Ophthalmological composition containing at least one nicotinic acetylcholine receptor modulator for topical administration to the eye for preventing or treating inflammation of the eye

Abstract

The present invention relates to an ophthalmological composition, comprising at least one nicotinic acetylcholine receptor (nAChR) modulator, in particular varenicline, mecamylamine and derivatives, and / or at least one substance of the endogenous Kennedy metabolic pathways, 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, particular preference is given to choline, phosphocholine, CDP-choline (citicoline), phosphatidylcholine (for example lecithin having a phosphatidylcholine content ≥ 80 wt.%, for example soy lecithin), ethanolamine, phosphoethanolamine, CDP-ethanolamine, phosphatidylethanolamine, L-α-glycerylphosphorylcholine, phosphatidylcholine, and phosphatidylethanolamine.

Description

[0001] Ophthalmic composition containing at least one nicotinic acetylcholine receptor modulator for topical application to the eye in the prevention or treatment of inflammation of the eye

[0002] The present invention relates to an ophthalmic composition comprising

[0003] • at least one nicotinic acetylcholine receptor (nAChR) modulator, in particular varenicline, mecamylamine and derivatives, and / or

[0004] • at least one substance of the body's own Kennedy metabolic pathways, as well as salts and derivatives or pharmaceutically acceptable salts of these substances, as well as choline-containing phospholipids, salts and derivatives of these substances and from these groups, particularly preferred are choline, phosphocholine (e.g. lecithin with a phosphatidylcholine content > 80 wt.%), CDP-choline (citicholin), phosphatidylcholine (lecithin, e.g. soy lecithin), ethanolamine, phosphoethanolamine, CDP-

[0005] Ethanolamine, Phosphatidylethanolamine, La-Glycerylphosphorylcholine. For use in the prevention or treatment (ie reduction

[0006] REPLACEMENT LEAF (RULE 26) or elimination) of inflammatory diseases or reactions of the eye and / or wetting disorders.

[0007] The ophthalmic composition is applied to the open and / or closed eye of a patient.

[0008] Inflammation of the eye and ocular surface is triggered by a variety of exogenous or endogenous noxious substances or stressors, such as UV light, mechanical stimuli such as friction, chemical influences, allergens, pathogens such as bacteria, viruses, wetting disorders, reactive oxygen species, drug treatments, etc. This leads to pathological changes in the ocular surface and / or frequently to inflammatory reactions.

[0009] Typical symptoms of such persistent and / or excessive immune reactions in the eye include complaints such as reddened, painful or itchy eyes or a feeling of pressure in the eyes, swelling of the conjunctiva and / or eyelids, increased sensitivity to light, discharge of watery or purulent secretions, and sticky eyelids.

[0010] Various inflammatory mediators, such as cytokines, other growth factors, matrix metalloproteases (MMPs), etc., play an important role in corneal homeostasis and its pathological conditions. Their formation and release occurs, among other things, by immune cells that reside in the cornea or infiltrate it during the inflammatory process, e.g., macrophages, B lymphocytes, T lymphocytes, natural killer cells, but also by many non-immunological cells such as fibroblasts (repair cells), keratinocytes, endothelial cells, corneal epithelial cells, etc.

[0011] While normal inflammatory reactions have positive effects (e.g., contain damaging stimuli and repair damaged tissue, e.g., by means of MMPs such as MMP9), a persistent and / or excessive immune reaction has an undesirable damaging effect (e.g., pathological changes and defects in the eye tissue mediated by, e.g., an increased MMP9 level and / or by reactive oxygen species released by immune cells, etc.). An excessive release of inflammatory mediators, MMPs, and / or an imbalance between pro- and anti-inflammatory inflammatory mediators, or MMPs and their inhibitors, plays a role here.

[0012] REPLACEMENT SHEET (RULE 26) plays an important role. Inflammation is a complex process involving various genes and signaling pathways.

[0013] State-of-the-art treatments for dry eye disease involve administering nAChR agonists, such as varenicline, which are applied nasally in the form of a nasal spray. Varenicline binds to AChRs in nerve cells in the nasal mucosa. This results in activation of the trigeminal nerve, anterior ethmoidal nerve, or nasolacrimal reflex. Nerve signals ultimately influence the lacrimal gland, resulting in increased tear release.

[0014] The disadvantage is that this can only influence the lacrimal gland and as a result only the amount of watery tear fluid in the eye is increased, so only the hyposecretory (lack of tear production) form of dry eye can be influenced.

[0015] Nasal application has no effect on the lipid layer and the mucin layer of the tear film and / or any inflammatory reactions in the eye.

[0016] However, the lipid layer and the mucin layer perform very important functions for the residence time of the aqueous tear film on the surface of the eye and its lubrication ability.

[0017] The lipid layer is the outermost layer of the tear film. Lipids produced by the meibomian gland form an oily layer on the surface of the tear fluid secreted by the lacrimal gland. They prevent rapid evaporation and rapid drainage over the tear rim (a watery eye). They therefore play a very important role in maintaining the retention time of the aqueous tear film on the eye. A prolonged retention time and thus lubrication of the ocular surface is important for the prevention and / or treatment of dry eye.

[0018] The innermost mucin layer, formed by goblet cells, in turn provides a good, stable adhesion of the aqueous tear film to the surface of the eye with the same goal and thus ensures not only long-lasting moisturizing but also lubricating properties on the surface of the eye.

[0019] REPLACEMENT LEAF (RULE 26) In addition to nasal application, no substitutes for mucins and / or lipids are added to the eye in order to increase the stability and retention time of the aqueous tear film and / or to exert additional soothing, alleviating, lubricating, friction-reducing effects.

[0020] Furthermore, inflammation of the eye cannot be treated with nasal application.

[0021] Another disadvantage is that the active ingredients can easily reach the brain when applied via the nasal mucosa. Through the openings in the ethmoid bone, through which nerve fibers of the olfactory nerve exit the brain into the nasal mucosa, active ingredients can pass from the nasal mucosa to the brain via a short route and almost without barriers. This poses the risk of undesirable neurological symptoms as side effects.

[0022] The aim of the present invention is to prevent, reduce, or completely eliminate persistent, damaging inflammatory reactions and their consequences, as well as wetting disorders from the group of Sjögren's syndrome, Sicca syndrome, and hyposecretory and / or hypo- or hyperevaporative forms of dry eye, through one, but preferably dual or multiple, mechanisms. These include:

[0023] • Downregulation of the formation and / or release of inflammatory mediators, e.g. pro-inflammatory cytokines (such as interleukin IL-1, IL-6, IL-8, tumor necrosis factor TNF-α), chemokines and specific enzymes, such as matrix metalloproteinases (MMPs) and / or

[0024] • increased wetting and moistening of the surface of the eye by stimulating the body’s own lacrimal gland to secrete tears and / or

[0025] • Maintenance of mucin and / or lipid layer by preventing inflammation of the eye and / or adding appropriate substitutes for lipids and / or mucins.

[0026] The object of the present invention is therefore to provide an improved method

[0027] REPLACEMENT LEAF (RULE 26) that is more effective and has fewer side effects. This can incorporate one or more complementary effects or mechanisms of action, thus regulating persistent and excessive inflammatory reactions at various levels and supporting necessary repair processes to restore molecular homeostasis at the cellular and tissue levels.

[0028] This problem is solved by means of the features of patent claim 1. The dependent patent claims represent advantageous developments.

[0029] The present invention thus relates to an ophthalmic composition containing at least one active ingredient selected from the group consisting of nicotinic acetylcholine receptor modulators and their derivatives, substances of the body's own Kennedy metabolic pathways, their salts and derivatives, and combinations thereof, e.g. cytidine-5'-diphosphocholine (CDP-choline), choline, phosphocholine, La-glycerylphosphorylcholine, phosphatidylcholine (lecithin), and metabolites, degradation products, and / or derivatives and salts thereof, for use in the prevention or treatment of inflammatory reactions or diseases of the eye and wetting disorders of the eye by topical application of the ophthalmic composition to the open and / or closed eye. The use of these active ingredients locally in the eye tissue for the prevention and / or treatment of inflammatory diseases such as those of the cornea, the eyelid margins, and / or dry eye is not yet known.

[0030] The advantage is that at least one active ingredient (selected from the group of AChR modulators and / or substances known from the Kennedy metabolic pathways) is applied as close as possible to the site of the disease, ensuring the most effective effect there. The topically applied ophthalmic composition directly intervenes in physiological inflammatory processes at the site of inflammation. Effector cells of the inflammatory process are directly reached by the inventive composition in the eye, and consequently, their internal cellular processes are modulated accordingly.

[0031] It is also particularly advantageous and surprising that the composition according to the invention can be applied to different cells, cell types and / or tissues

[0032] REPLACEMENT LEAF (RULE 26) and can even act in various sense organs (eye, nose), preferably exerting dual or multiple effects (physiological and / or physical). These multiple effects and effects include, in particular, but not exclusively, those selected from those described below:

[0033] • anti-inflammatory effects, e.g. mediated by interaction of nAChR modulators with nAChR receptors on non-neuronal cells in the eye tissue (physiological processes)

[0034] • Stimulation of the secretion of the aqueous tear film and thus increased wetting of the ocular surface due to the diversion of a part of the ophthalmic composition via the nasolacrimal duct to corresponding receptors on the nasal mucosa, followed by neuronal stimulation of the lacrimal gland, which then triggers the secretion of tear fluid in the eye (physiological processes).

[0035] • Increasing the residence time of the stimulated, natural tear film and / or reducing evaporation by adding known excipients to the ophthalmic composition, such as lipids, medium-chain triglycerides, carbomers, mucopolysaccharides, etc.,

[0036] • Relief of irritation and friction caused by inflammation and dryness by adding appropriate excipients to the ophthalmic composition, such as glycoglycans, glycosaminoglucans, cellulose derivatives, dexpanthenol, etc. (physical process)

[0037] With the ophthalmic composition according to the present invention, a downregulation or inhibition of the formation and / or release of, for example, pro-inflammatory cytokines (such as interleukin IL-1, IL-6, IL-8, tumor necrosis factor TNF-α), chemokines, specific enzymes such as MMPs, and / or the presentation of adhesion molecules (e.g., of or on epithelial cells, endothelial cells, fibroblasts, corneal epithelial cells, immune cells) that play a role in inflammatory processes can be achieved. This can be mediated by nicotinic acetylcholine receptors and subsequent signaling pathways, regulation of transcription, translation, and / or protein release, and / or mediated by as yet unknown mechanisms.

[0038] REPLACEMENT SHEET (RULE 26) It has surprisingly been shown that with topical application of the ophthalmic composition containing at least one active ingredient, i.e. an nAChR modulator and / or at least one substance known from cell membrane metabolism (substances of the body's own Kennedy metabolic pathways), the release of pro-inflammatory mediators, specific enzymes, e.g. MMP9 and / or adhesion molecules in the eye is reduced or prevented, and thus the development of a persistent inflammatory process can be prevented or an existing one can be alleviated or stopped. This is surprising, since the application of the at least one active ingredient is topically to the surface of the open and / or closed eye and is not distributed throughout the body through systemic administration (e.g. into the blood).

[0039] It is also unexpected that at least one of the administered active substances can reach the effector sites in the tissues, interact with them, and achieve the desired effect. The nAChR modulators, for example, interact with various immune cells and non-immune cells in the eye tissue that 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.

[0040] The advantage over systemic administration is that the effect remains largely localized to the site of application, i.e., the focus of inflammation, where it arrives virtually undiluted and acts directly on the cells involved in the inflammatory process. This stops excessive reactions, such as oxidative stress, in the inflammatory process. Consequently, the ocular surface is protected, thus contributing to the formation and maintenance of a smooth, healthy corneal surface. Local 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 very diverse processes within the body.

[0041] Following local topical application of the ophthalmic composition to the eye, the nAChR modulator binds or interacts with the receptor or one or more of its subunits and alters its activity, consequently influencing the triggered signaling and subsequent signal transduction pathways.

[0042] REPLACEMENT SHEET (RULE 26) Thus, the activation or modulation of cellular processes, preferably of non-neuronal cells, in the eye area occurs through one or more nAChR modulators, to prevent, reduce or eliminate inflammatory reactions in the eye tissue (non-neuronal pathway).

[0043] It is also surprising that, as is known from the Kennedy metabolic pathway, the substances reach the sites of action in the tissue after topical application to the eye and exert a modulating effect on immunological processes. For example, the application of phosphocholine or cytidine-5'-diphosphocholine to HCE-T cells in vitro can reduce TNF-alpha-stimulated expression of MMP9. Varenicline also exerts this effect. The exact mechanism of action of the various substances is still unknown.

[0044] MMP9 is a relevant inflammatory marker that has elevated levels in the tears of patients with dry eye disease.

[0045] According to a further aspect, the present invention relates to an ophthalmological composition containing at least one nicotinic acetylcholine receptor modulator and / or at least one substance of the body's own Kennedy metabolic pathways, for use in stimulating tear production by topical application of the ophthalmological composition to the open and / or closed eye.

[0046] Surprisingly, it has been found that the ophthalmic composition according to the present invention stimulates natural tear production.

[0047] This stimulation of natural tear production can be induced by the ophthalmic composition, which is discharged in a controlled manner via the nasolacrimal duct, and consequently, for example, activates nicotinic acetylcholine receptors in the nasal mucosa. As a result, the trigeminal nerve, anterior ethmoid nerve, or nasolacrimal reflex are activated, and these nerve signals ultimately influence the lacrimal gland to increase tear release. This beneficially supports the prevention and treatment of inflammation and lubricating disorders. This effect, triggered in the nasal mucosa following topical application of the formulation into or onto the open or closed eye, is very surprising and unexpected.

[0048] REPLACEMENT LEAF (RULE 26) By stimulating increased tear production, the ophthalmic composition promotes the formation of a natural moisturizing and protective film on the surface of the eye, thus ensuring continuous lubrication of the cornea and conjunctiva. As described above, this can prevent inflammation or inflammatory reactions, as well as tissue erosion of the eye, or, if present, alleviate them, and support healing. Foreign bodies adhering to the surface of the eye, such as dust, can also be rinsed out more effectively.

[0049] This effect of the composition according to the invention on different cells, cell types (e.g. immune cells and non-immune cells) and / or tissues and even in different sensory organs (eye, nose) exerting dual or multiple action processes (physiological and / or physical) is particularly advantageous and surprising.

[0050] Application can be to the open or closed eye. The eye / eye tissue, according to the present application, includes the cornea, the bulbar and palpebral (also tarsal) conjunctiva, limbal stem cells, the eyelids and eyelid margins, meibomian glands and epithelial cells, the lacrimal apparatus including the efferent lacrimal ducts, and / or immune cells of the eye tissue. All of these structures form a functional unit. Immune cells present in the eye tissue (resident and / or transient during inflammatory processes) are also specifically included here. The site of action thus encompasses the anterior segment of the eye, including all of the aforementioned structures. The term "anterior segment of the eye" is defined here as including the aforementioned components.

[0051] The process is mediated and initiated by the interaction of the at least one active ingredient of the present composition with nAChRs of cells of the ocular tissue and / or on immune cells and / or non-immune cells in the ocular tissue, or by 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 and specific enzymes such as MMPs. Likewise, the formation and / or presentation of adhesion molecules that support the infiltration of immune cells into inflammatory tissue is reduced.

[0052] REPLACEMENT LEAF (RULE 26) This can influence the transcription and consequently the expression of inflammatory mediators, e.g. pro-inflammatory cytokines, MMPs, etc., triggered by modulators and / or substances of the Kennedy pathways, these nicotinic acetylcholine receptors and / or other mechanisms.

[0053] The at least one nicotinic acetylcholine receptor modulator is preferably selected from the group consisting of (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h]-[3]benzazepine), 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)-l-methylpyrrolidin-2-yl]-l,2-oxazole (ABT-418), Acetylcholine, 3,6-diazabicyclo[3.1.1]heptane-3-carboxamides (TC-8831), 3-ethyl-2,4-dimethyl-lH-pyrrole (TC-10600), N-[l-(5-chloro-6-pyridin-2-ylpyridin-2-yl)piperidin-4-yl]-2-hydroxyethanesulfonamide (ABT-126), (3R)-3-{[6-(4-methylphenyl)pyridin-3-yl]oxy}-l-azabicyclo[2.2.2]octane (AQW-051), mecamylamine and acceptable derivatives or salts thereof and mixtures and combinations thereof.

[0054] Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent substance and do not promote undesirable toxicological effects, such as acidic salts such as acetates, tartrates, chlorides, phosphates, sulfates, sulfites, carbonates, bicarbonates and citrates.

[0055] A nicotinic acetylcholine receptor modulator, such as varenicline and its derivatives, ultimately leads to the downregulation of, for example, pro-inflammatory cytokines upon interaction with or binding to the nAChR and can thus prevent, reduce, or stop persistent and damaging inflammatory reactions in the eye. This occurs through targeted receptor-mediated modulation of the formation of pro-inflammatory mediators, such as pro-inflammatory cytokines, chemokines, inflammatory enzymes such as MMPs, and receptors, at the level of gene transcription, for example, mediated by NF-κB.

[0056] The at least one substance of the Kennedy metabolic pathways, as well as their salts and derivatives, which are suitable for the purposes of the present invention

[0057] REPLACEMENT SHEET (RULE 26) are, in particular, selected from the group consisting of choline, phosphatidylcholine, lecithin (a possible derivative of which is lysolecithin), ethanolamine, phosphoethanolamine, CDP-ethanolamine, phosphatidylethanolamine, 1A-glycerylphosphorylcholine, citicholine (CDP-choline), cytidine diphosphate-choline ([(2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydro- xyoxolan-2-yl]methyl-{oxido-[2-(trimethyl--azaniumyl)--ethoxy]-phosphoryl}-phosphate, citicoline), alpha-glyceryl-phosphorylcholine, phosphocholine, glycerophosphocholine and / or derivatives of these substances. Surprisingly, these substances have been shown to influence signaling pathways involved in the inflammatory process, modulating or inhibiting the transcription, release, and / or regulation of inflammatory mediators such as MMP9. This can occur through nAChRs or other pathways.

[0058] All substances of the Kennedy pathways are substances of natural cellular metabolism or salts and / or derivatives thereof. Phosphatidylcholine and phosphatidylethanolamine, the most abundant phospholipids in mammalian cells, are synthesized de novo from choline and ethanolamine, respectively, via the Kennedy pathways. Consequently, these endogenous substances are very well tolerated when applied to or in the eye. Surprisingly, these substances trigger down-regulation of, for example, pro-inflammatory cytokines, MMPs, and similar substances in the eye tissue. Excessive or persistent inflammation can thus be reduced or prevented. This can have a positive influence on inflammatory processes, diseases, and / or accompanying symptoms of various eye diseases.

[0059] Examples of this are infections and inflammations of the eye caused by wetting disorders, allergies, styes, corneal inflammation (keratitis), blepharitis, or dry eye (keratoconjunctivitis sicca), sicca syndrome, Sjögren's syndrome, etc.

[0060] Selective local administration to the eye in the area of ​​the inflammation site is advantageous because nicotinic acetylcholine receptors are also involved in the regulation of other processes in the body, and these are only affected to a very limited extent by local application, which leads to fewer side effects.

[0061] The composition may contain, in addition to an nAChR modulator and / or a

[0062] REPLACEMENT SHEET (RULE 26) Substance of the body's own Kennedy metabolic pathways, also contain known components for the protection and improvement of membrane properties, such as fluidity and permeability, since environmental pollutants and excessive inflammatory processes can have a negative effect on these membrane parameters.

[0063] Ubiquinone-10, in particular, is one such component. Its long, lipophilic isoprenoid side chains insert into cell membranes and influence the membrane's fluidity properties.

[0064] Dexpanthenol is also one such component. It stimulates the synthesis of membrane lipids and thus also promotes intact membrane homeostasis with physiological permeability. Dexpanthenol also plays a role in modulating gene expression (e.g., interleukins) during inflammatory processes. It has anti-inflammatory and anti-apoptotic effects and thus perfectly supports the effects of nAChR agonists and modulators via an alternative mechanism of action.

[0065] It is therefore particularly advantageous if the composition contains dexpanthenol and / or ubiquinone-10. However, in special embodiments, it can also be free of ubiquinone-10 and / or depanthenol.

[0066] Furthermore, components that serve as lipid phase replacement for the treatment of evaporative dry eye, such as medium-chain glycerides, oil- or lipid-containing substances, lipids e.g. castor oil, may be included.

[0067] It may also contain soothing components such as hyaluronic acid, povidone, plant extracts from Euphrasia (eyebright), mallow, blueberry, etc., dexpanthenol, heparin, ectoin and hydroectoin, among others.

[0068] The ophthalmic composition is preferably formulated in the form of an aqueous solution, an o / w nano- (micelle size 1-100 nm) or o / w microemulsion (micelle and / or liposome size 100-1000 nm).

[0069] For example, the at least one nicotinic acetylcholine receptor agonist can be contained in the ophthalmological composition in a total amount of 0.00001 to 3.0 wt.%, preferably 0.0001 to 2.0 wt.%, particularly preferably 0.001 to 1.5 wt.%.

[0070] REPLACEMENT LEAF (RULE 26) According to a further preferred embodiment, the ophthalmic composition is characterized by a kinematic viscosity of 1-150 mm 2 / s, preferably 7 to 100 mm 2 / s, particularly preferably 10 to 70 mm 2 / s, measured according to Chapter 2.2.8 of the European Pharmacopoeia 9.8. This promotes improved adhesion and tolerability (no foreign body sensation) at the application site.

[0071] For example, the ophthalmic composition has an osmolality of 150 to 340 mOsmol / kg, preferably 170 to 270 mOsmol / kg.

[0072] Preferably the pH is from 5.8 to 8.5, more preferably from 6.6 to 7.4.

[0073] In particular, the ophthalmic composition is free of omega-3 fatty acids and / or antioxidants. In a particular embodiment, the composition is free of phosphate buffer. In another particular embodiment, the composition is free of phosphate ions. For the purposes of the invention, "phosphate-free" refers to a pharmaceutical composition that contains less than 7 mmol / l phosphate ions, preferably less than 3 mmol / l phosphate ions, particularly preferably less than 1 mmol / l phosphate ions, and most preferably no phosphate ions (i.e., below the detection limit). The term "phosphate ions" encompasses all ions derived from phosphoric acid, i.e., dihydrogen phosphate, hydrogen phosphate, and phosphate.

[0074] In addition, the ophthalmic composition can also be free of hyaluronic acid.

[0075] Likewise, ophthalmologically compatible solutes and their derivatives, in particular selected from the group consisting of sugars such as sucrose, rutinose, trehalose, polyols e.g. glycerol, inositol, erythritol, amino acids e.g. proline, tetrahydropyrimidine derivatives such as ectoine, hydroxyectoine, glycine betaine, betaine, l-carnitine can be included in the ophthalmological composition.

[0076] The ophthalmic composition may also contain components to maintain and / or restore membrane fluidity and permeability, such as ubiquinone-10, cholesterol, resveratrol, etc.

[0077] REPLACEMENT LEAF (RULE 26) Furthermore, the composition may contain anti-inflammatory and / or soothing herbal extracts such as extracts or tinctures of calendula, ribwort plantain, mahonia, eyebright, chamomile, aloe vera, willow bark, echinacea, arnica, etc.

[0078] It is also possible for the ophthalmological composition to contain at least one ophthalmologically compatible buffer, in particular a buffer selected from the group consisting of inorganic and / or organic buffer substances, e.g. citrate buffer, phosphate buffer, phosphate-citrate buffer, trometamol buffer, borate buffer, acetate buffer, acetate-borate buffer and combinations thereof.

[0079] It is further preferred that the ophthalmic composition contains at least one mucoadhesive component and / or at least one component that influences the viscosity and thus the residence time on the eye, in particular 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, mycopolysaccharides such as heparan sulfate, heparin sulfate and heparin etc. and derivatives of the listed substances, as well as combinations thereof.

[0080] The concentration 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 the eye and nose. For effects in various sensory organs, a formulation composition containing only a small amount of mucoadhesive components (synonym: viscosity-increasing agents) is preferred, allowing partial drainage of the composition via the nasal mucosa. Therefore, the content of viscosity-increasing agents is preferably in a range of 0.01 to 0.5 wt.%, preferably 0.02 to 0.1 wt.%, based on the ophthalmic composition, e.g., in the case of hyaluronic acid.

[0081] According to a further embodiment, the ophthalmic composition contains at least one tonicity agent, in particular glycerol, NaCl, sorbitol and / or boric acid.

[0082] REPLACEMENT LEAF (RULE 26) Penetration enhancers, in particular isopropyl myristate and / or isopropyl palmitate, may also be included to achieve improved penetration into the ocular tissue, as already defined above, in particular into the cornea and conjunctiva.

[0083] The ophthalmic composition preferably further contains at least one emulsifier, in particular vitamin E TPGS, poloxamer, e.g. Kolliphor P 407 and / or Kolliphor P188.

[0084] Preferably, the pharmaceutical excipients are selected from the group consisting of organic buffer substances, inorganic buffer substances, inorganic and / or organic salts, viscosity regulators and consistency modifiers, emulsifiers, stabilizers, wetting agents, spreading agents, antioxidants, osmolarity regulators and mixtures thereof.

[0085] In particular, the ophthalmic composition is suitable for use in the prevention or treatment of inflammation caused by blepharitis, keratitis, uveitis, iritis, allergies such as pollen allergy, and inflammation resulting from other diseases such as sicca syndrome, keratoconjunctivitis sicca.

[0086] Insofar as the invention relates to the use of the composition for stimulating tear production, it is particularly suitable for use in the prevention or treatment of dry eye (sicca syndrome, keratoconjunctivitis sicca), in particular the hyposecretory and / or evaporative form of dry eye.

[0087] The ophthalmological composition is formulated in particular in the form of aqueous eye drops, a tincture, ointment, a gel, aerosol or a lotion, e.g. for instillation, rubbing in, spraying or finely nebulising.

[0088] Surprisingly, it has been shown that, even after application to the eye, the agonists are also absorbed via the lacrimal ducts (viae lacrimales), i.e., the lacrimal tubules, lacrimal sac, and / or nasolacrimal duct, and cause an activation of tear production. The exact site and mechanism of action are unknown. However, it is suspected that the agonists contained in the eye drops trigger the stimulation by activating the trigeminal afferent nerve fibers in the nasal mucosa.

[0089] REPLACEMENT LEAF (RULE 26) By adjusting certain composition parameters, such as viscosity, mucoadhesion, and spreading, the amount of drainage via the nasolacrimal duct can be controlled to a certain degree, i.e., from virtually no drainage to partial drainage to varying degrees. In the latter case, the ophthalmic composition according to the invention partially drains via the nasolacrimal duct after application to the eye and is thereby additionally applied to or onto the nAChR of nerve cells in the nasal mucosa. Nerve signals influence the lacrimal glands of the eye, resulting in increased secretion of the natural tear film and consequently improved hydration of the ocular surface.Particularly advantageous is the dual (and / or multiple) effect of the eye drops: the anti-inflammatory effect directly in the eye tissue (the administration of mucin and / or lipid substitutes) and the additional increase in natural tear production by draining the composition via the nasolacrimal duct onto the nasal mucosa after application into the eye. Since only a small amount of the applied active ingredient concentration reaches the nasal mucosa, side effects such as nasal irritation, sneezing, coughing, and undesirable neuronal symptoms (side effects of direct application into the nasal cavity) can be avoided. The amount of the composition drained via the nasolacrimal duct is regulated by the spreadability, mucoadhesion, and viscosity of the composition.

[0090] The addition of amino acids and / or peptides and their derivatives is also possible, e.g., N-acetylcysteine, taurine, L-proline, glycine, L-lysine hydrochloride, L-leucine. These improve wetting of the ocular surface. This also applies to tyloxapol, a non-ionic, liquid polymer that primarily serves as a wetting or spreading agent. Spreading agents can also potentially improve drainage and distribution via the nasolacrimal ducts.

[0091] For example, the ophthalmic composition may be applied or used 1 to 10 times, preferably 1 to 5 times per day.

[0092] The use can be done, for example, by dropping into the open eye or by dropping or spraying onto the lid of the closed eye, whereby

[0093] REPLACEMENT LEAF (RULE 26) preferably from 1 to 30 drops, more preferably 2 to 20 drops, particularly preferably 3 to 10 drops or sprays.

[0094] The ophthalmic composition may contain ophthalmologically acceptable preservatives, but is preferably free of preservatives.

[0095] The present invention is described in more detail with reference to the following embodiments, without limiting the invention thereto. All data are in wt. %.

[0096] Examples of wording:

[0097] REPLACEMENT SHEET (RULE 26)

[0098]

[0099]

[0100] To demonstrate the efficacy of the nicotinic acetylcholine receptor modulators underlying the present invention and their derivatives and pharmaceutically acceptable salts, substances of the body's own Kennedy metabolic pathways, their derivatives and pharmaceutically acceptable salts for the treatment of inflammatory diseases, the following model experiments were carried out.

[0101] Methods

[0102] Cell viability

[0103] The influence of the test substances in the concentrations used on the viability of HCE-T cells was determined using a commercially available MTT test.

[0104] MMP9 protein expression analyzed by ELISA

[0105] MMP9 protein expression was analyzed using the Human MMP-9 ELISA according to the manufacturer's protocol. HCE-T cells were seeded into 6-well plates (250,000 cells per well) and cultured for ten days. The HCE-T cells were first pre-incubated with the test substances for 30 minutes (concentrations as indicated in the graph), followed by immediate addition of 10 ng / ml TNF-α and incubation for 24 hours.

[0106] Dexamethasone (100 pM) served as a positive control.

[0107] The medium control (CGM) serves as a negative control.

[0108] The supernatants of the HCE-T cells were collected and stored at -20°C until use.

[0109] The content of MMP9 in the cell supernatant was detected using an ELISA kit according to the manufacturer's protocol.

[0110] Fig.l shows the protein expression of MMP9 in HCE-T cells after preincubation with mecamylamine, an nAchR modulator, or citicholine, a substance of the Kennedy pathway.

[0111] Result:

[0112] MMP9 is an inflammatory marker that is found at elevated levels in the tears of patients with dry eye disease. This inflammatory marker can be used in an in vitro model to evaluate the anti-inflammatory effect of

[0113] REPLACEMENT LEAF (RULE 26) Eye drops can be used (Voß et al., Int. J. Mol. Sci. 2023, 24, 1567).

[0114] TNF-α-induced protein expression of MMP9 in immortalized human corneal HCE-T cells can be inhibited by up to 30% by preincubation with mecamylamine, an nAchR modulator, or by preincubation with citicholine, a substance of the Kennedy pathway (Fig. 1).

[0115] Previously, a viability test showed that the concentrations used did not affect cell viability.

[0116] These results demonstrate that downregulation of the formation and / or release of inflammatory markers is possible using nAchR modulators and substances of the Kennedy pathway. Consequently, these substances can intervene in and inhibit damaging inflammatory reactions.

[0117] These results also demonstrate the regulation of cellular processes in non-neuronal cells, namely human corneal HCE-T cells, by an nAChR modulator, resulting in the reduction of inflammatory responses in the in vitro model.

[0118] REPLACEMENT SHEET (RULE 26)

Claims

Patent claims 1. An ophthalmic composition containing at least one active ingredient selected from the group consisting of nicotinic acetylcholine receptor modulators and their derivatives and pharmaceutically acceptable salts, substances of the body's own Kennedy metabolic pathways, their derivatives and pharmaceutically acceptable salts, and combinations thereof • for use in the treatment or prevention of inflammatory reactions or diseases of the eye and / or wetting disorders of the eye by topical application of the ophthalmic composition to the open and / or closed eye or • for use in stimulating tear production by topical application of the ophthalmic composition to the open and / or closed eye.

2. Ophthalmic composition for use according to any one of the preceding claims, characterized in that the nicotinic acetylcholine receptor modulators are selected from the group consisting of varenicline (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h]-[3]benzazepine), varenicline tartrate, varenicline hydrochloride, cytisine, 3-bromo-cytisine, desformylflustrabromine, desformylflustrabromine hydrochloride, pozanicline, pozanicline dihydrochloride, sofinicline, 3-(5,6-dichloropyridin-3-yl)-l(S),5(S)-3,6-diazabicyclo[3.2.0]-heptane (ABT-894), 3-Methyl-5-[(2S)-l-methylpyrrolidin-2-yl]-l,2-oxazole (ABT-418), acetylcholine, 3,6-diazabicyclo[3.1.1]heptane-3-carboxamiden (TC-8831), 3-ethyl-2,4-dimethyl-lH-pyrrole (TC-10600), N-[l-(5-chloro-6-pyridin-2-ylpyridin-2-yl)piperidin-4-yl]-2-hydroxyethanesulfonamide (ABT-126), (3R)-3-{[6-(4-methylphenyl)pyridin-3-yl]oxy}-l-azabi-cyclo[2.2.2]octane (AQW-051), mecamylamine and salts, Mixtures and combinations thereof.

3. Ophthalmological composition for use according to one of the preceding claims, characterized in that the at least one substance of the Kennedy metabolic pathway and / or salts and / or derivatives thereof is selected from the group consisting of choline, phosphatidylcholine, lecithin, lysolecithin, ethanolamine, phosphoethanolamine, CDP-ethanolamine, phosphatidylethanolamine, 1A-glycerylphosphorylcholine, citicholine (CDP-choline), cytidine diphosphate choline ([(2 / 3,3S,4 / 5,5 / 6)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydro-xyoxolan-2-yl]methyl-{oxido-[2-(trimethylazaniumyl)ethoxy]phosphoryl phosphate, citicoline), alpha-glycerylphosphorylcholine, phosphocholine, glycerophosphocholine and / or derivatives of these substances.

4. Ophthalmological composition for use according to any one of the preceding claims, characterized in that the application is to the cornea, the bulbar, palpebral and / or tarsal conjunctiva, the limbal stem cells, the eyelids and eyelid margins, the lacrimal secretory apparatus, the primary and accessory lacrimal glands, the meibomian glands, the conjunctival goblet cells, the epithelial cells, the nasolacrimal duct and / or immune cells of the ocular tissue.

5. An ophthalmic composition for use according to any one of the preceding claims, characterized in that it contains ubiquinone-10 and / or dexpanthenol.

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

7. Ophthalmological composition for use according to one of the preceding claims, characterized in that the at least one active ingredient is contained in the ophthalmological composition in a total amount of 0.00001 to 3.0 wt.%, preferably 0.0001 to 2.0 wt.%, particularly preferably 0.001 to 1.5 wt.%.

8. An ophthalmic composition for use according to any one of the preceding claims, characterized by a viscosity of 1-150 mm 2 / s, preferably 7 to 100 mm 2 / s, particularly preferably 10 to 70 mm 2 / s, measured according to Chapter 2.2.

8. European Pharmacopoeia 9.

8.

9. An ophthalmic composition for use according to any one of the preceding claims, characterized by an osmolality of 150 to 340 mOsmol / kg, preferably 170 to 270 mOsmol / kg.

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

4.

11. An ophthalmic composition for use according to any one of the preceding claims, characterized in that it is free from omega-3 fatty acids and / or antioxidants.

12. Ophthalmic composition for use according to any one of the preceding claims, characterized in that it is free from hyaluronic acid.

13. Ophthalmological composition for use according to one of the preceding claims, characterized in that it contains ophthalmologically compatible solutes and their derivatives, in particular selected from the group consisting of sugars such as sucrose, rutinose, trehalose, polyols e.g. glycerol, inositol, erythritol, amino acids e.g. proline, tetrahydropyrimidine derivatives such as ectoine, hydroxyectoine, glycine betaine, betaine, l-carnitine.

14. Ophthalmological composition for use according to one of the preceding claims, characterized in that it contains at least one ophthalmologically compatible buffer, in particular a buffer selected from the group consisting of citrate buffer, phosphate buffer, phosphate-citrate buffer, trometamol buffer, borate buffer, acetate buffer, acetate-borate buffer and combinations thereof.

15. Ophthalmic composition for use according to any of the preceding claims, characterized in that it contains at least one mucoadhesive component or at least one component which increases the residence time on the eye, in particular 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 mycopolysaccharides such as heparan sulfate, haparin sulfate, heaprin and derivatives of the listed substances, as well as combinations thereof.

16. Ophthalmological composition for use according to one of the preceding claims, characterized in that it contains at least one tonicity agent, in particular glycerol, NaCl, sorbitol and / or boric acid.

17. Ophthalmological composition for use according to one of the preceding claims, characterized in that it contains at least one penetration enhancer, in particular isopropyl myristate and / or isopropyl palmitate.

18. Ophthalmological composition for use according to one of the preceding claims, characterized in that it contains at least one emulsifier, in particular vitamin E TPGS and / or poloxamer, e.g. Kolliphor P 407, Kolliphor P188.

19. An ophthalmic composition for use according to any one of the preceding claims, characterized in that it is free from preservatives and phosphate ions.

20. An ophthalmic composition for use according to any one of the preceding claims for use in the prevention or treatment of inflammation of the anterior segment of the eye due to corneal injuries, e.g. epithelial damage due to mechanical influences, conjunctivitis, blepharitis, keratitis, uveitis, iritis, allergies, such as pollen allergy, and inflammations resulting from other diseases such as sicca syndrome, keratoconjunctivitis sicca, bacterial and / or viral infections.

21. An ophthalmic composition for use according to any one of the preceding claims for use in the prevention or treatment of dry eye (dry eye syndrome, keratoconjunctivitis sicca), in particular the hyposecretory and / or evaporative form of dry eye.

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

23. Ophthalmic composition according to one of the preceding claims, characterized in that after application to the eye, a partial derivation of the ophthalmic composition takes place via the nasolacrimal duct and an additional application takes place at the nicotinic acetylcholine receptors of nerve cells in the nasal mucosa.

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

25. An ophthalmic composition for use according to any one of the preceding claims, the ophthalmic composition in the form of eye drops, wherein the use is effected by instilling into the opened eye or by dropping or spraying onto the lid of the closed eye, preferably from 1 to 30 drops, more preferably 2 to 20 drops, particularly preferably 3 to 10 drops being instilled or applied.

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