WO2022123433A1

WO2022123433A1 - Oral pharmaceutical compositions of remdesivir

Info

Publication number: WO2022123433A1
Application number: PCT/IB2021/061398
Authority: WO
Inventors: Makarand Krishnakumar Avachat; Sajeev Chandran; Ashish Ashokrao Deshmukh; Venkata P. Palle; Vijay Kanoje; Sourav Roy
Original assignee: Lupin Limited
Priority date: 2020-12-08
Filing date: 2021-12-07
Publication date: 2022-06-16

Abstract

Disclosed herein are novel pharmaceutical compositions of remdesivir or a pharmaceutically acceptable salt thereof suitable for oral administration. The pharmaceutical compositions improve the oral bioavailability of remdesivir and are particularly useful for treatment/or prevention of coronavirus infections.

Description

ORAL PHARMACEUTICAL COMPOSITIONS OF REMDESIVIR

RELATED APPLICATIONS

This application is being filed as a PCT International patent application, and claims priority to at least Indian Patent Application No. 202021053448, filed on December 08, 2020 and Indian Patent Application No. 202121024794, filed on June 03, 2021. The entirety of each of the aforementioned applications is hereby incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions of remdesivir or a pharmaceutically acceptable salt thereof suitable for oral administration. The present invention also relates to a process of preparing and using said compositions for treating and/or preventing viral infections including coronavirus infections.

BACKGROUND OF THE INVENTION

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most people infected with the COVID- 19 virus experience mild to moderate respiratory illness and recover without requiring special treatment. Older people, and those with underlying medical problems like cardiovascular disease, diabetes, chronic respiratory disease, and cancer are more likely to develop serious illness.

Remdesivir, a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor, is one of the most promising drugs to treat the COVID-19 or coronavirus 2 (SARS-CoV- 2) infection based on its broad-spectrum antiviral mechanism of action. Its chemical name is 2-ethylbutyl N-{(S)-[2-C-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-2,5- anhydro-d-altrononitril-6-O-yl]phenoxy phosphoryl }-L-alaninate, and its chemical structure is shown below:

Remdesivir is currently marketed in the form of injectable intravenous formulations under the brand name Veklury® for the treatment of the CO VID- 19. These formulations are powder for concentrate for solution for infusion (lyophilized powder) and concentrate for solution for infusion (sterile concentrate), and contain betadex sulfobutyl ether sodium, water for injection, and may include hydrochloric acid and/or sodium hydroxide for pH adjustment.

For a variety of reasons, such as patient compliance, extravasation of drug, and thrombosis, an oral formulation is usually preferred over an injectable formulation. Nonetheless, oral administration is limited by problems related to physico-chemical properties of the drug, including bitter taste, poor solubility, low permeability, instability, and first past metabolism, all of which decrease oral bioavailability. Unfortunately, remdesivir is poorly soluble in water and due to its low solubility, it has a correspondingly low degree of oral bioavailability. Any oral formulation of Remdesivir should also be able to mask the bitter taste of the drug. Furthermore, remdesivir is not a first choice for oral delivery as its shows poor hepatic stability, which results in its complete first-pass metabolism. The aforementioned characteristics of remdesivir pose technical challenges to formulation scientists in the development of a suitable oral formulation with desired technical attributes.

U.S. Patent No. 10,065,958 discloses remdesivir or a pharmaceutically acceptable salt or ester thereof. This patent further provides a generic disclosure of pharmaceutical formulations prepared with conventional carriers and excipients.

U.S. Patent No. 20190083525 discloses a parenteral formulation comprising remdesivir, or a pharmaceutically acceptable salt thereof, cyclodextrin, and, optionally, pH adjusting agents.

Chinese Patent Publication No. 111821310 A discloses tablet formulation of remdesivir containing sorbitol monolaurate, mannitol and magnesium stearate.

PCT Patent Publication No. WO 2021168930 Al discloses a tablet formulation comprising remdesivir, a disintegrant, a binder, a lubricant and a filler.

Chinese Patent Publication No. 111494349 A discloses an oral fast dissolving film comprising remdesivir, a film forming material, a surfactant, a plasticizer, a corrigent and an auxiliary material.

Duxin Sun discloses that remdesivir is a prodrug of nucleoside monophosphate (Nuc-MP) designed specifically to improve the cell permeability of Nuc-MP. The design of this prodrug bypasses the rate-limiting first phosphorylation step of the nucleoside (Nuc). Therefore, remdesivir cannot be given by oral administration because the oral route will result in hydrolysis of the prodrug to Nuc-MP in the GI tract. This transformation will prevent absorption due to the charge of the phosphate group. (AAPS J. 2020 Aug 2;22(5): 102. doi: 10.1208/sl2248-020-00483-8)

Remdesivir is currently available as lyophilized powder and concentrate solution for intravenous infusion. This limits the application of this drug to only hospital setting in severe cases of coronavirus infection only. Orally delivered remdesivir has the potential to revolutionize the treatment in mild to moderate coronavirus infection who are subjected to home quarantine. The oral delivery of remdesivir is severely constrained due to its bitter taste, poor solubility, low permeability, instability, and high first past metabolism. A major challenge in the design of an oral formulation of remdesivir is to protect its hydrolysis in the GI tract. The present invention aims at circumventing the above challenges and design an orally palatable and bioavailable formulation of remdesivir using novel solubilization and stabilization techniques. The compositions of the present invention improve oral bioavailability of remdesivir without inducing hepatotoxicity and remain stable during the shelf life of the composition. The oral compositions have comparable relative bioavailability to that of the intravenous formulations of the drug. Furthermore, solid oral formulations of the present invention are more convenient than other formulation types in many ways, such as improved physical and chemical stability, better taste masking, dosing accuracy, ease of storage in all climactic zones, transportation, improved handling properties, and patient compliance. Moreover, the oral compositions of the present invention exhibit substantial bioequivalence to intravenous formulations.

SUMMARY OF THE INVENTION

The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope.

According to one aspect of the disclosure relates to an oral pharmaceutical composition comprising remdesivir or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Another aspect of the disclosure relates to an oral pharmaceutical composition comprising remdesivir or a pharmaceutically acceptable salt thereof and one or more solubilizing agents.

Another aspect of the disclosure relates to an oral pharmaceutical composition for increasing the bioavailability of remdesivir which comprises remdesivir or a pharmaceutically acceptable salt thereof and one or more solubilizing agents.

Another aspect of the disclosure relates to an oral pharmaceutical composition comprising remdesivir or a pharmaceutically acceptable salt thereof and one or more solubilizing agent, wherein the composition is bioequivalent to remdesivir for injection under fasting condition, wherein the bioequivalence of the composition is established by a 90% Confidence Interval for the relative mean AUCo-24 which is between 0.80 and 1.25 with respect to remedesivir mononucleoside (GS441524).

Another aspect of the disclosure relates to an oral pharmaceutical composition comprising remdesivir or a pharmaceutically acceptable salt thereof, one or more solubilizing agents and one or more vehicles or carriers.

Another aspect of the disclosure relates to an oral pharmaceutical composition comprising remdesivir or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients selected from the group consisting of one or more solubilizing agents, one or more vehicles, one or more coloring agents, one or more flavoring agents, one or more preservatives, one or more antioxidants, one or more sweetening agents, one or more buffering agents and one or more chelating agents.

Another aspect of the disclosure relates to an oral pharmaceutical composition comprising remdesivir or a pharmaceutically acceptable salt thereof, one or more solubilizing agents, one or more vehicles, optionally one or more coloring agents, optionally one or more flavoring agents, optionally one or more preservatives, optionally one or more antioxidants, optionally one or more sweetening agents, optionally one or more buffering agents, and optionally one or more chelating agents.

Another aspect of the disclosure relates to a process for preparing an oral liquid pharmaceutical composition comprising remdesivir or a pharmaceutically acceptable salt thereof, the method comprising the steps of: (i) mixing remdesivir and one or more vehicles in a mixing means to obtain a clear solution; (ii) adding and mixing one or more solubilizing agents; (ii) optionally adding and mixing one or more coloring agents, one or more flavoring agents, one or more preservatives, one or more antioxidants, one or more sweetening agents, one or more buffering agents and one or more chelating agents; and (iv) adding and mixing one or more vehicles to form an oral liquid pharmaceutical composition. Another aspect of the disclosure relates to an oral pharmaceutical composition comprising remdesivir or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients selected from the group consisting of one or more solubilizing agents, one or more carriers, optionally one or more taste masking agents, one or more diluents, one or more binding agents, one or more disintegrants, and one or more lubricants.

Another aspect of the disclosure relates to an oral solid pharmaceutical composition comprising remdesivir or a pharmaceutically acceptable salt thereof, one or more solubilizing agents, one or more carriers, optionally one or more taste masking agents, optionally one or more diluents, optionally one or more binding agents, optionally one or more disintegrants, and optionally one or more lubricants.

Another aspect of the disclosure relates to an oral pharmaceutical composition comprising remdesivir or a pharmaceutically acceptable salt thereof and one or more solubilizing agents wherein the ratio of the solubilizing agent to remdesivir ranges from about 1:1 to 30: 1 (wt:wt %).

Another aspect of the disclosure relates to a process for preparing an oral solid pharmaceutical composition comprising remdesivir or a pharmaceutically acceptable salt thereof, the method comprising the steps of: (i) mixing remdesivir and one or more carriers in a mixing means; (ii) adding and mixing one or more solubilizing agents; (iii) optionally adding and mixing one or more diluents, optionally one or more taste masking agents, one or more binding agents, one or more disintegrants, and one or more lubricants; and (iv) filling the mixture in the empty capsules.

Another aspect of the disclosure relates to a process for preparing an oral solid pharmaceutical composition comprising remdesivir or a pharmaceutically acceptable salt thereof, the method comprising the steps of: mixing remdesivir and one or more solubilizing agents, optionally one or more carriers, optionally one or more taste masking agents, optionally one or more diluents, optionally one or more binding agents, optionally one or more disintegrants, and optionally one or more lubricants in a mixing means; and compressing the mixture to form a tablet. A method for preventing or treating a subject at risk of or suffering from a viral infection, comprising administering to the subject an oral pharmaceutical composition wherein the composition comprises remdesivir or a pharmaceutically acceptable salt thereof, one or more solubilizing agents and one or more vehicles or carriers.

Additional embodiments of the present compositions and methods and the like, will be apparent from the following description, drawings, and examples. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention. Additional aspects and advantages of the present invention are set forth in the following description, particularly when considered in conjunction with the accompanying examples and drawings.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows linear plot of mean plasma concentrations of remdesivir mononucleoside (GS441524) vs. actual time for test product (T) and reference product (R)

FIG. 2 shows log linear plot of mean plasma concentrations of remdesivir mononucleoside (GS441524) vs. time for test product (T) and reference product (R)

FIG. 3 shows alanine transaminase (ALT) and aspartate transaminase (AST) levels post 5 days of remdesivir administration in rats DETAILED DESCRIPTION OF THE INVENTION

Various aspects now will be described more fully hereinafter. Such aspects may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art.

As used in this specification, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus for example, a reference to “a process” includes one or more process, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

As used herein, the term "about" means ±5%, ±10%, or ±20% of the value being modified.

The term ‘pharmaceutically acceptable’ as used herein, refers to materials that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, in keeping with a reasonable benefit-risk ratio, and effective for their intended use.

The term “oral pharmaceutical composition” as used herein include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, soft capsules, hard capsules, mini-tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for enteral administration. In some embodiments, the oral pharmaceutical composition is a liquid formulation. In a preferred embodiment, the oral pharmaceutical composition is a solution. In some embodiments, the oral pharmaceutical composition is a solid formulation. In some embodiments, the oral pharmaceutical composition is in the form of soft capsule. In a preferred embodiment, the oral pharmaceutical composition is in the form of hard capsule. In some embodiments, the capsule can be manufactured by filling the core of the capsule shell with powders, granules, beads, pellets, a tablet, semisolid mass, liquid, another capsule or combination or mixture thereof. One or more film forming polymers are the primary constituent by weight of the capsule shells according to the present disclosure, In some embodiments, the film forming polymers can be selected from cellulose derivatives, such as hydroxypropyl methylcellulose, gelatin, pullulan, polyvinyl alcohol and starch derivatives, such as hydroxypropyl starch and the like. The compositions of the present invention may be substantially free of water. The compositions according to present invention may be non-aqueous compositions.

In some embodiments, the oral pharmaceutical composition is in the form of tablet. In some embodiments, a tablet can be prepared by compressing or molding a powder or granules of the compound, together with one or more excipients. Compressed tablets can be prepared by compressing, in a suitable machine, a free- flowing composition, such as a powder or granules, comprising remdesivir optionally mixed with one or more binding agent(s), lubricant(s), inert diluent(s), wetting agent(s) and/or dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.

In some embodiments, the oral pharmaceutical composition increases the oral bioavailability of remdesivir.

The term "treatment" or "treating" means any administration of remdesivir according to the present disclosure to a subject (e.g. human) having or susceptible to a condition or disease disclosed herein for the purpose of: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; or 3) relieving the disease or condition that is causing the regression of clinical symptoms. In some embodiments, the term "treatment" or "treating" refers to relieving the disease or condition, i.e. which is causing the regression of clinical symptoms.

As used herein, the term "preventing" refers to the prophylactic treatment of a patient in need thereof. The prophylactic treatment can be accomplished by providing an appropriate dose of a therapeutic agent e.g. remdesivir, to a subject at risk of suffering from an ailment, thereby substantially averting onset of the ailment. The presence of a genetic mutation or the predisposition to having a mutation may not be alterable. However, prophylactic treatment (prevention) as used herein has the potential to avoid/ameliorate the symptoms or clinical consequences of having the disease engendered by such genetic mutation or predisposition.

"Subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.

The term "therapeutically effective amount", as used herein, is the amount of remdesivir, or a pharmaceutically acceptable salt thereof, present in a composition described herein that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a composition is administered by the chosen route of administration. The precise amount will depend upon numerous factors, for example the specific activity of the composition, the delivery device employed, the physical characteristics of the composition, its intended use, as well as animal considerations such as severity of the disease state, veterinarian cooperation, etc., and can readily be determined by one skilled in the art based upon the information provided herein.

Remdesivir is a viral RNA polymerase inhibitor with antiviral properties against Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, and Paramyxoviridae viruses. The IUPAC name for remdesivir is (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)- 5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-5-cy-ano-3,4-dihydroxytetrahydrofuran- 2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate. The other chemical name is 2-ethylbutyl N- { (S)-[2-C-(4-aminopyrrolo[2, 1 -f] [ 1 ,2,4]triazin-7-yl)-2,5-anhydro-d- altrononitril-6-O-yl]phenoxy phosphoryl } -L-alaninate. The CAS Registry Number for remdesivir is 1809249-37-3. Some of the main degradants of remdesivir are (2S,3R,4S,5R)-2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-carbonitrile (Remdesivir Impurity-A), (3aR,4R,6R,6aR)-4-(4-Aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-6-(hydroxymethyl)- 2,2-dimethyltetrahydrofuro[3,4-d] [ 1 ,3]dioxole-4-carbonitrile (Remdesivir Impurity - B), 2-Ethylbutyl ((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)- 6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate (Remdesivir Impurity-C) and N-[(S)- (4-nitrophenoxy)phenoxyphosphinyl]-L- Alanine 2-ethylbutyl ester (Remdesivir Impurity-D). In some embodiments, a composition comprising about 10 mg to about 200 mg of remdesivir or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprising about 25 mg to about 150 mg of remdesivir or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprising about 50 mg to about 100 mg of remdesivir or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprising about 50 mg of remdesivir or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprising about 100 mg of remdesivir or a pharmaceutically acceptable salt thereof. In some embodiments, a composition comprising about 50 mg of remdesivir or a pharmaceutically acceptable salt thereof wherein the composition is in the form of capsule. In some embodiments, a composition comprises about 100 mg of remdesivir or a pharmaceutically acceptable salt thereof wherein the composition is in the form of capsule. Dose units of compositions of the invention typically contain, for example, a 10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350 or 400 mg dose of remdesivir or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 1 wt/wt % to 20 wt/wt %, 2 wt/wt % to 10 wt/wt %, 3 wt/wt % to 7 wt/wt % remdesivir or a pharmaceutically acceptable salt thereof. In some embodiments, the composition can include remdesivir or a pharmaceutically acceptable salt thereof in an amount of about 1 wt/wt %, 2 wt/wt %, 3 wt/wt %, 4 wt/wt %, 5 wt/wt %, 6 wt/wt %, 7 wt/wt %, 8 wt/wt %, 9 wt/wt %, and 10 wt/wt %. In some embodiments, the solution composition can include 100 mg of remdesivir per 5.0 ml of the composition. Suitable solubilizing agents for use in the present invention include for example, but are not limited thereto: Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS); a mono fatty acid ester of polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20) sorbitan monooleate or polysorbate 80 (Tween® 80), polyoxyethylene (20) sorbitan monostearate or polysorbate 60 (Tween® 60), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40), polyoxyethylene (20) sorbitan monolaurate or polysorbate 20 (Tween® 20); polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.) or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor® RH 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor® RH 60); polyoxylglycerides e.g. Lauroyl polyoxylglycerides or hydrogenated coconut oil PEG 1500 esters (Gelucire® 44/14), Stearoyl polyoxylglycerides or hydrogenated palm oil PEG 1500 esters (Gelucire® 50/13) and polyoxyl stearate (Gelucire® 48/16), Linoleoyl polyoxylglycerides or Corn oil PEG 300 esters (Labrafil® M 2125 CS), Oleoyl polyoxylglycerides or Apricot kernel oil PEG 300 esters (Labrafil® M 1944 CS) or PEG-6 palm kernel oil (Labrafil® M 2130 CS), PEG-6 almond oil (Labrafil® M 1966 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6 peanut oil (Labralil® M 1969 CS), PEG-6 triolein (Labrafil® M 2735 CS), PEG-8 corn oil (Labrafil® WL 2609 BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 almond glycerides (Crovol A40), Caprylocaproyl polyoxylglycerides or macrogolglyceridorum caprylocaprates (Labrasol), Caprylocaproyl polyoxyl-8 glycerides (Labrasol® ALF); polyoxyethylene alkyl ethers, e.g. polyoxyethylene (3) lauryl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (5) stearyl ether; polyoxyethylene alkylaryl ethers, e.g. polyoxyethylene (2) nonylphenyl ether, polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4) nonylphenyl ether, polyoxyethylene (3) octylphenyl ether; polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG- 300 dioleate; alkylene glycol fatty acid mono esters, e.g. propylene glycol monolaurate (Lauroglycol®); sucrose fatty acid esters, e.g. sucrose monostearate, sucrose distearate, sucrose monolaurate, sucrose dilaurate; sorbitan fatty acid mono esters such as sorbitan monolaurate (Span® 20), sorbitan monooleate (Span® 80), sorbitan monopalmitate (Span® 40), or sorbitan stearate; block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer® 124, Poloxamer® 188, Poloxamer® 237, Poloxamer® 388, Poloxamer® 407 (BASF Wyandotte Corp.). In some embodiments, a mixture or a combination of solubilizing agents can be used in the compositions of the present invention. In some embodiments, a mixture or a combination of two or more solubilizing agents can be used. In some embodiments, a mixture or a combination of three or more solubilizing agents can be used. In some embodiments, a mixture or a combination of polysorbate 80 and polyoxyl 35 castor oil can be preferred.

A solubilizing agent employed in the present invention is preferably a non-ionic surfactant. Anionic and cationic surfactants may also be used. More preferably, a composition of the present invention comprises a pharmaceutically acceptable surfactant having an HLB value of from 2-20. A composition of the present invention can also include a mixture of pharmaceutically acceptable surfactants, with at least one surfactant having an HLB value of no less than 10 and at least another surfactant having an HLB value of below 10. In one example, each surfactant comprised in a composition of the invention has an HLB value of at least 10. In another example, each surfactant comprised in a composition of the invention has an HLB value of below 10. In yet another example, a composition of the present invention includes at least two pharmaceutically acceptable surfactants, one having an HLB value of at least 10 and the other having an HLB value of below 10. In another example, the solubilizing agent may be a surfactant having a hydrophilic lipophilic balance (HLB) value of from about 4 to about 10, preferably from about 7 to about 9. In another example, the composition of present invention may contain mixture of two solubilizing agents. In another example, the composition of present invention may contain a mixture of two non-ionic surfactants.

In one embodiment, the ratio of solubilizing agent to remdesivir (wt:wt %) in the composition ranges from about 1: 1 to 30:1, 1.5: 1 to 25:1, 2: 1 to 20:1, 3:1 to 15: 1 or 4:1 to 10:1. In another embodiment, the ratio of solubilizing agent to remdesivir (wt:wt %) in the composition ranges from about 3: 1 to 25:1, 5:1 to 20: 1, 7:1 to 15:1 or 7: 1 to 10: 1. In another embodiment, the ratio of solubilizing agent to remdesivir (wt:wt %) in the composition ranges from about 1:1 to 10: 1. In another embodiment, the ratio of solubilizing agent:remdesivir (wt:wt %) in the composition is about 1: 1, 1.5: 1, 3:1, 5:1, 6.5:1, 7: 1, 8:1, 9: 1 10: 1, 12: 1, or 15:1.

In one embodiment, the ratio of first solubilizing agent: second solubilizing agent: remdesivir (wt:wt:wt %) in the composition ranges from about 25: 10: 1 to 1:0.1: 1, 15:5:1 to 7:0.2: l or 10:3:1 to 5:0.3:l. In another embodiment, the ratio of first solubilizing agent: second solubilizing agent: remdesivir (wt:wt:wt %) in the composition is about 7:2:1 or 4:0.5: 1. In another embodiment, the ratio of first solubilizing agent: second solubilizing agent:remdesivir (wt:wt:wt %) in the composition ranges from about 25:15: 1 to 3: 1: 1, 15:7:1 to 5: 1:1 or 10:2:1 to 5: 1:1. In another embodiment, the ratio of first solubilizing agent: second solubilizing agent: remdesivir (wt:wt: wt %) in the composition is about 15:7:1, 10:5: 1, 8: 1.5: 1 or 7: 1.5: 1.

In some embodiments, the composition comprises about 3 wt/wt % to 60 wt/wt %, 7 wt/wt % to 50 wt/wt %, 10 wt/wt % to 45 wt/wt % solubilizing agent. In some embodiments, the composition comprises about 10 wt/wt % to 60 wt/wt %, 20 wt/wt % to 50 wt/wt %, 25 wt/wt % to 45 wt/wt % first solubilizing agent. In some embodiments, the composition comprises about 2 wt/wt % to 50 wt/wt %, 5 wt/wt % to 30 wt/wt %, 3 wt/wt % to 20 wt/wt %, 4 wt/wt % to 15 wt/wt % second solubilizing agent.

In some embodiments, the composition comprises about 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 wt/wt % solubilizing agent. Suitable carriers or vehicles according to the present invention are selected from water, ethanol, polyethylene glycols, propylene glycol, glycerin, sorbitol, polyvinyl pyrrolidone (Povidone), benzyl alcohol and the like or mixtures thereof. In one embodiment, the polyethylene glycol can be polyethylene glycol 200, 300, 400, 600 800, 1000, 1500, 2000, 3000, 3350, 4000, 6000, and 8000 or mixture thereof. In some embodiments, the composition comprises about 30 wt/wt % to 90 wt/wt %, 35 wt/wt % to 85 wt/wt %, 40 wt/wt % to 80 wt/wt %, 50 wt/wt % to 70 wt/wt % carrier or vehicle. In some embodiments, a mixture or a combination of carriers or vehicles can be used in the compositions of the present invention. In some embodiments, a mixture or a combination of two or more carriers or vehicles can be used. In some embodiments, a mixture or a combination of two or more polyethylene glycols can be used.

Suitable sweetening agents used according to the present invention are selected from the group consisting of sucrose, fructose, dextrose, sucralose, maltose, glucose, sodium saccharin, aspartame, lactitol, maltitol, acesulfame potassium and the like or mixture thereof. In some embodiments, the composition comprises about 10 wt/wt % to 20 wt/wt %, 5 wt/wt % to 15 wt/wt %, 7 wt/wt % to 10 wt/wt % sweetening agent.

Suitable diluents include, either individually or in combination, lactose USP; lactose USP, anyhydrous; lactose USP, spray dried; starch USP; directly compressible starch; mannitol USP; sorbitol; dextrose monohydrate; microcrystalline cellulose NF; dibasic calcium phosphate dihydrate NF; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate NF; calcium lactate trihydrate granular NF; dextrates, NF (e.g., Emdex); Celutab; dextrose (e.g., Cerelose); inositol; hydrolyzed cereal solids such as the Maltrons and Mor-Rex; amylose; Rexcel; powdered cellulose (e.g., Elcema); calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like. Such diluents, if present, constitute in total about 5 wt/wt % to about 99 wt/wt %, preferably about 10 wt/wt % to about 85 wt/wt %, and more preferably about 20 wt/wt % to about 80 wt/wt %), of the total weight of the composition. Suitable disintegrants include, either individually or in combination, starches; sodium starch glycolate; clays (such as Veegum HV); celluloses (such as purified cellulose, methylcellulose, sodium carboxymethylcellulose, and carboxymethylcellulose); alginates; pregelatinized corn starches (such as National 1551 and National 1550); crospovidone USP NF; and gums (such as agar, guar, locust bean, Karaya, pectin, and tragacanth). Disintegrants may be added at any suitable step during the preparation of the pharmaceutical composition, particularly prior to granulation or during the lubrication step prior to compression. Such disintegrants, if present, constitute in total about 0.2 wt/wt % to about 30 wt/wt %, preferably about 0.2 wt/wt % to about 10 wt/wt %, and more preferably about 0.2 wt/wt % to about 5 wt/wt %, of the total weight of the composition.

Suitable binding agents and adhesives include, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starch; cellulose materials such as, but not limited to, methylcellulose and sodium carboxymethylcellulose (e.g., Tylose); alginic acid and salts of alginic acid; magnesium aluminum silicate; polyethylene glycol; guar gum; polysaccharide acids; bentonites; polyvinylpyrrolidone; polymethacrylates; hydroxypropylmethylcellulose (HPMC); hydroxypropylcellulose (Klucel); ethylcellulose (Ethocel); pregelatinized starch (such as National 151 1 and Starch 1500). Such binding agents and/or adhesives, if present, constitute in total about 0.5 wt/wt % to about 25 wt/wt %, preferably about 0.75 wt/wt % to about 15 wt/wt %, and more preferably about 1 wt/wt % to about 10 wt/wt %, of the total weight of the composition.

Suitable lubricants and/or glidants include, either individually or in combination, glyceryl behapate (Compritol 888); stearates (magnesium, calcium, and sodium); stearic acid; hydrogenated vegetable oils (e.g., Sterotex); talc; waxes; Stearowet; boric acid; sodium berizoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene glycols (e.g., Carbowax 4000 and Carbowax 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if present, constitute in total about 0.1 wt/wt % to about 10 wt/wt %, preferably about 0.2 wt/wt % to about 8 wt/wt %, and more preferably about 0.25 wt/wt % to about 5 wt/wt %, of the total weight of the composition.

Other carrier materials (such as anti-adherent agents, colorants, flavors, sweeteners and preservatives) are known in the pharmaceutical art and can be included in compositions of the present invention.

Suitable preservatives used according to the present invention are selected from methyl paraben, propyl paraben, alkyl hydroxybenzoates; sorbic acid or a salt thereof; benzoic acid or a salt thereof; sodium metabisulfite, and mixtures thereof.

Suitable buffering systems according to the present invention include combinations of citric acid and salts and solvates thereof, for example citric acid (anhydrous or monohydrate) combined with sodium citrate dihydrate and the like or mixture thereof.

Suitable flavoring agents according to the present invention are selected from orange, strawberry, cherry, grape, anise, menthol and vanillin and the like or mixture thereof.

Suitable antioxidants according to the present invention are selected from sodium metabisulfite, sodium bisulfite, propyl gallate, sodium ascorbate and ascorbic acid and the like or mixture thereof.

Suitable chelating agents according to the present invention are selected from disodium EDTA, tartaric acid, malic acid and citric acid and the like or mixture thereof.

In an embodiment, the composition of the present invention has a pH from 3.0 to 7.0. In another embodiment, the composition of the present invention has a pH from 5.0 to 5.5.

The oral compositions of the present invention exhibit substantial bioequivalence to RemWin® (Remdesivir for Injection 100 mg) (Lyophilized) manufactured by Syngene International Limited and Covifor™ (Remdesivir for Injection 100 mg/20 ml) manufactured by Hetero Labs Limited.

The compositions of the present invention are stable under ambient, 30775% RH and 40775% RH stability conditions after at least about 3 months. The compositions of the present invention are substantially free of impurities, including, but not limited to, remdesivir Impurity-A under ambient, 30775% RH and 40775% RH stability conditions after at least about 3 months.

The compositions of the present invention are useful for preventing or treating a subject at risk of or suffering from viral infections wherein the infections can be caused by the virus including Arenaviridae virus, a Coronaviridae virus, a Filoviridae virus, or a Paramyxoviridae virus and the like. In some embodiments, the composition of the present invention is useful for preventing or treating a subject at risk of or suffering from viral infections including coronavirus infection. In some embodiments, the composition of the present invention is useful for treating a subject suffering from the coronavirus disease 2019 (COVID-19) or coronavirus 2 (SARS-CoV-2) infection.

In some embodiments, the present invention provides a method for treating a coronavirus infection comprising administering a therapeutically effective amount of a composition disclosed herein in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

EXAMPLES

Hereinafter, examples will be described, however, these examples are for better understanding of the present invention, and are not to limit the scope of the present invention.

TABLE 1

Manufacturing Process: Polyethylene glycol 400 was taken in a container. Remdesivir was then added and mixed with intermittent heating and sonicating to obtain a clear solution. Solubilizing agents were added and mixed to obtain a clear

5 solution. To above clear solution, sucralose aqueous solution was added. Additionally, suitable flavoring and sweeting agents also can be added after sucralose solution addition with final dilution with purified water to form a clear solution before oral administration. 0 TABLE 2

Manufacturing Process: Polyethylene glycol 400 was taken in a vessel preheated at a temperature of about 40°C to 45°C. Remdesivir was then added and mixed while maintaining the temperature at about 40°C to 45 °C to obtain the clear viscous solution. The temperature of the vessel was then reduced to a room temperature while the solution was stirred at a low speed. Polysorbate 80 NF was added and mixed. Polyoxy-35-Castor Oil NF was then added and mixed to obtain the clear solution. The required fill weight (eq. to 50 or 100 mg remdesivir/capsule) of the resultant solution was filled in hard gelatin capsules.

TABLE 3

Manufacturing Process: Polyethylene glycol 400 was taken in a vessel preheated at a temperature of 40°C to 45 °C. Remdesivir was then added and mixed while maintaining the temperature at 40°C to 45 °C to obtain the clear viscous solution. The temperature of the vessel was then reduced to a room temperature while the solution was stirred at a low speed. Polysorbate 80 NF was added and mixed. Poly oxy - 35-Castor Oil NF was then added and mixed to obtain the clear solution. The required fill weight (eq. to 50 or 100 mg remdesivir/capsule) of the resultant solution was filled in hard gelatin capsules. TABLE 4

Manufacturing Process: Polyethylene glycol 400 and Polyethylene glycol NF (4000/6000/8000) were taken in a vessel preheated at a temperature of 40°C to 45°C. Remdesivir was then added and mixed while maintaining the temperature at 40°C to 45 °C to obtain the clear viscous solution. The temperature of the vessel was then reduced to a room temperature while the solution was stirred at a low speed. Polysorbate 80 NF was added and mixed. Polyoxy-35-Castor Oil NF was then added and mixed to obtain the clear solution which turned to semi solid mass upon cooling. The required fill weight (eq. to 50 or 100 mg remdesivir/capsule) of the resultant semisolid mass was filled in hard capsules.

TABLE 5

Manufacturing Process: Polyethylene glycol 400 and Lauryl polyoxyl-32 glyceridesNF (Gelucire 44/14)/Stearoyl polyoxyl-32 glycerides (Gelucire 50/13)/Polyethylene glycol monostearate (Gelucire 48/16) were taken in a vessel preheated at a temperature of about 40°C to 45°C. Remdesivir was then added and mixed while maintaining the temperature at about 40°C to 45 °C to obtain the clear viscous solution. The temperature of the vessel was then reduced to a room temperature while the solution was stirred at a low speed. Polysorbate 80 NF was added and mixed. Polyoxy-35-Castor Oil NF was then added and mixed to obtain the clear solution which turned to semi solid mass upon cooling. The required fill weight (eq. to 50 or 100 mg remdesivir/capsule) of the resultant semisolid mass was filled in hard capsules.

Example SI: Oral Solution Composition Part A: Concentrate Composition TABLE 6

Manufacturing Process: Polyethylene glycol 400 (PEG 400- LQ) was taken in a stainless steel vessel and heated up to about 40 to 45°C. Remdesivir was added and mixed and the temperature was maintained at about 40 to 45 °C to obtain a clear viscous solution. Polysorbate 80 NF and polyoxyl 35 castor oil were added and mixed to obtain a clear solution. Part B: Diluent Composition

TABLE 7

Manufacturing Process: Glycerin was taken in a stainless steel vessel. Citric acid, sucralose and orange flavor powder were added and mixed sequentially to obtain a clear solution.

Preparation of Final Composition: The diluent composition (Part B) was added to the concentrate composition (Part A) and mixed well to obtain the final composition. The final composition contains 100 mg of remdesivir per 5.0 ml.

Example S2: Capsule Composition TABLE 8

Manufacturing Process: Polyethylene glycol 400 (PEG 400- LQ) and polyethylene glycol 4000 were taken in a stainless steel vessel and heated up to about 40 to 45 °C. Remdesivir was added and mixed and the temperature was maintained at about 40 to 45 °C to obtain a clear viscous solution. Polysorbate 80 NF and polyoxyl 35 castor oil were added and mixed to obtain semisolid mass. The resultant semisolid mass is filled in capsule shells of size 00EL with desired fill weight. ABSOLUTE ORAL BIOAVAILABILITY AND BIOEQUIVALENCE STUDY

The objective of the study was to assess the absolute bioavailability between test and reference formulation products, to optimize the oral dose and to assess the bioequivalence of test and reference formulation products. The study design and plan were as follows:

Test Product (T): SI, oral solution composition, 100 mg/5 ml

Reference Product (R): RemWin® (Remdesivir for Injection lOOmg) (Lyophilized) and Covifor™ (Remdesivir for Injection 100 mg/20 ml)

Study Design: Open label, balanced, randomized, single-dose, two period, crossover design.

Number of Subjects: A total of 24 healthy, adult, human male subjects aged between 18 and 45 years under were enrolled and dosed in the study. All subjects were fasted for at least 10.00 hours prior to dosing.

Administration: The test formulation was given orally and the reference formulation was infused with an IV drip to the subjects over a period of 60 minutes.

Sampling Schedule: The pre-dose (0.00 hours) blood sample of 5 ml was collected not more than one hour prior to dosing in each period. Further samples of 5 mL each were collected at 0.25 (15 minutes), 0.33 (20 minutes), 0.50 (30 minutes), 0.67 (40 minutes), 1.00 (60 minutes), 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00, 96.00 and 120.00 hours post-dose in each period via an indwelling cannula placed in one of the forearm veins of the subjects by syringe and transferred immediately into K2EDTA vacutainers containing 1 M sodium fluoride solution.

Pharmacokinetic Analysis: For Remdesivir, the calculated primary pharmacokinetic parameters were AUCo-t and secondary pharmacokinetic parameters were Cmax, T_max and AUCo <». For remedesivir mononucleoside (GS441524) the calculated primary pharmacokinetic parameters were AUCo-t and AUCo-24 and secondary pharmacokinetic parameter was Cmax, Tmax and AUCo-oo. Statistical Analysis: Statistical analyses were performed using SAS® system for windows version 9.4 (SAS® Institute Inc., USA). The log-transformed pharmacokinetic parameters AUCo-t for Remdesivir and AUCo-t & AUCo-24 for Remedesivir mononucleoside (GS441524) were analyzed using ANOVA. The Intra subject CV, Power, Ratio analysis and 90% confidence interval for the ratio of the geometric least squares mean were computed for log -transformed pharmacokinetic parameters AUCo-t and AUCo-24.

Bioequivalence Criteria: Bioequivalence of the test product with that of the reference product under fasting condition was concluded if the 90% confidence interval and the geometric mean ratio fall within the acceptance range of 80.00-125.00% for Ln-transformed pharmacokinetic parameters of AUCo-24 of Remedesivir mononucleoside (GS441524).

The results of the bioavailability and bioequivalence studies are summarized in the Tables 9 A to 10C below and Figures 1 and 2. The final analysis was done from data of two periods following crossover design.

The average ± SD of AUCo-24 and AUCo-t values for test vs. reference product were found to be 1136.9205 ± 356.1116 vs. 1068.7096 ± 166.2483 ng/mL and 1404.1468 ± 434.1963 vs. 2174.4008 ± 363.0078 hr*ng/mL, respectively. The median Tmax of 3.7500 hours was observed for both the test product (T) and reference product (R). The observed range of Tmax for test product (T) was 1.5000 - 6.0000 hours and for reference product (R) was 1.5000 - 8.0000 hours.

The ratio of Test (T) and Reference (R) product averages (least-squares means) and its 90% confidence interval derived from the analysis of log transformed pharmacokinetic parameters, AUCo-24 [103.25 (92.61 - 115.11)%] was within the limit of 80.00% to 125.00%. The intra subject variability for In-transformed data for AUCo- 24 was 22.20%. The power of the test for the In-transformed pharmacokinetic parameters AUCo-24 was found to be 91.94. The 90% confidence interval of the relative mean AUCo-24 of the test to reference formulation for log-transformed data was found to be within 80.00% to 125.00% with respect to Remedesivir mononucleoside (GS441524).

TABLE 9A: Absolute Bioavailability of Remedesivir Mononucleoside (GS441524) (N=24)

TABLE 9B: Descriptive Statistics of Pharmacokinetic Parameters of Test

Product (T) for Remedesivir Mononucleoside (GS441524)

TABLE 9C: Descriptive Statistics of Pharmacokinetic Parameters of Reference

Product (R) for Remedesivir Mononucleoside (GS441524)

TABLE 9D: Geometric Least Squares Mean, Ratios, 90% Confidence Interval, ISCV % and Power for Remedesivir Mononucleoside (GS441524)

TABLE 10A: Absolute Bioavailability of Remdesivir (N=24)

TABLE 10B: Descriptive Statistics of Pharmacokinetic Parameters of Test Product (T) for Remdesivir

did not exhibit/ showed terminal log linear phase were excluded.

TABLE 10C: Descriptive Statistics of Pharmacokinetic Parameters of Reference

Product (R) for Remdesivir

*Subjects who did not exhibit/ showed terminal log linear phase were excluded.

Conclusion: The 90% confidence interval of the relative mean AUCo-24 of the test to reference formulation for log-transformed data was found to be within 80.00% to 125.00% with respect to remedesivir mononucleoside (GS441524). Hence, it was concluded that remdesivir oral solution composition is bioequivalent to the remdesivir for injection with respect to the extent of absorption.

STABILITY STUDIES:

Stability of the remdesivir formulations according to Example SI (Part A: Concentrate Composition) and Example S2 (Capsule Composition) was measured by incubating each formulation at about 30775% RH and about 40775% RH conditions. The results of the stability studies are summarized in the Tables 11 and 12 below. The data contained in the Tables show that the formulations are stable after at least three months.

Example SI (Part A: Concentrate Composition):

TABLE 11

Example S2 (Capsule Composition):

TABLE 12

HEPATIC PARAMETERS

Hepatic parameters of remdesivir compositions prepared according to Example SI was determined. Rats (Male Sprague-Dawley) were used to test the compositions. The compositions were diluted with purified water to obtain 3 mg/ml remdesivir concentration. Each rat received either 60 mg/kg oral dose or 20 mg/kg of reference IV dose of remdesivir on day 1 , and 30 mg/kg oral dose and 30 mg/kg reference IV dose of remdesivir on subsequent days respectively. Blood samples were obtained prior to dosing and 1 and 5 days after administration. Plasma Alanine transaminase (ALT) and Aspartate transaminase (AST) levels were measured by using automatic biochemical analyzer (Daytona, Randox Inc. UK). All the samples were run as neat i.e. no dilution. Each composition was evaluated in a group containing 3-4 rats; the values reported are average ± standard deviation for each treatment. FIG. 3 shows that there is no significant change in AST or ALT level post 5 days of remdesivir administration in rats.

Claims

CLAIMS:

1. An oral pharmaceutical composition comprising remdesivir or a pharmaceutically acceptable salt thereof and one or more solubilizing agents wherein the ratio of the solubilizing agent to remdesivir ranges from about 1 : 1 to 30: 1 (wt:wt %).

2. The oral pharmaceutical composition according claim 1, wherein the solubilizing agent is selected from the group consisting of vitamin E polyethylene glycol succinate, a mono fatty acid ester of polyoxyethylene (20) sorbitan, polyoxyethylene castor oil derivates, polyoxylglycerides, polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, polyethylene glycol fatty acid esters, alkylene glycol fatty acid mono esters, sucrose fatty acid esters, sorbitan fatty acid mono esters and block copolymers of ethylene oxide and propylene oxide, or combinations thereof.

3. The oral pharmaceutical composition according claim 2, wherein the mono fatty acid ester of polyoxyethylene (20) sorbitan is selected from the group consisting of polysorbate 80, polysorbate 60 and polysorbate 20, or combinations thereof.

4. The oral pharmaceutical composition according claim 2, wherein the polyoxyethylene castor oil derivative is selected from the group consisting of polyoxyl 35 castor oil, polyethylenglycol 40 hydrogenated castor oil and polyethylenglycol 60 hydrogenated castor oil, or combinations thereof.

5. The oral pharmaceutical composition according claim 1, wherein the ratio of the solubilizing agent to remdesivir ranges from about 5:1 to 20: 1 (wt:wt %).

6. The oral pharmaceutical composition according claim 1, wherein the ratio of the solubilizing agent to remdesivir ranges from about 7: 1 to 15:1 (wt:wt %)

7. The oral pharmaceutical composition according claim 1, wherein the composition comprises a combination of two solubilizing agents.

35 The oral pharmaceutical composition according claim 7, wherein the first solubilizing agent is polyoxyl 35 -castor oil and the second solubilizing agent is polysorbate 80. The oral pharmaceutical composition according claim 7, wherein the ratio of first solubilizing agent:second solubilizing agent:remdesivir ranges from about 25:15: 1 to 3: 1: 1 (wt:wt:wt %). The oral pharmaceutical composition according claim 1, wherein the composition comprises about 1 wt/wt % to 20 wt/wt % remdesivir or a pharmaceutically acceptable salt thereof. The oral pharmaceutical composition according claim 1, wherein the composition comprises about 3 wt/wt % to 60 wt/wt % solubilizing agent. The oral pharmaceutical composition according claim 1 , wherein the composition is in the form of a solution. The oral pharmaceutical composition according claim 1 , wherein the composition is in the form of a capsule. The oral pharmaceutical composition according claim 1 , wherein the composition further comprises one or more vehicles. The oral pharmaceutical composition according claim 14, wherein the vehicle is selected from the group consisting of ethanol, polyethylene glycol, propylene glycol, glycerin and sorbitol, or combinations thereof. The oral pharmaceutical composition according claim 1, wherein the composition improve the oral bioavailability of remdesivir. A method for treating a subject suffering from a viral infection comprising administering to the subject the oral pharmaceutical composition according to claim 1. The method according to claim 17, wherein the viral infection is a coronavirus infection.