TW202211919A - Ophthalmic preparations of muscarinic agonist and methods of use - Google Patents

Abstract

The present invention provides stable topical ophthalmic preparations of muscarinic agonist for the treatment of dry eye disease. The composition can include a polyunsaturated fatty acid.

Description

Muscarinic agonist ophthalmic preparation and use thereof

The present invention relates to ophthalmic formulation compositions comprising muscarinic agonists alone or in combination with one or more other active agents such as steroids, immunomodulators, hormones, secretagogues, and/or polyunsaturated fatty acids (PUFAs), and its use in the treatment of dry eye.

Dry eye disease (DED), also known as dry keratoconjunctivitis, is a chronic disease that may cause damage, inflammation, and irritation to the surface of the eye. Dry eye is a multifactorial disease of the ocular surface that affects approximately 20 million patients in the United States. The International Dry Eye Workshop (DEWS) classifies dry eye on the basis of two basic pathogenic mechanisms: lack of tear fluid and abnormally rapid tear evaporation, and dry eye is also associated with localized inflammation of the surface of the eye and surrounding tissues. The relationship between chronic inflammation and the clinical manifestations of dry eye is currently unclear. Due to the complex causative factors of dry eye and the lack of understanding of the relationship between dry eye and inflammation, attempts to find effective dry eye treatments have been unsuccessful, leading both patients and clinicians to desperately hope for effective treatments .

Sjogren's syndrome (also known as "Mikulicz disease" and "Sicca syndrome") is classified as an autoimmune disorder in which immune cells attack and destroy the salivary and lacrimal glands. Sjogren's syndrome affects about 4 million people, second only to rheumatism. Although men and women of any age group are affected, 90% of the cases are women over the age of 40. The main cause may be rheumatoid arthritis, systemic lupus erythematosus, scleroderma, primary biliary cirrhosis and other diseases suffering from secondary Sjogren's syndrome for many years. There is currently no cure for Sjogren's dry eye syndrome, and treatment only reduces symptoms. Artificial tears, goggles to increase local humidity, or insertion of tear duct plugs to help preserve tears can temporarily relieve symptoms.

Lacrimal deficiency is the loss of the lacrimal gland's ability to maintain tear production. This can be attributed to lack of part of the lacrimal gland, blockage, systemic medications that impair tear line function, autoimmune disease, or changes in the lacrimal gland due to age that prevent the lacrimal gland from producing tears. Long-term contact lens wearers and patients who have undergone laser vision correction surgery may also suffer from a lack of tears due to loss of corneal nerve sensation.

Since most tears and tear components are secreted from the lacrimal gland, reduced lacrimal gland secretion can lead to a lack of tears and further damage and inflammation of the corneal epithelial cells. In addition, the tear fluid secreted by the lacrimal gland contains essential enzymes, proteins, and antibacterial components, which are essential for the protection and repair of corneal epithelial cell damage due to dry eyes. Therefore, theoretically increasing the secretion of the lacrimal gland is the main method for the treatment of dry eye.

Evaporative dry eye is usually caused by dysfunction of the meibomian glands, resulting in increased tear evaporation and decreased tear film-stabilizing lipids. Therefore, evaporative dry eye can have dry eye even if tear secretion is normal.

Lack of tears and/or dysfunction of the meibomian glands can cause inflammation of the surface of the eye. An immune-induced inflammatory response can also lead to corneal epithelial disease and dry eye. Therefore, we believe that dry eye is not only a lack of one or more components of the tear film, but a syndrome of inflammation on the surface of the eyeball. Most patients have a variety of dry eye causative factors. In general, it is not easy to pinpoint a specific cause; instead, dry eye is caused by a series of factors that contribute to the symptoms and symptoms of dry eye.

Typical symptoms of dry eye include burning, itchy eyes, feeling of a foreign object, stinging, dry eyes, photophobia, swelling, eye fatigue, and/or eye redness. In some cases, patients reported brief blurred vision. These symptoms are often more severe and can be triggered or exacerbated by certain environmental conditions, such as low humidity.

There are several tests that can be used to diagnose symptoms of dry eye. These include the use of diagnostic dyes to identify and monitor changes in the surface of the eyeball, tear break-up time (TBUT) to assess tear stability and performance, and the Schirmer test to assess tear production. In general, dry eye tests do not correlate with symptoms, but such tests are mainstream in the clinic, and physicians find the results of these tests useful.

Current treatments for dry eye include over-the-counter eye drops, a limited number of prescription eye drops, tear duct plugs, treatments for meibomian gland disorders, and nutritional supplements. However, the efficacy of such treatments is far from optimal, so there is a great need to develop products that can effectively treat dry eye. The goals of treatment are to relieve the signs and/or symptoms of dry eye, to improve patient comfort, to restore the eye surface and tear film to normal, and to prevent corneal damage.

Over-the-counter eye drops are lubricating eye drops that can be used to treat dry eyes and irritation associated with lack of tear production due to dry eye. Mild cases require lubricating eye drops four times a day, but severe cases must increase the frequency to 10-12 times a day.

Restasis® (cyclosporine A topical emulsion) is an immunomodulatory agent, the first topical approved for the treatment of dry eye, that prevents activation of T lymphocytes and thereby reduces the increase in goblet cells in the conjunctival epithelium. Inflammatory cytokine levels.

Diquas® (Diquafosol Sodium Formula) is a secretagogue that stimulates fluid transport and mucin secretion. Secretagogues also stimulate oil production within the meibomian glands. Mucosta (rebamipide formula) is another Japanese-approved secretagogue for dry eye.

Xiidra®, Lifitegrast is the most recently developed product to treat dry eye. It inhibits integrin and lymphocyte function-associated antigen 1 (LFA-1) by binding to intercellular adhesion molecule 1 (ICAM-1). This mechanism is thought to inhibit T lymphocyte-mediated inflammation.

The above are the currently approved topical preparations for the treatment of dry eye. But unfortunately, due to suboptimal clinical results, it is still not available all over the world.

In addition to the above-mentioned dry eye agents, oral intake of large amounts of polyunsaturated fatty acids (PUFAs) has been shown to benefit the eyes. It has been reported that long-chain PUFAs play a pivotal role in normal retinal function and vision development, and some epidemiological studies have suggested that PUFAs are essential for the prevention of age-related age-related macular degeneration (AMD) (J). Lipid Res. 2010 Nov;51(11):3217–3229). There are also reports in the literature that high doses of PUFA can alleviate symptoms of dry eye (J Fr Ophtalmol. 2006 Oct;29(8):868-73). In addition, a comprehensive analysis of relevant randomized controlled trials confirmed the help of PUFAs for dry eye (Nutr Rev. 2014 Oct;72(10):662-71. doi:10.1111/nure.12145. Epub 2014 Sep 18). Recently, various artificial eye drop compositions of polyunsaturated Omega-3 and Omega-6 fatty acids developed by TRB Chemedica International S.A (US Patent 8957110) enable direct application of PUFAs to the eye.

The two main types of PUFAs are omega-3 and omega-6 fatty acids. Since the body cannot manufacture omega-3 and omega-6 fatty acids and must obtain them from the diet, both omega-3 and omega-6 fatty acids are classified as essential fatty acids. Examples of omega-3 fatty acids include alpha-linolenic acid (ALA), gamma-linolenic acid (GLA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Linolenic acid (LA) and arachidonic acid (AA) are examples of omega-6 fatty acids.

Cevimeline (CEV) (CAS 107233-08-9 or CAS 153504-70-2 (hydrochloride hemihydrate); (2R,2R)-2'-Methylspiro [4-azabicyclo [2.2.2 ]octane-2,5'- [1,3] oxathiolane]; cis-2'-Methyl-spiro [1-azabicyclo [2.2.2]octane-3,5'- [1,3] oxathiolane] hydrate hydrochloride) With pilocarpine (CAS 92-13-7, 54-71-7 (hydrochloride); (3S,4R)-3-Ethyl-4-((1-methyl-1H-imidazol-5-yl) methyl) dihydrofuran-2(3H)-one) is a cholinergic agonist that binds to muscarinic receptors. Sufficient doses of muscarinic agonists increase secretion from exocrine glands such as salivary and sweat glands. Oral formulations of cevimeline and pilocarpine are currently available as systemic muscarinic agonists for the treatment of dry mouth symptoms in patients with Sjogren's syndrome. Although these oral products are not approved for the treatment of dry eye, dry eye is a problem associated with Sjogren's syndrome, so studies have been conducted to see if it can relieve dry eye symptoms in patients. Cevimeline oral formulation has been approved for the treatment of dry mouth symptoms of Sjogren's syndrome and is also being studied for the treatment of dry eye. However, it has not yet been developed as a stable external ophthalmic preparation for dry eye syndrome. Although oral forms of cevimeline and pilocarpine have been shown to significantly improve the treatment of dry eye, they are currently not widely accepted due to systemic side effects of oral administration.

The current patented formulations containing cevimeline or pilocarpine are as follows: US20070053964, US20120003296, and US20160008337. Patent publication US20070053964 discloses a formulation suitable for transdermal application on the outer surface of the eyelid, which is not suitable for direct application to the ocular surface due to significant eye irritation caused by transdermal application of a large amount of absorption enhancer and high drug concentration. Patent publication US20070053964 includes comparative examples of several pilocarpine 10% and 20% eye drop solution formulations for direct application to the eye and a cevimeline 20% eye drop solution formulation. From the viewpoint of tear production and side effects, patent publication US20070053964 recommends not to apply pilocarpine or cevimeline solutions directly to the eye compared to various transdermal formulations. Patent publication US20120003296 discloses ophthalmic formulations requiring insulin or insulin-like growth factors. Patent publication US20160008337 discloses an ophthalmic formulation in need of a cycloplegic agent.

Commercially available pilocarpine can be used as a topical ophthalmic preparation to treat glaucoma and has been reported to relieve dry eye. However, it has been difficult to prepare pilocarpine into stable and comfortable ophthalmic formulations. Commercial pilocarpine ophthalmic formulations are tingling and irritating when applied to the eyes. Pilocarpine topical formulations are also very unstable, and undesirably high levels of degradation impurities are found in commercial pilocarpine ophthalmic products. The key problem is that lowering the pH value (about 3-5) to increase the irritancy also increases the irritation, or lowering the irritation and increasing the pH (about 7) reduces the irritation but also reduces the stability, between the two. Difficulty finding balance.

For example, the muscarinic agonist pilocarpine is used topically to treat glaucoma. To maintain acceptable stability, pilocarpine topical ophthalmic formulations are prepared in the acidic pH range (3.5-5.5) which is irritating to the eye. In addition, muscarinic agonists stimulate sphincter contraction and cause pupillary miosis. Patients often experience adverse effects such as burning sensation or discomfort, transient or periorbital headache, ciliary muscle spasm, conjunctival vascular occlusion, superficial keratitis, and induced myopia.

Various companies have tried many treatments for dry eye without success over the years. Pilocarpine, an ophthalmic muscarinic agonist prepared in the acidic pH range (3.5-5.5) which is irritating to the eyes, has been reported to be used for dry eye. However, there have been no reports of preparation of an ophthalmic muscarinic agonist in the neutral pH range and in a drug concentration range suitable for direct application to the eye for the treatment of dry eye.

We are well aware of the need to develop formulations that are pharmaceutically stable, comfortable, safe, minimally irritating or non-irritating, based on potent muscarinic receptor agonists and applied directly to the ocular surface externally to treat dry eye. urgent need.

The present invention provides various stable external ophthalmic compositions for treating dry eye and keratoconjunctivitis. The composition can promote tear secretion and thereby treat dry eye. In particular, the compounds of the compositions described herein provide various stable compositions comprising a muscarinic agonist in a therapeutically effective amount suitable for ophthalmic use.

The present invention is based on the exciting discovery that an effective dose of a muscarinic receptor agonist can be provided in a stable, acceptable topical, and neutral physiological pH range ophthalmic composition, with The smallest dose is applied to the surface of the eye to be non-irritating and used to relieve signs or symptoms of dry eye. Suitable for ophthalmic use means that the composition can be applied directly externally to any surface of the eye and/or orbit, such as the sclera, cornea, conjunctiva, conjunctival sac, and other surfaces. The composition is not intended for transdermal application to the outer surface of the eyelid.

The ophthalmic composition is an aqueous (meaning that the main component contained is water) liquid or viscous liquid composition. In some embodiments, the composition is free of ointment compositions, cream compositions, implant compositions, embolic compositions, tape compositions, cream compositions, and/or non-aqueous compositions.

Preferably, the composition is sterile. Preferably, the composition has approximately the same osmolarity as tears, ranging from about 200 to 400 milliosmoles/liter (mOsm/L), or more preferably about 240 to 360 mOsm/L.

Preferably, the composition exhibits the same pH as tears, meaning that the composition has a pH in the range of about 6 to 9, about 6 to 8, about 7 to 9, about Between 6.5 and 8.5, or about 7 to 8.

One aspect of the present invention provides a stable ophthalmic composition comprising (or consisting essentially of, or consisting of) an effective amount of at least one muscarinic receptor agonist, wherein the combination The substance is therapeutically effective and stable at neutral pH. In some embodiments, the subject suffers from dry eye (disorder), Sjogren's syndrome, meibomian gland dysfunction, eye inflammation, keratoconjunctivitis, eye inflammation, and/or eye irritation.

The present invention also provides a method of treating dry eye, the method comprising directly externally administering to the eye of a subject in need thereof one or more doses of an ophthalmic composition comprising at least one muscarinic receptor agonist. The present invention focuses on stimulating the lacrimal gland to produce tears as the main way to treat dry eye.

A typical muscarinic receptor agonist is the M3 muscarinic receptor agonist (MRA). The MRA can be selected from aceclidine, acetylcholine, bethanechol, carbachol, cevimeline, oxotremorine ), pilocarpine, any M3 muscarinic receptor agonist effective in the treatment of dry eye, and a combination of two or more of the foregoing.

Another aspect of the present invention provides a stable ophthalmic composition formulation comprising (or consisting essentially of, or consisting of) an effective amount of at least one muscarinic receptor agonist, and one or Various other active ingredients. The present invention also provides a method of treating dry eye, the method comprising directly externally administering to the eye of a subject in need thereof one or more doses comprising at least one muscarinic receptor agonist and one or more other activities Ingredients for ophthalmic compositions.

In some embodiments, typically one or more of the other active ingredients may be selected from the group consisting of a) at least one steroid; b) at least one immunomodulatory agent; c) at least one hormone; d) at least one secretagogue; e) one A group consisting of lymphocyte function-associated antigen-1 (LFA-1) antagonists; and f) active ingredients effective in the treatment of meibomian gland dysfunction. In preferred embodiments, typical other active ingredients can be selected from a) at least one steroid, such as loteprednol etabonate, prednisolone acetate, fluticasone; b) at least an immunomodulatory agent (immunosuppressant) such as cyclosporine, tacrolimus, sirlolimus; c) at least one hormone such as testosterone, estrogen; d) at least one secretagogue such as rebamipide or diquafosol; e) a group consisting of lymphocyte function-associated antigen-1 (LFA-1) antagonists.

In some embodiments, the ophthalmic composition is free of insulin, IGF (an insulin-like growth hormone), somatomedin C, and cycloplegic agents. In some embodiments, the ophthalmic composition is free of an active ingredient not yet disclosed herein.

In some embodiments, the ophthalmic composition includes cevimeline as the sole active ingredient (drug), in addition to one or more pharmaceutically acceptable excipients.

Another aspect of the present invention provides a stable ophthalmic composition comprising (or consisting essentially of, or consisting of) an effective amount of at least one muscarinic receptor agonist, and at least one A polyunsaturated fatty acid (PUFA) wherein the composition is therapeutically effective and stable in the neutral pH range. In some embodiments, the subject suffers from dry eye (disorder), Sjogren's syndrome, meibomian gland dysfunction, eye inflammation, and/or eye irritation.

The PUFA is a fatty acid and contains about 12 to 26 carbon atoms per molecule. The scope of the present invention examines in detail the various homologs and derivatives of this PUFA. The scope of the invention examines two or more PUFA mixtures in detail. In some embodiments, the PUFA is selected from the group consisting of omega-3 fatty acids and omega-6 fatty acids. Typical PUFAs include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), gamma-linolenic acid (GLA), or a mixture of the above.

In preparing the ophthalmic composition, the PUFA can be added as a separate ingredient outside the MRA. Alternatively, the PUFA can be included as part of an ion pair containing the MRA and the PUFA.

The present invention also provides an ophthalmic composition comprising a mixture of at least one PUFA and at least one MRA. In some embodiments, the present invention also provides an ophthalmic composition comprising at least one ion pair complex comprising at least one PUFA and at least one MRA in a therapeutically effective dose. These PUFA-containing compositions can be used to treat diseases or disorders of the eye, such as those described herein, or otherwise found to be therapeutically responsive to MRA.

In some embodiments, the MRA refers to cevimeline, one or more salts of cevimeline. In some embodiments, the MRA is selected from the group consisting of cevimeline, one or more salts of cevimeline, and combinations thereof. In some embodiments, the MRA is selected from the group consisting of pilocarpine, one or more salts of pilocarpine, and combinations thereof. In some embodiments, the MRA is selected from the group consisting of cevimeline, one or more salts of cevimeline, pilocarpine, one or more salts of pilocarpine, and combinations thereof.

The MRAs of the present invention take one or more forms in the compositions of the present invention. The form of the MRA can be selected individually for each occurrence of the free base form and the salt form. A composition may comprise MRA in free base form, MRA in salt form, or a combination of free base form and salt form. Various pharmaceutically acceptable salt forms of the MRA include those prepared with PUFA.

In some embodiments, the ophthalmic composition comprises cevimeline (CEV) as the sole active ingredient. Cevimeline is present in concentrations ranging from 0.1% to 10.0% (w/v).

In another specific embodiment, the present invention provides a stable ophthalmic composition with MRA in combination with loteprednol (a steroid) and one or more pharmaceutically acceptable excipients. In certain specific embodiments, cevimeline in the composition is present at a concentration of 0.1% to 10.0% (w/v), or any concentration value within that range. In certain embodiments, the loteprednol (steroid) in the composition is present at a concentration of 0.1% to 1.0% (w/v), or any concentration value within this range, or about 0.5% w/v .

In another specific embodiment, the present invention provides a stable ophthalmic composition with MRA in combination with cyclosporine (an immunosuppressant, immunomodulator) and one or more pharmaceutically acceptable excipients. In certain specific embodiments, cevimeline in the composition is present at a concentration of 0.1% to 10.0% (w/v), or any concentration value within that range. In certain embodiments, the cyclosporine (an immunosuppressant) in the composition is present at a concentration of 0.05% to 0.1% (w/v), or any concentration value within that range.

In another specific embodiment, the present invention provides a stable ophthalmic composition with an MRA-binding hormone (androgen such as testosterone) and one or more pharmaceutically acceptable excipients. In certain specific embodiments, cevimeline in the composition is present at a concentration of 0.1% to 10.0% (w/v), or any concentration value within that range. In specific embodiments, the hormones are present in the composition at a concentration of 0.01% to 0.5% w/v, 0.03% to 0.5% w/v, 0.05% to 0.5% w/v.

In another specific embodiment, the present invention provides a stable ophthalmic composition with an MRA-binding secretagogue (eg, diquafosol or a diquafosol salt) and one or more pharmaceutically acceptable excipients . In particular embodiments, cevimeline in the composition is present at a concentration of about 0.1% to 10.0% (w/v), or any concentration within that range. In certain embodiments, the diquafosol in the composition is present at a concentration of about 1.0% to 5.0% (w/v), or any concentration value within that range. In particular embodiments, the lifitegrast in the composition is present at a concentration of about 1.0% to 5.0%, or about 1.0% to 10.0% (w/v), or any concentration value within the range.

In some embodiments, the composition comprises the specified active ingredient, and a carrier containing one or more pharmaceutically acceptable excipients, such as at least one osmotic pressure adjuster, at least one buffer, at least one stabilizer, at least one surfactant, at least one solubilizer, at least one tackifier, at least one antioxidant, at least one acid, at least one base, at least one chelating agent, at least one preservative, or a combination of any two or more of the above .

This disclosure includes all aspects, embodiments, and sub-embodiments disclosed herein in their entirety. Other features, advantages, and embodiments of the present invention will become more apparent to those skilled in the art from the following description, accompanying examples, and claims.

Ophthalmic compositions comprise at least one MRA and one or more pharmaceutically acceptable excipients in an aqueous carrier, which means a carrier that is primarily aqueous. The aqueous carrier can be in the form of pure water, tear fluid, and/or autologous serum.

The present invention is based in part on the discovery that cevimeline can be formulated as a stable and pleasantly neutral pH composition particularly useful in the treatment of dry eye disease of the eye. The formulation has a neutral pH value and is suitable for use in the eye for topical administration. The MRA-containing composition, such as cevimeline, exhibits high storage stability at room temperature (eg, 15 to 25°C). In some embodiments, storage of the MRA at 25°C for 18 to 24 months results in less than 3% w degradation.

The characteristics of the present invention are: the novel external ophthalmic composition comprises an effective dose of cevimeline in a pharmaceutically acceptable preparation, and cevimeline can be used as a free base and/or a pharmaceutically acceptable free base of salt. In particular embodiments, the present invention provides various stable ophthalmic formulations of cevimeline with cevimeline as the sole active agent in these formulations. The present invention also has the following properties: various cevimeline ophthalmic formulations in combination with cyclosporine, loteprednol etabonate, testosterone, diquafosol or diquafosol salt, and/ or one or more of the other active ingredients of lifitegrast.

In preparing the ophthalmic composition, the PUFA can be added as a separate ingredient in addition to the MRA. In some embodiments, the PUFA is present at a concentration of about 0.1% to 10.0% w/v, preferably 0.2% to 5.0% w/v, or more preferably 0.5% to 2.0% w/v. Alternatively, the PUFA can be included as part to form a transition between the MRA and the PUFA. The molar ratio of the PUFA to MRA ranges from about 2:1 to 1:2, or about 1:1.

The present invention also provides a medically stable external ophthalmic preparation, which comprises polyunsaturated fatty acid ions and muscarinic agonist amine drugs for treating eye conditions, especially dry eye.

The PUFA can be selected from the group consisting of essential fatty acids, wherein the essential fatty acids contain more than one double bond in their backbone. Typical suitable PUFAs include omega-3 fatty acids and omega-6 fatty acids. Typical omega-3 fatty acids include alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and other known homologues and derivatives of these acids. Typical omega-6 fatty acids include linoleic acid (LA), gamma-linolenic acid (GLA), and other known homologues and derivatives of these acids.

In some embodiments, various ophthalmic formulations provided herein comprise an effective dose of cevimeline and cyclosporine. These preferred combined preparations can further effectively relieve the signs and symptoms of dry eye.

In another embodiment, the present invention provides an ophthalmic formulation comprising an effective dose of cevimeline and testosterone.

In another embodiment, the present invention provides an ophthalmic formulation comprising an effective dose of cevimeline and diquafosol.

In another embodiment, the present invention provides an ophthalmic formulation comprising an effective dose of cevimeline and lifitegrast.

In another embodiment, the present invention provides a stable ophthalmic formulation of PUFA ions combined with cevimeline. In certain embodiments, cevimeline is present in the formulation at a concentration of between about 0.1% to 10.0% (w/v), or any concentration value within that range.

Those skilled in the art cannot predict the stability, comfort, safety, and efficacy of the ophthalmic formulations of the present invention.

The various pharmaceutical compositions disclosed in the present invention contain only an effective dose of cevimeline, or cevimeline in combination with loteprednol, cyclosporine, testosterone, diquafosol, or formulated where it can be administered to the eye Quaphossol salt. These formulations are useful in the treatment of dry eye.

A formulation for administration to the eye can be formulated so that the formulation can be administered from the outside of the eye. Although optimal comfort may sometimes not be achieved based on formulation considerations (eg, drug stability), maximal comfort is still achieved.

Concentrations for all ingredients are expressed in % weight/volume (%w/v) unless otherwise stated.

In a number of specific compositions, the concentration of cevimeline ranges from about 0.1% to 10.0%.

In certain compositions, the concentration of cevimeline ranges from about 0.1% to 10.0%, and the concentration of loteprednol ranges from about 0.1% to 0.5%.

In certain compositions, the concentration of cevimeline ranges from about 0.1% to 10.0%, and the concentration of cyclosporine ranges from about 0.05% to 0.1%, about 0.01% to 0.1% between, or about 0.03% to 0.1%.

In particular compositions, the concentration of cevimeline ranges from about 0.1% to 10.0%, and the concentration of testosterone ranges from about 0.01% to 0.1%.

In certain compositions, the concentration of cevimeline ranges from about 0.1% to 10.0%, and the concentration of diquafosol ranges from about 1% to 3.0%, or from about 1% to between 5% w/v.

In certain embodiments, the pH of the ophthalmic composition of the present invention is between 6 and 9, or preferably between 7 and 8. The pH of this tear fluid is approximately 7.4. It should be understood that acids or bases may be used to adjust the pH of the composition as desired.

The ophthalmic composition may or may not satisfy isotonicity. In some embodiments, the osmotic pressure of the ophthalmic composition of the present invention is between about 200 and 400 mOsm/L, or preferably between about 240 and 360 mOsm/L. In some embodiments, the composition comprises NaCl at a concentration of about 0.9%, or NaCl at a concentration of about 0.7% to 1.5%.

A pharmaceutical composition (formulation) according to the present invention may include one or more pharmaceutically acceptable excipients, which are selected from the group consisting of buffers, osmotic pressure regulators, surfactants, solubilizers, viscosifiers, etc. selected from the group consisting of pH adjusters (eg, acids and/or bases), chelating agents, preservatives, antioxidants, or a combination of any two or more of the above.

Various typical buffers include, but are not limited to, phosphates, borates, citrates, acetates, carbonates, bicarbonates, boric acid polyol complexes, boric acid, sodium acetate, amino acids, tris, carbonic acid Hydrogen salts, BIS-Tris or BIS-Tris salts, combinations of the above, etc. Dosages of the buffer range from about 5 to 200 mM, or about 10 to 100 mM.

Examples of various osmotic pressure regulators include, but are not limited to, mannitol, sorbitol, potassium chloride, sodium chloride, xylitol, glycerol, trehalose, taurine, erythritol, or combinations thereof, and the like. The dosage of the osmolarity modifier in the composition will be as desired to obtain the osmotic composition, eg, equal to the osmolarity of tears.

Examples of various surfactants include, but are not limited to, poloxamers, tyloxapol, polysorbates (eg: polysorbate 80, polysorbate 20), polyoxyethylene castor oil Derivatives, sorbitan esters, combinations thereof, etc. The composition typically contains less than 5%, less than 2%, or less than 1% surfactant. Some embodiments of the present invention are free of surfactants.

Examples of various solubilizers include, but are not limited to, solutol®, soluplus®, cyclodextrins, vegetable oils, combinations thereof, and the like. The composition typically contains less than 5%, less than 2%, or less than 1% solubilizer. Some embodiments of the present invention do not contain solubilizers.

Various tackifiers refer to hydrophilic polymers added to various ophthalmic solutions for two main reasons: (1) to control the rate at which droplets flow out of the container (and thus enhance ease of application); and more importantly, (2) Control the residence time of the solution in the precorneal environment. The ophthalmic composition has a viscosity of less than about 55 mPa/s or less than about 30 mPa/s.

Examples of various tackifiers include, but are not limited to, carboxymethyl cellulose, hyaluronic acid, chondroitin sulfate, polyvinyl alcohol, hydroxypropyl methylcellulose, polylysine, polyacrylic acid, polyacrylamide, methyl alcohol Hydroxypropyl Acrylate (HPMA), Xanthan Gum, Pectin, Chitosan, Dextran, Hydroxypropyl Cellulose, Hydroxyethyl Cellulose, Carrageenan, Guanhua Bean Gum, Polyethylene Glycol Ester 40, Polyethylene Glycol Vinylpyrrolidone, polyethylene glycol, propylene glycol, combinations thereof, and the like.

Hydroxypropyl methylcellulose (USP Hypromellose). Hydroxypropyl methylcellulose (HPMC) refers to a part of its structure with methyl and O-(2-hydroxypropyl) cellulose derivatives added. In various aqueous ophthalmic formulations, HPMC is used at a concentration of 0.45 to 1.0% w/w (the actual concentration depends on the molecular weight of the polymer used).

polyvinyl alcohol. Polyvinyl alcohol is a water-soluble ethylene polymer available in three grades: (1) high viscosity (average molecular weight 200 000 g/mol); (2) medium viscosity (average molecular weight 130 000 g/mol); and (3) Low viscosity (average molecular weight 20 000 g/mol). The use of polyvinyl alcohol in concentrations ranging from 0.25% to 3.00% w/w (the actual concentration depends on the molecular weight of the polymer used) can enhance the viscosity of various ophthalmic formulations.

Polyacrylic acid. Polyacrylic acid is a water-soluble acrylate polymer that is cross-linked with allyl sucrose or allyl ether of pentaerythritol. Polyacrylic acid is mainly used in various ophthalmic aqueous formulations to treat dry eye symptoms. However, polyacrylic acid can also be used to increase the viscosity of various ophthalmic formulations containing therapeutic agents.

Various typical preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, parabens (eg, methylparaben or ethylparaben), benzyl alcohol, phenethyl alcohol, sorbitan Acid or sorbate, citric acid or citrate, thimerosal, chlorobutanol, quaternary amines, chlorhexidine gluconate, stabilized oxychlorides, combinations thereof, and the like. These preservatives, if included, must be administered in a dose that passes the requirements of the US Pharmacopeia and/or the European Pharmacopoeia for antibacterial preservative efficacy testing for eye drops.

Various benzalkonium chlorides should be used in ophthalmic solutions/suspensions at concentrations between 0.002% and 0.02% w/v (usually between 0.005 and 0.01% w/v). Various ophthalmic formulations in which benzalkonium chloride is customarily used will include disodium EDTA at a concentration of 0.01-0.1% w/v. Benzethonium chloride (unlike benzalkonium chloride) is a pure compound (and not a mixture of compounds). Benzethonium chloride is commonly used in various ophthalmic formulations at concentrations ranging from 0.01 to 0.02% w/v (although benzethonium chloride has been reported to have lower antimicrobial activity than benzalkonium chloride). Parabens can be used. Methylparaben or propylparaben mixtures are typically used at a combined concentration of 0.2% w/w in various ophthalmic formulations. Various non-irritating (meaning non-irritating to the eyes) organic alcohols can be used as preservatives in ophthalmic formulations: (1) chlorobutanol; and (2) phenylethyl alcohol. The concentration of chlorobutanol used in various ophthalmic formulations is approximately 0.5% w/v. The properties of phenethyl alcohol are similar to those of chlorobutanol. Typical concentrations used in various ophthalmic formulations are 0.25 to 0.50% v/v. Typical concentrations of preservatives do not exceed the effective dose required to pass the USP and/or European Pharmacopoeia tests for antibacterial preservative efficacy in eye drops.

Antioxidants can be added to the ophthalmic composition. The term "antioxidant" is used herein for the purpose of denoting an agent that inhibits oxidation and thus can be used to prevent the deterioration of various formulations due to the oxidative process. Typical various antioxidants include, but are not limited to, ascorbic acid, malic acid, citric acid, sodium citrate, butylated hydroxyanisole, dibutylhydroxytoluene (BHT), propyl gallate, sodium ascorbate, sodium metabisulfite, hydrogen sulfite Sodium, amino acids, ascorbyl palmitate, hypophosphorous acid, thioglycerol, propyl gallate, sodium formaldehyde sulfoxylate, and mixtures of other materials known to those of ordinary skill in the art. Where antioxidants are used, the dose (concentration) of antioxidants should be sufficient to minimize oxidative degradation of one or more active ingredients.

Examples of various alkaline agents that can be used as pH adjusters include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), tromethamine, ethanolamine, sodium bicarbonate (NaHCO3), and other organic and inorganic alkali.

Examples of various acids that can act as pH adjusters include, but are not limited to, for example, hydrochloric acid (HCl), citric acid, tartaric acid, lactic acid, acetic acid, and other organic and inorganic acids, etc., and mixtures thereof.

Examples of various chelating agents include, but are not limited to, sodium ethylenediaminetetraacetate (EDTA, ethylenediaminetetraacetate), sodium citrate, concentrated sodium phosphate, combinations thereof, and the like. The dosage of various chelating agents is usually between about 0.01 to 0.2% w/v.

Unless otherwise specified, the term cevimeline is used to denote the free base form, the salt form, or a mixture of the free base form and the salt form. Unless otherwise specified, the term pilocarpine is used to denote the free base form, the salt form, or a mixture of the free base form and the salt form. Unless otherwise specified, the term MRA is used to mean the free base form, the salt form, or a mixture of the free base form and the salt form.

The following embodiments are specifically considered next:

Example 1: A stable, aqueous, topical ophthalmic composition comprising cevimeline at a concentration of about 0.1% to 10%, neutral pH between 6 and 9, and one or more pharmaceutically acceptable excipient.

Embodiment 2: The composition of Embodiment 1, wherein the cevimeline is in the free base form, the salt form, or a combination of the free base and salt forms.

Embodiment 3: The composition of embodiment 1 or 2, wherein the cevimeline is present at a concentration of between about 0.1% and 10% w/v, between about 0.5% and 5% w/v, or About 0.2% to 2% w/v.

Embodiment 4: The composition of any of the above embodiments further comprises at least one PUFA.

Embodiment 5: The composition of Embodiment 4, wherein the PUFA is present at a concentration of between about 0.1% and 10% w/v, between about 0.5% and 5% w/v, or between about 0.2% and between 2% w/v.

Embodiment 6: The composition of Embodiment 4 or 5, wherein each molecule of the PUFA contains about 12 to 26 carbon atoms.

Embodiment 7: The composition of embodiments 4, 5, or 6, wherein the PUFA is selected from the group consisting of omega-3 fatty acids, omega-6 fatty acids, and mixtures of omega-3 and omega-6 fatty acids .

Embodiment 8: The composition of embodiment 4, 5, 6, or 7, wherein the PUFA is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha- The group consisting of linolenic acid (ALA), gamma-linolenic acid (GLA), and mixtures of eicosapentaenoic acid, docosahexaenoic acid, alpha-linolenic acid and gamma-linolenic acid.

Embodiment 9: The composition of any of the preceding embodiments further comprises a buffer, an osmotic pressure regulator, and moisture.

Example 10: The composition of Example 9 can optionally further comprise at least one preservative, at least one chelating agent, at least one tackifier, at least one surfactant, at least one solubilizer, and/or at least one antioxidant. one or more of.

Embodiment 11: The composition of any of the preceding embodiments, wherein the composition has an osmotic pressure between 200 and 400 mOsm/L and a pH between about 6 and 9.

Embodiment 12: The composition of any of the above embodiments further comprises one or more other active ingredients selected from a) at least one steroid; b) at least one immunomodulatory agent (immunosuppressant); c) at least one hormone (androgen); d) a lymphocyte function-associated antigen-1 (LFA-1) antagonist; and f) at least one active ingredient effective in treating meibomian gland dysfunction.

Embodiment 13: The composition of Embodiment 12, wherein a) the steroid is present at a concentration of about 0.1% to 1% w/v; b) the immunomodulatory agent is present at a concentration of about 0.05% to 0.1% w/v c) the hormone is present at a concentration of about 0.01% to 0.5% w/v; or d) the secretagogue is present at a concentration of about 1% to 5% w/v; or e) the lymphocyte function Related antigen-1 (LFA-1) antagonists are presented at concentrations between approximately 1% and 5% w/v.

Embodiment 14: The composition of embodiment 12 or 13, wherein a) the steroid refers to loteprednol etabonate, prednisolone acetate, fluticasone, or loteprednol , a combination of penicillin acetate, and fluticasone; b) the immunomodulator refers to cyclosporine, tacrolimus, sirlolimus, or cyclosporine, tacrolimus, The combination with sirolimus; c) the hormone refers to testosterone, estrogen, or a combination of testosterone and estrogen; d) the secretagogue refers to rebamipide, diquafos diquafosol, or a combination of rebamipide and diquafosol; or e) the lymphocyte function-associated antigen-1 (LFA-1) antagonist refers to lifitegrast.

Embodiment 15: The composition of any of the preceding embodiments, wherein the composition is free of ointment compositions, cream compositions, patch compositions, cream compositions, and non-aqueous compositions.

Embodiment 16: The composition of any of the preceding embodiments, wherein the composition is free of insulin, IGF (an insulin-like growth hormone), somatomedin C, and a cycloplegic agent.

Embodiment 17: The composition of any one of the preceding embodiments, wherein cevimeline can be replaced by pilocarpine, aceclidine, acetylcholine, bethanechol , carbachol, oxotremorine, or any muscarinic receptor agonist that has efficacy in the treatment of dry eye.

Example 18: A pharmaceutically acceptable ion pair comprising a muscarinic receptor agonist amine drug and selected from the group consisting of polyunsaturated fatty acids (PUFAs) for the treatment of dry eye a fatty acid component.

Embodiment 19: The ion pair of Embodiment 18, wherein the molar ratio of PUFA to muscarinic receptor agonist amine drug ranges from 2:1 to 1:2, or about 1:2 1.

Embodiment 20: The ion pair of Embodiment 18 or 19, wherein a) each molecule of the PUFA contains a mixture of about 12 to 26 carbon atoms or more; b) wherein the PUFA is selected from the group consisting of omega- 3 fatty acids, omega-6 fatty acids, or a mixture of omega-3 fatty acids and omega-6 fatty acids; or c) the PUFA is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), gamma-linolenic acid (GLA), or a mixture of eicosapentaenoic acid, docosahexaenoic acid, alpha-linolenic acid and gamma-linolenic acid group.

Embodiment 21: The composition of any one of embodiments 1-17 further comprising the ion pair of any one of embodiments 18-20.

Embodiment 22: A method of treating a dry eye disorder, xerophthalmia, or dry eye condition comprising externally administering a composition according to any one of Embodiments 1 to 17 to the eye of a subject in need thereof.

Embodiment 23: A method of treating a dry eye disorder, xerophthalmia, or dry eye condition comprising externally administering an ion pair according to any one of embodiments 18 to 20 to the eye of a subject in need thereof.

Typical composition 1A: contains cevimeline (concentration about 0.1% to 10.0% w/v), buffer, osmotic pressure regulator, and moisture; osmotic pressure ranges from about 200 to 400 mOsm/L, The pH range is between about 6 to 9; further options may include preservatives, chelating agents, tackifiers, surfactants, solubilizers, and/or antioxidants.

Typical Composition IB: Comprising cevimeline (concentration about 0.1% to 10.0% w/v), steroid (concentration about 0.1% to 1% w/v), buffer, osmotic pressure regulator, and water; osmotic The pressure ranges from about 200 to 400 mOsm/L, and the pH ranges from about 6 to 9; it can be further selected to contain preservatives, chelating agents, tackifiers, surfactants, solubilizers, and / or antioxidants.

Typical Composition 1C: Comprising cevimeline (at a concentration of about 0.1% to 10.0% w/v), an immunosuppressant (at a concentration of about 0.05% to 0.1% w/v, about 0.1 to 1 mg/mL, or about 0.5 mg /mL), buffers, osmotic pressure regulators, and water; osmotic pressure ranges from about 200 to 400 mOsm/L, and pH ranges from about 6 to 9; may further optionally contain preservatives agents, chelating agents, tackifiers, surfactants, solubilizers, and/or antioxidants.

Typical composition ID: comprising cevimeline (concentration about 0.1% to 10.0% w/v), androgen (concentration about 0.01% to 0.5% w/v), buffer, osmotic pressure regulator, and water; The osmotic pressure ranges from about 200 to 400 mOsm/L, and the pH ranges from about 6 to 9; further options include preservatives, chelating agents, tackifiers, surfactants, solubilizers, and/or antioxidants.

Typical composition 1E: Comprising cevimeline (concentration about 0.1% to 10.0% w/v), secretagogue (concentration about 1% to 5% w/v), buffer, osmotic pressure regulator, and moisture ; The range of osmotic pressure is between about 200 to 400 mOsm/L, and the range of pH value is between about 6 to 9; it can be further selected to contain preservatives, chelating agents, tackifiers, surfactants, solubilizers , and/or antioxidants.

Typical composition IF: contains cevimeline (concentration about 0.1% to 10.0% w/v), AARA (concentration about 0.01% to 0.1% w/v, and about 0.025% w/v), buffer, osmotic pressure regulator, and water; the osmotic pressure ranges from about 200 to 400 mOsm/L, and the pH ranges from about 6 to 9; it can be further selected to contain preservatives, chelating agents, and tackifiers , surfactants, solubilizers, and/or antioxidants.

Typical composition 1G: contains cevimeline (concentration about 0.1% to 10.0% w/v), PUFA (concentration about 0.1% to 10.0%), buffer, osmotic pressure regulator, and water; range of osmotic pressure Between about 200 to 400 mOsm/L, and pH values in the range of about 6 to 9; may be further selected to contain preservatives, chelating agents, tackifiers, surfactants, solubilizers, and/or antiseptics. oxidizing agent.

Typical composition 1H: contains cevimeline (concentration about 0.1% to 10.0% w/v), steroid (concentration about 0.1% to 1% w/v), polyunsaturated fatty acid (concentration about 0.1% to 10.0%) , buffer, osmotic pressure regulator, and water; the osmotic pressure is in the range of about 200 to 400 mOsm/L, and the pH value is in the range of about 6 to 9; it can be further selected to contain preservatives, chelating agents Admixtures, tackifiers, surfactants, solubilizers, and/or antioxidants.

Typical Composition 1J: Comprising cevimeline (at a concentration of about 0.1% to 10.0% w/v), an immunosuppressant (at a concentration of about 0.05% to 0.1% w/v, about 0.1 to 1 mg/mL, or about 0.5 mg /mL), PUFA (concentration about 0.1% to 10.0%), buffers, osmotic pressure regulators, and water; osmotic pressure ranges from about 200 to 400 mOsm/L, pH ranges from about Between 6 and 9; may further optionally contain preservatives, chelating agents, tackifiers, surfactants, solubilizers, and/or antioxidants.

Typical composition 1K: contains cevimeline (concentration about 0.1% to 10.0% w/v), androgens (concentration about 0.01% to 0.5% w/v), PUFA (concentration about 0.1% to 10.0%), buffer agent, osmotic pressure regulator, and water; the osmotic pressure ranges from about 200 to 400 mOsm/L, and the pH ranges from about 6 to 9; it can be further selected to contain preservatives, chelating agents, Tackifiers, surfactants, solubilizers, and/or antioxidants.

Typical composition 1L: contains cevimeline (concentration about 0.1% to 10.0% w/v), secretagogue (concentration about 1% to 5% w/v), PUFA (concentration about 0.1% to 10.0%), Buffers, osmotic pressure regulators, and water; the osmotic pressure ranges from about 200 to 400 mOsm/L, and the pH ranges from about 6 to 9; may further include preservatives, chelating agents , tackifiers, surfactants, solubilizers, and/or antioxidants.

Typical composition 1M: contains cevimeline (concentration about 0.1% to 10.0% w/v), AARA (concentration about 0.01% to 0.1% w/v, and about 0.025% w/v), PUFA (concentration about 0.025% w/v) 0.1% to 10.0%), buffers, osmotic pressure regulators, and water; the osmotic pressure ranges from about 200 to 400 mOsm/L, and the pH ranges from about 6 to 9; further Options include preservatives, chelating agents, tackifiers, surfactants, solubilizers, and/or antioxidants.

Typical composition 1N: contains cevimeline (concentration about 0.1% to 10.0% w/v), lifitegrast (concentration about 1% to 10%, or about 5% w/v), buffer, osmotic pressure regulator, and moisture; the osmotic pressure ranges from about 200 to 400 mOsm/L, and the pH ranges from about 6 to 9; it can be further selected to contain preservatives, chelating agents, tackifiers, surfactants , solubilizers, and/or antioxidants.

It should be understood that the various compounds employed in the pharmaceutical process generally perform various functions or purposes of an excipient. Thus, if a compound indicated herein is mentioned only once, or used to define more than one term herein, its purpose or function should not be construed as being limited only to the indicated purpose or function. For example, citric acid can be used as an antioxidant, chelating agent, buffering agent, preservative or antimicrobial agent.

As used herein, a "salt" active ingredient means a pharmaceutically acceptable salt. As used herein, a "pharmaceutically acceptable salt" refers to the combination of the active ingredient and an acid. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the active ingredient, eg, MRA. The pharmaceutically acceptable salts include the common non-toxic salts formed from non-toxic inorganic or organic acids. For example, such common non-toxic salts include salts derived from various inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, sulfamic acid, phosphoric acid, nitric acid, and those known to those of ordinary skill in the art. other inorganic acids; salts prepared with organic acids: such as amino acids, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, cis Butenedioic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid acid, oxalic acid, isethionic acid, and other organic acids known to those of ordinary skill. The interested party may find a list of suitable salts in the Remington's Pharmacy 17th Edition (Mack Publishing Company, Easton, PA, 1985, p. 1418), which is hereby incorporated by reference.

The phrase "pharmaceutically acceptable" as used herein refers to various compounds, materials, compositions, and/or dosage forms, which, within the scope of sound medical judgment, can be used in contact with human and animal tissue without excessive toxicity, irritation, allergy reaction, or other problems or complications commensurate with a reasonable benefit-risk ratio.

The amount of therapeutic compound contained in each composition (or dosage form containing the composition) is at least one or more doses and can be selected according to known principles of pharmacy. We specifically consider the effective amount of the therapeutic compound. It should be understood that the term "effective amount" refers to consideration of a pharmaceutically effective amount of a drug. A pharmaceutically effective dose refers to the amount of active ingredient (drug) that is sufficient to produce a desired or desired therapeutic response, or in other words, an amount sufficient to produce an appreciable biological response when the drug is administered to a patient.

The following examples are provided to further illustrate the advantages and characteristics of the present invention, but are not intended to limit the scope of the present invention. These examples are for illustrative purposes only. The following formulations were prepared using a variety of pharmaceutical grade ingredients. The table below shows the quantitative compositions of these examples.

Each formulation contained cevimeline prepared substantially as described in Examples 1-4. The following table details the compositions of typical formulations Cevi-1 to Cevi-8. Table 1 : Composition of a typical aqueous liquid formulation containing cevimeline Ingredients (%w/w) Cevi-1 Cevi-2 Cevi-3 Cevi-4 Cevi-5 Cevi-6 Cevi-7 Cevi-8 Cevimeline HCl x 0.5 H ₂ O (free base equivalent) 0.6 0.6 0.6 0.6 0.6 0.6 0.2 2 Citric acid monohydrate 0.014 0.014 0.014 0.014 0.014 0.014 0.014 0.014 Disodium hydrogen phosphate heptahydrate 0.268 0.268 0.268 0.268 0.268 0.268 0.268 0.268 pH 7.4 7.4 7.4 7.4 7.4 7.4 7.4 7.4 EDTA 0.01 0.00 0.01 0.00 0.01 0.00 0.00 0.00 NaCl qs qs 0 0 0 0 qs qs Sorbitol 0 0 qs qs 0 0 0 0 trehalose 0 0 0 0 qs qs. 0 0 BAK 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005 pure water qs qs qs qs qs qs qs qs

In some embodiments, a formulation of the present invention comprises at least MRA free base equivalent (active ingredient) at a concentration between about 0.1 to 10% w/w, lemon at a concentration between about 10 to 100 mM acid and/or at least one buffer, at least one chelating agent (EDTA) at a concentration between about 0.01 to 0.2% w/w, at least one osmotic pressure regulator to adjust the isotonic pressure range to about 200 to 400 mOsm, With moisture (remaining to 100% weight balance). Optionally, a preservative may be added in an amount sufficient to pass the requirements of the test for antibacterial efficacy of eye drops in accordance with the US Pharmacopeia and/or the European Pharmacopoeia.

The formulations of the invention can be evaluated according to the Schirmer test, tear break-up time (TBUT), lissamine corneal staining (Van Bijsterveld score), fluorescein staining (Oxford scale), and eyelid examination. Various applicable tests are also described in the scientific literature.

The following examples are intended to illustrate only some of the specific embodiments of the invention, and the following examples should not be construed as limiting the entire scope of the invention. Example 1

Cevimeline compositions Cevi-1 and Cevi-2 were prepared as described below. Cevimeline hydrochloride was added and dissolved in an aqueous solution containing citric acid and sodium phosphate as a buffer, sodium chloride as an osmotic agent, and benzalkonium chloride as a preservative. Add 0 or 0.01% disodium ethylenediaminetetraacetate (EDTA). If necessary, add hydrochloric acid and/or sodium hydroxide to adjust the pH to approximately 7.4. The composition can be further sterile filtered through a 0.22 micron filter. The compositions prepared as above were tested for physical appearance, content, impurities, pH, and osmotic pressure, and were stored at 25°C, 40°C for six months, and at 60°C for three months. stability. No significant content loss and no change in test parameters were observed. The formulation is considered stable when stored at room temperature. Example 2

Cevimeline compositions Cevi-3 and Cevi-4 were prepared as described below. Cevimeline hydrochloride was added and dissolved in an aqueous solution containing citric acid and sodium phosphate as buffers, sorbitol as osmotic agent, and benzalkonium chloride as preservative. Add disodium ethylenediaminetetraacetate (EDTA) at a concentration of 0 to 0.01%. If necessary, add hydrochloric acid and/or sodium hydroxide to adjust the pH to approximately 7.4. The composition can be further sterile filtered through a 0.22 micron filter. The compositions prepared as above were tested for physical appearance, content, impurities, pH and osmotic pressure, and were tested for storage at 25°C for up to 27 months, at 40°C for six months, and at 60°C Stability under storage for six months. No significant content loss and no change in test parameters were observed. The formulation is considered stable when stored at room temperature. Example 3

Cevimeline compositions Cevi-5 and Cevi-6 were prepared as described below. Cevimeline hydrochloride was added and dissolved in an aqueous solution containing citric acid and sodium phosphate as buffers, trehalose as osmotic agent, and benzalkonium chloride as preservative. Add disodium ethylenediaminetetraacetate (EDTA) at a concentration of 0 to 0.01%. If necessary, add hydrochloric acid and/or sodium hydroxide to adjust the pH to approximately 7.4. The composition can be further sterile filtered through a 0.22 micron filter. The compositions prepared as above were tested for physical appearance, content, impurities, pH and osmotic pressure, and were tested for storage at 25°C for up to 27 months, at 40°C for six months, and at 60°C Stability under storage for six months. No significant content loss and no change in test parameters were observed. The formulation is considered stable when stored at room temperature. Example 4

Cevimeline compositions Cevi-7 and Cevi-8 were prepared as described below. Cevimeline hydrochloride was added and dissolved in a concentration of 0.2% and 2.0% containing citric acid and sodium phosphate as a buffer, sodium chloride as an osmotic pressure agent, and benzalkonium chloride as a preservative in aqueous solution. Add disodium ethylenediaminetetraacetate (EDTA) at a concentration of 0 to 0.01%. If necessary, add hydrochloric acid and/or sodium hydroxide to adjust the pH to approximately 7.4. The composition can be further sterile filtered through a 0.22 micron filter. The compositions prepared as above were tested for physical appearance, content, impurities, pH and osmotic pressure, and were tested for storage at 25°C for up to 27 months, at 40°C for six months, and at 60°C Stability under storage for six months. No significant content loss and no change in test parameters were observed. The formulation is considered stable when stored at room temperature. Example 5

Each formulation contains cevimeline substantially prepared as described in Examples 1 to 4 herein, and cevimeline meets actual time (25°C) and accelerated (40°C and 60°C) stabilization conditions . High performance liquid chromatography (HPLC) assays were performed to assess cevimeline and impurity (degradation) content and other quality attributes (pH, osmolarity, and physical appearance). We found that all formulations remained stable. Table 2A : Stability of Cevimeline Formulation Examples formula parameter time Storage conditions 25 °C / 60% RH time ( months ) 0 3 6 10 27 Cevi-1 content% 100.8 99.9 97.4 99.3 99.4 Impurity content, % 0.15 0.17 0.17 0.20 0.05 pH 7.3 7.3 7.4 7.2 7.1 Osmolality mOsmol/kg 287 286 291 312 296 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-2 content% 100.6 99.9 100.5 99.8 100.2 Impurity content, % 0.15 0.16 0.17 0.15 - pH 7.4 7.4 7.5 7.3 7.3 Osmolality mOsmol/kg 276 279 288 283 295 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-3 content% 102.1 100.7 101.6 100.6 100.8 Impurity content, % 0.14 0.16 0.16 0.16 -0.06 pH 7.3 7.3 7.1 7.1 7.2 Osmolality mOsmol/kg 284 296 302 303 306 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-4 content% 102.6 100.8 99.0 100.5 101.2 Impurity content, % 0.15 0.17 0.15 0.14 - pH 7.3 7.2 7.2 7.0 7.3 Osmolality mOsmol/kg 296 300 297 303 308 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-5 content% 103.3 102.4 99.3 102.2 102.6 Impurity content, % 0.15 0.18 0.17 0.24 0.4 pH 7.3 7.1 7.1 7.1 7.3 Osmolality mOsmol/kg 324 325 334 332 336 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-6 content% 102.3 102.3 95.1 102.3 102.8 Impurity content, % 0.15 0.18 0.16 0.16 - pH 7.3 7.2 7.2 7.2 7.3 Osmolality mOsmol/kg 314 329 329 327 338 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-7 content% 97.9 97.6 97.1 97.1 97.1 Impurity content, % 0.17 0.18 0.17 0.18 - pH 7.5 7.4 7.2 7.3 7.2 Osmolality mOsmol/kg 270 274 276 281 287 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-8 content% 100.2 102.5 92.0 100.8 96.4 Impurity content, % 0.16 0.18 0.16 0.18 - pH 7.4 7.3 7.4 7.4 7.3 Osmolality mOsmol/kg 293 294 301 293 306 physical appearance Colorless clear solution (CC) CC CC CC CC Table 2B : Stability of Cevimeline Formulation Examples formula parameter time Storage conditions 40 °C / 75% RH time ( months ) 0 1 2 3 6 Cevi-1 content% 100.8 99.1 98.8 100.2 98.9 Impurity content, % 0.15 0.14 0.14 0.16 0.27 pH 7.3 7.3 7.5 7.4 7.3 Osmolality mOsmol/kg 287 289 292 284 289 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-2 content% 100.6 99.1 100.0 98.5 97.6 Impurity content, % 0.15 0.14 0.14 0.86 0.14 pH 7.4 7.4 7.5 7.5 7.4 Osmolality mOsmol/kg 276 290 287 282 284 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-3 content% 102.1 100.4 100.9 101.5 98.5 Impurity content, % 0.14 0.14 0.14 0.15 0.27 pH 7.3 7.3 7.3 7.3 7.3 Osmolality mOsmol/kg 284 284 304 298 298 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-4 content% 102.6 100.5 100.2 101.6 98.6 Impurity content, % 0.15 0.13 0.13 0.16 0.16 pH 7.3 7.3 7.4 7.3 7.3 Osmolality mOsmol/kg 296 306 299 298 299 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-5 content% 103.3 103.1 103.5 102.6 100.3 Impurity content, % 0.15 0.14 0.14 0.16 0.49 pH 7.3 7.3 7.4 7.3 7.3 Osmolality mOsmol/kg 324 337 326 326 329 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-6 content% 102.3 103.6 103.1 103.1 100.4 Impurity content, % 0.15 0.14 0.15 0.16 0.37 pH 7.3 7.2 7.3 7.2 7.1 Osmolality mOsmol/kg 314 336 328 332 330 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-7 content% 97.9 98.0 97.8 98.1 96.1 Impurity content, % 0.17 0.15 0.16 0.16 0.16 pH 7.5 7.4 7.5 7.4 7.4 Osmolality mOsmol/kg 270 283 277 273 279 physical appearance Colorless clear solution (CC) CC CC CC CC Cevi-8 content% 100.2 101.0 101.4 99.2 99.2 Impurity content, % 0.16 0.16 0.16 0.17 0.17 pH 7.4 7.4 7.5 7.5 7.4 Osmolality mOsmol/kg 293 298 295 294 295 physical appearance Colorless clear solution (CC) CC CC CC CC Table 2C : Stability of Cevimeline Formulation Examples formula parameter time Storage conditions 60 °C time ( weeks ) 0 3 6 Cevi-1 content% 100.8 103.0 98.7 Impurity content, % 0.15 0.14 0.13 pH 7.3 7.4 7.4 Osmolality mOsmol/kg 287 292 300 physical appearance Colorless clear solution (CC) CC CC Cevi-2 content% 100.6 99.3 98.7 Impurity content, % 0.15 0.13 0.13 pH 7.4 7.5 7.4 Osmolality mOsmol/kg 276 292 294 physical appearance Colorless clear solution (CC) CC CC Cevi-3 content% 102.1 100.5 99.3 Impurity content, % 0.14 0.13 0.13 pH 7.3 7.4 7.2 Osmolality mOsmol/kg 284 301 301 physical appearance Colorless clear solution (CC) CC CC Cevi-4 content% 102.6 100.5 98.9 Impurity content, % 0.15 0.13 0.13 pH 7.3 7.4 7.2 Osmolality mOsmol/kg 296 301 301 physical appearance Colorless clear solution (CC) CC CC formula parameter time Storage conditions 60 °C time ( weeks ) 0 3 6 Cevi-5 content% 103.3 102.0 99,5 Impurity content, % 0.15 0.20 0.30 pH 7.3 7.3 7.1 Osmolality mOsmol/kg 324 330 315 physical appearance Colorless clear solution (CC) CC CC Cevi-6 content% 102.3 102.5 99.9 Impurity content, % 0.15 0.18 0.25 pH 7.3 7.4 7.1 Osmolality mOsmol/kg 314 325 333 physical appearance Colorless clear solution (CC) CC CC Cevi-7 content% 97.9 96.4 96.3 Impurity content, % 0.17 0.15 0.16 pH 7.5 7.5 7.3 Osmolality mOsmol/kg 270 288 272 physical appearance Colorless clear solution (CC) CC CC Cevi-8 content% 100.2 101.6 99.8 Impurity content, % 0.16 0.15 0.16 pH 7.4 7.4 7.3 Osmolality mOsmol/kg 293 299 299 physical appearance Colorless clear solution (CC) CC CC Example 6

The irritation of the various formulations described herein was assessed by the well-documented Rabbit Draize Eye Test. The surface of the rabbit eyeballs was well tolerated by repeated instillation of each formulation without any obvious signs of toxicity. Example 7

A formulation comprising MRA and the other active ingredient is prepared according to any one of Examples 1 to 4, but further comprising another desired or described herein dosage (concentration) of the active ingredient. Example 8

A mixture of PUFA and MRA, or an ion pair containing the composition, is prepared as follows. Various cevimeline PUFA formulations are generally prepared in the following manner. Cevimeline hydrochloride was added and dissolved in an aqueous PUFA-containing solution to prepare a concentrated cevimeline PUFA mixture. This step may add one or more surfactants along with the PUFA. The concentrated mixture was homogenized in a high shear homogenizer to form a translucent to milky mixture. A stock solution containing citric acid with sodium phosphate (buffer), sodium chloride (osmotic agent), and benzalkonium chloride (preservative) and the ion-pair mixture are then mixed to bring the concentration of cevimeline to 0.1% to 10%. Disodium EDTA (EDTA) can be added at a concentration of 0.01 to 0.2%. At least one suitable antioxidant can be added. At least one surfactant can be added. At least one viscosity enhancer can be added to the stock solution. If necessary, add hydrochloric acid and/or sodium hydroxide to adjust the pH to about 7.4. The composition can be sterile filtered through a 0.22 micron filter.

Therefore, the aqueous ophthalmic composition of the present invention is stable in the neutral pH range.

All numerical values disclosed herein may have the standard technical error of measurement (standard deviation) of ± 10%. The word "about" is intended to mean ±10%, ±5%, ±2.5%, or ±1% of a given value, that is, "about" 20% means 20±2%, 20±1% , 20±0.5%, or 20±0.25%.

The foregoing are detailed descriptions of specific embodiments of the present invention. It must be understood that although specific embodiments of the invention are described herein for illustrative purposes, various modifications can be made without departing from the spirit and scope of the invention. Therefore, the present invention is not limited only to the scope of the patent application. Embodiments disclosed and claimed herein can be performed without undue experimentation in accordance with the disclosure of this patent specification.

Claims (22)

A stable aqueous topical ophthalmic composition comprising cevimeline at a concentration of about 0.1% to 10% and a neutral pH in the range of 6 to 9, and one or more pharmaceutically acceptable excipients. The composition of claim 1, wherein cevimeline is in free base form, salt form, or a combination of free base and salt form, and further comprising a second active ingredient, wherein the second active ingredient The ingredients contain a steroid, an immunomodulator, an immunosuppressant, a hormone, an androgen, a secretagogue, a lymphocyte function-associated antigen-1 (LFA-1) antagonist, a meibomian gland A dysfunctional active ingredient, or a combination of the above. The composition of claim 1 or 2, wherein the cevimeline is present at a concentration of between about 0.1% to 10.0% w/v, about 0.5% to 5% w/v, or about 0.2% to 2% w/v. The composition of claim 1 or 2, further comprising at least one polyunsaturated fatty acid. The composition of claim 4, wherein the polyunsaturated fatty acid is present at a concentration of between about 0.1% to 10% w/v, about 0.5% to 5% w/v, or about 0.2% to 2% w/ v. The composition of claim 4, wherein the polyunsaturated fatty acid contains about 12 to 26 carbon atoms per molecule. The composition of claim 4, wherein the polyunsaturated fatty acid is an omega-3 fatty acid, an omega-6 fatty acid, or a mixture of omega-3 and omega-6 fatty acids. The composition of claim 4, wherein the polyunsaturated fatty acid is eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), gamma-linolenic acid (GLA), or a mixture of the above. The composition of claim 1 or 2, further comprising a buffer, an osmotic pressure regulator, and moisture. The composition of claim 9, further comprising a preservative, a chelating agent, a tackifier, a surfactant, a solubilizer, an antioxidant, or a combination of the above substances. The composition as claimed in claim 1 or 2, wherein the osmotic pressure of the composition ranges from 200 to 400 mOsm/L, and the pH ranges from 6 to 9. The composition of claim 2, wherein a) the steroid is present at a concentration of about 0.1% to 1% w/v; b) the immunomodulatory agent is present at a concentration of about 0.05% to 0.1% w/v; c) the Hormone presented at a concentration of approximately 0.01% to 0.5% w/v; or d) the secretagogue presented at a concentration of approximately 1% to 5% w/v; or e) the lymphocyte function-associated antigen-1 (LFA-1) The concentration of antagonist is approximately 1% to 5% w/v. The composition of claim 2 or 12, wherein a) the steroid refers to loteprednol, pericticortisol acetate, fluticasone, or a combination of loteprednol, pernicortisol acetate, and fluticasone; b) the immunomodulator refers to cyclosporine, tacrolimus, sirolimus, or a combination of cyclosporine, tacrolimus, and sirolimus; c) the hormone refers to testosterone, estrogen a sex hormone, or a combination of a testosterone and an estrogen; d) the secretagogue refers to rebamipide, diquafosol, or a combination of rebamipide and diquafosol; or e) the lymphocyte Function-Associated Antigen-1 (LFA-1) antagonists refer to Rifester. The composition of claim 1, wherein the composition is free of ointment compositions, cream compositions, plaster compositions, cream compositions, and/or non-aqueous compositions. The composition of claim 1, wherein the composition is free of insulin, IGF (an insulin-like growth hormone), somatomedin C, and cycloplegic agents. The composition of claim 1, wherein cevimeline can be replaced with pilocarpine, aceclidine, acetylcholine, methacholine, carbachol, oxytremorine, or for the treatment of dry eye Any muscarinic receptor agonist with curative effect. An ophthalmically acceptable ion pair comprising a cevimeline and a polyunsaturated fatty acid for the treatment of dry eye. The ion pair of claim 17, wherein the molar ratio of polyunsaturated fatty acid to cevimeline ranges from about 2:1 to 1:2, or about 1:1. The ion pair of claim 17 or 18, wherein a) the polyunsaturated fatty acid contains a mixture of about 12 to 26 carbon atoms or more per molecule; b) the polyunsaturated fatty acid is selected from omega- 3 fatty acids, omega-6 fatty acids, or the group consisting of omega-3 fatty acids in combination with omega-6 fatty acids; or c) the polyunsaturated fatty acid is selected from the group consisting of eicosapentaenoic acid (EPA), docosahexanoic acid A group consisting of alkenoic acid (DHA), alpha-linolenic acid (ALA), gamma-linolenic acid (GLA), or a mixture of the above. The composition of claim 1, wherein cevimeline is provided by an ophthalmically acceptable ion pair comprising the cevimeline and a polyunsaturated fatty acid for the treatment of dry eye. A method of treating a dry eye disorder, dry eye syndrome or symptom, the method comprising externally administering to the eye of a subject in need thereof and a composition as claimed in claim 1 or 2. A method of treating a dry eye disorder, dry eye syndrome or symptom, the method comprising externally administering to the eye of a subject in need thereof and a composition as claimed in claim 17 or 18.