KR20220014025A - Pharmaceutical composition comprising napamostat mesylate and dexamethasone or a salt thereof as an active ingredient - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising nafamostat mesylate and dexamethasone or a salt thereof as active components, wherein the composition according to one aspect is an antiviral pharmaceutical composition which has a preventive or therapeutic effect on coronavirus infection (COVID-19), and can exhibit an increased prevention and treatment effect of coronavirus infection compared to single administration by administering two components in combination, and thus has an effect of alleviating side effects that can be caused by an overdose or long-term administration of each drug.

Description

Pharmaceutical composition comprising napamostat mesylate and dexamethasone or a salt thereof as active ingredients {Pharmaceutical composition comprising napamostat mesylate and dexamethasone or a salt thereof as an active ingredient}

The present invention relates to a pharmaceutical composition for preventing or treating coronavirus infection (COVID-19), and more particularly, to a coronavirus infection (COVID-19) comprising nafamostat mesylate and dexamethasone or a salt thereof as active ingredients. ) relates to a pharmaceutical composition for prevention or treatment.

Nafamostat mesilate (NM) is a drug used as a continuous renal replacement therapy (CRRT) anticoagulant to replace renal function in critically ill patients. Alternatively, it is also used in patients with low platelets.

Napamostat mesylate is a serine protease inhibitor, has a very short half-life of 5 to 8 minutes, and a low molecular weight of 539.6 Da, so it can be easily excreted from the body through extracorporeal circulation, and coagulation factors IX, X, XIIa and VIIa to exhibit an anticoagulant effect, so it is widely used as a thrombosis treatment or anticoagulant (Shuji Mori et al. J. Pharmacol. Sci. 92:420-423, 2003).

Napamostat mesylate has been developed and marketed only as an injection formulation so far, and is used by dissolving it in a solvent immediately before use and administering it intravenously. However, such an intravenous administration method may have a risk of contamination or infection in the dissolution process or administration process prior to use, and is a suitable method for obtaining a fast-acting effect. There is a need to develop various dosage forms for use in new indications of

Dexamethasone (1-Dehydro-16α-methyl-9α-fluorohydrocortisone; Dexamethasone; C ₂₂ H ₂₉ FO ₅ ) is a known compound represented by the following Chemical Formula 3, and is a type of corticosteroid drug. Dexamethasone is a derivative of prednisolone, which has been widely used in the past, and is used to treat various diseases such as rheumatism, skin diseases, severe allergies, asthma, and chronic obstructive pulmonary disease. It is effective in preventing nausea and vomiting. In addition, there is little retention of sodium and water, and the anti-inflammatory action is about 35 times that of cortisone, about 6 times that of prednisolone, and about 5 times that of triamcinolone, so it shows an excellent effect even with a small dose. is known

[Formula 3]

Dexamethasone is a white, odorless, crystalline powder that is easily absorbed from the gastrointestinal tract after oral administration. Transcortin and albumin are plasma proteins that bind glucocorticosteroids. The parts remaining free without binding to the two proteins exhibit biological activity, and the binding of dexamethasone to plasma proteins occurs less than most other corticosteroids. Therefore, high-dose and long-term administration of dexamethasone increases the proportion of free form, which increases toxicity and side effects. After oral administration, dexamethasone reached the highest plasma concentration within 1 hour and decreased by half.

The period is about 36-54 hours, and the bioavailability is about 80-90%. It is known that taking with food does not decrease the amount of absorption, but the absorption time is slightly delayed. Dexamethasone is soluble in organic solvents and relatively insoluble in water. However, as a low-dose drug, solubility is not a problem in drug action. Dexamethasone has been reported to have a distribution volume of 2 L/kg after absorption, is slightly metabolized in the liver, and excreted up to 65% in the urine within 24 hours. Dexamethasone is currently being developed and marketed in the form of injections, eye drops, and tablets depending on indications. For tablets, 0.5-8 mg is recommended to be administered in divided doses 1-4 times a day depending on age and symptoms. If the indication is nausea and vomiting after chemotherapy, the recommended dose is 4-20 mg.

Recently, it has been reported that nafamostat has an antiviral effect to inhibit the infection of Corona Virus Infectious Disease-19 (COVID-19).

Specifically, Markus Hoffmann et al. published a paper that the participation of TMPRSS2 is required to help the binding of ACE2 and SARS-CoV-2 when SARS-CoV-2 enters the host cell (Hoffmann et al., Cell 181, 271). ?280 April 16, 2020). Also, as a result of analysis through SARS-CoV-2 cell culture experiments, Meehyun Ko et al. showed that nafamostat had the strongest antiviral efficacy against COVID-19 among about 3000 drugs, and inhibited 50% of viral infections. It was reported that the IC50 of nafamostat was 600 times (2.2nm vs. 1.3㎛) superior to that of remdesivir (Meehyun Ko, bioRxiv, May 12, 2020, https://doi.org/10.1101/2020.05.12.090035).

Accordingly, the inventors of the present application have prepared nafamostat mesylate and dexamethasone or a salt thereof to exhibit an effective preventive or therapeutic effect on coronavirus infection-19 (COVID-19) and to be used safely without side effects even when taken for a long time. The present invention was completed by preparing a pharmaceutical composition comprising an active ingredient.

An object of the present invention is (1) as an active ingredient, nafamostat, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof; And (2) as an active ingredient, dexamethasone, pharmaceutically acceptable salts, stereoisomers, solvates or tautomers thereof; to provide a composition.

Another object of the present invention is (1) as an active ingredient, nafamostat, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof; And (2) as an active ingredient, dexamethasone, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof; a pharmaceutical for preventing or treating coronavirus infection (COVID-19) by mixing To provide a method for preparing a composition.

Another object of the present invention is to provide a method for preventing or treating coronavirus infection (COVID-19) in an individual, comprising administering the pharmaceutical composition according to the present invention to an individual in need thereof.

One aspect of the present invention is (1) as an active ingredient, nafamostat, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof; and (2) as an active ingredient, dexamethasone, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, for preventing or treating a pharmaceutical composition for coronavirus infection (COVID-19) provides

As used herein, the term “nafamostat” refers to “6-[amino(imino)methyl]-2-naphthyl 4-{[amino(imino)methyl]amino}benzoate”, It may be a compound represented by the following formula (1).

[Formula 1]

The napamostat may be commercially available or directly synthesized.

As used herein, the term “pharmaceutically acceptable salt” refers to conventional acid addition salts used in the pharmaceutical field, for example, derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid. Salts and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid or salts derived from organic acids such as trifluoroacetic acid. The salts also include conventional metal salt forms, for example salts derived from metals such as lithium, sodium, potassium, magnesium, or calcium. The acid addition salt or metal salt may be prepared according to a conventional method.

For example, the pharmaceutically acceptable salt of nafamostat may be nafamostat mesilate salt.

The nafamostat mesylate salt may be a compound represented by the following formula (2).

[Formula 2]

As used herein, the term “stereoisomer” may mean a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but optically or sterically different, and specifically, a diastereomer, enantiomer, geometric isomer, or It may be a conformational isomer.

As used herein, the term “solvate” may refer to a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. . Preferred solvents therefor may be solvents that are volatile, non-toxic, and/or suitable for administration to humans, for example, the solvate may be a hydrate.

As used herein, the term “tautomer” is a type of structural isomer that has the same chemical formula or molecular formula but has a different connection method of members, for example, a keto-enol (keto-eno) structure. It may mean that the structure changes by continuing to cycle between both isomers.

As used herein, the term “dexamethasone” is “1-Dehydro-16α-methyl-9α-fluorohydrocortisone”, and may be a compound represented by the following formula (3).

[Formula 3]

The dexamethasone may be commercially available or directly synthesized.

The definition of 'pharmaceutically acceptable salt', 'stereoisomer', 'solvate' or 'tautomer' for dexamethasone is the same as defined for nafamostat above.

For example, the pharmaceutically acceptable salt of dexamethasone may be dexamethasone monosodium phosphate salt, dexamethasone disodium phosphate salt or dexamethasone acetate salt.

As used herein, the term "active ingredient" or "pharmaceutically effective amount" refers to a disease, disorder, condition or condition, or one or more symptoms thereof, sufficient for alleviating, inhibiting the progression, or preventing in the course of practicing the invention provided herein. It may mean any amount of the composition employed. The effective amount (or dosage) is 0.0001 mg to 10,000 mg, 0.001 mg to 1,000 mg, 0.01 mg to 1,000 mg, 0.01 mg to 500 mg, 0.01 mg to 100 mg, 0.1 mg to 1,000 mg, 0.1 mg to 500 mg per day. , 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 1 mg to 1,000 mg, 1 mg to 500 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 25 mg, 5 mg to 1,000 mg, 5 mg to 500 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 10 mg to 1,000 mg, 10 mg to 500 mg, 10 mg to 100 mg, 10 mg to 50 mg, or 10 mg to 25 mg.

The nafamostat, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof is 0.001 wt% to 95 wt%, for example, 0.01 wt% to 80 wt%, 0.01 wt% to the total weight of the composition 60% by weight, 0.01% to 40% by weight, 0.01% to 30% by weight, 0.01% to 20% by weight, 0.01% to 10% by weight, 0.01% to 5% by weight, 0.05% to 60% by weight %, 0.05% to 40% by weight, 0.05% to 30% by weight, 0.05% to 20% by weight, 0.05% to 10% by weight, 0.05% to 5% by weight, 0.1% to 60% by weight, 0.1 wt% to 40 wt%, 0.1 wt% to 30 wt%, 0.1 wt% to 20 wt%, 0.1 wt% to 10 wt%, or 0.1 wt% to 5 wt% may be included.

The nafamostat, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof may be included in the composition in an amount of 20 to 250 mg, for example, 20, 30, 50, 75, 100, 150, 200 or 250 mg may be included.

The napamostat, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof may have a particle size of 1 to 250 microns, 1 to 100 microns, or 1 to 10 microns in the composition.

The dexamethasone, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof is 0.001 wt% to 95 wt%, for example, 0.01 wt% to 80 wt%, 0.01 wt% to 60 wt%, based on the total weight of the composition %, 0.01% to 40%, 0.01% to 30%, 0.01% to 20%, 0.01% to 10%, 0.01% to 5%, 0.05% to 60%, 0.05% to 40% by weight, 0.05% to 30% by weight, 0.05% to 20% by weight, 0.05% to 10% by weight, 0.05% to 5% by weight, 0.1% to 60% by weight, 0.1% by weight % to 40% by weight, 0.1% to 30% by weight, 0.1% to 20% by weight, 0.1% to 10% by weight, or 0.1% to 5% by weight.

The dexamethasone, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof may be included in the composition in an amount of 20 to 250 mg, for example, 20, 30, 50, 75, 100, 150, 200 or 250 mg. can be included as

The dexamethasone, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof may have a particle size of 1 to 250 microns, 1 to 100 microns, or 1 to 10 microns in the composition.

The nafamostat, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, and the dexamethasone, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof are 10:1 to 1:10 It is preferably included in a weight ratio, and more preferably included in a weight ratio of 3:1 to 1:3.

As used herein, the term "Coronavirus disease 2019 (COVID-19)" is a coronavirus, the official name is SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2: SARS-CoV-2), It refers to a disease with symptoms such as fever, cough, fatigue, shortness of breath, loss of sense of smell and loss of taste.

The composition may exhibit antiviral activity by decomposing the TMPRSS2 enzyme protein that helps the corona virus to bind to ACE2 when it enters the host cell.

The pharmaceutical composition may be formulated in a suitable form together with a pharmaceutically acceptable carrier, and may further contain an excipient or diluent. The carrier includes all kinds of solvents, dispersion media, oil-in-water or water-in-oil emulsions, aqueous compositions, liposomes, microbeads and microsomes.

The pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. In addition, various drug delivery materials used for oral administration may be included. In addition, the carrier for parenteral administration may include water, a suitable oil, saline, aqueous glucose and glycol, and the like, and may further include a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, etc. in addition to the above components. For other pharmaceutically acceptable carriers and agents, reference may be made to those described in the following literature (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).

The pharmaceutical composition of the present invention may be administered to mammals including humans by any method. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration. can be

The pharmaceutical composition of the present invention may be formulated as a formulation for oral administration or parenteral administration according to the administration route as described above. In the case of a formulation for oral administration, the composition of the present invention may be formulated as a powder, granule, tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension, etc. using methods known in the art. can For example, oral preparations can be obtained by mixing the active ingredient with a solid excipient, grinding it, adding suitable adjuvants, and processing it into a granule mixture to obtain tablets or dragees. Examples of suitable excipients include sugars, including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches, including corn starch, wheat starch, rice starch and potato starch, cellulose, Cellulose, including methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose, and the like, fillers such as gelatin, polyvinylpyrrolidone, and the like may be included. In addition, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant if necessary. Furthermore, the pharmaceutical composition of the present invention may further include an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, and a preservative. Formulations for parenteral administration may be formulated in the form of injections, creams, lotions, external ointments, oils, moisturizers, gels, aerosols and nasal inhalants by methods known in the art. These formulations are described in Remington's Pharmaceutical Science, 19th ed., Mack Publishing Company, Easton, PA, 1995, which is a commonly known recipe for all pharmaceutical chemistry.

The total effective amount of the composition of the present invention may be administered to a patient as a single dose, or may be administered by a fractionated treatment protocol in which multiple doses are administered for a long period of time. The dosage is determined by considering various factors such as the formulation method, administration route, and number of treatments, as well as the patient's age, weight, health status, sex, disease severity, diet, and excretion rate, etc. Those of ordinary skill in the art will be able to determine an appropriate effective dosage of the composition of the present invention when considering.

The pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route and administration method as long as the effect of the present invention is exhibited.

Another aspect of the present invention is (1) as an active ingredient, nafamostat, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof; (2) as an active ingredient, dexamethasone, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof; (3) one or more diluents; (4) one or more glidants; And (5) provides an oral pharmaceutical composition for the prevention or treatment of corona virus infection (COVID-19) comprising one or more disintegrants.

The oral pharmaceutical composition may further include a pharmaceutically acceptable diluent or carrier. The diluent may be any one or more selected from the group consisting of microcrystalline cellulose, lactose, pregelatinized starch, mannitol, and dicalcium phosphate. The carrier may be an excipient, a disintegrant, a binder, a lubricant, a glidant, or a combination thereof. The excipient may be microcrystalline cellulose, lactose, low-substituted hydroxycellulose, or a combination thereof. The disintegrant may be at least one selected from the group consisting of sodium starch glycolate, croscarmellose sodium, and combinations thereof. The disintegrant may be included in the composition in an amount of 2.5 wt% to 25 wt% based on the weight of the composition. The binder may be polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, or a combination thereof. The lubricant may be magnesium stearate, silicon dioxide, talc, or a combination thereof. The glidant may be colloidal silicon dioxide. The glidant may be included in the composition in an amount of 1% to 10% by weight based on the weight of the composition. The diluent or carrier, such as a glidant or disintegrant, may have a particle size of 1 to 250 microns, 1 to 100 microns, or 1 to 10 microns.

The oral pharmaceutical composition may further include a surfactant. The surfactant may be at least one selected from the group consisting of sodium lauryl sulfate and Poloxamer 188. The sodium lauryl sulfate may be included in the composition in an amount of 0.5 wt% to 1.5 wt% based on the weight of the composition.

The oral pharmaceutical composition may further include a lubricant. The lubricant may be at least one selected from the group consisting of magnesium stearate and talc. The magnesium stearate may be included in the composition in an amount of 0.5 wt% to 1.5 wt% based on the weight of the composition.

The oral pharmaceutical composition comprises 10 to 85% of microcrystalline cellulose; 4% sodium starch glycolate; 0.5% magnesium stearate; 2.5% colloidal silicon dioxide; 1% sodium lauryl sulfate; and 25% croscarmellose sodium.

The oral pharmaceutical composition comprises 10 to 85% of microcrystalline cellulose; 4% sodium starch glycolate; 0.5% magnesium stearate; 2.5% colloidal silicon dioxide; and 25% croscarmellose sodium.

The oral pharmaceutical composition comprises 10 to 85% of microcrystalline cellulose; 4% sodium starch glycolate; 0.5% magnesium stearate; and 2.5% of colloidal silicon dioxide may be further included.

The oral pharmaceutical composition may be formulated as a dosage form for oral administration. For example, the pharmaceutical composition may be in the form of tablets, pills, powders, dispersions, granules, capsules, suspensions, internal solutions, emulsions, or syrups. Specifically, the pharmaceutical composition may be in the form of a tablet, capsule or dispersion formulation. In the case of formulation, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used.

The disintegration time of the oral pharmaceutical composition may be 15 minutes or less. The dissolution rate of the composition may be 80% or more within 30 minutes.

Another aspect of the present invention is (1) as an active ingredient, nafamostat, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof; And (2) as an active ingredient, dexamethasone, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof; a pharmaceutical for preventing or treating coronavirus infection (COVID-19) by mixing To provide a method for preparing a composition.

The pharmaceutical composition may be formulated in a suitable form together with a pharmaceutically acceptable carrier, and may further contain an excipient or diluent.

The pharmaceutical composition may be formulated as a formulation for oral or parenteral administration.

Another aspect of the present invention is (1) as an active ingredient, nafamostat, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof; (2) as an active ingredient, dexamethasone, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof; (3) one or more diluents; (4) one or more glidants; And (5) to provide a method for preparing an oral pharmaceutical composition for preventing or treating coronavirus infection (COVID-19) by mixing one or more disintegrants.

The oral pharmaceutical composition may be prepared by further comprising a pharmaceutically acceptable diluent or carrier.

The oral pharmaceutical composition may be formulated as a dosage form for oral administration. For example, the pharmaceutical composition may be prepared in the form of tablets, pills, powders, dispersions, granules, capsules, suspensions, internal solutions, emulsions, syrups, and the like.

Another aspect of the present invention provides a method for preventing or treating coronavirus infection (COVID-19) in an individual, comprising the step of orally or parenterally administering the pharmaceutical composition to an individual in need thereof.

The pharmaceutical composition is as described above.

The subject may be a mammal, such as a human, cow, horse, pig, dog, sheep, goat, or cat. The subject may be an individual in need of prevention or treatment of coronavirus infection.

The administration is 0.0001 mg to 10,000 mg, 0.001 mg to 1,000 mg, 0.01 mg to 1,000 mg, 0.01 mg to 500 mg, 0.01 mg to 100 mg, 0.1 mg to 1,000 mg, 0.1 mg to 500 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 1 mg to 1,000 mg, 1 mg to 500 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 25 mg , 5 mg to 1,000 mg, 5 mg to 500 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 10 mg to 1,000 mg, 10 mg to 500 mg, 10 mg to 100 mg, 10 mg to 50 mg, or 10 mg to 25 mg may be administered. However, the dosage may be prescribed in various ways depending on factors such as formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate and reaction sensitivity, and those skilled in the art The dosage may be appropriately adjusted in consideration of these factors. The number of administration may be once a day or two or more times within the range of clinically acceptable side effects, and may be administered to one or two or more places for the administration site, and total daily or at intervals of 2 to 5 days The number of days of administration may range from 1 to 30 days per treatment. If necessary, the same treatment can be repeated after a titration period. For animals other than humans, the same dose as that of humans per kg or, for example, the above dose is converted by the volume ratio (for example, average value) of an organ (heart, etc.) between the target animal and human. One dose can be administered.

The pharmaceutical composition may be administered together with other drugs to effectively prevent or treat coronavirus infection. For example, the other drug may be another drug that is effective in preventing or treating coronavirus infection. The administration may be sequential, simultaneous, or individually administered to the subject.

The composition according to one aspect is an antiviral pharmaceutical composition that has a preventive or therapeutic effect on corona virus infection (COVID-19), has convenience in administration, and can be safely used without side effects even when taken for a long time.

In particular, the composition according to an aspect has excellent antiviral efficacy and remarkably excellent stability compared to the case of using napamostat alone.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes of one or more embodiments, and the scope of the present invention is not limited to these examples.

Formulation Example 1. Preparation of capsules (1)

(i) about 5.5% w/w of nafamostat mesylate salt;

(ii) about 5.5% w/w of dexamethasone disodium phosphate salt;

(iii) about 82% w/w of Avicel PH 102;

(iv) about 2.5% w/w colloidal silicon dioxide;

(v) about 4% w/w sodium starch glycolate; and

(vi) about 0.5% w/w magnesium stearate.

After mixing the above ingredients according to a conventional capsule preparation method, the capsules were prepared by filling the capsules.

Formulation Example 2. Preparation of capsules (2)

(i) about 10.5% w/w of nafamostat mesylate salt;

(ii) about 10.5% w/w of dexamethasone disodium phosphate salt;

(iii) about 72% w/w of Avicel PH 112;

(iv) about 2.5% w/w colloidal silicon dioxide;

(v) about 4% w/w sodium starch glycolate; and

(vi) about 0.5% w/w magnesium stearate.

After mixing the above ingredients according to a conventional capsule preparation method, the capsules were prepared by filling the capsules.

Formulation Example 3. Preparation of capsules (3)

(i) about 16% w/w of nafamostat mesylate salt;

(ii) about 16% w/w of dexamethasone disodium phosphate salt;

(iii) about 61% w/w of Avicel PH 301;

(iv) about 2.5% w/w colloidal silicon dioxide;

(v) about 4% w/w sodium starch glycolate; and

(vi) about 0.5% w/w magnesium stearate.

After mixing the above ingredients according to a conventional capsule preparation method, the capsules were prepared by filling the capsules.

Formulation Example 4. Preparation of capsules (4)

(i) about 21% w/w of nafamostat mesylate salt;

(ii) about 21% w/w of dexamethasone disodium phosphate salt;

(iii) about 51% w/w of Avicel PH 301;

(iv) about 2.5% w/w colloidal silicon dioxide;

(v) about 4% w/w sodium starch glycolate; and

(vi) about 0.5% w/w magnesium stearate.

After mixing the above ingredients according to a conventional capsule preparation method, the capsules were prepared by filling the capsules.

Formulation Example 5. Preparation of capsules (5)

(i) about 5.5% w/w of nafamostat mesylate salt;

(ii) about 5.5% w/w of dexamethasone disodium phosphate salt;

(iii) about 57% w/w of Avicel PH 301;

(iv) about 2.5% w/w colloidal silicon dioxide;

(v) about 4% w/w sodium starch glycolate;

(vi) about 0.5% w/w magnesium stearate; and

(vii) about 25% w/w croscarmellose sodium.

After mixing the above ingredients according to a conventional capsule preparation method, the capsules were prepared by filling the capsules.

Formulation Example 6. Preparation of capsules (6)

(i) about 21.5% w/w of nafamostat mesylate salt;

(ii) about 21.5% w/w of dexamethasone disodium phosphate salt;

(iii) about 24% w/w of Avicel PH 301;

(iv) about 2.5% w/w colloidal silicon dioxide;

(v) about 4% w/w sodium starch glycolate;

(vi) about 0.5% w/w magnesium stearate;

(vii) about 25% w/w croscarmellose sodium; and

(viii) about 1% w/w sodium lauryl sulfate

After mixing the above ingredients according to a conventional capsule preparation method, the capsules were prepared by filling the capsules.

Formulation Example 7. Preparation of Injection (1)

(i) about 1% w/w of nafamostat mesylate salt;

(ii) about 1% w/w dexamethasone disodium phosphate salt;

(iii) about 2.25% w/w of glycerin;

(iv) about 0.01 % w/w ededate disodium;

(v) about 0.026 % w/w of methylparaben;

(vi) about 0.014 % w/w propylaraben; and

(vii) remaining amount of water for injection;

After mixing the above ingredients according to a conventional injection preparation method, the injection was prepared by filling in a container.

Formulation Example 8. Preparation of Injection (2)

(i) about 1.5% w/w of nafamostat mesylate salt;

(ii) about 0.5% w/w dexamethasone disodium phosphate salt;

(iii) about 2.25% w/w of glycerin;

(iv) about 0.01 % w/w ededate disodium;

(v) about 0.026 % w/w of methylparaben;

(vi) about 0.014 % w/w propylaraben; and

(vii) remaining amount of water for injection;

After mixing the above ingredients according to a conventional injection preparation method, the injection was prepared by filling in a container.

Formulation Example 9. Preparation of Injection (3)

(i) about 2% w/w of nafamostat mesylate salt;

(ii) about 0.5% w/w dexamethasone disodium phosphate salt;

(iii) about 2.25% w/w of glycerin;

(iv) about 0.01 % w/w ededate disodium;

(v) about 0.026 % w/w of methylparaben;

(vi) about 0.014 % w/w propylaraben; and

(vii) remaining amount of water for injection;

After mixing the above ingredients according to a conventional injection preparation method, the injection was prepared by filling in a container.

Comparative Example 1.

(i) about 11% w/w of nafamostat mesylate salt;

(ii) about 82% w/w of Avicel PH 102;

(iii) about 2.5% w/w colloidal silicon dioxide;

(iv) about 4% w/w sodium starch glycolate; and

(v) about 0.5% w/w magnesium stearate.

After mixing the above ingredients according to a conventional capsule preparation method, the capsules were prepared by filling the capsules.

Comparative Example 2.

(i) about 11% w/w of nafamostat mesylate salt;

(ii) about 57% w/w of Avicel PH 301;

(iii) about 2.5% w/w colloidal silicon dioxide;

(iv) about 4% w/w sodium starch glycolate;

(v) about 0.5% w/w magnesium stearate; and

(vi) about 25% w/w croscarmellose sodium.

After mixing the above ingredients according to a conventional capsule preparation method, the capsules were prepared by filling the capsules.

Example 1. Test for confirming the content of related substances in capsules

A test for confirming the content of related substances was performed on the capsules of Formulation Example 1.

Initial 1 month (room temperature) 1 month (accelerated) 3 months (room temperature) 3 months (accelerated) Formulation Example 1 0.28% 0.29% 0.78% 0.38% 1.25% Comparative Example 1 0.36% 0.99% 3.78% 3.01% 4.86% Comparative Example 2 0.40% 0.81% 3.92% 2.45% 5.23%

From the above description, those skilled in the art to which the present invention pertains will understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention, rather than the above detailed description, all changes or modifications derived from the meaning and scope of the following claims and their equivalents.

Claims (8)

(1) as an active ingredient, nafamostat, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof; and
(2) as an active ingredient, dexamethasone, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof;
A pharmaceutical composition for preventing or treating coronavirus infection (COVID-19) comprising a.
The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of nafamostat is a nafamostat mesylate salt.
The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of dexamethasone is dexamethasone monosodium phosphate, dexamethasone disodium phosphate, or dexamethasone acetate.
The method according to claim 1, wherein (1) and (2) is 10: 1 to 1: 10, the pharmaceutical composition comprising a weight ratio of 1: 10.
The method according to claim 1, wherein the composition decomposes the enzyme protein TMPRSS2 (transmembrane protease serine subtype 2) that helps to bind with ACE2 (angiotensin-converting enzyme 2) when the corona virus enters the host cell, thereby exhibiting antiviral activity , pharmaceutical composition.
The pharmaceutical composition according to claim 1, wherein the composition is an oral or parenteral dosage form.
(1) as an active ingredient, nafamostat, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof; and
(2) as an active ingredient, dexamethasone, a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof;
A method of preparing a pharmaceutical composition for preventing or treating coronavirus infection (COVID-19).
A method for preventing or treating coronavirus infection (COVID-19) in an individual, comprising administering the pharmaceutical composition of claim 1 to an individual other than humans.