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WO2025040605A1 - Composition ophtalmologique contenant au moins un modulateur des récepteurs nicotiniques de l'acétylcholine pour une administration topique dans l'œil pour prévenir ou traiter une inflammation de l'œil - Google Patents

Composition ophtalmologique contenant au moins un modulateur des récepteurs nicotiniques de l'acétylcholine pour une administration topique dans l'œil pour prévenir ou traiter une inflammation de l'œil Download PDF

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Publication number
WO2025040605A1
WO2025040605A1 PCT/EP2024/073158 EP2024073158W WO2025040605A1 WO 2025040605 A1 WO2025040605 A1 WO 2025040605A1 EP 2024073158 W EP2024073158 W EP 2024073158W WO 2025040605 A1 WO2025040605 A1 WO 2025040605A1
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Prior art keywords
eye
ophthalmological composition
use according
composition
ophthalmological
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PCT/EP2024/073158
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German (de)
English (en)
Inventor
Ute Steinfeld
Hyeck Hee Lee
Frank Holzer
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Ursapharm Arzneimittel GmbH
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Ursapharm Arzneimittel GmbH
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide

Definitions

  • Ophthalmological 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
  • the present invention relates to an ophthalmic composition
  • an ophthalmic composition comprising
  • choline e.g. lecithin with a phosphatidylcholine content > 80% by weight
  • CDP-choline citicholin
  • phosphatidylcholine lecithin, e.g. soya lecithin
  • ethanolamine phosphoethanolamine
  • the ophthalmic composition is applied to the open and/or closed eye of a patient.
  • Inflammations of the eye and the ocular surface are triggered by a variety of exogenous or endogenous noxae or stressors, such as UV light, mechanical stimuli such as friction, chemical influences, chemicals, 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 often to inflammatory reactions.
  • the 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 eye, swelling of the conjunctiva and/or eyelids, increased sensitivity to light, discharge of watery or purulent secretions, sticky eyelids.
  • inflammatory mediators such as cytokines, other growth factors, matrix metalloproteinases (MMPs), etc.
  • MMPs matrix metalloproteinases
  • 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.
  • a persistent and/or excessive immune reaction has an undesirable damaging effect (e.g., pathological changes and defects in 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.
  • REPLACEMENT BLADE plays an important role. Inflammations are complex processes in which various genes and signaling pathways are involved
  • nAChR agonists such as varenicline
  • varenicline binds to AChR of nerve cells in the nasal mucosa. This results in the trigeminal nerve, anterior ethmoid nerve or nasolacrimal reflex being activated. Nerve signals ultimately influence the lacrimal gland to increase tear release.
  • 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.
  • 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 lubricity.
  • the lipid layer is the outermost layer of the tear film.
  • the lipids produced by the meibomian gland form an oily layer on the surface of the tear fluid secreted by the lacrimal gland and prevent it from evaporating quickly and running over the tear rim ("watery eye"), thus playing a very important role in the retention time of the aqueous tear film on the eye.
  • a long retention time and thus wetting of the surface of the eye is important for the prevention and/or treatment of dry eyes.
  • 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 lubricity on the surface of the eye. Furthermore,
  • REPLACEMENT BLADE (RULE 26) During nasal application, no substitutes for mucins and/or lipids are supplied to the eye in order to increase the stability and retention time of the aqueous tear film and/or to exert additional calming, soothing, lubricating, friction-reducing effects.
  • 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 the nerve fibers of the olfactory nerve exit the brain into the nasal mucosa, active ingredients can travel from the nasal mucosa to the brain via a short route and almost without barriers. This means there is a risk of undesirable neurological symptoms as side effects.
  • the aim of the present invention is to prevent, reduce or completely prevent 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:
  • inflammatory mediators e.g. pro-inflammatory cytokines (such as interleukin IL-1, IL-6, IL-8, tumor necrosis factor TNF-a), chemokines and specific enzymes, such as matrix metalloproteinases (MMPs) and/or
  • the object of the present invention is therefore to provide an improved method
  • REPLACEMENT BLADE (RULE 26) which is more effective and has fewer side effects. This can include one or more complementary effects or mechanisms of action and thus intervene in a regulating manner at various levels in persistent and excessive inflammatory reactions and support necessary repair processes in order to restore molecular homeostasis at the cellular and tissue level.
  • the present invention thus relates to an ophthalmological 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, L-a-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 ophthalmological composition to the open and/or closed eye.
  • active ingredients locally in the eye tissue to prevent and/or treat inflammatory diseases such as the cornea, the eyelid margins and/or dry eyes is not yet known.
  • 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 in order to be able to act there as efficiently as possible.
  • the superficially applied ophthalmological composition intervenes directly 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 cell processes are modulated accordingly.
  • composition according to the invention can be applied to different cells, cell types and/or tissues
  • the advantage over systemic administration is that the effect remains largely localized to the application site, i.e. the inflammation site, where it arrives virtually undiluted and acts directly on the cells that are involved in the inflammation process. This stops excessive reactions, such as oxidative stress, in the inflammation process. As a result, the surface of the eye is protected and thus contributes to the formation and maintenance of a smooth, healthy surface of the cornea.
  • 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 different processes in the body.
  • the ophthalmological composition according to the present invention stimulates natural tear production.
  • This stimulation of natural tear production can be caused by the ophthalmological composition, which is discharged in a controlled manner via the nasolacrimal duct and consequently activates, for example, nicotinic acetylcholine receptors in the nasal mucosa.
  • the trigeminal nerve, anterior ethmoid nerve or nasolacrimal reflex are activated and these nerve signals ultimately influence the lacrimal gland to increase tear release.
  • Prevention and treatment of inflammation and wetting disorders are thus advantageously supported.
  • This effect triggered in the nasal mucosa after topical application of the formulation in or on the open or closed eye is very surprising and unexpected.
  • REPLACEMENT BLADE By stimulating increased tear production, the ophthalmological composition stimulates the formation of a natural moist and protective film on the surface of the eye, thus ensuring continuous wetting of the cornea and conjunctiva. As described above, this can prevent inflammation or inflammatory reactions, and possibly 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.
  • 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) by exerting dual or multiple action processes (physiological and/or physical) is particularly advantageous and surprising.
  • the process is mediated and initiated by interaction of the at least one active ingredient of the present composition with nAChRs of cells of the eye tissue and/or on immune cells and/or non-immune cells in the eye tissue or by an unknown mechanism.
  • This reduces or completely prevents the release of inflammatory mediators and/or the transcription of various genes, including those that encode, for example, cytokines and chemokines and special enzymes such as MMPs.
  • the formation and/or presentation of adhesion molecules that support the infiltration of immune cells into the inflammatory tissue is reduced.
  • REPLACEMENT BLADE 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 metabolic pathways, these nicotinic acetylcholine receptors and/or other mechanisms.
  • inflammatory mediators e.g. pro-inflammatory cytokines, MMPs, etc.
  • 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-diazabic
  • 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.
  • a nicotinic acetylcholine receptor modulator such as varenicline and its derivatives, ultimately leads to the down-regulation of, for example, pro-inflammatory cytokines after interaction with or binding to the nAChR and can thus prevent, reduce or stop persistent and damaging inflammatory reactions in the eye.
  • 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
  • REPLACEMENT BLADE are in particular selected from the group consisting of choline, phosphatidylcholine, lecithin (a possible derivative of this is lysolecithin), ethanolamine, phosphoethanolamine, CDP-ethanolamine, phosphatidylethanolamine, La-glycerylphosphorylcholine, citicholine (CDP-choline), cytidine diphosphate-choline ([(2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-l-yl)-3,4-dihydro- xyoxolan-2-yl]methyl- ⁇ oxido-[2-(trimethyl--azaniumyl)--ethoxy]-phosphoryl ⁇ - phosphate, citicoline), alpha-glyceryl-phosphoryl choline, phosphocholine, glycerophosphocholine and/or derivatives of these substances.
  • All substances in the Kennedy pathways are substances of natural cell metabolism or salts and/or derivatives thereof.
  • Phosphatidylcholine and phosphatidylethanolamine the most common phospholipids in mammalian cells, are synthesized de novo from choline and ethanolamine via the Kennedy pathways in natural cell metabolism. Consequently, these endogenous substances are very well tolerated when applied to or in the eye.
  • these substances trigger down-regulation of, for example, pro-inflammatory cytokines, MMPs, etc. in the eye tissue. Excessive or persistent inflammation can be alleviated or prevented in this way. This can have a positive influence on inflammatory processes, diseases and/or accompanying symptoms of various eye diseases.
  • infections and inflammations of the eye caused by wetting disorders, allergies, styes, corneal inflammation (keratitis), eyelid inflammation (blepharitis), or dry eye (keratoconjunctivitis sicca), sicca syndrome, Sjögren's syndrome, etc.
  • 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.
  • composition may, in addition to a nAChR modulator and/or a
  • REPLACEMENT BLADE (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.
  • Ubiquinone-10 in particular is one such component. Its long lipophilic isoprenoid side chains insert into the cell membranes and influence the fluidity properties of the membrane.
  • Dexpanthenol is also such a component. It stimulates the synthesis of membrane lipids and thus also promotes intact membrane homeostasis with physiological permeability. Dexpanthenol also plays a role in the modulation of gene expression (e.g. of interleukins) in inflammatory processes. It has an anti-inflammatory and anti-apoptotic effect and thus perfectly supports the effect of nAChR agonists and modulators via an alternative mechanism of action.
  • the composition contains dexpanthenol and/or ubiquinone-10. In special embodiments, however, it can also be free of ubiquinone-10 and/or depanthenol.
  • components may be included 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.
  • anti-irritant components such as hyaluronic acid, povidone, herbal extracts from Euphrasia (eyebright), mallow, blueberry, etc., dexpanthenol, heparin, ectoin and hydroectoin, etc.
  • 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).
  • 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.%.
  • the ophthalmological 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. European Pharmacopoeia 9.8. This promotes improved adhesion and tolerability (no foreign body sensation) at the application site.
  • the ophthalmic composition has an osmolality of 150 to 340 mOsmol/kg, preferably 170 to 270 mOsmol/kg.
  • the pH is from 5.8 to 8.5, more preferably from 6.6 to 7.4.
  • the ophthalmological composition is free of omega-3 fatty acids and/or antioxidants.
  • the composition is free of phosphate buffer.
  • the composition is free of phosphate ions.
  • phosphate-free means 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 extremely preferably no phosphate ions (i.e. below the detection limit).
  • phosphate ions here includes all ions derived from phosphoric acid, i.e. dihydrogen phosphate, hydrogen phosphate and phosphate.
  • the ophthalmological composition can also be free of hyaluronic acid.
  • 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, I-carnitine can be contained in the ophthalmological composition.
  • the ophthalmic composition may also contain components to maintain and/or restore membrane fluidity and permeability, such as ubiquinone-10, cholesterol, resveratrol, etc.
  • composition can contain anti-inflammatory and/or soothing herbal extracts such as extracts or tinctures from calendula, ribwort plantain, mahonia, eyebright, chamomile, aloe vera, willow bark, echinacea, arnica, etc.
  • anti-inflammatory and/or soothing herbal extracts such as extracts or tinctures from calendula, ribwort plantain, mahonia, eyebright, chamomile, aloe vera, willow bark, echinacea, arnica, etc.
  • the ophthalmological composition contains 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.
  • 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.
  • the ophthalmological 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.
  • cellulose derivatives such as carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), hyaluronic acid, chondroitin sulfate, poly
  • a formulation composition that contains only a small amount of mucoadhesive components is preferred for the effect in various sensory organs, so that the composition can partially drain through the nasal mucosa.
  • the content of viscosity-increasing agents is therefore preferably in a range of 0.01 to 0.5% by weight, preferably 0.02 to 0.1% by weight, based on the ophthalmological composition, e.g. in the case of hyaluronic acid.
  • the ophthalmological composition contains at least one tonicity agent, in particular glycerin, NaCl, sorbitol and/or boric acid.
  • Penetration enhancers in particular isopropyl myristate and/or isopropyl palmitate, may also be included in order to achieve improved penetration into the eye tissue, as already defined above, in particular into the cornea and conjunctiva.
  • the ophthalmological composition further contains at least one emulsifier, in particular vitamin E TPGS, poloxamer e.g. Kolliphor P 407 and/or Kolliphor P188.
  • at least one emulsifier in particular vitamin E TPGS, poloxamer e.g. Kolliphor P 407 and/or Kolliphor P188.
  • 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 influencers, emulsifiers, stabilizers, wetting agents, spreading agents, antioxidants, osmolarity regulators and mixtures thereof.
  • the ophthalmological composition is suitable for use in the prevention or treatment of inflammations caused by blepharitis, keratitis, uveitis, ulceris, allergies such as pollen allergy, and inflammations resulting from other diseases such as sicca syndrome, keratoconjunctivitis sicca.
  • 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.
  • 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, spraying or fine nebulization.
  • the agonists are also drained via the lacrimal ducts (viae lacrimales) after application to the eye, i.e. the lacrimal canaliculi, lacrimal sac and/or nasolacrimal duct, and cause an activation of tear production.
  • the exact site and mechanism of action are unknown.
  • the agonists contained in the eye drops trigger the stimulation by activating the trigeminal afferent nerve fibers in the nasal mucosa.
  • the amount of drainage via the nasolacrimal duct can be controlled to a certain extent, ie from practically no drainage to partial drainage to varying degrees.
  • the ophthalmological composition according to the invention partially drains via the nasolacrimal duct after application to the eye and is thereby additionally applied to or on the nAChR of nerve cells in the nasal mucosa. Nerve signals influence the tear glands of the eye to increase secretion of the natural tear film and consequently improved hydration of the surface of the eye.
  • the double (and/or multiple) effect of the eye drops is particularly advantageous, namely the anti-inflammatory effect directly in the eye tissue (the administration of mucin and/or lipid substitutes) and additionally the increase in natural tear production by drainage of the composition via the nasolacrimal duct onto the nasal mucosa after application to the eye. Since only a small amount of the applied active ingredient concentration reaches the nasal mucosa, side effects such as irritated nasal mucosa, 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.
  • amino acids and/or peptides and their derivatives e.g. N-acetylcysteine, taurine, L-proline, glycine, L-lysine hydrochloride, L-leucine.
  • N-acetylcysteine taurine
  • L-proline glycine
  • L-lysine hydrochloride L-leucine
  • tyloxapol a non-ionic, liquid polymer that primarily serves as a wetting agent or spreading agent.
  • Spreading agents can also improve drainage and distribution via the nasolacrimal ducts.
  • the application of the ophthalmic composition or its use can be carried out 1 to 10 times, preferably 1 to 5 times per day.
  • the use can be done, for example, by instilling drops into the open eye or by dripping or spraying onto the lid of the closed eye, whereby
  • REPLACEMENT BLADE preferably from 1 to 30 drops, more preferably 2 to 20 drops, particularly preferably 3 to 10 drops or sprays.
  • the ophthalmic composition may contain ophthalmologically acceptable preservatives, but is preferably free of preservatives.
  • test substances 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.
  • HCE-T cells were seeded in 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 the immediate addition of 10 ng/ml TNF-a and incubation for 24 hours.
  • Dexamethasone (100 pM) served as a positive control.
  • the medium control serves as a negative control.
  • HCE-T cell supernatants were collected and stored at -20°C until use.
  • the content of MMP9 in the cell supernatant was detected using an ELISA kit according to the manufacturer's protocol.
  • Fig.l shows the protein expression of MMP9 in HCE-T cells after preincubation with mecamylamine, a nAchR modulator, or citicholine, a substance of the Kennedy pathway.
  • MMP9 is an inflammatory marker that is found at elevated levels in the tears of patients with dry eye. This inflammatory marker can be used in the in vitro model to evaluate the anti-inflammatory effect of
  • TNF- ⁇ -induced protein expression of MMP9 in immortalized human corneal HCE-T cells can be inhibited by up to 30% by preincubation with mecamylamine, a nAchR modulator, or by preincubation with citicholine, a substance of the Kennedy pathway (Fig. 1).

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Abstract

La présente invention concerne une composition ophtalmologique, comprenant au moins un modulateur des récepteurs nicotiniques de l'acétylcholine (nAChR), en particulier la varénicline, la mécamylamine et des dérivés, et/ou au moins une substance des voies métaboliques Kennedy endogènes, ainsi que des sels et dérivés ou des sels pharmaceutiquement acceptables de ces substances, et des phospholipides, sels et dérivés de ces substances contenant de la choline. Dans ces groupes, une préférence particulière est donnée à la choline, la phosphocholine, la CDP-choline (citicoline), la phosphatidylcholine (par exemple la lécithine ayant une teneur en phosphatidylcholine ≥ 80% en poids, par exemple la lécithine de soja), l'éthanolamine, la phosphoéthanolamine, la CDP-éthanolamine, la phosphatidyléthanolamine, la L-α-glycérylphosphorylcholine, la phosphatidylcholine et la phosphatidyléthanolamine.
PCT/EP2024/073158 2023-08-23 2024-08-16 Composition ophtalmologique contenant au moins un modulateur des récepteurs nicotiniques de l'acétylcholine pour une administration topique dans l'œil pour prévenir ou traiter une inflammation de l'œil Pending WO2025040605A1 (fr)

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