Ophthalmic composition comprising at least one nicotinic acetylcholine receptor modulator for topical application to eye to prevent or treat inflammation of eye

Abstract

The present invention relates to ophthalmic compositions comprising at least one substance of at least one nicotinic acetylcholine receptor (nAChR) modulator, in particular varenicline, megamine and derivatives thereof, and / or the endogenous Kennedy metabolic pathway, as well as salts and derivatives or pharmaceutically acceptable salts of these substances, and choline-containing phospholipids, salts and derivatives of these substances. From these groups, particularly preferred are choline, phosphocholine, CDP-choline (citicoline), phosphatidylcholine (e.g. Lecithin having a phosphatidylcholine content of > = 80% by weight, e.g. Soybean lecithin), ethanolamine, phosphoethanolamine, CDP-ethanolamine, phosphatidylethanolamine, L-alpha-glycerophosphorylcholine, phosphatidylcholine, phosphatidylethanolamine.

Description

[0001] This invention relates to ophthalmic compositions comprising

[0002] • At least one nicotinic acetylcholine receptor (nAChR) modulator, particularly varenicline, mecamylamine, and their derivatives.

[0003] and / or

[0004] • At least one substance from the endogenous Kennedy metabolic pathway, and salts and derivatives of such substances or pharmaceutically acceptable salts, and choline-containing phospholipids, salts and derivatives of such substances, and choline, phosphoric acid choline (e.g., lecithin with a phosphatidylcholine content ≥80% by weight), CDP-choline (cytidine diphosphate choline), phosphatidylcholine (lecithin, such as soy lecithin), ethanolamine, phosphate ethanolamine, CDP-ethanolamine, phosphatidylethanolamine, L-α-glucosidylcholine,

[0005] It is used to stimulate tear production to prevent or treat (i.e., to reduce or eliminate) inflammatory diseases or reactions of the eyes and / or lubrication disorders.

[0006] In this case, the ophthalmic composition is applied to the patient's open and / or closed eyes.

[0007] Inflammation of the eye and its surface is caused by various exogenous or endogenous toxins or stressors, such as UV light, mechanical irritation like friction, chemical effects, chemicals, allergens, pathogens like bacteria and viruses, impaired wetting, reactive oxygen species, and drug treatments. This leads to pathological changes and / or frequent inflammatory responses on the ocular surface.

[0008] Diseases such as red, painful, or itchy eyes, or a feeling of pressure in the eyes, swelling of the conjunctiva and / or eyelids, increased sensitivity to light, watery or purulent discharge, and sticky eyelids are typical symptoms of any persistent and / or excessive immune response in the eyes.

[0009] Various inflammatory mediators, such as cytokines, other growth factors, and matrix metalloproteinases (MMPs), play important roles in corneal homeostasis and its pathological conditions. These mediators are produced and released by immune cells that reside in the cornea or infiltrate the cornea during inflammation, such as macrophages, B lymphocytes, T lymphocytes, and natural killer cells, but are also produced and released by many non-immune cells such as fibroblasts (repair cells), keratinocytes, endothelial cells, and corneal epithelial cells.

[0010] While normal inflammatory responses have positive effects (e.g., controlling harmful stimuli and repairing damaged tissue through MMPs such as MMP9), persistent and / or excessive immune responses have undesirable harmful effects (e.g., pathological changes and defects in ocular tissues mediated by, for example, elevated MMP9 levels and / or reactive oxygen species released by immune cells). Inflammatory mediators, excessive release of MMPs, and / or the imbalance between pro-inflammatory and anti-inflammatory mediators, or the imbalance between MMPs and their inhibitors, play a crucial role here. Inflammation is a complex process involving various genes and signaling pathways.

[0011] Existing technologies include treatments for dry eye syndrome involving the administration of an nAChR agonist, such as varenicline, via nasal spray. In this process, varenicline binds to the AChRs of nerve cells in the nasal mucosa. This leads to activation of the trigeminal nerve, anterior ethmoidal nerve, or the nasolacrimal reflex. The nerve signals ultimately affect the lacrimal glands to increase tear release.

[0012] Its drawback is that it only affects the lacrimal glands and therefore only increases the amount of water-containing tears in the eye, meaning it only affects hypoposecretory dry eye (insufficient tear production).

[0013] Its application to the intranasal cavity has no effect on the lipid and mucin layers of the tear film and / or any inflammatory response in the eye.

[0014] However, the lipid and mucin layers perform very important functions in terms of the residence time of the aqueous tear film and its lubrication on the surface of the eye.

[0015] The lipid layer is the outermost layer of the tear film. Lipids produced by the meibomian glands form an oily layer on the surface of tears secreted by the lacrimal glands, preventing rapid evaporation and dripping from the edges of the eye (“tearful eye”). Therefore, it plays a crucial role in the residence time of the water-containing tear film on the eye. Prolonged residence time and the resulting moisturization of the ocular surface are important for the prevention and / or treatment of dry eye.

[0016] The innermost mucin layer, formed by goblet cells, mediates the good and stable adhesion of the aqueous tear film to the ocular surface to achieve the same goal, thus ensuring the long-lasting moisture and lubrication of the ocular surface. Furthermore, intranasal application does not allow for the delivery of mucin and / or lipid substitutes to the eye to increase the stability and residence time of the aqueous tear film or to exert additional soothing, relieving, lubricating, and friction-reducing effects.

[0017] Furthermore, intranasal application cannot treat eye inflammation.

[0018] Another drawback is that when administered via the nasal mucosa, the active substance can easily enter the brain. Through the opening in the ethmoid bone—the passage through which the nerve fibers of the olfactory nerve leave the brain and enter the nasal mucosa—the active substance travels in the opposite direction from the nasal mucosa, taking a shorter route and reaching the brain almost unimpeded. Therefore, there is a risk of unwanted neurological symptoms as a side effect.

[0019] The object of this invention is to prevent, reduce, or completely eliminate persistent, harmful inflammatory responses and their consequences, as well as wetting disorders in dry eyes, including Sjögren's syndrome, Sicca-Syndrom, and hyposecretionary and / or low- or high-evaporation types, through one mechanism, but preferably a dual or multiple mechanism. These mechanisms include:

[0020] • Downregulate the formation and / or release of inflammatory mediators, such as pro-inflammatory cytokines (e.g., interleukins IL-1, IL-6, IL-8, tumor necrosis factor TNF-α), chemokines, and specific enzymes, such as matrix metalloproteinases (MMPs), and / or

[0021] • By stimulating the body's own lacrimal glands to produce tears, the lubrication and moisture of the eye surface are increased, and / or

[0022] • Maintain the mucin and / or lipid layer by preventing eye inflammation and / or adding appropriate lipid and / or mucin substitutes.

[0023] Therefore, the object of this invention is to provide an improved method that is more effective and has fewer side effects. This may involve one or more complementary effects or mechanisms of action to modulate persistent and excessive inflammatory responses at different levels and support necessary repair processes to restore molecular homeostasis at the cellular and tissue levels.

[0024] This objective is achieved through the features of claim 1. The corresponding dependent claims are equivalent to advantageous developments herein.

[0025] Therefore, this invention relates to ophthalmic compositions containing at least one active substance selected from nicotinic acetylcholine receptor modulators and their derivatives, substances from the body's own Kennedy metabolic pathway and their salts and derivatives, and combinations thereof, such as cytidine 5'-bisphosphate choline (CDP-choline), choline, phosphocholine, L-α-glycerylphosphorylcholine, phosphatidylcholine (lecithin) and their metabolites, degradation products and / or their derivatives and salts, for the purpose of preventing or treating ocular inflammation or disease and ocular moisture disorders by topical application of the ophthalmic composition to open and / or closed eyes. To date, the use of these active substances for topical application to ocular tissues to prevent and / or treat, for example, inflammatory diseases of the cornea, eyelid margin and / or dry eye is unknown.

[0026] Its advantage is that at least one active substance (selected from AChR modulators and / or known substances from the Kennedy metabolic pathway) is applied as close as possible to the site of disease so that it can exert its effects as effectively as possible there. Topically applied ophthalmic compositions act directly on physiological inflammatory processes and responses at the site of inflammation. The compositions of the present invention directly target effector cells in the eye involved in the inflammatory process, thereby correspondingly modulating their internal cellular processes.

[0027] Furthermore, it is particularly advantageous and unexpected that the compositions of the present invention can act on different cells, cell types and / or tissues, and even on different sensory organs (eyes, nose), preferably exerting dual or multiple modes of action (physiological and / or physical). These multiple effects and processes include, in particular, those selected from:

[0028] • Anti-inflammatory effects, such as those mediated by the interaction between nAChR modulators and nAChR receptors on non-neuronal cells in ocular tissues (physiological processes).

[0029] • Stimulates the secretion of the water-containing tear film, thereby increasing the moisture of the eye surface. This is because some ophthalmic components are drained through the nasolacrimal duct to corresponding receptors in the nasal mucosa, which then triggers nerve stimulation of the lacrimal gland, which in turn triggers the secretion of tears in the eye (physiological process).

[0030] • By adding known excipients, such as lipids, medium-chain triglycerides, carbomer, mucopolysaccharides, etc., to ophthalmic compositions, the residence time on the irritated natural tear film can be increased and / or evaporation reduced.

[0031] • By adding appropriate excipients, such as glycoglycans, glycosaminoglycans, cellulose derivatives, and dextropanthenol, inflammation and dryness-related irritation and friction (physical processes) can be relieved.

[0032] Therefore, the ophthalmic compositions according to the invention can be used to downregulate or inhibit the presentation of, for example, pro-inflammatory cytokines (such as interleukins IL-1, IL-6, IL-8, tumor necrosis factor TNF-α), chemokines, specific enzymes such as MMPs, and / or adhesion molecules (e.g., originating from or located on epithelial cells, endothelial cells, fibroblasts, corneal epithelial cells, immune cells) that play a role in inflammation. This can be mediated through nicotinic acetylcholine receptors and subsequent signaling pathways, regulation of transcription, translation, and / or protein release, and / or through mechanisms that are still unknown.

[0033] Surprisingly, it has been found that topical application of ophthalmic compositions containing at least one active substance, namely an nAChR receptor modulator and / or at least one known substance derived from cell membrane metabolism (substances of the body's own Kennedy metabolic pathway), can reduce or prevent the release of pro-inflammatory mediators, specific enzymes such as MMP9, and / or adhesion molecules from the eye, thereby preventing the development of a persistent inflammatory process or alleviating or stopping existing inflammation. This is unexpected because the application of at least one active substance is performed topically on the open and / or closed surface of the eye, rather than through systemic distribution (e.g., into the bloodstream).

[0034] Equally surprising is that at least one of the applied active substances can reach the effector site in the tissue, interact with it, and achieve the desired effect. For example, nAChR modulators interact with various immune and non-immune cells in ocular tissue that express nicotinic acetylcholine receptors and play a role in the inflammatory process. These cells in the eye are non-neuronal cells, which contribute to achieving the desired effect.

[0035] Its advantage over systemic application is that its effect remains largely confined to the application site—the site of inflammation—where it acts virtually undiluted and directly on the cells involved in the inflammatory process. This prevents excessive reactions in the inflammatory process, such as oxidative stress. Therefore, the surface of the eye is protected, contributing to the formation and maintenance of a smooth, healthy corneal surface. Topical application is also particularly advantageous in avoiding side effects, as nAChR, for example, is ubiquitous in the body and participates in regulating very different processes.

[0036] When an ophthalmic composition is applied topically to the eye, the nAChR modulator binds to or interacts with the receptor or one or more of its subunits and alters its activity, thereby affecting the triggered signal transduction and subsequent signal transduction pathways.

[0037] The activation or regulation of cellular processes in the ocular region, particularly those in non-neuronal cells, is achieved through one or more nAChR modulators to prevent, reduce, or eliminate inflammatory responses (non-neuronal pathways) in ocular tissues.

[0038] Equally surprising, as known from the Kennedy metabolic pathway, these substances, when applied topically to the eyes, can reach their sites of action in tissues and modulate immune processes. For example, in vitro administration of phosphocholine or cytidine-5'-bisphosphate choline to HCE-T cells reduces TNF-α-stimulated MMP9 expression. Administration of varenicline also has this effect. The exact mechanisms of action of these substances remain unknown.

[0039] MMP9 is a relevant inflammatory marker that is elevated in the tears of patients with dry eye.

[0040] According to other aspects, the present invention relates to an ophthalmic composition containing at least one nicotinic acetylcholine receptor modulator and / or at least one substance of the body’s own Kennedy metabolic pathway, for stimulating tear production by topical application of the ophthalmic composition to open and / or closed eyes.

[0041] Surprisingly, the ophthalmic composition according to the invention was found to stimulate natural tear formation.

[0042] This stimulation of natural tear production can be induced by an ophthalmic composition that drains in a controlled manner through the nasolacrimal duct, thereby activating, for example, nicotinic acetylcholine receptors in the nasal mucosa. As a result, the trigeminal nerve, anterior ethmoidal nerve, or nasolacrimal reflex is activated, and these nerve signals ultimately stimulate the lacrimal glands to increase tear production. This provides valuable support in the prevention and treatment of inflammation and lubrication disorders. This effect occurring in the nasal mucosa after topical application of the formulation to the open or closed eye is quite surprising and unexpected.

[0043] The ophthalmic composition stimulates increased tear production, thereby promoting the formation of a natural moisturizing and protective film on the eye's surface, and thus ensuring continuous lubrication of the cornea and conjunctiva. As mentioned above, this can prevent inflammation or inflammatory reactions, as well as possible tissue erosion of the eye, or alleviate these conditions and support healing. Foreign matter adhering to the eye's surface, such as dust, can also be more effectively flushed away.

[0044] The effects produced by the compositions of the present invention through dual or multiple modes of action (physiological and / or physical) on different cells, cell types (e.g., immune and non-immune cells) and / or tissues, and even different sensory organs (eye, nose), are particularly advantageous and unexpected.

[0045] It can be applied to either open or closed eyes. According to this application, the eye / ocular tissue includes the cornea, bulbar conjunctiva and palpebral conjunctiva (including the tarsal conjunctiva), limbal stem cells, eyelids and palpebral margins, meibomian glands and epithelial cells, lacrimal apparatus including the tear drainage system, and / or immune cells of the ocular tissue. All these structures form a functional unit. Immune cells present in ocular tissues (resident and / or transient during inflammation) are also particularly involved. Therefore, the site of action includes the anterior segment of the eye, encompassing all the aforementioned structures. Thus, by definition, the term "anterior segment of the eye" includes the aforementioned components.

[0046] This process is mediated and initiated by the interaction of at least one active substance of the composition of the present invention with nAChRs on cells and / or immune and / or non-immune cells in ocular tissue, or through an unknown mechanism. This reduces or completely inhibits the release of inflammatory mediators and / or the transcription of various genes, including those encoding cytokines and chemokines, as well as specific enzymes such as MMPs. Similarly, the formation and / or presentation of adhesion molecules that support immune cell infiltration into inflamed tissues are reduced.

[0047] This means that, triggered by regulators and / or substances in the Kennedy metabolic pathway, these nicotinic acetylcholine receptors and / or other mechanisms can influence the transcription of inflammatory mediators, such as pro-inflammatory cytokines and MMPs, and thus affect their expression.

[0048] The at least one nicotinic acetylcholine receptor modulator is preferably selected from (7,8,9,10-tetrahydro-6,10-methyl-6H-pyrazino[2,3-h]-[3]benzozazepine), varenicline tartrate, varenicline hydrochloride, cytisine, 3-bromo-cytisine, desformylflustrabromine, desformylflustrabromine hydrochloride, pozanicline, pozanicline dihydrochloride, bupropion, sofinicline, 3-(5,6-dichloropyridin-3-yl)-l(S),5(S)-3,6-diazabicyclo [3.2.0] Heptane (ABT-894), 3-methyl-5-[(2S)-1-methylpyrrolidin-2-yl]-1,2-oxazole (ABT-418), acetylcholine, 3,6-diazabicyclo[3.1.1]heptane-3-carboxamide (TC-8831), 3-ethyl-2,4-dimethyl-1H-pyrrole (TC-10600), N-[1-(5-chloro-6-pyridin-2-ylpyridin-2-yl)piperidin-4-yl]-2-hydroxyethanesulfonamide (ABT-126), (3R)-3-{[6-(4-methyl-phenyl)pyridin-3-yl]oxy}-1-azabicyclo[2.2.2]octane (AQW-051), mecain, and acceptable derivatives or salts thereof, as well as mixtures and combinations thereof.

[0049] Pharmaceutically acceptable salts are those that retain the desired biological activity of the starting material without promoting any undesirable toxicological effects, such as acid salts, including acetates, tartrates, chlorides, phosphates, sulfates, sulfites, carbonates, bicarbonates, and citrates.

[0050] Nicotinic acetylcholine receptor modulators, such as varenicline and its derivatives, ultimately lead to the downregulation of pro-inflammatory cytokines upon interaction with or binding to nAChR, and thus can prevent, reduce, or stop persistent and harmful inflammatory responses in the eye. This occurs through receptor-mediated regulation at the gene transcriptional level of pro-inflammatory mediators, such as pro-inflammatory cytokines, chemokines, inflammatory enzymes such as MMPs, and receptor formation, for example mediated by NF-κB.

[0051] At least one substance of the Kennedy metabolic pathway suitable for the purposes of this invention, and its salts and derivatives, particularly selected from choline, phosphatidylcholine, lecithin (a possible derivative of which is lysophosphatidylcholine), ethanolamine, phosphoethanolamine, CDP-ethanolamine, phosphatidylethanolamine, L-α-glycine, citicoline (CDP-choline), cytidine diphosphate choline ([(2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxacyclopentan-2-yl]methyl-{oxidized-[2-(trimethylammonium)ethoxy]-phosphoryl}-phosphate, citicoline), α-glycine, phosphocholine, glycerophosphorylcholine, and / or derivatives of these substances. Surprisingly, these substances have been shown to influence signaling pathways involved in inflammatory processes and, for example, regulate or inhibit the transcription or release and / or regulation of inflammatory mediators such as MMP9. This can be mediated by nAChR or other means.

[0052] All substances in the Kennedy pathway are substances involved in natural cellular metabolism or their salts and / or derivatives. In natural cellular metabolism, phosphatidylcholine and phosphatidylethanolamine, respectively, are synthesized de novo from choline and ethanolamine via the Kennedy pathway; these are the most common phospholipids in mammalian cells. Therefore, these endogenous substances are well tolerated when applied to or in the eye. Surprisingly, these substances induce the downregulation of pro-inflammatory cytokines, MMPs, and similar substances in ocular tissues. Thus, excessive or persistent inflammation can be alleviated or prevented. This can have a positive impact on the inflammatory process, disease, and / or accompanying symptoms of various eye diseases.

[0053] Examples include eye infections and inflammations caused by wetting disorders, allergies, styes, corneal inflammation (keratitis), eyelid inflammation (blepharitis) or dry eye (keratoconjunctivitis sicca), Sjögren's syndrome, etc.

[0054] Selective topical application to areas of ocular inflammation is advantageous because nicotinic acetylcholine receptors are also involved in the regulation of other bodily processes, and topical application has a very limited effect on these processes, resulting in fewer side effects.

[0055] In addition to nAChR regulators and / or substances derived from the body’s own Kennedy metabolic pathway, the composition may also contain components known to protect and improve membrane properties such as fluidity and permeability, as environmental toxins and excessive inflammatory processes can negatively affect these membrane parameters.

[0056] Coenzyme Q-10 is a component in particular. Its long, lipophilic isoprene side chains integrate into the cell membrane and affect the membrane's fluidity properties.

[0057] Dextropanol is another such component. It stimulates the synthesis of membrane lipids and thus promotes intact membrane homeostasis with physiological permeability. Dextropanol also plays a role in regulating gene expression (e.g., interleukin) during inflammation. It has anti-inflammatory and anti-apoptotic effects, thus providing excellent support for the actions of nAChR agonists and regulators through alternative mechanisms of action.

[0058] Therefore, it is particularly advantageous if the composition contains dextropaneol and / or coenzyme Q-10. However, in certain embodiments, it may also be without coenzyme Q-10 and / or dextropaneol.

[0059] In addition, it may contain components that serve as lipid-phase alternatives for treating evaporative dry eye, such as medium-chain triglycerides, oily or lipid-containing substances, or lipids such as castor oil.

[0060] It may also contain soothing ingredients such as hyaluronic acid, povidone, plant extracts from eyebright, mallow, blueberry, etc., dexpanthenol, heparin, tetrahydropyrimidine, and hydroectoine.

[0061] Ophthalmic compositions are preferably formulated as aqueous solutions, o / w nanoemulsions (micelle sizes of 1 nm to 100 nm), or o / w microemulsions (micelle and / or liposome sizes of 100 nm to 1000 nm).

[0062] For example, at least one nicotinic acetylcholine receptor A agonist may be present in the ophthalmic composition in a total amount of 0.00001% to 3.0% by weight, preferably 0.0001% to 2.0% by weight, and particularly preferably 0.001% to 1.5% by weight.

[0063] According to other preferred embodiments, the ophthalmic composition is envisioned to have a kinematic viscosity of 1 mm, as measured according to European Pharmacopoeia 9.8, section 2.2.8. 2 / s to 150mm 2 / s, preferably 7mm 2 / s to 100mm 2 / s, optimal value 10mm 2 / s to 70mm 2 / s. This promotes improved adhesion and tolerance at the application site (no foreign body sensation).

[0064] For example, the ophthalmic composition has a weight molar osmolality of 150 mOsmol / kg to 340 mOsmol / kg, preferably 170 mOsmol / kg to 270 mOsmol / kg.

[0065] The pH value is preferably 5.8 to 8.5, and more preferably 6.6 to 7.4.

[0066] Specifically, the ophthalmic composition is free of ω-3 fatty acids and / or antioxidants. In one specific embodiment, the composition is free of phosphate buffers. In one specific embodiment, the composition is free of phosphate ions. In the context of this invention, "phosphate-free" means that the pharmaceutical composition contains less than 7 mmol / L of phosphate ions, preferably less than 3 mmol / L of phosphate ions, particularly preferably less than 1 mmol / L of phosphate ions, and extremely preferably free of phosphate ions (i.e., below the detection limit). The term "phosphate" encompasses all ions derived from phosphoric acid, namely dihydrogen phosphate, hydrogen phosphate, and phosphate.

[0067] In addition, ophthalmic compositions may also be hyaluronic acid-free.

[0068] Similarly, ophthalmic compositions may also contain ophthalmologically compatible solutes and their derivatives, particularly selected from sugars such as sucrose, rutinose, trehalose, polyols such as glycerol, inositol, erythritol, amino acids such as proline, and tetrahydropyrimidine derivatives such as tetrahydropyrimidine, hydroxytetrahydropyrimidine, glycine betaine, betaine, and L-carnitine.

[0069] Ophthalmic compositions may also contain components for maintaining and / or restoring membrane fluidity and permeability, such as coenzyme Q-10, cholesterol, resveratrol, etc.

[0070] In addition, the composition may contain anti-inflammatory and / or soothing herbal extracts, such as extracts or tinctures from calendula, plantain, magnolia, eyebright, chamomile, aloe vera, willow bark, echinacea, arnica, etc.

[0071] The ophthalmic composition may also contain at least one ophthalmologically compatible buffer, particularly a buffer selected from inorganic and / or organic buffering substances, such as citrate buffers, phosphate buffers, phosphate-citrate buffers, tromethamine buffers, borate buffers, acetate buffers, acetate-borate buffers, and combinations thereof.

[0072] Other preferred embodiments include at least one mucoadhäsive (mucoashous) component and / or at least one component that affects viscosity and thus influences the duration of stay on the eye, particularly selected from cellulose derivatives such as carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hyaluronic acid, chondroitin sulfate, polyvinyl alcohol, povidone (polyvinylpyrrolidone), hydroxypropyl guar gum, hydroxypropyl cellulose, tamarind seed polysaccharide, polyacrylic acid (carbomer), polyethylene glycol, mucopolysaccharides such as heparan sulfate, heparin sulfate and heparin, and derivatives thereof.

[0073] The concentration of these substances in the formulation should be carefully adjusted depending on whether the formulation is intended to act only on the anterior segment of the eye or on both the eye and nose. For effects on various sensory organs, formulation compositions containing a small amount of mucosal adhesion components (synonyms: thickeners) are preferred so that the composition can be partially drained through the nasal mucosa. Therefore, based on ophthalmic compositions, the content of the thickener is preferably 0.01% to 0.5% by weight, more preferably 0.02% to 0.1% by weight, for example in the case of hyaluronic acid.

[0074] According to other embodiments, the ophthalmic composition contains at least one tonicity agent, particularly glycerol, NaCl, sorbitol and / or boric acid.

[0075] To achieve improved penetration into the ocular tissues as defined above, particularly the cornea and conjunctiva, a penetration enhancer may also be included, particularly isopropyl myristate and / or isopropyl palmitate.

[0076] Preferably, the ophthalmic composition also contains at least one emulsifier, particularly vitamin E TPGS, poloxamer, such as Kolliphor P 407 and / or Kolliphor P188.

[0077] Preferred pharmaceutical excipients are selected from organic buffering substances, inorganic buffering substances, inorganic salts and / or organic salts, viscosity modifiers and consistency improvers, emulsifiers, stabilizers, wetting agents, spreading agents, antioxidants, osmolarity regulators and mixtures thereof.

[0078] Ophthalmic compositions are particularly suitable for the prevention or treatment of inflammation caused by blepharitis, keratitis, uveitis, iritis, allergies such as pollen allergies, and other conditions such as Sjögren's syndrome and keratoconjunctivitis sicca.

[0079] With regard to the use of the compositions of the present invention for stimulating tear production, they are particularly suitable for the prevention or treatment of dry eye (Sjögren's syndrome, keratoconjunctivitis sicca), especially hyposecretionary and / or evaporative dry eye.

[0080] Ophthalmic compositions are specially formulated as aqueous eye drops, tinctures, ointments, gels, aerosols, or lotions, for example, for application by dripping, wiping, spraying, or atomizing.

[0081] Surprisingly, even after application to the eye, the agonist was found to induce additional drainage through the lacrimal ducts (lacrimal canaliculi), lacrimal sac, and / or nasolacrimal duct, and to activate tear production. The exact site of action and mechanism of action are unknown. However, it is believed that the agonist in the eye drops triggers stimulation by activating trigeminal nerve afferent fibers in the nasal mucosa.

[0082] By adjusting certain parameters of the composition, such as viscosity, mucoadhesion, and spreadability, the amount of drainage through the nasolacrimal duct can be controlled to a certain extent, ranging from almost no drainage to varying degrees of partial drainage. In the latter case, it is envisioned that after application to the eye, the ophthalmic composition according to the invention will partially drain through the nasolacrimal duct, thereby additionally applying it to the nAChR of nerve cells in the nasal mucosa. The nerve signals stimulate the lacrimal glands of the eye to increase the secretion of the natural tear film, thereby improving hydration of the ocular surface. The dual (and / or multiple) effects of the eye drops are particularly beneficial, namely, the direct anti-inflammatory effect on ocular tissue (application of mucin and / or lipid substitutes), and, furthermore, the increased natural tear production after application to the eye by draining the composition through the nasolacrimal duct to the nasal mucosa. Since only a small concentration of the applied active ingredient reaches the nasal mucosa, side effects such as nasal mucosal irritation, sneezing, coughing, and undesirable neurological symptoms (side effects associated with direct nasal application) can be avoided. The amount of composition used for nasolacrimal duct drainage is adjusted by the spreadability, mucosal adhesion, and viscosity of the composition.

[0083] Amino acids and / or peptides and their derivatives, such as N-acetylcysteine, taurine, L-proline, glycine, L-lysine hydrochloride, and L-leucine, can also be added. These can improve the wettability of the ocular surface. This also applies to tyloxapol, a nonionic liquid polymer primarily used as a wetting agent or spreader. Spreaders can also improve drainage and distribution through the nasolacrimal duct.

[0084] For example, the ophthalmic composition can be applied or used once or 10 times a day, preferably once or 5 times a day.

[0085] For example, it can be used by instilling drops into an open eye or by applying drops or spraying onto the eyelid of a closed eye, applying 1 to 30 drops, more preferably 2 to 20 drops, particularly preferably 3 to 10 drops, or by applying a spray.

[0086] Ophthalmic compositions may contain ophthalmologically acceptable preservatives, but are preferably preservative-free.

[0087] The present invention will be described in more detail with reference to the following configuration, but the invention is not limited to the described embodiments. All data are given in weight percent.

[0088] Examples of formulations:

[0089]

[0090]

[0091] To demonstrate the efficacy of nicotinic acetylcholine receptor modulators and their derivatives and pharmaceutically acceptable salts, substances from the body's own Kennedy metabolic pathway and their derivatives and pharmaceutically acceptable salts, on the basis of this invention, in treating inflammatory diseases, the following model experiments were conducted.

[0092] method

[0093] Cell vitality

[0094] The effect of the concentration of the test substance on HCE-T cell viability was determined using a commercially available MTT assay.

[0095] MMP9 protein expression was analyzed using ELISA.

[0096] According to the manufacturer's protocol, MMP9 protein expression was analyzed using a human MMP-9 ELISA. HCE-T cells were seeded in 6-well plates (250,000 cells per well) and cultured for ten days. HCE-T cells were first pre-incubated with the test material for 30 minutes (concentrations shown in the graph), then 10 ng / ml of TNF-α was added directly and incubated for 24 hours.

[0097] Dexamethasone (100 µM) was used as a positive control.

[0098] The culture medium control (KGM) was used as a negative control.

[0099] Collect the supernatant of HCE-T cells and store at -20°C until use.

[0100] According to the manufacturer's instructions, the MMP9 content in the cell supernatant was determined using an ELISA kit.

[0101] Figure 1The protein expression of MMP9 in HCE-T cells was shown after pre-incubation with the nAchR regulator mecamine or citicoline, a substance involved in the Kennedy metabolic pathway.

[0102] result:

[0103] MMP9 is a relevant inflammatory marker that is elevated in the tears of patients with dry eye. This inflammatory marker can be used in in vitro models to assess the anti-inflammatory effects of eye drops (Voß et al., Int. J. Mol. Sci. 2023, 24, 1567).

[0104] Pre-incubation with the nAchR regulator mecamine or with citicoline, a substance found in the Kennedy metabolic pathway, can inhibit TNF-α-induced MMP9 protein expression in immortalized human corneal HCE-T cells by up to 30%. Figure 1 Previously, viability tests showed that the concentration used did not impair cell viability.

[0105] These results indicate that the use of nAchR modulators and substances from the Kennedy metabolic pathway can downregulate the formation and / or release of inflammatory markers. Therefore, these substances can intervene in and inhibit harmful inflammatory responses.

[0106] These results also demonstrate the regulatory effect of nAChR modulators on cellular processes in non-neuronal cells, namely human corneal HCE-T cells, leading to a reduction in inflammatory responses in in vitro models.

Claims

1. An ophthalmic composition comprising at least one active substance selected from nicotinic acetylcholine receptor modulators and their derivatives and pharmaceutically acceptable salts, substances of the endogenous Kennedy metabolic pathway and their derivatives and pharmaceutically acceptable salts, and combinations thereof. • It is used to treat or prevent inflammatory reactions or diseases of the eye and / or eye wetting disorders by topically applying the ophthalmic composition to open and / or closed eyes, or • It is used to stimulate tear production by applying the ophthalmic composition topically to open and / or closed eyes.

2. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, The nicotinic acetylcholine receptor modulators are selected from varenicline (7,8,9,10-tetrahydro-6,10-methylbridge-6H-pyrazino[2,3-h]-[3]benzozazepine), varenicline tartrate, varenicline hydrochloride, cytisine, 3-bromo-cytisine, desformylflustrabromine, desformylflustrabromine hydrochloride, pazaclan, pazaclan dihydrochloride, soficlan, 3-(5,6-dichloropyridin-3-yl)-1(S),5(S)-3,6-diazabicyclo[3.2.0]heptane (ABT-894), 3-methyl-5 -[(2S)-1-methylpyrrolidone-2-yl]-1,2-oxazole (ABT-418), acetylcholine, 3,6-diazabicyclo[3.1.1]heptane-3-carboxamide (TC-8831), 3-ethyl-2,4-dimethyl-1H-pyrrole (TC-10600), N-[1-(5-chloro-6-pyridin-2-ylpyridin-2-yl)piperidin-4-yl]-2-hydroxyethanesulfonamide (ABT-126), (3R)-3-{[6-(4-methylphenyl)pyridin-3-yl]oxy}-1-azabicyclo[2.2.2]octane (AQW-051), mecamin, and their salts, mixtures thereof, and combinations thereof.

3. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, At least one substance and / or its salt and / or derivative thereof from the Kennedy metabolic pathway is selected from choline, phosphatidylcholine, lecithin, lysophosphatidylcholine, ethanolamine, phosphoethanolamine, CDP-ethanolamine, phosphatidylethanolamine, L-α-glycine, citicoline (CDP-choline), cytidine diphosphate choline ([(2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxacyclopentan-2-yl]methyl-{oxidized-[2-(trimethylammonium)ethoxy]phosphoyl}phosphate, citicoline), α-glycine, phosphate choline, glycerophosphocholine and / or derivatives thereof.

4. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, It is applied to immune cells in the cornea, bulbar conjunctiva, palpebral conjunctiva and / or tarsal conjunctiva, limbal stem cells, eyelids and eyelid margins, lacrimal apparatus (main and accessory lacrimal glands), meibomian glands, conjunctival goblet cells, epithelial cells, nasolacrimal ducts and / or ocular tissues.

5. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, It contains coenzyme Q-10 and / or dextropaneol.

6. An ophthalmic composition for use according to any one of the preceding claims, wherein it is in the form of an aqueous solution, a nanoemulsion, or a microemulsion.

7. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, The total amount of the at least one active substance contained in the ophthalmic composition is from 0.00001% to 3.0% by weight, preferably from 0.0001% to 2.0% by weight, and more preferably from 0.001% to 1.5% by weight.

8. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, Its viscosity, measured according to Chapter 2.2.8 of the European Pharmacopoeia, is 1 mm. 2 / s to 150mm 2 / s, preferably 7mm 2 / s to 100mm 2 / s, with a preferred thickness of 10mm 2 / s to 70mm 2 / s.

9. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, Its weight molar osmotic pressure concentration is from 150 mOsmol / kg to 340 mOsmol / kg, preferably from 170 mOsmol / kg to 270 mOsmol / kg.

10. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, Its pH value is 5.8 to 8.5, preferably 6.6 to 7.

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11. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, It does not contain omega-3 fatty acids and / or antioxidants.

12. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, It does not contain hyaluronic acid.

13. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, It contains ophthalmologically compatible solutes and their derivatives, specifically selected from sugars such as sucrose, rutin, trehalose, polyols such as glycerol, inositol, and erythritol, amino acids such as proline, and tetrahydropyrimidine derivatives such as tetrahydropyrimidine, hydroxytetrahydropyrimidine, glycine betaine, betaine, and L-carnitine.

14. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, It contains at least one ophthalmologically compatible buffer, particularly a buffer selected from citrate buffers, phosphate buffers, phosphate-citrate buffers, tromethorphan buffers, borate buffers, acetate buffers, acetate-borate buffers, and combinations thereof.

15. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, It contains at least one mucosal adhesion component or at least one component that increases the time of residence on the eye, particularly selected from cellulose derivatives such as carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hyaluronic acid, chondroitin sulfate, polyvinyl alcohol, povidone (polyvinylpyrrolidone), hydroxypropyl guar gum, hydroxypropyl cellulose, tamarind polysaccharide, polyacrylic acid (carbomer), polyethylene glycol and mucopolysaccharides such as heparan sulfate, heparin sulfate, heparin, and derivatives thereof, and combinations thereof.

16. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, It contains at least one tensioning agent, particularly glycerol, NaCl, sorbitol and / or boric acid.

17. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, It contains at least one penetration enhancer, particularly isopropyl myristate and / or isopropyl palmitate.

18. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, It contains at least one emulsifier, particularly vitamin E TPGS and / or poloxamer, such as Kolliphor P 407 and Kolliphor P188.

19. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, It contains no preservatives or phosphates.

20. An ophthalmic composition for use according to any one of the preceding claims, for the prevention or treatment of inflammation of the anterior segment of the cornea caused by corneal injury, such as epithelial damage caused by mechanical influence, conjunctivitis, blepharitis, keratitis, uveitis, iritis, allergies such as pollen allergy, and inflammation caused by other diseases such as Sjögren's syndrome, keratoconjunctivitis sicca, bacterial and / or viral infections.

21. An ophthalmic composition for use according to any one of the preceding claims, for the prevention or treatment of dry eye (Sjögren's syndrome, keratoconjunctivitis sicca), particularly secretory and / or evaporative dry eye.

22. An ophthalmic composition for use according to any one of the preceding claims, wherein it is in the form of eye drops, aqueous solution, tincture, ointment, gel, emulsion, aerosol or lotion.

23. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, After application to the eye, the ophthalmic composition undergoes partial drainage via the nasolacrimal duct and additional delivery to the nicotinic acetylcholine receptors of nerve cells in the nasal mucosa.

24. An ophthalmic composition for use according to any one of the preceding claims, characterized in that, It can be used 1 to 10 times a day, preferably 1 to 5 times.

25. An ophthalmic composition for use according to any one of the preceding claims, wherein the ophthalmic composition is in the form of an eye drop, wherein it is used by instilling it into an open eye or by applying it to the eyelid of a closed eye, wherein preferably 1 to 30 drops are instilled or applied, more preferably 2 to 20 drops, and particularly preferably 3 to 10 drops.

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