The present disclosure relates generally to the field of pharmaceutical
compositions. Specifically, it pertains to pharmaceutical compositions comprising ivermectin and doxycycline to directly target the lungs, and processes of preparing the same.
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] Till date, no marketed drug or oral drug delivery system has been approved for the rational treatment of COVID-19. More than 40 different drugs are currently being explored for efficacy against COVID-19. Anti-viral Drugs used in COVID-19 have shown several side effects with high toxicity index, so limit their use. Clinical studies have shown low potency and have not found any significant difference in standardized cumulative COVID-19 mortality with Hydroxychloroquine as per Lancet study 2021. It can cause potentially fatal acute cardiac toxicity and make it unattractive as a preventive measure. Drug composition and delivery strategies such as targeted delivery could expand the use of existing drugs (Drug Repurposing).
[0004] Oxford University declared 'Ivermectin and Doxycycline as wonder drugs' to reduce mortality in COVID-19 pandemic. However, there is no combination of Ivermectin and doxycycline available in the market for Anti¬microbial activities.
[0005] Ivermectin has been reported in recent studies, as a miracle drug in the treatment of COVID-19 along with doxycycline, but efficacious only at higher doses (12mg/day), and this higher dose is also accompanied by several side effects such as cardiac toxicity. Since COVID-19 mainly affects the respiratory system, especially Lungs, therefore current proposal emphasizes the development of a

carrier system of Ivermectin targeting the lungs directly so that maximum drug
reaches the target site.
[0006] To reduce the dose-related toxicity and increase efficacy, a
combination of Ivermectin and doxycycline carrier systems in the micron size
range can be helpful in the treatment of COVID-19.
[0007] Ivermectin has been reported in recent studies, a miracle drug in the
treatment of COVID-19 along with doxycycline, but efficacious only at higher
doses (12mg/day), and this higher dose is also accompanied by several side effects
such as cardiac toxicity. Since, COVID-19 mainly affects the respiratory system,
especially the Lungs, therefore current proposal emphasizes the development of
carrier system of Ivermectin targeting the lungs directly so that maximum drug
reaches the target site. A drug delivery system composed of a combination of both
drugs helps in reducing the dose and thereby dose-related toxicity issue can be
resolved.
[0008] Polymer PLGA is found to have the proven effect to show lung
targeting. PEG will be helpful to stop the defense mechanisms. PLGA is helpful
in providing drug safety, better and controlled drug release by diffusion method,
avoid opsonisation and enzymatic degradation of loaded drug, shows lung
targeting. PEG is also proved to inhibit opsonization, macrophages and
engulfment, phagocytosis and pinocytosis.
[0009] Micronized dosage form comprising PLGA-PEG will help in better
penetration of the drugs from the epithelial layers and in turn the bioavailability.
OBJECTS OF THE INVENTION
[00010] An object of the present invention is to provide a pharmaceutical
composition comprising ivermectin or pharmaceutically active salts thereof and doxycycline or pharmaceutically active salts thereof.
[00011] An object of the present invention is to provide a pharmaceutical
composition comprising ivermectin or pharmaceutically active salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the composition is formulated as microparticles /microsphere composition.

[00012] An object of the present invention is to provide a pharmaceutical
composition comprising ivermectin or pharmaceutically active salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the composition is formulated as a micronized pharmaceutical composition.
[00013] An object of the present invention is to provide a micronized
pharmaceutical composition comprising ivermectin or pharmaceutically active salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the composition directly targets the lungs.
[00014] An object of the present invention is to provide a micronized
pharmaceutical composition comprising ivermectin or pharmaceutically active
salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the
micronized composition comprises the microspheres of PLGA-PEG copolymers.
[00015] Another object of the present invention is to provide a method for
preparing micronized pharmaceutical composition comprising ivermectin or pharmaceutically active salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the micronized composition comprises the microspheres of PLGA-PEG copolymers.
[00016] Yet another object of the present invention is to provide a
pharmaceutical composition comprising ivermectin or pharmaceutically active
salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the
composition is used for treating lung infections associated with COVID-19.
[00017] Yet another object of the present invention is to provide a nasal
composition comprising ivermectin or pharmaceutically active salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the composition is used for treating lung infections associated with COVID-19.
SUMMARY OF THE INVENTION
[00018] The present disclosure relates generally to the field of pharmaceutical compositions. Specifically, it pertains to pharmaceutical compositions comprising ivermectin and doxycycline to directly target the lungs, and processes of preparing the same.

[00019] The present disclosure pertains to a composition for the treatment of COVID and related respiratory ailments, said composition comprising a combination of one or more mixtures, wherein a first mixture comprises one or more pharmaceutical ingredients that include Ivermectin, and Doxycycline in a predetermined proportion, and a second mixture that comprises one or more polymers identified as PLGA and PEG in a plurality of proportions. [00020] In an aspect, the present disclosure relates to a pharmaceutical composition comprising ivermectin or pharmaceutically active salts thereof and doxycycline or pharmaceutically active salts thereof.
[00021] In an aspect, the present disclosure provides a pharmaceutical
composition comprising ivermectin or pharmaceutically active salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the composition is formulated as micronized pharmaceutical composition.
[00022] In an aspect, the present disclosure relates to a micronized
pharmaceutical composition comprising ivermectin or pharmaceutically active salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the composition directly targets the lungs.
[00023] In an aspect, the present disclosure relates to a micronized
pharmaceutical composition comprising ivermectin or pharmaceutically active
salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the
micronized composition comprises the microspheres of PLGA-PEG copolymers.
[00024] In another aspect, the present disclosure relates to a method for
preparing micronized pharmaceutical composition comprising ivermectin or pharmaceutically active salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the micronized composition comprises the microspheres of PLGA-PEG copolymers.
[00025] In yet another aspect, the present disclosure relates to a
pharmaceutical micronized pharmaceutical composition comprising ivermectin or pharmaceutically active salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the composition is used for treating lung infections associated with COVID-19.

[00026] In yet another aspect, the present disclosure relates to a nasal
composition comprising ivermectin or pharmaceutically active salts thereof and
doxycycline or pharmaceutically active salts thereof, wherein the composition is
used for treating lung infections associated with COVID-19.
[00027] Other aspects of the invention will be set forth in the description
which follows, and in part will be apparent from the description, or may be learned by the practice of the invention.
BRIEF DESCRIPTION OF DRAWINGS
[00028] The accompanying drawings are included to provide a further
understanding of the present disclosure and are incorporated in and constitute a
part of this specification. The drawings illustrate exemplary embodiments of the
present disclosure and, together with the description, serve to explain the
principles of the present disclosure. The diagrams are for illustration only, which
thus is not a limitation of the present disclosure.
[00029] In the figures, similar components and/or features may have the
same reference label. Further, various components of the same type may be
distinguished by following the reference label with a second label that
distinguishes among the similar components. If only the first reference label is
operated in the specification, the description is applicable to any one of the similar
components having the same first reference label irrespective of the second
reference label.
[00030] FIG 1 illustrates an exemplary representation of the operation of
the composition for treatment covid and related respiratory ailments, in
accordance with an embodiment of the present disclosure.
[00031] FIG 2 illustrates an exemplary representation of FTIR spectra of
drug-loaded microspheres in accordance with an embodiment of the present
disclosure.
[00032] FIG 3 illustrates a graphical representation of release rate of the
composition for the treatment covid and related respiratory ailments, in
accordance with an embodiment of the present disclosure.

DETAILED DESCRIPTION
[00033] The following is a detailed description of the 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.
[00034] 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.
[00035] The present disclosure generally relates to pharmaceutical
formulations and compositions and processes of preparing these formulations and
compositions for viral infections or diseases.
[00036] The present disclosure pertains to a composition for the treatment
of COVID and related respiratory ailments, said composition comprises a
formulation of one or more mixtures, wherein a first mixture comprises one or
more pharmaceutical ingredients that include Ivermectin, and Doxycycline in a
predetermined proportion, and a second mixture that comprises one or more
polymers identified as PLGA and PEG in a plurality of proportions.
[00037] In an embodiment, the first mixture may comprise Ivermectin, and
Doxycycline in a proportion of 6 to 20 respectively, and a second mixture
includes PLGA and PEG in a proportion ranging from 50 to 200 in any or a
combination of weight and volume.
[00038] In an embodiment, the composition may include one or more
polymers identified as PLGA and PEG are conjugated chemically in the presence
ofEDC/NHS.
[00039] In an embodiment, The composition may include a plurality of
microspheres comprising PLGA and PEG formed through solvent evaporation

technique, where a solution designated as A is composed of PLGA and
doxycycline in a predetermined amount ranging from lOmL to 20 mL of acetone,
and another solution designated as B is composed of an amount ranging from 10
mL to 20 mL of a PVA solution ranging from 2 to 6 percent having PEG and
Ivermectin.
[00040] In an embodiment, The plurality of formulations yield results of
the plurality of compositions ranging from 75 percent to 90 percent.
[00041] In an embodiment, The composition including a plurality of
formulations may utilize one or more methods incuding the nebulisation technique
for achieving high lung targeting.
[00042] In an embodiment, the present disclosure relates to pharmaceutical
compositions comprising ivermectin or a pharmaceutically acceptable salt thereof
and doxycycline or pharmaceutically active salts thereof.
[00043] Referring to figure 1 that illustrates an exemplary representation of
the operation of the composition for treatment covid and related respiratory
ailments. Ivermectin is a pharmaceutically active salt that is experimentally
observed to be effective in treatment of COVID-19. This is due to a fact that the
salt is successfully observed to be effective against replication of a bacterial or
viral cell by inhibiting its protein synthesis. As COVID-19 is pharmaceutically
observed to be mainly affecting the respiratory system of a living being especially
Lungs in a body, Therefore a specific salt dose is required that may actively affect
at a target in lungs. The process of targeting lung of a being can be effective in
reducing a quantity of dose of drug for a body, and hence may eliminate the
toxicity of a pharmaceutically active salt that includes Ivermectin.
[00044] In an embodiment, the effectiveness of a pharmaceutically active
salt Ivermectin is enhanced if it can be provided in one or more combinations with
another salt doxycycline. In this manner, the pharmaceutically active salt has to
endure resistance at one or more body parts in a body that are firstly in air passage
of body, where the pharmaceutically active salt needs to resist with one or more
living cells including mucus, epithelium layers etc for the purpose of penetrating
through the one or more living cells so as to activate against the bacterial and viral

cell. Further, the pharmaceutically active salt needs to resist with one or more cells at alveolus, where it has to resist one or more body immunity mechanisms including opsonisation, macrophages, neutophils etc.
[00045] In an embodiment, the present disclosure relates to a micronized
pharmaceutical formulation comprising ivermectin or pharmaceutically active salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the formulation directly targets the lungs.In an embodiment, the present disclosure relates to a micronized pharmaceutical formulation comprising ivermectin or pharmaceutically active salts thereof and doxycycline or pharmaceutically active salts thereof, wherein the micronized formulation comprises the microspheres of PLGA-PEG co-polymers.
[00046] FIG 2 illustrates an exemplary representation of FTIR spectra of
drug loaded microspheres in accordance with an embodiment of the present disclosure.
[00047] The present disclosure relates to a pharmaceutical compositions
comprising doxycycline in a weight of at least 10 mg, at least 20 mg, at least 30 mg, at least 50 mg, at least 75mg, at least 100 mg, at least 125mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 500 mg. More preferably at least 200 mg. In an embodiment, the present disclosure relates to pharmaceutical compositions comprising ivermectin in weight of at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 10 mg, at least 11 mg, at least 12 mg. More preferably 3mg or 7mg.
[00048] In an embodiment, one or more PLGA-PEG based blank
microspheres can be prepared utilizing one or more processes that include solvent evaporation technique. For an instance, a solution designated as A (organic phase) is prepared with an addition of PLGA and doxycycline in one or more proportions that include 20 mL of acetone. Further, a solution designated as B (aqueous phase) is prepared in one or more proportions that include 20 mL of 4% PVA solution having PEG-4000 and Ivermectin. In an embodiment, the solution designated as A was poured in B solution by dripping with an aid of a micro syringe and stirred on

a magnetic stirrer for a duration say 5 hrs. The final solution obtained is
homogenized and the solvent is evaporated utilising continuous magnetic stirring
at room temperature. The final product was lyophilized in order to get drug loaded
polymeric conjugates. The composition of drug loaded microspheres.
[00049] In an embodiment, the composition includes Ivermectin and
Doxycycline in one or more formulations comprising weight to weight ratio of 6:20 and one or more proportions of PLGA and PEF in on eor more proportion ranging from 50 to 200. Further, the percentage yield of one or more formulations range from 75 percent to 90 percent. In an embodiment, the Pharmaceutically active salt embedded microsphere is evaluated for drug and polymer interaction. Further, the spectrum and its characteristic peaks including several newer peaks are observed in the FTIR spectrum that include 1506.94, 1343.51 and 1278.95, and the composition is experimentally observed to showcase no drug-polymer interaction.
[00050] In an embodiment, the pharmaceutical composition may be
formulated as an oral dosage form, selected from the group comprising tablet,
pellets, capsule, granules, sachets, lozenges, liquids, suspension, gel,
microparticles, nanoparticles and the like. In another embodiment the particle size
is in the range 1 to 10 microns, such as 2 to 7 microns, particularly 2 or 5 microns,
for example at least 50%, at least 60%>, at least 70%, at least 75%, at least 80%>, at
least 85%, at least 90%, at least 95%, at least 98% such as at least 99% of the
particles are the relevant size or within said range. Thus in one embodiment of the
invention at least 95%, at least 98% or at least 99% of the particles of the
pharmaceutical composition have a diameter of between 2 and 7 microns. In
another embodiment at least 95%, at least 98% or at least 99% of the particles of
the pharmaceutical composition have a diameter of between 2 and 5 microns.
[00051] FIG 3 illustrates a graphical representation of release rate of the
composition for treatment covid and related respiratory ailments, in accordance with an embodiment of the present disclosure.
[00052] The figure illustrates drug action of the composition for treatment
of COVTD and related respiratory ailments in terms of drug release with time. The

in vitro drug releasent behaviors of doxycycline is represented respectively. The
composition comprising doxycycline and ivermectin represented approximately
90-50% of drug release from a plurality of formulations designated as Fl to F4.
Thus it can be concluded that with an increase of one or more polymers including
PLGA and PEG, the percentage of drug release also decreases due to formation
of complex matrix system between the polymers.
[00053] Most capillary beds allow free passage of particles with a diameter
of <6 microns in diameter, the microspheres of this disclosure should have a
diameter >6 microns, and preferably of ~15 microns. Particles in the range of 20
microns in diameter or larger lodge into pre-capillary arterioles or arterioles and
block the blood flow to several capillaries at once. Therefore, they might create
microscopic infarctions. Thus for the delivery of regenerative therapies the most
suitable diameter of the microspheres is in the range of 15 microns. In addition,
however, particles having diameters of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18,
19, 20, 21, 22, 23, 24 and 25 are contemplated for use according to the present
invention.
[00054] In one embodiment the formulation does not contain particles less
than 1 micron in diameter.
[00055] In a preferred embodiment, the pharmaceutical formulation
comprising ivermectin or pharmaceutically active salts thereof and doxycycline or
pharmaceutically active salts thereof, wherein the composition is a formulation
adapted for nasal delivery.
[00056] In a preferred embodiment, the pharmaceutical formulation is
dispensed into the subject's nasal cavity i.e. intranasal composition.
[00057] In a preferred embodiment, the pharmaceutical formulation
dispensed into the subject's nasal cavity via drops, inhaler, nasal spray, nasal gel,
and the like.
[00058] In a preferred embodiment, the intranasal composition is applied to
the nasal mucosa via topical application (spray and/or drops) of a safe and
effective amount of the composition. The frequency of administration of the

composition may vary, depending upon personal or medical needs, but generally ranges from about once per day to about four times daily.
[00059] In an embodiment of the present disclosure, the pharmaceutical
formulation further comprise at least one pharmaceutically acceptable excipient.
[00060] In an embodiment of the present disclosure, the pharmaceutically
acceptable excipients include but are not limited to, binders, diluents, thickeners,
flow agents, absorbents, disintegrants, superdisintegrants, preservatives,
emulsifiers, taste makers, stabilizers, sugars, anti-foaming agents, anti-caking
agents, lubricants, coloring agents, coating materials, and combinations thereof.
The excipients may be selected from those well known in the art.
[00061] In an embodiment of the present disclosure, the pharmaceutical
composition may further comprise sugars selected from the group comprising of sucrose, glucose, dextrose, lactose, fructose, maltose, galactose, maltodextrin and the like.
[00062] In an embodiment of the present disclosure, the pharmaceutical
formulation may further comprise additional active ingredient(s) selected from one or more of group consisting of: ace-inhibitors, anti-Alzheimer's agents, antianginal drugs, anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics, anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents, anti-diarrhea preparations, antidotes, anti-emetics, anti-histamines, anti¬hypertensive drugs, anti-inflammatory agents, anti-lipid agents, anti-manics, anti¬migraines, anti-nauseants, anti-stroke agents, anti-thyroid preparations, anti-tumor drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, anti¬tussives, anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemic and non-systemic anti-infective agents, anti-neoplasties, anti-parkinsonian agents, anti-rheumatic agents, anxiolytics, anti-psychotics, appetite stimulants, biological response modifiers, blood modifiers, bone metabolism regulators, bronchodilators, cardiovascular agents, central nervous system stimulates, cholinesterase inhibitors, contraceptives, decongestants, dietary supplements, dopamine receptor agonists, endometriosis management agents, enzymes, erectile dysfunction agents, fertility agents, gastrointestinal agents, H2-antagonists,

homeopathic remedies, hormones, hypercalcemia and hypocalcemia management agents, immunomodulators, immunosuppressives, migraine preparations, motion sickness treatments, muscle relaxants, non-steroidal anti-inflammatories (NSAID's), obesity management agents, osteoporosis preparations, oxytocics, parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic agents, respiratory agents, sedatives, serotonin 5-HT3 receptor antagonists, smoking cessation aids, sympatholytics, tremor preparations, urinary tract agents, vasodilators, laxatives, antacids, ion exchange resins, anti-pyretics, appetite suppressants, expectorants, anti-anxiety agents, anti-ulcer agents, anti¬inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs, anti-coagulants, anti-thrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics, anti-obesity drugs, erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics, DNA and genetic modifying drugs, and combinations thereof.
[00063] In an embodiment of the present disclosure, the pharmaceutical
composition may further be formulated into a solid oral dosage form, selected
from the group comprising tablet, pellets, capsule, granules, sachets, lozenges,
micro-particles, suppositories, re-constitutable powders, powder and the like.
[00064] In an embodiment of the present disclosure, may also be
formulated in other dosage forms, including, liquids, suspensions, semi-solids, solutions, syrups, gels, emulsions and the like.
[00065] In an embodiment of the present disclosure, the micronized
pharmaceutical formulation comprises the ivermectin or pharmaceutically active
salts thereof; and the doxycycline or pharmaceutically active salts thereof.
[00066] In another embodiment, the present disclosure relates to a method
of preparing pharmaceutical formulation comprising the ivermectin or pharmaceutically active salts thereof; and the doxycycline or pharmaceutically active salts thereof.

[00067] In another embodiment, the present disclosure relates to a method
of treatment, amelioration or prevention of a viral diseases by administering the
pharmaceutically effective amount of the formulation comprising the ivermectin
or pharmaceutically active salts thereof; and the doxycycline or pharmaceutically
active salts thereof.
[00068] In another embodiment, the present disclosure relates to a method
of treatment, amelioration or prevention of coronavirus-related diseases by
administering the pharmaceutically effective amount of the formulation
comprising the ivermectin or pharmaceutically active salts thereof; and the
doxycycline or pharmaceutically active salts thereof.
[00069] In another embodiment, the present disclosure relates to a method
of treatment, amelioration or prevention of COVID-19 by administering the
pharmaceutically effective amount of the formulation comprising the ivermectin
or pharmaceutically active salts thereof; and the doxycycline or pharmaceutically
active salts thereof.
[00070] In an embodiment, the present disclosure relates to processes of
preparing a pharmaceutical composition comprising ivermectin or a
pharmaceutically acceptable salt thereof and doxycycline or pharmaceutically
active salts thereof.
[00071] In an embodiment, the present disclosure relates to a method for
preparing micronized pharmaceutical formulation comprising ivermectin or
pharmaceutically active salts thereof and doxycycline or pharmaceutically active
salts thereof, wherein the micronized formulation comprises the microspheres of
PLGA-PEG co-polymers.
[00072] In an embodiment, the present disclosure relates to a method for
preparing microparticles /microsphereformulation comprising ivermectin and
doxycyclineby emulsification / solvent evaporation, which will be reconstituted
before use.
[00073] In an embodiment, the present disclosure relates to a method for
preparing microparticles /microsphereformulation comprising ivermectin, and
doxycycline comprise the steps of dissolving PLGA-PEG conjugate in organic

solvent(s) to achieve the solid content of 10% w/w, mixing the drug or combination of drugs in the organic phase, emulsifying the organic solvent into 800 ml of the aqueous phase containing 0.25% w/v PVA as an emulsifying agent at room temperature, continuously agitating the resulting emulsion by a propeller mixer until the organic solvent completely evaporated and solid microparticles were formed, collecting the microparticlesby filtration, washing with distilled water, drying in an oven at 40°C for 24 h, and
collection and storing of the dried microparticles of required sizes at room temperature.
In an embodiment of the present disclosure, the method of preparing the pharmaceutical formulation may involve the steps of milling (wet or dry), weighing, packaging, binder preparation, binding, mixing, lubricating, granulating, melt granulation, blending, sifting, sieving, sizing, direct compression, freeze drying, compaction, refining, and the like well-known in the art.
[00074] In an embodiment, the present disclosure relates to a micronized
pharmaceutical formulation comprising ivermectin or pharmaceutically active
salts thereof and doxycycline or pharmaceutically active salts thereof, where the
formulation is used for treating lung infections associated with COVID-19.
[00075] 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.
[00076] 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.
[00077] In some embodiments, numbers have been used for quantifying
weight percentages, angles, and so forth, to describe and claim certain embodiments of the invention and 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.
[00078] 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.
[00079] 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.
[00080] 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."

[00081] 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.
[00082] 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.
[00083] 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.
[00084] 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.
[00085] The headings and abstract of the invention provided herein are for
convenience only and do not interpret the scope or meaning of the embodiments.
[00086] 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.
[00087] As described herein, the term "active ingredient" has the meaning
known in the state of the art. The term denotes a pharmaceutical drug or
compound that produces a desired biological activity in the body.
[00088] As described herein, the term "matrix material" has the meaning
present in the state of the art. The term denotes a homogeneous phase in which the
pharmaceutical actives are present.
[00089] While a particular form of the invention has been illustrated and
described, it will be apparent that various modifications can be made without
departing from the spirit and scope of the invention. The pharmaceutical
composition of the present invention maybe used in any manner known to a
person skilled in the art.
EXAMPLES
FTIR SPECTROSCOPY OF DRUG AND POLYMER
[00090] The present disclosure is further explained in the form of following
examples. However, it is to be understood that 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.
[00091] The FTIR spectrum of doxycycline, ivermectin, PLGA and PEG-
4000 is shown in Fig and the table below.

Frequency KBr (cm1) Vibrations
3392.57 Primary -OH group
3335.91 -NH group
2993.31 C-H stretching
1664.21 C-0 group

1616.27 C-C stretching
1579.14 Aromatic C=C bonds
1358.35 Hydroxyl group
1242.36 C-0 bond
XRD analysis
[00092] X-RD graphs of Doxycycline, ivermectin, PLGA, PEG-4000
conclude that, the doxycycline, ivermectin, PEG-4000 were crystalline in nature and in formulation, the formulation was successfully modified to amorphous nature.
SEM analysis
[00093] The SEM studies are conducted to evaluate morphology of the
pharmaceutically active salt, and one or more polymer and a formulation. The doxycycline is observed to have long crystalline structure and ivermectin comprised of small regular crystalline surfaces. Further, PLGA and PVA consisted of a mixture comprising one or more large and small crystals, that indicate crystalline nature. Further, FE-SEM of final optimized formulation Fl is experimentally conducted and show cased to comprise round spheres like structure in agglomerated form. MOLECULAR DOCKING ANALYSIS
[00094] The analysis is conducted to understand the binding interactions
and selectivity of pharmaceutically active salts that include doxycycline and Ivermectin against main protease (3CLPro) involved in Coronavirus, molecular docking simulation was carried out with CHARMm based docking tool, CDOCKER of Discovery Studio Client v20.1.0.19295 software. The test drugs (Doxycycline & Ivermectin) was sketched and cleaned in DiscoveryStudio Client v20.1.0.19295 workspace followed by energy minimization in 'Prepare Ligands' program of DiscoveryStudio Client at pH of 7.4. The X-ray crystallographic structure of main protease (3CLPro) (PDB code 6LU7) was obtained from the Protein Data Bank and optimized for docking analysis. The optimization protocol includes addition of hydrogen atoms, deletion of water molecules, completion of

bond orders, and assignment of hydrogen bonds. The test compound was docked into the active site of the protein using CHARMm based docking tool of CDOCKER program. The binding energy of the hits with proteins was estimated as negative of CDOCKER interaction energy.
[00095] The molecular docking studies revealed that the test drugs have
good interactions with the target enzymes with good binding energies. The position of the test drugs (Doxycycline & Ivermectin) with respect to the key residues in the binding site of main protease (3CLPro). The binding of the test drugs (Doxycycline & Ivermectin) with the essential residues of these target sites may describe their ability to manage COVID-19.
Table 1 active sites of target protein through various binding interactions
with crucial amino acid residues

sund -CDOCKER
Interaction
Energy Binding Amino acid residues
(1EVE)

ycline 56.2115 S-0 Binding Met 165

H-Bonding Cysl45, Serl44, Hisl63, Phel40,
Glul66

Attractive charges Glul66

Pi-Alkyl Met 165

Van der Waals Leu27, Glyl43, Hisl64, Glnl89,
Argl88, Glnl92, Thrl90, Prol68, Leul67, Leul41, Hisl72,
ectin 56.3596 S-0 Binding Metl65, Met49

H-Bonding Glyl43, Glul66, Asnl42, Hisl64,
Asp 187

Pi-Pi &Pi- His41, Prol68, Metl65, Cysl45
AlkylBinding

Van der Waals Thr24, Leu27, Ser46, Argl88, Glnl92, Thrl90, Alal91, Leu 167,Glnl89, Tyr54, Phel40, Leul41, His 172, Serl44, Hisl63
ESTIMATION OF TUMOR NECROSIS FACTOR ALPHA (TNF-A)
[00096] The estimation is experimentally conducted to observe TNF-a that
is used for the evaluation of suspected systemic infection in the body. It has been seen that TNF-a inhibitor may serve as an effective therapeutic strategy for attenuating disease progression in severe SARS-CoV-2 infection. Further, the levels of TNF-a have been elevated in Endotoxin-lipopolysaccharide (LPS) (lOmg/kg) disease control group as compared to the vehicle control group. However, the combination of Ivermectin (250 mg/kg) and Doxycycline (20 mg/kg) have lower levels of TNF-a as compared to the disease control group. The administration of low dose Ivermectin (250ug/kg i.p) have lower the levels of TNF-a as compared to disease control group; whereas the administration of high dose Ivermectin (500ug/kg i.p) have significantly lower the levels of TNF-a when compared to disease control group and low dose ivermectin (250ug/kg i.p). Low dose doxycycline (20 mg/kg i.p) also lowers the levels of TNF-a than disease control group, whereas the high dose of doxycycline (40mg/kg i.p) have significantly lower the levels of TNF-a when compared to disease control group and low dose doxycycline (20 mg/kg i.p).
[00097] As described herein, the term "matrix material" has the meaning
present in the state of the art. The term denotes a homogeneous phase in which the pharmaceutical actives are present.
[00098] While a particular form of the invention has been illustrated and
described, it will be apparent that various modifications can be made without departing from the spirit and scope of the invention. The pharmaceutical composition of the present invention maybe used in any manner known to a person skilled in the art. ADVANTAGES OF THE PRESENT INVENTION

[00099] The present disclosure provides a micronized pharmaceutical
formulation comprising ivermectin and doxycycline that satisfies the existing
needs, as well as others, and generally overcomes the deficiencies found in the
prior art.
[000100] The present disclosure provides a micronized pharmaceutical
formulation that directly target the lungs so that maximum drug reaches the target
site.
[000101] The present disclosure provides a combination of Ivermectin and
doxycycline carrier system in micron size range can be helpful in the treatment of
COVID-19.
[000102] The present disclosure provides a micronized pharmaceutical
formulation that reduces dose related toxicity and increase efficacy.
[000103] The present disclosure provides a micronized pharmaceutical
formulation comprising PLGA - PEG, which is helpful in providing drug safety,
better and controlled drug release by diffusion method, avoid opsonisation and
enzymatic degradation of loaded drug, shows lung targeting. PEG is also proved
to inhibit opsonisation, macrophages and engulfment, phagocytosis and
pinocytosis.
[000104] The present disclosure provides a micronized pharmaceutical
formulation comprising PLGA - PEG, which will help in better penetration of the
drugs from the epithelial layers and in-turn the bioavailability.

We Claim:

1. A composition for treatment of COVID and related respiratory ailments,
said composition comprising:
a formulation comprising one or more mixtures, wherein a first mixture comprises one or more pharmaceutically active salts that include Ivermectin, in a predetermined concentration ranging from 5% to 10% by weight of the active constituents, and Doxycycline in a predetermined concentration ranging from 15% to 25% by weight of the active constituents; and
a microsphere consisting a second mixture that comprises one or more polymers identified as PLGA and PEG in a plurality of proportions.
2. The composition as claimed in claim 1, wherein the second mixture comprises one or more polymers identified as PLGA and PEG in a proportion ranging from 50 to 200 in any or a combination of weight and volume.
3. The composition as claimed in claim 1, wherein one or more polymers identified as PLGA and PEG are conjugated chemically in the presence of EDC/NHS.
4. The composition as claimed in claim 1, wherein the composition utilizes one or more methods that incude a nebulisation method for an efficient action at one or more target locations.
5. The composition as claimed in claim 1, wherein the microsphere is formed utilizing one or more methods that include solvent evaporation technique.

6. The composition as claimed in claim 1, wherein the composition comprising the formulation and the microsphere, yields one or more results ranging from 75 percent to 90 percent.