EA042670B1 - PHARMACEUTICAL KIT FOR COMBINED THERAPY FOR COVID-19 (SARS-CoV-2) AND METHOD FOR ITS USE - Google Patents

Description

This invention relates to a new pharmaceutical kit for combination therapy

COVID-19 (SARS-CoV-2) and how to use it.

The sudden outbreak of the novel coronavirus in 2019, later named SARS-CoV-2, in Wuhan, China, which quickly turned into a global pandemic, marked the third introduction of a virulent coronavirus into human society, affecting not only the healthcare system, but also the global economy . The total number of people infected with coronavirus in the world by the morning of August 19 exceeded 22.05 million people in 188 countries, more than 14.1 million people recovered and 779,557 infected people died.

Coronavirus SARS-CoV-2 belongs to the group of so-called RNA viruses, which are characterized by high mutation rates during the period of distribution. Despite the fact that SARS-CoV-2 has a relatively low mutation rate, the first reports of a new coronavirus mutation with different immune characteristics and virulence have appeared.

Considering that SARS-CoV-2 poses a serious threat to public health and the economy around the world, it seems appropriate to search for new effective anti-coronavirus drugs and conditions for their storage and delivery.

Effective approaches to the prevention and treatment of SARS-CoV-2 (COVID-19) and epidemiological control are still extremely limited. There is an intensive search for therapeutic agents worldwide for the prevention and treatment of SARS-CoV-2 (COVID-19). In this regard, the World Health Organization and national ministries of health are issuing temporary and constantly updated guidelines for the prevention, diagnosis and treatment of coronavirus infection using existing therapeutic agents previously intended for other viral infections (influenza, AIDS, Ebola, etc.).

One of the first drugs redirected to the treatment of COVID-19 were SARS-CoV-2 replication inhibitors: Favipiravir (FVP) [https://static0.rosminzdrav.ru/system/attachments/attaches/000/050/584/original/03062020_% D0%9CR_COVID-19_v7.pdf], Remdesivir (RMD) [https://nypost.com/2020/05/01/fda-approves-remdesivir-as-emergencv-coronavirustreatment/] and an inhibitor of SARS-CoV-2 entry into cell Aprotinin (APR) [A. Azimi.TMPRSS2 inhibitors, Bromhexine, Aprotinin, Camostat and Nafamostat as potential treatments for COVID-19 [pfile:///C:/Users/av/Downloads/ TMPRSS2inhibitors.pdf].

FVP (6-fluoro-3-hydroxy-2-pyrazinecarboxamide, Favipiravir, has RN: 259793-96-9 CA), which has antiviral activity against COVID-19, is part of a number of drugs that are tablets containing 200 mg of FVP , including: Avigan [https://www.cdc.gov.tw/File/Get/ht8jUiB_MI-aKnlwstwzvw], Favilavir [https://www.singlecare.com/blog/news/favilavir-forcoronavirus/], Avifavir [https://medum.ru/avifavir], Areplivir

[https://www.rbc.ru/rbcfreenews/5ef4f1219a7947ef15c93899], Coronavir

[https://www.rbc.ru/rbcfreenews/5f05d1f69a7947c3dcc66cf7] and Fabiflu

[https://myhep.com.ua/preparaty/oncology/fabiflu/]. The adult dose for COVID-19 is 1600 mg twice on the first day (hereinafter day 1) followed by 600 mg twice for 2-10 days (then on day 2-10) for patients weighing <75 kg, 2000 mg twice daily on day 1 and thereafter 800 mg twice daily on day 2-10 for patients weighing 75-90 kg (inclusive), and 2400 mg twice daily on day 1 and 1000 mg twice daily on day 2 -10 for patients weighing >90 kg. All doses are in the range of 44 to 64 mg/kg. Duration of treatment 10 days or less in case of confirmed eradication of the virus

RMD (ethylbutyl(2S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo(2,1-f)(1,2,4)triazine-7 -yl)-5-cyano3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-propanoate, Remdesivir, has RN: 1809249-37-3 CA) is used in the treatment of viral infections (COVID-19) : for injection (100 mg) as a sterile, preservative-free lyophilized powder in disposable vials. Unopened lyophilized powder vials can be stored below 30°C (86°F). Lyophilized RMD powder is dissolved and diluted in 19 ml of sterile water for injection before use and further diluted with saline in an infusion bag [https://www.fda.gov/media/137566/download]. RMD is used for injection (5 mg/mL) as a concentrated solution in single dose vials. Adult dose for COVID-19: Loading dose of 200 mg IV once (Day 1) followed by maintenance dose of 100 mg IV once daily (Days 2 to 5 or 10). The duration of therapy for invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO) is 10 days or not required for invasive mechanical ventilation and/or ECMO - only 5-10 days [https; https://www.drugs.com/dosage/remdesivir.html].

APR - aprotinin (RN: 9087-70-1 Polypeptide derived from the lungs of cattle. Blocks the kallikrein-kinin system. Inhibits both total proteolytic activity and the activity of individual proteolytic enzymes. It is a polyvalent inhibitor of proteases (including plasmin , kininogenase, trypsin, chymotrypsin, kallikrein, including activating fibrinolysis).Reduces fibrinolytic activity of the blood, inhibits fibrinolysis, has a hemostatic effect in coagulopathy). APR has been used in medical practice for more than 50 years and is recommended for

- 1 042670 application in doses for intravenous, jet or drip administration from 100,000 to 1,000,000 CIE.

Aprotinin activity is expressed in kallikrein inactivating units (KIE or KIU). 100000

CIE APR corresponds to 14 mg of aprotinin [A.V. Ovcharenko a and O.P. Zhirnov. Antiviral Research 1994,

23, 107-118].

APR is part of a number of preparations, which are lyophilizates for the preparation of solutions for intravenous administration, solutions for intravenous and infusion administration and aerosols for inhalation, including: Aprox, lyophilisate, 133000 CIE/vial, excipients (BB): lactose, sodium hydroxide ; Vero-Narcap, lyophilisate, 30,000 ATP/vial (1 ATP = 1.33 CIE), BB: lactose, sodium hydroxide (http://www.webvidal.ru/2011/drug/LP_12027.htm]; Ingitril, lyophilisate, 10000 ATRE/vial [https://www.vidal.ru/drugs/ingitril_6970]; Contrykal, 10000 Atre, BB: mannitol [https://www.vidal.ru/drugs/contrykal_37338]; Contrisel, lyophilisate, 10000 CIE / vial, IV: lactose monohydrate, trisodium citrate for injection, with 2 ml of 0.9% sodium chloride solution as a solvent in ampoules [https://medplaza.uz/drugs/drug/kontrisel]; Trasilol®, solution for injection , 500,000 CIE/50 ml bottle), BB: sodium chloride, sodium hydroxide and/or hydrochloric acid solution (for pH adjustment), water for injection [https://med.obozrevatel.com/lekarstva/trasilol.htm]; Ingiprol, solution for infusion, 10000 CIE/ml, 2 ml ampoule, and lyophilisate for solution for infusion [https://www.rlsnet.ru/tn_index_id_5562.htm; https://www.webapteka.ru/ drugbase/name506.html]; Aprotimbin, injection, 100,000 CIE and 500,000 CIE, 10 ml ampoules [http://dalinsaat.net/aprotimbin/]; Gordox®, solution for injection, 100,000 CIE, 10 ml ampoule, BB: 85 mg sodium chloride, 100 mg benzyl alcohol, water for injection up to 10 ml. [https://www.eapteka.ru/goods/id21876/; https://pharmacynew.org/gordox-ampoules.]; Contriven, solution for injections, 10000 cfu/ml aprotinin, amp.1 ml, IV: sodium chloride, water for injections

[https://tabletki.ua/%D0%9A%D0%BE%D0%BD%D1%82%D1%80%D0%B8%D0%B2%D0%B5%D0%BD/# %D0% A1%D0%BE% D1%81%D1%82%D0%B0%D0%B2]; Traskolan, solution for injection, 100,000 CIE and 500,000 CIE, 10 ml ampoules [https://www.rlsnet.ru/tn_index_id_3198.htm]; Aerus, dosed aerosol for inhalation, in a metal (aluminum) cylinder with a capacity of 30 or 20 ml, respectively, with a dosing device (valve), 35,000 CIE (350 doses) or 25,000 CIE (250 doses), BB: 0.045 ml propellant HFC-134A (1 ,1,1,2-tetrafluoroethane), 0.000045 ml peppermint leaf oil, 0.0075 ml ethanol 96%, 0.0035 ml glycerol 96% and purified water (EurPh), one dose of Aerus® aerosol is 85 CIE, and the recommended daily dose does not exceed 2000 CIE. [https://www.rlsnet.ru/tn_index_id_44141.htm]. The present inventors have found that the use of an antiviral combination agent comprising a SARS-CoV-2 replication inhibitor and aprotinin (APR) or a drug based on it in a therapeutically effective amount and ratio for combination therapy of COVID-19 (SARS-CoV-2) leads to a significant increase in the effectiveness of treatment of patients. In particular, the duration of treatment is significantly reduced and the risk of unwanted side effects is reduced.

It is known that in order to quickly use, protect against external factors of influence, as well as increase the shelf life of combined drugs for the treatment of various diseases, including viral diseases, pharmaceutical kits placed in a package are used. This describes how to use such kits (see, for example, patents RU 2661028 C2 and RU 2571687 C2).

The objective of the present invention is to find a pharmaceutical kit for combination therapy of coronavirus disease COVID-19 (SARS-CoV-2). Thus, the object of the present invention is a new pharmaceutical kit for combination therapy of coronavirus disease COVID-19 (SARS-CoV-2), comprising:

A) aprotinin (APR) in a therapeutically effective amount in the form of a finished drug product or in the form of finished drug components suitable for its administration;

B) an inhibitor of SARS-CoV-2 replication in a therapeutically effective amount in the form of a finished medicinal product or in the form of ready-made components of the drug suitable for its administration, with a therapeutically effective ratio of APR and replication inhibitor, placed in a package that protects the drugs from external factors, And

B) instructions for use.

The subject of the invention is also a method of using the specified pharmaceutical kit for the combination therapy of coronavirus disease COVID-19 (SARS-CoV-2), which consists in the simultaneous or sequential administration of the components of the kit - Aprotinin (APR) or a finished drug based on it to a patient with COVID-19 and an inhibitor of SARS-CoV-2 replication in a therapeutically effective amount and ratio.

Combination therapy using said combined agent results in a novel and synergistic effect unknown in the prior art, which is not obvious to a person skilled in the art. Thus, a median improvement in clinical status of 2 points in patients hospitalized with COVID-19 with a clinical status of 4, when using a combined

- 2 042670 funds according to this invention, had a value of 5 days, i.e. 1.6 times faster than in the treatment of FVP (8 days) and 2.2 times faster than in the treatment of APR (11 days), and the median normalization of the concentration of C reactive protein (CRP - indicating the presence or absence of an acute inflammatory process in the body) had a value of 1 day, i.e. 13 times shorter than in the treatment of FVP and 9 times shorter than in the treatment of APR (Table 1). A radical reduction in the time of normalization of the CRP in the patient's blood indicates the presence of synergy when using the combined agent according to this invention.

The following are definitions of terms that are used in the description of this invention.

The term drug is a substance or mixture of substances with established pharmacological activity, which is used for prophylactic or therapeutic purposes.

The term drug is a drug in the form of a specific dosage form.

The term pharmaceutical composition means a composition comprising a drug and at least one of the additional components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and receiving agents, delivery vehicles such as preservatives, stabilizers, fillers, grinders, humectants, emulsifiers, suspending agents, thickeners, sweeteners, flavors, flavors, antibacterial agents, fungicides, lubricants, sustained delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, such as parabens, chlorobutanol, sorbic acid, and the like. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be provided with agents that slow down the absorption of the active component, for example, aluminum monostearate and gelatin.

Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate).

Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and spreaders are starch, alginic acid and its salts, silicates.

Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.

The term excipient as used herein refers to a compound that is used to prepare a pharmaceutical composition and is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for use in veterinary, as well as pharmacologically acceptable for human use.

The compounds of this invention may be administered alone, but generally they will be administered in admixture with one or more pharmaceutically acceptable excipients, diluents or carriers, selected in consideration of the intended route of administration and standard pharmaceutical practice.

The term therapeutically effective amount as used herein means the amount of a substance or drug required to reduce the symptoms of a disease in a subject. The dose of the substance or drug will be tailored to the individual requirements in each case. This dosage may vary widely depending on numerous factors such as the severity of the disease being treated, the age and general health of the patient, other drugs the patient is being treated with, the mode and form of administration, and the experience of the attending physician.

Typically, treatment is started with a large initial loading dose to rapidly reduce or eliminate the virus, followed by a tapering dose to a level sufficient to prevent a resurgence of infection.

The term subject means a mammal, which includes, but is not limited to, cattle, pigs, sheep, chickens, turkeys, buffaloes, llamas, ostriches, dogs, cats, and a human, preferably a human.

Below is a detailed description of the implementation of specific embodiments of the present invention. However, these data illustrate the present invention, but do not limit the claims of the applicant. Various modifications of the invention are possible within the scope of the claimed claims.

Median improvement in clinical status of 2 points in patients hospitalized with COVID-19 with clinical status 4 when using the combined agent of this invention,

- 3 042670 had a value of 5 days (Table 1), i.e. 1.6 times faster than with FVP treatment (8.0 days) and 2.2 times faster than with APR treatment (11 days).

One of the important indicators indicating the presence or absence of an acute inflammatory process in the body is the concentration of C-reactive protein (CRP, C-Reactives protein - CRP) in the patient's blood. The concentration of CRP = 5 mg/l was taken as the norm, and it does not depend on age and gender [https://sosudinfo.ru/krov/c-reaktivnyj-belok/]. With COVID-19, the appearance and increase in the concentration of CRP is observed, which indicates the presence of an acute inflammatory process in the patient's body.

From Table. Table 6 shows that patients treated with FVP had an initial value of CRP=67.5 (45.3-108.6) mg/l, and the median of its normalization was 8 days (Table 1).

In the treatment of APR, patients had an initial value of CRP=21.5±8.2 mg/l (Table 9) and the median of its normalization was 11 days (Table 1).

In the treatment with the combined agent according to this invention, patients had an initial value of CRP=38.7±7.5 mg/l (Table 3), and the median of its normalization was only 1 day, i.e., the normalization of CRP when using the combined agent according to this invention was 8 times and 11 times faster than in the treatment of FVP and APR, respectively. This indicates that in the treatment of patients with a combined agent according to this invention, the suppression of an acute inflammatory process in the patient's body is radically more effective than in the treatment of the components included in the combined agent (FVP and APR), i.e. there is a synergistic anti-inflammatory action.

One of the important markers that predicts the severity of COVID-19 is D-dimer, which is formed during the breakdown of fibrin, a fibrous protein that is the basis of blood clots. An increase in the concentration of D-dimer indicates that small blood clots are forming in the body. An analysis for D-dimer allows you to evaluate 2 factors in a complex at once: coagulation (blood clotting) and fibrinolysis (dissolution of blood clots). The marker makes it possible to timely detect an imbalance between them in case of diseases of the circulatory system (varicose veins, thrombophilia, pulmonary embolism, etc.). A significant increase in D-dimer concentration is a strong predictor of mortality. This indicator is an early and useful marker and should be determined in patients entering dangerous phases of the disease. Normal D-dimer should not exceed 250 ng/mL (0.55 µg FEU/mL). [https.//aif.ru/health/coronavirus/pokazateli_smerti_uchenye_obnaruzhrli_markery_tyazhelogo_techeniya_covid19. http://cardiobook.ru/d-imer/. https://www.diagnos.ru/procedures/analysis/koagulogramma/d-dimer].

The initial value of the concentration of D-dimer 855.5 ± 142.5 ng / ml in the blood of hospitalized patients with COVID-19 with clinical status 4 in the treatment with a combined agent according to this invention had a value of 855.5 ± 142.5 ng / ml (Table 3) and returned to normal after 5 days. Elimination of SARS-CoV-2 proceeded just as quickly in patients (median 3.5 days) and the temperature returned to normal in 1 day (Table 1).

All patients (100%) showed an improvement in lung damage on Day 14 CT scans with the combined agent of the invention, while patients treated with FVP had a value of 72.7% with 9.1% of patients still having lung damage. unchanged, and in 18.2% of patients worsening lung damage was observed. In the treatment of patients with APR, this indicator was 60.0%, while in 40.0% of patients, lung damage remained unchanged (Table 1).

Thus, the agent according to this invention has demonstrated high efficiency in the combined therapy of human coronavirus diseases, significantly exceeding the effectiveness of its constituent components.

No serious adverse events were recorded during the study. Adverse reactions noted in some cases were mild or moderate in severity and in most cases did not require additional treatment.

- 4 042670

Table 1. Effectiveness of treatment of hospitalized patients with COVID-19 with clinical status 4 with ______ according to this invention and its components. ______

Index APR + FVP FVP APR Median improvement in clinical status by 2 points, days 5 (5-5) 8(6-11) 11.0 (6-11) Median CRP normalization, days 1 (1-3) 13(13-) 9(6-0) Median D-dimer normalization, days 5 (4-5) n.k. 4.5 (3-6) Median elimination of SARS-CoV-2, days 3.5 (3-4) 4.5 (4-6) 7.5 (6-9) Median body temperature normalization <37°С, days 1 (1-3) 3 (2-4) 3 (2-4) CT on!4th day: % improvement 10 (100.0%) 8 (72.7%) 6 (60.0%) % without change 1 (9.1%) 4 (40.0%) % deterioration 2(18.2%)

The effective amounts of SARS-CoV-2 replication inhibitors and APR administered are indicated above and are traditional for these compounds. The clinical dosage of the components of the drug may vary depending on the age, sex, weight and stage of the disease of the patient. The effective ratio of the components will be determined by the effective amount of the respective active component administered.

As a means for the combined therapy of human coronavirus diseases, a ready-made dosage form containing APR selected from the well-known drugs Aprox, Vero-Narcap, Ingitril, Contrykal, Contrisel, Trasilol®, Ingiprol, Aprotimbin, Gordox®, Contriven, Traskolan or Aerus can be used. .

As a component of FVP, you can use the finished dosage form, which is Avigan, Favilavir, Avifavir, Areplivir, Coronavir or Fabiflu.

FVP is administered to the patient orally, APR and RMD - parenterally (for example, intravenously, subcutaneously, intraperitoneally, inhalation, in the form of a spray or in the form of drops.

For APR, the preferred daily dose, depending on the severity of the disease and the route of administration, is from 500,000 CIE to 1,000,000 CIE per day.

For FVP, the preferred adult dose is 1200–1600 mg twice daily on Day 1, depending on the severity of the disease, followed by 400–600 mg twice daily on Day 2–10 for patients weighing <75 kg, 2000 mg twice daily on day 1 and thereafter 800 mg twice daily on days 2-10 for patients weighing 7590 kg (inclusive), and 2400 mg twice daily on day 1 and 1000 mg twice daily 2-10 for patients weighing >90 kg. All doses are in the range of 44 to 64 mg/kg. Duration of treatment 10 days or less in case of confirmed eradication of the virus.

For RMD, the preferred adult dose is 200 mg IV once daily (Day 1) followed by a maintenance dose of 100 mg IV once daily (Days 2 to 5 or 10).

The size of the doses of anti-coronavirus components may vary depending on the severity of the condition to be alleviated. It should be understood that for each particular subject, the specific dosage regimen and schedule may be adjusted in time according to the needs of the individual and the professional judgment of the person who is treating or supervising the combination therapy.

Combination therapy may be sequential, ie. treatment first with one component and then with the other, for example, when each stage of treatment involves a different component of the present invention, or there may be therapy with the introduction of both components at the same time.

Sequential therapy may include a significant time after completion of treatment with one component and before treatment with the second component. Treatment with both components at the same time can be in the same daily dose or in different doses.

More preferred is an agent that includes, in a therapeutically effective amount, the anti-coronavirus components of APR and FVP.

For combination therapy of coronavirus disease, concomitant therapeutic agents may be used, which may be useful when combined with and compatible with the anti-coronavirus agent of the present invention.

As concomitant therapeutic drugs according to this invention can be used

- 5 042670 analgesics (acetylsalicylic acid, paracetamol), angioprotectors (diosmin), antibacterial drugs for systemic use (avelox, azithromycin, amoxicillin), amoxicillin in combination with enzyme inhibitors (levofloxacin, meropenem, metronidazole, cefazolin, ceftriaxone), antihistamines for systemic action, anticoagulants (fraxiparin, enoxaparin), beta-blockers (bisoprolol, metoprolol), calcium channel blockers (amlodipine, tifedipine), vitamins (ascorbic acid, vitamin C), lipid-lowering drugs (rosuvastatin), diuretics (spironolactone, hypothiazide, indapamide, furosemide), immunosuppressants (tocilizumab, etanercept), systemic corticosteroids (dexamethasone, methylprednisolone, prednisolone), plasma-substituting and perfusion solutions (glucose, sodium chloride, isotonic sterofundin), drugs for the treatment of diseases associated with acid disorders (omeprazole), drugs for the treatment of heart disease (cardiket, nitroglycerin), drugs for the treatment of thyroid diseases (L-thyroxine), drugs for the treatment of obstructive airway diseases (fenoterol), drugs that affect the renin-angiotensin system (valsartan, losartan, lorista, enalapril ), antivirals for systemic use (lopinavir, ritonavir), antidiarrheal drugs (acipol, diosmectite, sulfosalazine), antitussives and colds (ambroxol, acetylcysteine, mukaltin), anticancer hormonal drugs (tamoxifen), other drugs for the treatment of diseases of the gastrointestinal tract and metabolic disorders (ademetionine), drugs for the treatment of diabetes mellitus (apidra, levemir, metformin, novomix), etc.

The present invention is illustrated but not limited by the following examples.

Example 1. Kits of drugs for combination therapy of coronavirus disease.

Drug sets for combination therapy of coronavirus disease are made up of finished drugs in the required therapeutically effective amount and ratio (Table 2), which are placed in a package that provides protection for drugs from external factors and contains instructions for use. As APR containing finished medicinal products, APR lyophilizates are used: Aproteks, Ingitril, Kontrykal, Kontrisel; solutions for injections and infusions: Trasilol®, Ingiprol, Aprotimbin, Gordox®, Contriven, Traskolan; or aerosol for inhalation - Aerus; and their analogues. Avigan, Avifavir, Favilavir, Coronavir, Fabiflu and their analogues are used as FVP-containing finished drugs. [https://myhep.com.ua/preparaty/oncology/fabiflu/].

Table 2. Compositions of packages of an anti-coronavirus agent, including APR and FVP or RMD, for the 1st course of treatment for 1 patient

Set #1: 1. APR containing finished medicinal products: 50 ampoules of solution for injections, 100,000 IU/ampoule 10 ml or 10 vials of solution for injection, 500,000 IU/vial 50 ml or 25 vials of lyophilisate, 200,000 IU/vial for the preparation of 50 ml solution for injection or 10 vials of lyophilisate, 500,000 IU/vial for the preparation of 50 ml solution for injection. 2. FVP containing finished medicinal products (tablets containing 200 mg of FVP): 7 blisters of 10 tablets each or 1 vial - 70 tablets Set #2: 1. APR containing finished medicinal products: 50 solution ampoules for injections, 100,000 cfu/ampoule 10 ml or 10 bottles of solution for injections, 500,000 CIE/50 ml vial or 25 vials of lyophilisate, 200 000 CIE/vial for the preparation of 50 ml solution for injection or 10 vials of lyophilisate, 500,000 CIE/vial for preparation 50

- 6 042670

ml of solution for injection. 2. FVP containing finished medicinal products (tablets containing 200 mg of FVP): 10 blisters of 10 tablets each or 1 vial - 92 tablets. Set #3: 1. APR containing finished medicinal products: 50 ampoules of solution for injections, 100,000 IU/ampoule 10 ml or 10 vials of solution for injection, 500,000 IU/vial 50 ml or 25 vials of lyophilisate, 200,000 IU/vial for the preparation of 50 ml solution for injection or 10 vials of lyophilisate, 500,000 IU/vial for the preparation of 50 ml solution for injection. 2. FVP containing finished medicinal products (tablets containing 200 mg of FVP): 12 blisters of 10 tablets each or 1 bottle - 114 tablets. Set #4: 1. APR containing finished medicinal products: 50 ampoules of solution for injections, 100,000 IU/ampoule 10 ml or 10 vials of solution for injection, 500,000 IU/vial 50 ml or 25 vials of lyophilisate, 200,000 IU/vial for the preparation of 50 ml solution for injection or 10 vials of lyophilisate, 500,000 IU/vial for the preparation of 50 ml solution for injection. 2. RMD (Veklury) for injection 7 vials of 100 mg of sterile, preservative-free lyophilized RMD powder in each single-use vial, which is dissolved and diluted in 19 ml of sterile water for injection before use and further diluted with saline in an infusion bag. Set #5: 1. APR containing finished medicinal products: 50 ampoules of solution for injections, 100,000 IU/ampoule 10 ml or 10 vials of solution for injection, 500,000 IU/vial 50 ml or 25 vials of lyophilisate, 200,000 IU/vial for the preparation of 50 ml solution for injection or 10 vials of lyophilisate, 500,000 IU/vial for the preparation of 50 ml solution for injection. 2. RMD (Veklury) for injection 12 vials of 100 mg sterile, without preservatives of RMD lyophilized powder in each single-use vial, which is dissolved and diluted in 19 ml of sterile water for injection and further diluted with saline in an infusion bag before use.

The clinical study included 3 groups of hospitalized COVID patients, including: 10 patients receiving intravenous APR + oral FVP (group 1), 11 patients receiving oral FVP (group 2), 10 patients receiving intravenous APR (group 3). Patients received a combined agent from sets No. 1-3. Demographic and other baseline characteristics of patients are presented in the tables below. The effectiveness of the combined treatment of hospitalized patients with COVID-19 and clinical status 4 with an anti-coronavirus agent according to this invention and its components is shown in table. 1.

Example 2 Efficacy of treatment with a combined agent of this invention in hospitalized patients with moderate COVID-19 and clinical status 4.

The clinical study included 10 hospitalized patients with moderate COVID-19 and clinical status 4 who received separate intravenous APR and oral FVP. Demographic and other baseline characteristics of patients are presented in Table. 3.

Table 3. Demographic and other baseline characteristics of hospitalized COVID-19 patients with clinical status 4 treated with the combined _________________ agent of this invention _________________

Status Meaning Age(years) 46.7±10.6 18-44 years old 4 (40.0%) 45-59 years old 5 (50.0%) > 60 years old 1 (10.0%) Men 8 (80.0%) Women 2 (20.0%) Body weight (kg) 80.7±6 BMI (kg/m2) 26.4±1.5 Duration, ill. (days) 3.4±0.8 < 7 days 10(100.0%) > 7 days 0 (0.0%) SpO2 (%) 95.0±0.9 >95 6 (60.0%) <95 4 (40.0%)

Status Meaning Temperature (°C) 38.5±0.4 <37 0 (0.0%) 37-38 1 (10.0%) >38 9 (90.0%) NPV (per minute) 21.8±1 <22 7 (70.0%) >22 3 (30.0%) CRP (mg/l) 38.7±7.5 Norm 0 (0.0%) Promoted 7 (70.0%) D-dimer (ng/ml) 855.5±142.5 Norm 0 (0.0%) Promoted 10 (100.0%)

Clinical studies were carried out in one of the clinics in Smolensk, Russia, in accordance with the Clinical Research Protocol.

Primary Objective: To evaluate and compare the efficacy of an anti-coronavirus agent (intravenous APR + oral FVP) in patients hospitalized with COVID-19 and clinical status 4 in terms of the following indicators:

time to elimination of SARS-CoV-2 virus up to day 10;

time to CRP normalization to day 10;

time to D-dimer normalization up to day 10.

Additional objectives: Additional objectives of the study include evaluating the following efficacy and safety measures in patients hospitalized with COVID-19:

time to normalization of body temperature (<37°С);

dynamics of changes in laboratory parameters on day 4, day 5, day 6, day 10 and day 14 relative to baseline values: complete blood count (neutrophils, leukocytes and their ratio, platelets), CRP, coagulogram (D-dimer, fibrinogen, prothrombin according to Quick, INR);

dynamics of changes in laboratory parameters on day 4, day 5, day 6, day 10 and day 14 relative to baseline values: complete blood count (neutrophils, leukocytes and their ratio, platelets), CRP, coagulogram (D-dimer, fibrinogen, prothrombin according to Quick, INR);

frequency of improvement in clinical status by 2 points on the Ordinal Scale of Clinical Improvement or hospital discharge before day 14;

the frequency of transfer to the intensive care unit (ICU), the frequency of non-invasive ventilation (NIVL), the frequency of mechanical ventilation (ALV) and mortality;

the frequency of adverse events (AE) and serious adverse events (SAE) of varying severity according to subjective complaints, physical examination, vital signs, laboratory tests and ECG.

Study design.

All 10 patients received the combined agent (Table 3). APR was administered intravenously drip (slowly over 15-20 minutes) depending on the patient's health, 500,000 CIE - 1,000,000 CIE 1 time per day for 5 days in addition to FVP in tablets: for patients weighing less than 75 kg and depending on the state of health, 1200-1600 mg 2 times a day on day 1 and then 400-600 mg 2 times a day on days 2-10; for patients weighing from 75 to 90 kg (inclusive) 2000 mg 2 times a day on day 1 and then 800 mg 2 times a day on days 2-10; for patients weighing more than 90 kg, 2400 mg 2 times a day on day 1 and then 1000 mg 2 times a day on days 2-10 (Table 4).

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Table 4. Daily doses of the components of the combination agent received by patients in the treatment of COVID-19.

Patient Age, years Height, cm Body weight, kg Index Masses body Dose of APR (KIE), 1 time per day Dose of FVP (mg) 2 times a day Day 1-5 Day 1 Day 2- 10 16-2 36 181 85.3 26.04 1,000,000 2000 800 17-2 46 182 88.5 26.72 1,000,000 2000 800 21-2 34 172 80.2 27.2 1,000,000 2000 800 22-2 40 175 72.1 23.6 500 000 1200 400 23-2 59 166 77.5 28.2 1,000,000 2000 800 25-2 35 177 78.4 25 1,000,000 2000 800 26-2 48 180 86.3 26.6 1,000,000 2000 800 28-2 65 167 81.2 29.1 1,000,000 2000 800 29-2 52 181 85.9 26.22 1,000,000 2000 800 30-2 52 166 71.1 25.8 1,000,000 1600 600

Depending on the state of health and concomitant COVID-19 diseases, patients received concomitant therapy (Table 5).

Table 5. Concomitant Therapeutics Used in the Treatment of Hospitalized COVID-19 Patients with Clinical Status 4 with the Combination Agent of the Invention ____

A drug X Η Paracetamol 1 9.1 1 Azithromycin 3 27.3 3 Amoxiclav 1 9.1 1 Imipenem and dehydropeptidase inhibitor 1 9.1 1 Levofloxacin 1 9.1 1 Meropenem 1 9.1 1 Sulbactam 1 9.1 1 thiamphenicol 2 18.2 2 Cefoperazone 2 18.2 2 Ceftriaxone 1 9.1 1 Enoxaparin 4 36.4 4 Hydroxychloroquine 1 9.1 1 bisoprolol 1 9.1 1 Amlodipine 1 9.1 1 Ascorbic acid 2 18.2 2 Hydrochlorothiazide 1 9.1 1

A drug X m %* mustache Spironolactone 1 9.1 9.1 Tocilizumab 1 9.1 9.1 Dexamethasone 1 9.1 9.1 Glucose 1 9.1 9.1 Sodium chloride 2 18.2 3 Omeprazole 1 9.1 1 Levothyroxine sodium 1 9.1 1 Drotaverine 1 9.1 1 Losartan 1 9.1 1 Losartan in combination with diuretics 1 9.1 1 Pancreatin 1 9.1 1 Ambroxol 1 9.1 1 Insulin 1 9.1 1 insulin glulisine 1 9.1 1 insulin detemir 1 9.1 1 Metronidazole 1 9.1 1

X and % - the number and percentage of patients who had at least one event in this group,

Y is the total number of events in this group.

The results of the effectiveness of treatment with a combined agent according to this invention in hospitalized patients with COVID-19 of moderate severity and clinical status 4 are presented in table. 1.

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Example 3 Efficacy of Favipiravir (FVP) Treatment in Hospitalized Patients with

COVID-19 and clinical status 4.

The clinical study included 11 patients receiving oral FVP. Clinical studies were carried out in one of the clinics in Smolensk, Russia, in accordance with the Clinical Research Protocol. In the studies, identical protocols for all analyzes were used for all patients. Demographic and other baseline characteristics of patients are presented in Table. 6.

Table 6. Demographic and other baseline characteristics of hospitalized patients with COVID-19 and clinical status 4, ______ treated with favipiravir (FVP)______

Status Meaning Age(years) 57.5±15.9 18-44 years old 2(18.2%) 45-59 years old 5 (45.5%) > 60 years old 4 (36.4%) Men 3 (27.3%) Women 8 (72.7%) Body weight (kg) 84.0±16.8 BMI (kg/m2) 30.7±5.3 Duration, ill. (days) 7.3±3 < 7 days 3 (27.3%) > 7 days 8 (72.7%)

Status Meaning SpO2 (%) 93.4±1.8 >95 3 (27.3%) <95 8 (72.7%) Temperature (°C) 37.5±0.7 <37 2(18.2%) 37-38 7 (63.6%) >38 2 (18.2%) NPV (per minute) 20.4±1.5 <22 10 (90.9%) >22 1 (9.1%) CRP (mg/l) 67.5 (45.3-108.6) Norm 0 (0.0%) Promoted 11 (100.0%)

Primary Objective: To evaluate the efficacy of favipiravir (FVP) on the following in patients hospitalized with COVID-19 and clinical status 4:

time to elimination of SARS-CoV-2 virus up to day 10;

time to CRP normalization up to day 10.

Additional goals: the same as in example 2.

Study design: all 11 patients took oral FVP in tablets: for patients weighing less than 75 kg and depending on the state of health, 1200-1600 mg 2 times a day on day 1 and then 400-600 mg 2 times a day on days 2-10; for patients weighing from 75 to 90 kg (inclusive) 2000 mg 2 times a day on day 1 and then 800 mg 2 times a day on days 2-10; for patients weighing more than 90 kg, 2400 mg 2 times a day on day 1 and then 1000 mg 2 times a day on days 2-10 (Table 7).

Table 7. Daily doses of the components of the combination agent received by patients treated with COVID-19 with favipiravir (FVP)

Patient Age, years Height, cm Weight body, kg Body Mass Index kg/m ² Dose of FVP (mg) 2 times a day Day 1 Day 2-10 02-001 53 170 120 41.52 1800 800 02-003 49 173 95 31.74 1600 600 04-001 83 158 90 May 36 1600 600 04-007 59 158 83 33.25 1600 600 05-001 60 158 70 28.04 1800 800 05-002 36 176 80 25.83 1800 800 05-003 76 160 82 32.03 1800 800 05-005 56 175 92 30.04 1800 800 05-009 56 158 63 25.24 1600 600 05-011 74 170 90 31.14 1800 800 05-012 31 161 59 22.76 1600 600

Depending on the state of health and concomitant COVID-19 diseases, patients received concomitant therapy (Table 8).

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Table 8. Comorbidities considered in the treatment of hospitalized patients with COVID-19 and clinical status 4 with favipiravir (FVP)

Disease X ^th % ^th U ^s Disease X ^th % ⁶ U ^s Chronic pancreatitis 2 18.2 2 Chronic illness kidney 1 9.1 1 Chronic gastritis 1 9.1 1 Myocardial ischemia 3 27.3 3 Pneumonia 9 81.8 9 Arteriosclerosis 1 9.1 1 Pneumonia viral 1 9.1 1 Varicose veins 1 9.1 1 Hyperlipidaemia 1 9.1 1 hypertension 6 54.5 6 Dyslipidemia 1 9.1 1 Deep vein thrombosis 1 9.1 1 Obesity 6 54.5 6 Phlebitis 1 9.1 1 Type 2 diabetes 4 36.4 4 Menopause 6 54.5 6 Bronchitis, chronic 1 9.1 1 Fracture of the thoracic vertebra 1 9.1 1 Back pain 1 9.1 1 Ostearthritis 1 9.1 1 tendon rupture 1 9.1 1 Osteochondrosis 1 9.1 1 Appendectomy 1 9.1 1 Headache 1 9.1 1 Hysterectomy 1 9.1 1 cerebral ischemia 1 9.1 1 Vein ligation 1 9.1 2 Glaucoma 1 9.1 2 Polypectomy stomach 1 9.1 1 Myopia 1 9.1 1 Vertigo 1 9.1 1 Retinal laser coagulation 1 9.1 2 Cholecystitis 1 9.1 1 Cholecystitis 1 9.1 1 Cholecystectomy 1 9.1 1 Endocrine disorders 1 9.1 1 Hypothyroidism 1 9.1 1

The results of the effectiveness of treatment with favipiravir in hospitalized patients with COVID-19 and clinical status 4 are shown in Table. 1.

Example 4 Efficacy of Aprotinin (APR) Treatment in Hospitalized Patients with COVID19 and Clinical Status 4.

The clinical study included 10 patients who received APR intravenously. Demographic and other baseline characteristics of patients are presented in Table. 9.

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Status Meaning Age (years) 44.9± 11.2 18-44 years old 4 (40.0%) 45-59 years old 6 (60.0%) > 60 years old 0 (0.0%) Men 3 (30.0%) Women 7 (70.0%) Body weight (kg) 74.3±4.7 BMI (kg/m2) 25.9±1.7 Duration sick (days) 3.4±1.1 < 7 days 10(100.0%) > 7 days 0 (0.0%) SpO2 (%) 96.7±1.1 >95 10(100%) <95 0 (0.0%)

Table 9. Demographic and other baseline characteristics of hospitalized COVID-19 patients with clinical status 4 treated with aprotinin (APR).

Status Meaning Temperature (°C) 38.3±0.1 <37 0 (0.0%) 37-38 0 (0.0%) >38 10 (100%) NPV (per minute) 21.4±1.6 <22 8 (80.0%) >22 2 (20.0%) CRP (mg/l) 21.5±8.2 Norm 0 (0.0%) Promoted 10 (100.0%) D-dimer (ng/ml) 525.4±175.7 Norm 0 (0.0%) Promoted 10 (100.0%)

Clinical studies were carried out in one of the clinics in Smolensk, Russia, in accordance with the Protocols of Clinical Studies. In the studies, identical protocols for all analyzes were used for all patients.

Primary Objective: To evaluate the efficacy of intravenous APR for the following in patients hospitalized with COVID-19 and clinical status 4:

time to elimination of SARS-CoV-2 virus up to day 10;

time to CRP normalization to day 10;

time to D-dimer normalization up to day 10.

Additional goals: the same as in example 21.

Study design: all 10 patients received APR intravenously (slowly over 15-20 minutes) 1,000,000 CIE 1 time per day for 3 days (Table 10).

Table 10. Daily doses of the components of the combination agent received by patients treated with COVID-19 with aprotinin (APR)

Patient Age, years Height, cm Weight body, kg Index body weight Dose of APR (KIE) 1 time per day 01 56 173 81.4 27.20 1,000,000 02 55 166 72.5 26.31 1,000,000 03 50 169 73.6 25.77 1,000,000 04 24 160 72.1 28.16 0 05 43 176 78.7 25.41 0 06 31 170 75.5 26.12 0 07 41 168 65.2 23.10 0 08 48 179 73.5 22.94 0 09 49 169 79.3 27.77 0 10 60 165 71.4 26.23 0

Depending on the state of health and concomitant COVID-19 diseases, patients received concomitant therapy (Table 11).

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Claims (2)

Table I. Concomitant Therapies Used in the Treatment of Hospitalized Patients _____ with COVID-19 and Clinical Status 4 Aprotinin (APR) A drug X A %* Y With Paracetamol 10 (100.0% ) 1 0 Azithromycin 9 (90.0%) 9 Levofloxacin 1 (10.0%) 1 Enoxaparin 10 (100.0% ) 1 0 A drug X A %* Y With Hydroxychloroquine 9 (90.0% ) 9 Ringer's solution 1 (10.0% ) 1 Lopinavir + Ritonavir 1 (10.0% ) 1 Ritonavir 1 (10.0% ) 1 The results of the effectiveness of treatment with aprotinin in hospitalized patients with COVID-19 and clinical status 4 are shown in Table. 1. CLAIM 1. Pharmaceutical kit for combination therapy of coronavirus disease COVID19 (SARS-CoV-2), including: A) aprotinin (APR) in a therapeutically effective amount in the form of a finished medicinal product, and B) favipiravir (FVP) as an inhibitor of SARS-CoV-2 replication in a therapeutically effective amount in the form of a finished drug, where these finished drugs containing a therapeutically effective amount of APR and FVP are placed in a therapeutically effective amount in a package that provides protection for the drugs from external influences, and B) instructions for use. 2. The use of the pharmaceutical kit according to claim 1 for combination therapy of coronavirus disease COVID-19 (SARS-CoV-2). Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 -