Claims:
1. A formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, along with a carrier and polymer, for systemic delivery, wherein the surfactant is selected from Lauric acid, monolaurin, monocaprylin, monocaprin, monomyristin, monoolein, monolinolein, butyric acid, caproic, acid caprylic acid, palmitic acid, stearic acid, sodium lauryl sulfate or a combination thereof.
2. The formulation as claimed in claim 1, wherein the surfactant is selected from lauric acid, monolaurin, and sodium lauryl sulfate.
3. The formulation as claimed in claim 1, wherein the carrier is selected from mannitol, lactose, trehalose, maltose, glucose and L-leucine, preferably mannitol.
4. The formulation as claimed in claim 1, wherein polymer is selected from Polyvinyl pyrollidone K30 (PVP K30), Poloxamer 407 and combinations thereof.
5. The formulation as claimed in claim 1, wherein the size of inhalable microparticles is in the range of 1 µm to 5µm in diameter.
6. The formulation as claimed in claim 1, wherein the bulk density of inhalable microparticles is less than 0.5 g/cc preferably, the bulk density of inhalable microparticles is less than 0.3 g/cc.
7. The formulation as claimed in claim 1, wherein the formulation is optimized using box-behnken design (BBD) to produce porous freeze dried inhalable microparticles (FDIMs).
8. A process for preparing the formulation as claimed in claim 1, wherein the process comprises the steps of:
a) Preparing an aqueous phase by dissolving the active drug Hydroxychloroquine, carrier and surfactant(s) in water;
b) Preparing organic phase by dissolving polymer PVP K-30 in organic solvent;
c) Slowly mixing the organic phase of step b) into aqueous phase prepared in step a);
d) Stirring the mixture prepared in step c) for 30 min to produce a fine dispersion of microparticles;
e) Collecting the microparticles by centrifugation;
f) Membrane filterating the microparticles using 0.22µm filter;
g) Collecting the microparticles by ultracentrifugation; and
h) Freeze drying the microparticles in the presence of cryoprotectant to generate fine porous inhalable powder.
9. The process as claimed in claim 8, wherein the size of inhalable microparticles is in the range of1µm to 5µm in diameter, with correspondingly low mass median diameter.
10. The process as claimed in claim 8, wherein the bulk density of inhalable microparticles is less than 0.5 g/cc, preferably the bulk density of inhalable microparticles is less than 0.3 g/cc.
11. The process as claimed in claim 8, wherein the cryoprotectant can be selected from trehalose, glucose, mannitol, and sucrose.
12. The process as claimed in claim 8, wherein hydroxychloroquine is encapsulated into freeze dried inhalable microparticles.
13. The process as claimed in claim 8, wherein the freeze dried microparticles are obtained as fine, porous powder with reduced particle size and lesser bulk density, as required for lung deposition and retention.
14. The process as claimed in claim 8, wherein the resulting formulation can be used in metered-dose inhalers, small-volume nebulizers, or in dry powder inhalers.

Description:
FIELD OF THE INVENTION
[0001] The present invention relates to inhalable microparticles for systemic delivery. Specifically, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant. The present invention further relates to a process for preparing the formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant based on quasi-emulsification solvent evaporation technique followed by freeze drying. The present invention also provides a method for the management of Acute Respiratory Syndrome associated with COVID and viral morbidities comprising administering pharmaceutically effective amount of inhalable microparticles.

BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Looking towards today’s scenario of increased environmental pollution, occupational chemicals, noxious particles and tobacco smoke; the pulmonary disease i.e. asthma, chronic in?ammation, chronic obstructive pulmonary disease (COPD), and bronchoconstriction has been most prevalent worldwide health concern (Mehta et al., 2018). Pulmonary drug administration has been considered paramount route for delivery of medicament. Pulmonary diseases are usually cured using different synthetic molecules for management of Acute Respiratory Syndrome associated with COVID and viral morbidities (Beck-Broichsitteret al., 2012; Patton et al., 2007; Rave et al., 2005).
[0004] COVID-19 (Coronavirus Disease-2019) is a public health emergency of international concern. Patients contracting the severe form of the disease constitute approximately 15% of the cases. As of this time there is no known specific, effective, proven, pharmacological treatment. Antiviral drugs like lopinavir/ritonavir, favipiravir and remdesivir are being explored. Currently, hydroxychloroquine has been the focus of research attempts to treat viral infections like COVID (Cortegiani et al., 2020, Das et al., 2020). Preliminary evidence suggests potential benefit with chloroquine or hydroxychloroquine.
[0005] In-vitro studies have suggested that chloroquine, an immunomodulant drug traditionally used to treat malaria, is effective in reducing viral replication in other infections, including the SARS-associated corona virus (CoV) and MERS-CoV. Chloroquine has been used worldwide for more than 70 years, and it is part of the World Health Organization (WHO) model list of essential medicines. It is also cheap and has an established clinical safety profile. (Das et al., 2020; Scuccimarri et al., 2020; Zhou et al., 2020).
[0006] Hydroxychloroquine (an analogue of chloroquine) has been demonstrated to have an anti SARS-CoV activity in vitro. Hydroxychloroquine clinical safety profile is better than that of chloroquine. Hydroxychloroquine and chloroquine inhibit receptor binding and membrane fusion. Therefore, hydroxychloroquine could serve as a better therapeutic approach than chloroquine for the treatment of SARS-CoV-2 infection. There are three major reasons for this: (i) hydroxychloroquine is likely to attenuate the severe progression of COVID-19 through inhibiting the cytokine storm by reducing CD154 expression in T cells; (ii) hydroxychloroquine may confer a similar antiviral effect at both pre- and post- infection stages, as found with chloroquine; (iii) hydroxychloroquine has fewer side effects, is safe in pregnancy.
[0007] Given the fast-growing number of COVID-19 patients, there is an urgent need for effective and safe drugs in the clinic. Lauric acid (C12) and its derivative, monolaurin, have been known for many years to have significant antiviral activity. Lauric acid is a medium-chain fatty acid which makes up about 50% of coconut oil; monolaurin is a metabolite that is naturally produced by the body’s own enzymes upon ingestion of coconut oil and is also available in pure form as a supplement. Sodium lauryl sulfate, a common surfactant that is made from lauric acid, has been shown to have potent antiviral properties. Lauric acid, monolaurin, and sodium lauryl sulfate are used in a wide range of products for their antiviral properties. Three mechanisms have been proposed to explain the antiviral activity of lauric acid and monolaurin: first, they cause disintegration of the virus envelope; second, they can inhibit late maturation stage in the virus replicative cycle; and third, they can prevent the binding of viral proteins to the host cell membrane (Cortegiani et al., 2020; Scuccimarri et al., 2020; Zhou et al., 2020).

[0008] Systemic delivery of freeze dried inhalable micro-particles (FDIMs) through inhalation (oral and nasal) is an attractive alternative for pulmonary delivery for management of Acute Respiratory Syndrome associated with COVID and viral morbidities. Drug delivery to lungs through inhalation has advantages such as high bioavailability, rapid onset of action due to its large surface area for absorption, improved patient compliance, limited drug degradation, and high solute permeability. An important consideration in pulmonary delivery is aerosolization of the drug which leads to disintegration of the virus envelope and can inhibit late maturation stage in the virus replicative cycle that leads to prevention of binding of viral proteins to the host cell membrane. Delivery of drug to lungs has to go through physical obstruction and physiological obstruction which includes the multiple bifurcation of respiratory tract and the innate immunological response
[0009] There is, therefore, a need to further develop therapeutic approach for the treatment of Acute Respiratory Syndrome associated with COVID and viral morbidities and SARS-CoV-2 infection that can overcome deficiencies associated with the known arts. The present invention provides inhalable microparticles and process for their preparation, for the treatment of Acute Respiratory Syndrome.

OBJECTS OF THE INVENTION
[0010] An object of the present invention is to provide treatment option for treatment of Acute Respiratory Syndrome associated with COVID and viral morbidities that satisfy the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.
[0011] Another object of the present invention is to provide inhalable microparticles for systemic delivery.
[0012] Yet another object of the present invention is to provide inhalable microparticles for the treatment of Acute Respiratory Syndrome associated with COVID and viral morbidities.
[0013] Still another object of the present invention is to provide a process for preparation of inhalable microparticles for the treatment of Acute Respiratory Syndrome associated with COVID and viral morbidities.
[0014] Another object of the present invention is to provide a formulation comprising inhalable microparticles and its quality-by-design optimization.
[0015] The other objects and preferred embodiments and advantages of the present invention will become more apparent from the following description of the present invention when read in conjunction with the accompanying examples and figures, which are not intended to limit scope of the present invention in any manner.

SUMMARY OF THE INVENTION
[0016] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in Detailed Description section. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
[0017] The present invention relates to inhalable microparticles for systemic delivery. Specifically, the present invention relates to inhalable microparticles for the management of Acute Respiratory Syndrome associated with COVID and viral morbidities.
[0018] In one aspect, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant.
[0019] In another aspect, the present invention relates to a process for preparing the formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant.
[0020] In another aspect, the present invention relates to a process for preparing the formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant based on quasi-emulsification solvent evaporation technique followed by freeze drying.
[0021] In yet another aspect, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein hydroxychloroquine is encapsulated into freeze dried inhalable Microparticles (FDIMs).
[0022] In yet another aspect, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant wherein the freeze dried microparticles are obtained as fine, porous powder having very less density.
[0023] In still another aspect, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the formulation is optimized using box-behnken design (BBD) to produce porous FDIMs.
[0024] In another aspect, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein FDIMs are prepared with reduced particle size and lesser bulk density as required for lung deposition and retention.
[0025] In another aspect, the present invention provides a method for the management of Acute Respiratory Syndrome associated with COVID and viral morbidities comprising administering pharmaceutically effective amount of inhalable microparticles to a subject in need thereof.
[0026] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments

BRIEF DESCRIPTION OF DRAWINGS THE INVENTION
[0027] The following drawings form part of the present specification and are included to further illustrate aspects of the present disclosure. The disclosure may be better understood by reference to the drawings in combination with the detailed description of the specific embodiments presented herein.
Figure 1: Production methodology for freeze dried inhalable microparticles of Hydroxychloroquine and surfactant.

DETAILED DESCRIPTION
[0028] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0029] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[0030] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0031] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.”Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0032] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[0033] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0034] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0035] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written
description of all Markush groups used in the appended claims.
[0036] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0037] It should also be appreciated that the present disclosure can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
[0038] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0039] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0040] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0041] As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art.. The carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient. The carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation.
[0042] The present invention relates to inhalable microparticles for systemic delivery. Specifically, the present invention relates to inhalable microparticles for the treatment and prophylaxis of Acute Respiratory Syndrome associated with COVID and viral morbidities.
[0043] In one embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant.
[0044] In another embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the formulation further comprises a carrier and polymer.
[0045] In another embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the surfactant is selected from but not limited to Lauric acid, monolaurin, monocaprylin, monocaprin, monomyristin, monoolein, monolinolein, butyric acid, caproic, acid caprylic acid, palmitic acid, stearic acid, sodium lauryl sulfate and combinations thereof.
[0046] In a preferred embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the surfactant is selected from lauric acid, monolaurin, and sodium lauryl sulfate.
[0047] In another embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the carrier can be selected from but not limited to mannitol, lactose, trehalose, maltose, glucose and L-leucine.
[0048] In a preferred embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the carrier is mannitol. Mannitol is added for surface modification with the intention of enhancing their aerodynamic property.
[0049] In another embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the polymer can be selected from but not limited to Polyvinyl pyrollidone K30 (PVP K30), Poloxamer 407,chitosan, gelatin, locust bean gum, hyaluronic acid, alginate, eudragits, polylactic acid, polyglycolic acid, polylactide-co-glycolide, ethyl cellulose, hydroxyl propyl methyl celluloseand combinations thereof.
[0050] In a preferred embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the polymer is Polyvinyl pyrollidone K30 (PVP K30), Poloxamer 407 and combinations thereof.
[0051] In another embodiment, the present invention relates to a formulation comprising inhalable microparticles, wherein the size of inhalable microparticles is in the range of 1µmto 5µm in diameter.
[0052] In another embodiment, the present invention relates to a formulation comprising inhalable microparticles, wherein the bulk density of inhalable microparticles is less than 0.5g/cc preferably, the bulk density of inhalable microparticles is less than 0.3g/cc.
[0053] In another embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the formulation is optimized using box-behnken design (BBD) to produce porous freeze dried inhalable microparticles (FDIMs) with reduced particle size and lesser bulk density as required for lung deposition and retention.
[0054] In another embodiment, the present invention relates to a process for preparing the formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant along with polymer and carrier.
[0055] In another embodiment, the present invention relates to a process for preparing the formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant based on quasi-emulsification solvent evaporation technique followed by freeze drying. The entire sequence of process is described in detail in Figure 1.
[0056] In another embodiment, the present invention relates to a process for preparing the formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the process comprises the steps of:
a) Preparing an aqueous phase by dissolving the active drug Hydroxychloroquine, carrier and surfactant(s) in water;
b) Preparing organic phase by dissolving polymer PVP K-30 in organic solvent;
c) Slowly mixing the organic phase of step b) into aqueous phase prepared in step a);
d) Stirring the mixture prepared in step c) for 30 min to produce a fine dispersion of microparticles;
e) Collecting the microparticles by centrifugation;
f) Membrane filterating the microparticles using 0.22µm filter;
g) Collecting the microparticles by ultracentrifugation;
h) Freeze drying the microparticles in the presence of cryoprotectant to generate fine porous inhalable powder with very less density.
The entire sequence of process, used for the preparation of inhalable microparticles is illustrated in detail in Figure 1.
[0057] In another embodiment, the present invention relates to the process for preparing the formulation comprising inhalable microparticlin the range of 1µmto 5µm in diameter, with correspondingly low mass median diameter.
[0058] In another embodiment, the present invention relates to the process for preparing the formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the bulk density of inhalable microparticles is less than 0.5g/cc, preferably the bulk density of inhalable microparticles is less than 0.3g/cc.
[0059] In another embodiment, the present invention relates to the process for preparing the formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the cryoprotectant can be selected from but not limited to trehalose, glucose, mannitol, and sucrose.
[0060] In yet another embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein hydroxychloroquine is encapsulated into freeze dried inhalable Microparticles (FDIMs).
[0061] In yet another embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant wherein the freeze dried microparticles are obtained as fine, porous powder having very less density.
[0062] In still another embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the formulation is optimized using box-behnken design (BBD) to produce porous FDIMs.
[0063] In another embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein FDIMs are prepared with reduced particle size and lesser bulk density as required for lung deposition and retention.
[0064] In another embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the formulation can be used in metered-dose inhalers, small-volume nebulizers, or in dry powder inhalers.
[0065] Numerous inhalation delivery systems have been developed and studied to treat lung diseases such as asthma, COPD, and other pulmonary infections. All are encompassed in the scope of present invention. Among them, three approaches, that is, nebulizers, pressurized metered-dose inhalers (pMDIs), and dry powder inhalers (DPI), are preferred for the inhalable microparticles to be used for treatment of acute respiratory syndromes like COVID and viral morbidities.
[0066] In another embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the formulation may require the additional use of ancillary equipment like holding chamber or spacer.
[0067] In another embodiment, the present invention provides a method for the treatment and prophylaxis of Acute Respiratory Syndrome associated with COVID and viral morbidities comprising administering pharmaceutically effective amount of inhalable microparticles to a subject in need thereof. The dose of the formulation can be titrated according to the disease, age and other requirements of the patient as well known to a person skilled in the art.
[0068] In yet another embodiment, the present invention provides the use of pharmaceutically effective amount of inhalable microparticles for the treatment and prophylaxis of Acute Respiratory Syndrome associated with COVID and viral morbidities, in a subject in need thereof.
[0069] In another embodiment, the present invention provides a method for manufacture of a medicament comprising pharmaceutically effective amount of inhalable microparticles of the present invention, for the treatment and prophylaxis of Acute Respiratory Syndrome associated with COVID and viral morbidities, in a subject in need thereof.
[0070] In another embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein onset of therapeutic effect is faster with inhalation than with oral administration.
[0071] In another embodiment, the present invention relates to a formulation comprising inhalable microparticles of Hydroxychloroquine and surfactant, wherein the drug is delivered directly to the target organ.
[0072] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
[0073] The present invention is further explained in the form of following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.
[0074] All the starting materials are commercially available.PVP K-30, mannitol, lauric acid, monolaurin, and sodium lauryl sulfate were procured from Loba Chemicals Private Limited, Mumbai, India. Poloxamer 407 was procured from Sigma-Aldrich. Hydroxychloroquine was procured from ZydusCadila Health Care Ltd, Baddi.
[0075] Example 1:Formulation of freeze dried inhalable Microparticles (FDIMs)
Table 1 describes the different formulations of freeze dried inhalable microparticles prepared by varying the ratio of drug hydroxychloroquine, polymer, carrier (mannitol) and surfactant.

Table 1.Independent and response variables for FDIMs
Independent variables -1 (Low) 0 (Medium) +1 (High)
X1= Drug: Polymer (w/w) 1:2 1:3 1:4
X2 = Mannitol (% w/v) 2 4 6
X3 = Surfactant (% v/v) 2 3 4
Response variables Constraints Importance
Y1 = Mean Diameter (µm) Minimize +++++
Y2 = Bulk Density (g/cc) Minimize +++++

[0076] Example 2: Box-behnken design (BBD) layouts.
Table 2 indicates different batches of FDIMs and their Box-behnken design (BBD) layouts.
Table 2: Box-behnken design (BBD) layout for different batches of FDIMs
FDIM Drug: Polymer (w/w) Mannitol
(% w/v) Surfactant
(% v/v) Mean diameter (µm) Bulk density (g/cc)
1 1:2 2 3 1.9 0.29
2 1:4 2 3 7.8 0.68
3 1:2 6 3 1.6 0.33
4 1:4 6 3 7.5 0.67
5 1:2 4 2 2.4 0.32
6 1:4 4 2 7.7 0.69
7 1:2 4 4 1.1 0.21
8 1:4 4 4 7.2 0.69
9 1:3 2 2 4.4 0.33
10 1:3 6 2 3.9 0.43
11 1:3 2 4 3.4 0.37
12 1:3 6 4 3.7 0.32
13 1:3 4 3 3.4 0.34
14 1:3 4 3 3.3 0.38
15 1:3 4 3 3.6 0.34
16 1:3 4 3 3.4 0.35
17 1:3 4 3 3.7 0.36

[0077] Example 3: Fabrication of freeze dried inhalable Microparticles (FDIMs)
Hydroxychloroquine (500 mg), mannitol (2, 4, 6 gm for 2, 4, 6 % w/v), and Poloxamer 407 (500 mg), were dissolved in distilled water (30 ml), followed by addition of surfactants (Lauric acid, monolaurin, and sodium lauryl sulfate in 1:1:1) (2, 3, 4 gm for 2, 3, 4 % w/v). PVP K-30 (1000, 1500, 2000 mg for 1:2, 1:3, 1:4 drug polymer ratio), was dissolved in ethanol (70 ml), to produce organic phase which was added slowly to aqueous phase with continuous magnetic stirring (REMI, India) at 2000 rpm for 30 minutes to produce fine dispersion of microparticles which were collected by centrifugation (~ 6-13 gm for various batches), succeeded by membrane filtration using 0.22µm filter. The microparticles were further collected by ultracentrifugation at 20,000 rpm for 30 minutes (REMI, India) followed by freeze drying at -55oC and 0.5 kPa (vacuum; ISIC Make) in presence of mannitol as lyoprotectant to generate fine, porous powder (~ 7-14 gm yield for various batches), having very less density (ranging from 1.1-7.8 µm mean diameter and 0.21-0.69 g/cc bulk density). The entire sequence is depicted in Figure 1. These freeze dried inhalable microparticles are intended to be filled in 100 hard gelatin capsule shells (each shell containing FDIM equivalent to 5 mg Hydroxychloroquine) and further are useful for dry powder inhaler (DPI) devices i.e. single-dose devices.
[0078] Example 4:Evaluation of Inhalable Microparticles
[0079] Mean diameter (Y1):Mean diameters of FDIMs was determined by optical microscopy using compound microscope (Erma, 23 Tokyo, Japan). All samples were diluted with distilled water before measurement. The particle size measurement was conducted for minimum 300 particles of sample to find out mean particle size. Measurement was executed in triplicate (n = 3) to obtain mean diameter.
[0080] Bulk density (Y2) :The bulk density of FDIMs was determined using 10 mL graduated cylinder. 1 gram of FDIMs was poured into the cylinder and bulk density was calculated using the formula:
Eq. 1
[0081] Example 5: Optimized formulation of FDIMs as per Design-expert® 11.1.2.0 software
[0082] The formulation for Inhalable microparticles was optimized using Design-expert® 11.1.2.0 software and the results are depicted in Table 3.
Table 3.Optimized formulation as per the Design-expert® 11.1.2.0 software
Independent variables Criteria Importance Value D?
X1= *Drug: Polymer (w/w) In range +++ 1:2
X2 = Mannitol (% w/v) In range +++ 4.616
X3 = Surfactant (% v/v) In range +++ 1.5
Response variables
Y1 = Mean Diameter (µm) Minimize +++++ 1.326
Y2 = Bulk Density (g/cc) Minimize +++++ 0.244 0.977
?Desirability
[0083] The foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

ADVANTAGES OF THE PRESENT INVENTION
[0084] The present invention provides a treatment option for treatment of Acute Respiratory Syndrome associated with COVID and viral morbidities that satisfy the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.
[0085] The present invention provides inhalable microparticles for systemic delivery.
[0086] The present invention provides inhalable microparticlesfor the treatment of Acute Respiratory Syndrome associated with COVID and viral morbidities.
[0087] The present invention provides a process for preparation of inhalable microparticles for the treatment of Acute Respiratory Syndrome associated with COVID and viral morbidities.
[0088] The present invention provides a formulation comprising inhalable microparticles and its quality-by-design optimization.