Composition, method and formulation for ophthalmic application

Abstract

This document relates to compositions, methods, and formulations for evaluating and / or treating subjects (e.g., humans) having ophthalmic diseases, disorders, and pathological conditions. For example, the methods and compositions disclosed herein include ophthalmic pharmaceutical compositions comprising L-alanyl-L-glutamine suitable for the eye.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] The present application claims priority to U.S. patent application serial number 63 / 604,809 filed November 30, 2023; U.S. patent application serial number 63 / 604,817 filed November 30, 2023; and U.S. patent application serial number 63 / 604,819 filed November 30, 2023, each of which is incorporated herein by reference in its entirety.

[0003] Technology field

[0004] The present disclosure falls within the technical field of ophthalmic drugs, and specifically relates to peptides and pharmaceutical compositions containing the same, and ophthalmic applications thereof in the manufacture of ophthalmic drugs for the reduction, improvement, and / or treatment of ophthalmic diseases and symptoms associated with ophthalmic diseases. Background Technology

[0005] background

[0006] Ophthalmic diseases, disorders, and conditions may include symptoms or discomfort related to the cornea, conjunctiva, and tear film. Ophthalmic diseases, disorders, and conditions include, but are not limited to, infectious eye diseases caused by bacteria (e.g., Chlamydia sp.), viruses, fungi, and other pathogens; non-infectious eye diseases include ocular surface diseases such as dry eye, allergic keratoconjunctivitis, autoimmune or inflammatory eye diseases, ocular surgery and trauma, and damage to the ocular surface (e.g., anterior and posterior).

[0007] summation

[0008] Treatment of ophthalmic diseases, disorders, and conditions may include lifestyle management and medicine. An ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine, which is a peptide (e.g., a dipeptide), a method of preparing the same, a method of treatment, and a method of use for treating, alleviating, and improving symptoms of ophthalmic diseases, disorders, and conditions, including ocular surface symptoms, are disclosed herein.

[0009] Dipeptides, such as L-alanyl-L-glutamine, are compounds formed by linking two amino acids—alanine and glutamine—through peptide bonds. This structure is fundamentally different from that of a single amino acid. When applied to complex structures like the eye, this difference is impactful. The ocular environment is a complex system with specific structural considerations, such as the blood-eye barrier, that influence how compounds are delivered and interact with eye tissues. Dipeptides and individual amino acids will interact differently with these structures due to their distinct characteristics.

[0010] For example, L-alanyl-L-glutamine has different solubility, polarity, charge distribution, and metabolic pathways compared to alanine alone or glutamine alone. Its larger size and larger molecular weight affect how it is absorbed, distributed, metabolized, and excreted by the body. These factors collectively affect the bioavailability of the dipeptide and how the dipeptide is distributed within ocular tissues.

[0011] In contrast, individual amino acids are likely to interact differently with ocular tissues due to their smaller size and distinct chemical properties, and are unlikely to produce the same pharmacological effects as dipeptides. Particularly when studying the pharmacological activity of peptides such as L-alanyl-L-glutamine in complex environments like the eye, their behavior cannot be assumed to be identical to that of individual amino acids. Since each possesses unique characteristics and interacts differently with biological systems, a separate, specific approach is required for their study.

[0012] One aspect of this document features a composition, method, and formulation of an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine, which is a peptide (e.g., a dipeptide). In some exemplary embodiments, the composition may comprise, or essentially consist of, an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine suitable for the eye. In some embodiments, the ophthalmic composition is in the form of eye drops, suspensions, ointments, emulsions, eye patches, eye masks, eye films, eye creams, sprays, gels, injections, or implants. In some embodiments, the concentration of L-alanyl-L-glutamine is about 0.2% to about 0.8% (w / v) of the composition. In some embodiments, the concentration of L-alanyl-L-glutamine is about 1.8% to about 2.2% (w / v) of the composition. In some embodiments, the concentration of L-alanyl-L-glutamine is about 0.5% (w / v) of the composition. In some embodiments, the concentration of L-alanyl-L-glutamine is about 1.0% (w / v) of the composition. In some embodiments, the concentration of L-alanyl-L-glutamine is about 2.0% (w / v) of the composition.

[0013] In some embodiments, the pharmaceutical composition further comprises a bacteriostatic agent or an antimicrobial agent. For example, the bacteriostatic agent or antimicrobial agent comprises one or more of benzalkonium chloride, benzalkonium bromide, chlorhexidine acetate, chlorhexidine gluconate, chlorobutanol, phenoxyethyl alcohol, methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, and combinations thereof. For example, the concentration of the bacteriostatic agent or antimicrobial agent is about 0.003 to about 0.5% (w / v) of the composition. In some embodiments, the pharmaceutical composition further comprises a viscosity modifier. For example, the viscosity modifier comprises one or more of sodium hyaluronate, sodium carboxymethyl cellulose, methyl cellulose, polyethylene glycol, polyvinyl alcohol, povidone, and combinations thereof. For example, the concentration of the viscosity modifier is about 0.01% to about 0.5% (w / v) of the composition.

[0014] In some embodiments, the pharmaceutical composition further comprises one or more pH adjusters. For example, the pH adjuster comprises one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, boric acid, borax, acetic acid, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, hydrochloric acid, phosphoric acid, and combinations thereof. For example, the pH of the pharmaceutical composition is about 5.0 to about 9.0.

[0015] In some exemplary embodiments, the method provided herein may comprise, or essentially comprise, preparing the pharmaceutical composition disclosed herein, wherein the method comprises the steps of: suspending or dissolving L-alanyl-L-glutamine in water to form an aqueous solution; adjusting the pH to about 5.0 to about 9.0; and filtering the resulting solution through a microporous filter membrane for sterilization. In other embodiments, the method provided herein may comprise, or essentially comprise, reducing, alleviating, and treating ocular surface symptoms and discomfort in a subject in need, wherein the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to a subject.

[0016] In some embodiments, the method provided herein may include, or essentially consist of, alleviating, improving, and treating ocular surface symptoms caused by ocular surface disease in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0017] In some embodiments, the method provided herein may include, or essentially consist of, alleviating, improving, and treating ocular surface symptoms caused by non-ocular surface disease in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to a subject.

[0018] In some embodiments, the method provided herein may include, or essentially consist of, alleviating, improving, and treating ocular surface symptoms caused by dry eye disease in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0019] In some embodiments, the method provided herein may include, or essentially consist of, alleviating, improving, and treating ocular surface symptoms induced by allergy in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0020] In some embodiments, the method provided herein may include, or essentially consist of, alleviating, improving, and treating ocular surface symptoms caused by infection in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0021] In some embodiments, the method provided herein may include, or essentially consist of, alleviating, improving, and treating ocular surface symptoms caused by a neuropathic condition in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0022] In some embodiments, the method provided herein may include, or essentially consist of, alleviating, improving, and treating ocular surface symptoms caused by injury or surgery in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0023] In some embodiments, the method provided herein may include, or essentially consist of, alleviating, improving, and treating ocular surface symptoms caused by the wearing of a foreign body in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0024] In some embodiments, the method provided herein may include, or essentially consist of, alleviating, improving, and treating ocular surface symptoms caused by immune-mediated diseases or inflammatory conditions in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0025] In some embodiments, the method provided herein may include, or essentially consist of, alleviating, improving, and treating ocular surface symptoms induced by diabetes in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0026] In some embodiments, the method provided herein may include, or essentially consist of, alleviating, improving, and treating ocular surface symptoms induced by surgery-related factors in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0027] In some embodiments, the method provided herein may include, or essentially consist of, alleviating, improving, and treating ocular surface symptoms caused by meibomian gland disease in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject. For example, the ocular surface symptoms described herein may include one or more of dryness, burning sensation, gritty sensation, nystagmus, soreness, abnormally frequent blinking, eye fatigue, blurred vision, reduced tear production, pain, foreign body sensation, hyperemia, itching, photophobia (sensitivity to light), tearing, changes in goblet cell fusion, delayed epithelial tissue healing, reduced tear film stability, damage to ocular surface epithelium, impaired barrier function of corneal epithelium, reduced density of conjunctival goblet cells, squamous metaplasia of ocular surface epithelium, and / or ocular surface inflammation.

[0028] In some embodiments, the method provided herein may include, or essentially consist of, alleviating symptoms of dry eye disease in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0029] In some embodiments, the method provided herein may include, or essentially consist of, improving symptoms of dry eye disease in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0030] In some embodiments, the method provided herein may include, or essentially consist of, treating symptoms of dry eye disease in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0031] In some embodiments, the method provided herein may include, or essentially consist of, reducing ocular surface damage in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to a subject.

[0032] In some embodiments, the method provided herein may include, or essentially consist of, reducing corneal epithelial damage in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to a subject.

[0033] In some embodiments, the method provided herein may include, or essentially consist of, restoring ocular surface health in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0034] In some embodiments, the method provided herein may include, or essentially consist of, restoring the conjunctival epithelial condition in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0035] In some embodiments, the method provided herein may include, or essentially consist of, reducing conjunctival hyperemia in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to a subject.

[0036] In some embodiments, the method provided herein may include, or essentially consist of, restoring tear film stability in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0037] In some embodiments, the method provided herein may include, or essentially consist of, increasing the tear film breakup time (BUT) in a subject requiring it, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to a subject.

[0038] In some embodiments, the method provided herein may include, or essentially consist of, increasing goblet cells of the eye in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0039] In some embodiments, the method provided herein may include, or essentially consist of, increasing mucin production in the eye of a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0040] In some embodiments, the method provided herein may include, or essentially consist of, restoring or increasing the level of lymphotoxin-alpha in the tear film of a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0041] In some embodiments, the method provided herein may include, or essentially consist of, restoring ocular surface immune homeostasis in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0042] In some embodiments, the method provided herein may include, or essentially consist of, increasing tear secretion in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to a subject.

[0043] In some embodiments, the method provided herein may include, or essentially consist of, increasing goblet cells of the eye in a subject in need, and the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions disclosed herein to the subject.

[0044] In some embodiments, the method provided herein may include, or essentially consist of, steps for alleviating, improving, and treating symptoms of dry eye disease, including one or more of dryness, burning sensation, sandy sensation, nystagmus, stinging, abnormally frequent blinking, eye fatigue, blurred vision, reduced tear production, pain, foreign body sensation, redness, itching, photophobia (sensitivity to light), tearing, changes in goblet cell fusion, delayed epithelial tissue healing, reduced tear film stability, damage to ocular surface epithelium, damage to the barrier function of corneal epithelium, reduced density of conjunctival goblet cells, squamous metaplasia of ocular surface epithelium, and / or ocular surface inflammation.

[0045] As used herein, "one (a)," "an," "the," "at least one," and "more than one" are used interchangeably.

[0046] As used herein, the term “about” refers to a value that is contextually similar to the referenced value when used in relation to a value. Generally, a person skilled in the art familiar with the context will understand the relevant degree of variation encompassed by “about” in that context. For example, in some embodiments, the term “about” may include a range of values ​​within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% or less of the mentioned value.

[0047] The term "comprising" and its variations do not have a limited meaning when such terms appear in the description and claims.

[0048] The terms "treat" or "treating" are used herein to indicate delaying, preventing, suppressing, reducing the effects of, or reversing a disease or its symptoms in a subject.

[0049] The terms “therapeutic effective dose” and “effective dose” as used herein refer to an amount or concentration of the composition or treatment described herein used during an effective period (including acute or chronic administration and periodic or continuous administration) within the context of its administration to induce an intended effect or physiological result.

[0050] The term “subject” is used throughout the specification to describe an animal, human, or non-human to which treatment according to the method of the present disclosure is provided. Human and veterinary applications are anticipated by the present disclosure. The term includes, but is not limited to, birds, reptiles, amphibians, and mammals, e.g., humans, other primates, pigs, rodents, e.g., mice and rats, rabbits, guinea pigs, hamsters, horses, cattle, cats, dogs, sheep, chickens, and goats. In some embodiments, the subject is a human, a chicken, or a mouse. In some embodiments, the subject is a human. Both pediatric and adult subjects are included. For example, in any of the methods described herein, the subject is at least 6 months of age (e.g., 6 months of age or older, 12 months of age or older, 18 months of age or older, 2 years of age or older, 4 years of age or older, 6 years of age or older, 10 years of age or older, 13 years of age or older, 16 years of age or older, 18 years of age or older, 21 years of age or older, 25 years of age or older, 30 years of age or older, 35 years of age or older, 40 years of age or older, 45 years of age or older, 50 years of age or older, 60 years of age or older, 65 years of age or older, 70 years of age or older, 75 years of age or older, 80 years of age or older, 85 years of age or older, 90 years of age or older, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 18, 20, 21, 24, 25, 27, 28, 30, (May be 33, 35, 37, 39, 40, 42, 44, 45, 48, 50, 52, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, 100, 101, 102, 103, or 104 years of age or older).

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art to which this invention pertains. Methods and materials similar or identical to those described herein may be used to carry out the invention, but suitable methods and materials are described below. All disclosures, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, this specification, including definitions, shall prevail. Furthermore, materials, methods, and embodiments are illustrative only and are not intended to be limiting. Brief explanation of the drawing

[0052] Figure 1 shows an exemplary schematic diagram of a phase 2, multicenter, double-masking, randomized, vehicle-controlled, dose-response, parallel-group study designed to evaluate the ocular and systemic safety and ocular efficacy of an L-alanyl-L-glutamine ophthalmic solution over a treatment period of 60 days in subjects with moderate to severe DED. Figure 2 shows the change from baseline in total corneal fluorescein staining (tCFS), where the change from baseline was calculated on each visit day (days 7, 14, and 28). Figure 3 shows the change from baseline in dry eye sensation (VAS), where the change from baseline was calculated on each visit day (days 7, 14, and 28). Figure 4 shows the change from baseline in subjects with SANDE's DED symptom severity score in the subgroup (baseline tear MMP-9 > 31.6 ng / mL (1.5 on the Log 10 scale)). Figure 5 shows the change from baseline in subjects with dry eye sensation (VAS) in the subgroup (baseline tear MMP-9 > 31.6 ng / mL (1.5 on the Log 10 scale)). Figure 6 shows the change from baseline in subjects with central CFS in the subgroup (baseline tear MMP-9 > 31.6 ng / mL (1.5 on the Log 10 scale)). Figure 7 shows the change from baseline in subjects with a 0.5% L-alanyl-L-glutamine ophthalmic solution with tear MMP-9 > 31.6 ng / mL (1.5 on the Log 10 scale). Figure 8 shows the change from baseline in subjects with SANDE DED symptom severity scores in the subgroup having baseline Schirmer test scores ≤ 10 at baseline. Figure 9 shows the change from baseline in subjects with dry eyes (VAS) in the subgroup having a Schirmer test score ≤ 10 at baseline. Figure 10 shows the change from baseline in subjects with a central CFS in a subgroup having a Schirmer test score ≤ 10 at baseline. Figure 11 shows the change from baseline in a subject with a 0.5% SY-201 ophthalmic solution having a Schirmer test score ≤ 10 at baseline. Specific details for implementing the invention

[0053] Detailed description

[0054] Ophthalmic diseases, disorders, and conditions encompass various conditions affecting the eye. For example, ophthalmic diseases, disorders, and / or conditions include neuropathic conditions (e.g., diabetic neuropathy, trigeminal neuralgia, and peripheral neuropathy); diabetes (e.g., diabetic retinopathy, diabetic macular edema); ocular surface diseases, disorders, or conditions (Dry Eye Disease (DED), dry eye symptoms, trauma / injury, surgery, allergy-related conditions, infection, immune-related conditions, contact lens wear, foreign body interactions, neuropathic conditions, foreign bodies, immune-mediated diseases or inflammatory conditions, diabetes, meibomian gland disorders); surgery-related diseases, disorders, and / or conditions; injury; contact lens wear; chemical-induced ophthalmic diseases, disorders, or conditions; drug-induced ophthalmic diseases, disorders, or conditions; Corneal conditions (e.g., keratoconus, Fuchs' dystrophy, corneal dystrophy, pterygium), meibomian gland diseases, inflammatory conditions (e.g., anterior uveitis, posterior uveitis, scleritis, episcleritis, orbital cellulitis, sarcoidosis), orbital disorders (e.g., thyroid eye disease (Graves' ophthalmopathy), orbital tumor, orbital inflammation), and / or neuro-ophthalmic conditions (e.g., vascular disease, demyelinating disease (e.g., multiple sclerosis), tumor, trauma) may be included, but not limited thereto.

[0055] Ophthalmic diseases, disorders, and / or conditions can affect the surface of the eyeball. Many of the ophthalmic diseases, disorders, and conditions listed above can cause ocular surface symptoms. For example, non-limiting examples of the ophthalmic diseases, disorders, and conditions listed above that can cause ocular surface symptoms include dry eye disease (DED), dry eye symptoms, trauma / injury, surgery, allergy-related conditions, infection, immune-related conditions, contact lens wear, foreign body interactions, neuropathic conditions, foreign bodies, immune-mediated or inflammatory conditions, diabetes, and / or meibomian gland disorders.

[0056] DED is characterized by inadequate tear production or poor tear quality, leading to ocular surface discomfort and potential visual impairment. Conjunctivitis, commonly known as pink eye, involves inflammation of the conjunctiva and can be triggered by infection, allergies, or irritants. Corneal dystrophy, a group of genetic disorders, affects corneal transparency and health and often causes visual distortion. Blepharitis, involving inflammation of the eyelid margins, causes irritation and can contribute to ocular surface symptoms. Pterygium, characterized by the growth of flesh-like tissue on the white of the eye, can potentially invade the cornea, affect vision, and cause ocular surface symptoms.

[0057] Additionally, conditions such as contact lens-related disorders and various forms of trauma can disrupt the delicate balance of the ocular surface, leading to discomfort and, in some cases, more severe vision problems. These range from infections and inflammations involving the cornea, such as keratitis, often caused by various microorganisms, to autoimmune disorders like Sjögren's syndrome, which lead to ocular surface symptoms. Some individuals may experience ocular herpes, a viral condition that can lead to recurrent inflammation and potential corneal scarring. In the case of chemical exposure, the eyes can suffer chemical burns, resulting in acute injury and discomfort. Furthermore, severe skin reactions, such as Stevens-Johnson syndrome, can extend their effects to the eyes, leading to ocular surface symptoms.

[0058] Ophthalmic diseases, disorders, and / or conditions may include symptoms and discomfort on the surface of the eyeball. Symptoms and / or discomfort affecting the surface of the eyeball may include, but are not limited to, dryness, burning sensation, gritty sensation, nystagmus, soreness, abnormally frequent blinking, eye fatigue, blurred vision, decreased tear production, pain, foreign body sensation, redness, itching, photophobia (sensitivity to light), tearing, changes in goblet cell fusion, delayed epithelial tissue healing, decreased tear film stability, damage to the ocular surface epithelium, impaired barrier function of the corneal epithelium, decreased density of conjunctival goblet cells, squamous metaplasia of the ocular surface epithelium, and / or inflammation of the ocular surface.

[0059] Symptoms affecting the surface of the eye impact daily activities and tasks such as reading, computer use, contact lens use, watching television, and driving, and can cause long-term ocular discomfort, which can severely impair the quality of life. Severe dry eye syndrome can cause keratitis, corneal neovascularization, corneal ulcers, and visual impairment that may lead to blindness. The onset and development of dry eye syndrome are influenced by multiple factors. Some examples of risk factors include age, gender, meibomian gland dysfunction, race, contact lens use, hematopoietic stem cell transplantation, air pollution, digital screen use, vitamin A deficiency, diet, refractive surgery, diabetes, psychological factors, genetic factors, systemic diseases, and medication.

[0060] Dry eye disorders (e.g., DED) may develop as a result of one or more ophthalmic diseases, disorders, and conditions through different mechanisms involving inflammation, physical changes in the eye, or autoimmune responses, which may lead to the development or exacerbation of dry eye disease. Symptoms of dry eye may include, but are not limited to, dryness, burning sensation, gritty sensation, nystagmus, soreness, abnormally frequent blinking, eye fatigue, blurred vision, decreased tear production, pain, foreign body sensation, redness, itching, photophobia (sensitivity to light), tearing, changes in goblet cell fusion, delayed epithelial tissue healing, decreased tear film stability, damage to the ocular surface epithelium, impaired barrier function of the corneal epithelium, decreased density of conjunctival goblet cells, squamous metaplasia of the ocular surface epithelium, and / or ocular surface inflammation.

[0061] Accordingly, the present invention discloses an ophthalmic pharmaceutical composition comprising a dipeptide (e.g., L-alanyl-L-glutamine), a method for preparing the same, a method for treatment, and a method for use for treating, alleviating, or improving symptoms of ophthalmic diseases, disorders, and pathological conditions.

[0062] composition

[0063] The present invention discloses an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine suitable for the eye. Such a solution suitable for the eye may comprise one or more of an osmotic agent, a bacteriostatic or antimicrobial agent, a viscosity modifier, one or more pH modifiers, a preservative, and water.

[0064] In some embodiments, the ophthalmic pharmaceutical composition comprises L-alanyl-L-glutamine in an amount of about 0.1% to about 10.0% (w / v) of the composition (e.g., about 0.1% to about 9.0% (w / v), about 0.1% to about 8.0% (w / v), about 0.1% to about 7.0% (w / v), about 0.1% to about 6.0% (w / v), about 0.1% to about 5.0% (w / v), about 0.1% to about 4.0% (w / v), about 0.1% to about 3.0% (w / v), about 0.1% to about 2.5% (w / v), about 0.1% to about 2.0% (w / v), about 0.1% to about 1.5% (w / v), about 0.1% to about 1.0%(w / v), about 0.1% to about 0.5%(w / v), about 0.5% to about 10.0%(w / v), about 0.5% to about 9.0%(w / v), about 0.5% to about 8.0%(w / v), about 0.5% to about 7.0%(w / v), about 0.5% to about 6.0%(w / v), about 0.5% to about 5.0%(w / v), about 0.5% to about 4.0%(w / v), about 0.5% to about 3.0%(w / v), about 0.5% to about 2.5%(w / v), about 0.5% to about 2.0%(w / v), about 0.5% to about 1.5%(w / v), about 0.5% to about 1.0%(w / v), about 1.0% to about 10.0% (w / v), about 1.0% to about 9.0% (w / v), about 1.0% to about 8.0% (w / v), about 1.0% to about 7.0% (w / v), about 1.0% to about 6.0% (w / v), about 1.0% to about 5.0% (w / v), about 1.0% to about 4.0% (w / v), about 1.0% to about 3.0% (w / v), about 1.0% to about 2.5% (w / v), about 1.0% to about 2.0% (w / v), about 1.0% to about 1.5% (w / v), about 1.5% to about 10.0% (w / v), about 1.5% to about 9.0% (w / v), about 1.5% to about 8.0%(w / v), about 1.5% to about 7.0%(w / v), about 1.5% to about 6.0%(w / v), about 1.5% to about 5.0%(w / v), about 1.5% to about 4.0%(w / v), about 1.5% to about 3.0%(w / v), about 1.5% to about 2.5%(w / v), about 1.5% to about 2.0%(w / v), about 2.0% to about 10.0%(w / v), about 2.0% to about 9.0%(w / v), about 2.0% to about 8.0%(w / v), about 2.0% to about 7.0%(w / v), about 2.0% to about 6.0%(w / v), about 2.0% to about 5.0%(w / v), about 2.0% to about 4.0%(w / v), about 2.0% to about 3.0%(w / v), about 2.0% to about 2.5% (w / v), about 2.5% to about 10.0% (w / v), about 2.5% to about 9.0% (w / v), about 2.5% to about 8.0% (w / v), about 2.5% to about 7.0% (w / v), about 2.5% to about 6.0% (w / v), about 2.5% to about 5.0% (w / v), about 2.5% to about 4.0% (w / v), about 2.5% to about 3.0% (w / v), about 3.0% to about 10.0% (w / v), about 3.0% to about 9.0% (w / v), about 3.0% to about 8.0% (w / v), about 3.0% to about 7.0% (w / v), about 3.0% to about 6.0%(w / v), about 3.0% to about 5.0%(w / v), about 3.0% to about 4.0%(w / v), about 4.0% to about 10.0%(w / v), about 4.0% to about 9.0%(w / v), about 4.0% to about 8.0%(w / v), about 4.0% to about 7.0%(w / v), about 4.0% to about 6.0%(w / v), about 4.0% to about 5.0%(w / v), about 5.0% to about 10.0%(w / v), about 5.0% to about 9.0%(w / v), about 5.0% to about 8.0%(w / v), about 5.0% to about 7.0%(w / v), about 5.0% to about 6.0%(w / v), About 6.0% to about 10.0% (w / v), about 6.0% to about 9.0% (w / v), about 6.0% to about 8.It is included at concentrations of 0% (w / v), about 6.0% to about 7.0% (w / v), about 7.0% to about 10.0% (w / v), about 7.0% to about 9.0% (w / v), about 7.0% to about 8.0% (w / v), about 8.0% to about 10.0% (w / v), about 8.0% to about 9.0% (w / v), and about 9.0% to about 10.0% (w / v). In some embodiments, the ophthalmic pharmaceutical composition includes L-alanyl-L-glutamine at a concentration of about 0.2% to about 0.8% (w / v) of the composition. In some embodiments, the ophthalmic pharmaceutical composition includes L-alanyl-L-glutamine at a concentration of about 1.8% to about 2.2% (w / v) of the composition. In some embodiments, the ophthalmic pharmaceutical composition contains L-alanyl-L-glutamine at a concentration of about 0.5% (w / v) of the composition. In some embodiments, the ophthalmic pharmaceutical composition contains L-alanyl-L-glutamine at a concentration of about 1.0% (w / v) of the composition. In some embodiments, the ophthalmic pharmaceutical composition contains L-alanyl-L-glutamine at a concentration of about 2.0% (w / v) of the composition.

[0065] In some embodiments, the osmotic agent comprises one or more of sodium chloride, potassium chlorite, boric acid, borax, sodium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, sodium acetate, mannitol, glycerin, propylene glycol, 2-(4-octylphenylethyl)-2-amino-propylene glycol hydrochloride, glucose, or a combination thereof. In some embodiments, the osmotic agent is about 0.01% to about 3% (w / v) of the composition (e.g., about 0.01% to about 0.05%, about 0.05% to about 0.1%, about 0.1% to about 0.5%, about 0.5% to about 1%, about 1.5% to about 2%, about 2.5% to about 3%, about 0.01%, about 0.1%, about 0.4%, about 0.8%, or about 0.5% (w / v)).

[0066] In some embodiments, the bacteriostatic or antimicrobial agent comprises one or more of benzalkonium chloride, benzalkonium bromide, chlorhexidine acetate, chlorhexidine gluconate, chlorobutanol, phenoxyethyl alcohol, methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, or combinations thereof. In some embodiments, the bacteriostatic agent or antimicrobial agent is about 0.003% to about 0.5% (w / v) of the composition (e.g., about 0.003% to about 0.01%, about 0.01% to about 0.05%, about 0.05% to about 0.1%, about 0.1% to about 0.5%, about 0.003% to about 0.05%, about 0.05% to about 0.5%, about 0.01% to about 0.1%, about 0.003%, about 0.03%, about 0.05%, about 0.1% or about 0.5% (w / v)).

[0067] In some embodiments, the viscosity modifier comprises one or more of sodium hyaluronate, sodium carboxymethyl cellulose, methyl cellulose, polyethylene glycol, polyvinyl alcohol, povidone, or combinations thereof. In some embodiments, the viscosity modifier is about 0.01% to about 0.5% (w / v) of the composition (e.g., about 0.01% to about 0.05%, about 0.05% to about 0.1%, about 0.1% to about 0.5%, about 0.05% to about 0.5%, about 0.01% to about 0.1%, about 0.2%, about 0.15%, or about 0.1% (w / v)).

[0068] In some embodiments, one or more pH adjusters comprise sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, boric acid, borax, acetic acid, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, hydrochloric acid, phosphoric acid, or combinations thereof. In some embodiments, the pH adjuster adjusts the pH to about 5 to about 9 (e.g., about 6.0 to about 8.0, about 6.5 to about 7.5, or about 7.0).

[0069] In some embodiments, the preservative comprises one or more of benzalkonium chloride and edetate disodium. The preservative may be used at any suitable concentration. For example, the preservative may be used at a concentration of about 0.005% to about 0.5% (w / v) (e.g., about 0.005% to about 0.01%, about 0.01% to about 0.05%, about 0.05% to about 0.1%, about 0.1% to about 0.5%, about 0.005% to about 0.05%, about 0.05% to about 0.5%, about 0.01% to about 0.1%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, or about 0.5% (w / v)).

[0070] Method and Use

[0071] The present invention provides a method comprising the step of administering an ophthalmic pharmaceutical composition containing L-alanyl-L-glutamine to the eye of a subject during a treatment period.

[0072] In some embodiments, the present invention provides a method for treating an ophthalmic disease, disorder, or pathological condition in a subject, wherein the method comprises the step of administering a therapeutically effective amount of an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the affected eye of the subject.

[0073] In some embodiments, ophthalmic diseases, disorders, or conditions include neuropathic conditions (e.g., diabetic neuropathy, trigeminal neuralgia, and peripheral neuropathy); diabetes (e.g., diabetic retinopathy, diabetic macular edema); ocular surface diseases, disorders, or conditions (dry eye disease (DED), dry eye symptoms, trauma / injury, surgery, allergy-related conditions, infection, immune-related conditions, contact lens wear, foreign body interaction, neuropathic conditions, foreign bodies, immune-mediated diseases or inflammatory conditions, diabetes, meibomian gland diseases); surgery-related diseases, disorders, and / or conditions; injury; contact lens wear; chemical-induced ophthalmic diseases, disorders, or conditions; drug-induced ophthalmic diseases, disorders, or conditions; Corneal conditions (e.g., keratoconus, Fuchs' dystrophy, corneal dystrophy, pterygium), conjunctivitis, blepharitis, meibomian gland disease, inflammatory conditions (e.g., anterior uveitis, posterior uveitis, scleritis, episcleritis, orbital cellulitis, sarcoidosis), orbital disorders (e.g., thyroid eye disease (Graves' ophthalmopathy), orbital tumor, orbital inflammation), and / or neuro-ophthalmic conditions (e.g., vascular disease, demyelinating disease (e.g., multiple sclerosis), tumor, trauma), may include, but are not limited to.

[0074] In some embodiments, ophthalmic diseases, disorders, and / or conditions may affect the ocular surface of the eye. In some embodiments, ophthalmic diseases, disorders, and conditions that may cause ocular surface symptoms include dry eye disease DED, dry eye symptoms, trauma / injury, surgery, allergy-related conditions, infection, immune-related conditions, contact lens wear, foreign body interactions, neuropathic conditions, foreign bodies, immune-mediated diseases or inflammatory conditions, diabetes mellitus, and / or meibomian gland diseases.

[0075] In some embodiments, a dry eye disorder (e.g., DED) may develop as a result of one or more ophthalmic diseases, disorders, and conditions through different mechanisms involving inflammation, physical changes in the eye, or autoimmune responses, which may lead to the development or exacerbation of the dry eye disorder. Symptoms of dry eye may include, but are not limited to, dryness, burning sensation, gritty sensation, nystagmus, soreness, abnormally frequent blinking, eye fatigue, blurred vision, reduced tear production, pain, foreign body sensation, redness, itching, photophobia (sensitivity to light), tearing, changes in goblet cell fusion, delayed epithelial tissue healing, reduced tear film stability, damage to the ocular surface epithelium, damage to the barrier function of the corneal epithelium, reduced density of conjunctival goblet cells, squamous metaplasia of the ocular surface epithelium, and / or ocular surface inflammation.

[0076] In some embodiments, ophthalmic diseases, disorders and / or conditions may also include conditions such as contact lens-related disorders and various forms of trauma, wherein the trauma may lead to: discomfort and, in some cases, more severe vision problems by disturbing the delicate balance of the ocular surface; infections and inflammation such as keratitis, often caused by various microorganisms; autoimmune disorders such as Sjögren's syndrome, leading to ocular surface symptoms; ocular herpes, a viral condition that may lead to recurrent inflammation and potential corneal scarring; chemical burns causing acute injury and discomfort; and / or severe skin reactions such as Stevens-Johnson syndrome, the effects of which may extend to the eye and lead to ocular surface symptoms. In some embodiments, ophthalmic diseases, disorders and / or conditions may include symptoms and discomfort on the ocular surface of the eye, wherein the symptoms and / or discomfort affecting the ocular surface may include, but are not limited to, dryness, burning sensation, gritty sensation, nystagmus, soreness, abnormally frequent blinking, eye fatigue, blurred vision, reduced tear production, pain, foreign body sensation, redness, itching, photophobia (sensitivity to light), tearing, changes in goblet cell fusion, delayed epithelial tissue healing, reduced tear film stability, damage to the ocular surface epithelium, damage to the barrier function of the corneal epithelium, reduced density of conjunctival goblet cells, squamous metaplasia of the ocular surface epithelium, and / or inflammation of the ocular surface.

[0077] In some embodiments, ophthalmic diseases, disorders, and / or conditions may include adverse eye events resulting from treatment (TEAE). In some embodiments, ophthalmic diseases, disorders, and / or conditions may include eye disorders, wherein eye disorders include conjunctival hyperemia, eye irritation, blurred vision, blepharitis, abnormal sensation of the eye, and / or orbital edema. In some embodiments, ophthalmic diseases, disorders, and / or conditions may include bacterial conjunctivitis and / or styes.

[0078] In some embodiments, the composition and method provided herein may be useful for preventing, inhibiting, slowing down, or regressing any one of the ophthalmic diseases, disorders, or conditions in the eye described herein by administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine.

[0079] In some embodiments, the present invention provides the use of an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine for preventing, inhibiting, slowing down, or regressing any of the ophthalmic diseases, disorders, or conditions described herein.

[0080] In some embodiments, the present invention provides a method for manufacturing an ophthalmic medicine for the reduction, improvement, and / or treatment of any one of the ophthalmic diseases, disorders, or conditions described herein, comprising the steps of: suspending or dissolving L-alanyl-L-glutamine in an isotonic solution; adjusting the pH to about 5.0 to about 9.0; and filtering the resulting solution through a microporous filter membrane to sterilize it.

[0081] In some embodiments, the method provided herein comprises the step of alleviating symptoms of any one of the ophthalmic diseases, disorders, or conditions described herein in a subject in need, and the method comprises the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0082] In some embodiments, the method provided herein comprises the step of improving any one of the ophthalmic diseases, disorders, or conditions described herein in a subject in need, and the method comprises the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0083] In some embodiments, the ophthalmic disease, disorder, or condition includes ocular surface symptoms and / or is an ocular surface disease, disorder, or condition.

[0084] In some embodiments, the method provided herein for treating ocular surface symptoms in a subject comprises the step of administering a therapeutically effective amount of an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the affected eye of the subject.

[0085] In some embodiments, the composition and method provided herein may be useful for preventing, inhibiting, slowing down, or regressing the progression of ocular surface symptoms or pathological conditions in the eye by administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine.

[0086] In some embodiments, the present invention provides an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine for preventing, inhibiting, slowing down, or regressing the progression of ocular surface symptoms.

[0087] In some embodiments, the present invention provides a method for manufacturing an ophthalmic medicine for the reduction, improvement, and / or treatment of ocular surface symptoms, the method comprising the steps of: suspending or dissolving L-alanyl-L-glutamine in an isotonic solution; adjusting the pH to about 5.0 to about 9.0; and filtering the resulting solution through a microporous filter membrane to sterilize it. In some embodiments, the present invention provides a method for manufacturing an ophthalmic medicine for the reduction, improvement, and / or treatment of ocular surface symptoms, the method comprising the step of suspending or dissolving L-alanyl-L-glutamine at a concentration of about 0.5% (w / v). In some embodiments, the present invention provides a method for manufacturing an ophthalmic medicine for the reduction, improvement, and / or treatment of ocular surface symptoms, the method comprising the step of suspending or dissolving L-alanyl-L-glutamine at a concentration of about 1.0% (w / v). In some embodiments, the present invention provides a method for manufacturing an ophthalmic medicine for the reduction, improvement, and / or treatment of ocular surface symptoms, the method comprising the step of suspending or dissolving L-alanyl-L-glutamine at a concentration of about 2.0% (w / v).

[0088] In some embodiments, the method provided herein comprises the step of alleviating ocular surface symptoms or conditions in a subject requiring alleviation, and the method comprises the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0089] In some embodiments, the method provided herein includes the step of improving ocular surface symptoms in a subject requiring improvement, and the method includes the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0090] In some embodiments, the ophthalmic disease, disorder, or pathological condition is DED.

[0091] In some embodiments, a treatment method for a subject provided herein comprises the step of administering a therapeutically effective amount of an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the affected eye of the subject.

[0092] In some embodiments, the composition and method provided herein may be useful for preventing, inhibiting, slowing down, or regressing the progression of DED in the eye by administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine.

[0093] In some embodiments, the present invention provides an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine for preventing, inhibiting, slowing, or regressing the progression of DED. In some embodiments, the present invention provides an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine at a concentration of about 0.5% (w / v) for preventing, inhibiting, slowing, or regressing the progression of any one of the ophthalmic diseases, disorders, or conditions in the eye described herein. In some embodiments, the present invention provides an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine at a concentration of about 0.5% (w / v) for preventing, inhibiting, slowing, or regressing the progression of DED. In some embodiments, the present invention provides an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine at a concentration of about 1.0% (w / v) for preventing, inhibiting, slowing, or regressing any of the ophthalmic diseases, disorders, or conditions in the eye described herein. In some embodiments, the present invention provides an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine at a concentration of about 1.0% (w / v) for preventing, inhibiting, slowing, or regressing the progression of DED. In some embodiments, the present invention provides an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine at a concentration of about 2.0% (w / v) for preventing, inhibiting, slowing, or regressing any of the ophthalmic diseases, disorders, or conditions in the eye described herein. In some embodiments, the present invention provides an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine at a concentration of about 2.0% (w / v) for preventing, inhibiting, slowing, or regressing the progression of DED.

[0094] In some embodiments, the present invention provides a method for manufacturing an ophthalmic medicine for the reduction, improvement, and / or treatment of DED, the method comprising the steps of: suspending or dissolving L-alanyl-L-glutamine in an isotonic solution; adjusting the pH to about 5.0 to about 9.0; and filtering the resulting solution through a microporous filter membrane to sterilize it.

[0095] In some embodiments, the method provided herein includes the step of alleviating symptoms of DED in a subject in need, and the method includes the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0096] In some embodiments, the method provided herein includes the step of improving symptoms of DED in a subject in need, and the method includes the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject. In some embodiments, the method provided herein includes the step of increasing tear secretion in a subject in need, and the method includes the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0097] In some embodiments, the method provided herein comprises the step of increasing goblet cells in the eye of a subject in need, and the method comprises the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0098] In some embodiments, the method provided herein comprises the step of reducing ocular surface damage in the eye of a subject in need, and the method comprises the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0099] In some embodiments, the method provided herein comprises the step of reducing corneal epithelial damage in the eye of a subject in need, and the method comprises the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0100] In some embodiments, the method provided herein comprises the step of reducing ocular surface damage in the eye of a subject in need, and the method comprises the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0101] In some embodiments, the method provided herein comprises the step of restoring ocular surface health in the eye of a subject in need, and the method comprises the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0102] In some embodiments, the method provided herein comprises the step of restoring the conjunctival epithelial condition in the eye of a subject in need, and the method comprises the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0103] In some embodiments, the method provided herein includes the step of restoring tear film stability in the eye of a subject in need, and the method includes the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0104] In some embodiments, the method provided herein comprises the step of increasing goblet cells in the eye of a subject in need, and the method comprises the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0105] In some embodiments, the method provided herein comprises the step of increasing mucin production in the eye of a subject in need, and the method comprises the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0106] In some embodiments, the method provided herein comprises the step of restoring or increasing the level of lymphotoxin-alpha in the eye of a subject in need, and the method comprises the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0107] In some embodiments, the method provided herein comprises the step of restoring ocular surface immune homeostasis in the eye of a subject in need, and the method comprises the step of administering an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine to the subject.

[0108] In some embodiments, an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine as disclosed herein may be administered to a subject who requires it to prevent, / or alleviate, / or improve, or / or relieve symptoms of ophthalmic diseases, disorders, and conditions. For example, an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine as disclosed herein may be administered to a subject who requires it to prevent, / or alleviate, / or improve, or / or relieve ocular surface symptoms. In some embodiments, ocular surface symptoms are caused by ocular surface diseases, disorders, or conditions.

[0109] In some embodiments, diagnostic tests (qualitative and quantitative) may be used to diagnose, monitor, or identify a disease, disorder, or pathological condition. For example, diagnostic tests may be performed to confirm that ocular surface symptoms have improved after administration of the ophthalmic pharmaceutical composition disclosed herein. In some embodiments, a subject may report an improvement in symptoms. For example, a subject may self-report an improvement in symptoms (e.g., foreign body sensation or pain) after administration of the ophthalmic pharmaceutical composition disclosed herein.

[0110] In some embodiments, the diagnostic test used is a cell staining procedure. For example, the diagnostic test used may be total corneal fluorescein staining. Total corneal fluorescein staining may be used to detect and evaluate the degree of damage or abnormality on the surface of the cornea. This procedure involves applying a fluorescein dye to the eye, and the fluorescein dye is a fluorescent compound that temporarily stains the tear film on the surface of the cornea. In some cases, the scale used to determine severity is as measured by the National Eye Institute (e.g., 0 (none) to 20 (severe)). In some embodiments, subjective tools may be used. For example, the subject may self-report pain, foreign body sensation, dryness, photophobia, etc. For example, the subject may record their symptoms in a journal. In some cases, the subject may report symptoms as a score (e.g., a dry eye score). In some embodiments, the score may be measured by a visual analog scale (0 (none) to 100 (severe)). In some cases, the time frame in which this diagnostic procedure is performed / observed is about 30 to 90 days (e.g., about 30 days, about 60 days, about 90 days, about 30 to 60 days, or about 60 to 90 days).

[0111] For example, an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine disclosed herein may prevent, / or alleviate, / or improve, or / or relieve one or more of dryness, burning sensation, sandy sensation, nystagmus, stinging, abnormally frequent blinking, eye fatigue, blurred vision, reduced tear production, pain, foreign body sensation, redness, itching, photophobia (sensitivity to light), tearing, changes in goblet cell fusion, delay in epithelial tissue healing, reduced tear film stability, damage to ocular surface epithelium, damage to the barrier function of corneal epithelium, reduced density of conjunctival goblet cells, squamous metaplasia of ocular surface epithelium, and / or ocular surface inflammation.

[0112] In some embodiments, the ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine disclosed herein is administered in a therapeutically effective amount to a subject who requires it to prevent, / or alleviate, / or improve, or alleviate ocular surface symptoms. As described above, the therapeutically effective amount comprises an amount or concentration of the composition or treatment described herein used during an effective period (including acute or chronic administration and periodic or continuous administration) within the context of its administration to induce the intended effect or physiological result. For example, diagnostic tests may be performed to confirm that ocular surface symptoms and / or discomfort have improved after administering the ophthalmic pharmaceutical composition disclosed herein in a therapeutically effective amount. In some embodiments, the subject may report an improvement in symptoms. For example, the subject may self-report an improvement in symptoms (e.g., foreign body sensation or pain) after administering the ophthalmic pharmaceutical composition disclosed herein in a therapeutically effective amount.

[0113] In some embodiments, the therapeutically effective amount of L-alanyl-L-glutamine is about 0.1% to about 10.0% (w / v) of the composition (e.g., about 0.1% to about 9.0% (w / v), about 0.1% to about 8.0% (w / v), about 0.1% to about 7.0% (w / v), about 0.1% to about 6.0% (w / v), about 0.1% to about 5.0% (w / v), about 0.1% to about 4.0% (w / v), about 0.1% to about 3.0% (w / v), about 0.1% to about 2.5% (w / v), about 0.1% to about 2.0% (w / v), about 0.1% to about 1.5% (w / v), about 0.1% to about 1.0% (w / v), about 0.1% to about 0.5% (w / v), about 0.5% to about 10.0% (w / v), about 0.5% to about 9.0% (w / v), about 0.5% to about 8.0% (w / v), about 0.5% to about 7.0% (w / v), about 0.5% to about 6.0% (w / v), about 0.5% to about 5.0% (w / v), about 0.5% to about 4.0% (w / v), about 0.5% to about 3.0% (w / v), about 0.5% to about 2.5% (w / v), about 0.5% to about 2.0% (w / v), about 0.5% to about 1.5% (w / v), about 0.5% to about 1.0% (w / v), about 1.0% to about 10.0%(w / v), about 1.0% to about 9.0%(w / v), about 1.0% to about 8.0%(w / v), about 1.0% to about 7.0%(w / v), about 1.0% to about 6.0%(w / v), about 1.0% to about 5.0%(w / v), about 1.0% to about 4.0%(w / v), about 1.0% to about 3.0%(w / v), about 1.0% to about 2.5%(w / v), about 1.0% to about 2.0%(w / v), about 1.0% to about 1.5%(w / v), about 1.5% to about 10.0%(w / v), about 1.5% to about 9.0%(w / v), about 1.5% to about 8.0%(w / v), About 1.5% to about 7.0% (w / v), about 1.5% to about 6.0% (w / v), about 1.5% to about 5.0% (w / v), about 1.5% to about 4.0% (w / v), about 1.5% to about 3.0% (w / v), about 1.5% to about 2.5% (w / v), about 1.5% to about 2.0% (w / v), about 2.0% to about 10.0% (w / v), about 2.0% to about 9.0% (w / v), about 2.0% to about 8.0% (w / v), about 2.0% to about 7.0% (w / v), about 2.0% to about 6.0% (w / v), about 2.0% to about 5.0% (w / v), about 2.0% to about 4.0% (w / v), about 2.0% to about 3.0% (w / v), about 2.0% to about 2.5%(w / v), about 2.5% to about 10.0%(w / v), about 2.5% to about 9.0%(w / v), about 2.5% to about 8.0%(w / v), about 2.5% to about 7.0%(w / v), about 2.5% to about 6.0%(w / v), about 2.5% to about 5.0%(w / v), about 2.5% to about 4.0%(w / v), about 2.5% to about 3.0%(w / v), about 3.0% to about 10.0%(w / v), about 3.0% to about 9.0%(w / v), about 3.0% to about 8.0%(w / v), about 3.0% to about 7.0%(w / v), about 3.0% to about 6.0%(w / v), About 3.0% to about 5.0% (w / v), about 3.0% to about 4.0% (w / v), about 4.0% to about 10.0% (w / v), about 4.0% to about 9.0% (w / v), about 4.0% to about 8.0% (w / v), about 4.0% to about 7.0% (w / v), about 4.0% to about 6.0% (w / v), about 4.0% to about 5.0% (w / v), about 5.0% to about 10.0% (w / v), about 5.0% to about 9.0% (w / v), about 5.0% to about 8.0% (w / v), about 5.0% to about 7.0% (w / v), about 5.0% to about 6.0% (w / v), about 6.0% to about 10.0%(w / v), about 6.0% to about 9.0%(w / v), about 6.0% to about 8.0%(w / v), about 6.It is added to ophthalmic formulations of the present disclosure at concentrations of 0% to about 7.0% (w / v), about 7.0% to about 10.0% (w / v), about 7.0% to about 9.0% (w / v), about 7.0% to about 8.0% (w / v), about 8.0% to about 10.0% (w / v), about 8.0% to about 9.0% (w / v), and about 9.0% to about 10.0% (w / v). In some embodiments, a therapeutically effective amount of L-alanyl-L-glutamine is added to the ophthalmic formulation of the present disclosure at a concentration of about 0.2% to about 0.8% (w / v) in the composition (e.g., about 0.2% to about 0.8%, about 0.3% to about 0.8%, about 0.4% to about 0.8%, about 0.5% to about 0.8%, about 0.6% to about 0.8%, about 0.7% to about 0.8%, about 0.2% to about 0.7%, about 0.2% to about 0.6%, about 0.2% to about 0.5%, about 0.2% to about 0.4%, about 0.2% to about 0.3%, or about 0.4% to about 0.6% (w / v)). In some embodiments, a therapeutically effective amount of L-alanyl-L-glutamine is added to the ophthalmic formulation of the present disclosure at a concentration of about 1.8% to about 2.2% (w / v) of the composition (e.g., about 1.8% to about 2.1% (w / v), about 1.8% to about 2.0% (w / v), about 1.8% to about 1.9% (w / v), about 1.9% to about 2.2% (w / v), about 1.9% to about 2.1% (w / v), about 1.9% to about 2.0% (w / v), about 2.0% to about 2.2% (w / v), about 2.0% to about 2.1% (w / v), and about 2.1% to about 2.2% (w / v)). In some embodiments, a therapeutically effective amount of L-alanyl-L-glutamine is added to the ophthalmic formulation of the present disclosure at a concentration of about 0.5% (w / v) of the composition. In some embodiments, a therapeutically effective amount of L-alanyl-L-glutamine is added to the ophthalmic formulation of the present disclosure at a concentration of about 1.0% (w / v) of the composition.In some embodiments, a therapeutically effective amount of L-alanyl-L-glutamine is added to the ophthalmic formulation of the present disclosure at a concentration of about 2.0% (w / v) of the composition.

[0114] For example, ophthalmic agents comprising L-alanyl-L-glutamine disclosed herein may prevent, / or alleviate, / or improve, or / or relieve one or more symptoms and / or discomforts of the ocular surface, such as dryness, burning, gritty sensation, nystagmus, soreness, abnormally frequent blinking, eye fatigue, blurred vision, reduced tear production, pain, foreign body sensation, redness, itching, photophobia (sensitivity to light), tearing, changes in goblet cell fusion, delayed epithelial tissue healing, reduced tear film stability, damage to the ocular surface epithelium, impairment of the barrier function of the corneal epithelium, reduced density of conjunctival goblet cells, squamous metaplasia of the ocular surface epithelium, and / or ocular surface inflammation.

[0115] In some embodiments, the provided pharmaceutical composition is formulated to be compatible with the intended route of administration. Examples of routes of administration include local ocular administration. Forms of such local ocular administration may include one or more of eye drops, suspensions, ointments, creams, patches, eye masks, eye patches, eye films, eye creams, sprays, gels, injections, or implants. In some embodiments, the pharmaceutical composition may be used in combination with an ocular medical device such as a lens. Pharmaceutically acceptable carriers may include solvents, dispersion media, and isotonic agents and absorption retardants, etc., that are compatible with pharmaceutical administration. A supplementary active compound may also be incorporated into the composition.

[0116] In some embodiments, the topical formulation has a liquid carrier and may be an aqueous solution, a suspension, or an emulsion. In some embodiments, the topical formulation may include a solution, a suspension, an emulsion, a gel, or a sustained-release formulation, and may include, for example, an ocular device such as an implant or a lens.

[0117] In some embodiments, the composition or formulation (e.g., an ophthalmic preparation) may be applied to a liquid carrier. In some embodiments, the carrier is an aqueous carrier. In some embodiments, the carrier is water. In some embodiments, a rapid-dissolving form of the medicine may be administered in powder form or applied to the eye by rubbing from various types of applicators. Eye sprays, ophthalmic drops, and other methods of application may be used.

[0118] In some embodiments, the formulation is packaged as a sterile solution in a dropper bottle, as is standard in ophthalmic formulations. Other containers including eye cups may also be used. In some embodiments, the formulation may be packaged with instructions for using the formulation to administer one to two drops of the solution to each eye, in some embodiments, for use in treating presbyopia.

[0119] In some embodiments, the composition described herein may be administered in a pharmaceutically acceptable formulation (e.g., an ophthalmic formulation) and may be administered topically, for example, by applying the formulation to the eye in a non-irritating sterile solution or suspension. In some embodiments, the formulation is preferably a pH compatible with the eye (e.g., about 6.5 to about 7.5).

[0120] Dosage levels may vary depending on the individual to be treated, the progression of the disease, and / or the specific medicine(s) used. In some embodiments, the method described herein comprises 1 to 2 drops per application. In some embodiments, the method described herein comprises 1 drop per application. In some embodiments, the drop size is about 10 μL to about 80 μL (e.g., about 20 μL to about 80 μL, about 30 μL to about 80 μL, about 40 μL to about 80 μL, about 50 μL to about 80 μL, about 60 μL to about 80 μL, about 70 μL to about 80 μL, about 10 μL to about 70 μL, about 20 μL to about 70 μL, about 30 μL to about 70 μL, about 40 μL to about 70 μL, about 50 μL to about 70 μL, about 60 μL to about 70 μL, about 10 μL to about 60 μL, about 20 μL to about 60 μL, about 30 μL to about 60 μL, about 40 μL to about 60 The range is μL, about 50 μL to about 60 μL, about 10 μL to about 50 μL, about 20 μL to about 50 μL, about 30 μL to about 50 μL, about 40 μL to about 50 μL, about 10 μL to about 40 μL, about 20 μL to about 40 μL, about 30 μL to about 40 μL, about 10 μL to about 30 μL, about 20 μL to about 30 μL, and about 10 μL to about 20 μL. In some embodiments, the drop size may be about 35 μL. In some embodiments, an exemplary dose may be in the range of about 10 μL to about 480 μL per application. Exemplary dosage regimens useful in some embodiments of the method described herein include application once a day, application twice a day, application three times a day, application four times a day, application five times a day, application six times a day, application once every other day, application once a week, application twice a week, or application three times a week.In some embodiments, the method described herein includes application once per day. In some embodiments, the method described herein includes application once per week (e.g., every 7 days). In some embodiments, the method described herein includes application once per week for a period of 60 days.

[0121] In some embodiments, an ophthalmic pharmaceutical composition containing L-alanyl-L-glutamine may be administered during the treatment period. In some embodiments, the exemplary treatment period is 1 day, up to about 5 days, up to about 10 days, up to about 30 days, up to about 1 week, up to about 2 weeks, up to about 3 weeks, up to about 4 weeks, up to about 5 weeks, up to about 1 month, up to about 2 months, up to about 3 months, up to about 4 months, up to about 5 months, up to about 6 months, up to about 7 months, up to about 8 months, up to about 9 months, up to about 10 months, up to about 11 months, up to about 1 year, up to about 2 years, up to about 3 years, up to about 4 years, up to about 5 years, or up to about 10 years, about 1 day to about 10 years, about 1 month to about 10 years, about 2 months to about 10 years, about 3 months to about 10 years, about 4 months to about 10 years, about 5 months to about 10 years, about 6 months to about 10 years, about It includes 6 months to about 9 years, about 6 months to about 8 years, about 6 months to about 7 years, about 6 months to about 6 years, about 6 months to about 5 years, about 1 day to about 60 months, about 6 months to about 4 years, about 6 months to about 3 years, about 6 months to about 2 years, and about 6 months to about 1 year, etc. In some embodiments, an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine may be administered for a treatment period of 2 months (e.g., 60 days). In some embodiments of the method described herein, the treatment regimen may be periodically interrupted and resumed as needed by the subject.

[0122] In some embodiments, an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine may be administered 1 to 6 times per day, 1 to 5 times per day, 1 to 4 times per day, 1 to 3 times per day, or 1 to 2 times per day during the treatment period. In some embodiments, an ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine may be administered once per day during the treatment period. In some embodiments, the composition or formulation described herein (e.g., a composition or formulation comprising a cholinesterase antagonist, a miotic, or a combination thereof) may be administered to the subject before the subject's sleep period, e.g., within 2 hours, 1 hour, 45 minutes, 30 minutes, 15 minutes, 10 minutes, or 5 minutes.

[0123] Examples

[0124] The present invention is further described in the following examples, which do not limit the scope of the invention as described in the claims.

[0125] Example 1 - Multicenter, double-masking, randomized, vehicle-controlled, dose-response, parallel-group study of L-alanyl-L-glutamine ophthalmic solution versus vehicle control in subjects with dry eye disease

[0126] Overall Research Design and Planning - Explanation

[0127] A phase 2, multicenter, double-masking, randomized, vehicle-controlled, dose-response, parallel-group study was designed to evaluate the ocular and systemic safety and ocular efficacy of L-alanyl-L-glutamine ophthalmic solution over a 60-day treatment period in subjects with moderate to severe dry eye disease (DED).

[0128] During a 14-day single-masking introduction period, the vehicle was administered as a single drop in both eyes (OU) to approximately 200 subjects. At Visit 2, subjects were randomized in a 1:1:1:1 ratio to four treatment groups: vehicle (n=50) and L-alanyl-L-glutamine ophthalmic solution 2.0% (n=50), 1.0% (n=50), and 0.5% (n=50). Double-masking IP was administered as a single drop in the OU BID for 60 days. The study consisted of the following six clinic visits: Visit 1 (-14 days, screening), Visit 2 (Day 1, randomization), Visit 3 (Day 7 ± Day 2), Visit 4 (Day 14 ± Day 2), Visit 5 (Day 28 ± Day 2), and Visit 6 (Day 60 ± Day 3, termination / early termination of study) (Error! Source not found).

[0129] Discussion of research design including selection of control group and study group

[0130] This study investigated the ocular and systemic safety and ocular efficacy of an L-alanyl-L-glutamine ophthalmic solution compared to a vehicle administered OU BID for 60 days in subjects with moderate to severe DED.

[0131] L-alanyl-L-glutamine ophthalmic solution and vehicle were administered as topical ophthalmic solutions. During the single-masking introductory period, the vehicle was administered to all subjects OU BID to normalize baseline conditions between subjects. Subjects self-administered the first dose at the clinic on Visit 1 and all remaining doses at home. During the double-masking treatment period, subjects self-administered a single dose of IP at the clinic on Visit 2 (Day 1) and Visit 6 (Day 60), and all remaining doses at home OU BID. Direct drip administration is the most efficient method for delivery to the ocular surface and is an accepted and widely used method for local application to the eye. Each dose was delivered by administering one drop (approximately 35 μL of L-alanyl-L-glutamine ophthalmic solution) from a single-use vial to each eye.

[0132] The study population consisted of 201 adult subjects with moderate to severe DED. The study eye (SE) was defined as the eye that met all inclusion criteria, did not meet exclusion criteria, and had the highest tCFS score at randomization (visit 2, day 1). When both eyes met inclusion criteria, did not meet exclusion criteria, and had the same tCFS score, the right eye would be used as the SE.

[0133] therapy

[0134] During this study, four (4) IPs were administered:

[0135] L-Alanyl-L-Glutamine Ophthalmic Solution 2.0%

[0136] L-Alanyl-L-Glutamine Ophthalmic Solution 1.0%

[0137] L-Alanyl-L-Glutamine Ophthalmic Solution 0.5%

[0138] Vehicle solution

[0139] Two primary ocular efficacy endpoints (one sign and one symptom) were tested sequentially on day 60:

[0140] Average change from baseline (CFB) in total corneal fluorescein staining (tCFS; modified National Eye Institute [mNEI] scale, 0-20).

[0141] Mean CFB in dry eye scores on the Visual Analog Scale (VAS, 0-100 points).

[0142] The primary secondary endpoint includes a sequential test of the primary endpoint on day 28.

[0143] The following secondary ocular efficacy endpoints were tested:

[0144] Average change from baseline (CFB) in central corneal fluorescein staining (cCFS; modified National Eye Institute [mNEI] scale, 0-4)

[0145] Average CFB in ocular conjunctival hyperemia using the Corneal and Contact Lens Research Unit (CCLRU, 0-4) grading scale

[0146] Average CFB in MMP-9 scores (Study [SE])

[0147] Average CFB on the Dry Eye Symptom Assessment Questionnaire (SANDE)

[0148] Average CFB in unanesthetized Schirmer test scores

[0149] Use of rescue preservative-free artificial tears (AT) after baseline visit (Visit 2)

[0150] All efficacy evaluations are based on the visit and examination schedule ( Table 1 It was performed at the point indicated in ).

[0151] Table 1. Schedule of Procedures and Evaluation

[0152]

[0153] Abbreviations: AE = Adverse Event; AT = Artificial Tears; BCVA = Best Corrected Visual Acuity; CCLRU = Corneal and Contact Lens Study Unit; CFS = Corneal Fluorescein Stain; ET = Early Termination; IOP = Intraocular Pressure; IP = Investigational Product; MMP-9 = Matrix Metalloproteinase-9; POC = Point of Care; SANDE = Dry Eye Symptom Assessment Questionnaire; SE = Study Eye; UPT = Urine Pregnancy Test; WOCBP = Women of Pregnancy

[0154] a MMP-9 evaluated OU at visits 1 and 2 and then SE.

[0155] b Wait at least 15 minutes after the CFS rating before performing the Schirmer test.

[0156] Determination of planned statistical methods and sample size in the protocol

[0157] Summary statistics on the data collected during this study were presented to provide a general description of the studied subjects. Data from all sites were integrated into the calculation of these technical summaries.

[0158] The number of subjects, minimums, and maximums were calculated to the same number of decimal places as the source data. The mean, median, standard deviation, and quartiles were calculated to one more decimal place than the source data. Percentages were calculated to the nearest single decimal place. Zero-count cells were indicated as "0" along with the percentage (0%). Unless otherwise noted, summaries were performed by treatment group and presented in the following order: L-alanyl-L-glutamine 2.0% or 1.0% or 0.5% (efficacy analysis only), L-alanyl-L-glutamine, 2.0%; L-alanyl-L-glutamine, 1.0%; L-alanyl-L-glutamine, 0.5%; vehicle.

[0159] Statistical tests were presented as two-sided p-values ​​rounded to four decimal places. Unless otherwise indicated, statistical tests were performed at a significance level of α = 0.05.

[0160] The baseline value was defined as the last measurement prior to administration of the double-masking study drug. Ocular measurements will use the most recent measurement for each eye.

[0161] The detection limits for the tear biomarker MMP-9 test were 5 ng / mL and 1000 ng / mL. When the MMP-9 test result was less than 5, the test data would be recorded by the analyzer as < 5 ng / mL, and when it exceeded 1000 ng / mL, it would be recorded as > 1000 ng / mL. When summarizing the data, the original values ​​were converted to 4 ng / mL or 1010 ng / mL, respectively. In the data list, the actual recorded values ​​from the MMP-9 test analyzer are presented. The MMP-9 test values ​​were first log-10 transformed prior to statistical analysis.

[0162] All data collected in this study were presented as individual subject data lists for all subjects. Unless otherwise specified, calculations for all results were performed using the SAS (version 9.4, SAS / STAT 15.2) computer software package (SAS Institute, Inc, 2013, 2020).

[0163] Subgroup analysis will include testing the mean CFB for secondary endpoints, including tCFS, dry eye score, and central CFS and SANDE severity scores, for subgroups based on baseline Schirmer I test scores < 10 mm / 5 min. Subgroup analysis will include testing the mean CFB for secondary endpoints, including tCFS, dry eye score, and central CFS and SANDE severity scores, for subgroups based on baseline tear biomarker MMP-9 test scores < 32 ng / mL. Subgroup analysis by sex and age group (< 65 years, ≥ 65 years) may also be performed.

[0164] Arrangement of objects

[0165] A total of 284 subjects were screened, and 201 were randomized into the following four groups: 50 in the 2% L-alanyl-L-glutamine group, 51 in the 1% L-alanyl-L-glutamine group, 51 in the 0.5% L-alanyl-L-glutamine group, and 49 in the vehicle group. Three subjects dropped out before treatment began: 1 (2.0%) in the 2% L-alanyl-L-glutamine group, 1 (2.0%) in the 0.5% L-alanyl-L-glutamine group, and 1 (2.0%) in the vehicle group. Of these 201 subjects, 198 (98.5%) received IP treatment, and 196 (97.5%) completed the treatment. Overall, 195 subjects (97.0%) completed the study, 2 subjects discontinued due to adverse events (AEs) (1 subject (2.0%) in the 2% L-alanyl-L-glutamine group (acute bacterial conjunctivitis) and 1 subject (2.0%) in the vehicle group (worsening of osteoarthritis), and 1 subject (2.0%) in the vehicle group was terminated early due to subject dropout ( Error! Source not found ).

[0166] Table 2. Analysis Set - All Randomized Subjects

[0167]

[0168] Demographic and other baseline characteristics

[0169] The demographic characteristics of the 189 subjects in PPAS were the characteristics of the subjects in SAS (Error! Source not found).

[0170] Table 3. Demographics - Protocol Compliance Analysis Set (PPAS)

[0171]

[0172] Table of efficacy results and individual subject data

[0173] In addition to the primary outcome measure at day 60, the change from baseline was calculated at each visit (days 7, 14, and 28). For both primary signs and primary symptoms, the onset of activity occurred in all treatment groups starting at the first visit on day 7. This effect increased over the 60 days of treatment ( Fig. 3 and 4 ).

[0174] The secondary efficacy measures presented here included central corneal fluorescein staining (cCFS), conjunctival hyperemia (CCLRU), SANDE dry eye symptom severity score, SANDE total score, and SANDE dry eye symptom frequency score for the PPAS group ( Table 4 ).

[0175] Table 4. Secondary efficacy measure: Change from baseline at Day 60 - PPAS

[0176]

[0177] Safety results

[0178] Overall, 19 out of 198 subjects (9.6%) experienced at least one ocular TEAE (in either eye) during the study (8 / 49 (16.3%), 3 / 41 (5.9%), 4 / 50 (8.0%), and 4 / 48 (8.3%) in the L-alanyl-L-glutamine 2%, 1%, 0.5%, and vehicle groups, respectively). Most ocular TEAEs were moderate to mild (95%, 18 / 19 subjects) and were deemed treatment-related (79%, 15 / 19 subjects). There were no ocular SAEs. Two subjects discontinued due to adverse events (AEs) (1 subject (2.0%) in the 2% L-alanyl-L-glutamine group (acute bacterial conjunctivitis) and 1 subject (2.0%) in the vehicle group (worsening of osteoarthritis).

[0179] No deaths occurred in this study. Two serious adverse events were reported in two subjects (one in the 0.5% L-alanyl-L-glutamine treatment group (sepsis secondary to urinary tract infection) and one in the 2.0% L-alanyl-L-glutamine treatment group (deep vein thrombosis). Both were determined to be unrelated to the investigational drug. Overall, 19 out of 198 subjects (9.6%) had at least one ocular TEAE (in either eye) during the study (8 / 49 subjects (16.3%), 3 / 41 subjects (5.9%), 4 / 50 subjects (8.0%), and 4 / 48 subjects (8.3%) in the L-alanyl-L-glutamine 2%, 1%, 0.5%, and vehicle groups, respectively). Table 5 ).

[0180] Pain at the infusion site was relatively rare but appeared to have a dose-related incidence: 0, 3 / 50 (6%), 2 / 51 (3.9%), and 6 (10.2%) in the vehicle, 0.5%, 1.0%, and 2.0% L-alanyl-L-glutamine treatment groups, respectively. Other adverse events were relatively rare, and there was no clear dose-response.

[0181] Table 5. Cases of ocular abnormalities due to treatment by major organ system classification and preferred terminology - SAS (one eye)

[0182]

[0183] Abbreviations: SAS = Safety Analysis Set; AE = Adverse Event; MedDRA = Medical Dictionary for Regulatory Activities; TEAE = Treatment-Related Adverse Event.

[0184] Note: A TEAE is defined as an AE that begins on or after the date of the first dose of the double-masking study medicine and occurs up to the date of the last dose of the double-masking study medicine plus 30 days.

[0185] Note: Subjects with one or more adverse events within a MedDRA level are counted only once at that level.

[0186] Note: The percentage is based on the number of subjects for each treatment.

[0187] Other embodiments

[0188] Although the present invention has been described together with its detailed description, it should be understood that the foregoing description is intended to illustrate and not limit the scope of the invention as defined by the scope of the appended claims. Other embodiments, advantages, and variations are within the scope of the following claims.

Claims

Claim 1 An ophthalmic pharmaceutical composition comprising L-alanyl-L-glutamine suitable for the eye. Claim 2 The ophthalmic pharmaceutical composition according to claim 1, wherein the ophthalmic composition is in the form of eye drops, suspension, ointment, emulsion, eye patch, eye mask, eye film, eye cream, spray, gel, injection, or implant. Claim 3 A pharmaceutical composition according to claim 1 or 2, wherein the concentration of L-alanyl-L-glutamine is about 0.2% to about 0.8% (w / v) of the composition. Claim 4 A pharmaceutical composition according to claim 3, wherein the concentration of L-alanyl-L-glutamine is about 0.5% (w / v) of the composition. Claim 5 A pharmaceutical composition according to claim 1 or 2, wherein the concentration of L-alanyl-L-glutamine is about 1.8% to about 2.2% (w / v) of the composition. Claim 6 A pharmaceutical composition according to claim 5, wherein the concentration of L-alanyl-L-glutamine is about 2.0% (w / v) of the composition. Claim 7 A pharmaceutical composition according to claim 1 or 2, wherein the concentration of L-alanyl-L-glutamine is about 1.0% (w / v) of the composition. Claim 8 A pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition further comprises a bacteriostatic agent or an antimicrobial agent. Claim 9 A pharmaceutical composition according to claim 8, wherein the bacteriostatic agent or antimicrobial agent comprises one or more of benzalkonium chloride, benzalkonium bromide, chlorhexidine acetate, chlorhexidine gluconate, chlorobutanol, phenoxyethyl alcohol, methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, and combinations thereof. Claim 10 A pharmaceutical composition according to any one of claims 8 to 9, wherein the concentration of the bacteriostatic agent or antimicrobial agent is about 0.003 to about 0.5% (w / v) of the composition. Claim 11 A pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition further comprises a viscosity modifier. Claim 12 A pharmaceutical composition according to claim 11, wherein the viscosity modifier comprises one or more of sodium hyaluronate, sodium carboxymethyl cellulose, methyl cellulose, polyethylene glycol, polyvinyl alcohol, povidone, and combinations thereof. Claim 13 A pharmaceutical composition according to any one of claims 11 to 12, wherein the concentration of the viscosity modifier is about 0.01% to about 0.5% (w / v) of the composition. Claim 14 A pharmaceutical composition according to any one of claims 1 to 13, wherein the pharmaceutical composition further comprises one or more pH adjusters. Claim 15 A pharmaceutical composition according to claim 14, wherein one or more pH adjusters comprise one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, boric acid, borax, acetic acid, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, hydrochloric acid, phosphoric acid, and combinations thereof. Claim 16 A pharmaceutical composition according to any one of claims 14 to 15, wherein the pH of the pharmaceutical composition is about 5.0 to about 9.

0. Claim 17 A method for preparing a pharmaceutical composition according to any one of claims 1 to 16, the method comprising the steps of: suspending or dissolving L-alanyl-L-glutamine in water to form an aqueous solution; adjusting the pH to about 5.0 to about 9.0; and filtering the resulting solution through a microporous filter membrane for sterilization. Claim 18 A method for alleviating, improving, and treating ocular surface symptoms and discomfort in a subject in need, wherein the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 19 A method for alleviating, improving, or treating ocular surface symptoms caused by ocular surface disease in a subject in need, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 20 A method for alleviating, improving, or treating ocular surface symptoms caused by a non-ocular surface disease in a subject in need, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 21 A method for alleviating, improving, and treating ocular surface symptoms caused by dry eye syndrome in a subject in need, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 22 A method for alleviating, improving, and treating ocular surface symptoms caused by allergies in a subject in need, wherein the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 23 A method for alleviating, improving, and treating ocular surface symptoms caused by infection in a subject in need, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 24 A method for alleviating, improving, and treating ocular surface symptoms caused by a neuropathic condition in a subject in need, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 25 A method for alleviating, improving, or treating ocular surface symptoms caused by damage or surgery in a subject in need, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 26 A method for alleviating, improving, and treating ocular surface symptoms caused by the wearing of a foreign object in a subject requiring treatment, wherein the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 27 A method for alleviating, improving, or treating ocular surface symptoms caused by immune-mediated diseases or inflammatory conditions in a subject in need, wherein the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 28 A method for alleviating, improving, and treating ocular surface symptoms caused by diabetes in a subject in need, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 29 A method for alleviating, improving, and treating ocular surface symptoms induced by surgery-related factors in a subject in need, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 30 A method for alleviating, improving, and treating ocular surface symptoms caused by meibomian gland disease in a subject in need, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 31 A method according to any one of claims 17 to 30, wherein the ocular surface symptoms include one or more of dryness, burning sensation, sandy sensation, nystagmus, stinging, abnormally frequent blinking, eye fatigue, blurred vision, decreased tear production, pain, foreign body sensation, redness, itching, photophobia (sensitivity to light), tearing, changes in goblet cell fusion degree, delay in epithelial tissue healing, decreased tear film stability, damage to ocular surface epithelium, damage to the barrier function of corneal epithelium, decreased density of conjunctival goblet cells, squamous metaplasia of the ocular surface epithelium, and / or ocular surface inflammation. Claim 32 A method for alleviating symptoms of dry eye syndrome in a subject in need, wherein the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 33 A method for improving symptoms of dry eye syndrome in a subject in need, wherein the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 34 A method for treating symptoms of dry eye disease in a subject in need, wherein the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 35 A method for reducing ocular surface damage in a subject requiring treatment, wherein the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 36 A method for reducing corneal epithelial damage in a subject requiring treatment, wherein the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 37 A method for restoring ocular surface health in a subject in need, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 38 A method for restoring the conjunctival epithelial condition in a subject requiring treatment, wherein the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 39 A method for reducing conjunctival hyperemia in a subject requiring treatment, wherein the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 40 A method for restoring tear film stability in a subject requiring such restoration, wherein the method comprises the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 41 A method for increasing the tear film breakup time (BUT) in a subject requiring it, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 42 A method for increasing goblet cells in the eye of a subject requiring a need, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 43 A method for increasing mucin production in the eye of a subject requiring it, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 44 A method for restoring or increasing the level of lymphotoxin-alpha in the tear film of a subject in need, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 45 A method for restoring ocular surface immune homeostasis in a subject in need, the method comprising the step of administering a therapeutically effective amount of any one of the pharmaceutical compositions of claims 1 to 16 to the subject. Claim 46 A method according to any one of claims 32 to 34, wherein the dry eye symptoms include one or more of dryness, burning sensation, sandy sensation, eye twitching, stinging, abnormally frequent blinking, eye fatigue, blurred vision, decreased tear production, pain, foreign body sensation, redness, itching, photophobia (sensitivity to light), tearing, changes in goblet cell fusion degree, delay in epithelial tissue healing, decreased tear film stability, damage to ocular surface epithelium, damage to the barrier function of corneal epithelium, decreased density of conjunctival goblet cells, squamous metaplasia of ocular surface epithelium, and / or ocular surface inflammation.

Images