TW202019424A - Methods of treating ocular conditions - Google Patents

Abstract

Described herein are methods of treating dry eye disease, increasing tear production, or reducing ocular discomfort in an individual with compound 1 having the structure

Description

Treatment of eye symptoms

The present invention provided herein relates to a method for treating dry eye disease, increasing tear production, or reducing eye discomfort in individuals with nicotinic acetylcholine receptor (nAChR) agonists.

An estimated 16 million American adults have been diagnosed with dry eye disease, a multifactorial, age-related ocular surface condition characterized by tear film destruction. Healthy tear film protects and lubricates the eyes and flushes away foreign particles, contains antimicrobial agents that reduce the risk of infection, and produces a smooth surface that helps refraction to make vision clear.

Dry eye disease can have a significant impact on an individual's quality of daily life because it can cause persistent tingling, scratching, burning sensation, light sensitivity, blurred vision, and eye fatigue. Dry eye disease can also cause severe pain, visual impairment, high osmotic pressure and instability of the tear film, inflammation and corneal injury. Dry eye disease can be characterized by a loss of tear film homeostasis. Although the prevalence of dry eye is difficult to report due to different definitions and diagnostic criteria, it is estimated that 5% to 35% of the global population over 50 years of age suffer from this condition (2007). In the United States (US), it is estimated that as many as 3.2 million women and 1.7 million men (over 50 years old) have dry eyes, and the number of affected patients is expected to increase by 40% by 2030.

Medical treatment options for dry eye include: artificial tear replacements, ointments, gels, hot compresses, environmental changes, topical cyclosporine (Restasis ^® ), lifitegrast (Xiidra ^® ) and omega-3 fatty acid supplements . None of these options provide substantial efficacy for most groups and all have poor patient compliance due to side effects, i.e. stinging/burning and poor taste after instillation (dysgeusia).

A variety of medical device options that can be used for the treatment of dry eye include: punctal plugs, wet air goggles, and vector hot eyelid pulsation (Lipiflow ^® ). Recently, TrueTear ^™ (an intranasal nerve stimulator) has been approved for the treatment of dry eye disease. The device is designed to increase tear production via a controlled current that stimulates the nasolacrimal reflex path.

Regardless of the prevalence of dry eye and disease burden, there is still a significant unmet need for effective treatment. In addition, there is a need for effective treatments that increase tear production and reduce eye discomfort.

， 或其醫藥學上可接受之鹽。The present invention relates to nicotinic acetylcholine receptor (nAChR) agonists that affect the parasympathetic nervous system. The trigeminal nerve provides parasympathetic control for the glands and cells that produce the natural tear film of the eye. In one aspect, the present invention provides a method for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual, which promotes natural tear film production by stimulating the trigeminal parasympathetic pathway. The description of the present invention includes the delivery of nAChR agonists to the trigeminal nerve through the nasal cavity, and methods for effectively treating dry eye disease, increasing tear production, or reducing eye discomfort for individuals. The nAChR agonist in the method described herein is Compound 1 with the following structure:

, Or a pharmaceutically acceptable salt thereof.

Provided herein is a method for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual, which comprises administering an effective amount of a first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of an individual in need And one or more subsequent doses as appropriate; where the method results in effective treatment of the individual in need.

The present invention provides an immediate and immediate use of nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors or combinations thereof in individuals in need A method of long-term pharmacological stimulation, which comprises administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of an individual in need, and optionally selecting one or more subsequent doses.

The present invention provides a compound for a method for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method includes An effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered into the nasal cavity of an individual, and one or more subsequent doses are selected as appropriate.

The present invention provides an immediate and long-term pharmacology for nicotinic acetylcholine α4β2 receptor, nicotinic acetylcholine α3β4 receptor, nicotinic acetylcholine α3α5β4 receptor or a combination thereof in an individual in need Compound of the method of chemical stimulation, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method comprises administering an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of an individual in need The first dose, and one or more subsequent doses as appropriate.

The present invention provides the use of a nicotinic acetylcholine receptor agonist, which is used in the manufacture of a medicament, wherein the medicament is used to treat dry eye disease, increase tear production, or reduce eye discomfort for an individual in need. The choline receptor agonist is Compound 1 or a pharmaceutically acceptable salt thereof.

The present invention provides the use of a nicotinic acetylcholine receptor agonist, which is used in the manufacture of medicines, wherein the medicine is used for the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or The nicotinic acetylcholine α3α5β4 receptor or a combination thereof undergoes immediate and long-term pharmacological stimulation, wherein the nicotinic acetylcholine receptor agonist is Compound 1 or a pharmaceutically acceptable salt thereof, and the method includes An effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered into the nasal cavity of the individual in need, and one or more subsequent doses are selected as appropriate.

The present invention provides a pharmaceutical formulation for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need. The formulation includes Compound 1 or a pharmaceutically acceptable salt thereof.

The present invention provides a pharmaceutical formulation for use in nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors in individuals in need or In a method for immediate and long-term pharmacological stimulation of the combination, the formulation contains Compound 1 or a pharmaceutically acceptable salt thereof.

The present invention provides a pharmaceutical formulation for use in nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors in individuals in need, Or a method for immediate and long-term pharmacological stimulation of the nicotinic acetylcholine α4α6β2 receptor or a combination thereof, the formulation contains Compound 1 or a pharmaceutically acceptable salt thereof.

Cross-reference of related applications

This application claims U.S. Provisional Application No. 62/696,310 filed on July 10, 2018; No. 62/773,996 filed on November 30, 2018; and No. 62/814,762 filed on March 6, 2019 The contents of the rights and interests are incorporated into this article by citation.

The present invention provides a method to improve or reconstruct the tear film homeostasis. In some embodiments, individuals in need do not have tear film homeostasis.

This article provides a method for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual. In some embodiments described herein, eye discomfort is associated with contact lens intolerance. In some embodiments described herein, individuals in need have discomfort when wearing contact lenses. In some embodiments described herein, the method includes improving tear film homeostasis. In some embodiments described herein, the method includes reconstructing tear film homeostasis. In some embodiments described herein, the individual in need does not have tear film homeostasis or tear film homeostasis is impaired.

， 或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量；其中該方法造成有效治療該有需要之個體。在本文所述之一些實施例中，增加有需要之個體之淚液產生之方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量，及視情況選用之一或多個後續劑量；其中該方法造成有效治療該有需要之個體。在本文所述之一些實施例中，減少有需要之個體之眼部不適之方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量，及視情況選用之一或多個後續劑量；其中該方法造成有效治療該有需要之個體。In some embodiments described herein, a method of treating dry eye disease in an individual in need comprises administering an effective amount of Compound 1 having the following structure to the nasal cavity of an individual in need

, Or the first dose of its pharmaceutically acceptable salt and one or more subsequent doses as appropriate; where the method results in effective treatment of the individual in need. In some embodiments described herein, the method of increasing tear production in an individual in need comprises administering an effective amount of a first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of an individual in need, And one or more subsequent doses as appropriate; where the method results in effective treatment of the individual in need. In some embodiments described herein, a method of reducing eye discomfort in an individual in need includes administering an effective amount of a first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of an individual in need , And choose one or more subsequent doses as appropriate; where the method results in effective treatment of the individual in need.

Compound 1 patent related information can be found in US Patent 7,098,331, US Patent 7,714,001, US Patent 8,063,068, US Patent 8,067,443, US Patent 8,604,191, US Patent 9,145,396, US Patent 9,981,949, US Patent 8,633,222 and PCT Publication WO 2017/177024.

。Compound 1 as described herein refers to the following structure:

.

。化合物1亦可藉由其化學名稱提及。舉例而言，化合物1可稱為(R)-5-((E)-2-吡咯啶-3-基乙烯基)嘧啶，或其變化形式，包括5-{(E)-2-[(3R)-吡咯啶-3-基]乙烯基}嘧啶及(R,E)-5-((2-吡咯啶-3-基)乙烯基)嘧啶。The alternative structure of compound 1 is expressed as:

. Compound 1 can also be mentioned by its chemical name. For example, Compound 1 may be referred to as (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or variations thereof, including 5-{(E)-2-[( 3R)-pyrrolidin-3-yl]vinyl}pyrimidine and (R,E)-5-((2-pyrrolidin-3-yl)vinyl)pyrimidine.

The present invention provides a compound for a method for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method includes An effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered into the nasal cavity of an individual, and one or more subsequent doses are selected as appropriate. In some embodiments described herein, the present invention provides a compound for a method for treating dry eye disease in an individual in need thereof, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method comprises An effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered into the nasal cavity of the individual in need, and one or more subsequent doses are selected as appropriate. In some embodiments described herein, the present invention provides a compound for a method for increasing tear production in an individual in need thereof, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method comprises An effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered into the nasal cavity of the individual in need, and one or more subsequent doses are selected as appropriate. In some embodiments described herein, the present invention provides a compound for a method for reducing eye discomfort in an individual in need thereof, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method includes An effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof is administered into the nasal cavity of an individual in need, and one or more subsequent doses are selected as appropriate. In some embodiments described herein, the method results in effective treatment of the individual in need.

The severity of dry eye disease can be evaluated by one of the following series of basic tests: dry eye score test according to visual analog scale, Schirmer's test, corneal fluorescein stain test, and eye surface disease index test. These tests can also be used to assess an individual's tearfulness or eye discomfort. Tests well known in the art are also covered, such as tear film rupture time test.

In some embodiments described herein, the effective treatment of the individual is indicated by one or more tests selected from the group consisting of: a) dry eye scoring test according to the visual analog scale, b) Sgormer test, c ) Corneal luciferin staining test, and d) Eye surface disease index test. In some embodiments described herein, the effective treatment of the individual is indicated by a dry eye score test and a Sgormer test based at least on the visual analog scale. In some embodiments described herein, the effective treatment of the individual is indicated by at least a dry eye score test, a Sgormer test, and an ocular surface disease index test according to a visual analog scale. In some embodiments described herein, effective treatment of an individual is indicated by at least a dry eye score test according to a visual analogue scale, a Sgormer test, an ocular surface disease index test, and a corneal fluorescein stain test. In some embodiments described herein, the corneal fluorescein staining test is based on the National Eye Institute (NEI) grading system.

The nicotinic acetylcholine receptor may be interchangeably referred to as nAChR throughout the present invention. nAChR is a type of pentameric ligand-gated ion channel that has high affinity and selectivity for both nicotine and acetylcholine and includes a combination of alpha and beta subunits. Specific nAChR subtypes may include α4β2 nicotinic receptors, α3β4 nicotinic receptors, α3α5β4 nicotinic receptors, and α4α6β2 nicotinic receptors.

The "α7" mentioned in this article refers to the homopolymeric α7 subtype, in which the pentameric subunit of nAChR is composed entirely of α7 subunits. Therefore, nAChR agonists that bind and activate nAChR α7 are agonists that bind and activate nAChR homopolymeric α7 receptors. In some embodiments described herein, the nAChR agonist is not an α7 receptor agonist. In some embodiments described herein, the nAChR agonist is not a full α7 receptor agonist.

The nAChR agonist binds to nAChR and activates the receptor to produce related biological responses, such as increased or reduced tearing of eye discomfort or other biological responses to treat dry eye disease.

An nAChR agonist may be characterized as a full or partial agonist, as determined by its ability to activate the receptor to produce a response compared to the response to acetylcholine (ACh) at a given receptor. In general, an nAChR agonist is a full agonist if it induces a response equal to or greater than that of ACh after binding to a given receptor. An nAChR agonist is a partial agonist if it induces a lower response than the response produced by ACh after binding to the receptor.

Appropriate cell-based assays can be used, for example, to generate nAChR agonist responses that can measure receptor activation. Cells designed to exhibit specific nAChR receptor subtypes and generate electrical responses when bound to nAChR agonists and activated by nAChR agonists can be used to characterize compound agonist profiles and the amount of receptor activation thus determined . Examples of general schemes are described below.

Cells expressing specific human nAChR subtypes are first exposed to ACh. ACh binds and activates receptors, thereby inducing electrical current. The concentration of ACh is chosen to elicit the maximum response of the receptor (eg 1280 micromolar ACh). This current is recorded as an ACh reaction and acts as a 100% nAChR agonist response and is compared to reactions against other nAChR agonists. After washing, cells are exposed to nAChR agonists at various concentrations (eg, 0.1, 0.3, 1, 3, 10, 30, 100, and 300 micromolar). The current induced by nAChR agonist exposure was measured and recorded for each nAChR concentration. This nAChR agonist response data is then normalized to units of maximum ACh evoked current and plotted as a function of logarithm of nAChR agonist concentration. The nAChR agonist response is then calculated as the percentage of ACh response.

In some cases, the method of determining the relative agonistic activity of an nAChR agonist includes conditions in which the ACh response is induced from 1 or more millimolar ACh solutions.

An nAChR agonist that induces a response equal to or greater than the maximum ACh response measured at the same receptor type is a full agonist. In some cases, considering experimental variability, nAChR agonists that elicit responses that are less than 100% ACh responses may still be characterized as full agonists. For example, the variability and statistical errors between test or measurement methods may explain the difference in response results. In some cases, nAChR agonists that induce 80% to 120% of the ACh response are considered to be full agonists. In some cases, nAChR agonists that induce 99% or greater ACh responses are considered to be full agonists. In some cases, nAChR agonists that induce 95% or greater ACh responses are considered full agonists. In some cases, nAChR agonists that induce 90% or more of the ACh response are considered full agonists. In some cases, nAChR agonists that induce an ACh response of 85% or more are considered to be full agonists. In some cases, nAChR agonists that induce an ACh response of 80% or more are considered to be full agonists.

Considering the experimental variability, if the nAChR agonist induces an ACh response of less than 100%, the agonist is generally regarded as a partial agonist. In some cases, nAChR agonists that induce less than 95% of ACh responses are considered partial agonists. In some cases, nAChR agonists that induce less than 90% of the ACh response are considered partial agonists. In some cases, nAChR agonists that induce an ACh response of less than 85% are considered partial agonists. In some cases, nAChR agonists that induce less than 80% of the ACh response are considered partial agonists.

In some cases, nAChR agonists that induce 5% to 95% of ACh responses are considered partial agonists. In some cases, nAChR agonists that induce 5% to 90% of the ACh response are considered partial agonists. In some cases, nAChR agonists that induce 5% to 85% of ACh responses are considered partial agonists. In some cases, nAChR agonists that induce 5% to 80% of the ACh response are considered partial agonists.

In some cases, nAChR agonists that induce 10% to 95% of ACh responses are considered partial agonists. In some cases, nAChR agonists that induce 10% to 90% of the ACh response are considered partial agonists. In some cases, nAChR agonists that induce 10% to 85% of ACh responses are considered partial agonists. In some cases, nAChR agonists that induce 10% to 80% of ACh responses are considered partial agonists.

NAChR agonists that produce low levels of electrical activity at relatively high agonist concentrations can be described as weak partial agonists. In some cases, nAChR agonists that induce ACh responses of 30% or less are considered weak partial agonists. In some cases, nAChR agonists that induce an ACh response of less than 25% or less are considered weak partial agonists. In some cases, nAChR agonists that induce ACh responses of 20% or less are considered weak partial agonists. In some cases, the relatively high nAChR agonist concentration is at least 100 micromolar. In some cases, the relatively high nAChR agonist concentration is at least 200 micromolar. In some cases, the relatively high nAChR agonist concentration is at least 300 micromolar or greater. For example, an nAChR agonist with a concentration of 300 micromolar that induces a 25% maximum Ach evoked current is considered a weak partial agonist.

In some embodiments, the nAChR agonist is a full agonist. In some embodiments, the nAChR agonist is a partial agonist. In some embodiments, the nAChR agonist is a weak partial agonist.

Compound 1 is a complete agonist of nAChR subtypes α4β2, α3β4, α3α5β4 and α4α6β2.

Compound 1 is a partial agonist of subtype α3β2.

Compound 1 is a weak partial agonist of subtype α7. In one example, Compound 1 citrate at a concentration of 300 micromolar induced only 25% of the maximum ACh evoked current.

In some embodiments described herein, the nAChR agonist or a pharmaceutically acceptable salt thereof may be Compound 1 or a pharmaceutically acceptable salt thereof.

The present invention provides a method for nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine in individuals in need A method for immediate and long-term pharmacological stimulation of choline α4α6β2 receptor or a combination thereof. The present invention provides an immediate and immediate use of nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors or combinations thereof in individuals in need Method of long-term pharmacological stimulation. In some embodiments described herein, the method comprises administering to the nasal cavity of an individual in need an effective amount of a first dose of Compound 1 or a pharmaceutically acceptable salt thereof, and optionally one or more Subsequent doses.

The present invention provides an immediate and immediate use of nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors or combinations thereof in individuals in need A compound of a method of long-term pharmacological stimulation, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method comprises administering an effective amount of Compound 1 or a pharmaceutically acceptable salt to the nasal cavity of an individual in need The first dose of salt, and one or more subsequent doses as appropriate.

The present invention provides a compound for the use of nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or tobacco Alkaline acetylcholine α4α6β2 receptor or a combination thereof for immediate and long-term pharmacological stimulation, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method includes administering to the nasal cavity of an individual in need A first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, and optionally one or more subsequent doses.

In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual The stimulation is indicated by one or more tests selected from the group consisting of: a) dry eye scoring test according to the visual analog scale, b) Sgormer test, c) corneal luciferin staining test, and d) eye surface Disease index test. In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual Stimulation is indicated by the dry eye score test according to the visual analog scale. In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual The stimulus is indicated by the Gomer test. In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual The stimulation is indicated by the corneal luciferin staining test. In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual The irritation is indicated by the eye surface disease index test.

In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by one or more tests selected from the group consisting of: a) dry eye score test according to the visual analog scale, b) Sgormer test, c) cornea Fluorescein staining test, and d) Eye surface disease index test. In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by the dry eye score test according to the visual analog scale. In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by the Gomer test. In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of choline α4α6β2 receptor or a combination thereof is indicated by corneal fluorescein staining test. In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of choline α4α6β2 receptor or its combination is indicated by the ocular surface disease index test.

In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof selectively stimulates the nicotinic acetylcholine α4β2 receptor. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof selectively stimulates the nicotinic acetylcholine α3β4 receptor. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof selectively stimulates the nicotinic acetylcholine α3α5β4 receptor. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof selectively stimulates the nicotinic acetylcholine α4α6β2 receptor. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is a dual agonist and stimulates the nicotinic acetylcholine α4β2 receptor and the nicotinic acetylcholine α3β4 receptor. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is a dual agonist and stimulates the nicotinic acetylcholine α4β2 receptor and the nicotinic acetylcholine α3α5β4 receptor. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is a dual agonist and stimulates the nicotinic acetylcholine α3β4 receptor and the nicotinic acetylcholine α3α5β4 receptor. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is a dual agonist and stimulates the nicotinic acetylcholine α4β2 receptor and the nicotinic acetylcholine α4α6β2 receptor. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is a dual agonist and stimulates the nicotinic acetylcholine α3β4 receptor and the nicotinic acetylcholine α4α6β2 receptor. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is a dual agonist and stimulates the nicotinic acetylcholine α3α5β4 receptor and the nicotinic acetylcholine α4α6β2 receptor. In some embodiments described herein, the nicotinic acetylcholine receptor is a peripheral nicotinic acetylcholine receptor.

Subsequent chapters provide additional details about the Dry Eye Scoring Test, Sgormer Test, Corneal Luciferin Staining Test, and Ocular Surface Disease Index Test according to the Visual Analogue Scale. Dry eye score test

The dry eye score test according to the visual analog scale can be used to assess an individual's dry eye disease, tearing volume, or eye discomfort. The test involves the use of a visual analog scale and contains a 100 mm horizontal line, where one end point at 0 is marked as "no discomfort" and the other end point at 100 is marked as "maximum discomfort". Figure 11 shows an example of a visual analog scale. Individuals are required to rate their eye symptoms caused by dry eyes by placing a vertical marker on a horizontal line to indicate their level of discomfort. The dry eye score is then obtained by identifying where the individual's response is on a 100 mm scale. For example, individuals can be asked about their discomfort level with respect to dry eyes. The individual then self-assessed and indicated their level of discomfort on the visual analogue scale. This number can be used by clinicians to determine the individual's dry eye score.

The dry eye score (measured in mm) can be used to assess the severity of eye symptoms and the effectiveness of specific treatments in the individual. This test has the advantage of being administered to the individual every 5 minutes, which allows the test administrator to closely monitor the individual's symptoms over time. Compared to a lower number indicating a relatively lower level of discomfort, a higher number indicates that the eye symptoms are more uncomfortable. The decrease in dry eye score over time demonstrates the reduction or relief of eye symptoms and generally indicates an improvement in the individual's condition. A decrease in dry eye score proves that the treatment is effective in treating dry eye disease, increasing tear production, or improving eye discomfort.

In some of the embodiments described, effective treatment is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is when the individual is administered an effective amount of Compound 1 or The first dose of a pharmaceutically acceptable salt, or one or more subsequent doses as appropriate, are determined and the dry eye score of the individual is compared to a) after administration of Compound 1 or its pharmaceutically acceptable The dry eye score of the individual before the first dose of saline; b) the dry eye score of the individual who received the control; or c) the dry eye score of the individual who received the comparative compound.

In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual Irritation is indicated by a statistically significant decrease in the individual's dry eye score, and the statistically significant decrease in the individual's dry eye score is the first to administer an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof to the individual The dose or one or more subsequent doses are selected after the determination, and the individual's dry eye score is compared to a) the individual's dryness before administration of the first dose of Compound 1 or its pharmaceutically acceptable salt Eye score; b) dry eye score of the individual receiving the control; or c) dry eye score of the individual receiving the comparative compound.

In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is when administering an effective amount of Compound 1 to the individual or The first dose of the pharmaceutically acceptable salt or one or more subsequent doses are optionally determined after the determination, and the individual's dry eye score is compared to a) after administration of Compound 1 or its pharmacologically acceptable The dry eye score of the individual before the first dose of salt received; b) the dry eye score of the individual who received the control; or c) the dry eye score of the individual who received the comparative compound.

In some embodiments described herein, the individual's dry eye score is compared to the individual's dry eye score prior to administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments described herein, the dry eye score of the individual is compared to the dry eye score of the individual receiving the control. In some of the embodiments described herein, the dry eye score of the individual is compared to the dry eye score of the individual receiving the comparative compound.

In some embodiments described herein, the individual's dry eye score is statistically significantly reduced by at least 5%, 10%, 15%, 20%, 25%, 50%, 75%, 80%, 90%, 95% , 100%, 125%, 150%, 200%, 250%, 300% or 350%.

In some embodiments described herein, the individual's dry eye score is statistically significantly reduced by at least 3 mm, at least 5 mm, at least 10 mm, at least 15 mm, at least 20 mm, at least 25 mm, at least 30 mm, at least 35 mm, at least 40 mm, at least 45 mm, or at least 50 mm.

In some embodiments described herein, the individual's dry eye score is statistically significantly reduced between 3 mm and 10 mm, between 3 mm and 20 mm, between 3 mm and 25 mm, between 3 mm and Between 30 mm, between 3 mm and 35 mm, between 3 mm and 40 mm, between 3 mm and 45 mm, between 3 mm and 50 mm, between 5 mm and 10 mm, Between 5 mm and 20 mm, between 5 mm and 25 mm, between 5 mm and 30 mm, between 5 mm and 35 mm, between 5 mm and 40 mm, between 5 mm and 45 between mm, between 5 mm and 50 mm, between 10 mm and 15 mm, between 10 mm and 20 mm, between 10 mm and 25 mm, between 10 mm and 30 mm, at Between 10 mm and 35 mm, between 10 mm and 40 mm, between 10 mm and 45 mm, between 10 mm and 50 mm, between 15 mm and 20 mm, between 20 mm and 30 mm Between, between 25 mm and 35 mm, between 30 mm and 40 mm, between 30 mm and 45 mm or between 30 mm and 50 mm.

In some embodiments described herein, the statistically significant decrease in the individual's dry eye score is characterized by a p-value of 0.05 or less, 0.01 or less, 0.005 or less, or 0.001 or less.

In some embodiments described herein, the statistically significant decrease in the individual's dry eye score is within 5 minutes, 10 minutes of administering the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof , Within 15 minutes, within 20 minutes, within 30 minutes, within 45 minutes, or within 60 minutes. In some of the embodiments described herein, the statistically significant decrease in the individual's dry eye score is immediate.

In some embodiments described herein, the statistically significant decrease in the individual's dry eye score has been maintained at 10% for at least 30 minutes since the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof was administered .

In some embodiments described herein, between measuring the individual's dry eye score, the individual is present in an environment with reduced humidity. In some embodiments described herein, between measuring the individual's dry eye score, the individual is present in an environment with reduced humidity and a temperature below or above room temperature. Sgomer score test

Dry eye disease affects tear volume and tear production. The Gomer test can be used to assess tear production and the severity of dry eye disease, insufficient tearing, or eye discomfort in an individual. This test measures the amount of tears produced by one or both eyes. This test usually involves first placing the anesthetic in one or both eyes of the individual. These drops prevent the eyes from weeping in response to the test strip. Next, the test administrator placed a piece of filter paper inside the lower eyelid and the individual closed their eyes. After 5 minutes, the test administrator removed the filter paper and evaluated how far the tears traveled on the paper.

In general, the smaller the amount of water on the paper, the less tears the individual produces. In healthy eyes, each paper strip usually contains more than 10 mm of water. A Stommer score of less than 10 mm of water can indicate one or more of the following conditions: including dry eye disease, abnormally low tear volume, or eye discomfort.

The Gomer test can be used to assess the effectiveness of a particular treatment in an individual and can be administered multiple times to monitor any change in the severity of an individual's symptoms over a period of time. An increase in the Stommer score in individuals who treat dry eye disease, insufficient tearing, or eye discomfort demonstrates an increase in tear volume or tear production and generally indicates an improvement in the individual's condition. The increase in Sgormer score over time proves that the treatment is effective for treating dry eye disease, increasing tear production, or improving eye discomfort.

In some embodiments described herein, the effective treatment is indicated by a statistically significant increase in the individual's Sgormer score, and wherein the statistically significant increase in the individual's Sgormer score is in administering an effective amount of the compound to the individual The first dose of 1 or its pharmaceutically acceptable salt or one or more subsequent doses are selected after the determination, and the individual’s Sgormer score is compared to a) after administration of Compound 1 or its medicine The Sgomer score of the individual before the first dose of the academically acceptable salt; b) the Sgormer score of the individual receiving the control; or c) the Sgormer score of the individual receiving the comparative compound.

In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual Stimulation is indicated by a statistically significant increase in the individual's Sgormer score, and wherein the statistically significant increase in the individual's Sgormer score is when an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered to the individual The first dose or one or more subsequent doses are selected after the determination, and the individual's Sgormer score is compared to a) before administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof Sgormer score for an individual; b) Sgormer score for an individual receiving a control; or c) Sgormer score for an individual receiving a comparative compound.

In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by a statistically significant increase in the individual's Sgormer score, and wherein the statistically significant increase in the individual's Sgormer score is the administration of an effective amount of the compound to the individual The first dose of 1 or its pharmaceutically acceptable salt or one or more subsequent doses are selected after the determination, and the individual’s Sgormer score is compared to a) after administration of Compound 1 or its medicine The Sgomer score of the individual before the first dose of the academically acceptable salt; b) the Sgormer score of the individual receiving the control; or c) the Sgormer score of the individual receiving the comparative compound.

In some embodiments described herein, the individual's Sgormer score is compared to the individual's Sgormer score prior to administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments described herein, the Sgormer score of an individual is compared to the Sgormer score of an individual receiving a control. In some embodiments described herein, the individual's Sgormer score is compared to the Sgormer score of the individual receiving the administered compound.

In some embodiments described herein, the individual's Sgormer score is statistically significantly increased by at least 5%, 10%, 15%, 20%, 25%, 50%, 75%, 80%, 90%, 95 %, 100%, 125%, 150%, 200%, 250%, 300% or 350%. In some embodiments described herein, the increase in the individual's Sgormer score is at least 100%, 200%, or 300%.

In some embodiments described herein, the individual's Sgormer score is statistically significantly increased by at least 3 mm, at least 5 mm, at least 10 mm, at least 15 mm, at least 20 mm, at least 25 mm, at least 30 mm, at least 35 mm, at least 40 mm, at least 45 mm, or at least 50 mm.

In some of the embodiments described herein, the statistical increase in the individual’s Sgormer score is significantly between 3 mm and 5 mm, between 3 mm and 10 mm, between 3 mm and 15 mm, and between 3 between mm and 20 mm, between 3 mm and 25 mm, between 3 mm and 30 mm, between 5 mm and 10 mm, between 5 mm and 15 mm, between 5 mm and 20 mm Between, between 5 mm and 25 mm, between 5 mm and 30 mm, between 10 mm and 15 mm, between 10 mm and 20 mm, between 10 mm and 25 mm, between 10 mm With 30 mm, between 15 mm and 20 mm, between 15 mm and 25 mm, between 15 mm and 30 mm, between 20 mm and 25 mm or between 20 mm and 30 mm.

In some embodiments described herein, the statistically significant increase in the individual's Sgormer score is characterized by a p-value of 0.05 or less, 0.01 or less, 0.005 or less, or 0.001 or less.

In some embodiments described herein, the statistically significant increase in the individual's Sgormer score is within 5 minutes, 10 minutes of administering the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof Within, within 15 minutes, within 20 minutes, within 30 minutes, within 45 minutes, or within 60 minutes. In some embodiments described herein, the statistically significant increase in the individual's Sgormer score is immediate.

In some of the embodiments described herein, the individual is present in an environment with reduced humidity between the determination of the Sgormer score of the individual. In some embodiments described herein, between determining an individual's Sgormer score, the individual exists in an environment with reduced humidity and a temperature below or above room temperature. In some embodiments described herein, the reduced humidity at room temperature is less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. The room temperature is between 15°C (59°F) and 25°C (77°F).

In some embodiments described herein, administration of Compound 1 or a pharmaceutically acceptable salt thereof comprises an effective amount of a first dose of Compound 1 or a pharmaceutically acceptable salt thereof and one or more subsequent doses. One or more subsequent doses are administered after a period of time after the first dose. This period between the first dose and the next subsequent dose is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, or at least 8 hours. The period between the first dose and the next subsequent dose is between 1-3 hours, 2-4 hours, 3-6 hours or 4-8 hours. The period between one or more subsequent doses is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, or at least 8 hours. The period between one or more subsequent doses is between 1-3 hours, 2-4 hours, 3-6 hours, or 4-8 hours.

In some of the embodiments described herein, the individual's Sgormer score is statistically significantly increased after the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

In some of the embodiments described herein, where the statistically significant increase is based on the Sgomer score of the individual measured after administration of an effective amount of Compound 1 or one or more subsequent doses of its pharmaceutically acceptable salts . Corneal luciferin staining test

Corneal surface changes are associated with insufficient tear flow and excessive dryness, as well as dry eye disease and eye discomfort. Corneal surface changes may include the destruction of the mucin coating that protects the surface epithelial cells, and/or damage to the epithelial cell wall.

The corneal fluorescein staining test is a diagnostic test used to determine the health of the corneal surface and can indicate damaged areas on the corneal surface. The normal corneal surface does not absorb the water-soluble dye dripped into the tear film. However, the damaged epithelial cells allow the water-soluble dye to diffuse into the surface cells. Luciferin staining damaged epithelial cells can be observed on the surface of the cornea, indicating damage caused by drying on the surface of the cornea.

To administer the corneal luciferin staining test, luciferin is applied to one or both eyes. Let luciferin penetrate and stain the area between the surface cells. By this staining, inactivated cells and inactivated surface tissue bundles (filamentous fibers) can be observed. The test administrator then uses the developed corneal surface scoring system to rate the observed severity of damage. This scoring system is suitable for monitoring dry eye treatment over time. Figure 9 depicts the NEI/Industry Workshop scale used in the scoring system. Other equivalent standardized scoring systems can be used. The test administrator grades the damaged corneal surface area and calculates a corneal score that reflects the severity of damage to the corneal surface.

Test administrators can use corneal scores to assess the effectiveness of specific treatments in individuals. The test can be administered multiple times to monitor any changes in the severity of the individual's eye surface over a period of time. In general, a higher number indicates a greater damage to the corneal surface than a lower number, and a lower number indicates a lower level of damage to the corneal surface. The decrease in corneal score over time proves that the damage to the corneal surface is reduced. A decrease in corneal score generally indicates an improvement in the individual's condition. The decrease in corneal score over time also proves that the treatment is effective for treating dry eye disease, increasing tear production, or improving eye discomfort.

In some embodiments described herein, effective treatment is indicated by a statistically significant decrease in the individual's corneal score, and wherein the statistically significant decrease in the individual's corneal score is when an effective amount of Compound 1 or its medicine is administered to the individual The first dose of a scientifically acceptable salt or one or more subsequent doses as appropriate may be determined, and the individual's corneal score is compared to a) after administration of Compound 1 or a pharmaceutically acceptable salt thereof The corneal score of the individual before the first dose; b) the corneal score of the individual receiving the control; or c) the corneal score of the individual receiving the comparative compound. In some embodiments described herein, the corneal fluorescein staining test is based on the National Institute of Ophthalmology (NEI) grading system.

In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual Irritation is indicated by a statistically significant decrease in the individual's corneal score, and wherein the statistically significant decrease in the individual's corneal score is the first dose or an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof administered to the individual Choose one or more subsequent doses as appropriate, and determine after the individual’s corneal score is compared to a) the individual’s corneal score before administration of the first dose of Compound 1 or its pharmaceutically acceptable salt; b ) The corneal score of the individual receiving the control; or c) the corneal score of the individual receiving the comparative compound.

In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's corneal score, and wherein the statistically significant decrease in the individual's corneal score is when an effective amount of Compound 1 or its medicine is administered to the individual The first dose of a scientifically acceptable salt or one or more subsequent doses as appropriate may be determined, and the individual's corneal score is compared to a) after administration of Compound 1 or a pharmaceutically acceptable salt thereof The corneal score of the individual before the first dose; b) the corneal score of the individual receiving the control; or c) the corneal score of the individual receiving the comparative compound.

In some embodiments described herein, the individual's corneal score is compared to the individual's corneal score prior to administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments described herein, the corneal score of the individual is compared to the corneal score of the individual receiving the control. In some embodiments described herein, the individual's corneal score is compared to the corneal score of the individual receiving the administration of the comparative compound.

In some embodiments described herein, the individual's corneal score is statistically significantly reduced by at least 5%, 10%, 15%, 20%, 25%, 50%, 75%, 80%, 90%, 95% or 100.

In some embodiments described herein, the statistically significant drop in the individual's corneal score is characterized by a p-value of 0.05 or less, 0.01 or less, 0.005 or less, or 0.001 or less.

In some of the embodiments described herein, the statistically significant decrease in the individual's corneal score is within 5 minutes, within 10 minutes of administering the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, Within 15 minutes, within 20 minutes, within 30 minutes, within 45 minutes, or within 60 minutes. In some embodiments described herein, the statistically significant decrease in the individual's corneal score is immediate.

In some of the embodiments described herein, between measuring the individual's corneal score, the individual is present in an environment with reduced humidity. In some embodiments described herein, between measuring an individual's corneal score, the individual exists in an environment with reduced humidity and a temperature below or above room temperature. In some embodiments described herein, the reduced humidity at room temperature is less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. The room temperature is between 15°C (59°F) and 25°C (77°F).

In some embodiments described herein, administration of Compound 1 or a pharmaceutically acceptable salt thereof comprises an effective amount of a first dose of Compound 1 or a pharmaceutically acceptable salt thereof and one or more subsequent doses. One or more subsequent doses are administered after a period of time after the first dose. This period between the first dose and the next subsequent dose is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, or at least 8 hours. The period between the first dose and the next subsequent dose is between 1-3 hours, 2-4 hours, 3-6 hours or 4-8 hours. The period between one or more subsequent doses is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, or at least 8 hours. The period between one or more subsequent doses is between 1-3 hours, 2-4 hours, 3-6 hours, or 4-8 hours.

In some embodiments described herein, the statistically significant decrease in the individual's corneal score is based on the individual's corneal score determined after administration of an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof.

In some of the embodiments described herein, where the statistically significant decrease is based on the corneal score of the individual determined after subsequent administration of an effective amount of Compound 1 or one or more of its pharmaceutically acceptable salts. Ocular surface disease index test

Individuals who treat dry eye disease, increase tear production, or improve eye discomfort can provide important information for diagnosing their condition and measuring the severity of dry eye symptoms (via questionnaire). A carefully designed questionnaire confirms reproducibility and should consist of relevant questions that trigger responsive answers. An example of a dry eye questionnaire is the Ocular Surface Disease Index (OSDI), which is a survey of 12 questions for dry eye patients and has been shown to be a reliable and effective tool for directly assessing the frequency of symptoms. The eye symptoms evaluated included burning/tingling, itching, foreign body sensation, eye discomfort, dry eyes, photophobia, and pain. Most people are familiar with the questionnaire and understand that it is an efficient way for health providers to collect information. The questionnaire also reduces deviations because no words or visual cues unintentionally affect the respondents. An example of the OSDI questionnaire is shown in Figure 10. The test administrator collects responses from individuals and calculates OSDI based on the individuals' answers to questions.

The OSDI score can be used to assess the severity of ocular symptoms and the effectiveness of individual specific treatments. A higher number indicates a higher severity of dry eye disease. The decrease in OSDI score over time demonstrates the reduction or remission of ocular symptoms and generally indicates an improvement in the individual's condition. The decreased OSDI score also proves that the treatment is effective in treating dry eye disease, increasing tear production, or improving eye discomfort.

In some of the embodiments described, effective treatment is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the statistically significant decrease in the individual's OSDI score is when an effective amount of Compound 1 or its pharmacy is administered to the individual The first dose of the acceptable salt, or one or more subsequent doses as appropriate, is determined, and the individual’s OSDI score is compared to a) after administration of Compound 1 or its pharmaceutically acceptable salt The OSDI score of the individual before the first dose; b) the OSDI score of the individual who received the control; or c) the OSDI score of the individual who received the comparative compound.

In some embodiments described herein, the pharmacology of the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof in the individual Stimulation is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the statistically significant decrease in the individual's OSDI score is the first dose or an effective amount of Compound 1 or its pharmaceutically acceptable salt administered to the individual One or more subsequent doses are selected as appropriate and determined, and the individual's OSDI score is compared to a) the individual's OSDI score before administration of the first dose of Compound 1 or its pharmaceutically acceptable salt; b ) The OSDI score of the individual receiving the control; or c) the OSDI score of the individual receiving the comparative compound.

In some embodiments described herein, the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetyl acetyl The pharmacological stimulation of the choline α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the statistically significant decrease in the individual's OSDI score is when an effective amount of Compound 1 or its medicine is administered to the individual The first dose of a scientifically acceptable salt, or one or more subsequent doses as appropriate, is determined, and the individual’s OSDI score is compared to a) when administering Compound 1 or a pharmaceutically acceptable salt thereof The OSDI score of the individual before the first dose; b) the OSDI score of the individual receiving the control; or c) the OSDI score of the individual receiving the comparative compound.

In some embodiments described herein, the individual's OSDI score is compared to the individual's OSDI score prior to administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments described herein, the individual's OSDI score is compared to the individual's OSDI score receiving the control. In some embodiments described herein, the individual's OSDI score is compared to the individual's OSDI score receiving the administered comparative compound.

In some embodiments described herein, the individual's OSDI score is statistically significantly reduced by at least 5%, 10%, 15%, 20%, 25%, 50%, 75%, 80%, 90%, 95%, 100%, 125%, 150%, 200%, 250%, 300% or 350%.

In some embodiments described herein, a statistically significant decrease in an individual's OSDI score is characterized by a p-value of 0.05 or less, 0.01 or less, 0.005 or less, or 0.001 or less.

In some embodiments described herein, the statistically significant decrease in the individual's OSDI score is within 5 minutes, within 10 minutes of administering the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, Within 15 minutes, within 20 minutes, within 30 minutes, within 45 minutes, or within 60 minutes. In some embodiments described herein, the statistically significant decrease in the individual's OSDI score is immediate.

In some embodiments described herein, between determining the individual's OSDI score, the individual is present in an environment with reduced humidity. In some embodiments described herein, between determining the individual's OSDI score, the individual exists in an environment where the humidity is reduced and the temperature is below or above room temperature. In some embodiments described herein, the reduced humidity at room temperature is less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. The room temperature is between 15°C (59°F) and 25°C (77°F).

In some embodiments described herein, administration of Compound 1 or a pharmaceutically acceptable salt thereof comprises an effective amount of a first dose of Compound 1 or a pharmaceutically acceptable salt thereof and one or more subsequent doses. One or more subsequent doses are administered after a period of time after the first dose. This period between the first dose and the next subsequent dose is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, or at least 8 hours. The period between the first dose and the next subsequent dose is between 1-3 hours, 2-4 hours, 3-6 hours or 4-8 hours. The period between one or more subsequent doses is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, or at least 8 hours. The period between one or more subsequent doses is between 1-3 hours, 2-4 hours, 3-6 hours, or 4-8 hours.

In some embodiments described herein, wherein the statistically significant decrease in the individual's OSDI score is based on the individual's OSDI score determined after administration of an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof .

In some embodiments described herein, wherein the statistically significant decrease is based on the individual's OSDI score determined after administration of an effective amount of Compound 1 or one or more subsequent doses of a pharmaceutically acceptable salt thereof. Maintain effective treatment over time

The present invention provides effective treatment over a period of time, where statistically significant improvements in maintaining individual scores are maintained. The term "maintenance" as used in the present invention and related to maintaining a statistically significant improvement in individual scores (EDS, Stommer, cornea, or OSDI) means that the statistically significant improvement does not fall below a certain threshold over time value. Even if the individual score changes at a later time point, statistically significant improvements can be maintained. The improvement after the first dose can be maintained without additional administration or after one or more subsequent doses.

For example, a dry eye score "maintained within 10%" means that the individual's dry eye score does not decrease by more than 10% within a specified time. Another improvement in the individual's dry eye score will also be regarded as maintaining a statistically significant improvement (for example, some eye scores will be further improved by 15% within a specified time, then this will be considered "maintained within 10%").

In another example, if 30 minutes after taking the first dose, the individual's dry eye score is statistically significantly reduced (improved), and at a later time point, the individual's score is the same or less (indicating the individual's Benefit), the statistically significant improvement is said to be maintained. Alternatively, if at a subsequent time point, the individual's dry eye score exceeds the dry eye score 30 minutes after taking the first dose, then the individual can still receive therapeutic benefit and the score determined subsequently can still be compared to the previous administration The statistical significance of the first dose or its baseline score before treatment improved significantly.

It should be noted that the elements that make up the improvement vary depending on the measured score. For example, the improvement in dry eye score, corneal score, and OSDI score is a decrease in score value. For the Sgormer test, the improvement is usually an increase in the Sgormer score.

In some embodiments described herein, maintaining a statistically significant improvement in an individual’s score (eg, EDS, Sgormer, cornea, or OSDI) means that the statistically significant improvement does not decrease by more than 10%, 20%, 30%, 40% , 50% or 60%.

In some embodiments described herein, the statistically significant improvement in individual scores (eg, EDS, Gomer, cornea, or OSDI) is maintained for at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 2 hours, at least 4 hours, At least 6 hours, at least 8 hours, at least 1 day, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiments described herein, the statistically significant improvement in the individual score is maintained for at least 30 minutes from the first dose of the effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, wherein the statistically significant improvement does not Reduce by more than 30%.

In some embodiments described herein, the statistical score of the individual score (eg, EDS, Stommer, cornea, or OSDI) significantly improves the first dose of Compound 1 or its pharmaceutically acceptable salt administered in an effective amount Then maintain for at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 1 day, at least 1 week, at least 1 month, at least 3 months, at least 6 Months, at least 9 months, or at least 12 months, where the statistically significant improvement is not statistically significant compared to the individual scores within 5 minutes after the first dose of an effective amount of Compound 1 or its pharmaceutically acceptable salt Reduce by more than 10%, 20%, 30%, 40%, 50% or 60%.

In some embodiments described herein, the statistical score of the individual score (eg, EDS, Stommer, cornea, or OSDI) significantly improves the first dose of Compound 1 or its pharmaceutically acceptable salt administered in an effective amount Then maintain for at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 1 day, at least 1 week, at least 1 month, at least 3 months, at least 6 Month, at least 9 months, or at least 12 months, in which the corresponding dry eye score and corneal score of the individual within 5 minutes after the administration of the effective dose of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof Or OSDI score, statistically significant improvement does not decrease by more than 20%.

In some of the embodiments described herein, the statistically significant improvement in individual scores (eg, EDS, Stommer, cornea, or OSDI) is maintained for at least 30 minutes after administration of the first dose of an effective amount of Compound 1, where compared The individual score within 5 minutes after administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof does not decrease statistically significantly by more than 10%, 20%, or 30%.

In some of the embodiments described herein, compared to the corresponding Sgormer score of an individual within 5 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, the effective amount is administered At least 30 minutes, at least 45 minutes, at least 60 minutes, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 1 day after the first dose of Compound 1 or a pharmaceutically acceptable salt thereof 1 week, at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 12 months, the individual's Sgormer score does not decrease by more than 10%, 20%, 30%, 40%, 50% or 60%.

In some of the embodiments described herein, compared to the corresponding Sgormer score of an individual within 5 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, the effective amount is administered At least 30 minutes, at least 45 minutes, at least 60 minutes, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 1 day after the first dose of Compound 1 or a pharmaceutically acceptable salt thereof At 1 week, at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 12 months, the individual's Sgormer score does not decrease by more than 30%.

In some of the embodiments described herein, compared to the corresponding Sgormer score of an individual within 5 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, the effective amount is administered At least 30 minutes after the first dose of Compound 1 or a pharmaceutically acceptable salt thereof, the individual’s Sgormer score does not decrease by more than 30%, 20%, or 10%.

In some embodiments described herein, compared to the corresponding dry eye score, corneal score, or OSDI score of an individual within 5 minutes after administration of an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof, At least 30 minutes, at least 45 minutes, at least 60 minutes, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours after administration of an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof At least 1 day, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 12 months, the individual's dry eye score, corneal score, or OSDI score does not increase by more than 10%, 20%, 30%, 40%, 50% or 60%.

In some embodiments described herein, compared to the corresponding dry eye score, corneal score, or OSDI score of an individual within 5 minutes after administration of an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof, At least 30 minutes, at least 45 minutes, at least 60 minutes, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours after administration of an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof At least 1 day, at least 1 week, at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 12 months, the individual's dry eye score, corneal score, or OSDI score does not increase by more than 30%.

In some embodiments described herein, compared to the corresponding dry eye score, corneal score, or OSDI score of an individual within 5 minutes after administration of an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof, At least 30 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, the individual's dry eye score, corneal score, or OSDI score does not increase by more than 30%, 20%, or 10%. Dose and volume

In some embodiments described herein, the doses described herein are administered for prophylactic and/or therapeutic treatments. The dose effective for therapeutic treatment depends on the severity and course of the disease or condition; previous therapy; the patient's health, condition, weight, and response to the drug; and the judgment of the treatment health provider. The therapeutically effective amount is determined by methods including but not limited to dose escalation clinical trials, as appropriate.

In prophylactic applications, the pharmaceutical formulations described herein are administered to patients susceptible to or otherwise at risk for a particular disease, disorder or condition. Such amounts are defined as "prophylactically effective amounts or doses". In this use, the amount will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drug, and the judgment of the treatment health provider.

In some embodiments described herein, the amount of Compound 1 administered to an individual is 5-4000 mcg, 5-1000 mcg, 10-2000 mcg, 10-700 mcg, 100-700 mcg, 100-600 Mcg, 100-500 mcg, 200-700 mcg, 200-600 mcg, 200-500 mcg, 300-600 mcg, 300-500 mcg, 900-4000 mcg, 900-3000 mcg, 900-2500 mcg, 900-2000 Mcg, 1000-4000 mcg, 1000-2500 mcg, 1000-2000 mcg, 1250-4000 mcg, 1250-2500 mcg, 1250-2000 mcg, 1500-4000 mcg, 1500-3000 mcg, 1500-2500 mcg, 1500-2000 Micrograms, 1800-4000 micrograms, 1800-3000 micrograms, 1800-2500 micrograms, 1800-2250 micrograms, 2000-4000 micrograms, 2000-3000 micrograms or 2000-2500 micrograms, or the corresponding amounts of pharmaceutically acceptable salts thereof. In some embodiments described herein, the amount of Compound 1 administered to an individual is 900-2500 μg, 1000-2500 μg, 1500-3000 μg, 1800-2500 μg, 1800-2250 μg, or a medicine thereof The corresponding amount of academically acceptable salt. In some embodiments described herein, the amount of Compound 1 administered to an individual is 150-300 micrograms, 900-1200 micrograms, or 2100-2400 micrograms, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments described herein, the pharmaceutically acceptable salt of Compound 1 is administered. In some embodiments described herein, the free base of Compound 1 is administered.

The volume of pharmaceutical formulation administered to an individual depends on various factors, including the route of administration and the type of delivery device. For nasal administration, the volume of the pharmaceutical formulation should be sufficient to deliver an effective amount of drug to the nasal cavity. If the volume is too small, the medicine cannot reach the nasal cavity. On the other hand, the volume should not be too large to be practical, uncomfortable, or too difficult to administer to the individual. In addition, excessive volume can cause delivery of pharmaceutical formulations to areas of the body where delivery is not expected. This can result in wasted pharmaceutical formulations or tissue irritation. For example, reducing the dose volume from 200 microliters to 100 microliters can reduce the incidence of upper larynx/soft palate stimulation by reducing post-nasal instillation after instillation.

In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally, and the total volume of each pharmaceutical formulation is 50-250 microliters, 75 -125 microliters, 150-250 microliters or 175-225 microliters.

In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally, and the total volume of each pharmaceutical formulation is about 50 microliters, about 75 Microliter, about 100 microliter, about 125 microliter, about 150 microliter, about 175 microliter, about 200 microliter, about 225 microliter, or about 250 microliter.

In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally, and the total volume of the pharmaceutical formulation per nostril is 50-250 microliters , 75-125 microliters, 150-250 microliters or 175-225 microliters.

In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation for nasal administration, and the total volume of the pharmaceutical formulation for each nostril is about 50 microliters, About 75 microliters, about 100 microliters, about 125 microliters, about 150 microliters, about 175 microliters, about 200 microliters, about 225 microliters, or about 250 microliters.

In some embodiments described herein, Compound 1 is administered as a pharmaceutical formulation administered nasally, the pharmaceutical formulation comprising between 1 mg/mL and 40 mg/mL, 1 mg/mL and 30 mg/mL Between, between 1 mg/mL and 20 mg/mL, between 1 mg/mL and 10 mg/mL, between 1 mg/mL and 5 mg/mL, between 2 mg/mL and 40 mg/mL , 2 mg/mL and 30 mg/mL, 2 mg/mL and 20 mg/mL, 2 mg/mL and 10 mg/mL, 2 mg/mL and 5 mg/mL, 5 mg/ between mL and 40 mg/mL, between 5 mg/mL and 30 mg/mL, between 5 mg/mL and 20 mg/mL, between 5 mg/mL and 10 mg/mL, or between 5 mg/mL and 15 mg/mL of Compound 1, or the corresponding amount of its pharmaceutically acceptable salt.

In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally, wherein the concentration of Compound 1 or a pharmaceutically acceptable salt thereof per dose 0.01% (w/v) to 0.5% (w/v), 0.01% (w/v) to 1.0% (w/v), 0.01% (w/v) to 1.5% (w/v), 0.01 % (w/v) to 2.0% (w/v), 0.01% (w/v) to 2.5% (w/v), 0.01% (w/v) to 3.0% (w/v), 0.5% ( w/v) to 1.0% (w/v), 0.5% (w/v) to 1.5% (w/v), 0.5% (w/v) to 2.0% (w/v), 0.5% (w/ v) to 2.5% (w/v), 0.5% (w/v) to 3.0% (w/v), 1.0% (w/v) to 1.5% (w/v), 1.0% (w/v) To 2.0% (w/v), 1.0% (w/v) to 2.5% (w/v), 1.0% (w/v) to 3.0% (w/v), 1.5% (w/v) to 2.0 % (w/v), 1.5% (w/v) to 2.5% (w/v), 1.5% (w/v) to 3.0% (w/v), 2.0% (w/v) to 2.5% ( w/v) or 2.0% (w/v) to 3.0% (w/v).

In some embodiments described herein, Compound 1 is a pharmaceutically acceptable salt. In some embodiments described herein, the pharmaceutically acceptable salt of Compound 1 is galactate (eg, galactate dihydrate dihydrate) or citrate (eg, monocitrate) . In some embodiments described herein, Compound 1 is the free base.

The amount of nAChR agonist free base administered to an individual in need and the corresponding amount of salt can be calculated based on the concentration of the nAChR agonist administered to the individual in need and the volume of the pharmaceutical formulation. The following examples illustrate the relationship between the concentration and volume of pharmaceutical formulation administered to an individual and the amount of nAChR agonist salt and free base.

For example, a 2.0% compound 1 hemi-galactonate dihydrate solution is equivalent to a 20 mg salt/1 mL solution. A 2.0% compound 1 hemi-galactonate dihydrate solution corresponds to a 1.1% compound 1 free base solution. The 1.1% free base solution is equivalent to 11.1 mg/mL Compound 1 free base.

A 50 µL 2.0% compound 1 galactate dihydrate dihydrate solution contains about 1000 µg of compound 1 galactose dihydrate dihydrate, which is equivalent to about 554 µg of compound 1 free base. Similarly, a 100 µL 2.0% compound 1 galactate dihydrate dihydrate solution contains about 2000 µg compound 1 galactose dihydrate dihydrate, which is equivalent to about 1108 µg compound 1 free base. The amount of salt and the corresponding amount of free base can be calculated in a similar manner for other concentrations or volumes.

In another example, a 2.3% Compound 1 monocitrate solution is equivalent to 23.2 mg salt/1 mL solution. A 2.3% compound 1 monocitrate solution corresponds to a 1.1% compound 1 free base solution. The 1.1% free base solution is equivalent to 11.1 mg/mL Compound 1 free base.

A 50 µL 2.3% Compound 1 monocitrate solution contains approximately 1161 µg Compound 1 monocitrate, which is equivalent to approximately 554 µg Compound 1 free base. Similarly, a 100 µL 2.3% Compound 1 monocitrate solution contains approximately 2322 µg Compound 1 monocitrate, which is equivalent to approximately 1108 µg Compound 1 free base. The amount of salt and the corresponding amount of free base can be calculated in a similar manner for other concentrations or volumes.

The corresponding amount of salt form can be calculated by multiplying the amount of free base by a multiplication factor. The multiplication factor is calculated by dividing the molecular weight of the salt form by the molecular weight of the free base. For example, the multiplication factor for converting a certain amount of compound I free base to monocitrate is 2.096. The multiplication factor for converting a certain amount of the free base of the compound of formula I to galactose dihydrate dihydrate is 1.805.

The corresponding amount of free base can be calculated by multiplying the amount of salt form by the multiplication factor. This factor is calculated by dividing the molecular weight of the free base by the molecular weight of the salt form. The multiplication factor for converting a certain amount of the compound of formula I monocitrate into free base is 0.477. The multiplication factor for converting a certain amount of the compound of formula I hemi-galactonate dihydrate to the free base is 0.554.

The pharmaceutical formulations described herein are administered to the individual's nasal cavity. The pharmaceutical formulations described herein include, but are not limited to, liquids, suspensions, aerosols, gels, ointments, dry powders, creams, slurries, lotions, or balsams.

In some embodiments disclosed herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the nasal cavity of an individual. The pharmaceutical formulations described herein include, but are not limited to, liquids, suspensions, aerosols, gels, ointments, dry powders, creams, slurries, lotions, or balsams.

In some embodiments disclosed herein, Compound 1 or a pharmaceutically acceptable salt thereof is provided by a spray pump, syringe, dropper, bottle sprayer, atomizing pump, inhaler, powder spray device, vaporizer, patch, A medicine stick, pipette or liquid ejector is administered into the nasal cavity. Investment timing and method

The schedule of doses administered to an individual depends on various considerations, including the duration of effectiveness of each dose, the pharmacokinetic profile of the drug, and the effect of the dose on the body. For example, where the condition of the patient is not improved according to the judgment of the health provider, the administration of a dose of Compound 1 or a pharmaceutically acceptable salt thereof may increase the frequency or long-term administration to improve or otherwise control or limit the patient’s Symptoms of a disease or condition. In another example, if the individual's condition has improved according to the judgment of the health provider, the frequency of administration of a dose of Compound 1 or a pharmaceutically acceptable salt thereof can be reduced while maintaining the individual's effective treatment. For example, the period of time between administration of one or more doses is extended, or the period of time between administration of one or more doses to an individual is extended. As a non-limiting example, one or more doses administered daily are modified to administer one or more doses every other day or once a week.

In some embodiments described herein, one to four times a day after the first day of administration, once a day after the first day of administration, twice a day after the first day of administration, or three times a day after the first day of administration Individuals in need are dosed.

In some of the embodiments described herein, one or more subsequent doses are administered to the individual over time, wherein even the amount of Compound 1 or a pharmaceutically acceptable salt thereof administered to the individual over time is reduced Under the circumstances, maintain effective treatment of the individual. In some embodiments described herein, the frequency of dosage of Compound 1 or a pharmaceutically acceptable salt thereof administered to an individual decreases over time. For example, the dose administered twice a day is reduced to the dose administered once a day.

In some embodiments described herein, the length of time between administrations increases. For example, a dose administered every 4 hours is modified to a dose administered every 8 or 12 hours. In some embodiments described herein, the total amount of Compound 1 per dose, or the corresponding amount of its pharmaceutically acceptable salt, decreases over time. For example, a dose of 2000 micrograms is reduced to 1000 micrograms of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, wherein administration of the reduced dose maintains effective treatment in the individual. In some embodiments described herein, the reduced dose is provided by reducing the administration of Compound 1 or a pharmaceutically acceptable salt thereof. For example, when administered as a nasal spray, the dose of two administrations or "spray" comprising Compound 1 or a pharmaceutically acceptable salt thereof is reduced to only one "spray".

In some embodiments described herein, the dosage comprises Compound 1 or a pharmaceutically acceptable salt thereof administered multiple times to each nostril. In some embodiments described herein, the dosage comprises Compound 1 or a pharmaceutically acceptable salt thereof administered multiple times to one nostril.

In some embodiments described herein, the dosage comprises Compound 1 or a pharmaceutically acceptable salt thereof administered to each nostril in a single administration. In some embodiments described herein, the dosage comprises Compound 1 or a pharmaceutically acceptable salt thereof administered to a nostril in a single administration.

In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered to one nostril per dose. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered to both nostrils per dose.

In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered for at least 28 days. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered for at least one or more months.

In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered for at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least one year. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered for 2-52 weeks, 2-40 weeks, 2-36 weeks, 2-24 weeks, 2-12 weeks, 2 -8 weeks, 4-52 weeks, 4-40 weeks, 4-36 weeks, 4-24 weeks, 4-12 weeks, 4-8 weeks, 5-52 weeks, 5-40 weeks, 5-36 weeks, 5 -24 weeks, 5-12 weeks, 5-8 weeks, 6-52 weeks, 6-40 weeks, 6-36 weeks, 6-24 weeks, 6-12 weeks or 6-8 weeks.

In some embodiments described herein, the method comprises an effective amount of a first dose of Compound 1 or a pharmaceutically acceptable salt thereof and one or more subsequent doses. One or more subsequent doses are administered after a period of time after the first dose. This period between the first dose and the next subsequent dose is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, or at least 8 hours. The period between the first dose and the next subsequent dose is between 1-3 hours, 2-4 hours, 3-6 hours or 4-8 hours. The period between one or more subsequent doses is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, or at least 8 hours. The period between one or more subsequent doses is between 1-3 hours, 2-4 hours, 3-6 hours, or 4-8 hours.

In some embodiments described herein, a first dose comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof administered to the nasal cavity of an individual in need thereof and optionally one or more subsequent doses , Where the method results in effective treatment of the individual in need. In some embodiments described herein, the effective treatment of the individual is indicated by one or more tests selected from the group consisting of: a) dry eye score test according to the visual analog scale and b) Sgormer test. In some embodiments, the individual's dry eye score is compared to the individual's dry eye score before administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; the individual's dry eye score is statistically significantly reduced It is within 5 minutes of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, and is characterized by a p value of less than 0.05. In some embodiments described herein, the individual's dry eye score is statistically significantly reduced by at least 10 mm. In some embodiments described herein, the individual's dry eye score is statistically significantly reduced by at least 5 mm. In some embodiments described herein, the individual's dry eye score is statistically significantly reduced by at least 3 mm. In other embodiments of any of the embodiments described herein, the individual is administered 1800-2500 micrograms of Compound 1 per dose, or a corresponding amount of a pharmaceutically acceptable salt thereof. In other embodiments of any of the embodiments described herein, the individual is administered 3500-4500 micrograms of Compound 1 per dose, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally, and the total volume of each dosage of the pharmaceutical formulation is 50 μl-250 μm Rise. In some embodiments described herein, the total volume of the pharmaceutical formulation per dose is from 75 microliters to 150 microliters. In some embodiments described herein, the total volume of the pharmaceutical formulation per dose is 150 microliters to 250 microliters. In some embodiments described herein, the total volume of the pharmaceutical formulation per dose is about 100 microliters or about 200 microliters. In some embodiments described herein, the pharmaceutical formulation for nasal administration contains between 1 mg/mL and 40 mg/mL of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments described herein, the pharmaceutical formulation for nasal administration contains Compound 1 between 5 mg/mL and 25 mg/mL, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments described herein, the pharmaceutical formulation for nasal administration contains 2 mg/mL, 10 mg/mL, or 20 mg/mL Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments described herein, the statistically significant decrease in the individual's dry eye score is maintained within at least 30 minutes from the first dose of the effective dose of Compound 1 or a pharmaceutically acceptable salt thereof Within 10% or 20%. In some embodiments described herein, the statistically significant decrease in the individual's dry eye score is maintained at least 60 minutes after the first dose of the effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered Within 10% or 20%. In some embodiments described herein, the dry eye score of an individual 30 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is Within 10 minutes of the subject's dry eye score within 5 minutes after the first dose of the acceptable salt.

In some embodiments described herein, the method comprises administering to the nasal cavity of an individual in need an effective amount of a first dose of Compound 1 or a pharmaceutically acceptable salt thereof and optionally one or more Subsequent doses, where the method results in effective treatment of the individual in need. In some embodiments described herein, the effective treatment of an individual is indicated by one or more tests selected from the group consisting of: a) Sgormer score test according to the visual analog scale and b) Sgormer test. In some embodiments described herein, the individual's Sgormer score is compared to the individual's Sgormer score prior to administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; the individual's Sgormer score The statistically significant increase in the silent score is within 5 minutes of administering the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, and is characterized by a p value of less than 0.05. In some embodiments described herein, the individual's Sgormer score is statistically significantly increased by at least 100%, 200%, or 300%. In some embodiments described herein, the individual's Sgormer score increases statistically significantly by at least 10 mm. In some embodiments described herein, the individual's Sgormer score increases statistically significantly by at least 5 mm. In some embodiments described herein, the individual's Sgormer score increases statistically significantly by at least 3 mm. In other embodiments of any of the embodiments described herein, 1800-2500 micrograms of a pharmaceutically acceptable salt of Compound 1 per dose is administered to the individual. In other embodiments of any of the embodiments described herein, the individual is administered a pharmaceutically acceptable salt of Compound 1 at 3500-4500 micrograms per dose. In some embodiments described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally, and the total volume of each dosage of the pharmaceutical formulation is 50 μl-250 μm Rise. In some embodiments described herein, the total volume of the pharmaceutical formulation per dose is from 75 microliters to 150 microliters. In some embodiments described herein, the total volume of the pharmaceutical formulation per dose is 150 microliters to 250 microliters. In some embodiments described herein, the total volume of the pharmaceutical formulation per dose is about 100 microliters or about 200 microliters. In some embodiments described herein, the pharmaceutical formulation for nasal administration contains between 1 mg/mL and 40 mg/mL of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments described herein, the pharmaceutical formulation for nasal administration contains Compound 1 between 5 mg/mL and 25 mg/mL, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments described herein, the pharmaceutical formulation for nasal administration contains about 2 mg/mL, 10 mg/mL, or 20 mg/mL Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments described herein, the individual's Sgormer score increases statistically significantly and is maintained at least 30 minutes after the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered Within 10% or 20%. In some of the embodiments described herein, the individual's Sgormer score increases statistically significantly from at least 60 minutes after the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered Within 10% or 20%. In some of the embodiments described herein, 30 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof Within 10 minutes of the subject's Sgormer score within 5 minutes after the first dose of the academically acceptable salt. Refractive surgery

In some embodiments described herein, the individual will undergo or have undergone eye refractive surgery. Examples of refractive surgery include laser assisted in situ keratomileusis (LASIK), astigmatism keratectomy (AK), refractive keratectomy (PRK), and limbal keratolysis (LRI). In some embodiments of the method, use, and composition used, the refractive surgery is laser assisted in situ keratomileusis (LASIK). In some embodiments of the method, use, and composition used, the refractive surgery is astigmatism keratectomy (AK). In some embodiments of the method, use, and composition used, the refractive surgery is refractive keratectomy (PRK). In some embodiments of the method, use, and composition used, the refractive surgery is a limbal keratolytic incision (LRI). In some embodiments, the compounds or compositions described herein are administered before surgery. In some embodiments, the compounds or compositions described herein are administered before surgery. In some embodiments, the compounds or compositions described herein are administered before and after surgery. In some embodiments described herein, the individual has undergone eye refractive surgery within 2 weeks or is scheduled to perform eye refractive surgery within 2 weeks. LASIK group

In some embodiments, the compounds or compositions described herein are administered before surgery. In some embodiments, the compounds or compositions described herein are administered before surgery. In some embodiments, the compounds or compositions described herein are administered before and after surgery. In some embodiments described herein, the individual has undergone laser in situ lamellar keratoplasty (Lasik) surgery within 2 weeks or is scheduled to perform Lasik surgery within 2 weeks. Keratitis

Normal tear film contains a variety of biologically active growth factors, including nerve growth factor, epidermal growth factor, transforming growth factor-β, hepatocyte growth factor, platelet-derived growth factor, vascular endothelial growth factor, fibroblast growth factor, keratinocyte growth Factor and insulin-like growth factor. When the cornea feels irritation or pressure, the eyelids will close and tears will be produced to protect the cornea and eyes.

Neurotrophic keratitis causes decreased corneal sensitivity. The corneal function of individuals with neurotrophic keratitis (NK) is impaired because the nerves that innervate the cornea cannot function properly; these nerves carry impulses to assist corneal function. Because these nerves do not function properly in NK, the outer layer of the cornea (called the epithelium) can rupture, leading to epithelial defects. In more advanced neurotrophic keratitis, the inner layer called the corneal stroma can also rupture, resulting in thinning of the cornea. This is called "melting" of the matrix. In late stromal melting, the cornea can thin to a severe degree, which can cause holes or openings inside the eye, which can lead to infection and potentially blindness. NK can cause a variety of complications, including poor corneal wound healing, corneal scarring, and loss of vision. There are many different conditions that can damage the nerves that serve the cornea.

A variety of therapies can be used to treat this disorder, depending on the degree of progression of the disorder in the individual. Recently, recombinant human nerve growth factor (rhNGF) (Oxervate, Dompe) has been approved for the treatment of NK. Unfortunately, this therapy has several drawbacks, including the fact that the product needs to be administered 6 times a day at 2-hour intervals for 8 weeks; the product is delivered with a straw, which can be cumbersome for self-administration; the product must Frozen; and the cost of supply for 4 weeks is greater than $10K.

The present invention provides methods, uses, and compositions for treating keratitis in an individual. In some embodiments, the keratitis is NK. In some embodiments, the methods and compositions disclosed herein for treating individuals with NK stimulate natural tear film. In some embodiments, the composition provided herein is administered to an individual with NK once or twice a day. In some embodiments, the composition provided herein is administered to an individual with NK once or twice a day for at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, or at least 8 weeks. In some embodiments, the composition provided herein is administered to an individual with NK twice a day for at least 8 weeks. In some embodiments, the composition provided herein is administered intranasally to an individual with NK twice a day for at least 8 weeks. side effect

The present invention provides a method of topical administration (intranasal) of Compound 1 or a pharmaceutically acceptable salt thereof. Local administration has advantages over systemic administration, including by reducing the amount of drugs that can cross the blood-brain barrier to reduce potential side effects. In some embodiments disclosed herein, Compound 1 administered or a pharmaceutically acceptable salt thereof is not systemically bioavailable. In some embodiments disclosed herein, this method does not cause undesirable systemic side effects. In some embodiments disclosed herein, this method does not cause undesirable mental side effects.

In some embodiments described herein, the individual does not experience one or more side effects selected from the group consisting of excessive tear production, cough, throat irritation, drip site irritation, sneezing, nasopharyngitis, nasal irritation , Toothache, dry mouth and headache.

In some embodiments described herein, wherein within 5-60 minutes of administration of the first dose or one or more subsequent doses, the individual will not experience one or more side effects selected from the group consisting of: overproduction Tears, cough, throat irritation, irritation at the instillation site, sneezing, nasopharyngitis, nasal irritation, toothache, dry mouth and headache.

In some embodiments described herein, excessive tear production is indicated by an increase in the individual's Sgormer score of more than 20 mm. In some embodiments described herein, excessive tear production is indicated by excessive tearing in an amount that will not be practical or undesirable. For example, tearing in amounts that will interfere with the individual's eye makeup or cause the individual to wipe off or absorb excessive tears through a tissue are both unpractical and undesirable effects. humidity

The term humidity may refer to relative humidity, which is the ratio of the partial pressure of water vapor at a given temperature to the equilibrium vapor pressure of water. The relative humidity depends on the temperature and pressure of the system of interest. At low temperatures, less water vapor is required to achieve high relative humidity; more warm water or hot air is required to achieve high relative humidity. In some embodiments described herein, the individual is present in a reduced relative humidity environment between the determination of individual scores (dry eye, gosmer, cornea, OSDI).

Between using specific tests to determine individual scores, the individual may be present or exposed to an environment created artificially to adversely stimulate the individual. For example, an individual may be in a room where temperature, humidity, and airflow are controlled to create undesirable conditions. In another example, an individual may wear a dehumidifying mirror and his eyes may be stimulated by low relative humidity.

In some embodiments described herein, between measuring the individual's dry eye score, between measuring the individual's Sgormer score, between measuring the individual's corneal score, and between measuring the individual's OSDI score, The individual exists in an environment with reduced humidity. In some embodiments described herein, between measuring the individual's dry eye score, between measuring the individual's Sgormer score, between measuring the individual's corneal score, and between measuring the individual's OSDI score, The individual exists in an environment with reduced humidity and a temperature below or above room temperature. In some embodiments described herein, the reduced relative humidity at room temperature is less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. The room temperature is between 15°C (59°F) and 25°C (77°F).

In some embodiments described herein, the reduced humidity at room temperature is less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. The room temperature is between 15°C (59°F) and 25°C (77°F). Cmax plasma concentration

The methods and uses described herein include topical intranasal administration. Since the disclosed method and use is for local intranasal administration, compared to the concentration achieved from the systemic administration form (eg ingestion of oral formulations), the circulating plasma nAChR agonist or its pharmaceutically acceptable salt The concentration is lower. The low plasma concentration of nAChR agonists avoids potential undesirable side effects associated with systemic circulating nAChR agonists, such as nausea, sleep disorders, constipation, gastrointestinal gas, vomiting, skin diseases (such as rashes and itching), headaches, Abdominal pain, indigestion, gastroesophageal reflux disease and dry mouth.

A method for characterizing the plasma concentration of an nAChR agonist or its pharmaceutically acceptable salt in an individual is to measure after administering the nAChR agonist or its pharmaceutically acceptable salt to the individual and after administering the second Prior to the dose, the Cmax-maximum or peak serum concentration achieved by the nAChR agonist or its pharmaceutically acceptable salt. Methods for determining Cmax are known in the art. A non-limiting example of a protocol for determining the pharmacokinetics of the compound of Formula I, including the determination of Cmax is provided in Example 4.

In some embodiments described herein, Cmax is calculated for individuals. In some embodiments described herein, Cmax is calculated from the average Cmax of two or more individuals. In some embodiments described herein, Cmax is calculated from the average Cmax of the subgroup.

In some embodiments described herein, the plasma Cmax of nAChR agonists or pharmaceutically acceptable salts of individuals in need is less than 5 ng/mL, less than 4 ng/mL, less than 3 ng/mL or Less than 2 ng/mL.

In some embodiments described herein, the plasma Cmax of nAChR agonists or pharmaceutically acceptable salts of individuals in need is less than 5 ng/mL, less than 4 ng/mL, less than 3 ng/mL or Less than 2 ng/mL; and in which the doses containing the following are administered to individuals in need: 10 μg to 150 μg, 10 μg to 100 μg, 10 μg to 50 μg, 50 μg to 150 μg, 50 μg to 100 μg, 100 μg to 1500 μg, 100 μg to 600 μg, 150 μg to 300 μg, 200 μg to 400 μg, 400 μg to 600 μg, 750 μg to 1200 μg, 900 μg to 1200 μg, or 2100 to 2400 μg Agent, or a corresponding amount of its pharmaceutically acceptable salt.

In some embodiments described herein, the plasma Cmax of Compound 1 or a pharmaceutically acceptable salt thereof in an individual in need thereof is less than 5 ng/mL, less than 4 ng/mL, less than 3 ng/mL, or less than 2 ng/mL; and wherein the individual in need is administered a dose containing the following: 100 to 1500 micrograms, 100 to 600 micrograms, 200 to 400 micrograms, 400 to 600 micrograms, or 750 to 1200 micrograms of Compound 1 , Or a corresponding amount of its pharmaceutically acceptable salt.

In some embodiments described herein, the plasma Cmax of Compound 1 or a pharmaceutically acceptable salt thereof in an individual in need thereof is less than 5 ng/mL, less than 4 ng/mL, less than 3 ng/mL, or less than 2 ng/mL; and where the individual in need is administered a dose containing the following: 150-300 micrograms, 900-1200 micrograms or 2100-2400 micrograms, or a corresponding amount of its pharmaceutically acceptable salt.

In some embodiments described herein, the plasma Cmax of Compound 1 or a pharmaceutically acceptable salt thereof in an individual in need is less than 5 ng/mL; and wherein the individual in need is administered a dose comprising the following: 150-300 mcg, 900-1200 mcg or 2100-2400 mcg, or corresponding amounts of its pharmaceutically acceptable salts.

In some embodiments described herein, the statistically significant decrease in the individual's dry eye score is based on the individual's dry eye determined after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof score.

In some of the embodiments described herein, wherein the statistically significant decrease is based on the dry eye score of the individual determined after administration of an effective amount of one or more subsequent doses of Compound 1 or a pharmaceutically acceptable salt thereof.

In some embodiments described herein, the method does not include administering a positive ectopic modulator to the individual.

In some embodiments described herein, the comparative compound is Restasis® or Xiidra®.

The present invention provides the use of a nicotinic acetylcholine receptor agonist, which is used in the manufacture of a medicament, wherein the medicament is used to treat dry eye disease, increase tear production, or reduce eye discomfort for an individual in need. The choline receptor agonist is Compound 1 or a pharmaceutically acceptable salt thereof.

The invention provides the use of a nicotinic acetylcholine receptor agonist, which is used to manufacture a medicament, wherein the medicament is used for the nicotinic acetylcholine α4β2 receptor in an individual in need, or the nicotinic acetylcholine The base α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof performs pharmacological stimulation, wherein the nicotinic acetylcholine receptor agonist is Compound 1 or a pharmaceutically acceptable salt thereof.

The present invention provides the use of a nicotinic acetylcholine receptor agonist, which is used in the manufacture of a medicament, wherein the medicament is used for the nicotinic acetylcholine α4β2 receptor in an individual in need, or the nicotinic acetylcholine Alkali α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof for pharmacological stimulation, wherein the nicotinic acetylcholine receptor agonist is Compound 1 or Its pharmaceutically acceptable salt.

The present invention provides a pharmaceutical formulation for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need. The formulation includes Compound 1 or a pharmaceutically acceptable salt thereof.

The present invention provides a pharmaceutical formulation for use in nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors in individuals in need or The combination is subjected to pharmacological stimulation, wherein the formulation contains Compound 1 or a pharmaceutically acceptable salt thereof.

The present invention provides a pharmaceutical formulation for use in nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 receptors in individuals in need, Or nicotinic acetylcholine α4α6β2 receptor or a combination thereof for pharmacological stimulation, the formulation contains Compound 1 or a pharmaceutically acceptable salt thereof.

Throughout the present invention, the various embodiments discussed in the context of methods for treating dry eye disease, increasing tear production, and reducing eye discomfort can also be applied to compounds used in the manufacture of drugs, compounds used in various methods, and pharmaceutical formulations Examples related to things. In addition, the various embodiments discussed in the context of a method for treating dry eye disease, increasing tear production, and reducing eye discomfort can also be applied to the receptor for nicotinic acetylcholine α4β2 or nicotinic acetylcholine α3β4. Examples of methods for pharmacological stimulation of the body, or the nicotinic acetylcholine α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor, or a combination thereof. Pharmacology of nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor, or a combination thereof The various embodiments discussed in the context of stimulation methods can also be applied to embodiments related to compounds used in the manufacture of drugs, compounds used in various methods, and pharmaceutical formulations.

Statistically significant changes as used herein to describe individual scores can be calculated from the increase or decrease in individual scores. Non-limiting examples of determining whether individual score changes are statistically significant and whether the two data sets are significantly different from each other include calculations based on the ANCOVA model, and statistical hypothesis tests, such as t-tests and nonparametric Wilcoxon ranks And inspection. Covers other models and statistical hypothesis testing well known in the art.

Throughout the present invention, the amount of Compound 1 disclosed refers to the amount of Compound 1 free form present in the formulation. The term "corresponding amount" as used herein refers to the amount of the pharmaceutically acceptable salt of Compound 1 required to obtain the amount of Compound 1 free form listed in the formulation. Those skilled in the art know how to consider the molecular weight difference between the free form and the salt form of a compound and calculate the "corresponding amount" of the compound's salt, such as the corresponding amount of the pharmaceutically acceptable salt of compound 1. For example, 175.24 g of Compound 1 free base will correspond to 316.34 g of gal-galactonate dihydrate salt or 367.36 g of monocitrate.

As used herein, the term "about" is used synonymously with the term "substantially." Illustratively, the use of the term "about" to indicate an amount slightly exceeds the enumerated value, such as ±0.1% to 20%, ±0.1% to 10%, ±0.1% to 5%, or ±0.1% to 2%. Illustrative embodiment

， 或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量； 其中該方法造成有效治療該有需要之個體。Example I-1. A method for treating dry eye disease, increasing tear production or reducing eye discomfort for an individual in need, which comprises administering an effective amount of Compound 1 having the following structure to the nasal cavity of an individual in need

, Or the first dose of its pharmaceutically acceptable salt and one or more subsequent doses as appropriate; where the method results in effective treatment of the individual in need.

， 或其醫藥學上可接受之鹽； 其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量，及視情況選用之一或多個後續劑量。Example I-2. A compound for a method for treating dry eye disease, increasing tear production or reducing eye discomfort in an individual in need thereof, wherein the compound is Compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof; wherein the method comprises administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of an individual in need, and one of them is selected as appropriate Or multiple subsequent doses.

Example I-3. The compound as used in Example I-2, wherein the method results in effective treatment of the individual in need.

Example I-4. The method as in Example I-1 or the compound used in Example I-3, wherein the effective treatment of the individual is indicated by one or more tests selected from the group consisting of: a) According to the dry eye scoring test of the visual analogue scale, b) Sgormer test, c) Corneal fluorescein staining test according to the National Institute of Ophthalmology (NEI) classification system, and d) Eye surface disease index test.

Example I-5. As in the method of Example I-4 or the compound used, wherein the effective treatment is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is Measured after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt or one or more subsequent doses as appropriate to the individual, and wherein the individual's dry eye score is compared to a) Dry eye score of the individual before administration of the first dose of Compound 1 or its pharmaceutically acceptable salt; b) Dry eye score of the individual receiving the control; or c) Dry eye score of the individual receiving the comparative compound.

Example I-6. As in the method of Example I-5 or the compound used, the statistically significant reduction in the individual's dry eye score is at least 15%.

Example I-7. As in the method of Example I-5 or Example I-6 or the compound used, the dry eye score of the individual statistically decreased between 10 mm and 20 mm.

Example I-8. The method or the compound used as in any one of Examples I-5 to I-7, wherein the individual's dry eye score statistically decreases by at least 10 mm.

Example I-9. The method or compound used in any one of Examples I-5 to I-8, wherein the statistically significant reduction in the individual's dry eye score is at least 3 mm.

Example I-10. The method or the compound used as in any one of Examples I-5 to I-9, wherein the statistically significant decrease in the individual's dry eye score is by 0.05 or less, 0.01 or more The p value of small, 0.005 or less or 0.001 or less is characterized.

Example I-11. The method or the compound used as in any one of Examples I-5 to I-10, wherein the statistically significant decrease in the individual's dry eye score is when administering an effective amount of Compound 1 or Within 5 minutes of the first dose of a pharmaceutically acceptable salt.

Example I-12. The method or the compound used as in any one of Examples I-5 to I-11, wherein the statistical evaluation of the individual's dry eye score significantly improves the self-administered effective amount of Compound 1 or its medicine The first dose of academically acceptable salt is maintained for at least 30 minutes.

Example I-13. The method or the compound used as in any one of Examples I-5 to I-11, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The dry eye score of the individual within 5 minutes after a dose, the dry eye score of the individual does not increase by more than 10% at least 30 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

Example I-14. The method as in Example I-12 or I-13 or the compound used, in which the individual is present in an environment with reduced humidity between the determination of the individual's dry eye score.

Example I-15. The method or the compound used as in any one of Examples I-1 to I-14, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered comprising an effective amount of Compound 1 or The first dose and one or more subsequent doses of a pharmaceutically acceptable salt.

Example I-16. The method or the compound used as in any one of Examples I-5 to I-15, wherein the statistically significant decrease in the individual's dry eye score is based on administering an effective amount of Compound 1 or The individual's dry eye score determined after the first dose of its pharmaceutically acceptable salt.

Example I-17. The method or the compound used as in any one of Examples I-5 to I-15, wherein the statistically significant decrease is based on the administration of an effective amount of Compound 1 or its pharmaceutically acceptable The dry eye score of the individual measured after one or more subsequent doses of the salt.

Example I-18. The method or compound used as in any one of Examples I-4 to I-17, wherein the effective treatment is indicated by a statistically significant increase in the individual's Sgormer score, and wherein the individual's The statistically significant increase in the Sgomer score of at least one eye is after administering to the individual an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof or one or more subsequent doses as appropriate Measured, and the individual’s Sgormer score is compared to a) Sgormer score for the same eye of the individual before administration of the first dose of Compound 1 or its pharmaceutically acceptable salt; b) Sgormer score for the individual receiving the control; or c) Sgormer scores for individuals receiving the comparative compound.

Example I-19. As in the method of Example I-18 or the compound used, the Sgormer score of the individual increases statistically significantly by at least 15%.

Example I-20. The method as in Example I-18 or I-19 or the compound used, wherein the individual's Sgormer score statistically significantly increased between 10 mm and 20 mm.

Example I-21. The method as in Example I-18 or I-19 or the compound used, wherein the individual's Sgormer score statistically significantly increased by at least 3 mm.

Example I-22. As in the method of Example I-18 or I-19 or the compound used, the individual's Sgormer score statistically significantly increased by at least 10 mm.

Example I-23. The method or the compound used in any one of Examples I-18 to I-22, wherein the statistically significant increase in the individual's Sgormer score is by 0.05 or less, 0.01 or A p value of less, 0.005 or less or 0.001 or less is characterized.

Example I-24. The method or the compound used as in any one of Examples I-18 to I-23, wherein the statistically significant increase in the individual's Sgormer score is when administering an effective amount of Compound 1 or Within 5 minutes of the first dose of its pharmaceutically acceptable salt.

Example I-25. The method or the compound used as in any one of Examples I-18 to I-24, wherein the statistical improvement of the individual's Sgormer score significantly improves the self-administered effective amount of Compound 1 or its The first dose of pharmaceutically acceptable salt is maintained for at least 30 minutes.

Example I-26. The method or the compound used as in any one of Examples I-18 to I-24, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The Sgomer score of an individual within 5 minutes after a dose is not reduced by more than 10% at least 30 minutes after the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

Example I-27. The method or the compound used as in any one of Examples I-18 to I-26, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered Compound 1 or a pharmaceutically acceptable salt thereof The first dose of acceptable salt and one or more subsequent doses.

Example I-28. The method or the compound used as in any one of Examples I-18 to I-27, wherein the statistically significant increase in the individual's Sgormer score is based on determination after administration of the first dose Gomer score of the individual.

Example I-29. The method or the compound used as in any one of Examples I-18 to I-27, wherein the statistically significant increase is based on the administration of Compound 1 or a pharmaceutically acceptable salt thereof The Sgomer score of an individual determined after one or more subsequent doses.

Example I-30. The method or the compound used as in any one of Examples I-4 to 29, wherein the effective treatment is indicated by a statistically significant decrease in the individual's corneal score, and wherein the individual's corneal score is statistically The significant decrease is determined after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt or one or more subsequent doses as appropriate, and the dry eye score of the individual is relative Compared to a) The individual's corneal score before administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) corneal score of the individual receiving the control; or c) The corneal score of the individual who received the comparative compound.

Example I-31. As in the method of Example I-30 or the compound used, the statistically significant decrease in the individual's corneal score is at least 15%.

Example I-32. The method or the compound used as in Example I-30 or I-31, wherein the statistically significant decrease in the individual's corneal score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.

Example I-33. The method or the compound used as in any one of Examples I-30 to I-32, wherein the statistically significant decrease in the individual's corneal score is when an effective amount of Compound 1 or its medicine is administered Within 5 minutes of the first dose of the academically acceptable salt.

Example I-34. The method or the compound used as in any one of Examples I-30 to I-33, wherein the statistical evaluation of the individual's corneal score significantly improves the self-administered effective amount of Compound 1 or its medicine The first dose of the acceptable salt is maintained for at least 30 minutes.

Example I-35. The method or the compound used as in any one of Examples I-30 to I-33, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The corneal score of an individual within 5 minutes after a dose, the corneal score of an individual does not increase by more than 10% at least 30 minutes after the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

Example I-36. The method as in Example I-34 or I-35 or the compound used, in which the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.

Example I-37. The method or the compound used as in any one of Examples I-30 to I-36, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered comprising an effective amount of Compound 1 or The first dose and one or more subsequent doses of a pharmaceutically acceptable salt.

Example I-38. The method or the compound used as in any one of Examples I-30 to I-37, wherein the statistically significant decrease in the individual's corneal score is based on the administration of an effective amount of Compound 1 or The corneal score of an individual measured after the first dose of a pharmaceutically acceptable salt.

Example I-39. The method or the compound used as in any one of Examples I-30 to I-37, wherein the statistically significant decrease is based on the administration of an effective amount of Compound 1 or its pharmaceutically acceptable The corneal score of an individual is determined after one or more subsequent doses of the salt.

Example I-40. The method or the compound used as in any one of Examples I-4 to I-39, wherein the effective treatment is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the individual's OSDI score The statistically significant decrease is determined after the administration of an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt or one or more subsequent doses as appropriate, and the individual’s OSDI score is Compared to a) The individual's OSDI score before administering the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) OSDI score of the individual receiving the control; or c) The OSDI score of the individual receiving the comparative compound.

Example I-41. As in the method of Example I-40 or the compound used, the statistically significant decrease in the individual's OSDI score is at least 15%.

Example I-42. The method or the compound used as in Example I-40 or I-41, wherein the statistically significant decrease in the individual's OSDI score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.

Example I-43. The method or the compound used as in any one of Examples I-40 to I-42, wherein the statistically significant decrease in the individual's OSDI score is when an effective amount of Compound 1 or its medicine is administered Within 5 minutes of the first dose of the academically acceptable salt.

Example I-44. The method or the compound used as in any one of Examples I-40 to I-43, wherein the statistically significant improvement in the individual's OSDI score improves the self-administered effective amount of Compound 1 or its pharmaceuticals The first dose of the acceptable salt is maintained for at least 30 minutes.

Embodiment I-45. The method or the compound used as in any one of Embodiments I-40 to I-43, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The individual's OSDI score within 5 minutes after a dose, the individual's OSDI score does not increase by more than 10% at least 30 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

Example I-46. The method or the compound used as in Example I-44 or I-45, wherein the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.

Example I-47. The method or the compound used as in any one of Examples I-40 to I-46, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered comprising an effective amount of Compound 1 or The first dose and one or more subsequent doses of a pharmaceutically acceptable salt.

Example I-48. The method or the compound used as in any one of Examples I-40 to I-47, wherein the statistically significant decrease in the individual's OSDI score is based on the administration of an effective amount of Compound 1 or The individual's OSDI score determined after the first dose of a pharmaceutically acceptable salt.

Example I-49. The method or the compound used as in any one of Examples I-40 to I-47, wherein the statistically significant decrease is based on the administration of an effective amount of Compound 1 or its pharmaceutically acceptable The individual's OSDI score determined after one or more subsequent doses of the salt.

， 或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量。Example I-50. A nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor or a combination thereof in an individual in need A method for immediate and long-term pharmacological stimulation, which comprises administering an effective amount of Compound 1 having the following structure to the nasal cavity of an individual in need

, Or the first dose of its pharmaceutically acceptable salt and one or more subsequent doses as appropriate.

， 或其醫藥學上可接受之鹽； 其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量，及視情況選用之一或多個後續劑量。Example I-51. A nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor or a combination thereof in an individual in need A compound for immediate and long-term pharmacological stimulation, wherein the compound is compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof; wherein the method comprises administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of an individual in need, and one of them is selected as appropriate Or multiple subsequent doses.

Example I-52. The method as in Example I-50 or the compound as used in Example I-51, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 receptor in the individual , Or the pharmacological stimulation of the nicotinic acetylcholine α3α5β4 receptor or a combination thereof is indicated by one or more tests selected from the group consisting of: a) According to the dry eye scoring test of the visual analogue scale, b) Sgormer test, c) Corneal fluorescein staining test according to the National Institute of Ophthalmology (NEI) classification system, and d) Eye surface disease index test.

Example I-53. The method or the compound used in Example I-52, wherein the nicotinic acetylcholine α4β2 receptor in the individual, or the nicotinic acetylcholine α3β4 receptor, or nicotinic acetylacetate The pharmacological stimulation of the choline α3α5β4 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is when the individual is administered an effective amount of Compound 1 or The first dose of the pharmaceutically acceptable salt or one or more subsequent doses are optionally determined after the determination, and the individual's dry eye score is compared to a) The dry eye score of the individual before administration of the first dose of Compound 1 or its pharmaceutically acceptable salt; b) Dry eye score of the individual receiving the control; or c) Dry eye score of the individual receiving the comparative compound.

Example I-54. As in the method of Example I-53 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 15%.

Example I-55. As in the method of Example I-53 or I-54 or the compound used, the individual's dry eye score statistically decreased between 10 mm and 20 mm.

Example I-56. As in the method of Example I-53 or I-54 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 10 mm.

Example I-57. As in the method of Example I-53 or I-54 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 3 mm.

Example I-58. The method or the compound used as in Example I-53 or I-54, wherein the statistically significant decrease in the individual's dry eye score is by 0.05 or less, 0.01 or less, 0.005 or A p value of less or 0.001 or less is characterized.

Example I-59. The method or the compound used as in any one of Examples I-53 to I-58, wherein the statistically significant decrease in the individual's dry eye score is when administering an effective amount of Compound 1 or Within 5 minutes of the first dose of a pharmaceutically acceptable salt.

Example I-60. The method or the compound used as in any one of Examples I-53 to I-59, wherein the individual's dry eye score statistically significantly improves the self-administered effective amount of Compound 1 or its medicine The first dose of academically acceptable salt is maintained for at least 30 minutes.

Embodiment I-61. The method or the compound used as in any one of Embodiments I-53 to I-59, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The dry eye score of the individual within 5 minutes after a dose, the dry eye score of the individual does not increase by more than 10% at least 30 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

Example I-62. The method as in Example I-60 or I-61 or the compound used, wherein the individual is present in an environment with reduced humidity between the determination of the individual's dry eye score.

Example I-63. The method or the compound used as in any one of Examples I-53 to I-62, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered comprising an effective amount of Compound 1 or The first dose and one or more subsequent doses of a pharmaceutically acceptable salt.

Example I-64. The method or the compound used as in any one of Examples I-53 to I-63, wherein the statistically significant decrease in the individual's dry eye score is based on administering an effective amount of Compound 1 or The individual's dry eye score determined after the first dose of its pharmaceutically acceptable salt.

Example I-65. The method or the compound used as in any one of Examples I-53 to I-63, wherein the statistically significant decrease is based on the administration of an effective amount of Compound 1 or its pharmaceutically acceptable The dry eye score of the individual measured after one or more subsequent doses of the salt.

Embodiment I-66. The method or the compound used as in any one of Embodiments I-52 to I-65, wherein the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof, is indicated by a statistically significant increase in the individual's Sgormer score, and the statistics of the Sgormer score in at least one eye of the individual The significant increase is determined after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt or one or more subsequent doses as appropriate to the individual, and the individual’s Sgormer score is Compared to a) Sgormer score for the same eye of the individual before administration of the first dose of Compound 1 or its pharmaceutically acceptable salt; b) Sgormer score for the individual receiving the control; or c) Sgormer scores for individuals receiving the comparative compound.

Example I-67. As in the method of Example I-66 or the compound used, the Sgormer score of the individual increases statistically significantly by at least 15%.

Example I-68. As in the method of Example I-66 or I-67 or the compound used, the Sgormer score of the individual statistically increased between 10 mm and 20 mm.

Example I-69. As in the method of Example I-66 or I-67 or the compound used, the Sgormer score of the individual increases statistically significantly by at least 3 mm.

Example I-70. As in the method of Example I-66 or I-67 or the compound used, the individual's Sgormer score increases statistically significantly by at least 10 mm.

Example I-71. The method or the compound used as in any one of Examples I-66 to I-70, wherein the statistically significant increase in the individual's Sgormer score is by 0.05 or less, 0.01 or A p value of less, 0.005 or less or 0.001 or less is characterized.

Example I-72. The method or the compound used as in any one of Examples I-66 to I-71, wherein the statistically significant increase in the individual's Sgormer score is when administering an effective amount of Compound 1 or Within 5 minutes of the first dose of its pharmaceutically acceptable salt.

Example I-73. The method or the compound used as in any one of Examples I-66 to I-72, wherein the statistical increase in the individual’s Sgormer score significantly improves the self-administered effective amount of compound 1 or The first dose of pharmaceutically acceptable salt is maintained for at least 30 minutes.

Embodiment I-74. The method or the compound used as in any one of Embodiments I-66 to I-72, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The Sgomer score of an individual within 5 minutes after a dose is not reduced by more than 10% at least 30 minutes after the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

Embodiment I-75. The method or the compound used as in any one of Embodiments I-66 to I-74, wherein administration of Compound 1 or a pharmaceutically acceptable salt thereof includes Compound 1 or a pharmaceutically acceptable salt thereof The first dose of acceptable salt and one or more subsequent doses.

Example I-76. The method or the compound used as in any one of Examples I-66 to I-75, wherein the statistically significant increase in the individual's Sgormer score is based on determination after administration of the first dose Gomer score of the individual.

Example I-77. The method or the compound used as in any one of Examples I-66 to I-75, wherein the statistically significant increase is based on the administration of Compound 1 or a pharmaceutically acceptable salt thereof The Sgomer score of an individual determined after one or more subsequent doses.

Embodiment I-78. The method or the compound used as in any one of Embodiments I-52 to I-77, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof, is indicated by a statistically significant decrease in the individual's corneal score, and wherein the statistically significant decrease in the individual's corneal score is administered to the individual An effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof, or one or more subsequent doses as appropriate, is determined, and the individual's dry eye score is compared to a) The individual's corneal score before administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) corneal score of the individual receiving the control; or c) The corneal score of the individual who received the comparative compound.

Example I-79. As in the method of Example I-78 or the compound used, a statistically significant decrease in the individual's corneal score is at least 15%.

Example I-80. The method or the compound used as in Example I-78 or I-79, wherein the statistically significant decrease in the individual's corneal score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.

Example I-81. The method or the compound used as in any one of Examples I-78 to I-80, wherein the statistically significant decrease in the individual's corneal score is when an effective amount of Compound 1 or its medicine is administered Within 5 minutes of the first dose of the academically acceptable salt.

Example I-82. The method or the compound used as in any one of Examples I-78 to I-81, wherein the statistical evaluation of the individual's corneal score significantly improves the self-administered effective amount of Compound 1 or its medicine The first dose of the acceptable salt is maintained for at least 30 minutes.

Embodiment I-83. The method or the compound used as in any one of Embodiments I-78 to I-81, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The corneal score of an individual within 5 minutes after a dose, the corneal score of an individual does not increase by more than 10% at least 30 minutes after the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

Example I-84. The method or the compound used as in Example I-82 or I-83, wherein the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.

Example I-85. The method or the compound used as in any one of Examples I-78 to I-84, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered comprising an effective amount of Compound 1 or The first dose and one or more subsequent doses of a pharmaceutically acceptable salt.

Example I-86. The method or the compound used as in any one of Examples I-78 to I-85, wherein the statistically significant decrease in the individual's corneal score is based on the administration of an effective amount of Compound 1 or The corneal score of an individual measured after the first dose of a pharmaceutically acceptable salt.

Example I-87. The method or the compound used as in any one of Examples I-78 to I-85, wherein the statistically significant decrease is based on the administration of an effective amount of Compound 1 or its pharmaceutically acceptable The individual's corneal score is determined after one or more of the salts.

Embodiment I-88. The method or the compound used as in any one of Embodiments I-52 to I-87, wherein the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor or a combination thereof, is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the statistically significant decrease in the individual's OSDI score is when administered to the individual The effective amount of the first dose of Compound 1 or its pharmaceutically acceptable salt is determined after one or more subsequent doses are selected, and the individual’s OSDI score is compared to a) The individual's OSDI score before administering the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) OSDI score of the individual receiving the control; or c) The OSDI score of the individual receiving the comparative compound.

Example I-89. As in the method of Example I-88 or the compound used, the statistically significant decrease in the individual's OSDI score is at least 15%.

Example I-90. The method or compound used as in Example I-88 or I-89, wherein the statistically significant decrease in the individual's OSDI score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.

Example I-91. The method or the compound used as in any one of Examples I-88 to I-90, wherein the statistically significant decrease in the individual's OSDI score is when an effective amount of Compound 1 or its medicine is administered Within 5 minutes of the first dose of the academically acceptable salt.

Example I-92. The method or the compound used as in any one of Examples I-88 to I-91, wherein the statistically significant improvement of the individual's OSDI score improves the self-administered effective amount of Compound 1 or its pharmacy The first dose of the acceptable salt is maintained for at least 30 minutes.

Embodiment I-93. The method or the compound used as in any one of Embodiments I-88 to I-91, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The individual's OSDI score within 5 minutes after a dose, the individual's OSDI score does not increase by more than 10% at least 30 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

Example I-94. The method as in Example I-92 or I-93 or the compound used, wherein the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.

Embodiment I-95. The method or the compound used as in any one of Embodiments I-88 to I-94, wherein administration of Compound 1 or a pharmaceutically acceptable salt thereof comprises an effective amount of Compound 1 or The first dose and one or more subsequent doses of a pharmaceutically acceptable salt.

Example I-96. The method or the compound used as in any one of Examples I-88 to I-95, wherein the statistically significant decrease in the individual's OSDI score is based on the administration of an effective amount of compound 1 or The individual's OSDI score determined after the first dose of a pharmaceutically acceptable salt.

Example I-97. The method or the compound used as in any one of Examples I-88 to I-95, wherein the statistically significant decrease is based on the administration of an effective amount of Compound 1 or its pharmaceutically acceptable The individual's OSDI score determined after one or more subsequent doses of the salt.

Example I-98. The method or the compound used as in any one of Examples I-50 to I-97, wherein at least the nicotinic acetylcholine α4β2 receptor is pharmacologically stimulated.

Embodiment I-99. The method or the compound used as in any one of Embodiments I-50 to I-97, wherein at least the nicotinic acetylcholine α3β4 receptor is pharmacologically stimulated.

Embodiment I-100. The method or the compound used as in any one of Embodiments I-50 to I-97, wherein at least the nicotinic acetylcholine α3α5β4 receptor is pharmacologically stimulated.

Embodiment I-101. The method or the compound used in any one of Embodiments I-1 to I-100, wherein 5-4000 micrograms of Compound 1 per dose, or a corresponding amount of a pharmaceutically acceptable salt thereof The system is administered to the individual.

Embodiment I-102. The method or the compound used as in any one of Embodiments I-1 to I-100, wherein 900-3000 micrograms of Compound 1 per dose, or a corresponding amount of a pharmaceutically acceptable salt thereof The system is administered to the individual.

Embodiment I-103. The method or the compound used as in any one of Embodiments I-1 to I-100, wherein 1000-2500 micrograms of Compound 1 per dose, or a corresponding amount of a pharmaceutically acceptable salt thereof The system is administered to the individual.

Embodiment I-104. The method or the compound used as in any one of Embodiments I-1 to I-100, wherein each dose of 1500-3000 micrograms of Compound 1, or a corresponding amount of a pharmaceutically acceptable salt thereof The system is administered to the individual.

Embodiment I-105. The method or the compound used as in any one of Embodiments I-1 to I-104, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally And, and the total volume of each pharmaceutical formulation is 50-250 microliters.

Embodiment I-106. The method or the compound used as in any one of Embodiments I-1 to I-104, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation for nasal administration And, and the total volume of each dose of pharmaceutical formulation is 150-250 microliters.

Embodiment I-107. The method or the compound used as in any one of Embodiments I-1 to I-106, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally In contrast, the pharmaceutical formulation contains between 1 mg/mL and 40 mg/mL of Compound 1, or a corresponding amount of its pharmaceutically acceptable salt.

Embodiment I-108. The method or the compound used as in any one of Embodiments I-105 to I-107, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation for nasal administration And, and the total volume of the pharmaceutical formulation administered to each nostril is 50-250 microliters.

Embodiment I-109. The method or the compound used as in any one of Embodiments I-1 to I-108, wherein Compound 1 is a pharmaceutically acceptable salt.

Example I-110. The method or the compound used as in any one of Examples I-1 to I-109, wherein the dose is administered to an individual in need one to four times a day after the first day of administration.

Example I-111. The method or the compound used as in any one of Examples I-1 to I-109, wherein the dose is administered to an individual in need once a day after the first day of administration.

Example I-112. The method or the compound used as in any one of Examples I-1 to I-109, wherein the dose is administered to an individual in need twice a day after the first day of administration.

Example I-113. The method or the compound used as in any one of Examples I-1 to I-109, wherein the dose is administered to an individual in need three times a day after the first day of administration.

Embodiment I-114. The method or the compound used as in any one of Embodiments I-1 to I-109, wherein a) The frequency of doses of Compound 1 or its pharmaceutically acceptable salts administered to individuals decreases over time, or b) The total amount of Compound 1 per dose, or the corresponding amount of its pharmaceutically acceptable salt, decreases over time.

Example I-115. The method or compound used as in Example I-114, wherein each dose comprises administering Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of the individual more than once, and wherein over time Progression to reduce the total amount of Compound 1 per dose or the corresponding amount of its pharmaceutically acceptable salt is achieved by reducing the number of times Compound 1 or its pharmaceutically acceptable salt is administered to the individual's nasal cavity .

Embodiment I-116. The method or the compound used as in any one of Embodiments I-1 to I-115, wherein the dose comprises multiple administrations of Compound 1 or its pharmaceutically acceptable to one or both nostrils Salt.

Embodiment I-117. The method or the compound used as in any one of Embodiments I-1 to I-115, wherein the dosage comprises a single administration of Compound 1 to one or both nostrils or a pharmaceutically acceptable Salt.

Embodiment I-118. The method or the compound used as in any one of Embodiments I-1 to I-117, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered to one nostril per dose.

Example I-119. The method or the compound used as in any one of Examples I-1 to I-117, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered to both nostrils per dose.

Embodiment I-120. The method or the compound used as in any one of Embodiments I-1 to I-119, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered for at least 28 days.

Embodiment I-121. The method or the compound used as in any one of Embodiments I-1 to I-119, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered for at least 3 months.

Embodiment I-122. The method or the compound used as in any one of Embodiments I-1 to I-121, wherein the individual has undergone Lasik surgery within 2 weeks or is scheduled to undergo Lasik surgery within 2 weeks.

Embodiment I-123. The method or the compound used as in any one of Embodiments I-1 to I-122, wherein the individual does not experience one or more side effects selected from the group consisting of: excessive tear production, Cough, throat irritation, drip irritation, sneezing, nasopharyngitis, nasal irritation, toothache, dry mouth and headache.

Example I-124. The method or the compound used as in Example I-123, wherein within 5-60 minutes of administration of the first dose or one or more subsequent doses, the individual does not experience One or more side effects of the group: excessive tear production, cough, throat irritation, irritation at the instillation site, sneezing, nasopharyngitis, irritation of the nose, toothache, dry mouth and headache.

Example I-125. The method or the compound used as in any one of Examples I-1 to I-124, wherein excessive tear production is indicated by an increase in the Sgomer score of the individual by more than 20 mm.

Embodiment I-126. The method or the compound used as in any one of Embodiments I-1 to I-125, wherein the method does not include administering a positive ectopic modulator to the individual.

， 或其醫藥學上可接受之鹽。Example I-127. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to treat dry eye disease, increase tear production or reduce eye discomfort for individuals in need, The nicotinic acetylcholine receptor agonist is compound 1 with the following structure

, Or a pharmaceutically acceptable salt thereof.

， 或其醫藥學上可接受之鹽。Example I-128. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to stimulate the nicotinic acetylcholine α4β2 receptor in an individual in need, or Nicotine acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor or a combination thereof, wherein the nicotinic acetylcholine receptor agonist is a compound having the following structure 1

, Or a pharmaceutically acceptable salt thereof.

， 或其醫藥學上可接受之鹽。Embodiment I-129. A pharmaceutical formulation for treating dry eye disease, increasing tear production or reducing eye discomfort for an individual in need, the formulation comprises Compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof.

Embodiment I-130. The pharmaceutical formulation of Embodiment I-129, wherein the use comprises the method as defined in any one of Embodiments I-1 to I-128.

， 或其醫藥學上可接受之鹽。Example I-131. A pharmaceutical formulation for the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 in an individual in need Receptor or a combination thereof for pharmacological stimulation, the formulation contains compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof.

Embodiment I-132. The pharmaceutical formulation as used in Embodiment I-131, wherein the formulation comprises as defined in any one of Embodiments I-1 to I-130, or II-1 to II-4 Compound.

Example II-1. The method or the compound used as in any one of Examples I-1 to I-126, wherein the plasma Cmax of Compound 1 or a pharmaceutically acceptable salt thereof of an individual in need is less than 5 ng/mL.

Example II-2. The method or the compound used in any one of Examples I-1 to I-126 or II-1, wherein each dose of 150-300 micrograms of Compound 1, or a corresponding amount of its pharmacological Acceptable salts are administered to individuals.

Example II-3. The method or the compound used as in any one of Examples I-1 to I-126 or II-1, wherein 900-1200 micrograms of Compound 1 per dose, or a corresponding amount of its pharmaceutical Acceptable salts are administered to individuals.

Example II-4. The method or the compound used as in any one of Examples I-1 to I-126 or II-1, wherein 900-1200 micrograms of Compound 1 per dose, or a corresponding amount of its pharmaceutical Acceptable salts are administered to individuals.

， 或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量； 其中該方法造成有效治療該有需要之個體。Example III-1. A method for treating dry eye disease, increasing tear production or reducing eye discomfort for an individual in need, which comprises administering an effective amount of Compound 1 having the following structure to the nasal cavity of an individual in need

, Or the first dose of its pharmaceutically acceptable salt and one or more subsequent doses as appropriate; where the method results in effective treatment of the individual in need.

， 或其醫藥學上可接受之鹽； 其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量，及視情況選用之一或多個後續劑量。Example III-2. A compound for a method for treating dry eye disease, increasing tear production, or reducing eye discomfort in an individual in need thereof, wherein the compound is Compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof; wherein the method comprises administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of an individual in need, and one of them is selected as appropriate Or multiple subsequent doses.

Example III-3. The compound as used in Example III-2, wherein the method results in effective treatment of the individual in need.

Example III-4. The method as in Example III-1 or the compound as in Example III-3, wherein the effective treatment of the individual is indicated by one or more tests selected from the group consisting of: a) According to the dry eye scoring test of the visual analogue scale, b) Sgormer test, c) Corneal fluorescein staining test according to the National Institute of Ophthalmology (NEI) classification system, and d) Eye surface disease index test.

Example III-5. The method or compound used as in Example III-4, wherein the effective treatment is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is Measured after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt or one or more subsequent doses as appropriate to the individual, and wherein the individual's dry eye score is compared to a) The dry eye score of the individual before administration of the first dose of Compound 1 or its pharmaceutically acceptable salt; b) Dry eye score of the individual receiving the control; or c) Dry eye score of the individual receiving the comparative compound.

Example III-6. The method as in Example III-5 or the compound used, wherein the individual's dry eye score is statistically significantly reduced by at least 15%.

Example III-7. The method as in Example III-5 or III-6 or the compound used, wherein the individual's dry eye score statistically decreased between 10 mm and 20 mm.

Example III-8. The method or the compound used as in any one of Examples III-5 to III-7, wherein the statistically significant decrease in the individual's dry eye score is at least 10 mm.

Example III-9. The method or the compound used as in any one of Examples III-5 to III-8, wherein the statistically significant decrease in the individual's dry eye score is at least 3 mm.

Example III-10. The method or the compound used as in any one of Examples III-5 to III-9, wherein the statistically significant decrease in the individual's dry eye score is by 0.05 or less, 0.01 or more The p value of small, 0.005 or less or 0.001 or less is characterized.

Example III-11. The method or the compound used as in any one of Examples III-5 to III-10, wherein the statistically significant decrease in the individual's dry eye score is when administering an effective amount of Compound 1 or Within 5 minutes of the first dose of a pharmaceutically acceptable salt.

Example III-12. The method or the compound used as in any one of Examples III-5 to III-11, wherein the statistical evaluation of the individual's dry eye score significantly improves the self-administered effective amount of Compound 1 or its medicine The first dose of academically acceptable salt is maintained for at least 30 minutes.

Example III-13. The method or the compound used in any one of Examples III-5 to III-11, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The dry eye score of the individual within 5 minutes after a dose, the dry eye score of the individual does not increase by more than 10% at least 30 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

Example III-14. As in the method of Example III-12 or III-13 or the compound used, the individual is present in an environment with reduced humidity between the determination of the individual's dry eye score.

Example III-15. The method or the compound used as in any one of Examples III-1 to III-14, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered containing an effective amount of Compound 1 or The first dose and one or more subsequent doses of a pharmaceutically acceptable salt.

Example III-16. The method or compound used in any one of Examples III-5 to III-15, wherein the statistically significant decrease in the individual's dry eye score is based on the administration of an effective amount of Compound 1 or The individual's dry eye score determined after the first dose of its pharmaceutically acceptable salt.

Example III-17. The method or the compound used in any one of Examples III-5 to III-15, wherein the statistically significant decrease is based on the administration of an effective amount of Compound 1 or its pharmaceutically acceptable The dry eye score of the individual measured after one or more subsequent doses of the salt.

Example III-18. The method or compound used in any one of Examples III-4 to III-17, wherein the effective treatment is indicated by a statistically significant increase in the individual's Sgormer score, and wherein the individual's The statistically significant increase in the Sgomer score of at least one eye is after administering to the individual an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof or one or more subsequent doses as appropriate Measured, and the individual’s Sgormer score is compared to a) Sgormer score for the same eye of the individual before administration of the first dose of Compound 1 or its pharmaceutically acceptable salt; b) Sgormer score for the individual receiving the control; or c) Sgormer scores for individuals receiving the comparative compound.

Example III-19. As in the method of Example I-18 or the compound used, the Sgormer score of the individual statistically increased significantly by at least 15%.

Example III-20. As in the method of Example III-18 or III-19 or the compound used, the Sgormer score of the individual increases statistically significantly between 10 mm and 20 mm.

Example III-21. As in the method of Example III-18 or III-19 or the compound used, the Sgormer score of the individual increases statistically significantly by at least 3 mm.

Example III-22. As in the method of Example III-18 or III-19 or the compound used, the Sgormer score of the individual increases statistically significantly by at least 10 mm.

Example III-23. The method or compound used in any one of Examples III-18 to III-22, wherein the statistically significant increase in the individual’s Sgormer score is by 0.05 or less, 0.01 or A p value of less, 0.005 or less or 0.001 or less is characterized.

Example III-24. The method or the compound used in any one of Examples III-18 to III-23, wherein the statistically significant increase in the individual's Sgormer score is when an effective amount of Compound 1 or Within 5 minutes of the first dose of its pharmaceutically acceptable salt.

Example III-25. The method or the compound used in any one of Examples III-18 to III-24, wherein the individual's Sgormer score statistically significantly improves the self-administered effective amount of Compound 1 or its The first dose of pharmaceutically acceptable salt is maintained for at least 30 minutes.

Example III-26. The method or the compound used as in any one of Examples III-18 to III-24, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The Sgomer score of an individual within 5 minutes after a dose is not reduced by more than 10% at least 30 minutes after the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

Example III-27. The method or the compound used as in any one of Examples III-18 to III-26, wherein Compound 1 or a pharmaceutically acceptable salt thereof comprises Compound 1 or a pharmaceutically acceptable salt thereof The first dose of acceptable salt and one or more subsequent doses.

Example III-28. The method or the compound used as in any one of Examples III-18 to III-27, wherein the statistically significant increase in the individual's Sgormer score is based on determination after administration of the first dose Gomer score of the individual.

Example III-29. The method or compound used in any one of Examples III-18 to III-27, wherein the statistically significant increase is based on the administration of Compound 1 or a pharmaceutically acceptable salt thereof The Sgomer score of an individual determined after one or more subsequent doses.

Example III-30. The method or compound used in any one of Examples III-4 to III-29, wherein the effective treatment is indicated by a statistically significant drop in the individual's corneal score, and wherein the individual's corneal score The statistically significant decrease is determined after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the individual or optionally selecting one or more subsequent doses, and wherein the individual's dry eye score Compared to a) The individual's corneal score before administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) corneal score of the individual receiving the control; or c) The corneal score of the individual who received the comparative compound.

Example III-31. As in the method of Example III-30 or the compound used, the individual's corneal score statistically decreased by at least 15%.

Example III-32. The method or compound used in Example III-30 or III-31, wherein the statistically significant decrease in the individual's corneal score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.

Example III-33. The method or the compound used in any one of Examples III-30 to III-32, wherein the statistically significant decrease in the individual's corneal score is due to the administration of an effective amount of Compound 1 or its medicine Within 5 minutes of the first dose of the academically acceptable salt.

Example III-34. The method or the compound used in any one of Examples III-30 to III-33, wherein the statistical evaluation of the individual's corneal score significantly improves the self-administered effective amount of Compound 1 or its medicine The first dose of the acceptable salt is maintained for at least 30 minutes.

Example III-35. The method or the compound used as in any one of Examples III-30 to III-33, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The corneal score of an individual within 5 minutes after a dose, the corneal score of an individual does not increase by more than 10% at least 30 minutes after the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

Example III-36. As in the method of Example III-34 or III-35 or the compound used, between the determination of the individual's corneal score, the individual is present in an environment with reduced humidity.

Example III-37. The method or the compound used as in any one of Examples III-30 to III-36, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered comprising an effective amount of Compound 1 or The first dose and one or more subsequent doses of a pharmaceutically acceptable salt.

Example III-38. The method or the compound used in any one of Examples III-30 to III-37, wherein the statistically significant decrease in the individual's corneal score is based on the administration of an effective amount of Compound 1 or The corneal score of an individual measured after the first dose of a pharmaceutically acceptable salt.

Example III-39. The method or the compound used as in any of Examples III-30 to III-37, wherein the statistically significant decrease is based on the administration of an effective amount of Compound 1 or its pharmaceutically acceptable The individual's corneal score is determined after one or more of the salts.

Example III-40. The method or the compound used in any one of Examples III-4 to III-39, wherein the effective treatment is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the individual's OSDI score The statistically significant decrease is determined after the administration of an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt or one or more subsequent doses as appropriate, and the individual’s OSDI score is Compared to a) The individual's OSDI score before administering the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) OSDI score of the individual receiving the control; or c) The OSDI score of the individual receiving the comparative compound.

Example III-41. As in the method of Example III-40 or the compound used, the statistically significant decrease in the individual's OSDI score is at least 15%.

Example III-42. The method or compound used in Example III-40 or III-41, wherein the statistically significant decrease in the individual’s OSDI score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.

Example III-43. The method or the compound used in any one of Examples III-40 to III-42, wherein the statistically significant decrease in the individual's OSDI score is the administration of an effective amount of Compound 1 or its medicine Within 5 minutes of the first dose of the academically acceptable salt.

Example III-44. The method or the compound used in any one of Examples III-40 to III-43, wherein the statistically significant improvement in the individual's OSDI score improves the self-administered effective amount of Compound 1 or its pharmacy The first dose of the acceptable salt is maintained for at least 30 minutes.

Example III-45. The method or the compound used in any one of Examples III-40 to III-43, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The individual's OSDI score within 5 minutes after a dose, the individual's OSDI score does not increase by more than 10% at least 30 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

Example III-46. As in the method of Example III-44 or III-45 or the compound used, the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.

Example III-47. The method or the compound used as in any one of Examples III-40 to III-46, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered comprising an effective amount of Compound 1 or The first dose and one or more subsequent doses of a pharmaceutically acceptable salt.

Example III-48. The method or compound used in any one of Examples III-40 to III-47, wherein the statistically significant decrease in the individual's OSDI score is based on the administration of an effective amount of Compound 1 or The individual's OSDI score determined after the first dose of a pharmaceutically acceptable salt.

Example III-49. The method or the compound used as in any one of Examples III-40 to III-47, wherein the statistically significant decrease is based on the administration of an effective amount of Compound 1 or its pharmaceutically acceptable The individual's OSDI score determined after one or more subsequent doses of the salt.

， 或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量。Example III-50. For use in individuals in need of nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or tobacco Method for immediate and long-term pharmacological stimulation of the base acetylcholine α4α6β2 receptor or a combination thereof, which comprises administering an effective amount of compound 1 having the following structure to the nasal cavity of an individual in need

, Or the first dose of its pharmaceutically acceptable salt and one or more subsequent doses as appropriate.

, 或其醫藥學上可接受之鹽； 其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量，及視情況選用之一或多個後續劑量。Example III-51. For use in individuals in need of nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or tobacco Alkaline acetylcholine α4α6β2 receptor or a combination thereof for immediate and long-term pharmacological stimulation of the compound, wherein the compound is compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof; wherein the method comprises administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of an individual in need, and one of them is selected as appropriate Or multiple subsequent doses.

Example III-52. The compound as in the method of Example III-50 or the compound used in Example III-51, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 receptor in the individual , Or the nicotinic acetylcholine α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor, or a combination thereof, the pharmacological stimulation is indicated by one or more tests selected from the group consisting of: a) According to the dry eye scoring test of the visual analogue scale, b) Sgormer test, c) Corneal fluorescein staining test according to the National Institute of Ophthalmology (NEI) classification system, and d) Eye surface disease index test.

Example III-53. The method as in Example III-52 or the compound used in which the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylate in the individual The pharmacological stimulation of the choline α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's dry eye score, and the statistically significant decrease in the individual's dry eye score is Determined after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt or one or more subsequent doses as appropriate to the individual, and wherein the individual's dry eye score is compared to a) The dry eye score of the individual before administration of the first dose of Compound 1 or its pharmaceutically acceptable salt; b) Dry eye score of the individual receiving the control; or c) Dry eye score of the individual receiving the comparative compound.

Example III-54. As in the method of Example III-53 or the compound used, the statistically significant reduction in the individual's dry eye score is at least 15%.

Example III-55. As in the method of Example III-53 or III-54 or the compound used, the individual's dry eye score statistically decreased between 10 mm and 20 mm.

Example III-56. As in the method of Example III-53 or III-54 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 10 mm.

Example III-57. As in the method of Example III-53 or III-54 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 3 mm.

Example III-58. As in the method of Example III-53 or III-54 or the compound used, the statistically significant decrease in the individual's dry eye score is by 0.05 or less, 0.01 or less, 0.005 or A p value of less or 0.001 or less is characterized.

Example III-59. The method or the compound used as in any one of Examples III-53 to III-58, wherein the statistically significant decrease in the individual's dry eye score is when administering an effective amount of Compound 1 or Within 5 minutes of the first dose of a pharmaceutically acceptable salt.

Example III-60. The method or the compound used in any one of Examples III-53 to III-59, wherein the individual's dry eye score statistically significantly improves the self-administered effective amount of Compound 1 or its medicine The first dose of academically acceptable salt is maintained for at least 30 minutes.

Example III-61. The method or the compound used as in any one of Examples III-53 to III-59, wherein compared to the first step of administering an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The dry eye score of the individual within 5 minutes after a dose, the dry eye score of the individual does not increase by more than 10% at least 30 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

Example III-62. The method as in Example III-60 or III-61 or the compound used, where the individual exists in an environment with reduced humidity between the determination of the individual's dry eye score.

Example III-63. The method or the compound used as in any one of Examples III-53 to III-62, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered comprising an effective amount of Compound 1 or The first dose and one or more subsequent doses of a pharmaceutically acceptable salt.

Example III-64. The method or the compound used as in any one of Examples III-53 to III-63, wherein the statistically significant decrease in the individual's dry eye score is based on the administration of an effective amount of Compound 1 or The individual's dry eye score determined after the first dose of its pharmaceutically acceptable salt.

Example III-65. The method or the compound used in any one of Examples III-53 to III-63, wherein the statistically significant decrease is based on the administration of an effective amount of Compound 1 or its pharmaceutically acceptable The dry eye score of the individual measured after one or more subsequent doses of the salt.

Embodiment III-66. The method or the compound used in any one of Embodiments III-52 to III-65, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor, or a combination thereof is indicated by a statistically significant increase in the individual’s Sgormer score, and of which the individual’s The statistically significant increase in the Sgomer score of at least one eye is after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the individual or optionally selecting one or more subsequent doses Measured, and the Sgormer score of the individual is compared to a) Sgormer score for the same eye of the individual before administration of the first dose of Compound 1 or its pharmaceutically acceptable salt; b) Sgormer score for the individual receiving the control; or c) Sgormer scores for individuals receiving the comparative compound.

Example III-67. As in the method of Example III-66 or the compound used, the Sgormer score of the individual statistically increased significantly by at least 15%.

Example III-68. As in the method of Example III-66 or III-67 or the compound used, the Sgormer score of the individual statistically increased significantly between 10 mm and 20 mm.

Example III-69. As in the method of Example III-66 or III-67 or the compound used, the Sgormer score of the individual statistically increased significantly by at least 3 mm.

Example III-70. As in the method of Example III-66 or III-67 or the compound used, the Sgormer score of the individual statistically increased significantly by at least 10 mm.

Example III-71. The method or compound used in any one of Examples III-66 to III-70, wherein the statistically significant increase in the individual’s Sgormer score is by 0.05 or less, 0.01 or A p value of less, 0.005 or less or 0.001 or less is characterized.

Example III-72. The method or the compound used in any one of Examples III-66 to III-71, wherein the statistically significant increase in the individual's Sgormer score is when an effective amount of Compound 1 or Within 5 minutes of the first dose of its pharmaceutically acceptable salt.

Example III-73. The method or the compound used as in any one of Examples III-66 to III-72, wherein the statistical increase in the individual’s Sgormer score significantly improves the self-administered effective amount of compound 1 or The first dose of pharmaceutically acceptable salt is maintained for at least 30 minutes.

Example III-74. The method or the compound used as in any one of Examples III-66 to III-72, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The Sgomer score of an individual within 5 minutes after a dose is not reduced by more than 10% at least 30 minutes after the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

Example III-75. The method or the compound used as in any one of Examples III-66 to III-74, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered including Compound 1 or a pharmaceutically acceptable salt thereof The first dose of acceptable salt and one or more subsequent doses.

Example III-76. The method or the compound used as in any of Examples III-66 to III-75, wherein the statistically significant increase in the individual's Sgormer score is based on determination after administration of the first dose Gomer score of the individual.

Example III-77. The method or the compound used as in any of Examples III-66 to III-75, wherein the statistically significant increase is based on the administration of Compound 1 or a pharmaceutically acceptable salt thereof The Sgomer score of an individual determined after one or more subsequent doses.

Example III-78. The method or the compound used in any one of Examples III-52 to III-77, in which the α4β2 receptor in an individual, or the nicotinic acetylcholine α3β4 receptor, or nicotine The pharmacological stimulation of acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's corneal score, and the statistically significant decrease in the individual's corneal score is Measured after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt or one or more subsequent doses as appropriate to the individual, and wherein the individual's dry eye score is compared to a) The individual's corneal score before administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) corneal score of the individual receiving the control; or c) The corneal score of the individual who received the comparative compound.

Example III-79. As in the method of Example III-78 or the compound used, the statistically significant reduction in the individual's corneal score is at least 15%.

Example III-80. As in the method of Example III-78 or III-79 or the compound used, the statistically significant decrease in the individual's corneal score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.

Example III-81. The method or the compound used in any one of Examples III-78 to III-80, wherein the statistically significant decrease in the individual's corneal score is when an effective amount of Compound 1 or its medicine is administered Within 5 minutes of the first dose of the academically acceptable salt.

Example III-82. The method or the compound used in any one of Examples III-78 to III-81, wherein the statistical evaluation of the individual's corneal score significantly improves the self-administered effective amount of Compound 1 or its medicine The first dose of the acceptable salt is maintained for at least 30 minutes.

Example III-83. The method or the compound used as in any one of Examples III-78 to III-81, wherein compared to the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The corneal score of an individual within 5 minutes after a dose, the corneal score of an individual does not increase by more than 10% at least 30 minutes after the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered.

Example III-84. As in the method of Example III-82 or III-83 or the compound used, between the determination of the individual's corneal score, the individual exists in an environment with reduced humidity.

Example III-85. The method or the compound used as in any of Examples III-78 to III-84, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered in an effective amount of Compound 1 or The first dose and one or more subsequent doses of a pharmaceutically acceptable salt.

Example III-86. The method or the compound used in any one of Examples III-78 to III-85, wherein the statistically significant decrease in the individual's corneal score is based on the administration of an effective amount of Compound 1 or The corneal score of an individual measured after the first dose of a pharmaceutically acceptable salt.

Example III-87. The method or the compound used as in any one of Examples III-78 to III-85, wherein the statistically significant decrease is based on the administration of an effective amount of Compound 1 or its pharmaceutically acceptable The individual's corneal score is determined after one or more of the salts.

Embodiment III-88. The method or the compound used in any one of Embodiments III-52 to III-87, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor, or a combination thereof is indicated by a statistically significant decrease in the individual’s OSDI score, and the individual’s OSDI score The statistically significant decrease is determined after the administration of an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt or one or more subsequent doses as appropriate, and the individual’s OSDI score is Compared to a) The individual's OSDI score before administering the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) OSDI score of the individual receiving the control; or c) The OSDI score of the individual receiving the comparative compound.

Example III-89. As in the method of Example III-88 or the compound used, the statistically significant decrease in the individual's OSDI score is at least 15%.

Example III-90. The method or compound used in Example III-88 or III-89, wherein the statistically significant decrease in the individual's OSDI score is by 0.05 or less, 0.01 or less, 0.005 or more A p value of small or 0.001 or less is characterized.

Example III-91. The method or compound used in any one of Examples III-88 to III-90, wherein the statistically significant decrease in the individual’s OSDI score is when an effective amount of Compound 1 or its medicine is administered Within 5 minutes of the first dose of the academically acceptable salt.

Example III-92. The method or the compound used in any one of Examples III-88 to III-91, wherein the statistically significant improvement of the individual's OSDI score improves the self-administered effective amount of Compound 1 or its medicine The first dose of the acceptable salt is maintained for at least 30 minutes.

Example III-93. The method or the compound used as in any one of Examples III-88 to III-91, wherein compared to the first step of administering an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The individual's OSDI score within 5 minutes after a dose, the individual's OSDI score does not increase by more than 10% at least 30 minutes after the administration of the first dose of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

Example III-94. As in the method of Example III-92 or III-93 or the compound used, the individual exists in an environment with reduced humidity between the determination of the individual's corneal score.

Example III-95. The method or the compound used as in any one of Examples III-88 to III-94, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered comprising an effective amount of Compound 1 or The first dose and one or more subsequent doses of a pharmaceutically acceptable salt.

Example III-96. The method or compound used in any one of Examples III-88 to III-95, wherein the statistically significant decrease in the individual's OSDI score is based on the administration of an effective amount of Compound 1 or The individual's OSDI score determined after the first dose of a pharmaceutically acceptable salt.

Example III-97. The method or the compound used as in any one of Examples III-88 to III-95, wherein the statistically significant decrease is based on the administration of an effective amount of Compound 1 or its pharmaceutically acceptable The individual's OSDI score determined after one or more subsequent doses of the salt.

Example III-98. The method or the compound used in any one of Examples III-50 to III-97, wherein at least the nicotinic acetylcholine α4β2 receptor is pharmacologically stimulated.

Example III-99. The method or the compound used in any one of Examples III-50 to III-97, wherein at least the nicotinic acetylcholine α3β4 receptor is pharmacologically stimulated.

Embodiment III-100. The method or the compound used as in any one of Embodiments III-50 to III-97, wherein at least the nicotinic acetylcholine α3α5β4 receptor is pharmacologically stimulated.

Example III-101. The method or the compound used in any one of Examples III-1 to III-100, wherein each dose of 5-4000 micrograms of Compound 1, or a corresponding amount of its pharmaceutically acceptable salt The system is administered to the individual.

Example III-102. The method or the compound used as in any of Examples III-1 to III-100, wherein each dose of 900-3000 micrograms of Compound 1, or a corresponding amount of its pharmaceutically acceptable salt The system is administered to the individual.

Example III-103. The method or the compound used in any one of Examples III-1 to III-100, wherein 1000-2500 micrograms of Compound 1 per dose, or a corresponding amount of its pharmaceutically acceptable salt The system is administered to the individual.

Example III-104. The method or the compound used in any one of Examples III-1 to III-100, wherein each dose of 1500-3000 micrograms of Compound 1, or a corresponding amount of its pharmaceutically acceptable salt The system is administered to the individual.

Example III-105. The method or the compound used in any one of Examples III-1 to III-104, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally And, and the total volume of each pharmaceutical formulation is 50-250 microliters.

Example III-106. The method or the compound used as in any of Examples III-1 to III-104, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally And, and the total volume of each dose of pharmaceutical formulation is 150-250 microliters.

Example III-107. The method or the compound used as in any one of Examples III-1 to III-106, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally In contrast, the pharmaceutical formulation contains between 1 mg/mL and 40 mg/mL of Compound 1, or a corresponding amount of its pharmaceutically acceptable salt.

Example III-108. The method or the compound used in any one of Examples III-105 to III-107, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally And, and the total volume of the pharmaceutical formulation administered to each nostril is 50-250 microliters.

Example III-109. The method or the compound used as in any one of Examples III-1 to III-108, wherein Compound 1 is a pharmaceutically acceptable salt.

Example III-110. The method or the compound used in any one of Examples III-1 to III-109, wherein the dose is administered to an individual in need one to four times a day after the first day of administration.

Example III-111. The method or the compound used in any one of Examples III-1 to III-109, wherein the dose is administered to an individual in need once a day after the first day of administration.

Example III-112. The method or the compound used in any one of Examples III-1 to III-109, wherein the dose is administered to an individual in need twice a day after the first day of administration.

Example III-113. The method or the compound used in any one of Examples III-1 to III-109, wherein the dose is administered to an individual in need three times a day after the first day of administration.

Example III-114. The method or the compound used as in any one of Examples III-1 to III-109, wherein a) The frequency of doses of Compound 1 or its pharmaceutically acceptable salts administered to individuals decreases over time, or b) The total amount of Compound 1 per dose, or the corresponding amount of its pharmaceutically acceptable salt, decreases over time.

Example III-115. The method as in Example III-114 or the compound used, wherein each dose includes more than one administration of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of the individual, and Wherein the total amount of Compound 1 per dose or its pharmaceutically acceptable salt is reduced over time by reducing the administration of Compound 1 or its pharmaceutically acceptable salt to the nasal cavity of the individual Times.

Example III-116. The method or the compound used as in any one of Examples III-1 to III-115, wherein the dose includes multiple administrations of Compound 1 or its pharmaceutically acceptable to one or both nostrils Salt.

Example III-117. The method or the compound used as in any one of Examples III-1 to III-115, wherein the dose comprises a single administration of Compound 1 to one or both nostrils or its pharmaceutically acceptable Salt.

Example III-118. The method or the compound used as in any one of Examples III-1 to III-117, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered to one nostril per dose.

Example III-119. The method or the compound used as in any one of Examples III-1 to III-117, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered to two nostrils per dose.

Example III-120. The method or the compound used as in any one of Examples III-1 to III-119, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered for at least 28 days.

Example III-121. The method or the compound used as in any one of Examples III-1 to III-119, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered for at least 3 months.

Example III-122. The method or the compound used as in any one of Examples III-1 to III-121, wherein the individual has undergone Lasik surgery within 2 weeks or is scheduled to undergo Lasik surgery within 2 weeks.

Example III-123. The method or the compound used as in any one of Examples III-1 to III-122, wherein the individual does not experience one or more side effects selected from the group consisting of: excessive tear production, Cough, throat irritation, drip irritation, sneezing, nasopharyngitis, nasal irritation, toothache, dry mouth and headache.

Example III-124. The method as in Example III-123 or the compound used, wherein within 5 minutes to 60 minutes of the administration of the first dose or one or more subsequent doses, the individual does not experience One or more side effects of the group: excessive tear production, cough, throat irritation, irritation at the instillation site, sneezing, nasopharyngitis, irritation of the nose, toothache, dry mouth and headache.

Example III-125. The method or the compound used as in any one of Examples III-1 to III-124, wherein excessive tear production is indicated by an increase in the Sgomer score of the individual by more than 20 mm.

Embodiment III-126. The method as in any of Embodiments III-1 to III-125 or the compound used, wherein the method does not include the administration of a positive ectopic modulator to the individual.

Example III-127. The method or the compound used in any one of Examples III-1 to III-126, wherein the plasma Cmax of Compound 1 or a pharmaceutically acceptable salt thereof of an individual in need is less than 5 ng/mL.

Example III-128. The method or the compound used in any one of Examples III-1 to III-127, wherein 150-300 micrograms of Compound 1 per dose, or a corresponding amount of a pharmaceutically acceptable salt thereof The system is administered to the individual.

Example III-129. The method or the compound used in any one of Examples III-1 to III-127, wherein 900-1200 micrograms of Compound 1 per dose, or a corresponding amount of a pharmaceutically acceptable salt thereof The system is administered to the individual.

Embodiment III-130. The method or the compound used in any one of Embodiments III-50 to III-97, wherein at least the nicotinic acetylcholine α4α6β2 receptor is pharmacologically stimulated.

Example III-131. The method or the compound used as in any one of Examples III-1 to III-130, wherein the pharmaceutically acceptable salt is the hemi-galactonate salt of Compound 1.

Embodiment III-132. The method or the compound used as in any one of Embodiments III-1 to III-130, wherein the pharmaceutically acceptable salt is the citrate salt of Compound 1.

， 或其醫藥學上可接受之鹽。Example III-133. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to treat dry eye disease, increase tear production or reduce eye discomfort for individuals in need, The nicotinic acetylcholine receptor agonist is compound 1 with the following structure

, Or a pharmaceutically acceptable salt thereof.

， 或其醫藥學上可接受之鹽。Example III-134. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to stimulate the nicotinic acetylcholine α4β2 receptor in an individual in need, or tobacco Alkaline acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof, wherein the nicotinic acetylcholine receptor agonist has the following structure Compound 1

, Or a pharmaceutically acceptable salt thereof.

， 或其醫藥學上可接受之鹽。Example III-135. A pharmaceutical formulation for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need, the formulation comprises Compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof.

， 或其醫藥學上可接受之鹽。Example III-136. A pharmaceutical formulation for use in nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 in individuals in need Receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof for pharmacological stimulation, the formulation contains compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof.

Embodiment III-137. The pharmaceutical formulation as in Embodiment III-135 or III-136, wherein the use includes the method as defined in any one of Embodiments III-1 to III-132.

Example III-138. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 5-4000 micrograms of Compound 1 per dose, or a corresponding amount of its pharmaceutically acceptable salt.

Example III-139. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 900-3000 micrograms of Compound 1 per dose, or a corresponding amount of its pharmaceutically acceptable salt.

Example III-140. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 1000-2500 micrograms of Compound 1 per dose, or a corresponding amount of its pharmaceutically acceptable salt.

Example III-141. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 1500-3000 micrograms of Compound 1 per dose, or a corresponding amount of its pharmaceutically acceptable salt.

Example III-142. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 150-300 micrograms of Compound 1 per dose, or a corresponding amount of its pharmaceutically acceptable salt.

Example III-143. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 900-1200 micrograms of Compound 1 per dose, or a corresponding amount of its pharmaceutically acceptable salt.

Example III-144. The pharmaceutical formulation of any one of Examples III-135 to III-137, which contains 900-1200 micrograms of Compound 1 per dose, or a corresponding amount of its pharmaceutically acceptable salt.

Embodiment III-145. The pharmaceutical formulation according to any one of embodiments III-135 to III-144, wherein the volume of the pharmaceutical formulation per dose is 50-250 microliters.

Embodiment III-146. The pharmaceutical formulation of any one of Embodiments III-135 to III-144, wherein the volume of the pharmaceutical formulation per dose is 150-250 microliters.

Example III-147. The pharmaceutical formulation according to any one of Examples III-135 to III-146, which contains Compound 1 between 1 mg/mL and 40 mg/mL, or a corresponding amount of its pharmaceutical Acceptable salt.

Example III-148. The pharmaceutical formulation according to any one of Examples III-135 to III-147, wherein Compound 1 is a pharmaceutically acceptable salt.

Embodiment III-149. The pharmaceutical formulation according to any one of Embodiments III-135 to III-148, wherein the pharmaceutically acceptable salt is the hemi-galactonate salt of Compound 1.

Embodiment III-150. The pharmaceutical formulation of any one of Embodiments III-135 to III-148, wherein the pharmaceutically acceptable salt is the citrate salt of Compound 1.

Example IV-1. A method for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need, which includes

，或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量；其中該方法造成有效治療該有需要之個體。An effective amount of Compound 1 having the following structure is administered to the nasal cavity of an individual in need

, Or the first dose of its pharmaceutically acceptable salt and one or more subsequent doses as appropriate; where the method results in effective treatment of the individual in need.

，或其醫藥學上可接受之鹽；其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量，及視情況選用之一或多個後續劑量。Example IV-2. A compound for a method for treating dry eye disease, increasing tear production or reducing eye discomfort in an individual in need thereof, wherein the compound is Compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof; wherein the method comprises administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of an individual in need, and one of them is used as appropriate Or multiple subsequent doses.

Example IV-3. The compound as used in Example IV-2, wherein the method results in effective treatment of the individual in need.

Example IV-4. The method as in Example IV-1 or the compound as in Example IV-3, wherein the effective treatment of the individual is indicated by one or more tests selected from the group consisting of: a) according to vision The dry eye score test on the analog scale, b) Sgormer test, c) corneal fluorescein stain test according to the National Institute of Ophthalmology (NEI) grading system, and d) ocular surface disease index test.

Example IV-5. As in the method of Example IV-4 or the compound used, wherein the effective treatment is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is Determined after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof or one or more subsequent doses as appropriate to the individual, and wherein the individual's dry eye score is compared to a) The dry eye score of the individual prior to the administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) the dry eye score of the individual receiving the control; or c) the individual receiving the comparative compound Dry eye score.

Example IV-6. As in the method of Example IV-5 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 15%.

Example IV-7. The method as in Example IV-5 or IV-6 or the compound used, wherein the individual's dry eye score statistically decreased between 10 mm and 20 mm.

Example IV-8. The method or the compound used as in any of Examples IV-5 to IV-7, wherein the statistically significant decrease in the individual's dry eye score is at least 3 mm.

Example IV-9. The method or the compound used as in any one of Examples IV-5 to IV-8, wherein the statistically significant decrease in the individual's dry eye score is when an effective amount of Compound 1 or its Within 5 minutes of the first dose of a pharmaceutically acceptable salt.

Example IV-10. The method or the compound used in any one of Examples IV-5 to IV-9, wherein the individual's dry eye score statistically significantly improves the self-administered effective amount of Compound 1 or its medicine The first dose of academically acceptable salt is maintained for at least 30 minutes.

Example IV-11. As in the method of Example IV-10 or the compound used, the individual is present in an environment with reduced humidity between the determination of the individual's dry eye score.

Example IV-12. The method or the compound used in any one of Examples IV-4 to IV-11, wherein the effective treatment is indicated by a statistically significant increase in the individual's Sgormer score, and wherein the individual's The statistically significant increase in the Sgomer score of at least one eye is after administering to the individual an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof or one or more subsequent doses as appropriate Measured, and where the individual's Sgormer score is compared to a) the Sgormer score of the same eye of the individual before administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) receiving the administration Sgormer scores for individuals in the control; or c) Sgormer scores for individuals receiving the comparative compound.

Example IV-13. As in the method of Example IV-12 or the compound used, the Sgormer score of the individual statistically increased significantly by at least 15%.

Example IV-14. As in the method of Example IV-12 or IV-13 or the compound used, the Sgormer score of the individual increases statistically significantly between 10 mm and 20 mm.

Example IV-15. As in the method of Example IV-12 or IV-13 or the compound used, the Sgormer score of the individual increases statistically significantly by at least 3 mm.

Example IV-16. The method or the compound used as in any one of Examples IV-12 to IV-15, wherein the statistically significant increase in the individual's Sgormer score is when an effective amount of Compound 1 or Within 5 minutes of the first dose of its pharmaceutically acceptable salt.

Example IV-17. The method or the compound used in any one of Examples IV-12 to IV-16, wherein the statistical increase in the individual's Sgormer score significantly improves the self-administered effective amount of Compound 1 or its The first dose of pharmaceutically acceptable salt is maintained for at least 30 minutes.

Example IV-18. The method or compound used in any one of Examples IV-4 to IV-17, wherein the effective treatment is indicated by a statistically significant drop in the individual's corneal score, and wherein the individual's corneal score The statistically significant decrease is determined after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the individual or optionally selecting one or more subsequent doses, and wherein the individual's dry eye score Compared to a) the corneal score of the individual before administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) the corneal score of the individual who received the control; or c) the individual who received the comparative compound Corneal score.

Example IV-19. As in the method of Example IV-18 or the compound used, the individual's corneal score statistically decreased by at least 15%.

Example IV-20. The method or the compound used in any one of Examples IV-18 to IV-19, wherein the statistically significant decrease in the individual's corneal score is the administration of an effective amount of Compound 1 or its medicine Within 5 minutes of the first dose of the academically acceptable salt.

Example IV-21. The method or the compound used in any one of Examples IV-18 to IV-20, wherein the statistical evaluation of the individual's corneal score significantly improves the self-administered effective amount of Compound 1 or its pharmacology The first dose of the acceptable salt is maintained for at least 30 minutes.

Example IV-22. As in the method of Example IV-21 or the compound used, the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.

Example IV-23. The method or compound used in any one of Examples IV-4 to IV-22, wherein the effective treatment is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the individual's OSDI score The statistically significant decrease is determined after the administration of an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt or one or more subsequent doses as appropriate, and the individual’s OSDI score is Compared to a) the OSDI score of the individual before administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) the OSDI score of the individual who received the control; or c) the administration of the comparative compound The individual's OSDI score.

Example IV-24. As in the method of Example IV-23 or the compound used, the statistically significant decrease in the individual's OSDI score is at least 15%.

Example IV-25. The method or the compound used in any one of Examples IV-23 to IV-24, wherein the statistically significant decrease in the individual's OSDI score is when an effective amount of Compound 1 or its medicine is administered Within 5 minutes of the first dose of the academically acceptable salt.

Example IV-26. The method or compound used in any one of Examples IV-23 to IV-25, wherein the statistically significant improvement of the individual's OSDI score improves the self-administered effective amount of Compound 1 or its pharmaceuticals The first dose of the acceptable salt is maintained for at least 30 minutes.

Example IV-27. As in the method of Example IV-26 or the compound used, the individual is present in an environment with reduced humidity between the determination of the individual's corneal score.

之化合物1或其醫藥學上可接受之鹽之第一劑量及視情況選用之一或多個後續劑量。Example IV-28. A method for nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or tobacco in an individual in need Alkaline acetylcholine α4α6β2 receptor or a combination thereof for immediate and long-term pharmacological stimulation, which comprises administering an effective amount of a structure to the nasal cavity of an individual in need

The first dose of Compound 1 or its pharmaceutically acceptable salt and one or more subsequent doses are selected as appropriate.

之化合物1或其醫藥學上可接受之鹽；其中該方法包含向有需要之個體之鼻腔中投與有效量的化合物1或其醫藥學上可接受之鹽之第一劑量，及視情況選用之一或多個後續劑量。Example IV-29. A compound for use in an individual in need of nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor , Or a method for immediate and long-term pharmacological stimulation of nicotinic acetylcholine α4α6β2 receptor or a combination thereof, wherein the compound has a structure

Compound 1 or a pharmaceutically acceptable salt thereof; wherein the method comprises administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of an individual in need, and optionally One or more subsequent doses.

Example IV-30. The method as in Example IV-28 or the compound used in Example IV-29, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 receptor in the individual , Or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination of pharmacological stimuli is indicated by one or more tests selected from the group consisting of: a) according to visual analogue Table of dry eye score test, b) Sgormer test, c) corneal fluorescein staining test according to the National Institute of Ophthalmology (NEI) grading system, and d) eye surface disease index test.

Example IV-31. The method or the compound used in Example IV-30, wherein the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine in the individual The pharmacological stimulation of the choline α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's dry eye score, and the statistically significant decrease in the individual's dry eye score is Determined after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt or one or more subsequent doses as appropriate to the individual, where the individual's dry eye score is compared to a) at The dry eye score of the individual prior to the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) the dry eye score of the individual receiving the control; or c) the dry eye of the individual receiving the comparative compound Eye score.

Example IV-32. As in the method of Example IV-31 or the compound used, the statistically significant reduction in the individual's dry eye score is at least 15%.

Example IV-33. As in the method of Example IV-31 or IV-32 or the compound used, the individual's dry eye score statistically decreased between 10 mm and 20 mm.

Example IV-34. As in the method of Example IV-31 or IV-32 or the compound used, the statistically significant decrease in the individual's dry eye score is at least 3 mm.

Example IV-35. The method or the compound used as in any one of Examples IV-31 to IV-34, wherein the statistically significant decrease in the individual's dry eye score is when administering an effective amount of Compound 1 or Within 5 minutes of the first dose of a pharmaceutically acceptable salt.

Example IV-36. The method or the compound used in any one of Examples IV-31 to IV-35, wherein the statistical evaluation of the individual's dry eye score significantly improves the self-administered effective amount of Compound 1 or its medicine The first dose of academically acceptable salt is maintained for at least 30 minutes.

Example IV-37. The method or the compound used in any one of Examples IV-30 to IV-36, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor, or a combination thereof is indicated by a statistically significant increase in the individual’s Sgormer score, and of which the individual’s The statistically significant increase in the Sgomer score of at least one eye is after administering to the individual an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof or one or more subsequent doses as appropriate Measured, and where the individual's Sgormer score is compared to a) the Sgormer score of the same eye of the individual before administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) receiving the administration Sgormer scores of individuals in the control; or c) Sgormer scores in individuals receiving the comparative compound.

Example IV-38. As in the method of Example IV-37 or the compound used, the Sgormer score of the individual statistically increased by at least 15%.

Example IV-39. As in the method of Example IV-37 or IV-38 or the compound used, the Sgormer score of the individual statistically increased significantly between 10 mm and 20 mm.

Example IV-40. As in the method of Example IV-37 or IV-38 or the compound used, the Sgormer score of the individual statistically increased significantly by at least 3 mm.

Example IV-41. The method or the compound used in any one of Examples IV-30 to IV-40, in which the α4β2 receptor in an individual, or the nicotinic acetylcholine α3β4 receptor, or nicotine The pharmacological stimulation of acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's corneal score, and the statistically significant decrease in the individual's corneal score is Determined after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof or one or more subsequent doses as appropriate to the individual, and wherein the individual's dry eye score is compared to a) The corneal score of an individual prior to the administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) the corneal score of the individual receiving the control; or c) the corneal score of the individual receiving the comparative compound .

Example IV-42. As in the method of Example IV-41 or the compound used, a statistically significant drop in the individual's corneal score is at least 15%.

Example IV-43. The method or the compound used in any one of Examples IV-30 to IV-42, wherein the nicotinic acetylcholine α4β2 receptor or nicotinic acetylcholine α3β4 in the individual The pharmacological stimulation of the receptor, or the nicotinic acetylcholine α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor, or a combination thereof is indicated by a statistically significant decrease in the individual’s OSDI score, and the individual’s OSDI score The statistically significant decrease is determined after the administration of an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt or one or more subsequent doses as appropriate, and the individual’s OSDI score is Compared to a) the OSDI score of the individual before administration of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) the OSDI score of the individual who received the control; or c) the administration of the comparative compound The individual's OSDI score.

Example IV-44. As in the method of Example IV-43 or the compound used, the statistically significant decrease in the individual's OSDI score is at least 15%.

Example IV-45. The method or the compound used in any one of Examples IV-28 to IV-44, wherein at least the nicotinic acetylcholine α4β2 receptor is pharmacologically stimulated.

Example IV-46. The method or the compound used in any one of Examples IV-28 to IV-44, wherein at least the nicotinic acetylcholine α3β4 receptor is pharmacologically stimulated.

Example IV-47. The method or the compound used in any one of Examples IV-28 to IV-44, wherein at least the nicotinic acetylcholine α3α5β4 receptor is pharmacologically stimulated.

Example IV-48. The method or the compound used in any one of Examples IV-1 to IV-47, wherein 5-4000 micrograms of Compound 1 per dose, or a corresponding amount of its pharmaceutically acceptable salt The system is administered to the individual.

Example IV-49. The method or the compound used in any one of Examples IV-1 to IV-48, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally And, and the total volume of each dose of pharmaceutical formulation is 150-250 microliters.

Example IV-50. The method or the compound used in any one of Examples IV-1 to IV-49, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally In contrast, the pharmaceutical formulation contains between 1 mg/mL and 40 mg/mL of Compound 1, or a corresponding amount of its pharmaceutically acceptable salt.

Example IV-51. The method or compound used in any one of Examples IV-49 to IV-50, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally And, and the total volume of the pharmaceutical formulation administered to each nostril is 50-250 microliters.

Example IV-52. The method or the compound used in any one of Examples IV-1 to IV-51, wherein the dose is administered to an individual in need one to four times a day after the first day of administration.

Example IV-53. The method or the compound used in any one of Examples IV-1 to IV-51, wherein the dose is administered to an individual in need once a day after the first day of administration.

Example IV-54. The method or the compound used as in any one of Examples IV-1 to IV-51, wherein a) the dosage frequency of Compound 1 or a pharmaceutically acceptable salt thereof administered to an individual Decrease over time, or b) the total amount of Compound 1 per dose, or the corresponding amount of its pharmaceutically acceptable salt, decreases over time.

Example IV-55. As in the method of Example IV-54 or the compound used, wherein each dose includes administration of Compound 1 or a pharmaceutically acceptable salt thereof to the individual's nasal cavity more than once, and over time Progression to reduce the total amount of Compound 1 per dose or the corresponding amount of its pharmaceutically acceptable salt is achieved by reducing the number of times Compound 1 or its pharmaceutically acceptable salt is administered to the individual's nasal cavity .

Example IV-56. The method or the compound used as in any one of Examples IV-1 to IV-55, wherein the dose includes multiple administrations of Compound 1 to one or both nostrils or its pharmaceutically acceptable Salt.

Example IV-57. The method or the compound used as in any one of Examples IV-1 to IV-55, wherein the dose includes a single administration of Compound 1 to one or both nostrils or its pharmaceutically acceptable Salt.

Example IV-58. The method or compound used in any one of Examples IV-1 to IV-57, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered for at least 28 days.

Embodiment IV-59. The method or the compound used as in any of Embodiments IV-1 to IV-57, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered for at least 3 months.

Example IV-60. The method or the compound used in any one of Examples IV-1 to IV-59, wherein the individual has undergone Lasik surgery within 2 weeks or is scheduled to perform Lasik surgery within 2 weeks.

Example IV-61. The method or compound used in any one of Examples IV-1 to IV-60, wherein the individual does not experience one or more side effects selected from the group consisting of: excessive tear production, Cough, throat irritation, drip irritation, sneezing, nasopharyngitis, nasal irritation, toothache, dry mouth and headache.

Example IV-62. The method as in Example IV-61 or the compound used, wherein within 5 minutes to 60 minutes of the administration of the first dose or one or more subsequent doses, the individual will not experience One or more side effects of the group: excessive tear production, cough, throat irritation, irritation at the instillation site, sneezing, nasopharyngitis, irritation of the nose, toothache, dry mouth and headache.

Example IV-63. The method or the compound used as in any of Examples IV-1 to IV-62, wherein excessive tear production is indicated by an increase in the Sgomer score of the individual by more than 20 mm.

Example IV-64. The method or the compound used in any one of Examples IV-1 to IV-63, wherein the method does not include the administration of a positive ectopic modulator to the individual.

Example IV-65. The method or the compound used in any one of Examples IV-1 to IV-64, wherein the plasma Cmax of Compound 1 or a pharmaceutically acceptable salt of an individual in need thereof is less than 5 ng/mL.

Example IV-66. The method or the compound used in any one of Examples IV-1 to IV-65, wherein 150-300 micrograms of Compound 1 per dose, or a corresponding amount of a pharmaceutically acceptable salt thereof The system is administered to the individual.

Example IV-67. The method or the compound used in any one of Examples IV-1 to IV-65, wherein 900-1200 micrograms of Compound 1 per dose, or a corresponding amount of a pharmaceutically acceptable salt thereof The system is administered to the individual.

Example IV-68. The method or the compound used in any one of Examples IV-1 to IV-67, wherein the pharmaceutically acceptable salt is the hemi-galactonate salt of Compound 1.

Example IV-69. The method or the compound used in any one of Examples IV-1 to IV-67, wherein the pharmaceutically acceptable salt is the citrate salt of Compound 1.

之化合物1或其醫藥學上可接受之鹽。Example IV-70. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to treat dry eye disease, increase tear production, or reduce eye discomfort for individuals in need, The nicotinic acetylcholine receptor agonist has a structure

Compound 1 or a pharmaceutically acceptable salt thereof.

之化合物1或其醫藥學上可接受之鹽。Example IV-71. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to stimulate the nicotinic acetylcholine α4β2 receptor in an individual in need, or smoke Alkaline acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof, wherein the nicotinic acetylcholine receptor agonist is structured

Compound 1 or a pharmaceutically acceptable salt thereof.

之化合物1或其醫藥學上可接受之鹽。Example IV-72. A pharmaceutical formulation for treating dry eye disease, increasing tear production, or reducing eye discomfort for an individual in need, the formulation comprises a structure

Compound 1 or a pharmaceutically acceptable salt thereof.

之化合物1或其醫藥學上可接受之鹽。Example IV-73. A pharmaceutical formulation for the use of nicotinic acetylcholine α4β2 receptors, or nicotinic acetylcholine α3β4 receptors, or nicotinic acetylcholine α3α5β4 in individuals in need Receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof for pharmacological stimulation, the formulation contains a structure

Compound 1 or a pharmaceutically acceptable salt thereof.

Example IV-74. The pharmaceutical formulation as in Example IV-72 or IV-73, wherein the use includes the method as defined in any one of Examples IV-1 to IV-69.

Example IV-75. The pharmaceutical formulation according to any one of Examples IV-72 to IV-74, which contains 5-4000 micrograms of Compound 1 per dose, or a corresponding amount of its pharmaceutically acceptable salt.

Embodiment IV-76. The pharmaceutical formulation of any of embodiments IV-72 to IV-75, wherein the volume of the pharmaceutical formulation per dose is 50-250 microliters.

Example IV-77. The pharmaceutical formulation as in any of Examples IV-72 to IV-76, which contains Compound 1 between 1 mg/mL and 40 mg/mL, or a corresponding amount of its pharmaceutical Acceptable salt.

Example IV-78. The pharmaceutical formulation according to any one of Examples IV-72 to IV-77, wherein the pharmaceutically acceptable salt is the hemi-galactonate salt of Compound 1.

Example IV-79. The pharmaceutical formulation of any one of Examples IV-72 to IV-77, wherein the pharmaceutically acceptable salt is the citrate salt of Compound 1. EXAMPLES Example 1: Compound 1 Semi - mucate dihydrate of the human nAChR agonist and antagonist properties

5.2    參考 產品編號/代碼：       HiQACh 同義名：                 氯化乙醯膽鹼 化合物製劑              重蒸餾水中之100 mM儲備溶液 5.3    測試系統 設備：                    Automated Injection and Recording Apparatus，HiQScreen 供體動物物種：        爪蟾屬 動物品系：              非洲爪蟾 動物體重：              150 g至300 g 動物飼養                 每個飼養室3至5隻 室溫：                    20-22℃ 光照時間：              飼養室暴露於日光及額外人工照明(在夏季6 am-8 pm；在冬季8 am-7 pm)。 食物：                    食物糰粒，任意 生物材料來源及分離程序： 腹部切口以移除卵巢 活體外實驗條件：     卵母細胞培育：Barth溶液，含有(以mM計) NaCl 88、KCl 1、NaHCO₃ 2.4、HEPES 10、MgSO₄ .7H₂ O 0.82、Ca(NO₃ )₂ .4H₂ O 0.33、CaCl₂ .6H₂ O 0.41，pH 7.4，且補充有100單位/毫升青黴素 卵母細胞記錄：OR2培養基，含有(以mM計)：NaCl 88.5、KCl 2.5、HEPES 5、CaCl₂ .2H₂ O 1.8、MgCl₂ .6H₂ O 1，pH 7.4。 測試程序：              雙電極電壓鉗，使用Geneclamp放大器(Axon Instrument, Foster City, California, USA)或HiClamp (Multichannel Systems, Germany)之專用自動系統 5.4    觀測及量測 5.4.1  卵母細胞製備This example description was conducted to characterize the human neuron nicotinic acetylcholine receptor (nAChR) α3β4, α3α5β4, α4β2, and α7 expressed in compound 1 galactose dihydrate dihydrate in Xenopus oocytes Experiment of the role of the place. List of abbreviations ACh Acetylcholine nAChR Nicotinic Acetylcholine Receptor SEM Mean Standard Error 5 Materials and Methods 5.1 Test Compound

5.2 Reference product number/code: HiQACh Synonymous name: 100 mM stock solution of acetylcholine chloride compound preparation in distilled water 5.3 Test system equipment: Automated Injection and Recording Apparatus, HiQScreen Donor animal species: Xenopus animal strains: Xenopus animal body weight: 150 g to 300 g Animal feeding 3 to 5 animals per feeding room Room temperature: 20-22°C Lighting time: The feeding room is exposed to sunlight and additional artificial lighting (in summer 6 am-8 pm; in Winter 8 am-7 pm). Food: Food pellets, any source of biological materials and separation procedures: Intra-abdominal incision to remove ovaries In vitro experimental conditions: Oocyte cultivation: Barth solution, containing (in mM) NaCl 88, KCl 1, NaHCO ₃ 2.4, HEPES 10. MgSO ₄ .7H ₂ O 0.82, Ca(NO ₃ ) ₂ .4H ₂ O 0.33, CaCl ₂ .6H ₂ O 0.41, pH 7.4, and supplemented with 100 units/ml penicillin oocyte Record: OR2 medium, containing (In mM): NaCl 88.5, KCl 2.5, HEPES 5, CaCl ₂ .2H ₂ O 1.8, MgCl ₂ .6H ₂ O 1, pH 7.4. Test procedure: Two-electrode voltage clamp, using Geneclamp amplifier (Axon Instrument, Foster City, California, USA) or HiClamp (Multichannel Systems, Germany) special automatic system 5.4 Observation and measurement 5.4.1 Oocyte preparation

All experiments were performed on human nAChR expressed in Xenopus oocytes using the cDNA expression method. Xenopus oocyte cell lines were prepared and injected using standard procedures.

Briefly, ovaries were harvested from female clawed toads, which had been cooled by 4°C and sodium bicarbonate containing tricaine mesylate (MS-222, concentration 150 mg/L) (300 mg/L) deep anesthesia. Once anesthetized, animals are deheaded and marrowed in accordance with the animal rights rules of the Canton of Geneva. A small piece of ovary is isolated for immediate preparation, while the rest is placed in a sterile Barth solution at 4°C, which contains (in mM) NaCl 88, KCl 1, NaHCO ₃ 2.4, HEPES 10, MgSO ₄ .7H ₂ O 0.82, Ca(NO ₃ ) ₂ .4H ₂ O 0.33, CaCl ₂ .6H ₂ O 0.41 at pH 7.4, supplemented with 20 µg/ml concomycin and 100 units/ml penicillin. All recordings were performed at 18°C and cells were poured with OR2 medium containing (in mM): NaCl 88, KCl 2.5, HEPES 5, CaCl ₂ .2H ₂ O 1.8, MgCl ₂ .6H ₂ O 1, pH 7.4 . 5.4.2 Electrophysiological records

The current induced by ACh or other agonists is recorded using an automatic process equipped with a standard two-electrode voltage clamp configuration (TEVC). The data was acquired and analyzed using HiQScreen special data acquisition and analysis software running according to Matlab (Mathworks Inc.). 5.4.3 Preparation of agonists

ACh is prepared as a concentrated stock solution (10 ^-1 M) in water and then diluted in recording medium to obtain the desired test concentration. The compound was dissolved in OR2 as a stock solution (1 mM) and was finally diluted to the desired concentration on the day of the experiment.

The tested concentrations of Compound 1 galactate diacid salt were (in micromolar) 0.1, 0.3, 1, 3, 10, 30, 100 and 300. The test concentration of acetylcholine chloride is 1280 micromolar. 5.4.4 Data analysis and statistics

For statistical analysis, the values are calculated using Excel (Microsoft) or Matlab (Mathworks Inc.). To obtain an average measurement with standard deviation, all experiments were performed using at least three cells. 5.4.5 Experimental procedures

Injection of cDNA encoding human α3β4, α3α5β4, α4β2 was performed in at least 95 oocytes, using a dedicated automatic injection device (Hogg et al., J. Neurosci. Methods, 2008) and the recipient performance was checked at least two days later . The oocyte has two electrodes and its membrane potential is maintained at -80 mV throughout the experiment (unless indicated). Protocol to determine putative agonistic activity at human nAChR

The protocol sequence begins with steps 4-5 of taking oocytes from the load tray (step 1) and detecting the holding current and response to a short ACh test pulse (1280 µM). The cells showing steady current are then washed for 90 seconds (step 9). The recording sequence starts at step 10 and the compound is continuously applied for 10 seconds at 2 minute intervals (step 12). For the α7 receptor compound, the application was reduced to 5 seconds. The process itself (step 14) is repeated for the number of compounds and the number of cells (step 15).

To evaluate the potency properties of Compound 1 galactate dihydrate dihydrate, a protocol of short-term exposure to a series of growth concentrations of Compound 1 galactate dihydrate dihydrate was used.

To determine the possible antagonistic properties of the compound, the compound is applied pre-and co-applied, the cellular response to ACh (near EC ₅₀₎ of the first embodiment separately and then after exposure to the test compound application. The antagonistic properties of Compound 1 galactose dihydrate dihydrate were measured at human α3β4, α3α5β4, α4β2, and α7 nicotinic receptors. 7 results

The measurement of the agonistic effect of compound 1 gal-galactonate dihydrate at α3β4, α3α5β4, α4β2 and α7 receptors revealed that this compound acts as an agonist at these receptors in the range of 10 to 100 μM. However, significant differences were observed in the function of receptor subtypes. That is, compound 1 hemi-galactose dihydrate dihydrate is an inferior agonist at the human α7 receptor and induces only 24% of the maximum ACh evoked current at 300 μM. In contrast, the data from α4β2 revealed that Compound 1 galactate dihydrate dihydrate induced a current greater than about 2 times the maximum ACh response. In addition, exposure to Compound 1 hemi-galactonate dihydrate enhanced the subsequent ACh-induced current. The data recorded at α3β4 and α3α5β4 show that Compound 1 galactose dihydrate dihydrate acts as an agonist at these receptors, evoking about 94% of the maximum ACh evoked current.

Experiments were conducted to determine the hypothetical agonistic activity of compound 1 galactose dihydrate dihydrate at human α3β4, α3α5β4, α4β2, and α7 nAChR. It was confirmed that compound 1 galactose dihydrate dihydrate was The body acts as an agonist. However, it is worth noting that compound 1 hemi-galactose dihydrate dihydrate induces a greater current at the heteromeric α4β2 receptor than the endogenous ligand acetylcholine (ACh), and also This receptor subtype is displayed at higher potency.

The determination of the antagonistic activity of Compound 1 galactate dihydrate dihydrate was performed using cumulative exposure in a low concentration range. The results obtained for compound 1 hemi-galactate dihydrate dihydrate show that this compound inhibits the α3α5β4 and α4β2 receptors in a concentration-dependent manner and the inhibition is incomplete and a flat line area is reached for the highest tested concentration. In contrast, no significant inhibition was observed at α3β4 or α7 receptors within the range tested in these experiments.

Desensitization experiments conducted with α3β4, α3α5β4, α4β2, and α7 nAChR showed significant differences in receptor subtype function. Although α3β4 and α7 receptors were not sensitive to continuous exposure to Compound 1 galactose dihydrate dihydrate at concentrations up to 300 nM, significant inhibition was observed at α3α5β4 and α4β2 receptors. However, inhibition of reaching the level of the flat line at the highest concentration tested indicates that this compound can only cause partial desensitization within the experimental conditions. Desensitization experiments performed at α3β4, α3α5β4, α4β2, and α7 nAChR revealed that significant differences can be observed between these different receptor subtypes.

These data indicate that the performance of human nAChR in Xenopus oocytes provides an effective model for testing the functional agonistic and antagonistic activity against a given compound and that the agonist causes receptors at lower concentrations than required for activation Desensitization.

Compound 1 hemi-galactose dihydrate dihydrate acts almost as a full agonist at the α3β4 receptor. The EC50 is at 42.09±5.36 µM.

Compound 1 hemi-galactose dihydrate dihydrate acts almost as a full agonist at the α3α5β4 receptor. The EC50 is at 32.15±2.16 µM.

Compound 1 hemi-galactonate dihydrate acts as a more potent agonist at the α4β2 receptor than ACh. The EC50 is at 48.82±17.41 µM.

Compound 1 hemi-galactonate dihydrate is a more potent agonist at the α7 receptor than ACh. It should be noted that the EC50 is only an assessment in view of the small portion of the current induced by Compound 1 hemi-galactose dihydrate dihydrate. The EC50 is at 1261±500 µM.

The antagonistic properties of compound 1 hemi-galactose dihydrate dihydrate at human α3β4 nAChR were tested, however, since minimal inhibition of ACh-induced current was observed, no attempt was made to meet these results.

The antagonistic properties of Test Compound 1 gal-galactonate dihydrate at human α3α5β4 nAChR, and compared to α3β4, significant inhibition was observed at human α3α5β4 nAChR.

The test compound 1 galactose dihydrate dihydrate has antagonistic properties at human α4β2 nAChR, and compared with α3β4, significant inhibition with a stationary phase was also observed at human α4β2 nAChR.

The antagonistic properties of compound 1 hemi-galactonate dihydrate at human α7 nAChR were tested, and no significant inhibition at α7 nAChR was observed. Example 2: Compound 1 Semi - mucate dihydrate over 2 weeks, at low, clinical studies under the medium and high dose concentrations 2

縮寫清單

This example describes a study used to evaluate the safety and efficacy of Compound 1 Hemi-Galactose Dihydrate Nasal Spray for the signs and symptoms of dry eye disease compared to placebo. The results demonstrated that Compound 1 Hemi-Galactose Dihydrate Dihydrate (0.2%, 1.0%, 2.0%) nasal spray induces aqueous tear production and reduces the symptoms of dry eye disease in individuals diagnosed with dry eye disease. summary

List of abbreviations

When delivered in the form of an intranasal spray, Compound 1 hemi-galactonate dihydrate can promote nasolacrimal reflex activation and therefore represents a novel candidate for improving the signs and symptoms of dry eye disease.

This study will use artificially created adverse environmental models to assess dry eye symptoms. The artificially created unfavorable environment consists of rooms that standardize environmental conditions by regulating humidity, temperature, airflow, lighting conditions, and visual task assignment. Dry eye patients are exposed to an artificially created adverse environment for up to two hours, during which subjective and objective parameters can be evaluated before, during, and after exposure. The artificially created unfavorable environment represents the daily conditions encountered by patients with dry eyes, such as forced hot air heating systems, aircraft travel and computer use and allows the standardization of these variables. Overall study design

This is a phase 2, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety of Compound 1 Hemi-Galactose Dihydrate Nasal Spray for adult participants with dry eye disease Sex and efficacy. Approximately 160 individuals at least 22 years of age with a history of dry eye reported by the individual and meeting all other study eligibility criteria will be randomized to receive Compound 1 galactose dihydrate dihydrate or placebo on Visit 1 and Visit 2 Agent administration.

Participants who terminate early during the administration period will be required to complete a safety assessment (if the participant agrees) before the study exit. Participants who have terminated the study early will not be replaced. Research community

It is estimated that approximately 160 participants (approximately 40 per group) will register at up to 3 locations in the United States. Individuals will be randomly grouped to receive one of the following four dose distributions: Ÿ Placebo (vehicle) delivered as a 100 microliter (µL) intranasal spray in each nostril Ÿ 0.11% Compound 1 free base (0.2% Compound 1 hemi-galactose dihydrate dihydrate) delivered as a 100 µL intranasal spray in each nostril Ÿ 0.55% Compound 1 Free Base (1.0% Compound 1 Hemi-Galactose Dihydrate Dihydrate) delivered as a 100 µL intranasal spray in each nostril Ÿ 1.1% Compound 1 free base (2.0% Compound 1 hemi-galactose dihydrate dihydrate) delivered as 100 µL intranasal spray in each nostril

The individual will be administered Compound 1 galactose dihydrate dihydrate/placebo at Interview 1 and Interview 2.

All individuals must be at least 22 years old, of any gender, and of any ethnic origin, and must meet all inclusion criteria and do not meet any exclusion criteria. For inclusion and exclusion criteria, see the summary above.

Withdrawal criteria: If the individual’s safety has been compromised at any time during the study, the individual may withdraw from the study. Individuals may withdraw consent from the study at any time. Any individual may be discontinued during the study due to non-compliance or any effective medical reason. Main efficacy measure

The following main endpoints will be tested: Ÿ Stommer test at the 1st time of consultation Ÿ EDS at 2 o'clock Safety measures: adverse events (AE). Other measures: eye discomfort scale, urine pregnancy test (day 1)Formulation Ÿ Placebo (nasal spray of Compound 1 hemi-galactose dihydrate dihydrate vehicle) Ÿ 0.11% Compound 1 free base (0.2% Compound 1 hemi-galactose dihydrate dihydrate) Ÿ 0.55% Compound 1 free base (1.0% Compound 1 hemi-galactose dihydrate dihydrate) Ÿ 1.1% Compound 1 Free Base (2.0% Compound 1 Hemi-Galactose Dihydrate Dihydrate)Distribution schedule

At Interview 1, eligible individuals will be randomly grouped and the first dose of study drug will be administered in the office. At Interview 2, the individual will receive their second dose during the exposure of the artificially created adverse environment.

Compound 1 hemi-galactonate dihydrate/placebo will be formulated in sterile aqueous solution in phosphate buffered saline at the desired concentration (depending on dose group allocation) and presented in a single seal with a rubber stopper Used in glass bottles. The product contains no preservatives and is only intended for intranasal use. If the product is cloudy or if particles are present, it should not be used. The compound 1 hemi-galactose dihydrate dihydrate solution must be administered without dilution. Participant enters the program

Participants as defined by the inclusion criteria will be considered to enter this study.

Before the participant participates in the trial (that is, before the research-related procedures), the study will be discussed with each potential participant and the participant who wishes to participate must be regulated and use the Informed Consent Form (ICF) approved by the Institutional Review Board (IRB) ) Provide written informed consent. The ICF must be the latest version approved by the well-structured IRB.

Clearance interval: Prohibited drugs, treatments and activities are outlined in the exclusion criteria.

Final research entry procedure: The individual must meet all inclusion criteria and not meet any exclusion criteria. Assignment to treatment group

Screening numbers will be assigned to qualified individuals. All screening numbers will be assigned in a strict numerical sequence at one location and the numbers will not be skipped or omitted. If all the inclusion and exclusion criteria are met at the time of consultation 1, each eligible individual will then be assigned a random group number.

Random group scheduling will be provided to each research site. The randomization schedule will be stratified by the venue so that approximately equal numbers of individuals will be assigned to each of the four treatment groups at each venue. The site staff will assign the patient to the study set marked with the corresponding random group number. The random group number will be recorded on the patient's source file and electronic medical record report form (eCRF). Researchers will be masked during randomization and throughout the study. Concurrent therapy

The use of any concurrent medication, prescription or over-the-counter will be recorded on the individual's source file and corresponding eCRF along with the reason for taking the medication. It is not allowed to be enrolled in another study drug or device study at the same time. Prohibited drugs / treatment

Drugs/treatments not allowed during the study are outlined in the exclusion criteria. Drug evasion

This study does not require drug evasion. Special diet or activity

No special diet or activities are required for this study. Procedures for research objectives to be executed during each research consultation

The following procedures will be performed (for the description, see the section below titled Inspection Procedures, Tests, Equipment and Technology).inquiry 1 ( First 1 day ) : Screening and Sgormer Test Evaluation filter Ÿ Informed consent/Consent of Health Information Portability and Accountability Act (HIPAA) Ÿ Demographics, medical/medical treatment and eye history Ÿ Eligibility criteria Ÿ OSDI© Ÿ EDS (Visual Analogue Scale) Ÿ Eye Discomfort Scale Ÿ BCVA Ÿ Slit lamp biopsy Ÿ Corneal fluorescein staining Ÿ Gomer test (the procedure will be performed after corneal luciferin staining) Ÿ Sgormer test under nasal irritation (Cotton swab; Sgormer test under nasal irritation will be performed 10 minutes after the first Sgormer test) Ÿ Intranasal examination Ÿ Urine pregnancy test (if feasible) Ÿ Concomitant medication Ÿ AE inquirytreatment ( Skimer Test Evaluation ) Pre-treatment procedures:

Randomization: Qualified participants will be assigned to one of the following treatment groups: Ÿ Placebo (vehicle) delivered as a 100 µL intranasal spray in each nostril Ÿ 0.11% Compound 1 free base (0.2% Compound 1 hemi-galactose dihydrate dihydrate) delivered as a 100 µL intranasal spray in each nostril Ÿ 0.55% Compound 1 Free Base (1.0% Compound 1 Hemi-Galactose Dihydrate Dihydrate) delivered as a 100 µL intranasal spray in each nostril Ÿ 1.1% Compound 1 free base (2.0% Compound 1 hemi-galactose dihydrate dihydrate) delivered as 100 µL intranasal spray in each nostrilTreatment procedures : Ÿ Instruct individuals to administer research drugs/placebo Ÿ Treatment with research drugs/placeboPost-treatment procedures: Ÿ Gomer test after treatment (immediately after administration of research drug) Ÿ BCVA Ÿ Slit lamp biopsy Ÿ Endoscopic endoscopy Ÿ Concomitant medication Ÿ AE inquiry Ÿ Arrangement of participants in consultation 2inquiry 2 ( First 15+4 day ) : Unfavorable environment created artificially Ÿ Medical/medical treatment and eye history update Ÿ EDS Ÿ Eye Discomfort Scale Ÿ About 120 minutes of exposure to the artificially created adverse environment Ÿ EDS collected when entering an artificially created adverse environment and every 5 minutes thereafter. Ÿ Eye discomfort scale collected when entering an artificially created adverse environment and every 5 minutes thereafter. Ÿ Instruct individuals to administer research drugs/placebo Ÿ Treatment with research drugs/placebo Ÿ After using the Eye Discomfort Scale, participants will report the eye discomfort score of ≥3 in at least one eye at two or more consecutive time points during the artificially created adverse environmental exposure, and then invest in the research Drug/placebo treatment (if the participant has an eye discomfort rating of 3 for one eye at time=0, he must report an eye discomfort rating of 4 for that eye in two consecutive measurements). Participants will resume symptom evaluation every 5 minutes 1 minute after the end of administration. Ÿ BCVA Ÿ Slit lamp biopsy Ÿ Intranasal examination Ÿ Urine pregnancy test (if feasible) Ÿ Concomitant medication Ÿ AE inquiry Ÿ Research exportScheduled consultation

See the section below titled Interview and Measurement Schedule. Unscheduled consultation

These consultations can be conducted to ensure individual safety. All procedures performed during an unscheduled consultation will be recorded in the source file and on the unscheduled consultation eCRF page. Any unprocessed procedures indicated in the eCRF should be indicated as "Not done".

Assessments that can be performed during unscheduled consultations include: Ÿ slit lamp biopsy; Ÿ vision; Ÿ intranasal examination; Ÿ urine pregnancy test (if feasible); Ÿ assessment of AE; Ÿ assessment of concurrent medication and/or treatment; and Ÿ Any other assessment as judged by the investigator is necessary. Program compliance

Individuals will be instructed on how the study drug will be administered at visits 1 and 2 and provide detailed written instructions for review.

Dosage compliance will be based on the study drug used/unused at visits 1 and 2. Individual disposal

Completed individuals are those who have not been discontinued from the study.

The individual may be discontinued at any time before completing the study due to the following: Ÿ AE; Ÿ Unmask when medically necessary; Ÿ program violation; Ÿ Management reasons (for example, unable to continue, lost to follow-up); Ÿ Research termination; Ÿ Individual choice (eg withdrawal of consent); and Ÿ Other

Note: In addition, any individual may be suspended for any reasonable medical reason.

The notice of individual suspension and the reason for suspension will be clearly recorded on eCRF.

Suspended individuals will not be replaced. Study termination

Research can be stopped at any time. Study duration

Individual participation will involve 2 consultations and quality assurance in about 2 weeks (14 days)

During the research process, monitors or designated personnel will conduct routine on-site inspections to check protocol compliance, assess study drug traceability, individual safety, and ensure that research is conducted in accordance with relevant regulatory requirements. The review of individual medical records will be conducted in a way that maintains the confidentiality of the individual. Other details of the research monitoring will be outlined in the monitoring plan.

The supervisory authority may conduct on-site inspections and/or audits, which may include source data inspections. Therefore, inspection and/or auditing will require direct access to the original source material. All inspections and audits will be conducted taking into account data protection and individual confidentiality to the extent applicable by local, state, and federal laws. Adverse events

AE is defined as any adverse medical event related to the use of drugs in the human body, regardless of whether the event is considered to be drug-related. AE can therefore be any adverse and unexpected symptoms (eg, abnormal laboratory findings), symptoms, or disease that occur after starting to administer the study drug to the individual without any judgment of causality. Any pre-existing medical conditions that deteriorate after administration of the study drug will also be considered a new AE.

Study drugs include research drugs and placebos that are being evaluated.

The documentation about AE should be about the nature, start date, end date, severity, relationship with study drug, action taken, severity, and any signs or symptoms observed by the investigator or reported by the individual after indirect inquiry The results are carried out. Severity

The severity of AE is defined as the qualitative assessment of the degree of AE intensity as determined by the investigator or reported to it by the patient/individual. Severity assessments are conducted without regard to the relationship with the study drug or the severity of the event and should be evaluated according to the following scale:

Mild : The event is obvious to the individual, but is easily tolerated and does not interfere with the individual's daily activities.

Moderate : The event is troublesome, may require additional therapy, and may interfere with the individual's daily activities.

Severe : The event is intolerable, requires additional or altered therapy, and interferes with the individual's daily activities. Relationship with research drugs

The relationship between each AE and the research product should be determined by the investigator (in a blinded manner) using these interpretations:

Identify : When there is a good cause and sufficient documentation to demonstrate the direct causal relationship between the research product and AE

Most likely : when there are good reasons and sufficient documentation to assume causality in the sense that it seems reasonable, conceivable, possible but not necessarily highly likely

Possible : When there is sufficient information to accept the possibility of causality in the sense that it is not impossible and not unlikely, even though the association is due to, for example, missing data or insufficient evidence and is uncertain or in doubt

None : When there is enough information to accept a non-causal relationship (in the sense of impossible and unlikely)

Unclassified: When causality attributable to the lack of evidence for any of the causes of poor data or documents not conflict when assessing prospective

The anticipation of AE should be based on existing safety information about the study drug using these interpretations to determine:

Unexpected : AE not listed in the Investigator's Handbook (IB) or not under the specificity or severity observed.

Expected : AE listed in the specificity and severity observed in IB.

Not applicable : Any AE not related to the study drug.

Mentioned in IB as occurring in the case of a class of drugs or expected from the pharmacological properties of the drug, but not specifically mentioned as appearing in the case of the specific drug under investigation is considered unexpected. The investigator should initially classify the AE's expectations, but the final classification is subject to the medical inspector's judgment. Serious adverse event

If, in the eyes of the investigator, AE causes any of the following results, it is considered serious (SAE): Ÿ death Ÿ Life-threatening AE

Note: If it appears to the investigator that the occurrence of AE places the patient or individual at immediate risk of death, it is considered "life-threatening". It does not include AEs that may cause death if they occur in a more serious form. Ÿ Hospitalization or extension of existing hospitalization

Note: The term "hospitalization" refers to any admission (even if less than 24 hours). For chronic or long-term inpatients, admission includes transfer to emergency/intensive care inpatient wards within the hospital. Hospitalization does not include: emergency department; outpatient/same day/ambulatory surgery; observation/short stay in ward; rehabilitation facility; hospice facility; nursing home; or clinical research/1 phase unit.

Note: The term "extension of existing hospitalization" refers to any extended hospitalization that exceeds the expected or required stay for the initial admission determined by the investigator or treating physician. Ÿ Sustained or significant incapacity or significant disruption of normal life functions

Note: SAE, especially related to visual threats, will be interpreted as any potential loss or damage to the individual's eyes (such as bleeding, retinal detachment, central corneal ulcer, or optic nerve damage). Ÿ Congenital anomalies/born defects.

When, based on appropriate medical judgment, a patient or individual may be endangered and medical or surgical intervention may be required to prevent one of the results listed in this definition, a major medical event that may not result in death, life-threatening and requires hospitalization may be considered serious. Procedures for reporting adverse events

All AEs and their results must be reported to the investigator and IRB/IEC, as required by the IRB/IEC, federal, state or local regulations, and health management authorities, and recorded on the appropriate eCRF.

All "suspicious" and "unexpected" AEs should be reported to investigators and IRB/IEC, as required by IRB/IEC, federal, state or local regulations and health management authorities.

To ensure individual safety, all SAEs must report immediately regardless of the relationship with the study drug. All information related to SAE must be recorded on the appropriate CRF. In addition to the information reported on the CRF, the investigator is also obliged to pursue and obtain the information requested by the investigator. All individuals undergoing SAE must be followed up and report the results.

If SAE occurs, the investigator must obtain and maintain all relevant medical records, information, and medical judgments from colleagues who assist the individual in treatment and follow-up in their files; provide a complete medical record, including information about whether the event is suspected to be related to the use of study drugs Statement; and inform SAE's IRB to report SAE in its guidelines. Procedures for unmasking research drugs

All individuals, investigators, and researchers involved in conducting the study will be covered regarding treatment allocation. When medically necessary, the investigator may need to determine to which treatment group the individual has been assigned. Unmasking the individual will stop the study. Type and duration of individual follow-up after adverse events

The investigator will track unresolved AEs until resolution, until the individual is lost to follow-up or until AEs are classified in other ways. Resolution means that the individual has returned to baseline health or the investigator does not expect any further improvement or deterioration of AE. If the patient is lost to follow-up, the investigator should make 3 reasonable attempts to contact the patient by phone, mail or guarantee mail. All follow-up visits will be recorded in the source file of the individual. The non-serious AE identified at the last scheduled contact must be recorded on the AE eCRF with the status noted.

If the investigator is aware of any new information about the existing SAE (ie, resolution, status change, or new treatment), then the new SAE/unexpected report form must be completed and faxed within 24 hours of being aware of the new information. The original SAE table is unchanged. The report should describe how the incident has been resolved or continued and how to handle the incident.Statistical assumptions and methods of analysis Analysis group

The following analysis groups will be considered:

Treatment Intention Group-The treatment intent (ITT) group includes all randomly grouped individuals. Individuals in the ITT group will be analyzed in random groups.

Compliant protocol groups-Compliant protocol (PP) groups include individuals in the ITT population who do not have significant protocol deviations and complete the study. Plan deviations will be evaluated before the database is locked and unmasked. Individuals in the PP group will be analyzed in the form of treatment.

Safe group-The safe group includes all individuals who receive at least one dose of the research product. Individuals in the safe group will be analyzed in the form of treatment.

The safety data will be statistically analyzed for the safety groups. The baseline and efficacy data of the ITT population will be analyzed. The efficacy analysis of the PP population will also be conducted as a sensitivity analysis. Statistical assumptions

H ₀₁ : There is no difference between the stommer test result and the placebo in the nasal spray of Compound 1 hemi-galactate dihydrate nasal spray (low dose, medium dose or high dose).

H ₁₁ : There is a difference between the compound 1 gal-galactonate dihydrate nasal spray (low dose, medium dose or high dose) and placebo in the change of the Sgormer test results from the baseline.

H ₀₂ : In the change of EDS from before treatment to after treatment, there was no difference between Compound 1 galactose dihydrate dihydrate nasal spray (low dose, medium dose or high dose) and placebo.

H ₁₂ : In the change of EDS from before treatment to after treatment, there is a difference between Compound 1 galactate dihydrate dihydrate nasal spray (low dose, medium dose or high dose) and placebo.

A successful result will be the result of rejecting the two null hypotheses (H ₀₁ and H ₀₂ ). Sample size

The sample size of this study is not based on statistical power considerations. We expect that approximately 40 individuals will be registered in each of the four treatment groups, for a total of approximately 160 randomized individuals. Assuming a 5% withdrawal rate, it is expected that approximately 38 individuals from each group will be fully studied.Statistical Analysis General considerations

Quantitative variables will be summarized using the number of individuals (n), mean, median, standard deviation, minimum and maximum. Qualitative variables are outlined using counts and percentages.

All overviews will be presented by the treatment group. The overview will be provided for demographic data, medical history, concomitant medications and individual treatment.

For overview purposes, medical history, concomitant medications, and AEs will be coded according to MedDRA and the World Health Organization Drug Dictionary as needed.

Baseline measurement is defined as the last measurement prior to the initiation of study treatment, usually at the time of Screening for Interview 1. Unit of analysis

Analyze the safety endpoint of both eyes. For the efficacy endpoint, the unit of analysis will be the research eye defined as follows:

Research eyes are defined as those that meet all inclusion/elimination criteria; if both eyes are qualified, the use of cotton swabs to stimulate the eyes that produce the most tears during screening interviews, or if there is no difference in the stimulation of tears, then Eyes with a lower basic Sgormer score at the time of screening. If there is no difference in any measurement, the right eye is used as the research eye. Missing data

The preliminary analysis will be performed using observation data (without filling in missing data). The sensitivity analysis of the main efficacy analysis will be performed using the Markov Chain Monte Carlo multiple filling method to fill in the missing data. It is expected that the rate of missing data is low; however, if the rate of missing data exceeds 5%, additional missing data filling methods (such as critical point analysis) will be used to understand the potential impact of missing data on preliminary results.

Only observed data will be used for other power analysis. Multiple considerations

This early study will not implement adjustments for multiple tests. Main efficacy analysis

The main efficacy analysis will be based on the following endpoints: Stommer test at 1 o'clock At the time of consultation 2, the dry eye score during the exposure to the artificially created adverse environment

The Gomer test and dry eye scoring will be summarized using quantitative descriptive statistics (n, mean, median, standard deviation, minimum and maximum) by questioning, time point (where appropriate) and treatment.

The ANCOVA model was used to compare the results of the Sgormer test for the simultaneous treatment of nasal sprays of Compound 1 hemi-galactate dihydrate nasal spray and placebo at each dose. The ANCOVA model will include a baseline Sgormer test (taken at the time of screening), with treatment and study site as covariates. From this ANCOVA model, the minimum mean square (LS mean) of each treatment method, the corresponding 95% confidence interval (CI), and the dose of Compound 1 galactose dihydrate dihydrate nasal spray and placebo were calculated. The difference between the estimated processing methods. In addition, in an independent model, the study site is explored through interaction of treatment methods to assess possible differences in treatment effects between study sites.

The change of EDS from before treatment to after treatment will be analyzed using the ANCOVA model, with pre-treatment EDS as a covariate and treatment and time point as a fixed effect (considering repeated measurements). The LS mean of each treatment, the corresponding treatment difference between 95% CI and each dose of Compound 1 galactate dihydrate nasal spray and placebo will be calculated from this ANCOVA model. The study site will also be explored by treatment interaction in an independent model to assess how treatment effects can differ across study sites.

Based on the observation data, a preliminary analysis of the ITT population will be conducted. Two-sample t-test and non-parametric Wilcoxon rank sum test will be used to compare treatments in an unadjusted sensitivity analysis format. Sensitivity analysis will also be performed on the ITT population that uses missing data (MI) to fill in missing data, and the PP population that uses observation data only. Other power analysis

The changes in EDS from before treatment to after treatment will also be analyzed at various time points in a manner similar to the initial analysis of the Sgormer test. These ANCOVA models will include pre-treatment EDS, treatment and study site as covariates.

The changes in the results of the Ocular Discomfort Scale from before to after treatment will be summarized by questioning, time point (when appropriate) and quantitative quantitative descriptive statistics for treatment and will be analyzed at various time points in a similar manner to EDS.

The analysis will only be performed on the observation data of the ITT and PP populations. Security variable

AE will use MedDRA dictionary encoding. The frequency and percentage of individuals with treatment-induced AE (TEAE), severe TEAE, and TEAE causing premature discontinuation will be provided by the treatment group. If AE appears or worsens after the first dose of study treatment, it is treatment-induced. In addition, by system organ class; by system organ class and preferred term; by system organ class, preferred term and maximum severity; by system organ class, preferred term and strongest relationship; and by system Organ category, preferred terms, maximum severity, and strongest relationship give the frequency of individuals with TEAE. Eye specificity and all AEs (including systemic) will be analyzed independently.

Other safety endpoints including vision, slit lamp biopsy, and endoscopic nasal endoscopy will be used by the treatment group and the descriptive statistical summary of the consultation. Changes or deviations from the baseline will also be summarized as appropriate. For the evaluation by eye, the research eye and the contralateral eye will be summarized separately. In addition, the worst treatment period values from baseline to ocular safety assessment will be summarized. Interim analysis

No mid-term analysis for this research plan. Compliance with good clinical practice, ethical considerations, and management issues

This study will be conducted in accordance with Good Clinical Practices of the protocol, including the International Conference on Harmonization (ICH) guidelines, and is generally consistent with the Declaration of Helsinki. In addition, all applicable local, state, and federal requirements related to the use of research drugs in the countries involved will be complied with. Human individual protection

Informed consent (consent/assent) must be done before starting any research-specific procedures. The signed and dated written informed consent must be obtained from the parent or legal guardian of each individual and/or individual before being selected for the study. If the individual is younger than the legal age of consent, the consent must be signed by the legal guardian or, if necessary, by state and/or local laws and regulations.

All informed consents must be approved for use before their use and receive approval/favorable opinions from the IRB. If the consent form needs to be corrected (for example, due to amendments to the plan or significant new safety information), the investigator is responsible for ensuring that the amended informed consent form is reviewed and approved before being submitted to the regulatory IRB, and that it is selected by all recipients of the subsequent enrolled study As well as the individual reading, signature and date marking of the current selected study.

This research was conducted in accordance with IRB regulations [U.S. 21 Code of Federal regulations (CFR) Part 56.103]. The investigator must obtain appropriate IRB approval before starting the study and at least annually reapproval. Only IRB approved versions of informed consent will be used.

This research will be based on the ethical principles derived from the Declaration of Helsinki. Individual confidentiality

All personal research individual data collected and processed for the purpose of this research should be maintained by investigators and their staff with adequate protective measures to ensure the confidentiality of the data in accordance with local, state, and federal laws and regulations. Marking, packaging

The investigational drug will be provided in a single-use vial and will be dispensed before each treatment at Visit 1 and Visit 2. Record information on source documents and electronic case report forms

All individual data will be extracted from individual source files and will be transcribed in eCRF. The investigator is responsible for ensuring that the research materials are completely and accurately recorded on the eCRF, source files, and all research-related materials of each entity. All research materials should also be attributable, easy to read, contemporaneous and original. The recorded data should only be corrected in a way that does not eliminate, destroy, or make it illegible (eg, by drawing a single line through the incorrect input and writing the correction next to the corrected data). Individuals with input of corrected data should clarify who and when the correction was made by adding their initials and the date of correction to the correction.

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R. and P. J. Wormald (2006). "Endoscopic vidian neurectomy."Am J Rhinol 20(2): 197-202. Schaumberg, D. A., R. Dana, J. E. Buring and D. A. Sullivan (2009). "Prevalence of dry eye disease among US men: estimates from the Physicians' Health Studies."Arch Ophthalmol 127(6): 763-768. Schaumberg, D. A., D. A. Sullivan, J. E. Buring and M. R. Dana (2003). "Prevalence of dry eye syndrome among US women."Am J Ophthalmol 136(2): 318-326. Schaumberg, D. A., D. A. Sullivan and M. R. Dana (2002). "Epidemiology of dry eye syndrome."Adv Exp Med Biol 506(Pt B): 989-998. Semba, CP, GL Torkildsen, JD Lonsdale, EB McLaurin, JA Geffin, TK Mundorf, KS Kennedy and GW Ousler (2012). "A phase 2 randomized, double-masked, placebo-controlled study of a novel integrin antagonist (SAR 1118 ) for the treatment of dry eye."Am J Ophthalmol 153(6): 1050-1060 e1051. Sheppard, JD, GL Torkildsen, JD Lonsdale, FA D'Ambrosio, Jr., EB McLaurin, RA Eiferman, KS Kennedy, CP Semba and O.-S. Group (2014). "Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study."Ophthalmology 121(2): 475-483. Sosne, G. and G. W. Ousler (2015). "Thymosin beta 4 ophthalmic solution for dry eye: a randomized, placebo-controlled, Phase II clinical trial conducted using the controlled adverse environment (CAE) model."Clin Ophthalmol 9: 877-884. Stapleton, J. A. and G. Sutherland (2011). "Treating heavy smokers in primary care with the nicotine nasal spray: randomized placebo-controlled trial."Addiction 106(4): 824-832. Tauber, J., P. Karpecki, R. Latkany, J. Luchs, J. Martel, K. Sall, A. Raychaudhuri, V. Smith, CP Semba and O.-. Investigators (2015). "Lifitegrast Ophthalmic Solution 5.0 % versus Placebo for Treatment of Dry Eye Disease: Results of the Randomized Phase III OPUS-2 Study."Ophthalmology 122(12): 2423-2431. Thuerauf, N., K. Markovic, G. Braun, S. Bleich, U. Reulbach, J. Kornhuber and J. Lunkenheimer (2006). "The influence of mecamylamine on trigeminal and olfactory chemoreception of nicotine."Neuropsychopharmacology 31(2): 450-461. Tsubota, K. (1991). "The importance of the Schirmer test with nasal stimulation."Am J Ophthalmol 111(1): 106-108. Tsubota, K., M. Yamada and K. Urayama (1994). "Spectacle side panels and moist inserts for the treatment of dry-eye patients."Cornea 13(3): 197-201. Walt JG, R. M., Stern KL (1997). "Evaluating the functional impact of dry eye: the Ocular Surface Disease Index [abstract]."Drug In J 31: 1436.Interview and measurement schedule

Inspection procedures, tests, equipment and technology

The following inspection procedures, tests, equipment and techniques are listed below: Vision procedures

LogMAR vision must be evaluated using the ETDRS form. The procedures used will be consistent with the recommendations provided for the use of ETDRS vision charts. Vision should be assessed at the beginning of each consultation in the study (ie, before the slit lamp examination). Participants should use the most recent correction to obtain their corrected distance vision (CDVA); if they forget their glasses, this solution can be placed in the trial frame. equipment

The vision chart to be used is the ETDRS form. If a smaller reproduction (18" x 18", for example from the Prevent Blindness) wall chart is used, the participant's viewing distance should be exactly 10 feet (or as specified by the manufacturer). In all cases, for the purpose of standardizing the test conditions during the study, all locations must use only ETDRS Series 2000 Chart 1 and 2, and the right eye should be tested first. For reflection (hanging) charts, the chart should be placed in front and fully illuminated. Measurement Technology

The chart should be in a comfortable perspective. The right eye should be tested first. Participants should try to read the letters from left to right line by line, starting at line 1 at the top of the chart. Participants should be informed that the chart has only letters and no numbers. If the participants read the numbers, they should be reminded that the chart contains no numbers, and the examiner should then ask for letters instead of numbers. Participants should be asked to read slowly to achieve the best identification of the letters. It does not advance to the next letter until a definite answer is given.

If the participant changes the answer before he reads the next letter aloud (for example, "It is "C" instead of "O""), the change must be acceptable. If the participant changes the answer after having read the next letter, the change is not acceptable. The examiner should never point to the chart or specific letters on the chart during the test.

Every effort should be made to identify the letters on the chart. When participants say that they cannot read the letters, they should be encouraged to make guesses. If the participant identifies a letter as one of two letters, they should be asked to choose a letter and make guesses if necessary. When it is obvious that meaningful reading is no longer possible (regardless of encouraging reading or guessing), the examiner should stop testing the eye. However, all letters on the last line should be tried, as the difficulty of the letters varies and the last line can be the only line correctly read. The number of missing or incorrectly read letters should be marked. LogMAR vision calculation

The last line of the letter after correct reading will be regarded as the basic logMAR reading. The number “N×0.02” will be added to this value, where “N” represents the total number of letters missed (and included) in the last line of reading. This sum represents the logMAR vision of the eye.

Example: Participants correctly read 4 out of 5 letters on line 0.2 and 2 out of 5 letters on line 0.1.

Repeat the procedure for the left eye.

In order to provide standardized and well-controlled assessments of vision during the study period, all vision assessments at a single location must be conducted continuously using the same lighting conditions and the same corrections (if possible) throughout the study period. If the same correction cannot be used (ie, the participant broke their glasses), the reason for the change in correction should be recorded.

Note: The clinically significant visual acuity reduction (defined as a 0.22 or greater increase in logMAR score) from the screening interview (interview 1) should be evaluated by the investigator as a potential AE.

Slit-lamp biopsy: Slit-lamp biopsy will be performed during the study. The observation result will be classified as normal or abnormal. Clinically significant abnormal findings will be described. The following will be examined at each consultation: Ÿ cornea Ÿ conjunctiva Ÿ anterior chamber Ÿ eyelid cornea fluorescein staining

The examiner should inject 5 μL of 2% sodium luciferin solution without preservatives into the conjunctival blind tube under each eye. Alternatively, corneal staining can be evaluated using 1.0 mg luciferin sodium strips. After wetting the tip of the strip with sterile buffered saline, the excess is thrown out into the trash bin by a flick. The lower eyelid is then pulled down and the flat end of the tip should be gently applied to the conjunctiva of the lower tarsal plate, with the intention of not inducing reflective tearing and instilling a very small volume of dye.

Participants will be instructed to blink naturally several times without forcibly closing the eyelids to distribute luciferin. To achieve maximum fluorescence, the examiner should wait at least two minutes after infusion before evaluating corneal fluorescein staining. Wratten #12 yellow filter paper will be used to enhance the ability to classify luciferin stains. The staining will be graded using the NEI scale. The upper eyelid is slightly lifted to grade the entire corneal surface.

Provide the test administrator with a NEI/Industry Workshop scale chart to grade and score each of the five areas on the cornea of each eye. Figure 9 depicts a pattern used to grade the corneal surface after luciferin staining. The diagram shows the division of the corneal surface to measure luciferin absorption. A standardized grading system of 0-3 is used for each of the five areas on each cornea. When there is no staining, it will be designated as level 0. The maximum score is 15. Each of the five areas on the cornea of each eye was scored. Intranasal examination

Eligible study participants must undergo nasal endoscopy to make a final eligibility determination (eg, severe nasal airway obstruction, such as severe nasal septal deviation or inferior turbinate hypertrophy, or vascularized polyps (visible during examination) as the cause of exclusion). In order to monitor the integrity of the nasal mucosa during the study for the safety of the participants, a nasal cavity examination will be performed via an endoscope at the screening interview (after all other screening procedures have been completed). This examination will be performed by an ENT specialist, an otolaryngologist, or other suitably qualified medical practitioner (ie, a physician who has been trained to perform nasal endoscopy). Can still capture images or videos. Participants should be instructed not to perform nasal irritation on the day the nasal endoscopy will be performed. Sgormer test under local anesthesia

During the screening interview, a basic Sgormer test will be performed, followed by a Sgormer test under the nasal stimulation of the cotton swab. The Sgormer test under local anesthesia will be used to assess tear production using the following steps:

Drops of local anesthetic, such as 0.5% promethaine hydrochloride or equivalent, should be instilled into both eyes of the participant.

Participants will be instructed to keep their eyes closed for one minute.

After opening your eyes and allowing them to recover for another minute, use a spear to gently remove excess water from the lower dome.

The gomer strip (35 mm×5 mm size filter paper strip) will be placed at the junction of the middle of the lower eyelid and the lateral third of each eye.

Under ambient light, the participant will be instructed to look forward and blink normally during the test. The test should be conducted in a room without direct air on the participant's face.

The gomer bar should remain in place until five minutes have passed or both bars have reached their maximum score.

After five minutes, the strip will be removed from both eyes and the amount of wetting will be recorded. Articles should be pasted to CRF. Sgormer test for nasal irritation using cotton swabs

During the screening interview, a cotton swab nasal stimulus should be used for the Gomer test. New anesthetic drops should be infused following the same procedure as specified in steps #1 to 3 above.

With the new strip in place, the examiner should simultaneously insert cotton swabs in both nostrils of the participant and gently probe the two middle turbinates for approximately 30 seconds. Thereafter, the inspector can simply hold the cotton swab in place, apply gentle pressure, and repeat the probe intermittently as needed.

Alternatively, the participant may be instructed to hold the cotton swab while simultaneously probing the two middle turbinates gently, resting intermittently before re-probing. The examiner should continually instruct participants on how to perform this test appropriately.

The gomer bar should remain in place until five minutes have passed or both bars have reached their maximum score.

Two Sgomer scores will be recorded and verified to meet the inclusion criteria. Ocular Surface Disease Index ^©

To minimize deviations, after instructions have been provided by field personnel, participants will be required to complete the OSDI questionnaire independently and privately.

OSDI is a 12-item questionnaire produced by Outcomes Research Group at Allergan (Irvine, CA), (Walt JG 1997), which requires participants to describe the severity and nature of their irritation symptoms. Participants will answer 12 questions by circled the number that best represents each answer: 4 (all time), 3 (most time), 2 (half time), 1 (some time) or 0 (no time) ). The final score of the questionnaire is calculated as follows: Ÿ Sum of parts from parts I, II and III = A Ÿ Determine the total number of questions answered from parts I, II and III (excluding N/A) = B Ÿ Final OSDI score = A × 25 divided by B

An example of the questionnaire is shown in Figure 10. Using visual analogue scale (VAS) score of dry eye (EDS)

During exposure to artificially created adverse environments, participants will be asked the following questions about dry eyes every 5 minutes.

Participants will be asked to assess their eye symptoms caused by dry eyes (both eyes at the same time), by placing a vertical marker on a horizontal line to indicate the level of discomfort; 0 corresponds to "no discomfort" and 100 corresponds to "maximum Discomfort". The length of the evaluation line of the scale will be 100 mm. An example of a visual analog scale is shown in Figure 11.

EDS is an instrument that has been used by others in studies related to ocular symptoms. Eye Discomfort Scale

The eye discomfort score will be subjectively graded by participants according to the following scale, and each eye will be rated separately. 0 = no discomfort 1 = intermittent consciousness 2 = continuous awareness 3 = intermittent discomfort 4 = persistent discomfort

Compound 1 galactate dihydrate dihydrate nasal spray was studied in a multi-center, randomized, controlled, double-blind clinical trial to evaluate the compound 1 galactose dihydrate dihydrate nasal spray pair Efficacy of the symptoms and symptoms of dry eye disease described above ("PEARL" study) The PEARL study is designed as a dose range study to evaluate the symptoms of dry eye disease (Sgormer test) and symptoms (dry eye score [EDS]) Comparison of 0.11% Compound 1 free base (0.2% Compound 1 hemi-galactose dihydrate dihydrate) [low dose], 0.55% Compound 1 free base (1.0% Compound 1 hemi-galactose dihydrate dihydrate ) [Medium dose, and 1.1% Compound 1 free base (2.0% Compound 1 hemi-galactonate dihydrate) [high dose] compared to placebo (Compound 1 hemi-galactonate dihydrate) Vehicle nasal spray) safety and effectiveness. The research was conducted at 3 centers in the United States (US).

結果 在用 0.20% 、 1.00% 及 2.00% 化合物 1 半 - 半乳糖二酸鹽二水合物治療後的斯戈默測試結果 Baseline demographic data indicates that the dose group is well-balanced. The overall population is mainly composed of more women than men, consistent with the epidemiology of dry eye disease (Table 1).

Results with 0.20%, 1.00% and 2.00% of Compound 1 semi - Mr. Schirmer test results after mucate treatment dihydrate

The main symptom efficacy measure in this study is the average change in the Sgormer test at the time of evaluation of visit 1. In general, a higher Sgormer score indicates a larger amount of tears than a lower Sgormer score. As outlined in Figure 1, individuals who received a 0.20% concentration had an average increase in Sgormer score of 8.6 mm (p=0.0018, n=41), and a 1.00% concentration of 17.1 mm (p<0.001, n=41), and The 2.00% concentration was 19.3 mm (p<0.001, n=42). In contrast, the Gomer score of the placebo group (n=41) was only observed to have an average increase of 2.6 mm. The Sgomer score of the drug treatment group increased compared to placebo and the increase was in a dose-dependent manner. In addition, the score change is statistically significant because the p-value is much lower than 0.05. The statistically significant increase in the Sgormer score and the corresponding increase in tear production indicate that the individual diagnosed with dry eye disease is effective and immediate with the treatment of compound 1 galactose dihydrate dihydrate. This proves that Compound 1 hemi-galactonate dihydrate can be used to immediately increase tearing, treat dry eye disease and reduce eye discomfort. Figure 1 summarizes the results of the Sgormer test after treatment with 0.20%, 1.00%, and 2.00% Compound 1 hemi-galactonate dihydrate. With 0.20%, 1.00% and 2.00% of Compound 1 semi - Test of dry eye mucate dihydrate results after treatment

The main symptom efficacy measure in this study was the average change in dry eye scores evaluated in an artificially created adverse environmental chamber at the time of consultation 2. In general, a lower dry eye score indicates that it reduces the discomfort caused by dry eye symptoms compared to a higher dry eye score (which indicates a higher discomfort). Therefore, a decrease in dry eye score is an improvement in individual symptoms.

As outlined in Figure 2, the dry eye score of individuals in the 1.0% and 2.0% dose groups showed a statistically significant decrease at the 5-minute mark. The dry eye score in the 1.0% dose group decreased by 16.5 mm (p=0.0067, n=41, dry eye score was -16.5 mm) and the dry eye score in the 2.0% group decreased by 19 mm (p=0.0006, n=37, The dry eye score is -19 mm). In contrast, the dry eye score of the placebo group (n=41) was only reduced by an average of 6.8 mm (dry eye score of -6.8). The dry eye score of the drug-treated group was lower than that of the placebo group, and the rate of decrease was a function of dose. In addition, the changes in the scores of the 1.00% and 2.00% groups were statistically significant because the p-value was much lower than 0.05. A statistically significant decrease in dry eye score and a corresponding decrease in eye discomfort indicate that the treatment with Compound 1 galactose dihydrate dihydrate in individuals diagnosed with dry eye disease is effective and immediate. This data demonstrates that Compound 1 hemi-galactonate dihydrate can be used to immediately reduce eye discomfort and improve symptoms related to dry eye disease. With 0.20%, 1.00% and 2.00% of Compound 1 half - 60 minutes after mucate dihydrate treatment of dry eye scores

Figure 3 summarizes the dry eye scores obtained every 5 minutes during the 60-minute period. This example demonstrates the immediate improvement of the dry eye score at the 5 minute mark (which is a statistically significant improvement) in individuals diagnosed with dry eye disease, at the 1.0% and 2.0% dose concentrations of Compound 1 galactosaltate Under dihydrate, maintain for a period of 60 minutes. For example, at 60 minutes after the 1.0% dose was administered, the improvement in dry eye score was within 10% of the improvement measured at the 5-minute mark (5 minutes, -16.5 mm; 60 minutes, -15.3 mm). At 30 minutes after the 2.0% dose was administered, the improvement in dry eye score was less than 10% compared to the improvement measured at the 5 minute mark (5 minutes, -19.0 mm; 60 minutes, -16.1 mm). At 60 minutes after the 2.0% dose was administered, the improvement in dry eye score was less than 10% compared to the improvement measured at the 5-minute mark (5 minutes, -19.0 mm; 60 minutes, -16.1 mm). These results show that the ocular discomfort that decreases immediately after treatment with the drug can be maintained for at least 60 minutes, depending on the dose. This data demonstrates that the statistically significant decrease in ocular discomfort of individuals diagnosed with dry eye disease and treated with Compound 1 galactate dihydrate dihydrate can be maintained for more than 60 minutes. The upper limit effect of the Sgormer score at the higher dose level after treatment with 0.20%, 1.00%, and 2.00% Compound 1 galactose dihydrate dihydrate

Figure 4 summarizes the% of individuals with a 35 mm Sgormer score after treatment with Compound 1 galactose dihydrate dihydrate at a concentration of 0.2%, 1.0%, or 2.0%. The 35 mm score is the maximum tear level measured by the Sgormer test. The individuals selected in the study had a Sgormer score of less than 10 mm at the time of screening before treatment. Among these individuals, 4.9% in the 0.2% dose group, 29.3% in the 1.0% dose group and 41.5% in the 2.0% dose group were measured to have a 35 mm Sgormer score. This is the maximum score of the Sgormer test. 0% of individuals in the placebo group had a Sgormer score increase greater than 35 mm. This data additionally supports the dose-dependent response of Compound 1 hemi-galactonate dihydrate in increasing tear production in individuals diagnosed with dry eye disease. This information can be used to determine the appropriate amount of tears to achieve increased tearing, but to avoid excessive tear production. With 0.20%, 1.00% and 2.00% of Compound 1 Semi - increase mucate dihydrate treatment rates among values Housigemo

Figure 5 summarizes the change in the median value of the Sgormer score after treatment with Compound 1 galactose dihydrate dihydrate at a concentration of 0.2%, 1.0%, or 2.0%. An increase of 5.0 mm (n=41) in the 0.2% dose group, 16.0 mm (n=41) in the 1.0% dose group, and 24.0 mm (n=42) in the 2.0% dose group was measured. Only 2.0 mm median increase was observed in individuals in the placebo group (n=41). This data additionally supports the dose-dependent response of Compound 1 hemi-galactonate dihydrate in increasing tear production in individuals diagnosed with dry eye disease. Sgormer score > 10 mm for category changes

Figure 6 summarizes the% of individuals with a change in the Sgormer score greater than 10 mm after treatment with Compound 1 galactose dihydrate dihydrate at a concentration of 0.2%, 1.0%, or 2.0%. The individuals selected in the study had a Sgormer score of less than 10 mm at the time of screening before treatment. Among these individuals, 29.3% individuals in the 0.2% dose group (n=41, p=0.0107), 29.3% individuals in the 1.0% dose group (n=41, p<0.0001), and 2.0% dose group (n =42, p<0.0001) 41.5% of the individuals experienced an increase in the scorer score greater than 10 mm. Only 7.1% of individuals in the placebo group (n=41) had a Sgormer score increase greater than 10 mm. This data supports the statistically significant categorical change (>10 mm) in the Sgormer score of individuals diagnosed with dry eye disease caused by treatment with Compound 1 galactosyl dihydrate dihydrate. Sgormer score > 20 mm for category changes

Figure 7 summarizes the% of individuals with a change in the Sgormer score greater than 20 mm after treatment with Compound 1 galactose dihydrate dihydrate at a concentration of 0.2%, 1.0%, or 2.0%. The individuals selected in the study had a Sgormer score of less than 10 mm at the time of screening before treatment. Among these individuals, 14.6% of the individuals in the 0.2% dose group (n=41, p=0.0119), 43.9% of the individuals in the 1.0% dose group (n=41, p<0.001), and 2.0% of the dose group (n =42, p<0.001) 56.1% of the individuals experienced an increase in the scorer score greater than 20 mm. 0% of individuals in the placebo group (n=41) had a Sgormer score increase greater than 20 mm. This data supports the statistically significant categorical change (>20 mm) in the Sgomer score of individuals diagnosed with dry eye disease caused by treatment with Compound 1 galactose dihydrate dihydrate. This information can be used to determine the appropriate amount of tears to achieve increased tearing, but to avoid excessive tear production. Adverse events

Figure 8 summarizes the most common adverse events, >5% in any treatment group observed in clinical studies. Overall, 40.6% of individuals showed one or more adverse events. There was a single serious adverse event in dysplasia in the 0.2% dose group, which was deemed not related to research therapy. Figure 8 also depicts a non-limiting example of a 100 microliter delivery device and a 50 microliter nasal spray device, where the delivery amount is each administration of a pharmaceutical formulation ("spray").

Compared with the 0.2% and placebo dose groups, there was a higher percentage of individuals with drug-related stimuli (cough, throat irritation) of the larynx/soft palate in the 1.0% and 2.0% dose groups. Many of this upper larynx/soft palate stimulation can be related to the delivery volume (100 μL of each nostril) and the use of the MAD Nasal™ intranasal mucosal nebulizer device (MAD) to increase the likelihood of post-nasal instillation of research drugs. In addition, compared with the 0.2% and placebo dose groups, nasal irritation (drip site stimulation and sneezing) was present in a higher percentage in individuals in the 1.0% and 2.0% dose groups. About 88.5% of the severity of throat irritation is considered mild, and 11.5% is indicated as moderate. The severity of irritation at the instillation site is considered mild in 100% of individuals. All drug-related events are transient and self-limiting.

In the future, the clinical delivery of Compound 1 hemi-galactonate dihydrate will use a volume of 50 μL in each nostril and should reduce the incidence of upper larynx/soft palate irritation by reducing post-nasal instillation after instillation Use a spray pump. Example 3: After four weeks of compound 1 Semi - mucate dihydrate clinical study 2.0% of 2

¹ 研究用眼睛將定義為符合所有納入標準之眼睛；若兩隻眼睛均合格，則為在篩選問診時藉由用棉花棒刺激而具有淚液產生最大增加之眼睛，或若刺激之淚液產生無差異，則為在篩選時具有較低基礎斯戈默評分之眼睛。若任一量度均無差異，則右眼將用作研究用眼睛。 縮寫清單

The summary of the Phase 2 study is presented below. summary

^{1 The} research eye will be defined as the eye that meets all the inclusion criteria; if both eyes are qualified, it is the eye that has the largest increase in tears by stimulation with a cotton swab during screening interviews, or if the stimulated tears produce no difference , Is an eye with a low basic Sgormer score at the time of screening. If there is no difference in any measurement, the right eye will be used as the research eye. List of abbreviations

When delivered in the form of an intranasal spray, Compound 1 hemi-galactonate dihydrate can promote the activation of the trigeminal parasympathetic pathway and therefore represents a novel candidate for improving the signs and symptoms of dry eye disease.

This study will use artificially created adverse environmental models to assess dry eye symptoms. The artificially created unfavorable environment consists of rooms that standardize environmental conditions by regulating humidity, temperature, airflow, lighting conditions, and visual task assignment. Dry eye patients are exposed to an artificially created adverse environment for up to two hours, during which subjective and objective parameters can be evaluated before, during, and after exposure. The artificially created unfavorable environment represents the daily conditions encountered by patients with dry eyes, such as forced hot air heating systems, aircraft travel and computer use and allows the standardization of these variables. 1 Previous clinical experience

Previous clinical experience can be found in Example 2. 2 Research objectives

The goal of this study was to evaluate the safety and effectiveness of Compound 1 Hemi-Galactose Dihydrate Nasal Spray for the signs and symptoms of dry eye disease over a period of 4 weeks compared to placebo. 3 Clinical hypothesis

This study tested the hypothesis that Compound 1 Hemi-Galactose Dihydrate Nasal Spray is superior to placebo in treating the signs and symptoms of dry eye disease. 4 Overall research design

Protocol OPP-003 is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate Compound 1 Hemi-Galactose Dihydrate Nasal Spray Nasal Spray for Adult Participation in Dry Eye Disease The safety and efficacy of people. Approximately 45 individuals at least 22 years old who were diagnosed with dry eye disease by a physician and met all other study eligibility criteria will be randomized to receive Compound 1 galactose dihydrate dihydrate administered twice daily (BID) Or placebo for 4 weeks.

Participants who terminate early during the administration period will be required to complete a safety assessment (if the participant agrees) before the study exit. Participants who have terminated the study early will not be replaced. 5 Research groups 5.1 Number of individuals

Approximately 45 participants (approximately 30 points to 2.0% Compound 1 galactate dihydrate dihydrate and 15 points to Compound 1 galactose dihydrate dihydrate vehicle nasal spray) will be in About two locations in the United States are registered. Individuals randomized 2:1 to receive one of the following dose distributions. Ÿ Placebo (nasal spray of Compound 1 hemi-galactose dihydrate dihydrate vehicle) Ÿ 2.0% Compound 1 Hemi-Galactose Dihydrate Dihydrate Nasal Spray

All doses will be delivered in each nostril as a 50 microliter (µL) intranasal spray BID for a total of 4 weeks. 5.2 Studying group characteristics

All individuals must be at least 22 years old, of any gender, and of any ethnic origin, and must meet all inclusion criteria and do not meet any exclusion criteria. 5.3 Inclusion criteria

The individual must : 1. be at least 22 years of age at the time of screening interview 2. have used and/or expect to use artificial tear substitutes for dry eye symptoms within 60 days prior to consultation 1. 3. have an OSDI of ≥ 23 at the time of screening interview ^© Scoring and ≤3 times of "N/A" reaction 4. At the time of the screening interview, all of the following are included in the research eye: Ÿ Corneal fluorescein staining score of ≥2 in at least one corneal area or ≥3 in all corneal areas Sum of 4 Ÿ Baseline stommer test (under local anesthesia) ≤10 mm every 5 minutes, the cotton swab nasal irritation stommer test score in the same eye is at least 7 mm greater The difference between the Stommer test and the contralateral eye is less than 20 mm. The doctor’s dry eye diagnosis study will be defined as the eye that meets all the inclusion criteria; if both eyes are qualified, the cotton swab will be used for screening and consultation Eyes that have the greatest increase in tear production when irritated, or if there is no difference in the production of irritated tears, are those with a lower basic Sgormer score at the time of screening. If there is no difference in any measurement, the right eye will be used as the research eye. 5. BCVA with a minimum logarithmic angular logarithm (logMAR) of 0.7 or better (logMAR <0.7; 20/100 or better Snellen equivalent score) in each eye at the time of screening and consultation 6. With normal eyelid/lash anatomy, Blink function and closure, as determined by the investigator 7. Can read and speak English and be able to independently complete the questionnaire 8. Can participate in the study for approximately four consecutive hours at the time of the consultation 9. Can and willing to use the study drug and participate in all study evaluations And consultation 10. Oral and written informed consent has been provided 11. If it is not used, acceptable birth control methods (acceptable contraceptive methods include: hormones-oral, implantable, injectable or transdermal contraceptives, mechanical- Women with fertility potential who combine spermicides with barriers such as uterine caps or condoms, IUDs or surgical sterilization of partners have a negative urine pregnancy test on day 1 5.4 Exclusion criteria

The individual must not : 1. Have a clinically significant corneal epithelial defect on Day 1 of the study prior to the Sgormer test 2. Have chronic or recurrent nosebleeds, coagulopathy, or other factors that would appear clinically significant to the investigator The conditions of increased risk of bleeding 3. These areas have undergone nasal or sinus surgery (including a history of nasal cauterization) or have significant trauma 4. With vascularized polyps, severely deviated nasal septum, chronic recurrent nosebleeds or Severe nasal airway obstruction, as confirmed by intranasal examination conducted before day 1. 5. Currently being treated with continuous nasal continuous positive airway pressure (CPAP) 6. Has been in any eye within three months of consultation 1 Perform any intraocular surgery (such as cataract surgery), extraocular surgery (such as blepharoplasty) or perform refractive surgery within 12 months (such as laser epithelial keratomileusis, laser-assisted in situ keratomileusis , Refractive keratectomy or corneal implantation) 7. A corneal transplant has been performed in either eye 8. Used within the past 60 days or Restasis ^® or Xiidra ^® . 9. Have used contact lenses within 7 days prior to consultation 1 or are expected to use contact lenses during the study period 10. Have any form of punctum or intratubular obstruction 11. Have any eye disease or condition in any eye Medical history or presence, which may appear to the investigator to interfere with the interpretation of study results or participant safety, such as significant corneal or conjunctival scars; pterygium or nodular conjunctival macula; current eye infection, conjunctivitis, or not with dry eye Related inflammation; anterior (epithelial) basement corneal dystrophy or other clinically significant corneal dystrophy or degeneration; ocular herpes infection; evidence of keratoconus; etc. Blepharitis that does not require treatment and mild meibomian gland diseases usually associated with dry eye disease are allowed. 12. A history of epilepsy or other factors that lower the individual's seizure threshold. 13. Have a systemic condition or disease that is unstable or determined by the investigator to be incompatible with the study or the lengthy assessment required for the study (eg current systemic infection, uncontrolled autoimmune disease, uncontrolled immune deficiency disease, (Myocardial infarction or history of heart disease, etc.) 14. Known allergic to any of the procedural agents or study drug components 15. Current concomitant use of snuff, chewing tobacco, or cigarettes/cigars during the study or within 30 days of the previous 16. current accompanying nicotine acetylcholine receptor agonist ^{[Nicoderm ®, Nicorette ®, Nicotrol} NS ® ( nicotine), Tabex ^®, Desmoxan ^® (cytisine) and Chantix ^® (varenicline)] Or within the previous 30 days 17. Have active or uncontrolled severity: a. Systemic allergy b. Chronic seasonal allergy at active risk during the study period c. Need for antihistamines, decongestants, etc. during screening interview , Oral or aerosol steroid treatment of rhinitis or sinusitis d. Untreated nasal infection at the time of questioning 18. 18. Having an investigator's opinion that it may interfere with study compliance, outcome measurement, safety parameters and/or individual Any medical condition or history of a general medical condition 19. It is a woman who was pregnant, nursing a baby or planning to become pregnant at the time of questioning. Females with fertility potential who have not used acceptable birth control methods; acceptable contraceptive methods include: hormone-oral, implantable, injectable or transdermal contraceptives, mechanical-spermicides and such as uterine caps or condoms Barrier combination; IUD; or surgical sterilization of partner 20. Currently enrolled in a research drug or device study or have used the research drug or device within 30 days prior to question 1 5.5 Withdrawal criteria

If at any time during the study, the investigator determines that the individual's safety has been compromised, the individual may withdraw from treatment, but will be followed up on safety for the duration of the study unless they refuse to participate in the follow-up.

Individuals may withdraw consent from the study at any time.

The investigator may suspend research treatment for any individual during the research process due to non-compliance or any effective medical reason (see Section 9.6.2). 6 Research parameters 6.1 Efficacy measures 6.1.1 Main efficacy measures

The following primary endpoints will be tested: Ÿ Gomer's test at the time of consultation 5 (day 28) 6.1.2 Secondary efficacy measure Ÿ EDS 6.2 at the time of consultation 4 (day 21) 6.2 Other efficacy measures Appropriate scale Ÿ Corneal staining 6.3 Safety measures Ÿ Adverse events 6.4 Other measures Ÿ Urine pregnancy test (Inquiry 1 and Inquiry 4/ET) 7 Research materials 7.1 Research drugs 7.1.1 protocol

The study drug will be delivered in each nostril as a 50 microliter (µL) intranasal spray BID: ￭ 2.0% Compound 1 Hemi-Galactose Dihydrate Nasal Spray ￭ Placebo Nasal Spray (Compound 1 Semi- Galactose dihydrate dihydrate vehicle nasal spray) 7.1.2 Dispensing schedule Ÿ At the time of consultation 1, qualified individuals will be randomly divided and the first dose of study drug will be administered in the office. The second daily administration will occur at home. Ÿ At Interview 4, the individual will receive the first daily dose of study drug during the artificially created adverse environmental exposure. The second daily administration will occur at home. Ÿ During Interview 2, Interview 3, and Interview 5, the first-day dose of study drug will be administered in the office at the same time as the Sgormer test. The second daily administration will occur at home. Ÿ Between clinical visits, the individual will self-administer BID in each nostril in the form of 50 µL intranasal spray of compound 1 galactose dihydrate dihydrate/placebo. 7.1.3 General instructions for use Ÿ Compound 1 hemi-galactonate dihydrate/placebo will be formulated at the desired concentration in phosphate-buffered saline in the form of a sterile aqueous solution (depending on the dosage group allocation), and at Presented multiple times with a preservative-free nasal pump. Ÿ The product contains no preservatives and is only intended for intranasal use. If the product is cloudy or if particles are present, it should not be used. Ÿ Compound 1 hemi-galactose dihydrate dihydrate solution must be administered without dilution. 7.2 Other research supplies Ÿ Urine pregnancy test kit Ÿ Fluorescein sodium solution or luciferin strip Ÿ Sgormer test strip Ÿ Proparacaine 8 Research methods and procedures 8.1 Participant entry procedure 8.1.1 Overview

Participants as defined by the criteria in Sections 6.2, 6.3 and 6.4 will be deemed to have entered this study. 8.1.2 Informed consent

Before participants are enrolled in the trial (that is, before any research-related procedures), the study will be discussed with each potential participant and participants who wish to participate must be regulated and use the Informed Consent Form approved by the Institutional Review Board (IRB) ( ICF) Provide written informed consent. The ICF must be the latest version approved by the well-structured IRB. 8.1.3 Clear interval

Prohibited drugs, treatments and activities are outlined in the exclusion criteria (Section 6.4). 8.1.4 Procedures for final research entry

The individual must meet all inclusion criteria and not meet any exclusion criteria. 8.1.5 Method of allocation to treatment group

Entering the research screening period (defined as the time point when an individual signs an informed consent (ICF)) Individuals receive a unique individual identification number before conducting any research-related activities/procedures. This number is used to identify individuals throughout the clinical study and must be used For all research documents related to the individual.

The individual identification number must remain constant throughout the clinical study. This number will not necessarily be the same as the random group number.

Individuals who meet the eligibility requirements will be randomly assigned to one of the two treatment groups. 8.2 Concurrent therapy

The use of any concurrent medication, prescription or over-the-counter will be recorded on the individual's source file and corresponding eCRF along with the reason for taking the medication.

It is not allowed to be enrolled in another study drug or device study at the same time. 8.2.1 Prohibited drugs / treatment

Drugs/treatments that were not allowed during the study are outlined in the exclusion criteria (Section 6.4) 8.2.2 Escaping drugs

This study does not require drug evasion. 8.2.3 Special diet or activities

No special diet or activities are required for this study. 8.3 Inspection procedures 8.3.1 Procedures for research objectives to be executed at the time of consultation in each study

The following procedures will be performed (for the description, see the section below titled Inspection Procedures, Tests, Equipment and Technology). Screening/Interview 1 (Day 1): Screening and Sgormer Test Evaluation Ÿ Informed Consent/Health Information Portability and Accountability Act (HIPAA) Consent Ÿ Demographic data, medical history, previous drug treatment and eye history Ÿ Eligibility criteria Ÿ Urine pregnancy test (if feasible) Ÿ OSDI ^© questionnaire Ÿ EDS (visual analogue scale) Ÿ Eye discomfort scale BCVA (pre-treatment and post-treatment procedures) Ÿ Slit lamp biopsy (pre-treatment) And post-treatment procedures) Ÿ corneal fluorescein staining Ÿ Gomer test (pre- and post-treatment procedures; the procedure will be performed after corneal luciferin staining) Stommer test under nasal irritation (cotton stick; in the nose The Sgormer test under stimulation will be performed at least 10 minutes after the first Sgormer test) Ÿ Intranasal examination Ÿ Random group Ÿ Assign new study drug/placebo intranasal pump / Placebo Ÿ Concomitant medication Ÿ AE questioning 2 (Day 7±2): Sgormer test assessment BCVA (before and after treatment) Ÿ Slit lamp biopsy (before and after treatment) Ÿ cast With study drug/placebo Ÿ Sgormer test (after treatment) Ÿ Concomitant medical treatment Ÿ AE interrogation 3 (Day 14±2): Sgormer test evaluation BCVA (before and after treatment) Ÿ Slit lamp activity Tissue Examination (Before and After Treatment) Ÿ Administration of study drug/placebo Ÿ Sgormer test (simultaneous with treatment) Ÿ Allocation of new study drug/placebo intranasal pump Ÿ Concomitant drug therapy Ÿ AE Interview 4 (No. 21±2 days): Exposure to artificially created adverse environment. Procedure before assessing artificially created adverse environment: Ÿ urine pregnancy test (if feasible) Ÿ EDS (visual analogue scale) Ÿ eye discomfort scale Ÿ concomitant medication Ÿ AE inquires about the assessment of the unfavorable environment exposed to artificial creation before treatment Ÿ EDS (Visual Analogue Scale) until the threshold is met Ÿ Eye discomfort scale until the threshold is met Administer study drug/placebo

After using the Eye Discomfort Scale, participants report an eye discomfort score of ≥3 in at least one eye at two or more consecutive time points during the artificially created adverse environmental exposure, and will be administered the investigational drug /Placebo treatment (participants with an eye discomfort rating of 3 at time=0 must report an eye discomfort rating of 4 for that eye in two consecutive measurements). Participants will resume symptom assessment every 5 minutes, starting 1 minute after the end of administration. Assessment of the adverse environment artificially created after treatment Ÿ EDS (Visual Analogue Scale) Ÿ Eye Discomfort Scale BCVA (decided by investigator as necessary) Ÿ Slit lamp biopsy (decided by investigator as necessary) Ÿ AE inquiry Interview 5 (Day 28±2): Sgormer test assessment BCVA (before and after treatment) Ÿ slit lamp biopsy (before and after treatment) Ÿ intranasal examination Ÿ study drug/placebo Ÿ Corneal fluorescein staining (after treatment) Ÿ Gomer test (simultaneous with treatment) Ÿ EDS (Visual Analogue Scale; after treatment) Ÿ Concomitant medication Ÿ AE inquiry for early termination (if feasible) Ÿ BCVA Ÿ Slit lamp activity Tissue Examination Ÿ Intranasal Examination Ÿ Urine Pregnancy Test (if applicable) Ÿ Accompanying medication Ÿ AE Interview 8.4 Interview, Measurement and Dosing Schedule 8.4.1 Scheduled Interview

See the section below titled Interview and Measurement Schedule. 8.4.2 Unscheduled consultation

These consultations can be conducted to ensure individual safety. All procedures performed during an unscheduled consultation will be recorded in the source file and on the unscheduled consultation eCRF page. Any unprocessed procedures indicated in the eCRF should be indicated as "Not done".

Assessments that can be performed during unscheduled consultations include: Ÿ Slit lamp biopsy; Ÿ Vision; Ÿ intranasal examination; Ÿ urine pregnancy test (if feasible); Ÿ Evaluate AE; Ÿ Assess concurrent medication and/or treatment; and Ÿ Any other assessment as judged by the investigator is necessary. 8.5 Compliance with the plan

Individuals will be instructed to properly use and store study medication at visits 1, 2, 3, and 4, and provide written instructions after their study medication is dispensed at visits 1 and 3. 8.6 Individual Disposition 8.6.1 Completed Individual

Completed individuals are those who have completed 4 weeks of study interviews. 8.6.2 Discontinued individuals

The individual can suspend treatment at any time before completing the study due to the following: Ÿ AE; Ÿ Unmask when medically necessary; Ÿ program violation; Ÿ Management reasons (for example, unable to continue, lost to follow-up); Ÿ Research termination; Ÿ Individual choice (eg withdrawal of consent); and Ÿ Other

Note: In addition, any individual may suspend treatment or suspend research participation for any reasonable medical reason determined by the investigator.

The notice of individual suspension and the reason for suspension will be clearly recorded on eCRF.

Suspended individuals will not be replaced. 8.7 Termination of research

Research can be stopped by an investigator at any time. 8.8 Research duration

Individual participation will involve 5 visits within approximately 4 weeks (28 days) 8.9 Monitoring and quality assurance

During the research process, monitors or designated personnel will conduct routine on-site inspections to check protocol compliance, assess study drug traceability, individual safety, and ensure that research is conducted in accordance with relevant regulatory requirements. The review of individual medical records will be conducted in a way that maintains the confidentiality of the individual. The monitoring plan will outline other details of the research monitoring.

Supervisory authorities of domestic and foreign institutions may conduct on-site inspections and/or audits, which may include original source data inspections. Therefore, inspection and/or auditing will require direct access to the original source material. All inspections and audits will be conducted taking into account data protection and individual confidentiality to the extent applicable by local, state, and federal laws. 9 Safety definition, safety monitoring and reporting 9.1 9.1 Adverse events

An adverse event (AE) is defined as any adverse medical event related to the use of drugs in the human body, regardless of whether the event is considered to be drug-related. AE can therefore be any adverse and unexpected symptoms (eg, abnormal laboratory findings), symptoms, or disease that occur after starting to administer the study drug to the individual without any judgment of causality. Any pre-existing medical conditions that deteriorate after administration of the study drug will also be considered a new AE.

Study drugs include research drugs and placebos that are being evaluated.

The documentation about AE should be about the nature, start date, end date, severity, relationship with study drug, action taken, severity, and any signs or symptoms observed by the investigator or reported by the individual after indirect inquiry The results are carried out. 9.1.1 Severity

The severity of AE is defined as the qualitative assessment of the degree of AE intensity as determined by the investigator or reported to it by the patient/individual. Severity assessments are conducted without regard to the relationship with the study drug or the severity of the event and should be evaluated on the following scale: Ÿ Mild : The event is obvious to the individual, but is easily tolerated and does not interfere with the individual's daily activities. Ÿ Moderate : The event is troublesome, may require additional therapy, and may interfere with the individual's daily activities. Ÿ Severe : The event is intolerable, requires additional therapy or changes in therapy, and interferes with the individual's daily activities. 9.1.2 Relationship with research drugs

The relationship between each AE and the research product should be determined by the investigator (in a blinded manner) using these interpretations: y determined: when there is a good cause and sufficient documentation to demonstrate the direct causal relationship between the research product and the AE, it is likely : When there are good reasons and sufficient documentation to assume causality in the sense that it seems reasonable, conceivable, possible, but not necessarily highly likely, it is possible: when there is enough information to accept in the sense that it is not impossible and not unlikely Possibility of causality, although the association is due to, for example, missing data or insufficient evidence and is uncertain or questionable. None: When there is enough information to accept a non-causal relationship (in the unlikely and unlikely sense). Unclassified: When the cause and effect relationship cannot be assessed for any reason attributed to insufficient evidence, conflicting data, or poor documentation 9.1.3 Expectancy

The predictability of AEs should be determined using these interpretations based on the existing safety information about the study drug: Unexpected : AEs that are not listed in the Investigator's Handbook (IB) or are not listed in the observed specificity or severity . ŸExpectation : AE listed in IB under the observed specificity and severity. Ÿ Not applicable: Any AE not related to the study drug.

Mentioned in IB as occurring in the case of a class of drugs or expected from the pharmacological properties of the drug, but not specifically mentioned as appearing in the case of the specific drug under investigation is considered unexpected.

The investigator should initially classify the AE's expectations, but the final classification is subject to the medical inspector's judgment. 9.2 Serious adverse events

If, in the eyes of the investigator, AE causes any of the following results, it is considered "serious" (SAE): Ÿ death Ÿ Life-threatening AE Note: If it appears to the investigator that the occurrence of AE places the patient or individual at immediate risk of death, it is considered "life-threatening". It does not include AEs that may cause death if they occur in a more serious form. Ÿ Hospitalization or extension of existing hospitalization Note: The term "hospitalization" refers to any admission (even if less than 24 hours). For chronic or long-term inpatients, admission includes transfer to emergency/intensive care inpatient wards within the hospital. Hospitalization does not include: emergency department; outpatient/same day/ambulatory surgery; observation/short stay in ward; rehabilitation facility; hospice facility; nursing home; or clinical research/1 phase unit. Note: The term "extension of existing hospitalization" refers to any extended hospitalization that exceeds the expected or required stay for the initial admission determined by the investigator or treating physician. Ÿ Sustained or significant incapacity or significant disruption of normal life functions Note: SAE, especially related to visual threats, will be interpreted as any potential loss or damage to the individual's eyes (such as bleeding, retinal detachment, central corneal ulcer, or optic nerve damage). Ÿ Study congenital anomalies/inherent defects of individual offspring.

When, based on appropriate medical judgment, a patient or individual may be endangered and medical or surgical intervention may be required to prevent one of the results listed in this definition, a major medical event that may not result in death, life-threatening and requires hospitalization may be considered serious. 9.3 Procedures for reporting adverse events

All AEs and their results must be reported to the IRB/IEC, as required by the IRB/IEC, federal, state or local regulations, and health management authorities, and recorded on the appropriate eCRF. 9.3.1 Report suspected unanticipated adverse reactions

All "suspicious" and "unexpected" AEs should be reported to the IRB/IEC, as required by the IRB/IEC, federal, state or local regulations and health management authorities. 9.3.2 Report serious adverse events

To ensure individual safety, all SAEs must report immediately regardless of the relationship with the study drug. All information related to SAE must be recorded on the appropriate CRF. Investigators are obliged to pursue and obtain the information reported on the CRF. All individuals undergoing SAE must be followed up and report the results.

If an SAE occurs, the investigator must notify the investigator immediately; obtain and maintain all relevant medical records, information, and medical judgments from colleagues who assist the individual in treatment and follow-up in their files; provide a complete medical record, including information about whether the event is suspected and Statements related to study drug use; and inform SAE's IRB to report SAE within its guidelines. 9.4 Procedures for unmasking research drugs

All individuals, investigators, and researchers involved in conducting the study will be covered regarding treatment allocation. When medically necessary, the investigator may need to determine what treatment plan has been assigned to the individual. If guaranteed by an investigator in consultation with the medical inspector, the unmasked individual will continue to study. 9.5 Type and duration of individual follow-up after adverse events

The investigator will track unresolved AEs until resolution, until the individual is lost to follow-up or until AEs are classified in other ways. Resolution means that the individual has returned to baseline health or the investigator does not expect any further improvement or deterioration of AE. If the patient is lost to follow-up, the investigator should make 3 reasonable attempts to contact the patient by phone, mail or guarantee mail. All follow-up visits will be recorded in the source file of the individual. The non-serious AE identified at the last scheduled contact must be recorded on the AE eCRF with the status noted.

If the investigator is aware of any new information about the existing SAE (ie, resolution, status change, or new treatment), then the new SAE/unexpected report form must be completed and faxed within 24 hours of being aware of the new information. The original SAE table is unchanged. The report should describe how the incident has been resolved or continued and how to handle the incident. 10 Statistical analysis

The statistical considerations and methods for the analysis of this study are provided below; the accompanying Statistical Analysis Plan (SAP) contains complete details of the planned analysis. 10.1 Sample size and ability considerations

The study randomly divided approximately 45 individuals into two treatment groups at a 2:1 ratio. Approximately 28 out of 30 individuals in the 2.0% Compound 1 galactate dihydrate dihydrate treatment group and placebo (Compound 1 galactose dihydrate dihydrate vehicle) nasal spray treatment group Thirteen of the 15 individuals completed their assigned treatment and had an endpoint assessment at the time of consultation 5.

The primary efficacy endpoint was the change in the Sgormer Test Score (STS) from baseline to visit 5. Dunnett will be used to correct for a two-sided t-test at 5% significance.

A previous phase 2b study (OPP-001) showed a standard deviation (SD) of approximately 10 units of STS change. Assuming a standard deviation of 10 units and an average difference of 16.7 units between the high dose and placebo, the comparison will have a significant probability (ie, ability) of approximately 99%. 10.2 Analysis group 10.2.1 Intention-to-treat group

The intention-to-treat (ITT) population will include all randomly grouped individuals. Analysis using the ITT population will group individuals according to the treatment they are randomly assigned to. 10.2.2 Security groups

The safe population will include all randomized individuals who receive at least one dose of study drug. Safety group analysis will group individuals according to the actual treatment received. 10.3 Statistical assumptions

STS mean change from baseline to the inquiry of 5 and 2.0% for placebo semi Compound 1 - mucate dihydrate are represented by μ _p and μ _h. H ₀₁ : µ _{p =} µ _h H ₁₁ : µ _{p ≠} µ _p ≠ µ _h

A successful result will be the result of rejecting the null hypothesis of a given dose. 10.4 Statistical analysis

This chapter briefly outlines the efficacy analysis of the plan. SAP details the method to be used. If SAP is inconsistent with the plan, the details and methods of SAP will prevail. 10.4.1 General considerations

Quantitative variables will be summarized using the number of individuals (n), mean, SD, median, 25th and 75th percentiles, and minimum and maximum values. Qualitative variables are outlined using counts and percentages.

All overviews will be presented by the treatment group. The overview will be provided for demographic data, medical history, concomitant medications and individual treatment.

For an overview, medical history, concomitant medication, and AE will be coded according to MedDRA and the World Health Organization Drug Dictionary as needed.

Baseline measurement is defined as the last measurement prior to the initiation of study treatment, usually at the time of Screening for Interview 1. 10.4.2 Analysis unit

For the end point of efficacy, the unit of analysis will be the research eye defined as the eye that meets all inclusion and exclusion criteria. If both eyes are qualified, the research eye will be the one with the largest increase in tears by stimulation with a cotton swab during screening interviews. If there is no difference in the irritated tears, it is an eye with a lower basic Sgormer score at the time of screening. If there is no difference in any measurement, the right eye will be used as the research eye.

For the safety endpoint, two eyes will be analyzed. 10.4.3 individual demographics and baseline characteristics

A continuous summary statistic will be generated for age in years (based on treatment group) and all individuals. Discrete summary statistics will be generated for the following qualitative demographic variables: age group, gender, race, ethnicity, and other baseline intranasal examination results, according to the treatment group and for all individual lists. Individual individual data lists will support summary tables. 10.4.4 Main efficacy analysis

The primary efficacy endpoint was the change of STS from baseline at the 5th visit. The primary endpoint will be summarized by questioning and by quantitative descriptive statistics for treatment (n, mean, median, standard deviation, 25th quartile, 75th quartile, minimum and maximum).

The main efficacy analysis of STS change from baseline will use analysis of the covariate analysis (ANCOVA) to compare treatment group differences (2.0% Compound 1 hemi-galactonate dihydrate vs. placebo). The ANCOVA model will include the treatment group and baseline STS as covariates. The difference in the average difference of the comparison will be calculated and reported along with its 95% confidence interval.

A preliminary analysis will be conducted on the ITT community. The censored mean will be used to treat individuals who have not completed the 5 STS visit. Dunnett's Test will be used for pairwise multiple comparisons.

SAP provides details describing the power analysis model and the method of dealing with missing data. 10.4.5 Secondary power analysis

EDS will use a continuous summary statistics summary. The average difference between the 2.0% Compound 1 galactate dihydrate dihydrate group and the placebo group and the related 95% CI will be calculated.

SAP will provide details describing the statistical methods planned for the results, the correction of multiplicity, and the methods for processing missing data. 10.4.6 Other power analysis

Corneal staining assessment and eye discomfort scale will be analyzed for other efficacy. Descriptive statistics will be summarized by consultation and treatment. SAP will provide details describing the statistical methods planned for these results, the correction of multiplicity, and the methods for processing missing data. 10.4.7 Safety analysis

All safety analyses will be conducted on the safety groups.

The safety of Compound 1 hemi-galactonate dihydrate will be mainly evaluated by the incidence of AE. If AE appears or worsens at or after the start of treatment, it is considered treatment-induced AE (TEAE). A general overview of TEAE will be presented in several categories based on severity, relationship to treatment, and severity according to the treatment group for TEAE, including the number of events and the number of individuals with events (along with percentages).

Other safety endpoints including vision, slit lamp biopsy, and intranasal examination will be summarized by the treatment group and the use of descriptive statistics. Changes or offsets from the baseline will be summarized as appropriate. For the evaluation by eye, the research eye and the contralateral eye will be summarized separately. In addition, the worst treatment period values from baseline to ocular safety assessment will be summarized.

SAP will present a detailed analysis of these defined parameters. 10.4.8 Interim analysis

No mid-term analysis for this research plan. 11 Compliance with good clinical practice, ethical considerations and management issues

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"Nicotinic acetylcholine receptors: from basic science to therapeutics." Pharmacol Ther 137(1): 22-54. Lee, LY, NK Burki, DC Gerhardstein, Q. Gu , YR Kou and J. Xu (2007). "Airway irritation and cough evoked by inhaled cigarette smoke: role of neuronal nicotinic acetylcholine receptors." Pulm Pharmacol Ther 20(4): 355-364. Meero vitch, K., G. Torkildsen, J. Lonsdale, H. Goldfarb, T. Lama, G. Cumberlidge and GW Ousler, 3rd (2013). "Safety and efficacy of MIM-D3 ophthalmic solutions in a randomized, placebo-controlled Phase 2 clinical trial in patients with dry eye." Clin Ophthalmol 7: 1275-1285. Morales-Perez, CL, Noviello, CM, & Hibbs, RE (2016). X-ray structure of the human alpha4beta2 nicotinic receptor. Nature , 538 (7625), 411. Mundorf, T., KA Wilcox, GW Ousler, 3rd, D. Welch and MB Abelson (2003). "Evaluation of the comfort of Alphagan P compared with Alphagan in irritated eyes." Adv Ther 20( 6): 329-336. Ousler, GW, 3rd, MB Abelson, LA Nally, D. Welch and JS Casavant (2002). "Evaluation of the time to "natural compensation" in normal and dry eye subject populations during exposure to a controlled adverse environment." Adv Exp Med Biol 506(Pt B): 1057-1063. Ousler, GW, PJ Gomes, D. Welch and MB Abelson (2005). "Methodologies for the study of ocular surface disease." Ocul Surf 3 (3): 143-154. Patane, MA, A. Cohen, S. From, G. Torkildsen, D. Welch and GW Ousler, 3rd (2011). "Ocular iontophoresis of EGP-437 (dexamethasone phosphate) in dry eye patients: results of a randomized clinical trial." Clin Ophthalmol 5: 633-643. Petrov, A., N. Perekhvatova, M. Skulachev, L. Stein and G. Ousler (2016). "SkQ1 Ophthalmic Solution for Dry Eye Treatment: Results of a Phase 2 Safety and Efficacy Clinical Study in the Environment and During Challenge in the Controlled Adverse Environment Model." Adv Ther 33(1): 96-115. Pfizer, I. (2010). "Nicotrol NS (nicotine nasal spray): Prescribing information.". Pflugfelder, SC, SC Tseng , K. Yoshino, D. Monroy, C. Felix and BL Reis (1997). "Correlation of goblet cell density and mucosal epithelial membrane mucin expression with rose bengal staining in patients with ocular irritation." Ophthalmology 104(2): 223- 235. Philip, G., FM Baroody, D. Proud, RM Naclerio and AG Togias (1994). "The human nasal response to capsaicin." J Allergy Clin Immunol 94(6 Pt 1): 1035-1045. Razantsev, SV, KA Nikitin and NA Russkikh (1992). "[Diagnostic significance of the study of lacrimal secretion in otorhinolaryngology]." Vestn Otorinolaringol (2): 14-16. Robinson, SR and PJ Wormald (2006). "Endoscopic vidian neurectomy." Am J Rhinol 20(2): 197-202. Schaumberg, DA, R. Dana, JE Buring and DA Sullivan (2009). "Prevalence of dry eye disease among US men: estimates from the Physicians' Health Studies ." Arch Ophthalmol 127(6): 763-768. Schaumberg, DA, DA Sullivan, JE Buring and MR Dana (2003). "Prevalence of dry eye syndrome among US women." Am J Ophthalmol 136(2): 318- 326. Schaumberg, DA, DA Sullivan and MR Dana (2002). "Epidemiology of dry eye syndrome." Adv Exp Med Biol 506(Pt B): 989-998. Semba, CP, GL Torkildsen, JD Lonsdale, EB McLaurin, JA Geffin, TK Mundorf, KS Kennedy and GW Ousler (2012). "A phase 2 randomized, double-masked, placebo-controlled study of a novel integrin antagonist (SAR 1118) for the treatment of dry eye." Am J Ophthalmol 153 (6): 1050-1060 e1051. Sheppard, JD, GL Torkildsen, JD Lonsdale, FA D'Ambrosio, Jr., EB McLaurin, RA Eiferman, KS Kennedy, CP Semba and O.-S. Group (2014). "Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study." Ophthalmology 121(2): 475-483. Sosne, G. and GW Ousler (2015). "Thymosin beta 4 ophthalmic solution for dry eye: a randomized, placebo- controlled, Phase II clinical trial conducted using the controlled adverse environment (CAE) model." Clin Ophthalmol 9: 877-884. Stapleton, JA and G. Sutherland (2011). "Treating heavy smokers in primary care with the nicotine nasal spray: randomized placebo-controlled trial." Addiction 106(4): 824-832. Tauber, J., P. Karpecki, R. Latkany, J. Luchs, J. Martel, K. Sall, A. Raychaudhuri, V. Smith, CP Semba and O.-. Investigators (2015). "Lifitegrast Ophthalmic Solution 5.0% versus Placebo for Treatment of Dry Eye Disease: Results of the Randomized Phase III OPUS-2 Study." Ophthalmology 122(12): 2423-2431. Thuerauf , N ., K. Markovic, G. Braun, S. Bleich, U. Reulbach, J. Kornhuber and J. Lunkenheimer (2006). "The influence of mecamylamine on trigeminal and olfactory chemoreception of nicotine." Neuropsychopharmacology 31(2): 450 -461. Tsubota, K. (1991). "The importance of the Schirmer test with nasal stimulation." Am J Ophthalmol 111(1): 106-108. Tsubota, K., M. Yamada and K. Urayama (1994) . "Spectacle side panels and moist inserts for the treatment of dry-eye patients." Cornea 13(3): 197-201. Walt JG, RM, Stern KL (1997). "Evaluating the functional impact of dry eye: the Ocular Surface Disease Index [abstract]." Drug In J 31: 1436. Consultation and measurement schedule

Inspection procedures, tests, equipment and technology

For a description of inspection procedures, tests, equipment, and technology, see the chapter entitled Inspection procedures, tests, equipment, and technology in Example 2. result

Based on the protocol described above, 53 individuals diagnosed with dry eye disease were evaluated for 2.0% Compound 1 galactose dihydrate dihydrate (1.1% Compound 1 free base) nasal spray for dry eye disease Multi-center, randomized, controlled, double-blind clinical trials on the efficacy of symptoms and symptoms. These individuals exhibited a Sgormer score of 10 mm or less and an OSDI score of 23 or more. Each system was randomly divided into a placebo group (19) or a treatment group (34), to which a nasal spray containing vehicle control or 2.0% Compound 1 hemi-galactate dihydrate dihydrate solution was administered. 50 microliters of nasal spray (a total of 100 microliters) was administered to each nostril twice a day over a period of 4 weeks.

The results of the study support that compound 1 hemi-galactonate dihydrate effectively improves the signs and symptoms of dry eye disease after 4 weeks of treatment. In particular, the individual exhibited (a) an improvement in the Stommer score of the study eye and the contralateral eye at week 4; (b) an improvement in the dry eye score inside and outside the control adverse environment at week 3; and ( c) Improvement of corneal fluorescein staining results at the 4th week. In addition, the individual does not display any meaningful systemic or ocular adverse events caused by their Compound 1 galactosate treatment. The individual may experience side effects, such as sneezing, coughing or irritation, which is consistent with any nasal spray treatment. Changes in Sgormer score over a period of 4 weeks after treatment with 2.0% Compound 1 galactose dihydrate dihydrate

The main measure of efficacy was the Sgormer test on the 28th day of the study. Generally speaking, a higher Sgormer score indicates a larger amount compared to a lower score. As outlined in Figure 12, the average change in the Sgormer score of subjects treated with Compound 1 hemi-galactate dihydrate compared to the baseline score was 10.3 mm on Day 28 (Week 4) of the study (p=0.08), and the average increase in the placebo group from the baseline Sgormer score was 5.9 mm. The Sgomer score of the treatment group increased by an average of more than 4 mm compared to the placebo indicating that Compound 1 galactose dihydrate dihydrate effectively increased tears after 4 weeks of treatment.

In addition, based on the average time on day 1 (15.7 mm, p<0.001), day 7 (week 1, 9.5 mm, p<0.05) and day 14 (week 2, 10.4 mm, p=0.001) The Gomer score is statistically significantly changed from the baseline score, and treatment with Compound 1 hemi-galactonate dihydrate provides an immediate and sustained increase in tearing. These results are summarized in Figure 12.

Also shown in the individual's contralateral eye compared to placebo, after treatment with Compound 1 hemi-galactate dihydrate dihydrate, the average Sgormer score changed significantly over a 4-week period. (The selection of research eyes and corresponding contralateral eyes is discussed in the above scheme). The results of the study showed that after treatment with Compound 1 hemi-galactose dihydrate dihydrate, on day 1 (16.2 mm, p<0.001), day 7 (week 1, 9.6 mm, p<0.05), the first Statistically significant changes from baseline scores were found on day 14 (Week 2, 9.6 mm, p<0.05) and day 28 (Week 4, 9.9 mm, p=0.003). These results are summarized in Figure 13.

Combined with the results from the research eye and the contralateral eye to include all eyes that meet the conditions of the regimen, the study showed that after treatment with Compound 1 hemi-galactonate dihydrate compared to placebo, the average Sgormer The score changed significantly from baseline over a period of 4 weeks. The results of the study showed that after treatment with Compound 1 hemi-galactonate dihydrate, on Day 1 (16 mm), Day 7 (Week 1, 9.8 mm), and Day 14 (Week 2, 10.6 mm) and the 28th day (week 4, 10.9 mm) Sgormer score compared with the baseline score change. These results are summarized in Figure 14.

Compared with the placebo group, the study with the compound 1 hemi-galactate dihydrate dihydrate group used the Stommer score in the eye and the contralateral eye to increase from day 1 to day 28 to prove that compound 1 Galactal diacid dihydrate can be used to immediately increase tearing and maintain increased tearing over a four-week period. This evidence supports the use of the compound to effectively treat dry eye disease and reduce eye discomfort. Changes in the Sgormer score category

Individuals selected for the study had a Sgormer score (baseline score) of less than 10 mm at the time of screening and before treatment. The percentage of Compound 1 hemi-galactate dihydrate dihydrate treated subjects exhibiting a 10 mm or greater increase in Sgormer score (change in category) compared to the baseline Sgormer score was greater than the percentage of individuals in the placebo group. In the treatment group, 64.7% of the individuals were on day 1, 38.2% of the individuals were on day 7, 47.1% of the individuals were on day 14, and 41.2% of the individuals had 10 mm or more on the 28th day Silent rating. In the placebo group, 21.1% of individuals were on Day 1, 21.1% of individuals were on Day 7, 10.5% of individuals were on Day 14, and 15.8% of individuals had a baseline score of 10 mm or more on Day 28. The bigger sgomer score. These results are summarized in Figure 15.

These results support that treatment with Compound 1 hemi-galactate dihydrate dihydrate results in a categorical change in the Sgormer score of individuals diagnosed with dry eye disease ( > 10 mm increase). Compound 1 with 2.0% semi - dry eye score results after mucate dihydrate 21 and 28 days treatment

The secondary measure of efficacy was EDS at the 21st day (week 3) of the study. In general, larger EDS indicates greater discomfort caused by dry eye symptoms than lower EDS that indicates less discomfort. The results from the study showed that the EDS of the treatment group decreased by -9.6 mm on day 21 compared to the baseline score. In contrast, EDS in the placebo group decreased by -4.3 mm. These results are summarized in Figure 16(A). After 3 weeks of treatment, a greater reduction in EDS in the treatment group compared to the placebo group indicates less discomfort and greater improvement in dry eye symptoms. This result proves that Compound 1 hemi-galactonate dihydrate is effective in reducing eye discomfort and symptoms associated with dry eye disease.

Figure 16(B) summarizes the EDS at 28 days (Week 4). The bar graph shows that the EDS of the treatment group decreased by -16.9 mm and the placebo group decreased by -19.8 mm.

At 21 days, the subject experienced a controlled adverse environment and was then administered a placebo or Compound 1 galactate dihydrate dihydrate. The EDS of the individual was measured at 5, 10 and 15 minutes after administration. The average EDS reduction in the group given Compound 1 hemi-galactonate dihydrate was -7.2 mm at 5 minutes, -11.4 mm at 10 minutes, and -11.4 mm at 15 minutes. The average EDS reduction in the placebo-administered group was -6.1 mm at 5 minutes, -7.7 mm at 10 minutes, and -5.9 mm at 15 minutes. These results are summarized in Figure 17.

The greater reduction in EDS in the treatment group compared to the placebo group indicates that among individuals diagnosed with dry eye disease and treated with Compound 1 galactose dihydrate dihydrate, those individuals experienced more eye discomfort Great reduction. This result proves that Compound 1 hemi-galactonate dihydrate can be used to effectively treat the symptoms of dry eye. Changes in corneal staining

Another measure of therapeutic efficacy is the corneal luciferin staining test. In general, a higher number indicates a greater damage to the corneal surface, and a lower number indicates a lower level of damage to the corneal surface. The decrease in corneal fluorescein staining score over time proves that the damage to the corneal surface is reduced and the health of the ocular surface is improved. Results from the study showed that after 28 days of treatment with Compound 1 hemi-galactate dihydrate dihydrate, the average corneal staining of the nose (-0.12), upper corneal surface area (-0.06) and lower corneal area (-0.12) The decrease in score. In contrast, the placebo group showed an increase in the corneal score of the nasal (0.17) and upper (0.22) corneal regions, and a decrease in the corneal score of the lower regions (-0.06). These results are summarized in Figure 18.

The reduction in corneal fluorescein staining scores in the nose, upper and lower areas of the treatment group with Compound 1 galactose dihydrate dihydrate demonstrates the improvement in corneal health after 28 days of treatment. These results are consistent with the effective treatment of dry eye disease, increased tear production, and improved eye discomfort with Compound 1 galactose dihydrate dihydrate. Safety Overview

Events that are potentially related to the administration of Compound 1 hemi-galactonate dihydrate and appear in more than 5% of the study group include (from more frequent to less frequent): sneezing, coughing, throat, and drops Injection site irritation, and the throat and administration site feel dull. The results are summarized in Figure 19. Each event is transient in nature and mild in severity. These events are consistent with the side effects caused by any nasal spray administration. No significant systemic or ocular adverse events have been observed since the study. These results support the strong safety results after 28 days of intranasal treatment with Compound 1 hemi-galactate dihydrate dihydrate. Example 4: Measuring the maximum plasma concentration

This example describes the measurement of the maximum plasma concentration (Cmax) of an nAChR agonist or a pharmaceutically acceptable salt in an individual after administration of a pharmaceutical formulation containing the nAChR agonist or a pharmaceutically acceptable salt thereof Methods. Administration

A dose of nAChR agonist or a pharmaceutically acceptable salt is administered to the individual. Examples of dose and volume ranges are described herein. Blood collection and sample processing

Blood samples are collected from the individual before administration of the nAChR agonist or its pharmaceutically acceptable salt. After the individual is administered the nAChR agonist or a pharmaceutically acceptable salt thereof, multiple blood samples are collected at specific intervals over a period of time. For example, blood samples are collected at 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, and 4 hours after administration of the nAChR agonist or a pharmaceutically acceptable salt thereof.

A blood sample (4 mL in a K ₂ EDTA tube) was collected from the arm vein into a Vacutainer tube containing K ₂ EDTA. Blood samples were gently mixed and kept cold until centrifuged within 2 hours of collection.

Plasma samples were separated into two equal aliquots and labeled with individual identification and nominal time points and stored frozen (at <-70°C) until analysis. Pharmacokinetic sample bioanalysis method

Blood samples from individuals are processed to obtain plasma, and liquid chromatography followed by tandem mass spectrometry (LC-MS/MS) biological analysis method (high performance liquid chromatography [HPLC] with mass spectrometry detection) is used to obtain nAChR The plasma concentration of the effective agent or its pharmaceutically acceptable salt. Pharmacokinetic analysis

All pharmacokinetic (PK) analyses and reports are conducted in accordance with generally accepted standard operating procedures and protocol specifications. Pharmacokinetic parameters are calculated by using commonly accepted software tools, such as Phoenix® WinNonlin® 8.0.

Plasma concentration time curve is generated by plotting the change of nAChR agonist or its pharmaceutically acceptable salt concentration with time. Cmax is calculated by examining the plasma concentration time curve of the individual. Another Cmax-related parameter is the maximum observed concentration of the nAChR agonist or its pharmaceutically acceptable salt divided by the milligram dose, (Cmax/D). Cmax is calculated for individuals after treatment. If the Cmax of more than one individual is calculated, the arithmetic mean Cmax and median Cmax of the group can also be calculated. Example 5 : Cmax measured after treatment with Compound 1

Plasma lines of 30 individuals treated with 1.1% Compound 1 free base (2.0% Compound 1 hemi-galactonate dihydrate) via nasal spray (200 μl total volume; approximately 2216 μg Compound 1 free base) Analysis using the protocol described in Example 4. The average Cmax of Compound 1 measured was 2.92 ng/mL. Example 6: performance metal compound of oocytes of a human nAChR agonist activity in citrate Xenopus

This example describes an experiment characterizing the agonistic activity of Compound 1 citrate on human neuron nicotinic acetylcholine receptor (nAChR) α3β4, α3α5β4, α4β2, α4α6β2, and α7 expressed in Xenopus oocytes. method

Test compound: Compound 1 citrate

Reference compound: Acetylcholine chloride

Test system: see example 1.

Oocyte preparation: see Example 1.

Electrophysiological records: see Example 1.

Accelerator preparation: see Example 1. The tested concentrations of Compound 1 citrate were 0.1, 0.3, 1, 3, 10, 30, 100 and 300 (micromolar). The test concentration of acetylcholine chloride is 1280 micromolar.

Data analysis and statistics: see example 1.

Experimental procedure: cDNA encoding human α3β4, α3α5β4, α4β2, α4α6β2 and α7 were injected into at least 95 oocytes using a dedicated automatic injection device. Check cell receptor performance after at least two days. The oocyte has two electrodes and its membrane potential is maintained at -80 mV throughout the experiment (unless indicated).

Develop protocols to measure the agonistic activity in oocytes that exhibit nAChR. Cells were exposed to a series of increasing concentrations of nAChR agonist for 10 seconds each, with an interval of two minutes. The test concentration of nAChR agonist is 0.1, 0.3, 1, 3, 10, 30, 100, 300 (micromolar). The current induced by exposure to various concentrations of agonist was recorded. For oocytes expressing α7 nAChR, reduce exposure to agonists to 5 seconds. This process is repeated for each agonist tested for each type of nAChR expressing cell. result

The effect of compound 1 citrate at the human neuron nicotinic acetylcholine receptors expressed in Xenopus oocytes was studied using two electrode voltage clamps. The measurement of the agonistic effect of compound 1 citrate at α3β4, α3α5β4, α4β2, α4α6β2 and α7 receptors revealed that this compound acts as an agonist at these receptors in the range of 10 to 300 micromolar. However, significant differences were observed in the responses between receptor subtypes. That is, Compound 1 Citrate is a weak partial agonist at the human α7 receptor at a concentration of 300 micromolar. 300 micromolar Compound 1 citrate solution induced only 25% of the ACh induced current. In contrast, data recorded for the nAChR subtypes α3β4, α3α5β4, α4β2, and α4α6β2 show that compound 1 citrate acts as an almost complete agonist at these receptors.

Compound 1 citrate acts almost as a full agonist at nAChR α3β4, producing an EC _{50 of} 34.87±4.53 micromolar.

Compound 1 citrate acts almost as a full agonist at nAChR α3α5β4, yielding an EC _{50 of} 83.00±9.05 micromolar.

Compound 1 citrate acts almost as a full agonist at nAChR α4β2, producing an EC _{50 of} 13.48±2.06 micromolar. The significant inhibition of the current induced by the second Ach exposure was attributed to desensitization caused by Compound 1 citrate exposure.

Compound 1 citrate acts almost as a full agonist at nAChR α4α6β2, producing an EC _{50 of} 13.14±3.68 micromolar.

Compound 1 citrate acts as a poor agonist at nAChR α7, inducing only 25% of the maximum ACh evoked current at 300 micromolar, resulting in an EC _{50 of} 125.63±28.52 micromolar. In view of the small portion of the current induced by Compound 1 citrate, EC ₅₀ is only an evaluation. Example 7: Intranasal administration of Compound 1 and a half - mucate human subject in the pharmacokinetic measurements after 28 days of

This example describes studies to determine plasma systemic exposure and pharmacokinetics after four weeks of treatment with 1.1% Compound 1 (2.0% galactose diacid salt) and after a single bilateral nasal spray on day 29 . The results showed that Compound 1 was detected in all individuals 10 minutes after administration, indicating rapid nasal absorption of Compound 1. In addition, this example shows that Compound 1 exhibits low systemic exposure after intranasal administration and should not exhibit any accumulation in systemic circulation after repeated administration.

Seven patients were administered 1.1% Compound 1 (2.0% hemi-galactonate) in each nostril as a 50 μL intranasal spray with BID for 28 days. On Day 29, patients were given a single intranasal administration of 1.1% Compound 1 (2.0% hemi-galactonate).

A series of time points (10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 5 hours, 6 hours, 7) before the administration on day 29 (time 0) and after a single administration of the drug Hours, 8 hours, and 24 hours) after collecting patient plasma. Plasma was analyzed for compound 1.

Ÿ AUC%Extrap：藉由外推法獲得之AUCinf之百分比(AUC%Extrap)將計算如下：

Ÿ半衰期： 終末消除半衰期。Calculate the following pharmacokinetic parameters of Compound 1: Cmax : the maximum observed concentration observed by examining the plasma concentration time curve of individual study participants. Ÿ Tmax : the time of the maximum observed concentration obtained directly from the observed concentration time data. Ÿ AUClast : The area under the plasma concentration time curve from time 0 to the last measurable non-zero concentration is calculated by a combination of linear and logarithmic trapezoidal methods (linear up/log down method). Ÿ AUC0-4h : the area under the plasma concentration time curve from time 0 to 4 h, calculated by the combination of linear and logarithmic trapezoidal methods (linear up/log down method). Ÿ AUCinf : The area extrapolated from zero hour (before dosing) to infinite time (AUCinf) will be calculated as follows:

Ÿ AUC%Extrap: The percentage of AUCinf obtained by extrapolation (AUC%Extrap) will be calculated as follows:

ŸHalf -life: Eliminate the half-life at the end.

Plasma concentration data. 28 days after BID administration of 1.1% Compound 1, Compound 1 was detected in 4 of 7 individuals at time zero (pre-dose) with an average concentration of 0.264 ng/mL. Ten minutes after administration, Compound 1 was detected in the plasma of all individuals, indicating rapid nasal absorption. The average compound 1 plasma exposure increased with time after intranasal administration, with a peak exposure of 2.07 ng/mL at 1 h and then decreased during the 24 h sampling period. The decline is biphasic, with a flat area between 2 and 4 h. Four of the seven individuals had quantifiable levels at 5 h after dosing and at the following three time points, one individual with quantifiable Compound 1 was lost at each of 6, 7, and 8 h. There was only one individual with quantifiable compound 1 at 8 h after administration, and no individual with quantifiable compound 1 at a lower quantitation limit of higher than 0.200 ng/mL at 24 h after administration.

Pharmacokinetic parameter data. The average (SD) Cmax of Compound 1 was 2.26±1.96 ng/mL, and the maximum of individual individuals among the 7 individuals was 5.49 ng/mL. The median Tmax appeared at 0.50 h and the average (SD) half-life was 1.58±0.818 h. The AUC%Extrap of 4 of the 7 individuals is >20%, which should exclude the calculation of half-life and AUCinf. However, these individual individual values are reported and included in the summary statistics of the PK parameters AUCinf and half-life. The mean (SD) AUClast varied within 5.22±4.52 h*ng /mL and the maximum single individual value was at 12.1 h*ng /mL. However, the one with the lowest AUC%Extrap at 3.69% was also the one with the largest AUClast and AUCinf at 12.1 h*ng /mL and 12.5 h*ng /mL, respectively. At 6.22±4.63 h*ng /mL, the average (SD) AUCinf was greater than the average AUClast 21.3%. The maximum individual half-life is 2.83 h, which will indicate that, in general, if Compound 1 is administered every 12 hours, for all individuals, >94% (4 half-lives) of Compound 1 will be cleared from the systemic circulation before the next administration . Overall, the systemic exposure of Compound 1 is low.

The pharmacokinetic results are summarized in the table below.

Conclusion: 28 days after BID administration of 1.1% Compound 1, Compound 1 exhibited low systemic exposure in 4 out of 7 individuals (57.1%) exhibiting systemic exposure before administration, with an average concentration of 0.264 ng/mL. Ten minutes after administration, Compound 1 was detected in the plasma of all individuals, indicating rapid nasal absorption. The clearance rate of Compound 1 is biphasic in nature, with a flat line area between 2 and 4 h, which may indicate that the oral component may be absorbed into the systemic profile. However, there was only one individual with a quantifiable amount of Compound 1 at 8 h after administration and no individual at 24 h after administration. This is related to the observed mean (SD) half-life of 1.58±0.818 h. The maximum individual half-life is 2.83 h, which will indicate that, in general, if Compound 1 is administered every 12 hours, for all individuals, >94% (4 half-lives) of Compound 1 will be cleared from the systemic circulation before the next administration . Overall, the systemic exposure of Compound 1 was low, with an average (SD) Cmax of 2.26±1.96 ng/mL, of which the individual maximum of 7 individuals was 5.49 ng/mL.

Figure 1 shows a bar graph summarizing the average change in the Sgormer score of an individual in a clinical study as a function of three concentrations of Compound 1 galactate dihydrate dihydrate.

FIG. 2 shows a bar graph summarizing the average change in dry eye scores of individuals with three concentrations of Compound 1 galactate dihydrate dihydrate 5 minutes after administration in a clinical study.

Figure 3 shows a graph summarizing the average change in dry eye scores of individuals in a clinical study that varied with three concentrations of Compound 1 galactate dihydrate dihydrate within 60 minutes.

Figure 4 shows a bar graph summarizing the% of individuals in the clinical study that had a 35 mm Sgormer score as a function of three different concentrations of Compound 1 galactate dihydrate dihydrate.

Figure 5 shows a bar graph summarizing the median change in the Sgormer score of an individual in a clinical study as a function of three different concentrations of Compound 1 galactate dihydrate dihydrate.

Figure 6 shows a bar graph summarizing the% of individuals in clinical studies that had a change in the Sgormer score (change in category) of more than 10 mm as a function of three different concentrations of Compound 1 galactate dihydrate dihydrate.

Figure 7 shows a bar graph summarizing the% of individuals in the clinical study that had a change in the Sgormer score (change in category) of more than 20 mm as a function of three different concentrations of Compound 1 galactose dihydrate dihydrate.

Figure 8 shows a graph summarizing the most common adverse events experienced by individuals in the clinical study of Compound 1 galactate dihydrate dihydrate.

Fig. 9 shows a diagram for dividing the corneal surface based on the NEI/Industry Workshop scale to measure the absorption of luciferin.

Figure 10 shows an example of a questionnaire used to determine an individual's OSDI score.

Figure 11 shows an example of a Visual Analogue Scale (VAS) used to perform dry eye testing on individuals to record their symptom severity.

FIG. 12 shows a bar graph summarizing the Sgormer score of individuals treated with 2.0% Compound 1 galactate dihydrate dihydrate and the score of individuals treated with placebo over a 4-week period compared to The average change in the baseline score.

Fig. 13 shows a bar graph summarizing the Stommer score of the contralateral eye of individuals treated with 2.0% Compound 1 galactose dihydrate dihydrate and the individuals treated with placebo over a 4-week period The average score of the contralateral eye compared to the baseline score.

Figure 14 shows a bar graph summarizing the Sgormer scores of all eligible eyes of individuals treated with 2.0% Compound 1 galactate dihydrate dihydrate and individuals treated with placebo over a 4-week period Average change from baseline score.

Figure 15 shows a bar graph summarizing that after treatment with 2.0% Compound 1 hemi-galactonate dihydrate or placebo, Sgormer has a score of 10 mm or more compared to the baseline score over a 4-week period % Of individuals with a change in score (change in category).

16A-16B show a bar graph summarizing the comparison of 2.0% Compound 1 galactate dihydrate dihydrate or placebo treatment regimen at (A) week 3 and (B) week 4 Change in dry eye score at baseline.

FIG. 17 shows a bar graph summarizing the change in dry eye score of an individual in a controlled unfavorable environment compared to the baseline score after administration of 2.0% Compound 1 galactate dihydrate dihydrate or placebo ( In 5 minute increments).

Figure 18 shows a bar graph summarizing the average change in corneal fluorescein staining compared to baseline scores at 4 weeks of treatment with 2.0% Compound 1 galactate dihydrate dihydrate or placebo.

Figure 19 shows a chart summarizing the most common events experienced by an individual within 4 weeks of treatment with 2.0% Compound 1 galactate dihydrate dihydrate or placebo.

Claims (79)

A method for treating dry eye disease, increasing tear production or reducing eye discomfort for an individual in need, which comprises administering an effective amount of Compound 1 having the following structure to the nasal cavity of the individual in need

, Or the first dose of its pharmaceutically acceptable salt and one or more subsequent doses as appropriate; where the method results in effective treatment of the individual in need. A compound used in a method for treating dry eye disease, increasing tear production or reducing eye discomfort for an individual in need, wherein the compound is Compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof; wherein the method comprises administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of the individual in need, and optionally One or more subsequent doses. The compound as used in claim 2, wherein the method results in effective treatment of the individual in need. The method of claim 1 or the compound of claim 3, wherein the effective treatment of the individual is indicated by one or more tests selected from the group consisting of: a) According to the dry eye scoring test of the visual analogue scale, b) Schirmer's test, c) Corneal luciferin staining test according to the National Eye Institute (NEI) classification system, and d) Eye surface disease index test. The method of claim 4 or the compound used, wherein the effective treatment is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is directed to the individual The first dose of the effective amount of Compound 1 or a pharmaceutically acceptable salt thereof or one or more subsequent doses as appropriate is determined after administration, and wherein the individual's dry eye score is compared to a) The individual's dry eye score before receiving the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) Dry eye score of the individual receiving the control; or c) Dry eye score of the individual receiving the comparative compound. As in the method of claim 5 or the compound used, the individual's dry eye score is statistically significantly reduced by at least 15%. As in the method of claim 5 or 6, or the compound used, the dry eye score of the individual statistically significantly decreases between 10 mm and 20 mm. The method or compound used according to any one of claims 5 to 7, wherein the individual's dry eye score is statistically significantly reduced by at least 3 mm. The method or compound used in any one of claims 5 to 8, wherein the statistically significant decrease in the dry eye score of the individual is the administration of an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof Within 5 minutes of this first dose. The method or compound used in any one of claims 5 to 9, wherein the individual's dry eye score statistically significantly improves the self-administered effective amount of Compound 1 or a pharmaceutically acceptable salt thereof Start a dose for at least 30 minutes. The method of claim 10 or the compound used, wherein the individual is present in an environment with reduced humidity between the determination of the individual's dry eye score. The method or compound used as claimed in any one of claims 4 to 11, wherein the effective treatment is indicated by a statistically significant increase in the subject’s Sgormer score, and in which the subject has at least one eye The statistically significant increase in the silent score is determined after administration of an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof or one or more subsequent doses as appropriate to the individual, and The Sgormer score of the individual is compared to a) Sgormer score before receiving the first dose of Compound 1 or its pharmaceutically acceptable salt in the same eye of the individual; b) Sgormer score for the individual receiving the control; or c) Sgormer scores for individuals receiving the comparative compound. As in the method of claim 12, or the compound used, the Sgormer score of the individual is statistically significantly increased by at least 15%. As in the method of claim 12 or 13, or the compound used, the Sgormer score of the individual is statistically significantly increased between 10 mm and 20 mm. As in the method of claim 12 or 13 or the compound used, the Sgormer score of the individual statistically significantly increases by at least 3 mm. The method or compound used in any one of claims 12 to 15, wherein the statistically significant increase in the individual's Sgormer score is when an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered Within 5 minutes of the first dose. A method or a compound used as claimed in any one of claims 12 to 16, wherein the statistically significant improvement of the individual's Sgormer score significantly improves the self-administered effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The first dose is maintained for at least 30 minutes. The method or compound used in any one of claims 4 to 17, wherein the effective treatment is indicated by a statistically significant decrease in the individual's corneal score, and wherein the statistically significant decrease in the individual's corneal score Is determined after administering to the individual an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof or one or more subsequent doses as appropriate, and wherein the individual's dry eye score is Compared to a) Corneal score before the individual receives the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) corneal score of the individual receiving the control; or c) The corneal score of the individual who received the comparative compound. The method of claim 18 or the compound used, wherein the individual's corneal score is statistically significantly reduced by at least 15%. The method or compound used as claimed in any one of claims 18 to 19, wherein the statistically significant decrease in the individual's corneal score is when the effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered Within 5 minutes of the first dose. The method or compound used in any one of claims 18 to 20, wherein the subject's corneal score statistically significantly improves the first self-administered effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. The dose begins to be maintained for at least 30 minutes. The method of claim 21 or the compound used, wherein the individual is present in an environment with reduced humidity between the determination of the individual's corneal score. The method or compound used in any one of claims 4 to 22, wherein the effective treatment is indicated by a statistically significant decrease in the individual's OSDI score, and wherein the statistically significant decrease in the individual's OSDI score It is determined after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof or one or more subsequent doses as appropriate to the individual, and wherein the individual's OSDI score is relative Compared to a) OSDI score of the individual before receiving the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) OSDI score of the individual receiving the control; or c) The OSDI score of the individual receiving the comparative compound. As in the method of claim 23 or the compound used, the individual's OSDI score is statistically significantly reduced by at least 15%. The method or the compound used as in any one of claims 23 to 24, wherein the statistically significant decrease in the individual's OSDI score is when the effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered Within 5 minutes of the first dose. The method or compound used in any one of claims 23 to 25, wherein the statistically significant improvement of the individual's OSDI score improves the first self-administered effective amount of Compound 1 or a pharmaceutically acceptable salt thereof The dose begins to be maintained for at least 30 minutes. The method of claim 26 or the compound used, wherein the subject is present in an environment with reduced humidity between the determination of the subject's corneal score. A kind of nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor in individuals in need Or a combination thereof for immediate and long-term pharmacological stimulation, which comprises administering an effective amount of Compound 1 having the following structure to the nasal cavity of the individual in need

, Or the first dose of its pharmaceutically acceptable salt and one or more subsequent doses as appropriate. It is used for nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 in individuals in need A compound of a method of immediate and long-term pharmacological stimulation of a receptor or a combination thereof, wherein the compound is compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof; wherein the method comprises administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of the individual in need, and optionally One or more subsequent doses. The method according to claim 28 or the compound used according to claim 29, wherein the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 in the individual The pharmacological stimulation of the receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof, is indicated by one or more tests selected from the group consisting of: a) According to the dry eye scoring test of the visual analogue scale, b) Sgormer test, c) Corneal fluorescein staining test according to the National Institute of Ophthalmology (NEI) classification system, and d) Eye surface disease index test. The method of claim 30 or the compound used, wherein the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor in the individual, or The pharmacological stimulation of the nicotine acetylcholine α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's dry eye score, and wherein the statistically significant decrease in the individual's dry eye score is in response to the The first dose or one or more subsequent doses of Compound 1 or a pharmaceutically acceptable salt thereof are administered after the individual is administered an effective amount, and the dry eye score of the individual is compared to a) The individual's dry eye score before receiving the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) Dry eye score of the individual receiving the control; or c) Dry eye score of the individual receiving the comparative compound. As in the method of claim 31 or the compound used, the individual's dry eye score is statistically significantly reduced by at least 15%. As in the method of claim 31 or 32 or the compound used, wherein the individual's dry eye score statistically significantly decreases between 10 mm and 20 mm. The method or compound used as claimed in claim 31 or 32, wherein the individual's dry eye score is statistically significantly reduced by at least 3 mm. The method or compound used in any one of claims 31 to 34, wherein the statistically significant decrease in the dry eye score of the individual is when an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered Within 5 minutes of this first dose. The method or compound used in any one of claims 31 to 35, wherein the individual's dry eye score statistically significantly improves the self-administered effective amount of Compound 1 or a pharmaceutically acceptable salt thereof Start a dose for at least 30 minutes. The method or the compound used according to any one of claims 30 to 36, wherein the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine in the individual The pharmacological stimulation of the base α3α5β4 receptor, or the nicotinic acetylcholine α4α6β2 receptor or a combination thereof is indicated by a statistically significant increase in the subject’s Sgormer score, and in which the subject has at least one eye The statistically significant increase in the Gomer score is determined after administering to the individual an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof or one or more subsequent doses as appropriate, and The Sgormer score of the individual is compared to a) Sgormer score before receiving the first dose of Compound 1 or its pharmaceutically acceptable salt in the same eye of the individual; b) Sgormer score for the individual receiving the control; or c) Sgormer scores for individuals receiving the comparative compound. As in the method of claim 37 or the compound used, the Sgormer score of the individual is statistically significantly increased by at least 15%. As in the method of claim 37 or 38 or the compound used, the Sgormer score of the individual is statistically significantly increased between 10 mm and 20 mm. As in the method of claim 37 or 38 or the compound used, the Sgormer score of the individual is statistically significantly increased by at least 3 mm. The method or the compound used in any one of claims 30 to 40, wherein the α4β2 receptor in the individual, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor, or The pharmacological stimulation of the nicotine acetylcholine α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual's corneal score, and wherein the statistically significant decrease in the individual's corneal score is the The first dose of the effective amount of Compound 1 or a pharmaceutically acceptable salt thereof or one or more subsequent doses optionally selected are determined afterwards, and wherein the individual's dry eye score is compared to a) the individual's corneal score before receiving the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) corneal score of the individual receiving the control; or c) The corneal score of the individual who received the comparative compound. The method of claim 41 or the compound used, wherein the individual's corneal score is statistically significantly reduced by at least 15%. The method or compound used in any one of claims 30 to 42, wherein the nicotinic acetylcholine α4β2 receptor, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine in the individual The pharmacological stimulation of the base α3α5β4 receptor, or nicotine acetylcholine α4α6β2 receptor or a combination thereof is indicated by a statistically significant decrease in the individual’s OSDI score, and wherein the statistically significant decrease in the individual’s OSDI score It is determined after administering an effective amount of the first dose of Compound 1 or a pharmaceutically acceptable salt thereof or one or more subsequent doses as appropriate to the individual, and wherein the individual's OSDI score is relative Compared to a) OSDI score of the individual before receiving the first dose of Compound 1 or a pharmaceutically acceptable salt thereof; b) OSDI score of the individual receiving the control; or c) The OSDI score of the individual receiving the comparative compound. As in the method of claim 43 or the compound used, the individual's OSDI score is statistically significantly reduced by at least 15%. The method or the compound used according to any one of claims 28 to 44, wherein at least the nicotinic acetylcholine α4β2 receptor is pharmacologically stimulated. The method or the compound used according to any one of claims 28 to 44, wherein at least the nicotinic acetylcholine α3β4 receptor is pharmacologically stimulated. The method or the compound used according to any one of claims 28 to 44, wherein at least the nicotinic acetylcholine α3α5β4 receptor is pharmacologically stimulated. The method or compound used according to any one of claims 1 to 47, wherein the subject is administered 5 to 4000 micrograms of Compound 1 per dose, or a corresponding amount of a pharmaceutically acceptable salt thereof. The method or compound used in any one of claims 1 to 48, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally, and each dose of the pharmaceutical formulation The total volume is 150 to 250 microliters. The method or the compound used according to any one of claims 1 to 49, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally, the pharmaceutical formulation containing 1 mg/ Compound 1 between mL and 40 mg/mL, or a corresponding amount of its pharmaceutically acceptable salt. The method or compound used in any one of claims 49 to 50, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical formulation administered nasally, and each nostril is administered The total volume of the pharmaceutical formulation is 50 to 250 microliters. The method or the compound used in any one of claims 1 to 51, wherein the dose is administered to the individual in need one to four times a day after the first day of administration. The method or the compound used in any one of claims 1 to 51, wherein the dose is administered to the individual in need once a day after the first day of administration. The method or the compound used as in any one of claims 1 to 51, wherein a) Over time, reduce the frequency of doses of Compound 1 or its pharmaceutically acceptable salts administered to the individual, or b) Over time, reduce the total amount of Compound 1 per dose, or the corresponding amount of its pharmaceutically acceptable salt. The method of claim 54 or the compound used, wherein each dose comprises administering Compound 1 or a pharmaceutically acceptable salt thereof to the nasal cavity of the individual more than once, and Where the total amount of Compound 1 per dose or its pharmaceutically acceptable salt is reduced over time by reducing the number of administrations of Compound 1 or its pharmaceutically acceptable salt into the nasal cavity of the individual to fulfill. The method or compound used according to any one of claims 1 to 55, wherein the dose comprises multiple administrations of Compound 1 or a pharmaceutically acceptable salt thereof to one or both nostrils. The method or compound used according to any one of claims 1 to 55, wherein the dose comprises a single administration of Compound 1 or a pharmaceutically acceptable salt thereof to one or both nostrils. The method or the compound used according to any one of claims 1 to 57, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered for at least 28 days. The method or the compound used according to any one of claims 1 to 57, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered for at least 3 months. The method or compound used in any one of claims 1 to 59, wherein the individual has undergone laser in situ lamellar keratoplasty (Lasik) surgery within 2 weeks or scheduled Lasik surgery within 2 weeks. The method or compound used according to any one of claims 1 to 60, wherein the individual does not experience one or more side effects selected from the group consisting of: excessive tear production, cough, throat irritation, irritation at the instillation site , Sneezing, nasopharyngitis, nasal irritation, toothache, dry mouth and headache. The method of claim 61 or the compound used, wherein within 5 to 60 minutes of administering the first dose or one or more subsequent doses, the individual does not experience one or more selected from the group consisting of Side effects: Excessive tear production, cough, throat irritation, irritation at the instillation site, sneezing, nasopharyngitis, nasal irritation, toothache, dry mouth and headache. The method or compound used in any one of claims 1 to 62, wherein the excessive tear production is indicated by an increase in the Sgomer score of the individual by more than 20 mm. The method or compound used in any one of claims 1 to 63, wherein the method does not include administering a positive ectopic modulator to the individual. The method or the compound used according to any one of claims 1 to 64, wherein the plasma Cmax of the compound 1 or the pharmaceutically acceptable salt thereof of the individual in need is less than 5 ng/mL. The method or compound used according to any one of claims 1 to 65, wherein the subject is administered 150 to 300 micrograms of Compound 1 per dose, or a corresponding amount of a pharmaceutically acceptable salt thereof. The method or compound used according to any one of claims 1 to 65, wherein the subject is administered 900 to 1200 micrograms of Compound 1 per dose, or a corresponding amount of a pharmaceutically acceptable salt thereof. The method or the compound used according to any one of claims 1 to 67, wherein the pharmaceutically acceptable salt is the hemi-galactonate salt of Compound 1. The method or the compound used according to any one of claims 1 to 67, wherein the pharmaceutically acceptable salt is the citrate salt of compound 1. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to treat dry eye disease, increase tear production or reduce eye discomfort for an individual in need thereof, wherein the nicotinic acetyl acetyl Choline receptor agonists are compounds with the following structure 1

, Or a pharmaceutically acceptable salt thereof. Use of a nicotinic acetylcholine receptor agonist for the manufacture of a medicament, wherein the medicament is used to stimulate the nicotinic acetylcholine α4β2 receptor in an individual in need, or nicotinic acetylcholine α3β4 receptor, or nicotinic acetylcholine α3α5β4 receptor, or nicotinic acetylcholine α4α6β2 receptor or a combination thereof, wherein the nicotinic acetylcholine receptor agonist is compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof. A pharmaceutical formulation for treating dry eye disease, increasing tear production or reducing eye discomfort for individuals in need, the formulation comprises Compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof. A pharmaceutical formulation for the nicotinic acetylcholine α4β2 receptor, or the nicotinic acetylcholine α3β4 receptor, or the nicotinic acetylcholine α3α5β4 receptor, or nicotine in an individual in need Acetylcholine α4α6β2 receptor or a combination thereof undergoes pharmacological stimulation. The formulation contains compound 1 having the following structure

, Or a pharmaceutically acceptable salt thereof. The pharmaceutical formulation according to claim 72 or 73, wherein the use includes the method as defined in any one of claims 1 to 69. The pharmaceutical formulation according to any one of claims 72 to 74, which contains 5 to 4000 micrograms of Compound 1 per dose, or a corresponding amount of its pharmaceutically acceptable salt. The pharmaceutical formulation according to any one of claims 72 to 75, wherein the volume of each dosage of the pharmaceutical formulation is 50-250 microliters. The pharmaceutical formulation according to any one of claims 72 to 76, which contains Compound 1 between 1 mg/mL and 40 mg/mL, or a corresponding amount of its pharmaceutically acceptable salt. The pharmaceutical formulation according to any one of claims 72 to 77, wherein the pharmaceutically acceptable salt is the hemi-galactonate salt of Compound 1. The pharmaceutical formulation according to any one of claims 72 to 77, wherein the pharmaceutically acceptable salt is the citrate salt of Compound 1.

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