Ophthalmological collyrium and / or suitable pharmaceutical vehicle

Abstract

The present invention belongs to the field of ophthalmology, specifically the development of advanced ophthalmic collyria. This domain covers pharmaceutical formulations for treating chronic eye diseases. The developed technology combines innovative approaches in ocular tribology and tear film bioengineering, focusing on the restoration of the rheological properties of the tear film to improve the lubrication, stability and health of the eye surface. In addition, the invention falls within the sphere of controlled-release ophthalmic formulations, with technologies that optimise surface tension, osmolarity and viscosity, providing a more effective and longer lasting therapeutic solution.

Description

[0001] OPHTHALMIC EYE DROPS AND / OR PHARMACEUTICAL VEHICLE INDICATED FOR THE RESTORATION AND PROTECTION OF TEAR FILM HYSTERESIS

[0002] DESCRIPTION

[0003] TECHNOLOGY SECTOR

[0004] The present invention falls within the field of ophthalmology, specifically in the development of advanced eye drops. This field encompasses pharmaceutical formulations intended for the treatment of chronic eye diseases. The developed technology combines innovative approaches in ocular biology and tear film bioengineering, focusing on restoring its therapeutic properties to improve lubrication, stability, and ocular surface health. Furthermore, the invention is positioned within the realm of controlled-release ophthalmic formulations, with technologies that optimize surface tension, osmolarity, and viscosity, providing a more effective and longer-lasting therapeutic solution.

[0005] BACKGROUND OF THE INVENTION

[0006] Environmental pollution, excessive use of electronic devices, reduced sleep, and poor diet are factors that have been shown to degrade the protective balance of the tear glands. These conditions contribute to the development of various eye diseases such as dry eye syndrome and dry eye associated with Sjögren's syndrome.

[0007] Neuropathic dry eye or keratoconus significantly affects the quality of life of patients.

[0008] Various formulations for treating these conditions can be found in the literature. For example, US patent 8367746B describes silicone hydrogel contact lenses with a reduced modulus and an optimized contact angle, which improves wettability. These lenses are suitable for extended wear, allowing for continuous use of up to 30 days or more. Their flexible, hydrophilic design provides significant advantages in terms of comfort and eye protection.

[0009] On the other hand, patent ES2906431 presents a composition based on ectoine, hydroxyectoine, and their derivatives (salts, esters, or amides). This formulation is intended for the treatment and prevention of diseases associated with tear film disorders, such as hyperevaporative dry eye syndrome (HDS). The composition, presented in liposome form, improves the fluidization of the lipid layer secreted by the Meibomian glands, restoring tear film stability.

[0010] Furthermore, US patent 9561 191 B2 proposes an innovative method for forming a pharmaceutical product directly onto the surface of a container. This system allows for the creation of individual doses in the form of a soluble film, using water-soluble polymers deposited onto a substrate. This approach ensures precise and efficient dosing for ophthalmic applications.

[0011] Despite the aforementioned advances, the need remains for a product that comprehensively addresses the problems of the tear film and the ocular tribological system. In this context, the development of this product was carried out by rigorously applying the scientific method, beginning with a detailed observation of the ocular structure and, in particular, the tear film. This film is understood as a tribological system that regulates the mechanical interactions between surfaces in contact and movement, such as the eyelids, cornea, and conjunctival and palpebral epithelium.

[0012] From this observation, the question arose: How can the tear film and its essential components be comprehensively restored and protected? An unmet need was identified in the market, as most eye drops focus solely on replacing natural tears with artificial solutions, without addressing the comprehensive restoration of ocular tribology. This comprehensive approach is fundamental to reducing wear and friction caused by blinking, thus preserving long-term ocular health.

[0013] These pathologies, related to dry eye, inflammation, and cell damage, have driven the creation of formulations presented in this document, which are focused on the following objectives:

[0014] 1. To restore and protect the mucins secreted by goblet cells; these cells produce the Muc5AC proteins, which are responsible for the thiological properties of the tear film, such as thixotropy and rehopexy.

[0015] 2. Protect eye cells from oxidative stress

[0016] This aspect seeks to protect the tear film from endogenous (free radicals, cell damage) and exogenous (ultraviolet light, pollution) aggressions, which affect eye health, especially in conditions such as iatrogenic dry eye.

[0017] 3. Incorporate a controlled and prolonged release system. In the development of this new ophthalmic eye drops, a pharmaceutical vehicle is used that simulates the natural conditions of the tear film, providing a controlled and prolonged release of the active components that offers the following advantages: Improved bioavailability. Reduced toxicity. Greater stability of the active ingredient. Prolonged therapeutic action.

[0018] These three objectives are designed to restore and protect ocular tribology, which, as I mentioned earlier, encompasses the mechanical interactions between the eyeball and eyelids, ensuring adequate lubrication and optimal ocular function, essential for ocular surface health. By comprehensively addressing the theological properties of the tear film, these approaches improve its hysteresis, strengthening its thixotropic and rehopetic characteristics. This provides greater stability and more efficient lubrication, optimizing the tear film displacement angle during blinking.

[0019] DETAILED DESCRIPTION OF THE INVENTION

[0020] This new eye drop is indicated for patients suffering from chronic eye conditions related to dry eye, cellular degeneration due to oxidative stress, or inflammatory conditions, and its formulation includes the following compounds:

[0021] 1. ACTIVE INGREDIENTS

[0022] The following active ingredients are available for the treatment of these pathologies, and they can be included in the general formulation at concentrations ranging from 0.05% to 10%, either as the sole active ingredients or in combinations thereof. a. Cevimeline:

[0023] Cevimeline is a cholinergic agonist drug primarily used to treat dry mouth in patients with Sjögren's syndrome, an autoimmune disease affecting the exocrine glands. It has also demonstrated efficacy in treating dry eye syndrome due to its mechanisms of action, such as:

[0024] 1. Selective binding to muscarinic M3 receptors

[0025] Cevimeline binds to M3 receptors present in the lacrimal glands and other exocrine glands.

[0026] 2. Activation of the cholinergic pathway

[0027] It mimics the action of acetylcholine, activating M3 receptors. 3. Stimulation of tear secretion

[0028] It causes an increase in intracellular calcium flow and the activation of ion channels, stimulating the secretion of water and electrolytes.

[0029] 4. Increased tear production

[0030] It improves eye lubrication by increasing both the volume and quality of the tear film.

[0031] 5. Stimulation of other exocrine glands

[0032] It includes the Meibomian glands, contributing to improving the lipid layer of the tear film.

[0033] 6. Prolonged duration of action

[0034] It offers a sustained effect compared to natural acetylcholine.

[0035] 7. Limited systemic effects

[0036] Its high selectivity for M3 receptors and its pharmaceutical form in eye drops reduces systemic adverse effects.

[0037] Unlike conventional treatments that only provide artificial tears, cevimeline promotes natural tear production and improves the quality of the tear film, resulting in better ocular protection and lubrication. This drug represents a promising option for managing dry eye, especially in the context of Sjögren's syndrome, where dry eye is a chronic and debilitating symptom. b. Methylcobalamin

[0038] Methylcobalamin is especially useful in cases of damage to the ocular nerve fibers. This compound is used to slow the progression of age-related macular degeneration, as well as inflammation and retinal degeneration in patients with neuropathic dry eye. Its ability to promote nerve regeneration makes it a key ally in the management of these eye conditions. c. Riboflavin

[0039] Riboflavin, in combination with ultraviolet light, is used in corneal cross-linking, a treatment designed to strengthen the cornea in patients with keratoconus. This procedure improves the biomechanical strength of the cornea, slowing the progression of the disease and reducing the need for more invasive interventions, such as corneal transplantation. d. Alpha-tocopherol

[0040] Alpha-tocopherol, a potent fat-soluble antioxidant, plays a crucial role in protecting eye cells from oxidative damage. Its action helps reduce eye inflammation by neutralizing free radicals and protecting cell membranes. The main mechanisms of action of alpha-tocopherol include:

[0041] 1. Neutralization of free radicals

[0042] Free radicals are highly reactive molecules that damage cells and tissues, including those in the eyes. Alpha-tocopherol donates electrons to these compounds, halting the chain reactions that cause cellular damage.

[0043] 2. Protection of cell membranes

[0044] Cell membranes, composed primarily of lipids, are especially vulnerable to oxidative stress. Alpha-tocopherol, being lipid-soluble, is incorporated into these membranes, protecting them from lipid peroxidation and maintaining their functional integrity.

[0045] 3. Regeneration of other antioxidants

[0046] Alpha-tocopherol helps regenerate other antioxidants such as vitamin C, maximizing the overall antioxidant defense of eye cells against oxidative stress. Furthermore, alpha-tocopherol contributes to maintaining the tenacious properties of the tear film, promoting its pseudoplastic behavior, which is essential for proper eye lubrication. e. Lactoferrin

[0047] Lactoferrin plays multiple essential roles in eye health. This glycoprotein has antimicrobial, antioxidant, and anti-inflammatory properties, which help protect the ocular surface from infection and cell damage. It also acts as a mucin secretagogue, improving the quality of the tear film and contributing to its rheopeticity, a key property for maintaining tear stability and functionality under adverse conditions.

[0048] 2. FORMULATION AGENTS

[0049] The formulation agents are simple and are listed in the following table with their proportion ranges: a. Lubricants

[0050] The use of lubricants in eye drops is essential to improve eye comfort, protect the surface of the eye, and treat or prevent various conditions related to dry eye. The following lubricants are available, from which one or a mixture of them may be selected: Sodium Hyaluronate, Carboxymethylcellulose (CMC), Hydroxypropylmethylcellulose (HPMC), Glycerin, Polyethylene Glycol (PEG) and / or Propylene Glycol (PG), Dexpanthenol, Polyvinyl Alcohol (PVA), Trehalose, Mannitol, or Sorbitol. Solubilizers, emulsifiers, and controlled-release agents may also be included.

[0051] A solubilizer can form controlled-release complexes, which is useful in certain circumstances. These complexes not only facilitate the solubility of the active ingredient but can also modify its release profile, prolonging its therapeutic effect. The following are available in mixtures or as a single-use product.

[0052] Hydroxypropyl beta-cyclodextrin, sorbitol, polysorbate-80, poloxamer 188, poloxamer 407, Cremofor EL, Labrafil M1944 CS, Labrasol, beta-cyclodextrin sulfobutyl ether (SBE-CD), phosphatidylcholine, phosphatidylserine, Span 20, Span 80, caprylyl-caprylyl chloride. Preservatives

[0053] In ophthalmic formulations, preservatives are essential to prevent microbial contamination in multidose containers, but they must be carefully selected to avoid eye irritation or toxicity. These can be selected from the following list.

[0054] Sorbic acid, Benzalkonium chloride, Polyquaternium-1, Chlorhexidine, Thiomersal, Phenylethanol, EDTA (ethylenediaminetetraacetic acid), Potassium sorbate, Octoxynol, Sodium chlorite, Sodium perborate. d. Tonicity regulator

[0055] Incorrect osmolarity levels can cause osmotic stress in eye cells, potentially leading to inflammation, tissue damage, or even long-term complications such as dry eye. The following osmolarity regulators are available for this purpose; one or a combination of them can be selected:

[0056] Sodium Chloride, Potassium Chloride, Sodium Phosphate, Borate

[0057] Sodium, glycerol, mannitol, sorbitol and / or sodium lactate, e. pH regulator

[0058] pH regulators are essential in eye drops to maintain the pH of the formulation compatible with natural tears (normally around pH 7.4), minimizing eye irritation and ensuring the chemical stability of the active ingredient.

[0059] NaOH or HCl, monobasic sodium phosphate (NaH2PO4) and dibasic sodium phosphate (Na2HPO4), boric acid (H3BO3) and sodium borate (Na2B4O7), acetate buffers, lactates, carbonates, histidine.

[0060] These compounds, working together, provide eye drops for the management of various eye conditions, promoting the health and well-being of the ocular surface. Examples of formulations are shown below. EVALUATION OF PHYSICOCHEMICAL PROPERTIES

[0061] The developed formulations have strict control of the following physicochemical properties, key to their efficacy and safety:

[0062] 1. Surface Tension

[0063] This parameter, included as a claim in our patent, is maintained within a range of 40 ± 5 dynes / cm, similar to tear fluid. This prolongs the tear film breakup time, increasing the persistence of the active ingredient on the ocular surface.

[0064] 2. Osmolarity

[0065] The solution is slightly hypoosmolar, with a range of 260-290 mOsmol / Kg, facilitating the penetration of the active ingredient to the site of action, improving its therapeutic efficacy.

[0066] 3. Coefficient of Friction

[0067] This is regulated by viscosity, set between 20 and 30 millipoises. This characteristic gives the vehicle a hyperviscous solution condition, optimizing lubrication without causing blurred vision.

[0068] 4. Preservation System

[0069] The eye drops come in a multi-dose, preservative-free dropper bottle, guaranteeing product safety and avoiding adverse effects associated with prolonged use of preservatives.

Claims

AMENDED CLAIMS received by the International Bureau on December 17, 2025 (17.12.25) 1. Ophthalmic eye drops and / or pharmaceutical vehicle indicated for the restoration and protection of tear film hysteresis, characterized by having the following general formulation:

2. Ophthalmic eye drops and / or pharmaceutical vehicle indicated for the restoration and protection of tear film hysteresis according to claim 1, characterized in that the lubricant is selected from Sodium Hyaluronate, Carboxymethylcellulose (CMC), Hydroxypropylmethylcellulose (HPMC), Glycerin, Polyethylene Glycol (PEG), Propylene Glycol (PG), Dexpanthenol, Polyvinyl Alcohol (PVA), Trehalose, Mannitol, Sorbitol or mixtures thereof.

3. Ophthalmic eye drops and / or pharmaceutical vehicle indicated for the restoration and protection of tear film hysteresis according to claim 1, characterized in that the solubilizer is Select from Hydroxypropylbetacyclodextrin, sorbitol, Polysorbate-80, Poloxamer 188, Poloxamer 407, Cremofor EL, Labrafil M1944 CS, Labrasol, Betacyclodextrin sulfobutyl ether (SBE-CD), Phosphatidylcholine, Phosphatidylserine, Span 20, Span 80, Caprylyl-caprylyl or mixtures thereof 4. Ophthalmic eye drops and / or pharmaceutical vehicle indicated for the restoration and protection of tear film hysteresis according to claim 1, characterized in that the preservative agent is selected from Sorbic Acid, Benzalkonium Chloride, Polyquaternium-1, Chlorhexidine, Thiomersal, Phenylethanol, EDTA (ethylenediaminetetraacetic acid), Potassium Sorbate, Octoxynol, Sodium Chlorite, Sodium Perborate, or mixtures thereof.

5. Eye drops and / or pharmaceutical vehicle indicated for the restoration and protection of tear film hysteresis according to claim 1, characterized in that the tonicity regulator is selected from Sodium Chloride, Potassium Chloride, Sodium Phosphate, Sodium Borate, glycerol, mannitol, sorbitol and / or sodium lactate or mixtures thereof.

6. Eye drops and / or pharmaceutical vehicle indicated for the restoration and protection of tear film hysteresis according to claim 1 characterized in that the pH regulator is selected from NaOH or HCl, monobasic sodium phosphate (NaH2PO4) and dibasic sodium phosphate (Na2HPO4), boric acid (H3BO3) and sodium borate (Na2B4O7), acetate buffers, lactates, carbonates, histidine or mixtures thereof.

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