Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0043—Nose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears

Definitions

• compositions such as topical ophthalmic compositions or topical compositions for nasal administration, comprising a muscarinic agonist (MRA), specifically cevimeline, in combination with a medium-chain (Ce to Cio) polyunsaturated fatty acid (PUFA; e.g., C 6 to C12, or C 6 to Cio) such as sorbic acid, as well as methods for using the same in the treatment of diseases such as dry eye disease (DED), xerostomia and/or Sjogren’s syndrome.
• the compositions may comprise one or more further active agents such as steroids, immuno -modulators, hormones, and/or secretagogues.
• Xerostomia refers to a condition in which the salivary glands in mouth do not make enough saliva to keep mouth wet. Xerostomia is often due to the side effect of certain medications, Sjogren’s disease, or as a 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. Decreased saliva and dry mouth can have a major impact to the health of teeth and gums.
• Dry eye disease also called keratoconjunctivitis sicca or dry eye syndrome
• Dry eye syndrome is a chronic and potentially debilitating condition that involves ocular surface damage, inflammation, oxidative stress, and symptoms of irritation including discomfort and reduced visual quality. It is a multifactorial disorder of the ocular surface affecting an estimated 20 million patients in the United States alone.
• the Dry Eye Workshop (DEWS) has classified dry eye diseases based upon two basic causal mechanisms: tear deficiency and evaporative dry eye (i.e., a tear film instability due to abnormally rapid tear evaporation). Dry eye disease is also associated with localized inflammation of the ocular surface and periocular tissues.
• the pathology of tear deficiencies is a failure to maintain lacrimal gland function in tear secretion.
• the cause may be due to a failure of the lacrimal glands to produce tears based on a deficiency on the part of the lacrimal glands, an obstruction, systemic drugs that impair the function of the glands, autoimmune disease, or age-related changes in the lacrimal gland.
• Long-time contact lens wearers and patients who underwent LASIK may also develop deficiencies due to the loss of corneal nerve sensation.
• tears secreted from lacrimal gland contains essential enzymes, proteins and antimicrobial components that are crucial to protect and repair corneal epithelium cell damage as a result of dryness of the eye. It is, therefore, rational to target the increase in lacrimal gland secretion as the primary and main treatment of dry eye disease.
• Evaporative dry eye is typically caused by Meibomian gland dysfunction and lipid insufficiency that results in increased evaporation and decreased stability of the tear film. Evaporative dry eye causes ocular dry eye symptoms even in the presence of normal tear secretion.
• Ocular surface inflammation is among the consequences of tear deficiencies and/or Meibomian gland dysfunction.
• An immune-based inflammatory response also plays a major part in the corneal epithelial disease and ocular discomfort of dry eye.
• dry eye disease can be thought of as more than a simple 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 lead to dry eye disease. It is often difficult to point to one particular factor as the cause; instead, dry eye is caused by a cascade of problems or factors that lead to the dry eye disease signs and symptoms.
• Typical symptoms of dry eye disease include burning, itching, foreign body sensation, stinging, dryness, photophobia, swelling, ocular fatigue, and/or redness. In some cases, patients may report transient blurring of vision. These symptoms are typically worse later in the day and can be triggered or exacerbated by certain environmental conditions such as low humidity environment or wind.
• Therapeutic agents, or drugs, that are available in form of eye drop preparations for the treatment of dry eye disease include, for instance, the immunomodulator cyclosporine A (Restasis®), the secretagogues diquafosol sodium (Diquas®) or rebamipide (Mucosta®), and the lymphocyte function-associated antigen 1 (LFA-1) inhibitor lifitegrast (Xiidra®).
• Restasis® the immunomodulator cyclosporine A
• Diquas® secretagogues diquafosol sodium
• Micosta® rebamipide
• LFA-1 lymphocyte function-associated antigen 1
• Xiidra® lymphocyte function-associated antigen 1
• PUFAs polyunsaturated fatty acids
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• ALA alphalinolenic acid
• GLA gamma-linolenic acid
• LA linolenic acid
• AA arachidonic acid
• PUFAs have been demonstrated to offer numerous benefits to the eye when given orally in a large amount. For instance, it was reported that long-chain PUFAs (i.e., polyunsaturated fatty acids with 13 C-atoms or more, typically C13-C22) play important roles in normal human retinal function and visual development, and some epidemiological studies of PUFA-intake suggest a protective role against the incidence of advanced age-related macular degeneration (AMD). It was further reported that high doses of PUFA can alleviate dry eye symptoms, an effect that was confirmed by meta-analysis of the relevant randomized controlled trials.
• AMD advanced age-related macular degeneration
• PUFAs due to their lipophilic and often water-insoluble nature, formulating PUFAs into aqueous compositions for direct application to the eye or other mucosal surfaces, such as eye-drops or nasal sprays, is often challenging.
• a surfactant or cosolvent is required to sufficiently solubilize the PUFAs and/or to formulate them into emulsions, which can cause issues, for instance, because some of the most common preservatives for eye drops (e.g., benzalkonium chloride) are not compatible with emulsion formulations.
• the surfactants in emulsions can cause blurry vision and/or irritations to the eye.
• PUFAs are prone to oxidation and therefore require including antioxidant to stabilize them.
• US-patent US8957110B2 by TRB Chemedica International S.A discloses a hydrogel-based artificial tears type of eye-drop composition
• a hydrogel-based artificial tears type of eye-drop composition comprising long- chain (here Ci6 to C24) poly-unsaturated omega-3 and omega-6 fatty acids which enables direct administration of the PUFAs to the eye.
• the composition comprises vitamin E acetate as an antioxidant as well as gelling polymers such as crosslinked carboxyvinyl polymers as a stabilizer.
• Cevimeline (CAS 107233-08-9, or CAS 153504-70-2 for its HC1 salt hemihydrate; (2R,2R)-2’-methyl spiro[4-azabicyclo[2.2.2]octane-2,5’-[l,3]oxathiolane]; or cis-2'-methyl spiro[l-aza bicyclo[2.2.2]octane-3,5'-[l,3]oxathiolane] hydrate hydrochloride) is a choli- nergic agonist which binds to muscarinic receptors, in particular the Mi and M3 receptors, and thus is also referred to as a muscarinic receptor agonist (MRA).
• MRA muscarinic receptor agonist
• Cevimeline can increase secretion of exocrine glands, such as salivary and sweat glands. It has further been shown to promote tear production through stimulation of the lacrimal glands. Therefore, the oral cevimeline composition, although not currently approved for this purpose, has also been studied for its benefits in the treatment of dry eye disease. However, while oral cevimeline has shown significant improvement in treating dry eye disease, the treatment has not been widely accepted due to systemic side effects from oral administration, such as sweating, nausea, runny nose, flushing, frequent urge to urinate, dizziness, weakness, diarrhea, and blurred vision.
• Cevimeline containing ophthalmic formulations have been suggested, for instance, in US20070053964A1 (US’964) or in W02020072971A1 (W0’971).
• US'964 discloses formulations, such as adhesives or ointments, which are adapted for application onto the outer skin surface of the eyelid, and percutaneously deliver the cevimeline from the eyelidskin into the topical tissue of the eye by transdermal transfer.
• US’964 discloses a 20 % eye drop solution formulation of cevimeline that was administered directly into the eye (i.e., to the surface of the eyeball and/or (in)to the inner sides of the eyelids) but that acted only as a comparative example to a 20 % cevimeline ointment formulation. Said eyedrops were found to be inferior to the ointment applied to the eyelid in terms of the amount of lacrimal fluid secretion, and US’964 thus suggested that administration of cevimeline solution directly into the eye is not desirable compared to percutaneous preparations from tear production and side effect perspectives (such as miosis).
• Miosis is commonly expected to be aggravated when providing an MRA to the anterior segment (cornea) and iris/ciliary body of the eye; hence, these tissues are less desired delivery sites, which might explain US’964 teaching away from dosage forms that are instilled into the eye.
• the 'external’ percutaneous formulations described in US’964 are not suitable for direct administration onto the surface of the eye, because the high concentrations of drug and percutaneous absorption enhancer(s), that are required for sufficient transdermal drug transfer, would cause significant eye irritations (e.g., due to their high osmolality), especially when used long-term, as would need to be the case in DED -treatment.
• W0’971 describes topical ophthalmic compositions for the treatment of dry eye disease in the form of eye-drops comprising about 0.1-10 % of muscarinic receptor agonists (MRA), such as cevimeline, at a neutral pH range of pH 6-9, and one or more pharmaceutically acceptable excipients.
• MRA muscarinic receptor agonists
• 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 PUFA(s) being added as an ingredient separate from the MRA, and/or as part of an ion pair comprising the MRA and the PUFA.
• PUFAs long-chain polyunsaturated fatty acids
• goals of treatment include, for instance, to relieve signs and/or symptoms thereof, improve patient comfort, return the ocular surface and tear film to the healthy state, and, whenever possible, prevent corneal damage.
• preparations are preferably easier to formulate than prior art compositions, e.g., not requiring antioxidants, surfactants or co-solvents to solubilize and/or stabilize the PUFAs mentioned above.
• an object of the present invention to provide a stable aqueous composition that can be instilled into the eye, meaning onto the surface of the eye (e.g., eye drops) or applied topically into the nasal cavity, and which can be used for treating diseases such as dry eye disease, xerostomia and/or Sjogren’s syndrome. It is, in particular, an object of the present invention to provide a composition comprising cevimeline and a medium-chain polyunsaturated fatty acid (PUFA) that promotes tear production and, at the same time, diminishes oxidative stress. A further object of the present invention is to provide methods of treating dry eye disease, xerostomia and/or Sjogren’s syndrome by topically applied compositions comprising cevimeline and a medium-chain poly-unsaturated fatty acid (PUFA).
• PUFA medium-chain polyunsaturated fatty acid
• the invention in a first aspect, relates to an aqueous composition
• an aqueous composition comprising from 1 mg/mL to 50 mg/mL of cevimeline, or a pharmaceutically acceptable salt thereof; sorbic acid, or a pharmaceutically acceptable salt thereof; and an aqueous carrier, wherein the pH of the composition is in the range from pH 6.0 to pH 8.0, and wherein the composition comprises from 3 mg/mL to 10 mg/mL of sorbic acid.
• the invention in a second aspect, relates to a method of treating one or more of dry eye disease, xerostomia, or Sjogren syndrome, the method comprising a step of topically administering the composition according to the first aspect of the invention to a subject suffering from dry eye disease, xerostomia, and/or Sjogren syndrome.
• the invention in a third aspect, relates to an ophthalmic composition
• an ophthalmic composition comprising 2 mg/mL to 50 mg/mL cevimeline or a pharmaceutically acceptable salt thereof, 4.7 mg/mL potassium sorbate, sodium phosphate buffer, sodium chloride, and water.
• the invention relates to a method of treating one or more of dry eye disease, xerostomia, or Sjogren syndrome, the method comprising a step of administering an aqueous composition comprising cevimeline to the nasal mucosa of a subject suffering from dry eye disease, xerostomia, and/or Sjogren syndrome.
• the invention in a first aspect, relates to an aqueous composition
• an aqueous composition comprising from about 1 mg/mL to 50 mg/mL of cevimeline, or a pharmaceutically acceptable salt thereof; sorbic acid, or a pharmaceutically acceptable salt thereof; and an aqueous carrier, wherein the pH of the composition is in the range from about pH 6.0 to pH 8.0, and wherein the composition comprises from about 3 mg/mL to 10 mg/mL of sorbic acid, or a pharmaceutically acceptable salt thereof.
• the expression 'compound X, or a pharmaceutically acceptable salt thereof includes said compound X as well as its pharmaceutically acceptable salts, both in anhydrous form as well as e.g., hydrates thereof.
• cevimeline can be employed as such (i.e., in its free base form), as its hydrochloride salt (cevimeline HC1), as well as in its hydrate-forms such as cevimeline hydrochloride hemihydrate (cevimeline HC1 x 0.5 H2O).
• cevimeline may be present as the free base form, salt form, or a combination of free base and salt form.
• the term 'cevimeline’ means the free base form, the salt form, or combinations thereof.
• the expression 'compound X, or a pharmaceutically acceptable salt thereof in combination with a concentration provision shall be understood in such a way that the concentration refers to compound X; this means that in case of working with the heavier salts and/or hydrate forms of a compound X, a respectively higher amount of the salt shall be used to achieve a given concentration of X.
• Terms such as 'about’, 'approximately’, or 'ca.' are meant to compensate for the variability allowed for in the technical field concerned and inherent in the respective products (e.g., in the pharmaceutical industry), such as differences in content due to manufacturing variation, measurement variations, and/or time-induced product degradation.
• the terms in connection with an attribute or value include the exact attribute or the precise value, as well as any attribute or value typically considered to fall within a normal range or variability accepted in the technical field concerned.
• a variability range of up to ⁇ 10 % is common in e.g., the pharmaceutical industry.
• pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings, and optionally other animals, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• Sorbic acid is a hexadienoic acid with double bonds at C2 and C4, and with four geometrical isomers, the trans, trans-form of which is occurring naturally. Sorbic acid is also a mediumchain fatty acid (i.e., Ce to C12, or Ce to C10), and more specifically a medium-chain polyunsaturated fatty acid (PUFA).
• mediumchain fatty acid i.e., Ce to C12, or Ce to C10
• PUFA medium-chain polyunsaturated fatty acid
• the inventors surprisingly found that the addition of sorbic acid to an aqueous cevimeline composition according to the first aspect of the invention (e.g., eye-drops for instillation into the eye) increases the cevimeline exposure of the desired target tissues, mainly the lacrimal glands, while at the same time decreasing cevimeline exposure of eye-tissues such as the cornea and/or the iris/ciliary body.
• the desired target tissues mainly the lacrimal glands
• eye-tissues such as the cornea and/or the iris/ciliary body.
• the latter tissues are undesired sites for cevimeline exposure insofar as these tissues are responsible for side-effects such as miosis.
• the aqueous composition according to the first aspect of the invention is characterized in that it contains from 3 mg/mL to 10 mg/mL of sorbic acid, or a pharmaceutically acceptable salt thereof.
• Sorbic acid and its salts such as potassium sorbate, are known antimicrobial preservatives, with both antibacterial and antifungal properties, that are inter alia used in pharmaceuticals preparations.
• sorbic acids and salts thereof are generally used at concentrations of 0.1-0.2 % in oral or topical formulations (i.e., approx. 1-2 mg/mL in aqueous compositions).
• sorbic acid and salts like potassium sorbate are known to exhibit only minimal antibacterial properties in formulations above pH 6.
• concentration used for the aqueous composition according to the first aspect of the invention is higher than the concentrations recommended in the respective literature for use of sorbic acid or salts thereof as antimicrobial preservatives in topical compositions. This is due to the fact that according to the present invention, sorbic acid, or its salts, are not used, or at least not predominantly or purposefully used, based on its function as an antimicrobial preservative but instead due to its nature as a polyunsaturated acid (PUFA), specifically a water-soluble, medium-chain polyunsaturated acid.
• PUFA polyunsaturated acid
• the PUFA sorbic acid does not require surfactants and/or co-solvents in order to be solubilized into an aqueous composition.
• the PUFA sorbic acid is less sensitive to oxidative degradation than 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). Therefore, the aqueous composition does not necessarily require the presence of an antioxidant.
• the composition is free of, or essentially free of, added antioxidants.
• antioxidants are intended to mean an agent that inhibits oxidation and thus is used to prevent the deterioration of the composition, or components thereof, by the oxidative process.
• the terms 'free ofX’ or 'essentially free of X’ means that the respective material (e.g., a chemical compound or a composition) contains less than a functional amount of the ingredient 'X’, typically less than 2 wt.-%, or less than 1 wt.-%, preferably less than 0.1 wt.-% or even less than 0.01 wt.-%, and also including 0 wt.-% of the ingredient 'X’.
• the composition according to the first aspect of the invention is free of, or essentially free of, long-chain PUFAs (i.e., PUFAs with > 13 C-atoms, typically C13-C22)-
• the composition according to the first aspect of the invention comprises no antimicrobial preservative; or, more specifically, no further antimicrobial preservative, in case the sorbic acid or salts thereof are still considered antimicrobial preservatives, despite their reduced antibacterial activity at pH-values above 6.0, such as 6.0 to 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 salts thereof, thimerosal, chlorobutanol, quaternary amine, chlorhexidine gluconate, stabilized oxychloro complex, or combinations thereof.
• the (further) preservative if included, will be present in an amount or concentration required to pass USP and/or Ph. Eur. antimicrobial preservative effective test required for eye drops.
• BAK can be used at a concentration of 0.002-0.02 % (w/v), typically 0.005-0.01 % (w/v).
• the composition is provided in the form of a clear solution.
• a clear solution refers to transparent, or see-through, liquids or solutions free of any droplets or other suspended particles that are visible to the naked human eye; said clear liquids or solutions are not opalescent or 'milky’ white like most common emulsions, for instance.
• the clear solution is also colorless.
• the composition comprises water as a sole solvent, or in other words, water is the aqueous carrier, or at the main component.
• the composition comprises no co-solvent.
• no co-solvent, or no solvent other than water is needed to solubilize the PUFA when choosing sorbic acid as the PUFA.
• the composition comprises from 2 mg/mL to 50 mg/mL of cevimeline, or a pharmaceutically acceptable salt thereof. In more specific embodiments, the composition comprises from 2 mg/mL to 40 mg/mL of cevimeline, or a pharmaceutically acceptable salt thereof; or from 2 mg/mL to 20 mg/mL; or from 2 mg/mL to 10 mg/mL; or from 2 mg/mL to 6 mg/mL. In one embodiment, the composition comprises from 3 mg/mL to 8 mg/mL of sorbic acid, or a pharmaceutically acceptable salt thereof; or from 3 mg/mL to 6 mg/mL.
• the composition comprises 3.7 mg/mL to 5.7 mg/mL, or 4.2 mg/mL to 5.2 mg/mL of sorbic acid, or a pharmaceutically acceptable salt thereof, e.g., 4.7 mg/mL.
• cevimeline and sorbic acid are provided in the form of an ion-pair.
• the composition further comprises a complexing agent.
• the complexing agent comprises, or consists of, a cyclodextrin; or, in other words, the composition further comprises a cyclodextrin.
• cyclodextrins include, but are not limited to, derivatives of alpha-, beta-, and gamma-cyclodextrins 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(s).
• the cyclodextrin is hydroxypropyl-beta-cyclodextrin (HP- -CD), such as commercially available under the tradename Kleptose®.
• the cyclodextrin is present at an amount or concentration in the range 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. It should be understood, though, that the composition according to the first aspect of the invention does not necessarily require the presence of a complexing agent such as cyclodextrins.
• some embodiments of the invention are free of, or essentially free of, a complexing agent, or more specifically free of, or essentially free of, a cyclodextrin; or, in other words, some embodiments of the invention exclude a complexing agent, or more specifically some embodiments of the invention exclude cyclodextrin.
• the composition further comprises a viscosity-enhancing agent, typically a hydrophilic polymer that is 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 to (ii) prolong the residence time of the composition within the pre-corneal environment.
• a viscosity-enhancing agent typically a hydrophilic polymer that is 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 to (ii) prolong the residence time of the composition within the pre-corneal environment.
• viscosity-enhancing agents include, but are not limited to hyaluronic acid, polyvinyl alcohol (PVA), polyvinylpyrrolidone (or povidone), carboxyvinyl polymers, methylcellulose (MC), carboxymethylcellulose (CMC; or carmellose), hydroxypropyl methylcellulose (HPMC; or hypromellose), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyacrylic acid or salts thereof, xanthan gum, guar gum, chondroitin sulfate, polyethylene glycol, propylene glycol, or combinations thereof.
• PVA polyvinyl alcohol
• CMC carboxymethylcellulose
• HPMC hydroxypropyl methylcellulose
• HPC hydroxypropyl cellulose
• HEC hydroxyethyl cellulose
• polyacrylic acid or salts thereof xanthan gum, guar gum, chondroitin sulfate, polyethylene glycol, propylene glycol,
• composition further comprises a viscosity-enhancing agent selected from hyaluronic acid, povidone, hypromellose, carmellose, or combinations thereof.
• the composition further comprises one or more excipients selected from tonicity adjusting agents, buffering agents, and pH-adjusting agents.
• tonicity-adjusting agents include, but are not limited to mannitol, sorbitol, potassium chloride, sodium chloride, glycerin, trehalose, combinations thereof, and the like.
• the amount of tonicity-adjusting agent in the composition is chosen in such a way as to render the composition’s tonicity to fall within the isotonic range, e.g., isotonic with lacrimal fluid.
• the tonicity adjusting agent is sodium chloride.
• Exemplary buffering agents include, but are not limited to, phosphate salt, berate salt, citrate salt, acetate salt, carbonate salt, bicarbonate salt, borate-polyol complexes, boric acid, sodium acetate, amino acid, Tris, bicarbonate, BIS-Tris, or salt thereof, combinations thereof and the like.
• the buffering agent is a sodium phosphate buffer, for instance, a buffer of sodium phosphate monobasic mono- or dihydrate and sodium phosphate dibasic heptahydrate.
• the phosphate buffer uses 0.54 mg/mL of sodium phosphate monobasic monohydrate (alternatively, 0.61 mg/mL sodium phosphate monobasic dihydrate) and 1.63 mg/mL of sodium phosphate dibasic heptahydrate.
• alkaline agents that may be used as pH-adjusting agents, include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), tromethamine, monoethanolamine, sodium bicarbonate (NaHCOs) and other organic and inorganic bases.
• acidic agents that may be used as pH-adjusting agents include, but are not limited to, hydrochloric acid (HC1), citric acid, tartaric acid, lactic acid, acetic acid, and other organic and inorganic acids and the like and mixtures thereof.
• the pH-adjusting agent is selected from hydrochloric acid (HC1) or sodium hydroxide (NaOH).
• pH-adjusting agents can be used to adjust the pH of the composition as needed (q.s.), e.g., to achieve a specific pH in the pH-range of 6.0 to 8.0, or 6.0 to 7.5, such as about pH 7.4 (pH of lacrimal fluid).
• the composition comprises from 3 mg/mL to 10 mg/mL of potassium sorbate (K-sorbate). In one of the preferred embodiments, the composition comprises 3-8 mg/mL, or 3-6 mg/mL of K-sorbate, or more specifically 3.7-5.7 mg/mL, or 4.2-5.2 mg/mL of K-sorbate, e.g., 4.7 mg/mL.
• K-sorbate potassium sorbate
• the composition has a pH of about 6.0-7.4. In a more specific embodiment, the composition comprises from 3 mg/mL to 10 mg/mL of potassium sorbate and has a pH of about 6.0-7.4.
• the composition is provided in the form of a clear liquid that can be instilled into the eye, i.e., the liquid is applied either directly to the surface of the eyeball and/or (in)to the inner sides of the eyelids, such as into the lacrimal sac.
• the composition according to the first aspect of the invention can be administered topically directly onto any surface of the eye and/or eye socket (e.g., the sclera, cornea, conjunctiva, conjunctival sac, etc.) but is not intended for application to the outer surface of the eyelid and percutaneous delivery of cevimeline and/or sorbic acid.
• the composition may have a dynamic viscosity in the range of 1 cP to 60 cP, or 1 cP to 50 cP, or 1 cP to 20 cP, for instance, a dynamic viscosity of less than 5 cP.
• the term 'dynamic viscosity refers to the dynamic viscosity at room temperature (20 ⁇ 5 °C) as determined by, or measured using, a Brookfield rotating spindle viscometer which measures the force to turn the spindle in a test sample at a given rotation rate. The test sample is stored at room temperature for about 2 h prior to testing and then placed on the measurement chamber with a pipette.
• the composition is isotonic, or essentially isotonic, with lacrimal fluid (tear fluid).
• the composition has an osmolality in the range of about 200-600 mOsm/kg, or about 250-450 mOsm/kg, or about 250-400 mOsm/kg.
• the liquid composition has an osmolality in the range of about 270-350 mOsm/kg, or about 280-300 mOsm/kg.
• composition according to the first aspect of the invention is preferably sterile, especially when intended for - though not only then - for instillation into the eye.
• the composition is subjected to sterile filtration, for instance, by passing it through a 0.22 pm filter.
• the composition is an ophthalmic composition provided in the form of eye-drops.
• ophthalmic composition such as eye-drops are also referred to as topical compositions, or topical ophthalmic compositions, since they are applied to skin- and/or mucosal surfaces of the eyes.
• concentrations between 1-50 mg/mL of cevimeline for eye-drop compositions according to the first aspect of the invention an effective amount of cevimeline can typically be administered with a single drop.
• 'effective amount refers to the amount or quantity of active ingredient, or drug, (here cevimeline) which is sufficient to elicit the required or desired therapeutic response, or in other words, the amount which is sufficient to elicit an appreciable biological response when administered to a patient.
• the composition is not, provided in the form of an ointment, a cream, a paste, an insert, a punctum plug, and/or a plaster.
• the composition according to the first aspect of the invention excludes compositions in the form of an ointment, a cream, a paste, an insert, a punctum plug, and/or a plaster.
• the composition may optionally comprise one or more further active agents; for instance, active agents selected from (a) steroids such as loteprednol etabonate, prednisolone acetate, fluticasone, or a combination thereof, (b) immuno -modulators or immunosuppressants such as cyclosporine, tacrolimus, sirolimus, or a combination thereof, (c) hormones such as testosterone, estrogen, or a combination thereof,
• active agents selected from (a) steroids such as loteprednol etabonate, prednisolone acetate, fluticasone, or a combination thereof, (b) immuno -modulators or immunosuppressants such as cyclosporine, tacrolimus, sirolimus, or a combination thereof, (c) hormones such as testosterone, estrogen, or a combination thereof,
• lymphocyte function associated antigen-1 (LFA-1) antagonists such as lifitegrast
• active ingredients effective for treating Meibomian gland dysfunction.
• the composition is free of, or essentially free of, active agents and/or beneficial agents other than (i) cevimeline, or a pharmaceutically acceptable salt thereof, and/or (ii) sorbic acid as the PUFA, or a pharmaceutically acceptable salt thereof.
• the composition is free of, or essentially free of, insulin, insulin-like growth factor (IGF), somatomedin C, and cycloplegic agent.
• the invention in a second aspect, relates to a method of treating one or more of dry eye disease, xerostomia, or Sjogren syndrome, the method comprising a step of topically administering the composition according to the first aspect of the invention to a subject suffering from dry eye disease, xerostomia, and/or Sjogren syndrome.
• the invention in this second aspect the invention relates to the composition according to the first aspect of the invention for use in the treatment of one or more of dry eye disease, xerostomia, or Sjogren syndrome.
• the invention in this 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 disease, xerostomia, or Sjogren syndrome. Accordingly, any embodiments, or specific or preferred embodiments, disclosed herein in connection with the composition according to the first aspect of the invention, may be applied to the method or use according to the second aspect of the invention.
• the composition may be administered into the eye of the subject, typically, by instilling it into the eye (i.e., applying it either directly to the surface of the eye ball and/or to the inner sides of the eyelids, such as into the lacrimal sac of the eye).
• the composition may also be administered to the nasal mucosa of the subject, for instance, in the form of an aqueous nasal spray that is to be administered into the nasal cavity.
• the composition is administered once, twice, or three or four times a day.
• the composition is advantageous to, for instance, mere artificial tear- or saliva compositions that need to be applied up to 10-12 times a day.
• the composition is administered over a treatment period of at least 7 days.
• the composition does not cause miosis after administration, in particular after administration into the eye.
• the invention in a third aspect, relates to an ophthalmic composition
• an ophthalmic composition comprising 2 mg/mL to 50 mg/mL cevimeline or a pharmaceutically acceptable salt thereof, 4.7 mg/mL potassium sorbate, sodium phosphate buffer, sodium chloride, and water.
• the invention in one of the preferred embodiments, relates to an ophthalmic composition comprising 2 mg/mL to 40 mg/mL cevimeline or a pharmaceutically acceptable salt thereof, 4.7 mg/mL potassium sorbate, sodium phosphate buffer, sodium chloride, and water.
• the invention relates to a method of treating one or more of dry eye disease, xerostomia, or Sjogren syndrome, the method comprising a step of administering an aqueous composition comprising cevimeline to the nasal mucosa of a subject suffering from dry eye disease, xerostomia, and/or Sjogren syndrome.
• Example 1 (Ex. 11 - Stability of cevimeline/K-sorbate compositions [Panel
• compositions comprising cevimeline (here in its cevimeline HCl x O.S LhO 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 1 below, filtered (0.22 pm), then filled in high density polyethylene (HDPE) eye dropper bottles, and subsequently assessed in terms of stability.
• SA medium-chain polyunsaturated fatty acid sorbic acid
• the compositions are suited for instillation into the eye, e.g., in the form of eye-drops.
• 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 potassium sorbate-free control set to evaluate impact of potassium sorbate on cevimeline stability.
• Formulation variables evaluated were buffer species and pH (sodium phosphate/ citrate buffer at pH 7.0 and 8.0, citrate buffer at pH 6.0, and borate buffer at pH 8.0), as well as the effect of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of the presence of disodium
• EY4-1 (with sorbate) and EY4-11 (without sorbate) were most stable, indicating that formulating cevimeline in aqueous compositions with potassium sorbate as a PUFA in concentrations above 1-2 mg/mL is feasible.
• the EDTA containing formulations EY4-3, -7, -8, and -9 showed discoloration during storage at 40 °C, accompanied by higher drug losses.
• Table 2 Summary of stability data cevimeline compositions containing K-sorbate
• Aqueous compositions comprising different concentrations of cevimeline (here in its cevimeline HC1 x 0.5 H2O 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 pm), then filled in low density polyethylene (LDPE) eye dropper bottles which were further sealed in aluminum pouches, and subsequently assessed in terms of stability.
• SA medium-chain polyunsaturated fatty acid sorbic acid
• Formulation variables evaluated were cevimeline concentrations in the range of 2 mg/mL to 40 mg/mL (free base equivalent), pH-values in the range of pH 6.0 to 8.0, and potassium sorbate concentrations in the range of 4.7 mg/mL to 15 mg/mL, with or without the presence of benzalkonium chloride (BAK) as a preservative.
• BAK benzalkonium chloride
• the stability study was conducted at 25 °C / 40 % RH and 40 °C / 25 % RH and 60 °C. Stability test parameters monitored included percent drug assay (as measured by HPLC), impurity (degradant) content, pH, osmolality, and physical appearance.
• cevimeline was relatively more stable at lower pH-values (e.g., EY4-21, -29, and -30).
• a similar pH effect was also noticed for the formulations that do not contain potassium sorbate (EY4-25, -27, and -28).
• the preservative benzalkonium chloride (BAK) had no significant impact on cevimeline stability (e.g., EY4-21 vs. EY4-26) in this study.
• the inventors further found that the total amount of degradation impurities observed in some of the compositions does not correlate with the percent assay loss, suggesting that absorption of cevimeline to the LDPE container may have occurred.
• Example 3 (Ex. 3) - Stability of cevimeline/K-sorbate-compositions (Panel HI)
• a third panel of formulations was prepared using phosphate as a buffering system, and sodium chloride as a tonicity agent.
• Aqueous compositions comprising different concentrations of cevimeline (here in its cevimeline HC1 x 0.5 H2O 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 5 below.
• compositions which are suited for instillation into the eye, were filtered (0.22 pm) and filled in 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 (in)to the eye dropper container; both container types were further sealed in an aluminium pouch. Subsequently, the compositions assessed in terms of stability.
• HDPE high density polyethylene
• PET polyethylene terephthalate
• Formulation variables evaluated were cevimeline concentrations in the range of 2.0 mg/mL to 6.0 mg/mL (free base equivalent), and pH-values in the range of pH 6.0 to 7.4.
• Formulations containing polyoxyl 40 hydrogenated castor oil (here Kolliphor® RH40) and Hydroxypropyl-R-Cyclodextrin (HP-R-CD; here Kleptose®) were also included in the formulation panel to assess the effect of the two as potential stabilizers.
• the stability study was conducted at 25 °C / 40 % RH and 40 °C / 25 % RH and 60 °C. Stability test parameters monitored included percent drug assay (as measured by HPLC), impurity (degradant) content, pH, osmolality, and physical appearance.
• Table 5 Exemplary aqueous, liquid cevimeline/K-sorbate-compositions (Panel HI) * amount equivalent to 0.54 mg/mL Na-phosphate mono-basic monohydrate
• Table 6 Summary of stability data cevimeline compositions containing K-sorbate (Panel III) n.c.: not continued; ** bottle deformed; n/a: not available
• Example 4 (Ex. 41 - Container absorption of cevimeline/K-sorbate-compositions with and without HP-E-CD at 40 °C [Panel IV)
• a fourth panel of formulations was prepared to further investigate the effect of hydroxypropyl-beta-cyclodextrin (HP-E-CD) on drug absorption into eyedrop containers.
• HP-E-CD hydroxypropyl-beta-cyclodextrin
• formulations according to the present invention, with and without HP-E-CD were investigated in LDPE bottles (EY4-50 to EY4-55). Sorbate-free compositions were prepared as well for comparison.
• Aqueous compositions comprising 2 mg/mL cevimeline (here in its cevimeline HC1 x 0.5 H2O salt form), which are suited for instillation into the eye, were prepared by mixing the components according to Table 7 below, filtered (0.22 pm), and filled in the LDPE eye dropper bottles (3 mL fill). The containers were not sealed in an aluminium pouch for this panel.
• Formulation variables evaluated were (i) with and without the presence of HP-E-CD, and (ii) pH-values in the range of pH 7.0 to 8.0.
• the stability study was conducted at 40 °C / 25 % RH. Stability test parameters monitored included percent drug assay (as measured by HPLC), impurity (degradant) content, pH, osmolality, and physical appearance.
• the drug assays confirmed that HP-E-CD is able to mitigate cevimeline losses that are associated to absorption to the container, with both the change, or difference, of cevimeline assay between the initial and the 3 months timepoints (to and ts ) and the increase in impurity contents over time (a sign of drug degradation) being much less for the HP-E-CD containing formulations (EY4-53, EY4-54, EY4-55, EY4-57); see, for instance, EY4-50 to EY4-52 compared to their respective HP-E-CD containing compositions EY4-53 to EY4-55. Moreover, it could be observed that less drug was lost due to absorption by the container at lower pH-values.
• compositions comprising cevimeline (here in its HC1 x 0.5 H2O salt form) and sorbic acid as a PUFA (here in its potassium sorbate salt form) were successfully developed; for instance, compositions as outlined in Table 9 below.
• the compositions are suited for instillation into the eye, e.g., in the form of eye-drops. They may comprise a therapeutic effective amount of cevimeline, less than 15 mg/mL, potassium sorbate as the PUFA, a phosphate buffer, and sodium chloride as the tonicity agent.
• the compositions may optionally further contain benzalkonium chloride (BAK) as a preservative and/or HP-E-Cyclodextrin (e.g., Kleptose®).
• BAK benzalkonium chloride
• HP-E-Cyclodextrin e.g., Kleptose®
• the composition can be filled in a suitable eye-dropper bottle with proven acceptable compatibility where absorption of cevimeline into a primary container housing the composition is mitigated during storage shelf-life (i.e., typically up to 3 years), such as semi-permeable plastic bottles (e.g., high density polyethylene HDPE, low density polyethylene LDPE, polypropylene PP, or cyclic olefin copolymer COC), or similar pharmaceutical primary container closure systems.
• semi-permeable plastic bottles e.g., high density polyethylene HDPE, low density poly
• Table 9 Summary for aqueous, liquid cevimeline/K-sorbate-compositions Example 5 (Ex. 5) - Ocular Tolerability Study in New Zealand White Rabbits
• the purpose of this study was to evaluate the local and systemic tolerability of cevimeline when applied by topical ocular application 4 times daily, 40 pL to the left eye (right eye not dosed) for 7 consecutive days.
• the total administered volume was 160 pL/day, the dosing interval was 2 ⁇ 0.5 hr.
• test compositions (low-, mid-, and high dose), comprising various cevimeline- concentrations (6 mg/mL, 20 mg/mL, and 40 mg/mL, respectively) were tested on a total of 24 experimentally naive New Zealand White rabbits (12 male, 12 female), all 5 months old and weighing 2.7-3.4 kg at the outset of the study.
• the components of the cevimeline containing test compositions 1, 2 and 3 (cevimeline here in its cevimeline HCl x 0.5 H2O salt form) as well as of the vehicle alone (control), are summarized in Table 10 below.
• the testing schedule is summarized in Table 11 below.
• Table 10 Aqueous, liquid cevimeline/K-sorbate test compositions (low-, mid-, and high dose) and vehicle
• Mortality/morbidity observations were recorded twice daily, clinical observations once daily. Scoring for ocular irritation according to Draize was performed prior to treatment initiation, on days 1-7 prior to the 1 st daily dose and after the 4 th dose, and on day 1 also after the 1 st dose. In addition, pupil size for each eye was noted as normal, dilated or constricted. Body weights were recorded at the time of randomization/ selection and on days 1 and 7. Food consumption was recorded daily. Ophthalmological examinations were performed for all animals prior to treatment initiation and on day 7. All animals were released from the study and returned to the colony on Day 8 following a final clinical observation.
• the purpose of this study was to evaluate the pharmacokinetic (PK) behavior of cevimeline and exposure of ocular tissues and plasma to cevimeline following a single (i.e., once on day 1) bilateral, topical ocular instillation of four eye-drop test formulations F1-F4 to male New Zealand White rabbits (40 pL into each eye).
• the testing schedule is summarized in Table 12 below, indicating each test formulation was tested on a total of 16 male and experimentally naive New Zealand White rabbits.
• test formulations F1-F4 (low-, mid-, and high dose), comprising various cevimeline- concentrations (Fl 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 other than the sorbate-free control Fl (i.e., F2-F4) contained 4.7 mg/mL potassium sorbate. Cevimeline was used in the form of its cevimeline HC1 x 0.5 H2O salt, as obtained from Excella.
• a fill-volume of 3 mL of each of the tested F1-F4 eye-drop formulations was packaged in 5 mL white HDPE bottles (obtained from Gerresheimer AG; Germany).
• the bottles, as well as their drop-tips and caps, were sterilized prior to filling (e.g., here by gamma irradiation).
• At least three bottles per composition were filled; one bottle for the PK-study described in this example, and a further two bottles for a 2 -month storage stability test at 25 °C / 40% RH, pre- and post-dosing, as outlined in Example 7.
• Blood plasma was collected from two animals/group pre-dose (to), and at approximately 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose.
• tissue samples from each eye namely, cornea, aqueous humor, retina, conjunctiva, iris/ciliary body, lacrimal gland, and sclera
• All samples were analyzed for concentrations of cevimeline, and a composite plasma and tissue concentration-time profile was constructed for each dose group and eye from which pharmacokinetic parameters were derived, using model-independent methods.
• Table 13 Aqueous, liquid cevimeline/K-sorbate test compositions (low-, mid-, and high dose / low dose with and without K-sorbate) The PK-study reconfirmed that New Zealand White rabbits tolerated the cevimeline formulations up to the highest concentration of 40 mg/mL when applied topically to the eyes by ocular instillation.
• AUCo-24hr values i.e., the overall exposure to cevimeline
• Group 2 / F2 right lacrimal gland > left lacrimal gland > right cornea > left cornea
• 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
• Group 4 / F4 right lacrimal gland > left cornea > right cornea > left lacrimal gland
• the time to maximum cevimeline concentration (t ma x) in plasma and cornea was reached within 0.43-0.75 h post-dose for all of groups 1-4, whereas t max in the lacrimal glands was a little longer with about 1.5-2 h post-dose for all of groups 1-4.
• Cevimeline was typically still quantifiable after 24 h in all samples but the plasma-sample for the low-dose groups 1 and 2 (Fl and F2), where cevimeline could not be detected anymore at the 4- and 8-hour time-points, respectively.
• C max and AUCo-24hr The maximum concentration and exposure values (C max and AUCo-24hr) of cevimeline increased with increasing doses, both in plasma and in the eye-tissue samples, though not always in a dose-dependent manner.
• a 1:3.3:6.7-fold increase in cevimeline dose from 0.48, 1.6, and 3.2 mg per animal resulted in an approximate 1:3.1:3.8-fold or 1:2.5:4.9-fold increase in c max values found in the left and right lacrimal glands, respectively; and in an approximate 1:3.1:3.5-fold or l:2.7:4.5-fold increase in AUCo-24h values.
• Table 16 Summary of cevimeline assay results from compositions with or without sorbate as well as different doses.
• An aqueous composition comprising:
• composition (c) an aqueous carrier; wherein the pH of the composition is in the range from pH 6.0 to 8.0, or from pH 6.0 to pH 7.5, and wherein the composition comprises from 3 mg/mL to 10 mg/mL of sorbic acid, or a pharmaceutically acceptable salt thereof.
• composition of item 1 wherein the composition comprises no antimicrobial preservative.
• composition of item 1 or 2 wherein the composition is provided in the form of a clear solution.
• composition of item 6, wherein the complexing agent comprises, or consists of, a cyclodextrin.
• composition of item 7, wherein the cyclodextrin is hydroxypropyl-beta- cyclodextrin (HP- -CD).
• composition of item 7 or 8 wherein the cyclodextrin is present at an amount in the range from 2 mg/mL to 100 mg/mL. 10. The composition of any one of items 1 to 9, wherein the composition further comprises a viscosity-enhancing agent.
• composition of item 10 wherein the viscosity-enhancing agent is selected from hyaluronic acid, polyvinyl alcohol (PVA), polyvinylpyrrolidone (or povidone), carboxyvinyl polymers, methylcellulose (MC), carboxymethylcellulose (CMC; or carmellose), hydroxypropyl methylcellulose (HPMC; or hypromellose), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyacrylic acid or salts thereof, xanthan gum, guar gum, chondroitin sulfate, polyethylene glycol, propylene glycol, or combinations thereof.
• PVA polyvinyl alcohol
• PC polyvinylpyrrolidone
• HPMC hydroxypropyl methylcellulose
• HPC hydroxypropyl cellulose
• HEC hydroxyethyl cellulose
• polyacrylic acid or salts thereof xanthan gum, guar gum, chondroitin sulfate, polyethylene glycol
• composition of item 11 wherein the viscosity-enhancing agent is selected from hyaluronic acid, povidone, hypromellose, carmellose, or combinations thereof.
• excipients selected from tonicity adjusting agents such as sodium chloride, buffering agents such as a phosphate buffer, and pH-adjusting agents.
• composition of any one of items 1 to 16 having a dynamic viscosity in the range of 1 cP to 60 cP, or 1 cP to 50 cP, or 1 cP to 20 cP, for instance, a dynamic viscosity of less than 5 cP.
• LFA-1 lymphocyte function associated antigen-1
• active ingredients effective for treating Meibomian gland dysfunction.
• IGF insulin-like growth factor
• somatomedin C somatomedin C
• HDPE high density polyethylene
• LDPE low density polyethylene
• PP polypropylene
• COC cyclic olefin copolymer
• a method of treating one or more of dry eye disease, xerostomia, or Sjogren syndrome comprising a step of topically administering the composition of any one of items 1 to 24 to a subject suffering from dry eye disease, xerostomia, and/or Sjogren syndrome.
• An ophthalmic composition comprising 2 mg/mL to 50 mg/mL cevimeline or a pharmaceutically acceptable salt thereof, 4.7 mg/mL potassium sorbate, sodium phosphate buffer, sodium chloride, and water.
• a method of treating one or more of dry eye disease, xerostomia, or Sjogren syndrome comprising a step of administering an aqueous composition comprising cevimeline to the nasal mucosa of a subject suffering from dry eye disease, xerostomia, and/or Sjogren syndrome.

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