administered into the nasal cavity by an Surface during environmentally challenging conditions, the inhaler. In another embodiment of any of the aforemen nicotinic acetylcholine receptor agonist is administered into 45 tioned embodiments of protecting the ocular Surface during the nasal cavity as a liquid. In another embodiment of any environmentally challenging conditions, the nicotinic ace of the aforementioned embodiments of protecting the ocular tylcholine receptor agonist is administered into the nasal Surface during environmentally challenging conditions, the cavity by a powder spray device. In another embodiment of nicotinic acetylcholine receptor agonist is administered into any of the aforementioned embodiments of protecting the the nasal cavity as a suspension. In another embodiment of 50 ocular Surface during environmentally challenging condi any of the aforementioned embodiments of protecting the tions, the nicotinic acetylcholine receptor agonist is admin ocular Surface during environmentally challenging condi istered into the nasal cavity by a vaporizer. In another tions, the nicotinic acetylcholine receptor agonist is admin embodiment of any of the aforementioned embodiments of istered into the nasal cavity as an aerosol. In another protecting the ocular Surface during environmentally chal embodiment of any of the aforementioned embodiments of 55 lenging conditions, the nicotinic acetylcholine receptor ago protecting the ocular Surface during environmentally chal nist is administered into the nasal cavity by a patch. In lenging conditions, the nicotinic acetylcholine receptor ago another embodiment of any of the aforementioned embodi nist is administered into the nasal cavity as a gel. In another ments of protecting the ocular Surface during environmen embodiment of any of the aforementioned embodiments of tally challenging conditions, the nicotinic acetylcholine protecting the ocular Surface during environmentally chal 60 receptor agonist is administered into the nasal cavity by a lenging conditions, the nicotinic acetylcholine receptor ago medicated stick. In another embodiment of any of the nist is administered into the nasal cavity as an ointment. In aforementioned embodiments of protecting the ocular Sur another embodiment of any of the aforementioned embodi face during environmentally challenging conditions, the ments of protecting the ocular Surface during environmen nicotinic acetylcholine receptor agonist is administered into tally challenging conditions, the nicotinic acetylcholine 65 the nasal cavity by a pipette. In another embodiment of any receptor agonist is administered into the nasal cavity as a dry of the aforementioned embodiments of protecting the ocular powder. In another embodiment of any of the aforemen Surface during environmentally challenging conditions, the US 9,597,284 B2 43 44 nicotinic acetylcholine receptor agonist is administered into Some embodiments is a method of increasing mucin content the nasal cavity by a jet of liquid. on the ocular Surface, comprising the local administration of In another embodiment of any of the aforementioned a therapeutically effective amount of a nicotinic acetylcho embodiments of protecting the ocular surface during envi line receptor agonist into the nasal cavity of an individual in ronmentally challenging conditions, the trigeminal nerve is need thereof, wherein the agonist selectively binds to the activated. In a further embodiment of protecting the ocular peripheral nicotinic acetylcholine receptor and in an amount Surface during environmentally challenging conditions, the that does not result in undesired systemic side effects. In anterior ethmoidal nerve is activated. In another embodi Some embodiments is a method of increasing mucin content ment of any of the aforementioned embodiments of protect on the ocular Surface, further comprising the local admin ing the ocular surface during environmentally challenging 10 istration of one or more Substances that prevent or facilitate conditions, the nasolacrimal reflex is activated. the recovery of the nicotinic acetylcholine receptor from the Increasing Mucin Content on the Ocular Surface desensitized State. In some embodiments is a method of Provided herein, in some embodiments, is a method of increasing mucin content on the ocular surface, further increasing mucin content on the ocular Surface in a subject. comprising the local administration of one or more Sub In some embodiments, is a method of increasing mucin 15 stances that prevent the entry or reduce the entry of the content on the ocular surface, comprising the local admin nicotinic acetylcholine receptor into the desensitized State, istration of a therapeutically effective amount of a nicotinic or facilitate the recovery of the nicotinic acetylcholine acetylcholine receptor agonist into the nasal cavity of an receptor from the desensitized state. In some embodiments individual in need thereof, wherein the agonist selectively is a method of increasing mucin content on the ocular binds to the peripheral nicotinic acetylcholine receptor and Surface, further comprising the local administration of one or does not cross the blood-brain barrier in a pharmacologically more substances that prevent or facilitate the recovery of the relevant concentration. In some embodiments is method of nicotinic acetylcholine receptor from the desensitized State increasing mucin content on the ocular Surface, comprising selected from protein kinase C(PKC) or factors that upregu the local administration of a therapeutically effective amount late or up-modulate PKC. cAMP-dependent protein kinase of a nicotinic acetylcholine receptor agonist into the nasal 25 (PKA) or factors that upregulate or up-modulate PKA, and cavity of an individual in need thereof, wherein the agonist calcineurin inhibitors. In some embodiments is a method of does not cross the blood-brain barrier in a pharmacologically increasing mucin content on the ocular surface, further relevant concentration and selectively binds to at least one of comprising the local administration of one or more Sub the peripheral nicotinic acetylcholine receptor Subtypes stances that prevent the entry or reduce the entry of the selected from alpha3beta4, alpha-4beta2, and alpha7. In 30 nicotinic acetylcholine receptor into the desensitized State, Some embodiments is method of increasing mucin content or facilitate the recovery of the nicotinic acetylcholine on the ocular surface, comprising the local administration of receptor from the desensitized state selected from protein a therapeutically effective amount of a nicotinic acetylcho kinase C (PKC) or factors that upregulate or up-modulate line receptoragonist into the nasal cavity of an individual in PKC. cAMP-dependent protein kinase (PKA) or factors that need thereof, wherein the agonist does not cross the blood 35 upregulate or up-modulate PKA, and calcineurin inhibitors. brain barrier in a pharmacologically relevant concentration In some embodiments is a method of increasing mucin and selectively binds to the peripheral nicotinic acetylcho content on the ocular Surface, further comprising the local line receptor subtype alpha3beta4. In some embodiments is administration of protein kinase C (PKC) or factors that method of increasing mucin content on the ocular Surface, upregulate or up-modulate PKC. In some embodiments is a comprising the local administration of a therapeutically 40 method of increasing mucin content on the ocular Surface, effective amount of a nicotinic acetylcholine receptor ago further comprising the local administration of cAMP-depen nist into the nasal cavity of an individual in need thereof, dent protein kinase (PKA) or factors that upregulate or wherein the agonist does not cross the blood-brain barrier in up-modulate PKA. In some embodiments is a method of a pharmacologically relevant concentration and selectively increasing mucin content on the ocular surface, further binds to the peripheral nicotinic acetylcholine receptor sub 45 comprising the local administration of a calcineurin inhibi type alpha-4beta2. In some embodiments is method of tor. In some embodiments is a method of increasing mucin increasing mucin content on the ocular Surface, comprising content on the ocular Surface, further comprising the local the local administration of a therapeutically effective amount administration of a calcineurin inhibitor, wherein the cal of a nicotinic acetylcholine receptor agonist into the nasal cineurin inhibitor is selected from cyclosporine, pimecroli cavity of an individual in need thereof, wherein the agonist 50 mus, and tacrolimus. In some embodiments is a method of does not cross the blood-brain barrier in a pharmacologically increasing mucin content on the ocular surface, further relevant concentration and selectively binds to the peripheral comprising the local administration of cyclosporine. In some nicotinic acetylcholine receptor Subtype alpha7. In some embodiments is a method of increasing mucin content on the embodiments is a method of increasing mucin content on the ocular surface, further comprising the local administration ocular Surface, comprising the local administration of a 55 of pimecrolimus. In some embodiments is a method of therapeutically effective amount of a nicotinic acetylcholine increasing mucin content on the ocular surface, further receptoragonist into the nasal cavity of an individual in need comprising the local administration of tacrolimus. thereof, wherein the agonist selectively binds to the periph In a further embodiment of any of the aforementioned eral nicotinic acetylcholine receptor and is administered in embodiments of increasing mucin content on the ocular an amount that is not systemically bioavailable. In some 60 Surface, the nicotinic acetylcholine receptor agonist is embodiments is a method of increasing mucin content on the selected from nicotine, cytisine, epibatidine, Varenicline, ocular Surface, comprising the local administration of a tebanicline, DBO-83, CC4, ABT-418, ABT-366833, ABT therapeutically effective amount of a nicotinic acetylcholine 202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU receptoragonist into the nasal cavity of an individual in need 282987, LY-2087101, A85380, and 5-I-A85380. In another thereof, wherein the agonist selectively binds to the periph 65 embodiment of any of the aforementioned embodiments of eral nicotinic acetylcholine receptor and in an amount that increasing mucin content on the ocular Surface, the nicotinic does not result in undesired psychoactive side effects. In acetylcholine receptor agonist is nicotine. In another US 9,597,284 B2 45 46 embodiment of any of the aforementioned embodiments of administered into the nasal cavity. In another embodiment of increasing mucin content on the ocular Surface, the nicotinic any of the aforementioned embodiments of increasing mucin acetylcholine receptor agonist is cytisine. In another content on the ocular Surface, at least 25 micrograms of the embodiment of any of the aforementioned embodiments of nicotinic acetylcholine receptor agonist is administered into increasing mucin content on the ocular Surface, the nicotinic 5 the nasal cavity. In another embodiment of any of the acetylcholine receptor agonist is epibatidine. In another aforementioned embodiments of increasing mucin content embodiment of any of the aforementioned embodiments of on the ocular surface, at least 50 micrograms of the nicotinic increasing mucin content on the ocular Surface, the nicotinic acetylcholine receptor agonist is administered into the nasal acetylcholine receptor agonist is Varenicline. In another cavity. In another embodiment of any of the aforementioned embodiment of any of the aforementioned embodiments of 10 embodiments of increasing mucin content on the ocular increasing mucin content on the ocular Surface, the nicotinic Surface, at least 100 micrograms of the nicotinic acetylcho acetylcholine receptor agonist is tebanicline. In another line receptor agonist is administered into the nasal cavity. In embodiment of any of the aforementioned embodiments of another embodiment of any of the aforementioned embodi increasing mucin content on the ocular Surface, the nicotinic ments of increasing mucin content on the ocular Surface, at acetylcholine receptor agonist is DBO-83. In another 15 least 250 micrograms of the nicotinic acetylcholine receptor embodiment of any of the aforementioned embodiments of agonist is administered into the nasal cavity. In another increasing mucin content on the ocular Surface, the nicotinic embodiment of any of the aforementioned embodiments of acetylcholine receptor agonist is CC4. In another embodi increasing mucin content on the ocular Surface, at least 500 ment of any of the aforementioned embodiments of increas micrograms of the nicotinic acetylcholine receptoragonist is ing mucin content on the ocular Surface, the nicotinic administered into the nasal cavity. In another embodiment of acetylcholine receptor agonist is ABT-418. In another any of the aforementioned embodiments of increasing mucin embodiment of any of the aforementioned embodiments of content on the ocular surface, at least 750 micrograms of the increasing mucin content on the ocular Surface, the nicotinic nicotinic acetylcholine receptor agonist is administered into acetylcholine receptor agonist is ABT-366833. In another the nasal cavity. In another embodiment of any of the embodiment of any of the aforementioned embodiments of 25 aforementioned embodiments of increasing mucin content increasing mucin content on the ocular Surface, the nicotinic on the ocular surface, at least 1000 micrograms of the acetylcholine receptor agonist is ABT-202. In another nicotinic acetylcholine receptor agonist is administered into embodiment of any of the aforementioned embodiments of the nasal cavity. In another embodiment of any of the increasing mucin content on the ocular Surface, the nicotinic aforementioned embodiments of increasing mucin content acetylcholine receptor agonist is ABT-894. In another 30 on the ocular surface, between 1 microgram and 1000 embodiment of any of the aforementioned embodiments of micrograms of the nicotinic acetylcholine receptoragonist is increasing mucin content on the ocular surface, the nicotinic administered into the nasal cavity. In another embodiment of acetylcholine receptor agonist is SIB-1663. In another any of the aforementioned embodiments of increasing mucin embodiment of any of the aforementioned embodiments of content on the ocular Surface, between 5 micrograms and increasing mucin content on the ocular Surface, the nicotinic 35 1000 micrograms of the nicotinic acetylcholine receptor acetylcholine receptor agonist is GTS-21. In another agonist is administered into the nasal cavity. In another embodiment of any of the aforementioned embodiments of embodiment of any of the aforementioned embodiments of increasing mucin content on the ocular Surface, the nicotinic increasing mucin content on the ocular Surface, between 5 acetylcholine receptor agonist is PHA-543,613. In another micrograms and 100 micrograms of the nicotinic acetylcho embodiment of any of the aforementioned embodiments of 40 line receptor agonist is administered into the nasal cavity. In increasing mucin content on the ocular Surface, the nicotinic another embodiment of any of the aforementioned embodi acetylcholine receptor agonist is PNU-282987. In another ments of increasing mucin content on the ocular Surface, embodiment of any of the aforementioned embodiments of between 5 micrograms and 50 micrograms of the nicotinic increasing mucin content on the ocular Surface, the nicotinic acetylcholine receptor agonist is administered into the nasal acetylcholine receptor agonist is LY-2087101. In another 45 cavity. In another embodiment of any of the aforementioned embodiment of any of the aforementioned embodiments of embodiments of increasing mucin content on the ocular increasing mucin content on the ocular Surface, the nicotinic Surface, between 10 micrograms and 50 micrograms of the acetylcholine receptor agonist is A85380. In another nicotinic acetylcholine receptor agonist is administered into embodiment of any of the aforementioned embodiments of the nasal cavity. In another embodiment of any of the increasing mucin content on the ocular Surface, the nicotinic 50 aforementioned embodiments of increasing mucin content acetylcholine receptor agonist is 5-I-A85380. on the ocular surface, between 25 micrograms and 1000 In a further embodiment of any of the aforementioned micrograms of the nicotinic acetylcholine receptoragonist is embodiments of increasing mucin content on the ocular administered into the nasal cavity. In another embodiment of Surface, the nicotinic acetylcholine receptor agonist is any of the aforementioned embodiments of increasing mucin selected from a compound disclosed in WO 2008/057938, 55 content on the ocular surface, between 50 micrograms and WO 2009/111550, WO 2010/028011, or WO 2010/028033. 1000 micrograms of the nicotinic acetylcholine receptor In another embodiment of any of the aforementioned agonist is administered into the nasal cavity. In another embodiments of increasing mucin content on the ocular embodiment of any of the aforementioned embodiments of Surface, at least 1 microgram of the nicotinic acetylcholine increasing mucin content on the ocular Surface, between 100 receptor agonist is administered into the nasal cavity. In 60 micrograms and 1000 micrograms of the nicotinic acetyl another embodiment of any of the aforementioned embodi choline receptoragonist is administered into the nasal cavity. ments of increasing mucin content on the ocular Surface, at In another embodiment of any of the aforementioned least 5 micrograms of the nicotinic acetylcholine receptor embodiments of increasing mucin content on the ocular agonist is administered into the nasal cavity. In another surface, between 100 micrograms and 750 micrograms of embodiment of any of the aforementioned embodiments of 65 the nicotinic acetylcholine receptor agonist is administered increasing mucin content on the ocular Surface, at least 10 into the nasal cavity. In another embodiment of any of the micrograms of the nicotinic acetylcholine receptoragonist is aforementioned embodiments of increasing mucin content US 9,597,284 B2 47 48 on the ocular surface, between 150 micrograms and 750 In another embodiment of any of the aforementioned micrograms of the nicotinic acetylcholine receptoragonist is embodiments of increasing mucin content on the ocular administered into the nasal cavity. In another embodiment of Surface, the nicotinic acetylcholine receptor agonist is any of the aforementioned embodiments of increasing mucin administered into the nasal cavity as a liquid, Suspension, content on the ocular Surface, between 150 micrograms and aerosol, gel, ointment, dry powder, cream, paste, lotion, or 600 micrograms of the nicotinic acetylcholine receptor balm. In another embodiment of any of the aforementioned agonist is administered into the nasal cavity. embodiments of increasing mucin content on the ocular In another embodiment of any of the aforementioned Surface, the nicotinic acetylcholine receptor agonist is embodiments of increasing mucin content on the ocular administered into the nasal cavity as a liquid. In another Surface, the nicotinic acetylcholine receptor agonist is 10 embodiment of any of the aforementioned embodiments of increasing mucin content on the ocular Surface, the nicotinic administered once daily. In another embodiment of any of acetylcholine receptor agonist is administered into the nasal the aforementioned embodiments of increasing mucin con cavity as a suspension. In another embodiment of any of the tent on the ocular Surface, the nicotinic acetylcholine recep aforementioned embodiments of increasing mucin content tor agonist is administered at least once daily. In another on the ocular Surface, the nicotinic acetylcholine receptor embodiment of any of the aforementioned embodiments of agonist is administered into the nasal cavity as an aerosol. In increasing mucin content on the ocular Surface, the nicotinic another embodiment of any of the aforementioned embodi acetylcholine receptoragonist is administered twice daily. In ments of increasing mucin content on the ocular Surface, the another embodiment of any of the aforementioned embodi nicotinic acetylcholine receptor agonist is administered into ments of increasing mucin content on the ocular Surface, the the nasal cavity as a gel. In another embodiment of any of nicotinic acetylcholine receptor agonist is administered at the aforementioned embodiments of increasing mucin con least twice daily. In another embodiment of any of the tent on the ocular Surface, the nicotinic acetylcholine recep aforementioned embodiments of increasing mucin content tor agonist is administered into the nasal cavity as an on the ocular Surface, the nicotinic acetylcholine receptor ointment. In another embodiment of any of the aforemen agonist is administered three times daily. In another embodi 25 tioned embodiments of increasing mucin content on the ment of any of the aforementioned embodiments of increas ocular Surface, the nicotinic acetylcholine receptoragonist is ing mucin content on the ocular Surface, the nicotinic administered into the nasal cavity as a dry powder. In acetylcholine receptor agonist is administered at least three another embodiment of any of the aforementioned embodi times daily. In another embodiment of any of the aforemen ments of increasing mucin content on the ocular Surface, the tioned embodiments of increasing mucin content on the 30 nicotinic acetylcholine receptor agonist is administered into ocular Surface, the nicotinic acetylcholine receptoragonist is the nasal cavity as a cream. In another embodiment of any administered for one day. In another embodiment of any of of the aforementioned embodiments of increasing mucin the aforementioned embodiments of increasing mucin con content on the ocular Surface, the nicotinic acetylcholine tent on the ocular Surface, the nicotinic acetylcholine recep receptor agonist is administered into the nasal cavity as a tor agonist is administered for at least two days. In another 35 paste. In another embodiment of any of the aforementioned embodiment of any of the aforementioned embodiments of embodiments of increasing mucin content on the ocular increasing mucin content on the ocular Surface, the nicotinic Surface, the nicotinic acetylcholine receptor agonist is acetylcholine receptor agonist is administered for at least administered into the nasal cavity as a lotion. In another three days. In another embodiment of any of the aforemen embodiment of any of the aforementioned embodiments of tioned embodiments of increasing mucin content on the 40 increasing mucin content on the ocular Surface, the nicotinic ocular Surface, the nicotinic acetylcholine receptoragonist is acetylcholine receptor agonist is administered into the nasal administered for at least four days. In another embodiment cavity as a balm. of any of the aforementioned embodiments of increasing In another embodiment of any of the aforementioned mucin content on the ocular Surface, the nicotinic acetyl embodiments of increasing mucin content on the ocular choline receptor agonist is administered for at least five 45 Surface, the nicotinic acetylcholine receptor agonist is days. In another embodiment of any of the aforementioned administered into the nasal cavity by a syringe, dropper, embodiments of increasing mucin content on the ocular bottle nebulizer, atomization pump, inhaler, powder spray Surface, the nicotinic acetylcholine receptor agonist is device, vaporizer, patch, medicated Stick, pipette, or jet of administered for at least seven days. In another embodiment liquid. In another embodiment of any of the aforementioned of any of the aforementioned embodiments of increasing 50 embodiments of increasing mucin content on the ocular mucin content on the ocular Surface, the nicotinic acetyl Surface, the nicotinic acetylcholine receptor agonist is choline receptor agonist is administered for at least ten days. administered into the nasal cavity by a syringe. In another In another embodiment of any of the aforementioned embodiment of any of the aforementioned embodiments of embodiments of increasing mucin content on the ocular increasing mucin content on the ocular Surface, the nicotinic Surface, the nicotinic acetylcholine receptor agonist is 55 acetylcholine receptor agonist is administered into the nasal administered for at least fourteen days. In another embodi cavity by a dropper. In another embodiment of any of the ment of any of the aforementioned embodiments of increas aforementioned embodiments of increasing mucin content ing mucin content on the ocular Surface, the nicotinic on the ocular Surface, the nicotinic acetylcholine receptor acetylcholine receptor agonist is administered for at least agonist is administered into the nasal cavity by a bottle twenty one days. In another embodiment of any of the 60 nebulizer. In another embodiment of any of the aforemen aforementioned embodiments of increasing mucin content tioned embodiments of increasing mucin content on the on the ocular Surface, the nicotinic acetylcholine receptor ocular Surface, the nicotinic acetylcholine receptoragonist is agonist is administered for at least thirty days. administered into the nasal cavity by an atomization pump. In another embodiment of any of the aforementioned In another embodiment of any of the aforementioned embodiments of increasing mucin content on the ocular 65 embodiments of increasing mucin content on the ocular Surface, the nicotinic acetylcholine receptor agonist is Surface, the nicotinic acetylcholine receptor agonist is administered in alternating nostrils. administered into the nasal cavity by an inhaler. In another US 9,597,284 B2 49 50 embodiment of any of the aforementioned embodiments of acetylcholine receptor Subtype alpha-4beta2. In some increasing mucin content on the ocular Surface, the nicotinic embodiments is method of increasing the amount or con acetylcholine receptor agonist is administered into the nasal centration of one or more lacrimal proteins, comprising the cavity by a powder spray device. In another embodiment of local administration of a therapeutically effective amount of any of the aforementioned embodiments of increasing mucin a nicotinic acetylcholine receptor agonist into the nasal content on the ocular Surface, the nicotinic acetylcholine cavity of an individual in need thereof, wherein the agonist receptor agonist is administered into the nasal cavity by a does not cross the blood-brain barrier in a pharmacologically vaporizer. In another embodiment of any of the aforemen relevant concentration and selectively binds to the peripheral tioned embodiments of increasing mucin content on the nicotinic acetylcholine receptor Subtype alpha7. In some ocular Surface, the nicotinic acetylcholine receptoragonist is 10 embodiments is a method of increasing the amount or administered into the nasal cavity by a patch. In another concentration of one or more lacrimal proteins, comprising embodiment of any of the aforementioned embodiments of the local administration of a therapeutically effective amount increasing mucin content on the ocular Surface, the nicotinic of a nicotinic acetylcholine receptor agonist into the nasal acetylcholine receptor agonist is administered into the nasal cavity of an individual in need thereof, wherein the agonist cavity by a medicated Stick. In another embodiment of any 15 selectively binds to the peripheral nicotinic acetylcholine of the aforementioned embodiments of increasing mucin receptor and is administered in an amount that is not content on the ocular Surface, the nicotinic acetylcholine systemically bioavailable. In some embodiments is a method receptor agonist is administered into the nasal cavity by a of increasing the amount or concentration of one or more pipette. In another embodiment of any of the aforemen lacrimal proteins, comprising the local administration of a tioned embodiments of increasing mucin content on the therapeutically effective amount of a nicotinic acetylcholine ocular Surface, the nicotinic acetylcholine receptoragonist is receptoragonist into the nasal cavity of an individual in need administered into the nasal cavity by a jet of liquid. thereof, wherein the agonist selectively binds to the periph In another embodiment of any of the aforementioned eral nicotinic acetylcholine receptor and in an amount that embodiments of increasing mucin content on the ocular does not result in undesired psychoactive side effects. In Surface, the trigeminal nerve is activated. In a further 25 Some embodiments is a method of increasing the amount or embodiment of increasing mucin content on the ocular concentration of one or more lacrimal proteins, comprising surface, the anterior ethmoidal nerve is activated. In another the local administration of a therapeutically effective amount embodiment of any of the aforementioned embodiments of of a nicotinic acetylcholine receptor agonist into the nasal increasing mucin content on the ocular surface, the nasolac cavity of an individual in need thereof, wherein the agonist rimal reflex is activated. 30 selectively binds to the peripheral nicotinic acetylcholine Increasing the Amount or Concentration of One or More receptor and in an amount that does not result in undesired Lacrimal Proteins systemic side effects. In some embodiments is a method of Provided herein, in some embodiments, is a method of increasing the amount or concentration of one or more increasing the amount or concentration of one or more lacrimal proteins, wherein the lacrimal protein is epithelial lacrimal proteins in a subject. In some embodiments, is a 35 growth factor, lactoferin, lacritin, prolactin, adrenocortico method of increasing the amount or concentration of one or tropic, leucine enkephalin, ALS2CL, ARHGEF19, more lacrimal proteins, comprising the local administration KIAA1109, PLXNA1, POLG, WIPI1, ZMIZ2 or other pro of a therapeutically effective amount of a nicotinic acetyl teins of the tear proteome. In some embodiments is a method choline receptor agonist into the nasal cavity of an indi of increasing the amount or concentration of one or more vidual in need thereof, wherein the agonist selectively binds 40 lacrimal proteins, wherein at least one lacrimal protein is to the peripheral nicotinic acetylcholine receptor and does epithelial growth factor. In some embodiments is a method not cross the blood-brain barrier in a pharmacologically of increasing the amount or concentration of one or more relevant concentration. In some embodiments is method of lacrimal proteins, wherein at least one lacrimal protein is increasing the amount or concentration of one or more lactoferin. In some embodiments is a method of increasing lacrimal proteins, comprising the local administration of a 45 the amount or concentration of one or more lacrimal pro therapeutically effective amount of a nicotinic acetylcholine teins, wherein at least one lacrimal protein is lacritin. In receptoragonist into the nasal cavity of an individual in need Some embodiments is a method of increasing the amount or thereof, wherein the agonist does not cross the blood-brain concentration of one or more lacrimal proteins, wherein at barrier in a pharmacologically relevant concentration and least one lacrimal protein is prolactin. In some embodiments selectively binds to at least one of the peripheral nicotinic 50 is a method of increasing the amount or concentration of one acetylcholine receptor subtypes selected from alpha3beta4, or more lacrimal proteins, wherein at least one lacrimal alpha-4beta2, and alpha7. In some embodiments is method of protein is adrenocorticotropic. In some embodiments is a increasing the amount or concentration of one or more method of increasing the amount or concentration of one or lacrimal proteins, comprising the local administration of a more lacrimal proteins, wherein at least one lacrimal protein therapeutically effective amount of a nicotinic acetylcholine 55 is leucine enkephalin. In some embodiments is a method of receptoragonist into the nasal cavity of an individual in need increasing the amount or concentration of one or more thereof, wherein the agonist does not cross the blood-brain lacrimal proteins, wherein at least one lacrimal protein is barrier in a pharmacologically relevant concentration and ALS2CL. In some embodiments is a method of increasing selectively binds to the peripheral nicotinic acetylcholine the amount or concentration of one or more lacrimal pro receptor Subtype alpha3beta4. In some embodiments is 60 teins, wherein at least one lacrimal protein is ARHGEF19. In method of increasing the amount or concentration of one or Some embodiments is a method of increasing the amount or more lacrimal proteins, comprising the local administration concentration of one or more lacrimal proteins, wherein at of a therapeutically effective amount of a nicotinic acetyl least one lacrimal protein is KIAA1109. In some embodi choline receptor agonist into the nasal cavity of an indi ments is a method of increasing the amount or concentration vidual in need thereof, wherein the agonist does not cross the 65 of one or more lacrimal proteins, wherein at least one blood-brain barrier in a pharmacologically relevant concen lacrimal protein is PLXNA1. In some embodiments is a tration and selectively binds to the peripheral nicotinic method of increasing the amount or concentration of one or US 9,597,284 B2 51 52 more lacrimal proteins, wherein at least one lacrimal protein ABT-366833, ABT-202, ABT-894, SIB-1663, GTS-21, is POLG. In some embodiments is a method of increasing PHA-543613, PNU-282987, LY-2087101, A85380, and 5-I- the amount or concentration of one or more lacrimal pro A85380. In another embodiment of any of the aforemen teins, wherein at least one lacrimal protein is WIPI1. In some tioned embodiments of increasing the amount or concentra embodiments is a method of increasing the amount or tion of one or more lacrimal proteins, the nicotinic concentration of one or more lacrimal proteins, wherein at acetylcholine receptor agonist is nicotine. In another least one lacrimal protein is ZMIZ2. In some embodiments embodiment of any of the aforementioned embodiments of is a method of increasing the amount or concentration of one increasing the amount or concentration of one or more or more lacrimal proteins, further comprising the local lacrimal proteins, the nicotinic acetylcholine receptor ago administration of one or more Substances that prevent or 10 nist is cytisine. In another embodiment of any of the facilitate the recovery of the nicotinic acetylcholine receptor aforementioned embodiments of increasing the amount or from the desensitized state. In some embodiments is a concentration of one or more lacrimal proteins, the nicotinic method of increasing the amount or concentration of one or acetylcholine receptor agonist is epibatidine. In another more lacrimal proteins, further comprising the local admin embodiment of any of the aforementioned embodiments of istration of one or more Substances that prevent the entry or 15 increasing the amount or concentration of one or more reduce the entry of the nicotinic acetylcholine receptor into lacrimal proteins, the nicotinic acetylcholine receptor ago the desensitized state, or facilitate the recovery of the nist is varenicline. In another embodiment of any of the nicotinic acetylcholine receptor from the desensitized State. aforementioned embodiments of increasing the amount or In some embodiments is a method of increasing the amount concentration of one or more lacrimal proteins, the nicotinic or concentration of one or more lacrimal proteins, further acetylcholine receptor agonist is tebanicline. In another comprising the local administration of one or more Sub embodiment of any of the aforementioned embodiments of stances that prevent or facilitate the recovery of the nicotinic increasing the amount or concentration of one or more acetylcholine receptor from the desensitized state selected lacrimal proteins, the nicotinic acetylcholine receptor ago from protein kinase C (PKC) or factors that upregulate or nist is DBO-83. In another embodiment of any of the up-modulate PKC. cAMP-dependent protein kinase (PKA) 25 aforementioned embodiments of increasing the amount or or factors that upregulate or up-modulate PKA, and cal concentration of one or more lacrimal proteins, the nicotinic cineurin inhibitors. In some embodiments is a method of acetylcholine receptor agonist is CC4. In another embodi increasing the amount or concentration of one or more ment of any of the aforementioned embodiments of increas lacrimal proteins, further comprising the local administra ing the amount or concentration of one or more lacrimal tion of one or more Substances that prevent the entry or 30 proteins, the nicotinic acetylcholine receptoragonist is ABT reduce the entry of the nicotinic acetylcholine receptor into 418. In another embodiment of any of the aforementioned the desensitized state, or facilitate the recovery of the embodiments of increasing the amount or concentration of nicotinic acetylcholine receptor from the desensitized State one or more lacrimal proteins, the nicotinic acetylcholine selected from protein kinase C(PKC) or factors that upregu receptor agonist is ABT-366833. In another embodiment of late or up-modulate PKC. cAMP-dependent protein kinase 35 any of the aforementioned embodiments of increasing the (PKA) or factors that upregulate or up-modulate PKA, and amount or concentration of one or more lacrimal proteins, calcineurin inhibitors. In some embodiments is a method of the nicotinic acetylcholine receptor agonist is ABT-202. In increasing the amount or concentration of one or more another embodiment of any of the aforementioned embodi lacrimal proteins, further comprising the local administra ments of increasing the amount or concentration of one or tion of protein kinase C (PKC) or factors that upregulate or 40 more lacrimal proteins, the nicotinic acetylcholine receptor up-modulate PKC. In some embodiments is a method of agonist is ABT-894. In another embodiment of any of the increasing the amount or concentration of one or more aforementioned embodiments of increasing the amount or lacrimal proteins, further comprising the local administra concentration of one or more lacrimal proteins, the nicotinic tion of cAMP-dependent protein kinase (PKA) or factors acetylcholine receptor agonist is SIB-1663. In another that upregulate or up-modulate PKA. In some embodiments 45 embodiment of any of the aforementioned embodiments of is a method of increasing the amount or concentration of one increasing the amount or concentration of one or more or more lacrimal proteins, further comprising the local lacrimal proteins, the nicotinic acetylcholine receptor ago administration of a calcineurin inhibitor. In some embodi nist is GTS-21. In another embodiment of any of the ments is a method of increasing the amount or concentration aforementioned embodiments of increasing the amount or of one or more lacrimal proteins, further comprising the 50 concentration of one or more lacrimal proteins, the nicotinic local administration of a calcineurin inhibitor, wherein the acetylcholine receptor agonist is PHA-543,613. In another calcineurin inhibitor is selected from cyclosporine, pime embodiment of any of the aforementioned embodiments of crolimus, and tacrolimus. In some embodiments is a method increasing the amount or concentration of one or more of increasing the amount or concentration of one or more lacrimal proteins, the nicotinic acetylcholine receptor ago lacrimal proteins, further comprising the local administra 55 nist is PNU-282987. In another embodiment of any of the tion of cyclosporine. In some embodiments is a method of aforementioned embodiments of increasing the amount or increasing the amount or concentration of one or more concentration of one or more lacrimal proteins, the nicotinic lacrimal proteins, further comprising the local administra acetylcholine receptor agonist is LY-2087101. In another tion of pimecrolimus. In some embodiments is a method of embodiment of any of the aforementioned embodiments of increasing the amount or concentration of one or more 60 increasing the amount or concentration of one or more lacrimal proteins, further comprising the local administra lacrimal proteins, the nicotinic acetylcholine receptor ago tion of tacrolimus. nist is A85380. In another embodiment of any of the In a further embodiment of any of the aforementioned aforementioned embodiments of increasing the amount or embodiments of increasing the amount or concentration of concentration of one or more lacrimal proteins, the nicotinic one or more lacrimal proteins, the nicotinic acetylcholine 65 acetylcholine receptor agonist is 5-I-A85380. receptor agonist is selected from nicotine, cytisine, epibati In a further embodiment of any of the aforementioned dine, Varenicline, tebanicline, DBO-83, CC4, ABT-418, embodiments of increasing the amount or concentration of US 9,597,284 B2 53 54 one or more lacrimal proteins, the nicotinic acetylcholine one or more lacrimal proteins, between 10 micrograms and receptor agonist is selected from a compound disclosed in 50 micrograms of the nicotinic acetylcholine receptor ago WO 2008/057938, WO 2009/111550, WO 2010/028011, or nist is administered into the nasal cavity. In another embodi WO 201 OFO28O33. ment of any of the aforementioned embodiments of increas In another embodiment of any of the aforementioned ing the amount or concentration of one or more lacrimal embodiments of increasing the amount or concentration of proteins, between 25 micrograms and 1000 micrograms of one or more lacrimal proteins, at least 1 microgram of the the nicotinic acetylcholine receptor agonist is administered nicotinic acetylcholine receptor agonist is administered into into the nasal cavity. In another embodiment of any of the the nasal cavity. In another embodiment of any of the aforementioned embodiments of increasing the amount or aforementioned embodiments of increasing the amount or 10 concentration of one or more lacrimal proteins, between 50 concentration of one or more lacrimal proteins, at least 5 micrograms and 1000 micrograms of the nicotinic acetyl micrograms of the nicotinic acetylcholine receptoragonist is choline receptoragonist is administered into the nasal cavity. administered into the nasal cavity. In another embodiment of In another embodiment of any of the aforementioned any of the aforementioned embodiments of increasing the embodiments of increasing the amount or concentration of amount or concentration of one or more lacrimal proteins, at 15 one or more lacrimal proteins, between 100 micrograms and least 10 micrograms of the nicotinic acetylcholine receptor 1000 micrograms of the nicotinic acetylcholine receptor agonist is administered into the nasal cavity. In another agonist is administered into the nasal cavity. In another embodiment of any of the aforementioned embodiments of embodiment of any of the aforementioned embodiments of increasing the amount or concentration of one or more increasing the amount or concentration of one or more lacrimal proteins, at least 25 micrograms of the nicotinic lacrimal proteins, between 100 micrograms and 750 micro acetylcholine receptor agonist is administered into the nasal grams of the nicotinic acetylcholine receptor agonist is cavity. In another embodiment of any of the aforementioned administered into the nasal cavity. In another embodiment of embodiments of increasing the amount or concentration of any of the aforementioned embodiments of increasing the one or more lacrimal proteins, at least 50 micrograms of the amount or concentration of one or more lacrimal proteins, nicotinic acetylcholine receptor agonist is administered into 25 between 150 micrograms and 750 micrograms of the nico the nasal cavity. In another embodiment of any of the tinic acetylcholine receptor agonist is administered into the aforementioned embodiments of increasing the amount or nasal cavity. In another embodiment of any of the afore concentration of one or more lacrimal proteins, at least 100 mentioned embodiments of increasing the amount or con micrograms of the nicotinic acetylcholine receptoragonist is centration of one or more lacrimal proteins, between 150 administered into the nasal cavity. In another embodiment of 30 micrograms and 600 micrograms of the nicotinic acetylcho any of the aforementioned embodiments of increasing the line receptor agonist is administered into the nasal cavity. amount or concentration of one or more lacrimal proteins, at In another embodiment of any of the aforementioned least 250 micrograms of the nicotinic acetylcholine receptor embodiments of increasing the amount or concentration of agonist is administered into the nasal cavity. In another one or more lacrimal proteins, the nicotinic acetylcholine embodiment of any of the aforementioned embodiments of 35 receptor agonist is administered once daily. In another increasing the amount or concentration of one or more embodiment of any of the aforementioned embodiments of lacrimal proteins, at least 500 micrograms of the nicotinic increasing the amount or concentration of one or more acetylcholine receptor agonist is administered into the nasal lacrimal proteins, the nicotinic acetylcholine receptor ago cavity. In another embodiment of any of the aforementioned nist is administered at least once daily. In another embodi embodiments of increasing the amount or concentration of 40 ment of any of the aforementioned embodiments of increas one or more lacrimal proteins, at least 750 micrograms of the ing the amount or concentration of one or more lacrimal nicotinic acetylcholine receptor agonist is administered into proteins, the nicotinic acetylcholine receptor agonist is the nasal cavity. In another embodiment of any of the administered twice daily. In another embodiment of any of aforementioned embodiments of increasing the amount or the aforementioned embodiments of increasing the amount concentration of one or more lacrimal proteins, at least 1000 45 or concentration of one or more lacrimal proteins, the micrograms of the nicotinic acetylcholine receptoragonist is nicotinic acetylcholine receptor agonist is administered at administered into the nasal cavity. In another embodiment of least twice daily. In another embodiment of any of the any of the aforementioned embodiments of increasing the aforementioned embodiments of increasing the amount or amount or concentration of one or more lacrimal proteins, concentration of one or more lacrimal proteins, the nicotinic between 1 microgram and 1000 micrograms of the nicotinic 50 acetylcholine receptor agonist is administered three times acetylcholine receptor agonist is administered into the nasal daily. In another embodiment of any of the aforementioned cavity. In another embodiment of any of the aforementioned embodiments of increasing the amount or concentration of embodiments of increasing the amount or concentration of one or more lacrimal proteins, the nicotinic acetylcholine one or more lacrimal proteins, between 5 micrograms and receptor agonist is administered at least three times daily. In 1000 micrograms of the nicotinic acetylcholine receptor 55 another embodiment of any of the aforementioned embodi agonist is administered into the nasal cavity. In another ments of increasing the amount or concentration of one or embodiment of any of the aforementioned embodiments of more lacrimal proteins, the nicotinic acetylcholine receptor increasing the amount or concentration of one or more agonist is administered for one day. In another embodiment lacrimal proteins, between 5 micrograms and 100 micro of any of the aforementioned embodiments of increasing the grams of the nicotinic acetylcholine receptor agonist is 60 amount or concentration of one or more lacrimal proteins, administered into the nasal cavity. In another embodiment of the nicotinic acetylcholine receptor agonist is administered any of the aforementioned embodiments of increasing the for at least two days. In another embodiment of any of the amount or concentration of one or more lacrimal proteins, aforementioned embodiments of increasing the amount or between 5 micrograms and 50 micrograms of the nicotinic concentration of one or more lacrimal proteins, the nicotinic acetylcholine receptor agonist is administered into the nasal 65 acetylcholine receptor agonist is administered for at least cavity. In another embodiment of any of the aforementioned three days. In another embodiment of any of the aforemen embodiments of increasing the amount or concentration of tioned embodiments of increasing the amount or concentra US 9,597,284 B2 55 56 tion of one or more lacrimal proteins, the nicotinic acetyl into the nasal cavity as a paste. In another embodiment of choline receptor agonist is administered for at least four any of the aforementioned embodiments of increasing the days. In another embodiment of any of the aforementioned amount or concentration of one or more lacrimal proteins, embodiments of increasing the amount or concentration of the nicotinic acetylcholine receptor agonist is administered one or more lacrimal proteins, the nicotinic acetylcholine into the nasal cavity as a lotion. In another embodiment of receptor agonist is administered for at least five days. In any of the aforementioned embodiments of increasing the another embodiment of any of the aforementioned embodi amount or concentration of one or more lacrimal proteins, ments of increasing the amount or concentration of one or the nicotinic acetylcholine receptor agonist is administered more lacrimal proteins, the nicotinic acetylcholine receptor into the nasal cavity as a balm. agonist is administered for at least seven days. In another 10 In another embodiment of any of the aforementioned embodiment of any of the aforementioned embodiments of embodiments of increasing the amount or concentration of increasing the amount or concentration of one or more one or more lacrimal proteins, the nicotinic acetylcholine lacrimal proteins, the nicotinic acetylcholine receptor ago receptor agonist is administered into the nasal cavity by a nist is administered for at least ten days. In another embodi Syringe, dropper, bottle nebulizer, atomization pump, ment of any of the aforementioned embodiments of increas 15 inhaler, powder spray device, vaporizer, patch, medicated ing the amount or concentration of one or more lacrimal Stick, pipette, or jet of liquid. In another embodiment of any proteins, the nicotinic acetylcholine receptor agonist is of the aforementioned embodiments of increasing the administered for at least fourteen days. In another embodi amount or concentration of one or more lacrimal proteins, ment of any of the aforementioned embodiments of increas the nicotinic acetylcholine receptor agonist is administered ing the amount or concentration of one or more lacrimal into the nasal cavity by a syringe. In another embodiment of proteins, the nicotinic acetylcholine receptor agonist is any of the aforementioned embodiments of increasing the administered for at least twenty one days. In another amount or concentration of one or more lacrimal proteins, embodiment of any of the aforementioned embodiments of the nicotinic acetylcholine receptor agonist is administered increasing the amount or concentration of one or more into the nasal cavity by a dropper. In another embodiment of lacrimal proteins, the nicotinic acetylcholine receptor ago 25 any of the aforementioned embodiments of increasing the nist is administered for at least thirty days. amount or concentration of one or more lacrimal proteins, In another embodiment of any of the aforementioned the nicotinic acetylcholine receptor agonist is administered embodiments of increasing the amount or concentration of into the nasal cavity by a bottle nebulizer. In another one or more lacrimal proteins, the nicotinic acetylcholine embodiment of any of the aforementioned embodiments of receptor agonist is administered in alternating nostrils. 30 increasing the amount or concentration of one or more In another embodiment of any of the aforementioned lacrimal proteins, the nicotinic acetylcholine receptor ago embodiments of increasing the amount or concentration of nist is administered into the nasal cavity by an atomization one or more lacrimal proteins, the nicotinic acetylcholine pump. In another embodiment of any of the aforementioned receptor agonist is administered into the nasal cavity as a embodiments of increasing the amount or concentration of liquid, Suspension, aerosol, gel, ointment, dry powder, 35 one or more lacrimal proteins, the nicotinic acetylcholine cream, paste, lotion, or balm. In another embodiment of any receptor agonist is administered into the nasal cavity by an of the aforementioned embodiments of increasing the inhaler. In another embodiment of any of the aforemen amount or concentration of one or more lacrimal proteins, tioned embodiments of increasing the amount or concentra the nicotinic acetylcholine receptor agonist is administered tion of one or more lacrimal proteins, the nicotinic acetyl into the nasal cavity as a liquid. In another embodiment of 40 choline receptoragonist is administered into the nasal cavity any of the aforementioned embodiments of increasing the by a powder spray device. In another embodiment of any of amount or concentration of one or more lacrimal proteins, the aforementioned embodiments of increasing the amount the nicotinic acetylcholine receptor agonist is administered or concentration of one or more lacrimal proteins, the into the nasal cavity as a Suspension. In another embodiment nicotinic acetylcholine receptor agonist is administered into of any of the aforementioned embodiments of increasing the 45 the nasal cavity by a vaporizer. In another embodiment of amount or concentration of one or more lacrimal proteins, any of the aforementioned embodiments of increasing the the nicotinic acetylcholine receptor agonist is administered amount or concentration of one or more lacrimal proteins, into the nasal cavity as an aerosol. In another embodiment the nicotinic acetylcholine receptor agonist is administered of any of the aforementioned embodiments of increasing the into the nasal cavity by a patch. In another embodiment of amount or concentration of one or more lacrimal proteins, 50 any of the aforementioned embodiments of increasing the the nicotinic acetylcholine receptor agonist is administered amount or concentration of one or more lacrimal proteins, into the nasal cavity as a gel. In another embodiment of any the nicotinic acetylcholine receptor agonist is administered of the aforementioned embodiments of increasing the into the nasal cavity by a medicated Stick. In another amount or concentration of one or more lacrimal proteins, embodiment of any of the aforementioned embodiments of the nicotinic acetylcholine receptor agonist is administered 55 increasing the amount or concentration of one or more into the nasal cavity as an ointment. In another embodiment lacrimal proteins, the nicotinic acetylcholine receptor ago of any of the aforementioned embodiments of increasing the nist is administered into the nasal cavity by a pipette. In amount or concentration of one or more lacrimal proteins, another embodiment of any of the aforementioned embodi the nicotinic acetylcholine receptor agonist is administered ments of increasing the amount or concentration of one or into the nasal cavity as a dry powder. In another embodiment 60 more lacrimal proteins, the nicotinic acetylcholine receptor of any of the aforementioned embodiments of increasing the agonist is administered into the nasal cavity by a jet of amount or concentration of one or more lacrimal proteins, liquid. the nicotinic acetylcholine receptor agonist is administered In another embodiment of any of the aforementioned into the nasal cavity as a cream. In another embodiment of embodiments of increasing the amount or concentration of any of the aforementioned embodiments of increasing the 65 one or more lacrimal proteins, the trigeminal nerve is amount or concentration of one or more lacrimal proteins, activated. In a further embodiment of increasing the amount the nicotinic acetylcholine receptor agonist is administered or concentration of one or more lacrimal proteins, the US 9,597,284 B2 57 58 anterior ethmoidal nerve is activated. In another embodi substances that prevent or facilitate the recovery of the ment of any of the aforementioned embodiments of increas nicotinic acetylcholine receptor from the desensitized State. ing the amount or concentration of one or more lacrimal In some embodiments is a method of enhancing tear clear proteins, the nasolacrimal reflex is activated. ance, further comprising the local administration of one or Enhancing Tear Clearance more substances that prevent the entry or reduce the entry of Provided herein, in some embodiments, is a method of the nicotinic acetylcholine receptor into the desensitized enhancing tear clearance in a Subject. In some embodiments, state, or facilitate the recovery of the nicotinic acetylcholine is a method of enhancing tear clearance, comprising the receptor from the desensitized state. In some embodiments local administration of a therapeutically effective amount of is a method of enhancing tear clearance, further comprising a nicotinic acetylcholine receptor agonist into the nasal 10 the local administration of one or more Substances that cavity of an individual in need thereof, wherein the agonist prevent or facilitate the recovery of the nicotinic acetylcho selectively binds to the peripheral nicotinic acetylcholine line receptor from the desensitized state selected from receptor and does not cross the blood-brain barrier in a protein kinase C (PKC) or factors that upregulate or up pharmacologically relevant concentration. In some embodi modulate PKC. cAMP-dependent protein kinase (PKA) or ments is method of enhancing tear clearance, comprising the 15 factors that upregulate or up-modulate PKA, and calcineurin local administration of a therapeutically effective amount of inhibitors. In some embodiments is a method of enhancing a nicotinic acetylcholine receptor agonist into the nasal tear clearance, further comprising the local administration of cavity of an individual in need thereof, wherein the agonist one or more Substances that prevent the entry or reduce the does not cross the blood-brain barrier in a pharmacologically entry of the nicotinic acetylcholine receptor into the desen relevant concentration and selectively binds to at least one of sitized state, or facilitate the recovery of the nicotinic the peripheral nicotinic acetylcholine receptor Subtypes acetylcholine receptor from the desensitized state selected selected from alpha3beta4, alpha-4beta2, and alpha7. In from protein kinase C (PKC) or factors that upregulate or Some embodiments is method of enhancing tear clearance, up-modulate PKC. cAMP-dependent protein kinase (PKA) comprising the local administration of a therapeutically or factors that upregulate or up-modulate PKA, and cal effective amount of a nicotinic acetylcholine receptor ago 25 cineurin inhibitors. In some embodiments is a method of nist into the nasal cavity of an individual in need thereof, enhancing tear clearance, further comprising the local wherein the agonist does not cross the blood-brain barrier in administration of protein kinase C (PKC) or factors that a pharmacologically relevant concentration and selectively upregulate or up-modulate PKC. In some embodiments is a binds to the peripheral nicotinic acetylcholine receptor sub method of enhancing tear clearance, further comprising the type alpha3beta4. In some embodiments is method of 30 local administration of cAMP-dependent protein kinase enhancing tear clearance, comprising the local administra (PKA) or factors that upregulate or up-modulate PKA. In tion of a therapeutically effective amount of a nicotinic some embodiments is a method of enhancing tear clearance, acetylcholine receptor agonist into the nasal cavity of an further comprising the local administration of a calcineurin individual in need thereof, wherein the agonist does not inhibitor. In some embodiments is a method of enhancing cross the blood-brain barrier in a pharmacologically relevant 35 tear clearance, further comprising the local administration of concentration and selectively binds to the peripheral nico a calcineurin inhibitor, wherein the calcineurin inhibitor is tinic acetylcholine receptor Subtype alpha-4beta2. In some selected from cyclosporine, pimecrolimus, and tacrolimus. embodiments is method of enhancing tear clearance, com In some embodiments is a method of enhancing tear clear prising the local administration of a therapeutically effective ance, further comprising the local administration of amount of a nicotinic acetylcholine receptor agonist into the 40 cyclosporine. In some embodiments is a method of enhanc nasal cavity of an individual in need thereof, wherein the ing tear clearance, further comprising the local administra agonist does not cross the blood-brain barrier in a pharma tion of pimecrolimus. In some embodiments is a method of cologically relevant concentration and selectively binds to enhancing tear clearance, further comprising the local the peripheral nicotinic acetylcholine receptor Subtype administration of tacrolimus. alpha7. In some embodiments is a method of enhancing tear 45 In a further embodiment of any of the aforementioned clearance, comprising the local administration of a thera embodiments of enhancing tear clearance, the nicotinic peutically effective amount of a nicotinic acetylcholine acetylcholine receptor agonist is selected from nicotine, receptoragonist into the nasal cavity of an individual in need cytisine, epibatidine, Varenicline, tebanicline, DBO-83, thereof, wherein the agonist selectively binds to the periph CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB eral nicotinic acetylcholine receptor and is administered in 50 1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, an amount that is not systemically bioavailable. In some A85380, and 5-I-A85380. In another embodiment of any of embodiments is a method of enhancing tear clearance, the aforementioned embodiments of enhancing tear clear comprising the local administration of a therapeutically ance, the nicotinic acetylcholine receptoragonist is nicotine. effective amount of a nicotinic acetylcholine receptor ago In another embodiment of any of the aforementioned nist into the nasal cavity of an individual in need thereof, 55 embodiments of enhancing tear clearance, the nicotinic wherein the agonist selectively binds to the peripheral acetylcholine receptor agonist is cytisine. In another nicotinic acetylcholine receptor and in an amount that does embodiment of any of the aforementioned embodiments of not result in undesired psychoactive side effects. In some enhancing tear clearance, the nicotinic acetylcholine recep embodiments is a method of enhancing tear clearance, tor agonist is epibatidine. In another embodiment of any of comprising the local administration of a therapeutically 60 the aforementioned embodiments of enhancing tear clear effective amount of a nicotinic acetylcholine receptor ago ance, the nicotinic acetylcholine receptor agonist is Vareni nist into the nasal cavity of an individual in need thereof, cline. In another embodiment of any of the aforementioned wherein the agonist selectively binds to the peripheral embodiments of enhancing tear clearance, the nicotinic nicotinic acetylcholine receptor and in an amount that does acetylcholine receptor agonist is tebanicline. In another not result in undesired systemic side effects. In some 65 embodiment of any of the aforementioned embodiments of embodiments is a method of enhancing tear clearance, enhancing tear clearance, the nicotinic acetylcholine recep further comprising the local administration of one or more toragonist is DBO-83. In another embodiment of any of the US 9,597,284 B2 59 60 aforementioned embodiments of enhancing tear clearance, nicotinic acetylcholine receptor agonist is administered into the nicotinic acetylcholine receptor agonist is CC4. In the nasal cavity. In another embodiment of any of the another embodiment of any of the aforementioned embodi aforementioned embodiments of enhancing tear clearance, ments of enhancing tear clearance, the nicotinic acetylcho at least 1000 micrograms of the nicotinic acetylcholine line receptor agonist is ABT-418. In another embodiment of 5 receptor agonist is administered into the nasal cavity. In any of the aforementioned embodiments of enhancing tear another embodiment of any of the aforementioned embodi clearance, the nicotinic acetylcholine receptor agonist is ments of enhancing tear clearance, between 1 microgram ABT-366833. In another embodiment of any of the afore and 1000 micrograms of the nicotinic acetylcholine receptor mentioned embodiments of enhancing tear clearance, the agonist is administered into the nasal cavity. In another nicotinic acetylcholine receptor agonist is ABT-202. In 10 embodiment of any of the aforementioned embodiments of another embodiment of any of the aforementioned embodi enhancing tear clearance, between 5 micrograms and 1000 ments of enhancing tear clearance, the nicotinic acetylcho micrograms of the nicotinic acetylcholine receptoragonist is line receptor agonist is ABT-894. In another embodiment of administered into the nasal cavity. In another embodiment of any of the aforementioned embodiments of enhancing tear any of the aforementioned embodiments of enhancing tear clearance, the nicotinic acetylcholine receptor agonist is 15 clearance, between 5 micrograms and 100 micrograms of the SIB-1663. In another embodiment of any of the aforemen nicotinic acetylcholine receptor agonist is administered into tioned embodiments of enhancing tear clearance, the nico the nasal cavity. In another embodiment of any of the tinic acetylcholine receptor agonist is GTS-21. In another aforementioned embodiments of enhancing tear clearance, embodiment of any of the aforementioned embodiments of between 5 micrograms and 50 micrograms of the nicotinic enhancing tear clearance, the nicotinic acetylcholine recep acetylcholine receptor agonist is administered into the nasal tor agonist is PHA-543613. In another embodiment of any cavity. In another embodiment of any of the aforementioned of the aforementioned embodiments of enhancing tear clear embodiments of enhancing tear clearance, between 10 ance, the nicotinic acetylcholine receptor agonist is PNU micrograms and 50 micrograms of the nicotinic acetylcho 282987. In another embodiment of any of the aforemen line receptor agonist is administered into the nasal cavity. In tioned embodiments of enhancing tear clearance, the 25 another embodiment of any of the aforementioned embodi nicotinic acetylcholine receptor agonist is LY-2087101. In ments of enhancing tear clearance, between 25 micrograms another embodiment of any of the aforementioned embodi and 1000 micrograms of the nicotinic acetylcholine receptor ments of enhancing tear clearance, the nicotinic acetylcho agonist is administered into the nasal cavity. In another line receptor agonist is A85380. In another embodiment of embodiment of any of the aforementioned embodiments of any of the aforementioned embodiments of enhancing tear 30 enhancing tear clearance, between 50 micrograms and 1000 clearance, the nicotinic acetylcholine receptor agonist is micrograms of the nicotinic acetylcholine receptoragonist is 5-I-A85380. administered into the nasal cavity. In another embodiment of In a further embodiment of any of the aforementioned any of the aforementioned embodiments of enhancing tear embodiments of enhancing tear clearance, the nicotinic clearance, between 100 micrograms and 1000 micrograms acetylcholine receptor agonist is selected from a compound 35 of the nicotinic acetylcholine receptor agonist is adminis disclosed in WO 2008/057938, WO 2009/111550, WO tered into the nasal cavity. In another embodiment of any of 2010/028011, or WO 2010/028033. the aforementioned embodiments of enhancing tear clear In another embodiment of any of the aforementioned ance, between 100 micrograms and 750 micrograms of the embodiments of enhancing tear clearance, at least 1 micro nicotinic acetylcholine receptor agonist is administered into gram of the nicotinic acetylcholine receptor agonist is 40 the nasal cavity. In another embodiment of any of the administered into the nasal cavity. In another embodiment of aforementioned embodiments of enhancing tear clearance, any of the aforementioned embodiments of enhancing tear between 150 micrograms and 750 micrograms of the nico clearance, at least 5 micrograms of the nicotinic acetylcho tinic acetylcholine receptor agonist is administered into the line receptoragonist is administered into the nasal cavity. In nasal cavity. In another embodiment of any of the afore another embodiment of any of the aforementioned embodi 45 mentioned embodiments of enhancing tear clearance, ments of enhancing tear clearance, at least 10 micrograms of between 150 micrograms and 600 micrograms of the nico the nicotinic acetylcholine receptor agonist is administered tinic acetylcholine receptor agonist is administered into the into the nasal cavity. In another embodiment of any of the nasal cavity. aforementioned embodiments of enhancing tear clearance, In another embodiment of any of the aforementioned at least 25 micrograms of the nicotinic acetylcholine recep 50 embodiments of enhancing tear clearance, the nicotinic tor agonist is administered into the nasal cavity. In another acetylcholine receptor agonist is administered once daily. In embodiment of any of the aforementioned embodiments of another embodiment of any of the aforementioned embodi enhancing tear clearance, at least 50 micrograms of the ments of enhancing tear clearance, the nicotinic acetylcho nicotinic acetylcholine receptor agonist is administered into line receptor agonist is administered at least once daily. In the nasal cavity. In another embodiment of any of the 55 another embodiment of any of the aforementioned embodi aforementioned embodiments of enhancing tear clearance, ments of enhancing tear clearance, the nicotinic acetylcho at least 100 micrograms of the nicotinic acetylcholine recep line receptor agonist is administered twice daily. In another tor agonist is administered into the nasal cavity. In another embodiment of any of the aforementioned embodiments of embodiment of any of the aforementioned embodiments of enhancing tear clearance, the nicotinic acetylcholine recep enhancing tear clearance, at least 250 micrograms of the 60 tor agonist is administered at least twice daily. In another nicotinic acetylcholine receptor agonist is administered into embodiment of any of the aforementioned embodiments of the nasal cavity. In another embodiment of any of the enhancing tear clearance, the nicotinic acetylcholine recep aforementioned embodiments of enhancing tear clearance, tor agonist is administered three times daily. In another at least 500 micrograms of the nicotinic acetylcholine recep embodiment of any of the aforementioned embodiments of tor agonist is administered into the nasal cavity. In another 65 enhancing tear clearance, the nicotinic acetylcholine recep embodiment of any of the aforementioned embodiments of tor agonist is administered at least three times daily. In enhancing tear clearance, at least 750 micrograms of the another embodiment of any of the aforementioned embodi US 9,597,284 B2 61 62 ments of enhancing tear clearance, the nicotinic acetylcho administered into the nasal cavity as a lotion. In another line receptor agonist is administered for one day. In another embodiment of any of the aforementioned embodiments of embodiment of any of the aforementioned embodiments of enhancing tear clearance, the nicotinic acetylcholine recep enhancing tear clearance, the nicotinic acetylcholine recep tor agonist is administered into the nasal cavity as a balm. tor agonist is administered for at least two days. In another In another embodiment of any of the aforementioned embodiment of any of the aforementioned embodiments of embodiments of enhancing tear clearance, the nicotinic enhancing tear clearance, the nicotinic acetylcholine recep acetylcholine receptor agonist is administered into the nasal toragonist is administered for at least three days. In another cavity by a syringe, dropper, bottle nebulizer, atomization embodiment of any of the aforementioned embodiments of pump, inhaler, powder spray device, vaporizer, patch, medi enhancing tear clearance, the nicotinic acetylcholine recep 10 cated Stick, pipette, or jet of liquid. In another embodiment tor agonist is administered for at least four days. In another of any of the aforementioned embodiments of enhancing embodiment of any of the aforementioned embodiments of tear clearance, the nicotinic acetylcholine receptor agonist is enhancing tear clearance, the nicotinic acetylcholine recep administered into the nasal cavity by a syringe. In another tor agonist is administered for at least five days. In another embodiment of any of the aforementioned embodiments of embodiment of any of the aforementioned embodiments of 15 enhancing tear clearance, the nicotinic acetylcholine recep enhancing tear clearance, the nicotinic acetylcholine recep toragonist is administered into the nasal cavity by a dropper. toragonist is administered for at least seven days. In another In another embodiment of any of the aforementioned embodiment of any of the aforementioned embodiments of embodiments of enhancing tear clearance, the nicotinic enhancing tear clearance, the nicotinic acetylcholine recep acetylcholine receptor agonist is administered into the nasal tor agonist is administered for at least ten days. In another cavity by a bottle nebulizer. In another embodiment of any embodiment of any of the aforementioned embodiments of of the aforementioned embodiments of enhancing tear clear enhancing tear clearance, the nicotinic acetylcholine recep ance, the nicotinic acetylcholine receptor agonist is admin tor agonist is administered for at least fourteen days. In istered into the nasal cavity by an atomization pump. In another embodiment of any of the aforementioned embodi another embodiment of any of the aforementioned embodi ments of enhancing tear clearance, the nicotinic acetylcho 25 ments of enhancing tear clearance, the nicotinic acetylcho line receptor agonist is administered for at least twenty one line receptor agonist is administered into the nasal cavity by days. In another embodiment of any of the aforementioned an inhaler. In another embodiment of any of the aforemen embodiments of enhancing tear clearance, the nicotinic tioned embodiments of enhancing tear clearance, the nico acetylcholine receptor agonist is administered for at least tinic acetylcholine receptor agonist is administered into the thirty days. 30 nasal cavity by a powder spray device. In another embodi In another embodiment of any of the aforementioned ment of any of the aforementioned embodiments of enhanc embodiments of enhancing tear clearance, the nicotinic ing tear clearance, the nicotinic acetylcholine receptor ago acetylcholine receptor agonist is administered in alternating nist is administered into the nasal cavity by a vaporizer. In nostrils. another embodiment of any of the aforementioned embodi In another embodiment of any of the aforementioned 35 ments of enhancing tear clearance, the nicotinic acetylcho embodiments of enhancing tear clearance, the nicotinic line receptor agonist is administered into the nasal cavity by acetylcholine receptor agonist is administered into the nasal a patch. In another embodiment of any of the aforemen cavity as a liquid, Suspension, aerosol, gel, ointment, dry tioned embodiments of enhancing tear clearance, the nico powder, cream, paste, lotion, or balm. In another embodi tinic acetylcholine receptor agonist is administered into the ment of any of the aforementioned embodiments of enhanc 40 nasal cavity by a medicated Stick. In another embodiment of ing tear clearance, the nicotinic acetylcholine receptor ago any of the aforementioned embodiments of enhancing tear nist is administered into the nasal cavity as a liquid. In clearance, the nicotinic acetylcholine receptor agonist is another embodiment of any of the aforementioned embodi administered into the nasal cavity by a pipette. In another ments of enhancing tear clearance, the nicotinic acetylcho embodiment of any of the aforementioned embodiments of line receptor agonist is administered into the nasal cavity as 45 enhancing tear clearance, the nicotinic acetylcholine recep a Suspension. In another embodiment of any of the afore tor agonist is administered into the nasal cavity by a jet of mentioned embodiments of enhancing tear clearance, the liquid. nicotinic acetylcholine receptor agonist is administered into In another embodiment of any of the aforementioned the nasal cavity as an aerosol. In another embodiment of any embodiments of enhancing tear clearance, the trigeminal of the aforementioned embodiments of enhancing tear clear 50 nerve is activated. In a further embodiment of enhancing tear ance, the nicotinic acetylcholine receptor agonist is admin clearance, the anterior ethmoidal nerve is activated. In istered into the nasal cavity as a gel. In another embodiment another embodiment of any of the aforementioned embodi of any of the aforementioned embodiments of enhancing ments of enhancing tear clearance, the nasolacrimal reflex is tear clearance, the nicotinic acetylcholine receptor agonist is activated. administered into the nasal cavity as an ointment. In another 55 Certain Terminology embodiment of any of the aforementioned embodiments of Unless otherwise stated, the following terms used in this enhancing tear clearance, the nicotinic acetylcholine recep application, including the specification and claims, have the tor agonist is administered into the nasal cavity as a dry definitions given below. It must be noted that, as used in the powder. In another embodiment of any of the aforemen specification and the appended claims, the singular forms tioned embodiments of enhancing tear clearance, the nico 60 “a,” “an and “the99 include plural referents unless the tinic acetylcholine receptor agonist is administered into the context clearly dictates otherwise. In this application, the use nasal cavity as a cream. In another embodiment of any of the of 'or' or “and” means “and/or unless stated otherwise. aforementioned embodiments of enhancing tear clearance, Furthermore, use of the term “including” as well as other the nicotinic acetylcholine receptor agonist is administered forms, such as “include”, “includes,” and “included,” is not into the nasal cavity as a paste. In another embodiment of 65 limiting. The section headings used herein are for organi any of the aforementioned embodiments of enhancing tear Zational purposes only and are not to be construed as clearance, the nicotinic acetylcholine receptor agonist is limiting the subject matter described. US 9,597,284 B2 63 64 The terms “co-administration' or the like, as used herein, not limited to, anxiety, depression, hallucination, euphoria, are meant to encompass administration of the selected addiction, sleep disorder/disturbances, insomnia, abnormal therapeutic agents to a single patient, and are intended to dreams, and nightmares. include treatment regimens in which the agents are admin The term “undesired systemic side effects” as used herein, istered by the same or different route of administration or at refers to unintended effects in the body including, but not the same or different time. limited to, abdominal pain, vomiting, nausea, constipation, The terms “effective amount’ or “therapeutically effective diarrhea, flatulence, dyspepsia, and dry mouth. amount,” as used herein, refer to a sufficient amount of an The term "nicotinic acetylcholine receptor agonist formu agent or a compound being administered which will relieve lated to prevent desensitization” as used herein, refers to a 10 formulation that does not result in tolerance, dependence, to some extent one or more of the symptoms of the disease withdrawal, or loss of sensitivity to the effect of the nicotinic or condition being treated. The result can be reduction acetylcholine receptor agonist. and/or alleviation of the signs, symptoms, or causes of a The term “environmentally challenging conditions' as disease, or any other desired alteration of a biological used herein, refers to external conditions including naturally system. For example, an “effective amount” for therapeutic 15 and man-made conditions. Naturally occurring environmen uses is the amount of the pharmaceutical formulation com tally challenging conditions include, but are not limited to, prising a nicotinic acetylcholine receptor agonist as dis exposure to Smoke, wind, and dry climates. Man-made closed herein required to provide a clinically significant environmentally challenging conditions include, but are not decrease in disease symptoms. An appropriate “effective' limited to, exposure to pollution from automobiles, facto amount in any individual case may be determined using ries, and airplanes, as well as homes/offices with low humid techniques, such as a dose escalation study. ity, high airflow or poor air quality. In some embodiments, The terms “individual”, “subject', and “patient' encom “environmentally challenging conditions' refer to controlled pass mammals and non-mammals. Examples of mammals challenge environments commonly used for dry eye clinical include, but are not limited to, any member of the Mamma trials. lian class: humans, non-human primates Such as chimpan 25 The term “ocular discomfort” includes, but is not limited Zees, and otherapes and monkey species; farm animals such to, the symptoms of dry eye disease, such as itchiness, as cattle, horses, sheep, goats, Swine; domestic animals such dryness, photophobia, blurriness, pain, Sticky feeling, burn as rabbits, dogs, and cats; laboratory animals including ing, stinging, and foreign body sensation. In some embodi rodents, such as rats, mice and guinea pigs, and the like. In ments, ocular discomfort is associated with blepharitis, one embodiment, the mammal is a human. 30 meibomian gland dysfunction, allergic conjunctivitis, ocular A “tissue' comprises two or more cells. The two or more Surface toxicity and irritation, lacrimal drainage problems, cells may have a similar function and/or function. The tissue or eyelid disorders. may be a connective tissue, epithelial tissue, muscular The term “soft drug as used herein, refers to a drug tissue, or nervous tissue. Alternatively, the tissue is a bone, Substance that is rapidly metabolized into an inactive form tendon (both referred to as musculoskeletal grafts), cornea, 35 immediately after achieving the therapeutic effect. skin, heart valve, or vein. Nicotinic Acetylcholine Receptor Agonists An “organ” comprises two or more tissues. The two or The methods described herein comprise the local admin more tissues may perform a specific function or group of istration of a therapeutically effective amount of a nicotinic functions. In some instances, the organ is a lung, mouth, acetylcholine receptor agonist into the nasal cavity of an nose, parathyroid gland, pineal gland, pituitary gland, 40 individual in need thereof. In some embodiments of the carotid body, salivary gland, skin, gall bladder, pancreas, methods described herein, the nicotinic acetylcholine recep Small intestine, stomach, spleen, spinal cord, thymus, thy tor agonist is a full agonist. In some embodiments of the roid gland, trachea, uterus, or Vermiform appendix. Alter methods described herein, the nicotinic acetylcholine recep natively, the organ is an adrenal gland, appendix, brain, tor agonist is a partial agonist. In some embodiments of the bladder, kidney, intestine, large intestine, Small intestine, 45 methods described herein, the nicotinic acetylcholine recep liver, heart, or muscle. tor agonist is selected from nicotine, cytisine, epibatidine, The term “nicotinic acetylcholine receptor agonist' varenicline, tebanicline, DBO-83, CC4, ABT-418, ABT encompasses a full agonist or a partial agonist of the 366833, ABT-202, ABT-894, SIB-1663, GTS-21, PHA nicotinic acetylcholine receptor. 543613, PNU-282987, LY-2087101, A85380, and 5-I- The terms “treat,” “treating or “treatment,” as used 50 A85380. In some embodiments of the methods described herein, include alleviating, abating or ameliorating at least herein, the nicotinic acetylcholine receptor agonist is nico one symptom of a disease or condition, preventing addi tine. In some embodiments of the methods described herein, tional symptoms, preventing progression of the condition, the nicotinic acetylcholine receptor agonist is cytisine. In inhibiting the disease or condition, e.g., arresting the devel some embodiments of the methods described herein, the opment of the disease or condition, relieving the disease or 55 nicotinic acetylcholine receptor agonist is epibatidine. In condition, causing regression of the disease or condition, some embodiments of the methods described herein, the relieving a condition caused by the disease or condition, or nicotinic acetylcholine receptor agonist is Varenicline. In stopping the symptoms of the disease or condition. In one some embodiments of the methods described herein, the embodiment, treatment is prophylactic treatment. In another nicotinic acetylcholine receptor agonist is tebanicline. In embodiment, treatment refers to therapeutic treatment. 60 some embodiments of the methods described herein, the The term “does not cross the blood-brain barrier in a nicotinic acetylcholine receptor agonist is DBO-83. In some pharmacologically relevant concentration” as used herein, embodiments of the methods described herein, the nicotinic refers to an insufficient amount of a nicotinic acetylcholine acetylcholine receptoragonist is CC4. In some embodiments receptor agonist as disclosed herein passing through the of the methods described herein, the nicotinic acetylcholine blood-brain barrier to produce a pharmacological response. 65 receptor agonist is ABT-418. In some embodiments of the The term “undesired psychoactive side effects” as used methods described herein, the nicotinic acetylcholine recep herein, refers to unintended effects in the brain including, but tor agonist is ABT-366833. In some embodiments of the US 9,597,284 B2 65 66 methods described herein, the nicotinic acetylcholine recep -continued toragonist is ABT-202. In some embodiments of the meth ods described herein, the nicotinic acetylcholine receptor agonist is ABT-894. In some embodiments of the methods N N described herein, the nicotinic acetylcholine receptoragonist is SIB-1663. In some embodiments of the methods NNo/ is s NC described herein, the nicotinic acetylcholine receptoragonist 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 10 herein, the nicotinic acetylcholine receptor agonist is PNU NH2, 282987. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is C LY-2087101. In some embodiments of the methods 15 N described herein, the nicotinic acetylcholine receptoragonist N 2 is A85380. In some embodiments of the methods described C N 2 herein, the nicotinic acetylcholine receptor agonist is 5-I- N A85380. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is selected from a compound disclosed in WO 2008/057938, WO 2009/111550, WO 2010/028011, or WO 2010/028033. In some embodiments of the methods described herein, the nicotinic acetylcholine receptor agonist is a soft drug. 25 In some embodiments of the methods described herein is a nicotinic acetylcholine receptor agonist having the struc ture:

30

C

40

45

55

60 or a pharmaceutically acceptable salt thereof. Intranasal Route of Administration The methods described herein comprise the local admin 65 istration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need thereof. In some embodiments, the meth US 9,597,284 B2 67 68 ods described herein comprise the local administration of a embodiments of the methods described herein, the nicotinic therapeutically effective amount of a nicotinic acetylcholine acetylcholine receptor agonist is administered into the nasal receptoragonist into the nasal cavity of an individual in need cavity by a jet of liquid. thereof, wherein the nicotinic acetylcholine receptoragonist Pharmaceutical Formulations, Methods of Dosing, and is administered into the nasal cavity as a liquid, Suspension, Treatment Regimens aerosol, gel, ointment, dry powder, cream, paste, lotion, or Also provided herein are pharmaceutical formulations of balm. In some embodiments of the methods described nicotinic acetylcholine receptor agonists for local adminis herein, the nicotinic acetylcholine receptor agonist is admin tration into the nasal cavity of an individual. In some istered into the nasal cavity as a liquid. In some embodi embodiments is a pharmaceutical formulation for local ments of the methods described herein, the nicotinic acetyl 10 administration into the nasal cavity of an individual com choline receptor agonist is administered into the nasal cavity prising a nicotinic acetylcholine receptor agonist formulated as a Suspension. In some embodiments of the methods to prevent desensitization and in a dosage amount that is not described herein, the nicotinic acetylcholine receptoragonist systemically bioavailable. In some embodiments is a phar is administered into the nasal cavity as an aerosol. In some 15 maceutical formulation for local administration into the embodiments of the methods described herein, the nicotinic nasal cavity of an individual comprising a nicotinic acetyl acetylcholine receptor agonist is administered into the nasal choline receptor agonist formulated to prevent desensitiza cavity as a gel. In some embodiments of the methods tion and in a dosage amount that is not systemically bio described herein, the nicotinic acetylcholine receptoragonist available, further comprising one or more substances is administered into the nasal cavity as an ointment. In some selected from protein kinase C(PKC) or factors that upregu embodiments of the methods described herein, the nicotinic late or up-modulate PKC. cAMP-dependent protein kinase acetylcholine receptor agonist is administered into the nasal (PKA) or factors that upregulate or up-modulate PKA, and cavity as a dry powder. In some embodiments of the calcineurin inhibitors. In some embodiments is a pharma methods described herein, the nicotinic acetylcholine recep ceutical formulation for local administration into the nasal tor agonist is administered into the nasal cavity as a cream. 25 cavity of an individual comprising a nicotinic acetylcholine In some embodiments of the methods described herein, the receptor agonist formulated to prevent desensitization and in nicotinic acetylcholine receptor agonist is administered into a dosage amount that is not systemically bioavailable, fur the nasal cavity as a paste. In some embodiments of the ther comprising protein kinase C (PKC) or factors that methods described herein, the nicotinic acetylcholine recep upregulate or up-modulate PKC. In some embodiments is a tor agonist is administered into the nasal cavity as a lotion. 30 pharmaceutical formulation for local administration into the In some embodiments of the methods described herein, the nasal cavity of an individual comprising a nicotinic acetyl nicotinic acetylcholine receptor agonist is administered into choline receptor agonist formulated to prevent desensitiza the nasal cavity as a balm. tion and in a dosage amount that is not systemically bio In some embodiments, the methods described herein available, further comprising cAMP-dependent protein comprise the local administration of a therapeutically effec 35 kinase (PKA) or factors that upregulate or up-modulate tive amount of a nicotinic acetylcholine receptoragonist into PKA. In some embodiments is a pharmaceutical formulation the nasal cavity of an individual in need thereof, wherein the for local administration into the nasal cavity of an individual nicotinic acetylcholine receptor agonist is administered into comprising a nicotinic acetylcholine receptor agonist for the nasal cavity by a syringe, dropper, bottle nebulizer, mulated to prevent desensitization and in a dosage amount atomization pump, inhaler, powder spray device, vaporizer, 40 that is not systemically bioavailable, further comprising a patch, medicated Stick, pipette, or jet of liquid. In some calcineurin inhibitor. In some embodiments is a pharmaceu embodiments of the methods described herein, the nicotinic tical formulation for local administration into the nasal acetylcholine receptor agonist is administered into the nasal cavity of an individual comprising a nicotinic acetylcholine cavity by a Syringe. In some embodiments of the methods receptor agonist formulated to prevent desensitization and in described herein, the nicotinic acetylcholine receptoragonist 45 a dosage amount that is not systemically bioavailable, fur is administered into the nasal cavity by a dropper. In some ther comprising a calcineurin inhibitor, wherein the cal embodiments of the methods described herein, the nicotinic cineurin inhibitor is selected from cyclosporine, pimecroli acetylcholine receptor agonist is administered into the nasal mus, and tacrolimus. In some embodiments is a cavity by a bottle nebulizer. In some embodiments of the pharmaceutical formulation for local administration into the methods described herein, the nicotinic acetylcholine recep 50 nasal cavity of an individual comprising a nicotinic acetyl tor agonist is administered into the nasal cavity by an choline receptor agonist formulated to prevent desensitiza atomization pump. In some embodiments of the methods tion and in a dosage amount that is not systemically bio described herein, the nicotinic acetylcholine receptoragonist available, further comprising a calcineurin inhibitor, is administered into the nasal cavity by an inhaler. In some wherein the calcineurin inhibitor is cyclosporine. In some embodiments of the methods described herein, the nicotinic 55 embodiments is a pharmaceutical formulation for local acetylcholine receptor agonist is administered into the nasal administration into the nasal cavity of an individual com cavity by a powder spray device. In some embodiments of prising a nicotinic acetylcholine receptor agonist formulated the methods described herein, the nicotinic acetylcholine to prevent desensitization and in a dosage amount that is not receptor agonist is administered into the nasal cavity by a systemically bioavailable, further comprising a calcineurin vaporizer. In some embodiments of the methods described 60 inhibitor, wherein the calcineurin inhibitor is pimecrolimus. herein, the nicotinic acetylcholine receptor agonist is admin In some embodiments is a pharmaceutical formulation for istered into the nasal cavity by a patch. In some embodi local administration into the nasal cavity of an individual ments of the methods described herein, the nicotinic acetyl comprising a nicotinic acetylcholine receptor agonist for choline receptor agonist is administered into the nasal cavity mulated to prevent desensitization and in a dosage amount by a medicated stick. In some embodiments of the methods 65 that is not systemically bioavailable, further comprising a described herein, the nicotinic acetylcholine receptoragonist calcineurin inhibitor, wherein the calcineurin inhibitor is is administered into the nasal cavity by a pipette. In some tacrolimus. US 9,597,284 B2 69 70 In some embodiments is a pharmaceutical formulation for Some embodiments is a pharmaceutical formulation for local local administration into the nasal cavity of an individual administration into the nasal cavity of an individual com comprising a nicotinic acetylcholine receptor agonist for prising a nicotinic acetylcholine receptor agonist formulated mulated to prevent desensitization and in a dosage amount to prevent desensitization and in a dosage amount that is not that is not systemically bioavailable, wherein the nicotinic systemically bioavailable, wherein the nicotinic acetylcho acetylcholine receptor agonist is selected from nicotine, line receptor agonist is ABT-894. In some embodiments is a cytisine, epibatidine, Varenicline, tebanicline, DBO-83, pharmaceutical formulation for local administration into the CC4, ABT-418, ABT-366833, ABT-202, ABT-894, SIB nasal cavity of an individual comprising a nicotinic acetyl 1663, GTS-21, PHA-543613, PNU-282987, LY-2087101, choline receptor agonist formulated to prevent desensitiza A85380, and 5-I-A85380. In some embodiments is a phar 10 tion and in a dosage amount that is not systemically bio maceutical formulation for local administration into the available, wherein the nicotinic acetylcholine receptor nasal cavity of an individual comprising a nicotinic acetyl agonist is SIB-1663. In some embodiments is a pharmaceu choline receptor agonist formulated to prevent desensitiza tical formulation for local administration into the nasal tion and in a dosage amount that is not systemically bio cavity of an individual comprising a nicotinic acetylcholine available, wherein the nicotinic acetylcholine receptor 15 receptor agonist formulated to prevent desensitization and in agonist is nicotine. In some embodiments is a pharmaceu a dosage amount that is not systemically bioavailable, tical formulation for local administration into the nasal wherein the nicotinic acetylcholine receptoragonist is GTS cavity of an individual comprising a nicotinic acetylcholine 21. In some embodiments is a pharmaceutical formulation receptor agonist formulated to prevent desensitization and in for local administration into the nasal cavity of an individual a dosage amount that is not systemically bioavailable, comprising a nicotinic acetylcholine receptor agonist for wherein the nicotinic acetylcholine receptor agonist is mulated to prevent desensitization and in a dosage amount cytisine. In some embodiments is a pharmaceutical formu that is not systemically bioavailable, wherein the nicotinic lation for local administration into the nasal cavity of an acetylcholine receptor agonist is PHA-543,613. In some individual comprising a nicotinic acetylcholine receptor embodiments is a pharmaceutical formulation for local agonist formulated to prevent desensitization and in a dos 25 administration into the nasal cavity of an individual com age amount that is not systemically bioavailable, wherein prising a nicotinic acetylcholine receptor agonist formulated the nicotinic acetylcholine receptoragonist is epibatidine. In to prevent desensitization and in a dosage amount that is not Some embodiments is a pharmaceutical formulation for local systemically bioavailable, wherein the nicotinic acetylcho administration into the nasal cavity of an individual com line receptor agonist is PNU-282987. In some embodiments prising a nicotinic acetylcholine receptor agonist formulated 30 is a pharmaceutical formulation for local administration into to prevent desensitization and in a dosage amount that is not the nasal cavity of an individual comprising a nicotinic systemically bioavailable, wherein the nicotinic acetylcho acetylcholine receptor agonist formulated to prevent desen line receptoragonist is Varenicline. In some embodiments is sitization and in a dosage amount that is not systemically a pharmaceutical formulation for local administration into bioavailable, wherein the nicotinic acetylcholine receptor the nasal cavity of an individual comprising a nicotinic 35 agonist is LY-2087101. In some embodiments is a pharma acetylcholine receptor agonist formulated to prevent desen ceutical formulation for local administration into the nasal sitization and in a dosage amount that is not systemically cavity of an individual comprising a nicotinic acetylcholine bioavailable, wherein the nicotinic acetylcholine receptor receptor agonist formulated to prevent desensitization and in agonist is tebanicline. In some embodiments is a pharma a dosage amount that is not systemically bioavailable, ceutical formulation for local administration into the nasal 40 wherein the nicotinic acetylcholine receptor agonist is cavity of an individual comprising a nicotinic acetylcholine A85380. In some embodiments is a pharmaceutical formu receptor agonist formulated to prevent desensitization and in lation for local administration into the nasal cavity of an a dosage amount that is not systemically bioavailable, individual comprising a nicotinic acetylcholine receptor wherein the nicotinic acetylcholine receptor agonist is DBO agonist formulated to prevent desensitization and in a dos 83. In some embodiments is a pharmaceutical formulation 45 age amount that is not systemically bioavailable, wherein for local administration into the nasal cavity of an individual the nicotinic acetylcholine receptor agonist is 5-I-A85380. comprising a nicotinic acetylcholine receptor agonist for In some embodiments is a pharmaceutical formulation for mulated to prevent desensitization and in a dosage amount local administration into the nasal cavity of an individual that is not systemically bioavailable, wherein the nicotinic comprising a nicotinic acetylcholine receptor agonist for acetylcholine receptoragonist is CC4. In some embodiments 50 mulated to prevent desensitization and in a dosage amount is a pharmaceutical formulation for local administration into that is not systemically bioavailable, wherein the nicotinic the nasal cavity of an individual comprising a nicotinic acetylcholine receptor agonist is selected from a compound acetylcholine receptor agonist formulated to prevent desen disclosed in WO 2008/057938, WO 2009/111550, WO sitization and in a dosage amount that is not systemically 2010/028011, or WO 2010/028033. bioavailable, wherein the nicotinic acetylcholine receptor 55 In some embodiments is a pharmaceutical formulation for agonist is ABT-418. In some embodiments is a pharmaceu local administration into the nasal cavity of an individual tical formulation for local administration into the nasal comprising a nicotinic acetylcholine receptor agonist for cavity of an individual comprising a nicotinic acetylcholine mulated to prevent desensitization and in a dosage amount receptor agonist formulated to prevent desensitization and in that is not systemically bioavailable, wherein the nicotinic a dosage amount that is not systemically bioavailable, 60 acetylcholine receptor agonist selectively binds to at least wherein the nicotinic acetylcholine receptor agonist is ABT one of the peripheral nicotinic acetylcholine receptor Sub 366833. In some embodiments is a pharmaceutical formu types selected from alpha3beta4, alpha-4beta2, and alpha7. lation for local administration into the nasal cavity of an In some embodiments is a pharmaceutical formulation for individual comprising a nicotinic acetylcholine receptor local administration into the nasal cavity of an individual agonist formulated to prevent desensitization and in a dos 65 comprising a nicotinic acetylcholine receptor agonist for age amount that is not systemically bioavailable, wherein mulated to prevent desensitization and in a dosage amount the nicotinic acetylcholine receptor agonist is ABT-202. In that is not systemically bioavailable, wherein the nicotinic US 9,597,284 B2 71 72

acetylcholine receptor agonist selectively binds to the -continued peripheral nicotinic acetylcholine receptor Subtype alpha3beta4. In some embodiments is a pharmaceutical formulation for local administration into the nasal cavity of an individual comprising a nicotinic acetylcholine receptor 5 agonist formulated to prevent desensitization and in a dos age amount that is not systemically bioavailable, wherein the nicotinic acetylcholine receptoragonist selectively binds to the peripheral nicotinic acetylcholine receptor Subtype alpha-4-beta2. In some embodiments is a pharmaceutical 10 formulation for local administration into the nasal cavity of an individual comprising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dos age amount that is not systemically bioavailable, wherein the nicotinic acetylcholine receptoragonist selectively binds to the peripheral nicotinic acetylcholine receptor Subtype alpha7. In some embodiments is a pharmaceutical formulation for local administration into the nasal cavity of an individual comprising a nicotinic acetylcholine receptor agonist for mulated to prevent desensitization and in a dosage amount that is not systemically bioavailable, wherein the nicotinic acetylcholine receptor agonist is a soft drug. 25 In some embodiments is a pharmaceutical formulation for local administration into the nasal cavity of an individual comprising a nicotinic acetylcholine receptor agonist for mulated to prevent desensitization and in a dosage amount that is not systemically bioavailable, wherein the nicotinic 30 acetylcholine receptor agonist has a structure selected from:

35

C 40

45

50

55

60 or a pharmaceutically acceptable salt thereof Further described herein, in some embodiments, is a pharmaceutical formulation for local administration into the nasal cavity of an individual comprising a nicotinic acetyl choline receptor agonist formulated to prevent desensitiza 65 tion and in a dosage amount that does not result in undesired psychoactive side effects. In some embodiments is a phar maceutical formulation for local administration into the US 9,597,284 B2 73 74 nasal cavity of an individual comprising a nicotinic acetyl to prevent desensitization and in a dosage amount that does choline receptor agonist formulated to prevent desensitiza not result in undesired psychoactive side effects, wherein the tion and in a dosage amount that does not result in undesired nicotinic acetylcholine receptor agonist is nicotine. In some psychoactive side effects, further comprising one or more embodiments is a pharmaceutical formulation for local substances selected from protein kinase C (PKC) or factors administration into the nasal cavity of an individual com that upregulate or up-modulate PKC. cAMP-dependent pro prising a nicotinic acetylcholine receptor agonist formulated tein kinase (PKA) or factors that upregulate or up-modulate to prevent desensitization and in a dosage amount that does PKA, and calcineurin inhibitors. In some embodiments is a not result in undesired psychoactive side effects, wherein the pharmaceutical formulation for local administration into the nicotinic acetylcholine receptor agonist is cytisine. In some nasal cavity of an individual comprising a nicotinic acetyl 10 embodiments is a pharmaceutical formulation for local choline receptor agonist formulated to prevent desensitiza administration into the nasal cavity of an individual com tion and in a dosage amount that does not result in undesired prising a nicotinic acetylcholine receptor agonist formulated psychoactive side effects, further comprising protein kinase to prevent desensitization and in a dosage amount that does C (PKC) or factors that upregulate or up-modulate PKC. In not result in undesired psychoactive side effects, wherein the Some embodiments is a pharmaceutical formulation for local 15 nicotinic acetylcholine receptor agonist is epibatidine. In administration into the nasal cavity of an individual com Some embodiments is a pharmaceutical formulation for local prising a nicotinic acetylcholine receptor agonist formulated administration into the nasal cavity of an individual com to prevent desensitization and in a dosage amount that does prising a nicotinic acetylcholine receptor agonist formulated not result in undesired psychoactive side effects, further to prevent desensitization and in a dosage amount that does comprising cAMP-dependent protein kinase (PKA) or fac not result in undesired psychoactive side effects, wherein the tors that upregulate or up-modulate PKA. In some embodi nicotinic acetylcholine receptor agonist is Varenicline. In ments is a pharmaceutical formulation for local administra Some embodiments is a pharmaceutical formulation for local tion into the nasal cavity of an individual comprising a administration into the nasal cavity of an individual com nicotinic acetylcholine receptor agonist formulated to pre prising a nicotinic acetylcholine receptor agonist formulated vent desensitization and in a dosage amount that does not 25 to prevent desensitization and in a dosage amount that does result in undesired psychoactive side effects, further com not result in undesired psychoactive side effects, wherein the prising a calcineurin inhibitor. In some embodiments is a nicotinic acetylcholine receptor agonist is tebanicline. In pharmaceutical formulation for local administration into the Some embodiments is a pharmaceutical formulation for local nasal cavity of an individual comprising a nicotinic acetyl administration into the nasal cavity of an individual com choline receptor agonist formulated to prevent desensitiza 30 prising a nicotinic acetylcholine receptor agonist formulated tion and in a dosage amount that does not result in undesired to prevent desensitization and in a dosage amount that does psychoactive side effects, further comprising a calcineurin not result in undesired psychoactive side effects, wherein the inhibitor, wherein the calcineurin inhibitor is selected from nicotinic acetylcholine receptor agonist is DBO-83. In some cyclosporine, pimecrolimus, and tacrolimus. In some embodiments is a pharmaceutical formulation for local embodiments is a pharmaceutical formulation for local 35 administration into the nasal cavity of an individual com administration into the nasal cavity of an individual com prising a nicotinic acetylcholine receptor agonist formulated prising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dosage amount that does to prevent desensitization and in a dosage amount that does not result in undesired psychoactive side effects, wherein the not result in undesired psychoactive side effects, further nicotinic acetylcholine receptor agonist is CC4. In some comprising a calcineurin inhibitor, wherein the calcineurin 40 embodiments is a pharmaceutical formulation for local inhibitor is cyclosporine. In some embodiments is a phar administration into the nasal cavity of an individual com maceutical formulation for local administration into the prising a nicotinic acetylcholine receptor agonist formulated nasal cavity of an individual comprising a nicotinic acetyl to prevent desensitization and in a dosage amount that does choline receptor agonist formulated to prevent desensitiza not result in undesired psychoactive side effects, wherein the tion and in a dosage amount that does not result in undesired 45 nicotinic acetylcholine receptoragonist is ABT-418. In some psychoactive side effects, further comprising a calcineurin embodiments is a pharmaceutical formulation for local inhibitor, wherein the calcineurin inhibitor is pimecrolimus. administration into the nasal cavity of an individual com In some embodiments is a pharmaceutical formulation for prising a nicotinic acetylcholine receptor agonist formulated local administration into the nasal cavity of an individual to prevent desensitization and in a dosage amount that does comprising a nicotinic acetylcholine receptor agonist for 50 not result in undesired psychoactive side effects, wherein the mulated to prevent desensitization and in a dosage amount nicotinic acetylcholine receptor agonist is ABT-366833. In that does not result in undesired psychoactive side effects, Some embodiments is a pharmaceutical formulation for local further comprising a calcineurin inhibitor, wherein the cal administration into the nasal cavity of an individual com cineurin inhibitor is tacrolimus. prising a nicotinic acetylcholine receptor agonist formulated In some embodiments is a pharmaceutical formulation for 55 to prevent desensitization and in a dosage amount that does local administration into the nasal cavity of an individual not result in undesired psychoactive side effects, wherein the comprising a nicotinic acetylcholine receptor agonist for nicotinic acetylcholine receptoragonist is ABT-202. In some mulated to prevent desensitization and in a dosage amount embodiments is a pharmaceutical formulation for local that does not result in undesired psychoactive side effects, administration into the nasal cavity of an individual com wherein the nicotinic acetylcholine receptor agonist is 60 prising a nicotinic acetylcholine receptor agonist formulated selected from nicotine, cytisine, epibatidine, Varenicline, to prevent desensitization and in a dosage amount that does tebanicline, DBO-83, CC4, ABT-418, ABT-366833, ABT not result in undesired psychoactive side effects, wherein the 202, ABT-894, SIB-1663, GTS-21, PHA-543,613, PNU nicotinic acetylcholine receptoragonist is ABT-894. In some 282987, LY-2087101, A85380, and 5-I-A85380. In some embodiments is a pharmaceutical formulation for local embodiments is a pharmaceutical formulation for local 65 administration into the nasal cavity of an individual com administration into the nasal cavity of an individual com prising a nicotinic acetylcholine receptor agonist formulated prising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dosage amount that does US 9,597,284 B2 75 76 not result in undesired psychoactive side effects, wherein the -continued nicotinic acetylcholine receptor agonist is SIB-1663. In Some embodiments is a pharmaceutical formulation for local C N 2 administrationprising a nicotinic into acetylcholine the nasal cavity receptor of an agonist individual formulated com- 5 Clay HN N D to prevent desensitization and in a dosage amount that does 21 N not result in undesired psychoactive side effects, wherein the HN nicotinic acetylcholine receptor agonist is GTS-21. In some D s embodiments is a pharmaceutical formulation for local N 'Ns' administration into the nasal cavity of an individual com- 10 O prising a nicotinic acetylcholine receptor agonist formulated 2 to prevent desensitization and in a dosage amount that does C N not result in undesired psychoactive side effects, wherein the nicotinic acetylcholine receptor agonist is PHA-543,613. In NH Some embodiments is a pharmaceutical formulation for local administration into the nasal cavity of an individual com- 15 21 Cl, prising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dosage amount that does N-N not result in undesired psychoactive side effects, wherein the nicotinic acetylcholine receptor agonist is PNU-282987. In Some embodiments is a pharmaceutical formulation for local 20 administration into the nasal cavity of an individual com prising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dosage amount that does not result in undesired psychoactive side effects, wherein the nicotinic acetylcholine receptor agonist is LY-2087101. In as Some embodiments is a pharmaceutical formulation for local administration into the nasal cavity of an individual com prising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dosage amount that does not result in undesired psychoactive side effects, wherein the nicotinic acetylcholine receptor agonist is A85380. In some 30 embodiments is a pharmaceutical formulation for local administration into the nasal cavity of an individual com prising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dosage amount that does not result in undesired psychoactive side effects, wherein the 35 nicotinic acetylcholine receptor agonist is 5-I-A85380. In some embodiments is a pharmaceutical formulation for local administration into the nasal cavity of an individual comprising a nicotinic acetylcholine receptor agonist for mulated to prevent desensitization and in a dosage amount 40 that does not result in undesired psychoactive side effects, wherein the nicotinic acetylcholine receptor agonist is selected from a compound disclosed in WO 2008/057938, WO 2009/111550, WO 2010/028011, or WO 2010/028033. In some embodiments is a pharmaceutical formulation for 45 local administration into the nasal cavity of an individual comprising a nicotinic acetylcholine receptor agonist for mulated to prevent desensitization and in a dosage amount that does not result in undesired psychoactive side effects, wherein the nicotinic acetylcholine receptor agonist is a soft 50 drug. In some embodiments is a pharmaceutical formulation for local administration into the nasal cavity of an individual comprising a nicotinic acetylcholine receptor agonist for mulated to prevent desensitization and in a dosage amount 55 that does not result in undesired psychoactive side effects, wherein the nicotinic acetylcholine receptor agonist has a structure selected from:

60

\ / 65 N O US 9,597,284 B2 77 78 -continued selected from protein kinase C(PKC) or factors that upregu Cl, late or up-modulate PKC. cAMP-dependent protein kinase (PKA) or factors that upregulate or up-modulate PKA, and N calcineurin inhibitors. In some embodiments is a pharma ceutical formulation for local administration into the nasal cavity of an individual comprising a nicotinic acetylcholine (orN O receptor agonist formulated to prevent desensitization and in O a dosage amount that does not result in undesired systemic S H side effects, further comprising protein kinase C (PKC) or 10 factors that upregulate or up-modulate PKC. In some S yf embodiments is a pharmaceutical formulation for local S \ N administration into the nasal cavity of an individual com le prising a nicotinic acetylcholine receptor agonist formulated F, to prevent desensitization and in a dosage amount that does 15 not result in undesired systemic side effects, further com prising cAMP-dependent protein kinase (PKA) or factors '', '', that upregulate or up-modulate PKA. In some embodiments is a pharmaceutical formulation for local administration into O I O the nasal cavity of an individual comprising a nicotinic N N acetylcholine receptor agonist formulated to prevent desen sitization and in a dosage amount that does not result in 2 2 undesired systemic side effects, further comprising a cal N , and N s cineurin inhibitor. In some embodiments is a pharmaceutical formulation for local administration into the nasal cavity of or a pharmaceutically acceptable salt thereof 25 an individual comprising a nicotinic acetylcholine receptor In some embodiments is a pharmaceutical formulation for agonist formulated to prevent desensitization and in a dos local administration into the nasal cavity of an individual age amount that does not result in undesired systemic side comprising a nicotinic acetylcholine receptor agonist for effects, further comprising a calcineurin inhibitor, wherein mulated to prevent desensitization and in a dosage amount the calcineurin inhibitor is selected from cyclosporine, that does not result in undesired psychoactive side effects, 30 pimecrolimus, and tacrolimus. In some embodiments is a wherein the nicotinic acetylcholine receptor agonist selec pharmaceutical formulation for local administration into the tively binds to at least one of the peripheral nicotinic nasal cavity of an individual comprising a nicotinic acetyl acetylcholine receptor subtypes selected from alpha3beta4, choline receptor agonist formulated to prevent desensitiza alpha-4-beta2, and alpha7. In some embodiments is a phar tion and in a dosage amount that does not result in undesired maceutical formulation for local administration into the 35 systemic side effects, further comprising a calcineurin nasal cavity of an individual comprising a nicotinic acetyl inhibitor, wherein the calcineurin inhibitor is cyclosporine. choline receptor agonist formulated to prevent desensitiza In some embodiments is a pharmaceutical formulation for tion and in a dosage amount that does not result in undesired local administration into the nasal cavity of an individual psychoactive side effects, wherein the nicotinic acetylcho comprising a nicotinic acetylcholine receptor agonist for line receptor agonist selectively binds to the peripheral 40 mulated to prevent desensitization and in a dosage amount nicotinic acetylcholine receptor subtype alpha3beta4. In that does not result in undesired systemic side effects, further Some embodiments is a pharmaceutical formulation for local comprising a calcineurin inhibitor, wherein the calcineurin administration into the nasal cavity of an individual com inhibitor is pimecrolimus. In some embodiments is a phar prising a nicotinic acetylcholine receptor agonist formulated maceutical formulation for local administration into the to prevent desensitization and in a dosage amount that does 45 nasal cavity of an individual comprising a nicotinic acetyl not result in undesired psychoactive side effects, wherein the choline receptor agonist formulated to prevent desensitiza nicotinic acetylcholine receptor agonist selectively binds to tion and in a dosage amount that does not result in undesired the peripheral nicotinic acetylcholine receptor Subtype systemic side effects, further comprising a calcineurin alpha-4-beta2. In some embodiments is a pharmaceutical inhibitor, wherein the calcineurin inhibitor is tacrolimus. formulation for local administration into the nasal cavity of 50 In some embodiments is a pharmaceutical formulation for an individual comprising a nicotinic acetylcholine receptor local administration into the nasal cavity of an individual agonist formulated to prevent desensitization and in a dos comprising a nicotinic acetylcholine receptor agonist for age amount that does not result in undesired psychoactive mulated to prevent desensitization and in a dosage amount side effects, wherein the nicotinic acetylcholine receptor that does not result in undesired systemic side effects, agonist selectively binds to the peripheral nicotinic acetyl 55 wherein the nicotinic acetylcholine receptor agonist is choline receptor subtype alpha7. selected from nicotine, cytisine, epibatidine, Varenicline, Further described herein, in some embodiments, is a tebanicline, DBO-83, CC4, ABT-418, ABT-366833, ABT pharmaceutical formulation for local administration into the 202, ABT-894, SIB-1663, GTS-21, PHA-543613, PNU nasal cavity of an individual comprising a nicotinic acetyl 282987, LY-2087101, A85380, and 5-I-A85380. In some choline receptor agonist formulated to prevent desensitiza 60 embodiments is a pharmaceutical formulation for local tion and in a dosage amount that does not result in undesired administration into the nasal cavity of an individual com systemic side effects. In some embodiments is a pharma prising a nicotinic acetylcholine receptor agonist formulated ceutical formulation for local administration into the nasal to prevent desensitization and in a dosage amount that does cavity of an individual comprising a nicotinic acetylcholine not result in undesired systemic side effects, wherein the receptor agonist formulated to prevent desensitization and in 65 nicotinic acetylcholine receptor agonist is nicotine. In some a dosage amount that does not result in undesired systemic embodiments is a pharmaceutical formulation for local side effects, further comprising one or more substances administration into the nasal cavity of an individual com US 9,597,284 B2 79 80 prising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dosage amount that does to prevent desensitization and in a dosage amount that does not result in undesired systemic side effects, wherein the not result in undesired systemic side effects, wherein the nicotinic acetylcholine receptor agonist is GTS-21. In some nicotinic acetylcholine receptor agonist is cytisine. In some embodiments is a pharmaceutical formulation for local embodiments is a pharmaceutical formulation for local administration into the nasal cavity of an individual com administration into the nasal cavity of an individual com prising a nicotinic acetylcholine receptor agonist formulated prising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dosage amount that does to prevent desensitization and in a dosage amount that does not result in undesired systemic side effects, wherein the not result in undesired systemic side effects, wherein the nicotinic acetylcholine receptor agonist is PHA-543,613. In nicotinic acetylcholine receptor agonist is epibatidine. In 10 Some embodiments is a pharmaceutical formulation for local administration into the nasal cavity of an individual com Some embodiments is a pharmaceutical formulation for local prising a nicotinic acetylcholine receptor agonist formulated administration into the nasal cavity of an individual com to prevent desensitization and in a dosage amount that does prising a nicotinic acetylcholine receptor agonist formulated not result in undesired systemic side effects, wherein the to prevent desensitization and in a dosage amount that does nicotinic acetylcholine receptor agonist is PNU-282987. In not result in undesired systemic side effects, wherein the 15 Some embodiments is a pharmaceutical formulation for local nicotinic acetylcholine receptor agonist is Varenicline. In administration into the nasal cavity of an individual com Some embodiments is a pharmaceutical formulation for local prising a nicotinic acetylcholine receptor agonist formulated administration into the nasal cavity of an individual com to prevent desensitization and in a dosage amount that does prising a nicotinic acetylcholine receptor agonist formulated not result in undesired systemic side effects, wherein the to prevent desensitization and in a dosage amount that does nicotinic acetylcholine receptor agonist is LY-2087101. In not result in undesired systemic side effects, wherein the Some embodiments is a pharmaceutical formulation for local nicotinic acetylcholine receptor agonist is tebanicline. In administration into the nasal cavity of an individual com Some embodiments is a pharmaceutical formulation for local prising a nicotinic acetylcholine receptor agonist formulated administration into the nasal cavity of an individual com to prevent desensitization and in a dosage amount that does prising a nicotinic acetylcholine receptor agonist formulated 25 not result in undesired systemic side effects, wherein the to prevent desensitization and in a dosage amount that does nicotinic acetylcholine receptor agonist is A85380. In some not result in undesired systemic side effects, wherein the embodiments is a pharmaceutical formulation for local nicotinic acetylcholine receptor agonist is DBO-83. In some administration into the nasal cavity of an individual com embodiments is a pharmaceutical formulation for local prising a nicotinic acetylcholine receptor agonist formulated administration into the nasal cavity of an individual com 30 to prevent desensitization and in a dosage amount that does prising a nicotinic acetylcholine receptor agonist formulated not result in undesired systemic side effects, wherein the to prevent desensitization and in a dosage amount that does nicotinic acetylcholine receptor agonist is 5-I-A85380. not result in undesired systemic side effects, wherein the In some embodiments is a pharmaceutical formulation for nicotinic acetylcholine receptor agonist is CC4. In some local administration into the nasal cavity of an individual embodiments is a pharmaceutical formulation for local 35 comprising a nicotinic acetylcholine receptor agonist for administration into the nasal cavity of an individual com mulated to prevent desensitization and in a dosage amount prising a nicotinic acetylcholine receptor agonist formulated that does not result in undesired systemic side effects, to prevent desensitization and in a dosage amount that does wherein the nicotinic acetylcholine receptor agonist is not result in undesired systemic side effects, wherein the selected from a compound disclosed in WO 2008/057938, nicotinic acetylcholine receptor agonist is ABT-418. In some 40 WO 2009/111550, WO 2010/028011, or WO 2010/028033. embodiments is a pharmaceutical formulation for local In some embodiments is a pharmaceutical formulation for administration into the nasal cavity of an individual com local administration into the nasal cavity of an individual prising a nicotinic acetylcholine receptor agonist formulated comprising a nicotinic acetylcholine receptor agonist for to prevent desensitization and in a dosage amount that does mulated to prevent desensitization and in a dosage amount not result in undesired systemic side effects, wherein the 45 that does not result in undesired systemic side effects, nicotinic acetylcholine receptor agonist is ABT-366833. In wherein the nicotinic acetylcholine receptor agonist is a soft Some embodiments is a pharmaceutical formulation for local drug. administration into the nasal cavity of an individual com In some embodiments is a pharmaceutical formulation for prising a nicotinic acetylcholine receptor agonist formulated local administration into the nasal cavity of an individual to prevent desensitization and in a dosage amount that does 50 comprising a nicotinic acetylcholine receptor agonist for not result in undesired systemic side effects, wherein the mulated to prevent desensitization and in a dosage amount nicotinic acetylcholine receptor agonist is ABT-202. In some that does not result in undesired systemic side effects, embodiments is a pharmaceutical formulation for local wherein the nicotinic acetylcholine receptor agonist has a administration into the nasal cavity of an individual com structure selected from: prising a nicotinic acetylcholine receptor agonist formulated 55 to prevent desensitization and in a dosage amount that does not result in undesired systemic side effects, wherein the nicotinic acetylcholine receptor agonist is ABT-894. In some embodiments is a pharmaceutical formulation for local administration into the nasal cavity of an individual com 60 prising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dosage amount that does not result in undesired systemic side effects, wherein the C nicotinic acetylcholine receptor agonist is SIB-1663. In Some embodiments is a pharmaceutical formulation for local 65 administration into the nasal cavity of an individual com prising a nicotinic acetylcholine receptor agonist formulated US 9,597,284 B2 81 82 -continued -continued HN O o, Ul N - N N Ww" 5 s \ yf 2 S N C N le

F, NH NH

2n-1 10 \\ '', Vy. '', N N O I O N N

15 2 2 N , and N

or a pharmaceutically acceptable salt thereof 2O In some embodiments is a pharmaceutical formulation for local administration into the nasal cavity of an individual comprising a nicotinic acetylcholine receptor agonist for mulated to prevent desensitization and in a dosage amount that does not result in undesired systemic side effects, as wherein the nicotinic acetylcholine receptor agonist selec tively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from alpha3beta4, alpha-4-beta2, and alpha7. In some embodiments is a phar maceutical formulation for local administration into the 30 nasal cavity of an individual comprising a nicotinic acetyl choline receptor agonist formulated to prevent desensitiza tion and in a dosage amount that does not result in undesired systemic side effects, wherein the nicotinic acetylcholine receptor agonist selectively binds to the peripheral nicotinic 35 acetylcholine receptor subtype alpha3beta4. In some embodiments is a pharmaceutical formulation for local administration into the nasal cavity of an individual com prising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dosage amount that does 40 not result in undesired systemic side effects, wherein the nicotinic acetylcholine receptor agonist selectively binds to the peripheral nicotinic acetylcholine receptor Subtype alpha-4-beta2. In some embodiments is a pharmaceutical formulation for local administration into the nasal cavity of 45 an individual comprising a nicotinic acetylcholine receptor agonist formulated to prevent desensitization and in a dos age amount that does not result in undesired systemic side effects, wherein the nicotinic acetylcholine receptor agonist selectively binds to the peripheral nicotinic acetylcholine 50 receptor subtype alpha7. In another embodiment of any of the aforementioned pharmaceutical formulation embodiments, the pharmaceu tical formulation comprises about 0.1 mg/mL of the nico tinic acetylcholine receptor agonist. In another embodiment 55 of any of the aforementioned 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 aforemen tioned pharmaceutical formulation embodiments, the phar 60 maceutical formulation comprises about 0.5 mg/mL of the Cl, nicotinic acetylcholine receptor agonist. In another embodi ment of any of the aforementioned pharmaceutical formu lation embodiments, the pharmaceutical formulation com prises about 1 mg/mL of the nicotinic acetylcholine receptor O 65 agonist. In another embodiment of any of the aforemen N tioned pharmaceutical formulation embodiments, the phar maceutical formulation comprises about 2 mg/mL of the US 9,597,284 B2 83 84 nicotinic acetylcholine receptor agonist. In another embodi aforementioned pharmaceutical formulation embodiments, ment of any of the aforementioned pharmaceutical formu the pharmaceutical formulation comprises at least 500 lation embodiments, the pharmaceutical formulation com micrograms of the nicotinic acetylcholine receptor agonist prises about 3 mg/mL of the nicotinic acetylcholine receptor per dose. In another embodiment of any of the aforemen agonist. In another embodiment of any of the aforemen tioned pharmaceutical formulation embodiments, the phar tioned pharmaceutical formulation embodiments, the phar maceutical formulation comprises at least 750 micrograms maceutical formulation comprises about 4 mg/mL of the of the nicotinic acetylcholine receptor agonist per dose. In nicotinic acetylcholine receptor agonist. In another embodi another embodiment of any of the aforementioned pharma ment of any of the aforementioned pharmaceutical formu ceutical formulation embodiments, the pharmaceutical for lation embodiments, the pharmaceutical formulation com 10 mulation comprises at least 1000 micrograms of the nico prises about 5 mg/mL of the nicotinic acetylcholine receptor tinic acetylcholine receptor agonist per dose. In another agonist. In another embodiment of any of the aforemen embodiment of any of the aforementioned pharmaceutical tioned pharmaceutical formulation embodiments, the phar formulation embodiments, the pharmaceutical formulation maceutical formulation comprises about 6 mg/mL of the comprises between 1 microgram and 1000 micrograms of nicotinic acetylcholine receptor agonist. In another embodi 15 the nicotinic acetylcholine receptor agonist per dose. In ment of any of the aforementioned pharmaceutical formu another embodiment of any of the aforementioned pharma lation embodiments, the pharmaceutical formulation com ceutical formulation embodiments, the pharmaceutical for prises about 7 mg/mL of the nicotinic acetylcholine receptor mulation comprises between 5 micrograms and 1000 micro agonist. In another embodiment of any of the aforemen grams of the nicotinic acetylcholine receptor agonist per tioned pharmaceutical formulation embodiments, the phar dose. In another embodiment of any of the aforementioned maceutical formulation comprises about 8 mg/mL of the pharmaceutical formulation embodiments, the pharmaceu nicotinic acetylcholine receptor agonist. In another embodi tical formulation comprises between 5 micrograms and 100 ment of any of the aforementioned pharmaceutical formu micrograms of the nicotinic acetylcholine receptor agonist lation embodiments, the pharmaceutical formulation com per dose. In another embodiment of any of any of the prises about 9 mg/mL of the nicotinic acetylcholine receptor 25 aforementioned pharmaceutical formulation embodiments, agonist. In another embodiment of any of the aforemen the pharmaceutical formulation comprises between 5 micro tioned pharmaceutical formulation embodiments, the phar grams and 50 micrograms of the nicotinic acetylcholine maceutical formulation comprises about 10 mg/mL of the receptor agonist per dose. In another embodiment of any of nicotinic acetylcholine receptor agonist. In another embodi the aforementioned pharmaceutical formulation embodi ment of any of the aforementioned pharmaceutical formu 30 ments, the pharmaceutical formulation comprises between lation embodiments, the pharmaceutical formulation com 10 micrograms and 50 micrograms of the nicotinic acetyl prises about 12 mg/mL of the nicotinic acetylcholine choline receptor agonist per dose. In another embodiment of receptor agonist. In another embodiment of any of the any of the aforementioned pharmaceutical formulation aforementioned pharmaceutical formulation embodiments, embodiments, the pharmaceutical formulation comprises the pharmaceutical formulation comprises about 15 mg/mL 35 between 25 micrograms and 1000 micrograms of the nico of the nicotinic acetylcholine receptor agonist. In another tinic acetylcholine receptor agonist per dose. In another embodiment of any of the aforementioned pharmaceutical embodiment of any of the aforementioned pharmaceutical formulation embodiments, the pharmaceutical formulation formulation embodiments, the pharmaceutical formulation comprises about 20 mg/mL of the nicotinic acetylcholine comprises between 50 micrograms and 1000 micrograms of receptor agonist. 40 the nicotinic acetylcholine receptor agonist per dose. In In another embodiment of any of the aforementioned another embodiment of any of the aforementioned pharma pharmaceutical formulation embodiments, the pharmaceu ceutical formulation embodiments, the pharmaceutical for tical formulation comprises at least 1 microgram of the mulation comprises between 100 micrograms and 1000 nicotinic acetylcholine receptor agonist per dose. In another micrograms of the nicotinic acetylcholine receptoragonist is embodiment of any of the aforementioned pharmaceutical 45 per dose. In another embodiment of any of the aforemen formulation embodiments, the pharmaceutical formulation tioned pharmaceutical formulation embodiments, the phar comprises at least 5 micrograms of the nicotinic acetylcho maceutical formulation comprises between 100 micrograms line receptoragonist per dose. In another embodiment of any and 750 micrograms of the nicotinic acetylcholine receptor of the aforementioned pharmaceutical formulation embodi agonist per dose. In another embodiment of any of the ments, the pharmaceutical formulation comprises at least 10 50 aforementioned pharmaceutical formulation embodiments, micrograms of the nicotinic acetylcholine receptor agonist the pharmaceutical formulation comprises between 150 per dose. In another embodiment of any of the aforemen micrograms and 750 micrograms of the nicotinic acetylcho tioned pharmaceutical formulation embodiments, the phar line receptoragonist per dose. In another embodiment of any maceutical formulation comprises at least 25 micrograms of of the aforementioned pharmaceutical formulation embodi the nicotinic acetylcholine receptor agonist per dose. In 55 ments, the pharmaceutical formulation comprises between another embodiment of any of the aforementioned pharma 150 micrograms and 600 micrograms of the nicotinic ace ceutical formulation embodiments, the pharmaceutical for tylcholine receptor agonist per dose. mulation comprises at least 50 micrograms of the nicotinic In another embodiment of any of the aforementioned acetylcholine receptor agonist per dose. In another embodi pharmaceutical formulation embodiments, the pharmaceu ment of any of the aforementioned pharmaceutical formu 60 tical formulation is administered once daily. In another lation embodiments, the pharmaceutical formulation com embodiment of any of the aforementioned pharmaceutical prises at least 100 micrograms of the nicotinic acetylcholine formulation embodiments, the pharmaceutical formulation receptor agonist per dose. In another embodiment of any of is administered at least once daily. In another embodiment of the aforementioned pharmaceutical formulation embodi any of the aforementioned pharmaceutical formulation ments, the pharmaceutical formulation comprises at least 65 embodiments, the pharmaceutical formulation is adminis 250 micrograms of the nicotinic acetylcholine receptor tered twice daily. In another embodiment of any of the agonist per dose. In another embodiment of any of the aforementioned pharmaceutical formulation embodiments, US 9,597,284 B2 85 86 the pharmaceutical formulation is administered at least twice including throughout the duration of the patient’s life in daily. In another embodiment of any of the aforementioned order to ameliorate or otherwise control or limit the symp pharmaceutical formulation embodiments, the pharmaceu toms of the patient’s disease or condition. tical formulation is administered three times daily. In In certain embodiments wherein a patient's status does another embodiment of any of the aforementioned pharma 5 improve, the dose of the pharmaceutical formulation being ceutical formulation embodiments, the pharmaceutical for administered may be temporarily reduced or temporarily mulation is administered at least three times daily. In another Suspended for a certain length of time (i.e., a "drug holi embodiment of any of the aforementioned pharmaceutical day'). In specific embodiments, the length of the drug formulation embodiments, the pharmaceutical formulation holiday is between 2 days and 1 year, including by way of is administered for one day. In another embodiment of any 10 example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, of the aforementioned pharmaceutical formulation embodi ments, the pharmaceutical formulation is administered for at 10 days, 12 days, 15 days, 20 days, 28 days, or more than least two days. In another embodiment of any of the afore 28 days. The dose reduction during a drug holiday is, by way mentioned pharmaceutical formulation embodiments, the of example only, by 10%-100%, including by way of pharmaceutical formulation is administered for at least three 15 example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, days. In another embodiment of any of the aforementioned 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, pharmaceutical formulation embodiments, the pharmaceu and 100%. tical formulation is administered for at least four days. In In certain embodiments the dose of the pharmaceutical another embodiment of any of the aforementioned pharma formulation being administered may be temporarily reduced ceutical formulation embodiments, the pharmaceutical for or temporarily Suspended for a certain length of time (i.e., a mulation is administered for at least five days. In another “drug diversion'). In specific embodiments, the length of the embodiment of any of the aforementioned pharmaceutical drug diversion is between 2 days and 1 year, including by formulation embodiments, the pharmaceutical formulation way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, is administered for at least seven days. In another embodi 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more ment of any of the aforementioned pharmaceutical formu 25 than 28 days. The dose reduction during a drug diversion is, lation embodiments, the pharmaceutical formulation is by way of example only, by 10%-100%, including by way administered for at least ten days. In another embodiment of of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, any of the aforementioned pharmaceutical formulation 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, embodiments, the pharmaceutical formulation is adminis 95%, and 100%. After a suitable length of time, the normal tered for at least fourteen days. In another embodiment of 30 dosing schedule is optionally reinstated. any of the aforementioned pharmaceutical formulation In some embodiments, once improvement of the patients embodiments, the pharmaceutical formulation is adminis conditions has occurred, a maintenance dose is administered tered for at least twenty one days. In another embodiment of if necessary. Subsequently, in specific embodiments, the any of the aforementioned pharmaceutical formulation dosage or the frequency of administration, or both, is embodiments, the pharmaceutical formulation is adminis 35 reduced, as a function of the symptoms, to a level at which tered for at least thirty days. the improved disease, disorder or condition is retained. In In another embodiment of any of the aforementioned certain embodiments, however, the patient requires intermit pharmaceutical formulation embodiments, the pharmaceu tent treatment on a long-term basis upon any recurrence of tical formulation is administered in alternating nostrils. symptoms. In certain embodiments, the pharmaceutical formulations 40 The amount of a given agent that corresponds to such an described herein are administered for prophylactic and/or amount varies depending upon factors such as the particular therapeutic treatments. In certain therapeutic applications, pharmaceutical formulation, disease condition and its sever the pharmaceutical formulations are administered to a ity, the identity (e.g., weight, sex) of the Subject or host in patient already Suffering from a disease or condition, in an need of treatment, but can nevertheless be determined amount Sufficient to cure or at least partially arrest at least 45 according to the particular circumstances Surrounding the one of the symptoms of the disease or condition. Amounts case, including, e.g., the specific nicotinic acetylcholine effective for this use depend on the severity and course of the receptor agonist being administered, the condition being disease or condition, previous therapy, the patient’s health treated, and the Subject being treated. status, weight, and response to the drugs, and the judgment A pharmaceutical formulation, as used herein, refers to a of the treating physician. Therapeutically effective amounts 50 mixture of a nicotinic acetylcholine receptor agonist as are optionally determined by methods including, but not described herein with other chemical components (i.e. phar limited to, a dose escalation clinical trial. maceutically acceptable inactive ingredients). Such as car In prophylactic applications, the pharmaceutical formu riers, excipients, binders, filling agents, Suspending agents, lations described herein are administered to a patient Sus disintegrating agents, dispersing agents, Surfactants, lubri ceptible to or otherwise at risk of a particular disease, 55 cants, colorants, diluents, solubilizers, moistening agents, disorder or condition. Such an amount is defined to be a plasticizers, stabilizers, penetration enhancers, wetting “prophylactically effective amount or dose.” In this use, the agents, anti-foaming agents, antioxidants, preservatives, or precise amounts also depend on the patient's state of health, one or more combination thereof. In some embodiments, the weight, and the like. When used in a patient, effective pharmaceutical formulations described herein are mixed amounts for this use will depend on the severity and course 60 with other active ingredients, as in combination therapy. In of the disease, disorder or condition, previous therapy, the Some embodiments, the pharmaceutical formulations patient’s health status and response to the drugs, and the include other therapeutically valuable substances. In other judgment of the treating physician. embodiments, the pharmaceutical formulations include In certain embodiments wherein the patient’s condition other medicinal or pharmaceutical agents, carriers, adju does not improve, upon the doctor's discretion the admin 65 vants, preserving, stabilizing, wetting or emulsifying agents, istration of the pharmaceutical formulations are adminis Solution promoters, salts for regulating the osmotic pressure, tered chronically, that is, for an extended period of time, and/or buffers. US 9,597,284 B2 87 88 In some embodiments, the pharmaceutical formulations In certain embodiments, the pharmaceutical formulations described herein refer to a mixture of a nicotinic acetylcho provided herein include one or more preservatives to inhibit line receptor agonist and a buffer. In some embodiments, the microbial activity. Suitable preservatives include mercury pharmaceutical formulations described herein refer to a containing Substances such as merfen and thiomersal; sta mixture of a nicotinic acetylcholine receptor agonist and a bilized chlorine dioxide; and quaternary ammonium com phosphate buffer. In some embodiments, the pharmaceutical pounds Such aS benzalkonium chloride, formulations described herein refer to a mixture of a nico cetyltrimethylammonium bromide and cetylpyridinium tinic acetylcholine receptor agonist and a phosphate buffer, chloride. wherein the pH of the phosphate buffer is around 7.0. In In some embodiments, the pharmaceutical formulations 10 described herein benefit from antioxidants, metal chelating Some embodiments, the pharmaceutical formulations agents, thiol containing compounds and other general sta described herein refer to a mixture of a nicotinic acetylcho bilizing agents. Examples of Such stabilizing agents, line receptor agonist and a phosphate-citrate buffer. In some include, but are not limited to: (a) about 0.5% to about 2% embodiments, the pharmaceutical formulations described w/v glycerol, (b) about 0.1% to about 1% w/v methionine, herein refer to a mixture of a nicotinic acetylcholine receptor 15 (c) about 0.1% to about 2% w/v monothioglycerol, (d) about agonist and a phosphate-citrate buffer, wherein the pH of the 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% phosphate-citrate buffer is around 6.0. In some embodi w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysor ments, the pharmaceutical formulations described herein bate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) refer to a mixture of a nicotinic acetylcholine receptor arginine, (i) heparin, () dextran Sulfate, (k) cyclodextrins, (1) agonist and a phosphate-citrate buffer. In some embodi pentosan polysulfate and other heparinoids, (m) divalent ments, the pharmaceutical formulations described herein cations such as magnesium and Zinc, or (n) combinations refer to a mixture of a nicotinic acetylcholine receptor thereof. agonist and a phosphate-citrate buffer, wherein the pH of the The pharmaceutical formulations described herein, which phosphate-citrate buffer is around 5.0. include a nicotinic acetylcholine receptor agonist, are for The pharmaceutical formulation facilitates administration 25 mulated into any suitable dosage form, including but not of the compound to an organism. In practicing the methods limited to, liquids, Suspensions, aerosols, gels, ointments, provided herein, therapeutically effective amounts of nico dry powders, creams, pastes, lotions, or balms. The phar tinic acetylcholine receptor agonist described herein are maceutical formulations described herein, which include a administered in a pharmaceutical formulation to a mammal nicotinic acetylcholine receptor agonist are formulated into having a disease, disorder, or condition to be treated. In 30 any suitable dosage form, are administered into the nasal Some embodiments, the mammal is a human. A therapeuti cavity by a syringe, dropper, bottle nebulizer, atomization cally effective amount can vary widely depending on the pump, inhaler, powder spray device, vaporizer, patch, medi severity of the disease, the age and relative health of the cated Stick, pipette, or jet of liquid. Subject, the potency of the compound used and other factors. Combination Therapy The nicotinic acetylcholine receptor agonist can be used 35 In certain instances, it is appropriate to administer a singly or in combination with one or more therapeutic agents nicotinic acetylcholine receptor agonist in combination with as components of mixtures. another therapeutic agent. The pharmaceutical formulations described herein are In one embodiment, the compositions and methods administered to the nasal cavity of a Subject. The pharma described herein are also used in conjunction with other ceutical formulations described herein include, but are not 40 therapeutic reagents that are selected for their particular limited to, liquids, Suspensions, aerosols, gels, ointments, usefulness against the condition that is being treated. In dry powders, creams, pastes, lotions, or balms. general, the compositions described herein and, in embodi Pharmaceutical formulations including a nicotinic acetyl ments where combinational therapy is employed, other choline receptor agonist as described herein are manufac agents do not have to be administered in the same pharma tured in a conventional manner. 45 ceutical formulation or composition, and are, because of The pharmaceutical compositions will include a nicotinic different physical and chemical characteristics, administered acetylcholine receptor agonist as described herein as an by different routes. In one embodiment, the initial adminis active ingredient in free-acid or free-base form, or in a tration is made according to established protocols, and then, pharmaceutically acceptable salt form. In addition, the meth based upon the observed effects, the dosage, modes of ods and pharmaceutical formulations described herein 50 administration and times of administration, further modified. include the use of N-oxides (if appropriate), crystalline In various embodiments, a nicotinic acetylcholine recep forms, amorphous phases, as well as active metabolites of tor agonist, is administered concurrently (e.g., simultane these nicotinic acetylcholine receptor agonists having the ously, essentially simultaneously or within the same treat same type of activity. In some embodiments, the nicotinic ment protocol) or sequentially, with other therapeutic acetylcholine receptoragonists described herein may exist in 55 reagents that are selected for their particular usefulness unsolvated form or in solvated forms with pharmaceutically against the condition that is being treated. In certain embodi acceptable solvents such as water, ethanol, and the like. The ments, the determination of the order of administration, and Solvated forms of the nicotinic acetylcholine receptor ago the number of repetitions of administration of each thera nists presented herein are also considered to be disclosed peutic agent during a treatment protocol, is based upon herein. In some embodiments, the compounds may exist as 60 evaluation of the disease being treated and the condition of tautomers. All tautomers are included within the scope of the the patient. nicotinic acetylcholine receptor agonists presented herein. In some embodiments, a nicotinic acetylcholine receptor In some embodiments, the nicotinic acetylcholine recep agonist, is administered concurrently (e.g., simultaneously, tor agonists exist as enantiomers, diastereomers, or other essentially simultaneously or within the same treatment steroisomeric forms. The nicotinic acetylcholine receptor 65 protocol) or sequentially, with another therapeutic reagent agonists disclosed herein include all enantiomeric, diaste for treating dry disease. In some embodiments, a nicotinic reomeric, and epimeric forms as well as mixtures thereof. acetylcholine receptor agonist, is administered concurrently US 9,597,284 B2 89 90 (e.g., simultaneously, essentially simultaneously or within At screening visit 1, Schirmer test (with topical anesthesia the same treatment protocol) or sequentially, with Restasis(R) and nasal stimulation with cotton Swab) of at least 7 eye drops. In some embodiments, a nicotinic acetylcholine mm higher than the unstimulated value in at least one receptor agonist, is administered concurrently (e.g., simul eye; taneously, essentially simultaneously or within the same Baseline Ocular Surface Disease Index score of at least 23 treatment protocol) or sequentially, with artificial tears. In with no more than 3 responses of “not applicable' at the Some embodiments, a nicotinic acetylcholine receptor ago first screening visit nist, is administered concurrently (e.g., simultaneously, Normal lid/lash anatomy, blinking function and closure essentially simultaneously or within the same treatment Exclusion: protocol) or sequentially, with ocular steroids. 10 Chronic or recurrent epistaxis For combination therapies described herein, dosages of Use of tobacco or nicotine products (cigarettes, cigars, the co-administered compounds vary depending on the type electronic cigarettes) within the past 1 year of co-drug employed, on the specific drug employed, on the Coagulation disorders that may lead to increased bleeding disease or condition being treated and so forth. Such as hemophilia and thrombocytopenia The individual compounds of Such combinations are 15 Lacrimal gland, nasal or sinus neoplasia or significant administered either sequentially or simultaneously in sepa trauma; prior lacrimal gland, nasal or sinus Surgery or rate or combined pharmaceutical formulations. In one ablation leading to denervation of the gland or nasal embodiment, the individual compounds will be administered passages as evidenced by a lack of response with the simultaneously in a combined pharmaceutical formulation. cotton Swab nasal stimulation. Appropriate doses of known therapeutic agents will be Severe nasal airway obstruction (e.g. severe septal devia appreciated by those skilled in the art. tion or inferior turbinate hypertrophy) The combinations referred to herein are conveniently Ocular Surgery (such as refractive or cataract Surgery) in presented for use in the form of a pharmaceutical compo either eye within 3 months of the first screening visit; sitions together with a pharmaceutically acceptable diluent A systemic condition or disease not stabilized or judged (s) or carrier(s). 25 by the investigator to be incompatible with participa Administration of a combination of agents, as used herein, tion in the study (e.g. current systemic infection, includes administration of the agents described in a single uncontrolled autoimmune disease, uncontrolled immu composition or in a combination therapy wherein one or nodeficiency disease, history of myocardial infarction, more agent is administered separately from at least one other uncontrolled hypertension, etc.) or with the frequent agent. 30 assessments required by the study In some embodiments, a nicotinic acetylcholine receptor The history or presence of any ocular disorder or condi agonist is administered in combination with the use of a tion in either eye that would likely interfere with the medical device. In some embodiments, a nicotinic acetyl interpretation of the study results or patient safety Such choline receptor agonist is administered in combination with as a significant corneal or conjunctival scarring, ptery the use of punctal plugs. 35 gium or nodular pinguecula; current ocular infection or inflammation not associated with dry eye; clinically EXAMPLES significant anterior (epithelial) basement membrane corneal dystrophy or other clinically significant corneal The following specific examples are to be construed as dystrophy or degeneration; clinically significant merely illustrative, and not limitative of the remainder of the 40 blepharitis: ocular herpetic infection, etc. disclosure in any way whatsoever. Known hypersensitivity to any of the procedural agents or materials in the study drug that contact the nasal Example 1 a COSa. Active or uncontrolled severe systemic allergy, chronic Clinical Trial to Evaluate Safety and Efficacy of 45 seasonal allergies, rhinitis or sinusitis requiring treat Nasal Administration of Nicotinic Acetylcholine ment (i.e. antihistamines, decongestants, oral or aerosol Receptor Agonist Varenicline for Treatment of Dry steroids) at the time of initial screening Eye Disease (DED) Be currently taking any medication known to cause ocular drying (e.g., cyclosporine, antihistamines, tricyclic Purpose: 50 antidepressants, anxiolytics, antimuscarinics, beta This study evaluated the use of Varenicline 0.1% nasal blocking agents, diuretics, phenothiazines, Steroids, spray (OC-01) for the treatment of moderate to severe DED etc.) that has not been used on a stable dosing regimen in adult patients. This study investigated the safety and for 30 days prior to the first screening visit efficacy of using OC-01 to induce aqueous tear production Dissolvable punctal plugs (participants with silicone and reduce the symptoms of DED. 55 plugs or permanent occlusion of punctal ducts are Patients: eligible) A total of 30 participants with moderate to severe dry eye, Active contact lens use unless discontinued at least 7 days meeting the following inclusion and exclusion criteria were prior to the first screening visit and for the duration of enrolled. the study Criteria: 60 Participation in any clinical trial with a new active sub Inclusion: stance or a new device during the past 3 months Males and femalese 18 years of age Women who are pregnant, planning a pregnancy or nurs Willing to sign the informed consent and deemed capable ing at Study entry. A urine pregnancy test will be of complying with the requirements of the study pro administered to women of childbearing age. tocol 65 Known allergies or adverse reactions to Varenicline At screening visit 1, Schirmer tear test (with topical Any unstable or uncontrolled cardiac, pulmonary, renal, anesthesia) of s 10 mm/5 minutes in at least one eye; oncology, neurology, metabolic or other systemic con US 9,597,284 B2 91 92 dition that, in the opinion of the investigator, would like of each of the two nasal formulations will be assessed. The require the patient to seek emergent medical treatment symptom assessment will be performed using a well-estab during the course of this study. This includes but is not lished environmental challenge model, the ClimaTears limited to cardiac arrhythmias, hypertension, coagul Goggle System manufactured by Biocentric Developments, lopathies, renal failure and diabetes mellitus. LLC. Inclusion/Exclusion Exceptions: After testing on Day 0, all patients will receive a bottle of The investigator has the right to exclude any patients OC-01 to take home and self-administer once daily from participation in the study if he/she deems it in the best Day 1 and Day 6. On Day 7, patients will return to the clinic interest of the patient. where they will again be assessed for tear production and Minor exceptions to the inclusion/exclusion criteria 10 symptoms with administration of each nasal formulation. should be submitted to the sponsor and prospectively Tear Assessments approved with the advice of the medical monitor when The following ocular Surface and tear film assessments required. will be performed in the order shown: Major exceptions affecting patient safety/rights or data Ocular Surface Staining Corneal Staining Using Fluores validity should be reported promptly to the IRB/EC by 15 CC1 the investigator. Ocular surface staining using fluorescein and lissamine Primary Outcome: green will be assessed and recorded in the schematic rep The design of this study will enable the following mea resentation of 5 corneal and 6 conjunctival regions per eye surements with respect to OC-01 and tear production: on the case report form using the National Eye Institute Change in tear production associated with a single dose of grading system. A pictorial and descriptive grading scale OC-01 (grades 0 to 3) are included on the case report form (CRF). Secondary Outcome: 1. Corneal staining should be assessed using 1.0 mg The design of this study will enable the following mea Sodium fluorescein strips. surements with respect to OC-01 and tear production: 2. After wetting the end of the strip with a single drop of Change in tear production associated with a single dose of 25 buffered saline, the excess is shaken into a waste bin vehicle with a sharp flick. Change in Symptoms associated with a single dose of 3. The lower lid is then pulled down and the flat end of the OC-01 tip should be gently applied to the inferior tarsal Duration of symptomatic relief associated with a single conjunctiva with the intent of instilling a very small dose of OC-01 30 Volume of dye and not inducing reflex tearing. Change in Symptoms associated with a single dose of 4. The patient will be instructed to blink naturally several vehicle times without forced closure of the eyelid to distribute Duration of symptomatic relief associated with a single the fluorescein. dose of vehicle 5. After allowing fluorescein to remain on the eye for at Together these comparisons will provide valuable informa 35 least one minute, the 5 corneal regions will be graded tion about the safety and efficacy of OC-01 for increasing using a yellow (Wratten #12) barrier filter in conjunc tear production in patients with dry eye disease. tion with the cobalt (blue) filter to maximize the view The primary safety endpoint of this study is incidence and of the fluorescence. The upper eyelid is lifted slightly to relatedness of adverse events (AE). Descriptive statistics of grade the entire corneal Surface. To enhance the con adverse events will be provided as will narratives of any 40 trast, position the yellow barrier filter in the path of the serious, unexpected or drug-related AES. During the study, returning light (not in the path of the incident light). integrity of the nasal passages will be monitored by a Tear Film Breakup Time (TFBUT) Suitably qualified practitioner for patient safety. TFBUT will be assessed using slit lamp biomicroscopy Study Design: according to the following steps: This study is a prospective, single-arm crossover study to 45 1. The slit-lamp will be set to a magnification of approxi evaluate the safety and efficacy of OC-01 Varenicline 0.1% mately 10x. nasal spray in participants with moderate to severe dry eye. 2. With adequate fluorescein in place (preferably using DET Up to 30 participants will be enrolled and followed for a strips), the Subject will be asked to stare straight ahead duration of seven days. without blinking until told otherwise. The test should be At the first screening visit, all eligible participants will 50 performed in a room with no direct air on the patients cease taking their current artificial tears or lubricant drops face. for the duration of the study and will be provided unit dose 3. A stopwatch will be used to record the time between the unpreserved artificial tears to be taken if their dry eye last complete blink and the first appearance of a growing symptoms become intolerable. Empty unit dose vials will be micelle indicating tear-film breakup. collected at each study visit and counted. Patients will be 55 Note: If the patient blinks prematurely prior to the devel instructed not to use artificial tears within 30 minutes of opment of the breakup of the mires, the examiner nasal drug administration or within 2 hours of a study visit. should continue to try to obtain a reading. At the second screening visit/Study Day 0, all eligible 4. Once TFBUT is observed, instruct patient to blink freely. participants will be tested for their response two nasal This test should then be repeated a second time on the formulations: OC-01 and a vehicle control. Tear production 60 same eye. will be assessed immediately prior and after delivery of each 5. If the difference between the first and second readings intranasal dose using the Jones Schirmer Test in both eyes. differs by more than two seconds, a third measurement The order that each patient receives the OC-01 and vehicle should be performed and recorded. formulation will be randomly assigned, and both the patient 6 . This procedure will then be performed in the other eye. and examiner will be masked to the identity of the nasal 65 7. It is recommended that TFBUT be performed in a room formulation. At least 90 minutes following the tear produc with a temperature of approximately 18 C with a humidity tion assessment, change in Symptoms in response to delivery of approximately 50%. US 9,597,284 B2 93 94 Ocular Surface Staining Conjunctival Staining Using Lis Schirmer Test with Each of Two Nasal Spray Applications samine Green With each of the two nasal applications, the Jones Ocular Surface staining assessment will be completed Schirmer test with topical anesthetic will be used to assess with lissamine green conjunctival staining. tear production using the following steps: 1. The lissamine green ophthalmic strip should be wetted 1. Topical anesthetic drops such as 0.5% proparacaine with buffered saline and applied to the inferior tarsal hydrochloride or equivalent should be instilled in both conjunctiva. Care should be taken to instill adequate dye. eyes of the participant for each application. 2. After allowing lissamine green to remain on the eye for 2. The participant will be instructed to keep the eyes gently one minute, the six nasal and temporal conjunctival closed for one minute. regions will be graded. 10 3. After opening the eyes and allowing the eyes to recover 3. To grade the temporal Zone, the subject should be for approximately one additional minute, excess moisture instructed to look nasally, to grade the nasal Zone, the in the inferior fornix is gently removed with a spear. subject should be instructed to look temporally. 4. Schirmer strips (35 mmx5 mm size filter paper strip) will 4. This procedure should then be completed in the other eye. be placed in each eye at the junction of the middle and Schirmer Test 15 lateral thirds of the lower eye lid. At screening visit #1, one basal Jones Schirmer test will 5. Under ambient light, the participant will be instructed to be performed followed by a Schirmer test with cotton Swab look forward and to blink normally during the course of nasal stimulation. The Jones Schirmer test with topical the test. The test should be performed in a room with no anesthetic will be used to assess tear production using the direct air on the participants face. following steps: 6. After five minutes, strips will be removed from both eyes 1. Topical anesthetic drops such as 0.5% proparacaine and the amount of wetting will be recorded. The strips hydrochloride or equivalent should be instilled in both should be taped to the CRF. eyes of the patient. Dry Eye Provocation and Symptom Assessment 2. The patient will be instructed to keep the eyes gently The ClimaTears Goggle System (Biocentric Develop closed for one minute. 25 ments, LLC) will be used to reduce periocular humidity and 3. After opening the eyes and allowing the eyes to recover induce symptoms of dry eye in patients. This system was for approximately one additional minute, excess moisture designed for the purpose of standardizing testing conditions in the inferior fornix is gently removed with a cotton for clinical studies of dry eye patients. tipped applicator. Patients will wear the ClimaTears Goggles continuously 4. Schirmer strips (35 mmx5 mm size filter paper strip) will 30 for up to 90 min, with their symptoms recorded via the visual be placed in each eye at the junction of the middle and analog scale (VAS) every 5 minutes during the testing lateral thirds of the lower eye lid. period. The subject will be asked to rate their dryness 5. Under ambient light, the patient will be instructed to look symptoms (both eyes simultaneously) by placing a vertical forward and to blink normally during the course of the mark on the horizontal line to indicate the level of discom test. The test should be performed in a room with no direct 35 fort. 0 corresponds to “no dryness” and 5 corresponds to air on the patient’s face. “maximal dryness.” The assessment line length of the scale 6. After five minutes, strips will be removed from both eyes will be 100 mm. There are many symptoms of dry eye, and the amount of wetting will be recorded. The strips including dryness, Sticky feeling, burning, foreign body should be taped to the CRF. Note: Should the Schirmer sensation, itching, blurred vision, sensitivity to light, and score reach maximum prior to the 5 minute endpoint, the 40 pain. Please rate the severity of your current “dryness” strip can be removed and the time it took to reach symptoms (and no others) by drawing a vertical line on the maximum recorded. However, the strip from the contral line below: ateral eye should not be removed until it too has reached maximum score prior to the 5 minute endpoint. 7. As multiple Schirmer tests are performed, new anesthetic 45 drops should be added as necessary. Schirmer Test Using Cotton Swab Nasal Stimulation 1. At screening visit #1, the Schirmer test should be per O 1 2 3 4 5 formed using cotton swab nasal stimulation. With new None Severe strips in place, the examiner should insert cotton Swabs in 50 both participant’s nostrils simultaneously and gently probe both nasal middle turbinates for approximately 30 At Day 0, patients will begin wearing the goggles and be seconds. After this, the examiner can simply hold the monitored until they reach a symptom score of 45 mm or Swabs in place, applying gentle pressure, and repeat more for two consecutive measurements, at which time they probing intermittently as necessary. 55 will randomly receive a dose of either OC-01 nasal spray or 2. Alternatively, the participant can be instructed to hold the the control nasal spray, administered 2.5 minutes after the cotton Swabs and gently probe both nasal turbinates two consecutive 45 mm measurements. Symptoms will be simultaneously, resting intermittently before probing continued to be monitored until the patient again reaches a again. The examiner should continuously coach the par score of 45 mm or higher for two consecutive measure ticipant on how to perform this test properly. 60 ments, at which time the patient will receive a second nasal 3. The Schirmer strips should remain in place until five dose of which ever test article they did not receive the first minutes have elapsed or they have reached maximum time. After the second nasal dose, symptoms will be moni SCO. tored again until the patient reaches a score of a score of 45 Both Schirmer scores will be recorded and verified that they mm or higher for two consecutive measurements. At that meet the inclusion criteria. As two Schirmer tests are per 65 time, the goggles will be removed and the test will end. If formed, new anesthetic drops should be instilled as neces still ongoing, the test will be terminated after 90 minutes of Sary. exposure to the goggles environment. At the end of this US 9,597,284 B2 95 96 period, each patient will be asked to decide which of the Coagulation disorders that may lead to increased bleeding nasal sprays made provided more relief of their dry eye Such as hemophilia and thrombocytopenia symptoms. Lacrimal gland, nasal or sinus neoplasia or significant At Day 7, patients will begin wearing the goggles and be trauma; prior lacrimal gland, nasal or sinus Surgery or monitored until they reach a symptom score of 45 mm or ablation leading to denervation of the gland or nasal more for two consecutive measurements, at which time they passages as evidenced by a lack of response with the will receive a dose of the OC-01 nasal spray. Symptoms will cotton Swab nasal stimulation. continued to be monitored until the patient again reaches a Severe nasal airway obstruction (e.g. severe septal devia score of 45 mm or higher for two consecutive measure tion or inferior turbinate hypertrophy) ments, at which time the goggles will be removed and the 10 Ocular Surgery (such as refractive or cataract Surgery) in test will end. If still ongoing, the test will be terminated after either eye within 3 months of the first screening visit; 90 minutes of exposure to the goggles environment. A systemic condition or disease not stabilized or judged Patients entering with a baseline symptoms score of more by the investigator to be incompatible with participa than 45 mm will have a treatment threshold equal to this 15 tion in the study (e.g. current systemic infection, baseline score, and will thus receive treatment after two uncontrolled autoimmune disease, uncontrolled immu consecutive symptoms measurements of greater than or nodeficiency disease, history of myocardial infarction, equal to this value. uncontrolled hypertension, etc.) or with the frequent The instructions (in bold above) will be read to the patient assessments required by the study before the test begins, and before recording symptoms The history or presence of any ocular disorder or condi values immediately following the administration of either tion in either eye that would likely interfere with the nasal spray. interpretation of the study results or patient safety Such Results of Tear Film Assessments and Dry Eye Symp as a significant corneal or conjunctival scarring, ptery tOmS: gium or nodular pinguecula; current ocular infection or Tear production in patients receiving OC-01 increased in 25 inflammation not associated with dry eye; clinically a statitistically significant amount compared to both baseline significant anterior (epithelial) basement membrane and placebo (FIG. 1). In addition, patient reported symptoms corneal dystrophy or other clinically significant corneal of dry eye also improved in patients receiving OC-01 versus dystrophy or degeneration; clinically significant placebo (FIG. 2). blepharitis: ocular herpetic infection, etc. 30 Known hypersensitivity to any of the procedural agents or Example 1b materials in the study drug that contact the nasal Clinical Trial to Evaluate Safety and Efficacy of COSa. Nasal Administration of Nicotinic Acetylcholine Active or uncontrolled severe systemic allergy, chronic Receptor Agonist Cytisine for Treatment of Dry 35 seasonal allergies, rhinitis or sinusitis requiring treat Eye Disease (DED) ment (i.e. antihistamines, decongestants, oral or aerosol steroids) at the time of initial screening Purpose: Be currently taking any medication known to cause ocular This study evaluates the use of cytisine 0.1% nasal spray drying (e.g., cyclosporine, antihistamines, tricyclic (OC-02) for the treatment of moderate to severe DED in 40 antidepressants, anxiolytics, antimuscarinics, beta adult patients. This study will investigate the safety and blocking agents, diuretics, phenothiazines, Steroids, efficacy of using OC-02 to induce aqueous tear production etc.) that has not been used on a stable dosing regimen and reduce the symptoms of DED. for 30 days prior to the first screening visit Patients: Dissolvable punctal plugs (participants with silicone A total of 30 participants with moderate to severe dry eye, 45 plugs or permanent occlusion of punctal ducts are meeting the following inclusion and exclusion criteria will eligible) be enrolled. Active contact lens use unless discontinued at least 7 days Criteria: prior to the first screening visit and for the duration of Inclusion: the study Males and femalese 18 years of age 50 Participation in any clinical trial with a new active sub Willing to sign the informed consent and deemed capable stance or a new device during the past 3 months of complying with the requirements of the study pro Women who are pregnant, planning a pregnancy or nurs tocol ing at Study entry. A urine pregnancy test will be At screening visit 1, Schirmer tear test (with topical administered to women of childbearing age. anesthesia) of s 10 mm/5 minutes in at least one eye; 55 At screening visit 1, Schirmer test (with topical anesthesia Known allergies or adverse reactions to cytisine and nasal stimulation with cotton Swab) of at least 7 Any unstable or uncontrolled cardiac, pulmonary, renal, mm higher than the unstimulated value in at least one oncology, neurology, metabolic or other systemic con eye; dition that, in the opinion of the investigator, would like Baseline Ocular Surface Disease Index score of at least 23 60 require the patient to seek emergent medical treatment with no more than 3 responses of “not applicable' at the during the course of this study. This includes but is not first screening visit limited to cardiac arrhythmias, hypertension, coagul Normal lid/lash anatomy, blinking function and closure lopathies, renal failure and diabetes mellitus. Exclusion: Inclusion/Exclusion Exceptions: Chronic or recurrent epistaxis 65 The investigator has the right to exclude any patients Use of tobacco or nicotine products (cigarettes, cigars, participation in the study if he/she deems it in the best electronic cigarettes) within the past 1 year interest of the patient. US 9,597,284 B2 97 98 Minor exceptions to the inclusion/exclusion criteria where they will again be assessed for tear production and should be submitted to the sponsor and prospectively symptoms with administration of each nasal formulation. approved with the advice of the medical monitor when Tear Assessments required. The following ocular Surface and tear film assessments Major exceptions affecting patient safety/rights or data will be performed in the order shown: validity should be reported promptly to the IRB/EC by Ocular Surface Staining Corneal Staining Using Fluores the investigator. cein Primary Outcome: Ocular surface staining using fluorescein and lissamine The design of this study will enable the following mea green will be assessed and recorded in the schematic rep surements with respect to OC-02 and tear production: 10 resentation of 5 corneal and 6 conjunctival regions per eye Change in tear production associated with a single dose of on the case report form using the National Eye Institute OC-02 grading system. A pictorial and descriptive grading scale Secondary Outcome: (grades 0 to 3) are included on the case report form (CRF). The design of this study will enable the following mea 15 1. Corneal staining should be assessed using 1.0 mg Sodium surements with respect to OC-02 and tear production: fluorescein strips. Change in tear production associated with a single dose of 2. After wetting the end of the strip with a single drop of vehicle buffered saline, the excess is shaken into a waste bin with Change in Symptoms associated with a single dose of a sharp flick. OC-02 3. The lower lid is then pulled down and the flat end of the Duration of symptomatic relief associated with a single tip should be gently applied to the inferior tarsal conjunc dose of OC-02 tiva with the intent of instilling a very small volume of Change in Symptoms associated with a single dose of dye and not inducing reflex tearing. vehicle 4. The patient will be instructed to blink naturally several Duration of symptomatic relief associated with a single 25 times without forced closure of the eyelid to distribute the dose of vehicle fluorescein. Together these comparisons will provide valuable informa 5. After allowing fluorescein to remain on the eye for at least tion about the safety and efficacy of OC-02 for increasing one minute, the 5 corneal regions will be graded using a tear production in patients with dry eye disease. yellow (Wratten #12) barrier filter in conjunction with the The primary safety endpoint of this study is incidence and 30 cobalt (blue) filter to maximize the view of the fluores relatedness of adverse events (AE). Descriptive statistics of cence. The upper eyelid is lifted slightly to grade the adverse events will be provided as will narratives of any entire corneal surface. To enhance the contrast, position serious, unexpected or drug-related AES. During the study, the yellow barrier filter in the path of the returning light integrity of the nasal passages will be monitored by a (not in the path of the incident light). Suitably qualified practitioner for patient safety. 35 Tear Film Breakup Time (TFBUT) Study Design: TFBUT will be assessed using slit lamp biomicroscopy This study is a prospective, single-arm crossover study to according to the following steps: evaluate the safety and efficacy of OC-02 cytisine 0.1% 1. The slit-lamp will be set to a magnification of approxi nasal spray in participants with moderate to severe dry eye. mately 10x. Up to 30 participants will be enrolled and followed for a 40 2. With adequate fluorescein in place (preferably using DET duration of seven days. strips), the Subject will be asked to stare straight ahead At the first screening visit, all eligible participants will without blinking until told otherwise. The test should be cease taking their current artificial tears or lubricant drops performed in a room with no direct air on the patients for the duration of the study and will be provided unit dose face. unpreserved artificial tears to be taken if their dry eye 45 3. A stopwatch will be used to record the time between the symptoms become intolerable. Empty unit dose vials will be last complete blink and the first appearance of a growing collected at each study visit and counted. Patients will be micelle indicating tear-film breakup. instructed not to use artificial tears within 30 minutes of Note: If the patient blinks prematurely prior to the devel nasal drug administration or within 2 hours of a study visit. opment of the breakup of the mires, the examiner At the second screening visit/Study Day 0, all eligible 50 should continue to try to obtain a reading. participants will be tested for their response two nasal 4. Once TFBUT is observed, instruct patient to blink freely. formulations: OC-02 and a vehicle control. Tear production This test should then be repeated a second time on the will be assessed immediately prior and after delivery of each same eye. intranasal dose using the Jones Schirmer Test in both eyes. 5. If the difference between the first and second readings The order that each patient receives the OC-02 and vehicle 55 differs by more than two seconds, a third measurement formulation will be randomly assigned, and both the patient should be performed and recorded. and examiner will be masked to the identity of the nasal 6. This procedure will then be performed in the other eye. formulation. At least 90 minutes following the tear produc 7. It is recommended that TFBUT be performed in a room tion assessment, change in Symptoms in response to delivery with a temperature of approximately 18 C with a humidity of each of the two nasal formulations will be assessed. The 60 of approximately 50%. symptom assessment will be performed using a well-estab Ocular Surface Staining Conjunctival Staining Using Lis lished environmental challenge model, the ClimaTears samine Green Goggle System manufactured by Biocentric Developments, Ocular Surface staining assessment will be completed LLC. with lissamine green conjunctival staining. After testing on Day 0, all patients will receive a bottle of 65 1. The lissamine green ophthalmic strip should be wetted OC-02 to take home and self-administer once daily from with buffered saline and applied to the inferior tarsal Day 1 and Day 6. On Day 7, patients will return to the clinic conjunctiva. Care should be taken to instill adequate dye. US 9,597,284 B2 99 100 2. After allowing lissamine green to remain on the eye for 2. The participant will be instructed to keep the eyes gently one minute, the six nasal and temporal conjunctival closed for one minute. regions will be graded. 3. After opening the eyes and allowing the eyes to recover 3. To grade the temporal Zone, the subject should be for approximately one additional minute, excess moisture instructed to look nasally, to grade the nasal Zone, the in the inferior fornix is gently removed with a spear. subject should be instructed to look temporally. 4. Schirmer strips (35 mmx5 mm size filter paper strip) will 4. This procedure should then be completed in the other eye. be placed in each eye at the junction of the middle and Schirmer Test lateral thirds of the lower eye lid. At screening visit #1, one basal Jones Schirmer test will 5. Under ambient light, the participant will be instructed to be performed followed by a Schirmer test with cotton Swab 10 look forward and to blink normally during the course of nasal stimulation. The Jones Schirmer test with topical the test. The test should be performed in a room with no anesthetic will be used to assess tear production using the direct air on the participants face. following steps: 6. After five minutes, strips will be removed from both eyes 1. Topical anesthetic drops such as 0.5% proparacaine and the amount of wetting will be recorded. The strips hydrochloride or equivalent should be instilled in both 15 should be taped to the CRF. eyes of the patient. Dry Eye Provocation and Symptom Assessment 2. The patient will be instructed to keep the eyes gently The ClimaTears Goggle System (Biocentric Develop closed for one minute. ments, LLC) will be used to reduce periocular humidity and 3. After opening the eyes and allowing the eyes to recover induce symptoms of dry eye in patients. This system was for approximately one additional minute, excess moisture designed for the purpose of standardizing testing conditions in the inferior fornix is gently removed with a cotton for clinical studies of dry eye patients. tipped applicator. Patients will wear the ClimaTears Goggles continuously 4. Schirmer strips (35 mmx5 mm size filter paper strip) will for up to 90 min, with their symptoms recorded via the visual be placed in each eye at the junction of the middle and analog scale (VAS) every 5 minutes during the testing lateral thirds of the lower eye lid. 25 period. The subject will be asked to rate their dryness 5. Under ambient light, the patient will be instructed to look symptoms (both eyes simultaneously) by placing a vertical forward and to blink normally during the course of the mark on the horizontal line to indicate the level of discom test. The test should be performed in a room with no direct fort. 0 corresponds to “no dryness” and 5 corresponds to air on the patient’s face. “maximal dryness.” The assessment line length of the scale 6. After five minutes, strips will be removed from both eyes 30 will be 100 mm. There are many symptoms of dry eye, and the amount of wetting will be recorded. The strips including dryness, Sticky feeling, burning, foreign body should be taped to the CRF. Note: Should the Schirmer sensation, itching, blurred vision, sensitivity to light, and score reach maximum prior to the 5 minute endpoint, the pain. Please rate the severity of your current “dryness” strip can be removed and the time it took to reach symptoms (and no others) by drawing a vertical line on the maximum recorded. However, the strip from the contral 35 line below: ateral eye should not be removed until it too has reached maximum score prior to the 5 minute endpoint. 7. As multiple Schirmer tests are performed, new anesthetic drops should be added as necessary. Schirmer Test Using Cotton Swab Nasal Stimulation 40 1. At screening visit #1, the Schirmer test should be per O 1 2 3 4 5 formed using cotton swab nasal stimulation. With new strips in place, the examiner should insert cotton Swabs in None Severe both participant’s nostrils simultaneously and gently probe both nasal middle turbinates for approximately 30 45 At Day 0, patients will begin wearing the goggles and be seconds. After this, the examiner can simply hold the monitored until they reach a symptom score of 45 mm or Swabs in place, applying gentle pressure, and repeat more for two consecutive measurements, at which time they probing intermittently as necessary. will randomly receive a dose of either OC-02 nasal spray or 2. Alternatively, the participant can be instructed to hold the the control nasal spray, administered 2.5 minutes after the cotton Swabs and gently probe both nasal turbinates 50 two consecutive 45 mm measurements. Symptoms will be simultaneously, resting intermittently before probing continued to be monitored until the patient again reaches a again. The examiner should continuously coach the par score of 45 mm or higher for two consecutive measure ticipant on how to perform this test properly. ments, at which time the patient will receive a second nasal 3. The Schirmer strips should remain in place until five dose of which ever test article they did not receive the first minutes have elapsed or they have reached maximum 55 time. After the second nasal dose, symptoms will be moni SCO. tored again until the patient reaches a score of a score of 45 Both Schirmer scores will be recorded and verified that they mm or higher for two consecutive measurements. At that meet the inclusion criteria. As two Schirmer tests are per time, the goggles will be removed and the test will end. If formed, new anesthetic drops should be instilled as neces still ongoing, the test will be terminated after 90 minutes of Sary. 60 exposure to the goggles environment. At the end of this Schirmer Test with Each of Two Nasal Spray Applications period, each patient will be asked to decide which of the With each of the two nasal applications, the Jones nasal sprays made provided more relief of their dry eye Schirmer test with topical anesthetic will be used to assess symptoms. tear production using the following steps: At Day 7, patients will begin wearing the goggles and be 1. Topical anesthetic drops such as 0.5% proparacaine 65 monitored until they reach a symptom score of 45 mm or hydrochloride or equivalent should be instilled in both more for two consecutive measurements, at which time they eyes of the participant for each application. will receive a dose of the OC-02 nasal spray. Symptoms will US 9,597,284 B2 101 102 continued to be monitored until the patient again reaches a nodeficiency disease, history of myocardial infarction, score of 45 mm or higher for two consecutive measure uncontrolled hypertension, etc.) or with the frequent ments, at which time the goggles will be removed and the assessments required by the study test will end. If still ongoing, the test will be terminated after The history or presence of any ocular disorder or condi 90 minutes of exposure to the goggles environment. 5 tion in either eye that would likely interfere with the Patients entering with a baseline symptoms score of more interpretation of the study results or patient safety Such than 45 mm will have a treatment threshold equal to this as a significant corneal or conjunctival scarring, ptery baseline score, and will thus receive treatment after two gium or nodular pinguecula; current ocular infection or consecutive symptoms measurements of greater than or inflammation not associated with dry eye; clinically equal to this value. 10 significant anterior (epithelial) basement membrane The instructions (in bold above) will be read to the patient corneal dystrophy or other clinically significant corneal before the test begins, and before recording symptoms dystrophy or degeneration; clinically significant values immediately following the administration of either nasal spray. blepharitis: ocular herpetic infection, etc. 15 Known hypersensitivity to any of the procedural agents or Example 1c materials in the study drug that contact the nasal COSa. Clinical Trial to Evaluate Safety and Efficacy of Active or uncontrolled severe systemic allergy, chronic Nasal Administration of Nicotinic Acetylcholine seasonal allergies, rhinitis or sinusitis requiring treat Receptor Agonist Epibatidine for Treatment of Dry ment (i.e. antihistamines, decongestants, oral or aerosol Eye Disease (DED) steroids) at the time of initial screening Be currently taking any medication known to cause ocular Purpose: drying (e.g., cyclosporine, antihistamines, tricyclic This study evaluates the use of epibatidine 0.1% nasal antidepressants, anxiolytics, antimuscarinics, beta spray (OC-03) for the treatment of moderate to severe DED 25 blocking agents, diuretics, phenothiazines, Steroids, in adult patients. This study will investigate the safety and etc.) that has not been used on a stable dosing regimen efficacy of using OC-03 to induce aqueous tear production for 30 days prior to the first screening visit and reduce the symptoms of DED. Dissolvable punctal plugs (participants with silicone Patients: plugs or permanent occlusion of punctal ducts are A total of 30 participants with moderate to severe dry eye, 30 eligible) meeting the following inclusion and exclusion criteria will Active contact lens use unless discontinued at least 7 days be enrolled. prior to the first screening visit and for the duration of Criteria: the study Inclusion: Participation in any clinical trial with a new active sub Males and femalese 18 years of age 35 stance or a new device during the past 3 months Willing to sign the informed consent and deemed capable Women who are pregnant, planning a pregnancy or nurs of complying with the requirements of the study pro ing at Study entry. A urine pregnancy test will be tocol administered to women of childbearing age. At screening visit 1, Schirmer tear test (with topical Known allergies or adverse reactions to epibatidine anesthesia) of s 10 mm/5 minutes in at least one eye; 40 Any unstable or uncontrolled cardiac, pulmonary, renal, At screening visit 1, Schirmer test (with topical anesthesia oncology, neurology, metabolic or other systemic con and nasal stimulation with cotton Swab) of at least 7 dition that, in the opinion of the investigator, would like mm higher than the unstimulated value in at least one require the patient to seek emergent medical treatment eye; during the course of this study. This includes but is not Baseline Ocular Surface Disease Index score of at least 23 45 limited to cardiac arrhythmias, hypertension, coagul with no more than 3 responses of “not applicable' at the lopathies, renal failure and diabetes mellitus. first screening visit Inclusion/Exclusion Exceptions: Normal lid/lash anatomy, blinking function and closure The investigator has the right to exclude any patients Exclusion: participation in the study if he/she deems it in the best Chronic or recurrent epistaxis 50 interest of the patient. Use of tobacco or nicotine products (cigarettes, cigars, Minor exceptions to the inclusion/exclusion criteria electronic cigarettes) within the past 1 year should be submitted to the sponsor and prospectively Coagulation disorders that may lead to increased bleeding approved with the advice of the medical monitor when Such as hemophilia and thrombocytopenia required. Lacrimal gland, nasal or sinus neoplasia or significant 55 Major exceptions affecting patient safety/rights or data trauma; prior lacrimal gland, nasal or sinus Surgery or validity should be reported promptly to the IRB/EC by ablation leading to denervation of the gland or nasal the investigator. passages as evidenced by a lack of response with the Primary Outcome: cotton Swab nasal stimulation. The design of this study will enable the following mea Severe nasal airway obstruction (e.g. severe septal devia 60 surements with respect to OC-03 and tear production: tion or inferior turbinate hypertrophy) Change in tear production associated with a single dose of Ocular Surgery (such as refractive or cataract Surgery) in OC-03 either eye within 3 months of the first screening visit; Secondary Outcome: A systemic condition or disease not stabilized or judged The design of this study will enable the following mea by the investigator to be incompatible with participa 65 surements with respect to OC-03 and tear production: tion in the study (e.g. current systemic infection, Change in tear production associated with a single dose of uncontrolled autoimmune disease, uncontrolled immu vehicle US 9,597,284 B2 103 104 Change in Symptoms associated with a single dose of 3. The lower lid is then pulled down and the flat end of the OC-03 tip should be gently applied to the inferior tarsal conjunc Duration of symptomatic relief associated with a single tiva with the intent of instilling a very small volume of dose of OC-03 dye and not inducing reflex tearing. Change in Symptoms associated with a single dose of 5 4. The patient will be instructed to blink naturally several vehicle times without forced closure of the eyelid to distribute the Duration of symptomatic relief associated with a single fluorescein. dose of vehicle 5. After allowing fluorescein to remain on the eye for at least Together these comparisons will provide valuable informa one minute, the 5 corneal regions will be graded using a tion about the safety and efficacy of OC-03 for increasing 10 tear production in patients with dry eye disease. yellow (Wratten #12) barrier filter in conjunction with the The primary safety endpoint of this study is incidence and cobalt (blue) filter to maximize the view of the fluores relatedness of adverse events (AE). Descriptive statistics of cence. The upper eyelid is lifted slightly to grade the adverse events will be provided as will narratives of any entire corneal Surface. To enhance the contrast, position serious, unexpected or drug-related AES. During the study, 15 the yellow barrier filter in the path of the returning light integrity of the nasal passages will be monitored by a (not in the path of the incident light). Suitably qualified practitioner for patient safety. Tear Film Breakup Time (TFBUT) Study Design: TFBUT will be assessed using slit lamp biomicroscopy This study is a prospective, single-arm crossover study to according to the following steps: evaluate the safety and efficacy of OC-03 epibatidine 0.1% 1. The slit-lamp will be set to a magnification of approxi nasal spray in participants with moderate to severe dry eye. mately 10x. Up to 30 participants will be enrolled and followed for a 2. With adequate fluorescein in place (preferably using DET duration of seven days. strips), the Subject will be asked to stare straight ahead At the first screening visit, all eligible participants will without blinking until told otherwise. The test should be cease taking their current artificial tears or lubricant drops 25 performed in a room with no direct air on the patients for the duration of the study and will be provided unit dose face. unpreserved artificial tears to be taken if their dry eye 3. A stopwatch will be used to record the time between the symptoms become intolerable. Empty unit dose vials will be last complete blink and the first appearance of a growing collected at each study visit and counted. Patients will be micelle indicating tear-film breakup. instructed not to use artificial tears within 30 minutes of 30 Note: If the patient blinks prematurely prior to the devel nasal drug administration or within 2 hours of a study visit. opment of the breakup of the mires, the examiner At the second screening visit/Study Day 0, all eligible should continue to try to obtain a reading. participants will be tested for their response two nasal 4. Once TFBUT is observed, instruct patient to blink freely. formulations: OC-03 and a vehicle control. Tear production This test should then be repeated a second time on the will be assessed immediately prior and after delivery of each 35 same eye. intranasal dose using the Jones Schirmer Test in both eyes. 5. If the difference between the first and second readings The order that each patient receives the OC-03 and vehicle differs by more than two seconds, a third measurement formulation will be randomly assigned, and both the patient should be performed and recorded. and examiner will be masked to the identity of the nasal 6. This procedure will then be performed in the other eye. formulation. At least 90 minutes following the tear produc 40 7. It is recommended that TFBUT be performed in a room tion assessment, change in Symptoms in response to delivery with a temperature of approximately 18 C with a humidity of each of the two nasal formulations will be assessed. The of approximately 50%. symptom assessment will be performed using a well-estab Ocular Surface Staining Conjunctival Staining Using Lis lished environmental challenge model, the ClimaTears samine Green Goggle System manufactured by Biocentric Developments, 45 Ocular Surface staining assessment will be completed LLC. with lissamine green conjunctival staining. After testing on Day 0, all patients will receive a bottle of 1. The lissamine green ophthalmic strip should be wetted OC-03 to take home and self-administer once daily from with buffered saline and applied to the inferior tarsal Day 1 and Day 6. On Day 7, patients will return to the clinic conjunctiva. Care should be taken to instill adequate dye. where they will again be assessed for tear production and 50 2. After allowing lissamine green to remain on the eye for symptoms with administration of each nasal formulation. one minute, the six nasal and temporal conjunctival Tear Assessments regions will be graded. The following ocular Surface and tear film assessments 3. To grade the temporal Zone, the subject should be will be performed in the order shown: instructed to look nasally, to grade the nasal Zone, the Ocular Surface Staining Corneal Staining Using Fluores 55 subject should be instructed to look temporally. CC1 4. This procedure should then be completed in the other eye. Ocular Surface staining using fluorescein and lissamine Schirmer Test green will be assessed and recorded in the schematic rep At screening visit #1, one basal Jones Schirmer test will resentation of 5 corneal and 6 conjunctival regions per eye be performed followed by a Schirmer test with cotton Swab on the case report form using the National Eye Institute 60 nasal stimulation. The Jones Schirmer test with topical grading system. A pictorial and descriptive grading scale anesthetic will be used to assess tear production using the (grades 0 to 3) are included on the case report form (CRF). following steps: 1. Corneal staining should be assessed using 1.0 mg Sodium 1. Topical anesthetic drops such as 0.5% proparacaine fluorescein strips. hydrochloride or equivalent should be instilled in both 2. After wetting the end of the strip with a single drop of 65 eyes of the patient. buffered saline, the excess is shaken into a waste bin with 2. The patient will be instructed to keep the eyes gently a sharp flick. closed for one minute. US 9,597,284 B2 105 106 3. After opening the eyes and allowing the eyes to recover induce symptoms of dry eye in patients. This system was for approximately one additional minute, excess moisture designed for the purpose of standardizing testing conditions in the inferior fornix is gently removed with a cotton for clinical studies of dry eye patients. tipped applicator. 4. Schirmer strips (35 mmx5 mm size filter paper strip) will Patients will wear the ClimaTears Goggles continuously be placed in each eye at the junction of the middle and for up to 90 min, with their symptoms recorded via the visual lateral thirds of the lower eye lid. analog scale (VAS) every 5 minutes during the testing 5. Under ambient light, the patient will be instructed to look period. The subject will be asked to rate their dryness forward and to blink normally during the course of the symptoms (both eyes simultaneously) by placing a vertical mark on the horizontal line to indicate the level of discom test. The test should be performed in a room with no direct 10 air on the patient’s face. fort. 0 corresponds to “no dryness” and 5 corresponds to 6. After five minutes, strips will be removed from both eyes “maximal dryness.” The assessment line length of the scale and the amount of wetting will be recorded. The strips will be 100 mm. There are many symptoms of dry eye, should be taped to the CRF. Note: Should the Schirmer including dryness, Sticky feeling, burning, foreign body score reach maximum prior to the 5 minute endpoint, the 15 sensation, itching, blurred vision, sensitivity to light, and strip can be removed and the time it took to reach pain. Please rate the severity of your current “dryness” maximum recorded. However, the strip from the contral symptoms (and no others) by drawing a vertical line on the ateral eye should not be removed until it too has reached line below: maximum score prior to the 5 minute endpoint. 7. As multiple Schirmer tests are performed, new anesthetic drops should be added as necessary. Schirmer Test Using Cotton Swab Nasal Stimulation 1. At screening visit #1, the Schirmer test should be per formed using cotton swab nasal stimulation. With new strips in place, the examiner should insert cotton Swabs in 25 both participant’s nostrils simultaneously and gently probe both nasal middle turbinates for approximately 30 seconds. After this, the examiner can simply hold the At Day 0, patients will begin wearing the goggles and be Swabs in place, applying gentle pressure, and repeat monitored until they reach a symptom score of 45 mm or probing intermittently as necessary. 30 2. Alternatively, the participant can be instructed to hold the more for two consecutive measurements, at which time they cotton Swabs and gently probe both nasal turbinates will randomly receive a dose of either OC-03 nasal spray or simultaneously, resting intermittently before probing the control nasal spray, administered 2.5 minutes after the again. The examiner should continuously coach the par two consecutive 45 mm measurements. Symptoms will be ticipant on how to perform this test properly. 35 continued to be monitored until the patient again reaches a 3. The Schirmer strips should remain in place until five score of 45 mm or higher for two consecutive measure minutes have elapsed or they have reached maximum ments, at which time the patient will receive a second nasal SCO. dose of which ever test article they did not receive the first Both Schirmer scores will be recorded and verified that they time. After the second nasal dose, symptoms will be moni meet the inclusion criteria. As two Schirmer tests are per 40 tored again until the patient reaches a score of a score of 45 formed, new anesthetic drops should be instilled as neces mm or higher for two consecutive measurements. At that Sary. time, the goggles will be removed and the test will end. If Schirmer Test with Each of Two Nasal Spray Applications still ongoing, the test will be terminated after 90 minutes of With each of the two nasal applications, the Jones Schirmer exposure to the goggles environment. At the end of this test with topical anesthetic will be used to assess tear 45 period, each patient will be asked to decide which of the production using the following steps: nasal sprays made provided more relief of their dry eye 1. Topical anesthetic drops such as 0.5% proparacaine symptoms. hydrochloride or equivalent should be instilled in both eyes of the participant for each application. At Day 7, patients will begin wearing the goggles and be 2. The participant will be instructed to keep the eyes gently 50 monitored until they reach a symptom score of 45 mm or closed for one minute. more for two consecutive measurements, at which time they 3. After opening the eyes and allowing the eyes to recover will receive a dose of the OC-03 nasal spray. Symptoms will for approximately one additional minute, excess moisture continued to be monitored until the patient again reaches a in the inferior fornix is gently removed with a spear. score of 45 mm or higher for two consecutive measure 4. Schirmer strips (35 mmx5 mm size filter paper strip) will 55 ments, at which time the goggles will be removed and the be placed in each eye at the junction of the middle and test will end. If still ongoing, the test will be terminated after lateral thirds of the lower eye lid. 90 minutes of exposure to the goggles environment. 5. Under ambient light, the participant will be instructed to Patients entering with a baseline symptoms score of more look forward and to blink normally during the course of than 45 mm will have a treatment threshold equal to this the test. The test should be performed in a room with no 60 direct air on the participants face. baseline score, and will thus receive treatment after two 6. After five minutes, strips will be removed from both eyes consecutive symptoms measurements of greater than or and the amount of wetting will be recorded. The strips equal to this value. should be taped to the CRF. The instructions (in bold above) will be read to the patient Dry Eye Provocation and Symptom Assessment 65 before the test begins, and before recording symptoms The ClimaTears Goggle System (Biocentric Develop values immediately following the administration of either ments, LLC) will be used to reduce periocular humidity and nasal spray. US 9,597,284 B2 107 108 Example 1d Known hypersensitivity to any of the procedural agents or materials in the study drug that contact the nasal Clinical Trial to Evaluate Safety and Efficacy of COSa. Nasal Administration of Nicotinic Acetylcholine Active or uncontrolled severe systemic allergy, chronic Receptor Agonist Tebanicline for Treatment of Dry 5 seasonal allergies, rhinitis or sinusitis requiring treat Eye Disease (DED) ment (i.e. antihistamines, decongestants, oral or aerosol steroids) at the time of initial screening Purpose: Be currently taking any medication known to cause ocular This study evaluates the use of tebanicline 0.1% nasal drying (e.g., cyclosporine, antihistamines, tricyclic 10 antidepressants, anxiolytics, antimuscarinics, beta spray (OC-04) for the treatment of moderate to severe DED blocking agents, diuretics, phenothiazines, Steroids, in adult patients. This study will investigate the safety and etc.) that has not been used on a stable dosing regimen efficacy of using OC-04 to induce aqueous tear production for 30 days prior to the first screening visit and reduce the symptoms of DED. Dissolvable punctal plugs (participants with silicone Patients: 15 plugs or permanent occlusion of punctal ducts are A total of 30 participants with moderate to severe dry eye, eligible) meeting the following inclusion and exclusion criteria will Active contact lens use unless discontinued at least 7 days be enrolled. prior to the first screening visit and for the duration of Criteria: the study Inclusion: Participation in any clinical trial with a new active sub Males and femalese 18 years of age stance or a new device during the past 3 months Willing to sign the informed consent and deemed capable Women who are pregnant, planning a pregnancy or nurs of complying with the requirements of the study pro ing at Study entry. A urine pregnancy test will be tocol administered to women of childbearing age. At screening visit 1, Schirmer tear test (with topical 25 Known allergies or adverse reactions to tebanicline anesthesia) of s 10 mm/5 minutes in at least one eye; Any unstable or uncontrolled cardiac, pulmonary, renal, At screening visit 1, Schirmer test (with topical anesthesia oncology, neurology, metabolic or other systemic con and nasal stimulation with cotton Swab) of at least 7 dition that, in the opinion of the investigator, would like mm higher than the unstimulated value in at least one require the patient to seek emergent medical treatment 30 during the course of this study. This includes but is not eye; limited to cardiac arrhythmias, hypertension, coagul Baseline Ocular Surface Disease Index score of at least 23 lopathies, renal failure and diabetes mellitus. with no more than 3 responses of “not applicable' at the Inclusion/Exclusion Exceptions: first screening visit The investigator has the right to exclude any patients Normal lid/lash anatomy, blinking function and closure 35 participation in the study if he/she deems it in the best Exclusion: interest of the patient. Chronic or recurrent epistaxis Minor exceptions to the inclusion/exclusion criteria Use of tobacco or nicotine products (cigarettes, cigars, should be submitted to the sponsor and prospectively electronic cigarettes) within the past 1 year approved with the advice of the medical monitor when Coagulation disorders that may lead to increased bleeding 40 required. Such as hemophilia and thrombocytopenia Major exceptions affecting patient safety/rights or data Lacrimal gland, nasal or sinus neoplasia or significant validity should be reported promptly to the IRB/EC by trauma; prior lacrimal gland, nasal or sinus Surgery or the investigator. ablation leading to denervation of the gland or nasal Primary Outcome: passages as evidenced by a lack of response with the 45 The design of this study will enable the following mea cotton Swab nasal stimulation. surements with respect to OC-04 and tear production: Severe nasal airway obstruction (e.g. severe septal devia Change in tear production associated with a single dose of tion or inferior turbinate hypertrophy) OC-04 Ocular Surgery (such as refractive or cataract Surgery) in Secondary Outcome: either eye within 3 months of the first screening visit; 50 The design of this study will enable the following mea A systemic condition or disease not stabilized or judged surements with respect to OC-04 and tear production: by the investigator to be incompatible with participa Change in tear production associated with a single dose of tion in the study (e.g. current systemic infection, vehicle uncontrolled autoimmune disease, uncontrolled immu Change in Symptoms associated with a single dose of nodeficiency disease, history of myocardial infarction, 55 OC-04 uncontrolled hypertension, etc.) or with the frequent Duration of symptomatic relief associated with a single assessments required by the study dose of OC-04 The history or presence of any ocular disorder or condi Change in Symptoms associated with a single dose of tion in either eye that would likely interfere with the vehicle interpretation of the study results or patient safety Such 60 Duration of symptomatic relief associated with a single as a significant corneal or conjunctival scarring, ptery dose of vehicle gium or nodular pinguecula; current ocular infection or Together these comparisons will provide valuable informa inflammation not associated with dry eye; clinically tion about the safety and efficacy of OC-04 for increasing significant anterior (epithelial) basement membrane tear production in patients with dry eye disease. corneal dystrophy or other clinically significant corneal 65 The primary safety endpoint of this study is incidence and dystrophy or degeneration; clinically significant relatedness of adverse events (AE). Descriptive statistics of blepharitis: ocular herpetic infection, etc. adverse events will be provided as will narratives of any US 9,597,284 B2 109 110 serious, unexpected or drug-related AES. During the study, the yellow barrier filter in the path of the returning light integrity of the nasal passages will be monitored by a (not in the path of the incident light). Suitably qualified practitioner for patient safety. Tear Film Breakup Time (TFBUT) Study Design: TFBUT will be assessed using slit lamp biomicroscopy This study is a prospective, single-arm crossover study to according to the following steps: evaluate the safety and efficacy of OC-04 tebanicline 0.1% 1. The slit-lamp will be set to a magnification of approxi nasal spray in participants with moderate to severe dry eye. mately 10x. Up to 30 participants will be enrolled and followed for a 2. With adequate fluorescein in place (preferably using DET duration of seven days. strips), the Subject will be asked to stare straight ahead 10 without blinking until told otherwise. The test should be At the first screening visit, all eligible participants will performed in a room with no direct air on the patients cease taking their current artificial tears or lubricant drops face. for the duration of the study and will be provided unit dose 3. A stopwatch will be used to record the time between the unpreserved artificial tears to be taken if their dry eye last complete blink and the first appearance of a growing symptoms become intolerable. Empty unit dose vials will be 15 micelle indicating tear-film breakup. collected at each study visit and counted. Patients will be Note: If the patient blinks prematurely prior to the devel instructed not to use artificial tears within 30 minutes of opment of the breakup of the mires, the examiner nasal drug administration or within 2 hours of a study visit. should continue to try to obtain a reading. At the second screening visit/Study Day 0, all eligible 4. Once TFBUT is observed, instruct patient to blink freely. participants will be tested for their response two nasal This test should then be repeated a second time on the formulations: OC-04 and a vehicle control. Tear production same eye. will be assessed immediately prior and after delivery of each 5. If the difference between the first and second readings intranasal dose using the Jones Schirmer Test in both eyes. differs by more than two seconds, a third measurement The order that each patient receives the OC-04 and vehicle should be performed and recorded. formulation will be randomly assigned, and both the patient 25 6. This procedure will then be performed in the other eye. and examiner will be masked to the identity of the nasal 7. It is recommended that TFBUT be performed in a room formulation. At least 90 minutes following the tear produc with a temperature of approximately 18 C with a humidity tion assessment, change in Symptoms in response to delivery of approximately 50%. of each of the two nasal formulations will be assessed. The Ocular Surface Staining Conjunctival Staining Using Lis symptom assessment will be performed using a well-estab 30 samine Green lished environmental challenge model, the ClimaTears Ocular Surface staining assessment will be completed Goggle System manufactured by Biocentric Developments, with lissamine green conjunctival staining. LLC. 1. The lissamine green ophthalmic strip should be wetted After testing on Day 0, all patients will receive a bottle of with buffered saline and applied to the inferior tarsal OC-04 to take home and self-administer once daily from 35 conjunctiva. Care should be taken to instill adequate dye. Day 1 and Day 6. On Day 7, patients will return to the clinic 2. After allowing lissamine green to remain on the eye for where they will again be assessed for tear production and one minute, the six nasal and temporal conjunctival symptoms with administration of each nasal formulation. regions will be graded. Tear Assessments 3. To grade the temporal Zone, the subject should be The following ocular Surface and tear film assessments 40 instructed to look nasally, to grade the nasal Zone, the will be performed in the order shown: subject should be instructed to look temporally. Ocular Surface Staining Corneal Staining Using Fluores 4. This procedure should then be completed in the other eye. CC1 Schirmer Test Ocular Surface staining using fluorescein and lissamine At screening visit #1, one basal Jones Schirmer test will green will be assessed and recorded in the schematic rep 45 be performed followed by a Schirmer test with cotton Swab resentation of 5 corneal and 6 conjunctival regions per eye nasal stimulation. The Jones Schirmer test with topical on the case report form using the National Eye Institute anesthetic will be used to assess tear production using the grading system. A pictorial and descriptive grading scale following steps: (grades 0 to 3) are included on the case report form (CRF). 1. Topical anesthetic drops such as 0.5% proparacaine 1. Corneal staining should be assessed using 1.0 mg Sodium 50 hydrochloride or equivalent should be instilled in both fluorescein strips. eyes of the patient. 2. After wetting the end of the strip with a single drop of 2. The patient will be instructed to keep the eyes gently buffered saline, the excess is shaken into a waste bin with closed for one minute. a sharp flick. 3. After opening the eyes and allowing the eyes to recover 3. The lower lid is then pulled down and the flat end of the 55 for approximately one additional minute, excess moisture tip should be gently applied to the inferior tarsal conjunc in the inferior fornix is gently removed with a cotton tiva with the intent of instilling a very small volume of tipped applicator. dye and not inducing reflex tearing. 4. Schirmer strips (35 mmx5 mm size filter paper strip) will 4. The patient will be instructed to blink naturally several be placed in each eye at the junction of the middle and times without forced closure of the eyelid to distribute the 60 lateral thirds of the lower eye lid. fluorescein. 5. Under ambient light, the patient will be instructed to look 5. After allowing fluorescein to remain on the eye for at least forward and to blink normally during the course of the one minute, the 5 corneal regions will be graded using a test. The test should be performed in a room with no direct yellow (Wratten #12) barrier filter in conjunction with the air on the patient’s face. cobalt (blue) filter to maximize the view of the fluores 65 6. After five minutes, strips will be removed from both eyes cence. The upper eyelid is lifted slightly to grade the and the amount of wetting will be recorded. The strips entire corneal Surface. To enhance the contrast, position should be taped to the CRF. Note: Should the Schirmer US 9,597,284 B2 111 112 score reach maximum prior to the 5 minute endpoint, the pain. Please rate the severity of your current “dryness” strip can be removed and the time it took to reach symptoms (and no others) by drawing a vertical line on the maximum recorded. However, the strip from the contral line below: ateral eye should not be removed until it too has reached maximum score prior to the 5 minute endpoint. 7. As multiple Schirmer tests are performed, new anesthetic drops should be added as necessary. Schirmer Test Using Cotton Swab Nasal Stimulation 1. At screening visit #1, the Schirmer test should be per O 1 2 3 4 5 formed using cotton swab nasal stimulation. With new 10 None Severe strips in place, the examiner should insert cotton Swabs in both participant’s nostrils simultaneously and gently probe both nasal middle turbinates for approximately 30 At Day 0, patients will begin wearing the goggles and be monitored until they reach a symptom score of 45 mm or seconds. After this, the examiner can simply hold the more for two consecutive measurements, at which time they Swabs in place, applying gentle pressure, and repeat 15 will randomly receive a dose of either OC-04 nasal spray or probing intermittently as necessary. the control nasal spray, administered 2.5 minutes after the 2. Alternatively, the participant can be instructed to hold the two consecutive 45 mm measurements. Symptoms will be cotton Swabs and gently probe both nasal turbinates continued to be monitored until the patient again reaches a simultaneously, resting intermittently before probing score of 45 mm or higher for two consecutive measure again. The examiner should continuously coach the par ments, at which time the patient will receive a second nasal ticipant on how to perform this test properly. dose of which ever test article they did not receive the first 3. The Schirmer strips should remain in place until five time. After the second nasal dose, symptoms will be moni minutes have elapsed or they have reached maximum tored again until the patient reaches a score of a score of 45 SCO. mm or higher for two consecutive measurements. At that Both Schirmer scores will be recorded and verified that they 25 time, the goggles will be removed and the test will end. If meet the inclusion criteria. As two Schirmer tests are per still ongoing, the test will be terminated after 90 minutes of formed, new anesthetic drops should be instilled as neces exposure to the goggles environment. At the end of this Sary. period, each patient will be asked to decide which of the Schirmer Test with Each of Two Nasal Spray Applications nasal sprays made provided more relief of their dry eye With each of the two nasal applications, the Jones 30 symptoms. Schirmer test with topical anesthetic will be used to assess At Day 7, patients will begin wearing the goggles and be tear production using the following steps: monitored until they reach a symptom score of 45 mm or more for two consecutive measurements, at which time they 1. Topical anesthetic drops such as 0.5% proparacaine will receive a dose of the OC-04 nasal spray. Symptoms will hydrochloride or equivalent should be instilled in both continued to be monitored until the patient again reaches a eyes of the participant for each application. 35 score of 45 mm or higher for two consecutive measure 2. The participant will be instructed to keep the eyes gently ments, at which time the goggles will be removed and the closed for one minute. test will end. If still ongoing, the test will be terminated after 3. After opening the eyes and allowing the eyes to recover 90 minutes of exposure to the goggles environment. for approximately one additional minute, excess moisture Patients entering with a baseline symptoms score of more in the inferior fornix is gently removed with a spear. 40 than 45 mm will have a treatment threshold equal to this 4. Schirmer strips (35 mmx5 mm size filter paper strip) will baseline score, and will thus receive treatment after two be placed in each eye at the junction of the middle and consecutive symptoms measurements of greater than or lateral thirds of the lower eye lid. equal to this value. 5. Under ambient light, the participant will be instructed to The instructions (in bold above) will be read to the patient look forward and to blink normally during the course of 45 before the test begins, and before recording symptoms the test. The test should be performed in a room with no values immediately following the administration of either direct air on the participants face. nasal spray. 6. After five minutes, strips will be removed from both eyes Example 2 and the amount of wetting will be recorded. The strips should be taped to the CRF. 50 OC-01 Formulation Dry Eye Provocation and Symptom Assessment The ClimaTears Goggle System (Biocentric Develop OC-01 contains 0.1%. Varenicline in sterile phosphate ments, LLC) will be used to reduce periocular humidity and buffered saline (PBS) consisting of 137 mM sodium chlo induce symptoms of dry eye in patients. This system was ride, 2.7 mM potassium chloride and 10 mM phosphate designed for the purpose of standardizing testing conditions 55 buffer at pH 7.4 without preservatives. The formulation was for clinical studies of dry eye patients. packaged in a 20 mL opaque polyethylene nasal spray bottle Patients will wear the ClimaTears Goggles continuously that delivers a unit dose of 50 microliters. The vehicle for up to 90 min, with their symptoms recorded via the visual control was supplied in the identical packaging. Both OC-01 analog scale (VAS) every 5 minutes during the testing and vehicle are labeled with a code denoting the contents of period. The subject will be asked to rate their dryness 60 the package, which will not be known to the participants or symptoms (both eyes simultaneously) by placing a vertical masked study personnel. mark on the horizontal line to indicate the level of discom Example 3 fort. 0 corresponds to “no dryness” and 5 corresponds to “maximal dryness.” The assessment line length of the scale Additional Pharmaceutical Formulations will be 100 mm. There are many symptoms of dry eye, 65 including dryness, Sticky feeling, burning, foreign body To prepare pharmaceutical formulations suitable for sensation, itching, blurred vision, sensitivity to light, and administration intranasally, 10 mg of a nicotinic acetylcho US 9,597,284 B2 113 114 line receptor agonist is dissolved in 10 mL of a specified 4. The method of claim 1, wherein the agonist selectively vehicle. 1 mL of this solution is diluted in 9 mL of vehicle binds to the peripheral nicotinic acetylcholine receptor in an to afford a “0.1x dilution formulation. Following the first amount that does not result in undesired systemic side dilution, 1 mL of the '0.1x dilution' formulation is diluted effects. in 9 mL of vehicle to afford a "0.01 x dilution' formulation. 5. The method of claim 1, further comprising the local administration of one or more substances that prevent the The three formulations with varying concentrations of the entry or reduce the entry of the nicotinic acetylcholine nicotinic acetylcholine receptor agonist are stored at 4°C. receptor into the desensitized state, or facilitate the recovery While preferred embodiments of the present invention of the nicotinic acetylcholine receptor from the desensitized have been shown and described herein, it will be obvious to State. those skilled in the art that such embodiments are provided 10 6. The method of claim 5, wherein the one or more by way of example only. Numerous variations, changes, and substances are selected from protein kinase C (PKC) or substitutions will now occur to those skilled in the art factors that upregulate or up-modulate PKC. cAMP-depen without departing from the invention. It should be under dent protein kinase (PKA) or factors that upregulate or stood that various alternatives to the embodiments of the up-modulate PKA, and calcineurin inhibitors. invention described herein may be employed in practicing 15 7. The method of claim 6, wherein the calcineurin inhibi the invention. It is intended that the following claims define tor is selected from cyclosporine, pimecrolimus, and tacroli S. the scope of the invention and that methods and structures 8. The method of claim 1, wherein the nicotinic acetyl within the scope of these claims and their equivalents be choline receptor agonist is administered at least once daily. covered thereby. 9. The method of claim 1, wherein the nicotinic acetyl choline receptor agonist is administered at least twice daily. What is claimed is: 10. The method of claim 1, wherein the nicotinic acetyl 1. A method of treating dry eye, comprising the local choline receptor agonist is administered at least once administration of a therapeutically effective amount of a weekly. nicotinic acetylcholine receptor agonist into the nasal cavity 25 11. The method of claim 1, wherein the nicotinic acetyl of an individual in need thereof, wherein the agonist selec choline receptoragonist is administered into the nasal cavity tively binds to the peripheral nicotinic acetylcholine recep as a liquid, Suspension, aerosol, gel, ointment, dry powder, tor, is administered in a non-systemically bioavailable dose cream, paste, lotion, or balm. between 5 micrograms and 50 micrograms per dose, and 12. The method of claim 1, wherein the nicotinic acetyl does not cross the blood-brain barrier in a pharmacologically 30 choline receptoragonist is administered into the nasal cavity relevant concentration; and wherein the nicotinic acetylcho by a syringe, dropper, bottle nebulizer, atomization pump, line receptor agonist is Varenicline. inhaler, powder spray device, vaporizer, patch, medicated 2. The method of claim 1, wherein the agonist selectively Stick, pipette, or jet of liquid. binds to at least one of the peripheral nicotinic acetylcholine 13. The method of claim 1, wherein the trigeminal nerve receptor subtypes selected from alpha3beta4, alpha-4-beta2. is activated. and alpha7. 35 14. The method of claim 13, wherein the anterior ethmoi 3. The method of claim 1, wherein the agonist selectively dal nerve is activated. binds to the peripheral nicotinic acetylcholine receptor in an 15. The method of claim 1, wherein the nasolacrimal amount that does not result in undesired psychoactive side reflex is activated. effects.