Dry powder inhalation (DPI) formulation and preparation method thereof

Abstract

The present invention in general relates to a pharmaceutical formulation, specifically a dry powder inhalation formulation for treatment of Corona virus disease-19 (COVID-19). The formulation comprises of combination of an antiviral and a corticosteroid. The invention further describes the method of preparation of the dry powder inhalation formulation.

Description

[0001] DRY POWDER INHALATION (DPI) FORMULATION AND PREPARATION

[0002] METHOD THEREOF

[0003] PRIORITY:

[0004] This application claims the benefit of Indian application number 202421054076 dated 16thJuly 2024 entitled, ‘DRY POWDER INHALATION (DPI) FORMULATION AND PREPARATION METHOD THEREOF’, the contents of which are incorporated herein by reference.

[0005] TECHNICAL FIELD OF THE INVENTION

[0006] The present invention in general relates to a pharmaceutical formulation, specifically a dry powder inhalation formulation for treatment of Corona virus disease- 19 (COVID-19). The formulation comprises of combination of an antiviral and a corticosteroid. The invention further describes the method of preparation of the dry powder inhalation formulation.

[0007] BACKGROUND OF THE INVENTION

[0008] Coronaviruses (CoV) are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS- CoV) and severe acute respiratory syndrome (SARS-CoV). CoV is an enveloped, positivesense single-stranded RNA (ssRNA) virus belonging to the Coronaviridae family. The CoV family consists of several species and causes upper respiratory tract and gastrointestinal infections in mammals and birds. In humans, it mainly causes common cold, but complications including pneumonia and SARS can occur. The known human CoV (HCoV) includes HCoV-229E, -OC43, -NL63, -HKU1, and the more widely known severe acute respiratory syndrome coronavirus (SARS-CoV) which caused a global threat with high mortality in 2003. In 2012, the World Health Organization (WHO) designated a sixth type of HCoV infection identified as the Middle East respiratory syndrome coronavirus (MERS- CoV) which is associated with high fatality.

[0009] The outbreak of Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed a substantial global health challenge. Since its emergence in late 2019, COVID-19 has led to widespread morbidity and mortality, overwhelming healthcare systems worldwide. The clinical spectrum of COVID-19 ranges from asymptomatic infection to severe respiratory failure and death, with respiratory symptoms being the most common manifestation.

[0010] COVID-19 primarily affects the respiratory system, leading to symptoms such as cough, fever, and shortness of breath. In severe cases, it can progress to pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ failure. The rapid transmission and high mortality rate of severe cases have necessitated the development of effective therapeutic strategies.

[0011] Several therapeutic approaches have been explored to combat COVID-19, including antiviral agents, corticosteroids, immunomodulators, and supportive care. Among these, antiviral agents and corticosteroids have shown significant promise.

[0012] Antiviral Agents:

[0013] Antiviral drugs, such as remdesivir, favipiravir, and molnupiravir, have been investigated for their ability to inhibit viral replication. Remdesivir, for instance, has been approved for emergency use in the treatment of COVID-19 and has demonstrated efficacy in reducing the duration of symptoms and improving clinical outcomes. These antivirals work by targeting specific stages of the viral replication cycle, thereby reducing viral load and disease severity.

[0014] Corticosteroids:

[0015] Corticosteroids, such as dexamethasone, have been shown to reduce mortality in critically ill COVID-19 patients by dampening the excessive inflammatory response. Dexamethasone, in particular, has been widely adopted following the RECOVERY trial, which demonstrated its effectiveness in reducing deaths among patients requiring oxygen therapy or mechanical ventilation. Corticosteroids help mitigate the hyperinflammatory state, often referred to as a "cytokine storm," which is a significant contributor to the severity of COVID-19.

[0016] Immunomodulators and Other Treatments:

[0017] Other treatments include monoclonal antibodies, convalescent plasma, and immunomodulatory drugs. Supportive care remains essential, especially for severe cases requiring mechanical ventilation and intensive care. While systemic administration of these drugs has been beneficial, there are limitations related to systemic side effects and suboptimal drug concentrations at the site of infection. The respiratory tract, being the primary site of SARS-CoV-2 infection, represents an ideal target for localized drug delivery. Inhalation therapies can deliver drugs directly to the lungs, ensuring higher local concentrations and faster therapeutic action while minimizing systemic exposure and side effects.

[0018] A dry powder inhalation (DPI) formulation is a type of pharmaceutical preparation designed for administration via the respiratory route, specifically targeting the lungs. This formulation consists of finely micronized drug particles combined with suitable excipients, which are delivered to the lungs in the form of a dry powder using a dry powder inhaler device. DPIs are particularly advantageous due to their stability, ease of use, and ability to deliver a precise dose of medication to the lungs. DPIs contain a powdered formulation of the active drug and are designed to deliver the medication deep into the lungs where it can exert its therapeutic effect.

[0019] Dry powder inhalers (DPIs) offer several advantages for pulmonary drug delivery:

[0020] Direct Delivery to the Lungs: Inhalation delivers the drug directly to the site of infection, potentially increasing the concentration of the drug in the respiratory tract while minimizing systemic exposure.

[0021] Enhanced Efficacy: Localized delivery of antiviral agents and corticosteroids can enhance their therapeutic efficacy by ensuring higher local concentrations.

[0022] Reduced Side Effects: By targeting the lungs directly, inhalation can reduce the systemic side effects associated with oral or intravenous administration.

[0023] Patient Convenience: Dry powder inhalers (DPIs) are portable, easy to use, and do not require refrigeration or specialized handling, enhancing patient compliance and accessibility.

[0024] Stability: Dry powder formulations are generally more stable than liquid formulations, making them suitable for long-term storage without significant degradation.

[0025] An article entitled as ‘Efficacy and Safety of New and Emerging Drugs for COVID-19: Favipiravir and Dexamethasone’ by Shivani Sood, Gurpreet Kaur Bhatia, Prachi Seth, Pawan Kumar, Jagjit Kaur, Vidisha Gupta, Sandeep Punia & Hardeep Singh Tuli in Clinical Pharmacology (L Brunetti, Section Editor) February 2021 discloses a review that describes the path of favipiravir and dexamethasone from chemistry to mechanisms of action to combat SARS-CoV-2. In addition, the potential side effects are also summarized to study their potential to control corona virus 2019.

[0026] An article entitled as ‘Rational Development of a Carrier-Free Dry Powder Inhalation Formulation for Respiratory Viral Infections via Quality by Design: A Drug-Drug Cocrystal of Favipiravir and Theophylline’ by Si Nga Wong, Jingwen Weng, Ignatius Ip, Ruipeng Chen, Richard Lakerveld et. al. in Pharmaceutics January 2022 discloses a Quality-by-Design (QbD)-guided development of a carrier-free inhalable dry powder formulation containing a 1 : 1 favipiravir-theophylline (FAV-THP) cocrystal via spray drying, which may provide an alternative treatment strategy for individuals with concomitant influenza infections and chronic obstructive pulmonary disease / asthma.

[0027] The invention of a dry powder inhalation formulation that combines both antiviral agents and corticosteroids aims to leverage the benefits of both therapeutic classes. The antiviral component targets the replication of SARS-CoV-2, while the corticosteroid component reduces inflammation and immune-mediated damage. This dual-action approach can potentially enhance therapeutic efficacy, leading to better clinical outcomes for COVID-19 patients.

[0028] The synergistic effect of delivering these agents directly to the lungs can provide rapid symptom relief and prevent the progression of the disease to more severe stages. Moreover, by targeting the lungs specifically, the formulation minimizes systemic exposure and reduces the risk of adverse effects associated with oral or intravenous administration.

[0029] OBJECT OF THE INVENTION

[0030] Main object of the present invention is to provide a dry powder inhalation (DPI) formulation for treatment of Corona virus disease-19 (COVID-19).

[0031] Another object of the present invention is to provide dry powder inhalation (DPI) formulation comprising combination of an antiviral and a corticosteroid.

[0032] Yet another object of the present invention is to provide a method of preparation of the dry powder inhalation formulation. SUMMARY OF THE INVENTION

[0033] In an embodiment, the present invention relates to a dry powder inhalation formulation comprising an antiviral and a corticosteroid.

[0034] In an aspect of the embodiment, the antiviral is Favipiravir. In another aspect, the corticosteroid is Dexamethasone.

[0035] In another embodiment, a dry powder inhalation (DPI) formulation comprising; a) Favipiravir; b) Dexamethasone; and c) Pharmaceutically acceptable inert excipients.

[0036] In a further aspect of the embodiment, the formulation is fixed dose combination.

[0037] In an aspect of embodiment, the Favipiravir and Dexamethasone is present in the weight ratio of 4:1.

[0038] In another aspect of the embodiment, the formulation is in the form of solid lipid nanoparticles and then spray dried.

[0039] In a further aspect of the embodiment, the formulation is used for the treatment of COVID - 19.

[0040] In an aspect of embodiment, the pharmaceutically acceptable inert excipients are surfactant, lipid, and solvent.

[0041] In an aspect of embodiment, the surfactants are polysorbate and poloxamer.

[0042] In an aspect of embodiment, the lipid is glyceryl monostearate.

[0043] In another embodiment, the present invention relates to a dry powder inhalation formulation comprising; a) 0.04 % w / v of Favipiravir; a. 0.01 % w / v of Dexamethasone; b) 1 % w / v Glyceryl Monostearate; c) 1 % w / v Polysorbate; d) 1 % w / v Poloxamer; and e) Mili-Q water;

[0044] Wherein the percentages are with respect to total weight of the formulation.

[0045] In yet another embodiment, a process for preparation of dry powder inhalation formulation comprises steps of; a) Heating polysorbate and poloxamer in Mili-Q water to form aqueous phase; b) Melting glyceryl monostearate and dissolving favipiravir and dexamethasone to form lipid phase; c) Adding lipid phase into aqueous phase to form solid lipid nanoparticles (SLNPs); d) Micro-fluidizing the solid lipid nanoparticles (SLNPs) to form micro-fluidized solid lipid nanoparticles (SLNPs); e) Spray drying the micro-fluidized solid lipid nanoparticles (SLNPs) to form dry powder inhalation formulation.

[0046] In an aspect of embodiment, formulation is spray dried using mannitol as a diluent.

[0047] BRIEF DESCRIPTION OF THE DRAWINGS

[0048] The accompanying drawings are included to provide a further understanding of the present invention and are incorporated in and constitute a part of this specification. The drawings illustrate exemplary embodiments of the present invention and, together with the description, serve to explain the principles of the present disclosure.

[0049] • Figure (Fig.) 1 shows Particle size of SLNPs

[0050] • Figure 2 shows Zeta Potential of SLNPs

[0051] • Figure 3 shows In-vitro release of Solid lipid nanoparticles

[0052] • Figure 4 shows In-vitro release of Conventional DPI

[0053] • Figure 5a shows Particle deposition of spray dried SLNPs

[0054] • Figure 5b shows Particle deposition of Conventional DPI

[0055] DESCRIPTION OF THE INVENTION

[0056] The present invention in general relates to a pharmaceutical formulation, specifically a dry powder inhalation formulation for treatment of Corona virus disease- 19 (COVID-19). The formulation comprises of combination of an antiviral and a corticosteroid. The invention further describes the method of preparation of the dry powder inhalation formulation.

[0057] The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

[0058] Unless defined otherwise, all technical as well as scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

[0059] The term "a" and "an" refers to one or to more than one (i.e., to at least one) of the grammatical object of the article. The information provided in this document, and particularly the specific details of the described exemplary aspects, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood from there.

[0060] As used herein, the term "about" means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, "about" means the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments.

[0061] As used herein, the terms "treat," "treated," or "treating" mean both therapeutic treatment or prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e., not worsening) state of condition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder or disease. The term “Dry powder inhalation (DPI) formulation” refers to a type of pharmaceutical preparation designed to deliver active pharmaceutical ingredients (APIs) directly to the lungs in the form of a dry powder. This formulation is typically administered using a specialized inhaler device, which disperses the powder into fine particles that can be inhaled deeply into the respiratory tract. DPIs are commonly used for the treatment of respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD), offering advantages like ease of use, rapid onset of action, and targeted drug delivery to the lungs.

[0062] The term ‘Fixed dose combination (FDC)’ refers to a pharmaceutical formulation that contains two or more active ingredients combined in a fixed ratio of doses. In other words, the proportions of each active ingredient in the formulation remain constant across all doses of the medication.

[0063] As used the term ‘Solid lipid nanoparticles (SLNs)’ refers to a nanoscale colloidal carriers composed of solid lipids that are used as a delivery system for pharmaceuticals. These nanoparticles have a solid lipid core matrix stabilized by surfactants and can encapsulate both hydrophobic and hydrophilic substances.

[0064] The term ‘ Spray drying’ refers to a technique used in the formulation of dry powder inhalers (DPIs) to produce inhalable particles suitable for respiratory delivery. In DPI formulation, spray drying is employed to convert liquid formulations into fine powder particles. The process involves atomizing a liquid formulation into droplets, which are then dried rapidly using a stream of hot air or inert gas. As the droplets travel through the drying chamber, solvent evaporation occurs, leaving behind solid particles.

[0065] The term "pharmaceutically acceptable inert excipients", denotes any of the components of a pharmaceutical formulation other than the active and which are approved by regulatory authorities or are generally ‘regarded as safe’ for human or animal use. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.

[0066] Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.

[0067] In an embodiment, the present invention relates to a dry powder inhalation formulation comprising an antiviral and a corticosteroid.

[0068] In an aspect of the embodiment, the antiviral is Favipiravir. In another aspect, the corticosteroid is Dexamethasone.

[0069] In another embodiment, a dry powder inhalation (DPI) formulation comprising; a) Favipiravir; b) Dexamethasone; and c) Pharmaceutically acceptable inert excipients.

[0070] Favipiravir is an antiviral medication initially developed to treat influenza. It has a broadspectrum antiviral activity, primarily targeting RNA viruses by inhibiting RNA-dependent RNA polymerase. This mechanism disrupts the viral replication process, making Favipiravir effective against various RNA viruses, including influenza, Ebola, and coronaviruses like SARS-CoV-2. Clinical studies have explored its efficacy in treating COVID-19, where it has shown potential in reducing viral load and improving patient outcomes, particularly when administered early in the course of the infection.

[0071] Dexamethasone is a potent corticosteroid with strong anti-inflammatory and immunomodulatory properties. It is commonly used to treat conditions involving excessive inflammation and immune response, such as asthma, rheumatoid arthritis, and certain types of allergies. In the context of viral infections like COVID-19, Dexamethasone has been found to be particularly beneficial for patients with severe respiratory symptoms and those requiring supplemental oxygen or mechanical ventilation. By dampening the overactive immune response and reducing inflammation, Dexamethasone helps prevent the cytokine storm associated with severe cases, thereby improving survival rates and reducing the need for intensive medical interventions.

[0072] In a further aspect of the embodiment, the formulation is fixed dose combination. In an aspect of embodiment, the Favipiravir and Dexamethasone is present in the weight ratio of 4: 1.

[0073] In another aspect of the embodiment, the formulation is in the form of solid lipid nanoparticles and then spray dried.

[0074] In a further aspect of the embodiment, the formulation is used for the treatment of COVID - 19.

[0075] In an aspect of embodiment, the pharmaceutically acceptable inert excipients are surfactant, lipid, and solvent.

[0076] A surfactant, or surface-active agent, is a substance that reduces the surface tension between two liquids or a liquid and a solid. Surfactants are amphiphilic, meaning they contain both hydrophilic (water-attracting) and hydrophobic (water-repelling) components, which allows them to interact with various substances and surfaces. This dual nature enables surfactants to stabilize mixtures, and enhance the spreading, wetting, and penetration properties of liquids.

[0077] They are selected from Lecithin (Phosphatidylcholine), Dipalmitoyl phosphatidylcholine (DPPC), Poloxamers, Tween 20 and Tween 80, span 20, Span 40, and Span 60, Sodium Dodecyl Sulfate (SDS), Sodium Lauryl Sulfate (SLS), Cetyltrimethylammonium Bromide (CTAB), etc.

[0078] In an aspect of embodiment, the surfactants are polysorbate and poloxamer. In preferred aspect of embodiment, polysorbate and poloxamer is in weight ratio of 1 : 1.

[0079] Tween 80 (Polysorbate 80) and Poloxamer 188 (Pluronic F68) are widely used surfactants in pharmaceutical formulations, including solid lipid nanoparticles (SLNPs), due to their stabilizing properties and biocompatibility. Tween 80 provides strong surface coverage and reduces surface tension, which helps in initial particle formation and stability. Poloxamer 188 offers steric stabilization and can help in maintaining particle dispersion over time.

[0080] In an aspect of embodiment, the lipid is glyceryl monostearate. Glyceryl monostearate or Monostearin is solid at room temperature, which is essential for forming stable lipid nanoparticles. Its solid-state nature helps in maintaining the structural integrity of SLNPs during storage and administration. Monostearin acts as both a lipid matrix and an emulsifier due to its amphiphilic nature. It can stabilize emulsions and nanoparticles by reducing interfacial tension and preventing particle aggregation.

[0081] In another embodiment, the present invention relates to a dry powder inhalation formulation comprising; a) 0.04 % w / v of Favipiravir; b) 0.01 % w / v of Dexamethasone; c) 1 % w / v Glyceryl Monostearate; d) 1 % w / v Polysorbate; e) 1 % w / v Poloxamer; and f) Mili-Q water; wherein the percentages are with respect to total weight of the formulation.

[0082] In yet another embodiment, a process for preparation of dry powder inhalation formulation comprises steps of; a) Heating polysorbate and poloxamer in Mili-Q water to form aqueous phase; b) Melting glyceryl monostearate and dissolving favipiravir and dexamethasone to form lipid phase; c) Adding lipid phase into aqueous phase to form solid lipid nanoparticles (SLNPs); d) Micro-fluidizing the solid lipid nanoparticles (SLNPs) to form micro-fluidized solid lipid nanoparticles (SLNPs); e) Spray drying the micro-fluidized solid lipid nanoparticles (SLNPs) to form dry powder inhalation formulation.

[0083] In an aspect of embodiment, formulation is spray dried using mannitol as a diluent.

[0084] The spray drying process in dry powder inhaler (DPI) formulation is a critical method used to transform liquid formulations into inhalable dry powder particles. The spray drying process begins with; Atomization: The process begins with atomization, where the liquid formulation containing the active pharmaceutical ingredient (API) and excipients is converted into small droplets. This is typically achieved using a nozzle or atomizer that breaks up the liquid into fine droplets.

[0085] Drying Chamber: The droplets are then introduced into a drying chamber where they come into contact with a stream of hot air or inert gas. The purpose of the drying chamber is to facilitate rapid drying of the droplets.

[0086] Solvent Evaporation: As the droplets move through the drying chamber, the solvent (typically water or an organic solvent) evaporates under the influence of the hot air or gas. This results in the formation of solid particles composed of the API and excipients.

[0087] Particle Formation: The dried particles are collected at the bottom of the drying chamber or cyclone separator. The particle size and morphology can be controlled by adjusting parameters such as the atomization pressure, inlet air temperature, drying chamber pressure, and feed rate of the liquid formulation.

[0088] Stabilization and Collection: To ensure stability and prevent aggregation, surfactants or stabilizers may be added to the liquid formulation before atomization. The collected particles are then typically processed further to ensure uniformity and proper aerodynamic properties suitable for inhalation.

[0089] Mannitol is a preferred diluent in DPI formulations due to its beneficial properties in terms of particle size control, flowability, compatibility with APIs, safety profile, moisture protection, and stability enhancement. These attributes contribute to the effectiveness and reliability of DPIs for delivering medications to the lungs.

[0090] EXEMPLARY EMBODIMENTS OF THE INVENTION

[0091] Example 1 - Solid Lipid Nanoparticles according to the invention

[0092] Table 1 - Formulation of Solid Lipid Nanoparticles

[0093] Manufacturing process for Solid Lipid Nanoparticles - a) Aqueous phase: Both surfactants, Tween 80 and Poloxamer 188, were added to Milli-Q water. The mixture was heated on a magnetic stirrer until the temperature reached 50°C. b) Organic phase: When the aqueous phase reached around 50°C, the lipid, Glyceryl Monostearate, was melted in another beaker and both drugs were dissolved into it. Approximately 10 ml of Ethanol was added to the beaker to facilitate the transfer of the organic phase into the aqueous phase dropwise while stirring the aqueous phase with the help of a magnetic bead, maintaining the rpm at 1000. After the complete addition of the organic phase, it was stirred for around 20 minutes to evaporate the Ethanol. c) The formulated Solid Lipid Nanoparticles were then processed in a microfluidizer for further size reduction.

[0094] Example 2 - Spray drying for preparation of dry powder inhalation (DPI) formulation

[0095] 5 % w / w of Mannitol is added before spray drying the SLNPs.

[0096] Spray drying conditions: (Buchi mini spray dryer)

[0097] Table 2 - Spray drying conditions: (Buchi mini spray dryer) Method of preparation of Conventional DPI:

[0098] 5 % Mannitol solution was spray dried using the following conditions in Buchi mini spray dryer:

[0099] Table 3 - Spray drying conditions

[0100] After spray drying, the spray-dried mannitol, Favipiravir, and Dexamethasone were mixed in a double-cone blender for about 20 mins. The ratio of the drugs and mannitol was adjusted such that every 30 mg of powder blend consists of 5 mg of favipiravir and 2 mg of dexamethasone.

[0101] Characterization of Solid Lipid Nanoparticles and Dry Powder Inhalation (DPI) -

[0102] • Powder characteristics

[0103] Table 4 - Powder characteristics of SLNPs and Conventional DPI • Particle size and Zeta Potential

[0104] The SLNPs exhibited a particle diameter of 224 nm and a Zeta potential of -31 mV, indicating that the nanoparticles were within the nanoscale range and demonstrated substantial stability. (Refer figure 1 and 2)

[0105] • In-vitro release: (Solid lipid nanoparticles)

[0106] Conditions-

[0107] Apparatus: Franz diffusion cell.

[0108] Diffusion membrane: Dialysis bag

[0109] Diffusion medium: Simulated lung fluid pH 6.8

[0110] RPM: 300

[0111] Aliquote: 2ml

[0112] Volume of SLNPs: 2ml

[0113] The in-vitro release study of the SLNPs followed Zero-order kinetics and exhibited 94 % and 98 % release of favipiravir and dexamethasone in the time frame of 24 hrs and 14 hrs respectively. (Figure 3)

[0114] • In-vitro release: (Conventional DPI)

[0115] The in-vitro release study of the Conventional DPI followed Zero-order kinetics and exhibited 92.32 % and 91.64 % release of favipiravir and dexamethasone in 8 hrs. (Figure 4)

[0116] • Particle deposition studies

[0117] The Anderson Cascade Impactor studies demonstrated that both the formulations could effectively deposit in the lungs, with the highest drug deposition at stage 4 for SLNPs and at stage 5 for Conventional DPI. This suggests that the formulations can reach the lungs' secondary and terminal bronchi and exhibit aerodynamic diameters of 2.62pm and 3.67pm respectively. (Figure 5) • HET-CAM assay

[0118] Table 5 - Result of HET-CAM assay

Claims

We Claim:

1. A dry powder inhalation formulation (DPI) comprising; a) Favipiravir; b) Dexamethasone; and c) Pharmaceutically acceptable inert excipients.

2. The formulation as claimed in claim 1, wherein the formulation is in fixed dose combination.

3. The formulation as claimed in claim 1, wherein the formulation is in the form of solid lipid nanoparticles and then spray dried.

4. The formulation as claimed in claim 1, wherein the Favipiravir and Dexamethasone is present in the weight ratio of 4: 1.

5. The formulation as claimed in claim 1, wherein the pharmaceutically acceptable inert excipients are surfactant, lipid, and solvent.

6. The formulation as claimed in claim 5, wherein the surfactants are polysorbate and poloxamer.

7. The formulation as claimed in claim 5, wherein the lipid is glyceryl monostearate.

8. A dry powder inhalation (DPI) formulation comprising; a) 0.04 % w / v of F avipiravir; b) 0.01 % w / v of Dexamethasone; c) 1 % w / v Glyceryl Monostearate; d) 1 % w / v Polysorbate; e) 1 % w / v Poloxamer; and f) Mili-Q water;Wherein the percentages are with respect to total weight of the formulation.

9. A process for preparation of dry powder inhalation formulation comprises steps of;a) Heating polysorbate and poloxamer in Mili-Q water to form aqueous phase; b) Melting glyceryl monostearate and dissolving favipiravir and dexamethasone to form lipid phase; c) Adding lipid phase into aqueous phase to form solid lipid nanoparticles (SLNPs); d) Micro-fluidizing the solid lipid nanoparticles (SLNPs) to form micro-fluidized solid lipid nanoparticles (SLNPs); e) Spray drying the micro-fluidized solid lipid nanoparticles (SLNPs) to form dry powder inhalation formulation.

10. The formulation as claimed in claim 9, wherein the formulation is spray dried using mannitol as a diluent.

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