DESC:
FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

1.Title of the invention – LIQUID ORAL SUSPENSION OF FAVIPIRAVIR
2. Applicant(s)
NAME: AUXILLA PHARMACEUTICALS AND RESEARCH LLP
NATIONALITY: Indian
ADDRESS: Plot no. 194, Medows 2, Gokuldham, Village Sanathal, TA: Sanathal, Ahmedabad-382110, Gujarat, INDIA

3. PREAMBLE TO THE DESCRIPTION

The following specification particularly describes the invention and the manner in which it is to be performed

LIQUID ORAL SUSPENSION OF FAVIPIRAVIR

FIELD OF THE INVENTION

The present invention is all about a liquid oral suspension of Favipiravir. Particularly the present invention relates to liquid oral suspension of Favipiravir comprising Favipiravir and glycerin, the pH of the composition is 4 to 8. The present invention also relates to process for preparing the liquid oral suspension of Favipiravir.

BACKGROUND OF THE INVENTION

COVID-19, short for "coronavirus disease 2019," is the official name given by the World Health Organization to the disease caused by this newly identified coronavirus.

The COVID-19 is believed to be spread mainly from person to person. This can happen between people who are in close contact with one another. When infected person sneezes or coughs, may spread the droplets which can become also the concern for infection spread. Infected person may emit aerosols when they talk or breathe. A person even with asymptomatic infection may emit vey micro particles when they talk or breathe. Such microparticles are infectious viral particles that can float or drift around in the air for up to three hours. Another person can breathe in these aerosols and become infected with the COVID-19. COVID-19 can also spread from contact with infected surfaces or objects. Regarding the fatality rate, it appears that the risk of death with the pandemic COVID-19 infection (commonly estimated at about 1%) is far less than it was for SARS (approximately 11%) and MERS (about 35%), but will likely be higher than the risk from seasonal flu (which averages about 0.1%).

The current ongoing pandemic of COVID-19 caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for its prevention and treatment. COVID-19 has a spectrum of manifestations including early stage of mild illness dominated by virological response while the late phase of severe and critical illness dominated by dysregulated immunological response

In summary, the COVID-19 has been declared as pandemic and day by day number of cases are increasing globally and, on another side, all possible efforts are going on to identify effective treatment for COVID-19 by identifying new drug molecule, evaluating already approved drugs and development of vaccine. However, till date no any effective treatment or vaccine available.

Favipiravir (6-Fluoro-3-hydroxypyrazine-2-carboxamide), a purine nucleic acid analog that has been developed by Toyama Chemical in Japan for a treatment of viral infections including influenza and structurally can be represented as below;

Favipiravir has recently been evaluated and was found to be a promising choice in management of COVID-19. It works by inhibiting RNA dependent RNA polymerase (RdRp) enzyme, a key enzyme impeding replication of RNA viruses

Favipiravir is a pro-drug that is ribosylated and phosphorylated intracellularly to form the active metabolite Favipiravir ribofuranosyl-5'-triphosphate (Favipiravir- RTP). Favipiravir -RTP competes with purine nucleosides and interferes with viral replication by incorporating into the nascent viral RNA triggering inhibition of error-prone viral RdRp, leading to Chain termination and Viral mutagenesis.

Favipiravir is available as tablet dosage form in the strength of 200 mg and 400 mg.

CN105687152B discloses Favipiravir quick-release medicinal preparation, wherein a tablet comprises the following raw and auxiliary materials in parts by weight: 200 parts of Favipiravir; microcrystalline cellulose PH-102100-200 parts; 5-10 parts of a solubilizer; 20-50 parts of a disintegrating agent; 2-10 parts of a lubricant and 5-20 parts of a glidant.

CN111249229A discloses a stable Favipiravir injection and a preparation method thereof, wherein the injection comprises Favipiravir and a solubilizer, namely sulfobutyl ether- ß -cyclodextrin sodium, and can also comprise an acid-base regulator. Particularly the stable injection provided by the invention comprises Favipiravir, a solubilizing agent sulfobutyl ether- ß -cyclodextrin Sodium (SBECD), and a small amount of an acid-base regulator.

CN102348458B describes a tablet of Favipiravir with low-substituted hydroxypropyl cellulose or cross-linking sodium carboxymethyl cellulose and binding agent.

The dosage regimen of Favipiravir is very difficult to adhere. The 200 mg dosage of Favipiravir required patients to take 18 tablets on Day 1 (nine in the morning and nine in the evening), followed by eight tablets each day thereafter for a maximum of 14 days. With the new 400 mg version, patients need to consume nine tablets on Day 1 (4.5 in the morning and 4.5 in the evening), and thereafter two tablets twice a day from Day 2 till the end of the course.

Such dosage regimen is quite difficult to follow, especially for children and geriatric patients. Further children and geriatric patient was having the swallowing difficulties, such dosage regimen will lead to patient non-compliance and missing of dosage which ultimately lead to ineffective treatment.

There remains an enduring difficulty for patients, care takers and healthcare professionals (particularly those looking after children) with the administration of Favipiravir as currently there is no entirely suitable formulation available.

In summary, three major problems have been identified with the currently marketed Favipiravir tableted formulations. These are a lack of accuracy and flexibility in dosing, problems of administration and compliance.

Therefore, there is a need to develop a liquid dosage form or formulations which is ready to use for oral administration and also easy to titrate the dosage.

In summary there is still exist a need to have a ready to use liquid oral formulation of Favipiravir which overcomes all problems as mentioned in prior art.

The inventors in the present inention have arrived to the liquid oral suspension of Favipiravir with aims to ameliorate one or more of problems cited in above prior arts by preparing a liquid oral suspension of Favipiravir as described herein.

OBJECTIVES OF THE INVENTION

First objective of the present invention is to design and develop a liquid oral suspension of Favipiravir.

Another objective of the present invention is to provide a liquid oral suspension of Favipiravir which is ready to use for oral administration.

Yet another objective of the present invention is to provide liquid oral suspension of Favipiravir for the treatment of COVID-19.

Yet another objective of this invention is to provide an alternative dosage form to solid tablet formulation.

Yet another objective of this invention is to provide a liquid oral suspension of Favipiravir to overcome problems of patient non-compliance to children and geriatric patients.

Yet another objective of this invention is to provide a liquid oral suspension of Favipiravir which is stable.

Yet another objective of the present invention is to provide a liquid oral suspension of Favipiravir which exhibits bio equivalency against marketed tablet formulations.

SUMMARY OF THE INVENTION

The present invention is all about to provide a liquid oral suspension of Favipiravir.

The main aspect of the present invention is to provide liquid oral suspension of Favipiravir comprising Favipiravir, Glycerin and where Glycerin is more than 60% w/w, purified water is less than 40% w/w and the pH of the suspension is 4 to 6.

One more aspect is to provide a method for the treatment of COVID-19 in a human patient comprising administration of a therapeutically effective amount of a liquid oral suspension composition comprising Favipiravir, one or more buffering agent, stabilizing agent, wetting agent, suspending agent and one or more inactive ingredients.

In another aspect the present invention provides a process for the preparation of a liquid oral suspension of Favipiravir.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention overcomes the aforesaid drawbacks of the above, and other objects, features and advantages of the present invention will now be described in greater detail. Also, the following description includes various specific details and are to be regarded as merely exemplary. Accordingly, those of ordinary skill in the art will recognize that: without departing from the scope and spirit of the present disclosure and its various embodiments there may be any number of changes and modifications described herein.

The present invention relates to a liquid oral suspension of Favipiravir.

The non-aqueous suspension of the present invention represents an ideal dosage form to get freedom from complex dosage regimen and patient non-compliance.

The liquid oral suspension of present invention as described herein provide ready to use liquid oral suspension of Favipiravir.

As used in this document, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

Nothing in this disclosure is to be construed as an admission that the embodiments described in this disclosure are not entitled to antedate such disclosure by virtue of prior invention. As used in this document, the term "comprising" means "including, but not limited to."

"Optional" or "optionally' means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

As used herein the term “ready to use” or “ready to dilute” means the suspension is either to be used directly for oral administration without any reconstitution or just need to dilute in to the vehicle/water to adjust the dose before administration.

As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub ranges and combinations of sub ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, et cetera As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, et cetera As will also be understood by one skilled in the art all language such as “up to,” “at least,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

As used herein term “formulation” or “composition” or “dosage” conveys the same meaning and can be used interchangeably.

As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is being used.

"Administering" when used in conjunction with a therapeutic means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted.

The term "subject" as used herein includes, but is not limited to, humans and on-human vertebrates such as wild, domestic, and farm animals. In certain embodiments, the subject described herein is an animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a non-human mammal.

By "pharmaceutically acceptable", it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the topical formulation and not deleterious to the recipient thereof.

As used herein, the term "therapeutic" means an agent utilized to treat, combat, inhibit, ameliorate, prevent or improve an unwanted condition or disease of a patient.

A 'therapeutically effective amount" or "effective amount" of a composition is a predetermined amount calculated to achieve the desired effect, i.e., to induce a favorable therapeutic response.

The “liquid composition,” includes ready-to-use liquid composition or reconstituted liquid composition. The ready-to-use liquid composition comprises a solution, a suspension, a syrup, a concentrate, an elixir or an emulsion or like. The liquid oral compositions comprises solution and/or suspension which is comprising of dry powder pellets, granules, beads or the like. More the liquid composition is a suspension.

As per main embodiment, the present invention is all about a liquid oral suspension of Favipiravir comprising Favipiravir, Glycerin and where Glycerin is more than 60% w/w, purified water is less than 40% w/w and the pH of the suspension is 4 to 6.

As per one embodiment, Favipiravir is having specific particle size for the present invention. Particle size plays an important role in the formulation, especially in to the formulation development of suspension formulation. As per one embodiment, the Favipiravir is having the particle size in term of D90 in the range from 10 to 200 ?m, preferably in the range from 10 to 150 ?m.

As per one main embodiment the present invention is a liquid oral suspension of Favipiravir.

According to one preferred embodiment the a liquid oral suspension of Favipiravir comprising Favipiravir, Glycerin, wherein Glycerin is more than 60% w/w, purified water is less than 40% w/w and the pH of the suspension is 4 to 6.

The Favipiravir can be present in the suspension of present invention in an amount from about 10 to 1000 mg/mL, preferably in the range from about 10 to about 750 mg/mL , preferably in the range from about 10 to about 500 mg/mL, more preferably in the range from about 20 to 500 mg/mL, more preferably in the range from about 30 to 500 mg/mL, more preferably in the range from about 40 to 500 mg/mL, more preferably in the range from about 50 to 500 mg/mL or any other range in between thereof.

The stabilizing agent act as the main and critical ingredient to the formulation of present invention. The stabilizing agent make the formulation stable and effective. The stabilizing agent also helps the suspension of present invention more soluble when diluted and at the same time make it stable without increase in degradation.

As used herein the components and the ingredients used in the present invention are having their own properties which are subjected to target the stability of the liquid oral suspension of Favipiravir.

According to one preferred embodiment the stabilizer in the present invention plays a critical role as to make the formulation stable. The specific type of stabilizer used is dependent on the specific concentration to make the present invention stable at the claimed pH.

For present invention, stabilizing agent can be selected from glycerin, polyethylene glycol, propylene glycol, ethanol, medium chain triglycerides, N-methyl pyrrilidone, and Dimethyl sulfoxide. As per preferred embodiment, the stabilizing agent is glycerin.

As per preferred embodiment, the stabilizing agent is glycerin and is to be used in concentration of more than 60% w/w, preferably more than 70%.

As per one preferred embodiment the stabilizer i. e glycerin used herein is for stabilizing the liquid oral suspension of Favipiravir at the mentioned concentration which is the target to be achieved to have a stable liquid oral suspension of Favipiravir. It is known to person skilled in art that the specific ingredients in specific concentration gives the stability and so the person skilled in art can know that in the present invention the stabilizer i.e glycerin plays essential role to stabilize the present invention.

Vehicle for present invention can be used as a base for present invention. Vehicle can be considered as any inert substance, or mixture of substances, added to increase the volume of the liquid composition of present invention in order to make the liquid suspension of the present invention suitable form. The vehicle used in the suspension of the invention is preferably water, although other suitable water-containing (aqueous) vehicles known to the skilled person may also be used.

In an embodiment the water is used as a vehicle in the present invention which is having a property of the degradation, it is known to a person skilled in art that the water and its properties can be leading to degradation of the formulation. The use of the water as a vehicle in the specific quantity is made to target a stable liquid oral suspension of Favipiravir. It is known to a person skilled in the art that use of water in the specific quantity is leading to have a degrading property and thus the use of specific quantity of water in the present invention is essential to have a stable liquid oral suspension of Favipiravir.

In or more preferred embodiment the suspension is comprising of ingredients comprising suspending agent, anti-foaming agent, dispersing agent, wetting agent, buffering agent, and one or more inactive ingredients.

According to one preferred embodiment the suspension is comprising of Sodium carboxy methyl cellulose, Microcrystalline cellulose and carboxy methylcellulose sodium as suspending agent, Polysorbate 80 as wetting agent, Simethicone as anti-foaming agent, Colloidal Silicone dioxide as dispersing agent, Citric acid and Sodium citrate as buffering agent and one or more inactive agents.

As per one preferred embodiment suspension is comprising of one or more inactive ingredients comprising Sodium carboxy methyl cellulose, Microcrystalline cellulose (Avicel RC-591)and carboxy methylcellulose sodium as suspending agent in range 1-100mg/ml, Polysorbate 80 as wetting agent in range 0.01-50mg/ml, Simethicone as anti-foaming agent in range 0.01-50mg/ml, Colloidal Silicone dioxide as dispersing agent in range 0.1-100mg/ml, 0.01-50mg/ml of Citric acid and Sodium citrate as buffering agent and one or more inactive agents.

Buffering agent as used in the present invention is the buffer is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. The pH of the liquid suspension of the present invention can be adjusted to a pH in the range from 4 to 8. The buffer can include an organic acid, inorganic acid, or salts thereof. Examples of suitable acids include, but are not limited to, malic acid, citric acid, ascorbic acid, tartaric acid, adipic acid, lactic acid, furmaric acid, maleic acid, acetic acid, phosphoric acid, or salts thereof, singly or in combination. Examples of suitable bases include, but are not limited to, calcium and sodium carbonate, calcium and sodium bicarbonate, and salts of the organic or inorganic acids listed above. The above listed compatible acids can be used for pH reduction; however, the increase in pH can be obtained through the use of small amounts of food grade inorganic bases including, but not limited to, metal hydroxides or basic salts thereof including sodium hydroxide solution, potassium hydroxide solution, ammonium hydroxide solution, ammonium chloride solution, sodium citrate, sodium dihydrogen phosphate, etc. Such pH modifying or buffering agents are well known in the art and can be applied as needed.

As per one embodiment, the pH of the present formulation is in the range from 4 to 6, preferably in the range from 4 to 6, preferably the pH is 4 to 6, as preferably the pH is 4 to 6, more preferably in the range from 4 to 6, most preferably the range is 4 to 6.

Suitable wetting agents for use in the liquid oral suspensions according to the present invention are polyoxyethylene derivatives of sorbitan esters, e.g. polysorbate 20 and polysorbate 80, lecithin, polyoxyethylene- and polyoxypropylene ethers, sodium deoxycholate.

Suspending agent excipients help active pharmaceutical ingredients stay suspended in the formulation and prevent caking at the bottom of the container. One of the properties of a well-formulated suspension is that it can be easily re-suspended by the use of moderate agitation or shaking.

Suspending agents suitable for use in the liquid oral suspensions of the present invention include cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose and hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, alginate, guar gum, xanthan gum, acacia gum, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene and polyoxypropylene ether.

As per one embodiment, the one or more inactive excipients can be selected from flavoring agent, sweetening agent, antifoaming, anti-oxidant, dispersing agent, preservatives, chelating agents or combinations thereof will be well-known to those of skill in the art.

Non-limiting examples of flavoring agents are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plums pineapple, apricot, peppermint, Tutti Frutti flavor and so forth and the like or any combinations thereof. Solid forms, such as spray dried forms of flavoring agents, may also be useful in the liquid dosage forms disclosed herein.

Non-limiting examples of sweetening agents are Glucose, Sucralose, Trehalose, Fructose, Xylose, Dextrose, Galactose, Tagatose, Maltose, Sucrose, Glycerol, Dulcitol, Mannitol, Lactitol, Sorbitol, Xylitol, Saccharine or the corresponding sodium, potassium or calcium salt, Cyclamate or the corresponding sodium or calcium salt, Aspartame, or Acesulfame or the potassium salt thereof, Dulcin or Ammonium glycyrrhizinate, Alitame, Inulin, Isomalt, Neohesperidin dihydrochalcone, Thaumatin and the like or any combinations thereof.

Antifoaming agents are added in oral suspension pharmaceutical dosage form to lower the surface tension and cohesive binding of liquid phase. Antifoaming agents can be selected from but not limited to simethicone, organic phosphates, alcohols, paraffin oils, sterates and glycols.

A dispersant or a dispersing agent is a substance, typically a surfactant, which is added to a suspension of solid or liquid particles in a liquid to improve the separation of the particles and to prevent their settling or clumping.
Dispersing agent for present invention is selected from colloidal silicon dioxide (Aerosil 200), calcium silicate, magnesium alumino metasilicates and Neusilin®.

Preservatives for present invention of suspension are included to prevent the growth of microorganisms during the product manufacturing and shelf life. Preservatives can be selected from but not limited to benzoic acid, potassium sorbate, sodium benzoate, chlorobutanol, ethanol, butyl paraben, propyl paraben and methyl paraben.

Other known pharmaceutical excipients may be used in the ordinary amounts for their normal purposes, so long as they do not negatively affect the effectiveness or stability of the liquid suspension.

As per one embodiment, the present invention relates to liquid oral suspension of Favipiravir. Particularly, liquid oral suspension of present invention is to be administered via oral route.

As per one embodiment, the present invention relates to process for preparing a liquid oral suspension of Favipiravir. Particularly, a process for the preparation of a liquid oral suspension of Favipiravir, glycerin, purified water.

As per one preferred embodiment the process of preparation of the liquid oral suspension of Favipiravir is comprising steps of:
(a) Adding and dissolving required quantity of buffering agent, preservative and sweetening agent one by one,
(b) Adding anti-foaming agent in step a) and homogenizing till uniform dispersion;
(c) Adding wetting agent in step b) and mixing till uniform dispersion;
(d) Adding stabilizer in step c) and mixing till uniform dispersion;
(e) Adding dispersing agents to step d) one by one till uniform dispersion, and
(f) Adding Favipiravir to step e) and mixing till uniform homogenous suspension obtained.

In one embodiment, a liquid oral suspension of Favipiravir of present invention is useful for the treatment of COVID-19 disease in human.

The liquid oral suspension of Favipiravir of present invention may be used in therapeutic response to COVID-19 disease or condition in the treatment, prevention of a disease, ameliorating the disease, disorder or condition, reduce the disease, disorder appearance or condition.

The term & for the method of treating a subject used herein, "treatment" refers to alleviating, ameliorating, eliminating symptoms associated with COVID-19 disease.

As per one embodiment is to provide a method of treating COVID-19 disease in a subject comprising administering to that subject a therapeutically effective amount of liquid oral suspension of Favipiravir, one or more buffering agent, stabilizing agent, wetting agent, suspending agent and one or more inactive ingredients.

As per one embodiment, the present invention is having composition as below;

Sr. No Ingredients mg/ml
1 Favipiravir 10 mg to 1000 mg/ml
2 Buffering agent q.s to adjust pH
3 Preservative 0.01 to 10 mg/ml
4 Wetting agent 1 to 50 mg/ml
5 Suspending agent 1 to 50 mg/ml
6 Anti-foaming agent 0 to 10 mg/ml
7 Stabilizing agent 100 to 1200 mg/ml
8 Sweetening agent 0 to 1000 mg/ml
9 Flavoring agent 0 to 10 mg/ml
10 Vehicle Q.S

As per one embodiment the suspension is comprising of Favipiravir in range 10-1000 mg/ml, Sodium carboxy methyl cellulose, Microcrystalline cellulose and carboxy methylcellulose sodium in range 1-100 mg/ml, Polysorbate 80 in range 0.01-50mg/ml, Simethicone as in range 0.01-50 mg/ml, Colloidal Silicone dioxide in range 0.1-100mg/ml, 0.01-50mg/ml of Citric acid and Sodium citrate, and one or more inactive agents.

As per one embodiment the suspension is comprising of Favipiravir in range 10-1000 mg/ml, Sodium carboxy methyl cellulose, Microcrystalline cellulose and carboxy methylcellulose sodium in range 1 – 100 mg/ml, Polysorbate 80 in range 0.01 – 50 mg/ml, Simethicone as in range 0.01 – 50 mg/ml, Colloidal Silicone dioxide in range 0.1 - 100 mg/ml, 0.01 - 50mg/ml of Citric acid and Sodium citrate, and one or more inactive agents comprising sweetening agent, flavoring agent and preservative.

As per one embodiment the suspension is comprising of Favipiravir in range 10 - 1000 mg/ml, Sodium carboxy methyl cellulose, Microcrystalline cellulose and carboxy methylcellulose sodium in range 1-100mg/ml, Polysorbate 80 in range 0.01 - 50mg/ml, Simethicone as in range 0.01-50mg/ml, Colloidal Silicone dioxide in range 0.1 -100 mg/ml, 0.01 - 50 mg/ml of Citric acid and Sodium citrate, 0.01 - 10 mg/ml of Frozen peppermint, 1 - 50 mg of Sucralose and 0.01 - 10 mg/ml of Sodium benzoate.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. 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.

EXAMPLES

Example 1: Favipiravir Suspension

Ingredients mg/ml
Favipiravir 100 mg/ml
Citric acid 4 - 6 pH
Sodium citrate 4 – 6 pH
Purified water 190 mg/ml
Sodium benzoate 1 mg/ml
Polysorbate 80 5 mg/ml
Glycerine 900 mg/ml
Simethicone emulsion 3 mg/ml
Sodium carboxy methyl cellulose 2 mg/ml
Microcrystalline cellulose and carboxymethyl cellulose sodium 7.5 mg/ml
Colloidal silica 5 mg/ml
Aspartame 1 mg/ml
Frozen peppermint flavor 1 mg/ml
Glycerine q.s to 1 ml

Process:
(a) Required quantity of water was added and dissolved buffering agent, preservative and sweetening agent one by one,
(b) Anti-foaming agent was added in step a) and homogenized till uniform dispersion,
(c) Wetting agent was added in step b) and mixed till uniform dispersion,
(d) Stabilizer was added in step c) and mixed till uniform dispersion,
(e) Dispersing agent were added to step d) one by one till uniform dispersion, and
(f) Favipiravir was added to step e) and mixed till uniform homogenous suspension were obtained.

Example 2: Optimization of water content

A Prototype trial was taken with two different water content and evaluated the stability of the formulations. The formulation compositions are presented below:

Batch no.: FAVL1002 FAVL1006
Ingredients Quantity
(mg) /mL Quantity
(mg) /mL
Favipiravir 100 100
Glycerin 400 800
Sodium benzoate 1 1
Polysorbate 80 2.5 2.5
Simethicone 1 1
Aspartame 1 1
Frozen peppermint flavor 1 1
Purified water 300 600
Citrate buffer (50 mM) (pH 4.0) q.s to 1 ml q.s to 1 ml

Example 3: Optimization of the final formulation

Trials were taken with different concentration of water content and evaluated the stability of the formulations. The formulation compositions are presented below.

Batch no.: FAVL1006 FAVL1007
Ingredients Quantity
(mg/ml) /batch Quantity
(mg/ml) /batch
Favipiravir 100 100
Citrate buffer
(pH 4-5) 200 100
Glycerin 928 1056
Sodium benzoate 1 1
Simethicone 1 1
Aspartame 1 1
Frozen pippermint flavour 1 1
Sodium CMC 6 6
Avicel RC591 11 12
Purified water 128 158

Example 4: Liquid Oral Suspension of Favipiravir (FAVL1010)

The goal of formulation development study #3 was to initiate final stability study in final formulation. The formulation composition is presented below:

Ingredients Quantity
(mg/ml)
Favipiravir 100
Sodium benzoate 1
Citric acid 0.3
Sodium citrate 0.279
Sucralose 5
Polysorbate 80 5
Simethicone 3
Purified water 50
Sodium carboxy methyl cellulose 2
Microcrystalline cellulose and carboxy methylcellulose sodium 7.5
Colloidal Silicone dioxide 5
Frozen peppermint 0.5
Glycerin q.s to 1 ml
(approx. 1100mg)
pH 4 to 6

Batch Manufacturing Procedure for FAVL1010:
Procedure same as above in example 1.

Example 5: Stability study

Stability study of the optimized batch and final product. A Prototype trial was taken and evaluated for the stability of the product:

The stability study was performed at different conditions such as,
1. Temperature: 40±2O C and RH: 75%±5% RH
2. Temperature: 25±2O C and RH: 60%±5% RH

Example 5.1: Stability data of Favipiravir oral suspension 100 mg/ml batch FAVL1002 and FAVL1006 at different stability condition the results are shown below:

The table shows the stability study data and result obtained:
Parameters Specification Batch No - FAVL1002 Batch No - FAVL1006
Description Off white to yellowish suspension 40±20C/75%±5% RH -1M 25±20C/60%±5% RH-
1M 40±20C/75%±5% RH –
1M 25±20C/60%±5% RH-
1M
Dark yellow to brownish suspension Yellow to dark yellow suspension Yellow to dark yellow suspension Off white to yellowish suspension
Related impurities (By HPLC)
Single maximum unknown impurity NMT 0.2% 2.00% 0.36% 0.33% 0.07%
Total impurities NMT 1.0% 2.50% 0.57% 0.69% 0.07%
NMT: Not more than, 1M: 1 Month, HPLC: High Performance Liquid Chromatography

Result:
As per the Table, it was observed that composition contains higher aqueous buffer concentration (FAVL1002) or lower glycerine content had shown higher degradation as compared to the composition contains less buffer concentration or higher glycerine content (FAVL1006). Based on above results, it is concluded that Favipiravir is sensitive to water and it should be replaced as much as possible by glycerine.

Example 5.2: Stability data of Favipiravir oral suspension 100 mg/ml at different condition

The table shows the stability study data and result obtained:
Parameters Specification Batch No-FAVL1006 Batch No-FAVL1007
Description Off white to yellowish suspension Initial 40 ± 20C/75% ± 5% RH -1M 25 ± 20C/60% ± 5% RH-1M Initial 40±20C/75%±5% RH -1M 25±20C/60%±5% RH-1M
Off white to yellowish suspension Dark yellow to brownish suspension Yellow to dark yellow suspension Off white to yellowish suspension Light yellow to yellowish suspension Off white to yellowish suspension
Related impurities (By HPLC)
Single maximum unknown impurity NMT 0.2% 0.08% 0.33% 0.07% 0.08% 0.17% 0.08%
Total impurities NMT 1.0% 0.08% 0.69% 0.07% 0.08% 0.39% 0.08%

Result:
As per the above table, it was observed that composition contains less buffer and more glycerine (Batch no: FAVL1007) had shown lower degradation as compared to the composition contains higher buffer and less glycerine (Batch no: FAVL1006). Based on above results, it was observed that batch with glycerine content 90% has better impurity profile, so batch with 95% glycerine is considered as final formulation and initiated stability studies.

Example 5.3: Stability data of Favipiravir oral suspension 100 mg/ml batch FAVL 1010 at different stability condition

The table shows the stability study data and result obtained:
Parameters Specification limit Batch No-FAVL1010
Description Off white to yellowish suspension Initial 25±20C/60%±5% RH 40±20C/75%±5% RH
3M 1M 2M 3M
Assay of Favipiravir 95%-105% Off white to yellowish suspension Complies Complies Complies Complies
102.6% 99.10% 104.34% 102.05% 97.68%
Related impurities (By HPLC)
Single maximum unknown impurity NMT 0.2% 0.0912% 0.0491% 0.0829% 0.0546% 0.0600%
Total impurities NMT 1.0% 0.1429% 0.0981% 0.1233% 0.1219% 0.1447%
pH Between 4.0 to 6.0 4.73 4.80 5.10 4.90 4.80
Dissolution NLT 75 % of the labelled amount of API should dissolve in 30 mins. 102.77% 92.11% 98.18% 96.44% 94.43%

Result:
As per above table, it was observed that composition of FAVL1010 is final composition and stable at 40±2o C/ 75% ± 5% RH and 25±2o C /60% ± 5% RH.
,CLAIMS:CLAIMS

We claim,

1. A liquid oral suspension of Favipiravir comprising Favipiravir, Glycerin, wherein Glycerin is more than 60% w/w, purified water is less than 40% w/w and the pH of the suspension is 4 to 6.

2. The liquid oral suspension of Favipiravir as claimed in claim 1, wherein Favipiravir is present in range 10 - 1000 mg/ml.

3. The liquid oral suspension of Favipiravir as claimed in claim 1, wherein the buffering agent is selected from malic acid, citric acid, sodium hydroxide solution, potassium hydroxide solution, ammonium hydroxide solution, ammonium chloride solution, sodium citrate, sodium dihydrogen phosphate, calcium and sodium carbonate, calcium and sodium bicarbonate, and salts of the organic or inorganic acids ascorbic acid, tartaric acid, adipic acid, lactic acid, furmaric acid, maleic acid, acetic acid, phosphoric acid, or salts thereof, singly or in combination.

4. The liquid oral suspension of Favipiravir as claimed in claim 1, wherein the wetting agent is selected from polysorbate 20 and polysorbate 80, lecithin, polyoxyethylene- and polyoxypropylene ethers, sodium deoxycholate.

5. The liquid oral suspension of Favipiravir as claimed in claim 1, the suspending agent is selected from cellulose derivatives such as methylcellulose, sodium carboxy methylcellulose and hydroxy propyl methylcellulose, polyvinylpyrrolidone, microcrystalline cellulose, alginate, guar gum, xanthan gum, acacia gum, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene and polyoxypropylene ether.

6. The liquid oral suspension of Favipiravir as claimed in claim 1, consisting of Favipiravir, glycerin, purified water, Sodium carboxy methyl cellulose, microcrystalline cellulose and carboxy methylcellulose sodium, Polysorbate 80, Simethicone, Colloidal Silicone dioxide, Citric acid and Sodium citrate, and one or more inactive agents.

7. The liquid oral suspension of Favipiravir as claimed in claim 1, wherein the one or more inactive agents are sweetening agent, flavoring agent and preservatives.

8. The liquid oral suspension of Favipiravir as claimed in claim 1, suspension is comprising of Favipiravir in range 10-1000 mg/ml, Sodium carboxy methyl cellulose, Microcrystalline cellulose and carboxy methylcellulose sodium in range 1-100mg/ml, Polysorbate 80 in range 0.01-50mg/ml, Simethicone as in range 0.01-50mg/ml, Colloidal Silicone dioxide in range 0.1-100mg/ml, 0.01-50mg/ml of Citric acid and Sodium citrate, 0.01-10mg/ml of Frozen peppermint, 1-50mg of Sucralose and 0.01-10 mg/ml of Sodium benzoate.

9. A process of preparation of the liquid oral suspension of Favipiravir is comprising steps of,
a) Adding and dissolving required quantity of buffering agent, preservative and sweetening agent one by one,
b) Adding anti-foaming agent in step a) and homogenizing till uniform dispersion;
c) Adding wetting agent in step b) and mixing till uniform dispersion;
d) Adding stabilizer in step c) and mixing till uniform dispersion;
e) Adding dispersing agents to step d) one by one till uniform dispersion, and
f) Adding Favipiravir to step e) and mixing till uniform homogenous suspension obtained.

Dated this 09th Apr, 2021