TW202329958A - Aqueous cevimeline compositions and methods of use - Google Patents

Abstract

The invention provides stable aqueous compositions, in particular topical ophthalmic compositions, of cevimeline and sorbic acid or a salt thereof for the treatment of dry eye disease, xerostomia, and/or Sjogren syndrome. The compositions also comprise a water-soluble medium-chain polyunsaturated fatty acid (PUFA) such as sorbic acid, or a pharmaceuticallyacceptable salt thereof, e.g., potassium sorbate.

Description

Cevimeline aqueous solution compositions and methods of use

The present invention is concerned with several compositions, such as topical ophthalmic compositions or topical compositions for nasal application, which comprise a muscarinic agonist especially cevimeline , MRA), which can be combined with a medium chain (C ₆ to C ₁₀ ) polyunsaturated fatty acid (polyunsaturated fatty acid, PUFA; for example, C ₆ to C ₁₂ or C ₆ to C ₁₀ ), the present invention also uses these compositions It is related to methods for treating dry eye disease (DED), xerostomia, and/or Sjögren's syndrome (Sjogren's syndrome). These compositions may optionally contain one or several active ingredients, such as steroids, immunomodulators, hormones, and/or secretagogues.

The present invention relates to various compositions, such as topical ophthalmic compositions or compositions suitable for topical nasal administration, which comprise a muscarinic agent (MRA), in particular cevimeline, in combination with A medium chain (C ₆ to C ₁₀ ) polyunsaturated fatty acid (PUFA; for example C ₆ to C ₁₂ or C ₆ to C ₁₀ ), the present invention also uses these compositions to treat dry eye disease (DED), dry mouth syndrome, and/or methods of diseases such as Sjögren's syndrome. These compositions may optionally contain one or several active ingredients, such as steroids, immunomodulators, hormones, and/or secretagogues.

Xerostomia refers to a condition in which the salivary glands in the mouth do not produce enough saliva to keep the mouth moist. Dry mouth is often blamed on side effects of certain medications, Sjögren's disease, or as a result of radiation therapy for cancer. Saliva helps prevent tooth decay by neutralizing acids produced by bacteria, and it also limits bacterial growth and washes away food particles. Reduced saliva and dry mouth have major effects on teeth and gums.

Dry eye syndrome, also known as keratoconjunctivitis sicca or dry eye syndrome, is a chronic and potentially debilitating condition that involves trauma to the ocular surface, inflammation, oxidative stress, and irritative symptoms, including discomfort and visual quality reduce. Dry eye is a multifactorial disease of the ocular surface that affects approximately 20 million patients in the United States alone. The Dry Eye Workshop (DEWS) has classified dry eye according to two basic causal mechanisms: lack of tears and evaporative dry eye (ie tear film instability due to abnormally rapid evaporation of tears). Dry eye is also associated with localized inflammation of the eye surface and surrounding tissues. It is not known whether chronic inflammation contributes to the clinical manifestations of dry eye, or whether dry eye causes chronic inflammation. Due to the complex multifactorial etiology of dry eye and the unclear relationship between dry eye and inflammation, various attempts to find out how to effectively treat dry eye have been largely unsuccessful and to the disappointment of patients and clinicians.

One possible cause of dry eye and mouth is Sjögren's syndrome (also known as Mikulic's disease or Sjogren's syndrome), an autoimmune disorder in which immune cells attack and Destroys salivary and lacrimal glands. The condition affects nearly four million people and is second only to rheumatism. Although men and women of any age can be affected, approximately 90% of patients are women over the age of 40. The condition may also occur in the early or growing stages of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and primary biliary cirrhosis. Sjögren's associated dry eye syndrome is not curable, and treatment is palliative and at best temporary; eg, artificial tears or goggles to increase local moisturization, or punctal plugs to retain tears.

The condition of lack of tears refers to the inability to maintain the function of the lacrimal gland to secrete tears. Its etiology is based on the inability of the lacrimal gland to make tears based on factors such as lack of part of the lacrimal gland, blockage, systemic medications that disrupt lacrimal gland function, autoimmune diseases, and age-related changes in the lacrimal gland. Long-term wearers of contact lenses and patients who have undergone laser-assisted vision correction surgery (Laser-Assisted in Situ Keratomileusis, LASIK) will also suffer from lack of tears due to loss of corneal nerve sensation.

Since most tears and their components come from the lacrimal glands, decreased lacrimal gland secretions lead to a lack of tears and damage and inflammation of the corneal epithelium. In addition, the tears secreted by the lacrimal gland contain important enzymes, proteins, and antibacterial components, which are essential for protecting and repairing the damaged corneal epithelial cells due to red eyes. Therefore, it is a reasonable goal to increase lacrimal gland production as the primary treatment for dry eye.

Evaporative dry eye is usually caused by meibomian gland dysfunction and lipid insufficiency, which leads to more evaporation and reduced tear film stability. Evaporative dry eye can cause dry eye symptoms even when tear production is normal.

Inflammation of the eye surface is a consequence of lack of tear fluid and/or poor meibomian gland function. An immune inflammatory response plays a major role in corneal epithelial disease and ocular discomfort in dry eye. In view of this, dry eye is considered not only a simple lack of one or more tear film components; dry eye is also considered to be an ocular surface inflammatory syndrome, and most patients have various components that lead to dry eye. It is often not easy to pinpoint a specific factor as the cause of dry eye; rather, dry eye is caused by a range of problems or factors that lead to the signs and symptoms of dry eye.

Typical symptoms of dry eye include burning, itching, foreign object sensation, stinging, dryness, sensitivity to light, swelling, eye strain, and/or redness. In some cases, patients may report transient blurred vision. These symptoms are usually worse later in the day and are triggered or exacerbated by certain environmental conditions, such as low ambient humidity or wind.

There are several objective tests that can generally be used to diagnose dry eye symptoms. A diagnostic dye can be used to find and monitor changes in the surface of the eye. Tear break-up time (TBUT) can be used to assess tear stability and performance. Perform the Schirmer test to assess tear production. In general, dry eye testing has little to do with symptoms, but is a dominant practice in the field and clinicians continue to find useful results.

Current treatments for dry eye include over-the-counter lubricating eye drops (also known as artificial tears), which are used to treat the dryness and irritation associated with lack of tear production in dry eye. Mild dry eye conditions require lubricating eye drops four times a day, but severe cases require more frequent application (10 to 12 times a day). Similar treatment and administration methods are available for xerostomia, and patients are usually given artificial saliva compositions based on hydrophilic swelling polymers.

In addition, punctal embolization, procedures for treating meibomian gland insufficiency, nutritional supplements, and limited prescription eye drops may also be used. Therapeutics or drugs formulated as eye drops for the treatment of dry eye include the immunomodulator cyclosporine A (Restasis ^® ), the secretagogue bisquinofol sodium (Diquas ^® ), or rebamipide (Mucosta ® ). ^® ) and the lymphocyte function-associated antigen 1 (LFA‑1) inhibitor lifitegrast (Xiidra ^® ). However, not all of these drugs are universally approved worldwide due to suboptimal clinical outcomes. In addition, the effects of the above treatments are still not satisfactory, and there is still a great need to develop more effective products for the treatment of dry eye as well as dry mouth and Sjögren's syndrome.

Due to their anti-inflammatory and antioxidant properties, recent attempts have focused on various polyunsaturated fatty acids (PUFAs), including polyunsaturated omega‑3s (e.g., eicosapentaenoic acid (EPA), docosahexa Docosahexaenoic acid (DHA), alpha-linolenic acid (ALA) or gamma-linolenic acid (GLA), and polyunsaturated omega‑6 fatty acids (such as linolenic acid, LA) and arachidonic acid (Arachidonic acid, AA). It has been confirmed that oral administration of a large amount of PUFA can provide many benefits to the eyes. For example, it has been reported that long-chain PUFA plays an important role in the normal function of the retina of the human eye and the development of vision, while Some epidemiological studies on PUFA intake suggest that it has a protective effect on inhibiting the incidence of age-related macular degeneration (AMD). A report further pointed out that high doses of PUFA can slow down dry eye symptoms, and the relevant random A meta-analysis of controlled trials also confirmed its efficacy.

However, formulating PUFAs into aqueous compositions for direct application to the eye or other mucosal surfaces is often challenging due to their lipophilic and water-insoluble properties. In general, surfactants or co-solvents must be used to fully dissolve PUFAs and/or formulate PUFAs into emulsions. However, common preservatives for eye drops (such as benzalkonium chloride) are not compatible with the dosage forms of some emulsions. capacity, which can cause problems. Additionally, surfactants in emulsions can cause blurred vision and/or irritate the eyes. In addition, PUFA is prone to oxidation, so it needs to contain antioxidants to achieve a stable effect. For example, US Patent No. US8957110B2 filed by TRB Chemedica International SA discloses a hydrogel artificial tear type eye drop composition comprising long chain (C ₁₆ to C ₂₄ ) polyunsaturated omega-3 and omega-6 fatty acids , the PUFA can be applied directly to the eye. The composition comprises vitamin E acetate as an antioxidant and a gelling polymer such as cross-linked carboxyl polymer as a stabilizer.

In addition to the above drugs available as prescription eye drops, the US Food and Drug Administration (FDA) has also approved cevimeline in oral formulation for the systemic treatment of xerostomia in patients with Sjögren's syndrome. Cevimeline (CAS 107233‑08‑9 or CAS 153504‑70‑2 Cevimeline hydrochloride salt hemihydrate; (2R,2R)‑2'‑methyl spiro[4‑azabicyclo[2.2.2]octane ‑2,5'‑[1,3]oxathiolane]; or cis‑2′‑methylspiro[1‑aza bicyclo[2.2.2]octane‑3,5′‑[1,3]oxathiolane] hydrate hydrochloride) is a Cholinergic agonists, which can bind to muscarinic receptors, especially _M1 and _M3 receptors, are therefore also known as muscarinic receptor agonists (MRA). Cevimeline increases the secretion of exocrine glands such as salivary and sweat glands. It has been further proved that cevimeline can increase tear production by stimulating the lacrimal gland. Therefore, although oral cevimeline compositions are not yet approved for the above purposes, the advantages of oral cevimeline compositions for the treatment of dry eye have been studied. However, although oral cevimeline has demonstrated a significant improvement in the treatment of dry eye syndrome, due to systemic side effects of oral administration, such as occurrence of sweating, nausea, runny nose, flushing, frequent urination, dizziness, Weakness, diarrhea, and blurred vision, the treatment is still not widely accepted.

Furthermore, there are currently no topical (ie, applied to the skin and/or mucosal surfaces) ophthalmic or nasal formulations of cevimeline for the treatment of dry eye, xerostomia, and/or Sjögren's syndrome.

US20070053964A1 (US'964) or WO2020072971A1 (WO'971) suggest various ophthalmic dosage forms containing cevimeline. US'964 discloses various dosage forms, such as viscose or ointment, which can be applied to the external skin surface of the eyelid, and to deliver cevimeline from the eyelid skin into the external tissue of the eye in a transdermal manner. In addition, US'964 discloses a 20% concentration of cevimeline ophthalmic aqueous solution dosage form, which can be directly applied to the eyes (that is, applied to the surface of the eyeball and/or into the inner eyelid), but only as a comparison with a 20% cevimeline An example of a Merrill ointment formulation. With regard to tear production, these eye drops have been found to underperform ointments that can be applied to the eyelids; therefore, compared to transdermal formulations, US'964 It is not recommended to apply cevimeline solution directly to the eye. In addition, due to the high concentration of drugs and transdermal absorption accelerators that require sufficient transdermal drug delivery will cause significant eye irritation (due to high permeability), especially the long-term use of dry eye treatment, so US'964 The "external" transdermal dosage forms described are not suitable for direct application to the ocular surface.

WO'971 describes various topical ophthalmic compositions for the treatment of dry eye in the form of eye drops comprising a muscarinic receptor agonist (MRA) (e.g. Cevimeline) and one or more pharmaceutically acceptable excipients. WO'971 also proposes to add these PUFAs as a component different from MRA and/or a part containing the ion pair of the MRA and the PUFA, such as EPA, DHA, ALA, GLA, or a combination of the above substances A variety of long-chain polyunsaturated fatty acids (PUFA) can be added to the MRA composition.

However, even though WO'971 proposes an ophthalmic composition with a neutral pH value and a well-tolerated drug concentration, there are still ongoing efforts to develop pharmaceutically stable, comfortable, safe, non-irritating, effective preparations, and There is a medical need for muscarinic receptor agonists (such as cevimeline) that can be directly applied externally to the ocular and/or nasal mucosal surfaces for the treatment of dry eye, xerostomia, and/or Sjögren's syndrome. In the case of dry eye, treatment goals include relieving dry eye signs and/or symptoms, improving patient comfort, restoring the ocular surface and tear film to a healthy state, and preventing corneal damage if possible. In addition, these formulations are preferably easier to formulate than prior art compositions, eg, do not require antioxidants, surfactants, or co-solvents to dissolve and/or stabilize the aforementioned PUFAs.

It is therefore an object of the present invention to provide a stable aqueous solution composition which can be instilled into the eye, i.e. can be instilled onto the surface of the eye (e.g. eye drops) or applied externally to the nasal cavity, and which can be used for the treatment of various diseases, Examples include dry eye, dry mouth, and/or Sjögren's syndrome. In particular, the object of the present invention is to provide a composition comprising cevimeline and a medium-chain polyunsaturated fatty acid (PUFA) to enhance tear production and at the same time reduce oxidative stress. Yet another object of the present invention is to provide methods of externally administering compositions comprising cevimeline and a medium-chain polyunsaturated fatty acid (PUFA) for treating dry eye, dry mouth, and/or Sjögren's syndrome.

The following summary of the invention, examples, and patent claims can clearly illustrate the further purpose of the invention.

In the first part, the present invention relates to an aqueous solution composition comprising: cevimeline or a pharmaceutically acceptable salt of cevimeline at a concentration between 1 mg/mL and 50 mg/mL, Sorbic acid or a pharmaceutically acceptable salt of sorbate, and an aqueous carrier, wherein the composition has a pH in the range of pH 6.0 to pH 8.0, and wherein the composition comprises a concentration of 3 mg/mL to 10 mg/mL of sorbic acid.

In a second aspect, the invention relates to a method of treating one or more of dry eye, xerostomia or Sjögren's syndrome, the method comprising the step of topically administering the composition according to the first aspect of the invention to a patient suffering from Subjects with dry eye, dry mouth, and/or Sjögren's syndrome.

In the third part, the present invention relates to an ophthalmic composition comprising cevimeline at a concentration of 2 mg/mL to 50 mg/mL or a pharmaceutically acceptable cevimeline Salt, potassium sorbate at a concentration of 4.7 mg/mL, sodium phosphate buffer, sodium chloride and water.

Still further, the invention relates to a method of treating one or more of dry eye, xerostomia or Sjögren's syndrome comprising the step of administering an aqueous composition comprising cevimeline to a patient suffering from dry eye nasal mucosa of subjects with syndrome, xerostomia, and/or Sjögren's syndrome.

In the first part, the present invention relates to an aqueous solution composition comprising: cevimeline or a pharmaceutically acceptable salt of cevimeline at a concentration between 1 mg/mL and 50 mg/mL, Sorbic acid or a pharmaceutically acceptable salt of sorbate, and an aqueous carrier, wherein the composition has a pH in the range of pH 6.0 to pH 8.0, and wherein the composition comprises a concentration of 3 mg/mL to 10 mg/mL of sorbic acid or a pharmaceutically acceptable salt of sorbate.

"Compound X or a pharmaceutically acceptable salt of Compound X" as used herein includes the compound X and the pharmaceutically acceptable salt of the compound X, and both the anhydrous form and the hydrate of the compound X. For example, cevimeline can be used as the free base form, as cevimeline hydrochloride (cevimeline hydrochloride), and as a hydrated form, such as cevimeline salt salt hemihydrate (cevimeline hydrochloride x 0.5 H ₂ O). Mixtures of these substances may be selected for use; for example, cevimeline may be present in a free base form, a salt form, or a combination of a free base form and a salt form. Thus, unless otherwise stated, the term "cevimeline" may mean the free base form, the salt form, or a combination of the free base form and the salt form.

Furthermore, as used herein, the phrase "compound X or a pharmaceutically acceptable salt of compound X" accompanied by a concentration value is understood to mean that the concentration refers to compound X; this means that a heavier salt of compound X and/or or hydrate form, a higher amount of the salt should be used to achieve a specific concentration X.

Words such as "approximately", "approximately", or "approximately" indicate that variations permissible in relation to individual products and established technical fields (e.g., pharmaceutical industry) are compensated, for example due to manufacturing variations, measurement variations, and/or Differences in content due to product degradation over time. These terms in relation to a property or value include the exact property or value, as well as any property or value that is generally considered to be within a normal range or within variations accepted in the relevant art. Variations of ±10% are common in the pharmaceutical industry.

As used herein, the term "pharmaceutically acceptable" means any compound, material, composition, and/or dosage form that, within the scope of sound medical judgment, is suitable for use in contact with the human body and, optionally, with the tissues of other animals, without undue toxicity, Irritation, allergic reaction, or other problems or complications, and can cooperate with a reasonable benefit-risk ratio.

Sorbic acid is a hexadienoic acid with double bonds at C ₂ and C ₄ and four geometric isomers. It can be seen in trans form in nature. Sorbic acid is also a medium-chain fatty acid (ie, C ₆ to C ₁₂ or C ₆ to C ₁₀ ), more specifically a medium-chain polyunsaturated fatty acid (PUFA).

The aqueous composition according to the first aspect of the present invention is characterized by comprising sorbic acid or a pharmaceutically acceptable salt of sorbic acid at a concentration ranging from 3 mg/mL to 10 mg/mL. Sorbic acid and sorbates (eg, potassium sorbate) are known antimicrobial preservatives having antibacterial and antifungal properties, especially in the manufacture of pharmaceuticals. According to the literature, sorbic acid and sorbate are usually used in oral or topical dosage forms at a concentration of 0.1-0.2% (that is, the concentration in various aqueous compositions is approximately 1-2 mg/mL).

However, sorbic acid and sorbate salts (such as potassium sorbate) are known to exhibit only minimal antimicrobial activity at pH values above pH 6 in the respective dosage forms. In addition, the concentration used in the aqueous composition according to the first aspect of the present invention will be higher than the concentration of sorbic acid or sorbate salts suggested by individual literatures for use in topical compositions as antibacterial preservatives. This is based on the fact that, according to the present invention, in view of the function of sorbic acid or sorbate as an antimicrobial preservative, but because the characteristic of sorbic acid or sorbate is a polyunsaturated fatty acid (PUFA), especially A water-soluble medium-chain polyunsaturated fatty acid, so sorbic acid or sorbate will not be used, or at least not mainly or necessarily used.

One of the main advantages is that since the PUFA sorbic acid is water soluble, it can be dissolved in an aqueous composition without the need for surfactants and/or co-solvents. In addition, PUFA sorbic acid and long-chain PUFAs such as the above-mentioned eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha linolenic acid (ALA), gamma linolenic acid (GLA), linolenic acid (LA) or arachidonic acid (AA), the PUFA sorbic acid is less susceptible to oxidative degradation. Therefore, the aqueous composition does not necessarily need to have an antioxidant. Therefore, in one embodiment, the composition Free or substantially free of various added antioxidants. The term "antioxidant" as used herein means an agent capable of resisting oxidation and thus can be used to prevent the composition or components of the composition from being destroyed by oxidation processes. Deterioration. As used herein, the words "free of X" or "substantially free of X" mean that the individual material (such as a compound or a composition) contains less than the functional content of the ingredient "X", usually less than 2 wt.-% or less than 1 wt.-%, preferably less than 0.1 wt.-% or even less than 0.01 wt.-%, also including 0 wt.-% of the ingredient "X".

In one embodiment, the composition according to the first aspect of the invention does not contain an antimicrobial preservative; more specifically, while sorbic acid or sorbate still acts as an antimicrobial preservative Salts have lower antibacterial activity at pH values higher than 6.0 (eg 6.0 to 8.0), but the composition according to the first aspect of the invention still does not include an antibacterial preservative. Typical preservatives include, but are not limited to, benzalkonium chloride (BAK), benzethonium chloride, paraoxybenzone (e.g. methyl p-oxybenzoate or ethyl p-oxybenzoate), benzyl alcohol, phenylethyl alcohol, citric acid or citrate , thimerosal, chlorobutanol, quaternary amines, chlorhexidine gluconate, stabilized oxychloride complexes, or combinations of the above substances. If the preservative is included, the amount or concentration of the preservative must pass the USP and/or European Pharmacopoeia requirements for the antibacterial preservative effect test of eye drops. For example, BAK can be used in concentrations of 0.002‑0.02 % (w/v), typically 0.005-0.01 % (w/v).

In one embodiment, the composition is provided in the form of a clear solution. As used herein, the term "clear" means a liquid or solution that is transparent or see-through, and does not contain any liquid droplets or other suspended particles that can be discerned by the naked human eye; such clear liquid or solution is not milky white like most common emulsions Or "milk" white. The clear solution can also optionally be colorless.

In another embodiment, the composition contains water as the sole solvent, in other words, water is the carrier or the main component of the aqueous solution. In yet another embodiment, the composition is free of co-solvents. When sorbic acid is selected as the PUFA, it contains no other co-solvents or solvents other than preferably an aqueous solution in order to be able to dissolve the PUFA.

In one embodiment, the composition comprises cevimeline or a pharmaceutically acceptable salt of cevimeline at a concentration of 2 mg/mL to 50 mg/mL. In specific embodiments, the composition comprises a concentration between 2 mg/mL to 40 mg/mL (or a concentration between 2 mg/mL to 20 mg/mL, a concentration between 2 mg/mL to 10 mg/mL mL, cevimeline at a concentration between 2 mg/mL and 6 mg/mL) or a pharmaceutically acceptable salt of cevimeline.

In one embodiment, the composition comprises sorbic acid or a pharmaceutically acceptable salt of sorbic acid at a concentration of 3 mg/mL to 8 mg/mL (or at a concentration of 3 mg/mL to 6 mg/mL) . In a preferred embodiment, the composition comprises sorbic acid or a pharmaceutically acceptable salt of sorbic acid at a concentration of 3.7 mg/mL to 5.7 mg/mL or 4.2 mg/mL to 5.2 mg/mL , for example at a concentration of 4.7 mg/mL.

Optionally, the cevimeline and sorbic acid can be provided as an ion pair.

Optionally the composition further comprises a complexing agent. In a particular embodiment, the complexing agent comprises or consists of a cyclodextrin; in other words, the composition further comprises a cyclodextrin. Examples of cyclodextrins include, but are not limited to, alpha, beta, and gamma cyclodextrin derivatives or combinations of these derivatives. The composition typically comprises cyclodextrin at a concentration of less than 100 mg/mL, less than 50 mg/mL, less than 20 mg/mL, or less than 10 mg/mL. In a particular embodiment, the cyclodextrin is hydroxypropyl-β-cyclodextrin (HP-ß-CD), eg commercially available under the trademark Kleptose ^® . In yet another specific embodiment, the cyclodextrin is present in an amount or concentration ranging from 2 mg/mL to 100 mg/mL, from 2 mg/mL to 50 mg/mL, or from 2 mg/mL to 40 mg/mL. Nevertheless, it should be understood that the compositions according to the first aspect of the invention do not necessarily require a complexing agent (eg various cyclodextrins). Accordingly, some embodiments of the invention are free or substantially free of a complexing agent, more specifically, free or substantially free of a cyclodextrin; in other words, some embodiments of the present invention do not include a complexing agent, More specifically, some embodiments of the invention do not include cyclodextrins.

In one embodiment, the composition further comprises a thickener, typically comprising a hydrophilic polymer, which may be added to the aqueous composition of the present invention to increase its viscosity to (i) control the ratio such that the composition (eg, eye drops) can flow out of the container at this rate (thus enhancing ease of application), and (ii) prolong the residence time of the composition in the precorneal environment.

Examples of thickeners include, but are not limited to, hyaluronic acid, polyvinyl alcohol (PVA), polyvinylpyrrolidone (or povidone), carboxyvinyl polymers, methylcellulose (MC), hydroxymethylcellulose (CMC ; or carboxymethyl ether cellulose), hydroxypropyl methylcellulose (HPMC; or hypromellose), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyacrylic acid, or polyacrylic acid Salt, xanthan gum, guar gum, chondroitin sulfate, polyethylene glycol, propylene glycol, or combinations thereof.

In a specific embodiment, the composition further comprises a thickener, the thickener is selected from hyaluronic acid, polyvinylpyrrolidone, hypromellose, carboxymethyl ether cellulose, or a combination of the above substances.

In one embodiment, the composition further comprises one or more excipients selected from various tonicity regulators, buffers, and pH regulators.

Examples of various tonicity regulators include, but are not limited to, mannitol, sorbitol, potassium chloride, sodium chloride, glycerin, trehalose, or combinations thereof, and the like. The amount of tonicity adjusting agent selected in the composition is such that the tonicity of the composition falls within a certain isotonic range, eg equal to that of tear fluid. In one of the preferred embodiments, the tonicity regulator is sodium chloride.

Various typical buffers include, but are not limited to, phosphates, borates, citrates, acetates, carbonates, bicarbonates, boric acid polyol complexes, boric acid, sodium acetate, amino acids, tris, carbonic acid Hydrogen salts, BIS-Tris or BIS-Tris salts, combinations of the above substances, etc. In one preferred embodiment, the buffer is a sodium phosphate buffer, such as a buffer of sodium phosphate monohydrate or sodium phosphate monohydrate and sodium phosphate dibasic heptahydrate. In a specific embodiment, the phosphate buffer uses sodium phosphate monobasic monohydrate at a concentration of 0.54 mg/mL (or sodium phosphate monobasic dihydrate at a concentration of 0.61 mg/mL) and sodium phosphate dihydrate at a concentration of 1.63 mg/mL Yuan heptahydrate.

Examples of various alkaline agents that can be used as pH adjusters include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), tromethamine, ethanolamine, sodium bicarbonate (NaHCO ₃ ), and other organic and inorganic bases. Examples of various acid agents that can be used as pH adjusters include, but are not limited to, hydrochloric acid (HCl), citric acid, tartaric acid, lactic acid, acetic acid, and other organic and inorganic acids, etc., and mixtures thereof. In one preferred embodiment, the pH adjusting agent is selected from hydrochloric acid (HCl) or sodium hydroxide (NaOH). It can be understood that these pH value adjusting agents are used to adjust the pH value of the composition according to needs (appropriate amount), so as to achieve a certain pH value in the pH range between 6.0 and 8.0 (or between 6.0 and 7.5), for example About pH7.4 (the pH of tears).

In one embodiment 1, the composition comprises potassium sorbate (K-sorbate) at a concentration between 3 mg/mL and 10 mg/mL. In one of the preferred embodiments, the composition comprises potassium sorbate at a concentration of 3-8 mg/mL or 3-6 mg/mL, more specifically 3.7-5.7 mg/mL or 4.2-5.2 mg/mL Potassium sorbate, eg 4.7 mg/mL.

In yet another embodiment, the composition has a pH of about 6.0-7.4. In yet another specific embodiment, the composition comprises potassium sorbate at a concentration of 3 mg/mL to 10 mg/mL, and has a pH of about 6.0-7.4.

In one embodiment, the composition is provided in the form of a clear solution that can be instilled into the eye, ie, the liquid can be applied directly to the surface of the eyeball and/or the inside of the eyelid, eg, into the lacrimal sac. In this regard, it is understood that the composition according to the first aspect of the invention may be applied externally directly to any surface of the eye and/or orbit (e.g. sclera, cornea, conjunctiva, conjunctival sac, etc.) and/or sorbic acid applied to the outer surface of the eyelid and transdermally.

For instillation into the eye, the composition may contain a dynamic viscosity ranging from 1 cP to 60 cP, 1 cP to 50 cP, or 1 cP to 20 cP, for example a dynamic viscosity of less than 5 cP Spend. The term "dynamic viscosity" used herein means the dynamic viscosity determined or measured by a Brookfield rotary viscometer at room temperature (20 ± 5°C), which can measure The force at which the rotational axis of a sample under test is turned at the rotational rate. The test sample is stored at room temperature for about two hours before being tested, and then placed in the measuring chamber with a pipette. An appropriate rotation rate for the spindle is then selected based on the desired viscosity of the test solution. In addition, it is desirable to determine whether the composition is isobaric or substantially isobaric with tear fluid. In one embodiment, the composition has an osmolarity ranging from about 200 to 600 mOsm/kg, or from about 250 to 450 mOsm/kg, or from about 250 to 400 mOsm/kg. In some preferred embodiments, the liquid composition has an osmolality in the range of about 270 to 350 mOsm/kg or in the range of about 280 to 300 mOsm/kg.

Also, preferably, the composition according to the first aspect of the invention is sterile, especially when it is intended for instillation into the eye (though not exclusively). In one embodiment, the composition must be sterile filtered, for example by passing the composition through a 0.22 µm filter.

In yet another specific embodiment, the composition is an ophthalmic composition in the form of eye drops. Since the ophthalmic composition is to be applied to the skin and/or mucous membrane surface of the eye, an ophthalmic composition (such as eye drops) sometimes also means an external composition or an external ophthalmic composition. Assuming that the cevimeline concentration of the various eye drop compositions according to the first aspect of the present invention is between 1 and 50 mg/mL, usually a single drop is the effective amount of cevimeline. The term "effective amount" means the dose or amount of the active ingredient or drug (here referred to as cevimeline), which is sufficient to obtain the required or desired therapeutic response, in other words, the active ingredient or drug This dose is sufficient to obtain a significant biological response when administered to a patient.

In one embodiment, the compositions provided are not in the form of ointments, lotions, pastes, inserts, punctal plugs, and/or salves. In other words, the composition according to the first aspect of the present invention does not contain various components in the form of ointments, lotions, pastes, inserts, punctal plugs, and/or ointments.

In one embodiment, the composition may optionally comprise one or more active ingredients; for example, the active ingredients are selected from (a) steroids, such as loteprednol etabonate, prednisolone acetate , fluticasone, or a combination of the above, (b) an immunomodulator or immunosuppressant, such as cyclosporine, tacrolimus, sirlolimus, or a combination of the above, (c) hormones, such as testosterone, estrogen, or combinations thereof, (d) secretagogues, such as rebamipide, diquafosol, or combinations thereof, (e ) a lymphocyte function-associated antigen-1 (LFA-1) antagonist, such as lifitegrast, and/or (f) an active ingredient effective in the treatment of meibomian gland dysfunction.

In another embodiment, in addition to (i) cevimeline or a pharmaceutically acceptable salt of cevimeline and/or (ii) sorbic acid or a pharmaceutically acceptable salt of sorbic acid as a PUFA, The composition is free or substantially free of surfactants and/or co-solvents. In particular, the composition is free or substantially free of insulin, insulin-like growth factor (IGF), somatomodulin C, and cycloplegic agents.

In a second aspect, the invention relates to a method of treating one or more of dry eye, xerostomia or Sjögren's syndrome, the method comprising the step of topically administering the composition according to the first aspect of the invention to a patient suffering from Subjects with dry eye, dry mouth, and/or Sjögren's syndrome. In other words, in the second aspect, the invention relates to the use of the composition according to the first aspect of the invention for the treatment of one or more of dry eye, xerostomia or Sjögren's syndrome. In other words, in the second aspect, the invention relates to the use of the composition according to the first aspect of the invention in the manufacture of a medicament for the treatment of one or more of dry eye, xerostomia, or Sjögren's syndrome. Accordingly, any embodiment, or specific or preferred embodiment, disclosed herein in relation to the composition according to the first aspect of the invention may be used in the method or use according to the second aspect of the invention.

In one embodiment, the composition is administered to the subject's eye, typically by instillation (ie, directly onto the surface of the eyeball and/or inside the eyelid, eg, into the lacrimal sac of the eye). In another embodiment, or in addition to administration to the eyes of the subject, the composition may also be administered to the nasal mucosa of the subject, for example, as an aqueous nasal spray to the nasal cavity.

In one embodiment, the composition may be administered once, twice, three times, or four times per day. As such, the composition facilitates various artificial tear or saliva compositions that must be applied ten to twelve times a day.

In one embodiment, the composition may be administered over a treatment period of at least seven days.

The composition has the advantage that after application (especially to the eye) it does not cause miosis.

In the third part, the present invention relates to an ophthalmic composition comprising cevimeline or a pharmaceutically acceptable salt of cevimeline at a concentration between 2 mg/mL and 50 mg/mL , potassium sorbate at a concentration of 4.7 mg/mL, sodium phosphate buffer, sodium chloride, and water. For example, in one of the preferred embodiments, the present invention relates to an ophthalmic composition comprising cevimeline at a concentration of 2 mg/mL to 40 mg/mL or a pharmaceutically acceptable Cevimeline salt, potassium sorbate at a concentration of 4.7 mg/mL, sodium phosphate buffer, sodium chloride, and water.

In a further aspect, the invention relates to a method of treating one or more of dry eye, xerostomia or Sjögren's syndrome comprising the step of administering to a patient suffering from Nasal mucosa of subjects with dry eye, xerostomia, and/or Sjögren's syndrome.

The above is a detailed description of specific embodiments of the present invention. While specific embodiments of the invention have been described herein for purposes of illustration, it should be understood that various modifications could be made without departing from the spirit and scope of the invention. Therefore, the present invention is not limited only by the scope of the appended patent application. All of the embodiments disclosed and claimed herein can be implemented without undue experimentation as a result of the teachings of the present invention.

The following examples serve to illustrate the invention; however, these examples should not be construed as limiting the scope of the invention. All examples employed pharmaceutical grade ingredients to prepare the compositions described below.

example

Example 1 - Stability of Cevimeline/Potassium Sorbate Compositions (Panel I)

Mix these ingredients according to the following Table 1 to prepare cevimeline (here is the salt form of cevimeline hydrochloride x 0.5 H ₂ O) and medium chain polyunsaturated fatty acid sorbic acid (SA; here is sorbate form), which were filtered (0.22 µm) and filled into high-density polyethylene (HDPE) eye drop bottles, followed by evaluation of their stability. These compositions are suitable for instillation into the eye, for example in the form of eye drops.

Except for EY4‑11, which was included as a control without potassium sorbate, all other compositions contained 2 mg/mL of cevimeline, (free base equivalent) 4.7 mg/mL of potassium sorbate, and Sodium chloride as a tonicity agent to evaluate the effect of potassium sorbate on the stability of cevimeline. The formulation variables evaluated were buffer type and pH (sodium phosphate/citrate buffer at pH 7.0 and 8.0; citrate buffer at pH 6.0; borate buffer at pH 8.0), and Effect of the presence of disodium ethylenediaminetetraacetic acid (Na ₂ -EDTA), an antioxidant chelating agent.

After completion of the preparation, all the compositions were various solutions that were clear, colorless, without any oil film or oil droplets under human naked eye observation.

Stability studies were performed at 25 °C / 40 % RH (aka "instant" stability) and 40 °C / 25 % RH (accelerated stability). Stability test parameters monitored include percent drug content (measured by HPLC), impurity (degradation) content, pH, osmolarity, and physical appearance.

Table 1 : Typical cevimeline/potassium sorbate aqueous solution composition (Panel I)

Element [mg/mL] EY4-1 EY4-3 EY4-7 EY4-8 EY4-9 EY4-11 none EDTA EDTA pH6 ( Citrate ) pH8 pH8 ( borate ) control group Cevimeline 2.0 Potassium sorbate 4.7 --- Citric Acid Monohydrate 0.30 0.30 0.50 0.14 --- 0.30 Sodium Phosphate Dibasic Heptahydrate 3.0 3.0 --- 2.68 --- 3.0 Sodium citrate dihydrate --- --- 4.5 --- --- --- boric acid --- --- --- --- 6.0 --- Sodium borate decahydrate --- --- --- --- 0.45 --- Na ₂ -EDTA --- 0.50 --- NaCl Appropriate amount to achieve a tonicity of 280‑300 mOsm/kg (i.e. isotonicity) pure water Appropriate amount HCl or NaOH (Appropriate amount to achieve pH) 7.0 7.0 6.0 8.0 8.0 7.0

As described in Table 2 below, EY4‑1 (with sorbate) and EY4‑11 (without sorbate) were the most stable, shown in various aqueous solutions containing potassium sorbate (as a PUFA) (at high concentration It is feasible to formulate cevimeline at 1‑2 mg/mL). Along with higher drug loss, the EDTA-containing dosage forms such as EY4-3, ‑7, ‑8, and ‑9 showed discoloration when stored at 40 °C.

Of all the buffer classes studied, the formulation containing phosphate buffer (EY4-1) was the most stable and showed satisfactory results in terms of solution appearance, drug content, and impurity (degradation) content.

Table 2 : Summary of Stability Data for Various Cevimeline Compositions Containing Potassium Sorbate (Panel I) nc: Not Continued; * = Yellowing; LS = Labeled Concentration

Panel I Stability data EY4-1 EY4-3 EY4-7 EY4-8 EY4-9 EY4-11 0 month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] 94.4 0.15 6.97 282 96.2 0.15 6.96 291 96.6 0.15 5.96 283 95.4 0.15 7.99 290 97.2 0.15 7.97 281 96.9 0.15 6.99 280 25°C / 40% RH 3 -month content percentage LS pH Osmolality [mOsm/kg] 92.4 7.13 277 93.2 7.14 280 89.1 6.15 266 92.3 7.89 281 92.1 8.16 280 95.2 7.19 267 6 -month content percentage LS pH Osmolality [mOsm/kg] 94.5 7.10 275 n.c. n.c. n.c. n.c. 97.4 7.13 273 40 ° C / 25% RH l monthly content percentage LS pH osmolarity [mOsm/kg] 93.6 6.94 275 94.1 6.98 273 92.8* 6.03 261 90.3 7.64 277 87.4 8.01 277 95.9 7.01 262 3 -month content percentage LS pH Osmolality [mOsm/kg] 92.5 7.13 284 90.1* 7.19 283 86.7* 6.26 269 84.2* 7.70 286 76.0 8.09 285 95.5 7.10 271 6 -month content percentage LS pH Osmolality [mOsm/kg] 96.2 7.12 290 n.c. n.c. n.c. n.c. 98.7 7.09 275

Example 2 - Stability of Cevimeline/Potassium Sorbate Compositions (Panel II)

Based on the stability findings from the Panel I study, we prepared a second set of dosage forms using phosphate as a buffer system and sodium chloride as a tonicity agent. Mixing the ingredients according to the following Table 3 can prepare different concentrations of cevimeline (here, cevimeline hydrochloride x 0.5 H ₂ O salt form) and medium-chain polyunsaturated fatty acid sorbic acid (SA; Here, in the form of potassium sorbate), several aqueous compositions were filtered (0.22 µm), filled into low-density polyethylene (LDPE) eye drop bottles and further sealed in aluminum bag, then assess its stability. These compositions may be adapted for instillation into the eye, for example in the form of eye drops.

The dosage form variables evaluated were cevimeline concentrations ranging from 2 mg/mL to 40 mg/mL (free base equivalent), pH values ranging from pH 6.0 to 8.0, and potassium sorbate concentrations ranging from 4.7 mg /mL to 15 mg/mL, with or without benzalkonium chloride (BAK) as a preservative.

Stability studies were performed at 25 °C / 40 % RH and 40 °C / 25 % RH with 60 °C. Stability test parameters monitored include percent drug content (measured by HPLC), impurity (degradation) content, pH, osmolarity, and physical appearance.

Table 3 : Typical cevimeline/potassium sorbate aqueous solution composition (Panel II) Composition [mg/mL] EY4-20 EY4-21 EY4-22 EY4-23 EY4-24 EY4-25 EY4-26 EY4-27 EY4-28 EY4-29 EY4-30 Cevimeline --- 2.0 40 10 --- 2.0 2.0 2.0 2.0 2.0 2.0 Potassium sorbate 4.7 4.7 4.7 15 --- --- 4.7 --- --- 4.7 4.7 Sodium Phosphate Monohydrate 0.54 Sodium Phosphate Dibasic Heptahydrate 1.63 BAK --- --- --- --- --- --- 0.05 --- --- --- --- NaCl Appropriate amount to achieve a tonicity of 280‑300 mOsm/kg (ie isotonicity) pure water Appropriate amount HCl or NaOH (appropriate to achieve pH) 7.0 6.0 8.0 7.4 8.0

Table 4 : Summary of Stability Data for Various Cevimeline Compositions Containing Potassium Sorbate (Panel II) n/a: not analyzed; * = yellowing Panel II stability data EY4-20 EY4-21 EY4-22 EY4-23 EY4-24 EY4-25 EY4-26 EY4-27 EY4-28 EY4-29 EY4-30 0 month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] n/a n/a 7.03 281 99.6 0.17 6.99 285 100.9 0.17 7.01 493 99.5 0.12 7.00 305 n/a n/a 7.01 283 99.2 0.16 7.00 283 100.4 0.16 6.99 286 100.6 0.16 6.03 283 98.8 0.20 8.01 282 99.4 0.17 7.41 283 99.2 0.16 7.99 287 25°C / 40% RH 3 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] n/a n/a 6.83 296 97.6 0.57 6.82 286 102.2 0.22 6.93 451 100.1 0.43 6.96 310 n/a n/a 6.72 281 97.9 0.46 6.74 285 97.8 0.67 6.83 291 99.4 0.38 6.15 294 94.7 0.73 7.57 279 96.6 0.62 7.18 286 94.8 0.77 7.59 290 6 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] n/a n/a 6.85 296 96.4 1.19 6.84 294 101.4 0.35 6.79 447 98.0 0.67 6.97 310 n/a n/a 6.74 293 97.2 0.54 6.74 286 97.3 1.24 6.83 291 98.8 0.45 6.16 294 92.9 0.93 7.54 281 95.0 1.26 7.20 286 93.0 1.42 7.56 287 40 ° C / 25% RH l monthly content percentage LS total impurity percentage pH osmolarity [mOsm/kg] n/a n/a 6.95 291 93.9 1.06 6.85 285 98.6 0.27 6.75 447 95.4 0.85 6.95 313 n/a n/a 6.75 281 94.2 0.85 6.72 284 94.6 1.20 6.81 286 98.4 0.51 6.14 294 87.5 1.21 7.41 281 89.2 1.31 7.10 286 87.7 1.54 7.47 289 3 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] n/a n/a 6.81 291 92.8 1.60 6.76 287 101.6 0.44 6.57 450 96.3 1.23 6.83 312 n/a n/a 6.69 283 94.9 1.07 6.66 285 94.3 1.55 6.75 289 98.3 0.74 6.06 296 86.5 1.44 7.31 281 90.1 2.01 7.03 289 84.8 2.31 7.32 291 Panel II stability data EY4-20 EY4-21 EY4-22 EY4-23 EY4-24 EY4-25 EY4-26 EY4-27 EY4-28 EY4-29 EY4-30 6 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] n/a n/a 6.84 298 91.1 2.41 6.77 287 99.8 0.58 6.39 448 91.1* 4.58 6.88 310 n/a n/a 6.70 287 91.3 1.51 6.62 285 90.5 2.64 6.73 294 96.7 1.04 6.07 296 79.3 2.33 7.20 282 86.4 2.80 7.01 286 79.4 3.17 7.25 290 60 ° C l monthly content percentage LS total impurity percentage pH osmolarity [mOsm/kg] n/a n/a 6.80 292 89.3 2.91 6.73 287 96.8 0.46 6.13 447 89.4 4.52 6.66 308 n/a n/a 6.63 283 83.3 2.22 6.64 285 82.3 3.22 6.68 287 94.2 1.50 6.05 296 66.8 3.66 7.01 280 75.8 3.83 6.88 287 65.7 4.62 7.08 290 3 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] n/a n/a 6.73 296 89.7 5.97 6.66 290 98.7 1.05 5.95 449 74.1* 34.91 6.84 299 n/a n/a 6.63 289 79.3 4.43 6.26 289 75.3 5.30 6.50 289 95.4 2.39 5.91 298 60.0 5.57 6.77 283 72.6 6.47 6.79 289 60.3 7.37 6.91 292 6 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] n/a n/a 6.77 299 89.4 9.65 6.66 298 95.4 1.40 5.82 454 53.0* 52.60 6.81 288 n/a n/a 6.73 285 75.4 7.40 6.00 291 62.8 10.32 6.53 291 94.8 3.71 5.87 302 51.3 8.93 6.64 283 61.1 11.16 6.76 292 50.4 12.56 6.85 294

As shown in Table 4 above, we found that stability was dependent on drug concentration, pH, and potassium sorbate concentration. We found that cevimeline was more stable at higher drug concentrations (e.g. EY4‑21 versus EY4‑22). On the other hand, we found that compositions containing higher concentrations of potassium sorbate were relatively less stable in terms of degradation of cevimeline (e.g. EY4‑21 versus EY4‑23). For the composition containing potassium sorbate (EY-4-23) at a concentration of 15 mg/mL, only slight discoloration was observed despite storage at 40°C for six months.

In studies with pH values between pH 6.0 and pH 8.0, cevimeline was relatively more stable at lower pH values (e.g. EY4‑21, ‑29 and ‑30). For formulations without potassium sorbate (EY4‑25, ‑27 and ‑28), we observed a similar pH effect. Finally, the preservative benzalkonium chloride (BAK) had no significant effect on the stability of cevimeline in this study (e.g. EY4‑21 versus EY4‑26).

The inventors further found that the total amount of degraded impurities was not related to the percentage loss of content in some compositions, which suggested that the inhalation of cevimeline into the LDPE container might occur.

Example 3 - Stability of Cevimeline/Potassium Sorbate Compositions (Panel III)

We prepared a third group of dosage forms using phosphate as a buffer system and sodium chloride as a tonicity agent. Mixing these ingredients according to the following Table 5 can prepare cevimeline containing different concentrations (here is cevimeline hydrochloride x 0.5 H ₂ O salt form) and medium chain polyunsaturated fatty acid sorbic acid (SA; Here are several aqueous solutions in the form of potassium sorbate). These compositions suitable for instillation in the eye are filtered (0.22 µm) and then filled with high-density polyethylene (HDPE; EY4‑31 to ‑37) or polyethylene terephthalate (PET; EY4 ‑38 and ‑39) to mitigate possible absorption of the drug into these eye drop bottles; both containers are further sealed in aluminum pouches. The stability of these compositions will then be assessed.

The formulation variables evaluated were cevimeline concentration (range 2.0 mg/mL to 6.0 mg/mL; free base equivalent) and pH (pH range 6.0 to 7.4). The formulation group also includes formulations containing polyoxyethylene 40 hydrogenated castor oil (here Kolliphor ^® RH40) and hydroxypropyl‑ß-cyclodextrin (HP‑ß‑CD; here Kleptose ^® ) to evaluate The effect of both as potential stabilizers.

Stability studies were performed at 25 °C / 40 % RH and 40 °C / 25 % RH with 60 °C. Stability test parameters monitored include percent drug content (measured by HPLC), impurity (degradation) content, pH, osmolarity, and physical appearance.

Table 5 : Typical Cevimeline/Potassium Sorbate Aqueous Composition (Panel III) * The amount is equivalent to 0.54 mg/mL of sodium phosphate monohydrate Composition [mg/mL] EY4-31 EY4-32 EY4-33 EY4-34 EY4-35 EY4-36 EY4-37 EY4-38 EY4-39 Cevimeline 6.0 --- --- 2.0 6.0 Potassium sorbate 4.7 --- 4.7 Sodium Phosphate Monobasic Dihydrate 0.61* Sodium Phosphate Dibasic Heptahydrate 1.63 Polyoxyl 40 hydrogenated castor oil --- --- 5.0 --- --- --- 5.0 --- --- HP-ß-cyclodextrin --- --- --- 40 --- --- --- --- --- NaCl Appropriate amount to achieve a tonicity of 280‑300 mOsm/kg (ie isotonicity) pure water Appropriate amount HCl or NaOH (appropriate to achieve pH) 6.0 7.0 7.4 7.0

As shown in Table 6 below, the drug content in pouched HDPE bottles remained constant or decreased only slightly depending on pH, whereas samples stored in PET bottles showed an increase in drug content. These increases corresponded to a weight loss of PET bottles: 3% after 3 months at 25 °C / 40 % RH, 12 % after 3 months at 40 °C / 25 % RH, and 37 % after 3 months at 60 °C, which implies a significant moisture loss in (from) the PET bottle. We did not observe any discoloration of these compositions. Neither of the two stabilizers studied significantly reduced the degradation of cevimeline; however, as evidenced by the cevimeline content in EY4-34 (especially at 40 °C and 60 °C) and subsequent Example 4 showed that what we did not expect was that HP‑ß‑CD presented a problem that slowed the absorption of the drug into the container.

Table 6 : Summary of Stability Data for Various Cevimeline Compositions Containing Potassium Sorbate (Panel III) nc: not sustained; ** bottle deformed; n/a: no data Panel III stability data EY4-31 EY4-32 EY4-33 EY4-34 EY4-35 EY4-36 EY4-37 EY4-38 EY4-39 0 month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] 99.9 0.17 5.97 287 99.9 0.17 7.00 281 101.7 0.16 7.00 284 99.3 0.17 6.99 284 99.0 0.17 6.98 287 n/a n/a 7.03 282 n/a n/a 7.01 287 101.0 0.17 7.43 283 98.7 0.17 7.00 284 25°C / 40% RH 2 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] 98.1 0.20 5.95 290 99.2 0.20 6.98 282 100.4 0.15 6.99 285 100.1 0.22 6.91 282 99.3 0.15 6.63 283 n/a n/a 6.94 280 n/a n/a 7.02 284 103.3 0.15 7.43 291 102.3 0.20 7.01 290 3 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] 97.7 0.15 6.01 287 99.4 0.15 7.00 278 101.5 0.16 7.01 287 98.8 0.26 6.99 281 98.7 0.15 6.95 278 n/a n/a 7.02 277 n/a n/a 7.04 287 104.1 0.16 7.45 290 101.8 0.15 7.02 290 6 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] 98.9 0.16 6.0 289 99.2 0.21 6.7 282 100.5 0.15 7.0 289 100.7 0.27 7.0 283 100.3 0.15 6.9 281 n/a n/a 7.0 282 n/a n/a 7.1 293 108.9 0.16 7.4 302 107.3 0.21 7.0 305

Continued Table 6 : Summary of Stability Data for Various Cevimeline Compositions Containing Potassium Sorbate (Panel III) nc: not sustained; ** bottle deformed; n/a: no data Panel III stability data EY4-31 EY4-32 EY4-33 EY4-34 EY4-35 EY4-36 EY4-37 EY4-38 EY4-39 40 ° C / 25% RH l monthly content percentage LS total impurity percentage pH osmolarity [mOsm/kg] 98.8 0.16 6.00 291 98.0 0.16 6.95 294 99.9 0.15 6.97 285 100.4 0.22 6.95 288 98.7 0.16 6.89 282 n/a n/a 7.03 282 n/a n/a 7.03 287 104.9 0.21 7.41 296 103.4 0.16 6.99 296 2 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] 98.4 0.21 5.96 289 98.7 0.31 6.91 282 98.1 0.16 6.92 284 99.4 0.31 6.97 281 98.4 0.15 6.86 291 n/a n/a 6.99 279 n/a n/a 7.01 286 108.2 0.28 7.42 305 107.8 0.32 7.00 305 3 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] 97.5 0.29 6.07 283 96.3 0.31 6.89 280 97.9 0.27 6.89 287 98.8 0.32 6.97 279 96.9 0.15 6.85 277 n/a n/a 7.07 279 n/a n/a 7.04 289 112.5 0.31 7.43 312 112.2 0.29 7.01 319 6 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] 97.5 0.40 6.1 286 96.5 0.55 6.9 281 95.9 0.21 6.9 290 98.5 0.64 6.9 284 95.4 0.15 6.8 280 n/a n/a 7.1 282 n/a n/a 7.1 295 130.9 0.69 n/a n/a 129.9 0.70 7.0 377

Continued Table 6 : Summary of Stability Data for Various Cevimeline Compositions Containing Potassium Sorbate (Panel III) nc: not sustained; ** bottle deformed; n/a: no data Panel III stability data EY4-31 EY4-32 EY4-33 EY4-34 EY4-35 EY4-36 EY4-37 EY4-38 EY4-39 60 ° C l monthly content percentage LS total impurity percentage pH osmolarity [mOsm/kg] 97.2 0.49 6.00 295 93.3 0.66 6.68 284 93.4 0.68 6.69 285 96.6 0.66 6.91 287 93.6 0.16 6.63 282 n/a n/a 7.03 283 n/a n/a 7.05 289 112.6 0.72 7.37 316 112.3 0.67 6.99 318 2 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] 98.7 0.44 6.19 286 90.1 0.89 6.59 284 90.4 0.72 6.60 290 92.8 0.97 6.66 283 91.7 0.22 6.36 282 n/a n/a 7.06 283 n/a n/a 7.10 285 125.2** 1.36 7.37 354 130.9** 1.29 6.95 376 3 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] 100.1 2.89 6.35 289 90.7 1.69 6.60 277 88.5 1.32 6.52 286 93.8 1.62 6.44 279 89.7 0.37 7.18 277 n/a n/a 7.16 281 n/a n/a 7.10 291 143.1** 2.69 7.38 400 152.5** 2.59 6.94 432 6 -month content percentage LS total impurity percentage pH osmolarity [mOsm/kg] 89.0 7.82 6.30 286 84.1 3.01 6.40 279 83.5 4.40 6.52 286 90.4 2.92 6.50 285 88.6 0.58 6.30 283 n/a n/a 7.30 287 n/a n/a 7.20 298 212.1** 9.44 n/a n/a 433.9** 18.74 6.90 2252

Example 4 - Container Absorption at 40 °C of Cevimeline/Potassium Sorbate Compositions with or without HP‑ß‑CD (Panel IV)

We prepared a fourth set of dosage forms to further study the effect of hydroxypropyl-β-cyclodextrin (HP‑ß‑CD) on drug absorption into eye drop container. For this purpose, various dosage forms according to the invention (whether with or without HP-ß-CD) were placed in LDPE bottles for study (EY4-50 to EY4-55). At the same time, various sorbate-free compositions were prepared for comparison.

Various aqueous solutions containing cevimeline (here, cevimeline hydrochloride x 0.5 H ₂ O salt form) at a concentration of 2 mg/mL and suitable for instillation into the eyes can be prepared by mixing the ingredients according to the following table 7 Compositions, these aqueous compositions were filtered (0.22 µm) and filled into LDPE eye drop bottles (maximum capacity 3 mL). The containers of this group will not be sealed in aluminum bags. The formulation variables evaluated were (i) inclusion or absence of HP‑ß‑CD and (ii) pH range from pH 7.0 to 8.0.

Stability studies were performed at 40 °C / 25 % RH. Stability test parameters monitored include percent drug content (measured by HPLC), impurity (degradation) content, pH, osmolarity, and physical appearance.

Table 7 : Typical Cevimeline/Potassium Sorbate Aqueous Composition (Panel IV) * The amount is equivalent to 0.54 mg/mL of sodium phosphate monohydrate

Element [mg/mL] EY4-50 EY4-51 EY4-52 EY4-53 EY4-54 EY4-55 EY4-56 EY4-57 Cevimeline 2.0 Potassium sorbate 4.7 0 Sodium Phosphate Monobasic Dihydrate 0.61* Sodium Phosphate Dibasic Heptahydrate 1.63 HP-ß-cyclodextrin --- --- --- 40 40 40 --- 40 NaCl Appropriate amount to achieve a tonicity of 280‑300 mOsm/kg (i.e. isotonicity) pure water Appropriate amount HCl or NaOH (Appropriate amount to achieve pH) 7.0 7.4 8.0 7.0 7.4 8.0 7.4 7.4

Table 8 : Summary of results for cevimeline content of compositions with and without HP‑ß‑CD (Panel IV) dosage form HP‑ß‑CD t ₀ t ₁ ( 1 month ) t ₃ (3 months ) change t ₃ -t ₀ EY4-50 content percentage LS total impurity percentage Does not contain (pH7.0) 99.6 0.15 96.3 0.15 95.6 1.60 -4.3 1.45 EY4-51 content percentage LS total impurity percentage Does not contain (pH7.4) 98.6 0.14 95.1 0.25 92.7 2.89 -5.9 2.75 EY4-52 content percentage LS total impurity percentage Does not contain (pH8.0) 99.0 0.14 91.5 0.18 88.0 1.94 -11.0 1.80 EY4-53 content percentage LS total impurity percentage Contains (pH7.0) 98.7 0.14 99.1 0.22 98.5 1.40 0.2 1.26 EY4-54 content percentage LS total impurity percentage Contains (pH7.4) 98.5 0.13 98.1 0.19 97.3 1.46 -1.2 1.33 EY4-55 content percentage LS total impurity percentage Contains (pH8.0) 98.3 0.13 95.9 0.17 94.5 1.59 -3.8 1.46 EY4-56 content percentage LS total impurity percentage Does not contain (pH7.4) 99.3 0.14 95.7 0.18 93.6 1.31 -5.7 1.17 EY4-57 content percentage LS total impurity percentage Contains (pH7.4) 99.0 0.14 98.6 0.20 97.8 0.98 -1.2 0.84

As shown in Table 8 above, these drug levels demonstrate that HP‑ß‑CD slows down the effect of changes or differences in cevimeline levels due to absorption into the container between the beginning and after three months (t ₀ and t ₃ ). loss, and the dosage forms containing HP‑ß‑CD (EY4-53, EY4-54, EY4-55, and EY4-57) will also have much less time-added impurities (signals of drug degradation); Comparison of EY4-50 to EY4-52 with HP-ß-CD containing compositions EY4-53 to EY4-55. In addition, we also observed less drug loss due to container absorption when the pH was lower.

Summarizing the compositions exemplified in Examples 1-4 above, we have found that a compound comprising cevimeline (here, cevimeline hydrochloride x 0.5 H ₂ O salt form) and a PUFA can be successfully prepared. A stable aqueous solution composition of sorbic acid (here in the form of potassium sorbate); for example, various compositions listed in Table 9 below. These compositions can be adapted for instillation into the eye, for example in the form of eye drops. The compositions may comprise a therapeutically effective dose of cevimeline, potassium sorbate as a PUFA at a concentration of less than 15 mg/mL, a phosphate buffer, and sodium chloride as a tonicity agent . The pH range may be between pH 6.0 to 8.0, or preferably between pH 6.0 to 7.4. The compositions may further optionally include benzalkonium chloride (BAK) and/or HP-ß-cyclodextrin (eg Kleptose ^® ) as a preservative. The composition may be filled into an appropriate eye drop bottle of proven acceptable compatibility, wherein absorption of cevimeline into the primary container containing the composition is slowed during the shelf life (typically up to three years), Such as translucent plastic bottles (such as high-density polyethylene HDPE, low-density polyethylene LDPE, polypropylene PP, or cycloolefin copolymer COC) or similar primary pharmaceutical packaging containers.

Table 9 : Summary of Cevimeline/Potassium Sorbate Aqueous Compositions Element acceptable condition Target Cevimeline effective range of treatment 2.0–50 mg/mL (eg, 6mg/mL, 20 mg/mL, 40 mg/mL) Potassium sorbate ≤10 mg/mL 1-10 mg/mL (eg 4.7 mg/mL) Sodium Phosphate Monobasic Dihydrate Typical ranges for ophthalmic compositions 0.41–0.68 mg/mL (eg 0.54 mg/mL) Sodium Phosphate Dibasic Heptahydrate Typical ranges for ophthalmic compositions 1.2–2.0 mg/mL (eg 1.63 mg/mL) BAK contains or does not contain contains or does not contain NaCl Suitable osmolality for ophthalmic compositions, e.g. 200‑600 mOsm/kg 250‑450 mOsm/kg (eg 270‑350 mOsm/kg or 280‑300 mOsm/kg) pure water Appropriate amount Appropriate amount Optional excipients Cyclodextrin HP‑ß‑Cyclodextrin HCl or NaOH (adjust pH) pH6.0‑8.0 or pH6.0‑7.5 pH6.0–7.4 (eg pH7.0)

Example 5 - Ocular Tolerance Study in New Zealand White Rabbits

The aim of this study was to assess the local and systemic tolerability of cevimeline following four daily administrations of cevimeline to the eye (40 µL instillation to the left eye; no administration to the right eye) for seven days. The total administration volume was 160 µL per day, with administrations spaced 2 ± 0.5 hours apart.

Three test compositions (low, medium and high doses) containing different cevimeline concentrations (6 mg/mL, 20 mg/mL and 40 mg/mL, respectively) were administered to a total of 24 experimental New Zealand white puppies. Rabbits (12 males and 12 females) were tested, all of which were five months old and weighed 2.7 to 3.4 kg at the start of the study. Table 10 summarizes the various test compositions 1, 2 and 3 containing cevimeline (the cevimeline here is cevimeline hydrochloride x 0.5 H ₂ O salt form) and each of the control group (control group). class ingredients. Table 11 summarizes the trial schedule.

Table 10 : Summary of cevimeline/potassium sorbate test aqueous solution composition (low, medium and high doses) and matched group Composition [mg/mL] control group low dose medium dose high dose Cevimeline (free base equivalent) 0.0 6.0 20.0 40.0 Potassium sorbate 4.7 Sodium Phosphate Monobasic Dihydrate 0.61 Sodium Phosphate Dibasic Heptahydrate 1.63 NaCl (as appropriate to achieve a tonicity of 280‑300 mOsm/kg) 6.2 4.5 1.0 0.0 pure water Appropriate amount HCl or NaOH (appropriate to achieve pH) 7.0

Table 11 : Test schedule Concentration [mg/mL] number of animals male mother 1. Control group (control group) 0.0 3 3 2 low dose group 6.0 3 3 3 medium dose group 20.0 3 3 4 High dose group 40.0 3 3

Mortality/morbidity observations and clinical observations were recorded twice daily. Eye irritation scoring according to the Draize method was performed before the start of treatment: before the first application and after the fourth application each day during the period of one to seven days, and after the first application on the first day. In addition, the pupil size of each eye is noted as normal, dilated, or constricted. Body weights were recorded at random/selected times on day 1 and day 7. Food intake was recorded daily. All animals will have ophthalmic examinations performed prior to treatment initiation and on Day 7. All study animals will be released and returned to the rabbit group on the eighth day following completion of the final clinical observation.

We found that New Zealand male and female white rabbits tolerated various cevimeline formulations up to a maximum concentration of 40 when administered externally to the treated eyes of rabbits four times daily for seven days. mg/mL. We occasionally observed some minor clinical symptoms in these cevimeline dose groups, including ocular/conjunctival redness (6, 20, and 40 mg/mL) and squinting (40 mg/mL only). When the study was completed on the eighth day, all clinical symptoms were eliminated. There was no effect on body weight or food intake, no mortality or morbidity, no effect on pupil size; all pupils were observed to be normal in size after completion of dosing. All animals survived to day eight to complete the study.

When ophthalmic examination was performed on day 7, minimal conjunctival conjunctiva was found in four of the 12 eyes in the low-dose group 2 (6 mg/mL) and in two of the 12 eyes in the middle-dose group 3 (20 mg/mL) Symptoms of congestion; however, only one of the four eyes in Group 2 and only one of the two eyes in Group 3 was the left eye (ie, the treated eye). In addition, no animals in control group 1 or high dose group 4 (40 mg/mL) were found to have symptoms of conjunctival hyperemia. Clinical findings due to minimal conjunctival hyperemia (conjunctival erythema) were (i) occasional, (ii) both in the treated and non-medicated eye, (iii) in the absence of infusion correlation, and (iv) in combination with other The clinical symptoms are not related, we believe that the symptoms are related to the process (score/stimulus) rather than these cevimeline compositions. Additionally, only very few animals were affected, with a severity score not exceeding 1. No effect on pupil size. We observed that all pupils were of normal size.

The following numbered item list is each embodiment that the present invention comprises: 1. An aqueous solution composition comprising: (a) cevimeline or a pharmaceutically acceptable salt of cevimeline at a concentration between 1 mg/mL and 50 mg/mL; (b) sorbic acid or a pharmaceutically acceptable salt of sorbate; and (c) an aqueous carrier; wherein the pH of the composition ranges from pH 6.0 to 8.0, or from pH 6.0 to pH 7.5, and Wherein the composition comprises sorbic acid or a pharmaceutically acceptable sorbate at a concentration of 3 mg/mL to 10 mg/mL. 2. The composition according to item 1, wherein the composition does not contain antibacterial preservatives. 3. The composition according to item 1 or 2, wherein the composition is provided in the form of a clear aqueous solution. 4. The composition as in any one of items 1 to 3, wherein the composition comprises water as the only solvent. 5. The composition as in any one of items 1 to 4, wherein the composition comprises cevimeline at a concentration of 2 mg/mL to 50 mg/mL or a pharmaceutically acceptable cevimeline Merrill Salt. 6. The composition as in any one of items 1 to 5, wherein the composition further comprises a complexing agent. 7. The composition according to item 6, wherein the complexing agent comprises or consists of a cyclodextrin. 8. The composition according to item 7, wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin (HP-ß-CD). 9. The composition according to item 7 or 8, wherein the cyclodextrin is present in an amount ranging from 2 mg/mL to 100 mg/mL. 10. The composition as in any one of items 1 to 9, wherein the composition further comprises a thickener. 11. The composition according to item 10, wherein the thickener is selected from hyaluronic acid, polyvinyl alcohol (PVA), polyvinylpyrrolidone (or povidone), carboxyvinyl polymer, methyl cellulose (MC ), hydroxymethylcellulose (CMC; or carmellose), hydroxypropylmethylcellulose (HPMC; or hypromellose), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), polyacrylic acid or polyacrylate, xanthan gum, guar gum, chondroitin sulfate, polyethylene glycol, propylene glycol, or combinations thereof. 12. The composition according to item 11, wherein the thickener is selected from hyaluronic acid, polyvinylpyrrolidone, hypromellose, carmellose, or a combination of the above substances. 13. The composition as in any one of items 1 to 12, wherein the composition further comprises one or more excipients selected from various tonicity regulators (such as sodium chloride) , various buffers (such as a phosphate buffer), and various pH adjusting agents. 14. The composition according to any one of items 1 to 13, wherein the composition comprises potassium sorbate at a concentration of 3 mg/mL to 10 mg/mL. 15. The composition according to any one of items 1 to 14, wherein the composition has a pH of about 6.0 to 7.4. 16. The composition according to any one of items 1 to 15, wherein the composition is provided as a clear liquid which can be instilled into the eyes. 17. The composition according to any one of items 1 to 16, wherein the composition has a dynamic viscosity ranging from 1 cP to 60 cP, 1 cP to 50 cP cP, or 1 cP to 20 cP, such as a dynamic viscosity below 5 cP. 18. The composition according to any one of items 1 to 17, wherein the composition is an ophthalmic composition in the form of eye drops. 19. The composition according to any one of items 1 to 18, wherein the composition provided is not in the form of an ointment, emulsion, paste, insert, punctal plug, and/or ointment. 20. The composition according to any one of items 1 to 19, wherein the composition may optionally comprise one or more active ingredients selected from (a) steroids, (b) immunomodulators or immunosuppressants, (c) hormones, (d) secretagogues, (e) Lymphocyte function-associated antigen-1 (LFA-1) antagonists, and/or (f) Active ingredients effective in the treatment of meibomian gland dysfunction. 21. The composition according to any one of items 1 to 19, wherein in addition to (i) cevimeline or a pharmaceutically acceptable cevimeline salt and/or (ii) as PUFA Other than sorbic acid or a pharmaceutically acceptable salt of sorbate, the composition is free or substantially free of surfactants and/or co-solvents. 22. The composition according to any one of items 1 to 21, wherein the composition is substantially free of insulin, insulin-like growth factor (IGF), somatomodulin C, and cycloplegic agents. 23. The composition of any one of clauses 1 to 22, wherein the absorption of cevimeline from the composition into the primary container during the shelf life is slowed. 24. The composition as in any one of items 1 to 23, wherein the composition is packaged in high-density polyethylene (HDPE), low-density polyethylene (LDPE), polypropylene (PP), or ring A main container made of olefin copolymer (COC). 25. A method of treating one or more of dry eye, xerostomia or Sjögren's syndrome, the method comprising the step of externally administering the composition according to any one of items 1 to 24 to a patient suffering from dryness Subjects with eye disease, dry mouth, and/or Sjögren's syndrome. 26. The composition according to any one of items 1 to 24, for use in the treatment of one or more of dry eye, dry mouth or Sjögren's syndrome. 27. Use the composition as in any one of items 1 to 24 to make a medicament for treating one or more of dry eye, dry mouth, or Sjögren's syndrome. 28. The method according to item 25 or use according to item 26 or 27, wherein the composition is administered to the eye of the subject. 29. The method according to item 25 or use according to any one of items 26 to 28, wherein the composition is administered to the nasal mucosa of the subject. 30. The method according to item 25 or use according to any one of items 26 to 29, wherein the composition can be administered once, twice, three times, or four times a day. 31. The method according to item 25 or use according to any one of items 26 to 30, wherein the composition can be administered during a treatment period of at least seven days. 32. The method according to item 25 or use according to any one of items 26 to 31, wherein the composition does not cause miosis after administration. 33. The method or use according to item 32, wherein the composition does not cause miosis upon application to the eye. 34. An ophthalmic composition comprising cevimeline at a concentration of 2 mg/mL to 50 mg/mL or a pharmaceutically acceptable salt of cevimeline at a concentration of 4.7 mg/mL Potassium sorbate, sodium phosphate buffer, sodium chloride, and water. 35. A method of treating one or more of dry eye, xerostomia, or Sjögren's syndrome, the method comprising the step of administering an aqueous composition containing cevimeline to a patient suffering from dry eye, xerostomia , and/or the nasal mucosa of subjects with Sjögren's syndrome.

none.

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Claims (23)

An aqueous composition comprising: (a) Cevimeline or a pharmaceutically acceptable salt of cevimeline at a concentration between 1 mg/mL and 50 mg/mL; (b) sorbic acid or a pharmaceutically acceptable salt of sorbate; and (c) aqueous carrier; Wherein the pH value range of the aqueous solution composition is between pH 6.0 to 8.0, and Wherein the aqueous solution composition contains sorbic acid or pharmaceutically acceptable sorbate at a concentration of 3 mg/mL to 10 mg/mL. The aqueous solution composition as described in Claim 1, wherein the aqueous solution composition does not contain antibacterial preservatives. The aqueous solution composition as described in Claim 1, wherein the form of the aqueous solution composition is a clear solution. The aqueous solution composition according to claim 1, wherein the aqueous solution composition comprises water as the only solvent. The aqueous solution composition according to claim 1, wherein the aqueous solution composition contains cevimeline or a pharmaceutically acceptable cevimeline salt at a concentration of 2 mg/mL to 50 mg/mL. The aqueous solution composition according to claim 1, wherein the aqueous solution composition further comprises a complexing agent. The aqueous composition according to claim 6, wherein the complexing agent comprises cyclodextrin or consists of cyclodextrin. The aqueous composition according to claim 7, wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin. The aqueous solution composition as claimed in item 7, wherein the cyclodextrin exists in a concentration ranging from 2 mg/mL to 100 mg/mL. The aqueous solution composition as described in Claim 1, wherein the aqueous solution composition further comprises a thickener. The aqueous solution composition as described in claim item 10, wherein the thickener is selected from hyaluronic acid, polyvinyl alcohol, polyvinylpyrrolidone, povidone, carboxyvinyl polymer, methylcellulose, hydroxymethylcellulose, Carmellose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, polyacrylic acid or polyacrylate, xanthan gum, guar gum, chondroitin sulfate, polyethylene glycol, Propylene glycol, or a combination of the above. The aqueous solution composition according to claim 1, wherein the aqueous solution composition further comprises one or more excipients selected from various tonicity regulators, various buffers, and various pH value regulators. The aqueous solution composition as claimed in item 1, wherein the aqueous solution composition comprises potassium sorbate at a concentration between 3 mg/mL and 10 mg/mL. The aqueous solution composition as claimed in item 1, wherein the pH value of the aqueous solution composition is 6.0 to 7.4. The aqueous solution composition according to claim 1, wherein the dynamic viscosity of the aqueous solution composition ranges from 1 cP to 60 cP. A method of treating one or more of dry eye, xerostomia, or Sjögren's syndrome, the method comprising the step of externally applying the aqueous composition as described in claim 1 to patients with dry eyes, xerostomia, and / or subjects with Sjögren's syndrome. The method according to claim 16, wherein the aqueous solution composition can be administered to the eyes of the subject. The method according to claim 16, wherein the aqueous solution composition can be applied to the nasal mucosa of the subject. The method according to claim 16, wherein the aqueous solution composition can be administered once, twice, three times, or four times a day. The method of claim 16, wherein the aqueous composition is administered during at least seven days of treatment. The method according to claim 16, wherein the aqueous solution composition does not cause miosis. An ophthalmic composition comprising cevimeline at a concentration of 2 mg/mL to 50 mg/mL or a pharmaceutically acceptable cevimeline salt, potassium sorbate at a concentration of 4.7 mg/mL , sodium phosphate buffer, sodium chloride, and water. A method for treating one or more of dry eye, xerostomia, or Sjögren's syndrome, the method comprising the step of administering an aqueous composition containing cevimeline to patients with dry eyes, xerostomia, and/or or nasal mucosa of subjects with Sjögren's syndrome.