Treatment of viral conjunctivitis

Abstract

The present invention provides compositions and methods for treating, reducing, preventing, inhibiting, alleviating, reversing, or delaying replication or infections (such as viral conjunctivitis) in the eye. [Solution] The present invention relates to a combination of products comprising one or more ribonucleases (such as lampirases, or their variants, derivatives, analogs, fragments, or pharmaceutically acceptable salts) and one or more further therapeutic agents (such as vasoconstrictors, antibiotics, immunomodulatory compounds, or steroids).

Description

[Technical Field]

[0001] This disclosure describes the combination of products and the treatment of viral replication or infection in the eye. , and its use for prevention, inhibition, mitigation, recovery, or delay. Such eye infections The symptoms include viral infections caused by viruses belonging to the adenoviridae or herpesviridae families. These are some examples, but are not limited to them. [Background technology]

[0002] Conjunctivitis, commonly known as pink eye, is an inflammation of the eye that causes swelling and irritation. Conjunctivitis affects the conjunctiva (a transparent membrane that covers the sclera of the eyeball and lines the inner surface of the eyelids). It affects. Conjunctivitis is most often caused by viral or bacterial infection, but allergens can also be involved. Ghee, chemical irritants, and underlying diseases can also be causes. Symptoms of conjunctivitis include scleral and Redness / scarring at the inner corner of the eye, itchy eyes, foreign body sensation (rough or burning sensation) (stained eye), burning eye pain, blurred vision, increased photosensitivity or photophobia, swelling of the inner corner of the eye, tear production These include increased production, watery discharge, and mucopurulent discharge that can harden on the eyelashes during sleep. These are not the only causes. Both viral and bacterial conjunctivitis are highly contagious.

[0003] Typically, bacterial conjunctivitis is caused by pyrogenic bacteria such as Staphylococcus or Streptococcus. It can be treated with antibiotics in the form of eye drops, pills, or ointments, but currently Currently, there is no treatment for viral conjunctivitis. Viral conjunctivitis is caused by adenoviruses. It is primarily caused by a virus, which accounts for up to 90% of annual cases of viral conjunctivitis. Adenovirus conjunctivitis is often a self-limiting disease, but adenovirus Rustic conjunctivitis can cause corneal scarring, and some patients are at risk of severe blindness. Often, there are lingering after-effects. Herpes virus infection (the second most common virus) The form of rusian conjunctivitis is typically more severe, with a longer duration of infection and a more acute infection. It is accompanied by bedside signs and symptoms.

[0004] Therefore, there is a need to develop pharmaceutical compositions and treatments for viral conjunctivitis. [Overview of the Initiative]

[0005] Treatment, prevention, inhibition, mitigation, recovery, or delay of viral replication or infection in the eye. A composition containing a combination of products used in the process, and replication or infection of the virus in the eye. This specification describes how to use it for the treatment, prevention, inhibition, alleviation, recovery, or delay of the disease. These combinations can lead to multiple infections (e.g., bacterial and viral conjunctivitis). Treat (etc.) or enhance the therapeutic value within the scope of viral conjunctivitis (transmission and related The focus is on addressing both related clinical signs and symptoms.

[0006] Some embodiments provided herein describe products that inhibit or delay eye infections. This relates to combinations of products. In some embodiments, the combination of products is a therapeutically effective amount One or more ribonucleases (RNases), and one or more therapeutically effective doses. Further therapeutic agents include vasoconstrictors, anti- These are biomaterials, immunomodulatory compounds, steroids, or combinations thereof.

[0007] In some embodiments, one or more RNases, lampirase, and its anastomoses These are logs, variants, derivatives, or fragments. In some embodiments, one or more. The number of lampirases, their analogs, variants, derivatives, or fragments is approximately 0.001 It exists in an amount of approximately 1% w / v.

[0008] In some embodiments, one or more further therapeutic agents include naphadrine, tetra Hydrozoline, phenylephrine, oxymetazoline, brimonidine, apraclonidine, Ephedrine, Azithromycin, Erythromycin, Gentamicin, Neomycin, Tobramycin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin Xacin, Moxifloxacin, Ofloxacin, Bacitracin, Chloramphenicol Gramicidin, natamycin, polymyxin B, sulfacetamide, tetracycline Trimethoprim, vancomycin, dexamethasone, difluprednate, fluoromethasone Thoron, Loteprednol, Prednisolone, Rimexolone, Cyclosporine A, NLR P3 inhibitors, diclofenac, ketrolac, bromfenac, nepafenac, flur Biprofen, Lifitegrast, or any pharmaceutically acceptable salt or analogue thereof, if is a derivative. In some embodiments, the NLRP3 inhibitor is Ac-YVAD-c mk, 2-APB, algravin, BAPTA, BAY11-7082, β-hydroxy Butyrate (BHB), C172, CY-09, flufenamic acid, glibenclamide, I NF39, isoliquitigenin, MCC950, mefenamic acid, 3,4-methylenedioxy C-β-nitrostyrene (MNS), OLT1177, oridonine, parthenolide, ris beratrol, sulforaphane, tranilast, VX-765, or Z-VAD-FM is K. In some embodiments, the additional therapeutic agent is present at a concentration of 0.001% to 5% w / v.

[0009] In some embodiments, one or more RNases contain ranpirnase at a concentration of about 0.001% to about 1% w / v, and one or more additional therapeutic agents contain naphazoline, oxymetazoline, or brimonidine at a concentration of 0.001% to 0.1% w / v.

[0010] In some embodiments, the combination of products is present in an amount of about 0.03% w / v of ranpirnase and in an amount of about 0.01% to about 0.025% w / v of oxymetazoline. In some embodiments, the combination of products is present in an amount of about 0.03% w / v of ranpirnase and in an amount of about 0.01% to about 0.025% w / v of brimonidine.

[0011] In some embodiments, the eye infection is viral conjunctivitis. In some embodiments, viral conjunctivitis is epidemic keratoconjunctivitis, pharyngoconjunctival fever, nonspecific sporadic follicular conjunctivitis, or chronic papillary conjunctivitis. In some embodiments, viral conjunctivitis is caused by a viral infection from the Adenoviridae or Herpesviridae family (e.g., human adenovirus B, human adenovirus D, human adenovirus E, herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (CMV), or herpes zoster virus (HZV), etc.). ​​​​​​In one embodiment, human adenovirus B is human adenovirus B serotype 3, human adenovirus B Denovirus B serotype 7, human adenovirus B serotype 11, or any combination thereof In some embodiments, human adenovirus D is used in human adenovirus D blood Clean type 8, human adenovirus D serotype 13, human adenovirus D serotype 19, human adenovirus Novirus D serotype 37, or any combination thereof. In some embodiments, Human adenovirus E is human adenovirus E serotype 4.

[0012] In some embodiments, the product combination is one or more pharmaceutically acceptable The obtained carrier and further comprising one or more optionally pharmaceutically acceptable components nothing.

[0013] In some embodiments, one or more RNases and one or more further The therapeutic agent is formulated in a single formulation or in a single dose. In some embodiments, One or more RNases are prepared in the first composition, and one or more further therapeutic The agent is prepared in the second composition. In some embodiments, the first composition is the second composition It is distinguished from the substance. In some embodiments, the combination of products is administered via the eye route. It is formulated as an ophthalmic preparation for use in some embodiments. Treatment may involve eye drops, eye wash, intraocular injection, intracorneal injection, intravitreal injection, or subconjunctival injection. It is formulated for administration. In some embodiments, the combination of products is controlled by It is an outbound delivery platform. In some embodiments, it is a controlled outbound delivery platform. The product is a long-release formulation or a sustained-release formulation. In some embodiments, the combination of products These include ocular implants, ophthalmic implants, punctal plugs, intraocular implants, and intracorneal implants. It is a plant, or subconjunctival implant. In some embodiments, the combination of products The combination is administered twice a day. In some embodiments, the combination of products is administered daily. It is administered four times a day. In some embodiments, the product combination is administered eight times a day. In some embodiments, the product combination is mixed with about 25 mM of lampillase. It also contains oxymetazoline in amounts of 0.01% to 0.025% w / v.

[0014] Some embodiments provided herein reduce or inhibit eye infections in subjects. Regarding methods of causing harm. In some embodiments, the methods reduce or inhibit eye infections. Select a subject that requires the combination of products, and administer one of the aforementioned therapeutically effective doses to the subject. or multiple ribonucleases (RNases) and one or more therapeutically effective amounts The process includes administering a combination of products containing a therapeutic agent. In some embodiments, The combination of products is any combination of products described herein. In the embodiment, further therapeutic agents include vasoconstrictors, antibiotics, immunomodulatory compounds, and steroids. or a combination thereof. In some embodiments, one or more RNases. This refers to lampirase, its analogues, variants, derivatives, or fragments. In this embodiment, one or more further therapeutic agents include naphadrine, tetrahydrozoline Phenylephrine, oxymetazoline, brimonidine, apraclonidine, ephedridin Azithromycin, erythromycin, gentamicin, neomycin, tobramycin Syn, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, Moxifloxacin, ofloxacin, bacitracin, chloramphenicol, grammicin Zin, natamycin, polymyxin B, sulfacetamide, tetracycline, trimetho Prim, vancomycin, dexamethasone, difluprednate, fluorometholone, ro Teprednol, prednisolone, rimexolone, cyclosporine A, NLRP3 inhibitors Diclofenac, Ketrolac, Bromfenac, Nepafenac, Flurbiprofen N, Lifitegrast, or its pharmaceutically acceptable salts, analogs, or derivatives In some embodiments, the NLRP3 inhibitor is Ac-YVAD-cmk, 2- APB, Algravin, BAPTA, BAY11-7082, β-Hydroxybutyrate (BHB), C172, CY-09, flufenamic acid, glibenclamide, INF39, Isoliquitigenin, MCC950, Mefenamic acid, 3,4-Methylenedioxy-β- Trostyrene (MNS), OLT1177, Olidonine, Parthenolide, Risveratrol These are sulforaphane, tranilast, VX-765, or Z-VAD-FMK.

[0015] In some embodiments, the method involves using lampirase present in an amount of approximately 0.03% w / v. and the production of oxymetazoline present in amounts of approximately 0.01% to approximately 0.025% w / v. This includes the administration of a combination of substances. In some embodiments, the method is about 0.03% w / v Lampirase is present in a certain amount and in an amount of approximately 0.01% to approximately 0.025% w / v. This includes administration of a combination of products containing brimonidine.

[0016] In some embodiments, methods inhibit or delay eye infections, or eye infections To prevent the spread of infection. In some embodiments, the eye infection is viral conjunctivitis. In some embodiments, viral conjunctivitis includes epidemic keratoconjunctivitis, pharyngoconjunctival fever, and nonspecific sporadic cases. It is follicular conjunctivitis, chronic papillary conjunctivitis, or herpetic conjunctivitis. Several implementation forms In this configuration, the product combination is administered ophthalmologically to the subject. In some embodiments, One or more RNases are prepared in the first composition, and one or more further The therapeutic agent is prepared in the second composition. In some embodiments, the first composition is the second It is administered before, simultaneously with, or after the administration of the composition. In some embodiments, The drug is administered twice a day. In some embodiments, the drug is administered four times a day. In terms of administration, the drug is administered eight times a day.

[0017] Some embodiments provided herein relate to the manufacture of pharmaceuticals for the treatment of eye infections. This relates to the use of combinations of products. In some embodiments, the combination of products This involves a therapeutically effective amount of one or more ribonucleases (RNases) and a therapeutically effective amount The combination of one or more further therapeutic agents is included in some embodiments. This is any combination of products described herein. In some embodiments, Other therapeutic agents include vasoconstrictors, antibiotics, immunomodulatory compounds, steroids, or combinations thereof. It is a combination. In some embodiments, one or more RNases are used in Lampiller Ze, its analog, variant, derivative, or fragment. In some embodiments, One or more additional therapeutic agents include napadrine, tetrahydrozoline, and phenylephrine. N, oxymetazoline, brimonidine, apraclonidine, ephedrine, azithromycin Syn, erythromycin, gentamicin, neomycin, tobramycin, besifloxacin Sacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin N, ofloxacin, bacitracin, chloramphenicol, gramicidin, natamaisi Polymyxin B, sulfacetamide, tetracycline, trimethoprim, vancom Icin, Dexamethasone, Difluprednate, Fluorometholone, Loteprednol, Prednisolone, rimexolone, cyclosporine A, NLRP3 inhibitors, diclofenac Ketrolac, Bromfenac, Nepafenac, Flurbiprofen, Lifitegra It is a strain, or a pharmaceutically acceptable salt, analog, or derivative thereof. In this embodiment, the NLRP3 inhibitor is Ac-YVAD-cmk, 2-APB, Algra Bin, BAPTA, BAY11-7082, β-hydroxybutyrate (BHB), C1 72, CY-09, Flufenamic acid, Glibenclamide, INF39, Isoliquitigeni MCC950, mefenamic acid, 3,4-methylenedioxy-β-nitrostyrene (M NS), OLT1177, Oridonin, Parthenolide, Resveratrol, Sulforapha These are tranilast, VX-765, or Z-VAD-FMK. Several implementations In some embodiments, the drug inhibits or delays eye infections. This is viral conjunctivitis. In some embodiments, viral conjunctivitis is epidemic keratoconjunctivitis. It is conjunctivitis, pharyngoconjunctival fever, nonspecific sporadic follicular conjunctivitis, or chronic papillary conjunctivitis. In some embodiments, the pharmaceutical is formulated for ophthalmic administration. So, the product combination is lampirase and, which are present in an amount of approximately 0.03% w / v. It contains oxymetazoline present in amounts of approximately 0.01% to 0.025% w / v. In this embodiment, the product combination is present in an amount of approximately 0.03% w / v of lampiruna. It contains -ase and brimonidine present in amounts of approximately 0.01% to 0.025% w / v. [Modes for carrying out the invention]

[0018] The embodiments provided herein describe the replication of viruses in the eye or the treatment of infections, and prevention. Regarding combinations of products used for prevention, inhibition, mitigation, recovery, or delay. In the application form, the product combination is one or more vasoconstrictors, antibiotics, and immunomodulators. Compounds (including steroids or nonsteroidal anti-inflammatory drugs (NSAIDs)), and It contains one or more ribonucleases combined with any combination thereof. Some embodiments provided in the details relate to the replication or treatment of infection in the eye of a virus. , and the method of using combinations of products for prevention, inhibition, mitigation, recovery, or delay. .

[0019] The aspects of this disclosure generally described herein may be arranged in a wide variety of different configurations. They can be replaced, combined, separated, and designed, all of which are clearly intended in this specification. It will be easy to understand that this will be done.

[0020] Unless otherwise defined, the technical and scientific terms used herein are defined in this disclosure. It has the meaning generally understood by those skilled in the art. Unless otherwise stated, in this specification All patents, applications, published applications, and other publications referenced herein are clearly referenced in their entirety. It is used as such. For the purposes of this disclosure, the following terms are defined below.

[0021] "Approximately" refers to a standard quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, etc. For length, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or quantities, levels, values, numbers, frequencies, percentages, dimensions, sizes, amounts, weights, etc., that fluctuate by about 1%. Or it means length. When the term "approximately" precedes a value, the components are strictly to that value. It is not intended to be restricted to a specific value, but it is intended to include quantities different from the value.

[0022] Throughout this specification, unless the context indicates otherwise, the term "includes" (compri se) ), "comprises", and "comprising" This includes the described process or element or group of processes or elements, but also any other process. Alternatively, it can be understood as implying that elements, processes, or groups of elements are not excluded.

[0023] I. Eye infections The embodiments provided herein are for the treatment, prevention, and inhibition of viral replication or infection of the eye. The present invention relates to compositions and methods for reducing, mitigating, restoring, or delaying, in particular to compositions and The methods include treating, preventing, inhibiting, reducing, alleviating, and restoring viral replication or infection of the eye, as well as This relates to delay. In some embodiments, eye infections are caused by viruses of the Adenoviridae family ( Examples include adenovirus types 3, 4, 7, 8, 19, 29, 37, or 54. It is a viral infection caused by, but is not limited to, these. In some embodiments, Eye infections are caused by viruses of the Herpesviridae family (e.g., herpes simplex virus 1 or 2 (HSV-1 or HSV-2), Epstein-Barr virus (EBV), human cyst Tomegalovirus (CMV), varicella-zoster virus (HZV), or varicella-zoster virus It is a viral infection caused by (VZV is one example).

[0024] Adenoviruses (members of the Adenoviridae family) contain a double-stranded DNA genome with twelve regular DNA molecules. A medium-sized (90-100 nm) non-enveloped virus with a facet-shaped nucleocapsid. Yes, adenoviruses inhabit a wide range of vertebrates. There are approximately 60 different species of adenoviruses. The S serotype is associated with a weakened immune system, leading to mild respiratory infections (also known as the common cold) in young children. It has been shown to cause widespread diseases in humans, including life-threatening multi-organ diseases. It has been released.

[0025] Viral infections of the eye can have serious consequences. Regarding viral conjunctivitis, adeno Viral serotypes 3, 4, 7, 8, 11, 13, 19, 37, and 54 are the main causative factors. It appears that other adenovirus serotypes can also cause viral conjunctivitis. Novirus serotypes 3, 7, and 11 are classified as human adenovirus B; serotype 8 Serotypes 13, 19, and 37 are classified as human adenovirus D; serotype 4 is human adenovirus D. It is classified as denovirus E. In the general population, innate immunity to adenoviruses is low. Furthermore, all individuals are considered susceptible to infection. This triggers strong innate and adaptive immune responses. If this immune response can be regulated, It may help alleviate many of the clinical signs and symptoms associated with viral conjunctivitis.

[0026] Clinically, these adenoviruses can cause several different syndromes. , epidemic keratoconjunctivitis (EKC - mainly serotypes 8, 19, 37) and pharyngoconjunctival fever (PCF - mainly Serotypes 3, 4, and 7 are most commonly seen. EKC is the most common type of acute conjunctivitis. It is one of the syndromes, characterized by watery discharge, congestion (redness), conjunctival edema, and ipsilateral preauricular ligament. Clinical features include the sudden onset of acute follicular conjunctivitis accompanied by corneal adenopathy. Diffuse, microscopic, and / or superficial keratitis, epithelial defects, and even subepithelial infiltration. It can occur as a cloudy or opacity. In 20-50% of cases, corneal opacity can last for several weeks. These complications can significantly impair vision and cause glare. Treatment is... In cases of thrombosis, the aim is to suppress symptoms by using cold compresses and artificial tears. Clinical trials of antiviral drugs (such as cidofovir) and cyclosporine eye drops are underway. Although it was performed, no definitive effectiveness was observed. A very specific disease accompanied by severe membrane invasion. In this example, inflammation can be suppressed using a weak topical corticosteroid.

[0027] Different herpesviruses can infect various tissues of the eye. Types 1 and 2 Herpes simplex viruses of types 1 and 2 (HSV-1 and HSV-2) infect the anterior part of the eye and the conjunctiva. It causes inflammation and keratitis. CMV can infect the back of the eye and cause retinitis. It is common knowledge that HZV can cause chronic and serious eye diseases when it affects the trigeminal nerve region. It is possible. Ocular herpes zoster (a severe form of acute herpes zoster) is caused by the VZ of the trigeminal (fifth brain) nerve. This is caused by the reactivation of V.

[0028] One or more RNases (one or more lampirases, amphiases, etc.) (Variant, analog, derivative, or fragment of the same) and one or more further treatments Therapeutic agents (one or more vasoconstrictors, one or more antibiotics, one or more immunosuppressants) Includes a regulatory compound, or one or more steroids, or a combination thereof. The combination of products provided herein is used in the eyes of the virus described herein. It may be used for replication or treatment of infections (such as viral conjunctivitis). Examples of viral conjunctivitis include epidemic keratoconjunctivitis, pharyngoconjunctival fever, and nonspecific sporadic follicular conjunctivitis. Examples include conjunctivitis or chronic papillary conjunctivitis. Viral conjunctivitis as described herein is any virus replication or virus infection disclosed herein or known to those skilled in the art Infections (e.g., human adenovirus B, human adenovirus D, human adenovirus E, Adenoviruses or herpesviruses such as HSV, VZV, EBV, HZV, or CMV It can be caused by viral infections originating from the Viridae family.

[0029] II. Composition Some embodiments provided herein describe the treatment of replication or infection in the eye, and prevent Regarding combinations of products for preventing, inhibiting, mitigating, easing, restoring, or delaying. In some embodiments, the eye infection is a viral infection (for example, an adenoviral or hemoviral infection). Examples include viral infections caused by viruses of the Rupesviridae family. In the application form, the product combination consists of one or more ribonuclease enzymes and one or multiple vasoconstrictors, antibiotics, immunomodulatory compounds, or steroids, or the same Includes combinations.

[0030] Where used herein, the terms “treating” and “trea” are used in this specification. tment), therapeutic, or therapeutic (therapeutic) "y)" has its usual meaning as understood in light of this specification, and refers to a disease or condition. This does not necessarily mean complete cure or elimination.

[0031] Where used herein, the term “inhibit” is understood to be in accordance with this specification. It has the usual meaning of replicating or infecting the eye of a virus (Adenoviridae family) Delay or prevention of viral infections (such as those caused by viruses of the Herpesviridae family). This refers to. Where used herein, the term “delayed” is understood to have the same meaning as specified herein. It has its usual meaning, and the delay, postponement, or deferral of an event (Adenoviridae) Or viral infections caused by viruses of the Herpesviridae family, etc., can replicate in the eye. This refers to delays in the onset of infectious diseases, such as delays to a later time than originally expected. %, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, Or it can be a delay of an amount within the range defined by any two of the aforementioned values. The terms "and delay" are not necessarily interpreted as indicating a 100% inhibition or delay. This means that some inhibition or delay may occur.

[0032] The term "therapeutic dose" has its usual meaning as to be understood in light of this specification. This indicates the amount of active compound (i.e., drug) that induces the biological or medical response indicated. It is used for purposes such as: for example, a therapeutically effective dose of the compound is used to detect the replication or infection of the virus in the eye. This may be the amount necessary to prevent, reduce, mitigate, or reverse the infection. This response is due to the tissue This could include a reduction in the signs or symptoms of a disease occurring in a system, animal, or human and being treated. The determination of the therapeutically effective dose is within the capabilities of a person skilled in the art, considering the disclosures provided herein. The therapeutically effective amount of the compound disclosed herein required for administration is determined by the route of administration and the treatment. This may depend on the type of animal (humans are an example) and the physical characteristics of the specific animal being considered. The dosage can be adjusted to achieve the desired result, but factors such as weight, diet, and concomitant medications may affect the outcome. It may depend on the factors, and other factors recognized by those skilled in the medical field.

[0033] Where used herein, the term “derivative” shall be understood in light of this specification. It has its usual meaning and refers to a chemically modified compound, where modification is the current state of affairs in the field of chemistry. This is considered a routine operation by the company (acid ester or amide, or alcohol). A benzyl group for ols or thiols, or tert-butoxyca for amines. (Protecting groups such as the rubonyl group)

[0034] Where used herein, the term “analog” is understood to be in accordance with this specification. It has its usual meaning and includes chemically modified forms of a particular compound or class of compounds, and Compounds that maintain the characteristic pharmaceutical and / or pharmacological activity of the compound or class described above. It refers to.

[0035] As used herein, "ribonuclease enzyme," "ribonuclease," and Or, "RNase" has its usual meaning as to be understood in light of this specification, R Used to describe nucleases that catalyze the breakdown of NA into smaller components. In some embodiments, RNase is lampirase or amfinase, its It is a variant form, a rearranged form thereof, or a fragment thereof.

[0036] Lampirase is found in the oocytes and / or of Rana pipiens (leopard frogs). It is the first amphibian ribonuclease isolated from an early embryo. Initially, the P-30 protein The enzyme called ribonuclease or P-30 is a pancreatic ribonuclease (RNas). eA) It is a member of the protein superfamily. Lampirase is initially a precursor It is expressed as a polypeptide and processed to form a precursor peptide moiety and an initiation peptide. Both onines are removed, thereby resulting in yeast rich in basic lysine with a molecular weight of approximately 12 kD. A component is produced. The N-terminal pyroglutamyl residue is an essential part of the lampirase active site. Therefore, the catalytic activity and biological activity of lampirase, as well as its normal higher-order structure, It contributes significantly to stability. Another structural feature of lampirase is the compact structure of the protein. This is the C-terminal disulfide bond (87-104) that stabilizes it. To enhance the resistance of pyrnase to endogenous proteases. Another characteristic of enhanced rampillase is its ability to penetrate cells against specific RNase inhibitors. It has low binding affinity, which inhibits most mammalian RNases. On the other hand, lampirase can maintain its activity inside cells.

[0037] Lampirase binds to cell surface receptors and AP-2 / clathrin-mediated endoscopy. Cells that rapidly replicate and / or grow through internalization into the cytoplasm via itosis. It primarily targets [something]. Then, this enzyme travels back and forth through the endoplasmic reticulum, where it forms uracilnucleotides. It sequence-selectively degrades RNA substrates against ocidal and guanine nucleotides. For example, In vitro cleavage site mapping using natural transfer RNA (tRNA) substrates. This revealed the main cleavage sites at UG and GG residues, as well as cleavage at the CG site. Transfer RNA is preferentially targeted as a substrate by lampirase, and messenger RN A (mRNA) and ribosomal RNA (rRNA) appear to remain intact. When tRNA is degraded by propellantase, protein synthesis is inhibited.

[0038] However, explaining the biological effects of lampirase solely by reducing protein synthesis is insufficient. It cannot be revealed that additional or alternative RNA molecules are involved with lampirase. This suggests that it can be targeted. One alternative mechanism is the RNA interference pathway and mi It contributes to the degradation of RNA, siRNA, or their precursors. These are similar to tRNAs. These small RNAs are not protected by proteins, and are also affected by lampirase. It can be degraded. Also, since lampirase can degrade small RNA precursors, siR It can generate NA and affect gene expression. Recent findings suggest that small non-coding RNAs, In particular, a novel class of regulatory RNAs (30-40 nt) that may be derived from tRNA has been identified. Lampirase can directly generate siRNA from its intracellular tRNA substrate. This suggests that...

[0039] Furthermore, lampirase is a nuclear factor kappa light chain enhancer (NFκ) of activated B cells. B) It has been shown that the pathway interference has an immunomodulatory mechanism. In the tro study, it was shown that lampirase inhibits the translocation of NFκB into the nucleus. NFκB (a protein complex that regulates DNA transcription) responds to pro-inflammatory stimuli. It is important as a major regulator of inflammation. NFκB is found in almost all animal cells. , in response to stimuli (stress, free radicals, bacterial antigens and / or viral antigens, etc.) It controls cellular responses. Furthermore, NFκB is important in regulating the immune response to infection. It plays a vital role (κ light chains are important components of immunoglobulins). NFκB in the nucleus Inhibiting the transition to (NFκB is necessary for enhancing inflammation) reduces the inflammatory process. It is possible. Furthermore, tumor necrosis factor alpha (TNFα) and interleukin 1-β IL-1b) is activated by NFκB in a positive feedback loop, and this In this loop, genes regulated by NFκB also activate NFκB. Cytokines (such as TNFα and IL-1b) stimulate inflammatory cells at the site of inflammation. Enzymes, immune receptors, and adhesion molecules that attract and produce inflammatory mediators are found in neutrophils. And it plays an important role in the initial recruitment of macrophages to the site of inflammation. Therefore, N When FκB is activated and translocated, the expression of numerous genes increases in a coordinated manner, and these genes The products mediate inflammatory and immune responses. This type of positive regulatory loop is local inflammation. The response can be amplified and perpetuated. For example, lampirase can affect NFκB activity. Therefore, the finding that this enzyme blocked the mediated pro-inflammatory effect suggests that this enzyme effectively inhibits the inflammatory response. It is suggested that it can be suppressed. Acute trauma (mouse) or epidemic keratoconjunctivitis (adeno In both mice and humans, in patients diagnosed with a viral infection. It is interesting to note that NFκB translocated from the cytoplasm to the nucleus of conjunctival epithelial cells. This is because drugs such as lampirase have the ability to block such transitions. This is an important finding that it has the ability to knock down the inflammatory response to such triggers. ru.

[0040] In some embodiments, the lampirase disclosed herein is wild-type lampirase. Recombinant lampirase, lampirase variant, lampirase fragment, or so It is an analog of. In some embodiments, lampirase is SEQ ID NO: 1, SEQ ID NO: 1 2, Sequence ID 3, Sequence ID 4, Sequence ID 5, Sequence ID 6, Sequence ID 7, Sequence ID 8, Array Number 9, Sequence ID 10, Sequence ID 11, Sequence ID 12, Sequence ID 13, Sequence ID 14, Distribution Column number 15, Sequence ID 16, Sequence ID 17, Sequence ID 18, Sequence ID 19, Sequence ID 20 , Sequence ID 21, Sequence ID 22, Sequence ID 23, Sequence ID 24, Sequence ID 25, or The amino acid sequence described in any one of SEQ ID NOs: 26, or SEQ ID NOs: 1, SEQ ID NOs: 26 2, Sequence ID 3, Sequence ID 4, Sequence ID 5, Sequence ID 6, Sequence ID 7, Sequence ID 8, Array Number 9, Sequence ID 10, Sequence ID 11, Sequence ID 12, Sequence ID 13, Sequence ID 14, Distribution Column number 15, Sequence ID 16, Sequence ID 17, Sequence ID 18, Sequence ID 19, Sequence ID 20 , Sequence ID 21, Sequence ID 22, Sequence ID 23, Sequence ID 24, Sequence ID 25, or For any one of the sequence numbers 26, at least 75%, at least 80%, and less At least 85%, at least 86%, at least 87%, at least 88%, at least 8 9%, at least 90%, at least 91%, at least 92%, at least 93%, small At least 94%, at least 95%, at least 96%, at least 97%, at least It contains lampirase with 98% or at least 99% amino acid identity.

[0041] In some embodiments, lampirase is represented by SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, Sequence ID 4, Sequence ID 5, Sequence ID 6, Sequence ID 7, Sequence ID 8, Sequence ID 9, Sequence ID 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, Array Number 16, Sequence ID 17, Sequence ID 18, Sequence ID 19, Sequence ID 20, Sequence ID 21, Among sequence numbers 22, 23, 24, 25, or 26 For any one of the following: approximately 75% to approximately 100%, approximately 80% to approximately 100%, approximately 85% to approximately 1 00%, approximately 90% to 100%, approximately 95% to 100%, approximately 75% to 99%, approximately 80% ~99%, 85%~99%, 90%~99%, 95%~99%, 75% ~97%, ~80%~97%, ~85%~97%, ~90%~97%, or approximately It has amino acid identity ranging from 95% to approximately 97%.

[0042] In some embodiments, lampirase is represented by SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, Sequence ID 4, Sequence ID 5, Sequence ID 6, Sequence ID 7, Sequence ID 8, Sequence ID 9, Sequence ID 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, Array Number 16, Sequence ID 17, Sequence ID 18, Sequence ID 19, Sequence ID 20, Sequence ID 21, Sequence IDs 22, 23, 24, 25, or 26 Compared to any one of the following, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 Deletion, addition, and / or addition of 1, 12, 13, 14, or 15 consecutive amino acids This is a substitution; or sequence number 1, sequence number 2, sequence number 3, sequence number 4, sequence number 5, sequence number Sequence No. 6, Sequence No. 7, Sequence No. 8, Sequence No. 9, Sequence No. 10, Sequence No. 11, Sequence No. 1 2, Sequence ID 13, Sequence ID 14, Sequence ID 15, Sequence ID 16, Sequence ID 17, Sequence Number Number 18, Sequence ID 19, Sequence ID 20, Sequence ID 21, Sequence ID 22, Sequence ID 23, Distribution Compared to any one of the following: column number 24, sequence number 25, or sequence number 26, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 It has the deletion, addition, and / or substitution of 1 consecutive amino acids.

[0043] In some embodiments, lampirase is represented by SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, Sequence ID 4, Sequence ID 5, Sequence ID 6, Sequence ID 7, Sequence ID 8, Sequence ID 9, Sequence ID 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, Array Number 16, Sequence ID 17, Sequence ID 18, Sequence ID 19, Sequence ID 20, Sequence ID 21, Sequence IDs 22, 23, 24, 25, or 26 Compared to any one of the following, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 Deletion, addition, and / or addition of 1, 12, 13, 14, or 15 discontinuous amino acids This is a substitution; or sequence number 1, sequence number 2, sequence number 3, sequence number 4, sequence number 5, sequence number Sequence No. 6, Sequence No. 7, Sequence No. 8, Sequence No. 9, Sequence No. 10, Sequence No. 11, Sequence No. 1 2, Sequence ID 13, Sequence ID 14, Sequence ID 15, Sequence ID 16, Sequence ID 17, Sequence Number Number 18, Sequence ID 19, Sequence ID 20, Sequence ID 21, Sequence ID 22, Sequence ID 23, Distribution Compared to any one of the following: column number 24, sequence number 25, or sequence number 26, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 It has discontinuous deletions, additions, and / or substitutions of amino acids.

[0044] In some embodiments, the lampirase disclosed herein is pyroglutamic acid ( It can have an N-terminus blocked by PCA. In some embodiments, The N-terminal block of pyroglutamic acid is produced by the autocyclization of glutamine (Gln). In some embodiments, the lampirase disclosed herein is also pyrrolidone. It can have an N-terminus blocked by a carboxylic acid. In some embodiments, it can have an N-terminus blocked by a carboxylic acid. , Sequence ID 1, Sequence ID 2, Sequence ID 3, Sequence ID 4, Sequence ID 5, Sequence ID 6, Sequence ID No. Number 7, Sequence ID 8, Sequence ID 9, Sequence ID 10, Sequence ID 11, Sequence ID 12, Sequence ID 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, Array Number 19, Sequence ID 20, Sequence ID 21, Sequence ID 22, Sequence ID 23, Sequence ID 24, Lampill containing either the amino acid sequence of SEQ ID NO: 25 or SEQ ID NO: 26 The enzyme has an N-terminus blocked with pyroglutamic acid or pyrrolidone carboxylic acid. To possess.

[0045] Amphinases are members of the pancreatic RNase A protein superfamily. Furthermore, amphinases were isolated from amphibians, and these are more basic than lampirases. It is a highly variant. The amfinase initially expressed as a precursor polypeptide is The precursor peptide portion and the initiating methionine are both processed and removed, and then This produces an active enzyme with a molecular weight of approximately 13 kD. Similar to lampirase, amphi Nase primarily targets cells that rapidly replicate and / or grow by degrading RNA. The inhibition of protein synthesis is minimal.

[0046] In some embodiments, the amfinase disclosed herein is wild-type amfinase Recombinant amfinase, amfinase variant, amfinase fraction, or so It is an analog of. In some embodiments, amfinase is sequence number 27, sequence number No. 28, SEQ ID NO. 29, SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, Distribution Column number 34, sequence number 35, sequence number 36, sequence number 37, sequence number 38, or sequence number The amino acid sequence includes one of the amino acid sequences described in No. 39. In some embodiments, Infinase is represented by SEQ ID NOs. 27, 28, 29, 30, and SEQ ID NOs. 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, Array For any one of the following: number 37, sequence number 38, or sequence number 39, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, At least 88%, at least 89%, at least 90%, at least 91%, and 92%, at least 93%, at least 94%, at least 95%, at least 96% , having at least 97%, at least 98%, or at least 99% amino acid identity In some embodiments, the amfinase is sequence number 27, sequence number 28, sequence number Number 29, Sequence ID 30, Sequence ID 31, Sequence ID 32, Sequence ID 33, Sequence ID 34, Among sequence numbers 35, 36, 37, 38, or 39 For any one of the following: approximately 75% to approximately 100%, approximately 80% to approximately 100%, approximately 85% to approximately 1 00%, approximately 90% to 100%, approximately 95% to 100%, approximately 75% to 99%, approximately 80% ~99%, 85%~99%, 90%~99%, 95%~99%, 75% ~97%, ~80%~97%, ~85%~97%, ~90%~97%, or approximately It has amino acid identity ranging from 95% to approximately 97%.

[0047] In some embodiments, amfinase is represented by SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, Array Among sequence numbers 35, sequence number 36, sequence number 37, sequence number 38, or sequence number 39 For any one of them, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 1 Deletion, addition, and / or substitution of 2, 13, 14, or 15 consecutive amino acids ; or Sequence ID 27, Sequence ID 28, Sequence ID 29, Sequence ID 30, Sequence ID 31, Column number 32, Sequence ID 33, Sequence ID 34, Sequence ID 35, Sequence ID 36, Sequence ID 37 , compared to at most 1 or 2 of either sequence number 38 or sequence number 39. , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive It has the deletion, addition, and / or substitution of an amino acid. In some embodiments, Infinase is represented by SEQ ID NOs. 27, 28, 29, 30, and SEQ ID NOs. 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, Array Less than any one of the following: number 37, sequence number 38, or sequence number 39. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 Deletion, addition, and / or substitution of discontinuous amino acids; or Sequence ID No. 27, sequence Number 28, Sequence ID 29, Sequence ID 30, Sequence ID 31, Sequence ID 32, Sequence ID 33, Sequence IDs 34, 35, 36, 37, 38, or Compared to any one of the row numbers 39, at most 1, 2, 3, 4, 5, 6, 7, 8, Deletion, addition, or addition of 9, 10, 11, 12, 13, 14, or 15 discontinuous amino acids It has a name / or substitution.

[0048] Other RNase compounds that may be used in the compositions and methods described herein include: For example, U.S. Patent Nos. 5,559,212, 5,728,805, and 6,239 , No. 257, No. 6,175,003, No. 6,423,515, No. 7,229, No. 824, No. 7,442,535, No. 7,442,536, No. 7,473,5 No. 42, No. 7,556,953, No. 7,585,655, No. 7,763,44 No. 9, No. 7,556,951, No. 7,556,952, No. 7,585,654 No. 8,518,399, No. 8,663,964, No. 8,808,690 , and Nos. 9,682,130 (each of which, by reference of the whole, is the true The compounds of the disclosure are listed below (as referenced in the specific disclosures referred to in the details).

[0049] In some embodiments, RNase (a lampillase or an RNase disclosed herein) is used. Finase, etc., is manipulated by recombinant. In some embodiments, recombinant RNases are modified by adding a functional domain without inhibiting their endogenous activity. For example, eosinophil cationic proteins are used to provide or significantly improve bactericidal properties. Quality fragments can be added to RNase. Such constructs include Torrent, et al.,''Bactericidal Activity Engineered o n Human Pancreatic Ribonuclease and Onco nase'', Mol.Pharm.6(2):531-542(2009) (the whole thing) It is described in (which is referenced). Both bacterial and viral conjunctivitis. While still dealing with the general basic immune response to such stress, If it can be treated with a single medication, this could be extremely valuable.

[0050] In some embodiments, the RNase polypeptide is provided with one amino acid. Variant polypeptides that are either missing, deleted, or substituted with another amino acid. These include substitutions due to various factors (e.g., the physical properties of the substituted amino acid or the original amino acid). The amino acids in the polypeptide can be evaluated by methods that allow substitution. The selection of amino acids so that they can be substituted with other amino acids is known to those skilled in the art. That is the case.

[0051] In some embodiments, the combination of products provided herein may be one or more. A number of additional therapeutic agents (one or more vasoconstrictors, antibiotics, immunomodulatory compounds, or (This includes steroids, their derivatives, analogs, or pharmaceutically acceptable salts.) It also includes.

[0052] Where used herein, “vasoconstrictor” is understood in light of this specification. It has its usual meaning, and when administered to a subject, it causes vasoconstriction, or vasoconstriction of blood vessels (capillaries, for example). This refers to compounds that cause narrowing of the vasoconstrictor (which can be caused by adrenal glands). Examples of vasoconstrictors include the following: Narinergic receptor agonists are one example:

[0053] Nafadrine (including its pharmaceutically acceptable salts. Nafadrine is also known as naphcon) Or 2-(naphthalene-1-ylmethyl)-4,5-dihydro-1H-imidazole (They can be listed);

[0054] Tetrahydrozolines (including their pharmaceutically acceptable salts; as tetrahydrozolines) This is tetrizoline or (RS)-2-(1,2,3,4-tetrahydronaphthalene-1 (-yl)-4,5-dihydro-1H-imidazole is one example.

[0055] Phenylephrine (including its pharmaceutically acceptable salts. Phenylephrine is My dfrin, Altafrin, AK-dilate, Neofrin, (R)-3-[ [-1-hydroxy-2-(methylamino)ethyl]phenol is one example;

[0056] Oxymetazoline (including its pharmaceutically acceptable salts. Oxymetazoline is, Afrin, Ocuclear, Drixine, 3-(4,5-dihydro-1H-imi Dazole-2-ylmethyl)-2,4-dimethyl-6-tert-butylphenol (They can be listed);

[0057] Brimonidine (including its pharmaceutically acceptable salts. Brimonidine is Alpha agan, Mirvaso, Lumify, 5-bromo-N-(4,5-dihydro-1H Examples include imidazole-2-yl)quinoxaline-6-amine;

[0058] Apraclonidine (including its pharmaceutically acceptable salts. Apraclonidine is, Iopidine, 2,6-dichloro-N-(4,5-dihydro-1H-imidazole- Examples include 2-yl)benzene-1,4-diamine; or

[0059] Ephedrine (including its pharmaceutically acceptable salts. Ephedrine is Bron kaid, Primatene, rel-(R,S)-2-(methylamino)-1-fe (Examples include nylpropan-1-ol)

[0060] or derivatives, salts, analogs thereof, or combinations thereof.

[0061] Where used herein, “antibiotics” is understood in accordance with this specification. It has its usual meaning, and involves the death of bacteria, inhibition of bacterial growth, or a decrease in the ability of bacteria to grow. Antibiotics refer to compounds used to treat and / or prevent bacterial infections. Examples include macrolides, aminoglycosides, fluoroquinolones, or the following: Other possible antibiotics include:

[0062] Azithromycin (including its pharmaceutically acceptable salts. As for azithromycin, Zithromax, Azithrocin, 2R,3S,4R,5R,8R,10R, 11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-3, 5,6,8,10,12,14-heptamethyl-15-oxo-11-{[3,4,6- Trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy} -1-Oxa-6-Azacyclopentadeque-13-yl2,6-dideoxy-3C-methyl Lu-3-O-methyl-α-L-ribo-hexopyranoside, 9-deoxy-9α-aza-9 α-methyl-9α-homoerythromycin A is one example;

[0063] Erythromycin (including its pharmaceutically acceptable salts. Erythromycin is, Eryc、Erythrocin、3R,4S,5S,6R,7R,9R,11R,12 R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(dimethylamino) -3-hydroxy-6-methyloxan-2-yl]oxy}-14-ethyl-7,12 ,13-trihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4- Methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,7,9,11,1 Examples include 3-hexamethyl-1-oxacyclotetradecane-2,10-dione;

[0064] Gentamicin (including its pharmaceutically acceptable salts. As for gentamicin, Ci domycin, Septopal, Genticyn, Garamycin, 3R,4 R,5R)-2-{[(1S,2S,3R,4S,6R)-4,6-diamino-3-{[ (2R,3R,6S)-3-amino-6-[(1R)-1-(methylamino)ethyl]o Xan-2-yl]oxy}-2-hydroxycyclohexyl]oxy}-5-methyl- 4-(methylamino)oxane-3,5-diol is one example;

[0065] Neomycin (including its pharmaceutically acceptable salts. Neomycin is Neo- rx, 2RS, 3S, 4S, 5R)-5-amino-2-(aminomethyl)-6-((2R ,3S,4R,5S)-5-((1R,2R,5R,6R)-3,5-diamino-2-( (2R,3S,4R,5S)-3-amino-6-(aminomethyl)-4,5-dihydrox (Citetrahydro-2H-pyran-2-yloxy)-6-hydroxycyclohexyloxy (C)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yloxy )Tetrahydro-2H-pyran-3,4-diol is an example;

[0066] Tobramycin (including its pharmaceutically acceptable salts. Tobramycin is...) brex, Tobi, 2S,3R,4S,5S,6R)-4-amino-2-{[(1S, 2S,3R,4S,6R)-4,6-diamino-3-{[(2R,3R,5S,6R)- 3-amino-6-(aminomethyl)-5-hydroxyoxan-2-yl]oxy}-2 -Hydroxycyclohexyl]oxy}-6-(hydroxymethyl)oxane-3,5- Diols are mentioned;

[0067] Besifloxacin (including its pharmaceutically acceptable salts. As for besifloxacin, Besivance, 7-[(3R)-3-aminoazepam-1-yl]-8-chloro- 1-Cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-cal Bonic acid is one example;

[0068] Ciprofloxacin (including its pharmaceutically acceptable salts. As ciprofloxacin) This is Ciloxan, Cipro, Neofloxin, 1-Cyclopropyl-6-Fur Oro-4-oxo-7-(piperazine-1-yl)-quinoline-3-carboxylic acid is one example. (to be able to);

[0069] Gatifloxacin (including its pharmaceutically acceptable salts. As for gatifloxacin, Gatiflo, Tequin, Zymar, 1-Cyclopropyl-6-fluoro-8- Methoxy-7-(3-methylpiperazine-1-yl)-4-oxoquinoline-3-cal Bonic acid is one example;

[0070] Levofloxacin (including its pharmaceutically acceptable salts. Levofloxacin is, Levaquin, Tavanic, Iquix, (S)-9-fluoro-2,3-dihy Diro-3-methyl-10-(4-methylpiperazine-1-yl)-7-oxo-7H-py Lido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid is one example;

[0071] Moxifloxacin (including its pharmaceutically acceptable salts; as moxifloxacin) Avelox, Vigamox, Moxeza, 1-cyclopropyl-7-[(1S ,6S)-2,8-diazabicyclo[4.3.0]nonane-8-yl]-6-fluoro- 8-Methoxy-4-oxoquinoline-3-carboxylic acid is one example;

[0072] Ofloxacin (including its pharmaceutically acceptable salts. Ofloxacin is Fl oxin, Ocuflox, (±)-9-fluoro-2,3-dihydro-3-methyl-1 0-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de [1,4]Benzoxazine-6-carboxylic acid, (RS)-7-fluoro-2-methyl- 6-(4-methylpiperazine-1-yl)-10-oxo-4-oxa-1-azatrichy Kuro [7.3.1.0 5,13 ]Trideca-5(13),6,8,11-Tetraene-1 1-carboxylic acids are an example;

[0073] Bacitracin (including its pharmaceutically acceptable salts. Bacitracin is Baci im, (4R)-4-[(2S)-2-({2[(1S)-1-amino-2-methyl b [Thiyl]-4,5-dihydro-1,3-thiazole-5-yl}formamide)-4-meth Lupentanamide]-4-{[(1S)-1-{[(3S,6R,9S,12R,15S ,18R,21S)-18-(3-aminopropyl)-12-benzyl-15-(butane -2-yl)-3-(carbamoylmethyl)-6-(carboxymethyl)-9-(1H- Imidazole-5-ylmethyl)-2,5,8,11,14,17,20-heptaoxo [-1,4,7,10,13,16,19-heptazacyclopentacosan-21-yl] Carbamoyl-2-methylbutyl]carbamoyl-butanoic acid is one example.

[0074] Chloramphenicol (including its pharmaceutically acceptable salts). Chloramphenicol and Pentamycetin, Chloromycetin, 2,2-dichloro- N-[(1R,2R)-1,3-dihydroxy-1-(4-nitrophenyl)propane- 2-ylacetamide is one example;

[0075] Gramicidin (including its pharmaceutically acceptable salts. Gramicidin is formyl) -LX-Gly-L-Ala-D-Leu-L-Ala-D-Val-L-Val-D -Val-L-Trp-D-Leu-LYD-Leu-L-Trp=D-Lei-L Bacillus b, which has a linear pentadecapeptide chain of -Trp-ethanolamine Revis Gramicidin D is one example;

[0076] Natamycin (including its pharmaceutically acceptable salts. Natamycin is Nata cyn、1R,3S,5R,7R,8E,12R,14E,16E,18E,20E,2 2R,24S,25R,26S)-22-[(3-amino-3,6-dideoxy-D-ma [Nnopyranosyl)oxy]-1,3,26-trihydroxy-12-methyl-10-oxy So-6,11,28-trioxatricyclo[22.3.1.0 5,7 Octacosa-8 ,14,16,18,20-pentaene-e-25-carboxylic acid is an example;

[0077] Polymyxin B (including its pharmaceutically acceptable salts. As for polymyxin B, N- [4-amino-1-[[1-[[4-amino-1-oxo-1-[[6,9,18-tri (2-aminoethyl)-15-benzyl-3-(1-hydroxyethyl)-12-(2 -methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7 ,10,13,16,19-heptazacyclotricos-21-yl]amino]butane- 2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-o Xobutan-2-yl]-6-methyloctanamide is one example;

[0078] Sulfacetamide (including its pharmaceutically acceptable salts. Sulfacetamide is, Examples include Bleph-10 and N-[(4-aminophenyl)sulfonyl]acetamide. ru);

[0079] Tetracyclines (including their pharmaceutically acceptable salts. As for tetracyclines, Sumycin, (4S,6S,12aS)-4-(dimethylamino)-1,4,4a, 5,5a,6,11,12a-Octahydro-3,6,10,12,12a-Pentahyde One example is roxy-6-methyl-1,11-dioxonaphthalene-2-carboxamide. );

[0080] Trimethoprim (including its pharmaceutically acceptable salts. Trimethoprim is Pr oloprim, Monotrim, Triprim, 5-(3,4,5-trimethoxy) Examples include benzyl pyrimidine-2,4-diamine;

[0081] Vancomycin (including its pharmaceutically acceptable salts. As vancomycin, Va ncocin, (1S,2R,18R,19R,22S,25R,28R,40S)-4 8-{[(2S,3R,4S,5S,6R)-3-{[(2S,4S,5S,6S)-4 -amino-5-hydroxy-4,6-dimethyloxan-2-yl]oxy}-4,5- Dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-22-(cal Bamoylmethyl)-5,15-dichloro-2,18,32,35,37-pentahydrox C-19-[(2R)-4-methyl-2-(methylamino)pentanamide]-20,2 3,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41, 43-Pentazaoctacyclo[26.14.2.2 3,6 .2 14,17 .1 8,12 .1 29,33 .0 10,25 .0 34,39 Pentaconta-3, 5, 8 (48), 9 ,11,14,16,29(45),30,32,34,36,38,46,49-pen Tadecaene-40-carboxylic acid is one example;

[0082] or derivatives, salts, analogs thereof, or combinations thereof.

[0083] Where used herein, “immunomodulatory compound” is understood in accordance with this specification. It has the usual meaning and refers to a compound that modulates the immune response in a subject. Examples of nominal compounds include the following:

[0084] Cyclosporine A (including its pharmaceutically acceptable salts. As for cyclosporine A, CsA, Cyclosporine A, Cyclosporine A, Neoral, Sandimmune, (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-3 0-Ethyl-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hex [-1-yl]-6,9,18,24-tetraisobutyl-3,21-diisopropyl- 1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,1 3,16,19,22,25,28,31-Undecazacyclotriacontane-2 ,5,8,11,14,17,20,23,26,29,32-Undecone can be cited. );

[0085] Inhibitors of the NLRP3 inflammasome. Inhibitors of the NLRP3 inflammasome are, In the detailed document, it is also referred to as an NLRP3 antagonist or NLRP3 inhibitor. NLRP3, In other words, nucleotide-binding oligomer-forming domain (NOD)-like receptor (NLR) The domain-containing protein 3 inflammasome, when assembled, is caspase-1 It activates and mediates the processing and release of IL-1β, acting as a sensor of innate immunity. Examples of NLRP3 inhibitors include, for example, Ac-YVAD-cmk, 2-APB, and A Lugravin, BAPTA, BAY11-7082, β-hydroxybutyrate (BHB) C172, CY-09, flufenamic acid, glibenclamide, INF39, isoliqui Tigenin, MCC950, mefenamic acid, 3,4-methylenedioxy-β-nitrostile N (MNS), OLT1177, Oridonin, Parthenolide, Resveratrol, Sulfon Examples include Lafan, Tranilast, VX-765, and Z-VAD-FMK;

[0086] Ac-YVAD-cmk (including its pharmaceutically acceptable salts. Ac-YVAD-cm k is a chloromethyl ketone based on the target sequence in proIL-1β YVHD. Trapeptide, N-acetyl-tyrosyl-valyl-alanyl-aspartylchloromethyl Ketones are one example.

[0087] 2-APB (including its pharmaceutically acceptable salts. 2-APB includes 2-aminoethyl alcohols.) Examples include toxicidine borate and 2-diphenylboranyloxyethaneamine. ;

[0088] Algravin (including its pharmaceutically acceptable salts. Examples of Algravin include (3aR ,4aS,6aS,9aS,9bR)-1,4a-dimethyl-7-methylene-5,6,6 a,7,9a,9b-hexahydro-3H-oxireno[8,8a]azuleno[4,5- b]furan-8(4aH)-one);

[0089] BAPTA (including its pharmaceutically acceptable salts. Examples of BAPTA include 1,2-bis (o-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid);

[0090] BAY11-7082 (including its pharmaceutically acceptable salts. Examples of BAY11-7082 include (E)-3-tosylacrylonitrile);

[0091] BHB (including its pharmaceutically acceptable salts. Examples of BHB include β-hydroxybutyrate and 3-hydroxybutyrate);

[0092] C172 (including its pharmaceutically acceptable salts. Examples of C172 include CFTR(inh )-172 and (Z)-4-((4-oxo-2-thioxo-3-(5-(trifluoromethyl phenyl)thiazolidin-5-ylidene)methyl)benzoic acid);

[0093] CY-09 (including its pharmaceutically acceptable salts. Examples of CY-09 include (Z)-4-[[ID=!42]] ((4-oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazoli dine-5-ylidene)methyl)benzoic acid)

[0094] Flufenamic acid (including its pharmaceutically acceptable salts. Examples of flufenamic acid include Fl ufenerim, flufenoxuron, flufenisal, 2-((3-( trifluoromethyl)phenyl)amino)benzoic acid);

[0095] Glibenclamide (including its pharmaceutically acceptable salts. Examples of glibenclamide include glibenclamide, glibrid, Micronase, Maninil, 5-chloro-N -[2-[4-(cyclohexylcarbamoylsulfamoyl)phenyl]ethyl]-2 -methoxybenzamide);

[0096] INF39 (including its pharmaceutically acceptable salts. Examples of INF39 include ethyl 2-( 2-chlorobenzyl)acrylate);

[0097] Isoliquiritigenin (including its pharmaceutically acceptable salts. Examples of isoliquiritigenin include (E)-1-(2,4-dihydroxyphenyl)-3-(4-hydroxyphenyl) prop-2-en-1-one);

[0098] MCC950 (including its pharmaceutically acceptable salts. Examples of MCC950 include N-(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide);

[0099] Mefenamic acid (including its pharmaceutically acceptable salts. Examples of mefenamic acid include Pons tel, Ponstan, 2-(2,3-dimethylphenyl)aminobenzoic acid); );

[0100] 3,4-Methylenedioxy-β-nitrostyrene (MNS) (its pharmaceutically acceptable Contains salt;

[0101] OLT1177 (including its pharmaceutically acceptable salts. OLT1177 is 3- (Methylsulfonyl)-propannitrile is one example;

[0102] Oridonine (including its pharmaceutically acceptable salts. Oridonine is Isodon ol, 7a,20-epoxy-1a,6b,7,14-tetrahydroxy-kaula-16 -En-15-on can be mentioned);

[0103] Parthenolide (including its pharmaceutically acceptable salts. As parthenolide, (3aS ,9aR,10aS,10bS,E)-6,9a-dimethyl-3-methylene-3a,4, 5,8,9,9a,10a,10b-Octahydrooxyreno[2',3':9,10] One example is cyclodeca[1,2-b]furan-2(3H)-one;

[0104] Resveratrol (including its pharmaceutically acceptable salts. Resveratrol is, trans-3,5,4'-trihydroxystilbene, 3,4',5-stilbentri All, trans-resveratrol, (E)-5-(p-hydroxystyryl)resole Lucinol and (E)-5-(4-hydroxystyryl)benzene-1,3-diol are mentioned. (to be given)

[0105] Sulforaphane (including its pharmaceutically acceptable salts. As for sulforaphane, 1- Isothiocyanate-4-methylsulfinylbutane is one example;

[0106] Tranilast (including its pharmaceutically acceptable salts. As Tranilast, Riza ben, 2-{[(2E)-3-(3,4-dimethoxyphenyl)prop-2-enoyl amino}benzoic acid can be mentioned);

[0107] VX-765 (including its pharmaceutically acceptable salts. As VX-765, (S)- 1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-a mino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S )-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide can be mentioned );

[0108] Z-VAD-FMK (including its pharmaceutically acceptable salts. As Z-VAD-FMK is, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluorometh yl ketone can be mentioned).

[0109] As further immunomodulatory compounds, for example, the following can be mentioned:

[0110] Diclofenac (including its pharmaceutically acceptable salts. As Diclofenac is, Cataflam, Voltaren, [2-(2,6-dichloroanilino)phenyl] acetic acid can be mentioned);

[0111] Ketorolac (including its pharmaceutically acceptable salts. As Ketorolac is, Tora dol, Acular, Spric, ketorolac tromethamine, (±)-5-benzoyl

[0112] Bromfenac (including its pharmaceutically acceptable salts. Bromfenac is Br omday, Prolensa, Yellox, 2-[2-amino-3-(4-bromobe Examples include [Phenyl(Xoyl)phenyl]acetic acid);

[0113] Nepafenac (including its pharmaceutically acceptable salts. Nepafenac is Amna Examples include c, Ilevro, and 2-amino-3-benzoylbenzeneacetamide;

[0114] Flurbiprofen (including its pharmaceutically acceptable salts. As flurbiprofen) Ansaid, Ocufen, Strepfen, (±)-2-fluoro-α-methyl ru-(1,1'-biphenyl)-4-acetic acid, (RS)-2-(2-fluorobiphenyl- 4-yl)propanoic acid is one example;

[0115] Lifitegrast (including its pharmaceutically acceptable salts. Lifitegrast is, Xiidra, N-{[2-(1-benzofuran-6-ylcarbonyl)-5,7-diglycerides} [Roro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl}-3-(meth (L-phenylalanine) is an example;

[0116] or derivatives, salts, analogs thereof, or combinations thereof.

[0117] Where used herein, “steroids” shall be understood in light of this specification. This refers to naturally occurring steroids and their derivatives, as well as steroids, which have their usual meaning. This refers to synthetic or semi-synthetic steroid analogs that have steroid-like activity. Steroids are carbohydrate-containing compounds. It may be a luticoid or corticosteroid. Examples of steroids include: Possible examples:

[0118] Dexamethasone (including its pharmaceutically acceptable salts. Dexamethasone is (8 S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11, 17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethicone Lu-6,7,8,9,10,11,12,13,14,15,16,17-Dodecahydro -3H-cyclopenta[a]phenanthrene-3-one is one example;

[0119] Difluprednate (including its pharmaceutically acceptable salts. As difluprednate) is [(6S,8S,9R,10S,11S,13S,14S,17R)-17-(2- Acetyloxyacetyl)-6,9-difluoro-11-hydroxy-10,13-dimethyl Chil-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclop [a]phenantren-17-yl]butanoart is one example);

[0120] Fluorometholone (including its pharmaceutically acceptable salts. Fluorometholone is, Efflumidex, Flucon, FML Forte, FML, (6S,8S,9 R,10S,11S,13S,14S,17R)-17-acetyl-9-fluoro-11 ,17-dihydroxy-6,10,13-trimethyl-6,7,8,11,12,14, 15,16-Octahydrocyclopenta[a]phenanthrene-3-one, (1R,2S ,8S,10S,11S,14R,15S,17S)-14-acetyl-1-fluoro- 14,17-dihydroxy-2,8,15-trimethyltetracyclo[8.7.0.0 2 ,7 .0 11,15 heptadeca-3,6-dien-5-one);

[0121] Loteprednol (including its pharmaceutically acceptable salts. Examples of Loteprednol include Lotemax, 11β,17α,dihydroxy-21-oxa-21-chloromethylpro pregn-1,4-diene-3,20-dione 17α-ethylcarbonate, chloromethyl 17-ethoxycarbonyloxy-11-hydroxy-10,13-dimethyl-3-oxo -7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta a]phenanthrene-17-carboxylate);

[0122] Prednisolone (including its pharmaceutically acceptable salts. Examples of Prednisolone include 11 ,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-6 ,7,8,9,10,11,12,13,14,15,16,17-dodecahydrocyclo penta[a]phenanthrene-3-one, (11β)-11,17,21-trihydroxy cypregna-1,4-diene-3,20-dione);

[0123] Rimexolone (including its pharmaceutically acceptable salts. Examples of Rimexolone include Vexo l, Trimexolone, Org6216, 11β-hydroxy-16α,17α, 21-trimethylpregna-1,4-diene-3,20-dione, (8S,9S,10R ,11S,13S,14S,16R,17S)-11-hydroxy-10,13,16, 17-Tetramethyl-17-propanoyl-7,8,9,11,12,14,15,16 -Octahydro-6H-cyclopenta[a]phenanthrene-3-one is one example;

[0124] or derivatives, salts, analogs thereof, or combinations thereof.

[0125] In some embodiments, one or more further therapeutic agents are oxymetazoline. In some embodiments, one or more further therapeutic agents are brimonidine.

[0126] In some embodiments, one or more RNases include a single RNase, One or more further therapeutic agents include a single further therapeutic agent. In such embodiments, In this specification, any single RNase disclosed herein is used in any combination of products. It may be used in combination with further therapeutic agents disclosed in the details.

[0127] In some embodiments, one or more RNases include multiple RNases, One or more further therapeutic agents include a single further therapeutic agent. In such embodiments, Multiple RNases disclosed herein may be used in any single combination of products. It may be used in combination with further therapeutic agents disclosed in the details.

[0128] In some embodiments, one or more RNases include a single RNase, One or more further therapeutic agents include a plurality or further therapeutic agents. Such embodiments Therefore, any single RNase disclosed herein, any multiple in a combination of products A number of further therapeutic agents disclosed herein may be used in combination.

[0129] In some embodiments, one or more RNases include multiple RNases, One or more further therapeutic agents include a plurality of further therapeutic agents. In such embodiments, In this specification, any multiple RNases disclosed herein are used in any combination of products. It may be used in combination with further therapeutic agents disclosed in the details.

[0130] In some embodiments, one or more RNases are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or beyond in this Spec. The disclosed RNases include, At least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, few at least 12, at least 13, at least 14, or at least 15 in this specification The disclosure includes RNases. In some embodiments, one or more RNases are multiple. At most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7 , at most 8, at most 9, at most 10, at most 11, at most 12, at most 13 , including at most 14, or at most 15, RNases disclosed herein. In this embodiment, one or more RNases are 1-2, 1-3, 1-4, 1-5, 1 ~6, 1~7, 1~8, 1~9, 1~10, 1~11, 1~12, 1~13, 1~14, 1-15, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2- 11, 2-12, 2-13, 2-14, 2-15, 3-4, 3-5, 3-6, 3-7, 3 ~8, 3~9, 3~10, 3~11, 3~12, 3~13, 3~14, 3~15, 4~5 , 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-1 4, 4-15, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 5-12, 5- 13, 5-14, 5-15, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-14, 6-15, 7-8, 7-9, 7-10, 7-11, 7-12, 7- 13, 7-14, 7-15, 8-9, 8-10, 8-11, 8-12, 8-13, 8-1 4, 8-15, 9-10, 9-11, 9-12, 9-13, 9-14, 9-15, 10- 11, 10-12, 10-13, 10-14, 10-15, 11-12, 11-13, 1 1-14, 11-15, 12-13, 12-14, 12-15, 13-14, 13-15 , or including the RNases disclosed herein in paragraphs 14-15.

[0131] In some embodiments, one or more further therapeutic agents are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or more Honmyo Further therapeutic agents disclosed in the details are included. In some embodiments, one or more The therapeutic agent is at least 1, at least 2, at least 3, at least 4, at 5, at least 6, at least 7, at least 8, at least 9, at least 10, less at least 11, at least 12, at least 13, at least 14, or at least 15 Further therapeutic agents disclosed herein include, in some embodiments, one or more Further treatments include at most 1, at most 2, at most 3, at most 4, at most 5, At most 6, at most 7, at most 8, at most 9, at most 10, at most 11, many at most 12, at most 13, at most 14, or at most 15 of the further disclosures herein. The therapeutic agent comprises a therapeutic agent. In some embodiments, one or more further therapeutic agents are 1 to 2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-14, 1-15, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-11, 2-12, 2-13, 2-14, 2-15, 3- 4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 3-1 3, 3-14, 3-15, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-1 1, 4-12, 4-13, 4-14, 4-15, 5-6, 5-7, 5-8, 5-9, 5- 10, 5-11, 5-12, 5-13, 5-14, 5-15, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-14, 6-15, 7-8, 7-9, 7- 10, 7-11, 7-12, 7-13, 7-14, 7-15, 8-9, 8-10, 8-1 1, 8-12, 8-13, 8-14, 8-15, 9-10, 9-11, 9-12, 9-1 3, 9-14, 9-15, 10-11, 10-12, 10-13, 10-14, 10-1 5, 11-12, 11-13, 11-14, 11-15, 12-13, 12-14, 12 Further treatments disclosed herein for those between 15, 13-14, 13-15, or 14-15 Contains the agent.

[0132] In any of the embodiments described herein, the formulation of the product combination is Therefore, any combination of RNases can be combined with any combination of further therapeutic agents. You may do so.

[0133] Some embodiments provided herein are one or more further therapeutic agents (one or more of the vasoconstrictors, antibiotics, immunomodulatory compounds, or steroids described herein. Products comprising one or more RNases disclosed herein in combination with (e.g., ids) This relates to a combination of the following. In one embodiment, the combination of products is lampirase, or a composition comprising a variant, analog, or fragment thereof and one or more Therapeutic agents (one or more vasoconstrictors, antibiotics, immunomodulators described herein) The composition includes a compound or steroid. In one embodiment, the combination of the products The combination is a composition containing amfinase, or its variants, analogues, or fragments. The substance and one or more further therapeutic agents (one or more vascular The composition includes (such as a thoracic agent, antibiotic, immunomodulatory compound, or steroid).

[0134] In some embodiments, the combination of products is any of the lampills described herein. Nase (including any variant, analog, derivative, or fragment thereof) and one or multiple nafadrine, tetrahydrozoline, phenylephrine, oxymetazoline, b Limonidine, apraclonidine, ephedrine, azithromycin, erythromycin, Gentamicin, Neomycin, Tobramycin, Besifloxacin, Ciprofloxacin N, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, basil Tracin, Chloramphenicol, Gramicidin, Natamycin, Polymyxin B, Sul Phasetamide, tetracycline, trimethoprim, vancomycin, dexamethasone, Difluprednate, Fluorometholone, Loteprednol, Prednisolone, Rimexo Ron, cyclosporine A, NLRP3 inhibitors, diclofenac, ketrolac, brom Fenac, nepafenac, flurbiprofen, lifitegrast, or the pharmacy of the same This includes acceptable salts, analogs, or derivatives. Examples of NLRP3 inhibitors include B, Ac-YVAD-cmk, 2-APB, Algravin, BAPTA, BAY11-7 082, β-hydroxybutyrate (BHB), C172, CY-09, flufenamic acid Glibenclamide, INF39, Isoliquitigenin, MCC950, Mefenamic acid, 3,4-Methylenedioxy-β-nitrostyrene (MNS), OLT1177, Olidon N, parthenolide, resveratrol, sulforaphane, tranilast, VX-765, Alternatively, Z-VAD-FMK is another option.

[0135] In some embodiments, the combination of products is any of the amphies described herein. Nase (including any variant, analog, derivative, or fragment thereof) and one or multiple nafadrine, tetrahydrozoline, phenylephrine, oxymetazoline, b Limonidine, apraclonidine, ephedrine, azithromycin, erythromycin, Gentamicin, Neomycin, Tobramycin, Besifloxacin, Ciprofloxacin N, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, basil Tracin, Chloramphenicol, Gramicidin, Natamycin, Polymyxin B, Sul Phasetamide, tetracycline, trimethoprim, vancomycin, dexamethasone, Difluprednate, Fluorometholone, Loteprednol, Prednisolone, Rimexo Ron, cyclosporine A, NLRP3 inhibitors, diclofenac, ketrolac, brom Fenac, nepafenac, flurbiprofen, lifitegrast, or the pharmacy of the same This includes acceptable salts, analogs, or derivatives. Examples of NLRP3 inhibitors include B, Ac-YVAD-cmk, 2-APB, Algravin, BAPTA, BAY11-7 082, β-hydroxybutyrate (BHB), C172, CY-09, flufenamic acid Glibenclamide, INF39, Isoliquitigenin, MCC950, Mefenamic acid, 3,4-Methylenedioxy-β-nitrostyrene (MNS), OLT1177, Olidon N, parthenolide, resveratrol, sulforaphane, tranilast, VX-765, Alternatively, Z-VAD-FMK is another option.

[0136] In some embodiments, the product combination is combined with oxymetazoline. It contains primpinase. In some embodiments, the product combination is brimonidine and Contains combined lampirase.

[0137] In some embodiments, one or more RNases or pharmaceutically acceptable ones The salt is prepared in the composition, and one or more further therapeutic agents are prepared in the composition, each The compositions are distinct from one another. In some embodiments, the individual compositions are administered in combination. Prepared for the purpose of: a composition comprising an RNase or a pharmaceutically acceptable salt thereof, and 1 The order of administration of the composition containing one or more additional therapeutic agents may vary. In some embodiments, a composition comprising an RNase or a pharmaceutically acceptable salt thereof is used. It can be administered before all further therapeutic agents. In other embodiments, RNase or The composition containing the pharmaceutically acceptable salt thereof is used before at least one further therapeutic agent. It can be administered. In further other embodiments, an RNase or a pharmaceutically acceptable one thereof. A composition containing a possible salt can be administered simultaneously with one or more further therapeutic agents. In further embodiments, an RNase or a pharmaceutically acceptable salt thereof may be used. The composition containing the active ingredient can be administered after the administration of at least one further therapeutic agent. In some embodiments, a composition comprising an RNase or a pharmaceutically acceptable salt thereof is used. It can be administered after all further therapeutic agents have been administered.

[0138] Some embodiments provided herein involve one or more RNases or The kit includes a pharmaceutically acceptable salt and one or more additional therapeutic agents. In some embodiments, the kit includes instructions for administering the composition (to prepare the composition individually). Instructions on whether to administer the compositions sequentially or in parallel, and the product Instructions for administering a single formulation when a combination of drugs is prepared as a single-dose medication are provided. (which can be given) further includes. In some embodiments, one or more RNases or A pharmaceutically acceptable salt thereof is provided in a first container, and one or more further therapeutic agents This is then served in a second container.

[0139] In some embodiments, one or more RNases or pharmaceutically acceptable ones The salt and one or more additional therapeutic agents are formulated in a single formulation or in a single dose. It will be done.

[0140] III. Drug Preparations One or more RNases, their variants, derivatives, analogs, or pharmaceutically acceptable A salt that can be tolerated, one or more further therapeutic agents or their derivatives, analogs, or salt Embodiments of the product combination including the above are used in subjects using a cell uptake approach. It is formulated as a combination of products for administration. In some embodiments, one Alternatively, multiple RNases are prepared as a first pharmaceutical composition, and one or more further therapeutic agents are used. The therapeutic agent is prepared as a second pharmaceutical composition. In some embodiments, the first or second Pharmaceutical compositions are used in combination as a combination of products.

[0141] In some embodiments, the product combination is one or more RNases, Variants, derivatives, analogs, or pharmaceutically acceptable salts and one or more A single formulation containing a further therapeutic agent, or its derivatives, analogs, or salts.

[0142] The pharmaceutical compositions disclosed herein involve processing the active ingredient into a pharmaceutically acceptable composition. It may optionally include pharmaceutically acceptable carriers that facilitate the process. In this case, the term "pharmacologically acceptable carrier" is synonymous with "pharmacological carrier," and when administered... "Pharmacology" refers to any carrier whose adverse effects are not substantially long-term or permanent when the adverse effects occur. Terms such as "vehicles, stabilizers, diluents, additives, auxiliaries, or excipients that are generally acceptable." It includes. Such carriers are generally mixed with or may be diluted with the active compound, or active It may contain compounds and may be a solid, semi-solid, or liquid drug. The active ingredient is soluble. It is understood that it may be delivered as a suspension containing the desired carrier or diluent. Any of the various pharmaceutically acceptable carriers can be used, and as a carrier , aqueous media (e.g., water, physiological saline, glycine, hyaluronic acid, etc.); solid carriers (e.g. Ingredients include mannitol, lactose, starch, magnesium stearate, and sodium saccharin. Examples include tallow, talc, cellulose, glucose, sucrose, and magnesium carbonate; Solvents; dispersions; coatings; antimicrobial and antifungal agents; isotonic and absorption retarders; or Any other inactive component may be, but is not limited to, those that are pharmacologically acceptable. The choice of carrier may depend on the mode of administration. Any pharmacologically acceptable carrier can be used with the active ingredient. Unless otherwise specified, it is intended for use in pharmaceutically acceptable compositions. Examples of the non-limitation of the specific use of pharmaceutical carriers include Pharmaceutical Dosage. e Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams &Wilkins Publishers,7th ed.1999);REMINGT ON:THE SCIENCE AND PRACTICE OF PHARMACY( Alfonso R. Gennaro ed., Lippincott, William s&Wilkins,20th ed.2000);Goodman&Gilman's The Pharmacological Basis of Therapeuti cs(Joel G. Hardman et al., eds., McGraw-Hil (l Professional, 10th ed. 2001); and Handbook of Pharmaceutical Excipients(Raymond C. Rowe et al., APhA Publications, 4th edition These can be found in n 2003). These protocols are routine procedures. Any modifications are well within the scope of those skilled in the art from the teachings herein.

[0143] The pharmaceutical compositions disclosed herein may optionally include other pharmaceutically acceptable compositions. Ingredients (or pharmaceutical components) (buffers, preservatives, tonicity modifiers, salts, antioxidants, weight O Smolality adjusters, physiological substances, pharmacological substances, bulking agents, emulsifiers, humectants, sweeteners, Examples include, but are not limited to, flavoring substances. This does not limit the scope of the various buffers and pH adjustment methods disclosed herein. A pharmaceutical composition can be prepared, provided that the resulting preparation is pharmaceutically acceptable. This is a condition. Suitable buffers include acetate buffer, citrate buffer, and phosphate buffer. Examples include neutral buffered saline, phosphate-buffered saline, and borate buffer, however These are not limited to the following. The pH of the composition may be adjusted as needed using an acid or base. It is understood that this is possible. Among pharmaceutically acceptable antioxidants, sodium metabisulfite is used. Um, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and Examples include, but are not limited to, bibutylated hydroxytoluene. Useful preservatives and For example, benzalkonium chloride (BAK), chlorobutanol, thiromesal, and phenyl acetate. Phenylmercury, phenylmercury(II) nitrate, stabilized oxychloro composition (e.g., PURIT E (registered trademark), etc.), and chelating agents (e.g., DTPA or DTPA-bisamine). Examples include calcium DTPA and CaNaDTPA-bisamide, but These are not limited to these. Many of these preservatives have bactericidal properties. Useful in pharmaceutical compositions As a fermentation modifier, salts (e.g., sodium chloride, potassium chloride, etc.), mannitol, Alternatively, glycerin and other pharmaceutically acceptable tonic modifiers may be used, however these The pharmaceutical composition may be provided as a salt, and many acids (hydrochloric acid, sulfuric acid, acetic acid, Examples include lactic acid, tartaric acid, malic acid, succinic acid, etc., but are not limited to these. The salt can be formed by adding the corresponding free salt to an aqueous solvent or other protic solvent. These substances tend to be more soluble than their base form. These substances and other substances known in the field of pharmacology... It is understood that this can be included in a pharmaceutical composition.

[0144] The pharmaceutical compositions disclosed herein may be administered topically, ocularly, intestinally, or parenterally via any route of administration. They can be formulated for local or systemic delivery. Furthermore, the pharmaceutical combination disclosed herein The product may be produced as a liquid formulation, a semi-solid formulation, or a solid formulation. Disclosed herein The formulation can be produced in a manner that forms a single phase (e.g., oil or solid). Alternatively, the formulations disclosed herein may form two phases (e.g., colloidal formulations). It can be produced in such a manner. Pharmaceutical compositions disclosed herein intended for such administration. It can be prepared according to any method known in the field of pharmaceutical composition manufacturing. Topical and ocular Suitable liquid formulations for medical administration include, but are not limited to, liquid formulations and emulsions. No. Suitable semi-solid formulations for topical and ophthalmic administration include ointments, creams, plasters, and Examples include, but are not limited to, foams and gels. Topical and ophthalmic administration. Suitable solid formulations include gel implants, solid sol implants, and solid injections. Plants are one example, but are not limited to them.

[0145] One or more RNases in the product combination and 1 in the product combination The amount of one or more additional therapeutic agents is a therapeutically effective amount (e.g., viral replication or infection) To alleviate, prevent, inhibit, treat, relieve, or recover from symptoms of a disease (such as a viral infection), or The therapeutically effective dose is the amount that does not cause serious adverse side effects. Such amounts are found in the product combination of a specific RNase and a specific further therapeutic agent. In addition to the appropriate dosage, specify which particular RNase to administer, and which specific further It can vary depending on whether a therapeutic agent is administered. The optimal amount of a specific combination of products is used for inflammation. Observation of induced cytokine titers, anti-inflammatory cytokine titers, and prostaglandin titers. Relief of one or more symptoms associated with viral conjunctivitis, and other responses in the individual. This can be confirmed by standard research. The main pharmaceutical composition is anti One, two, three, or four doses of the pharmaceutical composition, spaced optimally to elicit an inflammatory response, are suggested. It can be done.

[0146] Generally, the effective and safe amount of RNase or further therapeutic agent in the product combination. The amount is in the range of approximately 1 fg to approximately 3,000 mg. In some embodiments, the combination of products The amount of RNase or further therapeutic agent disclosed herein contained in the combination is, individually , about 1fg, about 2fg, about 3fg, about 4fg, about 5fg, about 6fg, about 7fg, about 8fg , about 9fg, about 10fg, about 15fg, about 20fg, about 25fg, about 30fg, about 35f g, about 40fg, about 45fg, about 50fg, about 55fg, about 60fg, about 65fg, about 7 0fg, approx. 75fg, approx. 80fg, approx. 85fg, approx. 90fg, approx. 95fg, approx. 100fg , about 110fg, about 120fg, about 130fg, about 140fg, about 150fg, about 160 fg, approx. 170fg, approx. 180fg, approx. 190fg, approx. 200fg, approx. 210fg, approx. 2 20fg, approx. 230fg, approx. 240fg, approx. 250fg, 260fg, approx. 270fg, approx. 280fg, approx. 290fg, approx. 300fg, approx. 310fg, approx. 320fg, approx. 330fg , about 340fg, about 350fg, 360fg, about 370fg, about 380fg, about 390f g, approx. 400fg, approx. 410fg, approx. 420fg, approx. 430fg, approx. 440fg, approx. 45 0fg, 460fg, approx. 470fg, approx. 480fg, approx. 490fg, approx. 500fg, approx. 5 10fg, approx. 520fg, approx. 530fg, approx. 540fg, approx. 550fg, 560fg, approx. 570fg, approx. 580fg, approx. 590fg, approx. 600fg, approx. 610fg, approx. 620fg , about 630fg, about 640fg, about 650fg, 660fg, about 670fg, about 680f g, approx. 690fg, approx. 700fg, approx. 710fg, approx. 720fg, approx. 730fg, approx. 74 0fg, approx. 750fg, 760fg, approx. 770fg, approx. 780fg, approx. 790fg, approx. 8 00fg, approx. 810fg, approx. 820fg, approx. 830fg, approx. 840fg, approx. 850fg, 860fg, approx. 870fg, approx. 880fg, approx. 890fg, approx. 900fg, approx. 910fg , about 920fg, about 930fg, about 940fg, about 950fg, 960fg, about 970f g, approximately 980 fg, approximately 990 fg, or approximately 1,000 fg, or any of the aforementioned values. It can be a quantity within the range defined by the two.

[0147] In some embodiments, the RNa disclosed herein is included in the product combination. The amount of SE or further therapeutic agent is approximately 1 ng, 2 ng, 3 ng, 4 ng, individually. Approximately 5 ng, approximately 6 ng, approximately 7 ng, approximately 8 ng, approximately 9 ng, approximately 10 ng, approximately 15 ng, approximately 20 ng, about 25ng, about 30ng, about 35ng, ​​about 40ng, about 45ng, about 50ng, about 55ng, approximately 60ng, approximately 65ng, approximately 70ng, approximately 75ng, approximately 80ng, approximately 85ng Approximately 90ng, 95ng, 100ng, 110ng, 120ng, 130ng , about 140ng, about 150ng, about 160ng, about 170ng, about 180ng, about 190 ng, about 200ng, about 210ng, about 220ng, about 230ng, about 240ng, about 2 50ng, 260ng, approx. 270ng, approx. 280ng, approx. 290ng, approx. 300ng, approx. 310ng, about 320ng, about 330ng, about 340ng, about 350ng, 360ng, Approximately 370ng, approximately 380ng, approximately 390ng, approximately 400ng, approximately 410ng, approximately 420ng g, approx. 430ng, approx. 440ng, approx. 450ng, 460ng, approx. 470ng, approx. 480 ng, approx. 490ng, approx. 500ng, approx. 510ng, approx. 520ng, approx. 530ng, approx. 5 40ng, approximately 550ng, 560ng, approximately 570ng, approximately 580ng, approximately 590ng, approximately 600ng, approximately 610ng, approximately 620ng, approximately 630ng, approximately 640ng, approximately 650ng 660ng, approximately 670ng, approximately 680ng, approximately 690ng, approximately 700ng, approximately 710ng g, approx. 720ng, approx. 730ng, approx. 740ng, approx. 750ng, 760ng, approx. 770 ng, about 780ng, about 790ng, about 800ng, about 810ng, about 820ng, about 8 30ng, approximately 840ng, approximately 850ng, 860ng, approximately 870ng, approximately 880ng, approximately 890ng, approximately 900ng, approximately 910ng, approximately 920ng, approximately 930ng, approximately 940ng Approximately 950ng, 960ng, 970ng, 980ng, 990ng, or approximately The amount may be 1,000 ng, or within the range defined by any two of the aforementioned values. ru.

[0148] In some embodiments, the RNa disclosed herein is included in the product combination. The amount of SE or further therapeutic agent is approximately 1 μg, 2 μg, 3 μg, 4 μg, individually. Approximately 5μg, approximately 6μg, approximately 7μg, approximately 8μg, approximately 9μg, approximately 10μg, approximately 15μg, approximately 20 μg, approx. 25 μg, approx. 30 μg, approx. 35 μg, approx. 40 μg, approx. 45 μg, approx. 50 μg, approx. 55μg, about 60μg, about 65μg, about 70μg, about 75μg, about 80μg, about 85μg , about 90μg, about 95μg, about 100μg, about 110μg, about 120μg, about 130μg , about 140μg, about 150μg, about 160μg, about 170μg, about 180μg, about 190 μg, approx. 200 μg, approx. 210 μg, approx. 220 μg, approx. 230 μg, approx. 240 μg, approx. 2 50μg, 260μg, approx. 270μg, approx. 280μg, approx. 290μg, approx. 300μg, approx. 310μg, about 320μg, about 330μg, about 340μg, about 350μg, 360μg, Approx. 370 μg, approx. 380 μg, approx. 390 μg, approx. 400 μg, approx. 410 μg, approx. 420 μg g, approx. 430 μg, approx. 440 μg, approx. 450 μg, 460 μg, approx. 470 μg, approx. 480 μg, approx. 490 μg, approx. 500 μg, approx. 510 μg, approx. 520 μg, approx. 530 μg, approx. 5 40μg, approx. 550μg, 560μg, approx. 570μg, approx. 580μg, approx. 590μg, approx. 600 μg, approximately 610 μg, approximately 620 μg, approximately 630 μg, approximately 640 μg, approximately 650 μg , 660μg, about 670μg, about 680μg, about 690μg, about 700μg, about 710μg g, approx. 720 μg, approx. 730 μg, approx. 740 μg, approx. 750 μg, 760 μg, approx. 770 μg, approx. 780 μg, approx. 790 μg, approx. 800 μg, approx. 810 μg, approx. 820 μg, approx. 8 30μg, approx. 840μg, approx. 850μg, 860μg, approx. 870μg, approx. 880μg, approx. 890μg, approx. 900μg, approx. 910μg, approx. 920μg, approx. 930μg, approx. 940μg Approximately 950 μg, 960 μg, 970 μg, 980 μg, 990 μg, or approximately The amount may be 1,000 μg, or within the range defined by any two of the aforementioned values. ru.

[0149] In some embodiments, the RNa disclosed herein is included in the product combination. The amount of SE or further therapeutic agent is approximately 1 mg, 2 mg, 3 mg, 4 mg, individually. About 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 15mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg Approximately 90mg, 95mg, 100mg, 110mg, 120mg, 130mg , about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190 mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 2 50mg, 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, 360mg, Approx. 370mg, approx. 380mg, approx. 390mg, approx. 400mg, approx. 410mg, approx. 420m g, approx. 430mg, approx. 440mg, approx. 450mg, 460mg, approx. 470mg, approx. 480 mg, approx. 490 mg, approx. 500 mg, approx. 510 mg, approx. 520 mg, approx. 530 mg, approx. 5 40mg, about 550mg, 560mg, about 570mg, about 580mg, about 590mg, about 600mg, approximately 610mg, approximately 620mg, approximately 630mg, approximately 640mg, approximately 650mg , 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710m g, about 720mg, about 730mg, about 740mg, about 750mg, 760mg, about 770 mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 8 30mg, about 840mg, about 850mg, 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg , about 950mg, 960mg, about 970mg, about 980mg, about 990mg, about 1,00 0mg, approx. 1,250mg, approx. 1,500mg, approx. 1,750mg, approx. 2,000mg, Approximately 2,250 mg, approximately 2,500 mg, approximately 2,750 mg, or approximately 3,000 mg, Alternatively, it could be a quantity within the range defined by any two of the aforementioned values.

[0150] In some embodiments, lampirase in the combination of products described herein The abundance of a substance is expressed as a weight / volume percentage (%w / v) or molar concentration (M). In some embodiments, lampirase is present in an amount ranging from about 0.001% to about 5% w / v. (0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.00 6%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03 %, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0. 1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0. 9%, 1%, 2%, 3%, 4%, or 5% w / v, or any two of the aforementioned values Therefore, it exists in quantities within a defined range. In some embodiments, Lampiller Ze is approximately 0.001% to approximately 1% w / v, 0.01% to approximately 1% w / v, 0.001% to approximately 0 .1%w / v, about 0.01% to about 0.1%w / v, about 0.005% to about 5%w / v, 0. 05%~approx.1%w / v, 0.005%~approx.0.5%w / v, approx.0.05%~approx.0.05% w / v, approximately 0.02% to approximately 0.05% w / v, or approximately 0.02% to approximately 0.04% w / It exists within the range of v, or any range defined by any two of the aforementioned values. In some embodiments, the amount of lampirase is in the range of approximately 1 μM to approximately 4 M (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 6 0, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 8 00, 900, or 1000 μM, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 1 00, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, or 4000 mM, or before It exists within a range defined by any two of the values ​​described above (such as a quantity). Morphologically, lampirase is found in concentrations of approximately 1 μM to 30 μM, 10 μM to 30 μM, and 1 mM. It exists at approximately 30 mM, or in the range of 20 mM to approximately 30 mM.

[0151] In some embodiments, one or more of the product combinations described herein. The amount of further therapeutic agent is expressed in %w / v or M. In some embodiments, one Alternatively, multiple additional therapeutic agents may be used in concentrations of 0.001%, 0.002%, 0.003%, 0.00 4%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0. 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6 Amounts of %, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, or 5% w / v , or exist in quantities defined by any two of the aforementioned values. In the embodiment, one or more further therapeutic agents are present in a concentration of approximately 0.001% to approximately 1% w / v, 0 .01%~approx.1%w / v, 0.001%~approx.0.1%w / v, approx.0.01%~approx.0.1% w / v, approx. 0.005% to approx. 5%w / v, 0.05% to approx. 1%w / v, 0.005% to approx. 0.5%w / v, about 0.05% to about 0.05%w / v, about 0.02% to about 0.05%w / v, or a range of approximately 0.02% to approximately 0.04% w / v, or any two of the aforementioned values. It exists within any range defined by. In some embodiments, one or more Further therapeutic agents are used in amounts ranging from approximately 1 μM to approximately 4 μM (1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 μM, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 , 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2 500, 3000, 3500, or 4000 mM, or any two of the aforementioned values Therefore, it exists in quantities within a defined range. In some embodiments, Lampiller Ze is available in concentrations of approximately 1 μM to 30 μM, 10 μM to 30 μM, 1 mM to 30 mM, or 20 It exists in the range of mM to approximately 30 mM.

[0152] In some embodiments, the product combination is present in any amount as described herein. Regarding the lampirase and one or more further therapeutic agents, see herein. It contains oxymetazoline present in any amount as listed. In some embodiments, the product combination The combination involves lampirase, which is present in amounts of approximately 0.001% to approximately 5% w / v, and approximately 0. It contains oxymetazoline present in an amount of 0.01% to approximately 5% w / v. In some embodiments, The combination of products is present in amounts of approximately 0.01% to 0.05% w / v of lampill. Contains Nase and oxymetazoline present in amounts of approximately 0.01% to 0.05% w / v. In some embodiments, the product combination is about 0.02% to about 0.04% w / v Lampirase is present in a certain amount and in an amount of approximately 0.02% to approximately 0.03% w / v. It contains oxymetazoline. In some embodiments, the product combination is about 0.03 Lampirase present in %w / v amounts and amounts of approximately 0.01% to approximately 0.025% w / v It contains oxymetazoline, which is present in [the material].

[0153] In some embodiments, the product combination is present in any amount as described herein. Regarding the lampirase and one or more further therapeutic agents, see herein. It contains brimonidine present in any amount as listed. In some embodiments, the combination of products The waste contains lampirase and approximately 0.001% to 5% w / v. It contains brimonidine present in an amount of 1% to approximately 5% w / v. In some embodiments, The combination of substances contains lampillase present in amounts of approximately 0.01% to 0.05% w / v. It also contains brimonidine, which is present in amounts of approximately 0.01% to 0.05% w / v. In the embodiment, the product combination is present in an amount of approximately 0.02% to approximately 0.04% w / v. Rampillase and brimonidine, which are present in amounts of approximately 0.02% to 0.03% w / v. It includes. In some embodiments, the product combination exists in an amount of about 0.03% w / v. The present lampirase and brimo present in amounts of approximately 0.01% to 0.025% w / v Contains nidin.

[0154] One or more RNases and one or more further therapies disclosed herein The combination of products containing the agent is a controlled-release delivery platform (sustained-release formulations and long-term release formulations). It can be formulated into (for example, a drug formulation). The ocular surface produces tears upon administration to absorb the active ingredient. Because it dilutes rapidly, it is a difficult target tissue for drug administration. Furthermore, when the blink is administered... The active ingredient is diluted and removed. Using a controlled release delivery platform ensures that the active ingredient is properly absorbed. One or more RNases and one or more further therapeutic agents disclosed in the details may be used to treat The eyes are held for a sufficient amount of time to deliver the dose necessary to obtain the therapeutic effect. It adheres to the surface. Such a controlled emission delivery platform emits in a time-controlled manner. One or more RNases and one or more further therapeutics disclosed herein This improves the rate of drug delivery, thereby minimizing the number of eye drops required for a series of treatments. There is a possibility that this will happen.

[0155] Long-release formulations are one or more R's disclosed herein for a period of less than approximately 7 days. Nase and / or the release of one or more further therapeutic agents disclosed herein The sustained-release formulation contains one or more of the specified ingredients for a period of approximately 7 days or longer. RNases and / or one or more further therapeutic agents disclosed herein It refers to the release of [something].

[0156] In some embodiments, the sustained-release formulation is one or more RNas disclosed herein. e and / or one or more further therapeutic agents, at substantially zero-order release rates, for example For example, approximately 7 days, approximately 15 days, approximately 30 days, approximately 45 days, approximately 60 days, and approximately 75 days after administration. It is released over a period of days, or approximately 90 days. In some embodiments, the sustained-release formulation is 1 One or more RNases disclosed herein and / or one or more further The therapeutic agent is released at a substantially primary rate, for example, for about 7 days, about 15 days, and about Release over 30 days, approximately 45 days, approximately 60 days, approximately 75 days, or approximately 90 days. .

[0157] In some embodiments, the long-release formulation is one or more RNs disclosed herein. The ase and / or one or more additional therapeutic agents, at a substantially zero-order release rate, For example, approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or It is released over approximately 7 days. In some embodiments, the long-release formulation is one or more A number of RNases and / or one or more further therapeutic agents disclosed herein In effect, at the primary release rate, for example, approximately 1 day, 2 days, 3 days, and 4 days after administration, It is released over a period of approximately 5, 6, or 7 days.

[0158] Medication can be administered as a single dose or cumulatively (continuously), and this can be easily determined by a person skilled in the art. Yes, it is possible. For example, the replication or infection of viruses in the eye (viral conjunctivitis, epidemic horn). Treatment, inhibition, reduction, prevention, relief, and recovery of conjunctivitis and / or pharyngoconjunctival fever, as well This delays inflammation, reduces inflammation-inducing molecules and / or inflammation-inducing prostaglandin levels, or This inhibits, stimulates or increases peroxisome proliferation-activating receptor (PPAR) pathway signaling. Stronger, facilitates the determination of phenotypic changes from M1 to M2, and regulates Th1 and Th2 cytokines. Regulation, and / or reduction or suppression of NFκB pathway signaling, in effective amounts specified herein. This may include a single dose of the combination of the disclosed products. As a non-limiting example, an effective amount of A combination of products disclosed in the specification or a pharmaceutical composition disclosed in this specification, for example, It can be administered as a single dose to an individual. Alternatively, it can be used to monitor the replication of the virus in the eye. or infectious diseases (such as viral conjunctivitis, epidemic keratoconjunctivitis, and / or pharyngoconjunctival fever) Treatment, inhibition, reduction, prevention, mitigation, recovery, or delay, inflammation-inducing molecules and / or inflammation Reduction or suppression of induced prostaglandin levels, peroxisome proliferation-activating receptor Stimulation or enhancement of (PPAR) pathway signals, and determination of phenotypic changes from M1 to M2. Promotion, regulation of Th1 and Th2 cytokines, and / or NFκB pathway signaling. The reduction or suppression of an effective amount of the combination of products disclosed herein is within a certain range. Duration (for example, once or multiple times a day, once every few days, weekly, monthly, or yearly) This may include multiple doses administered over a period of time. A limited example is disclosed herein. The combination of the products is administered to the individual once, twice, three times, four times, five times, or six times a day. It is possible. The timing of administration depends on factors such as the severity of the subject's symptoms. This can vary from body to body. For example, a combination of effective amounts of the products disclosed herein. This is administered to the subject 3 to 6 times a day indefinitely, or until the subject no longer requires treatment. It can be administered. Those skilled in the art will monitor the subject's condition throughout the course of treatment. Therefore, an effective amount of the combination of products disclosed herein can be administered. They will recognize that it can be adjusted.

[0159] IV. Treatment Methods Some embodiments provided herein describe replication or infection of the eye (eye virus This specification is for the treatment, prevention, inhibition, reduction, mitigation, relief, recovery, or delay of (such as) Russ infections. A living organism comprising one or more RNases and one or more further therapeutic agents as described herein. This concerns methods for using combinations of components.

[0160] In some embodiments, the method involves a therapeutically effective amount of one or more RNases (Ran Piranase, amfinase, or its variants, derivatives, analogs, or fragments (etc.) and one or more additional therapeutic agents (one or more vasoconstrictors) in a therapeutically effective amount. A drug, one or more antibiotics, one or more immunomodulatory compounds, or one or more The treatment requires a combination of products containing several steroids (or combinations thereof). This includes the step of administering the test subject.

[0161] Some embodiments provided herein describe the viral levels in a subject, virus Methods that reduce or suppress saturates, viral replication, protein synthesis, and / or tRNA. Regarding the law. In some embodiments, the method involves a therapeutically effective amount of one or more RNas A first pharmaceutical composition comprising e and a therapeutically effective amount comprising one or more further therapeutic agents Administration to a subject requiring the combination of the products described herein, comprising two pharmaceutical compositions. This includes the process of measuring viral levels, viral titer, viral replication, and protein levels. Reduces or suppresses phosphate synthesis and / or tRNA. Viral levels in the subject. , reduce or suppress viral titer, viral replication, protein synthesis, and / or tRNA The use of combinations of products described herein for control is also disclosed.

[0162] In some embodiments, a combination of the products disclosed herein is administered to a subject. Adenoviridae or herpesviridae in the subject as required (e.g.) For example, human adenovirus B, human adenovirus D, human adenovirus E, HSV, Viral infections caused by viral infections originating from viruses such as VZV, EBV, HZV, or CMV. Treatment, inhibition, prevention, delay, relief, and recovery from conjunctivitis, epidemic keratoconjunctivitis, or pharyngoconjunctival fever. or a method or use that delays the onset of symptoms associated with viral conjunctivitis, and the administration of such a method reduces the symptoms associated with viral conjunctivitis. To provide a method or use that is performed. In some embodiments, the method disclosed herein These include human adenovirus B serotype 3, human adenovirus B serotype 7, and human adenovirus Serovirus B serotype 11, human adenovirus D serotype 8, human adenovirus D serotype 13, Toadenovirus D serotype 19, human adenovirus D serotype 37, human adenovirus Viral conjunctivitis caused by serotype E 4 or any combination thereof, epidemic keratoconjunctivitis or treat pharyngoconjunctival fever.

[0163] Some embodiments provided herein describe the levels of inflammation-inducing molecules in a subject. This relates to methods for reducing or suppressing. In some embodiments, the method involves one therapeutically effective dose. or a first pharmaceutical composition comprising multiple RNases and one or more therapeutically effective amounts A combination of products described herein, comprising a second pharmaceutical composition containing the following therapeutic agents, is required. This includes the step of administering the substance to the target subject. Such administration reduces the level of inflammation-inducing molecules and It suppresses. The use of a combination of products to reduce or suppress the levels of inflammation-inducing molecules. The use of these is also disclosed. Inflammation-inducing molecules disclosed herein include substance P, calcitonin Examples include gene-related peptides, glutamates, or combinations thereof.

[0164] Some embodiments provided herein involve the induction of inflammation-inducing prostaglandins in subjects. The present invention relates to a method for reducing or suppressing din levels. In some embodiments, the method is therapeutic A first pharmaceutical composition containing one or more RNases in a therapeutically effective amount, and one of them in a therapeutically effective amount. or a second pharmaceutical composition comprising a plurality of further therapeutic agents of the product described herein. The procedure includes administering a subject requiring a combination of agents. Such administration involves the induction of inflammation prostaglandins. Reduces or suppresses levels of grandins. Reduces levels of inflammation-inducing prostaglandins. The use of combinations of products for suppression is also disclosed. Inflammation-inducing prostaglandins One example is 15dPGJ2.

[0165] Some embodiments provided herein describe the peroxisome proliferation activity in subjects. This relates to methods for stimulating or enhancing the activity of sex receptor (PPAR) signaling pathways. In some embodiments, the method involves a first medical device containing one or more RNases in a therapeutically effective amount. A second pharmaceutical composition comprising a drug composition and one or more further therapeutic agents in a therapeutically effective amount. This includes administering to a subject requiring a combination of the products described herein. Such administration stimulates or enhances PPAR signaling pathway activity. The use of product combinations to stimulate or enhance signaling pathway activity is also disclosed. R signaling pathway activity includes PPAR-α signaling pathway activity and PPAR-γ signaling pathway activity. Gunal signaling pathway activity, and PPAR-δ (also known as PPAR-β) signaling pathway Road activity is one example.

[0166] Some embodiments provided herein describe the phenotype of the subject from M1 to M2. The present invention relates to a method for facilitating the determination of changes in the therapeutically effective amount. A first pharmaceutical composition comprising one or more RNases and one or more therapeutically effective amounts. A combination of the products described herein, comprising a second pharmaceutical composition containing a further therapeutic agent. The process includes administering to subjects who require it. Such administration involves the administration of macrophage M1 cells. It either induces potosis, promotes the differentiation of macrophage M2 cells, or both. This facilitates the determination of the phenotypic change from M1 to M2. The use of product combinations to facilitate the determination of type changes is also disclosed.

[0167] Some embodiments provided herein describe the regeneration of Th1 cytokines in subjects. Regarding methods for regulating the levels of bells and / or Th2 cytokines. Some practical In the application form, the method involves a first pharmaceutical composition containing one or more RNases in a therapeutically effective amount. The present invention comprises a second pharmaceutical composition comprising one or more further therapeutic agents in a therapeutically effective amount. The process includes administering the combination of products described in the details to a subject requiring such administration. The donor is interferon-gamma (IFNγ) released from Th1 cells, tumor necrosis factor. -Alpha (TNF-α), Interleukin-1b (IL-1b), Interleukin -12 (IL-12), or a combination thereof, reduces the level of Th2 cells, It increases the level of released IL-10, or both, thereby Th1 Adjust the levels of itakines and / or Th2 cytokines. Th1 cytokines A combination of products to regulate the levels of and / or Th2 cytokines. We will also disclose the use of se.

[0168] Some embodiments provided herein describe the NFκB signaling pathway in subjects. This relates to a method for reducing or suppressing pathway activity. In some embodiments, the method is therapeutically effective. A first pharmaceutical composition comprising one or more RNases in an effective therapeutic amount and one or A combination of the products described herein, comprising a second pharmaceutical composition containing multiple further therapeutic agents. The procedure includes administering the drug to a subject requiring treatment. Such administration is performed via the NFκB signaling pathway. To reduce or suppress pathway activity. To reduce or suppress NFκB signaling pathway activity. The use of combinations of the products is also disclosed.

[0169] In some embodiments, one or more RNases described herein and one Alternatively, multiple further therapeutic agents may be combined in the product combination as disclosed herein. They are combined. In some embodiments, the products are combined (one or more RNas (Examples include a combination of e and one or more additional therapeutic agents) which replicates in the eye. or infection (eye infection caused by viruses of the adenoviridae or herpesviridae families) To synergistically reduce, prevent, inhibit, alleviate, recover from, or treat (such as viral infections). In that embodiment, the combination of products is used to measure viral level, viral titer, and viral replication. , or reduce, inhibit, or suppress viral function (such as protein or RNA synthesis). In some embodiments, the combination of products is used to determine the viral level, viral titer, Or viral replication, or viral function (such as protein or RNA synthesis), for example. For example, at least 10%, at least 15%, at least 20%, at least 25%, At least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, At least 75%, at least 80%, at least 85%, at least 90%, or Reduce the amount by at least 95%, or within the range defined by any two of the aforementioned values. , inhibit, or suppress. In some embodiments, the combination of products is viral Bell, viral titer, or viral replication, or viral function (protein or RNA) (Synthesis of, for example) approximately 10% to approximately 100%, approximately 20% to approximately 100%, approximately 30% to approximately 100%, approximately 40% to approximately 100%, approximately 50% to approximately 100%, approximately 60% to approximately 100%, approximately 7 0% to approximately 100%, approximately 80% to approximately 100%, approximately 10% to approximately 90%, approximately 20% to approximately 90%, Approximately 30% to 90%, approximately 40% to 90%, approximately 50% to 90%, approximately 60% to 90%, Approximately 70% to 90%, approximately 10% to 80%, approximately 20% to 80%, approximately 30% to 80%, Approximately 40% to 80%, approximately 50% to 80%, or approximately 60% to 80%, approximately 10% to 70%, approximately 20% to approximately 70%, approximately 30% to approximately 70%, approximately 40% to approximately 70%, or approximately 5 Reduce the range from 0% to approximately 70%, or the range defined by any two of the aforementioned values. To inhibit or suppress.

[0170] In some embodiments, the combination of products provided herein is an inflammation-inducing molecule. It has anti-inflammatory activity that can reduce the level. In some embodiments, this specification The combination of products disclosed in the book is Substance P (SP), related to the calcitonin gene. Reducing the levels of peptides (CGRP), glutamates, or combinations thereof It has anti-inflammatory activity. In other embodiments of this embodiment, the product disclosed herein The combination involves SP, CGRP, glutamates, or other substances released from sensory neurons. For example, levels of combinations such as at least 10%, at least 15%, and at least 2 0%, at least 25%, at least 30%, at least 35%, at least 40%, small At least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, By at least 90%, or at least 95%, or any two of the aforementioned values It has anti-inflammatory activity that can reduce the amount within a defined range. In other embodiments, the combination of products disclosed herein is released from sensory neurons. The levels of SP, CGRP, glutamate, or a combination thereof, for example, about 10 %~approximately 100%, approximately 20%~approximately 100%, approximately 30%~approximately 100%, approximately 40%~approximately 100% Approximately 50% to 100%, approximately 60% to 100%, approximately 70% to 100%, approximately 80% to 100% 100%, approximately 10% to approximately 90%, approximately 20% to approximately 90%, approximately 30% to approximately 90%, approximately 40% to Approximately 90%, approximately 50% to approximately 90%, approximately 60% to approximately 90%, approximately 70% to approximately 90%, approximately 10% to Approximately 80%, approximately 20% to approximately 80%, approximately 30% to approximately 80%, approximately 40% to approximately 80%, approximately 50% to Approximately 80%, or approximately 60% to approximately 80%, approximately 10% to approximately 70%, approximately 20% to approximately 70%, approximately A range of 30% to approximately 70%, approximately 40% to approximately 70%, or approximately 50% to approximately 70%, or before It has anti-inflammatory activity that can be reduced within a range defined by any two of the values ​​described above. ru.

[0171] In some embodiments, the combination of products disclosed herein induces inflammation. It has anti-inflammatory activity that can reduce the level of taglandins. Several embodiments Therefore, the combination of products disclosed herein is an inducement of inflammation released from sensory neurons. For example, the level of the derivative prostaglandin, at least 10%, at least 15%, less at least 20%, at least 25%, at least 30%, at least 35%, at least 4 0%, at least 45%, at least 50%, at least 55%, at least 60%, small At least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, or any two of the aforementioned values It has anti-inflammatory activity that can reduce the amount within the range defined by several. In embodiments, the product combination disclosed herein is released from sensory neurons. The levels of inflammation-inducing prostaglandins were, for example, approximately 10% to approximately 100%, approximately 20% to Approximately 100%, approximately 30% to approximately 100%, approximately 40% to approximately 100%, approximately 50% to approximately 100%, approximately 60% to approximately 100%, approximately 70% to approximately 100%, approximately 80% to approximately 100%, approximately 10% to approximately 90% %, approximately 20% to 90%, approximately 30% to 90%, approximately 40% to 90%, approximately 50% to 90% %, approximately 60% to 90%, approximately 70% to 90%, approximately 10% to 80%, approximately 20% to 80% %, approximately 30% to 80%, approximately 40% to 80%, approximately 50% to 80%, or approximately 60% ~80%, 10%~70%, 20%~70%, 30%~70%, 40% ~70%, or within the range of approximately 50% to approximately 70%, or any two of the aforementioned values. It has anti-inflammatory activity that can reduce inflammation within a defined range.

[0172] In some embodiments, the product combination disclosed herein is 15dPGJ2 It has substantially similar anti-inflammatory activity. In some embodiments, the disclosed herein The product combination is, for example, at least 5% of the activity observed with 15dPGJ2. At least 15%, at least 25%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, At least 85%, at least 90%, or at least 95%, or the aforementioned values It has anti-inflammatory activity in an amount defined by either of the two. Several implementations In this context, the product combinations disclosed herein are observed, for example, in 15dPGJ2. Approximately 5% to 100% of the activity, approximately 50% to 100%, approximately 60% to 100%, and approximately 70%. ~approximately 100%, approximately 80%~approximately 100%, approximately 25%~approximately 90%, approximately 50%~approximately 90%, approximately 6 0% to approximately 90%, approximately 70% to approximately 90%, approximately 80% to approximately 90%, approximately 25% to approximately 80%, approximately 5 0% to approximately 80%, approximately 60% to approximately 80%, approximately 70% to approximately 80%, approximately 25% to approximately 70%, approximately 5 0% to approximately 70%, approximately 25% to approximately 60%, approximately 50% to approximately 60%, or approximately 25% to approximately 50% It has anti-inflammatory activity within a range defined by a percentage or any two of the aforementioned values. .

[0173] In some embodiments, the product combination disclosed herein is all PPAR It possesses anti-inflammatory activity that can stimulate or enhance activity derived from signaling pathways. In some embodiments, the product combinations disclosed herein are used to transmit PPAR signals. It has anti-inflammatory activity that can stimulate or enhance the activity of one or two of the pathways. In some embodiments, the product combinations disclosed herein are PPAR- It has anti-inflammatory activity that can stimulate or enhance α-signaling pathway activity. In one embodiment, the combination of products disclosed herein transmits a PPAR-α signal. For example, at least 5%, at least 15%, at least 25%, less 50% each, at least 60%, at least 70%, at least 80%, or less The amount of stimulation is within the range defined by 90% or any two of the aforementioned values. Enhance. In some embodiments, the combination of products disclosed herein is PPA For example, R-α signaling pathway activity, approximately 5% to approximately 100%, approximately 50% to approximately 100%, Approximately 60% to 100%, approximately 70% to 100%, approximately 80% to 100%, approximately 25% to 9% 0%, approximately 50% to 90%, approximately 60% to 90%, approximately 70% to 90%, approximately 80% to 90% 0%, approximately 25% to approximately 80%, approximately 50% to approximately 80%, approximately 60% to approximately 80%, approximately 70% to approximately 8 0%, approximately 25% to approximately 70%, approximately 50% to approximately 70%, approximately 25% to approximately 60%, approximately 50% to approximately 6 Defined by 0%, a range of approximately 25% to 50%, or any two of the aforementioned values. Stimulate or enhance the area.

[0174] In some embodiments, the product combination disclosed herein is PPAR-δ. It has anti-inflammatory activity that can stimulate or enhance the activity of the Gunar signaling pathway. In embodiments, the product combinations disclosed herein are used in the PPAR-δ signaling pathway. For example, of the pathway activity, at least 5%, at least 15%, at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, or at least Stimulate or enhance an amount within the range defined by 90%, or any two of the aforementioned values. In some embodiments, the product combinations disclosed herein are PPAR- For example, δ signaling pathway activity, approximately 5% to approximately 100%, approximately 50% to approximately 100%, approximately 6% 0% to approximately 100%, approximately 70% to approximately 100%, approximately 80% to approximately 100%, approximately 25% to approximately 90% Approximately 50% to 90%, approximately 60% to 90%, approximately 70% to 90%, approximately 80% to 90% Approximately 25% to 80%, approximately 50% to 80%, approximately 60% to 80%, approximately 70% to 80% Approximately 25% to 70%, approximately 50% to 70%, approximately 25% to 60%, approximately 50% to 60% , or a range defined by approximately 25% to approximately 50%, or any two of the aforementioned values. To stimulate or enhance.

[0175] In some embodiments, the product combination disclosed herein is PPARγSIG It has anti-inflammatory activity that can stimulate or enhance the activity of the cellular signaling pathway. In this application, the combination of products disclosed herein activates the PPARγ signaling pathway. Sexual, for example, at least 5%, at least 15%, at least 25%, at least 50 %, at least 60%, at least 70%, at least 80%, or at least 90% Stimulate or enhance an amount within the range defined by a percentage, or any two of the aforementioned values. In some embodiments, the product combinations disclosed herein are PPARγ-SIG For example, the activity of the signaling pathway is approximately 5% to 100%, 50% to 100%, 60% to Approximately 100%, approximately 70% to approximately 100%, approximately 80% to approximately 100%, approximately 25% to approximately 90%, approximately 5 0% to approximately 90%, approximately 60% to approximately 90%, approximately 70% to approximately 90%, approximately 80% to approximately 90%, approximately 2 5% to approximately 80%, approximately 50% to approximately 80%, approximately 60% to approximately 80%, approximately 70% to approximately 80%, approximately 2 5% to approximately 70%, approximately 50% to approximately 70%, approximately 25% to approximately 60%, approximately 50% to approximately 60%, if The range is approximately 25% to approximately 50%, or a range defined by any two of the aforementioned values. To stimulate or enhance.

[0176] In some embodiments, the combination of products disclosed herein goes from M1 to M2. It has anti-inflammatory activity that can facilitate the determination of phenotypic changes. Several embodiments Therefore, the combination of products disclosed herein is used to apoptose macrophage M1 cells. It has anti-inflammatory activity that can induce inflammatory response. In some embodiments, as described herein The combination of the disclosed products can promote the differentiation of macrophage M2 cells. It has inflammatory activity. In some embodiments, the combination of products disclosed herein is It induces apoptosis in macrophage M1 cells and promotes differentiation of macrophage M2 cells. It has anti-inflammatory activity that can be promoted. In some embodiments, as disclosed herein The combination of products is based on the levels of Th1 cytokines and / or Th2 cytokines. It has anti-inflammatory activity that can regulate the effects of certain embodiments. The product combination shown is interferon-gamma (IF) released from Th1 cells. Nγ), tumor necrosis factor-alpha (TNF-α), interleukin-1b (IL-1b) ), reduce the levels of interleukin-12 (IL-12), or a combination thereof. It has anti-inflammatory activity that can be expressed in some embodiments. The combination is IFNγ, TNF-α, IL-1b, IL- released from Th1 cells. 12, or a combination of these levels, for example, at least 10%, at least 20% , at least 30%, at least 40%, at least 50%, at least 60%, less 70%, at least 80%, or at least 90%, or any of the aforementioned values. It has anti-inflammatory activity that can reduce the amount within the range defined by two factors. In that embodiment, the combination of products disclosed herein is released from Th1 cells. The levels of IFNγ, TNF-α, IL-1b, IL-12, or a combination thereof, For example, approximately 5% to 100%, approximately 10% to 100%, approximately 20% to 100%, and approximately 30%. ~approximately 100%, approximately 40%~approximately 100%, approximately 50%~approximately 100%, approximately 60%~approximately 100%, Approximately 70% to 100%, approximately 80% to 100%, approximately 10% to 90%, approximately 20% to 90% %, approximately 30% to 90%, approximately 40% to 90%, approximately 50% to 90%, approximately 60% to 90% %, approximately 70% to 90%, approximately 10% to 80%, approximately 20% to 80%, approximately 30% to 80% %, approximately 40% to 80%, approximately 50% to 80%, or approximately 60% to 80%, approximately 10% ~70%, approximately 20%~70%, approximately 30%~70%, approximately 40%~70%, or A range of approximately 50% to 70%, or a range defined by any two of the aforementioned values. It has anti-inflammatory activity that can reduce inflammation.

[0177] In some embodiments, the product combination disclosed herein is obtained from Th2 cells It has anti-inflammatory activity that can increase the level of released IL-10. In embodiments, the product combination disclosed herein is derived from I released from Th2 cells. Levels L-10, for example, at least 10%, at least 15%, at least 20% , at least 25%, at least 30%, at least 35%, at least 40%, less 45%, at least 50%, at least 55%, at least 60%, at least 65% %, at least 70%, at least 75%, at least 80%, at least 85%, less Defined by at least 90%, or at least 95%, or any two of the aforementioned values. It has anti-inflammatory activity that can increase the amount within the specified range. In some embodiments, The combination of products disclosed herein is a regeneration of IL-10 released from Th2 cells. For example, Bell's ranges are approximately 5% to 100%, 10% to 100%, 20% to 100%, Approximately 30% to 100%, approximately 40% to 100%, approximately 50% to 100%, approximately 60% to 1 00%, approximately 70% to 100%, approximately 80% to 100%, approximately 10% to 90%, approximately 20% ~90%, 30%~90%, 40%~90%, 50%~90%, 60% ~90%, 70%~90%, 10%~80%, 20%~80%, 30% ~80%, approximately 40%~80%, approximately 50%~80%, or approximately 60%~80% Approximately 10% to 70%, approximately 20% to 70%, approximately 30% to 70%, approximately 40% to 70%, Alternatively, it can be defined as a range of approximately 50% to 70%, or by any two of the aforementioned values. It possesses anti-inflammatory activity that can increase the range of activity.

[0178] In some embodiments, the combination of products disclosed herein is obtained from Th1 cells Released IFNγ, TNF-α, IL-1b, IL-12, or combinations thereof Anti- It has inflammatory activity. In some embodiments, the combination of products disclosed herein is IFNγ, TNF-α, IL-1b, IL-12, or other substances released from Th1 cells For example, levels of combinations such as at least 10%, at least 15%, and at least 2 0%, at least 25%, at least 30%, at least 35%, at least 40%, small At least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, By at least 90%, or at least 95%, or any two of the aforementioned values It can reduce the amount within a defined range, and the amount of IL-10 released from Th2 cells Bell's, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, At least 50%, at least 55%, at least 60%, at least 65%, and at least 70%, at least 75%, at least 80%, at least 85%, at least 90% , or at least 95%, or within the range defined by any two of the aforementioned values. It has anti-inflammatory activity that can increase the amount of [something]. In some embodiments, as specified herein The combination of products disclosed is IFNγ, TNF-α, and IL released from Th1 cells. Levels of -1b, IL-12, or a combination thereof, for example, approximately 5% to approximately 100%. Approximately 10% to 100%, approximately 20% to 100%, approximately 30% to 100%, approximately 40% to 1 00%, approximately 50% to approximately 100%, approximately 60% to approximately 100%, approximately 70% to approximately 100%, approximately 80 %~approximately 100%, approximately 10%~approximately 90%, approximately 20%~approximately 90%, approximately 30%~approximately 90%, approximately 4 0% to approximately 90%, approximately 50% to approximately 90%, approximately 60% to approximately 90%, approximately 70% to approximately 90%, approximately 1 0% to approximately 80%, approximately 20% to approximately 80%, approximately 30% to approximately 80%, approximately 40% to approximately 80%, approximately 5 0% to approximately 80%, or approximately 60% to approximately 80%, approximately 10% to approximately 70%, approximately 20% to approximately 70% %, in the range of approximately 30% to 70%, approximately 40% to 70%, or approximately 50% to 70%, Alternatively, the range defined by any two of the aforementioned values ​​can be reduced, and Th2 cells The levels of IL-10 released from, for example, approximately 10% to approximately 100%, approximately 20% to approximately 1 00%, approximately 30% to approximately 100%, approximately 40% to approximately 100%, approximately 50% to approximately 100%, approximately 60 %~approximately 100%, approximately 70%~approximately 100%, approximately 80%~approximately 100%, approximately 10%~approximately 90%, Approximately 20% to 90%, approximately 30% to 90%, approximately 40% to 90%, approximately 50% to 90%, Approximately 60% to 90%, approximately 70% to 90%, approximately 10% to 80%, approximately 20% to 80%, Approximately 30% to 80%, approximately 40% to 80%, approximately 50% to 80%, or approximately 60% to 80% 80%, approximately 10% to approximately 70%, approximately 20% to approximately 70%, approximately 30% to approximately 70%, approximately 40% to approximately Determined by 70%, or a range of approximately 50% to approximately 70%, or any two of the aforementioned values. It possesses anti-inflammatory activity that can increase the range of efficacy.

[0179] In some embodiments, the combination of products disclosed herein is NFκB signaling It has anti-inflammatory activity that can suppress or reduce the activity of the signaling pathway. In terms of form, the combination of products disclosed herein has NFκB signaling pathway activity For example, at least 10%, at least 20%, at least 30%, at least 40% , at least 50%, at least 60%, at least 70%, at least 80%, or This suppresses at least 90% or an amount within the range defined by any two of the aforementioned values. It has anti-inflammatory activity that can suppress or reduce inflammation. In some embodiments, as specified herein The combination of products disclosed herein exhibits, for example, approximately 5% of NFκB signaling pathway activity. Approximately 100%, approximately 10% to approximately 100%, approximately 20% to approximately 100%, approximately 30% to approximately 100%, approximately 40% to approximately 100%, approximately 50% to approximately 100%, approximately 60% to approximately 100%, approximately 70% to approximately 10 0%, approximately 80% to approximately 100%, approximately 10% to approximately 90%, approximately 20% to approximately 90%, approximately 30% to approximately 90%, approximately 40% to approximately 90%, approximately 50% to approximately 90%, approximately 60% to approximately 90%, approximately 70% to approximately 90%, approximately 10% to approximately 80%, approximately 20% to approximately 80%, approximately 30% to approximately 80%, approximately 40% to approximately 80%, approximately 50% to approximately 80%, or approximately 60% to approximately 80%, approximately 10% to approximately 70%, approximately 2 0% to approximately 70%, approximately 30% to approximately 70%, approximately 40% to approximately 70%, or approximately 50% to approximately 70% Suppress or reduce a range defined by a percentage range or any two of the aforementioned values. It has anti-inflammatory activity that can be utilized.

[0180] In some embodiments, the combination of products disclosed herein is used for ophthalmic formulations and It is administered using a delivery route to the eye. For example, a combination of products can be used as a topical formulation (e.g. For example, enteral preparations (e.g., tablets) such as eye drops, punctal plugs, ointments, lotions, etc. It can be used as a drug, capsule, syrup, etc., or as a parenteral preparation (e.g., injection or intraocular powder). It can be formulated as (for example, ophthalmic solution). Such formulations can be used, for example, as eye drops, eye washes, or Can it be administered ophthalmologically via a local implant (punctal plug), or via intraocular injection? Alternatively, implants, intravitreal injections, intracorneal injections or implants, or subconjunctival injections. It can be administered parenterally via injection or implant. In some embodiments, One or more RNases, as a separate formulation from one or more additional therapeutic agents. They are formulated. In such embodiments, individual formulations may be administered in combination. In one embodiment, one or more RNases combine the products as the same formulation. It is formulated in combination with one or more additional therapeutic agents.

[0181] In some embodiments, viral replication or infection (viruses described herein) Those who treat, alleviate, inhibit, prevent, relieve, recover from, or delay symptoms of an infectious disease. A method is provided. In some embodiments, the method is one or more described herein. A set of products comprising an RNase and one or more further therapeutic agents described herein. The process includes administering the combination. Where used herein, the term “administer” means “dosage.” The document includes one or more RNases and one or more further therapeutic agents disclosed herein. The combination of products is provided to the subject, resulting in clinical, therapeutic, or experimental advantages. This refers to any delivery mechanism that yields the desired result. The composition disclosed herein is administered to a subject. A person skilled in the art can describe the actual delivery mechanism used for eye infections (such as viral conjunctivitis) Ip, location of eye infections (viral conjunctivitis, etc.), eye infections (viral conjunctivitis, etc.) Cause, severity of eye infection (viral conjunctivitis, etc.), eye infection (viral conjunctivitis, etc.) Desired degree of weight-bearing relief, desired duration of weight-bearing relief for eye infections (such as viral conjunctivitis), Viral levels to which treatment, inhibition, mitigation, recovery, prevention, reduction, or suppression is desired. , viral titer, viral replication, protein synthesis, or tRNA, specific signatures that are regulated Virus transmission pathways, inflammatory molecules, prostaglandins, and / or cytokines, viruses Pathogens, specific RNases used and further therapeutic agents, specific R Nase and further drug excretion rate, specific RNase and further Pharmacodynamics of therapeutic agents, properties of any further compounds to be included in the pharmaceutical composition, specific dosage The pathway, specific characteristics of the subject, medical history, and risk factors (e.g., age, weight, overall health). Factors such as health, or any combination thereof, are considered, but are not limited to these. It can be decided by considering the matter.

[0182] In some embodiments, the administration of the combination of products disclosed herein is Administration of the test substance to the conjunctival surface, administration to the ocular surface of the subject, or administration to the conjunctiva and / or of the subject One example is administration to the surface of the eye.

[0183] In some embodiments, the administration of the combination of products disclosed herein is Administration of implants to the conjunctiva of the subject, administration of implants to the eyes of the subject, or the subject This includes the administration of implants to the conjunctiva and / or eye.

[0184] In some embodiments, the administration of the combination of products disclosed herein is point These include injections into the eye, eye irrigation, intraocular injection, intracorneal injection, intravitreous injection, or subconjunctival injection.

[0185] In some embodiments, the combination of products disclosed herein replicates in the eye. or infections (such as viral conjunctivitis, epidemic keratoconjunctivitis, and / or pharyngoconjunctival fever) Treat and reduce the levels of inflammation-inducing molecules and / or inflammation-inducing prostaglandins. Stimulate or enhance the oxisome proliferation-activating receptor (PPAR) pathway signaling, M1 or This facilitates the determination of phenotypic changes to M2, modulates Th1 and Th2 cytokines, and It is administered in a dose sufficient to reduce or suppress NFκB pathway signaling. In some embodiments, one or more RNases and one in the product combination Alternatively, the dosage of multiple additional therapeutic agents may be used for eye infections (viral conjunctivitis, epidemic keratoconjunctivitis). One or more physiological conditions or symptoms associated with fever and / or pharyngoconjunctival fever, etc. It reduces the levels of inflammation-inducing molecules and / or inflammation-inducing prostaglandins, Stimulate or enhance peroxisome proliferation-activating receptor (PPAR) pathway signaling, M1 It facilitates the determination of phenotypic changes from M2 and modulates Th1 and Th2 cytokines. And / or it is administered in a dose sufficient to reduce or suppress NFκB pathway signaling. As used herein, the term "sufficient amount" is equivalent to "effective amount," "effective dose," Examples include "therapeutic effective dose" or "therapeutic effective amount," and RNases disclosed herein This refers to the amount of and / or additional therapeutic agent needed to achieve the desired therapeutic effect, and eye infections (viruses) One or more (such as antacid conjunctivitis, epidemic keratoconjunctivitis, and / or pharyngoconjunctival fever) associated with A sufficient amount to alleviate the physiological condition or symptoms, including inflammatory molecules and / or inflammatory inducers. A sufficient amount to reduce prostaglandin levels, peroxisome proliferation-activating receptor A sufficient amount to stimulate or enhance somatic (PPAR) pathway signaling, M1 to M2 expression To regulate Th1 and Th2 cytokines in sufficient quantities to facilitate the determination of type change A sufficient amount to reduce or suppress NFκB pathway signaling. It can be listed.

[0186] The actual effective dose of RNase and / or further therapeutic agents to a subject can be determined by a person skilled in the art. , type of eye infection (viral conjunctivitis, etc.), position of eye infection (viral conjunctivitis, etc.) Causes of eye infections (such as viral conjunctivitis), severity of eye infections (such as viral conjunctivitis) Severity of symptoms, desirable degree of weight-bearing relief for eye infections (viral conjunctivitis, etc.), eye infections (viral Desired duration of relief from the burden of conjunctivitis, etc., and viruses that are desired to be reduced or suppressed. Level, viral titer, viral replication, protein synthesis, or tRNA, specifically regulated Signaling pathways, inflammatory molecules, prostaglandins, and / or cytokines, specifically A specific viral pathogen, a specific RNase used, and further therapeutic agents used. The excretion rate of specific RNases and further therapeutic agents, the specific RNases and other substances used The pharmacodynamics of various therapeutic agents, the properties of any further compounds to be included in the pharmaceutical composition, and their identification. The route of administration, specific characteristics of the subject, medical history, and risk factors (e.g., age, weight, overall) Examples of factors that may include, but are not limited to, general health, or any combination thereof. This can be determined by considering the factors. Furthermore, the combination of products can be repeatedly applied. If administered, the actual therapeutically effective dose depends on the RNase used and the frequency of administration of further therapeutic agents. Factors such as the degree of decay, half-life, or any combination thereof may be present, but are not limited to these. Further dependence may be possible. RNases and further therapeutic agents disclosed herein or herein The effective amount of the pharmaceutical composition disclosed herein is used in in vitro assays and before administration to humans. Those skilled in the art will know that this can be extrapolated from in vivo administration studies using physical models. It is a matter of knowledge. Considering the differences in effectiveness of various administration routes, the required effective dose can vary greatly. This should be anticipated. For example, ophthalmic administration generally requires a higher dosage level than oral administration. It is expected that oral administration will be performed by intravenous or intravitreal injection. It is expected that a higher dosage level than that of the above will be required. Adjusting for these fluctuations using routine optimizations based on standard experience well known to those skilled in the art. This is possible. The appropriate medication level and pattern for effective treatment will be determined by the attending physician based on the information above. It is preferable to make the decision by considering the factors.

[0187] In some embodiments, one or more RNases disclosed herein Or, the effective amount of any of the further therapeutic agents disclosed herein is, individually, generally about 0 The range is from 0.001 mg / kg / day to approximately 100 mg / kg / day. In some embodiments, This refers to one or more RNases or one or more further therapeutic agents disclosed herein. The effective dose of the therapeutic agent is, individually, at least 0.001 mg / kg / day and at least 0.01 m g / kg / day, at least 0.1 mg / kg / day, at least 1.0 mg / kg / day, small At least 5.0 mg / kg / day, at least 10 mg / kg / day, at least 15 mg / kg / day, at least 20 mg / kg / day, at least 25 mg / kg / day, at least 30 mg / kg / day, at least 35 mg / kg / day, at least 40 mg / kg / day, At least 45 mg / kg / day, at least 50 mg / kg / day, at least 60 mg / kg / day, at least 70 mg / kg / day, at least 80 mg / kg / day, at least 90 mg / kg / day, or at least 100 mg / kg / day, or any of the aforementioned values It can be a quantity within the range defined by any two of them.

[0188] In some embodiments, the combination of products is provided in dosage amounts. In the administration form, the dosage is formulated in the ophthalmic composition. In some embodiments, the ophthalmic composition This includes lampirase and one or more additional therapeutic agents (oxymetazoline and / It contains both (or brimonidine, etc.). In some embodiments, the ophthalmic composition is two Provided in individual compositions, one of which contains lampirase, and one of which This includes one or more additional therapeutic agents (such as oxymetazoline and / or brimonidine). ) includes. In some embodiments, the ophthalmic composition is taken once or more times a day (1 Administer to the subject (2, 3, 4, 5, 6, 7, 8, 9, or 10 times, etc.) several In this embodiment, one or more drops are instilled into one or both eyes in each dose. Therefore, it is administered. In some embodiments, the ophthalmic composition is administered at a given frequency (daily Apply a certain number of droplets to each eye (one or more drops per eye, for example) , over one or more days (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, or more days, or the aforementioned values It is administered for a period of time defined by any two of the following factors.

[0189] In some embodiments, the droplet for administration has a volume ranging from about 5 μL to about 50 μL. 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 μL, or as described above. This includes values ​​within a range defined by any two of the values.

[0190] In some embodiments, a unit dose comprises administering one drop to each eye, where each drop is Lampirase is present in an amount of approximately 0.03% w / v and approximately 0.01% to approximately 0.025% Contains %w / v amount of oxymetazoline. In some embodiments, the daily dose is 1 drop. This involves administering the solution to each eye four times daily, where each droplet is present in an amount of approximately 0.03% w / v. The lampirase and oxymetazoline in amounts of approximately 0.01% to approximately 0.025% w / v include.

[0191] In some embodiments, a unit dose comprises administering one drop to each eye, where each drop is Lampirase is present in an amount of approximately 0.03% w / v and approximately 0.01% to approximately 0.025% Contains %w / v amount of brimonidine. In some embodiments, a daily dose is one drop each The treatment involves administering the solution to the eye four times a day, where each droplet contains approximately 0.03% w / v of the solution present in the eye. It contains prupillase and brimonidine in amounts of approximately 0.01% to 0.025% w / v.

[0192] In some embodiments, the dosage is administered at a dose of approximately 0.03% w / v. Nase and oxymetazoline administered at a dose of approximately 0.01% to 0.025% w / v The dosage is one or more drops once or multiple times per day. In terms of form, the ophthalmic composition is administered to each eye of the subject four times a day, and the ophthalmic composition is approximately 0.03 % w / v amount of lampirase and approximately 0.01% to approximately 0.025% w / v amount of oxy Contains metazoline.

[0193] In some embodiments, the dosage is administered at a dose of approximately 0.03% w / v. It contains naze and brimonidine administered at a dose of approximately 0.01% to 0.025% w / v. The administration is one or more drops once or multiple times per day. Several embodiments The ophthalmic composition was administered to each eye of the subject four times a day, and the ophthalmic composition was approximately 0.03% w A w / v amount of lampirase and approximately 0.01% to approximately 0.025% w / v amount of brimonid It includes n. [Examples]

[0194] Embodiments of the present invention are further defined by the following examples. These examples are for illustrative purposes only. It should be understood that this is shown as a target. From the above considerations and these examples, a person skilled in the art will understand this The essential features of the invention can be confirmed, and without departing from its intent and scope, The embodiments of the invention can be varied and modified in various ways to suit various uses and conditions. Therefore, in addition to the embodiments shown and described herein, the present invention can be implemented. Various modifications of the form will be apparent to those skilled in the art from the above description. Such modifications include, It is also intended to be within the scope of the attached claims. Disclosure of each reference cited herein. The disclosure is incorporated herein by reference in its entirety. .

[0195] Example 1 Ranpirinase and therapeutic agent formulations The following examples show ribonuclears in combinations of products formulated for ophthalmic administration. We provide a formulation that contains -se together with a therapeutic agent.

[0196] Ophthalmic formulations of lampirase and oxymetazoline were prepared. The formulations were at pH 7.4. 0.03% w / v (25 mM) lampirase in PBS, 0.01%~0.025% w It contains oxymetazoline in amounts in the range of / v and benzalkonium chloride (BAK). Ta.

[0197] Example 2 Compatibility of lampirase and therapeutic agents The following examples illustrate ribonuclears in combinations of products formulated for ophthalmic administration. To demonstrate compatibility with the treatment agent for -ze.

[0198] It contains 0.03% w / v lampirase with oxymetazoline or brimonidine. A formulation was prepared. The formulation was analyzed by chromatography to determine that the therapeutic agent was present in lampirase. We investigated whether interference occurred. Several chromatography methods (cation exchange chromatography) were used. Examples include rough and size exclusion chromatography and benzalkonium chloride ( BAK analysis was used.

[0199] For cation exchange chromatography, the following solutions were used for analysis: Diluent ( PBS (pH 7.4), oxymetazoline HCl (0.5 mg / mL), placebo, and Birampirase. Prepare an oxymetazoline HCl (0.5 mg / mL) solution in a diluent. Prepared. Remove both the lampirase and its placebo from the refrigerator and warm to room temperature. Then, I put it into an HPLC vial.

[0200] Lampirase showed a peak at RT=20.8 min and a shoulder at RT=17.7 min. A peak was observed. For the oxymetazoline chromatogram, the diluted solution was measured at 1.4 min. Except for a small peak observed after the 'c', no oxymetazoline peak was observed. Therefore, oxymetazoline does not interfere in any way in the cation exchange method. It seems so.

[0201] For size exclusion chromatography, the following solution was used for analysis: Diluent (pH 7). 4 PBS), oxymetazoline HCl (0.5 mg / mL), placebo, and lanpi Lunaze. A solution of oxymetazoline HCl (0.5 mg / mL) was prepared in a diluent. Remove both the lampirase and its placebo from the refrigerator and warm them to room temperature. I put it in an LC vial.

[0202] Lampirase showed a peak at RT=17.4. Oxymetazoline chromatogram Regarding mu, no oxymetazoline peak was observed. Therefore, oxymetazoline Lynn does not appear to interfere in any way with the size exclusion method.

[0203] Benzalkonium chloride (BAK) analysis was performed using the following solution: Diluent (PBS p H7.4), oxymetazoline HCl (0.05 mg / mL), placebo, and lanpi Lunaze. Dilute oxymetazoline HCl (0.5 mg / mL) solution (10 times) with the diluent. Diluted to 0.05 mg / mL. Both lampirase and its placebo were removed from the refrigerator. The sample was removed, warmed to room temperature, and placed in an HPLC vial.

[0204] The diluent used in this method was 50:50 water:methanol, but oxymetazoline To determine whether it interferes with the BAK peak, dissolve the oxymetazoline solution in PBS. It was prepared in liquid form.

[0205] Typical time-to-shoot (RT) for the BAK peak is C12=6.3 mins, C14=8.0 mins, and C16=9 mins. The time is 4 minutes. Lampirase chromatograms were obtained at RT 6.8 min, 8.5 min, and 9.9 min. It showed a peak at RT2.36 min. Oxymetazoline showed a peak at RT2.36 min, but BAK The peak did not interfere. Oxymetazoline did not cause any interference in the BAK method. That's it.

[0206] These analyses assess the formulation compatibility of lampirase with oxymetazoline in ophthalmic formulations. It has been proven.

[0207] Example 3 Efficacy and safety of the product combination This example involves formulation into an ophthalmic preparation for treating patients with acute adenovirus conjunctivitis. The efficacy and safety of the combined product of lampirase and oxymetazoline. To demonstrate sexuality.

[0208] Approximately 0.03% w / v of lampirase and approximately 0.025% w / v of oxymethicone An ophthalmic preparation containing tazoline is prepared in the vehicle. Approximately 0.03% w / v is added to the vehicle. Prepare a control formulation containing either a certain amount of lampirase or the vehicle alone.

[0209] The formulation is instilled into each eye four times a day (QID) for five days. Patients are divided into a 2:1:1 ratio. Randomize to receive either a combination formulation, lampirase in the vehicle, or the vehicle alone. The drug will be administered once. The study will be conducted using a double-mask, blinded trial. A total of 352 patients will participate. Of these, 176 took combination formulations, and 88 had ranpirinase in their vehicle. 88 people took the medication, and only the vehicle was taken.

[0210] The selection criteria for the study include the following: Each patient must meet the following criteria: 1. On the first day of hospital visit (Day 1, baseline), the patient must be 18 years of age or older, and of either sex or This refers to people of any race. 2. Written informed consent or, if the patient cannot read it, local law and Consent as defined by the guidelines of the Human Relations Committee (HREC) for research involving human subjects. A person who has the will and ability to provide. 3. Individuals who have the willingness and ability to follow all instructions and attend all scheduled research visits. 4. A clinical diagnosis of suspected acute adenoviral conjunctivitis in at least one eye. Those who exhibit both of the following minimal clinical signs in the eyes as described above: • Conjunctival redness: Minimum grade "1" on a scale of 0-3 • Watery eye discharge: Minimum grade "1" on a scale of 0-3 5. Adenoviral conjunctivitis consistent with the first day of hospital visit within 72 hours in the same eye. Patients who have reported the presence of signs and symptoms (one eye showing signs / symptoms for more than 72 hours) If present, the other eye must have had signs / symptoms within the last 72 hours and meet all other selection / exclusion criteria. (Note that they may still be eligible if they meet the following conditions.) 6. In the same eye meeting the minimum grade 1+ for conjunctival redness and watery discharge, Patients who tested positive for AdenoPlus® on the first day of hospital visit. 7. Prohibited drug use and treatment during the study period (exclusion criteria 12, 14, and 19) Those who are willing to avoid (see reference). 8. Individuals willing to discontinue wearing contact lenses during the study period. 9. Do you agree to submit the results of your pregnancy test on the 1st and 4th day of your visit prior to registration? Those who are not likely to become pregnant. 10. Participants must agree to use a reasonable method of contraception during the study period or have no possibility of pregnancy. Contraceptive methods include: oral, transdermal, injectable, or implantable contraceptives. Pregnancy, intrauterine devices, abstinence, and sterilization of the partner. Female patients undergo hysterectomy and bilateral ovarian sterilization. If you have undergone a tubal removal or bilateral tubal ligation, or if at least 12 months have passed since menopause, There is no possibility of pregnancy. 11. Early Treatment Study of Diabetic Retinopathy (ETDRS) chart or illiteracy Minimum separation angle of each eye when measured using an ETDRS equivalent chart for patients The logarithm (logMAR) of 0.60 or better is the best corrected visual acuity (BSCVA) with glasses. A person who possesses something.

[0211] The exclusion criteria for the study include the following: Each patient must not meet the following criteria: 1. The patient is susceptible to or has low tolerance to any component of the test drug or diagnostic test. Someone who knows. 2. Do you have a history of eye surgery or trauma within the 12 weeks prior to the first day of your visit? Those who have such plans during that period. 3. Any active inflammation of the eye other than acute adenoviral conjunctivitis (e.g., uveitis) Individuals with allergic conjunctivitis, rosacea, or iritis. 4. Eye infections other than acute adenovirus conjunctivitis (e.g., bacterial, fungal, or other eye infections) Individuals exhibiting or presenting clinical signs of a viral infection (such as herpes). 5. Individuals with subepithelial corneal infiltration in the eye being studied at baseline. 6. At baseline, interventions not included as part of the study protocol procedure must be performed on the target eye. Those who possess a pseudomembrane as a key component. 7. Recurrent corneal erosion syndrome, ulcerative keratitis, or xerophthalmolysis (meibomian gland dysfunction) Those with a history of other eye surface diseases (including the following). 8. Individuals with significant blepharitis, eyelid abnormalities, significant inflammation of the eyelid margin, or ptosis. 9. Individuals with lacrimal duct obstruction in either eye. 10. Can the study parameters during slit-lamp examination be interfered with, or should the principal investigator be informed otherwise? Therefore, any other clinically significant findings that may interfere with the determined data. 11. Any clinically significant findings of the retina or optic nerve (observed on non-dilated fundus examination) Or, the research parameters may be interfered with in either eye, or otherwise the principal investigator A person who has received a pre-diagnosis that could disrupt the data determined by [the relevant authority]. 12. Within 7 days of registration, any topical or systemic antiviral drug or topical antiviral drug Alternatively, systemic corticosteroid use was performed, and no localized ocular symptoms occurred during the study period. Those who have not yet started systemic antiviral medication. Inhalation, intranasal, and Topical dermatological steroids (excluding those applied to the face) are acceptable. 13. Anyone who starts or continues using a hot or cold compress during the examination period. 14. Within two hours of the first day of hospital visit, any topical eye drops (such as tear substitutes and diagnostic agents) should be administered. (The study uses) and all topical eye drops (as required for this protocol) were used during the study period. Those who cannot discontinue (excluding diagnostic drugs and antibiotics). Furthermore, patients In the past 72 hours, have you used any other topical ophthalmic medications formulated in artificial tears or hydrogels? If that were the case. 15. A woman who is pregnant, breastfeeding, or planning to become pregnant; or who has tested positive on a pregnancy test. woman. 16. Any uncontrolled systemic disease (not having received a stable regimen in the past 30 days) A patient suffering from or debilitating disease (e.g., cardiovascular disease, hypertension, diabetes, or cystic fibrosis) If you have an illness or are taking medications known to affect the ocular surface and / or tear film Those who are doing so. 17. Anyone planning an overnight hospital stay during their research. 18. Any uncontrolled autoimmune disease (not having received a stable regimen in the past 30 days) If you have a disease or are taking drugs known to affect the ocular surface and / or tear film, Those who are taking the medication. 19. Will the investigational drug or investigational device be used prior to the study (within 30 days of the start of the study procedure)? Those who are expected to use it simultaneously. 20. As the principal investigator, is there a possibility that the patient's risk may increase or that the research data may be confused? Patients who may or may have a condition or circumstances that could significantly interfere with their participation in the study. 21. You are unlikely to follow the study instructions or will not complete all required visits for the study. Is the likelihood of completion low, or, in the opinion of the principal investigator, is the patient risk significant? Having a condition or situation that could confuse research results or significantly hinder patient participation in the research. patient.

[0212] The efficacy endpoints include the following: The primary efficacy endpoint includes: conjunctival redness of the eye Severity (classified into scales 0-3 using a valid photo-based reference scale) and water Acute adenoid in the eyes of study subjects on day 2 of hospital visit, measured by the total amount of conjunctival discharge. Clinical improvement from baseline in inflammatory conjunctivitis.

[0213] The primary secondary efficacy endpoints include: 1. Cell culture immunofluorescence assay (CC-IF) A) Eradication of adenovirus on the second day of hospital visit as assessed by; 2. Watery conjunctival volume on each day of hospital visit The sum of the scores using the reference scale for secretions and conjunctival redness is none (score = 0) When measured, complete recovery of acute adenoviral conjunctivitis in the eyes of study subjects on the second day of hospital visit. Complete clinical healing; and 3. Presence or absence of subepithelial invasion on day 5 of hospital visit.

[0214] Secondary efficacy endpoints include: 1. Cell culture immunofluorescence assay (CC-IFA) 1. Eradication of adenovirus at each follow-up visit (except on the second day of the visit), as assessed by [method not specified]; 2. Study subjects at each follow-up visit were evaluated by quantitative polymerase chain reaction (qPCR). 3. Change from baseline in mean viral titer levels in the eye by qPCR Percentage of patients with viral titers lower than the assessed limit of detection (LLOD); 4.qPC Percentage of patients with a viral titer of less than 100 copies / mL as assessed by R; 5. Severity of conjunctival redness (using a valid photo-based reference scale, scale 0-3) Each visit day (independently measured by classification) (Day 2, Day 3, Day 4 of the visit, and Clinical improvement of acute adenoviral conjunctivitis in the eyes of the study subjects (on the 5th day after hospital visit); 6. The severity of watery conjunctival discharge (classified into 0-3 on a valid reference scale) This measurement was taken on each visit day (independently on the 2nd, 3rd, 4th, or 5th visit days). Clinical improvement of acute adenoviral conjunctivitis in the eyes of the study subjects (Day 7); 7. Conjunctiva of the eye No redness (score = 0) (using a valid photo-based reference scale, scale 0-3) When measured by (classified as) each day of visit (independently on the 2nd day of visit, the 3rd day of visit, the 2nd day of visit, the 3rd day of visit) Clinical aspects of acute adenoviral conjunctivitis in the eyes of study subjects (day 4, or day 5 after hospital visit) Complete healing; 8. No watery conjunctival discharge (score = 0) (using a valid reference scale) Each visit day (classified into 0-3) was measured independently on the 2nd day of visit, the 3rd day of visit, and the 2nd day of visit. Clinical aspects of acute adenoviral conjunctivitis in the eyes of study subjects (4th day of hospitalization, or 5th day of hospitalization) Bedside healing; 9. Sum of scores using the reference score for watery conjunctival discharge and bulbar conjunctival redness. If the result is "none" (score = 0), then each visit day (independently, on the 3rd and 4th visit days) Complete clinical resolution of acute adenoviral conjunctivitis on day 5 of hospital visit; 10. Study subjects for each visit day (independently on the 2nd, 3rd, 4th, or 5th day of the visit) Expansion of clinical cure for acute adenoviral conjunctivitis in elephant eyes. Expansion of clinical cure is, The following two clinical signs are defined as scores of 0 or 1: watery conjunctival discharge and bulbar conjunctival discharge. Red; 11. Mean baseline conjunctival redness score in the eyes of the study subjects on each visit day. Changes in these; 12. Mean baseline of watery conjunctival secretion score in the eyes of the study subjects on each visit day. Changes from the baseline; 13. Total scores for conjunctival redness and watery conjunctival discharge on each visit day. Average change from baseline; 14. Presence or absence of subepithelial invasion on each visit day other than the 5th visit day. 15. Severity of subepithelial invasion on each visit; and 16. Other clinical findings for each visit. Severity of bed signs and clinical symptoms: lacrimation, burning sensation, blurred vision, photophobia, foreign body sensation, itching, eyelid dizziness Swelling, or erythema of the eyelids.

[0215] Safety is assessed by the following: 1. Slit-lamp biomicroscopy (non-dilated fundus examination) 2. BSCVA; 3. Urine pregnancy test; 4. Adverse events (AEs); 5. Study reference manual Patients using the visual analog scale defined in the eye drop measurement method 5 minutes after instillation (self-administered) Tolerability based on the patient's evaluation of droplet comfort in the same eye on the first day of hospital visit.

[0216] The overview of a continuous variable includes sample size, mean, standard deviation, median, minimum, and maximum. The details of the discrete variables include frequency and percentage. Generally, the data is summarized by treatment group. The difference between treatment groups is calculated as the study vehicle and the change from baseline (CF). B) is calculated as follow-up visits - baseline. Baseline visits are calculated during the clinical trial. Defined as the last non-missing value before the start of treatment. Unless otherwise specified, all efficacy analyses. This is a two-tailed α=0.05 test.

[0217] The study population includes the following: The inclusive trial (ITT) population consists of all randomized patients. In ITT, subjects are analyzed under a randomized treatment regimen.

[0218] The modified inclusive trial (mITT) population had taken the investigational drug at least once and visited the hospital on the first day. In eyes that meet the clinical requirements (conjunctival redness and watery discharge, grade 1+) The mITT population consists of a subset of ITT patients who tested positive for CCIFA on the first day of hospital visit. It is used for efficacy analysis, where patients are analyzed under randomized treatment.

[0219] The protocol-following (PP) group is a subset of the mITT group and is the main focus of the study. Includes patients without significant protocol violations that are likely to have a serious impact on the outcome. PP The population is used for sensitivity analysis of effectiveness, which analyzes patients under the conditions they actually received. Important considerations related to study selection or exclusion criteria, trial implementation, patient management, or patient assessment. Key protocol deviations are identified before the unmasking procedure.

[0220] The safety population is defined as all randomized patients who have received at least one dose of the study drug. Includes. The safety population is analyzed at the time of treatment and used for safety analysis. For any reason Even if there is a problem, the data will not be excluded.

[0221] The unit of analysis is the eyes of the study subject for an overview of all efficacy and ocular safety. Both eyes met the clinical requirements on the first day of visit (conjunctival redness and watery discharge, grade 1+). If the following conditions are met and CC-IFA is positive on day 1 of the visit, the eyes to be studied will be considered as follows: This eye has the highest overall clinical symptom score (conjunctival redness + watery discharge). Both eyes visited the clinic once. If the total clinical symptom score is the same on day 1, the eye studied is the right eye (OD); the other eye The eye is considered the designated partner eye. Only one eye of the subject meets the clinical symptom requirements on the first day of hospital visit (eye The patient met the criteria of grade 1+ (bulbar conjunctival redness and watery ocular discharge) and tested positive for CC-IFA on day 1 of hospital visit. If the eye is of the same sex, this eye is the eye of study. The other eye is considered an uncertified companion eye. .

[0222] The subjects of study in the ITT population and the safety population were the mITT population and the subjects within the mITT population. Defined as the eye of the body being studied. For subjects not in the mITT population, the eye of the body being studied. This is defined as the eye with the highest total clinical symptom score (conjunctival redness + watery discharge) on the first day of hospital visit. If the total clinical symptom score on the first day of visit is the same for both eyes, the right eye will be the one studied. Yes (OD). The other eye met the clinical symptom score requirements on the first day of visit (conjunctival redness and watery sclera). If the eye meets the criteria for Grade 1+ of ocular secretions, the other eye is considered the designated companion eye. If so, the other eye is considered the uncertified companion eye. The subject level scale is the subject level It is represented as follows.

[0223] Subjects treated with the formulation show improvement in eye infections. Combination formulation (combina Treatment with (tion formation) (rampilase and oxymetazoline) Total clinical experience on day 2 of hospital visit between the eyes of the study subjects treated with the vehicle alone and the eyes of the study subjects treated with the vehicle alone. Mean change from baseline (CFB) of symptom score (conjunctival redness + watery discharge) The difference ≠ 0, and as a result, the combination formulation had a higher average total CFB on the second day of hospital visit than the vehicle alone. The clinical signs score was excellent, and the following primary secondary endpoints were evaluated with a two-sided α=0.05: Test in a hierarchical order:

[0224] Between eyes of study subjects treated with the combination formulation and eyes of study subjects treated with the vehicle Adenovirus was eradicated on the second day of hospital visit (evaluated by CC-IFA) in the eyes of the study subjects. The difference in percentages is 0.

[0225] Between eyes of study subjects treated with the combination formulation and eyes of study subjects treated with the vehicle Adenovirus was eradicated on the second day of hospital visit (evaluated by CC-IFA) in the eyes of the study subjects. The difference in percentages is not 0.

[0226] Eyes of study subjects treated with the combination formulation and eyes treated with lampirase in the vehicle. Total clinical sign score (conjunctival redness + watery discharge) on the second day of visit, compared to the eyes of the study subjects. The difference in change from the mean baseline (CFB) is 0.

[0227] Eyes of study subjects treated with the combination formulation and eyes treated with lampirase in the vehicle. The mean total clinical signs score (conjunctival redness + watery sclera) on day 2 of the study compared to the eyes of the study subjects. The difference in eye secretions is ≠ 0.

[0228] Eyes of study subjects treated with lampirase in the vehicle and eyes of study subjects treated with the vehicle Adenovirus was eradicated on the second day of hospital visit in the case of elephant eye disease (assessed by CC-IFA). The percentage difference in the eyes studied is 0.

[0229] Eyes of study subjects treated with lampirase in the vehicle and eyes of study subjects treated with the vehicle Adenovirus was eradicated on the second day of hospital visit in the case of elephant eye disease (assessed by CC-IFA). The percentage difference in the eyes studied is ≠ 0.

[0230] Between eyes of study subjects treated with the combination formulation and eyes of study subjects treated with the vehicle The difference in the percentage of eyes in the study that were completely clinically healed on the second day of hospital visit was 0.

[0231] Between eyes of study subjects treated with the combination formulation and eyes of study subjects treated with the vehicle The difference in the percentage of eyes in the study that were completely clinically healed on the second day of hospital visit was ≠ 0.

[0232] Between eyes of study subjects treated with the combination formulation and eyes of study subjects treated with the vehicle The difference in the percentage of eyes in the study that did not have subepithelial invasion on the 5th day after hospital visit was 0.

[0233] Between eyes of study subjects treated with the combination formulation and eyes of study subjects treated with the vehicle The difference in the percentage of eyes in the study that did not have subepithelial invasion on the 5th day after hospital visit was 0.

[0234] To maintain the Type I misclassification rate, a hierarchical fixed-order test is used.

[0235] Approximately 50% of patients were randomized and either after two days of hospitalization or after the study was discontinued. An interim analysis will be conducted. The decisions to be made in the interim analysis will take into account the futility based on the following key outcome measures. The question is whether to discontinue the trial: mean CFB total clinical symptom score on day 2 of hospital visit. Superiority The O'Brien-Fleming type α consumption function (Z for superiority in the middle) Statistic = 2.96259, one-sided alpha = 0.00153; Note: This is an interim analysis. This is a penalty for a type I error, and the study was discontinued midway due to its high effectiveness. (and not intended) and futility (Z-statistic for futility in the middle = 0.02379, Unconstrained power family α consumption function for one-sided alpha = 0.49055 We will use a group succession method with the phi parameter = 3. Therefore, the remaining unilateral alpha for the final analysis is 0.02450 (bilateral alpha = 0.049). The Z-statistic is equivalent to 1.96860.

[0236] Patients who tested positive in the AdenoPlus® test had a positive rate of 8% when confirmed by culture. Since the rate was 0%, approximately 352 patients will be randomized in this study. 9% of the treatment group Eight mITT subjects (study eyes) and 49 mITT patients in the vehicle treatment group. Regarding the sample size of the subjects (the eyes studied), the average CFB of the eyes studied on the second day of hospital visit. True difference in total clinical symptom scores -1.0, common standard deviation 1.75, and sequential intermediate scores for designated groups. Assuming an analysis strategy, the average total clinical symptom score of the eyes of the study subjects on the second day of hospital visit will be... The detection power for detecting the difference in A is 90%. The safety profile of the combination formulation is... Aiming to create the study, 140 mITT subjects (study subjects' eyes) and bihik We assume a sample size of 70 mITT subjects (study eyes) in the treatment group. Furthermore, the power of the study for its primary outcome measure exceeds 97%.

[0237] Furthermore, the 140 mITT subjects (study subjects' eyes) and vehicle treatment in the treatment group were also investigated. In the 70 mITT subjects (study subjects' eyes) in the control group, the CC-IFA assay was performed. The true ratio of eyes in the study where adenovirus eradication was confirmed is related to the combination formulation. The values ​​for the alpha are 0.65, and for the vehicle, they are 0.35, and the two-sided alpha = 0.049. Assuming this is the case, adenovirus eradication will be confirmed by CC-IFA assay on the second day of hospital visit. The detection power for detecting differences in the ratio of eyes in the studied subjects exceeds 97%.

[0238] In the lampirase vehicle treatment group, approximately 70 mITT subjects (study eyes) In the 70 mITT subjects (study eyes) in the vehicle treatment group, CC-IFA The true ratio of eyes in the study in which adenovirus eradication was confirmed by assay was combined. The ratio for the formulation is 0.65, and for the vehicle it is 0.35, and both sides are alpha. Assuming a value of 0.049, adenovirus can be detected by CC-IFA assay on the second day of hospital visit. The detection power for detecting differences in the ratio of eyes in the study subjects where eradication has been confirmed is 95%.

[0239] Mean CFB total clinical symptom score and CC-I score of the study subjects' eyes on day 2 of hospital visit The proportion of eyes in the study in which adenovirus eradication was confirmed by the FA assay was observed in both eyes. Therefore, with the planned sample size, we will demonstrate the superiority of the combination formulation over the vehicle. The detection power for this is over 95%.

[0240] Primary analyses of the primary efficacy endpoint and primary secondary efficacy endpoint in the mITT population This analysis utilizes observational data only if more than 5% of the primary efficacy measures are not missing. In the event of missing data, the intervention event was handled in the following format:

[0241] 1) Ignoring discontinuation of investigational drug and suboptimal compliance [treatment strategy] —].

[0242] 2) If discontinued due to lack of efficacy or adverse events, the missing data should be a. Non-simple For significant missing data, we use the vehicle-based Markov chain Monte Carlo (MCMC) methodology. For monotonic missing data, regression methodology was used to determine the CFB total clinical symptom score of the eyes of the study subjects. [Virtual strategy] to perform multiple substitutions; b. The eradication of adenovirus in the eyes of the study failed and Substitute a single value; c. Complete clinical assessment of acute adenoviral conjunctivitis in the eyes of study. [Virtual Strategy] substitute a single value as a failure of target healing; d. For non-monotonic missing values, use Using Hickle-based Markov chain Monte Carlo (MCMC) methodology, monotonic missing data can be processed. Then, using the logistic regression methodology, we apply multiple substitutions to the subepithelial invasion of the eye being studied [tentative]. [Thought Strategy]

[0243] 3) If discontinuation was not performed, or if discontinuation was due to reasons other than lack of efficacy or adverse events If missing data occurs, a. For non-monotonic missing data, a treatment-based approach is used. The Lukoff chain Monte Carlo (MCMC) methodology is used, and the regression methodology is used for monotonic missing data. This is used to perform multiple substitution on the CFB total clinical symptom score of the eyes under study [hypothetical strategy]; b. Treatment-based Markov chain Monte Carlo (MCMC) methodology for non-monotonic missing data. Using this method, and for monotonic missing data, regression methodology was used to determine the adenovirus level of the eyes of the study subjects. [Virtual Strategy]: Multiple substitutions are made to the level (determined to be adenovirus eradicated); c For non-monotonic missing data, treatment-based Markov chain Monte Carlo (MCMC) methodologies are used. For monotonically missing data, regression methodology was used to analyze the total clinical symptoms score of the CFB of the eyes of the study subjects. Substitute multiple values ​​into A (the score indicating complete clinical recovery from acute adenovirus conjunctivitis). [Virtual Strategy]; d. For non-monotonic missing data, use a treatment-based Markov chain Monte. We use the Carlo (MCMC) methodology, and for monotonic missing data, we use the logistic regression methodology. [Hypothetical strategy] involves multiple substitutions for subepithelial invasion of the eye being studied. Acute adenoiditis Adenovirus eradication (evaluated by CC-IFA) and complete clinical cure of rustic conjunctivitis. Multiple substitution of missing values ​​for binary primary and secondary outcome measures of healing was performed using continuous measurement (each in CC-IFA). Therefore, the assessment of adenovirus levels and CFB total clinical symptom score was completed. Next, the response variable is determined from these.

[0244] Sensitivity analysis of the primary and primary secondary effectiveness variables was performed, failing to process all missing data (A (Denovirus eradication, complete clinical cure, and subepithelial infiltration) are substituted, and vehicle Multiple substitution of mITT using the methodology (CFB Total Clinical Symptom Score) for all missing data Substitute "T" as success (adenovirus eradication, complete clinical cure, and subepithelial infiltration). mITT; observations using a treatment-based methodology (CFB Total Clinical Symptom Score) with multiple substitutions This will be done using mITT with observational data and PP groups with observational data. Which further sensitivity analyses may be performed, and which analyses should be specified in the statistical analysis plan (SAP)? .

[0245] The primary efficacy endpoint of the CFB total clinical symptom score on the second day of hospital visit was measured using a sequential method across treatment groups. Summarize using summary statistics. Primary analysis of the primary efficacy endpoint of the CFB total clinical symptom score. This includes a linear model that includes the fixed effect of baseline total clinical symptom score as a covariate and treatment. Complete using the LSM. Least Squares Mean (LSM) CFB Total Clinical Symptom Score and LSM The difference in CFB total clinical symptom scores, along with the corresponding two-sided 95% confidence interval (CI) and p-value. The following is shown: A two-sample t-test is used as a sensitivity analysis for the above major models to compare the treatments. .

[0246] Adenovirus eradication on day 2 of hospital visit (evaluated by CC-IFA), CFB on day 2 of hospital visit Total clinical symptom score, adenovirus eradication (assessed by CC-IFA), complete recovery on the second day of hospital visit. The primary secondary efficacy endpoints were overall clinical resolution and the absence of subepithelial invasion on day 5 of hospital visit. Discrete or continuous summary statistics (CFB total clinical symptom score only) were used for treatment groups. To summarize: The primary secondary efficacy endpoints for adenovirus eradication and complete clinical cure, respectively. The primary analysis of the eye includes the fixed effects of the corresponding baseline score as a covariate and treatment. The analysis is completed using a logistic regression model. The adjusted odds ratio and a small percentage of the added odds ratio are used. Adenovirus eradication (and clinical cure) and a small percentage of adenovirus eradication (and clinical cure) The difference in bed-induced healing is shown along with the corresponding two-sided 95% confidence interval (CI) and p-value.

[0247] Sensitivity analysis for the above major models and primary analysis of subepithelial invasion: Pearson's Chi Square test or Fisher's exact test (if any predicted number of cells is less than 5) Compare the treatments using the following: the difference between the combination formulation and the lampirase in the vehicle. The primary analysis of the primary secondary efficacy endpoint of the CFB Total Clinical Symptom Score on the second day of hospitalization was performed, and the primary efficacy The analysis will be completed using the same analytical strategy as the primary analysis of the evaluation items.

[0248] Continuous summary statistics for the ITT population showing the change from baseline total clinical symptom score. Summarize using the quantity, identical strategies to the mITT population, primary substitution strategies, and observations. The study will be conducted using data only, comparing treatment groups.

[0249] Safety analysis uses discrete summaries at the patient and event levels to analyze all procedures. Treatment-induced adverse events (TEAEs) in the patient's study eye and the adjoining eye (ocular and systemic adverse events) Summarize all TEAEs (both TEAEs and TEAEs). (During the first treatment or afterward) To identify organ-specific major classifications and basic terms (defined as AEs that occur or worsen in the organs), Encoding is performed using the International Medical Terminology Dictionary.

[0250] The performance of slit-lamp biomicroscopy is summarized at each visit using discrete summary statistics. BSCVA data, discrete summaries (change in row count from baseline and previous visits) (The percentage of patients whose numbers changed by 3 or more rows (greater than 0.3 LogMAR) is used for each Please summarize this information upon your arrival at the clinic.

[0251] Demographic characteristics (i.e., age, sex, race, ethnicity, and iris color), medical history, The historical data of the eye was summarized and aggregated by treatment group and, as needed, discrete or continuous summaries were created. Use measurements to present a complete summary of all patients.

[0252] Example 4 In vivo antiviral effect of the product combination The antiviral activity of the product combination was evaluated in viv using a rabbit eye replication model. Evaluate with o. To perform this assay, 25 New Zealand White cattle (NZ Rabbits (W) were given the general anesthetics ketamine and xylazine, and the local anesthetic propalaquinol. Anesthetize using [a specific method]. In each rabbit's eye, administer 50 μL of adenovirus serotype Ad5(3) ×10 7 pfu / mL) is used to randomly cut corneal epithelial segments (12 cross-hatched segments with a 25-gauge sterile needle). (Troc) Inject locally afterwards. Close your eyes and make sure the virus comes into contact with the entire surface of your eye. Gently rub the area for 5 seconds. When administered to both eyes, it is necessary without sacrificing statistical validity. It is possible to reduce the number of animals that are affected. After 24 hours, the rabbits were subjected to the following five local treatments. Randomly assign to one of the treatment groups: (1A) 25 μM lampirase only (n= 5); (1B) 25 μM lampirase + one or more additional therapeutic agents (n=5); (1C) 10 μM lampirase + one or more additional therapeutic agents (n=5); (1D ) 0.9% physiological saline as a negative control (n=5); and (CC) 0 as a positive control 0.5% cidofovir (n=5). Both eyes of treated rabbits (1A, 1B, 1C, and 1D) The treatment is administered 8 times a day for 9 days. Both eyes of the control group (CC) are treated 2 times a day for 7 days. All spheres Dispense the solution (37 μL droplets) into an electronic pipette (EDP;Rai) set to multiplex dispensing mode. Instill eye drops using (nin, Oakland, Calif.). 0, 1, 3, 4, 5 after vaccination. Proparacaine should be administered at least one hour after the final dose on days 7, 9, 11, and 14. After local anesthesia is administered, the eye is wiped with a cotton swab to remove any residue from the tear film and the surface of the cornea and conjunctiva. Collect the novirus. Place each eye sample from a different eye into a tube containing 1 mL of culture medium, and then... Freeze at -70°C until the splaque assay.

[0253] The Ad5 titer of eye samples was assayed by performing a plaque reduction assay. The sample is diluted 1:10, and these dilutions are mixed in a 24-well container containing A549 monolayer. Inoculate onto two wells of a cytoplasmic plate. Allow the virus to breathe under a 5% CO2-water vapor atmosphere. Adsorb at 37°C for 3 hours. After adsorption, add 1 mL of culture medium + 0.5% methylcellulose to each wafer. Add to the solution and incubate the plate at 37°C in a 5% CO2-water vapor atmosphere. Seven days later, the cells were stained with 0.5% gentian violet and examined using a dissecting microscope (25×). Use to count the number of plaques. Next, calculate the viral titer and the amount per milliliter. It is expressed as plaque-forming units (PFU / mL). The data obtained from the study is Fischer's Analysis of variance (ANOVA) with pairwise comparisons and True Epista and / or M The analysis will be performed using X² analysis with initab statistical software. Confidence level P ≤ 0. We consider a value of 05 to be significant.

[0254] Animals administered the product combinations were either lampirase alone (1A) or physiological saline alone. Compared to animals administered (1D) or cidofovir alone (CC), the ocular virus Replication or infection will decrease.

[0255] Example 5 In vivo anti-herpes effect of the product combination The antiviral efficacy of the product combination is measured by viral replication and clinical signs and clinical We will evaluate both symptoms in vivo using a herpes rabbit model. To perform this assay, 20 female rabbits weighing 1.5–2.0 kilograms were subjected to general anesthesia. The anesthetics ketamine (40 mg / kg) and xylazine (4 mg / kg), as well as local anesthetics. Anesthesia is administered using propalacine.

[0256] On day 1, after corneal epithelial irregular segmentation (three interconnected circles using 7.5 mm trefin) Each rabbit received 50 μL of HSV-1 (3.2 × 10) into both eyes. 5 Local injection of pfu (eye) Close your eyes and gently rub them for 5 seconds to ensure the virus makes contact with all surfaces of your eyes.

[0257] Rabbits will be randomly assigned to one of the following four topical treatment groups: (1) Pharmaceutical (2) Negative control containing only the carrier; (2) 10 μM lampirase + one or more further treatments Test composition of therapeutic agent; (3) 25 μM lampirase + one or more further therapeutic agents Test composition; and (4) 0.15% ganciclovir ophthalmic gel as a positive control. Each group consisted of 5 animals. This includes rabbits. Both eyes of the rabbits were examined four times a day for 10 days for each of groups 1, 2, and 3. For item 4, the treatment will be administered 5 times a day for 10 days. Treatment will begin on the second day.

[0258] On days 2, 3, 5, 7, 9, 11, and 14, both eyes of each rabbit were examined using a slit lamp. Test using the following method to grade HSV-1 dendritic keratitis on a scale of 0 to 4. The light inspection was performed using a 0.1% sodium fluorescein and cobalt blue filter. This procedure visualizes typical corneal epithelial keratitis caused by ocular HSV-1 infection, and each test... The HSV-1 dendritic keratitis will be evaluated and graded during the examination. The grading scale for dendritic keratitis is as follows: As follows: 0 = No dendrites 0.5 = 1 to 5 dendrites 1.0 = 6 to 10 dendrites 1.5 = 11-15 dendrites 2.0 = 16-20 dendrites or geographic ulcers covering less than a quarter of the corneal surface. 2.5 = More than 20 dendrites or a geographic pattern covering more than 1 / 4 but less than 1 / 3 of the corneal surface. ulcer 3.0 = Multiple corneal ulcers covering more than one-third but less than half of the corneal surface, accompanied by geographic ulcers or interstitial invasion. Dendrites 3.5 = Multiple corneal ulcers covering more than half but less than two-thirds of the corneal surface, accompanied by geographic ulcers or interstitial invasion. Dendrites 4.0 = Multiple dendrites covering more than two-thirds of the corneal surface with geographic ulcers or interstitial invasion

[0259] Furthermore, after each slit-lamp examination, the viral cultures of the eye were subjected to local anesthesia with 0.5% proparacaine. The eye virus is then obtained by wiping the upper and lower fornix of each eye with a cotton swab. Obtain the culture at least one hour after the final dose of the test drug to avoid lesion expansion. Do not culture the cornea. Place each swab from each eye individually into a tube containing 1 ml of growth medium, and Freeze at -80°C until the illus plaque assay.

[0260] Each frozen HSV-1 eye sample to be titrated was thawed and serially diluted (1:10) into three portions. Dilutions are obtained. Then, each dilution (0.1 ml / well) is placed in a 24-well plate. Inoculate Vero cells or A549 cells in the wells of the solution. Inoculate the virus with 5% CO2- Adsorption is carried out at 37°C for 1 hour under a water vapor atmosphere. After adsorption, 1 ml of growth medium + 0.5% methyl Chill cellulose was added to each well, and the plate was placed in a 5% CO2-water vapor atmosphere for 37 minutes. Incubate at °C. Stain the plate with 0.5% gentian violet after 5 days. The number of plaques per well is counted under a dissecting microscope (25×). Ocular HSV-1 The titer is calculated and expressed as plaque-forming units per ml (PFU / ml). The data is then processed. Statistics using True Epistat and / or Minitab statistical software The analysis will be conducted accordingly. The outcome measure will be the number of HSV-1 positive cultures per day per total culture, and the number of U Virus titer, discharge period, 1-day keratitis score, number of eyes with keratitis, and time of resolution of keratitis. Includes intervals. A confidence level of p ≤ 0.05 is considered statistically significant.

[0261] Animals administered with the combination of products either received the carrier alone (1) or ganciclovir alone ( 4) Compared to animals administered, viral replication or infection in the eye was reduced, and dendritic cornea Clinical signs / symptoms based on the inflammation severity scale improve.

[0262] Example 6 In vivo anti-congestive effect of the product combination The anti-congestive activity of the product combination was evaluated in vivo using a rabbit congestion model. Worth it. To perform this assay, 25 New Zealand White (NZW) cattle were used. Rabbits were given the general anesthetics ketamine and xylazine, and the local anesthetic propalacaine. Anesthetize using a drug. Administer 0.01% histamine or 0.3% arachidonic acid locally. This induces redness in both eyes of each rabbit. The degree or severity of redness is assessed for each rabbit. We will assess it.

[0263] After 24 hours, the rabbits will be randomly assigned to one of the following five topical treatment groups: (1A) 25 μM lampillase only (n=5); (1B) 25 μM lampillase + 1 One or more additional therapeutic agents (such as vasoconstrictors) (n=5); (1C) 10 μM ampoules Lunaze + one or more additional therapeutic agents (such as vasoconstrictors) (n=5); (1D) Negative 0.9% physiological saline as a control (n=5); and (CN) 0.1% as a positive control. % Nafadrine (n=5). All rabbit groups (1A, 1B, 1C, 1D, and CN) Treat both eyes eight times a day for nine days. All topical solutions (37 μL droplets) are administered using a multiplex dispensing method. The electronic pipette (EDP; Rainin, Oakland, Calif.) set to D Apply the eye drops. Monitor the degree of redness daily throughout the course of treatment.

[0264] Animals administered the combination of products showed different results: lampirase alone (1A), and physiological saline solution. Compared to animals administered only (1D) or napadrine alone (CDV), ocular redness was observed. It decreases.

[0265] Example 7 Arterial explantation culture model of vasoconstriction Arterial explant cultures are provided in the culture medium as a vasoconstriction model. It is prepared by obtaining the arterial segment, with a coverslip containing a chamber with culture medium. Transfer to the following: Treat the explant culture with the treatment group described in Example 6, i.e., as follows: (1A) 25 μM lampirase only; (1B) 25 μM lampirase + one or more other Therapeutic agents (vasoconstrictors, etc.); (1C) 10 μM rampilase + 1 or more Other therapeutic agents (such as vasoconstrictors); and (CN) 0.1% Nafadoli as a positive control. Use a negative control consisting only of culture medium. Replace the culture medium and treatment agent daily.

[0266] The vasoconstrictive effect of arterial explant cultures will be monitored in each group. Cultures administered with the combination of drugs were either treated with lampirase alone, napadrine alone, or cultures. Compared to cultures treated with only the culture medium, the vasoconstrictive effect is improved.

[0267] Example 8 Eye tolerance and toxicity of the product combination The tolerability and toxicity of the product combination will be assessed.

[0268] To assess the tolerability of the product combination, NZW treated in Examples 4 and 5 Rabbits were assayed for eye irritation using the Draize scale for eye lesions. The classification of eye irritation will be done using the Maximum Mean Score (MMTS) on days 3 and 9. Each rabbit's eyes are evaluated. The MMTS score is as follows: 0.0~ 0.5, Non-irritating (N); 0.6-2.5, Substantially non-irritating (PN); 2.6-15.0 Minimal stimulation (M1): 15.1-25.0, mild stimulation (M2): 25.1-50.0 Moderate stimulation (M3): 50.1-80.0, Severe stimulation (S): 80.1-100.0 Extreme stimulation (E); and maximum stimulation (Mx) between 100.1 and 110.0. Set of products. It is highly tolerable and low-irritation.

[0269] To assess in vitro cytotoxicity, 1 × 10⁶ units were placed in a 96-well plate. 5 Seed A549 cells at a concentration of cells / mL and incubated overnight at 37°C in 5% CO2. The product combination was analyzed using lampirase at concentrations of 1.0 μM, 10 μM, and 50 μM. Dilute sequentially to include [the specified substance]. After removing the tissue culture medium, 100 μL of each dilution is 80%~ Add to 3 wells of a 96-well plate containing 100% confluent cells. Control For example, 100 μL of lysis buffer containing 0.25% TRITON(registered trademark) X-100. Add the solution to 6 wells (positive cytotoxic control) and either do not contain lampirase or do not contain lampirase. Add 100 μL of tissue culture medium containing only the enzyme to 6 wells (negative cytotoxicity control). Each test reagent-treated and control-treated sample was incubated on an A549 monolayer in 5% CO2 at 37°C for 2 days. Incubate. Add 100 μL aliquot of fluorescent stain to each well and stain the cells. Incubate in 5% CO2 at 37°C for 1 hour. Fluorescent stain (ALAMARBLUE (Registered Trademark, Invitrogen, Carlsbad, Calif.) is metabolically It acts as a redox indicator that is reduced to a fluorescent form by active living cells. Using a 00 / 27-nm excitation filter and a 620 / 40-nm emission filter, sensitivity Using a plate reader (Biotek Synergy 2; Biotek) at 35 To interpret, cytotoxicity is the percentage of surviving cells after exposure to lampirase (% cell damage). Harmfulness = 100 - [(Median fluorescence with fluorescent agent / Median fluorescence without drug) × 100] (where "drug" is the median fluorescence with the fluorescent agent) The "product" is one of the three concentrations of lampirase in the product combination. (This is a lysis buffer, and "no drug" or "ranpirinase only" are negative controls.) Therefore, the determination is made. The recognized difference is determined by the nonparametric Klaskal-Wallis ANOVA. The results were statistically evaluated using the Duncan multiple comparison method, and significance was defined as a confidence level of P ≤ 0.05.

[0270] From the test, a combination of products containing lampirase was found in A549 cells 2 days after exposure. It has been clearly shown to exhibit significant cytotoxicity.

[0271] While aspects of this specification are emphasized by reference to specific embodiments, those skilled in the art will be able to do so. These embodiments of disclosure are intended solely to illustrate the principles of the inventions disclosed herein. It should be understood that this is easily recognizable. Therefore, unless explicitly instructed otherwise The subject matter of the disclosed invention is a specific compound, composition, article, apparatus, methodology described herein. It should be understood that there are absolutely no restrictions on protocols and / or reagents, etc. Furthermore, a person skilled in the art can make certain changes, modifications, rearrangements, alterations, additions, subtractions, and The subcombinations thereof may not deviate from the intent of this specification, and the teachings contained herein may not deviate from the intent of this specification. It will be recognized that this is possible in accordance with the following attached claims and Any claims introduced thereafter will not include all such changes, modifications, rearrangements, alterations, additions, or replacements. Includes pulls and subcombinations as if they were in their true intent and scope. This is intended.

[0272] Certain embodiments of the present invention are described herein, and these embodiments are used to carry out the invention. This includes the best known form to the inventor for doing so. Of course, if you read the above description, you will see these Modifications of the described embodiments will be obvious to those skilled in the art. With the expectation that various modified forms will be used as needed, the inventors have stated that the present invention is described herein. It is intended to be implemented in a form different from what is specifically described. The inventions described in the claims attached to this specification, as permitted by applicable law, are all modifications of the subject matter of the inventions described herein. This includes states and equivalents. Furthermore, unless otherwise indicated or clearly stated in this specification, Unless there is a contradiction, all possible variations obtained by arbitrarily combining the above embodiments are this It is included in the invention.

[0273] Any grouping of other embodiments, elements, or processes of the present invention shall be construed as limiting the present invention. Each group member shall not be a member of any other group disclosed herein. - May be mentioned or stated in any combination of the following in the claims: convenience and / or For patentability reasons, one or more members of a group may be included in or removed from the group. It is expected that in the event of any such inclusion or deletion, this specification will be amended. It is believed that this includes, and therefore all Markush Groups used in the attached claims. It satisfies the description.

[0274] Unless otherwise indicated, the features, items, quantities, and parameters used in this specification and claims are not specified. All numbers representing periods, characteristics, and durations are expressed in all cases with the term "approximately". It shall be understood that it is decorated. Where used herein, the term "about" means The modified feature, item, quantity, parameter, property, or duration is the feature, item described. A value greater than or less than the value of an item, quantity, parameter, property, or period, positive or negative. It means to include a range of 10 percent. Therefore, it does not indicate otherwise. To the extent that otherwise, the numerical parameters described herein and in the attached claims are subject to change. They are similar values. For example, in a mass spectrometer, the mass of the given analyte is determined by slight variations in its mass. Therefore, the term "approximately" in the context of the mass of an ion or the mass-to-charge ratio of an ion can be + / This refers to -0.50 atomic mass units. At a minimum, it limits the application of the doctrine of equivalents to the scope of the claim. Since it is not intended to be so, each numerical representation should take into account at least the reported significant figures. It should be interpreted by applying standard rounding techniques.

[0275] The term "may" or "can" relating to an embodiment or aspect of an embodiment. When using "(can)", this term means "may not". Alternatively, it can also have the meaning of "cannot." This specification may include embodiments or aspects of embodiments as part of the subject matter of the invention. When disclosing that it is possible to do so, any negative limitation or exclusive provisos are also clearly implied. The embodiments or forms of the invention may or may not be included as part of the subject matter of the invention. This means that it is not possible. In a similar manner, relating to an embodiment or aspect of an embodiment When using the term "optionally," such embodiments or aspects of embodiments are considered to be related to the invention. This means that it may or may not be included as part of the subject matter of the invention. To taste. Whether such negative limitation or exclusive proviso applies depends on the negative limitation. Or, based on whether the exclusive proviso is referenced in the subject matter of the claimed invention. ru.

[0276] Although the present invention is described extensively using approximate values ​​for numerical ranges and values, specifically The numerical ranges and values ​​listed in the examples are reported as accurately as possible. However, any The numerical range or value is necessarily due to the standard deviation found in each of the test measurements. It inherently contains certain errors. Numerical ranges of values ​​cited herein refer to each number within the range. It is intended solely to function as an abbreviation for referring to values ​​individually. Unless otherwise indicated, each value in the numerical range is cited individually in this specification. Thus, it is incorporated into this specification.

[0277] The term "a" as used in the context of describing the present invention (particularly in the context of the following claims) The terms "an," "the," and similar references are used unless otherwise indicated in this specification. Unless otherwise clearly contradictory, it shall be interpreted as referring to both singular and plural. Furthermore, ordinal markers (such as "first," "second," "third," etc.) are applied to the identified elements. ) is used to distinguish elements, and unless otherwise specifically indicated, this ordinal marker is used for such elements Without indicating or implying that the number of such elements is required or limited, This does not indicate a specific position or order. Unless otherwise indicated in this specification or from the context, Unless there is a clear contradiction, all methods described herein may be performed in any appropriate order. This is possible. Any example or language used to indicate an example provided herein (for example, "na When using "do"), it is intended solely to make the present invention easier to understand, and the original clay The scope of the present invention as described herein is not limited. Unless otherwise stated herein, the implementation of the present invention may not be limited. This shall be interpreted as indicating any element not described in the essential claim.

[0278] Specific embodiments disclosed herein consist of "languages" or "essentially from languages." The use of "to become" may further restrict the claim. When used in a claim, Whether requested or added in amendment, the transitional phrase "consisting of" in the claim Eliminate any elements, processes, or components that are not explicitly stated. Transitional term: "to essentially become from." This does not substantially affect the identified materials or processes, as well as the fundamental and novel characteristics. The scope of the claim is limited to embodiments of the present invention as described in the claim. This is essentially or explicitly described and enabled in this specification.

[0279] All patents, patent publications, and other publications mentioned and identified herein, even if If so, the compositions and methodologies described in such publications that may be used in connection with the present invention are described. For the purpose of disclosure, the entirety thereof is incorporated separately and expressly as reference herein. These publications are provided solely for the purpose of disclosure prior to the filing date of this application. Furthermore, the inventors may not claim that any of the content is prior art or for any other reason constitutes prior art. This should not be interpreted as an acknowledgment that they do not have prior rights to such disclosure. All statements regarding dates or expressions relating to the content of the documents are made available to the applicants. This information is based on facts and does not constitute any endorsement regarding the accuracy of the dates or content of these documents. It is not that.

[0280] The terminology used herein is intended solely to describe specific embodiments. Without intending to limit the scope of the invention, this invention is defined solely by the claims. Therefore, the present invention is not limited to what has been accurately shown and described.

Claims

[Claim 1] A combination of products that inhibit or delay eye infections, wherein the combination of products is A therapeutically effective dose of one or more ribonucleases (RNases), and The present invention comprises one or more further therapeutic agents in a therapeutically effective amount, wherein the further therapeutic agent is a vasoconstrictor, an antibiotic, an immunomodulatory compound, a steroid, or a combination thereof. The combination of products.