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Title:
EFLORNITHINE COMPOSITION AND DOSAGE FORMS FOR THE TREATMENT OF VIRAL INFECTION
Document Type and Number:
WIPO Patent Application WO/2021/191928
Kind Code:
A1
Abstract:
The invention discloses compositions of eflornithine or its salt and prodrugs thereof in a dose range of 0.1 g to 26 g per day in different dosage forms, such as scored tablet, scored chewable tablet, capsule, oral solution and oral suspension, granules or powder composition in a sachet, intravenous infusion in the form of bolus intravenous infusion, continuous intravenous infusion and pulse intravenous infusion and in the form of intravenous injection for different routes of administration. The invention further provides method of treating viral infection specifically novel corona virus (COVID 19) using the eflornithine formulations as monotherapy or in combination with other antiviral, antimicrobial drugs, anti-malarial, antiprotozoal medications and vaccines. The invention also relates to polyamines and/or protein controlled diet for the said treatment. The said treatment to be applicable on patient with body surface area of 0.2 to 2 m2 and/or Body mass index between 10 to 45 Kg/m2. The invention also relates to administration of different doses on single and multiple dosage regimen at every 4 hour to 24 hour. The said administration produces plasma concentration level in human varying from 5 mcg/ml to 150mcg/ml with Tmax of 30min to 500min with AUC of 30 mcg.hr/ml to 1000mcg.hr/ml after oral administration.

Inventors:
SAXENA NAVIN (IN)
SAXENA KUNAL (IN)
SAXENA AAKARSH (IN)
Application Number:
PCT/IN2021/050301
Publication Date:
September 30, 2021
Filing Date:
March 23, 2021
Export Citation:
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Assignee:
NAVIN SAXENA RESEARCH & TECH PVT LTD (IN)
International Classes:
A61K45/06; A61K9/00
Foreign References:
AU2017339781A12019-05-16
Attorney, Agent or Firm:
P., Aruna Sree (IN)
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Claims:
We claim:

1. A pharmaceutical composition of efl ornithine or a pharmaceutically acceptable salt or a prodrug thereof, for treating viral infections comprising: a) eflornithine of about 0.01% w/w to 90% w/w, and b) other pharmaceutically acceptable excipients.

2. The pharmaceutical composition as claimed in claim 1 for treating viral infection comprising of: a) eflornithine or a pharmaceutically acceptable salt thereof in the range of 0.01% w/w to 90% w/w; b) one or more diluent(s) in the range of 5% w/w to 35.5% w/w; c) one or more taste-masking agent(s) in the range of 0.1% w/w to 50% w/w; d) one or more flavouring agent(s) in the range of 0.1% w/w to 10% w/w; e) one or more glidant(s) in the range of 0.1% w/w to 15% w/w; f) one or more binder in the range of 0.1% w/w to 50%w/w; g) one or more lubricant in the range of 0.1% w/w to 10% w/w; h) one or more preservative in the range of 0.1% w/w to 15%w/w; i) one or more thickening agent in the range of 0.1% w/w to 50% w/w; j) one or more pH modifier in the range of 0.1% to 25%w/w; and k) one or more antioxidant in the range of 0.01% w/w to 5.0% w/w.

3. The pharmaceutical composition as claimed in claim 1, wherein the eflornithine is eflornithine hydrochloride monohydrate.

4. The pharmaceutical composition as claimed in claim 2, wherein the diluent is selected from the group consisting of microcrystalline cellulose (e.g. Avicel®), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, Pearlitol® mannitol, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc which are used individually or in a mixture in the range of 5.0% w/w to 35.5% w/w of total composition.

5. The pharmaceutical composition as claimed in claim 2, wherein the taste- masking agent is selected from the group consisting of Eudragit EPO®, Eudragit E 100®, aspartame EP, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol and polyvinyl acetate which are used individually or in a mixture in the range of 0.1% w/w to 50% w/w of the total composition.

6. The pharmaceutical formulation as claimed in claim 2, wherein the flavouring agent is selected from the group consisting of lemon, cherry, strawberry, grape, cream, mocha, spearmint which are used individually or in a mixture in the range of 0.1% w/w to 10% w/w of total composition.

7. The pharmaceutical formulation as claimed in claim 2, wherein the glidant is selected from the group consisting of silica, talc, colloidal silicone dioxide (Aerosil® 200, Syloid®, Cab-O-Sil®), magnesium trisilicate, colloidal anhydrous silica cellulose powder, magnesium stearate and corn starch which are used individually or in a mixture in the range of 0.1% w/w to 15% w/w of total composition.

8. The pharmaceutical formulation as claimed in claim 2, wherein the pH modifiers and/or buffering agents which includes, but not limited to, citric acid, sodium and potassium salts of citric acid, sodium and potassium bicarbonate, sodium hydroxide and hydrochloric acid or a mixture thereof in a range of 0.1% w/w to 25% w/w of total formulation composition. 9. The pharmaceutical composition as claimed in claim 1, wherein, the eflornithine compositions are formulated in the form of scored tablet, scored chewable tablet, capsule, oral solution and oral suspension, granules or powder composition in a sachet, intravenous infusion in the form of bolus intravenous infusion, continuous intravenous infusion and pulse intravenous infusion and in the form of intravenous injection.

10. The pharmaceutical composition as claimed in claim 1, wherein, the said composition is in the form of granules or powder composition in a sachet suitable for oral administration, for treating viral infection comprising: a) eflornithine of about 0.01 mg to 30,000 mg, and b) other pharmaceutically acceptable excipients.

11. The pharmaceutical composition as claimed in claim 1, wherein the viral infections are caused by severe acute respiratory syndrome coronavirus 2 (SARS COV-2 also known as COVID-19) and a wide variety of virus infections including, but not limited, to Cowpox virus, Herpes viridae, Herpes simplex viruses, Epstein-Barr virus, human adenoviruses, human papillomaviruses, hepatitis B virus, Retroviridae (such as human immunodeficiency virus), rotavirus, Filoviridae (such as Marburg virus and Ebola viruses), Dengue virus, influenza viruses, hanta virus, Severe acute respiratory syndrome coronavirus, Entero viruses, Rhino virus, Hepatitis virus, Noro virus, Norwalk virus, Alpha viruses, Chikungunya virus, Venezuelan equine encephalitis virus, Western equine encephalitis virus, Eastern equine encephalitis virus, St. Louis encephalitis virus, West Nile virus, Yellow fever virus, and Creutzfeldt-Jakob- Disease, Arbovirus, Flavivirus and other RNA viruses.

12. The pharmaceutical composition as claimed in claim 11 , wherein, the compositions are useful for the treatment patients suffering from mild to severe symptoms of COVID-19 infection. 13. The pharmaceutical composition as claimed in claim 11 wherein, the COVID-19 patients may either be symptomatic or asymptomatic.

14. The pharmaceutical composition as claimed in claim 11 wherein, the COVID-19 patients may either be treated at home or may be hospitalized.

15. The pharmaceutical composition claimed in claim 11, wherein, the symptoms may include; Fever, Cough, Fatigue, Shortness of breath, Expectoration, Myalgia, Rhinorrhea, Sore throat, Diarrhea, Loss of smell (anosmia) or Loss of taste (ageusia) preceding the onset of respiratory symptoms.

16. A method for the prevention, treatment and prophylactic intervention against a variety of viral infections with body surface area of 0.2 to 2 m2 and/or Body mass index between 10 to 45 Kg/m2 in a human patient suffering from or at risk from the said viral infection, wherein, the said method comprises treating the said patient with a pharmaceutical composition comprising eflornithine or its pharmaceutical salt or its prodrug of about 0.01% w/w to 90% w/w, and other pharmaceutically acceptable excipients.

17. The method as claimed in claim 16, wherein, the method comprises administrating granules in a sachet orally every 4 to 24 hrs, with or without food intake, as a monotherapy or combination therapy with other drugs to patients showing mild to severe symptoms of COVID-19 infection, and having a pharmaceutical composition comprising: a) eflornithine of about 0.01 mg to 30,000 mg, and b) other pharmaceutically acceptable excipients.

18. The method as claimed in claim 16, wherein the food administered is polyamine and/or protein controlled. 19. The pharmaceutical composition as claimed in claim 16, wherein, the compositions can be administered either as a single dose or as a multiple dose every 4 to 24 hr for the treatment of viral infection(s).

20. The pharmaceutical composition as claimed in claim 16, wherein, the composition, after single dose oral administration in human, produces maximum plasma concentration (Cmax) between the range of 5mcg/ml to 75mcg/ml, Time to reach maximum plasma concentration (Tmax) between the range of 30min to 500min and Area under curve (AUC) between the range of 30mcg.hr/ml to 600mcg.hr/ml.

21. The pharmaceutical composition as claimed in claim 16, wherein, the composition, after multiple oral dose oral administration in human, produces Cmax between the range of 5 mcg/ml to 150mcg/ml, Tmax between the range of 30min to 500min and AUC between the range of 30mcg.hr/ml to 1000 meg. hr/ml.

Description:
“EFLORNITHINE COMPOSITION AND DOSAGE FORMS FOR THE TREATMENT OF VIRAL INFECTION”

Field of the invention

The present invention relates to pharmaceutical compositions of eflornithine or its pharmaceutical salts or prodrugs thereof in different dosage forms useful for the treatment of and prophylactic intervention against a wide variety of viral infections including COVID-19. The present invention also relates to novel dosage forms of eflornithine which can be administered as a monotherapy and optionally in combination with other antiviral or antimicrobial or antimalarial or antiprotozoal medications and vaccines for the prevention and treatment of viral infections.

Background of the invention

Several drugs have been developed that can target the polyamine biosynthetic pathway. Polyamines are important for the replication of a diverse group of RNA viruses including several viruses involved in recent outbreaks, in vitro and in vivo. Such viruses are Dengue virus, Zika virus, Ebola virus, Chikunguniya virus, Sindhis virus, MERS-CoV virus, Japanese encephalitis virus, Yellow fever virus, Enterovirus, Coxsackie virus, Polio virus, Rift valley fever virus, Vesicular stomatitis virus and Rabies virus (Bryan C. Mounce, Teresa Cesaro, Gonzalo Moratorio et ah; Inhibition of Polyamine Biosynthesis Is a Broad-Spectrum Strategy against RNA Viruses; Journal of Virology; (November 2016) Volume 90; 9683-9692).

Difluoro-methylomithine (DFMO; also called eflornithine) has the anti-viral effect by reducing polyamine levels which has a negative effect on these diverse RNA viruses. Eflornithine, an FDA-approved drug is used to treat trypanosomiasis and hirsutism, as well as some cancers. DFMO irreversibly inhibits ornithine decarboxylase, a critical enzyme in polyamine biosynthesis. DFMO is well tolerated in humans, with side effects that are mild and reversible, and can be taken long-term. Additionally, DFMO can be administered via several routes, including orally, and the compound, dissolved in water and at room temperature, is stable for extended periods of time. These characteristics suggest that DFMO may be well suited for treatment of viral infection (Bryan C. Mounce, Teresa Cesaro, Gonzalo Moratorio et al.; Inhibition of Polyamine Biosynthesis Is a Broad-Spectrum Strategy against RNA Viruses; Journal of Virology; (November 2016) Volume 90; 9683-9692). The Eflomithine 13.9% cream formulation (Vaniqa ® ) has been used for treatment of unwanted facial hair in women. Another established use of eflomithine is in African trypanosomiasis (sleeping sickness) under brand name Omidyl ® .

Coronaviruses (CoV) are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV). Coronavirus disease (COVID-19) is a new strain that was discovered in 2019 and has not been previously identified in humans.

Coronavirus disease 2019 (COVID-19) is caused by SARS-COV2 and represents the causative agent of a potentially fatal disease that is of great global public health concern. Based on the large number of infected people that were exposed to the wet animal market in Wuhan City, China, it is suggested that this is likely the zoonotic origin of COVID-19. Person-to-person transmission of COVID-19 infection led to the isolation of patients that were subsequently administered a variety of treatments. Extensive measures to reduce person-to-person transmission of COVID-19 have been implemented to control the current outbreak.

The common signs of infection of COVID-19 include respiratory symptoms, fever, cough, and shortness of breath and breathing difficulties. In more severe cases, infection can cause pneumonia, severe acute respiratory syndrome, kidney failure and even death. Therefore it is an object of the present disclosure to provide new compositions and methods for the treatment of patients with Coronavirus infection alone or patients infected co-infected with an additional Coronavirus. Preclinical studies have shown that the inhibition of ornithine decarboxylase (ODC) by eflomithine and resultant decrease in tissue concentrations of polyamines (putrescine and spermine) prevents neoplastic developments in many tissue types. Increased levels of polyamines have been implicated in epithelial tumorigenesis, starting with early work by O’Brien et al. showing induction of polyamine biosynthetic enzymes in response to tumour-promoting agents. A double-blind, placebo-controlled phase 3 trial was planned to enrol 334 subjects with a prior history of skin cancer, either basal, squamous and randomized them to 500 mg/m 2 /day by oral liquid formulation of DFMO after mixing the assigned amount with fruit juice or another liquid to mask the flavour. The inhibition of skin concentrations of putrescine and spermidine in subjects taking DMFO was observed at 24 and 36 months but not at 48 months. These findings most likely reflect a moderate decrease in skin putrescine and spermidine concentrations when taking oral DMFO at 500 mg/m 2 /day. After DMFO became available in tablet form and was shown to have satisfactory bioequivalence to the liquid formulation when the subjects were switched to receive tablets of 250 mg DFMO per tablet. (Howard H Bailey, KyungMann Kim, Ajit K Verma et al; A Randomized, Double-Blind, Placebo-Controlled Phase 3 Skin Cancer Prevention Study of {Alpha}- Difluoromethylomithine in Subjects With Previous History of Skin Cancer; Cancer Prev Res (Phila), 3 (1), 35-47).

A phase I clinical study was designed to determine and compare toxicity and the maximally tolerated dose of a 4-day course of DFMO given to patients in oral, continuous intravenous infusion or pulse intravenous infusion forms. The maximally tolerated dose of a four-day course of oral DFMO was 3.75 gm/m2 every 6 hours. The maximally tolerated dose of intravenous pulse and continuous infusion DFMO was not attained. Pharmacokinetic studies demonstrated that the intravenous schedules achieved higher plasma levels of DFMO than those previously obtained with chronic oral dosing. C A Griffin 1, M Slavik, S C Chien, J Hermann; Phase I Trial and Pharmacokinetic Study of Intravenous and Oral Alpha-Difluoromethylomithine; Invest New Drugs, 5 (2), 177-86 (1987). The different types of pharmaceutical compositions of eflomithine which are known for treating, preventing, controlling the growth of and/or reducing the risk of cancer, tumours and related neoplastic disorders wherein the eflomithine composition is formulated for oral, buccal and sublingual administration which is in the form of solutions or suspensions and in the form of gelcaps, caplets, tablets, capsules or powders; injectable solution and injectable suspension for intra muscular injection; intravenous infusion by continuous or by pulse intravenous infusions.

WO9825603 discloses a composition of Eflomithine for use in the treatment of cancer, tumours and/or related neoplastic disorders comprising a therapeutic amount of a pharmaceutical composition comprising (-)-DFMO or a defined non- racemic ratio of (+)-DFMO: (-)-DFMO, or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

US6277411 discloses an oral sustained release composition of solid DFMO- containing formulation for the treatment or prophylaxis of cancer wherein the solid DFMO-containing formulation includes a core having a rapid release eflomithine- containing granules and slow release granules and an outer layer surrounding the core comprising a pH responsive coating.

US10786470 discloses a pharmaceutical composition that is in the physical form of a solution for oral administration comprising from about 16.2% to 19.8% of eflomithine hydrochloride hydrate, water and one or more pharmaceutically acceptable excipients and the method of use of the composition for the treatment of glioma. The composition is in the form of eflomithine powder for oral solution and oral suspension.

Therefore it is an object of the present invention to provide different pharmaceutical compositions of eflomithine for the prevention and treatment of a wide variety of viral infections including COVID-19. The recently identified coronavirus MERS- CoV has over 40% mortality rate among the infected individuals. This virus also demonstrates person-to-person transmission, posing a continuous threat to public health worldwide. Thus, development of suitable dosage forms of eflornithine as antiviral agent against this new virus, Covid-19 is urgently needed.

Summary of the invention

The present invention provides pharmaceutical compositions of eflornithine which can be administered to the patient, intravenously in the form of intravenous infusion and intravenous injection by using vials and ampoules, orally in the form of tablets and capsules, oral solution using granules in a sachet composition, liquid orals in the form of oral solution and oral suspension, for the prevention and treatment of a wide variety of viral infections including COVID 19.

The primary aspect of the invention is to provide the compositions of eflornithine in different dosage forms for the prevention and treatment of viral infections caused by COVID-19 and a wide variety of other viral infections including, but not limited, to Cowpox virus, Herpes viridae, Herpes simplex viruses, Epstein-Barr virus, human adenoviruses, human papillomaviruses, hepatitis B virus, Retroviridae (such as human immunodeficiency virus), rotavirus, Filoviridae (such as Marburg virus and Ebola viruses), Dengue virus, influenza viruses, hanta virus, Severe acute respiratory syndrome coronavirus, Entero viruses, Rhino virus, Hepatitis virus, Noro virus, Norwalk virus, Alpha viruses, Chikungunya virus, Venezuelan equine encephalitis virus, Western equine encephalitis virus, Eastern equine encephalitis virus, St. Louis encephalitis virus, West Nile virus, Yellow fever virus, and Creutzfeldt- Jakob- Disease, Arbovirus, Flavivirus and RNA viruses.

Another aspect of the invention provides a method for the treatment of a patient who has the symptoms of mild to severe COVID 19, which method comprises, administering to the said patient, the dosage forms of eflornithine or its pharmaceutical salts or prodrugs thereof provided according to the present invention.

Another aspect of the invention is to provide compositions of eflornithine or a pharmaceutically acceptable salt or prodrug thereof suitable for oral administration in the form of solid oral composition or in the form of granules or powder filled into a sachet wherein the sachet contains the dose of 100 mg to 30000 mg of eflornithine.

Another aspect of the invention is to provide compositions of eflornithine or a pharmaceutically acceptable salt or prodrug thereof suitable for the administration of eflornithine through intravenous infusion which is either as a continuous intravenous infusion or as a pulse intravenous infusion.

Another aspect of the invention is to provide compositions of eflornithine or a pharmaceutically acceptable salt or prodrug thereof suitable for the administration in the form of intravenous injection by using a vial or an ampoule wherein the vial contains the dose of 100 mg/ml to 500 mg/ml of eflornithine.

Another aspect of the invention is to provide pharmaceutical compositions of eflornithine or a pharmaceutically acceptable salt or prodrug thereof suitable for oral administration in the form of tablet which includes scored coated and uncoated tablet containing the dose of 100 mg to 1000 mg of eflornithine and scored chewable tablet with or without taste-masking containing the dose of 100 mg to 1000 mg of eflornithine in one tablet and also in the form of capsule which containing the dose of 100 mg to 1000 mg of eflornithine.

Another aspect of the invention is to provide pharmaceutical compositions of eflornithine or a pharmaceutically acceptable salt or prodrug thereof suitable for oral administration as liquid oral dosage in the form of oral solution and oral suspension in a bottle wherein the bottle contains the dose of 100 mg/ml to 1000 mg/ml of eflomithine.

Another aspect of the invention is to provide pharmaceutical compositions of eflomithine or a pharmaceutically acceptable salt or prodrug thereof which is administered as a monotherapy or in combination with other drugs for the prevention and treatment of viral infections including COVID 19.

Another aspect of the invention is to provide pharmaceutical compositions of eflomithine or a pharmaceutically acceptable salt or prodrug thereof which is administered in combination with food with low polyamine content (preferably less than 300 micromol) for the prevention and treatment of viral infections including COVID 19.

Another aspect of the invention is to provide different compositions of eflomithine in various dosage forms for the prevention and treatment in patients who has the symptoms of moderate to severe COVID 19.

Another aspect of the present invention is to provide different compositions of eflomithine in various dosage forms which can be given as a monotherapy or in combination with other therapeutic agents such as, but not limited to, antiviral or antimicrobial or anti-malarial or antiprotozoal medications, which serves as a prophylactic and/or a symptomatic relief and a reduction in viral load in children, adults and geriatric patients in both sexes with viral infections including COVID 19 wherein the duration of the treatment may vary between 3 to 30 days.

Another aspect of the present invention is to provide different compositions of eflomithine in various dosage forms for the treatment of patients with viral infection who has the Body Surface Area (BSA) in the range of 0.2 to 2.0 g/m 2 . Another aspect of the present invention is to provide the oral administration of eflornithine composition in the form of tablets and capsules, eflornithine granules or powder composition filled into a sachet for the treatment of viral infection with the oral dosage of 0.1 g/day to 26 g/day.

Brief description of drawings:

Figure 1 Linear plot of mean plasma concentrations versus time curves of eflornithine in fasting conditions.

Figure 2 Linear plot of mean plasma concentrations versus time curves of eflornithine in fed conditions.

Figure 3: Linear plot of mean plasma concentrations versus time curves of eflornithine for 6 hours.

Figure 4: Linear plot of mean plasma concentrations versus time curves of eflornithine for 8 hours.

Description of invention

The present invention provides novel pharmaceutical compositions of eflornithine with different dosage forms for the administration of eflornithine intravenously in the form of intravenous infusion and intravenous injection by using vials and ampoules, orally in the form of tablets and capsules, solid oral composition in the form of granules or powder is filled into sachet, liquid orals in the form of oral solution and oral suspension compositions for the treatment of a wide variety of viral infections including COVID 19.

Composition and Administration:

An antiviral composition of the invention can be formulated for intravenous route for administration either as continuous infusion or as a pulse intravenous infusion, by injection (e.g., intravenous in vials or ampoules), liquid oral dosage form (solution) in a bottle, solid oral composition in the form of granules or powder is filled into sachet and oral administration in the form of scored tablet, chewable tablet and capsule. The antiviral composition can be administered therapeutically or prophylactically, for the treatment of viral infections.

1. Intravenous infusion:

Intravenous infusion therapy is a therapy that delivers fluids directly to the vein wherein the drug is administered by using only the pressure supplied by gravity or via an external force such as pump. a. Continuous intravenous infusion:

The present invention provides a formulation of eflornithine which is filled into ampoule or vial and which can be administered as continuous intravenous infusion. The eflornithine composition is added into a sterile intravenous solution of 5% dextrose or 0.9% normal saline in a suitable container of 100 ml to 1 litre and infused into the patient over a period of 24 hours. b. Pulse intravenous infusion:

A pulse intravenous infusion means the administration of high doses of drugs in an intermittent manner to enhance the therapeutic effects and reduce the side-effects. The present invention provides an eflornithine composition which can be administered as a pulse intravenous infusion wherein the eflornithine composition is diluted to the required concentration of 50 to 100 ml with 5% dextrose in water or 0.9% normal saline. The resultant solution is infused intravenously into the patient over a period of 30 minutes to 2 hours and repeated every 4 to 12 hours.

2. Intravenous (IV) injection by using vials and ampoules:

The present invention provides an eflornithine injection which contains 50 mg/ml to 500 mg/ml of eflornithine which is filled into Type I, glass vials wherein each vial is sealed with a halobutyl rubber stopper and aluminium ferrule. 3. Oral Solid Composition:

The eflornithine compositions are formulated for oral administration in the form of scored tablet, scored chewable tablet and capsule. a. Scored tablet:

The present invention provides a scored tablet (coated or uncoated) composition which contains about 100 mg to 1000 mg of eflornithine. In some embodiments, the formulation further comprises one or more disintegrants which includes, but are not limited to, methylcellulose, hydroxypropylmethylcellulose (HPMC) microcrystalline cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. AC -DI-SOL™, PRIMELLOSE™), povidone, guar gum, magnesium aluminum silicate, colloidal silicon dioxide (e.g. AEROSIL™ CARBOSIL™), polacrilin potassium, starch, pregelatinized starch, sodium starch glycolate (e.g. EXPLOTAB™), sodium alginate, maize starch, com starch, potato starch, individually or in any mixtures thereof in a range of 0.1% to 50% of total formulation composition.

In another embodiments, the formulation further comprises one or more binders which includes, but are not limited to, methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethyl propylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, povidone 30, starch and pregelatinized starch individually or in any mixtures thereof in a range of 0.1% w/w to 50% w/w of the total composition by weight.

In another embodiments, the formulation further comprises a suitable lubricant or a mixture of two or more binders which includes, but are not limited to, colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, glyceryl behenate, sodium stearyl fumarate and silica gel or in any mixtures thereof in a range of 0.1% w/w to 10% w/w of the total composition by weight. In another embodiments, the formulation further comprises a taste-masking agent which includes, but not limited to, methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethyl propylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, povidone 30, titanium dioxide and talc or in any mixtures thereof in a range of 1% w/w to 10% w/w of the total composition by weight. b. Scored chewable tablet:

The present invention provides a scored chewable tablet (with or without taste masking) which contains about 100 mg to 2000 mg of efl ornithine. In some embodiments, the formulation further includes taste-masking agents which include polymers, but not limited to, Eudragit EPO ® , Eudragit E 100 ® , ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol and polyvinyl acetate and a sweetener which include, but not limited to, sucralose, aspartame, mannitol, sorbitol and acesulfame potassium or in mixtures thereof in a range of 1% w/w to 50% w/w of total composition by weight. In another embodiment, the formulation further includes flavorants but not limited to, lemon, cherry, strawberry, grape, cream, mocha and spearmint or in any mixtures thereof in a range of 0.1% to 5% of total composition by weight.

In another embodiments, the formulation further comprises one or more lubricants which include, but not limited to, aerosil, talc, stearic acid, magnesium stearate, calcium stearate, glyceryl behenate, sodium stearyl fumarate, colloidal anhydrous silicate and silica gel or in any mixtures thereof in a range of 0.1% to 10% of total composition by weight.

In another embodiments, the formulation further comprises one or more binders which includes, but are not limited to, methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethyl propylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, povidone 30, starch and pregelatinized starch individually or in any mixtures thereof in a range of 0.1% w/w to 50% w/w of total composition by weight. In some embodiments, the formulation further comprises one or more disintegrants which includes, but are not limited to, methylcellulose, hydroxypropylmethylcellulose (HPMC) microcrystalline cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. AC-DI-SOL™, PRIMELLOSE™), povidone, guar gum, magnesium aluminium silicate, colloidal silicon dioxide (e.g. AEROSIL™ CARBOSIL™), polacrilin potassium, starch, pregelatinized starch, sodium starch glycolate (e.g. EXPLOTAB™), sodium alginate, maize starch, corn starch, potato starch, individually or in any mixtures thereof in a range of 0.1% w/w to 25% w/w of total composition by weight. c. Capsule:

The present invention provides a capsule composition which includes about 100 mg to 1000 mg of efl ornithine. In some embodiments, the formulation further comprises one or more disintegrants, which includes, but not limited to, methylcelluloses, microcrystalline celluloses, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, maize starch, com starch and potato starch, individually or in any mixtures thereof in a range of 0.1% w/w to 50% w/w of total composition by weight.

In another embodiments, the formulation further includes one or more lubricants, which includes, but not limited to, colloidal silicon dioxide, aerosil, talc, stearic acid, magnesium stearate, calcium stearate, glyceryl behenate, sodium stearyl fumarate and silica gel in a range of 0.1% to 10% of total composition by weight. In another embodiments, the formulation further includes one or more binders such as methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethyl propylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, povidone 30, starch and pregelatinized starch in a range of 0.1% to 50% of total composition by weight. 4. Liquid Oral Solution and Liquid Oral Suspension:

The present invention provides a liquid oral dosage form which is available in a bottle wherein the bottle contains an amount of 100-1000 mg/ml of efl ornithine.

In some embodiments, the formulation contains one or more taste-masking agents as polymers, but not limited to, Eudragit EPO ® , Eudragit E 100 ® , ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol and polyvinyl acetate and a sweetener which include, but not limited to, sucralose, aspartame, mannitol, sorbitol and acesulfame potassium or in mixtures thereof in a range of 0.1% w/w to 50% w/w of total composition by weight. In another embodiment, the formulation further includes flavorants but not limited to, lemon, cherry, strawberry, grape, cream, mocha and spearmint or in any mixtures thereof in a range of 0.1% w/w to 10% w/w of total composition by weight.

In another embodiments, the formulation further comprises one or more preservatives which includes, but not limited to, methyl paraben, propyl paraben, citric acid, sodium metabisulphide and sodium benzoate or a mixture thereof in a range of 0.1% w/w to 15% w/w of total composition.

In another embodiments, the formulation further comprises one or more thickening agent and/or suspending agent which includes, but not limited to, methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethyl propylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, povidone 30, starch and pre-gelatinized starch or a mixture therefore in a range of 0.1% w/w to 50% w/w of total formulation composition.

In another embodiments, the formulation further comprises one or more pH modifiers and/or buffering agents which includes, but not limited to, citric acid, sodium and potassium salts of citric acid, sodium and potassium bicarbonate, sodium hydroxide and hydrochloric acid or a mixture thereof in a range of 0.1% w/w to 25% w/w of total formulation composition. In another embodiments, the formulation further comprises one or more anti oxidants and/or stabilizing agents which includes, but not limited to, butylated hydroxy toluene, tocopherol, ascorbic acid, sodium bisulfite and sodium metabi sulfite or a mixture thereof in a range of 0.01% w/w to 5.0% w/w of total formulation composition.

5. Eflornithine powder or granules filled into sachet:

The solid oral composition in the form of powder or granules filled into sachet which contains the dose of 100 mg to 30000 mg of eflornithine.

In some embodiments, the formulation further contains one or more taste-masking agents include Eudragit EPO ® , Eudragit E 100 ® , ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol and polyvinyl acetate or the sweeteners include sucralose, aspartame, mannitol, sorbitol, acesulfame potassium which are used individually or in a mixture in the range of 0.1% w/w to 50% w/w of total formulation composition. The flavourant is selected from the group consisting of lemon, cherry, strawberry, grape, cream, mocha, spearmint which are used individually or in a mixture in the range of 0.1% w/w to 10% w/w of total formulation composition.

In some embodiments, the formulation further comprises excipients as preservatives that can be used in pharmaceutical formulations which includes but not limited to methyl paraben, propyl paraben, citric acid, sodium metabisulphide, which are used individually or in a mixture in the range of 0.1% w/w to 15% w/w of total formulation composition.

In some embodiments, the formulation further comprises one or more thickening and/or suspending agent such as methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethyl propylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, povidone 30, starch and pregelatinized starch which are used individually or in a mixture in the range of 0.1% w/w to 50% w/w of total formulation composition.

In some embodiments, the formulation further comprises pH modifier and/or buffering agents such as citric acid, sodium and potassium salts of citric acid, sodium and potassium bicarbonate, sodium hydroxide, hydrochloric acid which are used individually or in a mixture in the range of 0.1% w/w to 25% w/w of total composition.

In some embodiments, the formulation further comprises one or more diluents such as microcrystalline cellulose (e.g. Avicel ® ), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, Pearlitol ® mannitol, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc which are used individually or in a mixture in the range of 5.0% w/w to 35.5% w/w of total composition.

In some embodiments, the formulation further comprises anti-oxidant and stabilizing agent such as butylated hydroxy toluene, tocopherol, ascorbic acid, sodium bisulfite, sodium metabisulfite which are used individually or in a mixture in the range of 0.01% w/w to 5.0% w/w of total formulation composition.

Eflornithine composition is administered as a monotherapy or in combination with other drugs

In some embodiments, eflornithine formulation given for prophylactic, symptomatic relief and for treatment by reduction in viral load as monotherapy or as a combination therapy with other therapeutic agents such as but not limited to antiviral (Remdesivir, Lopinavir, Ritonavir and like), antimicrobial (Azithromycin, Clarithromycin and like) or anti-malarial or antiprotozoal (Chloroquine, Hydroxychloroquine and like) medications. The duration of said treatment on patient with body mass index of 0.2 to 2 m 2 shall range from 3 to 30 days. Eflornithine formulations in combination with food

In some embodiments, eflornithine formulation administered with food with low poly amine content (less than 300 micromol) like but not limited to egg, cereal, vegetable, fruits, legumes, beverages, meat, chicken, dairy products, nuts, desserts individually or in a mixture thereof.

Examples:

Example 1:

Manufacturing Formula of Eflornithine Injection Table 1:

Manufacturing Process:

Step I:

Eflornithine hydrochloride was dissolved in water for injections at ambient temperature and made up to volume with Water for Injections. The solution was stirred to aid dissolution and to achieve homogeneity. The duration of the mixing time is not a critical processing parameter because eflornithine hydrochloride is very soluble in water. The pH of the solution was recorded.

Step II:

The solution was filtered through a 0.22 pm cellulose membrane filter into a sterilised container. The integrity of the filter was checked before and after filtration.

Step III:

The solution was filled into clean, sterilised vials and sealed. (Type I glass vials. Each vial was sealed with a halobutyl rubber stopper and aluminium ferrule). The filled vials were sterilised by autoclaving at 121° C for 20 minutes.

Step IV: All sterilisation procedures have been fully validated and were monitored during the processes.

All filled and sterilised ampoules were leak tested. All units were inspected for particulate contamination.

Finally, the units were labelled and packaged.

Example 2:

Manufacturing Formula of Eflomithine Scored Tablet

Table 2:

Manufacturing Formula:

Sifting:

Sifted dispensed quantity of Eflomithine Hydrochloride #40 and Microcrystalline cellulose # 40 were collected in IPC lined with double polybags; Magnesium Stearate #40 and Colloidal silicon dioxide # 80 Sifted were collected in separate IPC lined with double polybags.

Granulation:

Transferred sifted material Eflomithine Hydrochloride and Microcrystalline cellulose in Rapid mixer granulator, mixed for 3 min for 15 RPM. After that added binding solution (dissolve Hydroxypropylmethylcellulose in water) and granulated for 5 min for 15 RPM.

Drying and Milling:

Granulated wet mass dried in FBD.

Dried granules were milled in multimill using 0.5mm screen.

Pre-lubrication:

Transferred the sifted Colloidal silicon dioxide in to above blend and mixed the blend in blender for 3 min at 15 RPM.

Lubrication:

Transferred the sifted Magnesium Stearate in to above blend and mixed the blend in blender for 2 min at 15 RPM.

Compression:

Recorded the punch identification number issued for usage. Verifiedy Appearance, Dimensions and marking of individual punch sets.

Used punch (6.0 mm) round shaped concave, Breakline on both upper punches and lower punches.

Efl ornithine Tablet 100 mg: 6.00 mm, round, concave, Breakline on both sides. Transferred the lubricated granules to compression area.

Transferred the lubricated granules into hopper of the compression machine. Set and run the compression machine as per the compression parameters.

Example 3:

Manufacturing Formula of Eflornithine Chewable Tablet

Table 3:

Manufacturing Process:

Sifting:

Sifted dispensed quantity of Eflornithine Hydrochloride #40 and Microcrystalline cellulose # 40 were collected in IPC lined with double polybags; Mannitol #40, Sorbitol #40, Acesulfame Potassium #40, Lemon flavour #40 and Magnesium Stearate #40 Sifted dispensed were collected in separate IPC lined with double polybags.

Granulation:

Transferred sifted material Eflornithine Hydrochloride and Microcrystalline cellulose in Rapid mixer granulator mix for 3 min for 15 RPM. After that added binding solution (dissolve Hydroxypropylmethylcellulose in water) and granulated for 5 min for 15 RPM.

Drying and Milling:

Granulated wet mass dried in FBD.

Dried granules were milled in multimill using 0.5mm screen.

Pre-lubrication:

Transferred the sifted Mannitol, Sorbitol, Acesulfame Potassium, Lemon flavour and Colloidal anhydrous silica in to above blend and mixed the blend in blender for 5 min at 15 RPM.

Lubrication:

Transferred the sifted Magnesium Stearate in to above blend and mixed the blend in blender for 3 min at 15 RPM.

Compression: Above blend was compressed by suitable punch.

Example 4:

Manufacturing Formula of Eflornithine Capsule:

Table 4:

Manufacturing Process:

Sifting:

Sifted dispensed quantity of Eflornithine Hydrochloride #40 and Microcrystalline cellulose # 40 were collected in IPC lined with double polybags; Magnesium Stearate #40 and Colloidal silicon dioxide # 80 Sifted dispensed were collected in separate IPC lined with double polybags.

Granulation:

Transferred sifted material Eflornithine Hydrochloride and Microcrystalline cellulose in Rapid mixer granulator, mixed for 3 min for 15 RPM. After that added binding solution (dissolve Hydroxypropylmethylcellulose in water) and granulated for 5 min for 15 RPM.

Drying and Milling:

Granulated wet mass was dried in FBD.

Dried granules were milled in multimill using 0.5mm screen.

Pre-lubrication: Transferred the sifted Colloidal silicon dioxide in to above blend and mixed the blend in blender for 3 min at 15 RPM.

Lubrication:

Transferred the sifted Magnesium Stearate in to above blend and mixed the blend in blender for 2 min at 15 RPM.

Capsule Filling:

Lubricated blend was filled in capsule shell size “00”.

Example 5:

Manufacturing Formula of Eflornithine Liquid oral dosage form (Solution):

Table 5:

Manufacturing Process:

Sifting:

Sifted dispensed quantity of Eflornithine Hydrochloride #40 and Microcrystalline cellulose # 40 were collected in IPC lined with double polybags; Sifted dispensed quantity of Mannitol #40, Sorbitol #40, Acesulfame Potassium #40, Lemon flavour #40 and Magnesium Stearate #40 were collected in separate IPC lined with double polybags.

Granulation:

Transferred sifted material Eflomithine Hydrochloride and Microcrystalline cellulose in Rapid mixer granulator mixed for 3 min for 15 RPM. After that added binding solution (dissolve Hydroxypropylmethylcellulose in water) and granulated for 5 min for 15 RPM.

Drying and Milling:

Granulated wet mass was dried in FBD.

Dried granules were milled in multimill using 0.5mm screen.

Pre-lubrication:

Transferred the sifted Mannitol, Sorbitol, Acesulfame Potassium, Lemon flavour and Colloidal anhydrous silica in to above blend and mixed the blend in blender for 5 min at 15 RPM.

Lubrication:

Transferred the sifted Magnesium Stearate in to above blend and mixed the blend in blender for 3 min at 15 RPM.

Bottle Filling:

Above blend was ready for bottle packing.

Example 6

Manufacturing formula of eflomithine granules or powder composition filled into a sachet, as shown in table 6 and table 7:

Table 6:

Table 7

Manufacturing process of eflornithine granules or powder composition filled into a sachet:

The present invention provides a process for preparing solid oral granules or powder composition filled into a sachet wherein the process comprising the steps which include sifting eflornithine hydrochloride monohydrate, Pearlitol ® 300 DC- Mannitol, Aspartame EP, Flavour Orange Fresh DM, Colloidal Anhydrous Silica through the sieve #30 mesh nylon filter cloth and cooled at room temperature, blending the sifted materials in cube blender for blending for 20 minutes at 8 rpm, filled into the sachet by automatic sachet filling machine in 4 ply aluminium laminates or foil.

Example 7

Eflornithine granules or powder composition filled into a sachet:

Clinical trials:

A bioavailability study of eflornithine granules or powder composition filled into a sachet containing 1.25 g, 2.5 g and 5.0 g of eflornithine have conducted and determined the bioavailability, safety and tolerability of the oral liquid composition on subjects administered with the composition.

More specifically, the study of this Example 7 was to conduct pharmacokinetic parameters resulting from administering an oral liquid composition including eflornithine granules 1.25 g, 2.5 g and 5.0 g to healthy subjects under fed and fasting conditions.

The pharmacokinetic parameters of different doses of eflornithine granules or powder for oral solution was evaluated in an open label, balanced, randomized, single period, two phase, three treatment, six arm, single and multi-oral dose, parallel, pharmacokinetic study in human subjects under fasting and fed conditions. The study was conducted with 48 healthy, adult male subjects in an age range of 18 to 45 years with a body mass index of at least 18.5 kg/m2 and not more than 30.0 kg/m2, and with a body weight of not less than 50 kg. The subjects underwent screening evaluations to determine eligibility within 28 days prior to the check-in of 1st period. The subjects were randomized to receive either 1.25 g/dose or 2.5 g/ dose or 5.0 g/dose containing eflornithine which were administered along with 240 mL of drinking water at ambient temperature in sitting posture under fasting condition.

In Phase I (Single dose study, Fasting and Fed), blood samples were collected on day 2 including pre-dose (00.00) blood sample of 10 mL collected within 01.00 hour prior to dosing and 4 mL post-dose blood samples collected at 01.00, 02.00, 03.00, 03.33, 03.67, 04.00, 04.33, 04.67, 05.00, 05.50, 06.00, 08.00, 10.00, 12.00, 18.00 hours (within +2 minutes of schedule time) following drug administration and at 24.00 hours post dose.

In Phase II study multiple dose study was conducted by administration of above said doses at every 6 hourly and 8 hourly administration; corresponding to daily administration of 3.25, 7.5, 15. Og and 5.0, 10.0, and 20. Og daily dose respectively on Day 4, 5, 6 and check out on day 7. The blood samples were collected on day 4, day 5 and day 6 including pre-dose (00.00) blood sample of 10 mL collected within 01.00 hour prior to dosing and 4 mL post-dose blood samples collected at 06.00 hr, 12.00 hr, 18.00 hr (within +2 minutes of schedule time) following drug administration at 24 hours post dose.

The pharmacokinetic parameters includes Tmax, AUC(O-co), AUC(O-t), Cmax and AUC(O-tau) under fasting conditions, fed conditions and multi-dose conditions which were analysed by using a linear normal model. The model included fixed effects of dose and a random subject effect. Based on the statistical model, pairwise ratios between doses and their 90% confidence intervals was estimated. It was observed that after a single dose oral administration of the compositions of Eflomithine in a human produces maximum plasma concentration (Cmax) between the range of 5mcg/ml to 75mcg/ml, Time to reach maximum plasma concentration (Tmax) between the range of 30min to 500min and Area under curve (AUC) between the range of 30mcg.hr/ml to 600mcg.hr/ml after single dose administration.

Similarly, it was also observed that after multiple oral dose oral administration of the compositions of Eflomithine in a human produces Cmax between the range of 5 mcg/ml to 150mcg/ml, Tmax between the range of 30min to 500min and AUC between the range of 30mcg.hr/ml to 1000 meg. hr/ml after multiple dose administration.

A summary of the pharmacokinetic parameters determined in subjects participating in the study of the eflomithine granules or powder in a sachet includes eflomithine 1.25 g, 2.5 g and 5.0 g administered to subjects under fed conditions, fasting conditions and multi-dose conditions include:

Table 8:

Tmax-Time to peak (maximum) observed plasma drug concentration

Cmax -Peak ( maximum ) observed plasma drug concentration

AUC(0 to co )-Area under the concentration-time curve from time zero to infinity

To determine the bioavailability of eflornithine granules or powder in a sachet containing eflornithine 1.25 g, 2.5 g and 5.0 g under both fasting conditions, fed conditions and multi-dose conditions, the pharmacokinetic parameters Cmax, AU o- t) and AUC(o to ¥), Tmax and T1/2 were calculated. The criteria applied to conclude that the oral liquid composition including eflornithine administered to healthy adult subjects under the fasting conditions, fed conditions and multi-dose conditions, the dose-proportionality was established for fast and fed treatment arms for all the three pharmacokinetic parameters Cmax, AUC(o-t) and AU o to

Example 8

An open label, randomized, three treatments, three arm, parallel group, investigator initiated, comparative clinical trial to evaluate the safety and efficacy of oral eflornithine against the standard of care in human adult hospitalized COVID-19 patients.

The study was aimed to evaluate the antiviral efficacy of orally administered eflornithine in moderate to severe hospitalized COVID-19 patients.

Study design:

Patients were assessed for COVID-19 infection by an ICMR approved RT-PCR test kit, wherein the samples (swab) were taken from the nasopharynx and throat on days 1, 4, 7, 14, 21 and 28. All negative instances of RT-PCR tests were reconfirmed by taking fresh samples from the nasopharynx and throat at least > 24 hours from the first RT-PCR sample collection.

The eight-category ordinal scale consisting of the following categories: 0) Uninfected, no clinical or virological evidence of infection.

1) Not hospitalized, no limits of normal activities;

2) Not hospitalized, but limitations of normal activities;

3) Hospitalized, not requiring supplemental oxygen;

4) Hospitalized, requiring supplemental oxygen (by mask or nasal prongs);

5) Hospitalized, requiring nasal high-flow oxygen therapy, non-invasive mechanical ventilation, or both;

6) Hospitalized, intubation and mechanical ventilation;

7) Hospitalized, requiring extracorporeal membrane oxygenation (ECMO), invasive mechanical ventilation, or both;

8) Death.

Ordinal scales: have been used as end points in clinical trials in patients hospitalized with severe influenza and have also been recommended by the WHO R&D Blueprint for novel coronavirus Therapeutic Trial Synopsis. Patients with ordinal scores of 4, 5 and 6 were enrolled into the study.

Screening and Baseline tests:

Patients were screened for at least 3 days prior to treatment initiation. Screening included physical and clinical assessments which included RT-PCR test for COVID-19, demographic data (height, weight, body mass index [BMI], and age), gender, personal history, medical history, menstrual history, treatment history, audiometry, systemic examination, clinical laboratory tests (haematology, biochemistry, urine analysis and serology), serum pregnancy test (for female), 12- lead electrocardiogram (ECG), 2D-echo, ultrasound abdomen and chest X-ray posterio-anterior view within 24 hours from the day of check-in or admission. Patients were also assessed for meeting the inclusion and exclusion criteria as mentioned below:

Treatment arms and Standard of Care:

Eighteen patients were enrolled in three arms were treated with eflornithine (a- difluoromethylornithine; DFMO) and Standard of Care (SoC).

1. Treatment arm (10.0 grams per day): Eflornithine Granules in sachet (2.5 gram per dose) (Orange Flavour; Sugar Free) for oral solution was administered every 6 hours along with Standard of Care (SoC) excluding antimalarial and antiviral medications.

2. Treatment arm (20.0 grams per day): Eflornithine Granules in sachet (5.0 gram per dose) (Orange Flavour; Sugar Free) for oral solution was administered every 6 hours along with SoC excluding antimalarial and antiviral medications.

3. Treatment arm PI: SoC including antimalarial, antivirals and macrolides. Patient demographics:

Intent to treat (ITT) population:

Adult patients who were confirmed RT-PCR positive for COVID-19 infection, were enrolled as the ITT population in this study.

The demographics of the patients enrolled in the study were as follows:

Table 9:

Results and discussion:

1. Time to Negative Viral Test:

The mean time to negative RT-PCR for COVID-19 was 10.6 days, 12.17 days and 13.16 days in arms I, II and II respectively.

2. Time to Clinical Improvement (TTCI):

The mean TTCI was 7.36, 11.62 and 8.02 days for treatment arms I, II and III respectively.

3. Eight-point ordinal 14-dav analysis:

In treatment Arm I, by day-07, majority of the enrolled patients were in the ordinal scale 3 and did not require any oxygen support and there is a shift in number of patients from ordinal score 6 to 3 over a 14-day period.

In treatment Arm II, a similar shift/improvement (as in treatment arm I) in ordinal scales (6 to 3) over a 14 day period. By day 07, majority of the enrolled patients were in the ordinal scale 5 and required oxygen support.

In treatment Arm III, out of the 6 patients, one patient showed an ordinal score improvement from 4 to 3 by day 4 and the other patients showed an improvement from 5 to 3 by day 9 and day 14.

4. Oxygen free days:

Oxygen free days was assessed as the number of days each patient was having an ordinal score of 3, which meant that there was no requirement for supportive oxygen. Arm III had more number and percentage of oxygen free days as compared to arms I and II, as the number of severe COVID-19 patients recruited in arm III was less when compared to arm I and arm II.

5. Incidence of RT-PCR negative (14-dav analysis) in each treatment arm:

The incidence of RT-PCR negative was assessed across treatment arms by day 14. In treatment Arm I, five patients out of the six enrolled turned RT-PCR negative for COVID-19. In treatment Arm II, 4 patients out of the 6 enrolled turned RT-PCR negative for COVID-19. In treatment Arm III, 4 patients out of the 6 enrolled turned RT-PCR negative for COVID-19.

6. Percentage Recovery:

The percentage of patients who recovered in each arm was also assessed and calculated as a number of patients with negative RT-PCR for COVID-19 infection by day 14 divided by the intent to treat population, expressed as a percentage. The percentage of patient who recovered was 83%, 67% and 67% in treatment arms I, II and III respectively.

Conclusion:

A significant increase in incidence of RT-PCR negative in eflornithine arms I (83%) over the SoC (67%) is evident. The time to viral load clearance in patients appears to be comparable in all arms of the study (arm I - 10.6 days; arm II - 12.17 days and arm III - 13.16 days). The mean time to clinical improvement (TTCI) was comparable between treatment arms I (7.36 days) and III (8.02 days). Since, number of severe COVID-19 patients recruited in arm II (11.62 days) was higher; the mean TTCI was significantly more than arms I and III. The mean duration of hospitalization in arm I (12.14 days) and II (12.58 days) are similar. The mean duration of hospitalization in arm I (12.14 days) and III (12.58 days) are similar. The duration of hospitalization in treatment arm II (15.17 days), is significantly higher than the other two arms, which may be attributed to more number of severe patients enrolled in this treatment arm. The treatment arm III (39%) had more number and percentage of oxygen free days as compared to arms I (32.2.0%) and II (19.7%). The results of treatment arm II are consistent with the fact that more number of severe patients were enrolled in this arm and hence there is a lesser percentage of oxygen free days. As per the study data analysis, it is evident that oral eflornithine is a safe product, and when administered at 10.0 grams or 20.0 grams per day, shows promising antiviral efficacy in moderate to severe hospitalized COVID-19 patients as compared to the SoC.