Aqueous cevimeline compositions and methods of use

Abstract

The present invention provides a stable aqueous composition, particularly a topical ophthalmic composition, of cevimeline and sorbic acid or a salt thereof for treating dry eye disease, xerostomia, and / or Sjogren's syndrome. The composition also includes a water-soluble medium-chain polyunsaturated fatty acid (PUFA), such as sorbic acid, or a pharma- ceutically acceptable salt thereof, e.g., potassium sorbate.

Description

[Technical field]

[0001] The present invention relates to a muscarinic agonist (MRA), specifically cevimeline, which is a medium chain (C6-C 10 ) Polyunsaturated fatty acids (PUFAs, e.g., C6-C 12 , or C6~C 10 The present invention relates to compositions, such as topical ophthalmic compositions or topical compositions for nasal administration, comprising the same in combination with 5-aminoethyl-1,4-dihydro-2,5-trimethylamino-1 ... [Background technology]

[0002] Xerostomia, or dry mouth, refers to a condition in which the salivary glands in the mouth do not make enough saliva to keep the mouth wet. Xerostomia is often due to the side effects of certain medications, Sjogren's disease, or the result of radiation therapy for cancer. Saliva helps prevent tooth decay by neutralizing acids produced by bacteria, limiting bacterial growth, and washing away food particles. Reduced saliva and dry mouth can have a major impact on the health of teeth and gums.

[0003] Dry eye disease, also known as keratoconjunctivitis sicca or dry eye syndrome, is a chronic, potentially debilitating condition with symptoms of ocular surface damage, inflammation, oxidative stress, and irritation, including discomfort and impaired visual quality. It is a multifactorial disorder of the ocular surface that affects an estimated 20 million patients in the United States alone. The Dry Eye Workshop (DEWS) classified dry eye disease based on two basic causal mechanisms: aqueous tear deficiency and evaporative dry eye (i.e., tear film instability due to abnormally rapid tear evaporation). Dry eye disease is also associated with local inflammation of the ocular surface and periocular tissues. It is unclear whether chronic inflammation leads to the clinical symptoms of dry eye disease or, conversely, whether dry eye disease leads to chronic inflammation. Due to the complexity of the multifactorial causes of dry eye disease and the lack of a clear understanding of the relationship between dry eye disease and inflammation, attempts to explore effective dry eye disease treatments have been largely unsuccessful, resulting in disappointment for both patients and clinicians.

[0004] One of the causes of DED and xerostomia can be Sjögren's syndrome (also known as Mikulicz's disease or Sicca's syndrome), an autoimmune disorder in which immune cells attack and destroy the salivary and lacrimal exocrine glands. It affects about 4 million people, second only to rheumatic diseases. About 90% of patients are women over 40 years old, but men and women of any age group can be affected. It can be in the early or advanced stages, for example after rheumatoid arthritis, systemic lupus erythematosus, scleroderma, primary biliary cirrhosis. There is no cure for Sjögren's-associated dry eye syndrome, and treatments are palliative and at best provide temporary relief, proposing, for example, artificial tears or goggles to increase local humidity, or periodic plugs inserted to help retain tear fluid.

[0005] The pathology of aqueous tear deficiency is the inability to maintain the lacrimal gland's function in tear secretion. The cause may be due to failure of the lacrimal gland to produce tears based on a defect in part of the lacrimal gland, blockage, systemic drugs that impair the function of the sweat gland, autoimmune diseases, or age-related changes in the lacrimal gland. Long-term contact lens wearers and patients who have undergone LASIK may also develop defects due to loss of corneal nerve sensation.

[0006] Since most of the tears and its components are derived from the lacrimal gland, the decrease in its secretion leads to tear deficiency and corneal epithelial cell damage and inflammation.In addition, the tears secreted from the lacrimal gland contain essential enzymes, proteins and antibacterial components that are important for protecting and repairing corneal epithelial cell damage resulting from dry eye.Therefore, it is reasonable to target the increase in lacrimal gland secretion as the first and main treatment for dry eye disease.

[0007] Evaporative dry eye is typically caused by meibomian gland dysfunction and lipid deficiency, which results in increased evaporation and reduced stability of the tear film. Evaporative dry eye causes dry eye symptoms even in the presence of normal tear secretion.

[0008] Ocular surface inflammation is one of the consequences of tear deficiency and / or meibomian gland dysfunction. Immune-based inflammatory responses also play a major role in corneal epithelial disease and the ocular discomfort of dry eye. In light of this, dry eye disease can be considered as more than just a deficiency of one or more tear film components, it is also as an ocular surface inflammatory syndrome, and most patients have a combination of factors that cause dry eye disease. It is often difficult to point to one specific factor as the cause, and instead, dry eye is caused by a series of problems or factors that result in the signs and symptoms of dry eye disease.

[0009] Typical symptoms of dry eye disease include burning, itching, foreign body sensation, stinging, dryness, photophobia, swelling, eye fatigue and / or redness. In some cases, patients may report temporary blurred vision. These symptoms are typically worse later in the day and can be precipitated or exacerbated by certain environmental conditions, such as low humidity or wind.

[0010] Several objective tests are commonly used to diagnose the symptoms of dry eye disease. Diagnostic dyes are used to identify and monitor changes to the ocular surface. Tear breakup time (TBUT) is used to evaluate tear stability and performance. And Schirmer's test is performed to evaluate tear production. In general, dry eye tests do not correlate well with symptoms, but these tests are mainstays in the field and clinicians continue to find useful results.

[0011] Current treatments for dry eye disease include over-the-counter lubricating eye drops (also called artificial tears) that are used to treat the dryness and irritation associated with the failure of tear production in dry eye disease. Mild disease states of dry eye disease require the application of lubricating eye drops four times a day, while severe cases require more frequent administration (10-12 times a day). Similar treatments and dosing regimens exist for xerostomia, where patients generally receive artificial saliva compositions based on hydrophilic swellable polymers.

[0012] In addition, punctal plugs, procedures for treating meibomian gland disorders, dietary supplements, and a limited number of prescription eye drops are available. Therapeutic agents or drugs available in the form of eye drop formulations for treating dry eye disease include, for example, the immunomodulator cyclosporine A (Restasis®), the secretagogue diquafosol sodium (Diquas®), or rebamipide (Mucosta®), and the lymphocyte function-associated antigen 1 (LFA-1) inhibitor lifitegrast (Xiidra®). However, not all of them are approved worldwide due to suboptimal clinical results. Moreover, the efficacy of the above-mentioned treatments is still far from optimal, and there is still a great need to develop more effective products for the treatment of dry eye disease, as well as for the treatment of xerostomia and Sjogren's syndrome.

[0013] Due to their anti-inflammatory and antioxidant properties, recent efforts have focused on polyunsaturated fatty acids (PUFAs), including polyunsaturated omega-3, such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), or gamma-linolenic acid (GLA), and polyunsaturated omega-6 fatty acids, such as linoleic acid (LA) and arachidonic acid (AA). PUFAs have been demonstrated to provide many benefits to the eye when given orally in large amounts. For example, long-chain PUFAs (i.e., polyunsaturated fatty acids with 13 or more C atoms, typically C 13 ~C 22 ) have been reported to play an important role in normal human retinal function and visual development, and several epidemiological studies of PUFA intake have suggested a protective role against the development of advanced age-related macular degeneration (AMD). It has further been reported that high doses of PUFA can alleviate dry eye symptoms, and this effect was confirmed by a meta-analysis of relevant randomized controlled trials.

[0014] However, due to their lipophilic and often water-insoluble nature, it is often difficult to formulate PUFAs into aqueous compositions for direct application to the eye or other mucosal surfaces, such as eye drops or nasal sprays. Typically, surfactants or co-solvents are required to sufficiently solubilize PUFAs and / or to formulate them into emulsions, which can cause problems, for example, because some of the most common preservatives in eye drops (e.g., benzalkonium chloride) are not compatible with emulsion formulations. In addition, surfactants in emulsions can cause blurred vision and / or eye irritation. Furthermore, PUFAs are prone to oxidation, thus necessitating the inclusion of antioxidants to stabilize them. For example, U.S. Patent No. 8,957,110 by TRB Chemedica International SA describes long-chain (herein C) PUFAs that allow for direct administration of PUFAs to the eye. 16 ~C 24 ) discloses a hydrogel-based artificial tear-type eye drop composition containing polyunsaturated omega-3 and omega-6 fatty acids. The composition contains vitamin E acetate as an antioxidant and a gelling polymer, such as a cross-linked carboxyvinyl polymer, as a stabilizer.

[0015] In addition to the above drugs available as prescription eye drops, the US Food and Drug Administration (FDA) has also approved cevimeline in the form of an oral formulation for the systemic treatment of dry mouth (xerostomia) in patients with Sjögren's syndrome. Cevimeline (its HCl salt hemihydrate CAS107233-08-9 or CAS153504-70-2, (2R,2R)-2'-methylspiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxathiolane], or cis-2'-methylspiro[1-azabicyclo[2.2.2]octane-3,5'-[1,3]oxathiolane] hydrate hydrochloride) is a cholinergic agonist that binds to muscarinic receptors, particularly M1 and M3 receptors, and is therefore also referred to as a muscarinic receptor agonist (MRA). Cevimeline can increase secretion in exocrine glands such as salivary and sweat glands. It has also been shown to promote tear production through the stimulation of lacrimal gland.Therefore, oral cevimeline composition is also being studied for its benefits in the treatment of dry eye disease, although it is not currently approved for this purpose.However, although oral cevimeline has shown significant improvement in the treatment of dry eye disease, this treatment is not widely accepted due to systemic side effects from oral administration, such as sweating, nausea, runny nose, flushing, frequent urgency, dizziness, weakness, diarrhea, and blurred vision.

[0016] Additionally, there are currently no commercially available topical (i.e., applied to the skin and / or mucosal surfaces) ophthalmic or nasal cevimeline formulations available for the treatment of dry eye disease, xerostomia, and / or Sjogren's syndrome.

[0017] Ophthalmic formulations containing cevimeline have been proposed, for example, in US 20070053964 (US'964) or WO 2020072971 (WO'971). US'964 discloses formulations such as adhesives or ointments adapted to be applied to the outer skin surface of the eyelid and transdermally deliver cevimeline from the eyelid skin to local eye tissues by transdermal transfer. Furthermore, US'964 discloses a 20% cevimeline eye drop solution formulation that was administered directly to the eye (i.e., to the surface of the eyeball and / or inside (in) the eyelid), but only served as a comparative example to a 20% cevimeline ointment formulation. The eye drops were found to be inferior to ointments applied to the eyelids in terms of lacrimal fluid secretion, and US'964 suggested that administering cevimeline solutions directly to the eye was undesirable compared to transdermal formulations in terms of tear production and side effects (such as miosis). Providing MRA to the anterior segment of the eye (cornea) and iris / ciliary body is generally expected to exacerbate miosis, and therefore these tissues are less desirable delivery sites, which may explain US'964's teaching away from dosage forms that are instilled in the eye. Furthermore, the "external" transdermal formulations described in US'964 are not suitable for direct administration to the ocular surface, as the high concentrations of drug and transdermal absorption enhancers required for sufficient transdermal drug transport, as required for DED treatment, cause significant eye irritation (e.g., due to their high osmolality), especially when used for extended periods of time.

[0018] WO'971 describes a topical ophthalmic composition for treating dry eye disease in the form of eye drops comprising about 0.1-10% of a muscarinic receptor agonist (MRA), such as cevimeline, in the neutral pH range of pH 6-9, and one or more pharma- ceutically acceptable excipients. WO'971 also suggests the addition of long chain polyunsaturated fatty acids (PUFAs), such as EPA, DHA, ALA, GLA, or combinations thereof, to the MRA composition, with the PUFAs added as separate components from the MRA and / or as part of an ion pair comprising the MRA and the PUFA.

[0019] Nevertheless, there remains a continuing medical need to develop pharma- ceutically stable, comfortable, safe, non-irritating, and effective formulations of muscarinic receptor agonists such as cevimeline, suitable for direct topical administration to the mucosal surface of the eye and / or nasal cavity for the treatment of dry eye disease, xerostomia, and / or Sjogren's syndrome, with fewer side effects than the compositions of the prior art, even at well-tolerated drug concentrations, for the treatment of dry eye disease, xerostomia, and / or Sjogren's syndrome.For dry eye disease, the goals of treatment include, for example, relieving the signs and / or symptoms thereof, improving patient comfort, restoring the ocular surface and tear film to a healthy state, and preventing corneal damage as much as possible.Furthermore, the formulation is preferably easier to formulate than the compositions of the prior art, and does not require, for example, antioxidants, surfactants, or co-solvents to solubilize and / or stabilize the above-mentioned PUFAs. [Prior art documents] [Patent documents]

[0020] [Patent Document 1] U.S. Patent No. 8,957,110 [Patent Document 2] US Patent Publication No. 20070053964 [Patent Document 3] International Publication No. 2020072971 Summary of the Invention [Problem to be solved by the invention]

[0021] Therefore, it is an object of the present invention to provide a stable aqueous composition that can be instilled in the eye, meaning that it can be instilled on the surface of the eye (e.g., eye drops), or that can be applied topically in the nasal cavity, and can be used to treat diseases such as dry eye disease, xerostomia, and / or Sjogren's syndrome. In particular, it is an object of the present invention to provide a composition comprising cevimeline and medium-chain polyunsaturated fatty acids (PUFAs) that promotes tear production and at the same time reduces oxidative stress. A further object of the present invention is to provide a method of treating dry eye disease, xerostomia, and / or Sjogren's syndrome with a topically applied composition comprising cevimeline and medium-chain polyunsaturated fatty acids (PUFAs).

[0022] Further objects of the present invention will become apparent based on the following description of the invention, examples, and claims. [Means for solving the problem]

[0023] In a first aspect, the present invention relates to an aqueous composition comprising 1 mg / mL to 50 mg / mL of cevimeline or a pharma- ceutically acceptable salt thereof, sorbic acid or a pharma- ceutically acceptable salt thereof, and an aqueous carrier, wherein the pH of the composition is in the range of pH 6.0 to pH 8.0, and the composition comprises 3 mg / mL to 10 mg / mL of sorbic acid.

[0024] In a second aspect, the present invention relates to a method of treating one or more of dry eye disease, xerostomia, or Sjogren's syndrome, comprising topically administering a composition according to the first aspect of the invention to a subject suffering from dry eye disease, xerostomia, and / or Sjogren's syndrome.

[0025] In a third aspect, the present invention relates to an ophthalmic composition comprising 2 mg / mL to 50 mg / mL of cevimeline or a pharma- ceutically acceptable salt thereof, 4.7 mg / mL of potassium sorbate, sodium phosphate buffer, sodium chloride, and water.

[0026] In a further aspect, the present invention relates to a method of treating one or more of dry eye disease, xerostomia, or Sjogren's syndrome, comprising administering an aqueous composition comprising cevimeline to the nasal mucosa of a subject suffering from dry eye disease, xerostomia, and / or Sjogren's syndrome. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] In a first aspect, the present invention relates to an aqueous composition comprising about 1 mg / mL to 50 mg / mL of cevimeline or a pharma- ceutically acceptable salt thereof, sorbic acid or a pharma-ceutically acceptable salt thereof, and an aqueous carrier, wherein the pH of the composition is in the range of about pH 6.0 to pH 8.0, and the composition comprises about 3 mg / mL to 10 mg / mL of sorbic acid or a pharma-ceutically acceptable salt thereof.

[0028] As used herein, the expression "compound X or a pharma- ceutically acceptable salt thereof" includes said compound X and its pharma- ceutically acceptable salts in both anhydrous form and, for example, in its hydrate form. For example, cevimeline can be used as it is (i.e., in its free base form) as its hydrochloride salt (cevimeline HCl) and as its hydrate form, for example, cevimeline hydrochloride hemihydrate (cevimeline HCl x 0.5H2O). Optionally, mixtures thereof can be used, for example, cevimeline can be present as a free base form, a salt form, or a combination of a free base and a salt form. Thus, unless otherwise specified, the term "cevimeline" refers to a free base form, a salt form, or a combination thereof.

[0029] Furthermore, as used herein, the expression "compound X or a pharma- ceutically acceptable salt thereof" in combination with a concentration specification shall be understood as referring to compound X, meaning that when working with heavier salt and / or hydrate forms of compound X, a greater amount of salt, respectively, shall be used to achieve a given concentration of X.

[0030] Terms such as "about," "approximately," or "ca." are meant to compensate for variations that are accepted in the relevant art and are inherent to each product (e.g., the pharmaceutical industry), such as differences in content due to manufacturing variations, measurement variations, and / or product degradation over time. Terms relating to attributes or values ​​include exact attributes or precise values, as well as any attribute or value that is typically considered to be within a normal range or variation accepted in the relevant art. A variation range of up to ±10% is common, for example, in the pharmaceutical industry.

[0031] As used herein, the phrase "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans, and optionally other animals, without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0032] Sorbic acid is a hexadienoic acid with double bonds at C2 and C4 and four geometric isomers of which the trans, trans form occurs naturally. Sorbic acid is a medium chain fatty acid (i.e., C6-C 12 , or C6~C 10 ), more specifically a medium-chain polyunsaturated fatty acid (PUFA).

[0033] As shown in the following examples, the inventors have surprisingly found that the addition of sorbic acid to an aqueous cevimeline composition (e.g., eye drops for instillation into the eye) according to the first aspect of the invention increases the cevimeline exposure of the desired target tissues, primarily the lacrimal gland, while simultaneously decreasing the cevimeline exposure of ocular tissues such as the cornea and / or iris / ciliary body. In contrast to the targeted lacrimal gland, the latter tissues are undesirable sites for cevimeline exposure insofar as these tissues are responsible for side effects such as miosis.

[0034] The aqueous composition according to the first aspect of the present invention is characterized in that it contains 3 mg / mL to 10 mg / mL of sorbic acid or a pharma- ceutically acceptable salt thereof. Sorbic acid and its salts, such as potassium sorbate, are known antimicrobial preservatives with both antibacterial and antifungal properties, used inter alia in the preparation of medicinal products. According to the literature, sorbic acid and its salts are generally used in oral or topical formulations at a concentration of 0.1 to 0.2% (i.e. about 1 to 2 mg / mL in the aqueous composition).

[0035] However, both sorbic acid and salts such as potassium sorbate are known to exhibit minimal antimicrobial properties in formulations above pH 6. Moreover, the concentrations used in the aqueous composition according to the first aspect of the present invention are higher than those recommended in the respective literature for the use of sorbic acid or its salts as antimicrobial preservatives in topical compositions. This is because, according to the present invention, sorbic acid or its salts are not used, or at least not primarily or intentionally, based on its function as an antimicrobial preservative, but instead due to its properties as a polyunsaturated acid (PUFA), specifically a water-soluble medium-chain polyunsaturated acid.

[0036] One of the main advantages is that due to its water solubility, the PUFA sorbic acid does not require surfactants and / or co-solvents to be solubilized in aqueous compositions. Moreover, the PUFA sorbic acid is less susceptible to oxidative degradation than long-chain PUFAs such as eicosapentaenoic acid (EPA), docosa-hexaenoic acid (DHA), alpha-linolenic acid (ALA), gamma-linolenic acid (GLA), linoleic acid (LA) or arachidonic acid (AA) mentioned above. Thus, the aqueous composition does not necessarily require the presence of an antioxidant. Thus, in one embodiment, the composition does not contain or is essentially free of added antioxidants. As used herein, the term "antioxidant" is intended to mean an agent that is used to inhibit oxidation and thus prevent the deterioration of a composition or its components by the oxidative process. As used herein, the terms "free of X" or "essentially free of X" mean that the respective material (e.g., chemical compound or composition) contains less than a functional amount of component "X", typically less than 2% by weight, or less than 1% by weight, preferably less than 0.1% by weight, or even less than 0.01% by weight, and even 0% by weight of component "X".

[0037] In an optional embodiment, the composition according to the first aspect of the invention comprises long chain PUFAs (i.e. 13 or more C atoms, typically C 13 ~C 22 The present invention is free of or essentially free of PUFAs having the formula:

[0038] In one embodiment, the composition according to the first aspect of the invention does not contain an antimicrobial preservative, or, more specifically, does not contain an additional antimicrobial preservative, where sorbic acid or its salts are still considered antimicrobial preservatives despite the reduced antimicrobial activity at pH values ​​above 6.0, such as 6.0-8.0. Exemplary preservatives include, but are not limited to, benzalkonium chloride (BAK), benzethonium chloride, p-oxybenzoates such as methyl p-oxybenzoate or ethyl p-oxybenzoate, benzyl alcohol, phenethyl alcohol, citric acid or its salts, thimerosal, chlorobutanol, quaternary amines, chlorhexidine gluconate, stabilized oxychloro complexes, or combinations thereof. The (additional) preservative, if included, is present in an amount or concentration required to pass the USP and / or Ph.Eur antimicrobial preservative effectiveness tests required for eye drops. For example, BAK can be used at a concentration of 0.002 to 0.02% (w / v), typically 0.005 to 0.01% (w / v).

[0039] In one embodiment, the composition is provided in the form of a transparent solution.As used herein, the term "transparent" refers to a clear or see-through liquid or solution that does not contain any droplets or other suspended particles visible to the naked human eye, and said transparent liquid or solution is not opalescent or "milky" white, such as most common emulsions.Optionally, a transparent solution is also colorless.

[0040] In a further embodiment, the composition comprises water as the only solvent, or in other words, water is the aqueous carrier or the main component.In yet a further embodiment, the composition does not comprise co-solvent.Advantageously, when sorbic acid is selected as PUFA, no co-solvent or solvent other than water is required to solubilize PUFA.

[0041] In one embodiment, the composition comprises 2 mg / mL to 50 mg / mL of cevimeline or a pharma- ceutically acceptable salt thereof. In more specific embodiments, the composition comprises 2 mg / mL to 40 mg / mL, or 2 mg / mL to 20 mg / mL, or 2 mg / mL to 10 mg / mL, or 2 mg / mL to 6 mg / mL of cevimeline or a pharma- ceutically acceptable salt thereof.

[0042] In one embodiment, the composition comprises 3 mg / mL to 8 mg / mL, or 3 mg / mL to 6 mg / mL of sorbic acid or a pharma- ceutically acceptable salt thereof. In one of the preferred embodiments, the composition comprises 3.7 mg / mL to 5.7 mg / mL, or 4.2 mg / mL to 5.2 mg / mL, for example 4.7 mg / mL of sorbic acid or a pharma- ceutically acceptable salt thereof.

[0043] Optionally, the cevimeline and sorbic acid are provided in the form of an ion pair.

[0044] Optionally, the composition further comprises a complexing agent. In a specific embodiment, the complexing agent comprises or consists of cyclodextrin, or in other words, the composition further comprises cyclodextrin. Examples of cyclodextrin include, but are not limited to, alpha-, beta-, and gamma-cyclodextrin derivatives or combinations thereof. The composition typically comprises less than 100 mg / mL, less than 50 mg / mL, less than 20 mg / mL, or less than 10 mg / mL of cyclodextrin. In a more specific embodiment, the cyclodextrin is hydroxypropyl-beta-cyclodextrin (HP-β-CD), for example, commercially available under the trade name Kleptose®. In a more specific embodiment, the cyclodextrin is present in an amount or concentration ranging from 2 mg / mL to 100 mg / mL, or from 2 mg / mL to 50 mg / mL, or from 2 mg / mL to 40 mg / mL. However, it should be understood that the composition according to the first aspect of the invention does not necessarily require the presence of a complexing agent such as cyclodextrin.Accordingly, some embodiments of the invention are free or essentially free of complexing agents, or more specifically, free or essentially free of cyclodextrin, or in other words, some embodiments of the invention exclude complexing agents, or more specifically, some embodiments of the invention exclude cyclodextrin.

[0045] In one embodiment, the composition further comprises a thickening agent, typically a hydrophilic polymer, added to the aqueous composition of the invention to increase its viscosity so as to (i) control the rate at which the composition, e.g., eye drops, flows out of its container (thereby enhancing ease of application), and (ii) extend the residence time of the composition in the precorneal environment.

[0046] Examples of thickening agents include, but are not limited to, hyaluronic acid, polyvinyl alcohol (PVA), polyvinylpyrrolidone (or povidone), carboxyvinyl polymers, methylcellulose (MC), carboxymethylcellulose (CMC, or carmellose), hydroxypropylmethylcellulose (HPMC, or hypromellose), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), polyacrylic acid or a salt thereof, xanthan gum, guar gum, chondroitin sulfate, polyethylene glycol, propylene glycol, or a combination thereof.

[0047] In specific embodiments, the composition further comprises a viscosity increasing agent selected from hyaluronic acid, povidone, hypromellose, carmellose, or combinations thereof.

[0048] In one embodiment, the composition further comprises one or more excipients selected from a tonicity adjusting agent, a buffering agent, and a pH adjusting agent.

[0049] Examples of tonicity adjusters include, but are not limited to, mannitol, sorbitol, potassium chloride, sodium chloride, glycerin, trehalose, combinations thereof, etc. The amount of tonicity adjuster in the composition is selected to make the tonicity of the composition in the isotonic range, for example, isotonic with lacrimal fluid. In one of the preferred embodiments, the tonicity adjuster is sodium chloride.

[0050] Exemplary buffering agents include, but are not limited to, phosphate, berate, citrate, acetate, carbonate, bicarbonate, borate-polyol complex, boric acid, sodium acetate, amino acid, Tris, bicarbonate, BIS-Tris, or salts thereof, combinations thereof, and the like. In one of the preferred embodiments, the buffering agent is a sodium phosphate buffer, such as a buffer of sodium phosphate monobasic monohydrate or dihydrate and sodium phosphate dibasic heptahydrate. In a specific embodiment, the phosphate buffer uses 0.54 mg / mL of sodium phosphate monobasic monohydrate (or 0.61 mg / mL of sodium phosphate monobasic dihydrate) and 1.63 mg / mL of sodium phosphate dibasic heptahydrate.

[0051] Examples of alkaline agents that can be used as pH adjusters include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), tromethamine, monoethanolamine, sodium bicarbonate (NaHCO3) and other organic and inorganic bases. Examples of acidic 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, and the like, and mixtures thereof. In one of the preferred embodiments, the pH adjuster is selected from hydrochloric acid (HCl) or sodium hydroxide (NaOH). It is understood that these pH adjusters can be used to adjust the pH of the composition as needed (in appropriate amounts), for example, to achieve a specific pH in the pH range of 6.0-8.0, such as about pH 7.4, or 6.0-7.5 (pH of lacrimal fluid).

[0052] In one embodiment, the composition comprises 3 mg / mL to 10 mg / mL potassium sorbate (K-sorbate). In one of the preferred embodiments, the composition comprises 3 to 8 mg / mL or 3 to 6 mg / mL K-sorbate, more particularly 3.7 to 5.7 mg / mL or 4.2 to 5.2 mg / mL, for example 4.7 mg / mL K-sorbate.

[0053] In a further embodiment, the composition has a pH of about 6.0 to 7.4. In a more specific embodiment, the composition contains 3 mg / mL to 10 mg / mL potassium sorbate and has a pH of about 6.0 to 7.4.

[0054] In one embodiment, the composition is provided in the form of a clear liquid that can be dropped onto the eye, i.e. the liquid is applied either directly onto the surface of the eyeball and / or inside (in) the eyelid, such as the lacrimal sac. In this regard, it is understood that the composition according to the first aspect of the invention can be administered topically directly onto any surface of the eye and / or orbit (e.g. sclera, cornea, conjunctiva, conjunctival sac, etc.), but is not intended for application to the external surface of the eyelid and for transdermal delivery of cevimeline and / or sorbic acid.

[0055] For the purpose of instillation into the eye, the composition may have a kinematic viscosity in the range of 1 cP to 60 cP, or 1 cP to 50 cP, or 1 cP to 20 cP, for example, a kinematic viscosity of less than 5 cP. As used herein, the term "kinematic viscosity" refers to the kinematic viscosity at room temperature (20±5°C) determined by or measured using a Brookfield rotating spindle viscometer, which measures the force to rotate a spindle in a test sample at a given rotation speed. The test sample is stored at room temperature for about 2 hours before testing and then placed in the measurement chamber with a pipette. An appropriate rotation speed for the spindle is then selected depending on the expected viscosity of the test solution. Furthermore, it is also preferred if the composition is isotonic or essentially isotonic with lacrimal fluid (tear fluid). In one embodiment, the composition has an osmolality in the range of about 200 to 600 mOsm / kg, or about 250 to 450 mOsm / kg, or about 250 to 400 mOsm / kg. In some preferred embodiments, the liquid composition has an osmolality in the range of about 270-350 mOsm / kg, or about 280-300 mOsm / kg.

[0056] Furthermore, the composition according to the first aspect of the present invention is preferably sterile, particularly, but not exclusively, when intended for instillation into the eye. In one embodiment, the composition is subjected to sterile filtration, for example by passing it through a 0.22 μm filter.

[0057] In a further specific embodiment, the composition is an ophthalmic composition provided in the form of eye drops. In some cases, ophthalmic compositions such as eye drops are also referred to as topical compositions or topical ophthalmic compositions, since they are applied to the skin and / or mucosal surface of the eye. Assuming a concentration of cevimeline of 1-50 mg / mL for the eye drop composition according to the first aspect of the invention, an effective amount of cevimeline can be administered typically in one drop. The term "effective amount" refers to an amount or quantity of an active ingredient or drug (here cevimeline) sufficient to induce a necessary or desired therapeutic response, or in other words, an amount sufficient to induce a discernible biological response when administered to a patient.

[0058] In one embodiment, the composition is not provided in the form of an ointment, cream, paste, insert, punctal plug, and / or plaster, or in other words, the composition according to the first aspect of the invention excludes compositions in the form of an ointment, cream, paste, insert, punctal plug, and / or plaster.

[0059] In one embodiment, the composition may optionally comprise one or more additional active agents, such as an active agent selected from (a) steroids, such as loteprednol etabonate, prednisolone acetate, fluticasone, or a combination thereof; (b) immunomodulators or immunosuppressants, such as cyclosporine, tacrolimus, sirolimus, or a combination thereof; (c) hormones, such as testosterone, estrogen, or a combination thereof; (d) secretagogues, such as rebamipide, diquafozole, or a combination thereof; (e) lymphocyte function-associated antigen 1 (LFA-1) antagonists, such as lifitegrast; and / or (f) an active ingredient effective to treat meibomian gland dysfunction.

[0060] In an alternative embodiment, the composition is free of or essentially free of active and / or benefit agents other than (i) cevimeline or a pharma- ceutically acceptable salt thereof, and / or (ii) sorbic acid or a pharma-ceutically acceptable salt thereof as the PUFA. In particular, the composition is free of or essentially free of insulin, insulin-like growth factor (IGF), somatomedin C, and cycloplegic agents.

[0061] In a second aspect, the present invention relates to a method for treating one or more of dry eye disease, xerostomia, or Sjogren's syndrome, comprising topically administering a composition according to the first aspect of the present invention to a subject suffering from dry eye disease, xerostomia, and / or Sjogren's syndrome. In other words, in this second aspect, the present invention relates to a composition according to the first aspect of the present invention for use in treating one or more of dry eye disease, xerostomia, or Sjogren's syndrome. In other words, in this second aspect, the present invention relates to the use of a composition according to the first aspect of the present invention in the manufacture of a medicament for treating one or more of dry eye disease, xerostomia, or Sjogren's syndrome. Thus, any embodiment or specific or preferred embodiment disclosed herein in relation to a composition according to the first aspect of the present invention may be applied to a method or use according to the second aspect of the present invention.

[0062] In one embodiment, the composition may be administered to the subject's eye, typically by dropping it into the eye (i.e., applying it directly to either the surface of the eyeball and / or inside the eyelid, e.g., the lacrimal sac of the eye). In an alternative embodiment, or in addition to administration to the subject's eye, the composition may also be administered to the subject's nasal mucosa, e.g., in the form of an aqueous nasal spray administered to the nasal cavity.

[0063] In one embodiment, the composition is administered once, twice, or three or four times daily. In this regard, the composition is advantageous over, for example, merely an artificial tear composition or a saliva composition that needs to be applied up to 10-12 times per day.

[0064] In one embodiment, the composition is administered for a treatment period of at least 7 days.

[0065] Advantageously, the composition does not cause miosis following administration, particularly following administration to the eye.

[0066] In a third aspect, the present invention relates to an ophthalmic composition comprising 2 mg / mL to 50 mg / mL of cevimeline or a pharma- ceutically acceptable salt thereof, 4.7 mg / mL of potassium sorbate, sodium phosphate buffer, sodium chloride, and water. For example, in one of the preferred embodiments, the present invention relates to an ophthalmic composition comprising 2 mg / mL to 40 mg / mL of cevimeline or a pharma- ceutically acceptable salt thereof, 4.7 mg / mL of potassium sorbate, sodium phosphate buffer, sodium chloride, and water.

[0067] In a further aspect, the present invention relates to a method of treating one or more of dry eye disease, xerostomia, or Sjogren's syndrome, comprising administering an aqueous composition comprising cevimeline to the nasal mucosa of a subject suffering from dry eye disease, xerostomia, and / or Sjogren's syndrome.

[0068] The above is a detailed description of a specific embodiment of the present invention. Although specific embodiments of the present invention are described herein for illustrative purposes, it will be understood that various modifications can be made without departing from the spirit and scope of the present invention. Therefore, the present invention is not limited except as by the appended claims. All embodiments disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure.

[0069] The following examples serve to illustrate the present invention, but they should not be construed as limiting the scope of the invention. All examples used pharmaceutical grade ingredients in the preparation of the compositions described below. EXAMPLES

[0070] Example 1 (Ex.1) - Stability of Cevimeline / K-sorbate Compositions (Panel I) Several compositions containing cevimeline (here in its cevimeline HCl×0.5H2O salt form) and the medium chain polyunsaturated fatty acid sorbic acid (SA, here in its potassium sorbate salt form) were prepared by mixing the components according to Table 1 below, filtered (0.22 μm), then filled into high density polyethylene (HDPE) eye dropper bottles and subsequently evaluated for stability. The compositions are suitable for instillation into the eyes, for example in the form of eye drops.

[0071] All compositions contained 2 mg / mL cevimeline (free base equivalent), 4.7 mg / mL potassium sorbate, and sodium chloride as a tonicity agent, except for EY4-11, which was included as a control set without potassium sorbate to evaluate the effect of potassium sorbate on cevimeline stability. Formulation variables evaluated were the effect of buffer type and pH (sodium phosphate / citrate buffers at pH 7.0 and 8.0, citrate buffer at pH 6.0, and borate buffer at pH 8.0), and the presence of disodium ethylenediaminetetraacetate (Na2-EDTA) as an antioxidant chelating agent.

[0072] Immediately after preparation, all compositions were clear, colorless solutions free of any oily film or droplets visible to the naked human eye.

[0073] Stability studies were performed at 25° C. / 40% RH (i.e., "real-time" stability) and 40° C. / 25% RH (accelerated stability). Stability study parameters monitored included percent drug assay (as measured by HPLC), impurity (degradant) content, pH, osmolality, and physical appearance. [Table 1]

[0074] As can be seen in Table 2 below, EY4-1 (with sorbate) and EY4-11 (without sorbate) were the most stable, indicating that it is feasible to formulate cevimeline in aqueous compositions with potassium sorbate as the PUFA at concentrations above 1-2 mg / mL. The EDTA-containing formulations EY4-3, EY4-7, EY4-8, and EY4-9 exhibited discoloration during storage at 40° C., accompanied by higher drug loss.

[0075] Of all the buffer types tested, the formulation containing phosphate buffer (EY4-1) was the most stable and showed promising results in terms of solution appearance, drug assay, and impurity (degradant) content. [Table 2]

[0076] Example 2 (Ex.2) - Stability of Cevimeline / K-sorbate Compositions (Panel II) Based on the stability findings from Panel I study, a second panel of formulations was prepared using phosphate as the buffer system and sodium chloride as the isotonic agent. Aqueous compositions containing different concentrations of cevimeline (here in its cevimeline HCl×0.5H2O salt form) as well as the medium chain polyunsaturated fatty acid sorbic acid (SA, here in its potassium sorbate salt form) were prepared by mixing the components according to Table 3 below, filtered (0.22 μm), and then filled into low density polyethylene (LDPE) eye dropper bottles, which were further sealed in aluminum pouches, and then evaluated for stability. The compositions are suitable for instillation into the eyes, for example in the form of eye drops.

[0077] The formulation 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 the presence of benzalkonium chloride (BAK) as a preservative.

[0078] Stability studies were performed at 25° C. / 40% RH and 40° C. / 25% RH and 60° C. Stability study parameters monitored included percent drug assay (as measured by HPLC), impurity (degradant) content, pH, osmolality, and physical appearance. [Table 3] [Table 4] JPEG2025502242000005.jpg87166

[0079] As can also be seen in Table 4 above, stability was found to be dependent on drug concentration, pH, and potassium sorbate concentration. Cevimeline was found to be more stable at higher drug concentrations (e.g., EY4-21 vs. EY4-22). On the other hand, compositions containing higher concentrations of potassium sorbate were found to be relatively less stable with respect to cevimeline degradation (e.g., EY4-21 vs. EY4-23). ​​Only slight discoloration was observed for the composition containing 15 mg / mL potassium sorbate (EY4-23), but only when stored at 40° C. for 6 months.

[0080] Within the pH range of 6.0-8.0 tested, cevimeline was relatively stable at lower pH values ​​(e.g., EY4-21, EY4-29, and EY4-30). A similar pH effect was noted for formulations not containing potassium sorbate (EY4-25, EY4-27, and EY4-28). Finally, the preservative benzalkonium chloride (BAK) did not significantly affect cevimeline stability in this study (e.g., EY4-21 vs. EY4-26).

[0081] The inventors further found that the total amount of degradation impurities observed in some of the compositions did not correlate with the percent assay loss, suggesting that absorption of cevimeline into the LDPE container may have occurred.

[0082] Example 3 (Ex.3) - Stability of Cevimeline / K-sorbate Compositions (Panel III) A third panel of formulations was prepared using phosphate as a buffer system and sodium chloride as an isotonicity agent. Aqueous compositions containing different concentrations of cevimeline (here in its cevimeline HCl×0.5H2O salt form) and the medium chain polyunsaturated fatty acid sorbic acid (SA, here in its potassium sorbate salt form) were prepared by mixing the components according to Table 5 below. Compositions suitable for instillation into the eye were filtered (0.22 μm) and filled into eye dropper bottles made of either high density polyethylene (HDPE) (EY4-31 to -37) or polyethylene terephthalate (PET, EY4-38 and -39) to mitigate potential drug absorption into the eye dropper container (medium), and both container types were further sealed in aluminum pouches. The compositions were then evaluated for stability.

[0083] The formulation variables evaluated were cevimeline concentrations ranging from 2.0 mg / mL to 6.0 mg / mL (free base equivalent), and pH values ​​ranging from pH 6.0 to 7.4. Formulations containing polyoxyl 40 hydrogenated castor oil (here Kolliphor® RH40) and hydroxypropyl-β-cyclodextrin (HP-β-CD, here Kleptose®) were also included in the formulation panel to evaluate the effectiveness of the two as potential stabilizers.

[0084] Stability studies were performed at 25° C. / 40% RH and 40° C. / 25% RH and 60° C. Stability study parameters monitored included percent drug assay (as measured by HPLC), impurity (degradant) content, pH, osmolality, and physical appearance. [Table 5]

[0085] As can also be seen in Table 6 below, the drug assay remained unchanged or only slightly decreased in pouched HDPE bottles depending on the pH, while samples stored in PET bottles showed an apparent increased drug assay. The increased assay coincides with the weight loss of the PET bottles after 3 months, which was 3% at 25°C / 40% RH, 12% at 40°C / 25% RH, and 37% at 60°C, suggesting a significant loss of water in / from the PET bottles. No discoloration was observed for any of the compositions. Although both stabilizers investigated did not significantly reduce cevimeline degradation, unexpectedly, HP-β-CD appears to alleviate the problem of drug absorption into the container, as evidenced by the cevimeline assay of EY4-34 (particularly at 40°C and 60°C) and further by Example 4. [Table 6] JPEG2025502242000008.jpg91166JPEG2025502242000009.jpg91166

[0086] Example 4 (Ex.4) - Container absorption of cevimeline / K-sorbate compositions with and without HP-β-CD at 40° C. (Panel IV) To further investigate the effect of hydroxypropyl-beta-cyclodextrin (HP-β-CD) on drug absorption into eye drop containers, a fourth panel of formulations was prepared. For this purpose, formulations according to the invention with and without HP-β-CD were investigated in LDPE bottles (EY4-50 to EY4-55). For comparison, compositions without sorbate were also prepared.

[0087] Aqueous compositions containing 2 mg / mL cevimeline (here in its cevimeline HCl×0.5H2O salt form) suitable for instillation into the eye were mixed with the components according to Table 7 below, filtered (0.22 μm), and filled (3 mL fill) into LDPE eye dropper bottles. The containers were not sealed in aluminum pouches for this panel. The formulation variables evaluated were (i) the presence or absence of HP-β-CD, and (ii) pH values ​​ranging from pH 7.0 to 8.0.

[0088] The stability study was performed at 40° C. / 25% RH. Stability study parameters monitored included percent drug assay (as measured by HPLC), impurity (degradant) content, pH, osmolality, and physical appearance. [Table 7] [Table 8]

[0089] As can also be seen in Table 8 above, drug assays confirmed that HP-β-CD can reduce cevimeline losses associated with absorption into the container, with both the change or difference in cevimeline assay between the initial and 3 month time points (t0 and t3) and the increase in impurity content over time (indicative of drug degradation) being much less for HP-β-CD containing formulations (EY4-53, EY4-54, EY4-55, EY4-57), see for example EY4-50-EY4-52, compared to the respective HP-β-CD containing compositions EY4-53-EY4-55. Additionally, less drug was observed to be lost due to absorption by the container at lower pH values.

[0090] In summary of the compositions exemplified in Examples 1-4 above, it has been found to be successful in developing stable aqueous compositions comprising cevimeline (here in its HCl×0.5H2O salt form) and sorbic acid as a PUFA (here in its potassium sorbate salt form), such as the compositions outlined in Table 9 below. The compositions are suitable for instillation into the eye, for example in the form of eye drops. They may comprise a therapeutically effective amount of cevimeline, potassium sorbate as a PUFA less than 15 mg / mL, a phosphate buffer, and sodium chloride as an isotonic agent. A pH range of pH 6.0-8.0, or pH 6.0-7.4 is preferred. The compositions may optionally further contain benzalkonium chloride (BAK) and / or HP-β-cyclodextrin (e.g., Kleptose®) as preservatives. The composition can be filled into a suitable eye dropper bottle with demonstrated acceptable compatibility, such as a semi-permeable plastic bottle (e.g., high density polyethylene HDPE, low density polyethylene LDPE, polypropylene PP, or cyclic olefin copolymer COC) or similar pharmaceutical primary container closure system, such that absorption of cevimeline into the primary container housing the composition (i.e., typically for up to 3 years) is mitigated during storage. [Table 9]

[0091] Example 5 (Ex.5) - Ocular Tolerance Study in New Zealand White Rabbits The objective of this study was to evaluate the local and systemic tolerability of cevimeline when applied by topical ocular application of 40 μL to the left eye (without dosing the right eye) four times daily for seven consecutive days. The total dose was 160 μL / day, with a dosing interval of 2±0.5 hours.

[0092] Three test compositions (low, medium, and high doses) containing various cevimeline concentrations (6 mg / mL, 20 mg / mL, and 40 mg / mL, respectively) were tested in a total of 24 experimentally naive New Zealand White rabbits (12 males, 12 females), all 5 months of age and weighing 2.7-3.4 kg at the start of the study. The components of cevimeline-containing test compositions 1, 2, and 3 (here cevimeline in its cevimeline HCl×0.5H2O salt form) as well as the components of the vehicle alone (control) are summarized in Table 10 below. The test schedule is summarized in Table 11 below. [Table 10] [Table 11]

[0093] Mortality / morbidity observations were recorded twice daily and clinical observations were recorded once daily. Draize scoring for eye irritation was performed before treatment initiation, before the first and fourth doses on days 1-7, and also after the first dose on day 1. In addition, pupil size in each eye was recorded as normal, dilated, or constricted. Body weights were recorded at randomization / selection and on days 1 and 7. Food intake was recorded daily. Ophthalmological examinations were performed on all animals before treatment initiation and on day 7. All animals were released from the study and returned to the colony on day 8 after the final clinical observation.

[0094] Both male and female New Zealand White rabbits were found to tolerate cevimeline formulations up to a maximum concentration of 40 mg / mL when applied topically to the treated eye four times daily for seven consecutive days. Minor clinical signs including ocular / conjunctival redness (6, 20 and 40 mg / mL) and strabismus (40 mg / mL only) were observed sporadically in the cevimeline-treated groups. All clinical signs resolved by completion of the study on day 8. There was no effect on body weight or food consumption, no signs of mortality or morbidity, and no effect on pupil size, with all pupils observed to be of normal size following dose administration. All animals survived to completion of the study on day 8.

[0095] Ophthalmic examinations performed on day 7 showed less hyperemic conjunctiva in 4 of 12 eyes in low dose group 2 (6 mg / mL) and 2 of 12 eyes in mid dose group 3 (20 mg / mL), but only in 1 of 4 in group 2 and 1 of 2 in group 3 in the left (i.e., treated) eye. Furthermore, no conjunctival hyperemia was seen in any animal in either control group 1 or high dose group 4 (40 mg / mL). The clinical findings of less hyperemic conjunctiva (conjunctival erythema) were considered to be procedure-related (scoring / irritation) and not related to the cevimeline composition itself, since they were (i) sporadic, (ii) in both treated and untreated eyes, (iii) not dose-dependent, and (iv) did not correlate with other clinical signs. Furthermore, only a few animals were affected, and no severity scores exceeded 1. There was no effect on pupil size. All pupils were observed to be of normal size after dose administration.

[0096] Example 6 (Ex.6) - PK study in male New Zealand White rabbits The objective of this study was to evaluate the pharmacokinetic (PK) behavior of cevimeline and the exposure of ocular tissues and plasma to cevimeline following a single (i.e., once on day 1) bilateral topical instillation (40 μL in each eye) of four ophthalmic test formulations F1-F4 in male New Zealand White rabbits. The study schedule is summarized in Table 12 below and shows that each test formulation was tested in a total of 16 male and experimentally naive New Zealand White rabbits.

[0097] Test formulations F1-F4 (low, medium, and high doses) containing various cevimeline concentrations (F1 and F2: 6 mg / mL, F3: 20 mg / mL, and F4: 40 mg / mL, respectively) were prepared by dissolving all components listed in Table 13 in purified water followed by sterile filtration. All test formulations (i.e., F2-F4) contained 4.7 mg / mL potassium sorbate except for the control F1, which did not contain sorbate. Cevimeline was used in the form of its cevimeline HCl×0.5H2O salt as obtained from Excella.

[0098] After preparation, 3 mL fill volumes of each of the tested F1-F4 eye drop formulations were packaged in 5 mL white HDPE bottles (obtained from Gerresheimer AG, Germany). The bottles, as well as their drop tips and caps, were sterilized (e.g., here by gamma irradiation) prior to filling. At least three bottles were filled per composition, one for the PK study described in this Example and two for the 2-month storage stability study at 25° C. / 40% RH pre- and post-dosing as outlined in Example 7.

[0099] Plasma was collected from two animals / group pre-dose (t0) and approximately 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose. In addition, tissue samples from each eye (i.e., cornea, aqueous humor, retina, conjunctiva, iris / ciliary body, lacrimal gland, and sclera) were collected at terminal necropsy from two animals / group at the same time points.

[0100] All samples were analyzed for cevimeline concentration and model-independent methods were used to construct composite plasma and tissue concentration-time profiles for each dose group and eye from which pharmacokinetic parameters were derived. For each dose group, the following pharmacokinetic parameters were determined: maximum cevimeline concentration in plasma and tissues and the time to reach it (c max and t max ), and exposure (t0–t 24h and t0 to t last Both the half-life value (t 1 / 2 ) is the concentration at which the concentration-time profile is sufficient in the terminal elimination phase (t max (at least three samples not containing 2 , and were determined only if they had at least three half-lives of data. [Table 12] [Table 13]

[0101] PK studies reaffirmed that New Zealand White rabbits tolerate cevimeline formulations up to a maximum concentration of 40 mg / mL when applied topically to the eye via eye drops.

[0102] AUC of different ocular tissues for groups 1-4 (i.e., rabbits receiving test formulations F1, F2, F3, and F4, respectively) 0~24hr The values ​​(ie, overall exposure to cevimeline) yielded the following rank order from highest to lowest: Group 1 / F1 (no sorbate): Left lacrimal gland > right lacrimal gland > left cornea > right cornea > right conjunctiva > left iris / ciliary body > left conjunctiva > right iris / ciliary body > left aqueous humor > right aqueous humor > left sclera > right retina > right sclera > left retina, Group 2 / F2: Right lacrimal gland > left lacrimal gland > right cornea > left cornea > right conjunctiva > right iris / ciliary body > right aqueous humor > left iris / ciliary body > left aqueous humor > left conjunctiva > left sclera > right retina > right sclera > left retina, Group 3 / F3: Left lacrimal gland > right lacrimal gland > left cornea > right cornea > left iris / ciliary body > left aqueous humor > right conjunctiva > right iris / ciliary body > left conjunctiva > right aqueous humor > right sclera > left sclera > right retina > left retina, Group 4 / F4: Right lacrimal gland > left cornea > right cornea > left lacrimal gland > right conjunctiva > left iris / ciliary body > right iris / ciliary body > left aqueous humor > right aqueous humor > left conjunctiva > right sclera > left sclera > right retina > left retina.

[0103] These results indicate that using sorbate-containing eye drop formulations according to the present invention (as exemplified by formulations F1-F4 in this PK study), cevimeline is found or reaches primarily the lacrimal gland of the eye, which is the target tissue for cevimeline delivery for the treatment of dry eye disease.

[0104] The results found in plasma versus the tissues of highest drug distribution (lacrimal gland and cornea, average of both eyes for each) for Groups 1-4 are summarized below in Table 14. Comparing the data obtained for ocular tissues with that in plasma, it can be seen that (i) only very little cevimeline exposure occurs in plasma indicating a negligible, if any, risk of undesirable systemic side effects, and (ii) the highest cevimeline exposure (AUC) is found in the lacrimal gland. [Table 14]

[0105] As further seen in Table 14, the maximum cevimeline concentrations in plasma and cornea (t max ) was reached within 0.43 to 0.75 hours after administration in all of groups 1 to 4, while t maxwas slightly longer at approximately 1.5 to 2 hours post-dose for all of groups 1 to 4. Cevimeline was typically still quantifiable at 24 hours in all samples, except for plasma samples from low-dose groups 1 and 2 (F1 and F2), where cevimeline was no longer detectable at the 4 and 8 hour time points, respectively.

[0106] Maximum concentration and exposure values ​​of cevimeline (C max and AUC 0-24hr ) increased with increasing dose in both plasma and ocular tissue samples, but not necessarily in a dose-dependent manner. For example, a 1:3.3:6.7-fold increase in cevimeline doses from 0.48, 1.6, and 3.2 mg per animal was seen in the left and right lacrimal glands, respectively. max resulting in an approximately 1:3.1:3.8-fold or 1:2.5:4.9-fold increase in AUC 0-24h This resulted in an approximately 1:3.1:3.5-fold or 1:2.7:4.5-fold increase in values.

[0107] Furthermore, when comparing compositions with and without K-sorbate (F2 vs. F1, respectively), the C of cevimeline increased when K-sorbate was included in the composition. max and AUC 0-24hr was advantageously found to be lower at less desirable delivery sites (particularly the iris / ciliary body and cornea), see Table 15 below (each ocular tissue as an average of the left and right eyes). In contrast, the desired exposure of the lacrimal gland to cevimeline (c max and AUC 0-24hr ) did not decrease with the addition of potassium sorbate, but instead increased. [Table 15]

[0108] Example 7 (Ex. 7) - Stability of eye drop test formulations F1 to F4 of Example 6 In addition to the PK studies outlined in Example 6, the four test formulations F1-F4 were also monitored pre- and post-dosing (pre-dosing = t0, post-dosing = 2 months or t2) for the appearance, assay and related substances of cevimeline, assay of sorbate, osmolality and pH values.

[0109] As can be seen in Table 16 below, there was essentially no difference in the pre- and post-dosing analytical results. The eye drop compositions tested in the PK study according to Example 6 above were stable over the course of at least two months after dosing, with assay results ranging from 98.6% to 101.4% of the labeling intensity for cevimeline (F1-F4) and 100% to 102% of the labeling intensity for potassium sorbate (F2-F4). Osmolality was in the range of 278-300 mOsm / kg for low and medium dose formulations F1-3 and 436-441 mOsm / kg for high dose formulation F4. pH was 6.9-7.0 for all formulations F1-F4. [Table 16]

[0110] The following list of numbered items are embodiments encompassed by the present invention. 1. An aqueous composition comprising: (a) 1 mg / mL to 50 mg / mL of cevimeline or a pharma- ceutically acceptable salt thereof; (b) sorbic acid or a pharma- ceutically acceptable salt thereof; and (c) an aqueous carrier; The pH of the composition is in the range of pH 6.0 to 8.0, or pH 6.0 to pH 7.5; An aqueous composition, wherein the composition comprises from 3 mg / mL to 10 mg / mL of sorbic acid or a pharma- ceutically acceptable salt thereof. 2. The composition according to item 1, wherein the composition does not contain an antimicrobial preservative. 3. The composition according to item 1 or 2, wherein the composition is provided in the form of a clear solution. 4. The composition according to any one of items 1 to 3, wherein the composition comprises water as the only solvent. 5. The composition according to any one of items 1 to 4, wherein the composition comprises 2 mg / mL to 50 mg / mL of cevimeline or a pharma- ceutically acceptable salt thereof. 6. The composition according to 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-beta-cyclodextrin (HP-β-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 according to any one of the preceding claims, wherein the composition further comprises a thickening agent. 11. The composition according to item 10, wherein the thickening agent is selected from hyaluronic acid, polyvinyl alcohol (PVA), polyvinylpyrrolidone (or povidone), carboxyvinyl polymer, methylcellulose (MC), carboxymethylcellulose (CMC, or carmellose), hydroxypropyl methylcellulose (HPMC, or hypromellose), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyacrylic acid or a salt thereof, xanthan gum, guar gum, chondroitin sulfate, polyethylene glycol, propylene glycol, or a combination thereof. 12. The composition according to item 11, wherein the thickening agent is selected from hyaluronic acid, povidone, hypromellose, carmellose, or a combination thereof. 13. The composition according to any one of items 1 to 12, wherein the composition further comprises one or more excipients selected from a tonicity adjusting agent, such as sodium chloride, a buffering agent, such as a phosphate buffer, and a pH adjusting agent. 14. The composition according to any one of items 1 to 13, wherein the composition comprises 3 mg / mL to 10 mg / mL of potassium sorbate. 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 in the form of a clear liquid that can be dropped onto the eyes. 17. The composition according to any one of items 1 to 16, having a kinematic viscosity in the range of 1 cP to 60 cP, or 1 cP to 50 cP, or 1 cP to 20 cP, such as a kinematic viscosity of less than 5 cP. 18. The composition according to any one of items 1 to 17, wherein the composition is an ophthalmic composition provided in the form of eye drops. 19. The composition according to any one of items 1 to 18, wherein the composition is not provided in the form of an ointment, cream, paste, insert, punctal plug, and / or plaster. 20. The composition further comprises one or more additional active agents, optionally (a) steroids, (b) an immunomodulatory or immunosuppressive agent; (c) hormones, (d) secretagogues, (e) lymphocyte function-associated antigen 1 (LFA-1) antagonists, and / or (f) an active ingredient effective in treating meibomian gland dysfunction; 20. The composition according to any one of the preceding claims, comprising an active agent selected from: 21. The composition according to any one of items 1 to 19, wherein the composition is free or essentially free of active and / or benefit agents other than (i) cevimeline or a pharma- ceutically acceptable salt thereof, and / or (ii) sorbic acid or a pharma- ceutically acceptable salt thereof, as the PUFA. 22. The composition according to any one of items 1 to 21, wherein the composition is essentially free of insulin, insulin-like growth factor (IGF), somatomedin C, and cycloplegics. 23. The composition according to any one of items 1 to 22, wherein absorption of cevimeline from the composition into its primary container is mitigated during storage. 24. The composition according to any one of the preceding claims, wherein the composition is contained in a primary container formed from high density polyethylene (HDPE), low density polyethylene (LDPE), polypropylene (PP), or cyclic olefin copolymer (COC). 25. A method for treating one or more of dry eye disease, xerostomia, or Sjogren's syndrome, comprising topically administering a composition according to any one of items 1 to 24 to a subject suffering from dry eye disease, xerostomia, and / or Sjogren'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 disease, xerostomia, or Sjögren's syndrome. 27. Use of a composition according to any one of items 1 to 24 in the manufacture of a medicament for treating one or more of dry eye disease, xerostomia, or Sjogren's syndrome. 28. The method according to item 25 or the use according to items 26 or 27, wherein the composition is administered to the eye of the subject. 29. The method according to item 25 or the 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 the use according to any one of items 26 to 29, wherein the composition is administered once, twice, or three or four times a day. 31. The method according to item 25 or the use according to any one of items 26 to 30, wherein the composition is administered for a treatment period of at least 7 days. 32. The method according to item 25 or the 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 after administration to the eye. An ophthalmic composition comprising 34.2 mg / mL to 50 mg / mL of cevimeline or a pharma- ceutically acceptable salt thereof, 4.7 mg / mL of potassium sorbate, sodium phosphate buffer, sodium chloride, and water. 35. A method for treating one or more of dry eye disease, xerostomia, or Sjogren's syndrome, comprising administering an aqueous composition comprising cevimeline to the nasal mucosa of a subject suffering from dry eye disease, xerostomia, and / or Sjogren's syndrome.

Claims

1. 1. An aqueous composition comprising: (a) 1 mg / mL to 50 mg / mL of cevimeline or a pharma- ceutically acceptable salt thereof; (b) sorbic acid or a pharma- ceutically acceptable salt thereof; and (c) an aqueous carrier; and wherein the pH of the composition is in the range of pH 6.0 to pH 8.0; An aqueous composition, wherein the composition comprises from 3 mg / mL to 10 mg / mL of sorbic acid or a pharma- ceutically acceptable salt thereof.

2. The composition of claim 1 , wherein the composition is free of antimicrobial preservatives.

3. The composition of claim 1 , wherein the composition is provided in the form of a clear solution.

4. The composition of claim 1 , wherein the composition comprises water as the only solvent.

5. 2. The composition of claim 1, wherein the composition comprises 2 mg / mL to 50 mg / mL of cevimeline or a pharma- ceutically acceptable salt thereof.

6. The composition of claim 1 , wherein the composition further comprises a complexing agent.

7. The composition of claim 6, wherein the complexing agent comprises or consists of a cyclodextrin.

8. The composition of claim 7, wherein the cyclodextrin is hydroxypropyl-beta-cyclodextrin.

9. 8. The composition of claim 7, wherein the cyclodextrin is present in an amount ranging from 2 mg / mL to 100 mg / mL.

10. The composition of claim 1 , wherein the composition further comprises a thickening agent.

11. 11. The composition of claim 10, wherein the thickening agent is selected from hyaluronic acid, polyvinyl alcohol (PVA), polyvinylpyrrolidone (or povidone), carboxyvinyl polymer, methylcellulose (MC), carboxymethylcellulose (CMC or carmellose), hydroxypropylmethylcellulose (HPMC or hypromellose), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), polyacrylic acid or a salt thereof, xanthan gum, guar gum, chondroitin sulfate, polyethylene glycol, propylene glycol, or a combination thereof.

12. 10. The composition of claim 1, wherein the composition further comprises one or more excipients selected from a tonicity adjusting agent such as sodium chloride, a buffering agent such as a phosphate buffer, and a pH adjusting agent.

13. The composition of claim 1, wherein the composition comprises from 3 mg / mL to 10 mg / mL of potassium sorbate.

14. The composition of claim 1, wherein the composition has a pH of about 6.0 to 7.

4.

15. 10. The composition of claim 1 having a kinematic viscosity in the range of from 1 cP to 60 cP, or from 1 cP to 50 cP, or from 1 cP to 20 cP.

16. 11. A method of treating one or more of dry eye disease, xerostomia, or Sjogren's syndrome, comprising topically administering the composition of claim 1 to a subject suffering from dry eye disease, xerostomia, and / or Sjogren's syndrome.

17. The method of claim 16 , wherein the composition is administered to the eye of the subject.

18. The method of claim 16 , wherein the composition is administered to the nasal mucosa of the subject.

19. 17. The method of claim 16, wherein the composition is administered once, twice, or three or four times daily.

20. 17. The method of claim 16, wherein the composition is administered for a treatment period of at least 7 days.

21. The method of claim 16 , wherein the composition does not cause miosis.

22. An ophthalmic composition comprising 2 mg / mL to 50 mg / mL of cevimeline or a pharma- ceutically acceptable salt thereof, 4.7 mg / mL of potassium sorbate, sodium phosphate buffer, sodium chloride, and water.

23. 1. A method for treating one or more of dry eye disease, xerostomia, or Sjogren's syndrome, comprising administering an aqueous composition comprising cevimeline to the nasal mucosa of a subject suffering from dry eye disease.

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