DESC:“NOVEL FAVIPIRAVIR PARENTERAL COMPOSITIONS AND METHOD OF MANUFACTURING THEREOF”

FIELD OF THE INVENTION:
The present invention relates to a novel parenteral pharmaceutical composition of Favipiravir or a pharmaceutically acceptable salt thereof. The present invention provides more stable composition and more efficient to provide high dosage of active ingredient in emergency conditions with efficient drug release. Further, the present invention discloses the process for preparation of the same. The present invention provides a stable, economical dosage form over existing dosage form.

BACKGROUND OF THE INVENTION:
Favipiravir is an antiviral medication used to treat influenza in Japan. Favipiravir is developed and manufactured by Toyama Chemical (Fujifilm group) approved as brand name Avigan for medication to treat influenza in Japan in 2014.
It is also being studied to treat a number of other viral infections. Like the experimental antiviral drugs (T-1105 and T-1106), it is a pyrazinecarboxamide derivative.
Favipiravir is chemically known as 5-fluoro-2-oxo-1H-pyrazine-3-carboxamide, having the molecular formula C5H4FN3O2 and molecular weight 157.1 g/mol and is structurally represented as below:

FAVIPIRAVIR
The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase. Other research suggests that Favipiravir induces lethal RNA transversion mutations, producing a nonviable viral phenotype. Favipiravir is a prodrug that is metabolized to its active form, Favipiravir -ribofuranosyl-5'-triphosphate (Favipiravir-RTP), available in both oral and intravenous formulations.
Now a days, worldwide pandemic has been caused due to novel coronavirus originated in China and then spread to almost countries world-wide and till today took lives of around 316,925 people due to deadly disease COVID-19 that occur due to novel strain of coronavirus.
An outbreak of 2019-nCoV infection has spread across the world. No specific antiviral drugs have been approved for the treatment of COVID-2019. In addition to the recommended antiviral drugs, such as interferon-?, lopinavir/ ritonavir, ribavirin, and chloroquine phosphate, some clinical trials focusing on virus RNA-dependent RNA polymerase (RdRp) inhibitors have been registered and initiated. Favipiravir, a purine nucleic acid analog and potent RdRp inhibitor approved for use in influenza, is also considered in several clinical trials.
In February 2020, Favipiravir was being studied in China for experimental treatment of the emergent COVID-19. Trials are also being planned in Japan. In March 2020, Italy approved the drug for experimental use against COVID-19 and has begun conducting trials in three regions most affected by the disease.
Favipiravir is approved as oral tablet of 200mg that needs to take as daily dose of 3600 mg as loading dose in form of a large size tablet. So, patient needs to take around 18 tablets per days to fulfil the requirements of 3600mg dose of per each day. However, this would be so difficult to take these number of tablets for patients who are in critical stage of disease due to high-viral dose or have critical health conditions. Further, tablets in oral dosage form needs time to be effective with high bioavailability instantly in critical state conditions of certain patients. So, in such instances, there is a need for novel dosage form that be effective instantly by high dissolution directly into blood stream of serious health condition patients.
JPH08291071 disclosed the stable composition for parenteral injection containing buprenorphine or its salt and production of the same composition.
US4696814 discloses parenteral phenytoin compositions made using polyvinylpyrrolidone with or without an alcoholic solvent system.
US20060228411 pertains to pharmaceutical compositions having improved dissolution profiles for drugs therein.
US9090571 discloses a pharmaceutical composition of Favipiravir or a pharmaceutically acceptable salt thereof wherein the composition comprising of with a meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide and the preparation of pharmaceutical composition in form of injection.
Favipiravir or a salt thereof has a superior antiviral activity and is useful as a therapeutic agent for viral infection as per disclosed in prior arts. However, Favipiravir has low solubility in water and thus making of parenteral dosage in form of an injection of Favipiravir is quite challenging for formulation scientists.
Therefore, there is a need for the development of an injectable preparation of Favipiravir or a salt thereof with superior solubility to provide high bio-availability of drug in blood stream to patient.
To overcome such problems, the present invention discloses a novel parenteral pharmaceutical composition of Favipiravir. The present inventors have prepared various parenteral formulations of Favipiravir by using pharmaceutically acceptable excipients. The parenteral pharmaceutical composition of present invention in form of an injection can be administered to patients having difficulty in oral administration, children and aged persons has been desired.
The present compositions include ready to use injection, lyophilized powder composition for injection and reconstituted injection.
So, the present invention composition overcoming the short comings associated with the prior-arts and having rapid penetration in blood stream that provide high bio-availability and good stability, without harmful side-effects associated with certain excipients.

OBJECT OF THE INVENTION:
The primary object of the present invention is to provide a novel parenteral pharmaceutical composition of Favipiravir or a pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide the superior solubility in water and useful as a drug substance of an injectable preparation.
Another object of the present invention is to provide the higher bio-availability of the drug in blood stream in critical high-viral dose in patients.
Yet another object of the present invention is to provide a pharmaceutical composition of Favipiravir that provides higher stability of the active ingredient in humidity and warm storage conditions.
Another object of the present invention is to provide an economical and advanced dosage form over existing dosage form with the use of minimal amount of excipients that leads to less side-effects.
Another object of the present invention is to provide a pharmaceutical composition for preventing, reducing, delaying the onset of, or delaying the progression of, direct viral damage to the vascular system, respiratory system and/or immune system, in a subject, wherein the viral infection is caused by a coronavirus.
Yet another object of the present invention is to provide a novel, easy process for preparation of parenteral dosage pharmaceutical compositions of Favipiravir or a pharmaceutically acceptable salt thereof.
Still another object of the present invention is to provide a parenteral pharmaceutical composition comprising Favipiravir for the use in the treatment of viral infection including influenza and coronavirus in form of an injection that can be administered to patients having difficulty in oral administration, children and aged persons.
Another object of the present invention is to provide various parenteral pharmaceutical composition dosage for ready to use injection, lyophilized powder composition and reconstituted injections.
Another object of the present invention is to provide for the parenteral pharmaceutical composition comprising Favipiravir for fast recovery in patient who are in critical condition.

SUMMARY OF THE INVENTION:
The present invention discloses a novel parenteral pharmaceutical composition of Favipiravir or pharmaceutical salt thereof along with pharmaceutically acceptable excipients. The present invention compositions include ready to use injection, lyophilized powder composition for injection and reconstituted injection.
So, the present invention composition provides rapid release in blood stream that leads to high bio-availability and good stability, without harmful side-effects associated with certain excipients.
More preferably, the pharmaceutical composition comprising Favipiravir according to the present invention may be administered in a parenteral form of injection. The present invention compositions are administered by injection of various types that are intravenous (into a vein), subcutaneous (under the skin), and intramuscular (into muscle).
The pharmaceutical composition according to the present invention is economical and advanced dosage form over existing dosage form. It uses minimal amount of excipients that leads to less side-effects effects.
The present invention also discloses very simple process of preparation of pharmaceutical composition that is time efficient, especially for large-scale production, wherein the pharmaceutical composition shows a desired higher stability.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention also discloses novel parenteral pharmaceutical composition of Favipiravir or a pharmaceutically acceptable salt thereof. Parenteral drugs are most commonly administered as an injection without entering the mouth, stomach, intestines, rectum or respiratory tract. These are more widely used dosage forms for emergency situations for reason like it allows medication to be directly absorbed into the body quickly and more predictably.
The parenteral pharmaceutical composition of present invention in form of an injection can be administered to patients having difficulty in swallowing oral administration, children and aged persons or persons with critical conditions.
Parenteral administration of the present invention compositions includes intramuscular, subcutaneous, intravenous, and intradermal injection. The present invention also provides effective method for preventing diseases caused by viral infections includes influenza virus, coronavirus and the method comprising a step of administering a therapeutically effective amount of the composition to a subject having the disease.
In accordance with the present invention, a novel pharmaceutical composition comprising Favipiravir as an active ingredient and one or more pharmaceutically acceptable excipients including buffering agents, antioxidants, solubilizing agents, preservatives but not limited thereof.
In one preferable embodiment of the present invention, the present invention compositions may usually be administered by parenteral way of injection, intravenous drips, and administration to a rectal site to an adult in one to several divided dose(s) at dose(s) of an active ingredient in range selected from 250 to 1500 mg/kg per adult per day may be administered.
The dose of an active ingredient is generally determined in reference with dosage form, age and gender of a patient, conditions of a disease and other conditions. In the injectable preparation of the present invention, the dose of active ingredient Favipiravir or salt thereof is 250 to 1500 mg that may include dosages of 250 mg, 500 mg, 1000 mg, 1500 mg.
In one preferable embodiment of the present invention, the present invention compositions may usually be administered parenteral by way of injection, wherein the dosage of the drug Favipiravir or salt there in the range of 250mg to 1500 mg of active ingredient along with other pharmaceutically accepted excipients. In this, intravenous Favipiravir is administered for 7 to 14 days with maintenance doses to patients.
In one embodiment of the present invention, the pharmaceutical composition is prepared in lyophilized form for injection.
In the present invention, a superior lyophilized preparation can be produced by adding suitable excipients to an aqueous solution of drug to be subjected to lyophilization.
The lyophilized preparation are easily stored for long term without degradation of the active ingredient, also it can be maintained in aseptic conditions and from which insoluble foreign bodies can be easily removed. Therefore, the lyophilized preparation of injection is having high reliability, solubility and usability.
In the present invention, a process for producing a lyophilized preparation of Favipiravir includes the steps: (1) making and cooling the aqueous solution containing Favipiravir or salt thereof to produce a frozen product; (2) increasing the temperature of the frozen product; (3) further cooling the frozen product; and (4) carrying out lyophilization. The process can produce a lyophilized preparation of Favipiravir or salt thereof, which show high bioavailability.
In the above process for preparation of lyophilized preparation, wherein the temperature of the frozen product is maintained in the range of -20 to -5°C in the step of increasing the temperature of the frozen product. By maintaining the temperature in this range, high standard lyophilized product can be achieved.
In another embodiment of the present invention, a lyophilized preparation of a crystal of salt of Favipiravir can be produced which shows high dissolution. In this process, crystallization temperature is controlled in a range by providing a step of increasing temperature after the primary freezing of lyophilization. The resultant crystal has high solubility in water and significantly high dissolution rate. In the lyophilization process, freezing of Favipiravir is performed at -40° C or below. An injectable preparation can be produced by filling a vial, etc. with the crystal of drug and/or the milled crystal of the drug.
In the process for producing the lyophilized preparation of the present invention, a sterilization is carried out in accordance with the any conventional procedure employed.
Further, certain excipients are added to the lyophilized preparation of Favipiravir of the present invention for improving solubility and/or appearance with stability of the product for long duration.
Examples of the excipients include amino acids, saccharides, Sugar alcohols, salts, urea, ethyl urea, creatinine, nicotinic acid amide and trometamol. These may be used alone or as a mixture of two or more types. Examples of preferable additives include amino acids, saccharides, sugar alcohols, salts, urea, creatinine, nicotinic acid amide and trometamol.
Furthermore, conventional excipients, such as an osmo-regulator, a pH regulator, a buffer, a solubilizer, a stabilizer, a surfactant, a soothing agent, and/or a preservative, may be added to the preparation of the present invention.
The excipients used in the present composition are as listed above; however, it is not limited to the said excipients only.
In further aspect of the present invention, osmo-regulator may be selected from the group consisting of but not limited to sodium chloride, glycerin and propylene glycol.
In one aspect of the present invention, the pH regulator and/or the buffer may be selected from the group consisting of but not limited to acids such as hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, lactic acid, maleic acid, citric acid, tartaric acid, ascorbic acid and benzoic acid; salts such as sodium bicarbonate, sodium carbonate, sodium dihydrogenphosphate, potassium dihydrogenphosphate, disodium hydrogenphosphate, dipotassium hydrogenphos phate, trisodium phosphate, disodium citrate and sodium sulfite; and bases such as sodium hydroxide, trometamol. monoethanolamine, diethanolamine and triethanolamine.
In another aspect of the present invention, solubilizer may be selected from the group consisting of but not limited to macrogol and purified soybean lecithin.
In another aspect of the present invention, the stabilizer may be selected from the group consisting of but not limited to sodium hydrogen sulfite, sodium pyrosulfite, potassium pyrosulfite, sodium pyrophosphate, sodium thiosulfate, sodium metasulfoben zoate, sodium formaldehyde sulfoxylate, ethylene diamine, edetate sodium, thioglycolic acid, sodium gluconate, potassium L-glutamate, L-lysine-L-glutamate, sodium chondroitin sulfate, albumin, L-aspartic acid, L-cysteine and dibutylhydroxytoluene, mannitol, reducing sugars like lactose, glucose, fructose, galactose, glucose, glyceraldehyde, ribose, and xylose; L-arginine and L-lysine.
In another aspect of the present invention, the surfactant may be selected from the group consisting of but not limited to sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene Sorbitan monolaurate, polyoxyethylene polyoxypropylene glycol and polysorbate.
In one aspect of the present invention, the soothing agent may be selected from the group consisting of but not limited to lidocaine, procaine, meprylcaine and benzyl alcohol.
In one aspect of the present invention, the preservative may be selected from the group consisting of but not limited to cresol, phenol, methyl paraoxybenzoate, ethyl paraoxybenzoate, benzalkonium chloride and benzethonium chloride.
In an injectable preparation of the present invention, the excipients used are to be added for improving solubility in range from 0.1 to 115% (w/w) compare to the content of Favipiravir or salt thereof.
In another embodiment of the present invention, the pharmaceutical composition is prepared in ready to use form for injection solution.
In the present invention, a ready-to-use liquid pharmaceutical composition of Favipiravir is also prepared. This preparation provides an improved physiological tolerance and easy to handle in need of emergency as it can be used directly without any need of reconstitution. For example, the ready-to-use solution according to the present invention can be used directly, i. be administered without further preparation or only after a further preparation, such as a dilution to a desired drug concentration.
A ready-to-use liquid pharmaceutical solution of Favipiravir comprising an aqueous solvent, a Favipiravir which is contained in the solvent, is provided. So, present invention provides a ready to use liquid pharmaceutical composition of Favipiravir, comprising an aqueous solvent and drug that is dissolved in the solvent.
In one embodiment of the present invention, Favipiravir is used in ester form and then dissolved in an aqueous solvent to provide highly stable ready to use liquid pharmaceutical composition with high physiological tolerance with long storage capacity.
Ready-to-use active ingredient-containing solutions are known in the art and are referred to there as ready-to-use (RTU) solutions. The ready-to-use solution according to the invention comprises aqueous solvent. In the context of the present invention, an aqueous solvent is a solvent or a solvent mixture of individual components which are liquid at a temperature of 20° C, at least 50 wt. % consists of water, preferably at least 70 wt. % of water, more preferably at least 90% by weight of water and even more preferably at least 95% by weight % of water.
In this context, if the solvent is at least 99 wt. % consists of water and even more preferably 100 wt. % of water. In addition to water, the solvent of the solution according to the invention may further contain a certain proportion of one or more water-miscible liquid organic components. As examples of such organic components may be mentioned ethanol and isopropanol.
According to a further preferred embodiment of the present invention, the Favipiravir is dissolved in the solution comprising of the suitable solvent. In this, Favipiravir may be used in ester form wherein ester formation component is selected from the group consisting of arabitol, dulcitoi, erythritol, mannitol, ribitol, sorbitol and xylitol and in particular from the group consisting of mannitol, sorbitol and xylitol, with mannitol.
According to the present invention, it is provided that at least 90% of the Favipiravir contained in the solution is in the form of an ester, more preferably at least 95% and even more preferably at least 99%. This will give relatively high stability of the inventive solution.
According to a further preferred embodiment of the invention, it is provided that the solution has a pH in a range from 2 to 9. Generally, for adjusting the pH of the solution according to the present invention use of hydrochloric acid or sodium hydroxide, depending on which pH should be adjusted.
According to a further preferred embodiment of the invention, a method of making a ready-to-use liquid pharmaceutical composition of Favipiravir solution comprising the steps of but not limited to:
a) providing an aqueous solvent;
b) dissolving Favipiravir or a pharmaceutically acceptable salt thereof in the solvent;
c) reducing the oxygen content of the solvent.

According to a further preferred embodiment of the present invention, it is provided that the solution is suitable for parenteral administration, preferably for intravenous and / or subcutaneous administration.
In another embodiment of the present invention, the pharmaceutical composition of Favipiravir or salt thereof is prepared in form of concentrated solution for injection. The concentrated solutions are diluted with water for injection before they are administered through injection or through intravenous infusion.
In yet another embodiment, the present invention injectable formulation comprising Favipiravir free base or salt thereof and a pharmaceutically acceptable excipients selected from carrier, a lyoprotectant, an anti-oxidant, a stabilizer and antimicrobial preservative.
In yet another embodiment of the present invention, the of concentrated solution for injectable formulation preparation of Favipiravir includes following steps but not limited to:
a) prepare bulk solution by adding all excipients and API in pharmaceutically acceptable water, attain dissolve oxygen level;
b) attain the require pH of the solution;
c) filter and fill in the vial;
d) sterilize the solution by sterilization.
In one aspect of the present invention, the lyoprotectant may be selected from the group consisting of but not limited to sugars such as sucrose any other sugars.
In one aspect of the present invention, the antioxidants may be selected from the group consisting of but not limited to ascorbic acid, acetylcysteine, sulfurous acid salts (bisulfite, metabisulfite), monothioglyercol, disodium EDTA etc.
In one aspect of the present invention, the antimicrobial agents may be selected from the group consisting of but not limited to Phenol, meta-cresol, benzyl alcohol, parabens (methyl, propyl, butyl), benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric salts (acetate, borate, nitrate) etc.
In one aspect of the present invention, the preservatives may be selected from the group consisting of but not limited to benzyl alcohol, methylparaben propylparaben, etc.
The formulation of present invention may comprise pH adjusting agent may include sodium hydroxide, hydrochloric acid, sodium carbonate, citric acid, tromethamine, potassium hydroxide, sodium citrate etc.
In one aspect of the present invention, water for injection, any suitable solvent, etc. is used as a vehicle.
In one aspect of the present invention, the injectable formulation may be prepared by first charging a vessel with water and addition of lyoprotectant. Then, respectively acid, antioxidant, preservative is added. Then, pH was adjusted using acid or base, as appropriate. The weight of the resulting solution was adjusted with additional water. The mixture was then filtered through a sterile filter. Suitable type of glass vials was then filled with the appropriate amount of the solution per vial.
In another embodiment of the present invention, injectable formulations are packaged into containers made of glass or plastic, container systems include ampoules, vials, syringes, cartridges, bottles, and bags as per the requirement.
The present invention can be described by way of example or strategy only. It is to be recognized that modifications falling within the scope and spirit of the description or claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this disclosure.

EXAMPLES:
Example-1:
Favipiravir lyophilized formulation preparation:
1) A suspension of Favipiravir in water was prepared. After that, suitable solvent was added dropwise. The mixture was cooled and stirred. A solid substance was collected by filtration.
2) To a suspension of Favipiravir was added in water for Injection, and the mixture was stirred to dissolve Favipiravir. Then, the mixture was filtered through a membrane filter to obtain a liquid preparation.
3) Each vial was filled with the liquid preparation, lyophilized and then closed airtight to obtain a lyophilized preparation of product.

Lyophilization method used in preparation of product of above step-3 as below:
1) Vials were cooled at the temperature of around -60° C. to freeze the content;
2) The temperature of the vials was increased to the temperature of -20°C. under vacuum and the vials were maintained at the same pressure and the same temperature for 64 hours;
3) The temperature of the vials was increased to the temperature of -10°C. and the vials were maintained at the same pressure and the same temperature for 7 hours;
4) The temperature of the vials was increased to the shelf temperature of 0° C. and the vials were maintained at the same pressure and the same temperature for 11 hours;
5) The temperature of the vials was increased to the shelf temperature of 20° C. and the vials were maintained at the same pressure and the same temperature for 10 hours;
6) The temperature of the vials was increased to the shelf temperature of 40° C. and the vials were maintained at the same pressure and the same temperature for 17 hours.

Example-2: Lyophilized formulation:
Sr. No. Ingredient Mg/Unit mg/mL
1 Favipiravir 600 60.00
2 1N NaOH Solution QS QS
3 10 % Citric acid QS QS
4 WFI (ml) QS to 10 1

Process for preparation:
1. Water for injection was taken in a vessel followed by addition of Favipiravir;
2. the solution obtained in step-1 was then stirred properly and pH was checked;
3. pH of the solution obtained in step-2 was adjusted to 7.5 to 8.5 using 1 N NaOH solution or 10% Citric Acid solution to get the clear solution;
4. clear solution obtained in step-3 was then subject to lyophilize to get the final product.

Example-3: Lyophilized formulation:
Sr. No. Ingredient Mg/Unit mg/mL
1 Favipiravir 600 60.00
2 Mannitol 600 60.00
3 1N NaOH Solution QS QS
4 10 % Citric acid QS QS
5 WFI (ml) QS to 10 1

Process for preparation:
1. Water for injection was taken in a vessel followed by addition of mannitol and then followed by Favipiravir;
2. the solution obtained in step-1 was then stirred properly and pH was checked;
3. pH of the solution obtained in step-2 was adjusted to 7.5 to 8.5 using 1 N NaOH solution or 10% Citric Acid solution to get the clear solution;
4. clear solution obtained in step-3 was then subject to lyophilize to get the final product.

Example-4: Lyophilized formulation:
Sr. No. Ingredient Mg/Unit mg/mL
1 Favipiravir 600 60.00
2 L-Arginine 100 10.00
3 1N NaOH Solution QS QS
4 10 % Citric acid QS QS
5 WFI (ml) QS to 10 1

Process for preparation:
1. Water for injection was taken in a vessel followed by addition of L-arginine and then followed by Favipiravir;
2. the solution obtained in step-1 was then stirred properly and pH was checked;
3. pH of the solution obtained in step-2 was adjusted to 7.5 to 8.5 using 1 N NaOH solution or 10% Citric Acid solution to get the clear solution;
4. clear solution obtained in step-3 was then subject to lyophilize to get the final product.

Example-5: Lyophilized formulation:
Sr. No. Ingredient Mg/Unit mg/mL
1 Favipiravir 600 60.00
2 Meglumine 800 80.00
3 Lactose 200 20.00
4 1N NaOH Solution QS QS
5 10 % Citric acid QS QS
6 WFI (ml) QS to 10 1

Process for preparation:
1. Water for injection was taken in a vessel followed by addition of lactose, meglumine and then followed by Favipiravir;
2. the solution obtained in step-1 was then stirred properly and pH was checked;
3. pH of the solution obtained in step-2 was adjusted to 7.5 to 8.5 using 1 N NaOH solution or 10% Citric Acid solution to get the clear solution;
4. clear solution obtained in step-3 was then subject to lyophilize to get the final product.

Example-6: Liquid formulation:
Sr. No. Ingredient Mg/Unit mg/mL
1 Favipiravir 600 40.00
2 Monothioglycerol 10 0.67
4 1N NaOH Solution QS QS
5 10 % Citric acid QS QS
6 WFI (ml) QS to 15 1.5

Process for preparation:
1. Water for injection was taken in a vessel followed by addition of monothiol glycerol and then followed by Favipiravir;
2. the solution obtained in step-1 was then stirred properly and pH was checked;
3. pH of the solution obtained in step-2 was adjusted to 7.5 to 8.5 using 1 N NaOH solution or 10% Citric Acid solution to get the clear solution;
4. The above liquid injection was subjected to terminal sterilization to obtain the final product.

Example-7: Liquid formulation:
Sr. No. Ingredient Mg/Unit mg/mL
1 Favipiravir 600 40.00
2 Disodium EDTA 10 0.67
4 1N NaOH Solution QS QS
5 10 % Citric acid QS QS
6 WFI (ml) QS to 15 1.5

Process for preparation:
1. Water for injection was taken in a vessel followed by addition of disodium EDTA (Ethylene diamine tetra acetate) and then followed by Favipiravir;
2. the solution obtained in step-1 was then stirred properly and pH was checked;
3. pH of the solution obtained in step-2 was adjusted to 7.5 to 8.5 using 1 N NaOH solution or 10% Citric Acid solution to get the clear solution;
4. The above liquid injection was subjected to terminal sterilization to obtain the final product.

TEST EXAMPLE-1:
ACCELERATED STABILITY TESTING FOR LYOPHILIZED COMPOSITION:
Example-2 to 5 were tested for stability study testing. The products as per the present invention were placed under accelerated stability testing at conditions of room temperature.
Various parameters including % assay and pH were measured at least for six months which are reported as followed:
Parameters Initial After 3 months After 6 months
Example-2
% Assay 99.94 98.45 96.45
pH 8.00 8.15 8.60
Example-3
% Assay 99.86 99.01 97.38
pH 8.10 8.25 8.40
Example-4
% Assay 99.95 99.15 98.18
pH 8.05 8.15 8.30
Example-5
% Assay 99.98 99.91 99.25
pH 8.10 8.10 8.20

TEST EXAMPLE-2:
ACCELERATED STABILITY TESTING FOR LIQUID COMPOSITION:
Example-6 to 7 were tested for stability study testing. The products as per the present invention were placed under accelerated stability testing at conditions of 2-8°C.
Various parameters including % assay and pH were measured at least for six months which are reported as followed:
Parameters Initial After 3 months After 6 months
Example-6
% Assay 99.94 99.11 98.62
pH 8.15 8.25 8.40
Example-7
% Assay 99.86 99.56 98.75
pH 8.00 8.15 8.30

The inventors of the present invention have observed in Example-2 that % assay and pH was maintained properly; however, with due course of time, the stability of the product was very less. % Assay was reduced drastically. The inventors of the present invention have then used non-reducing sugar like mannitol. However, still stability of the final lyophilized product was not up to the mark. Therefore, the inventors of the present invention have also added stabilizer like L-Arginine to stabilize the composition and found that stability was increased at some extent. Surprisingly, when the inventors of the present invention used reducing sugar like lactose in combination with Meglumine, they found it very stable even at six months stability study. Hence, the inventors of the present invention have invented a composition having synergistic effect which helps to increase stability.
The inventors of the present invention have also developed liquid injections similar to that of lyophilized injections. From the results, it was surprisingly found that liquid injections are also stable similar to that of lyophilized injection; however, storage needs to be done at 2-8°C.
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. A lyophilized parenteral composition of Favipiravir comprising of:
a) Favipiravir and pharmaceutically acceptable salt thereof;
b) at least one reducing sugar; and
c) at least one stabilizer.

2. The lyophilized parenteral composition of Favipiravir as claimed in claim 1, wherein reducing sugar is selected form the group of lactose, glucose, fructose, galactose, glucose, glyceraldehyde, ribose, xylose and mixture thereof; preferably, lactose.

3. The lyophilized parenteral composition of Favipiravir as claimed in claim 1, wherein stabilizer is selected from meglumine, L-arginine, L-lysine and mixture thereof; preferably, meglumine or L-arginine.

4. A lyophilized parenteral composition of Favipiravir comprising of:
a) Favipiravir and pharmaceutically acceptable salt thereof; and
b) L-Arginine or Meglumine.

5. A liquid parenteral composition of Favipiravir comprising of:
a) Favipiravir and pharmaceutically acceptable salt thereof; and
b) Monothioglycerol or disodium EDTA.

6. A lyophilized parenteral composition of Favipiravir having following formula:
Sr. No. Ingredient mg/mL
1 Favipiravir 60.00
2 Meglumine 80.00
3 Lactose 20.00
4 1N NaOH Solution QS
5 10 % Citric acid QS
6 WFI (ml) QS to 1

7. A lyophilized parenteral composition of Favipiravir having following formula:
Sr. No. Ingredient mg/mL
1 Favipiravir 60.00
2 L-Arginine 10.00
3 1N NaOH Solution QS
4 10 % Citric acid QS
5 WFI (ml) QS to 1

8. A lyophilized parenteral composition of Favipiravir having following formula:
Sr. No. Ingredient mg/mL
1 Favipiravir 60.00
2 Mannitol 60.00
3 1N NaOH Solution QS
4 10 % Citric acid QS
5 WFI (ml) QS to 1

9. A liquid parenteral composition of Favipiravir having following formula:
Sr. No. Ingredient mg/mL
1 Favipiravir 40.00
2 Monothioglycerol 0.67
4 1N NaOH Solution QS
5 10 % Citric acid QS
6 WFI (ml) QS to 1.5

10. A liquid parenteral composition of Favipiravir having following formula:
Sr. No. Ingredient mg/mL
1 Favipiravir 40.00
2 Disodium EDTA 0.67
4 1N NaOH Solution QS
5 10 % Citric acid QS
6 WFI (ml) QS to 1.5