DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to Indian Provisional Patent Application No. 202121023147, filed 24th May 2021 which is incorporated herein in its entirety.

FIELD OF INVENTION
The present invention relates to a pharmaceutical composition comprising amorphous remdesivir. The invention also relates to processes for the preparation of the said pharmaceutical composition and its use for the prevention, treatment and prophylaxis of diseases caused by viruses including SARS Coronavirus.

BACKGROUND AND PRIOR ART
Remdesivir is chemically known as 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]phenoxyphosphoryl}-L-alaninate and is a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor.

Remdesivir is approved by FDA for use in adult and pediatric patients 12 years of age and older and weighing at least 40 kilograms (about 88 pounds) for the treatment of COVID-19 requiring hospitalization. Further, remdesivir needs to be administered in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care.

Remdesivir is available as VEKLURY for injection, 100 mg, is a sterile, preservative-free lyophilized powder that is to be reconstituted with 19 mL of Sterile Water for Injection and further diluted into 0.9% sodium chloride infusion bag prior to administration by intravenous infusion and is also available as VEKLURY (remdesivir) injection 100 mg/20 mL (5 mg/mL) that is to be diluted into 0.9% sodium chloride infusion bag prior to administration by intravenous infusion.

The inactive ingredients of both these formulations contain sulfobutylether-ß-cyclodextrin sodium salt (SBECD), water for injection and may include hydrochloric acid and/or sodium hydroxide for pH adjustment.

Because remdesivir has limited water solubility, the intravenous preparation contains the vehicle SBECD. SBECD is a large, cyclic oligosaccharide that is predominantly excreted through glomerular filtration with a t1/2 elimination of 2 hours in patients with normal kidney function.

Each 100 mg of lyophilized powder and solution of remdesivir contain 3 and 6 g of SBECD respectively which maintains remdesvir in solution form thus avoiding precipitation of the drug during its shelf life and in-use storage.

Although the approved formulations may seem to contain higher quantity of SBECD the quantity of SBECD is well below the maximum recommended safety threshold dose of 250 mg/kg per day of SBECD.

Further, each 100 mg of lyophilized powder as well as solution of remdesivir requires dilution with 0.9% sodium chloride solution requiring multiple solution transfer prior to intravenous administration. Also, the diluted solution needs to be prepared under aseptic conditions and on same day as administration. Further, the reconstituted product needs to be used immediately to prepare the diluted drug product. Any unused portion remaining in the reconstituted vial needs to be discarded since after a diluted solution is prepared the product contains no preservative. Any unused portion of a single-dose VEKLURY vial also needs to be discarded.

Further, it is generally known that a compound exists in some possible solid forms such as crystalline, amorphous, solvates, hydrates etc. An amorphous form of some drugs may exhibit much higher bioavailability, improved physical and chemical properties such as melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure and density than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage form development. Additionally, the aqueous solubility of crystalline form is lower than its amorphous form in some of the drugs, which may result in the difference in their in vivo bioavailability. Preventing the conversion of amorphous form to crystalline form is key requirement for the preparation and maintenance of amorphous pharmaceutical substance. Amorphous form and solid dispersion of amorphous form have better stability, higher solubility and better handling during large scale production that can be exploited by pharmaceutical scientists.

Thus, there still exists a need to provide a composition comprising amorphous remdesivir which is stable, exhibits improved solubility and bioavailability, exhibits improved dissolution profile and method for preparing such compositions which are simple, inexpensive, user friendly as well as commercially available.

OBJECT OF THE INVENTION
An object of the present invention to provide a pharmaceutical composition comprising amorphous remdesivir having improved solubility and stability.

Another object of the present invention to provide process for preparation of pharmaceutical composition comprising amorphous remdesivir.

Yet another object relates to the use of the pharmaceutical composition comprising amorphous remdesivir for prevention, treatment and prophylaxis of diseases caused by viruses including SARS Coronavirus.

Another object of the present invention is to provide a method for prevention, treatment and prophylaxis of diseases caused by viruses including SARS Coronavirus which method comprises administering a pharmaceutical composition of present invention.
SUMMARY OF THE INVENTION
In an embodiment of the present invention, there is provided a pharmaceutical composition comprising remdesivir in an amorphous form.

In another embodiment of the present invention there is provided a process for preparing a pharmaceutical composition comprising remdesivir in an amorphous form.

Also disclosed herein are method for prevention, treatment and prophylaxis of diseases caused by viruses including SARS Coronavirus which method comprises administering a pharmaceutical composition of remdesivir in an amorphous form.

DETAILED DESCRIPTION OF THE INVENTION
It has been found that remdesivir exhibits polymorphism. Amorphous remdesivir provides different advantages over crystalline forms such as, for example, in formulation, stability of the form, stability of the formulation, and in pharmacokinetic profiles. There is always a chance of the amorphous complex getting converted into crystalline form during shelf life of the composition and generating the impurities. This would in turn affect the stability, therapeutic effect and the bioavailability of the drug in an undesirable way.

The inventors of the present invention have found that the solubility, bioavailability, stability of amorphous remdesivir was greatly improved when remdesivir was formulated using different processes such as, but not limited to, hot melt technology, spray drying and spray granulation.

Hot melt extrusion process enables the crystalline form of complex to get converted to amorphous form having exceptional stability, desired dissolution profile and reduced degradation products. The inventors made sure that the extruded form of remdesivir contains the amorphous form of complex substantially free of crystalline form of complex.
The spray drying process, in general involves dissolving remdesivir and suitable excipient(s) in a common solvent to prepare a feed solution, pumping the feed solution into a spray nozzle, atomising the solution stream into fine droplets via an appropriate device and drying the fine droplets in a drying chamber; and separating and collecting the dried powders via a suitable collector.

The spray granulation process, in general involves dissolving remdesivir and suitable excipient(s) in a solvent and adding to an excipient blend to form compressible granules.

The term "amorphous" as used in the present invention refers to a non-crystalline solid. An amorphous pharmaceutical solid is one in which the constituent molecules are not ordered or organized, lack regular crystalline structure with respect to one another, but are arranged in a more or less random fashion and as a consequence give a diffuse i.e., non-distinctive, powder x-ray diffraction (PXRD) pattern.

The term “crystalline” as used in the present invention refers to solid-state particles having a regular ordered structure, which, in contrast to amorphous material, give a distinctive PXRD pattern with defined peaks.

The term “extrudates” as used herein refers to solid product solutions, solid dispersions and glass solutions of one or more drugs with one or more polymers and optionally one or more pharmaceutically acceptable excipients. More specifically, the term “extrudates” as used herein refers to solid product solutions, solid dispersions and glass solutions of remdesivir with one or more polymers and optionally pharmaceutically acceptable excipients.

As used herein, the term "solid dispersion" means any solid composition having at least two components. In certain embodiments, a solid dispersion as disclosed herein includes an active ingredient remdesivir dispersed among at least one other component, for example a polymer or SBECD.
The term "substantially free" means residual solvents within the permissible ICH limits suitable for pharmaceutical preparations. For example, but not limited to less than 0.5%, particularly less than 0.3% or more particularly 15 less than 0.2%.

The term “pharmaceutically acceptable” mentioned throughout the specification would be applied to a carrier, diluent or excipient which is compatible with the actives as employed.

As used herein, the term ‘about’ means up to 10 % change in the values on the higher as well as the lower side of the value.

In some embodiments of the invention, the term ‘drug’ and ‘drug product’ may be used interchangeably. However, in at least one embodiment, the meaning of the terms would differ. In a preferred embodiment drug or drug product means remdesivir prepared as per the process of the invention.

Thus, the present invention provides a pharmaceutical composition comprising an active substance which is remdesivir, preferably amorphous remdesivir, wherein the active substance is formed in-situ during the manufacturing of the composition.
The term “remdesivir " used in broad sense means includes without limitation, its free form and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.

It is a feature of the invention that the amorphous form of the remdesivir is formed during formation of the pharmaceutical composition. Most preferably, the crystalline form of remdesivir gets converted to amorphous form in-situ during manufacture of the pharmaceutical composition.

According to one embodiment of the invention, remdesivir is present in an amount of about 1% to about 90% (w/w) based on the total weight of the composition. In a preferred embodiment, remdesivir is present in an amount of about 10% to about 50 % (w/w) based on the total weight of the pharmaceutical composition.

In yet another embodiment of the present invention, there is a pharmaceutical composition comprising the extrudate comprising the active remdesivir with one or more polymers and optionally one or more pharmaceutically acceptable excipients prepared by hot melt extrusion process. In further preferred embodiment of the present invention, there is provided a pharmaceutical composition comprising the extrudate comprising the active remdesivir with one or more polymers and optionally one or more pharmaceutically acceptable excipients prepared by hot melt extrusion process and further processing the extrudate to form the suitable dosage form.

Thus, the present invention encompasses an extruded article comprising remdesivir. This extrudate typically comprises one or more pharmaceutically acceptable polymer in combination with the complex, wherein the complex is suitably homogeneously dispersed throughout the polymer. According to embodiment of present invention, during the hot melt extrusion process, the extrudate includes a polymer which is melt-processible and that reduces or prevents conversion of amorphous remdesivir to a crystalline form. The complex is preferably present in the extrudate in amorphous form. The amorphous form was preferably formed during the manufacture of the extrudate (i.e., the starting material actives were in form different from the amorphous form). The extrudate may also further include one or more pharmaceutically acceptable excipients.

The melt-processible polymer of the present invention generally comprises about 5% to about 80%, more preferably about 10% to about 60% of the resulting extrudate, based on weight.

Suitable polymers include those that reduce or prevent the conversion of amorphous remdesivir to a crystalline form, but are otherwise inert as defined above, and exhibit aqueous solubility over at least a portion of the pH range of 1 to 8, inclusive. Useful polymers thus include, without limitation, ionizable and nonionizable cellulosic polymers, including those having ether or ester or ether and ester substituents and copolymers thereof, including so-called “enteric” and “non-enteric” polymers; vinyl polymers and copolymers having hydroxy, alkylacyloxy, and cyclicamido substituents, including methacrylic acid copolymers and aminoalkyl methacrylate copolymers; various synthetic and naturally occurring polymeric ethers and esters of polyhydric alcohols; and mixtures thereof. In one embodiment, the melt-processible polymer is an ionic or ionizable cellulosic polymer as described herein. In one embodiment, the melt-processible polymer is a nonionizable cellulosic polymer as described herein. In one embodiment, the melt processible polymer is a vinyl polymer as described herein. In one embodiment, the melt-processible polymer is a vinyl co-polymer as described herein. In one embodiment, the melt-processible polymer is a methacrylic acid co-polymer as described herein. In one embodiment, the melt-processible polymer is an aminoalkyl methacrylate copolymer as described herein. In one embodiment, the melt-processible polymer is a polymeric ether of a polyhydric alcohol as described herein. In one embodiment, the melt-processible polymer is a polymeric ester of a polyhydric alcohol as described herein.

Exemplary ionic cellulosic polymers include, without limitation, carboxymethylcellulose (CMC) and its sodium or calcium salts; carboxyethylcellulose (CEC); carboxymethylethylcellulose (CMEC); hydroxyethylmethylcellulose acetate phthalate; hydroxyethylmethylcellulose acetate succinate; hydroxypropylmethylcellulose phthalate (HPMCP); hydroxypropylmethylcellulose succinate; hydroxypropylcellulo se acetate phthalate (HPCAP); hydroxypropylcellulose acetate succinate (HPCAS); hydroxypropylmethylcellulose acetate phthalate (HPMCAP); hydroxypropylmethylcellulose acetate succinate (HPMCAS); hydroxypropylmethylcellulose acetate trimellitate (HPMCAT); hydroxypropylcellulose butyrate phthalate; carboxymethylethylcellulose and its sodium salt; cellulose acetate phthalate (CAP); methylcellulose acetate phthalate; cellulose acetate trimellitate (CAT); cellulose acetate terephthalate; cellulose acetate isophthalate; cellulose propionate phthalate; cellulose propionate trimellitate; cellulose butyrate trimellitate; and mixtures thereof. Exemplary nonionic cellulosic polymers include, without limitation, methylcellulose (MC); ethyl cellulose (EC); hydroxyethyl cellulose (HEC); hydroxypropylcellulose (HPC); hydroxypropylmethylcellulose (HPMC); hydroxypropylmethylcellulose acetate; hydroxyethylmethylcellulose; hydroxyethylcellulose acetate; hydroxyethylethylcellulose; and mixtures thereof. Exemplary vinyl polymers and copolymers include, without limitation, methacrylic acid copolymers and aminoalkyl methacrylate copolymers, which are available, for example, from Rohm Pharma under the trade names EUDRAGIT® L, S, NE, RL, RS, and E. Other exemplary polymers include carboxylic acid functionalized polymethacrylates and amine-functionalized polymethacrylates; poly(vinyl acetal) diethylaminoacetate; polyvinyl alcohol (PVA); and polyvinyl alcohol/polyvinyl acetate (PVA/PVAc) copolymers; and mixtures thereof. Additional vinyl polymers and copolymers include, without limitation homopolymers of N-polyvinyl pyrrolidone (NVP), including, for example, Water-soluble polyvinylpyrrolidones (PVPs or povidones), such as KOLLIDON®12 PF, 17 PF, 25, 30, and 90 F; water-soluble copolymers of PVP and vinylacetate (VA), such as KOLLIDON® VA64; and water-insoluble cross-linked polyvinylpyrrolidones (crospovidone), such as KOLLIDON® CL, CL-M, and SR,which are available from BASF; and mixtures thereof. Exemplary polymeric ethers and esters of polyhydric alcohols include, Without limitation, polyethylene glycol (PEG) and polypropylene glycol (PPG) homopolymers and copolymers (PEG/PPG); polyethylene/polyvinyl alcohol (PE/PVA) copolymers; dextrin; pullulan; acacia; tragacanth; sodium alginate; propylene glycol alginate; agar powder; gelatin; starch; processed starch; glucomannan; chitosan; and mixtures thereof. Other exemplary polymeric ethers include polyethylene oxides, polypropylene oxides, and polyoxyethylene-polyoxypropylene block copolymers (poloxamers) such as those available from BASF under the trade names LUTROL® F 68, F 127, and F 127-M; and mixtures thereof.

Preferably, the pharmaceutical composition of present invention comprises polymer such as Kollidon VA 64. In an embodiment of the present invention, the composition comprises about 2% to about 80% polymer, preferably about 10% to about 80%, most preferably about 10% to about 50% of polymer by weight.

In another embodiment, cyclodextrins such as, but not limited to Sulfobutylether-beta-cyclodextrin can be used as a for solubility for remdesivir. Preferably, the pharmaceutical composition of present invention comprises by weight about 2% to about 80% SBECD, preferably about 10% to about 80%, most preferably about 10% to about 60% of SBECD by weight.

In addition to the complex and one or more polymer, the extrudate may further comprise additional excipients like plasticizers, disintegrants, flow regulators, lubricants, fillers, stabilizers such as antioxidants, light stabilizers, radical scavengers, stabilizers against microbial attack.

Plasticizers can be incorporated depending on the polymer and the process requirement. These, advantageously, when used in the hot melt extrusion process decrease the glass transition temperature of the polymer. Plasticizers also help in reducing the viscosity of the polymer melt and thereby allow for lower processing temperature and extruder torque during hot melt extrusion. Examples of suitable plasticizers which can be used in the present invention, include, but are not limited to, polysorbates such as sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate; citrate ester type plasticizers like triethyl citrate, citrate phthalate; propylene glycol; glycerin; low molecular weight polyethylene glycol; triacetin; dibutyl sebacate, tributyl sebacate; dibutyltartrate, dibutyl phthalate. The plasticizer is preferably present in an amount ranging from about 0% to about 30% by weight to the total weight of extrudate.
Suitable flow regulators are selected from highly dispersed silica (Aerosil), and animal or vegetable fats or waxes.

Various other additives may be used, for example dyes such as azo dyes, organic or inorganic pigments such as aluminium oxide or titanium dioxide, or dyes of natural origin; stabilizers such as antioxidants, light stabilizers, radical scavengers, stabilizers against microbial attack.

The extrudates can be in the form of beads, granulates, tube, strand or cylinder and this can be further processed into any desired shape.

The fraction of remdesivir in the extrudate that is amorphous may range from about 5% to about 100%, but generally ranges from about 50% to about 100%, based on weight. For the purposes of this disclosure, remdesivir is considered to be predominantly, substantially or essentially amorphous when the fraction of amorphous remdesivir is greater than or equal to about 60%, 75% or 90%, respectively, with the balance being crystalline. In practical terms, amorphous form of remdesivir may be characterized by PXRD patterns lacking peaks that are otherwise present in PXRD patterns of crystalline remdesivir.

In another embodiment, the pharmaceutical composition comprising extrudate of amorphous remdesivir is stable and does not convert to any other form after various stability stations as per pharmacopoeial requirement.

In another embodiment, the present invention is directed to pharmaceutical compositions comprising amorphous remdesivir characterized by powder X-ray diffraction (PXRD).

In an embodiment of present invention, the extrudate is cut into pieces after solidification and can be further processed into suitable dosage forms. More preferably the extrudates thus finally obtained from the above process are then milled and ground to granules or other solid forms by the means known to a person skilled in the art.

The present invention also provides a process to manufacture the extrudates and further processing the extrudates into suitable dosage forms. The melt-extrusion process, in general, comprises the steps of preparing a homogeneous melt of one or more drugs, the polymer and the excipients, and cooling the melt until it solidifies. “Melting” means a transition into a liquid or rubbery state in which it is possible for one component to get embedded homogeneously in the other. Melting usually involves heating above the softening point of the polymer. In an embodiment, the hot melt extrusion process of present invention to prepare extrudates involves forming a powder blend of complex and polymer and optionally one or more suitable excipients, transferring the blend through a heated barrel of the extruder, whereby the powder blend melts and molten solution product is collected on a conveyor whereby it is allowed to cool and form an extrudate. In another embodiment, the complex will melt and the polymer and optionally one or more pharmaceutically acceptable excipients will dissolve in the melt thus forming a solution. The preparation of the melt can take place in a variety of ways. In yet another embodiment, the mixing of the complex, polymer and optionally one or more pharmaceutically acceptable excipients can take place before, during or after the formation of the melt. For example, in another embodiment, the complex, one or more polymer and optionally one or more pharmaceutically acceptable excipients can be mixed first and then melt extruded. In yet another embodiment, the complex, one or more polymers and optionally one or more pharmaceutically acceptable excipients can be simultaneously mixed and melt extruded. In preferred embodiment, the melt is homogenized in order to disperse the complex efficiently. In another preferred embodiment, the one or more polymer may be conveniently melted first and then mixed with the complex in order to homogenize the complex.
In general terms, the process of hot melt extrusion is carried out in the conventional extruders as known to a person skilled in the art. Suitable extruders include single screw extruders, intermeshing screw extruders or else multiscrew extruders, preferably twin screw extruders, which can be co-rotating or counter-rotating and, optionally, be equipped with kneading disks. It will be appreciated that the working temperatures will also be determined by the kind of extruder or the kind of configuration within the extruder that is used.

In an embodiment of present invention, the melt temperature used during the process of hot melt extrusion is in the range from about 40° C. to about 200° C. In a preferred embodiment, the melt temperature used during the process of hot melt extrusio4 is in the range from about 70° C. to about 170° C.

According to one embodiment, of the present invention there is provided a hot melt extruded pharmaceutical formulation comprising remdesivir and at least one pharmaceutically acceptable water soluble and/or insoluble polymer or combination thereof wherein remdesivir is converted to amorphous form in-situ during manufacture of formulation and optionally one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention comprising remdesivir can be administered to a subject via any conventional means including, but not limited to, orally, rectally, ocularly, parenterally (e.g., intravenous, intramuscular, or subcutaneous), intracisternally, intravaginally, intraperitoneally, locally (e.g., powders, ointments or drops), or as a buccal or nasal spray. According to embodiment of present invention, the pharmaceutical composition of present invention is administered orally or sublingually.

Further, as remdesivir is known to undergo significant first pass metabolism, more preferably, the pharmaceutical composition of present invention is administered sublingually.

Moreover, the extrudates/granules of amorphous remdesivir according to the present invention may be formulated into any suitable dosage form, such as but not limited to, unit dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution, transdermal patches and sprinkles, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like. Liquid or semisolid dosage form (liquids, suspensions, solutions, dispersions, ointments, creams, emulsions, microemulsions, sprays, patches, spot-on), injection preparations, parenteral, topical, inhalations, buccal, nasal etc. may also be envisaged under the ambit of the invention.

According to embodiment of present invention, the pharmaceutical composition of present invention is a solid dosage form. Solid dosage forms according to the present invention are preferably in the form of tablets which may be coated or extrudates of the complex are filled in capsules but there also are other conventional dosages such as powders, pellets, capsules, suspensions, solutions, dry syrups, emulsions and sachets that may be provided. One or more optional pharmaceutically acceptable excipients required for the preparation of suitable dosage form may include, but are not limited to, bulking agents/ diluents, binders, disintegrating agents, lubricants, glidants, coloring agents, alkalinizing agents, plasticizers, chelating agents and coating agents.

Suitable bulking agents/diluents according to present invention, may include one or more of, but not limited to, dibasic calcium phosphate, calcium Sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, maltodextrin, dextrose excipients, croscarmellose sodium, isomalt, PVA, saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, sucralose, maltose, fructose, lactitol, lactose, mannitol, Sorbitol, starch, starch pregelatinized, sucrose, Sugar compressible, Sugar confectioners and mixtures thereof. The diluent may be present in a quantity from about 30% to about 85% by weight of the composition.

Suitable binders may include one or more of, but not limited, to methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, polyvinyl alcohol, pullulan, Starch, pregelatinized Starch, agar, tragacanth, sodium alginate, propylene glycol, alginate and other cellulose derivatives and equivalents thereof. Preferably the binder is present in a quantity from about 1% to about 15% by weight of composition.

Suitable disintegrants may include one or more of but not limited, to starches, clays, celluloses, algins, gums or crosslinked polymers one or more of low substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, Sodium starch glycolate, crospovidone, croscarmellose sodium, starch, crystalline cellulose, hydroxypropyl starch, partially pregelatinized starch resins such as polacrilin potassium. The disintegrant may be presenting quantity ranging from about 1% to about 50% by weight of the composition.

Suitable acidifying agents may include one or more of but not limited, to acetic acid, citric acid, fumaric acid, hydrochloric acid, tartaric acid and nitric acid

Suitable lubricants/glidants may include one or more of, but not limited to, Stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil. Sucrose esters of fatty acid, PEG microcrystalline wax, colloidal silicon dioxide and equivalents thereof. Optionally, the formulation may incorporate one or more of the above lubricants or glidants. The glidant and lubricant may each be present in an amount from about 0.5% to about 5% by weight of the composition. Suitable coloring agents may be added.
The composition may further comprise alkalinizing agents including, but not limited to, calcium carbonate, calcium phosphate, magnesium carbonate, magnesium oxide, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, Sodium hydrogen carbonate and equivalents thereof. The formulation may incorporate one or more of the above alkalinizing agents.

Plasticizers which may be used in the pharmaceutical composition of the present invention, include, but are not limited to proplylene glycol, polysorbates such as sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate; citrate ester type plasticizers like triethyl citrate, citrate phthalate; propylene glycol; glycerin; polyethylene glycol (low & high molecular weight); triacetin; dibutyl sebacate, tributyl sebacate; dibutyltartrate, dibutyl phthalate, glycerol palmitosterate and mixtures thereof.

Suitable solvents include, one or more of, but not limited to isopropyl alcohol (IPA), acetone, ethanol, methanol, ethyl acetate, dichloromethane and mixtures thereof.

Suitable chelating agents include, one or more of, but not limited to ethylenediaminetetraacetic acid (EDTA), disodium EDTA and derivatives thereof, citric acid and derivatives thereof, niacinamide and derivatives thereof, and sodium desoxycholate and derivatives thereof.

Flavouring agents are used to mask potential unpleasant tasting active ingredients and improve the likelihood that the patient will complete a course of medication. Such agents are particularly useful in case of orodispersible, chewable and sublingual tablets. Flavouring agents may be, for example, mint powder, menthol, vanillin, aspartame, acesulfame potassium, saccharin and Magnasweet.

The pharmaceutical composition, according to the present invention, may be seal coated. Preferably, the tablet may be seal coated and finally film coated or the tablet may be seal coated and further enteric coated.
According to an embodiment of the present invention, pharmaceutical composition may be film coated with Ready colour mix systems (such as Opadry colour mix systems).

The suitable dosage form from the extrudates and optionally one or more pharmaceutically acceptable excipients can be prepared by the conventional processes known in the art such as such as direct compression, wet granulation, fluidized bed granulation, extrusion, solvent evaporation and are not intended to limit the scope of the invention to form the desired dosage form.

According to a preferred embodiment, the extrudates as obtained above may be mixed, sieved, sifted and compressed into a single tablet or may be filled into capsules or sachets or the extrudates in the form of granules may be administered directly. Alternatively, the tablet may be seal coated and finally film coated.

Accordingly, the pharmaceutical composition of present invention comprises an extrudate comprising amorphous remdesivir in combination with one or more polymer, optionally one or more pharmaceutically acceptable excipients and one or more pharmaceutically acceptable excipients.

The present invention also provides a method of prevention, treatment and prophylaxis of diseases caused by viruses including SARS Coronavirus which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention.

The present invention also provides a use of the pharmaceutical composition according to the present invention, in the manufacture of a medicament prevention, treatment and prophylaxis of diseases caused by viruses including SARS Coronavirus
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.

It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Examples:
Active & Excipients Quantity (mg)
Remdesivir 20 20 20 20
Kollidon VA 64 80 40 20 10
Microcrystalline cellulose 52 57 37 47
Crospovidone 15 20 10 10
Sucralose 20 20 20 20
Mannitol 20 20 20 20
Starch 10 10 10 10
Aerosil 10 10 10 10
Magnesium Stearate 2 2 2 2
Flavour 1 1 1 1
Solvent q.s. q.s. q.s. q.s.
Total weight of tablet 230 200 150 150

Process:
1. Remdesivir and polymers were dissolved in suitable solvent and sprayed over an inert diluent bed.
2. The granules were sized and blended with extragranular materials.
3. The lubricated blend was compressed into tablets.

Active & Excipient Quantity (mg)
Remdesivir 20 20 20
SBECD 144 72 36
Microcrystalline cellulose 28 35 31
Crospovidone 15 20 10
Mannitol 20 20 20
Sucralose 20 20 20
Aerosil 10 10 10
Magnesium Stearate 2 2 2
Flavour 1 1 1
Solvent q.s. q.s. q.s.
Total weight of tablet 260 200 150

Process:
1. Remdesivir and SBECD were dissolved in suitable solvent and sprayed over an inert diluent bed.
2. The granules were sized and blended with extragranular materials.
3. The lubricated blend was compressed into tablets.

Active & Excipients Quantity (mg)
Remdesivir 20 20 20 20
Kollidon VA 64 80 40 20 10
Microcrystalline cellulose 32 37 27 37
Croscarmellose sodium 15 20 10 10
Sucralose 20 20 20 20
Mannitol 20 20 20 20
Aerosil 10 10 10 10
Magnesium Stearate 2 2 2 2
Flavour 1 1 1 1
Solvent q.s. q.s. q.s. q.s.
Total weight of tablet 200 170 130 130

Process:
1. Remdesivir and polymers were dissolved in suitable solvent and spray dried using a spray drier and blended with extragranular materials.
2. The lubricated blend was compressed into tablets.

Active & Excipients Quantity (mg)
Remdesivir 20 20 20
SBECD 144 72 36
Microcrystalline cellulose 38 35 31
Croscarmellose sodium 15 20 10
Sucralose 20 20 20
Mannitol 20 20 20
Aerosil 10 10 10
Magnesium Stearate 2 2 2
Flavour 1 1 1
Solvent q.s. q.s. q.s.
Total weight of tablet 270 200 150
Process:
1. Remdesivir and polymers were dissolved in suitable solvent, spray dried using a spray drier and blended with extragranular materials.
2. The lubricated blend was compressed into tablets

Active & Excipients Quantity (mg)
Remdesivir 20 20 20 20
Kollidon VA 64 80 40 20 10
PEG 8 4 2 1
Microcrystalline cellulose 44 23 35 26
Crospovidone 20 20 10 10
Sucralose 20 20 20 20
Mannitol 20 20 20 20
Aerosil 10 10 10 10
Magnesium Stearate 2 2 2 2
Flavour 1 1 1 1
Total weight of tablet 225 160 140 120

Process:
1. Remdesivir and polymers extrude were mixed at a suitable temperature using a hot melt extruder.
2. The extrudes were milled to form granules and were blended with extragranular materials.
3. The lubricated blend was compressed into tablets.
,CLAIMS:
1. A pharmaceutical composition comprising amorphous remdesivir or its salt, solvate, derivative, hydrate, anhydrate, enantiomer, polymorph, prodrug or complex.
2. A pharmaceutical composition according to claim 1 wherein the composition further comprises at least one pharmaceutically acceptable polymer.
3. A pharmaceutical composition according to claim 1 or 2, wherein the at least one pharmaceutically acceptable polymer is a water soluble polymer and /or a water swellable polymer and/or a water insoluble polymer.
4. A pharmaceutical composition according to claim 1, 2 or 3 wherein the composition is a hot melt extruded pharmaceutical composition.
5. A pharmaceutical composition according to any preceding claim, further comprising one or more pharmaceutically acceptable excipients selected from plasticizers, disintegrating agents, lubricants, glidants, diluents, anti-adherents, binders, chelating agents.
6. A pharmaceutical composition according to any preceding claim, wherein the composition is in the form of a tablet, coated tablet, powders, powders for reconstitution, pellets, beads, mini-tablets, bilayered tablets, tablet in tablet, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates, capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, modified release tablets or capsules, effervescent granules, granules, and microspheres, multiparticulates) and sprinkles.
7. A process for preparing a pharmaceutical composition according to any one of claims 1 to 6, wherein the process comprises hot melt extrusion of the remdesivir polymer blend to form extrudates and optionally mixing it with one or more pharmaceutically acceptable excipients.
8. A pharmaceutical composition according to any one of claims 1 to 7, for prevention, treatment and prophylaxis of diseases caused by viruses including SARS Coronavirus.
9. A pharmaceutical composition substantially as herein described with reference to the examples.
10. A process for preparing a pharmaceutical composition as substantially described herein, with reference to any one of the examples.