DESC:“HIGH DOSAGE STRENGTH ORAL FORMULATIONS OF FAVIPIRAVIR AND METHOD OF MANUFACTURING THEREOF”

FIELD OF THE INVENTION:
The present invention relates to high dosage strength oral formulations comprising Favipiravir and one or more pharmaceutically acceptable excipient(s). The present invention relates to solid oral dosage forms including immediate release tablets, sustained release tablets, capsules and granulated powder. The present invention further relates to liquid oral dosage forms including suspensions and solutions. The present invention also relates to improved processes for the preparation of Favipiravir whose incorporation is in high strength or load within the dosage providing high dissolution rate helping the drug to reach at the absorption site quickly and thereby providing increased therapeutic efficacy in a quite shorter span.

BACKGROUND OF THE INVENTION:
Favipiravir is an antiviral drug against influenza discovered by Toyama Chemical Co. Ltd. Favipiravir is metabolized into Favipiravir ribosyl triphosphate (Favipiravir RTP) by an intracellular enzyme, and Favipiravir RTP selectively inhibits RNA polymerase (RNA-dependent RNA polymerase) of the influenza like viruses, preventing replication of the influenza like viruses.
Chemically, Favipiravir is known as 6-fluoro-3-hydroxypyrazine-2-carboxamide having chemical structure as below: Favipiravir has empirical formula C5H4FN3O2 and the molecular weight is 157.10.

FAVIPIRAVIR
Physico-chemically, Favipiravir (CAS: 259793-96-9) is a white to light yellow powder. It is sparingly soluble in acetonitrile and in methanol, and slightly soluble in water and in ethanol. It is slightly soluble at pH 2.0 to 5.5 and sparingly soluble at pH 5.5 to 6.1.
Favipiravir is a purine nucleic acid analogue that was initially approved for therapeutic use in resistant cases of influenza in Japan. The antiviral targets RNA-dependent RNA polymerase (RdRp) enzymes, which are necessary for the transcription and replication of viral genomes.
Commercially, Favipiravir is available as AVIGAN® tablets by Toyama Chemical Co. Ltd. in the Japan market. Each AVIGAN® tablet contains 200 mg of Favipiravir. The inactive ingredients of AVIGAN® include low substituted hydroxypropylcellulose, crospovidone, colloidal silicon dioxide, povidone, Hypromellose and sodium stearyl fumarate. Additionally, the proprietary film coating mixture used for AVIGAN® 200 mg tablets is titanium oxide, talc and yellow ferric oxide.
Favipiravir inhibits replication of influenza A and B, as well as the drug has shown promise in the treatment of avian influenza, and may be an alternative option for influenza strains that are resistant to neuramidase inhibitors. Favipiravir has been investigated for the treatment of life-threatening pathogens such as Ebola virus, Lassa virus, and corona virus.
Corona viruses, having a total of 39 species under the broad realm of Riboviria, belong to the family Coronaviridae, suborder Cornidovirineae and order Nidovirales. All the SARS-CoV (Severe Acute Respiratory Syndrome - Coronavirus) fall under the species Severe acute respiratory syndrome-related coronavirus and genus Beta-coronavirus.
Currently, seven humans CoVs (HCoVs) have been confirmed. Specifically, they are named as Human coronavirus NL63 (HCoV-NL63) and Human coronavirus 229E (HCoV-229E), which belong to the alpha-coronavirus genus; whereas Human coronavirus OC43 (HCoV-OC43), Human coronavirus (HCoV-HKU1), SARS-CoV, SARS-CoV-2 and Middle East respiratory syndrome coronavirus (MERS-CoV), belong to the beta-coronavirus genus. HCoV-229E, HCoV-NL63, HCoV-HKU1 and HCoV-OC43 strains of coronavirus cause mild respiratory diseases in humans. The SARS-CoV-2 is a zoonotic virus that belongs to the Coronaviridae family that can infect human and several animal species.
Recently, an outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [initially known as novel corona virus] was reported in Wuhan, China in mid-December 2019, and declared a pandemic by the World Health Organization (WHO) on March 11, 2020. The Novel Corona Virus Disease-19 is a consequence of the infection due to SARS-CoV-2 which is abbreviated as COVID-19 by WHO, characterized by most common symptoms including fever, dry cough and shortness of breath. Less common symptoms include aches, pains, sore throat, diarrhea, conjunctivitis, headache, loss of taste or smell and rashes on skin or discoloration of fingers or toes. Serious complications due to SARS-CoV-2 include difficulty breathing or shortness of breath, chest pain or pressure and loss of speech or movement. This disease is more severe in men, the elderly, and people with other chronic health conditions, such as high cardiovascular disease, diabetes, chronic respiratory disease, and hypertension. As of May 2020, nearly 50,00,000 people have been diagnosed with COVID-19 and more than 300,000 deaths in the world.
The COVID-19 pandemic has entered a dangerous new phase. When compared with SARS and MERS, COVID-19 has spread more rapidly, due to increased globalization and adaptation of the virus in every environment. Slowing the spread of the COVID-19 cases will significantly reduce the strain on the healthcare system of the country by limiting the number of people who are severely sick by COVID-19 and need hospital care.
Hence, the recent outburst of COVID-19 highlights an urgent need for therapeutics targeting SARS-CoV-2. As escalating pandemic of COVID-19 and potential impact on global health preparing effective therapeutic options is urgently needed. In addition to other drugs such as Lopinavir, Ritonavir, and hydroxychloroquine, which are proposed to treat this disease, the use of Favipiravir is also being initiated in many clinical trials including the inventors of the present invention.
As shown in below representation, Coronavirus SARS-CoV-2 enters host cells via ligation of its spike protein (S glycoprotein) with host cell ACE2 receptor that is primed by TMPRSS2 protease. The inventors of the present invention have surprisingly observed that ACE2- and TMPRSS2-mediated cell entry can be blocked by Favipiravir. Virus replication and assembly can be inhibited by Favipiravir targeting viral RNA-dependent RNA polymerase (RdRP) and main protease (Mpro).

The usual adult dosage is 1600 mg of Favipiravir administered orally twice daily on Day 1, followed by 600 mg orally twice daily from Day 2 to Day 5. The total treatment duration is of 5 days.
The present invention relates to pharmaceutical compositions of Favipiravir and improved processes for the preparation thereof. Favipiravir is a pharmaceutical agent which would use to treat novel or re-emerging pandemic influenza virus infections. Further, the inventors of the present invention also propose its use in novel or re-emerging pandemic corona virus related infections.
WO2000/010569 discloses Favipiravir compound for the first time. This patent describes Favipiravir as an antiviral agent that exhibits an effect of preventing infection against various viruses, particularly an influenza virus, and exhibits a therapeutic effect. Further, this patent also discloses process for preparation of Favipiravir.
WO2001/60834 discloses improved process for the preparation of Favipiravir. The processes for producing Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarbonitrile), disclosed in this patent disclosed as the following:
1. A process in which 3,6-difluoro-2-pyrazinecarbonitrile is reacted with benzyl alcohol and the reaction product is debenzylated; and
2. A process in which 3,6-difluoro-2-pyrazinecarbonitrile is subjected to a reaction with water.
WO2009/041473 discloses an organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, wherein the organic amine is dicyclohexylamine. The organic amine salts of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile have excellent crystallinity, can be isolated from a reaction mixture in a high yield by a simple operation, and are useful as an intermediate for the preparation of T-705
WO2010/104170 discloses a tablet comprising (1) 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof, (2) low-substituted hydroxypropylcellulose or croscarmellose sodium, and (3) a binder. Present invention discloses tablets with 200 mg dosage form. These leads to patient incompliance because for loading dose the patient need to ingest about 18 tablets in one day followed by 8 to 9 tablets per day to maintain the therapeutic concentration of the drug in blood stream. Thus, this patent has very serious limitation of patient incompliance.
WO2012/043696 discloses meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a hydrate thereof. This patent discloses this meglumine salt in crystalline form as well as in amorphous form. In addition to this, the said patent also disclosed injectable lyophilized formulation of Favipiravir using this crystalline form as well as amorphous form.
WO2012/043700 discloses crystal form of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide sodium salt or hydrate thereof. In addition to this, the said patent also disclosed injectable lyophilized formulation of Favipiravir using this crystalline form.
WO2016/199824 discloses type-B crystal of 6-bromo-3-hydroxy-2-pyrazinecarboxamide having powder X-ray diffraction angles (2?) of 7.1°, 21.4°, 25.2°, 25.7°, 27.1° and 28.8°. This patent discloses preparation of type-B crystal of Favipiravir from type-A crystal. This patent has not disclosed any of composition therein.
In view of all these prior-art publications, there is still a need to prepare a stable pharmaceutical composition comprising Favipiravir prepared by simple and economically viable process, which provides desired dissolution profile with least deviation. Further, a high dosage pharmaceutical formulation of Favipiravir is an unmet need due to its high dose.
The inventors of the present invention have observed during clinical studies of Favipiravir that there is a need for a high dose of active ingredient in one unit dose. For convenient oral administration, generally the tablet weight should not exceed 800 mg. As the number of tablets required per dose can lead to compliance issues, it would be desirable to find a formulation that could be commercially made that resulted in fewer tablets required per dose with the resultant expectation that there would be improved patient compliance.
Thus, there is a need for developing tablet dosage forms containing a Favipiravir and pharmaceutically acceptable salt thereof that,
1. has suitable size in order to allow the patient to easily swallow the tablet,
2. has a high load of Favipiravir in order to minimize the number of tablets required per dose,
3. has suitable properties with respect to the release of the Favipiravir from the tablet, and
4. has the pharmaceutical behaviour that leads to the desired effect.
The inventors of the present invention have surprisingly developed an invention which overcome above all the problems. This invention is further described in detail in later sections.

OBJECTIVE OF THE INVENTION:
The principal objective of present invention is to provide oral dosage forms comprising Favipiravir and one or more pharmaceutically acceptable excipient(s), wherein oral dosage form includes solid oral dosage form as well as liquid oral dosage form.
One more objective of the present invention is to provide improved processes for the preparation of Favipiravir whose incorporation gives high loading capacity in the composition followed by high dissolution rate which helps Favipiravir to reach at the absorption site quickly and thereby providing increased therapeutic efficacy in shorter span.
Another objective of the present invention is to provide Favipiravir compositions which is in the form of immediate release tablets, sustained release tablets, capsules, powdered granules, suspensions or solutions.
Another objective of the present invention is to provide Favipiravir composition wherein the composition may be produced by either wet granulation process or dry granulation process.
Yet another objective of the present invention is to provide Favipiravir composition with improved economic processes wherein Favipiravir shows consistent dissolution profile in stability storage condition.

SUMMARY OF THE INVENTION:
Despite of extensive research on Favipiravir as reported in prior-art publications, high strength oral composition of Favipiravir which are stable one has not been reported. Surprisingly, inventors of the present invention have derived improved processes by using them stable compositions of Favipiravir may be obtained.
Accordingly, the present invention provides oral compositions of Favipiravir preferably as oral dosage form with pharmaceutically acceptable excipients and method of preparation thereof.
In one general aspect, a pharmaceutical composition as per the present invention is in the form of tablet or capsule or powdered granules.
In one general aspect, a pharmaceutical composition as per the present invention is in the form of tablet wherein tablet is immediate release or sustained release.
In one general aspect, a pharmaceutical composition as per the present invention is in the form of suspension or solution.
In yet another aspect, a pharmaceutical composition as per the present invention comprises Favipiravir and one or more pharmaceutically acceptable excipients wherein the tablet and capsule composition may be prepared using wet-granulation or dry granulation process.
Another embodiment according to the present invention, wherein the formulated product manufactured contains Favipiravir, which results in to enhanced in-vitro dissolution release.
In yet another embodiment of the present invention, wherein the pharmaceutical composition manufactured by number of stages in manufacturing process which may include wet-granulation which may be aqueous or non-aqueous.
In yet another embodiment of the present invention, wherein the pharmaceutical composition manufactured by number of stages in manufacturing process which may include dry-granulation or direct compression.
Embodiments of the pharmaceutical composition may include Favipiravir as an active ingredient with one or more selected from pharmaceutically acceptable excipients like fillers or diluents, binders, surfactants, disintegrants, lubricants, glidants, coloring agents and the like.
Accordingly, the present invention provides an oral composition of Favipiravir preferably as suspension dosage form with pharmaceutically acceptable excipients and method of preparation thereof.
One embodiment of the present invention also provides the pharmaceutical composition which establishes a dual release pattern owing to kind of solubilizes used in the formulation and thereby producing an immediate burst absorption followed by delayed absorption.
In yet another aspect, a pharmaceutical composition as per the present invention is in the form of liquid formulation.
In yet another aspect, a pharmaceutical composition as per the present invention comprises Favipiravir and one or more pharmaceutically acceptable excipients wherein the composition is in the form of a suspension or solution.
Additional embodiment according to the present invention, wherein the suspension formulation manufactured is having particle size ranging from nanometer to micrometer, which results in to enhanced bio-absorption about 40% to 90%.
In yet another embodiment of the present invention, wherein the suspension pharmaceutical composition manufactured by number of stages in manufacturing process including homogenization, sonication, mixing and/or evaporation by spray drying.
Embodiments of the pharmaceutical composition may include Favipiravir as an active ingredient with one or more selected from pharmaceutically acceptable excipients like diluent vehicles, stabilizers / anti-oxidants, suspending / thickening agents, chelating / complexing agents, solubility enhancing agents, permeability enhancers, preservatives, glidants, active carriers, sweeteners, anti-caking agents, wetting agents, preservatives, buffering agents, flavoring agents and the like.
In another embodiment of the present invention, wherein Favipiravir is present in the final formulation in amount ranging from 100 mg to 800 mg along with pharmaceutically acceptable excipients in one unit dose.
The details of one or more embodiments of the invention are set forth in the description below. Other features of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention will now be disclosed by describing certain preferred and optional embodiments, to facilitate various aspects thereof.
In accordance with the present invention, a pharmaceutical composition of Favipiravir comprising of Favipiravir as an active ingredient with pharmaceutically acceptable excipients.
The term "Favipiravir" as used herein includes Favipiravir free base, its pharmaceutically acceptable salt. Preferably, Favipiravir is Favipiravir free base. Favipiravir can be used in any crystalline, partly crystalline or amorphous form or modification. Favipiravir can be used in micronized or non-micronized form.
The term "added" or "mixed" or "adding" or "mixing" as used herein are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply mixing or adding or granulating Favipiravir or one or more pharmaceutically acceptable excipient(s) with said inert granules or other pharmaceutically acceptable excipient(s) to prepare mixture or blend.
The term “granulation” includes aqueous granulation, non-aqueous granulation as well as dry granulation.
The term “wet granulation” includes a fluidized bed granulation method, a centrifugal tumbling granulation method, a mixing/stirring granulation method, a high-speed mixing/stirring granulation method, a tumbling granulation method, a wet crushing granulation method and an extruding granulation method.
A pharmaceutical composition according to present invention is a solid composition for immediate release or sustained release for oral administration and it can be in the form of tablets, powdered granules or capsules.
Another pharmaceutical composition according to present invention is a liquid composition for immediate release or sustained release for oral administration and it can be in the form of suspensions or solutions.
The term "pharmaceutically acceptable excipient(s)" as used herein refers to additive(s) useful for converting pharmacologically active compound into pharmaceutical dosage forms which are suitable for administration to patients. Suitable pharmaceutically acceptable excipients include fillers or diluents, binders, surfactants, disintegrants, lubricants, glidants, coloring agents, diluent vehicles, stabilizers / anti-oxidants, suspending / thickening agents, chelating / complexing agents, solubility enhancing agents, permeability enhancers, preservatives, glidants, active carriers, sweeteners, anti-caking agents, wetting agents, preservatives, buffering agents, flavoring agents and the like. Other pharmaceutically acceptable excipients can also be included.
Diluent may be selected from cellulose derivatives such as powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose; starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate; saccharides such as lactose, sucrose or dextrose; sugar alcohols such as mannitol, sorbitol or erythritol and mixtures thereof The formulation may incorporate one or more of the above fillers, preferably, lactose and microcrystalline cellulose forms the filler. The diluent may be present in an amount ranging from 1% to 90% by weight of the composition.
Surfactant may be selected from anionic, cationic, non-ionic or amphoteric surfactants or those known to the person skilled in the art. The preferred surfactants according to present invention may include, but not limited to Sodium lauryl sulfate, polyoxyehtylene polyoxypropylene glycol, polyethylene glycol, polyoxyehtylene glycol and ethers, polysorbates (tweens), glycerol, Sorbitan esters. The preferred surfactant in the present invention is sodium lauryl sulfate. The surfactant may be present in an amount ranging from 0.5% to 25% by weight of the composition.
Disintegrant may be selected from calcium carboxymethyl cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked polyvinyl pyrrolidone, carboxymethylcellulose sodium, sodium starch glycolate, pregelatinized starch; low-substituted hydroxypropylcellulose; and mixtures thereof. The disintegrant may be present in an amount ranging from 1% to 20% by weight of the composition.
Lubricant may be selected from stearic acid or its derivatives or esters like sodium stearate, magnesium stearate and calcium stearate and the corresponding esters such as sodium stearyl Fumarate, talc and colloidal silicon dioxide respectively. The lubricant may be present in an amount ranging from 0.25% to 5% by weight of the composition.
Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch, microcrystalline cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hypromellose, ethyl cellulose, sodium carboxymethylcellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinylpyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth and other materials known to one ordinarily skilled in the art and mixtures thereof.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one ordinarily skilled in the art and mixtures thereof.
Suitable diluent vehicle may include one or more from aqueous vehicle, sugar, methylcellulose gel, citric acid, sucrose, sorbitol solution, sodium carboxy methylcellulose solution, xanthan gum solution, non-aqueous vehicle like refined fractionated coconut oil, hydrogenated castor oil, lecithin, aluminum stearate and the like.
Suitable stabilizers or anti-oxidants may include one or more from citric acid, butylated hydroxytoluene, butylated hydroxy anisole, sodium bisulphite, ascorbic acid, L-cysteine, magnesium bisulfite, sodium metabisulfite, tocopherol, ubiquinol, ß-carotenes, uric acid, lipoic acid, propyl gallate, thiourea, glutathione and the like.
Suitable suspending or thickening agents may include one or more from sodium alginate, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, acacia, tragacanth, xanthan gum, bentonite, carbomer, carrageen, gelatin and the like.
Suitable preservative may include one or more from propylene glycol, disodium EDTA, benzalkonium chloride, benzoic acid, butyl paraben, methyl paraben, propyl paraben, sodium benzoate and the like.
Suitable anti-caking agents may include one or more from colloidal silicon dioxide, tribasic calcium phosphate, magnesium trisilicate, starch and the like.
Suitable wetting agents may include one or more from the group comprising anionic, cationic, nonionic, or zwitterionic surfactants, or combinations thereof. Suitable examples of wetting agents are sodium lauryl sulphate, cetrimide, polyethylene glycols, polyoxyethylene-polyoxypropylene block copolymers such as poloxamers, polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate, polyethylene glycol fatty acid esters such as polyoxyethylene monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene castor oil and the like.
Suitable buffering agents may include one or more from the group comprising citric acid, sodium citrate, sodium phosphate, potassium citrate, acetate buffer and the like.
Suitable permeability enhancers may include one or more from the group comprising alcohols, Polyols, short chain glycerides, amines, amides, cyclodextrins, fatty acids, pyrrolidines, azones, sulfoxides, surfactants, terpenes and the like.
Suitable active carrier molecules may include one or more from the group comprising piperine and the like.
Suitable surfactants or co-surfactants may include one or more from anionic, cationic, non-ionic or amphoteric surfactants. Non-limiting examples of surfactants may include polyoxyethylene-polyoxypropylene co-polymers and block co-polymers, ethoxylated cholesterins, vitamin derivatives, e.g., vitamin E derivatives such as tocopherol polyethylene glycol succinate (TPGS), sodium dodecylsulfate or sodium lauryl sulfate; a bile acid or salt thereof, for example cholic acid, glycolic acid or a salt; and the like.
Suitable flavoring agents may include one or more from the group consisting of peppermint, grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grape, banana, cranberry, blueberry, black currant, red currant, gooseberry, lingon berries, cumin, thyme, basil, camille, valerian, fennel, parsley, chamomile, tarragon, lavender, dill, bargamot, salvia, aloe vera balsam, spearmint, piperine, eucalyptus, and the like.
Suitable chelating or complexing agents may include one or more from the group comprising cyclodextrin, ethylenediamine tetra acetic acid or derivatives/salts thereof, e.g., disodium edetate, dihydroxyethyl glycine, glucamine, citric acid, tartaric acid, gluconic acid, phosphoric acid and the like.
Suitable solubility enhancing agents may include one or more from the group comprising surfactants such as (1) non-ionic e.g., polyoxyethylene sorbitan fatty acid esters, sorbitan esters, polyoxyethylene ethers, (2) anionic e.g., sodium lauryl sulfate, sodium laurate, dialkyl sodium sulfosuccinates, particularly bis-(2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, and sodium oleate, (3) cationic e.g., benzalkonium chloride and bis-2-hydroxyethyl oleyl amine, and (4) zwitterionic / amphoteric surfactants; fatty alcohols such as lauryl, cetyl, and stearyl alcohols; glyceryl esters such as the naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of fatty alcohols and other alcohols such as propylene glycol, polyethylene glycol; sucrose; polymers e.g., poloxamers, polyvinylpyrrolidones, glycerides e.g., triacetin, glyceryl monocaprylate, glyceryl monooleate, glyceryl monostearate; diethylene glycol monoethyl ether; and the like.
It should be appreciated that there is considerable overlap between the above-listed excipients in common usage, since a given excipient is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed excipients should be taken as merely exemplary, and not limiting, of the types of excipients that can be included in compositions of the present invention. One or more of these excipients can be selected and used by the skilled artisan having regard to the particular desired properties of the dosage form by routine experimentation without any undue burden. The amount of each type of excipients employed may vary within ranges conventional in the art.
The overall physical properties and manufacturability of low drug loading formulations is determined predominantly by the inactive ingredients or excipients in the formulation. However, at high drug loading, the contribution of the physical properties of the active pharmaceutical ingredient ("API") to the manufacturability of a formulation becomes predominant. Not all APIs possess the necessary properties with respect to compressibility that are required in order to obtain a high load tablet using any granulation processes.
Most small molecule API's, can be formulated in low dose forms because the physical properties of the excipients utilized in the formulations dominate the properties of the solid composition, rather than the physical properties of the API itself. As drug loading increases the physicochemical characteristics of the drug substance become increasing dominant in the tablet manufacturing process. API's can have a full spectrum of physical properties and are not selected based on these physical properties, it is not to be expected that a particular API would have the physical properties to favorably contribute to an overall formulation in terms of manufacturability and stability. In fact, it is not infrequent that it is the physical properties of the API that actually present the largest obstacle to creating a workable formulation.
Further, Favipiravir or a salt thereof has such a property that no compressive molding property is available, specific volume is big, cohesive force is strong and fluidity is low. It is difficult that a tablet containing a large amount of the Favipiravir or a salt thereof and being in an easily ingestible size is manufactured by a conventional method.
The inventors of the present invention have also observed that it is not possible to improve the cohesive force of the Favipiravir or a salt thereof only by means of compounding a fluidity promoter. The mixed powder for tableting having poor fluidity shows a poor charging property into a mortar upon tableting. Therefore, discrepancies in the tablet masses become big and quality is deteriorated.
There has been a demand for a tablet in which the amount of Favipiravir or a salt thereof contained therein is high, the size is an easily ingestible size, the dissolution property is excellent and the hardness is durable against film coating, packaging and transportation whereby the tablet is stable for a long period of time and also for a mixed powder for tableting for the manufacture of the tablet as such.
It is therefore surprising and unanticipated where it is found that an API can be formulated with drug loads in excess of 45 to 95%. The inventors of the present invention have developed pharmaceutical compositions comprising Favipiravir wherein high dosage strength is incorporated after repeatedly carried out intensive studies and experiments. The inventors of the present invention surprisingly observed that when microcrystalline cellulose was added to the composition in the range of 10-50% w/w of total tablet, in that case only, the inventors got the better result in terms of compressibility. Without using microcrystalline cellulose in the the range of 10-50% w/w, it was difficult to even compress the tablet due to high cohesive force of Favipiravir.
High dosage strength formulation of Favipiravir offers several advantages. It has been observed in the art that for initial loading dosage a patient has to ingest 9 tablets of 200 mg AVIGAN® tablet twice in a day making 18 tablets per day. For maintenance dose, a patient has to ingest 4 to 4.5 tablets of 200 mg AVIGAN® tablet twice in a day making 8 to 9 tablets per day. First advantage of the present invention is of patient compliance. The inventors of the present invention have proposed high dosage strength formulation of Favipiravir 600 mg. A patient needs to ingest only 3 tablets of 600 mg tablets twice in a day for loading dose which reduces to 6 tablets per day. In addition, for maintenance dose, a patient needs to ingest only one tablet of 600 mg Favipiravir thrice in a day.

COMPARISON OF TABLETS TO BE INGESTED BY A PATIENT
Dosage forms Loading dose
(3600 mg) Maintenance dose
(1600 to 1800 mg) Total tablets during maintenance dose
(day 2 to 5) Total tablets during 5-day therapy
Existing dosage forms
(200 mg tablet) 9 tablets X Twice in a day =
18 tablets 4 to 4.5 tablets X Twice in a day =
8 to 9 tablets 8 to 9 tablets X 4 days =
32 to 36 tablets 18 tablets + 32 to 36 tablets =
50 to 54 tablets
Present invention
(600 mg tablet) 3 tablets X Twice in a day =
6 tablets 1 tablet X Thrice in a day =
3 tablets 3 tablets X 4 days =
12 tablets 6 tablets + 12 tablets =
18 tablets
Present invention
(800 mg tablet) 2 tablets X Twice in a day =
6 tablets
(1 tablet of 200 mg twice is added) 1 tablet X Twice in a day =
2 tablets 2 tablets X 4 days =
8 tablets 6 tablets + 8 tablets =
14 tablets
About 64 – 75% of reduction in tablets to be ingested by a patient with the present invention provide better patient compliance

Hence, due to this drastic change, patient compliance increases at a very good level. Following is the comparison between the existing therapy and the present invention where no. of tablets taken by a patient for the treatment is mentioned. From the following table, a person skilled in the art may easily understand the extent of patient compliance may increase.
One more advantage of these novel dosage forms includes ease of manufacturing. Ease of manufacturing provides advantage that the composition of formulation as prepared by the present invention is very economical during production. This gives an economic significance to the present invention making it an inventive. Further to this, the inventors of the present invention have also observed that these high dosage strength dosage forms have produced more effect in terms of therapeutic efficacy when compared with the existing dosage forms. Thus, the present invention also incorporates a technical advancement making it again inventive and thereby non-obvious to the person skilled in the art.
As we have noted that some patients including geriatric and having other diseases have more chance to convert into critical conditions wherein, they also require help of ventilator to survive themselves. In such patient having critical condition, high strength suspension and solution dosage form provide the unique advantage of patient compliance. Due to critical health condition, these patients are unable to swallow high strength tablets or capsules. At this stage, high dosage suspension and solution are proven to be helpful to these patients. They need to swallow small amount of liquid to reach to the loading or maintenance dose of Favipiravir. In this way, the present invention provides a number of advantages than the existing dosage forms making it a preferential choice by patients as well as manufacturers.
In yet another aspect of the embodiment, the process comprises the steps of compressing into suitable dosage form of Favipiravir and optionally coating the same. Coating may be performed by applying the coating composition as a solution/suspension/blend using any conventional coating technique known in the art, such as spray coating in a conventional coating pan. The coating may be functional or non-functional.
After experimenting more than dozen type of possible processes, inventors of the present invention observed only these processes surprisingly maintain the similar dissolution rate even after storage under stability conditions. This is the main advantage of above-mentioned processes. Because it is the prime motive of each scientist to develop a formulation which is stable over a longer period of time. This motive is fulfilled in this invention. In addition, due to maintenance of fast dissolution rate over six-month stability period, this composition would reach faster and completely to the site of absorption and thereby increasing bioavailability in shorter span.
The inventors of the present invention also noted that sequence of above processes is also crucial. Inventors tried to change the sequence which led to poor dissolution results than the earlier one. Hence, not only the processes but also the sequence of these processes does play a significant role in development of stable pharmaceutical formulation of Favipiravir wherein Favipiravir is present in high strength.
One embodiment of the present invention may include a solid pharmaceutical composition comprising about 400 mg to 800 mg of Favipiravir with pharmaceutically acceptable excipients in a unit dosage form.
The dissolution test for the tablet composition was conducted by a puddle method for a dissolution test according to the Japanese Pharmacopoeia. Revolutions of the puddle were made 50 rpm. A sample was poured into 900 mL of an acetate buffer (pH 4.5) followed by stirring for 15 minutes. The test solution was collected and the dissolution rate (%) of Favipiravir was determined by means of an absorbance method.
One embodiment of the present invention may include a liquid pharmaceutical composition comprising about 50 mg to 200 mg of Favipiravir per ml of the liquid composition.
The invention will be further described with respect to the following examples; however, the scope of the invention is not limited thereby. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Means, the foregoing examples are illustrative embodiments and are merely exemplary.
A person skilled in the art may make variations and modifications without deviating from the spirit and scope of the invention. All such modifications and variations are intended to be included within the scope of the claims.
EXAMPLES
GENERAL EXAMPLE:
Table-1
Ingredients % W/W
Favipiravir 45 – 99 %
Hypromellose 2 – 5%
Microcrystalline cellulose 2 – 5%
Sodium starch glycolate 2 – 5%
Pre-gelatinized starch 2 – 5%
Sodium lauryl sulphate 1 – 5%
Aerosil 1 – 4 %
Magnesium Stearate 1 – 2%

Process for preparation:
1. Hypromellose was dissolved in sodium lauryl sulphate and water to prepare binder solution.
2. Binder solution prepared in step-1 was added or sprayed to the pre-mix of Favipiravir, microcrystalline cellulose and pre-gelatinized starch which was granulated in rapid mixer granulator or fluidized bed dryer followed by drying of these granules.
3. Sodium starch glycolate was added to above dried granules obtained in step-2 and blended.
4. Blend obtained in step-3 was then lubricated using Aerosil and magnesium stearate.
5. Lubricated blend obtained in step-4 was then compressed to form tablets or filled in the capsule.
6. Tablets obtained in step-5 were optionally coated using Opadry® ready mixture.

EXAMPLE-1:
Sr. No. Ingredients % w/w mg/tab
(For 200 mg)
A. Intragranular
1 Favipiravir 66.67 200.00
2 Microcrystalline Cellulose PH 101 16.66 49.99
3 Low substituted hydroxypropylcellulose LH 11 (L-HPC-LH-11) 1.67 5.01
4 Crospovidone 2.50 7.50
B. Binder Solution
5 Polyvinylpyrrolidone K-30 (PVP K-30) 8.00 24.00
6 Purified Water NA Q. S.
C. Blending
7 Crospovidone 2.50 7.50
D. Lubrication
8 Colloidal Silicone Dioxide (Aerosil 200) 1.00 3.00
9 Sodium Stearyl Fumarate 1.00 3.00
Final Weight 100.00 300.00

General Process for preparation for Example-1 to 6:
1. Favipiravir, Microcrystalline cellulose (PH 101), L-HPC and Crospovidone were weighed accurately and sieved through mesh #20 to obtain intra-granular blend;
2. PVP K30 was dissolved in purified water to obtain binder solution;
3. binder solution obtained in step-2 was used to granulate the intra-granular blend obtained in step-1 in rapid mixer granulator or fluidized bed dryer followed by drying of these granules;
4. the dried granules obtained in step-3 were blended and lubricated with remaining Crospovidone, Sodium Stearyl Fumarate and Colloidal silicon dioxide to obtain the final blend ready for the compression;
5. the final blend obtained in step-4 was then compressed to form tablets;
6. optionally, the tablets obtained in step-5 were coated with Opadry yellow to obtained the final finished product.

EXAMPLE-2:
Sr. No. Ingredients % w/w mg/tab
(For 400 mg)
A. Intragranular
1 Favipiravir 66.67 400.00
2 Microcrystalline Cellulose PH 101 16.66 99.98
3 Low substituted hydroxypropylcellulose LH 11 (L-HPC-LH-11) 1.67 10.02
4 Crospovidone 2.50 15.00
B. Binder Solution
5 Polyvinylpyrrolidone K-30 (PVP K-30) 8.00 48.00
6 Purified Water NA Q. S.
C. Blending
7 Crospovidone 2.50 15.00
D. Lubrication
8 Colloidal Silicone Dioxide (Aerosil 200) 1.00 6.00
9 Sodium Stearyl Fumarate 1.00 6.00
Final Weight 100.00 600.00

EXAMPLE-3:
Sr. No. Ingredients % w/w mg/tab
(For 600 mg)
A. Intragranular
1 Favipiravir 66.67 600.00
2 Microcrystalline Cellulose PH 101 16.66 149.97
3 Low substituted hydroxypropylcellulose LH 11 (L-HPC-LH-11) 1.67 15.03
4 Crospovidone 2.50 22.50
B. Binder Solution
5 Polyvinylpyrrolidone K-30 (PVP K-30) 8.00 72.00
6 Purified Water NA Q. S.
C. Blending
7 Crospovidone 2.50 22.50
D. Lubrication
8 Colloidal Silicone Dioxide (Aerosil 200) 1.00 9.00
9 Sodium Stearyl Fumarate 1.00 9.00
Final Weight 100.00 900.00

EXAMPLE-4:
Sr. No. Ingredients % w/w mg/tab
(For 800 mg)
A. Intragranular
1 Favipiravir 66.67 800.00
2 Microcrystalline Cellulose PH 101 16.66 199.96
3 Low substituted hydroxypropylcellulose LH 11 (L-HPC-LH-11) 1.67 20.04
4 Crospovidone 2.50 30.00
B. Binder Solution
5 Polyvinylpyrrolidone K-30 (PVP K-30) 8.00 96.00
6 Purified Water NA Q. S.
C. Blending
7 Crospovidone 2.50 30.00
D. Lubrication
8 Colloidal Silicone Dioxide (Aerosil 200) 1.00 12.00
9 Sodium Stearyl Fumarate 1.00 12.00
Final Weight 100.00 1200.00

EXAMPLE-5:
Sr. No. Ingredients % w/w mg/tab
(For 800 mg)
A. Intragranular
1 Favipiravir 80.00 800.00
2 Microcrystalline Cellulose PH 101 10.00 100.00
3 Low substituted hydroxypropylcellulose LH 11 (L-HPC-LH-11) 1.75 17.50
4 Crospovidone 1.00 10.00
B. Binder Solution
5 Polyvinylpyrrolidone K-30 (PVP K-30) 5.00 50.00
6 Purified Water NA Q. S.
C. Blending
7 Crospovidone 1.0 10.00
D. Lubrication
8 Colloidal Silicone Dioxide (Aerosil 200) 0.75 7.50
9 Sodium Stearyl Fumarate 0.50 5.00
Final Weight 100.00 1000.00

EXAMPLE-6:
Sr. No. Ingredients % w/w mg/tab
(For 400 mg)
A. Intragranular
1 Favipiravir 48.78 400.00
2 Microcrystalline Cellulose PH 101 34.55 283.31
3 Low substituted hydroxypropylcellulose LH 11 (L-HPC-LH-11) 1.67 13.69
4 Crospovidone 2.50 20.50
B. Binder Solution
5 Polyvinylpyrrolidone K-30 (PVP K-30) 8.00 65.60
6 Purified Water NA Q. S.
C. Blending
7 Crospovidone 2.50 20.50
D. Lubrication
8 Colloidal Silicone Dioxide (Aerosil 200) 1.00 8.20
9 Sodium Stearyl Fumarate 1.00 8.20
Final Weight 100.00 820.00

TEST EXAMPLE-1: ACCELERATED STABILITY TESTING:
Example-1 to 4 were tested for stability study testing. The products as per the present invention were placed under accelerated stability testing at conditions of 40°C and 75% RH.
Various parameters including % dissolution after 60 minutes, % assay and % total impurities were measured at least for six months which are reported as followed:
Parameters Initial After 3 months After 6 months
Example-1 (Tablets with 200 mg Favipiravir)
% Dissolution in 60 min 99.98 99.40 99.21
% Assay 100.30 100.17 100.11
% Total Impurities 0.134 0.189 0.192
Example-2 (Tablets with 400 mg Favipiravir)
Dissolution (%) in 60 min 100.03 100.00 98.70
% Assay 100.06 99.91 99.59
% Total Impurities 0.139 0.173 0.133
Example-3 (Tablets with 600 mg Favipiravir)
Dissolution (%) in 60 min 99.80 100.30 99.90
% Assay 99.60 99.51 99.46
% Total Impurities 0.131 0.162 0.128
Example-4 (Tablets with 800 mg Favipiravir)
Dissolution (%) in 60 min 95.90 97.70 96.40
% Assay 100.35 99.97 100.06
% Total Impurities 0.180 0.193 0.209

From above data, the inventors of the present invention surprisingly found that Favipiravir formulations prepared as per the preset invention are stable even after six months of accelerated stability testing.
The inventors of the present invention surprisingly found from the above data that Favipiravir tablets prepared as per the present invention underwent rapid and complete dissolution even after 6 months of storage at accelerated stability testing. In addition, % assay of the composition as per the present invention shown consistency proving it a stable dosage form in long term storage as well. Similar results were obtained with all the examples described in the present invention. Thus, the final product of the present invention is found as stable due to its unique composition which is not just a mere admixture but provides synergistic effect.
The invention described herein comprises in various objects as mentioned above and their description in relation to characteristics, compositions and process adopted. While these aspects are emphasised in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.
The above-mentioned examples are provided for illustrative purpose only and these examples are in no way limitative on the present invention.
,CLAIMS:We claim:
1. An oral composition of Favipiravir comprising of Favipiravir or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient, wherein amount of Favipiravir is not less than 250 mg per unit dose.

2. The oral composition of Favipiravir as claimed in claim 1, wherein amount of pharmaceutical excipients is not more than 35% w/w of total composition.

3. The oral composition of Favipiravir as claimed in claim 1, further comprising of at least one pharmaceutically acceptable excipient which is microcrystalline cellulose.

4. The oral composition of Favipiravir as claimed in claim 1 to 3, wherein concentration of microcrystalline cellulose is in the range of 15-35% w/w of total composition.

5. The oral composition of Favipiravir as claimed in claim 1 to 2, wherein concentration of binder(s) is not more than 10% w/w of total composition.

6. The oral composition of Favipiravir as claimed in claim 1 to 2, wherein concentration of disintegrant(s) is not more than 5% w/w of total composition.

7. The oral composition of Favipiravir as claimed in claim 1 to 2, wherein concentration of lubricant(s) is not more than 2% w/w of total composition.

8. Oral compositions of Favipiravir having formulas as followed:
Ingredients Strengths Per Unit Dosage Form (mg)
Favipiravir 400.00 600.00 800.00
Microcrystalline Cellulose 99.98 149.97 199.96
Low substituted hydroxypropyl cellulose 10.02 15.03 20.04
Crospovidone 30.00 45.00 60.00
Polyvinylpyrrolidone 48.00 72.00 96.00
Colloidal Silicone Dioxide 6.00 9.00 12.00
Sodium Stearyl Fumarate 6.00 9.00 12.00

9. A Process for preparing an oral composition of Favipiravir comprising following steps:
a) mixing Favipiravir, Microcrystalline cellulose, L-HPC and Crospovidone to obtain dry blend;
b) dissolving PVP K30 in purified water to obtain binder solution;
c) granulating dry blend obtained in step-a using binder solution prepared in step-b to obtain the granules which are followed by drying;
d) blending and lubricating dried granules obtained in step-c using Crospovidone, Sodium Stearyl Fumarate and Colloidal silicon dioxide to obtain final blend;
e) compressing the final blend obtained in step-d to form the tablets; or
f) optionally, filling the final blend obtained in step-d in to capsules.
g) optionally, coating the tablets obtained in step-e to produce final finished dosage form.

10. The oral composition of Favipiravir as claimed in claim 1 to 9, wherein Favipiravir is in amorphous form or crystalline form.