Claims:1. A process for synthesis of Remdesivir with reduced and controlled particle size, desired shape and surface morphology, comprising
(i) Dissolving (2S)-2-ethylbutyl 2-(((4-nitrophenoxy) (phenoxy) phosphoryl) amino) propanoate in a solvent at ambient temperature followed by addition of (2R,3R,4S.5R)-2-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)-tetrahydro furan-2-carbonitrile and cooling the reaction mixture;
(ii) Adding solution of Isobutyl magnesium chloride to the reaction mass of step (i) followed by controlled addition of potassium carbonate, heating the mixture until completion of the reaction, distilling the solvent followed by washing, extraction and purification to obtain crude Remdesivir;
(iii) Transferring the solution mass of crude Remdesivir of step (ii) along with solvent to crystallization reactor and maintaining at low temperature to achieve complete precipitation, followed by filtering through centrifuge and drying under vacuum;
(iv) Dissolving the solid mass of step (iii) in a mixture of solvent selected from lower branched alcohols and aromatic hydrocarbons and performing chiral separation using preparative high performance liquid chromatography (HPLC) system, recovering the solvent and filtering the solid mass through centrifuge followed by drying under vacuum;
(v) Preparing uniform solution of Remdesivir of step (iv) with concentration of 1%wt/vol in a solvent selected from lower branched alcohols, ketones or combinations thereof and fluidizing the liquid mass;
(vi) Converting the fluidized liquid mass of step (v) into a fine spray (mist) in a cryogenic air medium under inert atmosphere followed by sublimation of the solvent to obtain ultrafine particles of Remdesivir powder; and
(vii) Transferring the Remdesivir powder of step (vi) to a drying chamber under inert atmosphere to obtain dried inhalation Remdesivir in the preferable shape of elongates with particle sizes in the range of 1 nm to 5000 nm.

2. The process as claimed in claim 1, wherein ultrafine particles of Remdesivir powder in the preferable shape of elongates having sizes in the range of 1 nm to 5000 nm may be obtained by atomizing crude Remdesivir solution and freezing simultaneously by mixing with a liquefied gas or supercritical fluid such as supercritical CO2 (carbon dioxide), liquid nitrogen, halocarbon refrigerants such as chlorofluorocarbon or fluorocarbon, hydrofluoroalkanes, hydrofluorocarbons, and their likes.

3. The process as claimed in claim 1, wherein the solvent is selected from polar or non-polar, protic or aprotic solvents selected from ethers such as THF, DMF; alcohols such as lower alcohols; chlorinated hydrocarbons such as Methylene dichloride; ketones, aliphatic or aromatic hydrocarbons and the like alone or combinations thereof.

4. Remdesivir in the preferable shape of elongates, having particle sizes in the range of 1nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3.

5. The process for synthesis of Remdesivir as claimed in claim 4, comprising;
(i) Dissolving crude Remedesivir in a solvent in a crystallization reactor and maintaining at low temperature to achieve complete precipitation, followed by filtering through centrifuge and drying under vacuum;
(ii) Dissolving the solid mass of step (i) in a mixture of solvents selected from lower branched alcohols and aromatic hydrocarbons and performing chiral separation using preparative high performance liquid chromatography (HPLC) system, recovering the solvent and filtering the solid mass through centrifuge followed by drying under vacuum;
(iii) Preparing uniform solution of Remdesivir of step (ii) with concentration of 1%wt./vol in a solvent selected from lower branched alcohols, ketones or combinations thereof and fluidizing the liquid mass;
(iv) Converting the fluidized liquid mass of step (iii) into a fine spray (mist) in a cryogenic air medium under inert atmosphere followed by sublimation of the solvent to obtain ultrafine particles of Remdesivir powder; and
(v) Transferring the Remdesivir powder of step (iv) to a drying chamber under inert atmosphere to obtain dried inhalation Remdesivir with particle size in the range of 1 nm to 5000 nm.

6. Dry powder inhalation (DPI) composition comprising;
(i) Remdesivir as claimed in claim 4 in an amount of 8.75 to 52.5 mg;
(ii) Carbohydrate (fine particles) in an amount ranging from 5% to 12.5% of the total composition; and
(iii) Carbohydrate (coarse particles) in an amount ranging from 35% to 60% of the total composition.
wherein the carbohydrates are selected from the group consisting of fructose, glucose, mannitol, maltose, trehalose, cellobiose, lactose, sucrose cyclodextrin, raffinose, xylitol, and maltodextrin in the form of a combination of fine and coarse particles.

7. The process for preparing a dry powder inhaler (DPI) composition as claimed in claim 6, comprising;
(i) Uniform mixing of carbohydrates of fine and coarse forms in desired ratio by using 3 dimensional blending followed by sifting;
(ii) Uniform mixing of carbohydrate blend with said Remdesivir by using 3 dimensional blending and encapsulating the blend in capsules or blister packs or reservoir packs thereof.

8. The dry powder inhalation (DPI) composition as claimed in claims 6 and 7, wherein said composition releases said Remdesivir in therapeutically effective amount ranging from 8.75 mg to 52.5 mg per inhalation in divided doses per day.

9. Remdesivir pressurized metered dose inhalation (pMDI) aerosol composition comprising;
(i) Remdesivir as claimed in claim 4 in an amount ranging from 2.9mg to 42.5 mg;
(ii) Propellant selected from Hydrofluoroalkane (HFAs), Chlorofluorocarbon (CFCs), CO2, Nitrogen, alone or mixtures thereof; preferably, 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or a mixture thereof;
(iii) Additionally or optionally Co-solvent(s) selected from the group of lower branched or linear alkyl (C1-C4) alcohols up to 25%w/w of the formulation;
(iv) Additionally or Optionally the surfactants selected from Sorbitan trioleate such as Span 85, Lecithin, Oleic Acid BP/EP/USP, Polyoxyethylene (20) sorbitan monolaurate,
Polyoxyethylene (80), sorbitan mono-oleate,
lecithins derived from natural sources and their likes or mixtures thereof in an amount of 0.1% w/w of the formulation;
(v) Additionally or optionally Sodium cromoglycate BP/EP/USP as mast cell stabilizer in an amount of 0.5% w/w of the formulation; and
(vi) Additionally or optionally pharmaceutically acceptable excipients in an amount of up to 1% w/w of the formulation.

10. The Remdesivir pressurized metered dose inhalation aerosol formulation as claimed in claim 9 in a canister-in-canister pMDI device.

11. The process for preparation of Remdesivir pressurized metered dose Inhalation (pMDI) for single stage pressurized suspension filling in metered dose Inhalers as claimed in claims 9 and 10 comprising;
(i) Preparing the suspension of said Remdesivir with suitable propellant in pressurized mixing vessel with or without co-solvents and additionally or optionally the surfactants and additionally or optionally Sodium cromoglycate BP/EP/USP and additionally or optionally pharmaceutically acceptable excipients;
(ii) Homogenizing the mixture under pressure and stirring for specific time interval to obtain uniform aerosol powder suspension; and
(iii) Filling the specific quantity of said suspension into sealed canisters under high pressure.

12. The process for preparation of Remdesivir pressurized metered dose Inhaler as claimed in claims 9 and 10 by 2 stage filling comprising;
(i) Filling the open canister with said Remdesivir;
(ii) Sealing the canisters with a metering valve provided with sealing rings and/or gasket;
(iii) Filling suitable propellant under pressure through the sealed valve into the sealed canisters;
(iv) Sonicating the filled canisters at specified frequency followed by rotatory spinning of the canisters at specified time interval to achieve uniform suspension inside the canisters.
13. The pressurized metered dose (pMDI) composition as claimed in claims 9 to 12, wherein said composition releases Remdesivir in therapeutically effective amount ranging from 2.9 mg to 42mg per actuation divided in multiple desired doses per day and actuations in volumes ranging from 50µl to 120µl per actuation.

14. A dry powder inhaler (DPI) device for delivering Remdesivir powder for Inhalation as claimed in claims 6 to 8 after encapsulation directly to the lungs with substantial reduction in physical resistance while inhalation comprising;
(i) a powder holding chamber (6)for receiving composition to be inhaled;
(ii) a mouth piece (2)with a top body (1), wherein an opening of the mouth portion leads into a mesh duct(3);
(iii) a capsule inlet (4)and air inlets (5)being attached to the top body(1), wherein a base body(7) opening leads into a powder holding chamber (6)and the powder holding chamber extends along a common longitudinal axis when the mouth piece abuts the base body (7);
wherein said device imparts a cyclonic motion onto air within chamber to ensure improved level of the composition is inhaled.

15. The inhaler device as claimed in claim 14, wherein said Remdesivir powder for inhalation in capsules has total powder content in the range between 14 mg to 100 mg.

16. A nebulizer composition comprising Remdesivir as claimed in claim 4 together with pharmaceutically acceptable excipients.

17. A method for treating patients infected with SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses comprising administering pressurized metered dose inhalation (pMDI) composition of Remdesivir as claimed in claim 4 in therapeutic amount ranging from 2.9 mg to 42 mg per actuation divided in multiple desired doses per day and volumes ranging from 50µl to 120µl per actuation to the subject in need thereof.
18. A method for treating patients infected with SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses comprising administering dry powder inhalation (DPI) composition of Remdesivir as claimed in claim 4 in therapeutically effective amount ranging from 8.75 mg to 52.5 mg per inhalation in divided doses per day to the subject in need thereof.
19. A method for treating patients infected with SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses comprising administering to the subject in need via a nebulizer, a formulation comprising Remdesivir as claimed in claim 4.
20. The pressurized metered dose inhalation (pMDI) composition comprising Remdesivir as claimed in claim 4 for use in the treatment of SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses.
21. The dry powder inhalation composition comprising Remdesivir as claimed in claim 4 for use in the treatment of SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses.
22. A nebulizer composition comprising Remdesivir as claimed in claim 4 for use in the treatment of SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses.
, Description:Field of Invention
The present invention relates to a process for preparation of Remdesivir with reduced and controlled particle size, desired shape and surface morphology suitable for formulating into pressurized metered dose inhalations (pMDI), dry powder inhalation (DPI) and nebulization compositions. The present invention further relates to processes and compositions for preparation of Remdesivir pressurized metered dose inhalations and dry powder for inhalations (DPI). The present invention further relates to a novel dry powder inhalation device with reduced physical resistance to the flow of the powder, higher product flowability and suitable for delivering Remdesivir with high drug and/or powder content.

Background of the Invention
Remdesivir is chemically described as 2-Ethylbutyl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl]methoxy}-(phenoxy)phosphoryl]amino} propanoate represented by structural figure given below


Remdesivir is a nucleotide prodrug RNA polymerase inhibitor developed for the treatment of emerging viruses such as 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 International Publication No. WO2017/184668. The PCT application describes in detail the effective method of inhibiting viral infections which include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples; laboratory samples; food, water, or air samples; biological derivatives such as extracts of cells, particularly recombinant cells synthesizing the desired glycoprotein; and the like and/or Ebola virus (EBOV), Marburg virus (MARV) and Nipah virus (NiV).

US10695357B2 describes the method for treating Filoviridae virus infections, particularly methods and nucleosides for treating the Ebola virus, Marburg virus, and Cueva virus by administering the therapeutically effective amount of the drug Remdesivir or its pharmaceutically acceptable salts.

US Patent No.US9724360B2 and many other known inventions as yet have been for manufacturing Remdesivir Intravenous powder for Infusion.

For ongoing pandemic of COVID-19, Remdesivir is a promising drug to treat COVID-19. It has also been authorized product by International Medical agencies and DCGI in India to be used as an alternative treatment for patients with mild to moderate symptoms of Covid-19.

The Intravenous (IV) injectable form of this drug is allowed to be administered to patients with Covid-19 in a hospital set-up on an investigational and compassionate use basis in a few countries.

The dose regimen of Remdesivir through the intravenous route is as follows:
1. Loading dose of 200 mg to be administered on day 1.
2. This loading doses is followed by daily intravenous maintenance doses of 100 mg for 5–9 days depending on the condition and severity of the patients and response to the dose.

However, Remdesivir with IV administration alone is unlikely to achieve high clinical efficacy because plasma exposures of Remdesivir and its active metabolite are unlikely to be correlated with its clinical efficacy. Remdesivir and its active metabolites, when administered through intravenous route are highly unlikely to be adequate in the lungs to kill the SARS-CoV-2 or Covid19 virus as its efficacy may get limited due to the IV route of administration.

Remdesivir when administered intravenously, it distributes into tissues and blood cells through passive diffusion. Once inside the cells, Remdesivir is converted into Nuc-MP by intracellular hydrolases, ultimately forming the active metabolite nucleoside triphosphate (Nuc-TP) intracellularly. Intracellular Nuc-TP is negatively charged and thus it is trapped inside cells with a half-life of 14–24 hours. Therefore, Nuc-TP cannot be detected in plasma, but is only detected in blood cells such as peripheral blood mononuclear cells at highly accumulated concentrations (20– 40 µM). The accumulation in PBMCs may be helpful to achieve antiviral activity against SARS-CoV-2 in these white blood cells. However, since COVID-19 patients typically have lymphopenia, this suggests SARS-CoV-2 may infect lymphocytes. If Nuc-TP accumulates in lymphocytes, an abundance of Nuc-TP in these cells may help to inhibit SARS-CoV-2. However, it is not known if the high intracellular accumulation of Nuc-TP in PBMCs is correlated with its clinical efficacy against COVID-19, nor if this intracellular distribution translates into the high intracellular concentration in the lung where SARS-CoV-2 infects.

The direct pulmonary delivery of Remdesivir, however, may provide higher lung concentrations of Remdesivir and Nuc-TP as well as reduce the systemic toxicity in COVID-19 patients. To reach an intracellular Nuc-TP concentration of 17.6 µM (IC90) in the human lungs, the total amount of Remdesivir to be delivered into the lung is projected to be approximately 10.5 mg (17.6 µM × 0.54 Lit ÷ 55% × 603 g/mol), where 0.54 Lit is the total intracellular fluid volume (46%) of human lung volume, and 55% of Remdesivir in human cells is converted into Nuc-TP.

Required
Intracell-ular IC90 of
Nuc-TP in the lung Percentage
of Remdesivir
metabolized into
Nuc-TP (%) Molecular
weight of
Remdesivir Intra-cellular
volume
of the
human lung Total
volume of the
human lung Required dose
of Remdesivir to
reach the lung
17.6 µM 55 603 0.54l 1.17l 10.5mg

This infers that the IV dose regimen of 100 mg per day for 5-9 days is too high and patient unfriendly. This targeted lesser drug delivery to the lungs can be achieved by developing suitable pMDI, DPI and nebulization dosage forms. However, the API of Remdesivir developed as per the prior art is not suitable for pMDI and DPI dosage forms due to its inappropriate surface morphology, shape and particle size.

There exist many more problems associated with the IV route of administration. The IV dosage form can only be administered in a hospital infrastructure under scrutiny by medical professionals only, thereby leading to a delay for start of treatment and also not being accessible to large masses of people.

Further, the final drug becomes expensive due to its formulation in Intravenous form. The IV dosage form cost per patient becomes quite high since additional costs get involved in administering the IV dose and hospital administration cost. The high dosage dependency in an IV form along with the add-on hospitalization expenses adds to the burden of the cost of the overall treatment.

Hence, there exists an urgency for developing different dosage forms and altering the drug administration method; targeting the increased bioavailability and efficacy of the drug and in tandem which shall drastically help in reducing the cost.
Inhalers are well known for administering pharmaceutically active ingredients to the respiratory tract by inhalation. The deposition of aerosol formulations such as pMDI and DPI is affected by several factors, of which one of the most important is the aerodynamic particle size. Solid particles and /or droplets in an aerosol formulation can be characterised by their mass median aerodynamic diameter (MMAD); the diameter around which the mass aerodynamic diameters are distributed equally.

Particle deposition in the lung depends largely upon three physical mechanisms:
1. Impaction, a function of particle inertia
2. Sedimentation due to gravity
3. Diffusion resulting from Brownian motion of fine sub micrometer particles.

The mass of the particles determines which of the three main mechanisms are the most important. The effective aerodynamic diameter is a function of the size, shape and density of the particles and will affect the magnitude of forces acting on them as inertial and gravitational effects increases with increasing particle size and particle density, the displacements produced by diffusion decrease. Diffusion also plays a part in deposition of medicament. Impaction and sedimentation can be assessed from a measurement of the MMAD which determine the displacement across streamlines under the influence of inertia and gravity, respectively.

Administration of antiviral drugs for COVID -19 by oral inhalation route is very much in focus because of advantages offered like rapid and predictable onset of action, cost effectiveness and high level of comfort for the user. Pressurized Metered dose inhalation and dry powder inhalation are preferred as an administration tool as compared to other administration route and dosage forms because of the flexibility they offer in terms of nominal dose range i.e. the amount of active substance that can be administered in single inhalation.

The changes in the particle size, shape and morphology of medicament, is known to significantly affect its deposition to the lungs and therefore, affect the bio-availability and efficacy. Different factors play role in functioning of the composition in terms of efficacy. Development of formulations in terms of particle size distribution, particle density, morphology, surface roughness, flowability and surface energy suitable for maximizing drug delivery to lungs is of paramount importance for therapeutic pMDIs and DPIs.

As the density of population is quite high in major parts of the world, the control of the spread of Covid19 shall remain challenging. Even after the pandemic subsides, there could be a resurgence of Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae infections at any time and it could always become endemic seasonally. A large population base may require Remdesivir Inhalations for direct pulmonary administrations since it offers the possibility of early and timely administration, ease of usage and the possibility of self-administration in an outpatient set-up and substantially reduce the cost of the treatment for the affected individuals. Hence, appropriate Inhalation dosage forms for direct drug delivery on lungs are primarily needed to be developed for Remdesivir for catering to the demand in India and for all over the world. Therefore, the current situation demonstrates the plausible need and immense potential for its commercialization.

Further, it is necessary to provide an inhalation device that could deliver the API powder in an amount of above 30mg.

Prior art document US 2003/0000523 AI discloses an inhaler device comprising an inhaler body defining a recess for receiving a container in which a substance to be inhaled is contained. A mouthpiece communicating with the container is also provided together with a perforating element which is coupled to the inhaler body and provided for perforating the container so as to allow an outside air flow to be mixed with the container content and inhaled through the mouthpiece.
Prior art document EP1238680B1 discloses an inhaler device comprising a compartment for receiving a container and a cutting element for cutting or perforating the container and thereby releasing medicament contained within the container. The inhaler further comprises a grid for catching pieces of container while allowing passage of medicament to be inhaled. The inhaler may be equipped with disposable accessories to be placed into the mouth.

Prior art document WO2005/113043 A1 discloses an inhaler device that operates to break a container of medicament when parts of the device are rotated relative to one another. On inhalation by a patient, air travels through an inlet into a chamber wherein the air is redirected through 180° before passing through a mouthpiece.

Dry powder Inhalers conventionally known in the art for administering doses of dry powdered medicaments are generally designed for convenient handling and inhalation of the medicament dose whereby the total powder content from the container to be delivered is less than 30 mg.

Further, some devices in prior art are for use with containers of dry powdered medicament and are typically designed in such a way so as to require a piercing of the container so that inhalation of the medicament can be effected. However, on continuous usage and cleaning of such devices, there often occurs operational difficulty as a result of rusting of the piercing mechanism which, in turn, results in an improper piercing of a container and decreases the efficiency of the drug delivery. It will be understood that the rusting of the piercing mechanism is a consequence of a frequent exposure of the piercing mechanism to cleaning solvents/agents and general moisture. Furthermore, as a consequence of piercing a container, fragmentation of a container shell results in a risk of inhalation of shell fragments.

Moreover, the single dose dry powder inhaler devices known in the prior art that pierce, open or break a capsule to deliver the powder composition have a mesh / grid / grate with perforations / apertures / openings designed in a way such that the capsule body/shell remain in the holding chamber that is separate from the mouth piece and whereas the powder composition flows through the mouthpiece. However, all such prior art devices use a mesh with more number ofphysical partitions leading to lesser residual airflow area.Designs of the prior art provide an air flow area percentage of maximum up to 86%, whereas the residual resistance area remains to as high as 14%. This constraint makes prior art designs to be not suitable for delivering compositions having powder content to be of more than 30 mg. Due to this, in case of container composition having more than 30 mg powder,sufficient quantity of the powder does not reach the lungs. Whereas, the chief objective of the device from a therapeutic aspect is the maximization of the quantity of powder that reaches the lungs. This objective is defeated with devices of the prior art for delivery powder quantity of more than 30 mg.

The European Respiratory Society and the International Society of Aerosolised Medicine (ERS/ISAM) task force have highlighted three factors that need to be considered in optimising the chances of inhaled medications reaching their targets in the lung. These three factors are:
Particle size — smaller particles are more likely to reach the airways in greater numbers, penetrate deeper into the lung, spread more evenly through the lung, pass through partially obstructed airways, and reach diseased and damaged areas;
Flow — lower flow rates of medicament avoid impaction of particles around corners; and
Breathing pattern - a slow, controlled deep inhalation or, if this cannot be achieved, normal relaxed tidal breathing will improve lung delivery, and airway penetration.

DPI device described under prior art WO2005/113043 A1, fails to embrace outlined factors in the ISAM report as extracted above to considerable manner. In particular, it requires a device which offers low resistance passage to achieve complete inhalation of drug and de-aggregate the particles directly to lungs as the device with high resistance explicitly at mesh will require patients to inhale deeply and forcefully in order to receive the specific dosage.

DPI device described under prior art WO2005/113043 A1, fails to embrace aggregated drug delivery during inhalation due to complex mesh grid leading to high content of drug retention at mesh walls and further reduction of inhaled volume and an air flow area percentage of maximum 86%, hence delivering very less quantity of medicament; making it not suitable especially for delivering compositions with high powder content of more than 30 mg.

DPI device described under prior art WO2005/113043 A1, fails to embrace mouth piece outlet and due to absence of virtuous vertex, during each inhalation the drug volume would be retained on mucosal surfaces when rounding corners, such as in the pharynx, glottic area and each branch in the airways resulting in only a small number (<30%) reaching the target areas in the lung. These factors become even more pertinent in diseased lungs where most drugs will preferentially follow the path of least resistance towards the “healthier” parts of the lung, with very little drug penetrating to areas where it is needed most.

The present inventors therefore felt that the need of the art may be met by providing Remdesivir with a reduced and controlled particle size, desired shape and surface morphology which would be suitable to formulate into Inhalation dosage forms. The present invention further relates to processes and compositions for preparation of Remdesivir pressurized metered dose inhalations and dry powder for inhalations (DPI).
The present invention also provides a dry powder inhalation device that could deliver the Remdesivir drug alongwith excipients with total powder content in an amount of above 30mg.

SUMMARY OF THE INVENTION
It is the primary objective of the present invention to provide a process for synthesis of Remdesivir with reduced and controlled particle size, desired shape and surface morphology suitable for inhalation.

The other objective is to formulate the Remdesiviras prepared into pressurized metered dose inhalations (pMDI) and dry powder inhalation (DPI) and nebulization compositions with high stability, increased shelf life for direct deposition onto the lungs through the pulmonary route with high efficacy and bio-availability.

Yet another objective of the present invention is to provide Remdesivir pMDI and DPI that can be self-administered with ease by patients so as to minimize the systemic damage and provide instant relief.

The other objective is to provide Remdesivir pMDI and DPI with better Patient compliance and which avoids hospitalization.

Yet another objective of the present invention is to provide inhalation device with reduced physical resistance to the flow of the powder, higher product flow-ability and suitable for administering medicaments with high drug and/or powder content.

In lieu with the above objectives, the present invention provides synthesis of Remdesivir with reduced and controlled particle size, desired shape and surface morphology, comprising
(i) Dissolving (2S)-2-ethylbutyl 2-(((4-nitrophenoxy) (phenoxy) phosphoryl) amino) propanoate in a solvent at ambient temperature followed by addition of (2R,3R,4S.5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-carbonitrile and cooling the reaction mixture;
(ii) Adding solution of Isobutyl magnesium chloride to the reaction mass of step (i) followed by controlled addition of potassium carbonate, heating the mixture until completion of the reaction, distilling the solvent followed by washing, extraction and purification to obtain crude Remdesivir;
(iii) Transferring the mass of crude Remdesivir of step (ii) in the solvent to crystallization reactor and maintaining at low temperature to achieve complete precipitation, followed by filtering through centrifuge and drying under vacuum;
(iv) Dissolving the solid mass of step (iii) in a mixture of solvents selected from lower branched alcohols and aromatic hydrocarbons and performing chiral separation using preparative high performance liquid chromatography (HPLC) system, recovering the solvent and filtering the solid mass through centrifuge followed by drying under vacuum;
(v) Preparing uniform solution of Remdesivir of step (iv)with concentration of 1%wt./vol in a solvent selected from lower branched alcohols, ketones or combinations thereof and fluidizing the liquid mass;
(vi) Converting the fluidized liquid mass of step (v) into a fine spray (mist) in a cryogenic air medium under inert atmosphere followed by sublimation of the solvent to obtain ultrafine particles of Remdesivir powder; and
(vii) Transferring the Remdesivir powder of step (vi) to a drying chamber under inert atmosphere to obtain dried inhalation Remdesivirin the preferable shape of elongates with particle sizes in the range of 1 nm to 5000 nm.

In an alternate aspect of the process, ultrafine particles of Remdesivir powder in the preferable shape of elongates in the particle size range of 1nm to 5000nm may be obtained by atomizing crude Remdesivir solution and freezing simultaneously by mixing with a liquefied gas or supercritical fluids such as supercritical CO2 (carbon dioxide), liquid nitrogen, halocarbon refrigerants such as chlorofluorocarbon or fluorocarbon, hydrofluoroalkanes, hydrofluorocarbons, and their likes.
In an aspect, the present invention provides Remdesivir in the preferable shape of elongates, with particle sizes in the range of 1nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3.

In yet another aspect, the present invention discloses a process for synthesis of Remdesivir in the form of elongates with particle sizes in the range of 1nm-5000nm comprising;
(i) Dissolving crude Remedesivir in a solvent in a crystallization reactor and maintaining at low temperature to achieve complete precipitation, followed by filtering through centrifuge and drying under vacuum;
(ii) Dissolving the solid mass of step (i) in a mixture of solvents selected from lower branched alcohols and aromatic hydrocarbons and performing chiral separation using preparative high performance liquid chromatography (HPLC) system, recovering the solvent and filtering the solid mass through centrifuge followed by drying under vacuum;
(iii) Preparing uniform solution of Remdesivir of step (ii) with concentration of 1%wt/vol in a solvent selected from lower branched alcohols, ketones or combinations thereof and fluidizing the liquid mass;
(iv) Converting the fluidized liquid mass of step (iii) into a fine spray (mist) in a cryogenic air medium under inert atmosphere followed by sublimation of the solvent to obtain ultrafine particles of Remdesivir powder; and
(v) Transferring the Remdesivir powder of step (iv) to a drying chamber under inert atmosphere to obtain dried inhalation Remdesivir in the preferable shape of elongates with particle sizes in the range of 1 nm to 5000 nm.

In another aspect, the present invention provides Remdesivir dry powder inhalation (DPI) composition comprising;
(i) Remdesivir in the preferable shape of elongates with particle sizes in the range of 1.0nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3,in an amount of 8.75 to 52.5 mg;
(ii) Carbohydrate (fine particles) in an amount ranging from 5% to 12.5% of the total composition; and
(iii) Carbohydrate (coarse particles) in an amount ranging from 35% to 60% of the total composition together.

The carbohydrates as pharmaceutically acceptable carriers are selected from the group consisting of fructose, glucose, mannitol, maltose, trehalose, cellobiose, lactose, sucrose cyclodextrin, raffinose, xylitol, and maltodextrin wherein the carbohydrate is present in the form of a combination of fine and coarse particles.

In an aspect, the present invention provides a process for synthesis of dry powder inhalation (DPI) composition, comprising;
(i) Uniform mixing of carbohydrates of fine and coarse forms in desired ratio by using innovative 3 dimensional blending followed by sifting;
(ii) Uniform mixing of carbohydrate blend with said Remdesivir by using innovative 3 dimensional blending and encapsulating the blend in capsules or blister packs or reservoir packs thereof.

The final powder mixture is filled in capsules, Blister packs or Reservoir packs and administered by using different range of inhalant devices.

In an aspect, the dry powder inhalation (DPI) composition of the present invention releases Remdesivir in therapeutically effective amount ranging from 8.75 mg to 52.5 mgper Inhalation in divided doses per day.

In yet another aspect, the present invention providesa method for treating patients infected with SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses comprising administering dry powder inhalation (DPI) composition of Remdesivir in therapeutically effective amount ranging from 8.75 mg to 52.5 mg per inhalation in divided doses per day to the subject in need thereof.

In another aspect, the present invention provides Pressurized metered dose inhalation (pMDI) aerosol composition comprising;

(i) Remdesivir in the preferable shape of elongates with particle sizes in the range of 1.0nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3,in an amount ranging from 2.5 to 42.5 mg;
(ii) Propellant selected from Hydrofluoroalkane (HFAs), Chlorofluorocarbon (CFCs), CO2, Nitrogen, alone or mixtures thereof;
(iii) Additionally or optionally co-solvent(s) selected from the group of lower branched or linear alkyl (C1-C4) alcohols upto 25%w/w of the formulation;
(iv) Additionally or Optionally the surfactants selected from Sorbitan trioleate such as Span 85, Lecithin, Oleic Acid BP/EP/USP, Polyoxyethylene (20) sorbitan monolaurate,
Polyoxyethylene (80), sorbitan mono-oleate,
lecithins derived from natural sources and their likes or mixtures thereof in an amount of 0.1% w/w of the formulation;
(v) Additionally or optionally Sodium cromoglycate BP/EP/USP as mast cell stabilizer in an amount of 0.5% w/w of the formulation; and
(vi) Additionally or optionally pharmaceutically acceptable excipients in an amount up to1% w/w of the formulation.
The pharmaceutical composition of Remdesivir powder suitable for pressurized metered dose inhalation is stable at room temperature and has pharmaceutically acceptable shelf life for direct deposition onto the lungs through the pulmonary route with high efficacy and bio-availability.

The pressurized metered dose inhalation (pMDI) aerosol formulation of the present invention which may additionally include cromoglycate (preferably sodium salt) of 0.5% by weight of the aerosol composition enhances the mast cell stabilization activity of the desired formulation.

In yet another aspect, the present invention discloses processes of preparation of Remdesivir pressurized metered dose Inhalation for single stage pressurized suspension filling in metered dose Inhalers comprising;
(i) Preparing the suspension of said Remdesivir with suitable propellant in pressurized mixing vessel with or without co-solvents, additionally or optionally the surfactants, and additionally or optionally Sodium cromoglycate BP/EP/USP and additionally or optionally pharmaceutically acceptable excipients;
(ii) Homogenizing the mixture under pressure and stirring for specific time interval to obtain uniform aerosol powder suspension; and
(iii) Filling the specific quantity of said Remdesivir suspension into sealed canisters under high pressure.

In yet another aspect, the present invention provides process for preparation of Remdesivir pressurized metered dose Inhaler by 2 stage filling comprising;
i. Filling the open canister with Remdesivir in the preferable shape of elongates having particle sizes in the range of 1.0nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30g.cm3with or without co-solvents,additionally or optionally the surfactants, and additionally or optionally Sodium cromoglycate BP/EP/USP and additionally or optionally pharmaceutically acceptable excipients,
ii. Sealing the canisters with a metering valve provided with sealing rings and/or gasket,
iii. Filling suitable propellant under pressure through the sealed valve into the sealed canisters;
iv. Sonicating the filled canisters at specified frequency followed by rotatory spinning of the canisters at specified time interval to achieve uniform suspension inside the canisters.

The process for filling the pressurized metered dose inhaler is carried out optionally under inert atmosphere for instance by insufflating nitrogen, in order to avoid the uptake of humidity from the air.

The aerosol formulation is filled in canisters of any suitable material of construction like plain aluminium or anodised aluminium or plasma aluminium or their likes with different sizes like 5 ml, 7ml, 10 ml preferably by using most suitable plasma aluminium canister of 5 ml capacity for desired formulation and most preferably in plasma aluminium canisters of 5 ml capacity of canister-in canister type design whereby the inner canister is housed inside of a standard shaped metered-dose inhaler canister, the outer can neck profile of which contains the inner can while keeping the outer dimensions of the assembled system the same as the comparable standard product of larger size.

In another aspect, the pressurized metered dose (pMDI) composition of the present invention releases Remdesivir in therapeutically effective amount ranging from 2.9 mg to 42 mg per actuation divided from multiple desired doses per day and actuations in volumes ranging from 50µl to 120µl per actuation.

In another aspect, the present invention provides a method for treating patients infected with SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses comprising administering pressurized metered dose inhalation (pMDI) composition of Remdesivir in therapeutic amount ranging from 2.9 mg to 42mg per actuation dividedfrom multiple desired doses per day and actuations in volumes ranging from 50µl to 120µl per actuation to the subject in need thereof.

In another aspect, the present invention provides nebulizer formulation comprising Remdesivir obtained after particle engineering together with pharmaceutically acceptable excipients.

In yet another aspect, the present invention provides a dry powder inhaler device that provides lesser physical resistance, higher product flow-ability and suitable for administering medicaments with high drug content. Accordingly, the dry powder inhaler device of the present invention for delivering Remdesivir powder directly to the lungs with substantial reduction in physical resistance while inhalation comprises of;
(i) a powder holding chamber (6)for receiving composition to be inhaled;
(ii) a mouth piece (2)with a top body (1), wherein an opening of the mouth portion leads into a mesh duct(3);
(iii) a capsule inlet (4)and air inlets (5)being attached to the top body(1), wherein a base body(7) opening leads into a powder holding chamber(6)and the powder holding chamber extends along a common longitudinal axis when the mouth piece abuts the base body (7);
wherein said device imparts a cyclonic motion onto air within chamber to ensure improved level of the composition is inhaled.

The inhaler device of the present invention comprises the total powder content of the present Remdesivir in the chamber ranging between 14 mg to 100 mg.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: DPI Device
Figure 2: Open view of DPI device
Figure 3: Top view of Mesh and sectional views of mesh

DETAILED DESCRIPTION OF THE INVENTION
The inventions will now be described in detail in connection with certain preferred and optional embodiments and aspects, so that various aspects thereof may be more fully understood and appreciated.
While the inventions have been described by reference to specific embodiments and aspects, this is done for purposes of illustration only and should not be construed to limit the spirit or the scope of the invention.

PARTICLE ENGINEERING
Controlling crystallization of drug molecule is at the heart of “particle engineering,” which is a term that is used with increasing frequency in the pharmaceutical industry. Control over the crystallization process could yield particles with precisely engineered morphology; co-crystallization could then become a formulation strategy, resulting in “supramolecular pharmaceutics” that is mostly suitable for pMDI, DPI and Nebulizer formulations.

The present invention is concerned with a novel crystallization method by reduction of particle size, change of shape and surface morphology to obtain the desired Remdesivir which shall be most suitable for providing pharmaceutical inhalation compositions for direct deposition onto the lungs through the pulmonary route with high efficacy and bio-availability.

In an embodiment, the present invention relates to a process for synthesis of Remdesivir with reduced and controlled particle size, desired shape and surface morphology, comprising
(i) Dissolving (2S)-2-ethylbutyl 2-(((4-nitrophenoxy) (phenoxy) phosphoryl) amino) propanoate in a solvent at ambient temperature followed by addition of (2R,3R,4S.5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-carbonitrile and cooling the reaction mixture;
(ii) Adding solution of Isobutyl magnesium chloride to the reaction mass of step (i) followed by controlled addition of potassium carbonate, heating the mixture until completion of the reaction, distilling the solvent followed by washing, extraction and purification to obtain crude Remdesivir;
(iii) Transferring the solution mass of crude Remdesivir of step (ii) to crystallization reactor and maintaining at low temperature to achieve complete precipitation, followed by filtering through centrifuge and drying under vacuum;
(iv) Dissolving the solid mass of step (iii) in a mixture of solvent selected from lower branchedalcohols and aromatic hydrocarbonsand performing chiral separation using preparative high performance liquid chromatography (HPLC) system, recovering the solvent and filtering the solid mass through centrifuge followed by drying under vacuum;
(v) Preparing uniform solution of Remdesivir of step (iv) with concentration of 1%wt./vol in a solvent selected from lowerbranched alcohols, ketones or combinations thereof and fluidizing the liquid mass;
(vi) Converting the fluidized liquid mass of step (v) into a fine spray (mist) in a cryogenic air medium under inert atmosphere followed by sublimation of the solventto obtain ultrafine particles of Remdesivir powder; and
(vii) Transferring the Remdesivir powder of step (vi) to a drying chamber under inert atmosphere to obtain dried inhalation Remdesivir in the preferable shape of elongates with particle sizes in the range of 1nm to 5000 nm.

In an alternate embodiment of the process, ultrafine particles of Remdesivir powder in the preferable shape of elongates in the particle size range of 1nm to 5000nm may be obtained by atomizing crude Remdesivir solution and freezing simultaneously by mixing with a liquefied gas or supercritical fluid such as supercritical CO2 (carbon dioxide), liquid nitrogen, halocarbon refrigerants such as chlorofluorocarbon or fluorocarbon, hydrofluoroalkanes, hydrofluorocarbons, and their likes.

Accordingly, (2S)-2-ethylbutyl 2-(((4-nitrophenoxy) (phenoxy) phosphoryl) amino) propanoate is dissolved in anhydrous solvent and stirred at room temperature (RT) to obtain clear, uniform solution. Further, (2R,3R,4S.5R)-2-(4-aminopyrrolo[2, 1-f] [1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile is added to the reaction mixture. The reaction mass is then cooled to about 20oC. A solution of Isobutyl magnesium chloride in solvent is slowly added to the reaction mass, followed by controlled addition of potassium carbonate below 20oC. The reaction mass is heated in the range of 50-70oC and maintained for about 8 hours. The reaction completion is checked by carrying out Thin layer chromatography test of reaction mass. The solvent is then recovered from the reaction mass by distillation under vacuum. The residue obtained after distillation containing crude Remdesivir is cooled to RT and then dissolved in water. The aqueous layer so formed is extracted in solvent such as chlorinated hydrocarbons which helps in the removal of impurities. The aqueous layer is further extracted in a suitable solvent followed by charcoal treatment and the clear filtrate so obtained is charged to a clean and dry reactor. Recovery of the solvent is done by vacuum distillation and the residue is cooled to RT, to which suitable lower alcohol is charged. The solution mass is then transferred to crystallization reactor and maintained at low temperature to achieve complete precipitation. The solid mass so obtained is then filtered through centrifuge and dried under vacuum.

Further the obtained solid mass is dissolved in a mixture of solvent selected from lower alcohol and aromatic hydrocarbon and the chiral separation is performed by using preparative high performance liquid chromatography (HPLC) system. The solvent recovery is performed and the solid mass so obtained is filtered through centrifuge and dried under vacuum.
The dried filtered mass is further dissolved in suitable solvent such as acetone or Isopropyl alcohol or mixture thereof and then the diluted mass is kept ready for further process of particle engineering for reducing particle size in the range of 1nm to 5000nm and to obtain desired shape and surface morphology of desired Remdesivir suitable for inhalation.

The shape of the Remdesivir molecule should ideally be elongated or needle shaped, but preferably elongated of minimum diameter and of substantial length. This is achieved using different particle engineering techniques like fluidized Jet milling, freeze drying, spray freeze drying etc.

In the preferred embodiment of the present invention, the spray freeze drying process is carried out with the exclusion of moisture, more preferably using an atmosphere such as cryogenic air, nitrogen or carbon dioxide. Initially Remdesivir molecule is dissolved in a solvent or mixture of solvents to obtain uniform solution. This solution is further converted into a fine spray (mist) in a cryogenic air medium by using a suitable equipment system, which results in frozen molecule droplets that undergo sublimation by means of the cryogenic air system. To obtain ultrafine particles of Remdesivir, mass flow rate is controlled by making fine orifice adjustment of an ultrasonic nozzle spray. Ultrafine particles of Remdesivir molecule are transferred into the drying chamber. Cryogenic dry air is passed through the heater and this recycled air passes through the drying chamber where the overall sublimation of co-solvent takes place. The inert atmosphere of nitrogen is maintained during the entire unit operation. Heat transfer rate of the drying chamber is controlled and adjusted to obtain dried Remdesivir in the preferable form of elongates with particle size in the range of 1 to 5000 nm.

In an alternate embodiment of the process, ultrafine particles of Remdesivir powder in the preferable shape of elongates in the particle size range of 1 nm to 5000 nm may be obtained by atomizing crude Remdesivir solution and freezing simultaneously by mixing with a liquefied gas or supercritical fluid such as supercritical CO2 (carbon dioxide), liquid nitrogen, halocarbon refrigerants such as chlorofluorocarbon or fluorocarbon, hydrofluoroalkanes, hydrofluorocarbons, and their likes. The most volatile organic solvents can be processed by freezing with liquid nitrogen.

The particle engineering technique of the present invention is beneficial in the following aspects:
1. Inhalation Drug Remdesivir in the preferable shape of elongateswith fine particle sizes in the range of 1 to 5000 nm is obtained which is suitable for making Inhalation formulations for direct delivery through the pulmonary route to achieve maximum drug delivery onto the lungs.
2. Inhalation Drug Remdesivir with suitable shape of drug particles to achieve desired morphology suitable for making DPI, pMDI and nebulization finished dosage forms.
3. The chemical decomposition and degradation of the molecule is controlled by using less temperature during the whole process of drying.
4. The improvement in physical and chemical stability of Remdesivir makes it better choice for making all types of Inhalation finished dosage forms.
5. This technique can be carried out by using different co-solvents such as methanol, ethanol, isopropanol, n-butanol, acetone, or mixture of solvents in different compositions.

In an embodiment, the solvent for the process of the present invention is selected from polar or non-polar, protic or aprotic solvents selected from ethers such as THF, DMF; alcohols such as lower alcohols; chlorinated hydrocarbons such as Methylene dichloride; ketones, aliphatic or aromatic hydrocarbons and the like alone or combinations thereof.

Route of synthesis of Remdesivir

In an embodiment, the present invention relates to Remdesivir in the preferable form of elongates with particle sizes in the range of 1nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3.

In yet another embodiment, the present invention discloses a process for synthesis of Remdesivir in the form of elongates with particle sizes in the range of 1nm-5000nm comprising;
(i) Dissolving crude Remedesivir in a solvent in a crystallization reactor and maintaining at low temperature to achieve complete precipitation, followed by filtering through centrifuge and drying under vacuum;
(ii) Dissolving the solid mass of step (i) in a mixture of solvents selected from lower alcohols and aromatic hydrocarbons and performing chiral separation using preparative high performance liquid chromatography (HPLC) system, recovering the solvent and filtering the solid mass through centrifuge followed by drying under vacuum;
(iii) Preparing uniform solution of Remdesivir of step (ii) with concentration of 1%wt./vol in a solvent selected from lower branched alcohols, ketones or combinations thereof and fluidizing the liquid mass; and
(iv) Converting the fluidized liquid mass of step (iii) into a fine spray (mist) in a cryogenic air medium under inert atmosphere followed by sublimation of the solvent to obtain ultrafine particles of Remdesivir powder; and
(v) Transferring the Remdesivir powder of step (iv) to a drying chamber under inert atmosphere to obtain dried inhalation Remdesivir with particle size in the range of 1 nm to 5000 nm.

In an embodiment, the present invention relates to Remdesivir in the preferable shape of elongates with particle size in the range of 1-3000 nm in DPI powder blend gives high fine powder particle dose (FPD), Remdesivir with particle size of 1-5000 nm gives moderate fine powder particle dose (FPD) and finally Remdesivir with particle size of 3000- 5000 nm gives low fine powder particle dose (FPD).

In another embodiment, the present invention discloses Dry powder inhalation (DPI) composition comprising;
(i) Remdesivir in the preferable shape of elongates with particle size range of 1nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3,in an amount of 8.75 to 52.5 mg;
(ii) Carbohydrate (fine particles) in an amount ranging from 5% to 12.5% of the total composition; and
(iii) Carbohydrate (coarse particles) in an amount ranging from 35% to 60% of the total composition.

The carbohydrates as pharmaceutically acceptable carriers are selected from the group consisting of fructose, glucose, mannitol, maltose, trehalose, cellobiose, lactose, sucrose cyclodextrin, raffinose, xylitol, and maltodextrin wherein the carbohydrate is present in the form of a combination of fine and coarse particles.
In another embodiment, the present invention discloses a process for preparation of dry powder inhalation (DPI) composition, comprising;
(i) Uniform mixing of carbohydrates of fine and coarse forms in desired ratio by using innovative 3 dimensional blending followed by sifting;
(ii) Uniform mixing of carbohydrate blend with said Remdesivir by using innovative 3 dimensional blending and encapsulating the blend in capsules or blister packs or reservoir packs thereof.

The final powder mixture is filled in capsules, Blister packs or Reservoir packs and may be administered by using any suitable inhalant device.
In case of capsule variant as above, the capsules are selected from size 0 to 3 and type of capsule may be of HPMC, hard gelatine, Starch, Pullulan, Polyvinyl acetate or of any other type which are suitable to carry the dry powder for Inhalation.

In another embodiment, the present invention relates to Pressurized metered-dose inhaler (pMDI) composition comprising;
(i) Remdesivirin the preferable shape of elongates with particle size range of 1nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3, in an amount ranging from 2.5 to 42.5 mg;
(ii) Propellant selected from Hydrofluoroalkanes (HFAs), Chlorofluorocarbons (CFCs), CO2, Nitrogen, or mixtures thereof in quantitative amount;
(iii) Additionally or Optionally Co-solvent(s) selected from the group of lower branched or linear alkyl (C1-C4) alcohols upto 25%w/w of the formulation;
(iv) Additionally or Optionally surfactants in an amount of 0.1% w/w of the formulation;
(v) Additionally or optionally sodium cromoglycate BP/EP/USP as mast cell stabilizer in an amount of 0.5% by weight of the formulation;
(vi) Additionally or Optionally pharmaceutically acceptable excipients in an amount of 1% w/w of the formulation

The propellant is more preferably Hydrofluoroalkanes (HFA)that may include 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or a mixtures thereof. The most preferred propellant is 1,1,1,2-tetrafluoroethane (HFA134a). An alternative propellant of interest is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227).

The pressurized metered-dose inhaler (pMDI) composition/aerosol formulations of the present invention may additionally or optionally include co-solvents having a higher polarity than that of the propellant and may include one or more additional co-solvent to solubilize the active ingredient in the propellant. Advantageously the co-solvent is selected from the group of lower branched or linear alkyl (C1-C4) alcohols such as ethyl alcohol and isopropyl alcohol. Preferably the co-solvent is Ethyl alcohol BP/USP/EP, (also known as ethanol) which is useful to increase solubility of Remdesivir in the desired formulation.

The aerosol formulation of the present invention may additionally or optionally include surfactants up to 0.1% by weight of the aerosol composition. The surfactants may be selected from Sorbitan trioleate such as Span 85, Lecithin such as commercially available under the trade name Lipoid S100 - Lipoid S100, Oleic Acid BP/EP/USP, Polyoxyethylene (20) sorbitan monolaurate,
Polyoxyethylene (80), sorbitan mono-oleate,
lecithins derived from natural sources such as those available under the trade name Epikuron particularly Epikuron 200, Lipoid S100 etc.

The aerosol formulation of the present invention may additionally include cromoglycate (preferably sodium salt) up to 0.5% by weight of the aerosol composition. The mast cell stabilization activity of the desired formulation is enhanced by inclusion of sodium cromoglycate BP/EP/USP.

The aerosol formulations of the present invention may additionally and optionally include one or more excipients in selected ratios with Remdesivir as obtained after particle Engineering in the pressurised metered dose Inhalation formulation, such that the actions of the excipient or excipients are as surface active agent, solubilising agent, co solvent, mast cell stabilizer, etc.

Advantageously, the excipients are selected from polyvidone, povidones, Polyvinylpyrrolidone, PVPK, and their like.

In yet another embodiment, the present invention discloses processes of preparation of Remdesivir pressurized metered dose Inhalation for single stage pressurized suspension filling in metered dose Inhalers comprising;
i. Preparing the suspension of Remdesivir in the preferable shape of elongates having particle size in the range of 1.0nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30g.cm3 with suitable propellant in pressurized mixing vessel with or without co-solvents, additionally or optionally the surfactants and additionally or optionally sodium cromoglycate BP/EP/USP and additionally or optionally pharmaceutically acceptable excipients;
ii. Homogenizing the mixture under pressure and stirring for specific time interval to obtain uniform aerosol powder suspension; and
iii. Filling the specific quantity of said Remdesivir suspension into sealed canisters under high pressure.

In yet another embodiment, the present invention discloses process of preparation of Remdesivir pressurized metered dose Inhaler by 2 stage filling comprising;
i. Filling the open canister with Remdesivir in the preferable shape of elongates having particle size in the range of 1.0nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30g.cm3with or without co-solvents and additionally or optionally the surfactants and additionally or optionally sodium cromoglycate BP/EP/USP and additionally or optionally pharmaceutically acceptable excipients;
ii. Sealing the canisters with a metering valve provided with sealing rings and/or gasket;
iii. Filling suitable propellant under pressure through the sealed valve into the sealed canisters;
iv. Sonicating the filled canisters at specified frequency followed by rotatory spinning of the canisters at specified time interval to achieve uniform suspension inside the canisters.

The process for filling the pressurized metered dose inhaler is carried out preferably under inert atmosphere for instance by insufflating nitrogen, in order to avoid the uptake of humidity from the air.

The canisters of the pressurized metered dose inhaler are of different sizes (ranging from 5 ml to 19 ml) and of any suitable material of construction such as aluminium, anodized aluminium, plasma aluminium etc. that shall be suitable for making pMDI formulations of medicament, Remdesivir. More preferable, the Canister-in-canister type of plasma aluminium canister of total volume less than 5 ml to be used for making the Remdesivir pMDI for achieving the desired residual in-canister pressure for formulation pack having less than 60 actuations.

In yet another embodiment, the present invention discloses the ultrafine particles of Remdesivir in the preferable shape of elongates having particle size in range of 1.0 nm - 5000 nm and of suitable shape and surface morphology as obtained after particle Engineering to be used for making pMDI finished dosage form.
The formulation is actuated by means of metering valve that shall be able to deliver volume in the range of 50µl to 120µl, preferably by using most suitable pMDI valve for desired formulation.

The aerosol formulation is filled in canisters of any suitable material of construction like plain aluminium or anodised aluminium or plasma aluminium or their likes with different sizes like 5 ml, 7ml, 10 ml preferably by using most suitable plasma aluminium canister of 5 ml capacity for desired formulation and most preferably in plasma aluminium canisters of 5 ml capacity of canister-in canister type design whereby the inner canister is housed inside of a standard shaped metered-dose inhaler canister, the outer can neck profile of which contains the inner can while keeping the outer dimensions of the assembled system the same as the comparable standard product of larger size. The canister-in-canister shall provide benefits in terms of filling the desired smaller fill volume of Remdesivir pressurized suspension in each canister in terms of achieving the desired uniformity of delivered dose, substantial residual pressure and use of the standard MDI actuator size.

In another embodiment, the pressurized metered dose (pMDI) composition of the present invention releases Remdesivir in therapeutically effective amount ranging from 2.9 mg to 42.0 mg per actuation divided in multiple desired doses per day and actuations in volumes ranging from 50µl to 120µl per actuation.

In yet another embodiment, the dry powder inhalation (DPI) composition of the present invention releases Remdesivir in therapeutically effective amount ranging from 8.75 mg to 52.5 mg per inhalation per day.

Table 1: Dosage Design in pMDI.
Dosage Design:
Targeted Remdesivir drug deposition on lungs in 24 hours = 10.5 mg
By considering dose deposition in pMDI = 25%
Thus drug content designed under the present invention to be delivered per day through pMDI = 10.5 mg / 25% = 42 mg
Dose Regimen Drug content on 1 actuation basis Drug content on 2 actuations basis
Once a day (OD) 42 mg 21 mg
Twice a day (BID) 21 mg 10.5 mg
Thrice in a day (TID) 14 mg 7 mg

Alternatively, by considering dose deposition in pMDI = 40%
Thus drug content under the present invention to be delivered per day through pMDI = 10.5 mg / 40% = 26.25 mg
Dose Regimen Drug content on 1 actuation basis Drug content on 2 actuations basis
Once a day (OD) 26.25 mg 13.13 mg
Twice a day (BID) 13.13 mg 6.56 mg
Thrice in a day (TID) 8.75 mg 4.38 mg

Table 2: Dosage Design in DPI
Dosage design:
Targeted Remdesivir drug deposition on lungs in 24 hours = 10.5 mg
By considering dose deposition in DPI = 20%
Thus Remdesivir drug content under the present invention to be delivered per day through DPI
= 10.5 mg / 20% = 52.5 mg
Dose Regimen Drug content per Inhalation
Once a day (OD) 52.5 mg
Twice a day (BID) 26.25 mg
Thrice in a day (TID) 17.5 mg

Alternatively, by considering dose deposition in DPI = 40%
Thus Remdesivir drug content under the present invention to be delivered per day through DPI
= 10.5 mg / 40% = 26.25 mg
Dose Regimen Drug content per Inhalation
Once a day (OD) 26.25 mg
Twice a day (BID) 13.13 mg
Thrice in a day (TID) 8.75 mg

In another embodiment, the present invention relates to nebulizer formulation comprising Remdesivir in the preferable shape of elongates having particle size range of 1nm-5000nm, tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3 together with pharmaceutically acceptable excipients.

In an embodiment, the present invention relates to method for treating patients infected with SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses comprising administering pressurized metered dose of Remdesivir in the preferable shape of elongates with particle size range of 1nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3in combination with pharmaceutically acceptable carriers, in therapeutic amount ranging from 2.9 mg to 42 mg per actuation per day divided in multiple desired doses and actuations in volumes ranging from 50µl to 120µl per actuation to the subject in need thereof.

The administration of Remdesivir aerosol formulation by pressurized metered dose inhalation enables highest amount of the inhaled drug to be delivered to the lungs.

The administration of Remdesivir in pressurized metered dose inhalation dosage form through the pulmonary route for direct drug deposition onto the lungs provides better efficacy of the drug with lesser dose in comparison to the existing Remdesivir Intra-venous products.
In yet another embodiment, the present invention discloses method for treating patients infected with SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses comprising administering dry powder inhalation (DPI) composition of Remdesivir in the preferable shape of elongates with particle size range of 1nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3in combination with pharmaceutically acceptable carriers, in therapeutically effective amount ranging from 8.75 mg to 52.5 mg per actuation per day to the subject in need thereof.

The Dry powder Inhalation (DPI) Remdesivir dosage form of the present invention through the pulmonary route for direct drug deposition onto the lungs provides better efficacy of the drug with lesser dose in comparison to the existing Remdesivir Intra-venous products.

In another embodiment, the present invention relates to method for treating patients infected with SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses comprising administering to the subject in need via a nebulizer, a formulation comprising Remdesivir in the preferable shape of elongates with particle size range of 1nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3 in combination with pharmaceutically acceptable carriers.

In yet another embodiment, the present invention discloses pressurized metered dose inhalation (pMDI) composition comprising Remdesivir in the preferable shape of elongates with particle size range of 1nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3in combination with pharmaceutically acceptable carriers for use in the treatment of SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses.

In an embodiment, the present invention discloses dry powder inhalation (DPI) composition comprising Remdesivir in the preferable shape of elongates having particle size range of 1nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3in combination with pharmaceutically acceptable carriers for use in the treatment of SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses.

In yet another embodiment, the present invention relates to a nebulizer formulation comprising Remdesivir in the preferable shape of elongates having particle size range of 1nm-5000nm, a tapped density in the range of 0.10 g.cm3 to 0.30 g.cm3 in combination with pharmaceutically acceptable carriers for use in the treatment of SARS, MARS, Covid19, Arenaviridae, Coronaviridae, Filoviridae, and Paramyxoviridae viruses or any other Flaviviridae family viruses.
In another embodiment, the present invention discloses single dose dry powder Inhaler (DPI) device that provides lesser physical resistance, higher product flow-ability and suitable for administering by inhalation encapsulated Dry powder for Inhalation medicament compositions having high powder content ranging between 10 mg to 100 mg.

Accordingly, the dry powder inhaler device of the present invention for delivering Remdesivir powder directly to the lungs with substantial reduction in physical resistance while inhalation comprises of a body defining;
(i) a powder holding chamber (6)for receiving composition to be inhaled;
(ii) a mouth piece (2)with a top body (1), wherein an opening of the mouth portion leads into a mesh duct(3);
(iii) a capsule inlet (4)and air inlets (5)being attached to the top body(1), wherein a base body(7) opening leads into a powder holding chamber (6)and the powder holding chamber extending along a common longitudinal axis when the mouth piece abuts the base body (7);
wherein said device imparts a cyclonic motion onto air within chamber to ensure improved level of the composition is inhaled.

The mesh size and its design of the present invention is such that it provides lesser number of physical partitions and a higher residual airflow area percentage of 92% making it most suitable for delivering dry powder inhalation compositions having powder content of more than 30 mg.

Description of Device under present invention:
1. Mesh size: The mesh size and shape of DPI device is such that maximum flow-ability of the formulation is achieved due to less hindrance, thus negligible drug particles are retained at mesh.
2. Mesh Shape: The particular shape of mesh allows the formulation to flow at lower pressure, as compared to the mesh shape of prior art devices which reduces mechanical performance. The mesh shape is engineered in flaring form, slightly conical, which minimizes retention of medicament particles at the mesh and hence improves drug content towards administration (Figure 3-Top view of mesh and sectional views of mesh)
3. Mesh grid: The total number of mesh grids in the device of the present invention are 9 (3 x 3) which are comparatively much lesser than devices under prior art. Thus device under present invention creates fewer barriers, less hindrance to the medicament powder and hence improves drug flow-ability towards pulmonary route.
4. Mouthpiece stem dimension: The modified mouthpiece stem (increase in mouthpiece stem) allows more powder particles to flow through DPI device leading towards more drug availability for administration purpose.
5. Air inlet: The provision of air inlet at 2 corners of DPI device allows more powder particles to flow through DPI device at uniform velocity and thus leading towards more drug availability for administration purpose.
6. Device design and capacity: The designed body provides abridged construction and is intended in such a way to be used unpretentious. The Device is designed to be used to administer the formulation ranging from 14 mg to 100 mg.

The composition received in the chamber will, upon inhalation by a user, be exposed to an air flow having a cyclonic motion. This particular motion ensures that a high proportion of medicament within said chamber becomes entrained in the air flow passing through said chamber and into the mouthpiece. The cyclonic motion thereby ensures that an improved level of medicament is inhaled as compared with prior art devices.

Due to cyclonic motion, air immediately enters in to the said chamber. The air inlet may extend through a side wall of said chamber and said cyclonic motion may comprise a curved surface defining said chamber. It is also desirable for said body to comprise first and second portions each having a cylindrical member, the cylindrical member of the second body portion being telescopically received in the cylindrical member of the first body portion. Furthermore, said air inlet may be defined by an aperture in said first body portion and an end of the cylindrical member of the second body portion which locates adjacent said aperture. Means may be provided on the first body portion for holding a container of composition within said chamber.

In yet another embodiment, single or multiple solid APIs mixed with solid carriers and having the suitable particle sizes for inhalation and that are encapsulated in capsules with body and shell and then required to be administered by inhalation can be administered with the device under the present invention.

The inhaler device of the present invention provides suitability for use with capsules containing powder for Inhalation with total powder content ranging between 14 mg to 100 mg.

It will be appreciated that the design, embodiments and aspects described above with suitable modifications, alterations, optimizations and alternations that are within the scope of a skilled person and are used for obtaining the products, designs and methods as cited aboveshould be construed to be within the scope of the present inventive concept as is disclosed anywhere in the specification.

EXAMPLES
The invention is further described by the following non-limiting examples, which provides the preferred mode of carrying out the process of the present invention. It is to be appreciated that several alterations, modifications, optimizations, alternations of the processes described herein are well within the scope of a person skilled in the art and such alterations, modifications, optimizations, alternations, etc. should be construed to be within the scope of the present inventive concept as is disclosed anywhere in the specification.

Synthesis of Remdesivir with reduced and controlled particle size:
Example 1:
A solution of (2S)-2-ethylbutyl 2-(((4-nitrophenoxy) (phenoxy) phosphoryl) amino) propanoate (10 g) in dimethyl formamide [DMF] (50 mL) was prepared at ambient temperature. The compound, (2R,3R,4S.5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-carbonitrile (10g) was added to the reaction mixture. The reaction mass was then cooled to 20oC. A solution of Isobutyl magnesium chloride (5g) in 50 ml of tetrahydrofuran (THF) was slowly added to the reaction mass, followed by controlled addition of potassium carbonate (10g) below 20oC. The reaction mass was heated to 60°C and maintained for 8 hours. The completion of reaction was checked on TLC. Further, DMF recovery was carried out by distillation under vacuum. The residue of crude Remdesivir so obtained was cooled to RT and then dissolved in water (100ml). The aqueous layer was washed with 3 portions of 100ml of methylene dichloride (MDC). Further aqueous layer was extracted with 3 portions of 100ml of ethyl acetate. The charcoal treatment was given and solvent, ethyl acetate was recovered by vacuum distillation. The solvent, methanol (50ml) was added to the residue, the crude Remdesivir compound (15g) was crystallized, filtered and dried. The dry, crude solid of Remdesivir was dissolved in the mixture of solvents [Isopropyl alcohol (500ml) + Toluene (300ml)] and the chiral separation was performed by using preparative high performance liquid chromatography (HPLC) system. The solvent recovery was performed and the solid mass so obtained was filtered through centrifuge and dried under vacuum.
Yield: 6 g, HPLC purity > 99 %.
A uniform solution of Remdesivir molecule with concentration of 1%wt./vol. was prepared in Isopropyl Alcohol. The liquid mass was fluidized and mass flow rate was controlled by the fine adjustment of the orifice of an ultrasonic nozzle. This fluidized mass was converted into a fine spray (mist) in a cryogenic air medium. Further sublimation of isopropyl alcohol takes place, leading to formation of ultrafine particles of Remdesivir in the preferable shape of elongates which are in the size range of 1 nm to 5000 nm. These ultrafine particles were further transferred into the drying chamber. Heat transfer rate of the drying chamber was controlled and adjusted to obtain dried Inhalation drug Remdesivir in the preferable shape of elongateswith suitable particle size in the range of 1 to 5000nm. The inert atmosphere of nitrogen was maintained during the entire unit operation. Finally, dried Inhalation drug Remdesivir was obtained with suitable size, shape and surface morphology.
Yield: 5.5 g,
Test results: HPLC purity> 99 %, Particle size distribution: D95 = less than 2000nm.

Example 2:
A solution of (2S)-2-ethylbutyl 2-(((4-nitrophenoxy) (phenoxy) phosphoryl) amino) propanoate (10 g) in dimethyl formamide [DMF] (50 mL) was prepared at ambient temperature. The compound, (2R,3R,4S.5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-carbonitrile (10g) was added to the reaction mixture. The reaction mass was then cooled to 20oC. A solution of Isobutyl magnesium chloride (5g) in 50 ml of tetrahydrofuran (THF) was slowly added to the reaction mass, followed by controlled addition of potassium carbonate (10g) below 20oC. The reaction mass was heated to 60°C and maintained for 8 hours. The completion of reaction was checked on TLC. DMF recovery was carried out by distillation under vacuum. The residue of crude Remdesivir so obtained was cooled to RT and then dissolved in water (100ml). The aqueous layer was washed with 3 portions of 100ml of methylene dichloride (MDC). Further aqueous layer was extracted with 3 portions of 100ml of ethyl acetate. The charcoal treatment was given and solvent, ethyl acetate was recovered by vacuum distillation. The solvent, methanol (50ml) was added to the residue, the crude Remdesivir compound (15g) was crystallized, filtered and dried. The dry, crude solid of Remdesivir was dissolved in the mixture of solvents [Isopropyl alcohol (500ml) + Toluene (300ml) + Ethyl Acetate (200ml)] and the chiral separation was performed by using preparative high performance liquid chromatography (HPLC) system. The solvent recovery was performed and the solid mass so obtained was filtered through centrifuge and dried under vacuum.
Yield: 7.0 g, HPLC purity> 99 %
A uniform solution of Remdesivir molecule with concentration of 1% wt./vol. was prepared in Acetone. The liquid mass was fluidized and mass flow rate was controlled by the fine adjustment of the orifice of an ultrasonic nozzle. This fluidized mass was converted into a fine spray (mist) in a cryogenic air medium. Further sublimation of acetone takes place, leading to formation of ultrafine particles of Remdesivir in the preferable shape of elongates which are in the size range of 1 nm to 5000 nm. These ultrafine particles were further transferred into the drying chamber. Heat transfer rate of the drying chamber was controlled and adjusted to obtain dried Inhalation drug Remdesivir in the preferable shape of elongates with suitable particle sizes in the range of 1 to 5000nm. The inert atmosphere of nitrogen was maintained during the entire unit operation. Finally, dried Inhalation drug Remdesivir was obtained with suitable size, shape and surface morphology.
Yield: 5.8 g,
Test results: HPLC purity > 99 %, Particle size distribution: D95 = less than 2000nm.

Example 3:
A solution of (2S)-2-ethylbutyl 2-(((4-nitrophenoxy) (phenoxy) phosphoryl) amino) propanoate (10 g) in dimethyl formamide [DMF] (50 mL) was prepared at ambient temperature. The compound, (2R,3R,4S.5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-carbonitrile (10g) was added to the reaction mixture. The reaction mass was then cooled to 20oC. A solution of Isobutyl magnesium chloride (5g) in 50 ml of tetrahydrofuran (THF) was slowly added to the reaction mass, followed by controlled addition of potassium carbonate (10g) below 20oC. The reaction mass was heated to 60°C and maintained for 8 hours. The completion of reaction was checked on TLC. Further, DMF recovery was carried out by distillation under vacuum. The residue of crude Remdesivir so obtained was cooled to RT and then dissolved in water (100ml). The aqueous layer was washed with 3 portions of 100ml of methylene dichloride (MDC). Further aqueous layer was extracted with 3 portions of 100ml of ethyl acetate. The charcoal treatment was given and solvent, ethyl acetate was recovered by vacuum distillation. The solvent, methanol (50ml) was added to the residue, the crude Remdesivir compound (15g) was crystallized, filtered and dried. The dry, crude solid of Remdesivir was dissolved in the mixture of solvents [Acetone (500ml) + Toluene (300ml) + Ethyl Acetate (200ml)] and the chiral separation was performed by using preparative high performance liquid chromatography (HPLC) system. The solvent recovery was performed and the solid mass so obtained was filtered through centrifuge and dried under vacuum.
Yield: 6.5 g, HPLC purity> 99 %
A uniform solution of Remdesivir molecule with concentration of 1% wt./vol. Was prepared in a mixture of solvents i.e. Isopropyl Alcohol and Acetone. The liquid mass was fluidized and mass flow rate was controlled by the fine adjustment of the orifice of an ultrasonic nozzle. The fluidized mass was converted into a fine spray (mist) in a cryogenic air medium. Further sublimation of isopropyl alcohol takes place, leading to formation of ultrafine particles of Remdesivir in the preferable shape of elongates which are in the size range of 1 nm to 5000 nm. The ultrafine particles were further transferred into the drying chamber. Heat transfer rate of the drying chamber was controlled and adjusted to obtain dried Inhalation drug Remdesivir in the preferable shape of elongates with suitable particle sizes in the range of 1 to 5000nm. The inert atmosphere of nitrogen was maintained during the entire unit operation. Finally, dried Inhalation drug Remdesivir was obtained with suitable size, shape and surface morphology.
Yield: 5.5 g,
Test results: HPLC purity > 99 %, Particle size distribution: D95 = less than 2000nm.
Pressurized Metered Dose Inhalations (pMDI)

Example 4
Compositions:
Formulation 4a 4b 4c 4d
Each actuation delivers 2.92 mg
of Remdesivir 7 mg
of Remdesivir 10.5 mg
of Remdesivir 42 mg
of Remdesivir
Propellant HFA 134a (w/w) q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%
Process:
Remdesivir Inhalation drug of suitable particle size, shape and surface morphology as obtained after particle engineering and HFA 134a was added in pressurized mixing vessel. The mixture was homogenized and stirred for specific time interval to obtain uniform aerosol powder suspension. The specific quantity of suspension was then filled into sealed canisters under high pressure.

Example 5
Compositions:
Formulation 5a 5b 5c 5d
Each actuation delivers 2.92 mg
of Remdesivir 7 mg
of Remdesivir 10.5 mg
of Remdesivir 42 mg
of Remdesivir
Propellant HFA 134a (w/w) q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Process:
Remdesivir Inhalation drug of suitable particle size, shape and surface morphology as obtained after particle engineering was filled into the canisters followed by valve sealing operation. Further, Propellant HFA 134a was filled under high pressure into the sealed canisters. Then sonication of the filled canisters was done at specified frequency followed by the rotatory spinning of the canisters at specified time interval to achieve uniform suspension inside the canisters.

Example 6
Compositions:
Formulation 6a 6b 6c 6d
Each actuation delivers 2.92 mg
of Remdesivir 7 mg
of Remdesivir 10.5 mg
of Remdesivir 42 mg
of Remdesivir
Ethanol anhydrous(w/w) 15% 15% 15% 15%
Oleic acid(w/w) 0.02% 0.02% 0.02% 0.02%
Propellant HFA 134a (w/w) q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%
Process:
Remdesivir Inhalation drug of suitable particle size, shape and surface morphology as obtained after particle engineering with Ethanol anhydrous, Oleic acid and HFA 134a was added in pressurized mixing vessel. The mixture was homogenized and stirred for specific time interval to obtain uniform aerosol powder suspension. The specific quantity of suspension was then filled into sealed canisters under high pressure.

Example 7
Compositions:
Formulation 7a 7b 7c 7d
Each actuation delivers 2.92 mg
of Remdesivir 7 mg
of Remdesivir 10.5 mg
of Remdesivir 42 mg
of Remdesivir
Ethanol anhydrous(w/w) 15% 15% 15% 15%
Oleic acid(w/w) 0.02% 0.02% 0.02% 0.02%
Propellant HFA 134a (w/w) q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%
Process:
Remdesivir Inhalation drug of suitable particle size, shape and surface morphology as obtained after particle engineering was filled into the canisters. The solution mixture of Ethanol anhydrous and Oleic acid was added in canisters with Remdesivir. Further, Propellant HFA 134a was filled under high pressure into the sealed canisters. Then sonication of the filled canisters was done at specified frequency followed by the rotatory spinning of the canisters at specified time interval to achieve uniform suspension inside the canisters.

Example 8
Compositions:
Formulation 8a 8b 8c 8d
Each actuation delivers 2.92 mg
of Remdesivir 7 mg
of Remdesivir 10.5 mg
of Remdesivir 42 mg
of Remdesivir
Ethanol anhydrous(w/w) 15% 15% 15% 15%
Propellant HFA 134a (w/w) q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%
Process:
Remdesivir Inhalation drug of suitable particle size, shape and surface morphology as obtained after particle engineering with Ethanol anhydrous HFA 134a was added in pressurized mixing vessel. The mixture was homogenized and stirred for specific time interval to obtain uniform aerosol powder suspension. The specific quantity of suspension was then filled into sealed canisters under high pressure.

Example 9
Compositions:
Formulation 9a 9b 9c 9d
Each actuation delivers 2.92 mg
of Remdesivir 7 mg
of Remdesivir 10.5 mg
of Remdesivir 42 mg
of Remdesivir
Ethanol anhydrous(w/w) 15% 15% 15% 15%
Propellant HFA 134a (w/w) q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%
Process:
Remdesivir Inhalation drug of suitable particle size, shape and surface morphology as obtained after particle engineering was filled into the canisters to which ethanol anhydrous was added. Further, Propellant HFA 134a was filled under high pressure into the sealed canisters. Then sonication of the filled canisters was done at specified frequency followed by the rotatory spinning of the canisters at specified time interval to achieve uniform suspension inside the canisters.

Example 10:
Compositions:
Formulation 10a 10b 10c 10d
Each actuation delivers 2.92 mg
of Remdesivir 7 mg
of Remdesivir 10.5 mg
of Remdesivir 42 mg
of Remdesivir
Sodium Cromoglycate (w/w) 0.5% 0.5% 0.5% 0.5%
Propellant HFA 134a (w/w) q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%
Process:
Remdesivir Inhalation drug of suitable particle size, shape and surface morphology as obtained after particle Engineering was mixed with Sodium cromoglycate. The powder blend and HFA 134a are added in pressurized mixing vessel. The mixture was homogenized and stirred for specific time interval to obtain uniform aerosol powder suspension. The specific quantity of suspension was then filled into sealed canisters under high pressure.

Example 11:
Compositions:
Formulation 11a 11b 11c 11d
Each actuation delivers 2.92 mg
of Remdesivir 7 mg
of Remdesivir 10.5 mg
of Remdesivir 42 mg
of Remdesivir
Sodium Cromoglycate (w/w) 0.5% 0.5% 0.5% 0.5%
Propellant HFA 134a (w/w) q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%
Process:
Remdesivir Inhalation drug of suitable particle size, shape and surface morphology as obtained after particle engineering was mixed with Sodium cromoglycate. The powder blend was then filled into the canisters followed by valve sealing operation. Further, Propellant HFA 134a was filled under high pressure into the sealed canisters. Then sonication of the filled canisters was done at specified frequency followed by the rotatory spinning of the canisters at specified time interval to achieve uniform suspension inside the canisters.

Example 12
Compositions:
Formulation 12a 12b 12c 12d
Each actuation delivers 2.92 mg
of Remdesivir 7 mg
of Remdesivir 10.5 mg
of Remdesivir 42 mg
of Remdesivir
Sodium cromoglycate(w/w) 0.5% 0.5% 0.5% 0.5%
Ethanol anhydrous(w/w) 15% 15% 15% 15%
Oleic acid(w/w) 0.02% 0.02% 0.02% 0.02%
Propellant HFA 134a (w/w) q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Process:
Remdesivir Inhalation drug of suitable particle size, shape and surface morphology as obtained after particle engineering with Sodium chromoglycate, Ethanol anhydrous, Oleic acid and HFA 134a was added in pressurized mixing vessel. The mixture was homogenized and stirred for specific time interval to obtain uniform aerosol powder suspension. The specific quantity of suspension was then filled into sealed canisters under high pressure.

Example 13
Compositions:
Formulation 13a 13b 13c 13d
Each actuation delivers 2.92 mg
of Remdesivir 7 mg
of Remdesivir 10.5 mg
of Remdesivir 42 mg
of Remdesivir
Sodium cromoglycate(w/w) 0.5% 0.5% 0.5% 0.5%
Ethanol anhydrous(w/w) 15% 15% 15% 15%
Oleic acid(w/w) 0.02% 0.02% 0.02% 0.02%
Propellant HFA 134a (w/w) q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%
Process:
Remdesivir Inhalation drug of suitable particle size, shape and surface morphology as obtained after particle engineering was mixed with Sodium cromoglycate. The powder blend was then filled into the canisters. The solution mixture of Ethanol anhydrous and Oleic acid was added in canisters followed by valve sealing operation. Further, Propellant HFA 134a was filled under high pressure into the sealed canisters. Then sonication of the filled canisters was done at specified frequency followed by the rotatory spinning of the canisters at specified time interval to achieve uniform suspension inside the canisters.

Example 14
Compositions:
Formulation 14a 14b 14c 14d
Each actuation delivers 2.92 mg
of Remdesivir 7 mg
of Remdesivir 10.5 mg
of Remdesivir 42 mg
of Remdesivir
Sodium cromoglycate(w/w) 0.5% 0.5% 0.5% 0.5%
Ethanol anhydrous(w/w) 15% 15% 15% 15%
Propellant HFA 134a (w/w) q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%
Process:
Remdesivir Inhalation drug of suitable particle size, shape and surface morphology as obtained after particle engineering with Sodium chromoglycate, Ethanol anhydrous and HFA 134a was added in pressurized mixing vessel. The mixture was homogenized and stirred for specific time interval to obtain uniform aerosol powder suspension. The specific quantity of suspension was then filled into sealed canisters under high pressure.

Example 15
Compositions:
Formulation 15a 15b 15c 15d
Each actuation delivers 2.92 mg
of Remdesivir 7 mg
of Remdesivir 10.5 mg
of Remdesivir 42 mg
of Remdesivir
Sodium cromoglycate(w/w) 0.5% 0.5% 0.5% 0.5%
Ethanol anhydrous(w/w) 15% 15% 15% 15%
Oleic acid(w/w) 0.02% 0.02% 0.02% 0.02%
Propellant HFA 134a (w/w) q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%
Process:
Remdesivir Inhalation drug of suitable particle size, shape and surface morphology as obtained after particle engineering was mixed with Sodium cromoglycate. The powder blend was then filled into the canisters to which ethanol anhydrous was added followed by valve sealing operation. Further, Propellant HFA 134a was filled under high pressure into the sealed canisters. Then sonication of the filled canisters wasdone at specified frequency followed by the rotatory spinning of the canisters at specified time interval to achieve uniform suspension inside the canisters.
Dry Powder Inhalations (DPI)

Example 16 to 19
Formulation Example 16 Example 17 Example 18 Example 19
Each capsule contains 8.75 mg
of Remdesivir 8.75 mg
of Remdesivir 8.75 mg
of Remdesivir 8.75 mg
of Remdesivir
Lactose monohydrate (w/w) [Fine powder]
2.50 mg
3.75 mg
5.00 mg
6.25 mg
Lactose monohydrate (w/w) [Coarse powder]
38.75 mg

37.50 mg

36.25 mg

35.00 mg

Net content of DPI capsule 50 mg 50 mg 50 mg 50 mg

Example 20 to 23
Formulation Example 20 Example 21 Example 22 Example 23
Each capsule contains 17.5 mg
of Remdesivir 17.5 mg
of Remdesivir 17.5 mg
of Remdesivir 17.5 mg
of Remdesivir
Lactose monohydrate (w/w) [Fine powder]
2.50 mg
3.75 mg
5.00 mg
6.25 mg
Lactose monohydrate (w/w) [Coarse powder]
30.00 mg

28.75 mg

27.50 mg

26.25 mg

Net content of DPI capsule 50 mg 50 mg 50 mg 50 mg

Example 24 to 27
Formulation Example 24 Example 25 Example 26 Example 27
Each capsule contains 26.25 mg
of Remdesivir 26.25 mg
of Remdesivir 26.25 mg
of Remdesivir 26.25 mg
of Remdesivir
Lactose monohydrate (w/w) [Fine powder]
2.50 mg
3.75 mg
5.00 mg
6.25 mg
Lactose monohydrate (w/w) [Coarse powder]
21.25 mg

20.00 mg

18.75 mg

17.50 mg

Net content of DPI capsule 50 mg 50 mg 50 mg 50 mg

Example 28 to 31
Formulation Example 28 Example 29 Example 30 Example 31
Each capsule contains 52.5 mg
of Remdesivir 52.5 mg
of Remdesivir 52.5 mg
of Remdesivir 52.5 mg
of Remdesivir
Lactose monohydrate (w/w) [Fine powder]
5.00 mg
7.50 mg
10.00 mg
12.50 mg
Lactose monohydrate (w/w) [Coarse powder]
42.50 mg

40.00 mg

37.50 mg

35.00 mg

Net content of DPI capsule 100 mg 100 mg 100 mg 100 mg

Process:
The mixing of previously dried Lactose (both fine & coarse) was carried out, followed by serial 3-Dimensional geometric mixing in stage-wise proportions for the specific time interval and sequence. Then sifting of Lactose blend was carried out. Finally layer-wise serial 3-Dimensional geometric mixing of the lactose blend was done with Remdesivir Inhalation drug of suitable particle size, shape and surface morphology as obtained after particle Engineering to obtain a uniform powder blend of desired composition.
Remdesivir MDI / Analytical Study-I
The study was performed to understand the compatibility of Remdesivir pMDI with canister’s material of construction at different time intervals.
Test & its limit:
Assay %: NLT 80.0 NMT 120.0 of the labelled amount

Table 1: pMDI Canister (MOC) Study
Canister details Aluminium Canister (Plain) Anodized Aluminium Canister Plasma Aluminium Canister
Sample details Initial
Assay% Assay % after 1 month Assay % after 3 months Initial
Assay% Assay % after 1 month Assay % after 3 months Initial
Assay% Assay % after 1 month Assay % after 3 months
Example 4a 92.36% 91.16% 90.23% 95.31% 94.25% 93.45% 99.26% 99.15% 99.01%
Example 5a 93.56% 91.98% 90.71% 93.56% 92.61% 91.56% 97.36% 97.56% 97.41%
Example 6a 99.21% 98.23% 96.56% 101.23% 101.14% 101.02% 102.98% 102.63% 101.91%
Example 7a 97.53% 96.91% 94.98% 98.76% 98.15% 96.98% 100.21% 100.02% 99.87%
Example 8a 97.87% 95.36% 93.89% 97.98% 96.15% 94.36% 98.37% 97.98% 97.88%
Example 9a 96.32% 94.36% 93.21% 97.52% 95.36% 92.36% 96.36% 96.12% 96.03%
Example 10a 95.15% 94.87% 93.21% 95.56% 94.36% 93.58% 96.98% 96.98% 96.98%
Example 11a 95.98% 95.15% 94.56% 94.21% 94.01% 93.11% 96.42% 96.42% 96.42%
Example 12a 96.56% 95.98% 94.23% 98.69% 98.26% 96.75% 98.69% 98.51% 98.31%
Example 13a 95.47% 95.36% 93.89% 97.98% 96.15% 94.36% 98.37% 97.98% 97.88%
Example 14a 95.59% 94.23% 93.56% 97.64% 95.94% 94.28% 97.12% 96.99% 96.73%
Example 15a 94.82% 94.36% 93.21% 97.52% 95.36% 92.36% 96.36% 96.12% 96.03%
Note:
1. pMDI canisters after filling operation were kept in inverted position.
2. % Assay of pMDI canisters were checked after 0, 1 and 3 months’ time interval
Conclusion:
Plasma Aluminium Canisters were found to be most suitable for Remdesivir pMDI formulation.
Remdesivir pMDI / Analytical Study-II
The study was done to check dose delivery performance by using metering valves with different volume capacity. The valve selection was based on the tests such as uniformity of delivered dose and % assay.
Test & its limit:
1. Uniformity of delivered dose limit: 9 out of 10 results lie between 75 per cent and 125 per cent of the average value and all lie between 65 per cent and 135 per cent.
2. Assay %: NLT 80.0 NMT 120.0 of the labelled amount
Table 2: Remdesivir pMDI Valve Suitability Study
Valve details 50mcl Valve 63 mcl Valve 100 mcl Valve
Sample details Uniformity of delivered dose Assay % Uniformity of delivered dose Assay %
Uniformity of delivered dose Assay %

Example 4a 9 out of 10 96.00 9 out of 10 97.29 9 out of 10 99.29
Example 5a 9 out of 10 96.29 9 out of 10 97.0 9 out of 10 98.71
Example 6a 10 out of 10 101.86 10 out of 10 102.71 10 out of 10 102.86
Example 7a 10 out of 10 98.71 10 out of 10 99.29 10 out of 10 99.57
Example 8a 9 out of 10 97.28 9 out of 10 97.71 9 out of 10 98.29
Example 9a 8 out of 10 95.57 9 out of 10 96.14 8 out of 10 96.86
Example 10a 8 out of 10 96.86 9 out of 10 99.29 8 out of 10 98.14
Example 11a 8 out of 10 94.14 9 out of 10 96.14 8 out of 10 97.86
Example 12a 9 out of 10 96.86 9 out of 10 100.14 9 out of 10 97.86
Example 13a 9 out of 10 97.28 9 out of 10 101.71 9 out of 10 98.29
Example 14a 9 out of 10 96.14 9 out of 10 99.29 9 out of 10 97.71
Example 15a 8 out of 10 95.57 9 out of 10 99.14 8 out of 10 96.86
Conclusion:
The metering valve of 63 mcl dispensing volume capacity was found to be most suitable for Remdesivir pMDI formulation.
Remdesivir pMDI / Analytical Study-III
The study was done to understand impact of available propellant pressure on the drug delivery in particular sized aluminium canister. The canister selection was based on the tests such as uniformity of delivered dose and % assay.
Test & its limit:
1. Uniformity of delivered dose: limit: 9 out of 10 results lie between 75 per cent and 125 per cent of the average value and all lie between 65 per cent and 135 per cent.
2. Assay %: NLT 80.0 NMT 120.0 of the labelled amount

Table 3: Remdesivir pMDI Canister (MOC & Volume) Suitability Study
Canister volume details Plasma Aluminium Canisters with volume capacity of 5.0 ml Plasma Aluminium Canisters with volume capacity of 7.0 ml Plasma Aluminium Canisters with volume capacity of 10.0 ml

Sample details Uniformity of delivered dose Assay % Uniformity of delivered dose Assay % Uniformity of delivered dose Assay %
Example 4a 9 out of 10 99.57 8 out of 10 99.29 9 out of 10 98.29
Example 5a 9 out of 10 99.71 9 out of 10 98.71 8 out of 10 98.14
Example 6a 10 out of 10 103.28 10 out of 10 102.86 9 out of 10 100.43
Example 7a 10 out of 10 99.86 10 out of 10 99.57 9 out of 10 98.29
Example 8a 9 out of 10 99.29 9 out of 10 98.29 9 out of 10 97.57
Example 9a 9 out of 10 97.57 8 out of 10 96.86 8 out of 10 95.86
Example 10a 9 out of 10 98.43 8 out of 10 98.14 8 out of 10 96.29
Example 11a 9 out of 10 99.29 8 out of 10 97.86 8 out of 10 96.29
Example 12a 9 out of 10 99.14 9 out of 10 94.86 9 out of 10 94.29
Example 13a 9 out of 10 99.29 9 out of 10 92.29 9 out of 10 96.57
Example 14a 9 out of 10 98.29 9 out of 10 97.71 9 out of 10 91.43
Example 15a 9 out of 10 97.57 8 out of 10 96.86 8 out of 10 95.86

Conclusion:
Plasma Aluminium Canister with 5.0 ml volume capacity was found to be most suitable for Remdesivir pMDI formulation.

Table 4: Remdesivir pMDI Canister-in-Canister Suitability Study
Canister volume details Plasma Aluminium Canisters with volume capacity of 5.0 ml Plasma Aluminium Canisters with volume capacity of 5.0 ml housed in standard larger canister

Sample details Uniformity of delivered dose Assay % Uniformity of delivered dose Assay %
Example 4a 9 out of 10 99.57 10 out of 10 101.78
Example 5a 9 out of 10 99.71 10 out of 10 102.32
Example 6a 10 out of 10 103.28 10 out of 10 104.24
Example 7a 10 out of 10 99.86 10 out of 10 103.46
Example 8a 9 out of 10 99.29 9 out of 10 100.29
Example 9a 9 out of 10 97.57 9 out of 10 99.68
Example 10a 9 out of 10 98.43 10 out of 10 99.34
Example 11a 9 out of 10 99.29 9 out of 10 100.34
Example 12a 9 out of 10 99.14 10 out of 10 98.78
Example 13a 9 out of 10 99.29 10 out of 10 98.16
Example 14a 9 out of 10 98.29 10 out of 10 99.94
Example 15a 9 out of 10 97.57 10 out of 10 100.28

Conclusion:
Plasma Aluminium Canister with 5.0 ml volume capacity which is housed in standard larger canisterby following Canister-in-Canister principle was found to be most suitable for Remdesivir pMDI formulation.

Remdesivir DPI / Analytical Study
The analytical study was performed to evaluate the qualitative status of Remdesivir DPIs with different compositions.
Test limit:
1. Uniformity of delivered dose: 9 out of 10 results lie between 75 per cent and 125 per cent of the average value
2. and all lie between 65 per cent and 135 per cent.
3. Assay %: NLT 80.0 NMT 120.0 of the labelled amount

Table 5: DPI Strength Suitability Study
Sample details Uniformity of delivered dose Assay %
Average assay of 9 out of 10 test results Average assay of all 10 test results
Example 16 84.42% 85.13% 98.86%
Example 17 85.46% 84.64% 97.76%
Example 18 87.34% 83.46% 99.64%
Example 19 85.68% 82.28% 100.36%
Example 20 90.56% 88.76% 103.34%
Example 21 91.74% 89.42% 104.64%
Example 22 92.36% 87.88% 101.26%
Example 23 90.84% 90.21% 102.04%
Example 24 89.76% 78.44% 101.06%
Example 25 88.92% 81.26% 99.82%
Example 26 89.14% 76.92% 98.96%
Example 27 87.74% 82.84% 99.26%
Example 28 86.26% 83.56% 102.20%
Example 29 88.84% 81.28% 104.32%
Example 30 82.64% 79.92% 101.08%
Example 31 84.36% 81.08% 101.76%
Conclusion:
DPI samples with different composition passes test criteria, but DPIs of 17.5 mg strength was found to be most suitable.
Remdesivir DPI: Device Comparison / Analytical Study
The analytical study was performed on DPI device under present invention againstDPI devices of prior art.

Table 6: Comparison of in vitro deposition of drug, Remdesivir using Cascade impactor
The composition of the examples of DPI under present invention are compared with the prior art devices, in terms of central deposition (2 to 5 micron), peripheral deposition (<2micron) and Oropharyngeal Deposition (>5 micron)
The results are tabulated as follows:
Device Name Device under present invention Plastiape Rotahaler
Deposition of drug-Remdesivir in mg. Deposition of drug-Remdesivir in mg. Deposition of drug-Remdesivir
in mg.
Central deposition
(2 to 5 microns) Peripheraldeposition
(< 2 microns) Orophar-yngeal Deposition
(>5 microns) Central deposition
(2 to 5 microns) Peripheraldeposition
(< 2 microns) Orophar-yngeal Deposition
(>5 microns) Central deposition
(2 to 5 microns) Peripheraldeposition
(< 2 microns) Orophar-yngeal Deposition
(>5 microns)
Example 16 2.15 3.28 1.32 1.65 2.98 2.18 2.04 3.06 1.42
Example 17 2.28 3.36 1.36 1.78 2.86 2.24 2.14 3.18 1.58
Example 18 2.22 3.42 1.28 1.82 2.72 2.38 1.92 3.22 1.64
Example 19 2.12 3.22 1.42 1.92 2.64 2.46 2.08 3.08 1.44
Example 20 4.58 6.82 2.76 4.16 5.96 3.16 4.42 6.48 2.92
Example 21 4.66 6.96 2.68 4.28 6.04 3.34 4.54 6.74 2.84
Example 22 4.48 7.04 2.84 3.86 6.22 3.28 4.62 6.66 3.06
Example 23 4.52 6.76 2.62 3.98 5.86 3.26 4.36 6.58 2.72
Example 24 6.90 10.46 3.62 5.92 9.24 4.02 6.54 10.04 3.84
Example 25 6.82 10.58 3.54 5.74 8.96 3.94 6.48 10.22 3.72
Example 26 6.74 10.38 3.58 6.08 9.38 4.18 6.36 9.92 3.66
Example 27 6.98 10.52 3.72 6.26 8.12 4.08 6.66 10.18 3.56
Example 28 14.24 19.32 4.72 12.44 18.44 6.24 13.76 19.04 5.04
Example 29 14.38 19.58 4.94 11.96 18.26 5.86 13.88 18.96 5.34
Example 30 14.18 19.24 4.86 12.28 18.04 5.62 13.62 18.84 5.48
Example 31 14.46 19.46 4.78 11.76 17.88 6.14 14.02 18.72 5.16
Note:
Examples 16 to 19: Each capsule contains 8.75 mg. of drug, Remdesivir
Examples 20 to 23: Each capsule contains 17.50 mg. of drug, Remdesivir
Examples 24 to 27: Each capsule contains 26.25 mg. of drug, Remdesivir
Examples 28 to 31: Each capsule contains 52.50 mg. of drug, Remdesivir
Conclusion:
Dry powder inhalation with DPI device of the present invention shows better central deposition.
Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.