DESC:FIELD OF INVENTION:
The present invention relates to an antiviral pharmaceutical composition administered in a form of inhalation comprising nucleotide analogue prodrug, in particular Remdesivir, 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 including SARS Coronavirus.

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 31 January and “pandemic on 11 March 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.

Chloroquine (Chloroquine) is an anti-malarial drug used to treat acute attacks of malaria and control the symptoms of malaria. Chloroquine phosphate (racemate) has two dosage forms: oral (0.75g/day) and intravenous drip (0.5g/day). The latter takes up medical resources for a long time. The mechanism of action is that the drug has a strong binding force with the nucleoprotein, inserted between the double helix strands of DNA, and forms a complex with DNA, thereby preventing DNA from assisting RNA transcription. Main side effects: anorexia, nausea, vomiting, abdominal pain, diarrhea; various skin rashes; headache, dizziness, vertigo; eye toxicity. In addition, chloroquine drugs can lead to prolonged QT interval and Tdp.
Hydroxychloroquine (Hydroxyl Chloroquine) is an antimalarial drug taken orally. It is a new type of antimalarial drug developed by scientists on the basis of synthetic antimalarial chloroquine in 1944. Its side effects are significantly lower than those of chloroquine. It was launched in the United States in 1955, and used to treat malaria, rheumatoid arthritis, lupus erythematosus and other diseases. Hydroxychloroquine sulfate (racemate) is a film-coated tablet (200-400mg/day). The mechanism is to deposit and connective tissue after oral absorption, which inhibits the viability of fibrocytes and leukocytes, and inhibits the synthesis of DNA nuclear antibodies, inhibits the release of interleukins. The autoantigen response is down-regulated, which plays a role in resisting light sensitivity, stabilizing lysosomal membrane and protecting cartilage. Later, it was discovered that hydroxychloroquine has mild immunosuppressive and immunomodulatory effects. It has been urgently approved by the US FDA on March 29, 2020 as a "sympathetic drug" for the treatment of severe COVID-19 virus pneumonia. Main side effects: (1) Mostly manifested as anorexia, heartburn, nausea, vomiting, abdominal distension and diarrhea, liver function damage, (2) various skin rashes; (3) headache, dizziness, insomnia; (4) eye toxicity; ( 5) It can lead to prolonged QT interval and Tdp.

Azithromycin is an antibiotic, a kind of macrolide antibiotics, and belongs to the same category as roxithromycin, clindamycin, and erythromycin. It is used to treat bronchitis and pneumonia. Commonly used drugs for lower respiratory tract infections, sinusitis, pharyngitis, tonsillitis and other upper respiratory tract infections. Azithromycin's mechanism of action prevents bacterial growth by interfering with bacterial protein synthesis. It binds to the 50S subunit of the bacterial ribosome, thereby inhibiting mRNA transcription. At present, there are two dosage forms of azithromycin: oral azithromycin (0.25g/tablet) and injection azithromycin lactobionate (0.25g/bottle). The latter usually requires 6 hours of intravenous infusion, which takes up medical resources. Main side effects: (1) indigestion, gastritis, abdominal distension and diarrhea, (2) allergy, itching; (3) headache, dizziness, drowsiness. (4) Can lead to prolonged QT interval, Tdp and sudden cardiac death.

"Hydroxychloroquine + Azithromycin" combination was apparently discovered by world-renowned French transfection expert Dr. Didir Raoulta that can effectively treat new coronavirus pneumonia. The clinical trial arranged 36 patients to be tested (6 asymptomatic, 22 with upper respiratory tract infection, 8 with lower respiratory tract infection). The rate of virus conversion from nasopharyngeal swabs in 6 days was as follows: (1) Negative rate of control group 12.5% (P<0.001); (2) only receiving hydroxychloroquine sulfate (200mg/day) single-drug treatment, the negative rate of 57%; (3) combined with azithromycin (500mg/day, 250mg/day) after the negative rate of 100 %. The combination of azithromycin significantly improved the efficacy, and the time to completely clear the virus was shortened from 20-37 days to 3-6 days. Dr. Vladimir Zelenko, an American doctor, apparently cured 699 patients with a combination of (hydroxychloroquine + azithromycin + zinc sulfate) with a success rate of 100%. Both chloroquine antiviral drugs and macrolide antibiotics have prolonged QT interval, cause side effects of Tdp and sudden cardiac death, and the combination of drugs significantly increases the risk.
Favipiravir, also known as Avigan, was developed by Japan's Toyama Chemical Company and was approved as a storage drug in Japan in 2014 for use in fighting the influenza pandemic. It is an experimental anti-influenza drug, which is a broad-spectrum anti-RNA virus drug, and has activity against many RNA viruses. Previous tests proved that Favipiravir has a certain effect on Ebola virus, Chikungunya virus and Norovirus. A recent study proved that in an in vitro cell line experiment, its EC50 for the new coronavirus COVID-19 reached 61.88µM. 2020On March 17, 2005, the press conference of the Joint Prevention and Control Mechanism Research Team of the Ministry of Science and Technology of China announced the "Clinical Study on the Safety and Effectiveness of Favipiravir in the Treatment of Patients with Novel Coronavirus Pneumonia (Registration Number CHiCTR2000029600)". As shown in Figure 2, the preliminary results confirm that fapilavir can speed up virus clearance and achieve the efficacy of relieving symptoms. It is safe and effective. The antiviral effect is better than that of Klitsch, and the side effects are also significantly lower than Klitsch. It is recommended for clinical application To scale up.

Remdesivir (Remdesivir) was discovered by Gilead Sciences Inc., however, Gilead Sciences originally developed this drug to eliminate Ebola virus and Marburg virus infection. In vitro tests have shown that Remdesivir is not only effective against Ebola virus and other filoviruses, but also against respiratory syncytial virus, coronavirus, Nipah virus, Hendra virus, and atypical pneumonia (SARS-CoV) and Middle East Respiratory Syndrome (MERS-CoV) virus pathogens are active. At present, Remdesivir is used for the emergency treatment of a small number of COVID-19 infected patients, initially showing good results, and officially started clinical trials for the treatment of severe patients, followed by clinical trials for patients with moderate symptoms. Remdesivir has been approved by the U.S. FDA as a "sympathetic drug" for the treatment of severe COVID-19 virus pneumonia and has been recognized as an orphan drug by the FDA, and its indication is a disease caused by the new coronavirus.

While it is not clear if any of these have been tried to the fullest extent and tested to target symptomatic association of the disease, it becomes important to take cognizance of certain patient pool which ultimately develop severe lung related complications as a prime site of infection in COVID-19. Additionally, most of the antiviral drugs available on the market are oral solid preparations and injections. Oral preparations enter the human body through the digestive tract system whereas injections also need to be injected intravenously (or other route) into the human body, and the common problem in both such administration routes is that they cannot directly reach the lung lesions.

Targeting lung related treatments through inhalation is well known medical paradigm, and having reviewed the above referenced literature, there is no sufficient knowledge over the success of such inhalation route of administering nucleotide analogue prodrug class of drugs, in particular, Remdesivir, in COVID-19.

Hence, there is an instant need to develop an appropriate inhalation composition involving nucleotide analogue prodrug, in particular Remdesivir which is cost effective, which can be produced by simple manufacturing techniques, and which also exhibits better or improved patient compliance.

OBJECT OF THE INVENTION:
An object of the present invention is to provide a pharmaceutical composition administered by inhalation comprising nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients.

Another object of the present invention is to provide a pharmaceutical composition administered by inhalation comprising nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients in combination with one or more active ingredients (e.g. steroids)

Another object of the present invention is to provide a process of preparing a pharmaceutical composition administered by inhalation comprising nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients.

Yet another object of the present invention is to provide a process of preparing pharmaceutical composition administered by inhalation comprising nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients in combination with one or more active ingredients (e.g. steroids)

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

Yet another object of the present invention is to provide a pharmaceutical composition administered by inhalation comprising nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients in combination with one or more active ingredients (e.g. steroids) 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 nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients.

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 nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients in combination with one or more active ingredients (e.g. steroids).

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

Yet another object is to provide the use of inhalable pharmaceutical composition comprising nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients in combination with one or more active ingredients (e.g. steroids) 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 nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients.

According to another aspect of the present invention there is provided a pharmaceutical composition administered by inhalation comprising nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients in combination with one or more active ingredients (e.g. steroids).

According to another aspect of the present invention there is provided a process of preparing a pharmaceutical composition administered by inhalation comprising nucleotide analogue prodrug, in particular Remdesivir 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 nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients in combination with one or more active ingredients (e.g. steroids).

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

According to yet another aspect of the present invention, there is provided a pharmaceutical composition administered by inhalation comprising nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients in combination with one or more active ingredients (e.g. steroids) 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 nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients.

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 nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients in combination with one or more active ingredients (e.g. steroids).
According to yet another aspect of the present invention there is provided a use of inhalable pharmaceutical composition comprising nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients in the treatment of infection caused by Coronaviridae virus (including COVID-19).

According to yet another aspect of the present invention there is provided a use of inhalable pharmaceutical composition comprising nucleotide analogue prodrug, in particular Remdesivir along with pharmaceutically acceptable excipients excipients in combination with one or more active ingredients (e.g. steroids) in the treatment of infection caused by Coronaviridae virus (including COVID-19).

DETAILED DESCRIPTION OF THE INVENTION:
The antiviral nucleotide analogue prodrug, in particular Remdesivir, chemically referred as (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate, referred to herein as Compound 1, is a viral RNA polymerase inhibitor and is known to exhibit antiviral properties against Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses as described in Warren, T. et al, Nature (2016) 531 :381-385, and antiviral activities against Flaviviridae viruses as described in co-pending International Publication No. WO2016/069826 and WO 2017/184668. The CAS Registry Number for Compound 1 is 1809249-37-3.

[Compound 1]
A composition comprising the antiviral nucleotide analogue prodrug, in particular Remdesivir would otherwise have experienced issues such as insolubility and relative chemical instability in aqueous media that are attributed to Remdesivir, however, a suitable pharmaceutical composition is disclosed in a PCT application viz. WO2019014247 which provides a parenteral composition of Remdesivir which comprises cyclodextrins and other whereby the composition exhibits improved solubility, improved usability for parenteral administration, and sufficient room-temperature and elevated temperature stability to avoid the use of cold-chain for transport and/or storage. The WO2019014247 application acknowledges that certain solubilizers may be used to improve the solubility of a compound to form a composition capable of being administered parenterally, however such solubilizers may have certain undesirable effects (Stella, et. al. Toxicologic Pathology (2008), Vol 36, Number 1, pages 30-42). For example, a formulation including polysorbate 80 may have potential hemodynamic effects, tubing limitations, extractables and leachables from tubing, limitations on stoppers, potential for precipitation upon dilution, or issues with adaptability for pediatric use. As another example, beta-cyclodextrin derivatives are known to have certain physiological effects on kidneys, thus there is also a need to be cautious in use of such solubilizers in a pharmaceutical formulation.

Given the shortcomings in the existing approach and also to overcome effects of large drug dosage, large toxic and side effects, low bioavailability, and slow onset of the above-mentioned drugs, it will be too difficult to predict the concentrations/ level of the drug that ultimately reaches the lungs, and therefore, targeted drug delivery approach would be something that would substantially impart greater success towards treatment and/ or alleviation of infection caused by SARS-CoV-2. Additionally, with the advent of such outbreak, it becomes important to consider socio-economical conditions in the health care settings and also reduce the patient burden on the hospitals who typically have to be hospitalized for parenteral administration of the drugs being used (e.g. Remdesivir).

The inventors of the present invention have developed pharmaceutical inhalation composition comprising Remdesivir along with pharmaceutically acceptable excipients either as sole active or in combination with one or more active ingredients (e.g. steroids) which not only acts as a targeted solution showcasing improved action for 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 effective amount of Remdesivir or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients either as sole active or in combination with one or more active ingredients (e.g. steroids). According to another embodiment, the pharmaceutical inhalable composition may be provided with a suitable inhalation device associated for inhalation of the said pharmaceutical inhalable composition comprise an effective amount of Remdesivir or a pharmaceutically acceptable salt thereof either as sole active or in combination with one or more active ingredients (e.g. steroids), and one or more pharmaceutically acceptable excipients as a drug product package. The deposition of the pharmaceutical inhalable composition in the lungs and thus a successful inhalation therapy substantially depends on the droplet size distribution and the aerosol output rate as well as on the respiratory pattern of the patient. The pharmaceutical inhalable composition has different characteristics and modes of action in the body. The inhalation device influences the aerosol size (MMD, MMAD), distribution (GSD) and output rate (TOR) of the respective liquid medicament. The structure and state (morphometry) of the patient's lungs also have a significant influence on the deposition in the lungs and the success of therapy.

As used in this specification, whether in a transitional phrase or in the body of the claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound or composition, the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

As used in this specification, the singular forms “a,” “an” and “the” specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise.

The term “about” is used herein to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%.

It will be well appreciated that the term “Remdesivir” as used herein is denoted in broad sense to include not only “Remdesivir” 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.

As used herein, the term " Remdesivir " refers to the above referred Compound 1 as discussed above which is incorporated herein by reference. This term may relate either to the free form of Remdesivir or to any pharmaceutically acceptable salt thereof.

The term “steroids” refers to interchangeable terms such as corticosteroids or glucocorticoids or ICS (Inhaled corticoids) which includes one or more active ingredients such as mometasone furoate, triamcinalone acetonide, flunisolide, fluticasone propionate, fluticasone furoate, budesonide, beclomethasone dipropionate, prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and ciclesonide or its pharmaceutically acceptable salts, esters or derivatives thereof.

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. Examples, without limitation, of pharmaceutically acceptable salts include salts comprising an anion such as a carboxylate or sulfate anion, and/or a cation such as, but not limited to, ammonium, sodium, potassium, and the like. Suitable salts are described in, e.g., Birge et ai. [J Pharma Sci 1977, 66: 1-19],

The term "pharmaceutical composition" or “pharmaceutical formulation” or similar term combination refers to a formulation of Remdesivir wherein Remdesivir is present as sole active or in combination with one or more steroids either as a fixed dose combination or as a kit presentation described herein 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(s)" 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, preservatives, 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 Remdesivir along with one or more pharmaceutically acceptable carriers wherein the composition comprises either Remdesivir as sole active or in combination with one or more steroids as defined hereinabove.

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. The nebuliser may be a jet nebuliser, a vibrating mesh nebuliser, an ultrasonic wave nebuliser, a soft-mist nebuliser or a high- efficiency nebuliser. Preferred are a jet nebuliser, a vibrating mesh nebuliser, an ultrasonic wave nebuliser or a high-efficiency nebuliser, and in this embodiment the inhalable pharmaceutical composition is advantageously administered to the patient via a face mask. It is advantageous because it allows the treatment of a wider group of patients who find it difficult to use an inhaler, such as paediatric patients, geriatric patients, and patients with poor hand-inhalation coordination. The nebuliser is most preferably a jet nebuliser, which are also known as "atomisers". Jet nebulizers are connected by tubing to a compressor which causes compressed air or oxygen to flow at high velocity through the liquid medicament to turn it into an aerosol, which is then inhaled by the patient. A suitable jet nebuliser is the Pari LC®. Nebulisers are well known in the art; see, for example, Drug Delivery to the Respiratory Tract, Eds. D. Ganderton and T. Jones, VCH Publishers, 1987, pages 124-132. The inhalation time is typically 1 -15 mins.

The present invention also provides a kit comprising the inhalable pharmaceutical composition as defined herein, a nebuliser and a face mask. In a preferred embodiment, the kit comprises a nebulizer, instructions for using a nebulizer, optionally face mask and at least two unit dose containers of the inhalable pharmaceutical composition according to the present invention wherein the composition comprises either Remdesivir as sole active or in combination with one or more steroids as defined hereinabove.

According to a preferred embodiment, the pharmaceutical inhalable composition may be presented in the form of liquid solution/ suspension or as powder for solution/ suspension or as liposomal formulation comprising a therapeutically effective amount of Remdesivir either as sole active or in combination with one or more active ingredients (e.g. steroids) along with one or more pharmaceutically acceptable 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 may comprise from about 0.1 mg to about 300 mg of Remdesivir, about 0.001 mg to about 20 mg of steroids, and the volume of the nebulization composition is about 0.5 ml to about 10 ml.

The nebulization composition of the present invention may comprise Remdesivir 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 Remdesivir or its pharmaceutically acceptable salt thereof. The particle size of Remdesivir 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 or other than acid variants which comprises sodium hydroxide. In one embodiment, the pH is adjusted with 1N hydrochloric acid or 1N sulfuric acid or sodium hydroxide. In another embodiment, the pH is adjusted with one or more organic acids selected from ascorbic acid, fumaric acid and citric acid. The pH adjuster in the nebulization composition may range from about 0.01-4.0 mg of pH adjuster e.g. sodium hydroxide or Hydrochoric acid.

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, sodium citrate.

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 tonicity adjusting agent in the nebulization composition of the present invention may range from 0.01% to 2% 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.

Suitable preservatives that may be used include, but are not limited to, benzalkonium chloride, benzoic acid or benzoates such as sodium benzoate however, one problem with these solutions is that the benzalkonium chloride may cause paradoxic bronchoconstriction if the solution is administered repeatedly over short intervals and frequent exposure to benzalkonium chloride may lead to occupational asthma. Another problem is that, when inhaled by patients, the benzalkonium chloride can cause dose-dependent bronchoconstriction. The inhalation solutions of the present invention may be provided with very minimal amount (i.e. substantially free) and/ or without benzalkonium chloride (i.e. completely free), thereby making them suitable, especially in situations where the inhalation solution is administered repeatedly over a short period of time. Also, administering a substantially benzalkonium chloride-free inhalation solution to a patient may reduce the concomitant liability of adverse effects associated with benzalkonium chloride alone or in combination other excipients and/or Remdesivir. It also negates the toxicity and other side effects associated with benzalkonium chloride. Alternatively, the preservatives in the nebulization composition of the present invention may range from about 0.001% to about 0.02%w/w.
Any cosolvent that is suitable for inhalation and capable of dissolving or dispersing the Remdesivir in the mixture of cosolvent and water can be used. Examples of suitable cosolvents include, for example, alcohols, ethers, hydrocarbons, perfluorocarbons, l-Leucine and cyclodextrins. 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. Examples of cyclodextrins include Sulfobutyl ether ß-cyclodextrin sodium. The cosolvents in the nebulization composition of the present invention may range from about 0.05 to about 50% w/w.

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, lecithin, polysorbates and sorbitans may be used as surfactants in the nebulization composition. The surfactants in the nebulization composition of the present invention may range from 0.001 - 20 % w/v.

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 another preferred embodiment, the inhalable pharmaceutical composition may be presented in the form of powder for solution/ suspension comprising a therapeutically effective amount of Remdesivir either as sole active ingredient or in combination with one or more active ingredients (e.g. steroids) along with one or more pharmaceutically acceptable excipients to be administered by means of suitable nebulizers as described herein. The powder for solution/ suspension may be diluted with a suitable solvent such as water and/ or ethanol or mixtures or other suitable solvents known, and then, may be administered by means of nebulizers.

Apart from the pharmaceutically acceptable excipients mentioned herein, other representative non-limiting examples of pharmaceutically acceptable excipients for use in the inhalable pharmaceutical composition presented as powder for solution/ suspension include, without limitation, sugars such as lactose, sucrose, or glucose, or their commercially available derivatives present in an amount ranging from about 5 mg to about 100 mg; phospholipids such as egg yolk phosphatidylcholide, hydrogenated soybean phosphatidylcholide, dimyristoyphosphatidylcholide, diolyeolyl-dipalmitoyleolylphosphatidylcholide and dipalmitoyl phosphatidylcholide (DPPC) present in an amount ranging from about 0.1 mg to about 10 mg.

According to the present invention, the amount of Remdesivir in the inhalable pharmaceutical composition ranges between about 0.1 mg to about 300 mg, or from about 0.25 mg to about 250 mg or from about 0.5 mg to about 150 mg including any integer within this range. In some embodiments, the amount of Remdesivir in the inhalable pharmaceutical composition ranges between about 3 mg to about 300 mg, including any integer within this range. In some embodiments, the amount of Remdesivir in the inhalable pharmaceutical composition is less than or equal to 10 mg. In as far as the concentration of the Remdesivir is concerned in the inhalable pharmaceutical composition, a person skilled in the art may envisage a concentration range of from about 0.1 mg/mL to about 60mg/mL. Additionally, in as far as the concentration of the steroids is concerned in the inhalable pharmaceutical composition, a person skilled in the art may envisage a concentration range of from about _0.001_ mg/ ml to about _5__ mg/ml.

According to the present invention, there is provided a process of preparing a pharmaceutical composition administered by inhalation comprising Remdesivir as sole active or in combination with one or more steroids with one or more pharmaceutically acceptable excipients.

According to preferred embodiment of the present invention, a nebulization composition may involve solution of dispersion of Remdesivir in suitable excipients like surfactants or lipids 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 the invention, there is provided a pharmaceutical composition administered by inhalation comprising Remdesivir with one or more pharmaceutically acceptable excipients 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.

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 remdesivir 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 remdesivir with one or more carriers or excipients.

According to a preferred embodiment of the present invention, a dry powder composition may involve mixing and/ or homogenization of remdesivir 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 remdesivir for the treatment of infection caused by Coronaviridae virus (including COVID-19). Preferably, the pharmaceutical inhalable composition may be in the form of a dry powder composition as described hereinabove.

It may be well appreciated by a person skilled in the art that the inhalable pharmaceutical composition comprising Remdesivir 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
Following are representative nebulization formulations with either Remdesivir as the sole active ingredient as well as formulations with Remdesivir in combination with several steroids, as envisaged per the invention:

1) Remdesivir Inhalation (Nebulization)
Ingredient Quantity
Remdesivir 5 - 200 mg
Polysorbate 80 0.0-0.02 %w/v
Propylene glycol 0 - 25 % w/v
Ethanol 0 – 5 % w/w
Hydrochloric acid (for pH adjustment) 0.0- 1.0 %w/w
Sodium hydroxide (for pH adjustment) 0.0 – 4.0 %w/v
Water for Injection Qst 5mL

Manufacturing Process:
i. Add and dissolve Remdesivir, Polysorbate 80 and propylene glycol and ethanol in Water for Injection in a suitable stainless-steel vessel and continuous mixing.
ii. Keep nitrogen flushing throughout the process.
iii. Check and adjust pH, using Hydrochloric acid and or Sodium hydroxide to the desired pH value. (5.0-6.0).
iv. Fill in vials and seal.
v. Sterilize using a suitable moist heat sterilization technique.

2) Remdesivir Inhalation (Nebulization)
Ingredients Quantity (mg/mL)
Remdesivir 5
Polysorbate 80 0.1
Disodium EDTA 0.3
Sodium chloride 12.5
Citric acid monohydrate 0.506
Sodium citrate dihydrate 0.8
HCl q.s. to pH
Water q.s.

Manufacturing Process:
i. Required quantity of water was taken in SS container.
ii. Required quantity of Sodium Chloride, Citric acid, sodium citrate & polysorbate 80 are dissolved in water sequentially to form a clear solution.
iii. Remdesivir was then added to the solution to form a uniform suspension.
iv. pH was adjusted appropriately as required.
v. Final volume was made up by adding water.
vi. The resultant suspension was filled in respules.

3) Remdesivir Inhalation (Nebulization)
Ingredients Quantity (mg/mL)
Remdesivir 5
Betadex Sulfobutyl ether 300
NaOH q.s. to pH
Water q.s. to 1mL

Manufacturing Process:
i. Required quantity of water was taken in SS container.
ii. Required quantity of Betadex sulfobutyl ether was dissolved in water to form a clear solution.
iii. pH of the solution was adjusted to about 2.0.
iv. Remdesivir was then added to the solution to form a clear solution.
v. pH was adjusted appropriately as required.
vi. Final volume was made up by adding water & filtered.
vi. The resultant solution was filled in respules.

4) Remdesivir Inhalation (Nebulization)
Ingredients mg/mL
Remdesivir 5
Polysorbate 80 150
Anhydrous Citric acid 4
PEG 300 175
NaOH q.s. to pH
Water q.s. to 1mL

Manufacturing Process:
i. Required quantity of PEG was taken in SS container.
ii. Required quantity of Citric acid, polysorbate 80 & Remdesivir are dissolved in PEG sequentially to form a clear solution.
iii. pH was adjusted appropriately as required.
iv. Final volume was made up by adding water & filtered.
v. The resultant solution was filled in respules.

5) Remdesivir Dry Powder Inhaler (DPI)
Ingredients mg
Remdesivir 4.8
L-Leucine 1.2
Lactose 18.0
Acetonitrile q.s
Water q.s

Manufacturing Process:
i. Required quantity of Acetonitrile & Water were mixed in SS container.
ii. L-Leucine & Remdesivir were dissolved in the above solution sequentially to form a clear solution.
iii. The solution was spray dried in a spray dryer at specified conditions.
iv. The resultant powder was blended with specified quantity of lactose.
v. The final powder was filled in capsules.

6) Remdesivir Dry Powder Inhaler (DPI)

Ingredients mg
Remdesivir 4.8
L-Leucine 1.2
Lactose 18.0
Acetonitrile q.s
Water q.s

Manufacturing Process:
i. Required quantity of Acetonitrile & Water were mixed in SS container.
ii. L-Leucine & Remdesivir were dissolved in the above solution sequentially to form a clear solution.
iii. The solution was dried in a freeze drier at specified conditions.
iv. The resultant powder was blended with specified quantity of lactose.
v. The final powder was filled in capsules.

7) Remdesivir for Inhalation (powder for solution).
Ingredient Quantity
Remdesivir micronized 5 - 200 mg
Polysorbate 80 0.0-0.02 %w/v
Lactose monohydrate 10 – 90 mg
Sodium chloride 0.0 -0.87 %w/v
Hydrochloric acid (for pH adjustment) 1.0 %w/w
Sodium hydroxide (for pH adjustment) 0.0 – 4.0 %w/v
Water for Injection Qst 3 - 5mL

Manufacturing Process:
i. Add and dissolve Remdesivir, Polysorbate 80 and Lactose and sodium chloride in Water for Injection in a suitable stainless-steel vessel and continuous mixing.
ii. Check and adjust pH, using Hydrochloric acid and or Sodium hydroxide to the desired pH value. (5.0-6.0).
iii. Keep nitrogen flushing throughout the process.
iv. Filter the solution through 0.2µ filter and subject the vials to the lyophilization process.
v. The lyophilized vials were then sealed.

8) Remdesivir Suspension
Ingredient Quantity
Remdesivir 5 - 200 mg
Polysorbate 80 0.0-0.02 %w/v
Propylene glycol 0 - 25 % w/v
Water for Injection Qst 3 - 5mL

Manufacturing Process:
i. Aseptically, add and disperse Remdesivir, in a mixture of Polysorbate 80 and Propylene glycol in Water for Injection in a suitable vessel. Nitrogen flushing is performed throughout the process.
ii. The suspension of obtained is subjected to size reduction by wet-milling/homogenization to obtain a suspension of desired particle size range.
iii. The suspension is then filled into presterilized depyrogenated glass vials. The vials are stoppered with pre-sterilized stoppers and then sealed.

9) Remdesivir Suspension (Lipid based formulation)
Ingredient Quantity
Remdesivir 5 - 200 mg
Polysorbate 80 0.001 - 0.2 % w/v
Dipalmitoyl phosphatidylcholine (DPPC) 0.1 - 6.5 mg
Water for Injection Qst 3 - 5mL

Manufacturing Process:
i. Aseptically, add and disperse Remdesivir, Dipalmitoyl Phosphatidyl choline in a mixture of Polysorbate 80 in Water for Injection in a suitable vessel. Nitrogen flushing is performed throughout the process.
ii. The suspension of obtained is subjected to size reduction by wet milling/homogenization to obtain a suspension of desired particle size range.
iii. The suspension is then filled into presterilized, depyrogenated glass vials. The vials are stoppered with pre-sterilized stoppers and then sealed.

10) Remdesivir suspension (Nebulization) – Powder for suspension
Ingredient Quantity
Remdesivir (micronized) 5 - 200 mg
Dipalmitoyl phosphatidylcholine (DPPC) 0.25 – 6.5 mg
Polysorbate 80 0.001 - 0.2 % w/v
Water for Injection Qst 3 - 5mL

Manufacturing Process:
i. Aseptically, add and disperse Remdesivir, Dipalmitoyl Phosphatidyl choline in a mixture of Polysorbate 80 in Water for Injection in a suitable vessel. Nitrogen flushing is performed throughout the process.
ii. The suspension of obtained is subjected to size reduction by homogenization to obtain a suspension of desired particle size range.
iii. The microparticulate suspension obtained in step ii was subjected to spray drying process to remove the solvent.
iv. The dried particles obtained were then filled into presterilized depyrogenated glass vials. The vials are stoppered with pre-sterilized stoppers and then sealed.

11) Remdesivir + Budesonide suspension for Inhalation (Nebulization)
Ingredient Quantity
Remdesivir 5 - 200 mg
Budesonide 0.1 – 1.0mg
Polysorbate 80 0.0-0.02 %w/v
Propylene glycol 0 - 25 % w/v
Hydrochloric acid (for pH adjustment) 1.0- 1.0 %w/w
Sodium hydroxide (for pH adjustment) 0.0 – 4.0 %w/v
Water for Injection Qst 3 - 5mL

Manufacturing Process: (Aseptic processing)
i. Add and dissolve Remdesivir, Polysorbate 80 and Propylene glycol and ethanol in Water for Injection in a suitable stainless-steel vessel with continuous mixing.
ii. pH of the solution was adjusted to the desired pH using hydrochloric acid and or sodium hydroxide. (pH 4.5- 6.5)
iii. Keep nitrogen flushing throughout the process.
iv. In a separate container add and disperse micronized budesonide, polysorbate 80 and water for injection to form uniform concentrated suspension.
v. The budesonide concentrate suspension is added to the solution of step two under continuous mixing to form a uniform suspension.
vi. Volume make up was done using water for injection.
vii. The suspension is then filled in presterilized vials and sealed.

12) Remdesivir + ciclesonide suspension for Inhalation (Nebulization)
Ingredient Quantity
Remdesivir 5 - 200 mg
Ciclesonide 1 – 200 mcg
Polysorbate 80 0.0-0.02 %w/v
Propylene glycol 0 - 25 % w/v
Edetate sodium 0.001 – 0.05 % w/w
Hydrochloric acid (for pH adjustment) 0.0 -1.0 % w/w
Sodium hydroxide (for pH adjustment) 0.0 – 4.0 %w/v
Water for Injection Qst 3 - 5mL

Manufacturing Process: (Aseptic processing)
i. Add and dissolve Remdesivir, Polysorbate 80 and Propylene glycol and ethanol in Water for Injection in a suitable stainless-steel vessel with continuous mixing.
ii. pH of the solution was adjusted to the desired pH using hydrochloric acid and or sodium hydroxide. (pH 4.5- 6.5)
iii. Keep nitrogen flushing throughout the process.
iv. In a separate container add and disperse micronized ciclesonide, polysorbate 80, edetate sodium and water for injection to form uniform concentrated suspension.
v. The ciclesonide concentrate suspension is added to the solution of step two under continuous mixing to form a uniform suspension.
vi. Volume make up was done using water for injection.
vii. The suspension is then filled in presterilized vials and sealed.

13) Remdesivir + Mometasone furoate suspension for Inhalation (Nebulization)
Ingredient Quantity
Remdesivir 5 - 200 mg
Mometasone furoate 0.001-0.5mg
Polysorbate 80 0.0-0.02 %w/v
Propylene glycol 0 - 25 % w/v
Glycerin 0.1 – 5%w/w
Hydrochloric acid (for pH adjustment) 0.0 -1.0 %w/w
Sodium hydroxide (for pH adjustment) 0.0 – 4.0 %w/v
Water for Injection Qst 3 - 5mL

Manufacturing Process: (Aseptic processing)
i. Add and dissolve Remdesivir, Polysorbate 80 and propylene glycol and ethanol in Water for Injection in a suitable stainless-steel vessel with continuous mixing.
ii. pH of the solution was adjusted to the desired pH using hydrochloric acid and or sodium hydroxide. (pH 4.5- 6.5)
iii. Keep nitrogen flushing throughout the process.
iv. In a separate container add and disperse micronized mometasone, polysorbate 80, glycerin and water for injection to form uniform concentrated suspension.
v. The Mometasone furoate concentrate suspension is added to the solution of step two under continuous mixing to form a uniform suspension.
vi. Volume make up was done using water for injection.
vii. The suspension is then filled in presterilized vials and sealed.

14) Remdesivir + Flunisolide suspension for Inhalation (Nebulization)
Ingredient Quantity
Remdesivir 5 - 200 mg
Flunisolide 0.01 – 0.3 % w/v
Polysorbate 80 0.0-0.02 %w/v
Propylene glycol 0 - 25 % w/v
Glycerin 0.1 – 5%w/w
Hydrochloric acid (for pH adjustment) 0.0 - 1.0 %w/w
Sodium hydroxide (for pH adjustment) 0.0 – 4.0 %w/v
Water for Injection Qst 3 - 5mL

Manufacturing Process: (Aseptic processing)
i. Add and dissolve Remdesivir, Polysorbate 80 and propylene glycol and ethanol in Water for Injection in a suitable stainless-steel vessel with continuous mixing.
ii. pH of the solution was adjusted to the desired pH using hydrochloric acid and or sodium hydroxide. (pH 4.5- 6.5)
iii. Keep nitrogen flushing throughout the process.
iv. In a separate container add and disperse micronized flunisolide, polysorbate 80, glycerin and water for injection to form uniform concentrated suspension.
v. The flunisolide concentrate suspension is added to the solution of step two under continuous mixing to form a uniform suspension.
vi. Volume make up was done using water for injection.
vii. The suspension is then filled in presterilized vials and sealed.

15) Remdesivir + beclomethasone dipropionate suspension for Inhalation (Nebulization)
Ingredient Quantity
Remdesivir 5 - 200 mg
Beclomethasone dipropionate 0.1 – 1.0mg
Polysorbate 80 0.0-0.02 %w/v
Propylene glycol 0 - 25 % w/v
Glycerin 0.1 – 5%w/w
Hydrochloric acid (for pH adjustment) 0.0 - 1.0 %w/w
Sodium hydroxide (for pH adjustment) 0.0 – 4.0 %w/v
Water for Injection Qst 3 - 5mL

Manufacturing Process: (Aseptic processing)
i. Add and dissolve Remdesivir, Polysorbate 80 and propylene glycol and ethanol in Water for Injection in a suitable stainless-steel vessel with continuous mixing.
ii. pH of the solution was adjusted to the desired pH using hydrochloric acid and or sodium hydroxide. (pH 4.5- 6.5)
iii. Keep nitrogen flushing throughout the process.
iv. In a separate container add and disperse microcrystalline beclomethasone dipropionate, polysorbate 80, glycerin and water for injection to form uniform concentrated suspension.
v. The Beclomethasone dipropionate concentrate suspension is added to the solution of step two under continuous mixing to form a uniform suspension.
vi. Volume make up was done using water for injection.
vii. The suspension is then filled in presterilized vials and sealed.

16) Remdesivir + Fluticasone propionate suspension for Inhalation (Nebulization)
Ingredient Quantity
Remdesivir 5 - 200 mg
Fluticasone propionate 1 – 200 mcg
Polysorbate 80 0.0-0.02 %w/v
Propylene glycol 0 - 25 % w/v
Edetate sodium 0.001 – 0.05 % w/w
Hydrochloric acid (for pH adjustment) 0.0 -1.0 % w/w
Sodium hydroxide (for pH adjustment) 0.0 – 4.0 %w/v
Water for Injection Qst 3 - 5mL

Manufacturing Process: (Aseptic processing)
i. Add and dissolve Remdesivir, Polysorbate 80 and Propylene glycol and ethanol in Water for Injection in a suitable stainless-steel vessel with continuous mixing.
ii. pH of the solution was adjusted to the desired pH using hydrochloric acid and or sodium hydroxide. (pH 4.5- 6.5)
iii. Keep nitrogen flushing throughout the process.
iv. In a separate container add and disperse micronized fluticasone propionate, polysorbate 80, edetate sodium and water for injection to form uniform concentrated suspension.
v. The fluticasone propionate concentrate suspension is added to the solution of step two under continuous mixing to form a uniform suspension.
vi. Volume make up was done using water for injection.
vii. The suspension is then filled in presterilized vials and sealed.

17) Remdesivir + Dexamethasone sodium phosphate solution for Inhalation (Nebulization)
Ingredient Quantity
Remdesivir 5 - 200 mg
Dexamethasone sodium phosphate 0.01 – 20 mg
Polysorbate 80 0.0-0.02 %w/v
Propylene glycol 0 - 25 % w/v
Sodium chloride 0.0 – 0.87 %w/v
Hydrochloric acid (for pH adjustment) 2.0- 1.0 %w/w
Sodium hydroxide (for pH adjustment) 0.0 – 4.0 %w/v
Water for Injection Qst 3 - 5mL

Manufacturing Process: (Aseptic processing)
i. Add and dissolve Remdesivir, Polysorbate 80 and Propylene glycol and ethanol in Water for Injection in a suitable stainless-steel vessel with continuous mixing.
ii. In a separate container add and dissolve dexamethasone sodium phosphate, sodium chloride, polysorbate 80 and water for injection with continuous stirring.
iii. Mix the solution of step ii to the solution of step I with continuous mixing to get a clear solution.
iv. pH of the solution was adjusted to the desired pH using hydrochloric acid and or sodium hydroxide. (pH 5.0 – 7.0)
v. Volume make up was done using water for injection.
i. The suspension is then filled in presterilized vials and sealed.

STABILITY DATA
Batch details 1045-019 (Suspension Strategy – Example 2)
Pack Limits Glass vial
Condition Initial 2-8C 30C/75%RH 40C/75%RH
Timepoints 1M 3M 1M 3M 1M 3M
Assay (%) 90-110 97.3 92.6 95.9 94 96.5 97.4 96.9
Related substances (%)
Imp A (GS441524) NMT 2% <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1
Des Alanine (GS711463) NMT 4% ND <0.1 ND <0.1 ND <0.1 ND
SMI NMT 1% <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1
Total IMP NMT 6% <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1
Conclusion: All the results are within acceptable limits
Batch number 1071-027 (Drug: SBECD::1:60 – Example 3)
Pack Limits Glass vial
Condition Initial 2-8C 25C/60%RH
Timepoints - 1M 3M 1M 3M
Assay (%) 90-110 99.2 97.9 99.3 96.6 94.1
Related substances (%)
Imp A
(GS-441524) NMT 2.0 <0.1 <0.1 <0.1 0.26 0.91
Des-Alanine Remdesivir (GS-711463) NMT 4.0 ND 0.1 0.26 0.49 1.03
SMI NMT 1.0 0.19 0.11 0.1 0.11 0.15
Total Imp NMT 6.0 0.3 0.21 0.36 0.82 2.19

Conclusion: All the results are within acceptable limits
Batch number 1071-050 (PEG and Polysorbate 80 – Example 4)
Pack Limits Glass vial
Condition Initial 2-8C 25C/60%RH
Timepoints - 1M 3M 1M 3M
Assay (%) 90-110 97.3 98.2 96.7 95.9 93.3
Related substances (%)
Imp A
(GS-441524) NMT 2.0 <0.1 <0.1 <0.1 <0.1 0.23
Des-Alanine Remdesivir
(GS-711463) NMT 4.0 <0.1 <0.1 <0.1 <0.1 1.09
SMI NMT 1.0 <0.1 <0.1 <0.1 <0.1 0.63
Total Imp NMT 6.0 <0.1 <0.1 <0.1 <0.1 2.8

Conclusion: All the results are within acceptable limits

,CLAIMS:
1. A pharmaceutical composition administered by inhalation comprising remdesivir or its pharmaceutically acceptable derivative thereof.
2. The pharmaceutical composition according to claim 1, comprising remdesivir in an amount from about 0.1 mg to about 300 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 5, wherein the surfactant is polysorbate 80.
6. The pharmaceutical composition according to claim 5, wherein the cosolvent is Sulfobutyl ether ß-cyclodextrin.
7. The pharmaceutical composition according to claim 1 or 2, wherein the composition is in a form suitable for use in a dry powder inhaler.
8. 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.
9. The pharmaceutical composition according to claim 1 or 2, wherein the composition is in a form suitable for use in a metered dose inhaler.
10. 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.
11. The pharmaceutical composition according to any preceding claim, comprising favipiravir for use in the treatment of an infection caused by COVID-19
12. A pharmaceutical composition substantially as herein described with reference to the examples.