DESC:FIELD OF INVENTION
The present invention relates to a pharmaceutical composition administered in a form of inhalation comprising favipiravir, a process for preparing such pharmaceutical composition, and use of the said pharmaceutical composition for the prevention, treatment and prophylaxis of diseases caused by viruses.

BACKGROUND AND PRIOR ART
Coronavirus disease 2019 (COVID-19) is an emerging infectious disease of potential zoonotic origin. Severe acute respiratory syndrome (SARS) corona virus – 2, (SARS-CoV-2), the etiological agent of COVID-19, can cause a serious or life-threatening disease or condition, including severe respiratory illness. The public health concerns caused by the outbreak of COVID-19 was declared as a “public health emergency of international concern” on January 31, 2020 and “pandemic on March 11, 2020 by World Health Organization. Impacts of the COVID-19 pandemic are currently ‘skyrocketing’ across the globe, causing enormous public health havoc and a colossal economic crisis.

The spread of COVID-19 is so accelerating that it needed 67 days from the first diagnosed case to reach the first 100,000 cases, 11 days for the second 100,000 cases, 4 days for the third 100,000 cases, 3 days for the fourth 100,000 cases and just extra 7 days for additional 400,000 cases around the globe. A similar pattern has been seen in the fatality as it required 17 days from the first death reported on 11 January 2020 to reach the first 100 deaths, 30 days for the 1,000 deaths, 61 days for the 5,000 deaths and 68 days for 10,000 deaths and just 9 additional days for additional 20,000 deaths. By 1 April 2020, the number of confirmed cases skyrocketed to approximately 823,000 and 40,598 deaths from 205 countries and territories around the globe. In the single day of 31 March, there were approximately 72,700 new confirmed cases and 4,193 deaths reported across the world. The reported mortality rate for COVID-19 is around 3% and the mortality rates vary depending on geographical regions, age distributions and co-morbidities.

With the advent of the devastating pandemic, many clinical trials have been initiated, and couple of them are pursuing already known drugs and evaluating whether such known drugs could be re-purposed towards alleviating and/ or treating the symptoms associated with COVID-19 patients.

One such approved product is favipiravir which is commercially available as 200 mg tablets under the trade name AVIGAN® for the treatment of patients with novel or re-emerging pandemic influenza virus infection. The recommended adult dosage of favipiravir is 3200 mg orally i.e. 1600 mg twice daily on Day 1 followed by 1200 mg orally i.e. 600 mg twice daily from Day 2 to day 5. Thus, currently a patient t needs to take, 16 tablets on Day 1 i.e. 8 tablets twice daily and 6 tablets on Day 2 to day 5 i.e. 3 tablets twice daily.

WO2016172205 discloses use of favipiravir in treatment of Ebola virus infection. It further discloses inhalation in an aerosol form through which favipiravir could be administered along with other modes of administration.

US20120190637 discloses a method of treating viral disease (caused by influenza or corona virus) combining administering antiviral agent (one of which is favipiravir as 6-fluoro-3-hydroxy-2 pyrazinecarboxamide) with EP4 receptor agonist (e.g. beraprost sodium). It further discloses that one of the delivery modes is through aerosol solution via inhalation.

WO2015173701 discloses a composition comprising danirixin in combination with favipiravir (for influenza). It further discloses solutions for inhalation by nebulization may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials.

Although all the above prior art documents disclose that favipiravir can be administered in the form of an inhalation for the treatment of viral diseases, none of the above disclose specific examples or formulations of favipiravir which is could be administered via inhalation route and provide evidence regarding its efficacy via inhalation.

Hence, there is a need to develop a pharmaceutical composition comprising favipiravir which would be economical, easy to manufacture as well as ensure fast recovery and patient compliance.

OBJECT OF THE INVENTION:
An object of the present invention is to provide a pharmaceutical composition administered by inhalation comprising favipiravir along with pharmaceutically acceptable excipients.

Another object of the present invention is to provide a process of preparing a pharmaceutical composition administered by inhalation comprising favipiravir along with pharmaceutically acceptable excipients.

Yet another object of the present invention is to provide a pharmaceutical composition administered by inhalation comprising favipiravir along with pharmaceutically acceptable excipients for the treatment of infection caused by Coronaviridae virus (including COVID-19).

Still another object is to provide a method of alleviating or treating infection caused by Coronaviridae virus (including COVID-19) by administering inhalable pharmaceutical composition comprising favipiravir along with pharmaceutically acceptable excipients.

Still another object is to provide the use of inhalable pharmaceutical composition comprising favipiravir along with pharmaceutically acceptable excipients in the treatment of infection caused by Coronaviridae virus (including COVID-19).

SUMMARY OF THE INVENTION:
According to one aspect of the present invention there is provided a pharmaceutical composition administered by inhalation comprising favipiravir along with pharmaceutically acceptable excipients.

According to another aspect of the present invention there is provided a process of preparing a pharmaceutical composition administered by inhalation comprising favipiravir along with pharmaceutically acceptable excipients.

According to yet another aspect of the present invention, there is provided a pharmaceutical composition administered by inhalation comprising favipiravir along with pharmaceutically acceptable excipients for the treatment of infection caused by Coronaviridae virus (including COVID-19).

According to still another aspect of the present invention, there is provided a method of alleviating or treating infection caused by Coronaviridae virus (including COVID-19) by administering inhalable pharmaceutical composition comprising favipiravir along with pharmaceutically acceptable excipients.

According to yet another aspect of the present invention there is provided a use of inhalable pharmaceutical composition comprising favipiravir along with pharmaceutically acceptable excipients in the treatment of infection caused by Coronaviridae virus (including COVID-19).

BRIEF DESCRIPTION OF THE FIGURES
Figure 1: Plasma concentration and lung concentration of Favipiravir Oral tablet 600 mg
Figure 2: Plasma concentration and lung concentration of Favipiravir Inhalation route 80 mg
Figure 3: Plasma concentration and lung concentration of Favipiravir Inhalation route 160 mg
Figure 4: Lung tissue concentration with oral dose regime of Favipiravir
Figure 5: Lung tissue concentration with proposed dose of Favipiravir via nebulization
Figure 6: Efficacy of Favipiravir Oral (600 mg) Vs Inhalation (160 mg)

DETAILED DESCRIPTION OF THE INVENTION
Favipiravir (T-705) is chemically known as 6-fluoro-3-hydroxy-2-pyrazinecarboxamide and has the following structural formula.

Favipiravir is an antiviral drug that selectively inhibits the RNA-dependent RNA polymerase of influenza virus. Favipiravir is phosphoribosylated by cellular enzymes to its active form, favipiravir-ribofuranosyl-5'-triphosphate (RTP). The antiviral effect of favipiravir is attenuated by the addition of purine nucleic acids, indicating the viral RNA polymerase mistakenly recognizes favipiravir-RTP as a purine nucleotide.

The inventors of the present invention have developed pharmaceutical inhalation composition comprising favipiravir which not only treats the infection caused by Coronaviridae virus (including COVID 19) but also improves patient compliance.

According to an aspect of some embodiments of the present invention there are provided pharmaceutical inhalable compositions in unit dosage form. The compositions according to this aspect of the present invention comprise an amount of favipiravir or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

It will be well appreciated that the term “favipiravir” as used herein is denoted in broad sense to include not only “favipiravir” per se but also its pharmaceutically acceptable derivatives thereof. Suitable pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes etc.

The term "treating" or "treatment" as used herein refers to relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease. For example, treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer. Within the meaning of the present invention, the term "treat" also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.

The term "pharmaceutically acceptable salt" refers to a charged species of the parent compound and its counter ion, which is typically used to modify the solubility characteristics of the parent compound and/or to reduce any significant irritation to an organism by the parent compound, while not abrogating the biological activity and properties of the administered compound.

The term "pharmaceutical composition" refers to a preparation of favipiravir with other chemical components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

The term "pharmaceutically acceptable carrier" refers to a carrier, adjuvant, or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
The term “excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples, without limitation, of excipients include surfactants, isotonicity agents, pH adjusters, buffers, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

According to the present invention, there is provided a pharmaceutical composition administered by inhalation comprising favipiravir along with one or more carriers.
Suitably, the pharmaceutical composition, according to the present invention are presented either in the form of inhalation solutions or suspensions to be administered with the help of a suitable nebulizer or in the form of dry powder inhaler to be administered either through capsule based inhalers or through blister and/ or cartridge comprising multiple pockets of storing the dry powder or reservoir based multidose inhalers. Alternatively, propellant driven aerosol compositions are also envisaged within the scope of the present invention which are administered either through conventional press-and-breathe inhalers or through breath actuated inhalers (both associated with dose counters/ indicators) well known in the art.

According to a preferred embodiment, the pharmaceutical inhalable composition may be presented in the form of liquid solution/ suspension comprising a therapeutically effective amount of favipiravir along with one or more excipients for administration through a suitable nebulizer (also known as “nebulization composition”). The liquid solution/ suspension may be packed in an ampoule (to be presented as single dose) or vial (to be presented as multidose).

The nebulization composition of the present invention may be provided in sterile unit dose treatments. The nebulization composition comprises an aqueous suspension comprising therapeutically effective amount of favipiravir and wherein the composition comprises one or more pharmaceutically acceptable excipients.
The nebulization composition may include from about 40 mg to about 320 mg of favipiravir. The volume of the nebulization composition is about 0.2 ml to about 6 ml.

The nebulization composition of the present invention may contain favipiravir in micronized form. Suitable micronization techniques like Microfluidizer, High pressure homogenizer, Ball mill, Sonication and other such techniques commonly known in the art can be employed to effectively size reduce the mometasone or its pharmaceutically acceptable salt thereof. The particle size of favipiravir desired for effective nebulization of the compositions of the present invention can range from about 0.1 micron to about 5 micron.

The nebulization composition of the present invention have a pH of about 2 to about 8. The pH may be adjusted by the addition of one or more pharmaceutically acceptable acids. Examples of suitable pharmaceutically acceptable acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and combinations thereof. Examples of other suitable pharmacologically acceptable acids include organic acids, such as ascorbic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, fumaric acid, acetic acid, formic acid, and/or propionic acid. In one embodiment, the pH is adjusted with 1N hydrochloric acid or 1N sulfuric acid. In another embodiment, the pH is adjusted with one or more organic acids selected from ascorbic acid, fumaric acid and citric acid. A preferred organic acid is citric acid. If desired, mixtures of the abovementioned acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying properties, e.g., those which act as flavorings or antioxidants, such as for example citric acid or ascorbic acid. The nebulization composition may contain 0.0001% to 0.53% w/v of citric acid, or 0.0001% to 2.20% w/v of sodium citrate, or 0.00937% to 9.5% w/v of monosodium phosphate dehydrate, or 0.0017% to 1.7% w/v of Dibasic sodium phosphate anhydrous.
The nebulization composition of the present invention may optionally include a buffer. General and biological buffers in the pH range of about 2.0 to about 8.0 include, but are not limited to, acetate, borate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate, citrate -phosphate -borate buffers.
Suitable tonicity adjusting agents may include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethyl sulfoxide, edetate disodium, edetate trisodium monohydrate, fluorescein sodium, fructose, galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, propylene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate, sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride, sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate, sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine, urea, urethan, uridine, zinc sulfate, and mixtures thereof. The nebulization composition of the present invention may contain 0.0001% to 1.13% w/v of sodium chloride, preferably 0.9% w/v.

Suitable osmotic adjusting agents that may be used include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof. Other osmotic adjusting agents may also include, but are not limited to, mannitol, glycerol, dextrose and mixtures thereof.

Any cosolvent that is suitable for inhalation and capable of dissolving or dispersing the favipiravir in the mixture of cosolvent and water can be used. Examples of suitable cosolvents include, for example, alcohols, ethers, hydrocarbons, and perfluorocarbons. Preferably, the cosolvent is a short chain polar alcohol. More preferably, the cosolvent is an aliphatic alcohol having from one to six carbon atoms, such as ethanol or isopropanol. The most preferred cosolvent is ethanol. Examples of suitable hydrocarbons include n-butane, isobutane, pentane, neopentane and isopentanes. Examples of suitable ethers include dimethyl ether and diethyl ether. Examples of suitable perfluorocarbons include perfluoropropane, perfluorobutane, perfluorocyclobutane, and perfluoropentane.

Suitable nonionic surfactants include all substances of this type that can normally be used in such nebulization compositions. Preferably mention may be made of polyethylene glycol ethers of linear alcohols, reaction products of fatty acids with ethylene oxide and/or propylene oxide, and also polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinyl alcohol and polyvinylpyrrolidone, polyethylene oxide -polypropylene oxide block copolymers and also copolymers of (meth)acrylic acid and (meth)acrylic esters, and also alkyl ethoxylates and alkylaryl ethoxylates, which optionally may be phosphated and optionally may be neutralized with bases, it being possible for mention to be made, by way of example, of sorbitol ethoxylates. Suitable anionic surfactants include all substances of this type that can normally be used in agrochemical compositions. Preference is given to alkali metal salts and alkaline earth metal salts of alkylsulphonic acids or alkylarylsulphonic acids. Examples of suitable cationic surfactants include but are not limited to ammnonium bromides; nonionic surfactants include but are not limited to alkyl ethoxylates, alkyl gluccosides and alkyl phenol ethoxylates; and amphoteric surfactants include but are not limited to betaines, amphoacetates, and amphodiacetates. A preferred anionic surfactant is sodium dodecyl sulfate (SDS) and a preferred cationic surfactant is dodecyl trimethyl ammonium bromide; SDS is most preferred for the methods of the present invention. Also possible is the incorporation of amphoteric surfactants, such as alkyl betaines, alkyl amido betaines, and alkyl amphoacetates. Preferably, Polysorbates, Cholesterol, Dipalmitoyl phosphatidylcholine and Sorbitans may be used as surfactants in the nebulization composition.
Suitable antioxidants that may be used include, but are not limited to, ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins or pro-vitamins occurring in the human body.

The nebulization composition may also contain a complexing agent, examples include but not limited to EDTA and salts thereof, such as edetate disodium. The nebulization composition comprising a complexing agent provides an improved stability with reduced levels of impurities and degradation products.

According to a preferred embodiment, the pharmaceutical inhalable composition may be presented in the form of dry powder inhaler comprising a therapeutically effective amount of favipiravir along with one or more excipients to be administered either through capsule based inhalers or through blister and/ or cartridge comprising multiple pockets of storing the dry powder or reservoir based multidose inhalers (also known as dry powder compositions).

Representative non-limiting examples of carriers for use in the pharmaceutical inhalable composition presented as dry powder inhaler include, without limitation, lactose, glucose, or sodium starch glycolate. In some embodiments, the particulate carrier is lactose. The particulate lactose is in some instances alpha lactose monohydrate. In general, the particle size of the lactose should be such that it can be entrained in an air stream but not deposited in the key target sites of the lung. Apart from these carriers, there may optionally be presence of lubricants/ anti-adherents such as stearates or stearic acid derivatives for e.g. magnesium stearate.
The dry powder compositions, according to the invention, may conveniently be presented in unit dosage form and may be prepared by conventional pharmaceutical techniques. Such techniques include the step of bringing into association the compound of the invention and the pharmaceutically acceptable carrier(s), or an excipient. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with finely divided solid carriers, and then, if necessary, preparing discrete dosage units of the product.

The dry powder composition may be metered and filled into capsules, e.g., gelatin or hydroxypropyl methylcellulose capsules, such that the capsule contains a unit dose of active ingredient.

When the dry powder is in a capsule containing a unit dose of active ingredient, the total amount of composition will depend on the size of the capsules and the characteristics of the inhalation device with which the capsules are being used. However, representative characteristic total fill weights of dry powder per capsule are between 1 and 25 mg, e.g., 5, 10, 15 or 20 mg.

Alternatively, the dry powder composition according to the invention may be filled into the reservoir of a multidose dry powder inhaler (MDPI), for example of the kind illustrated in WO 92/10229.

Another aspect of the invention provides for a dry powder inhaler comprising the inhaler and a composition according to the invention.

Another aspect of the invention provides a method for the administration of a particulate medicament, comprising inhalation of a composition of the invention from a multidose dry powder inhaler.

According to the present invention, there is provided a process of preparing a pharmaceutical composition administered by inhalation comprising favipiravir with one or more carriers or excipients.

According to preferred embodiment of the present invention, a nebulization composition may involve dispersion of favipiravir in suitable excipients like surfactants, followed by other excipients such as buffers, tonicity agents and making up of the volume with suitable solvent and filling in suitable containers like ampoule or vials. The containers may or may not require any form of sterilization. The nebulization composition of the present invention may be administered by a suitable nebulizer. Suitable nebulizers include, but are not limited to, a jet nebulizer, an ultrasonic nebulizer, vibrating mesh nebulizer and a breath actuated nebulizer. Preferably, the nebulizer is a jet nebulizer connected to an air compressor with adequate airflow. The nebulizer being equipped with a mouthpiece or suitable face mask. The nebulization compositions may be administered by nebulizers manufactured, designed or sold by Omron, such as the Omron MICRO AIR.TM. Ultrasonic Nebulizer. Other nebulizers may also include those manufactured, designed, or sold by Aerogen. Additionally, the compositions described herein can also be nebulized using inhalers other than those described above, for example jet-stream inhalers or by breath actuated jet nebulizers.

According to a preferred embodiment of the present invention, a dry powder composition may involve mixing and/ or homogenization of favipiravir followed by addition of lactose (or a specific grade). The lactose used may have uniform particle size or may be used in as two different particle size grades i.e. coarser grade and a finer grade. Alternatively, lubricant such as magnesium stearate may be added to the dry powder composition. The resulting powder blend could be either filed in capsules for delivery through capsule based inhalers or could be either filled in blister strips or multi-pocket cartridges which will eventually be loaded in respective multidose inhalers or could be filled in reservoir containers which will be loaded in respective multidose reservoir inhalers known in the art.

According to the invention, there is provided a pharmaceutical inhalable composition administered by inhalation comprising favipiravir for the treatment of infection caused by Coronaviridae virus (including COVID-19). Preferably, the pharmaceutical inhalable composition may be in the form of nebulization composition or dry powder composition as described hereinabove.
It may be well appreciated by a person skilled in the art that the pharmaceutical inhalable composition comprising favipiravir may require specific dosage amounts and specific frequency of administrations specifically considering their individual established doses, the dosing frequency, patient adherence and the regimen adopted. As described herein, considering that there are various parameters to govern the dosage and administration of the combination composition as per the present invention, it would be well acknowledged by a person skilled in the art to exercise caution with respect to the dosage, specifically, for special populations associated with other disorders.

In order that this invention be more fully understood, the following preparative and testing methods and examples are set forth. The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

EXAMPLES
Example 1 - PBPK Model - Inhalation Dose estimation for Favipiravir
The PBPK model for single dose was developed for Favipiravir on oral route in Preludium TM software using the literature data on IV absorption based compartmental analysis, followed by the PK of oral tablet dose. This model was then validated based on inhalation PK route for the 160 mg nebulized dose, then this validated model is used to predict the lung dose in oral route and inhalation route. as shown in Figure 1 - 3.

These studies provide to determine the inhalation dose that is required to match the plasma concentration as that of oral dose.

Example 2 - Steady state dose regime model
A steady state dose regime model is developed in MATLABTM Simbiology software which provides the PBPK model when Favipiravir is administered daily including the loading dose. In this process, first, solid oral dose of Favipiravir (repeated dose of 600 mg twice a day) is simulated and blood plasma concentration as a function of time is simulated up to 8 days. Then the lung dose (tissue concentration) for this profile is estimated for 8-day period as shown in the Figure 4 & 5.

From figures 4 & 5 it can be observed that favipiravir via inhalation route at 1/4th dose provides same plasma concentration and gives about 150- 2000% more lung dose and thus is very targeted in therapeutic action against COVID-19 and other RNA viruses where the lung is primary site of infection.

Example 3 - Efficacy of Favipiravir Oral (600 mg) Vs Inhalation (160 mg)
PK-PD Simulations were done using MATLABTM Simbiology software to compare the efficacy of oral dosage form with inhalation dosage form.

From Figure 6 the % efficacy for oral and inhalation dosage form perfectly overlap each other concluding that the inhalation dose of 160 mg is equivalent to oral dose of 600 mg in terms of efficacy.

Example 4 - Favipiravir solution for Inhalation (Nebulization)
Ingredient Quantity
Favipiravir 40 mg
Polysorbate 80 0.00015
Propylene glycol 0.25
Ethanol 0.05
Hydrochloric acid (for pH adjustment) Qs
Sodium hydroxide (for pH adjustment) Qs
Water for Injection QST 1 mL

Ingredient Quantity
Favipiravir 80 mg
Polysorbate 80 0.0003
Propylene glycol 0.5
Ethanol 0.1
Hydrochloric acid (for pH adjustment) Qs
Sodium hydroxide (for pH adjustment) Qs
Water for Injection QST 2 mL

Ingredient Quantity
Favipiravir 160 mg
Polysorbate 80 0.0004
Propylene glycol 0.5
Ethanol 0.1
Hydrochloric acid (for pH adjustment) Qs
Sodium hydroxide (for pH adjustment) Qs
Water for Injection QST 2 mL

Ingredient Quantity
Favipiravir 320 mg
Polysorbate 80 0.0008
Propylene glycol 1
Ethanol 0.2
Hydrochloric acid (for pH adjustment) Qs
Sodium hydroxide (for pH adjustment) Qs
Water for Injection QST 4mL

Example 5 - Favipiravir suspension for Inhalation (Nebulization)
Ingredient Quantity
Favipiravir (micronized) 40
Polysorbate 80 0.00015
Sodium Chloride 9
Water for Injection (QST) 1.0mL

Ingredient Quantity
Favipiravir (micronized) 80
Polysorbate 80 0.0003
Sodium Chloride 18
Water for Injection (QST) 2.0mL

Ingredient Quantity
Favipiravir (micronized) 160
Polysorbate 80 0.0004
Sodium Chloride 18
Water for Injection (QST) 2.0mL

Ingredient Quantity
Favipiravir (micronized) 320
Polysorbate 80 0.0008
Sodium Chloride 36

Example 6 - Favipiravir suspension for Inhalation (Nebulization)
Ingredient Quantity (mg)
Favipiravir 40
Cholesterol 2.6
Dipalmitoyl phosphatidylcholine (DPPC) 24
sodium chloride 9
Hydrochloric acid (for pH adjustment) Qs
sodium hydroxide (for pH adjustment) Qs
water for injection 1.0 mL

Ingredient Quantity (mg)
Favipiravir 80
Cholesterol 5.2
Dipalmitoyl phosphatidylcholine (DPPC) 48
sodium chloride 18
Hydrochloric acid (for pH adjustment) Qs
sodium hydroxide (for pH adjustment) Qs
water for injection 2.0mL

Ingredient Quantity (mg)
Favipiravir 160
Cholesterol 10.4
Dipalmitoyl phosphatidylcholine (DPPC) 96
sodium chloride 36
Hydrochloric acid (for pH adjustment) Qs
sodium hydroxide (for pH adjustment) Qs
water for injection 4.0mL

Ingredient Quantity
Favipiravir 320
Cholesterol 20.8
Dipalmitoyl phosphatidylcholine (DPPC) 192
sodium chloride 72
Hydrochloric acid (for pH adjustment) Qs
sodium hydroxide (for pH adjustment) Qs
water for injection 8.0mL

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to fall within the scope of the invention.

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

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.
,CLAIMS:
1. A pharmaceutical composition administered by inhalation comprising favipiravir or its pharmaceutically acceptable derivative thereof.

2. The pharmaceutical composition according to claim 1, comprising favipiravir in an amount from about 40 mg to about 320 mg based on the total weight of the composition.

3. The pharmaceutical composition according to the preceding claims, wherein the composition is an inhalation solution or suspension suitable for use in a nebulizer.

4. The pharmaceutical composition according to any preceding claim, wherein one or more pharmaceutically acceptable excipients is selected from buffers, pH adjusters, tonicity agents, osmotic agents, cosolvents, surfactants, antioxidants, complexing agents or any combination thereof.

5. The pharmaceutical composition according to claim 1 or 2, wherein the composition is in a form suitable for use in a dry powder inhaler.

6. The pharmaceutical composition according to claim 5, wherein one or more pharmaceutically acceptable excipients is selected from a saccharide and/or a sugar alcohol or any combination thereof.

7. The pharmaceutical composition according to claim 1 or 2, wherein the composition is in a form suitable for use in a metered dose inhaler.

8. The pharmaceutical composition according to claim 7, wherein one or more pharmaceutically acceptable excipients is selected from a co-solvent, an antioxidant, a surfactant, a bulking agent, a pH adjusting agent and a lubricant or any combination thereof.

9. The pharmaceutical composition according to any preceding claim, comprising favipiravir for use in the treatment of an infection caused by COVID-19

10. A pharmaceutical composition substantially as herein described with reference to the examples.