Simpinicline oral formulations and use thereof

Abstract

The current disclosure relates to the preparation of topical oral solutions of simpinicline ((R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) and pharmaceutically acceptable salts thereof and their use in treating dry mouth.

Description

[0001] Attorney Docket No. OYST-039 / 01WO (391206-00447) SIMPINICLINE ORAL FORMULATIONS AND USE THEREOF BACKGROUND OF THE INVENTION The current disclosure relates to the preparation of topical oral solutions of simpinicline ((R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) and pharmaceutically acceptable salts thereof and their use in treating dry mouth. Dry mouth is one of the most common yet underappreciated, underdiagnosed, and undermanaged oral health conditions affecting about 10% – 30% of the general population. The subjective sensation of dry mouth may be a consequence of reduced salivary flow (hyposalivation) due to a number of causes, such as endocrinological causes, autoimmune causes and / or infectious causes, and certain prescription and over-the-counter medications. Saliva plays a critical role in maintaining oropharyngeal health. It preserves the homeostasis of the oral environment and helps in mastication, taste perception, deglutition, digestion, speech, immunity, caries protection, lubricates oral mucosa, and protects it from desiccation. Three paired major salivary glands (parotid, sublingual, and submandibular) and hundreds of minor salivary glands distributed throughout the oral cavity contribute to secretion of saliva under the regulation of the sympathetic and parasympathetic divisions of the autonomic nervous system. The daily secretion of saliva normally ranges between 1.0 and 1.5 L at a rate of 0.5 mL / min. However, with dry mouth the amount of saliva decreases, wherein the unstimulated submandibular / sublingual or parotid saliva flow is < 0.05 mL / min; and / or the stimulated submandibular / sublingual or parotid saliva flow is < 0.15 mL / min. Conditions that interfere with the normal composition or quantity of saliva can cause significant discomfort and adversely affect oral and systemic health including tooth decay, gum disease, oral infections, mouth sores, bad breath, and trouble chewing and swallowing. Thus, current treatment methods are used to either replace the missing saliva with a solution that mimics saliva or by stimulating the salivary glands to increase salivary output. However, current saliva substitutes exhibit limited duration and must be reapplied frequently throughout the day. Saliva production can also be stimulated via mechanical means such as with chewing gum. In addition, pharmaceutical agents to treat dry mouth have been identified. For example, administration of cholinergic agents, such as the parasympathomimetic and muscarinic agonists Attorney Docket No. OYST-039 / 01WO (391206-00447) pilocarpine and cevimeline, stimulate residual glandular function. However, pharmaceutical stimulation can result in systemic adverse effects and, consequently, limited patient acceptance. For example, the use of orally administrated pilocarpine is contraindicated in patients suffering from gastric ulcers and uncontrolled asthma and may exhibit negative cardiovascular effects associated with systemic administration in some patients. Cevimeline is a salivary gland stimulant with a stronger affinity for M3muscarinic receptors. Since it has no effect on M2receptors, it was expected to present fewer adverse side effects when compared to pilocarpine. However, clinical trials revealed similar adverse side effects for cevimeline and pilocarpine. Thus, there is an urgent need to develop alternative therapies to the currently available treatments for dry mouth, where the alternatives exhibit long duration and minimal side effects. Simpinicline ((R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine)) is a neuronal nicotinic receptor (NNR) agonist with selectivity for the α4β2 nicotinic subtype over other nicotinic subtypes, for example, the α7 subtype, the ganglionic, and the muscle subtypes. The structural formula of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine is shown below: Previous studies have 3-ylvinyl)pyrimidine provides benefits in the treatment or prevention of central nervous system (CNS) disorders, inflammation, and pain. Furthermore, (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine underwent clinical trials for treating dry eye syndrome and irritable bowel syndrome (See WO 2011 / 112428; WO 2017 / 177024; G. L. Torkildsen et al., Efficacy and Safety of Single-dose OC-02 (Simpinicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease: The PEARL Phase II Randomized Trial, Clinical Therapeutics / Volume 44, Number 9, 2022; which are all hereby incorporated by reference in their entirety). This disclosure is related to simpinicline solutions formulated as topical oral solutions that can be used to treat dry mouth. Previously, a simpinicline solution was formulated as a nasal spray to treat dry eye disease in patients. This nasal spray underwent clinical study for dry eye disease (see G. L. Torkildsen et al., supra). Attorney Docket No. OYST-039 / 01WO (391206-00447) SUMMARY OF THE INVENTION The current disclosure is directed to topical oral solutions comprising simpinicline ((R)-5- ((E)-2-pyrrolidin-3-ylvinyl)pyrimidine)) as an active ingredient or pharmaceutically acceptable salts of simpinicline along with one or more of: a flavoring agent, a preservative, a buffering agent, and a sweetening agent. The disclosed topical oral solutions can be directly applied to the oral cavity and / or to the back of the throat to stimulate the salivary glands to produce saliva, thereby treating dry mouth. The disclosed topical oral solutions can be formulated as an oral rinse, oral mouth wash (or gargle), or oral spray. Compared to currently known pharmaceutical agents used to stimulate saliva production by the salivary glands, the disclosed topical oral solutions provide numerous benefits such as: 1) easy to use in various formulations thereby promoting patient compliance; 2) mild or no systemic side effects and 3) good stability when stored over time at various temperatures and humidities, thus producing no significant impurities. In one general aspect, the disclosure provides a topical oral solution comprising: simpinicline or a pharmaceutically acceptable salt thereof, wherein the concentration of simpinicline in the solution is from about 0.05 mg / ml to about 10 mg / ml; a flavoring agent; and a buffering agent. In some embodiments, the pharmaceutically acceptable salt of simpinicline in the solution is selected from a citrate salt, a hydrochloride salt, a hemigalactarate salt, and a galactarate salt. In some embodiments, the pharmaceutically acceptable salt of simpinicline in the solution is a hemigalactarate salt, such as a hemigalactarate dihydrate salt. In some embodiments, the concentration of simpinicline in the solution is from about 0.5 mg / ml to about 10 mg / ml or from about 1 mg / ml to about 10 mg / ml. In some embodiments, the simpinicline in the solution exhibits a diastereomeric excess of at least about 98% diastereomeric excess. In some embodiments, the flavoring agent is selected from a strawberry flavor, a peppermint flavor, an apple flavor, a fruit punch flavor, and a lemon flavor. In some embodiments, the flavoring agent is present in the solution in an amount ranging from about 0.2% to about 0.4% by weight. Attorney Docket No. OYST-039 / 01WO (391206-00447) In some embodiments, the buffering agent is a phosphate buffer selected from sodium phosphate, potassium phosphate, calcium phosphate, and magnesium phosphate. In some embodiments, the buffering agent is present in an amount ranging from about 0.7% to about 1% by weight based on the total weight of the solution. In some embodiments, the solution has a pH ranging from about 4.0 to about 7.0. In some embodiments, the solution has a pH ranging from about 5.0 to about 5.5. In some embodiments, the solution further comprising a preservative. In some embodiments, the preservative is sodium benzoate, benzyl alcohol and / or potassium sorbate. In some embodiments, the preservative is present in an amount of from about 0.1% to about 0.25% by weight based on the total weight of the solution. In some embodiments, the solution further comprises a sweetening agent. In some embodiments, the sweetening agent is selected from xylitol, sorbitol, glycerol, and any combinations thereof. In some embodiments, the sweetening agent is present in an amount of from about 10% to about 20% by weight based on the total weight of the solution. In some embodiments, the flavoring agent in the solution is a lemon flavor; the preservative in the solution is sodium benzoate, potassium benzoate or a combination thereof; the buffering agent in the solution is a sodium phosphate monobasic monohydrate buffer; and the sweetening agent in the solution is xylitol or sorbitol. In some embodiments, the solution further comprises a carrier solvent and / or additional agents selected from co-solvents, solubilizing agents, absorption enhancers, stabilizing agents, pH- adjusting agents, anti-microbial agents, and viscosity-modifying agents. In some embodiments, the solution is formulated as an oral spray, an oral rinse or an oral mouth wash. In some embodiments, the solution can be used to spray, rinse, or gargle a subject’s oral cavity or back of the throat. The current disclosure is further directed to methods of treating dry mouth by administering an effective amount of simpinicline ((R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine)) or a pharmaceutically acceptable salt thereof topically to the oral cavity and / or back of the throat of a subject in need thereof, wherein simpinicline ((R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine)) or a Attorney Docket No. OYST-039 / 01WO (391206-00447) pharmaceutically acceptable salt thereof is in a topical oral solution further comprising a flavoring agent and optionally a buffering agent. In a second general aspect, this disclosure provides a method of treating dry mouth comprising topically administering an effective amount of simpinicline ((R)-5-((E)-2-pyrrolidin- 3-ylvinyl)pyrimidine)) to the oral cavity and / or the back of throat of a subject in need thereof, wherein the administration comprises administering a topical oral solution as described herein to the subject’s oral cavity and / or back of throat. In a third general aspect, this disclosure provides a method of increasing the saliva flow of one or more salivary glands in a subject in need thereof comprising topically administering an effective amount of simpinicline to the oral cavity and / or the back of throat of the subject, wherein the administration comprises administering a topical oral solution as described herein to the subject’s oral cavity and / or back of throat. In some embodiments of the methods described in this disclosure, the topical oral solution as administered to the subject’s oral cavity or back of throat by spray. In some embodiments, the topical oral solution is administered to the subject’s oral cavity or back of throat by applying it with an applicator, such as a cotton swab or a hard stick applicator. In some embodiments, the topical oral solution is administered to the subject’s oral cavity or back of throat by drop, using a liquid dropper. In some embodiments, the topical oral solution is administered to the subject’s oral cavity by rinsing the oral cavity with it and / or by gargling with it. In some embodiments, the topical oral solution is administered to the subject’s oral cavity by rinsing the oral cavity with it, optionally including with gargling. In some embodiments of the methods described in this disclosure, the topical oral solution is administered to the subject’s oral cavity and / or back of throat by spray, using a metered spray pump device. In some embodiments of the methods, about 0.1 to about 0.3 mL of solution is delivered into the oral cavity and / or back of the throat of the subject with a single spray of the metered pump device. In some embodiments of the methods described in this disclosure, between about 0.5 micrograms and about 10,000 micrograms of simpinicline per dose of the solution is administered to the subject in need thereof. In some embodiments, about 0.5 micrograms to about 1000 micrograms of simpinicline per dose is delivered into the oral cavity and / or back of throat of the Attorney Docket No. OYST-039 / 01WO (391206-00447) subject. In some embodiments, about 0.5 micrograms to about 750 micrograms of simpinicline per dose is delivered into the oral cavity and / or back of throat of the subject. In some embodiments, about 0.5 micrograms to about 100 micrograms of simpinicline per dose is delivered into the oral cavity and / or back of throat of the subject. In some embodiments, about 0.5 micrograms and 1000 micrograms of simpinicline is administered to the subject per day. In some embodiments of the methods described in this disclosure, a dose of the topical oral solution is administered at least once a day. In some embodiments, a dose of the solution is administered one time per day. In some embodiments, a dose of the solution is administered at least twice a day. In some embodiments, a dose of the solution is administered twice a day. In some embodiments, a dose of the solution is administered at least once a week. In some embodiments, a dose of the solution is administered to the subject on an as-needed basis, i.e., when the subject is experiencing dry mouth. In some embodiments, a dose of the solution is administered no more than once every 5 minutes, once every 10 minutes, once every 15 minutes, once every ½ hour, once every hour, or once every 2, 3, 4, or 5 hours. In some embodiments of the methods described in this disclosure, a dose of the solution comprises one spray of the solution. In some embodiments, a dose of the solution comprises more than one spray of the solution, for example between 2 and 5 sprays. In some embodiments, a spray comprises particles of the solution having a median particle size diameter of about 1 to about 100 microns. In some embodiments of the methods described in this disclosure, the topical oral solution administered to the subject stimulates release of saliva from one or more salivary glands located in the oral cavity of the subject. In some embodiments, the topical oral solution is delivered directly into the oral cavity to stimulate one or more salivary glands and / or to promote the release of saliva from one or more salivary glands located in the oral cavity of the subject. In some embodiments, the solution stimulates saliva from a parotid gland of the subject, the subject’s submandibular gland and / or the subject’s sublingual gland. In some embodiments, the subject’s unstimulated saliva flow from the submandibular gland, the sublingual gland, and / or a parotid gland or glands is about > 0.05 mL / min. In some embodiments, the subject’s stimulated saliva flow from the submandibular gland, the sublingual gland, and / or a parotid gland or glands is about Attorney Docket No. OYST-039 / 01WO (391206-00447) > 0.15 mL / min. In some embodiments, the unstimulated saliva flow is about > 0.05 mL / min and the stimulated saliva flow is about > 0.15 mL / min. In some embodiments of the methods described in this disclosure, the subject’s dry mouth is caused by one or more medications, one or more infections, a hormonal imbalance, one or more radiation treatments to the head and / or neck, one or more radioactive iodine treatments, nerve damage to the head and / or neck, stroke, diabetes, hypertension, hepatitis C, lymphoma, Sjögren’s Syndrome, Alzheimer’s Disease and / or HIV / AIDS. In some embodiments of the methods described herein, the topical oral solution is co- administered with one or more additional therapeutic agents for treating dry mouth. In some embodiments of the topical oral solutions and methods described herein, (R)-5- ((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) is in the form of a hemigalactarate salt. In some embodiments the hemigalactarate salt is a hemigalactarate dihydrate salt. In some embodiments, the dry mouth being treated is caused by radiation treatments to the head and / or neck, radioactive iodine treatment, or Sjögren’s Syndrome. DESCRIPTION OF THE DRAWINGS FIG.1 shows a picture of various simpinicline oral spray formulations labeled 11A , 11B, 11C, 11D, and 11E corresponding to simpinicline oral spray formulations OP-0009-011A, OP- 0009-011B, OP-0009-011C, OP-0009-011D, and OP-0009-011E in Tables 2-11, respectively. DETAILED DESCRIPTION The presently disclosed subject matter will now be described more fully hereinafter. However, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains, having the benefit of the teachings presented in the descriptions herein. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein covers all alternatives, modifications, and equivalents. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. Attorney Docket No. OYST-039 / 01WO (391206-00447) Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in this field. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. 1. Definitions As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an alkyl group” or “a phenyl” includes mixtures of two or more such alkyl groups or phenyls. When ranges of values are disclosed, and language such as “from n1... to n2” or “between n1 . . . and n2” is used, where n1 and n2 are the numbers, then unless otherwise specified, this language is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the rang “from 1 to 3 µM (micromolar),” which is intended to include 1 µ, 3 µM, and everything in between to any number of significant figures (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.). Ranges can be expressed herein as from “about” one particular value and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. The phrase “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the subject being treated therewith. Attorney Docket No. OYST-039 / 01WO (391206-00447) The phrase “pharmaceutically acceptable salt” as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of this disclosure. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate (“mesylate”), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1′-methylene-bis-(2- hydroxy-3-naphthoate)) salts, galactarate salts, hemigalactarate salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt, the salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counter ion. The terms “treat” and “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, e.g., dry mouth. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented. In some embodiments, the condition or disorder is identified as being dry mouth and / or a reduction in saliva flow. The term “administration” or “administering” includes routes of introducing the compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (including, but not limited to, subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal and transdermal. Attorney Docket No. OYST-039 / 01WO (391206-00447) The term “effective amount” includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount may be determined by a person of ordinary skill in the art. The phrases “systemic administration” and “administered systemically” as used herein mean the administration of a compound(s), drug or other material, such that it enters the subject's circulatory system and, thus, is subject to metabolism and other like processes, The phrase “therapeutically effective amount” means an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of dry mouth, the therapeutically effective amount of the drug may stimulate the salivary glands to produce saliva; increase the daily saliva flow; promote and / or increase saliva flow from one or more salivary glands; and / or relieve to some extent one or more of the symptoms associated with the dry mouth. References herein to “the subject” mean, unless otherwise indicated, an animal such as a mammal, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human. I. Pharmaceutical Formulation Each component of the disclosed topical oral solution is discussed in more detail below. 1. Active Ingredient The structural formula of simpinicline is: Attorney Docket No. OYST-039 / 01WO (391206-00447) The structural formula of simpinicline shown above is the (R) enantiomer of 5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine, which can exist as a mixture of enantiomers. Thus, in some embodiments, (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine exhibits a certain degree of enantiomerical purity expressed in the form of enantiomeric excess to show that it does not contain the other enantiomer of 5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine , i.e., (S)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine. In some embodiments, (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) exhibits an enantiomeric excess of at least about 50% enantiomeric excess, at least about 60% enantiomeric excess, at least about 70% enantiomeric excess, at least about 80% enantiomeric excess, at least about 90% enantiomeric excess, at least about 95% enantiomeric excess, at least about 98% enantiomeric excess, or at least about 99.8% enantiomeric excess. In some embodiments, simpinicline ((R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine)) can be in its free base form or can be in the form of a pharmaceutically acceptable salt. Unless otherwise indicated, reference herein to “simpinicline”, without any subsequent salt ion, indicate simpinicline free base. Examples of suitable pharmaceutically acceptable salts include, include but are not limited to, inorganic acid addition salts such as chloride, bromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt; and salts with basic amino acid such as lysine salt and arginine salt. In some embodiments, the salt is selected from hydrochloric, sulfuric, methanesulfonic, maleic, phosphoric, 1-hydroxy-2-naphthoic, ketoglutaric, malonic, L-tartaric, fumaric, citric, L-malic, hippuric, L-lactic, benzoic, succinic, adipic, acetic, nicotinic, propionic, orotic, 4-hydroxybenzoic, di-p-toluoyl-D- tartaric, di-p-anisoyl-D-tartaric, di- benzoyl-D-tartaric, 10-camphorsulfonic or camphoric. In some embodiments, (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine is a galactarate salt. In some embodiments, (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine is a hemigalactarate salt. In some embodiments, the salts may be hydrates or ethanol solvates. In some embodiments, (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine is a dihydrate of a hemigalactarate salt. Attorney Docket No. OYST-039 / 01WO (391206-00447) The preparation of pharmaceutically acceptable salts of (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine can be prepared according to known methods in the art that a skilled artisan would generally be aware of. In some embodiments, a pharmaceutically acceptable salt of (R)-5- ((E)-2-pyrrolidin-3-ylvinyl)pyrimidine can be made by contacting (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine with an organic or inorganic acid. For example, in some embodiments, (R)-5- ((E)-2-pyrrolidin-3-ylvinyl)pyrimidine is contacted with galactaric acid with or without water to form (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine galactaric acid salt or (R)-5-((E)-2-pyrrolidin- 3-ylvinyl)pyrimidine hemigalactarate dihydrate salt, respectively. Here it was surprising and unexpected to observe that the hemigalactarate dihydrate salt form was more stable in solution compared to other salt forms, specifically the citrate salt of (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine. Furthermore, it was surprising and unexpected to observe that the preparation of the (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine hemigalactarate dihydrate salt was less exothermic and therefore safer to manufacture compared to other salt forms, particularly the citrate salt. The stoichiometry of the (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine salts can vary. For example, it is typical that the molar ratio of the acid used for salt formation to (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine is 1:2 or 1:1, but other ratios, such as 3:1, 1:3, 2:3, 3:2 and 2:1, are possible. In some embodiments, the salts described herein can have crystal structures that occlude solvents that are present during salt formation. Thus, the salts can occur as hydrates and other solvates of varying stoichiometry of solvent relative to (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine. For example, in some embodiments, (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine is in the form of a galactarate hydrate salt. The molar ratio of such hydrates can vary. For example, in some embodiments, such hydrates can exhibit molar ratios of acid to (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine to hydrate of about 0.5:1:2, but should not be limited thereto as other ratios, are possible. The structural formula of (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine hemigalactarate dihydrate is shown below: Attorney Docket No. OYST-039 / 01WO (391206-00447) The aforementioned simpinicline hemigalactarate dihydrate is shown in WO 2017 / 177024, supra. In some embodiments, the salts and / or hydrates of (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine exhibit an enantiomeric excess as described above for the free base of (R)-5- ((E)-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments, the salts and / or hydrates of (R)-5- ((E)-2-pyrrolidin-3-ylvinyl)pyrimidine exhibit a diastereomeric excess of at least about 50% de, about 60% de, about 70% de, about 80% de, about 90% de, about 95% de, about 98% de, or at least about 99.8% de. (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine has been shown to bind to human oc4 2- containing receptors nAChR with Ki = 17 nM as a full agonist at the human oc42-containing nAChR being more efficacious than nicotine (Emax = 120% compared to nicotine; EC50 = 600 nM). Studies with oral formulations of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine show desirable pharmacokinetics and a good safety profile, which is disclosed in more detail in International Patent Application Nos. PCT / US2017 / 026385 and PCT / US2017 / 026385, which are hereby incorporated by reference in their entirety. The amount of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine in the topical oral solution can vary. For example in some embodiments, the amount of (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine present in the topical oral solution ranges from about 0.1 mg / ml to about 20 mg / ml, from about 1 mg / ml to about 10 mg / ml, from about 2 mg / ml to about 8 mg / ml, from about 3 mg / ml to about 7 mg / ml, from about 4 mg / ml to about 6 mg / ml, or from about 4.5 mg / ml to about 5.5 mg / ml. In some embodiments, the amount of (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine present in the topical oral solution is less than about 20 mg / ml, less than about 18 mg / ml, less than about 16 mg / ml, less than about 14 mg / ml, less than about 12 mg / ml, less than about 10 mg / ml, less than about 9 mg / ml, less than about 8 mg / ml, less than about 7 mg / ml, less than about 6 mg / ml, less than about 5.5 mg / ml, less than about 5.25 mg / ml, less than about 5.0 mg / ml, less than about 4.0 mg / ml, less than about 3.0 mg / ml, less than about 2.0 mg / ml, less than about 1.0 mg / ml, or less than about 0.1 mg / ml. In addition, or in the alternative, the amount of (R)- 5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine present in the topical oral solution is at least about 0.1 mg / ml, at least about 0.5 mg / ml, at least about 1 mg / ml, at least about 1.5 mg / ml, at least about 2.0 mg / ml, at least about 2.5 mg / ml, at least about 3.0 mg / ml, at least about 3.5 mg / ml, at least about 4 mg / ml, at least about 4.5 mg / ml, at least about 4.75 mg / ml, at least about 5 mg / ml, at least Attorney Docket No. OYST-039 / 01WO (391206-00447) about 6 mg / ml or at least about 7 mg / ml. In some embodiments, the amount of (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine present in the topical oral solution is about 5 mg / ml. 2. Sweetening Agent In some embodiments, the disclosed topical oral solution contains one or more sweetening agents. Sweetening agents are generally used to increase the palatability of the active ingredient or other components present in the formulation. The main sweetening agents employed in topical oral solutions are sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium, xylitol, acesulfame, stevia and / or aspartame, but should not be limited thereto. In some embodiments, the topical oral solutions contain xylitol, sorbitol, glycerol or a combination thereof. In some embodiments, the topical oral solutions contain xylitol. In some embodiments, the topical oral solutions contain xylitol and glycerol. The amount of sweetening agent present in the topical oral solution can vary. For example, in some embodiments, the amount of sweetening agent present in the topical oral solution is less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 12%, less than about 10%, or less than about 5% by weight based on the total weight of the topical oral solution. Alternatively, or in addition to, the amount of sweetening agent present in the topical oral solution is at least about 1%, about 5%, about 8%, about 10%, about 15%, about 18%, about 20%, about 22%, or at least about 25% by weight based on the total weight of the topical oral solution. In some embodiments, the amount of sweetening agent present in the topical oral solution is from about 1% to about 30%, from about 3% to about 27%, from about 5% to about 25%, from about 8% to about 22%, or from about 10% to about 20% by weight based on the total weight of the topical oral solution. In some embodiments, the amount of sweetening agent ranges from about 10% to about 20% by weight based on the total weight of the topical oral solution. In some embodiments, the amount of sweetening agent is 10% by weight based on the total weight of the topical oral solution. In some embodiments, the amount of sweetening agent is 20% by weight based on the total weight of the topical oral solution. 3. Preservative Attorney Docket No. OYST-039 / 01WO (391206-00447) In some embodiments, the disclosed topical oral solution contains one or more preservatives. Exemplary preservatives include, but are not limited to, sodium benzoate, potassium sorbate, benzoic acid, benzyl alcohol, thimerosal, phenylethyl alcohol, benzalkonium chloride methyl paraben, ethyl paraben, butyl paraben or propyl paraben. In some embodiments, the preservatives are sodium benzoate, benzyl alcohol and / or potassium sorbate. The amount of the preservative(s) being present in the topical oral solution can vary. For example, in some embodiments, the amount of preservative(s) present in the topical oral solution ranges from about 0.1% to about 0.5%, from about 0.1% to about 0.45%, from about 0.1% to about 0.4%, from about 0.1% to about 0.3%, from about 0.1% to about 0.25%, from about 0.15% to about 0.25% by weight based on the total weight of the topical oral solution. In some embodiments, the amount of preservative(s) present in the topical oral solution is less than about 0.5%, less than about 0.45%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.15% by weight based on the total weight of the topical oral solution. In addition, or in the alternative, the amount of preservative present in the topical oral solution is at least about 0.05%, at least about 0.08%, at least about 0.10%, at least about 0.12%, at least about 0.15%, at least about 0.18%, at least about 0.20%, at least about 0.22%, at least about 0.25%, at least about 0.30%, at least about 0.35%, or at least about 0.38% by weight based on the total weight of the topical oral solution. In some embodiment, the preservative is sodium benzoate present in an amount of from about 0.22% to about 0.28% by weight based on the total weight of the topical oral solution. In some embodiments, the preservative is potassium sorbate present in an amount of from about 0.12% to about 0.18% by weight based on the total weight of the topical oral solution. 4. Flavoring Agent In some embodiments, the disclosed topical oral solution comprises a taste-masking or flavoring agent. Taste-masking or flavoring agents as used herein are agents that may mask or minimize any undesirable flavor such as a bitter or sour flavor. Examples of taste-masking or flavoring agents suitable for use in the disclosed topical oral solution include, but are not limited to, synthetic or natural peppermint oil, spearmint oil, citrus oil, fruit flavors (e.g., citrus, such as orange, lemon, lime; strawberry; apple; melon; fruit punch and mixtures thereof), chocolate, spice (e.g., anise, cinnamon), vanilla and / or bubblegum flavor. In some embodiments, the flavoring Attorney Docket No. OYST-039 / 01WO (391206-00447) agent is selected from a peppermint oil or a fruit flavor. In some embodiments, the flavoring agent is a fruit flavor. In some embodiments, the flavoring agent is selected from the group consisting of a strawberry flavor, an apple flavor, a fruit punch flavor, and a lemon flavor (e.g., lemon flavor W / S 2025383 (Carmi)). The taste-masking and / or flavoring agents may be evaluated in a formulation of the invention according to the Flavor Profile Method (see Keane, P. The Flavor Profile Method. In C. Hootman (Ed.), Manual on Descriptive Analysis Testing for Sensory Evaluation ASTM Manual Series: MNL 13. Baltimore, Md. (1992)), for example, to identify, characterize, and / or quantify sensory attributes of products, e.g., basic tastes, aroma, texture, and mouthfeel. The amount of flavoring agent can vary but should be present in a sufficient amount to fully mask any undesirable flavor. For example, in some embodiments, the amount of flavoring agent ranges from about 0.1% to about 0.5%, from about 0.15% to about 0.45%, from about 0.2% to about 0.4%, from about 0.25% to about 0.35%, or from about 0.28% to about 0.32% by weight based on the total weight of the topical oral solution. In some embodiments, the amount of flavoring agent is at least about 0.1%, at least about 0.15%, at least about 0.20%, or at least about 0.25% by weight based on the total weight of the topical oral solution. In addition, or in the alternative, the amount of flavoring agent present in the topical oral solution is less than about 0.5%, less than about 0.4%, less than about 0.35%, less than about 0.33%, or less than about 0.30% by weight based on the total weight of the topical oral solution. In some embodiments, the amount of flavoring agent ranges from 0.29% to about 0.31% by weight based on the total weight of the topical oral solution. In some embodiments, the amount of flavoring agent is about 0.30% by weight based on the total weight of the topical oral solution. 5. Buffering Agent In some embodiments, the disclosed topical oral solution comprises a buffering agent. For example, in some embodiments, the buffering agent can include one or more phosphate buffers. For example, suitable phosphate buffers can include one or more of sodium phosphate, potassium phosphate, calcium phosphate, and magnesium phosphate. Other phosphate forms may also be utilized. For example, polyphosphoric acid(s) and / or cyclic phosphates may be utilized. Non- limiting examples of further suitable buffers include alkali metals acetates, glycinates, glycerophosphates, citrates, carbonates, hydrogen carbonates, borates, or mixtures thereof. In Attorney Docket No. OYST-039 / 01WO (391206-00447) some embodiments, the buffering agent present in the topical oral solution is sodium phosphate (e.g., in the form of a monobasic monohydrate). In some embodiments, a suitable buffering agent can include one or more amino acids or salts thereof. The use of amino acid buffers can be beneficial in light of the presence of both acidic and basic groups in their structure, and the reduced occurrence of unpleasant taste that may accompany other buffers. In certain embodiments, the one or more amino acids or a salt thereof includes one or both of glycine and a salt thereof. In some embodiments, the amount of buffering agent present in the topical oral solution can vary as it can depend on the type of buffering agent being used. For example, in some embodiments, the buffering agent is present in an amount of less than about 3%, less than about 2%, less than about 1.5%, less than about 1.2%, less than about 1.0%, less than about 0.9%, less than about 0.85%, or less than about 0.8% by weight based on the total weight of the topical oral solution. In addition, or in the alternative, the buffering agent is present in an amount of at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.65%, at least about 0.7%, at least about 0.75%, at least about 0.78%, at least about 0.80%, at least about 0.82%, or at least about 0.85% by weight based on the total weight of the topical oral solution. In some embodiments, the buffering agent is present in an amount ranging from about 0.2% to about 0.4% by weight based on the total weight of the topical oral solution. Typically, the amount of buffering agent present in the topical oral solution can also depend on the pH of the oral spray composition. For example, in some embodiments, the buffering agent may be present in an amount sufficient to provide a pH of about 4.8 to about 6.0, from about 4.8 to about 5.5, from about 4.8 to about 5.4, from about 5.0 to about 5.4, from about 5.2 to about 5.4, or from about 5.2 to about 5.3 of the topical oral solution. In some embodiments, the buffering agent may be present in an amount sufficient to provide a pH of at least about 4.0, at least about 4.5, at least about 4.8, at least about 4.9, at least about 5.0, at least about 5.1, at least about 5.2, at least about 5.3, at least about 5.4, at least about 5.5. or at least about 6.0. In addition, or in the alternative, the buffering agent may be present in an amount sufficient to provide a pH of less than about 7.0, less than about 6.5, less than about 6.0, less than about 5.8, less than about 5.7, less than about 5.6, less than about 5.5, less than about 5.4, less than about 5.3, less than about 5.2, less than about 5.1, less than about 5.0, or less than about 4.8. Attorney Docket No. OYST-039 / 01WO (391206-00447) In some embodiments, the buffering agent is a phosphate buffer and is present in an amount sufficient to provide a pH of from about 4.0 to about 7.0 or from about 5.0 to about 5.5. 6. Carrier Solvent In some embodiments, the topical oral solution comprises a carrier solvent. Exemplary orally acceptable carrier solvents include water, ethanol, glycerol, glycol, propylene glycol, polyethylene glycol, sorbitol, vitamin E and derivatives of vitamin E, polyvinylpyrrolidone, water, and other orally acceptable solvents known in the field. In some embodiments, the carrier solvent is water. The amount of carrier solvent present in the topical oral solution can vary. In some embodiments, the amount of carrier solvent present in the topical oral solution ranges from about 0.1% to about 99%, from about 1% to about 98%, from about 5% to about 90%, from about 10% to about 90%, from about 20% to about 90%, from about 30% to about 90%, from about 40% to about 90%, from about 50% to about 90%, from about 60% to about 90%, from about 70% to about 90%, from about 80% to about 90%, from about 85% to about 90%, or from about 86% to about 88% by weight based on the total weight of the topical oral solution. 7. Additional Agents In some embodiments, the disclosed topical oral solution may further comprise one or more additional pharmaceutically acceptable excipients. Such additional agents may include, but are not limited to, co-solvents and / or solubilizing agents, absorption enhancers, stabilizing agents, pH- adjusting agents, anti-microbial agent, and viscosity-modifying agents. In some embodiments, the disclosed topical oral solution may further comprise one or more co-solvents. Co-solvents may include, but are not limited to, ethyl alcohol, propylene glycol, glycerol and polyethylene glycols having a nominal molecular weight of 200-600 g / mol, and N- methyl-2-pyrrolidone. In some embodiments, the disclosed topical oral solution may further comprise one or more solubilizing agents. Solubilizing agents may include, but are not limited to, purified diethylene glycol monoethyl ether, cyclodextrins, glycerol monostearate, lecithin, poloxomer, polyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, stearic acid, citric acid, and ascorbic acid and the like; DL-methionine, Attorney Docket No. OYST-039 / 01WO (391206-00447) caffeine, nicotinamide, vanillin, benzyl alcohol, ethanol, and Transcutol (diethylene glycol monoethyl ether); surface active agents such as polysorbates, sorbiton esters, polyvinyl alcohol, benzalkonium chloride, benzethonium chloride, cetrimide, docusate sodium, sodium lauryl sulphate, and octoxynol. In some embodiments, the disclosed topical oral solution may further comprise one or more stabilizing agents (e.g., sodium metabisulphite, sodium bisulphite, disodium EDTA, and ascorbic acid, but should not be limited thereto). In some embodiments, the disclosed topical oral solution may further comprise one or more anti-microbial agents (e.g., benzyl alcohol, benzalkonium chloride, phenyl mercuric acetate, and phenylethyl alcohol, but should not be limited thereto). In some embodiments, the disclosed topical oral solution may further comprise one or more of viscosity-modifying agents (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose (HEC), carboxymethyl cellulose (CMC), poly acrylic acid, or water-soluble polymers such as carbopol, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and various grades of polyvinylpyrrolidone (e.g., K-15, K-30, K-60, and K-90), but should not be limited thereto. In some embodiments, the disclosed topical oral solution may further comprise one or more of oral-absorption enhancer (e.g., orally acceptable surfactants or other compounds). The important consideration is that the absorption enhancer be effective for preparing the mucosa and / or salivary glands to absorb the active ingredient. Exemplary, suitable oral absorption enhancers include hydroxypropyl-beta-cyclodextrin and surfactants such as benzalkonium chloride, benzethonium chloride, polysorbate 80, sodium lauryl sulfate, Brij surfactants, Tween surfactants, and Pluronic surfactants. Surfactants of the Brij family may comprise polyoxy(n)- oleoether, wherein n is from 1 to 100. Notably, one or more of these and / or other surfactants may be included for other purposes such as increasing the miscibility of the formulation ingredients or reducing the size of the pharmaceutical agents to droplet size. As used herein, the term “droplet” refers to a single unit of atomized spray having a sufficiently small size that it is capable of being absorbed by a mucosa and / or salivary glands. In some embodiments, the topical oral solution may further comprise a pH adjusting agent. Such pH adjusters include organic and inorganic acids such as, but are not limited to, hydrochloric Attorney Docket No. OYST-039 / 01WO (391206-00447) acid, sodium acetate, glacial acetic acid, orthophosphoric acid, and potassium dihydrogen orthophosphate. In some embodiments, the pH adjuster can also be an organic or inorganic base such as, but not limited to, ammonium hydroxide, carbonate, citrate, glycine, maleate, and phosphate, including salts thereof. The disclosed topical oral solution is generally prepared by mixing the individual components to afford a mixture, which can then be adjusted with a pH adjusting agent to render to desired pH of the topical oral solution. In some embodiments, a method of making a topical oral solution as disclosed herein comprises mixing / combining simpinicline or a pharmaceutically acceptable salt thereof with a carrier solvent. In one embodiment, such a carrier solvent is water. In another embodiment, the pharmaceutically acceptable salt of simpinicline is simpinicline hemigalactarate. The amounts of the above-mentioned additional agents can vary, and it would be well within a person skilled in the art to determine suitable amounts / concentrations of one or more of these additional agents when used as a component in the disclosed topical oral solution. II. Exemplary Topical Oral Solutions Disclosed herein are various exemplary topical oral solutions. In one embodiment, the topical oral solution disclosed herein comprises active ingredient (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine) or a pharmaceutically acceptable salt thereof, a preservative, a sweetening agent, a flavoring agent, and a buffering agent, wherein the pH of the formulation ranges from about 4.0 to about 7.0. Disclosed herein are various exemplary topical oral solutions. In one embodiment, the topical oral solution disclosed herein comprises active ingredient (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine) or a pharmaceutically acceptable salt thereof, a preservative, a sweetening agent, a flavoring agent, and a buffering agent, wherein the pH of the formulation ranges from about 4.5 to about 6.5. Disclosed herein are various exemplary topical oral solutions. In one embodiment, the topical oral solution disclosed herein comprises active ingredient (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine) or a pharmaceutically acceptable salt thereof, a preservative, a sweetening Attorney Docket No. OYST-039 / 01WO (391206-00447) agent, a flavoring agent, and a buffering agent, wherein the pH of the formulation ranges from about 5.0 to about 5.5. In some embodiments, the topical oral solution disclosed herein comprises active ingredient (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) or a pharmaceutically acceptable salt thereof in an amount ranging from about 2.5 mg / ml to about 7.5 mg / ml, a preservative, a sweetening agent, a flavoring agent, and a buffering agent, wherein the pH of the formulation ranges from about 5.0 to about 5.5. In some embodiments, the topical oral solution disclosed herein comprises active ingredient (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) or a pharmaceutically acceptable salt thereof in an amount ranging from about 2.5 mg / ml to about 7.5 mg / ml, a preservative present in an amount of from about 0.15% to about 0.4% by weight based on the total weight of the topical oral solution, a sweetening agent, a flavoring agent, and a buffering agent, wherein the pH of the formulation ranges from about 5.0 to about 5.5. In some embodiments, the topical oral solution disclosed herein comprises active ingredient (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) or a pharmaceutically acceptable salt thereof in an amount ranging from about 2.5 mg / ml to about 7.5 mg / ml, a preservative present in an amount of from about 0.15% to about 0.4% by weight, a sweetening agent present in an amount of from about 10% to about 20% by weight, wherein all weights are based on the total weight of the topical oral solution, a flavoring agent and a buffering agent, wherein the pH of the formulation ranges from about 5.0 to about 5.5. In some embodiments, the topical oral solution disclosed herein comprises active ingredient (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) or a pharmaceutically acceptable salt thereof in an amount ranging from about 2.5 mg / ml to about 7.5 mg / ml, a preservative present in an amount of from about 0.15% to about 0.4% by weight, a sweetening agent present in an amount of from about 10% to about 20% by weight, a flavoring agent present in an amount of from about 0.25% to about 0.35% by weight, wherein all weights are based on the total weight of the topical oral solution and a buffering agent, wherein the pH of the formulation ranges from about 5.0 to about 5.5. In some embodiments, the topical oral solution disclosed herein comprises active ingredient (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) or a pharmaceutically acceptable salt Attorney Docket No. OYST-039 / 01WO (391206-00447) thereof in an amount ranging from about 2.5 mg / ml to about 7.5 mg / ml, a preservative present in an amount of from about 0.15% to about 0.4% by weight, a sweetening agent present in an amount of from about 10% to about 20% by weight, a flavoring agent present in an amount of from about 0.25% to about 0.35% by weight and a buffering present in an amount of from about 0.75% to about 1.0% by weight, wherein all weight are based on the total weight of the topical oral solution, wherein the pH of the formulation ranges from about 5.0 to about 5.5. In any of the above exemplary embodiments, the flavoring agent can be a lemon flavoring agent. In any of the above exemplary embodiments, the buffering agent can be a sodium phosphate (e.g., sodium phosphate monobasic monohydrate) buffer. In any of the above exemplary embodiments, the sweetening agent can be xylitol, sorbitol or a combination of xylitol and glycerol. In any of the above exemplary embodiments, the preservative can be sodium benzoate, potassium benzoate or a combination thereof. In some embodiments, the topical oral solution disclosed herein comprises active ingredient (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) in a concentration ranging from about 0.05 mg / ml to about 10 mg / ml, about 0.5 mg / ml to about 10 mg / ml, about 1 mg / ml to about 10 mg / ml, or about 2.5 mg / ml to about 7.5 mg / ml; a preservative selected from the group consisting of sodium benzoate, potassium benzoate and a combination thereof, present in an amount of from about 0.15% to about 0.4% by weight based on the total weight of the topical oral solution; a sweetening agent selected from the group consisting of xylitol, sorbitol and a combination of xylitol and glycerol; a lemon flavoring agent, and a sodium phosphate buffer, wherein the pH of the formulation ranges from about 5 to about 5.5. In some embodiments, the topical oral solution disclosed herein comprises active ingredient (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) in a concentration ranging from about 0.05 mg / ml to about 10 mg / ml, about 0.5 mg / ml to about 10 mg / ml, about 1 mg / ml to about 10 mg / ml, or about 2.5 mg / ml to about 7.5 mg / ml; a preservative selected from the group consisting of sodium benzoate, potassium benzoate and a combination thereof present in an amount of from about 0.15% to about 0.4% by weight based on the total weight of the topical oral solution; a sweetening agent selected from the group consisting of xylitol, sorbitol and a combination of xylitol and glycerol present in an amount of from about 10% to about 20% by weight based on the Attorney Docket No. OYST-039 / 01WO (391206-00447) total weight of the topical oral solution; a lemon flavoring agent, and a sodium phosphate buffer, wherein the pH of the formulation ranges from about 5 to about 5.5. In some embodiments, the topical oral solution disclosed herein comprises active ingredient (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) from about 0.05 mg / ml to about 10 mg / ml, about 0.5 mg / ml to about 10 mg / ml, about 1 mg / ml to about 10 mg / ml, or about 2.5 mg / ml to about 7.5 mg / ml; a preservative selected from the group consisting of sodium benzoate, potassium benzoate and a combination thereof present in an amount of from about 0.15% to about 0.4% by weight based on the total weight of the topical oral solution; a sweetening agent selected from the group consisting of xylitol, sorbitol and a combination of xylitol and glycerol present in an amount of from about 10% to about 20% by weight based on the total weight of the topical oral solution; a lemon flavoring agent present in an amount of from about 0.25% to about 0.35% by weight based on the total weight of the topical oral solution, and a sodium phosphate buffer, wherein the pH of the formulation ranges from about 5 to about 5.5. In some embodiments, the above disclosed exemplary topical oral solution comprises a pharmaceutically acceptable salt of the active ingredient (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine). In some embodiments, the above disclosed exemplary topical oral solution comprises a pharmaceutically acceptable salt of the active ingredient (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine), wherein the pharmaceutically acceptable salt is selected from the group consisting of citrate, mono citrate, hydrochloride (HCl), galactarate, and hemigalactarate. In some embodiments, the salt form is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) galactarate dihydrate. In some embodiments, the salt form is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) hemigalactarate dihydrate. Under stability analyses, the storage stable topical oral solution shows remarkable maintenance of the initial active agent concentration. For example, after three or six months at 25 °C and 60% RH, the concentration of impurities increases by only about 2% or less, about 1.8% or less, about 1.6% or less, about 1.4% or less, about 1.2% or less, about 1% of less, about 0.8% or less, about 0.75% or less, about 0.6% or less, about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, about 0.1% or less, about 0.01% or less or increase by only about 0.001% or less. In some embodiments, the topical oral solution has a total amount of impurities between about 1.0% to about 2.5%, between about 1.15% to about 1.85%, between about 1.19% Attorney Docket No. OYST-039 / 01WO (391206-00447) to about 1.65%, between about 1.19% to about 1.62%, or between 1.62% to about 1.82% when tested at 6 months. In some embodiments, the topical oral solution has a total amount of impurities between about 0.1% to about 1%, between about 0.40% to about 0.75%, between about 0.40% to about 0.65%, or between 0.40% to about 0.61% when tested at 3 months. In some embodiments, after three or six months at 40 °C and 75% RH, the concentration of impurities increased by only about 3% or less, about 2.8% or less, about 2.6% or less, about 2.4% or less, about 2.2% or less, about 2% or less, about 1.8% or less, about 1.6% or less, about 1.4% or less, about 1.2% or less, about 1% of less, about 0.8% or less, about 0.70% or less, about 0.65% or less, about 0.6% or less, about 0.50% or less, about 0.4% or less, about 0.35% or less, about 0.3% or less, about 0.25% or less, about 0.20% or less, about 0.15% or less, about 0.1% or less, about 0.01% or less or increase by only about 0.001% or less. In some embodiments, the topical oral solution has a total amount of impurities between about 0.1% to about 2%, between about 0.50% to about 1.50%, between about 0.70% to about 1.40%, between about 0.70% to about 1.36%, or between 0.76% to about 1.29% when tested at 3 months. In some embodiments, the topical oral solution has a total amount of impurities between about 0.1% to about 3%, between about 1.0% to about 2.50%, between about 1.50% to about 2.50%, between 1.80% to about 2.50%, or between 1.88% to about 2.50% when tested at 6 months. The stability results of examples of the topical oral solutions are discussed below and shown, for example, in Tables 2-12. As used herein, “storage stable” means liquid oral spray pharmaceutical formulations in which the concentration of the active ingredient is substantially maintained during storage stability testing, and degradation products and / or impurities which are typically observed in storage stability testing of such formulations are absent or significantly reduced during storage stability testing. In one embodiment, storage stability is determined at a temperature range from about 25 °C to about 40 °C. In another embodiment, storage stability is determined at a relative humidity (“RH”) range from about 60% RH to about 75% RH. Preferred time intervals for measuring storage stability are at 1 month, 3 months and 6 months’ time points. In addition, changes in pH were tested in this stability analyses. In some embodiments, the pH increased slightly overtime, e.g., less than about 0.5, less than about 0.45, less than about 0.4, less than about 0.35, less than about 0.3, less than about 0.25, less than about 0.20 less than about 0.15, or less than about 0.1 units. Attorney Docket No. OYST-039 / 01WO (391206-00447) III. Delivery Methods The topical oral solution can be suspended using a metered pump device (e.g., a metered valve pump and / or a metered valve spray pump) capable of delivering a certain amount of the formulation into the oral cavity and / or the back of the throat of a subject. This will not only allow for easy dispensing of the disclosed topical oral solution to the mouth of the subject but is also a convenient drug delivery method and promotes patient compliance. Direct delivery of the topical oral solution into the oral cavity and / or the back of the throat provides a targeted drug delivery mechanism to the site of action, i.e., the salivary glands (found in the oral cavity), and thereby substantially avoids any hepatic first pass effect compared to using other administration modes (e.g., intravenous). In addition, a faster onset of action of the active ingredient present in the topical oral solution can be observed when the topical oral solution is directly delivered to the site of action. Administration of the topical oral solution directly to the site of action requires a significantly lower concentration of the active agent (i.e., simpinicline) compared to other modes of administration (e.g., intravenous) where the active agent ends up in the systemic circulation at concentrations that can cause negative side effects. With the disclosed mode of administration, i.e., administration into the oral cavity, only a very small amount of the active agent is able to enter the systemic circulation (e.g., via absorption of the mucosa). However, these amounts are not sufficient to cause any undesirable side effects typically observed when active agents, i.e., simpinicline, are administered systemically in larger amounts (required to provide a therapeutic effect). Thus, in some embodiments, the topical oral solution is delivered to the salivary glands located in the oral cavity using a metered pump device, wherein one, two, three, four or five or more sprays of the topical oral solution may be administered per dose to the subject. The amount of the topical oral solution administered to the subject by each spray (e.g., one metered pump action) can vary. In some embodiments, the amount of topical oral solution administered to the subject by a single spray is between about 0.05 mL to about 0.5 mL per spray, between about 0.05 mL to about 0.25 mL per spray, between about 0.05 mL to about 0.20 mL per spray, between about 0.05 mL to about 0.15 mL per spray, about 0.08 mL to about 0.12 mL per spray, or between about 0.1 mL to about 0.12 mL per spray. In some embodiments, the amount of Attorney Docket No. OYST-039 / 01WO (391206-00447) topical oral solution administered to the subject by a single spray is between about 0.1 mL to about 0.3 mL per spray, between about 0.1 mL to about 0.2 mL per spray, between about 0.1 mL to about 0.15 ml per spray, or about 0.1 mL per spray. In some embodiments, the amount of topical oral solution delivered to the oral cavity per dose covers at least about 50%, about 60%, about 70%, about 80%, about 90%, about 92%, about 95%, about 98%, or at least about 99% of the oral cavity of the subject. In some embodiments, the amount of topical oral solution delivered to the back of the throat per dose covers at least about 50%, about 60%, about 70%, about 80%, about 90%, about 92%, about 95%, about 98%, or at least about 99% of the oral cavity of the subject. The topical oral solution as disclosed herein may deliver simpinicline in an amount of from about 0.0005 mg to about 10 mg (per spray), from about 0.001 mg to about 10 mg (per spray), from about 0.01 mg to about 5 mg (per spray), from about 0.1 mg to about 2.5 mg (per spray), from about 0.5 mg to about 2 mg (per spray), from about 0.5 mg to about 1.5 mg (per spray), from about 0.5 mg to about 1 mg (per spray). In some embodiments, the topical oral solution may be administered to a subject in a commercially available pump spray designed to deliver about 0.01 mg / 0.1 ml of solution per spray, about 0.1 mg / 0.1 ml of spray, about 0.2 mg / 0.1 ml / spray, about 0.3 mg / 0.1 ml / spray, about 0.4 mg / 0.1 ml / spray, about 0.5 mg / 0.1 ml / spray, about 0.6 mg / 0.1 ml / spray, about 0.7 mg / 0.1 ml / spray, about 0.8 mg / 0.1 ml / spray, about 0.9 mg / 0.1 ml / spray, or about 1 mg / 0.1 ml / spray. In some embodiments, the topical oral solution is delivered as an aerosol spray. In such instances, the topical oral solution may further comprise a propellant. Suitable propellants include, but are not limited to, hydrocarbons (butane, propane, etc.), carbon dioxide, chlorofluorocarbons (CFC-11, CFC-12, etc.), hydrofluorocarbons (HFA-134a, HFA-227ea, etc.), and ethers (dimethylether, diethylether, etc.). Ozone-depleting propellants, such as freon 12, freon 13, butane, and propane, also may be used but are less preferred. Typically, the propellant will be present in an amount of from 20% to 95% by weight, more preferably at about 50-80% by weight. The droplet size of droplets per spray being generated by either delivery method described above (e.g., metered valve pump and / or aerosol) of the topical oral solution can vary and is generally designed as being a suitable size for being absorbed by the tissue and / or organs present Attorney Docket No. OYST-039 / 01WO (391206-00447) in the oral cavity (e.g., the one or more salivary glands). Typically, the droplet size will be sized within the range of about 1 to 200 microns, more preferably within the range of 1-100 microns, most preferably within the range of 10-100 microns. The droplets may be presented to the mucosa and / or salivary glands in the oral cavity in the form of a mist. In some embodiments, the topical oral solution is formulated as an oral wash and / or rinse and is delivered to the oral cavity and / or back of the throat via rinsing, gargling, swishing the topical oral solution followed by expulsion from the oral cavity and / or back of the throat. In some instances the topical oral solution can be delivered to the oral cavity and / or back of the throat with the help of an applicator. IV. Methods of Treatment The disclosure provides methods for treating dry mouth in a subject in need thereof by administering an effective amount of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) or a pharmaceutically acceptable salt thereof topically to the oral cavity of the subject, wherein (R)-5- ((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) or a pharmaceutically acceptable salt thereof is in a topical oral solution as disclosed herein. In some embodiments, the topical oral solution is directly administered to the back of the throat (e.g., pharynx and / or larynx). In some embodiments, the topical oral solution is directly administered into the oral cavity where the salivary glands are located (i.e., below either side of the tongue, floor of the mouth, near upper molars, below the ear). Direct administration to the area(s) where salivary glands are located stimulates production of saliva. The extent of stimulation of the salivary glands can be measured as a function of saliva flow, i.e., as an increase in the saliva flow of the stimulated salivary glands (i.e. parotid, sublingual, submandibular, or any combination thereof). In some embodiments, the saliva flow is >0.05 ml / min, > 0.15 mL / min, > 0.20 mL / min, > 0.25 mL / min, > 0.30 mL / min, >0.35 ml / min, > 0.40 mL / min, or > 0.45 mL / min. In some embodiments, the saliva flow ranges from about 0.15 ml / min to about 0.5 mL / min, from about 0.16 ml / min to about 0.45 ml / min, from about 0.17 ml / min to about 0.40 mL / min, from about 0.18 ml / min to about 0.35 mL / min, or from about 0.20 mL / min to about 0.30 mL / min. In some embodiments, the amount of saliva released is from one or more of the salivary glands, which are stimulated. In some embodiments, the amount of saliva released is from one or more unstimulated salivary glands. The methods disclosed herein are also directed towards methods for stimulating one or more salivary glands located in the oral cavity a subject in need thereof, wherein the method Attorney Docket No. OYST-039 / 01WO (391206-00447) comprises administering a therapeutically effective amount of the disclosed topical oral solution to the oral cavity of the subject. In such embodiments, the one or more salivary glands are stimulated to increase the saliva flow of said subject by at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or at least by about 95% compared to subjects not administered with the disclosed topical oral solution. Furthermore, the methods disclosed herein are also directed towards methods for increasing the daily saliva secretion and / or saliva flow in a subject in need thereof, wherein the method comprises administering an effective amount of (R)-5-((E)-2-pyrrolidin-3- ylvinyl)pyrimidine) or a pharmaceutically acceptable salts thereof topically to the oral cavity of the subject, wherein (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) or a pharmaceutically acceptable salt thereof is in a topical oral solution as disclosed herein. In some embodiments, the daily saliva secretion and / or flow increases up to about 1.5 L daily, about 1.25 L daily, or about 1.0 L daily in the disclosed methods. In some embodiments, the daily saliva secretion and / or flow increases up to an amount ranging from about 1.0 L to about 1.5 L daily, from about 1.0 about 1.45 L daily, from about 1.0 L to about 1.40 L daily, from about 1.0 L to about 1.35 L daily, from about 1.0 L to about 1.30 L, from about 1.0 L to about 1.25 L, from about 1.0 L to about 1.20 L, from about 1.0 L to about 1.15 L, or about 1.0 L to about 1.10 L daily in the disclosed methods. In some embodiments, the topical oral solution is administered in a therapeutically effective amount, such as an amount that sufficiently promotes the stimulation of one or more salivary glands present in the oral cavity of the subject and / or stimulating one or more salivary glands to increase the saliva flow and / or increases the daily saliva secretion in the oral cavity. In some such embodiments, the therapeutically effective amount ranges from about 1 to about 5 sprays per dose, from about 1 to about 4 sprays per dose, from about 1 to 3 sprays per dose, or from about 1 to 2 sprays per dose of the disclosed topical oral solution. In some embodiments, the therapeutically effective amount is about 1 spray per dose of the disclosed topical oral solution. As already mentioned above, the amount of simpinicline (i.e., active agent) in each spray can vary. In addition, as already mentioned above the amount of the topical oral solution in each spray can vary. Attorney Docket No. OYST-039 / 01WO (391206-00447) In some embodiments, the amount of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) or a pharmaceutically acceptable salt thereof per dose administered to a subject in need thereof ranges from about 1 to about 1000 micrograms, from about 1 to about 750 micrograms, from about 1 to about 500 micrograms, from about 1 to about 250 micrograms, or from about 1 to about 100 micrograms. In some embodiments, the amount of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) or a pharmaceutically acceptable salt thereof per dose administered to a subject in need thereof ranges from about 100 to about 1000 micrograms, from about 300 to about 1000 micrograms, from about 500 to about 1000 micrograms, or from about 750 to about 1000 micrograms. In some embodiments, the methods disclosed herein allow for administration of the disclosed topical oral solution as a single dose or as multiple doses to a subject in need thereof. Generally, a skilled artisan would be aware that the number of doses to be administered to a subject in need thereof to elicit a therapeutic effect (i.e., increase in saliva flow, increased stimulation of salivary glands, etc.) can vary. For example, the number of doses to be administered to a subject in need would depend on parameters such sex, age, weight, ethnic group, overall health, etc. and a skilled artisan would be able to determine a suitable number of doses for such subjects. In some embodiments, the methods disclosed herein administer the topical oral solution to the subject as a single dose at least once a day. In some embodiments, the methods disclosed herein administer the topical oral solution to the subject as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses daily (i.e., within a 24- hour period). In some embodiments, the methods disclosed herein administer a single dose of the topical oral solution to the subject at least once daily, e.g., twice a day. In some embodiments, the methods disclosed herein comprise administering a single dose of the disclosed topical oral solution at least once a week, at least once a month, or at least once a year. In some embodiments, the methods disclosed herein comprise administering a single dose of the disclosed topical oral solution at least 1, 2, 3, 4, 5, 6, 7, 89, or 10 times a week. In some embodiments, the methods disclosed herein comprise administering a single dose of the disclosed topical oral solution no more than 21 times a week, no more than 14 times a week, or no more than 7 times a week. In some embodiments, the methods disclosed herein comprise administering a single dose of the disclosed topical oral solution at least 1, 2, 3, 4, 5, 6, 7, 89, or 10 times a month. In some embodiments, the methods disclosed herein comprise administering a single dose of the disclosed Attorney Docket No. OYST-039 / 01WO (391206-00447) oral formulation no more than 12 times a month, no more than 8 times a month, or no more than 4 times a month. In some embodiments, the methods disclosed herein comprise administering a dose of the disclosed oral formulation on an as-needed basis, i.e., when a person in need thereof is experiencing dry mouth. In some embodiments, the methods disclosed herein allow for daily administration of simpinicline in an amount ranging from about 0.001 mg to about 1 mg, from about 0.01 mg to about 1 mg, from about 0.1 mg to about 1 mg, from about 0.2 to about 1.0 mg, from about 0.3 mg to about 1.0 mg, from about 0.4 mg to about 1.0 mg, or from about 0.5 mg to about 1.0 mg. In some embodiments, the methods disclosed herein allow for weekly administration of simpinicline in an amount ranging from about 0.1 mg to about 10 mg, from about 0.1 mg to about 10 mg, from about 1 mg to about 9 mg, from about 2 to about 8 mg, from about 3 mg to about 7.5 mg, from about 3.5 mg to about 7.0 mg, or from about 4 mg to about 6 mg. In some embodiments, the methods disclosed herein comprise co-administration of one or more additional therapeutic agents for treating dry mouth and / or for stimulating one or more salivary glands and / or increasing the daily saliva secretion and / or saliva flow. Exemplary additional therapeutic agents include, but are not limited to, saliva production stimulators, artificial saliva products, and / or moisturizers or lubricants for the mouth. In some embodiments, the one or more additional therapeutic agents are saliva production stimulators selected from Cevimeline (Evoxac®), Pilocarpine (Salagen®) and xylitol-containing chewing gum. In some embodiments, the one or more additional therapeutic agents are artificial saliva products and / or moisturizers or lubricants for the mouth selected from Oasis®, OraCoat®, Aquoral®, SalivaSure®, Caphosol®, ACT®, Biotene®, MouthKote®, Mol-Stir®, SmartMouth®, Numoisyn®, NeutraSal® and XyliMelts®. In some embodiments, the one or more additional therapeutic agents are artificial saliva products and / or moisturizers or lubricants for the mouth such as carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, glycerin, sorbitol, xylitol, or combinations thereof. In some embodiments, the one or more additional therapeutic agents for treating dry mouth are in the form of an oral solution, oral spray, lozenge, oral gel, oral rinse, discs for extended release, powder for reconstitution. Attorney Docket No. OYST-039 / 01WO (391206-00447) In some embodiments, the one or more additional therapeutic agents are administered at the same time as the topical oral solution disclosed herein, i.e., the one or more additional therapeutic agents are administered simultaneously with the disclosed topical oral solution. In some embodiments, the one or more additional therapeutic agents are not administered at the same time as the topical oral solution disclosed herein, i.e., the one or more additional therapeutic agents and the disclosed topical oral solution are administered sequentially. In some embodiments, the sequential administration is separated by one or more minutes. In some embodiments, the sequential administration is separated by about 1 to about 60 minutes, by about 1 to about 50 minutes, by about 1 to about 40 minutes, by about 1 to about 30 minutes, by about 1 to about 20 minutes, by about 1 to about 10 minutes, by about 1 to about 9 minutes, by about 1 to about 8 minutes, by about 1 to about 7 minutes, by about 1 to about 6 minutes, by about 1 to about 5 minutes, by about 1 to about 4 minutes, by about 1 to about 3 minutes, or by about 1 to about 2 minutes. In some embodiments, the sequential administration is separated by one or more hours. In some embodiments, the sequential administration is separated by about 1 to about 24 hours, by about 1 to about 20 hours, by about 1 to about 15 hours, by about 1 to about 12 hours, by about 1 to about 10 hours, by about 1 to about 8 hours, by about 1 to about 6 hours, by about 1 to about 4 hours, or by about 1 to about 2 hours. In some embodiments, the methods disclosed herein are directed towards treating a subject suffering from dry mouth and / or reduced stimulation of one or more salivary glands and / or a reduction in daily saliva flow by administering a therapeutically effective amount of the disclosed topical oral solution. In some embodiments, said subject is suffering from dry mouth and / or reduced stimulation of one or more salivary glands and / or a reduction in daily saliva flow due to aging. In some embodiments, the cause for dry mouth and / or reduced stimulation of one or more salivary glands and / or a reduction in daily saliva flow in said subject is not due to aging. In some embodiments, dry mouth and / or reduced stimulation of one or more salivary glands and / or a reduction in daily saliva flow in said subject is caused by medications, infections, hormonal imbalances, radiation treatments to the head and / or neck, radioactive-iodine treatment, nerve damage to the head and / or neck, stroke, diabetes, hypertension, hepatitis C, lymphoma, Sjögren’s Syndrome, Alzheimer’s Disease and / or HIV / AIDS. In some embodiments, dry mouth and / or reduced stimulation of one or more salivary glands and / or a reduction in daily saliva flow in said subject is caused by medications such as, but not limited to, antidepressants, decongestants, pain Attorney Docket No. OYST-039 / 01WO (391206-00447) relievers, high blood pressure medication, anxiety medication, antihistamines, autoimmune medication, steroids, anti-inflammatories, muscle relaxants, chemotherapy drugs and / or Parkinson’s Disease medications. In a particular embodiment, dry mouth and / or reduced stimulation of one or more salivary glands and / or a reduction in daily saliva flow in said subject is caused by radiation treatments to the head and / or neck and / or Sjögren’s Syndrome. In some embodiments, said subject has been diagnosed with cancer in the head and / or neck region and has completed at least one cycle of radiation therapy. In some embodiments, said cancer subject has been diagnosed with cancer in the head and / or neck region and is currently undergoing radiation therapy. In some embodiments, said cancer subject is receiving anti-cancer therapy. Exemplary anti- cancer therapy for the head and neck region includes, but is not limited to, cisplatin (Platinol®), fluorouracil (Aluodrucil®), methotrexate (Rheumatrex®, Trexall®), carboplatin, paclitaxel (Abraxane®, Onxol®), docetaxel (Docefrez®, Taxotere®), cetuximab (Erbitux®), nivolumab (Opdivo®), and pembrolizumab (Keytruda®). Thus, in some embodiments, the disclosed methods for treating dry mouth and / or reduced stimulation of one or more salivary glands and / or a reduction in daily saliva flow in said subject comprise co-administration of the disclosed topical oral solution with one or more anti-cancer treatments for head and neck cancer. In some embodiments, said subject has been diagnosed with Sjögren’s Syndrome. In some embodiments, Sjögren’s Syndrome is termed primary if it is not associated with other autoimmune diseases. However, Sjögren’s Syndrome is termed secondary if it arises in association with other autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, mixed connective-tissue disease, relapsing polychondritis, or polymyositis. In some embodiments, said subject is already receiving treatment for Sjögren’s Syndrome. Exemplary treatment options for Sjögren’s Syndrome (primary and secondary) include but are not limited to corticosteroids (e.g., prednisone), non-steroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen), cyclophosphamide (Cytoxan ®), rituximab (Rituxan ®), disease-modifying anti-rheumatic drugs (DMARDs) (e.g., hydroxychloroquine (Plaquenil®), methotrexate (Trexall®, Rheumatrex®), azathioprine (Imuran®), mycophenolate (Cellcept®, Myfortic®), leflunomide (Arava®), cyclosporine (Sandimmune®, Neoral®), Restasis® Attorney Docket No. OYST-039 / 01WO (391206-00447) cyclosporine ophthalmic emulsion, Xiidra® lifitegrast ophthalmic solution, CEQUA™ Cyclosporine Ophthalmic Solution, TYRVAYA™ Varenicline Solution. In such embodiments, the disclosed method comprises co-administering the disclosed topical oral solution with one or more treatment options for treating Sjögren’s Syndrome. In some embodiments, the disclosed method further comprises co-administering the topical oral solution with one or more treatment options for treating autoimmune disorders associated with secondary Sjögren’s Syndrome such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, mixed connective-tissue disease, relapsing polychondritis, or polymyositis. In some embodiments, the disclosed methods comprise co-administering the disclosed topical oral solution with one or more treatment options for rheumatoid arthritis, wherein such treatment options comprise nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen and / or naproxen sodium), steroids (e.g., prednisone), DMARDs (e.g., methotrexate (Trexall®, Otrexup®), leflunomide (Arava®), hydroxychloroquine (Plaquenil®) and sulfasalazine (Azulfidine®)), biologic response modifiers (e.g., abatacept (Orencia®), adalimumab (Humira®), anakinra (Kineret®), certolizumab (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), infliximab (Remicade®), rituximab (Rituxan®), sarilumab (Kevzara®) and tocilizumab (Actemra®)), targeted synthetic DMARDs (e.g., Baricitinib (Olumiant®), tofacitinib (Xeljanz®) and / or upadacitinib (Rinvoq®). In some embodiments, the disclosed method comprises co-administering the disclosed topical oral solution with one or more treatment options for systemic lupus erythematosus, wherein such treatment options comprise antimalarial (e.g., hydroxychloroquine sulfate (Plaquenil®), anti- inflammatory drugs (NSAIDs) (e.g., ibuprofen (Advil®, Motrin®) and / or naproxen sodium (Aleve®, Anaprox®, Naprosyn®), diclofenac (Voltaren® XR, Cataflam®), cyclophosphamide, methotrexate (Otrexup®, Rasuvo®, azathioprine (Imuran®, Azasan®), mycophenolate (CellCept®, Myfortic®), immunomodulators (e.g., immunoglobulin IV (IGIV) (Bivigam®, Carimune®, Gammagard® S / D, Flebogamma®, Gamunex-C®)), rheumatologic agents (e.g., belimumab (Benlysta®), corticosteroids (e.g., methylprednisolone (A-Methapred®, Medrol®, Solu-Medrol®, Depo-Medrol®), prednisone), rituximab (Rituxan®), interferon antagonists (e.g., anifrolumab (Anifrolumab-fnia®, Saphnelo®), and / or calcineurin inhibitors (e.g., tacrolismus, voclosporin (Lupkynis®). Attorney Docket No. OYST-039 / 01WO (391206-00447) In some embodiments, the disclosed methods comprise co-administering the disclosed topical oral solution with one or more treatment options for scleroderma, wherein such treatment options comprise corticosteroids, cyclophosphamide (Cytoxan®, Neosar®), methotrexate, ACE inhibitors (e.g., captopril (Capoten®), enalapril (Vasotec®), quinapril (Accupril®), and lisinopril (Prinivil®, Zestril®), mycophenolate mofetil (Cellcept®), mycophenolate sodium (Myfortic®), Calcium-channel blockers (amlodipine (Norvasc®), nifedipine (Procardia®, Adalat®), and diltiazem (Cardizem®)), Bosentan (Tracleer®), macitentan (Opsumit®), ambrisentan (Letairis®), epoprostenol (Flolan®), treprostinil (Remodulin®), iloprost (Ventavis®), selexipag (Uptravi®), riociguat (Adempas®), sildenafil (Revatio®), tadalafil (Adcirca®), Omeprazole (Prilosec®), metoclopramide (Reglan®), and / or prucalopride (Motegrity®). In some embodiments, the disclosed method comprises co-administering the disclosed topical oral solution with one or more treatment options for mixed connective-tissue disease, wherein such treatment options comprise corticosteroids (Deltasone®, Rayos®), antimalarial drugs (e.g., hydroxychloroquine (Plaquenil®), calcium channel blockers (e.g., nifedipine (Adalat®CC, Procardia®), amlodipine (Norvasc®), and / or pulmonary hypertension medication (e.g., bosentan (Tracleer®), sildenafil (Revatio®, Viagra®). In some embodiments, the disclosed method comprises co-administering the disclosed topical oral solution with one or more treatment options for relapsing polychondritis, wherein such treatment options comprise colchicine, corticosteroids, dapsone, NSAIDs, cyclophosphamide, azathioprine, and / or methotrexate. In some embodiments, the disclosed method comprises co-administering the disclosed topical oral solution with one or more treatment options for relapsing polymyositis, wherein such treatment options comprise methotrexate (Rheumatrex®, Trexall®), azathioprine (Imuran®, Azasan®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®, Gengraf®, Neoral®), tacrolimus (Astagraf XL®, Hecoria®, Prograf®), mycophenolate (CellCept®, Myfortic®), immunoglobulins (IVIG) and / or rituximab (Rituxan®). In some embodiments, the one or more treatment options in the above-described methods are administered at the same time as the topical oral solution disclosed herein, i.e., the one or more treatment options are administered simultaneously with the disclosed topical oral solution. In some embodiments, the one or more treatment options are not administered at the same time as the Attorney Docket No. OYST-039 / 01WO (391206-00447) topical oral solution disclosed herein, i.e., the one or more treatment options and the disclosed topical oral solution are administered sequentially. The sequential administration may be separated by minutes, hours, days, and / or weeks. In some embodiments, the topical oral solution as described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the topical oral solution is administered to a subject already suffering from dry mouth and / or reduced stimulation of the salivary glands and / or decreased daily saliva flow, in an amount sufficient to provide a therapeutic beneficial effect (e.g., increase in saliva production). In prophylactic applications, the topical oral solutions described herein are administered to a subject susceptible to or otherwise at risk of developing dry mouth and / or reduced stimulation of salivary glands and / or decreased saliva flow. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the subject's state of health, weight, and the like. When used in a subject, effective amounts for this use will depend on the severity of dry mouth, decreased salivary gland stimulation and / or function, and / or decreased daily saliva flow, the subject's health status and response to the drugs, and the judgment of the treating clinician. Shown below are various preferred embodiments: 1. A topical oral solution comprising: simpinicline or a pharmaceutically acceptable salt thereof, wherein the concentration of simpinicline in the solution is from about 0.05 mg / ml to about 10 mg / ml; a flavoring agent; and a buffering agent. 2. The topical oral solution of embodiment 1, wherein the pharmaceutically acceptable salt of simpinicline is selected from the group consisting of a citrate salt, a hydrochloride salt, a hemigalactarate salt, and a galactarate salt. 3. The topical oral solution of embodiment 1 or 2, wherein the pharmaceutically acceptable salt of simpinicline is a hemigalactarate salt, such as a hemigalactarate dihydrate salt. Attorney Docket No. OYST-039 / 01WO (391206-00447) 4. The topical oral solution of any one of the preceding embodiments, wherein (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine) exhibits a diastereomeric excess of at least about 98% diastereomeric excess. 5. The topical oral solution of any one of the preceding embodiments, wherein the flavoring agent is selected from the group consisting of a strawberry flavor, a peppermint flavor, an apple flavor, a fruit punch flavor, and a lemon flavor. 6. The topical oral solution of any one of the preceding embodiments, wherein the buffering agent is a phosphate buffer selected from the group consisting of sodium phosphate, potassium phosphate, calcium phosphate, and magnesium phosphate. 7. The topical oral solution of any one of the preceding embodiments having a pH ranging from about 4.0 to about 7.0. 8. The topical oral solution of any one of the preceding embodiments further comprising a preservative. 9. The topical oral solution of embodiment 8, wherein the preservative is sodium benzoate, benzyl alcohol and / or potassium sorbate. 10. The topical oral solution of any one of the preceding embodiments further comprises a sweetening agent. 11. The topical oral solution of embodiment 10, wherein the sweetening agent is selected from xylitol, sorbitol, glycerol and a combination thereof. 12. The topical oral solution of any one of the preceding embodiments, wherein the flavoring agent is present in an amount ranging from about 0.2% to about 0.4% by weight. 13. The topical oral solution of any one of the preceding embodiments, wherein the buffering agent is present in an amount ranging from about 0.7% to about 1% by weight based on the total weight of the topical oral solution. 14. The topical oral solution of any one of embodiments 10-13, wherein the sweetening agent is present in an amount of from about 10% to about 20% by weight based on the total weight of the topical oral solution. Attorney Docket No. OYST-039 / 01WO (391206-00447) 15. The topical oral solution of any one of embodiments 8-14, wherein the preservative is present in an amount of from about 0.1% to about 0.25% by weight based on the total weight of the topical oral solution. 16. The topical oral solution of any one of the preceding embodiments having a pH ranging from about 5.0 to about 5.5. 17. The topical oral solution of any one of embodiments 10-16, wherein the flavoring agent is a lemon flavor; the preservative is sodium benzoate, potassium benzoate or a combination thereof; the buffering agent is a sodium phosphate monobasic monohydrate buffer; and the sweetening agent is xylitol or sorbitol. 18. The topical oral solution of any one of the preceding embodiments, wherein the topical oral solution is formulated as an oral spray, an oral rinse or an oral mouth wash. 19. The topical oral solution of any one of the preceding embodiments which can be used to spray, rinse, drop, dab, or gargle a subject’s oral cavity and / or back of throat. 20. The topical oral solution of any one of the preceding embodiments further comprising a carrier solvent and / or additional agents selected from the group consisting of co-solvents, solubilizing agents, absorption enhancers, stabilizing agents, pH-adjusting agents, anti-microbial agents, and viscosity-modifying agents. 21. The topical oral solution of any one of the preceding embodiments, wherein the concentration of simpinicline in the solution is from about 0.5 mg / ml to about 10 mg / ml or from about 1 mg / ml to about 10 mg / ml. 22. A method of treating dry mouth in a subject in need thereof, the method comprising: administering an effective amount of simpinicline topically to the oral cavity or back of throat of the subject, the simpinicline formulated in a topical oral solution comprising simpinicline or a pharmaceutically acceptable simpinicline salt, the solution further comprising a flavoring agent and a buffering agent. 23. A method of increasing the saliva flow of one or more salivary glands in a subject in need thereof, the method comprising: Attorney Docket No. OYST-039 / 01WO (391206-00447) administering an effective amount of simpinicline topically to the oral cavity or back of throat of the subject, the simpinicline formulated in a topical oral solution comprising simpinicline or a pharmaceutically acceptable simpinicline salt, the solution further comprising a flavoring agent and a buffering agent. 24. The method of embodiment 22 or 23, wherein the solution is administered by spraying into the subject’s oral cavity and / or back of the throat. 25. The method of embodiment 22 or 23, wherein the solution is administered by application with an applicator to the subject’s oral cavity and / or back of the throat. 26. The method of embodiment 22 or 23, wherein the solution is administered by rinsing the oral cavity. 27. The method of embodiment 22 or 23, wherein the solution is administered by gargling. 28. The method of any one of embodiments 22-27, wherein the simpinicline formulated into the solution is a simpinicline hemigalactarate salt, such as a hemigalactarate dihydrate salt. 29. The method of embodiment 28, wherein the simpinicline hemigalactarate has a molar ratio of 0.5:1:2 of galactaric acid to 5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) to hydrate. 30. The method of any one of embodiments 22-29, wherein the simpinicline exhibits a diastereomeric excess of at least about 98% diastereomeric excess. 31. The method of any one of embodiments 22-30, wherein the concentration of simpinicline in the solution ranges from about 0.05 mg / ml to about 10 mg / ml. 32. The method of any one of embodiments 22-31, wherein the flavoring agent in the solution is selected from the group consisting of peppermint oil, spearmint oil, citrus oil, fruit flavors, chocolate, spice, vanilla and / or bubblegum flavors. 33. The method of any one of embodiments 22-32, wherein the buffering agent in the solution is a phosphate buffer selected from the group consisting of sodium phosphate, potassium phosphate, calcium phosphate, and magnesium phosphate. 34. The method of any one of embodiments 22-33, wherein the pH of the solution ranges from about 4.0 to about 7.0. Attorney Docket No. OYST-039 / 01WO (391206-00447) 35. The method of any one of embodiments 22-34, the solution further comprising a sweetening agent. 36. The method of embodiment 35, wherein the sweetening agent is selected from the group consisting of sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium, xylitol, acesulfame, stevia and aspartame. 37. The method of any one of embodiments 22-36, the solution further comprising a preservative. 38. The method of embodiment 37, wherein the preservative is sodium benzoate and / or potassium sorbate. 39. The method of any one of embodiments 35-38, wherein the amount of sweetening agent present in the solution ranges from about 10% to about 20% by weight based on the total weight of the solution. 40. The method of any one of embodiments 37-39, wherein the amount of preservative present in the solution ranges from about 0.1% to about 0.25% by weight based on the total weight of the solution. 41. The method of any one of embodiments 22-40, wherein the flavoring agent is present in the solution in an amount ranging from about 0.2% to about 0.4% by weight based on the total weight of the solution. 42. The method of any one of embodiments 22-41, wherein the buffering agent in the solution is present in an amount 0.7% to about 1.0% by weight based on the total weight of the solution. 43. The method of any one of embodiments 35-42, wherein the sweetening agent in the solution is selected from the group consisting of xylitol, sorbitol, glycerol, and any combination thereof. 44. The method of any one of embodiments 22-43, wherein the flavoring agent in the solution is selected from the group consisting of a strawberry flavor, an apple flavor, a fruit punch flavor, and a lemon flavor. 45. The method of any one of embodiments 37-44, wherein the solution comprises simpinicline in a concentration ranging from about 0.5 mg / ml to about 10 mg / ml or about 2.5 mg / ml to about 7.5 mg / ml; a preservative present in an amount from about 0.15% to about 0.4% by weight Attorney Docket No. OYST-039 / 01WO (391206-00447) selected from the group consisting of sodium benzoate, potassium benzoate, and a combination thereof; a sweetening agent selected from the group consisting of xylitol, sorbitol, and a combination of xylitol and glycerol present in an amount from about 10% to about 20% by weight; a lemon flavoring agent present in an amount from about 0.25% to about 0.35% by weight, wherein all weights are based on the total weight of the solution. 46. The method of any one of embodiments 22-45, wherein the solution further comprises a carrier solvent and / or additional agents selected from the group consisting of co-solvents, solubilizing agents, absorption enhancers, stabilizing agents, pH-adjusting agents, anti-microbial agents, and viscosity-modifying agents. 47. The method of any one of embodiments 22-46, wherein the solution is administered to the subject using a metered pump device. 48. The method of any one of embodiments 22-47, wherein about 0.1 to about 0.3 mL of solution is delivered into the oral cavity and / or back of throat of the subject with a single spray of the metered pump device. 49. The method of any one of embodiments 22-48, comprising administering between about 0.5 micrograms and about 10,000 micrograms of simpinicline to the subject in need thereof. 50. The method of any one of embodiments 22-49, wherein about 0.5 micrograms to about 100 micrograms or about 0.5 micrograms to about 750 micrograms of simpinicline is delivered into the oral cavity and / or back of throat of the subject. 51. The method of any one of embodiments 22-50, wherein about 0.5 micrograms and 1000 micrograms of simpinicline is administered to the subject per day. 52. The method of any one of embodiments 22-51, wherein a dose of the solution is administered at least once a day. 53. The method of any one of embodiments 22-52, wherein a dose the solution is administered twice a day. 54. The method of any one of embodiments 22-53, wherein a dose of the solution is administered at least once a week. Attorney Docket No. OYST-039 / 01WO (391206-00447) 55. The method of any one of embodiments 22-54, wherein a dose of the solution being administered is between 1 to 5 sprays. 56. The method of embodiment 55, wherein the spray comprises particles having a median particle size diameter of about 1 to about 100 microns. 57. The method of any one of embodiments 22-56, wherein the solution administered to the subject stimulates release of saliva from one or more salivary glands located in the oral cavity of the subject. 58. The method of embodiment 57, wherein the one of more salivary glands are selected from the group consisting of the parotid glands, the submandibular gland and the sublingual gland. 59. The method of embodiment 58, wherein the unstimulated saliva flow from the submandibular gland, the sublingual gland, and / or a parotid gland or glands is about > 0.05 mL / min; and / or the stimulated saliva flow from the submandibular gland, the sublingual gland, and / or a parotid gland or glands ‘ is about > 0.15 mL / min. 60. The method of any one of embodiments 22 and 24-59, wherein the dry mouth is caused by one or more medications, one or more infections, a hormonal imbalance, one or more radiation treatments to the head and / or neck, one or more radioactive iodine treatments, nerve damage to the head and / or neck, stroke, diabetes, hypertension, hepatitis C, lymphoma, Sjögren’s Syndrome, Alzheimer’s Disease and / or HIV / AIDS. 61. The method of embodiment 60, wherein the one or more medications are selected from antidepressants, decongestants, pain relievers, high blood pressure medications, anxiety medications, antihistamines, muscle relaxants, chemotherapy drugs and / or Parkinson’s Disease medications. 62. The method of embodiment 60, wherein dry mouth is caused by one or more radiation treatments to the head and / or neck, one or more radioactive iodine treatments, or Sjögren’s Syndrome. 63. The method of any one of embodiments 22-62, wherein the solution is co-administered with one or more additional therapeutic agents for treating dry mouth. Attorney Docket No. OYST-039 / 01WO (391206-00447) 64. The method of embodiment 63, wherein the one or more additional therapeutic agents are selected from saliva production stimulators, artificial saliva products, and / or moisturizers or lubricants. 65. The method of embodiments 62 or 63, wherein the additional therapeutic agents a saliva production stimulator selected from Cevimeline (Evoxac®), Pilocarpine (Salagen®) and xylitol- containing chewing gum. 66. The method of embodiments 62 or 63, wherein the additional therapeutic agent is an artificial saliva product, moisturizer, or lubricant selected from Oasis®, OraCoat®, Aquoral®, SalivaSure®, Caphosol®, ACT®, Biotene®, MouthKote®, Mol-Stir®, SmartMouth®, Numoisyn®, NeutraSal® and XyliMelts®. 67. The method of embodiment 62 or 63, wherein the additional therapeutic agent is an artificial saliva product, moisturizer, or lubricant selected from carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, glycerin, sorbitol, xylitol, and any combination thereof. 68. The method of embodiment 62 or 63, wherein the additional therapeutic agents in the form of an oral solution, oral spray, lozenge, oral gel, oral rinse, disc for extended release, or a powder for reconstitution. EXAMPLES Example 1: Preparation of Simpinicline Spray Formulations. The simpinicline spray formulations set forth in the following Tables 1A-1E were prepared:

[0002] Attorney Docket No. OYST-039 / 01WO (391206-00447) Table 1A: OC-02 Oral Spray Formulation OP-009-011A mg / mL Description Batch Bulk Solution d p S l ti Attorney Docket No. OYST-039 / 01WO (391206-00447) Sodium Phosphate Monobasic Monohydrate 0.828% 8.28 Natural Lemon Flavor W / S 2025383 (Carmi) 0.30% 3 Sodium benzoate 0.25% 2.5 1. Add water for injection (80% of volume) to beaker with mixing. 2. Add excipients (buffer, flavor, sweetener and preservative) individually and make sure all excipients are dissolved. 3. Add simpinicline and confirm all API is dissolved. 4. Adjust pH with hydrochloric acid or sodium hydroxide to a range of 5.0 -5.5. 5. QS to final volume with water for injection. 6. Sterile filter through 0.22 micron filter. 7. Fill solution into bottles for stability study. Example 2: Stability Studies of Simpinicline Spray Formulations Various simpinicline formulations were screened in stability studies under various conditions. The results are shown below in Tables 2-11: Tables 2 through 11 Table 2: Stability Condition 25C / 60% RH OP-009-11A - Impurities Xylitol, Lemon, pH 24 32 29 36 Table 3: Stability Condition 25C / 60% RH OP-009-11B - Impurities pH Attorney Docket No. OYST-039 / 01WO (391206-00447) Benzoate , Pot Sorbate Initial 97.3 ND ND ND ND ND ND ND ND 5.39 1M 1 ND ND ND ND ND ND ND 5.47 .47 .52 - - - pu es Xylitol, Lemon, Pot Sorbate Assay RRT 1.468 RRT 1.626 RRT 1.683 RRT 1.737 RRT 1.803 RRT 1.978 RRT 2.355 Total Impurities pH .33 .39 .37 .46 OP-009-11D- Impurities Sorbitol, Lemon, Sod. Benzoate Assay RRT 1.468 RRT 1.626 RRT 1.683 RRT 1.737 RRT 1.803 RRT 1.978 RRT 2.355 Total Impurities pH .20 .29 .29 .32 OP-009-11E- Impurities Glycerol, Xylitol, Lemon Sod. pH .24 .28 .29 .35 Table 7: Stability Condition 40C / 75% RH OP-009-11A - Impurities Xylitol, Lemon, Sod. pH 5.2 5.3 5.3 5.3 Tab e 8: Stab ty Cond t on 40C / 75% RH OP-009-11B - Impurities Xylitol, Lemon, Sod. pH 5.3 5.4 5.4 5.4 Table 9: Stability Condition 40C / 75% RH OP-009-11C - Impurities Xylitol, Lemon, Pot pH 5.3 5.4 Attorney Docket No. OYST-039 / 01WO (391206-00447) 3M 95.3 ND ND ND 0.27 0.24 0.25 ND 0.76 5.4 6M 85.7 0.29 0.39 0.29 0.35 ND 0.7 0.19 2.21 5.3 Sorbitol, Lemon, Sod. BenzoateAssayRRT 1.468 RRT 1.626 RRT 1.683 RRT 1.737 RRT 1.803 RRT 1.978 RRT 2.355 Total Impurities pH 5.2 5.3 5.3 5.3 OP-009-11E- Impur t es Glycerol, Xylitol, Lemon, Sod. pH 5.2 5.2 5.2 5.1 simpinicline formulations. The results are shown below in Table 12: Table 12 Stability Condition 60C OP-009-11A – Xylitol, Lemon, Impurities Sod.Benzoate Assay RRT 1.117 RRT 1.524 RRT 1.564 RRT 1.694 RRT 1.760 Total Impurities pH Initi l 969 ND ND ND ND ND ND 524 T 2 . y . . . . . p pH 39 T 7 Pot Sorbate Assay RRT 1.117 RRT 1.524 RRT 1.564 RRT 1.694 RRT 1.760 Tota Impur t es pH 3 T 7 Sod.Benzoate Assay RRT 1.117 RRT 1.524 RRT 1.564 RRT 1.694 RRT 1.760 Total Impurities pH 0 T 2 Lemon, Sod. Assay RRT 1.117 RRT 1.524 RRT 1.564 RRT 1.694 RRT 1.760 Total Impurities pH 4 T 6

Claims

Attorney Docket No. OYST-039 / 01WO (391206-00447) THAT WHICH IS CLAIMED IS:

1. A topical oral solution comprising: simpinicline or a pharmaceutically acceptable salt thereof, wherein the concentration of simpinicline in the solution is from about 0.05 mg / ml to about 10 mg / ml; a flavoring agent; and a buffering agent.

2. The topical oral solution of claim 1, wherein the pharmaceutically acceptable salt of simpinicline is selected from the group consisting of a citrate salt, a hydrochloride salt, a hemigalactarate salt, and a galactarate salt.

3. The topical oral solution of claim 2, wherein the pharmaceutically acceptable salt of simpinicline is a hemigalactarate salt, such as a hemigalactarate dihydrate salt.

4. The topical oral solution of any one of claims 1-3, wherein simpinicline exhibits a diastereomeric excess of at least about 98% diastereomeric excess.

5. The topical oral solution of any one of claims 1-3, wherein the flavoring agent is selected from the group consisting of a strawberry flavor, a peppermint flavor, an apple flavor, a fruit punch flavor, and a lemon flavor.

6. The topical oral solution of any one of claims 1-3, wherein the buffering agent is a phosphate buffer selected from the group consisting of sodium phosphate, potassium phosphate, calcium phosphate, and magnesium phosphate.

7. The topical oral solution of any one of claims 1-3 having a pH ranging from about 4.0 to about 7.

0.

8. The topical oral solution of claim 1 further comprising a preservative.

9. The topical oral solution of claim 8, wherein the preservative is sodium benzoate, benzyl alcohol and / or potassium sorbate.

10. The topical oral solution of claim 1 further comprising a sweetening agent.Attorney Docket No. OYST-039 / 01WO (391206-00447) 11. The topical oral solution of claim 10, wherein the sweetening agent is selected from xylitol, sorbitol, glycerol and a combination thereof.

12. The topical oral solution of claim 5, wherein the flavoring agent is present in an amount ranging from about 0.2% to about 0.4% by weight based on the total weight of the topical oral solution.

13. The topical oral solution of claim 6, wherein the buffering agent is present in an amount ranging from about 0.7% to about 1% by weight based on the total weight of the topical oral solution.

14. The topical oral solution of claim 10, wherein the sweetening agent is present in an amount of from about 10% to about 20% by weight based on the total weight of the topical oral solution.

15. The topical oral solution of claim 8, wherein the preservative is present in an amount of from about 0.1% to about 0.25% by weight based on the total weight of the topical oral solution.

16. The topical oral solution of any one of claims 10-15, wherein the flavoring agent is a lemon flavor; the preservative is sodium benzoate, potassium benzoate or a combination thereof; the buffering agent is a sodium phosphate monobasic monohydrate buffer; and the sweetening agent is xylitol or sorbitol.

17. The topical oral solution of claim 16 having a pH ranging from about 5.0 to about 5.

5.

18. The topical oral solution of claim 4, wherein the topical oral solution is formulated as an oral spray, an oral rinse or an oral mouth wash.

19. The topical oral solution of claim 4 which can be used to spray, rinse, drop, dab, or gargle a subject’s oral cavity and / or back of throat.

20. The topical oral solution of claim 1 further comprising a carrier solvent and / or additional agents selected from the group consisting of co-solvents, solubilizing agents, absorption enhancers, stabilizing agents, pH-adjusting agents, anti-microbial agents, and viscosity- modifying agents.

21. The topical oral solution of claim 4, wherein the concentration of simpinicline in the solution is from about 0.5 mg / ml to about 10 mg / ml or from about 1 mg / ml to about 10 mg / ml.

22. A method of treating dry mouth in a subject in need thereof, the method comprising:Attorney Docket No. OYST-039 / 01WO (391206-00447) administering an effective amount of simpinicline topically to the oral cavity or back of throat of the subject, the simpinicline formulated in a topical oral solution comprising simpinicline or a pharmaceutically acceptable simpinicline salt, the solution further comprising a flavoring agent and a buffering agent.

23. A method of increasing the saliva flow of one or more salivary glands in a subject in need thereof, the method comprising: administering an effective amount of simpinicline topically to the oral cavity or back of throat of the subject, the simpinicline formulated in a topical oral solution comprising simpinicline or a pharmaceutically acceptable simpinicline salt, the solution further comprising a flavoring agent and a buffering agent.

24. The method of claim 22, wherein the solution is administered by spraying into the subject’s oral cavity and / or back of the throat.

25. The method of claim 23, wherein the solution is administered by spraying into the subject’s oral cavity and / or back of the throat.

26. The method of claim 22, wherein the solution is administered by application with an applicator to the subject’s oral cavity and / or back of the throat.

27. The method of claim 23, wherein the solution is administered by application with an applicator to the subject’s oral cavity and / or back of the throat.

28. The method of claim 22, wherein the solution is administered by rinsing the oral cavity.

29. The method of claim 23, wherein the solution is administered by rinsing the oral cavity.

30. The method of claim 22, wherein the solution is administered by gargling.

31. The method of claim 23, wherein the solution is administered by gargling.

32. The method of any one of claims 22-31, wherein the simpinicline formulated into the solution is a simpinicline hemigalactarate salt, such as a hemigalactarate dihydrate salt.

33. The method of any one of claim 32, wherein the simpinicline hemigalactarate has a molar ratio of 0.5:1:2 of galactaric acid to 5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine) to hydrate.Attorney Docket No. OYST-039 / 01WO (391206-00447) 34. The method of any one of claims 22-31, wherein the simpinicline exhibits a diastereomeric excess of at least about 98% diastereomeric excess.

35. The method of any one of claims 22-31, wherein the concentration of simpinicline in the solution ranges from about 0.05 mg / ml to about 10 mg / ml.

36. The method of any one of claims 22-31, wherein the flavoring agent in the solution is selected from the group consisting of peppermint oil, spearmint oil, citrus oil, fruit flavors, chocolate, spice, vanilla and / or bubblegum flavors.

37. The method of any one of claims 22-31, wherein the buffering agent in the solution is a phosphate buffer selected from the group consisting of sodium phosphate, potassium phosphate, calcium phosphate, and magnesium phosphate.

38. The method of claim 32, wherein the pH of the solution ranges from about 4.0 to about 7.

0.

39. The method of claim 32, the solution further comprising a sweetening agent.

40. The method of claim 39, wherein the sweetening agent is selected from the group consisting of sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium, xylitol, acesulfame, stevia and aspartame.

41. The method of claim 32, the solution further comprising a preservative.

42. The method of claim 41, wherein the preservative is sodium benzoate and / or potassium sorbate.

43. The method of claim 39, wherein the amount of sweetening agent present in the solution ranges from about 10% to about 20% by weight based on the total weight of the solution.

44. The method of claim 41, wherein the amount of preservative present in the solution ranges from about 0.1% to about 0.25% by weight based on the total weight of the solution.

45. The method of claim 36, wherein the flavoring agent is present in the solution in an amount ranging from about 0.2% to about 0.4% by weight based on the total weight of the solution.

46. The method of claim 37, wherein the buffering agent in the solution is present in an amount 0.7% to about 1.0% by weight based on the total weight of the solution.Attorney Docket No. OYST-039 / 01WO (391206-00447) 47. The method of claim 39, wherein the sweetening agent in the solution is selected from the group consisting of xylitol, sorbitol, glycerol, and any combination thereof.

48. The method of claim 32, wherein the flavoring agent in the solution is selected from the group consisting of a strawberry flavor, an apple flavor, a fruit punch flavor, and a lemon flavor.

49. The method of any one of claims 41-48, wherein the solution comprises simpinicline in a concentration ranging from about 0.5 mg / ml to about 10 mg / ml or about 2.5 mg / ml to about 7.5 mg / ml; a preservative present in an amount from about 0.15% to about 0.4% by weight selected from the group consisting of sodium benzoate, potassium benzoate, and a combination thereof; a sweetening agent selected from the group consisting of xylitol, sorbitol, and a combination of xylitol and glycerol present in an amount from about 10% to about 20% by weight; a lemon flavoring agent present in an amount from about 0.25% to about 0.35% by weight, wherein all weights are based on the total weight of the solution.

50. The method of claim 32, wherein the solution further comprises a carrier solvent and / or additional agents selected from the group consisting of co-solvents, solubilizing agents, absorption enhancers, stabilizing agents, pH-adjusting agents, anti-microbial agents, and viscosity-modifying agents.

51. The method of claim 32, wherein the solution is administered to the subject using a metered pump device.

52. The method of claim 51, wherein about 0.1 to about 0.3 mL of solution is delivered into the oral cavity and / or back of throat of the subject with a single spray of the metered pump device. 53.. The method of claim 32, comprising administering between about 0.5 micrograms and about 10,000 micrograms of simpinicline to the subject in need thereof.

54. The method of claim 32, wherein about 0.5 micrograms to about 100 micrograms or about 0.5 micrograms to about 750 micrograms of simpinicline is delivered into the oral cavity and / or back of throat of the subject.

55. The method of claim 32, wherein about 0.5 micrograms and 1000 micrograms of simpinicline is administered to the subject per day.

56. The method of claim 32, wherein a dose of the solution is administered at least once a day.Attorney Docket No. OYST-039 / 01WO (391206-00447) 57. The method of claim 32, wherein a dose of the solution is administered twice a day.

58. The method of claim 32, wherein a dose of the solution is administered at least once a week.

59. The method of claim 32, wherein a dose of the solution being administered is between 1 to 5 sprays.

60. The method of claim 59, wherein the spray comprises particles having a median particle size diameter of about 1 to about 100 microns.

61. The method of claim 32, wherein the solution administered to the subject stimulates release of saliva from one or more salivary glands located in the oral cavity of the subject.

62. The method of claim 61, wherein the one of more salivary glands are selected from the group consisting of the parotid glands, the submandibular gland and the sublingual gland.

63. The method of claim 62, wherein the unstimulated saliva flow from the submandibular gland, the sublingual gland, and / or a parotid gland or glands is about > 0.05 mL / min; and / or the stimulated saliva flow from the submandibular gland, the sublingual gland, and / or a parotid gland or glands is about > 0.15 mL / min.

64. The method of claim 61, wherein the dry mouth is caused by one or more medications, one or more infections, a hormonal imbalance, one or more radiation treatments to the head and / or neck, one or more radioactive iodine treatments, nerve damage to the head and / or neck, stroke, diabetes, hypertension, hepatitis C, lymphoma, Sjögren’s Syndrome, Alzheimer’s Disease and / or HIV / AIDS.

65. The method of claim 64, wherein the one or more medications are selected from antidepressants, decongestants, pain relievers, high blood pressure medications, anxiety medications, antihistamines, muscle relaxants, chemotherapy drugs and / or Parkinson’s Disease medications.

66. The method of claim 61, wherein dry mouth is caused by one or more radiation treatments to the head and / or neck, one or more radioactive iodine treatments, or Sjögren’s Syndrome.

67. The method of claim 66, wherein the solution is co-administered with one or more additional therapeutic agents for treating dry mouth.Attorney Docket No. OYST-039 / 01WO (391206-00447) 67. The method of claim 67, wherein the one or more additional therapeutic agents are selected from saliva production stimulators, artificial saliva products, and / or moisturizers or lubricants.

68. The method of claims 66 or 67, wherein the additional therapeutic agents a saliva production stimulator selected from Cevimeline (Evoxac®), Pilocarpine (Salagen®) and xylitol-containing chewing gum.

69. The method of claims 66 or 67, wherein the additional therapeutic agent is an artificial saliva product, moisturizer, or lubricant selected from Oasis®, OraCoat®, Aquoral®, SalivaSure®, Caphosol®, ACT®, Biotene®, MouthKote®, Mol-Stir®, SmartMouth®, Numoisyn®, NeutraSal® and XyliMelts®.

70. The method of claim 66 or 67, wherein the additional therapeutic agent is an artificial saliva product, moisturizer, or lubricant selected from carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, glycerin, sorbitol, xylitol, and any combination thereof.

71. The method of claim 66 or 67, wherein the additional therapeutic agents in the form of an oral solution, oral spray, lozenge, oral gel, oral rinse, disc for extended release, or a powder for reconstitution.