An ophthalmic composition comprising at least one nicotinic acetylcholine receptor modulator for topical administration to the eye to prevent or treat ocular inflammation.

Abstract

The present invention relates to ophthalmic compositions comprising at least one nicotinic acetylcholine receptor (nAChR) modulator, particularly varenicline, mecamillamine, and derivatives, and / or at least one substance of the endogenous Kennedy metabolic pathway, as well as salts and derivatives or pharmaceutically acceptable salts thereof, and choline-containing phospholipids, salts and derivatives thereof. Of these, choline, phosphocholine, CDP-choline (citicoline), phosphatidylcholine (e.g., lecithin with a phosphatidylcholine content of 80% by weight or more, e.g., soy lecithin), ethanolamine, phosphoethanolamine, CDP-ethanolamine, phosphatidylethanolamine, L-α-glycerylphosphorylcholine, phosphatidylcholine, and phosphatidylethanolamine are particularly preferred.

Description

Technical Field

[0001] The present invention relates to · at least one nicotinic acetylcholine receptor (nAChR) modulator, particularly varenicline, mecamylamine, and derivatives, and / or · at least one substance of the endogenous Kennedy metabolic pathway, as well as salts and derivatives of such substances or pharmaceutically acceptable salts, and choline-containing phospholipids, salts and derivatives of such substances, and choline, phosphocholine (e.g., lecithin with a phosphatidylcholine content of 80% by weight or more), CDP-choline (cytcholine), phosphatidylcholine (lecithin, e.g., soy lecithin), ethanolamine, phosphoethanolamine, CDP-ethanolamine, phosphatidylethanolamine, L-α-glycerophosphorylcholine from those groups an ophthalmic composition comprising for use in stimulating tear production for the prevention or treatment (i.e., reduction or elimination) of ocular inflammatory diseases or reactions and / or lubrication disorders relates to an ophthalmic composition.

[0002] In this case, the ophthalmic composition is administered to the open and / or closed eyes of the patient.

Background Art

[0003] Inflammation of the eye and ocular surface is induced by various exogenous or endogenous toxins or stresses, such as mechanical stimuli like UV light, friction, chemical influences, chemicals, allergens, pathogens such as bacteria and viruses, wetting disorders, reactive oxygen species, drug treatments, etc. This leads to pathological changes on the ocular surface and / or frequent inflammatory reactions.

[0004] Complaints such as red eyes, painful eyes, or eye itching, or a feeling of eye pressure, swelling of the conjunctiva and / or eyelids, increased sensitivity to light, watery or purulent secretions, and sticky eyelids are typical symptoms of any persistent and / or excessive immune reaction in the eye.

[0005] Various inflammatory mediators, such as cytokines, other growth factors, and matrix metalloproteinases (MMPs), play important roles in corneal homeostasis and its pathological state. These inflammatory mediators are produced and released not only by immune cells that reside in the cornea or infiltrate it during inflammatory processes, such as macrophages, B lymphocytes, T lymphocytes, and natural killer cells, but also by many non-immune cells, including fibroblasts (repair cells), keratinocytes, endothelial cells, and corneal epithelial cells.

[0006] While a normal inflammatory response has desirable effects (e.g., suppressing harmful stimuli and repairing tissue damaged by MMPs such as MMP9), a persistent and / or excessive immune response has undesirable adverse effects (e.g., pathological changes and deficiencies in ocular tissue mediated by elevated MMP9 levels and / or reactive oxygen species released by immune cells). Inflammatory mediators, excessive release of MMPs, and / or imbalances between inflammatory and anti-inflammatory mediators, or between MMPs and their inhibitors, play a crucial role here. Inflammation is a complex process involving various genes and signaling pathways.

[0007] Current technological advancements include treatments for dry eye syndrome involving the administration of nAChR agonists, such as varenicline administered intranasally in the form of a nasal spray. In this process, varenicline binds to AChRs in nerve cells in the nasal mucosa. This binding leads to activation of the trigeminal nerve, anterior ethmoid nerve, or nasolacrimal gland reflex. The nerve signaling ultimately affects the lacrimal gland, increasing tear secretion.

[0008] The drawback is that this only affects the lacrimal glands, and as a result only increases the amount of aqueous tears in the eye, meaning it only affects the tear-deficient (insufficient tear production) type of dry eye.

[0009] Nasal administration of this nAChR agonist has no effect on the lipid and mucin layers of the tear film and / or any inflammatory response in the eye.

[0010] However, the lipid layer and mucin layer play extremely important roles in terms of the residence time of the aqueous tear film on the ocular surface and its lubricity.

[0011] 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 the tear film secreted by the lacrimal glands, preventing the tear film from rapidly evaporating and from running down the edges of the eye ("epiphora"). Therefore, this lipid layer plays a very important role in the residence time of the aqueous tear film in the eye. Prolonged residence time, and consequently, moisture of the ocular surface, is important for the prevention and / or treatment of dry eye.

[0012] The innermost mucin layer, formed by goblet cells, in turn mediates the good and stable adhesion of the aqueous tear film to the ocular surface for the same purpose, thus ensuring prolonged humidification and lubrication of the ocular surface. Furthermore, intranasal administration cannot supply the eye with mucin and / or lipid substitutes to increase the stability and residence time of the aqueous tear film and / or to exert additional sedative, soothing, lubricating, and friction-reducing effects.

[0013] Furthermore, intranasal administration cannot treat eye inflammation.

[0014] Another drawback is that, when administered via the nasal mucosa, the active substance can easily enter the brain. Through the openings in the ethmoid bone through which olfactory nerve fibers exit the brain to the nasal mucosa, the active substance travels in the opposite direction from the nasal mucosa, reaching the brain almost unimpeded via a short pathway. Therefore, there is a risk of undesirable neurological symptoms as a side effect. [Overview of the project]

[0015] The object of the present invention is to prevent, reduce, or completely eliminate persistent and harmful inflammatory responses and their consequences, as well as moist damage from the group of dry eye conditions including Sjögren's syndrome, Sikka syndrome, and tear-deficient and / or evaporative-lowering or evaporative-enhancing dry eye, through a single, but preferably double or multiple, mechanism. These mechanisms include: • Downregulation of the formation and / or release of inflammatory mediators, e.g., inflammatory cytokines (e.g., interleukins IL-1, IL-6, IL-8, tumor necrosis factor TNF-α), chemokines, and certain enzymes, e.g., matrix metalloproteinases (MMPs), and / or • Increased lubrication and moisture of the eye surface by stimulating the body's own lacrimal glands to produce tears, and / or • Preventing eye inflammation and / or maintaining the mucin and / or lipid layers by adding appropriate substitutes for lipids and / or mucin. It includes.

[0016] Therefore, an object of the present invention is to provide an improved method that is more effective and has fewer side effects. This method may involve one or more complementary effects or mechanisms of action, thereby regulating persistent and excessive inflammatory responses at various levels and assisting the repair processes necessary to restore molecular homeostasis at the cellular and tissue levels.

[0017] This problem is solved by the features of claim 1. Each dependent claim represents a favorable development here.

[0018] Accordingly, the present invention relates to an ophthalmic composition comprising at least one active substance selected from the group consisting of nicotinic acetylcholine receptor modulators and derivatives thereof, substances of the body's own Kennedy metabolic pathway, salts and derivatives thereof, and combinations thereof, for example, cytidine 5'-diphosphocholine (CDP-choline), choline, phosphocholine, L-α-glycerylphosphorylcholine, phosphatidylcholine (lecithin), and their metabolites, degradation products and / or derivatives, and salts, for use in the prevention or treatment of inflammatory reactions or diseases of the eye and moist lesions of the eye by topical administration of the ophthalmic composition to the open eye and / or closed eye. Topical use of these active substances in ocular tissue for the prevention and / or treatment of inflammatory diseases, such as inflammatory diseases of the cornea, eyelid margins and / or dry eye, is not known to date.

[0019] The advantage is that at least one active substance (selected from the group of substances known from AChR modulators and / or Kennedy metabolic pathways) is administered as close as possible to the site of the disease and can be as effective as possible at that site. The topically administered ophthalmic composition acts directly on the physiological inflammatory process and response at the site of inflammation. Effector cells involved in the inflammatory process are directly targeted in the eye by the composition of the present invention, thereby appropriately regulating the internal cellular processes of those effector cells.

[0020] Furthermore, it is particularly advantageous and remarkable that the compositions of the present invention can act on various cells, cell types and / or tissues, and even on various sensory organs (eyes, nose), preferably exhibiting dual or multiple modes of action (physiological and / or physical). These multiple effects and processes include, in particular, • For example, the anti-inflammatory effect (physiological process) mediated by the interaction between nAChR receptors and nAChR modulators in non-neuronal cells in ocular tissue. · Stimulation of the secretion of the aqueous tear film and thus increased wetting of the ocular surface (physiological process), resulting from partial drainage of the ophthalmic composition through the nasolacrimal duct to the corresponding receptors in the nasal mucosa, followed by neural stimulation of the lacrimal gland, thereby inducing tear secretion in the eye · Increase in the retention time of the stimulated natural tear film and / or reduction of evaporation by adding known adjuvants, such as lipids, medium-chain triglycerides, carbomers, mucopolysaccharides, etc. to the ophthalmic composition · Alleviation of irritation and friction associated with inflammation and dryness (physical process) by adding appropriate additives, such as glycosaminoglycans, glycosaminoglycans, cellulose derivatives, dexpanthenol, etc. to the ophthalmic composition including, but not limited to, those selected from

[0021] Therefore, the ophthalmic composition according to the present invention can be used, for example, to down-regulate or inhibit the formation and / or release of inflammatory cytokines (such as interleukin IL-1, IL6, IL-8, tumor necrosis factor TNF-α), chemokines, specific enzymes, such as MMP, and / or the presentation of adhesion molecules (such as those derived from or in epithelial cells, endothelial cells, fibroblasts, corneal epithelial cells, immune cells) that play a role in the inflammatory process. This down-regulation or inhibition can be mediated by nicotinic acetylcholine receptors and subsequent signal transduction pathways, regulate transcription, translation and / or protein release, and / or can be mediated by yet unknown mechanisms

[0022] Surprisingly, topical administration of an ophthalmic composition comprising at least one active substance, namely an nAChR modulator and / or at least one substance known from cell membrane metabolism (substances of the body's own Kennedy metabolic pathway), reduces or prevents the release of inflammatory mediators, specific enzymes such as MMP9 and / or adhesion molecules in the eye, thereby preventing the expression of a persistent inflammatory process or alleviating or arresting an existing inflammatory process. This is surprising because the administration of at least one active substance is topical administration to the surface of the open and / or closed eye and does not distribute throughout the body (e.g., in the blood) as in the case of systemic administration.

[0023] It is also unexpected that the administered at least one active substance can reach the effector site in the tissue, interact with that effector site, and achieve the desired effect. nAChR modulators interact with various immune and non-immune cells in the eye tissue, for example, which express nicotinic acetylcholine receptors and play a role in the inflammatory process. These cells in the eye are non-neuronal cells that contribute to the desired effect.

[0024] The advantage over systemic administration is that the effect remains mostly localized at the site of administration, i.e., the site of inflammation, reaches that site without substantial dilution, and acts directly on the cells involved in the inflammatory process. This action halts excessive reactions in the inflammatory process, such as oxidative stress. Thus, the surface of the eye is protected and contributes to the formation and maintenance of a smooth and healthy surface of the cornea. Topical administration is also particularly advantageous for avoiding side effects because, for example, nAChRs are ubiquitous in the body and are involved in the regulation of various very different processes in the body.

[0025] After topical administration of the ophthalmic composition to the eye, the nAChR modulator binds to or interacts with one or more of the receptor or its subunits, changing the activity of the receptor or its subunits, and as a result, affecting the induced signal transduction and subsequent signal transduction pathways.

[0026] Cellular processes in the ocular region, preferably non-neuronal processes, are activated or modulated by one or more nAChR modulators (non-neuronal pathways) to prevent, reduce, or resolve inflammatory responses in ocular tissue.

[0027] It is also surprising that substances known from the Kennedy metabolic pathway can reach sites of action in tissues after topical administration to the eye and exert modulatory effects on immunological processes. For example, in vitro administration of phosphocholine or cytidine 5'-diphosphocholine to HCE-T cells can reduce TNF-α-stimulated expression of MMP9. Varenicline administration also has this effect. The precise mechanisms of action of various substances remain unknown.

[0028] MMP9 is an associated inflammatory marker that is elevated in the tear fluid of patients with dry eye.

[0029] In a further embodiment, the present invention relates to an ophthalmic composition comprising at least one nicotinic acetylcholine receptor modulator and / or at least one substance of the body's own Kennedy metabolic pathway, for use in stimulating tear production by topical administration of the ophthalmic composition to open and / or closed eyes.

[0030] Surprisingly, it was found that the ophthalmic composition according to the present invention stimulates natural tear production.

[0031] This natural tear production can be stimulated by ophthalmic compositions that are controlled and drained via the nasolacrimal duct and, consequently, activate nicotinic acetylcholine receptors in the nasal mucosa, for example. As a result, the trigeminal, anterior ethmoid nerve, or nasolacrimal gland reflex is activated, and these nerve signals ultimately stimulate the lacrimal gland to increase tear production. This provides a beneficial adjunct in the prevention and treatment of inflammation and lubrication disorders. This effect, which occurs in the nasal mucosa after topical application of the formulation in or over an open or closed eye, is quite remarkable and unexpected.

[0032] The ophthalmic composition stimulates increased tear production, thereby promoting the formation of a natural moist and protective film on the surface of the eye, and ultimately ensuring continuous lubrication of the cornea and conjunctiva. As described above, this can prevent inflammation or inflammatory reactions and potential ocular tissue erosion, or, if such inflammation or inflammatory reactions and ocular tissue erosion are present, it can alleviate the inflammation or inflammatory reactions and ocular tissue erosion and aid in healing. Foreign matter adhering to the surface of the eye, such as dust, can also be washed away more effectively.

[0033] The effects of the compositions of the present invention on various cells, cell types (e.g., immune cells and non-immune cells), and / or tissues, as well as various sensory organs (eyes, noses), by exerting dual or multiple modes of action (physiological and / or physical), are particularly advantageous and remarkable.

[0034] The administration may be performed on an open eye or a closed eye. According to this administration, the eye / ocular tissue includes the cornea, bulbar conjunctiva and tarsal conjunctiva, limbal stem cells, eyelids and eyelid 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 the ocular tissue (resident and / or transient during inflammatory processes) are also particularly involved here. Therefore, the site of action encompasses the anterior segment of the eye, including all of the aforementioned structures. Thus, the term “anterior segment of the eye” by definition includes the components described above.

[0035] This process is mediated and initiated by the interaction of at least one active substance of the composition with nAChRs of cells in ocular tissue and / or immune cells and / or non-immune cells in ocular tissue, or by an unknown mechanism. This process reduces or completely inhibits the release of inflammatory mediators and / or the transcription of various genes, including cytokines and chemokines and certain enzymes, such as genes encoding MMPs. Similarly, the formation and / or presentation of adhesion molecules that assist in the infiltration of immune cells into inflammatory tissue is reduced.

[0036] This means that these nicotinic acetylcholine receptors and / or other mechanisms may be induced by modulators and / or substances in the Kennedy metabolic pathway to affect transcription and, consequently, the expression of inflammatory mediators, such as inflammatory cytokines and MMPs.

[0037] At least one nicotinic acetylcholine receptor modulator is preferably (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h]-[3]benzazepine), varenicline tartrate, varenicline hydrochloride, cyticine, 3-bromocyticine, desformylfrustrabromin, desformylfrustrabromin hydrochloride, pozanicline, pozanicline dihydrochloride, bupropion, sofinicline, 3-(5,6-dichloropyridine-3-yl)-l(S),5(S)-3,6-diazabicyclo[3.2.0]heptane (ABT-894), 3-methyl-5-[(2S)-1-methylpyrrolidine-2-yl]-1,2-oxy Selected from the group consisting of sazole (ABT-418), acetylcholine, 3,6-diazabicyclo[3.1.1]heptan-3-carboxamide (TC-8831), 3-ethyl-2,4-dimethyl-1H-pyrrole (TC-10600), N-[1-(5-chloro-6-pyridine-2-ylpyridine-2-yl)piperidine-4-yl]-2-hydroxyethanesulfonamide (ABT-126), (3R)-3-{[6-(4-methylphenyl)pyridine-3-yl]oxy}-1-azabicyclo[2.2.2]octane (AQW-051), mecamillamine, and acceptable derivatives or salts thereof, as well as mixtures and combinations thereof.

[0038] A pharmaceutically acceptable salt is a salt that retains the desired biological activity of the starting material and does not promote any undesirable toxicological effects, such as acidic salts including acetates, tartrates, chlorides, phosphates, sulfates, sulfites, carbonates, bicarbonates, and citrates.

[0039] Nicotinic acetylcholine receptor modulators, such as varenicline and its derivatives, can ultimately lead to the downregulation of inflammatory cytokines, for example, after interacting with or binding to nAChRs, thereby preventing, reducing, or suspending persistent and harmful inflammatory responses in the eye. This downregulation occurs at the level of gene transcription, for example, through targeted receptor-mediated regulation of inflammatory mediators, such as inflammatory cytokines, chemokines, inflammatory enzymes, such as MMPs, and receptor formation, mediated by NF-κB.

[0040] At least one substance of the Kennedy metabolic pathway, as well as salts and derivatives thereof, suitable for the purposes of the present invention, is selected from the group consisting of choline, phosphatidylcholine, lecithin (a possible derivative thereof is lysolecithin), ethanolamine, phosphoethanolamine, CDP-ethanolamine, phosphatidylethanolamine, L-α-glycerylphosphorylcholine, citicoline (CDP-choline), cytidine diphosphate choline ([(2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidine-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl-{oxide-[2-(trimethylazaniumyl)ethoxy]phosphoryl}phosphate, citicoline), α-glycerylphosphorylcholine, phosphocholine, glycerophosphocholine and / or derivatives of these substances. Surprisingly, these substances have been shown to affect signaling pathways involved in inflammatory processes, modulating or inhibiting the transcription, release, and / or control of inflammatory mediators such as MMP9. This modulation or inhibition can be mediated by nAChRs or other means.

[0041] All substances in the Kennedy pathway are substances involved in natural cellular metabolism, or their salts and / or derivatives. Phosphatidylcholine and phosphatidylethanolamine, the most common phospholipids in mammalian cells, are de novo synthesized from choline and ethanolamine, respectively, via the Kennedy pathway in natural cellular metabolism. Therefore, these endogenous substances are very well tolerated when administered intraocularly or superocularly. Surprisingly, these substances induce downregulation of inflammatory cytokines, MMPs, and similar substances in ocular tissue. Thus, excessive or persistent inflammation can be alleviated or prevented. This can have a favorable effect on inflammatory processes, diseases, and / or the accompanying symptoms of various ocular diseases.

[0042] Examples include eye infections and inflammations caused by moist lesions, allergies, styes, keratitis, blepharitis, or dry eye (keratoconjunctivitis sicca), Sikka syndrome, Sjögren's syndrome, etc.

[0043] Selective topical administration to the eye in the area of ​​inflammation is advantageous because nicotinic acetylcholine receptors are also involved in regulating other bodily processes, and these processes are affected to a very limited extent by topical administration, resulting in fewer side effects.

[0044] The composition may also include known components to protect and improve membrane properties, such as fluidity and permeability, in addition to substances from the body's own Kennedy metabolic pathway, because environmental toxins and excessive inflammatory processes, in particular, can have undesirable effects on these membrane parameters.

[0045] Ubiquinone-10, in particular, is one such component. Its long lipophilic isoprenoid side chain is incorporated into the cell membrane, influencing the membrane's fluid properties.

[0046] Dexpanthenol is one such component. It stimulates membrane lipid synthesis and, consequently, promotes complete membrane homeostasis with physiological permeability. Dexpanthenol also plays a role in regulating gene expression (e.g., interleukins) in inflammatory processes. It has anti-inflammatory and anti-apoptotic effects and therefore completely supports the action of nAChR agonists and modulators through alternative mechanisms.

[0047] Therefore, it is particularly advantageous if the composition contains dexpanthenol and / or ubiquinone-10. However, in special embodiments, the composition does not need to contain ubiquinone-10 and / or dexpanthenol.

[0048] Furthermore, the formulation may include components that function as lipid phase substitutes for the treatment of evaporative dry eye, such as medium-chain glycerides, oils or lipid-containing substances, lipids, such as castor oil.

[0049] The product may also contain soothing ingredients such as hyaluronic acid, povidone, plant extracts derived from euphrasia (eyebright), mallow, blueberry, dexpanthenol, heparin, ectoin, and hydroectoin.

[0050] The ophthalmic composition is preferably formulated in the form of an aqueous solution, an O / W nanoemulsion (micelle size 1 nm to 100 nm), or an O / W microemulsion (micelle and / or liposome size 100 nm to 1000 nm).

[0051] For example, at least one nicotinic acetylcholine receptor agonist may be included 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.

[0052] According to a further preferred embodiment, the ophthalmic composition is measured in accordance with Section 2.2.8 of the European Pharmacopoeia 9.8, at 1 mm2 / s~150mm 2 / s, preferably 7mm 2 / s~100mm 2 / s, most preferably 10mm 2 / s~70mm 2 It is expected to have a kinematic viscosity characterized by / s. This promotes improved adhesion and tolerability (absence of foreign body sensation) at the administration site.

[0053] For example, the ophthalmic composition has a molar osmotic concentration of 150 mOsmol / kg to 340 mOsmol / kg, preferably 170 mOsmol / kg to 270 mOsmol / kg.

[0054] The pH value should preferably be 5.8 to 8.5, and more preferably 6.6 to 7.4.

[0055] In particular, the ophthalmic composition does not contain omega-3 fatty acids and / or antioxidants. In one particular embodiment, the composition does not contain phosphate buffers. In one particular embodiment, the composition does not contain phosphate ions. In the context of the present invention, “phosphate-free” means a pharmaceutical composition containing less than 7 mmol / L of phosphate ions, preferably less than 3 mmol / L, particularly preferably less than 1 mmol / L, and most preferably phosphate-free (i.e., below the detection limit). The term “phosphate” includes all ions derived from phosphate, namely dihydrogen phosphate, hydrogen phosphate, and phosphate.

[0056] Furthermore, the ophthalmic composition does not need to contain hyaluronic acid.

[0057] Similarly, ophthalmic compositions may include ophthalmologically suitable solutes and derivatives thereof, selected from the group consisting of sugars, such as sucrose, rutinose, and trehalose; polyols, such as glycerin, inositol, and erythritol; amino acids, such as proline; and tetrahydropyrimidine derivatives, such as ectoin, hydroxyectoin, glycine betaine, betaine, and L-carnitine.

[0058] The ophthalmic composition may also contain components for maintaining and / or restoring membrane fluidity and permeability, such as ubiquinone-10, cholesterol, resveratrol, etc.

[0059] Furthermore, the composition may also contain anti-inflammatory and / or sedative herbal extracts, such as extracts or tinctures derived from calendula, plantain, mahonia, eyebright, chamomile, aloe vera, willow bark, echinacea, arnica, etc.

[0060] The ophthalmic composition may also include at least one ophthalmologically suitable buffer, particularly a buffer selected from the group consisting of inorganic and / or organic buffering substances, such as citrate buffers, phosphate buffers, phosphate-citrate buffers, trometamol buffers, borate buffers, acetate buffers, acetate-borate buffers, and combinations thereof.

[0061] The ophthalmic composition more preferably contains at least one mucosal adhesion component and / or at least one component that affects viscosity and consequently residence time in the eye, particularly a component selected from the group consisting of cellulose derivatives, such as carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), hyaluronic acid, chondroitin sulfate, polyvinyl alcohol, povidone (polyvinylpyrrolidone), hydroxypropyl guar, hydroxypropyl cellulose, tamarind seed polysaccharide, polyacrylic acid (carbomer), polyethylene glycol, mucopolysaccharides, such as heparan sulfate, heparin sulfate, and heparin, and derivatives of the listed substances, as well as combinations thereof.

[0062] The concentrations of these substances in the formulation should be carefully adjusted depending on whether the formulation is intended to act only in the anterior segment of the eye or in both the eye and the nose. For effects on various sensory organs, formulations containing only small amounts of mucosal adhesive components (synonyms: thickeners) are preferred, thereby allowing the composition to be partially excreted through the nasal mucosa. Therefore, the content of the thickener, for example in the case of hyaluronic acid, is preferably in the range of 0.01% to 0.5% by weight, and preferably 0.02% to 0.1% by weight, based on the ophthalmic composition.

[0063] According to further embodiments, the ophthalmic composition comprises at least one isotonic agent, particularly glycerol, NaCl, sorbitol and / or boric acid.

[0064] To achieve improved penetration into the ocular tissues, particularly the cornea and conjunctiva, as defined above, penetration enhancers, especially isopropyl myristate and / or isopropyl palmitate, may be included.

[0065] Preferably, the ophthalmic composition further comprises at least one emulsifier, particularly vitamin E TPGS, poloxamer, such as Kolliphor P407 and / or Kolliphor P188.

[0066] The pharmaceutical additive is preferably selected from the group consisting of organic buffers, inorganic buffers, inorganic and / or organic salts, viscosity modifiers and consistency modifiers, emulsifiers, stabilizers, wetting agents, spreading agents, antioxidants, molar osmotic pressure concentration modifiers, and mixtures thereof.

[0067] The ophthalmic composition is particularly suitable for use in the prevention or treatment of inflammation resulting from blepharitis, keratitis, uveitis, iritis, allergies, such as pollen allergies, and other conditions, such as Siccani syndrome and keratoconjunctivitis sicca.

[0068] To the extent that the present invention relates to the use of compositions for stimulating tear production, the compositions are particularly suitable for use in the prevention or treatment of dry eye (Sikka syndrome, keratoconjunctivitis sicca), especially tear-deficient and / or evaporative dry eye.

[0069] Ophthalmic compositions are formulated, in particular, in the form of aqueous eye drops, tinctures, ointments, gels, aerosols, or lotions for, for example, dropping, rubbing, spraying, or fine spraying.

[0070] Surprisingly, even after administration to the eye, it has been found that the agonist is additionally drained through the lacrimal ducts (Viae lacrimales), i.e., the lacrimal canaliculi, lacrimal sac, and / or nasolacrimal duct, causing activation of tear production. The exact site of action and mechanism of action are unknown. However, it is thought that the agonist contained in the eye drops induces stimulation by activating afferent fibers of the trigeminal nerve in the nasal mucosa.

[0071] By adjusting specific parameters of the composition, such as viscosity, mucosal adhesion, and spreadability, the amount of discharge through the nasolacrimal duct can be controlled to some extent, from virtually no discharge to varying degrees of partial discharge. In the latter case, it is assumed that the ophthalmic composition according to the present invention will be partially discharged through the nasolacrimal duct after administration to the eye, thereby being additionally administered to or in the nAChRs 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, namely the direct anti-inflammatory effect in the ocular tissue (administration of mucin and / or lipid substitutes), and the increase in natural tear production by discharging the composition into the nasal mucosa via the nasolacrimal duct after administration to the eye, are particularly beneficial. Since only a small amount of the administered active ingredient concentration reaches the nasal mucosa, side effects, such as nasal mucosal irritation, sneezing, coughing, and undesirable neurological symptoms (side effects associated with direct intranasal administration), can be avoided. The amount of composition discharged through the nasolacrimal duct is controlled by the composition's spreadability, mucosal adhesion, and viscosity.

[0072] It is also possible to add amino acids and / or peptides and their derivatives, such as N-acetylcysteine, taurine, L-proline, glycine, L-lysine hydrochloride, and L-leucine. These amino acids and / or peptides and their derivatives improve the moistening of the ocular surface. This also applies to tyroxapol, a nonionic liquid polymer that functions primarily as a wetting or spreading agent. The spreading agent can also improve drainage and distribution through the nasolacrimal duct.

[0073] For example, the ophthalmic composition may be administered or used 1 to 10 times per day, preferably 1 to 5 times.

[0074] The ophthalmic composition can be used, for example, by dropping a drop into an open eye or by administering a drop or spray onto the eyelid of a closed eye, with 1 to 30 drops, more preferably 2 to 20 drops, and especially preferably 3 to 10 drops or 3 to 10 sprays being administered.

[0075] The ophthalmic composition may contain ophthalmologically acceptable preservatives, but preferably does not contain any preservatives.

[0076] The present invention will be described in more detail with reference to the following configurations, without limiting the invention to the embodiments described. All numerical values ​​are given in weight percent. Example of formulation:

[0077] [Table 1]

[0078] [Table 2]

[0079] To demonstrate the efficacy of the nicotinic acetylcholine receptor modulator and its derivatives and pharmaceutically acceptable salts, substances of the body's own Kennedy metabolic pathway, their derivatives and pharmaceutically acceptable salts, which underlie the present invention, in the treatment of inflammatory diseases, the following model experiments were conducted.

[0080] method Cell viability The effect of the test substance on HCE-T cell viability at the concentrations used was measured using a commercially available MTT test.

[0081] MMP9 protein expression analyzed using ELISA MMP9 protein expression was analyzed using human MMP-9 ELISA according to the manufacturer's protocol. HCE-T cells were seeded in 6-well plates (250,000 cells per well) and cultured for 10 days. HCE-T cells were first pre-incubated with the test substance for 30 minutes (at the concentrations shown in the graph), then 10 ng / mL of TNF-α was added directly and incubated for 24 hours.

[0082] Dexamethasone (100 μM) was used as a positive control.

[0083] A culture medium control (KGM) was used as a negative control.

[0084] The supernatant of HCE-T cells was collected and stored at -20°C until use.

[0085] The MMP9 content in the cell supernatant was measured using an ELISA kit according to the manufacturer's protocol. [Brief explanation of the drawing]

[0086] [Figure 1] This figure shows the protein expression of MMP9 in HCE-T cells after pre-incubation using mecamillamine, an nAChR modulator, or citicoline, a substance involved in the Kennedy metabolic pathway. [Modes for carrying out the invention]

[0087] result: MMP9 is an associated inflammatory marker that is elevated in the tears of patients with dry eye. This inflammatory marker can be used in in vitro models to evaluate the anti-inflammatory effects of eye drops (Voss et al., Int. J. Mol. Sci. 2023, 24, 1567).

[0088] TNF-α-inducible MMP9 protein expression in immortalized human corneal HCE-T cells can be inhibited by up to 30% through pre-incubation with the nAChR modulator mecamillamine, or through pre-incubation with citicoline, a substance found in the Kennedy metabolic pathway (Figure 1). Prior viability studies have shown that the concentrations used do not impair cell viability.

[0089] These results indicate that the formation and / or release of inflammatory markers can be downregulated by using nAChR modulators and substances from the Kennedy metabolic pathway. Therefore, these substances can intervene in and suppress harmful inflammatory responses.

[0090] These results also demonstrate that the nAChR modulator modulates cellular processes in non-neuronal cells, specifically human corneal HCE-T cells, resulting in a reduction of inflammatory responses in in vitro models.

Claims

1. An ophthalmic composition comprising at least one active substance selected from the group consisting of nicotinic acetylcholine receptor modulators, derivatives thereof and pharmaceutically acceptable salts, endogenous Kennedy metabolic pathway substances, derivatives thereof and pharmaceutically acceptable salts, and combinations thereof, - For use in the treatment or prevention of inflammatory reactions or diseases of the eye and / or moist lesions of the eye, by topical application of the ophthalmic composition to open and / or closed eyes, or - For use in stimulating tear production by topical administration of the ophthalmic composition to open and / or closed eyes. The ophthalmic composition.

2. The nicotinic acetylcholine receptor modulators include varenicline (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h]-[3]benzazepine), varenicline tartrate, varenicline hydrochloride, cyticine, 3-bromocyticine, desformylfrustrabromin, desformylfrustrabromin hydrochloride, pozanicline, pozanicline dihydrochloride, sofinicline, 3-(5,6-dichloropyridine-3-yl)-l(S),5(S)-3,6-diazabicyclo[3.2.0]heptane (ABT-894), and 3-methyl-5-[(2S)-1-methylpyrrolidine-2-yl]-1,2-oxazole (ABT-418). An ophthalmic composition for use according to claim 1, characterized by being selected from the group consisting of ), acetylcholine, 3,6-diazabicyclo[3.1.1]heptan-3-carboxamide (TC-8831), 3-ethyl-2,4-dimethyl-1H-pyrrole (TC-10600), N-[1-(5-chloro-6-pyridine-2-ylpyridine-2-yl)piperidine-4-yl]-2-hydroxyethanesulfonamide (ABT-126), (3R)-3-{[6-(4-methylphenyl)pyridine-3-yl]oxy}-1-azabicyclo[2.2.2]octane (AQW-051), mecamillamine, and salts, mixtures, and combinations thereof.

3. An ophthalmic composition for use according to claim 1 or 2, characterized in that at least one substance and / or a salt and / or derivative thereof of the Kennedy metabolic pathway is selected from the group consisting of choline, phosphatidylcholine, lecithin, lysolecithin, ethanolamine, phosphoethanolamine, CDP-ethanolamine, phosphatidylethanolamine, L-α-glycerylphosphorylcholine, citicoline (CDP-choline), cytidine diphosphate choline ([(2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidine-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl-{oxide-[2-(trimethylazaniumyl)ethoxy]phosphoryl}phosphate, citicoline), α-glycerylphosphorylcholine, phosphocholine, glycerophosphocholine and / or derivatives of these substances.

4. The ophthalmic composition for use according to any one of claims 1 to 3, characterized in that the ophthalmic composition is applied to the cornea, bulbar conjunctiva, palpebral conjunctiva and / or tarsal conjunctiva, limbal stem cells, eyelids and eyelid margins, lacrimal apparatus, i.e., main lacrimal gland and accessory lacrimal gland, meibomian gland, conjunctival goblet cells, epithelial cells, nasolacrimal duct and / or immune cells of ocular tissue.

5. The ophthalmic composition for use according to any one of claims 1 to 4, characterized in that the ophthalmic composition comprises ubiquinone-10 and / or dexpanthenol.

6. An ophthalmic composition for use according to any one of claims 1 to 5, in the form of an aqueous solution, a nanoemulsion, or a microemulsion.

7. The ophthalmic composition for use according to any one of claims 1 to 6, characterized in that the at least one active substance is contained 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 more preferably 0.001% to 1.5% by weight.

8. Measured according to Section 2.2.8 of European Pharmacopoeia 9.8, 1 mm ２ / s ~ 150mm ２ / s, preferably 7 mm ２ / s ~ 100mm ２ / s, particularly preferably 10 mm ２ / s ~ 70mm ２ An ophthalmic composition for use according to any one of claims 1 to 7, characterized by a viscosity of / s.

9. An ophthalmic composition for use according to any one of claims 1 to 8, characterized by a molar osmotic pressure concentration of 150 mOsmol / kg to 340 mOsmol / kg, preferably 170 mOsmol / kg to 270 mOsmol / kg.

10. An ophthalmic composition for use according to any one of claims 1 to 9, characterized by a pH value of 5.8 to 8.5, preferably 6.6 to 7.

4.

11. The ophthalmic composition for use according to any one of claims 1 to 10, characterized in that the ophthalmic composition does not contain omega-3 fatty acids and / or antioxidants.

12. The ophthalmic composition for use according to any one of claims 1 to 11, characterized in that the ophthalmic composition does not contain hyaluronic acid.

13. The ophthalmic composition for use according to any one of claims 1 to 12, characterized in that the ophthalmic composition comprises an ophthalmologically suitable solute and its derivative, particularly a solute and its derivative selected from the group consisting of sugars, such as sucrose, rutinose, trehalose, polyols, such as glycerol, inositol, erythritol, amino acids, such as proline, and tetrahydropyrimidine derivatives, such as ectoin, hydroxyectoin, glycine betaine, betaine, and L-carnitine.

14. The ophthalmic composition for use according to any one of claims 1 to 13, characterized in that the ophthalmic composition comprises at least one ophthalmologically suitable buffering agent, particularly a buffering agent selected from the group consisting of citrate buffering agents, phosphate buffering agents, phosphate-citrate buffering agents, trometamol buffering agents, borate buffering agents, acetate buffering agents, acetate-borate buffering agents, and combinations thereof.

15. The ophthalmic composition for use according to any one of claims 1 to 14, characterized in that the ophthalmic composition comprises at least one mucosal adhesion component or at least one component that increases the residence time in the eye, in particular a component selected from the group consisting of cellulose derivatives, such as carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), hyaluronic acid, chondroitin sulfate, polyvinyl alcohol, povidone (polyvinylpyrrolidone), hydroxypropyl guar, hydroxypropyl cellulose, tamarind seed polysaccharide, polyacrylic acid (carbomer), polyethylene glycol, and mucopolysaccharides, such as heparan sulfate, heparin sulfate, heparin, and derivatives of the listed substances, and combinations thereof.

16. The ophthalmic composition for use according to any one of claims 1 to 15, characterized in that the ophthalmic composition comprises at least one isotonic agent, particularly glycerol, NaCl, sorbitol and / or boric acid.

17. The ophthalmic composition for use according to any one of claims 1 to 16, characterized in that the ophthalmic composition comprises at least one penetration enhancer, particularly isopropyl myristate and / or isopropyl palmitate.

18. The ophthalmic composition for use according to any one of claims 1 to 17, characterized in that the ophthalmic composition comprises at least one emulsifier, particularly vitamin E TPGS and / or poloxamer, for example, Kolliphor P407, Kolliphor P188.

19. The ophthalmic composition for use according to any one of claims 1 to 18, characterized in that the ophthalmic composition does not contain a preservative and phosphoric acid.

20. An ophthalmic composition for use according to any one of claims 1 to 19, for use in the prevention or treatment of inflammation resulting from other diseases, such as Siccasi syndrome, keratoconjunctivitis, keratoconjunctivitis, bacterial and / or viral infections, for use in corneal damage, such as epithelial damage caused by mechanical effects, conjunctivitis, blepharitis, keratitis, uveitis, iritis, allergies, such as inflammation of the anterior segment of the eye caused by pollen allergies.

21. An ophthalmic composition for use according to any one of claims 1 to 20, for use in the prevention or treatment of dry eye (Sikka syndrome, keratoconjunctivitis sicca), particularly tear-deficient type and / or evaporative type dry eye.

22. An ophthalmic composition for use according to any one of claims 1 to 21, in the form of eye drops, aqueous solution, tincture, ointment, gel, emulsion, aerosol, or lotion.

23. The ophthalmic composition according to any one of claims 1 to 22, characterized in that, after administration to the eye, partial excretion of the ophthalmic composition occurs via the nasolacrimal duct, and additional application occurs at nicotinic acetylcholine receptors of nerve cells in the nasal mucosa.

24. The ophthalmic composition for use according to any one of claims 1 to 23, characterized in that the ophthalmic composition is used 1 to 10 times per day, preferably 1 to 5 times per day.

25. The ophthalmic composition for use according to any one of claims 1 to 24, wherein the ophthalmic composition is in the form of eye drops, and is used by dropping it into an open eye or by administering it to the eyelid of a closed eye, thereby preferably 1 to 30 drops, more preferably 2 to 20 drops, and particularly preferably 3 to 10 drops being dropped or applied.

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