Application of Areg in preparation of medicine for improving lacrimal gland function and treating xerophthalmia

Abstract

The invention provides application of Areg in preparation of drugs for improving lacrimal gland functions and treating xerophthalmia. The invention provides application of Areg or a variant thereof in preparation of a medicine for treating or preventing lacrimal gland dysfunction eye diseases. The invention further provides a pharmaceutical composition, a medicine box, a preparation method of the medicine and the like for treating or preventing the lacrimal gland dysfunction eye disease.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, and more specifically, this invention relates to the use of Areg in the preparation of drugs that improve lacrimal gland function and treat dry eye syndrome. Background Technology

[0002] Dry eye syndrome is a multifactorial mediated ocular surface disease that is extremely common in clinical practice and has become one of the most prevalent eye diseases worldwide, with a prevalence rate of 21.0%-52.4% in my country. Its core pathological mechanism lies in abnormalities in the quality and quantity of tears or disturbances in tear dynamics, leading to an imbalance in the ocular surface microenvironment and tear film instability. In the middle and late stages of the disease, ocular surface inflammation, tissue damage, and abnormal nerve function may also occur, ultimately resulting in a series of eye discomfort symptoms such as dryness, foreign body sensation, and redness. Dry eye syndrome can be broadly divided into two types: aqueous hypotaxis and evaporative dry eye. Aqueous hypotaxis, also known as lacrimal gland dysfunction-related dry eye, is caused by factors including congenital lacrimal gland hypoplasia, Sjögren's syndrome, drug side effects (such as antidepressants), and lacrimal gland damage. Reduced tear secretion manifests as persistent dryness and a foreign body sensation in the eyes, which worsens upon waking or after eye use. In severe cases, blurred vision, ocular surface congestion, and dry mouth may also occur.

[0003] For the pathological characteristics of aqueous hypohydration-related dry eye, artificial tear replacement is the first-line treatment, using preparations such as sodium hyaluronate and polyvinyl alcohol to replenish ocular surface moisture. Pivot occlusion can reduce tear loss; for patients with low secretion, removable non-permanent silicone plugs are preferred, while those that fail or dislodge can be permanently sealed using cauterization. Simultaneously, wearing moisture chamber glasses can maintain high ocular humidity, and avoiding dry environments and reducing the use of electronic devices are also important. Regarding etiological treatment, oral cholinergic drugs such as pilocarpine can directly stimulate lacrimal gland secretion, while ω-3 polyunsaturated fatty acids can regulate inflammatory pathways and indirectly improve lacrimal gland function. For immune-related aqueous hypohydration-related dry eye, corticosteroids or immunosuppressants are needed to control inflammation. For patients with meibomian gland dysfunction, warm compresses and massage can optimize the lipid layer and reduce aqueous layer evaporation.

[0004] However, the treatment of aqueous hypoxic dry eye still faces many challenges: conventional artificial tears require long-term and frequent use, and their effectiveness is limited for moderate to severe cases. Preservative-containing formulations may cause ocular surface toxicity, while preservative-free single-dose formulations are expensive, and some formulations may temporarily impair vision due to high viscosity. Traditional punctal embolization emboli are mostly imported and expensive, and may obstruct tear flushing, leading to the accumulation of immune mediators. Permanent cauterization is irreversible and may cause temporary epiphora. In terms of drug treatment, oral medications such as pilocarpine are prone to systemic side effects such as dry mouth and sweating, limiting their use in the elderly or those with underlying diseases. Omega-3 fatty acids have a slow onset of action, require long-term use, and show significant individual variability in effectiveness. Long-term use of glucocorticoids may cause increased intraocular pressure and cataracts. Immunosuppressants require monitoring of liver and kidney function and have low response rates in some severe cases of immune-related aqueous hypoxic dry eye.

[0005] Therefore, there is an urgent need in this field to explore therapeutic drugs for aqueous-deficient dry eye syndrome, break through the limitations of traditional drugs, and provide new ideas for the development of dry eye drugs. Summary of the Invention

[0006] The purpose of this invention is to provide the application of Areg in the preparation of drugs that improve lacrimal gland function and treat dry eye syndrome.

[0007] A first aspect of the invention provides the use of Areg or variants thereof in the preparation of a medicament for treating or preventing lacrimal gland dysfunction-type eye diseases.

[0008] In one or more embodiments, the Areg is the protein shown in SEQ ID NO:1.

[0009] In one or more embodiments, the Areg variant is selected from: (i) A protein having the same or similar biological function as said Areg, formed by substituting, deleting or adding one or more amino acid residues of the amino acid sequence shown in SEQ ID NO:1. (ii) Proteins with amino acid sequences that are ≥80% homologous to the amino acid sequence shown in SEQ ID NO:1 and have the same or similar biological functions as the Areg. (iii) A protein having the same or similar biological function as the Areg formed by adding a tag sequence or restriction enzyme site sequence to the N or C end of the polypeptide with the amino acid sequence shown in SEQ ID NO:1, or by adding a signal peptide sequence to its N end.

[0010] In one or more embodiments, the lacrimal gland dysfunction type eye disease is an eye disease caused by lacrimal gland dysfunction or lack of fluid; preferably, the lacrimal gland dysfunction type eye disease is lacrimal gland dysfunction type dry eye syndrome; more preferably, streptozotocin-induced diabetic dry eye syndrome, scopolamine injection combined with dry environment-induced dry eye syndrome; more preferably, the scopolamine injection combined with dry environment-induced dry eye syndrome includes local lacrimal gland inflammation and lacrimal gland dysfunction.

[0011] In one or more embodiments, the treatment or prevention of lacrimal gland dysfunction-related eye disease includes: increasing tear secretion, increasing tear weight, increasing the number of conjunctival goblet cells, and / or relieving dry eye symptoms; preferably, the dry eye symptoms include dry eyes, foreign body sensation in the eyes, blurred vision, and congestion of the ocular surface.

[0012] A second aspect of the invention provides a pharmaceutical composition for treating or preventing lacrimal gland dysfunction-related eye diseases, said pharmaceutical composition comprising a therapeutically effective amount of Areg or a variant thereof, and a pharmaceutically acceptable carrier.

[0013] In one or more embodiments, the lacrimal gland dysfunction ophthalmopathy, or the treatment or prevention of lacrimal gland dysfunction ophthalmopathy, is as described in any embodiment of the present invention.

[0014] In one or more embodiments, the Areg or its variants are as described in any embodiment of the present invention.

[0015] In one or more embodiments, the pharmaceutically acceptable carrier includes ophthalmologically acceptable salts.

[0016] In one or more embodiments, the ophthalmologically acceptable salt comprises a salt containing one or more cations selected from sodium, potassium, and ammonium, and one or more anions selected from chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, and bisulfite.

[0017] In one or more embodiments, the ophthalmologically acceptable salt is a phosphate.

[0018] In one or more embodiments, the pharmaceutical composition is applied topically under the conjunctiva, in the anterior chamber, in the vitreous body, under the eyeball, under the retina, under the choroid, on the choroid, in the conjunctival sac, or on the eyelid.

[0019] In one or more embodiments, the pharmaceutical composition is administered at a frequency of 1 to 2 drops each time, 2 to 5 times a day, with an interval of 3 to 6 hours between each administration.

[0020] In one or more embodiments, the pharmaceutical composition is administered at a frequency of 1 drop each time, 4 times a day, with each drop spaced 4 hours apart.

[0021] A third aspect of the present invention provides a medicine box for treating or preventing lacrimal gland dysfunction-type eye diseases, the medicine box containing Areg or a variant thereof as described in any embodiment of the present invention, or containing a pharmaceutical composition as described in any embodiment of the present invention.

[0022] In one or more embodiments, the lacrimal gland dysfunction ophthalmopathy, or the treatment or prevention of lacrimal gland dysfunction ophthalmopathy, is as described in any embodiment of the present invention.

[0023] A fourth aspect of the invention provides the use of Areg or variants thereof in the preparation of one or more pharmaceutical products selected from the group consisting of: (1) Drugs that increase tear secretion; (2) Medications that increase tear weight; (3) Drugs that increase the number of conjunctival goblet cells; (4) Medications to relieve dry eye syndrome; (5) Drugs that improve lacrimal gland function.

[0024] In one or more embodiments, the dry eye syndrome includes dry eyes, a foreign body sensation in the eyes, blurred vision, and bloodshot eyes.

[0025] In one or more embodiments, the Areg or its variants are as described in any embodiment of the present invention.

[0026] A fifth aspect of the present invention provides a method for preparing a medicament for treating or preventing lacrimal gland dysfunction-type eye diseases, the method comprising the step of mixing Areg or a variant thereof as an active ingredient with a pharmaceutically acceptable carrier and preparing the medicament.

[0027] In one or more embodiments, the pharmaceutically acceptable carrier is as described in any embodiment of the present invention.

[0028] In one or more embodiments, the lacrimal gland dysfunction ophthalmopathy, or the treatment or prevention of lacrimal gland dysfunction ophthalmopathy, is as described in any embodiment of the present invention.

[0029] Other aspects of the invention will be apparent to those skilled in the art from the disclosure herein. Attached Figure Description

[0030] Figure 1The results show the staining of ocular tissues after Areg eye drops were administered to normal mice; (A) shows the corneal fluorescence staining results after solvent eye drops and Areg eye drops; (B) shows the PAS staining results of the conjunctival sac after solvent eye drops and Areg eye drops, with the scale bar at 100 μm; (C) shows the H&E staining results of the lacrimal gland after solvent eye drops and Areg eye drops, with the scale bar at 200 μm.

[0031] Figure 2 The results show the changes in tear secretion after Areg eye drops were administered to normal mice; (A) is a diagram of the Areg eye drop administration protocol; (B) is a statistical graph of tear secretion in the solvent eye drop group and the Areg eye drop group; (C) is a statistical graph of lacrimal gland weight in the solvent eye drop group and the Areg eye drop group.

[0032] Figure 3 The following diagrams illustrate the therapeutic effect of Areg eye drops on diabetic dry eye: (A) Diagram of the diabetic mouse model (STZ model) and Areg eye drop treatment protocol; (B) Statistical graph of tear secretion after eye drop treatment in each group of mice; (C) Statistical graph of lacrimal gland weight after eye drop treatment in each group of mice; (D) Representative PAS staining diagram after eye drop treatment in mice, with a scale bar of 100 μm; (E) Statistical graph of PAS staining after eye drop treatment in each group of mice.

[0033] Figure 4 The following diagrams illustrate the therapeutic effect of Areg eye drops on scopolamine-induced dry eye syndrome: (A) is a diagram of the scopolamine mouse model and the Areg eye drop treatment protocol; (B) is a statistical diagram of tear secretion after eye drop treatment in each group of mice; (C) is a representative PAS staining diagram after eye drop treatment in mice, with a scale bar of 100 μm; (D) is a statistical diagram of PAS staining after eye drop treatment in each group of mice. Detailed Implementation

[0034] Through in-depth research, the inventors discovered that Areg protein can promote tear secretion in mice, and in both diabetic dry eye mouse models and scopolamine dry eye mouse models, it increases tear production, increases the number of conjunctival goblet cells, and alleviates dry eye symptoms. Furthermore, Areg eye drops exhibit high safety. Therefore, this invention provides the application of Areg in the preparation of drugs for treating dry eye syndrome, especially aqueous-deficient dry eye syndrome.

[0035] the term

[0036] In this invention, the term "lacrimal gland" generally refers to a gland located in the eye that secretes an aqueous fluid as well as specific types of proteins and electrolytes. The aqueous fluid and specific types of proteins and electrolytes secreted by the lacrimal gland are gradually distributed and extended to the surface of the eye through blinking, evaporate from the surface of the eye, and are discharged through the nasolacrimal duct to form tears.

[0037] The term "lacrimal gland dysfunction-related dry eye syndrome" refers to dry eye syndrome caused by various factors (such as, but not limited to, congenital lacrimal gland hypoplasia, Sjögren's syndrome, drug side effects, lacrimal gland damage, and reduced tear secretion), resulting in tear dysfunction. It is also known as aqueous hypotonia-related dry eye syndrome. In some implementations, the manifestations of lacrimal gland dysfunction-related dry eye syndrome include, but are not limited to: persistent dryness and foreign body sensation in the eyes, worsening upon waking or after eye use; in severe cases, blurred vision and ocular congestion; and sometimes accompanied by dry mouth. For example, lacrimal gland dysfunction-related dry eye syndrome includes, but is not limited to: streptozotocin (STZ)-induced diabetic dry eye syndrome, and scopolamine injection combined with a dry environment-induced dry eye syndrome (e.g., local lacrimal gland inflammation, lacrimal gland dysfunction, etc.).

[0038] The term "Areg" or "biregrin" refers to a key member of the epidermal growth factor (EGF) family and an important ligand for the EGF receptor (EGFR). Its precursor is a transmembrane protein, which, after being hydrolyzed by proteases, releases its mature active form. Areg is widely expressed in epithelial cells and cancer cell lines of various human tissues, including the colon, breast, and kidney. The Areg described in this invention also includes its variants.

[0039] The term "Areg variant" refers to a substance that is identical or similar to an Areg in structure, use, and / or intended effect. The Areg variant includes (but is not limited to) substances formed by the deletion, insertion, and / or substitution of several amino acids (typically 1-50, preferably 1-30, more preferably 1-20, most preferably 1-10, and even more preferably 1-8, 1-5) of an Areg or its precursor protein, and / or substances formed by the addition or deletion of one or more amino acids (typically up to 20, preferably up to 10, more preferably up to 5) at the C-terminus and / or N-terminus of an Areg or its precursor protein. Any protein that has high homology with the Areg (e.g., 70% or higher homology with the amino acid sequence shown in SEQ ID NO:1; preferably 80% or higher homology; more preferably 90% or higher homology, such as 95%, 98% or 99% homology) and has the same function as the Areg or its precursor protein is also included in this invention, such as, but not limited to: human soluble cleavage variants of Areg, recombinant engineered variants, species-specific homologous variants, and glycosylated modified variants.

[0040] The terms “subject” or “patient” may refer to a patient or other animal, especially a mammal, such as a human, mouse, rat, dog, monkey, cow, horse, etc., who receives the Areg or variant thereof described in this invention, or the pharmaceutical composition described in this invention to treat, prevent, improve and / or alleviate the lacrimal gland dysfunction type of dry eye.

[0041] The term "medicine" refers to a substance capable of treating, preventing, improving, and / or alleviating lacrimal gland dysfunction-related dry eye. The term "medicine" is used in a broad sense, encompassing various forms such as single-drug, multi-drug, and pharmaceutical compositions.

[0042] Pharmaceutical Composition

[0043] The pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and the Areg or a variant thereof as described in the present invention.

[0044] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or transporter, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in carrying or transporting a reagent from one organ or part of the body to another organ or part of the body. A carrier must be "acceptable" in terms of its compatibility with other components of the formulation; for example, the carrier should not diminish the therapeutic effect of the reagent. In other words, the carrier is pharmaceutically inert.

[0045] The composition can be formulated according to known methods for preparing pharmaceutical compositions, wherein the compound is mixed with a pharmaceutically acceptable carrier. Phosphate buffer is an example of a pharmaceutically acceptable carrier. Other suitable carriers are well known to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 19th edition (1995).

[0046] Pharmaceutical compositions suitable for topical administration can be formulated as solutions, ointments, creams, emulsions, suspensions, lotions, powders, pastes, gels, sprays, mists, aerosols, or oils. In some embodiments, the pharmaceutical composition is a solution, such as an ophthalmic solution. In some embodiments, the ophthalmic solution is administered topically to humans or non-human mammals at a dose of one or more drops per eye daily.

[0047] For ocular treatment, the composition can be applied as a topical ointment or cream. When formulated as an ointment, the active ingredient can be used in combination with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream using an oil-in-water or water-in-oil base.

[0048] Pharmaceutical compositions suitable for topical ocular administration include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier (especially an aqueous solvent). Formulations for ocular administration have ocularly compatible pH and osmotic pressure. The pharmaceutical compositions of the present invention may contain one or more ophthalmologically acceptable pH adjusters and / or buffers, including acids such as phosphoric acid, acetic acid, boric acid, citric acid, lactic acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, and sodium lactate; and buffers such as phosphates, citrates, dextran, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers may be contained in amounts necessary to maintain the pH of the composition within an ophthalmologically acceptable range. Pharmaceutical compositions may contain one or more ophthalmologically acceptable salts in amounts sufficient to maintain the osmotic pressure of the pharmaceutical composition within an ophthalmologically acceptable range. Such salts include salts containing sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions. In some embodiments, the pharmaceutical composition is an eye drop containing the Areg or a variant thereof described herein and a buffer solution containing phosphate ions.

[0049] The pharmaceutical compositions described herein can be applied topically to the eye via subconjunctival, intraocular, intravitreal, subocular, subretinal, subchoroidal, or suprachoroidal routes, into the conjunctival sac or eyelid, using ocular delivery devices or implants. Such devices or implants can be designed to achieve controlled release of one or more therapeutic agents according to various predetermined release rates, sustained-release kinetics, and osmotic pressures. Controlled release can be achieved by designing polymer matrices, selecting different polymers and utilizing their varying properties, such as biodegradable / biocorrosive polymers (e.g., poly(ethylene-vinyl) acetate (EVA), superhydrolyzed PVA), hydroxyalkyl cellulose (HPC), methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), polycaprolactone, polyglycolic acid, polylactic acid, polyanhydride), polymer molecular weight, polymer crystallinity, copolymerization ratio, processing conditions, surface finishing, geometry, excipient addition, and polymer coatings, thereby enhancing drug diffusion, dissolution, solubility, and penetration.

[0050] For pharmaceutical compositions delivered using ocular devices or implants, one or more active agents may be combined with adjuvants suitable for the designated route of administration. For example, the active agent may be mixed with any pharmaceutically acceptable excipient, lactose, sucrose, starch powder, cellulose esters, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gum arabic, gelatin, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, tableted, or encapsulated for routine administration. Alternatively, the compound may be dissolved in polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solution, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and / or various buffer solutions. The compound may also be mixed with compositions comprising biodegradable and / or non-biodegradable polymers, and with a carrier or diluent having delay properties. Representative examples of biodegradable compositions may include albumin, gelatin, starch, cellulose, dextran, polysaccharides, poly(D,L-lactide), poly(D,L-lactide-co-glycolic acid), poly(glycolic acid), poly(hydroxybutyrate), poly(alkyl carbonate), and poly(orthoester), and mixtures thereof. Representative examples of non-biodegradable polymers include EVA copolymers, silicone rubber, and poly(methacrylate), and mixtures thereof.

[0051] Pharmaceutical compositions for ocular delivery also include in-situ gellable aqueous compositions. Such compositions comprise a concentration of gelling agent that promotes gelation upon contact with the eye or tear film. Suitable gelling agents include, but are not limited to, thermosetting polymers. As used herein, the term "in-situ gellable" includes not only low-viscosity liquids that form a gel upon contact with the eye or tear film, but also more viscous liquids, such as semi-fluids and thixotropic gels, whose viscosity or gel hardness increases significantly after administration to the eye. See, for example, Ludwig (2005), incorporated herein by reference for his teachings on example polymers for ocular drug delivery.

[0052] Methods and Applications

[0053] This invention provides a method for treating lacrimal gland dysfunction-related dry eye syndrome, comprising administering to a subject a therapeutically effective amount of Areg, variants thereof, or a pharmaceutical composition thereof. This invention also provides the use of Areg or variants thereof in the preparation of medicaments for treating or preventing lacrimal gland dysfunction-related eye diseases.

[0054] In one or more embodiments, the lacrimal gland dysfunction type eye disease is an eye disease caused by lacrimal gland dysfunction or lack of fluid; preferably, the lacrimal gland dysfunction type eye disease is lacrimal gland dysfunction type dry eye syndrome; more preferably, streptozotocin-induced diabetic dry eye syndrome, scopolamine injection combined with dry environment-induced dry eye syndrome; more preferably, the scopolamine injection combined with dry environment-induced dry eye syndrome includes local lacrimal gland inflammation and lacrimal gland dysfunction.

[0055] In one or more embodiments, the treatment or prevention of lacrimal gland dysfunction-related eye disease includes: increasing tear secretion, increasing tear weight, increasing the number of conjunctival goblet cells, and / or relieving dry eye symptoms; preferably, the dry eye symptoms include dry eyes, foreign body sensation in the eyes, blurred vision, and congestion of the ocular surface.

[0056] Therefore, the present invention also provides the use of Areg or variants thereof in the preparation of one or more medicines selected from: (1) medicines that increase tear secretion; (2) medicines that increase tear weight; (3) medicines that increase the number of conjunctival goblet cells; (4) medicines that relieve dry eye syndrome; and (5) medicines that improve lacrimal gland function. In one or more embodiments, the dry eye syndrome includes dry eye, foreign body sensation in the eye, blurred vision, and congestion of the ocular surface.

[0057] The treatment described in this article is usually topical administration, such as applying it to the eye via the subconjunctival, intraocular, vitreous, subocular, subretinal, subchoroidal, or suprachoroidal routes, or to the conjunctival sac or eyelid.

[0058] As used herein, “treatment” includes any beneficial or desired effect on the symptoms or lesions of a disease or pathological condition, and may include symptoms of a disease or condition under treatment, particularly those of lacrimal gland dysfunction-related dry eye, including but not limited to decreased tear production, damage to lacrimal gland tissue structures (e.g., ducts and acini), lacrimal gland inflammation, and lacrimal gland lymphocyte infiltration. Treatment may optionally include a reduction or relief of symptoms of a disease or condition, or a delay in the progression of a disease or condition. “Treatment” does not necessarily mean the complete eradication or cure of a disease or condition or its associated symptoms. As used herein, “treatment” for a disease in a subject means (1) suppressing or preventing the development of lacrimal gland dysfunction-related dry eye; or (2) improving or causing the resolution of symptoms of lacrimal gland dysfunction-related dry eye. As understood in the art, “treatment” is a method for obtaining a beneficial or desired outcome, including clinical outcomes. Beneficial or desired outcomes may include, but are not limited to, relief or improvement of one or more symptoms, whether detectable or undetectable, reduction of the severity of symptoms (including disease), stabilization (i.e., non-worsening) of symptoms (including disease), delay or slowing of the progression of symptoms (including disease), improvement or relief of symptoms (including disease), status, and remission (whether partial or complete).

[0059] The "subject" or "patient" in the treatment can be an animal, especially a mammal, such as a human, mouse, rat, dog, monkey, cow, horse, etc. Subjects are not limited to a specific species, including non-human animals receiving diagnosis or treatment and those receiving infection or animal models, including but not limited to mouse, rat, ape, dog, or rabbit species, as well as other livestock, locomotor animals, or pets. In some embodiments, the subject or patient is a human.

[0060] The term "effective amount" as used herein is intended to mean an amount sufficient to achieve the desired effect. In the case of therapeutic or preventative application, the effective amount will depend on the type and severity of the condition in question and the characteristics of the individual subject or patient, such as general health, age, sex, weight, and tolerance to the pharmaceutical composition. In some embodiments, when Areg or its variants are administered, the effective amount is sufficient to cause partial or complete restoration of function of the lacrimal glands in the subject or patient with dysfunction, or to maintain, prevent progression, reduce, improve, or alleviate symptoms of lacrimal gland dysfunction-related dry eye. In some embodiments, the effective amount also depends on the nature and sensitivity of the target subject and the method of administration. Those skilled in the art will be able to determine the effective amount based on these and other considerations. According to embodiments, the effective amount may include one or more administrations of the pharmaceutical composition, consist substantially of one or more administrations of the pharmaceutical composition, or consist of one or more administrations of the pharmaceutical composition.

[0061] As used herein, the term "administration" is intended to mean the delivery of a substance to a subject or patient, such as an animal or human. Administration can be performed at a single dose, continuously or intermittently, throughout the course of treatment. Methods for determining the most effective manner and dosage of administration are known to those skilled in the art and will vary depending on the pharmaceutical composition used for treatment, the purpose of treatment, and the age, health, or sex of the subject being treated. Administration can be performed as a single or multiple doses, with the dosage level and pattern chosen by the treating physician, or, in the case of pets and other animals, by the treating veterinarian. In some specific embodiments, the administration is ocular surface administration, such as intraconjunctival administration.

[0062] Methods for determining the most effective route of administration and dosage are known to those skilled in the art and will vary depending on the pharmaceutical composition used for treatment, the purpose of treatment, and the subject being treated. Single or multiple administrations may be performed, with the dosage level and mode chosen by the treating physician. The dosage may be affected by the route of administration. Suitable dosage formulations and methods of administering the reagents are known in the art. A non-limiting example of such a suitable dosage for mice is an administration of 10–100 μg / mL of a pharmaceutical composition containing Areg or a variant thereof, for example, 40 μg / mL. Converting mouse dosages to human dosages is readily performed by those skilled in the art, for example, by using the Meeh-Rubner formula: Meeh-Rubner formula: A=k×(W 2 / 3 ) / 10,000.

[0063] In the formula, A is the body surface area, expressed in meters. 2 Calculation; W is body weight, expressed in g; K is a constant that varies depending on the animal species: 9.1 for mice and rats, 9.8 for guinea pigs, 10.1 for rabbits, 9.9 for cats, 11.2 for dogs, 11.8 for monkeys, and 10.6 for humans.

[0064] The administration of the Areg, its variants, or pharmaceutical compositions of the present invention can be achieved at a single dose, continuously or intermittently, throughout the treatment process. In some embodiments, the Areg, its variants, or pharmaceutical compositions of the present invention are administered by instillation onto the ocular surface, such as intraconjunctival sac of the eyelid. In some embodiments, the Areg, its variants, or pharmaceutical compositions of the present invention are administered at a frequency of 1 to 2 drops each time, 2 to 5 times daily, with intervals of 3 to 6 hours. In some preferred embodiments, the Areg, its variants, or pharmaceutical compositions of the present invention are administered at a frequency of 1 drop each time, 4 times daily, with intervals of 4 hours.

[0065] The Areg, its variants, and pharmaceutical compositions of the present invention can also be administered in combination with other known drugs and treatments.

[0066] The present invention also provides a method for preparing a medicament for treating or preventing lacrimal gland dysfunction-related eye diseases, the method comprising the step of mixing Areg or a variant thereof as an active ingredient as described in any embodiment of the present invention with a pharmaceutically acceptable carrier and preparing the medicament. In one or more embodiments, the pharmaceutically acceptable carrier is as described in any embodiment of the present invention. In one or more embodiments, the lacrimal gland dysfunction-related eye disease, or the treatment or prevention of lacrimal gland dysfunction-related eye diseases, is as described in any embodiment of the present invention.

[0067] medicine box

[0068] The present invention also provides a medicine box for treating lacrimal gland dysfunction-type dry eye syndrome, wherein the medicine box contains the Areg of the present invention, its variants or pharmaceutical compositions thereof.

[0069] In the pillbox of this invention, the Areg, its variants, or pharmaceutical compositions thereof can be placed in the same container as a pharmaceutically acceptable carrier, or they can be placed in separate containers. In some embodiments, the pillbox comprises: container 1 containing the Areg or its variants, and container 2 containing a pharmaceutically acceptable carrier. Prior to use, the substances in container 1 and container 2 are mixed together to formulate a pharmaceutical composition, which is then administered to the subject.

[0070] The medicine box of the present invention may also contain other known drugs for treating dry eye syndrome, such as, but not limited to: artificial tears, eye drops, ocular serum preparations, and drugs for treating ocular surface inflammation (including tetracyclines, glucocorticoids, nonsteroidal anti-inflammatory drugs, and immunosuppressants). The drugs may be placed in the same container within the medicine box, or they may be placed in separate containers.

[0071] In addition, the medicine box may also contain some auxiliary medication materials.

[0072] In addition, the medicine box may also contain instructions for use, explaining the method of treating lacrimal gland dysfunction-type dry eye syndrome.

[0073] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0074] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0075] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0076] In this example, Areg was purchased from Wuhan Yunclone (RPA006Mu01).

[0077] Areg's amino acid sequence (SEQ ID NO:1): SVRVEQVIKPKKKNTEGEKSTEKPKRKKKGKNGKGRRNKKKKNPCTAKFQNFCIHGECRYIENLEVVTCNCHQDYFGERCGEKSMKTHSEDDKDLSK.

[0078] The experimental animals used and their housing conditions are as follows in the following examples: Laboratory animals: C57Bl / 6JNifdc, male, 20-25g, purchased from the Experimental Animal Center of Tianjin Medical University, and housed in the clean-grade animal room of the Experimental Animal Center of Tianjin Medical University, with a temperature of 21℃-25℃, relative humidity of 30%-60%, 12-hour light cycle, and provided with sufficient food and water.

[0079] Example 1: Preparation and Use of Areg Eye Drops

[0080] In this embodiment, an eye drop containing Areg was prepared, which consists of Areg and phosphate buffer.

[0081] Preparation method of Areg eye drops: Dissolve Areg in phosphate buffer, adjust the pH to 7.2-7.4, and adjust the Areg concentration to 40 μg / mL. Filter the solution through a 0.22 μm microporous membrane for sterilization to obtain Areg eye drops.

[0082] Preparation method of solvent eye drops: Use phosphate buffer to adjust the pH to 7.2-7.4, filter and sterilize with a 0.22μm microporous membrane to obtain solvent eye drops.

[0083] Instructions for using Areg eye drops: Remove the cap from the Areg eye drop bottle, without touching the opening, and place the bottle with the inside of the cap facing up on a clean table. With your other hand, hold the Areg eye drop bottle and squeeze out one drop of eye drops, then drop it into the conjunctival sac of the mouse's lower eyelid. First, drop into the right eye, then the left eye. Gently close both eyelids of the mouse several times to allow the eye drops to spread fully. Release the mouse and observe the eye drop's presence on the ocular surface for two minutes before returning it to its cage.

[0084] Example 2: Safety assessment of Areg eye drops for ocular surface application

[0085] This embodiment evaluates the safety of Areg eye drops for use on the ocular surface.

[0086] Grouping and treatment of experimental animals: Eight wild-type male C57Bl / 6JNifdc mice, weighing 20-25 grams, were randomly divided into two groups and subjected to the following treatments: 1. Solvent control group: Equal volume of solvent eye drops, applied to the eyes; 2. Areg eye drop administration group: One drop of the prepared 40 μg / mL Areg eye drops was administered four times daily, with a four-hour interval between each administration. The Areg eye drops were prepared fresh on the day of use, and observation was conducted after seven days of administration.

[0087] After the above treatment, mice in each group were anesthetized by intraperitoneal injection of afodin (0.2 mL / 10 g), and 2 μL of 1% sodium fluorescein (purchased from Solarbio, catalog number F8140) was dripped into the lateral conjunctival sac of the mice. Three minutes later, the corneal epithelial staining was observed under cobalt blue light using a slit-lamp microscope, and photographs were taken using a slit-lamp imaging system.

[0088] Figure 1 Figure A shows the corneal epithelial staining in each group of mice, indicating that neither group showed any staining of the corneal epithelium; both groups exhibited intact, unstained corneal epithelium. This result suggests that there was no significant difference in corneal epithelial staining between the Areg eye drop group and the solvent control group.

[0089] Mice were euthanized by cervical dislocation, and the orbits were surgically removed. After fixation in 4% paraformaldehyde for at least 24 hours, the orbitals were embedded in paraffin and sectioned at 4 μm using a paraffin microtome. The sections were dewaxed and stained with a PAS staining kit (Solarbio, catalog number G1281). The morphology of the conjunctival sac and goblet cells was observed and photographed using an optical microscope.

[0090] Figure 1 Figure B shows the PAS staining results of orbital sections of mice in each group. It shows that the conjunctival goblet cells in the Areg eye drop group were stained purple-red and were evenly distributed in the conjunctival sacs of the palpebral and ocular conjunctiva. They were round and plump, and there was no significant change in morphology and number compared with the solvent group.

[0091] Mice were euthanized by cervical dislocation, and their lacrimal glands were harvested and fixed in 4% paraformaldehyde for at least 24 hours. The samples were washed, dehydrated in ethanol solutions of increasing concentrations, and cleared in xylene for 2 hours after a final wash with anhydrous ethanol. The samples were then immersed in soft paraffin at 59°C and hard paraffin at 63°C, respectively, and finally embedded. Sections were prepared at 5 μm using a paraffin microtome and stained with hematoxylin and eosin (Solarbio, catalog number G1120) for morphological examination. The morphology of the lacrimal glands was observed and photographed using an optical microscope.

[0092] Figure 1 Figure C shows the H&E staining results of lacrimal gland sections from each group of mice. It shows that the acinar and ductal epithelial cells in the Areg eye drop group are intact and regularly arranged, with no obvious inflammatory cell infiltration. Compared with the solvent group, the mice showed no significant changes in structure and morphology.

[0093] The above results indicate that Areg eye drops have no significant toxicity to the cornea, conjunctiva, lacrimal glands, and other tissues, and have a high safety profile when applied to the ocular surface.

[0094] Example 3: The effect of Areg eye drops on tear secretion when applied to the ocular surface

[0095] Grouping and treatment of experimental animals: Eight wild-type male C57Bl / 6JNifdc mice, weighing 20-25 grams, were randomly divided into two groups and subjected to the following treatments: 1. Solvent control group: treated with an equal amount of solvent as eye drops; 2. Areg eye drops administration group: The 40 μg / mL Areg eye drops prepared in Example 1 were used, 1 drop each time, 4 times a day, with an interval of 4 hours between drops. The Areg eye drops were prepared fresh on the day of use, and the patients were observed after 7 days of administration.

[0096] After the above treatment, the lower eyelids of the mice in each group were gently pulled back, and one end of a phenol red cotton thread was placed in the lateral conjunctival sac of the mouse's eye. The absorption of tears would cause the cotton thread to turn from yellow to red, thus reflecting the amount of tear secretion. After 30 seconds, the cotton thread was removed, and the length of the reddened portion was measured and recorded. This was repeated three times for each eye, and the average value of the measurements from both eyes was taken as the tear secretion flow rate. A higher tear secretion flow rate indicates better lacrimal gland function.

[0097] Figure 2 In the diagram, A represents the experimental protocol for administering Areg eye drops to mice; Figure 2 Figure B is a statistical graph of the results of the phenol red cotton thread experiment, which shows that compared with the mice in the solvent control group, the mice in the Areg eye drops application group had a significantly increased tear secretion. Figure 2 Figure C is a statistical graph showing the results of the lacrimal gland weighing experiment. It shows that compared with the mice in the solvent control group, the mice in the Areg eye drops administration group had a significantly increased lacrimal gland weight.

[0098] The above results indicate that Areg eye drops can improve tear secretion in mice.

[0099] Example 4: Evaluation of the efficacy of Areg eye drops in diabetic dry eye

[0100] Grouping and treatment of experimental animals: Eighteen wild-type C57Bl / 6JNifdc mice, female, weighing 20-25 grams, were divided into 3 groups and subjected to the following treatments: 1. Normal control group: Six male C57Bl / 6Jnifdc mice were used. After fasting for 4 hours with unlimited access to water, their body weight was measured and recorded. The mice were given the same amount of citrate buffer as the STZ model group via intraperitoneal injection once a day for 5 consecutive days. Starting from the first day after modeling, eye drops prepared with the solvent were used, one drop each time, applied 4 times a day at 4-hour intervals. Changes in tear secretion were observed after 1 week, 2 weeks, and 3 weeks of administration. In the third week, samples were taken for lacrimal gland weighing and PAS staining of conjunctival goblet cells. 2. STZ Model Group: Six male C57Bl / 6Jnifdc mice were used. After fasting for 4 hours with unlimited access to water, their weight was measured and recorded. Streptozotocin (STZ) was dissolved in citrate buffer and the concentration was adjusted to 7.5 mg / mL. The mice were then injected intraperitoneally at a concentration of 50 mg / kg for 5 consecutive days. Two weeks later, fasting blood glucose was measured from the tail vein of the mice. A blood glucose level ≥16.7 mol / L indicated successful modeling. Starting from the first day after modeling, eye drops prepared with the solvent were used, one drop each time, four times a day, with an interval of 4 hours between each dose. Changes in tear secretion were observed one, two, and three weeks after administration. In the third week, samples were collected for lacrimal gland weighing and PAS staining of conjunctival goblet cells. 3. STZ modeling combined with Areg eye drops: Six male C57Bl / 6Jnifdc mice were used. After fasting for 4 hours with unlimited access to water, their weight was measured and recorded. Streptozotocin (STZ) was dissolved in citrate buffer and the concentration was adjusted to 7.5 mg / mL. The mice were intraperitoneally injected at a concentration of 50 mg / kg for 5 consecutive days. Two weeks later, fasting blood glucose was measured from the tail vein of the mice. A blood glucose value ≥16.7 mol / L indicated successful modeling. Starting from the first day after modeling, 40 μg / mL Areg eye drops prepared in Example 1 were used, 1 drop each time, 4 times a day, with an interval of 4 hours between each time. The Areg eye drops were prepared fresh on the day of use. Changes in tear secretion were observed 1 week, 2 weeks and 3 weeks after administration. In the third week, samples were taken for lacrimal gland weighing and PAS staining of conjunctival goblet cells. The results are as follows Figure 3 As shown in Figure A, which illustrates the protocol for administering Areg eye drops to diabetic dry eye mouse models, Figure B shows the statistical results of the phenol red cotton thread experiment. Figure A shows that compared to the control mice, STZ mice exhibited significantly reduced tear secretion, while the STZ-based combined Areg eye drop group showed a significantly increased tear secretion compared to STZ mice. Figure C shows the statistical results of the lacrimal gland weighing experiment. Figure C shows that compared to the control mice, STZ mice showed a significantly reduced lacrimal gland weight after the third week of modeling, indicating severe lacrimal gland atrophy. Conversely, the STZ-based combined Areg eye drop group showed a significantly increased lacrimal gland weight compared to STZ mice, indicating a reduced degree of lacrimal gland atrophy. Figure D shows representative PAS staining of conjunctival goblet cells in each group; Figure E shows a statistical chart of PAS staining of conjunctival goblet cells, which shows that: compared with the control mice, the number of conjunctival goblet cells in STZ mice did not change significantly after the third week of modeling (PAS-positive cells are generally used to indicate conjunctival goblet cells; the fewer the number of conjunctival goblet cells, the worse the effect on stabilizing the tear film, that is, the stability of the tear film is positively correlated with the number of PAS-positive cells). The number of conjunctival goblet cells in the STZ modeling combined with Areg eye drops group did not change significantly compared with STZ mice and control mice.

[0101] The above results indicate that treating diabetic dry eye model mice with Areg eye drops can increase tear secretion and lacrimal gland weight, thereby alleviating dry eye symptoms.

[0102] Example 5: Evaluation of the efficacy of Areg eye drops in a dry eye model induced by scopolamine injection combined with a dry environment.

[0103] Grouping and treatment of experimental animals: Twelve wild-type male C57Bl / 6JNifdc mice, weighing 20-25 grams, were divided into three groups and subjected to the following treatments: 1. Normal control group: Four male C57Bl / 6Jnifdc mice were kept in a dry environment (humidity below 30%). Starting from the first day, they were given the solvent eye drops prepared in Example 1, one drop each time, four times a day at 4-hour intervals. The changes in tear secretion were observed on the 1st, 3rd, 5th and 7th days after administration, and samples were taken on the seventh day for PAS staining of conjunctival goblet cells. 2. Scopolamine model group: Four male C57Bl / 6Jnifdc mice were kept in a dry environment (humidity below 30%). Scopolamine (purchased from GLPBIO, catalog number GN10766) was dissolved in PBS and the concentration was adjusted to 2.5 mg / ml. At three time points each day, 9:00 AM, 3:00 PM, and 9:00 PM, for 7 consecutive days, 200 μl of scopolamine solution was injected subcutaneously into the back of the mice at each time point. At the same time, the solvent eye drops prepared in Example 1 were used from the first day, 1 drop each time, 4 times a day, with an interval of 4 hours each time. The changes in tear secretion were observed on the 1st, 3rd, 5th, and 7th days after administration, and PAS staining of conjunctival goblet cells was performed on the 7th day. 3. Scopolamine modeling combined with Areg eye drops: Four male C57Bl / 6Jnifdc mice were kept in a dry environment (humidity below 30%). Scopolamine (purchased from GLPBIO, catalog number GN10766) was dissolved in PBS and the concentration was adjusted to 2.5 mg / ml. At three time points each day, 9:00 AM, 3:00 PM, and 9:00 PM, for 7 consecutive days, 200 μl of scopolamine solution was injected subcutaneously into the back of the mice at each time point. At the same time, starting from the first day, 40 μg / mL Areg eye drops prepared in Example 1 were used, 1 drop each time, 4 times a day, with an interval of 4 hours each time. Changes in tear secretion were observed on days 1, 3, 5, and 7 after administration, and PAS staining of conjunctival goblet cells was performed on the seventh day. The results are as follows Figure 4As shown in Figure A, which illustrates the protocol for scopolamine modeling combined with Areg eye drops, and Figure B, which presents a statistical chart of the phenol red cotton thread experiment results, shows that compared to the control mice, the tear secretion of scopolamine-induced mice was significantly reduced from day one, while the tear secretion of the scopolamine-induced mice combined with Areg treatment group increased from day one compared to the scopolamine-induced mice, continuing until day seven. Figure C shows representative PAS staining of conjunctival goblet cells in each group; Figure D shows a statistical chart of PAS staining of conjunctival goblet cells, which shows that compared with control mice, the number of conjunctival goblet cells in scopolamine-induced model mice was significantly reduced on the seventh day after modeling (PAS-positive cells are generally used to indicate conjunctival goblet cells; the fewer the number of conjunctival goblet cells, the worse their effect on stabilizing the tear film, that is, the stability of the tear film is positively correlated with the number of PAS-positive cells). The number of conjunctival goblet cells in the scopolamine-induced model combined with Areg eye drops group was significantly increased compared with the scopolamine-induced model mice.

[0104] The above results indicate that treating scopolamine dry eye model mice with Areg eye drops can increase tear secretion and the number of conjunctival goblet cells, thereby alleviating dry eye symptoms.

[0105] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims. Furthermore, all documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference.

Claims

1. The use of Areg in the preparation of drugs for the treatment or prevention of lacrimal gland dysfunction-related eye diseases.

2. The application as described in claim 1, characterized in that, The Areg is the protein shown in SEQ ID NO:

1.

3. The application as described in claim 1 or 2, characterized in that, The aforementioned lacrimal gland dysfunction type of eye disease is an eye disease caused by lacrimal gland dysfunction or lack of fluid.

4. The application as described in claim 3, characterized in that, The lacrimal gland dysfunction type of eye disease is lacrimal gland dysfunction type of dry eye syndrome.

5. The application as described in claim 4, characterized in that, The lacrimal gland dysfunction-related dry eye syndrome includes streptozotocin-induced diabetic dry eye syndrome and scopolamine injection combined with a dry environment-induced dry eye syndrome.

6. The application as described in claim 5, characterized in that, The dry eye syndrome induced by scopolamine injection combined with a dry environment includes local lacrimal gland inflammation and lacrimal gland dysfunction.

7. The application as described in claim 1 or 2, characterized in that, The treatment or prevention of lacrimal gland dysfunction includes: increasing tear production, increasing tear weight, increasing the number of conjunctival goblet cells, relieving dry eye symptoms, and / or improving lacrimal gland function.

8. The application as described in claim 7, characterized in that, The symptoms of dry eye include dryness of the eyes, a foreign body sensation in the eyes, blurred vision, and bloodshot eyes.

9. A pharmaceutical composition for treating or preventing lacrimal gland dysfunction-related eye diseases, characterized in that, The pharmaceutical composition contains a therapeutically effective amount of Areg, as well as a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, characterized in that, Lacrimal gland dysfunction ophthalmopathy is an eye disease caused by lacrimal gland dysfunction or lack of fluid.

11. The pharmaceutical composition of claim 10, characterized in that, The lacrimal gland dysfunction type of eye disease is lacrimal gland dysfunction type of dry eye syndrome.

12. The pharmaceutical composition according to claim 11, characterized in that, The lacrimal gland dysfunction-related dry eye syndrome includes streptozotocin-induced diabetic dry eye syndrome and scopolamine injection combined with a dry environment-induced dry eye syndrome.

13. The pharmaceutical composition according to claim 12, characterized in that, The dry eye syndrome induced by scopolamine injection combined with a dry environment includes local lacrimal gland inflammation and lacrimal gland dysfunction.

14. The pharmaceutical composition according to claim 9, characterized in that, The treatment or prevention of lacrimal gland dysfunction includes: increasing tear production, increasing tear weight, increasing the number of conjunctival goblet cells, relieving dry eye symptoms, and / or improving lacrimal gland function.

15. The pharmaceutical composition according to claim 14, characterized in that, The symptoms of dry eye include dryness of the eyes, a foreign body sensation in the eyes, blurred vision, and bloodshot eyes.

16. The pharmaceutical composition according to claim 9, characterized in that, The Areg is the protein shown in SEQ ID NO:

1.

17. The pharmaceutical composition according to any one of claims 9-15, characterized in that, Pharmaceutically acceptable carriers include ophthalmologically acceptable salts.

18. The pharmaceutical composition of claim 17, characterized in that, The ophthalmologically acceptable salts include salts containing one or more cations selected from sodium, potassium, and ammonium, and one or more anions selected from chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, and bisulfite.

19. The pharmaceutical composition according to any one of claims 9-15, characterized in that, The pharmaceutical composition is applied topically under the conjunctiva, in the anterior chamber, in the vitreous body, under the eyeball, under the retina, under the choroid, on the choroid, in the conjunctival sac, or on the eyelid.

20. The pharmaceutical composition according to any one of claims 9-15, characterized in that, The drug composition is administered at a frequency of 1-2 drops each time, 2-5 times a day, with an interval of 3-6 hours between each application.

21. The pharmaceutical composition of claim 20, characterized in that, The drug composition is administered at a frequency of 1 drop each time, 4 times a day, with an interval of 4 hours between each application.

22. A medicine box for treating or preventing lacrimal gland dysfunction-related eye diseases, characterized in that, The kit contains Areg, or contains the pharmaceutical composition of any one of claims 9-21, wherein the Areg is the protein shown in SEQ ID NO:

1.

23. The medicine box as described in claim 22, characterized in that, Lacrimal gland dysfunction ophthalmopathy is an eye disease caused by lacrimal gland dysfunction or lack of fluid.

24. The medicine box as described in claim 23, characterized in that, The lacrimal gland dysfunction type of eye disease is lacrimal gland dysfunction type of dry eye syndrome.

25. The medicine box as described in claim 24, characterized in that, The lacrimal gland dysfunction-related dry eye syndrome includes streptozotocin-induced diabetic dry eye syndrome and scopolamine injection combined with a dry environment-induced dry eye syndrome.

26. The medicine box as described in claim 25, characterized in that, The dry eye syndrome induced by scopolamine injection combined with a dry environment includes local lacrimal gland inflammation and lacrimal gland dysfunction.

27. The medicine box as described in claim 22, characterized in that, The treatment or prevention of lacrimal gland dysfunction includes: increasing tear production, increasing tear weight, increasing the number of conjunctival goblet cells, relieving dry eye symptoms, and / or improving lacrimal gland function.

28. The medicine box as described in claim 27, characterized in that, The symptoms of dry eye include dryness of the eyes, a foreign body sensation in the eyes, blurred vision, and bloodshot eyes.

29. A method for preparing a medicament for treating or preventing lacrimal gland dysfunction-related eye diseases, characterized in that, The method includes the step of mixing Areg as an active ingredient with a pharmaceutically acceptable carrier and preparing a drug, wherein the Areg is the protein shown in SEQ ID NO:

1.

30. The method as described in claim 29, characterized in that, Pharmaceutically acceptable carriers include ophthalmologically acceptable salts.

31. The method as described in claim 30, characterized in that, The ophthalmologically acceptable salts include salts containing one or more cations selected from sodium, potassium, and ammonium, and one or more anions selected from chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, and bisulfite.

32. The method according to any one of claims 29-31, characterized in that, Lacrimal gland dysfunction ophthalmopathy is an eye disease caused by lacrimal gland dysfunction or lack of fluid.

33. The method as described in claim 32, characterized in that, The lacrimal gland dysfunction type of eye disease is lacrimal gland dysfunction type of dry eye syndrome.

34. The method as described in claim 33, characterized in that, The lacrimal gland dysfunction-related dry eye syndrome includes streptozotocin-induced diabetic dry eye syndrome and scopolamine injection combined with a dry environment-induced dry eye syndrome.

35. The method as described in claim 34, characterized in that, The dry eye syndrome induced by scopolamine injection combined with a dry environment includes local lacrimal gland inflammation and lacrimal gland dysfunction.

36. The method as described in claim 29, characterized in that, The treatment or prevention of lacrimal gland dysfunction includes: increasing tear production, increasing tear weight, increasing the number of conjunctival goblet cells, relieving dry eye symptoms, and / or improving lacrimal gland function.

37. The method as described in claim 36, characterized in that, The symptoms of dry eye include dryness of the eyes, a foreign body sensation in the eyes, blurred vision, and bloodshot eyes.

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