WO2021229514A1

WO2021229514A1 - Pharmaceutical ivermectin compositions

Info

Publication number: WO2021229514A1
Application number: PCT/IB2021/054132
Authority: WO
Inventors: Hiren Patel; Bikash Kumar Sahoo; Sanjay Saha
Original assignee: Orbicular Pharmaceutical Technologies Private Limited
Priority date: 2020-05-14
Filing date: 2021-05-14
Publication date: 2021-11-18

Abstract

The present invention relates to nasal and inhalation composition comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients for the prophylactic treatment and/or for treatment of respiratory disease and/ or disorders such as, respiratory obstruction, inflammatory or obstructive airway disease, respiratory obstruction due to coronavirus or Covid-19 infections, comprising administering a therapeutically effective amount of nasal and inhalation composition.

Description

PHARMACEUTICAL IVERMECTIN COMPOSITIONS

FIELD OF THE INVENTION

The present invention relates to nasal and inhalation compositions comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients for the treatment of respiratory disease and/ or disorders.

BACKGROUND OF THE INVENTION

Respiratory diseases, or lung diseases, are pathological conditions affecting the organs and tissues that make gas exchange difficult in air- breathing animals. They include conditions of the respiratory tract including the trachea, bronchi, bronchioles, alveoli, pleurae, pleural cavity, and the nerves and muscles of respiration. Respiratory diseases, or lung diseases, are pathological conditions affecting the organs and tissues that make gas exchange difficult in air-breathing animals. They include conditions of the respiratory tract including the trachea, bronchi, bronchioles, alveoli, pleurae, pleural cavity, and the nerves and muscles of respiration.

Respiratory disorders include asthma, Chronic obstructive pulmonary disease (COPD), chronic bronchitis. Chronic obstructive pulmonary disease (COPD) is a severe respiratory condition that are increasing its prevalence worldwide and these disorders are preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow obstruction is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs it also produces significant systemic consequences. COPD is associated with mucus hyper secretion, emphysema, bronchiolitis.

Currently, therapy for the treatment or prevention of COPD and asthma includes the use of one or more long acting bronchodilators and an inhaled corticosteroid (ICS). Inhaled bronchodilators are the foundation in the therapy of COPD because of their capacity to alleviate symptoms, decrease exacerbations of disease and improve quality of life. These drugs also improve airflow limitation and hyperinflation, thereby decreasing the work of breathing and improving exercise tolerance. In addition, bronchodilators may reduce respiratory muscle fatigue and improve mucociliary clearance.

The inventors of the present invention have investigated ivermectin for the treatment of respiratory disease or disorders. Ivermectin, a macrocyclic lactone, it is a semisynthetic derivative formed by a mixture of two components, 22,23-dihydroavermectin B1a and 22,23 dihydroavermectin B1b. Initial avermectin B1 is a macrocyclic lactone obtained from Streptomyces avermitilis culture fermentation broth and the selective hydrogenation of the existing double bonds in the position C22-C23 of avermectin B1 macrolid structures leads to the synthesis of ivermectin as described in literature. Ivermectin is disclosed in US Pat. No. 4,199,569, to Chabala and Fisher. Ivermectin is a mixture, in the ratio of approximately 80:20 of 22,23-dihydro C- 076 Bla and Bib.

Ivermectin is used as anthelmintic used to treat parasite infestations. Ivermectin is used to treat infections in the body that are caused by certain parasites to improve quality of life. Ivermectin is approved by several regulatory agencies. Ivermectin is used for treatment of threadworm (enterobiasis), lymphatic filariasis, treatment of whipworm (Trichuris trichiura), head lice infestations. Ivermectin, is available in oral dosage form in the world-wide market for treatment of Strongyloidiasis and Onchocerciasis. The pharmacokinetic post oral dose is very well defined and available in public domain. Following oral administration of ivermectin, plasma concentrations are approximately proportional to the dose. In two studies, after single 12-mg doses of STROMECTOL in fasting healthy volunteers (representing a mean dose of 165 mcg/kg), the mean peak plasma concentrations of the major component (H2B1a) were 46.6 (±21.9) (range: 16.4-101.1) and 30.6 (±15.6) (range: 13.9-68.4) ng/mL, respectively, at approximately 4 hours after dosing.

Ivermectin is approved by most of the regulatory agencies across the world. Ivermectin has an established safety profile for human use and is FDA- approved for a number of parasitic infections. Ivermectin is available as oral tablet, topical lotion and topical cream to treat various parasitic infestations.

US patent 4389397 discloses solubilization of Ivermectin in water wherein aqueous formulation comprising Ivermectin in a solution of a non- ionic or an anionic surface-active agent and water, characterized in that the formulation is stabilized by the inclusion of one or more water-miscible organic co-solvents suitable for parenteral or oral administration, the cosolvent(s) being glycerol formal, propylene glycol, glycerine, and/or polyethylene glycol; and/or one or more substrates also suitable for parenteral or oral administration, the substrate(s) being benzyl alcohol, lidocaine, a paraben, and/or choline.

Leon Caly et al., Antiviral Research, volume 178, June 2020, discloses ivermectin, an FDA-approved anti-parasitic previously shown to have broad- spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS- CoV-2), with a single addition to Vero-hSLAM cells 2 h post infection with SARS-CoV-2 able to effect ~5000-fold reduction in viral RNA at 48 h.

However, the article is silent on the type of dosage form.

Jorge Errecalde et al, Drug Delivery and Pharmaceutical Technology, Jan 2021, discloses that high ivermectin (IVM) concentrations suppress in vitro SARS-CoV- 2 replication. Nasal IVM spray administration may contribute to attaining high drug concentrations in nasopharyngeal tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performances of a novel IVM spray formulation were assessed in a pig model.

Niti Mittal, et al. , Medical Hypotheses 146 (2021) 110364, discloses an effort to curb the global pandemic due to coronavirus, the scientific community is exploring various treatment strategies with a special emphasis on drug repurposing. It is hypothesised that inhaled formulation of ivermectin may be effective against SARS-CoV-2. Therefore, ivermectin administered via inhalational route needs to be explored for potential beneficial role in COVID- 19 in preclinical and clinical studies. We also hypothesise the possibility of drug having anti-inflammatory action in coronavirus associated severe respiratory illness based on few in-vitro and in-vivo reports which however needs to be confirmed clinically.

US6492340 patent discloses a parasiticidal formulation is provided.

This formulation includes a pyrrolidone solvent, a bridging solvent, and a parasiticidal agent. One or more parasiticidal agents may be included in the formulation. Preferably, the formulation contains both closantel and ivermectin.

US7064108 patent discloses topical gel composition comprising between about 0.005 and 1.0% ivermectin, between about 30 and 40% of a pharmaceutically acceptable alcohol, between about 30 and 40% of a pharmaceutically acceptable glycol, and a pharmaceutically acceptable carrier.

W01997026895 patent application discloses formulation for administering an avermectin consisting of from 0.1 % to 40% by weight of an avermectin dissolved in a solvent comprising at least 5% by volume N- methylpyrrolidone, or2-pyrrolidone, or a mixture thereof.

W003051281 patent application discloses a composition for nasal administration to animals, including humans, applicants' composition includes lysozyme in combination with zinc. The composition further includes one or more anthelmentic compounds, a method to treat animals, including humans, having a pulmonary bacterial or viral infection by delivering a therapeutically effective amount of lysozyme to the animal's nasal pharynx.

US FDA approved broad spectrum anti-parasitic agent that in 27 recent years, along with other groups, have shown to have anti-viral activity against a broad range of viruses in vitro. Originally identified as an inhibitor of interaction between the human immunodeficiency virus-1 (HIV-1) integrase protein (IN) and the importin (IMP) a/b-1 heterodimer responsible for IN nuclear import Ivermectin has since been confirmed to inhibit IN nuclear import and HIV-1 replication.

The causative agent of the current COVID-19 pandemic, SARS-CoV-2, is a single stranded positive sense RNA virus that is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV). Studies on SARS-CoV proteins have revealed a potential role for IMRa/b-1 during infection in signal- dependent nucleocytoplasmic shutting of the SARS-CoV 51 Nucleocapsid protein, that may impact host cell division.

Considering the above literature disclosure, there is an highly unmet need and an immediate requirement of nasal dosage form of ivermectin. The inventors of the present invention have studied and evaluated ivermectin for the prophylaxis and potential treatment of respiratory disease and/ or disorders such as, respiratory obstruction, COPD, chronic bronchitis, inflammatory or obstructive airway disease, respiratory obstruction due to Covid-19 and related respiratory disease and /or disorders.

SUMMARY OF THE INVENTION

Important object of the present invention is to provide an ivermectin inhalation solution, suspension, dry powder inhaler (DPI) or metered dose inhaler (MDI) for the prophylaxis and potential treatment of respiratory disease and/ or disorder.

Another object of the present invention is to provide a prepackaged, sterile, premixed, premeasured, therapeutic dosage ivermectin nasal and inhalation composition for the treatment of respiratory disease and/ or disorder.

A further object of the present invention is to provide a method of administering an ivermectin inhalation composition for treatment of respiratory disease and/ or disorder.

An additional object of the present invention is to provide a kit or system for prophylaxis and treatment of respiratory disease and/ or disorder.

The present invention relates to a nasal and inhalation composition comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients.

The present invention relates to a nasal and inhalation composition comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients for the treatment of respiratory disease and/ or disorders such as, respiratory obstruction, COPD, chronic bronchitis, inflammatory or obstructive airway disease, respiratory obstruction due to Covid-19, comprising administering a therapeutically effective amount of nasal and inhalation composition.

The composition according to above embodiment, wherein suitable excipients are selected from solvents and/or co-solvents, surfactants and/or co-surfactants, buffering agents, complexing agents or chelating agents, preservatives, antioxidants, viscosity modifying agents and the like or mixtures thereof. The composition according to previous embodiment, further comprises of one or more active agents.

The composition according to previous embodiment, wherein active agents are antibiotics, antiemetics, anticholinergics, bronchodilators, corticosteroids, antihistamines, antivirals and the like or combinations thereof.

The composition according to previous embodiment, wherein composition can be administered as a metered dose inhalers (MDI), dry powder inhalers (DPI), nebuliser, nasal spray, nasal drops, inhalation spray, nasal inhalation, soft mist inhalation, nasal aerosol, propellant-containing metered-dose aerosols, inhalable solution or inhalable suspensions, propellant-free inhalable solutions, propellant-free inhalable suspensions and the like.

The composition according to above embodiment, wherein ivermectin is administered alone or in combination with other active agents to the upper respiratory tract and lower respiratory tracts.

The composition according to above embodiment, wherein ivermectin is administered alone or in combination with other active agents for prophylaxis of coronavirus or Covid-19 infections.

The composition according to above embodiment, wherein ivermectin is administered alone or in combination with other active agents for treatment of coronavirus or Covid-19 infections.

The composition according to above embodiment, wherein the nasal and inhalation compositions additionally provides kits for use in prophylaxis and treatment of the respiratory diseases.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as are commonly understood by one of skill in the art to which the inventions described herein belong. All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. The present invention relates to a nasal and inhalation composition comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients.

The present invention relates to nasal and inhalation composition comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients for prophylaxis and treatment of respiratory disease and/ or disorders.

The term “active agent” or “active pharmaceutical ingredient” or “API” includes the compound(s), pharmaceutically acceptable salts thereof, isomers, solvates, prodrugs, complexes and hydrates, anhydrous forms thereof, and any polymorphic or amorphous forms or combinations thereof.

The term “Ivermectin” includes the compound, pharmaceutically acceptable salts thereof, isomers, solvates, prodrugs, complexes and hydrates, anhydrous forms thereof, and any polymorphic or amorphous forms or combinations thereof.

The term “pharmaceutically acceptable salts” includes pharmaceutically acceptable salts, solvates, hydrates, anhydrates, enantiomers, esters, isomers, polymorphs, tautomers, complexes and thereof.

The term “nasal and inhalation” refers but not limited to metered dose inhalers (MDI), dry powder inhalers (DPI), nebuliser, nasal spray, nasal drops, inhalation spray, nasal inhalation, soft mist inhalation, nasal aerosol, propellant-containing metered-dose aerosols, inhalable solution or inhalable suspensions, propellant-free inhalable solutions, propellant-free inhalable suspensions.

The terms “composition” and “formulation” refer to preparations comprising ivermectin or pharmaceutically acceptable salts thereof; in a form suitable for administration to a mammal.

The term "stable" or "stability" as used herein includes both physical and chemical stability. Stability parameters include but not limited to potency, stable pH value and other physico-chemical parameters.

The term "physical stability" refers to compositions free from particles and that do not significantly change during storage.

The term "chemical stability" relates to a limited formation of impurities, limited decrease in potency and the like. In one embodiment the invention relates to a nasal and inhalation composition comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients for prophylaxis of respiratory disease and/ or disorders such as, respiratory obstruction, inflammatory or obstructive airway disease, respiratory obstruction due to coronavirus or Covid-19, comprising administering a therapeutically effective amount of nasal and inhalation composition.

In one embodiment the invention relates to a nasal and inhalation composition comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients for the treatment of respiratory disease and/ or disorders such as, respiratory obstruction, inflammatory or obstructive airway disease, respiratory obstruction due to coronavirus or Covid-19, comprising administering a therapeutically effective amount of nasal and inhalation composition.

The nasal and inhalation composition includes but not limited to a solution, a suspension, a dry powder inhaler, a metered dose inhaler, an aerosol and the like or combinations thereof.

The composition comprises of suitable excipients, selected from solvents and/or co-solvents, surfactants and/or co-surfactants, buffering agents, complexing agents or chelating agents, preservatives, antioxidants, viscosity modifying agents and the like or mixtures thereof.

The composition includes a solution which comprises of ivermectin with solvents and/ or co-solvents and other suitable excipients. The solvents include but not limited to glycols, alcohols, and the like or mixture thereof; glycols include ethylene glycol, butylene glycol, propylene glycol, polypropylene glycol, and the like or mixtures thereof; alcohols include ethanol, isopropanol and the like or mixtures thereof.

Co -solvents for use herein include, but are not limited to, hydroxylated solvents or other polar solvents, such as alcohols such as isopropyl alcohol, glycols such as propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and the like or mixtures thereof.

Surfactants and/or co-surfactants include but not limited to cationic surfactant, and non-ionic surfactants. Surfactants include, but not limited to Polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 65, polysorbate 85, sorbitan fatty acid esters such as Span 20, Span 40, Span 60, Span 80, Span 85, Span 120; sodium lauryl sulfate; polyethoxylated castor oil; polyethoxylated hydrogenated castor oil, sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide, Docusate sodium, Cetyl trimethyl ammonium bromide (CTAB) Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N,N-dimethyldodecylamine-N-oxide, Hexadecyltrimethylammonium bromide, Polyoxyl 10 lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil, Nonylphenol ethoxylate, Cyclodextrins, Lecithin, Methylbenzethonium chloride. Carboxylates, Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates, Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, ethoxylated & sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters Polyethylene glycol esters, Anhydrosorbitol ester & it’s ethoxylated derivatives, Glycol esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates, Polyoxyethylene fatty acid amides, Quaternary ammonium salts, Amines with amide linkages, Polyoxyethylene alkyl & alicyclic amines, N,N,N,N tetrakis substituted ethylenediamines 2-alkyl 1-hydroxyethyl 2-imidazolines, N-coco 3- aminopropionic acid/sodium salt, N-tallow 3-iminodipropionate disodium salt, N-carboxymethyl n-dimethyl n-9 octadecenyl ammonium hydroxide, n- cocoamidethyl n-hydroxyethylglycine sodium salt etc.

The present invention includes buffers in its composition and buffering agents comprise of one or more of organic or inorganic acids and its salt thereof, such as but not limited to citric acid/sodium hydrogensulphate borate buffer, phosphates (sodium hydrogen orthophosphate, disodium hydrogen phosphate), trometamol, tartrate buffer, acetate buffer, citrate buffer, sodium citrate dehydrate, citric acid monohydrate, sodium dihydrogen phosphate dehydrate, sodium chloride, anhydrous disodium hydrogen phosphate or equivalent conventional buffers.

In one embodiment, the buffer is selected from the group but not limited to acetic acid, citric acid, phosphoric acid, maleic acid, tartaric acid, citric acid/phosphate buffer, acetate buffer, citrate buffer, phosphate buffer, maleate buffer, tartrate buffer and the like or mixtures thereof. Buffers may also be used as pH adjusting agents.

Complexing agents or chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) or its salt thereof, such as the disodium salt, citric acid, nitrilotriacetic acid and the salts thereof. In one embodiment, the complexing agent is EDTA.

Preservatives include, but are not limited to, those that protect the solution from contamination with pathogenic particles, including benzalkonium chloride or benzoic acid, or benzoates such as sodium benzoate. Antioxidants include, but are not limited to, vitamins, provitamins, ascorbic acid, vitamin E or salts or esters thereof.

Viscosity modifiers include but not limited to hydroxy propyl methyl cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, microcrystalline cellulose/sodium carboxymethylcellulose, pectin, and the like or mixtures thereof.

Examples of other acceptable excipients include carriers which may be used to prepare the inhalable dry powders according to the invention include, for example, monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixture of these excipients with one another. Other carriers include, maltodextrins, inositol, sodium starch glycolate, leucine, and the like or mixtures thereof.

Representative non-limiting examples of carriers for use in the invention include, without limitation, lactose, glucose, or sodium starch glycolate particulates. In some embodiments, the carrier is lactose. The particulate lactose is in some instance alpha lactose monohydrate. In general, the particle size of the lactose should be such that it can be entrained in an air stream but not deposited in the key target sites of the lung. Accordingly, in some embodiments, lactose with a mean particle size of less than 40 pm is excluded. Particle size is determined using laser light scattering. The carrier particles have a VMD of from about 50 to about 250 pm. Within that range, the carrier particles of a given composition according to the invention may have a VMD of from about 50 to about 60 pm or from about 60 to about 90 pm or from about 90 to about 150 pm.

In another embodiment, the powder for inhalation according to the invention are prepared by mixing the coarser carrier fractions with the finer excipient fractions and subsequently mixing the resulting carrier mixtures with the ivermectin or its acceptable salt thereof.

In another embodiment, the powder for inhalation according to the invention are prepared by mixing the coarser carrier fractions with the finer carrier fractions and subsequently mixing the resulting carrier mixtures with the ivermectin and/or other active agent.

The nasal compositions comprise of propellants such as hydrofluoroalkane (HFA) propellants and the like; the nasal aerosol compositions comprise of propellants such as hydrofluoroalkane (HFA) propellants and the like; MDI compositions comprise of propellants such as hydrofluoroalkane (HFA) propellants and the like.

In one embodiment the composition includes a solution which comprises of ivermectin with suitable excipients.

In one embodiment the composition includes a suspension which comprises of ivermectin with suitable excipients.

The composition includes a dry powder inhaler which comprises of ivermectin with other suitable excipients.

The composition includes a metered dose inhaler which comprises of ivermectin with other suitable excipients.

The composition includes a nasal aerosol which comprises of ivermectin with other suitable excipients.

In one embodiment, the composition further comprises of one or more active agents, wherein the active agents include but not limited to antibiotics, antiemetics, anticholinergics, bronchodilators, corticosteroids, antihistamines, antiviral agents, anthelmintic and/or one or more anthelmintic and the like or combinations thereof. Antibiotics include, but not limited to azithromycin, tobramycin, enoxacin, doxycycline, minocycline and the like or combinations thereof. Antiemetics include, but not limited to emetine, prochlorperazine, aprepitant, rolapitant, ondansetron granisetron, and the like or combinations thereof.

Anticholinergics include, but not limited to aclidinium, glycopyrronium or glycopyrrolate, ipratropium, tiotropium, umeclidinium and the like or combinations thereof.

Bronchodilators include, but not limited to formoterol, arformoterol, salmeterol, olodaterol, vilanterol, carmoterol and the like or combinations thereof.

Corticosteroids include, but not limited to fluticasone, mometasone, beclomethasone, ciclesonide, budesonide, flunisolide and the like or combinations thereof.

Antihistamines include, but not limited to azelastine, phenylephrine, oxymetazoline, olopatadine, alcaftadine, and the like or combinations thereof.

Antiviral agents include, but not limited to ribavirin, lopinavir, nelfinavir, ritonavir, ganciclovir, favipravir, remdesivir, brincidofovir, and the like or combinations thereof.

In one embodiment the composition includes a solution which comprises of ivermectin and other active agent with suitable excipients.

In one embodiment the composition includes a suspension which comprises of ivermectin and other active agent with suitable excipients.

The composition includes a dry powder inhaler which comprises of ivermectin and other active agent with other suitable excipients.

The composition includes a metered dose inhaler which comprises of ivermectin and other active agent with other suitable excipients.

The composition includes a nasal aerosol which comprises of ivermectin and other active agent with other suitable excipients.

In another embodiment the composition can be administered but not limited to metered dose inhalers (MDI), dry powder inhalers (DPI), nebuliser, nasal spray, nasal drops, inhalation spray, nasal inhalation, soft mist inhalation, nasal aerosol, propellant-containing metered-dose aerosols, inhalable solution or inhalable suspensions, propellant- free inhalable solutions and the like. The present composition is administered alone or in combination with other active agents to the upper respiratory tract and lower respiratory tracts.

SARS-CoV-2 is a novel strain of coronaviruses or Covid-19 which is associated with a cluster of cases of pneumonia in China. Coronaviruses (CoV) are a broad family of viruses that includes SARS-CoV, MERS-CoV, HCoV-229E, HCoV-OC43, HCoVNL63 and HCoV-HKlM strains. HCoV-229E, HCoV-OC43, HCoVNL63 and HCoV-HKlM strains are usually associated with mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, people infected with MERS-CoV, SASRS-CoV or SARS-CoV-2 could develop severe respiratory illness.

A US government interagency group developed a variant Classification scheme that defines three classes of SARS-CoV-2 variants:

1. Variant of Interest: The B.1.526, B.1.526.1, B.1.525, B.1.617, B.1.617.1,

B.1.617.2, B.1.617.3, and P.2 variants circulating in the United States are classified as variants of interest.

2. Variant of Concern: The B.1.1.7, B.1.351, P.1, B.1.427, and B.1.429 variants circulating in the United States are classified as variants of concern.

3. Variant of High Consequence: To date, no variants of high consequence have been identified in the United States.

In one embodiment, the invention discloses ivermectin nasal and inhalation composition for targeted delivery to nasal cavity and nasopharyngeal area for prophylaxis and treatment of Corona virus(es) or Covid-19 infections.

In one embodiment the invention discloses, ivermectin with other active agents as nasal and inhalation composition for targeted delivery to nasal cavity and nasopharyngeal area for prophylaxis and treatment of Corona virus(es) or Covid-19 infections.

In one embodiment the ivermectin nasal spray composition for targeted delivery to nasal cavity and nasopharyngeal area via nasal spray would allow drug distribution across nasal cavity to allow maximal reduction of viral load in such an area which is responsible to maximal bioaerosol and cross infection. Saliva contains a high viral load in COVID-19 with up to T2^c10⁸ infective copies/mL when the saliva of patients was analysed at the time of admission to hospital. It has recently been found, through PCR assay techniques, that the nasopharynx appears to have a higher viral load than that found in the oropharynx.

Similarly, the ivermectin nasal spray composition is postulated to be effective in: 1. reduction of Bioaerosols from Covid-19 patients in hospital settings. 2. reduction in viral load in patients with Covid-19 as a treatment measure. 3. preventive measure for frontline workers, physicians, paramedics, police staff handling Covid-19 patients. 4. presymptomatic patients who are known to be highly infectious can use/ can be prescribed with nasal and inhalation composition of Ivermectin for reduction in viral transmission.

In another embodiment, nasal and inhalation ivermectin composition to lower respiratory tract holds great potential in reducing viral load at alevolar level. Inhalation composition could play a pivotal role in: i. eradicating viral sancturies, ii. reducing viral replication linked inflammatory reactions, iii. reducing possibility of Cytokine storm.

In another aspect ivermectin dose is selected ranging from about 0.1 pg to about 3 mg; from about 0.15 pg to about 2.5 mg; for example, 0.2 pg to about 2 mg. The dose may vary for each of the nasal and inhalation compositions.

Another aspect describes that ivermectin has an average particle size of from about 0.5 pm to about 10 pm; for example, from about 1 pm to about 6 pm, for example, from about 2 pm to about 5 pm. Another aspect describes that active agent has an average particle size of from about 0.5 p to about 10 pm; for example, from about 1 pm to about 6 pm, for example, from about 2 pm to about 5 pm.

The composition according to the present invention may be provided in suitable containers with suitable means enabling the application of the contained formulation to the respiratory tract.

The powder for inhalation intended for administration through DPI may either be encapsulated in capsules of gelatin or HPMC or in blisters or alternatively, the dry powder may be contained as a reservoir either in a single dose or multi-dose dry powder inhalation device.

Alternatively, the powder for inhalation intended to be used for MDI may be suspended or solubilized in a suitable liquid vehicle and packed in an aerosol container along with suitable propellants or mixtures thereof.

Further, the powder for inhalation intended to be used for DPI may also be dispersed in a suitable gas stream to form an aerosol composition.

The MDI composition according to the present invention may be packed in plain aluminum cans or SS (stainless steel) cans. Some aerosol drugs tend to adhere to the inner surfaces, i.e., walls of the cans and valves, of the MDI. This can lead to the patient getting significantly less than the prescribed amount of the active agent upon each activation of the MDI. Coating the inner surface of the container with a suitable polymer can reduce this adhesion problem. Suitable coatings include fluorocarbon copolymers such as FEPPES (fluorinated ethylene propylene and polywethersulphone) and PFA-PES (perfluoroalkoxyalkane and polyethersulphone), epoxy and ethylene. Alternatively, the inner surfaces of the cans may be anodized, plasma treated or plasma coated.

Another aspect relates to pharmaceutical compositions comprising nebulization are hereby provided. The nebulization compositions are sterilized and filled in ampoules or vials, including unit dose vials, providing sterile unit dose formulations for use in a nebulizer.

By sterile, it is meant that the resultant pharmaceutical composition meets the requirements of sterility enforced by medicine regulatory authorities, such as the FDA in the US or the MCA in the UK. Tests are included in current versions of the compendia, such as the US Pharmacopoeia and the British Pharmacopoeia.

In a further aspect, the present invention provides a container comprising a vial, an ampule, comprising a single unit dose in a sterile solution, or a plurality of such vials, for use in a nebulizer.

In another aspect, the nebulizer compositions are supplied as LDPE vials in aluminum pouch or other suitable equivalent materials.

In another aspect, the nasal spray compositions are supplied as LDPE/HDPE bottle and/ or glass/HDPE bottle with actuator and pump.

In another aspect, the MDI compositions are supplied in Aluminum cans and/ or bottles with actuator and pump.

In another aspect, the DPI compositions are supplied as capsule based dry powder device and/ or reservoir based dry powder device.

The invention additionally provides kits for use in prophylaxis and treatment of the diseases described herein. The kits comprise:

(1) a container, containing a required dose of a therapeutically effective amount of ivermectin; and/ or combination with other active agents,

(2) instructions on how the dose is to be used of specific nasal composition.

The present invention also provides a process to manufacture the compositions according to the present invention.

The present invention provides a process of preparing a metered dose inhalation composition which process comprises admixing of a pharmaceutically acceptable carrier or excipient with the actives and the propellant and providing the composition in precrimped cans.

The present invention provides a process of preparing a dry powder inhalation composition which process comprises admixing of a pharmaceutically acceptable carrier or excipient with the actives and providing the composition to be administered through dry powder inhaler.

The present invention also provides a process of preparing an inhalation solution/suspension respule which process comprises dissolving/dispersing the drugs, with solvent, optionally surfactant, optionally chelating agents, buffering agents and any other suitable ingredients and adjusting the pH using a suitable pH adjusting agent. The present invention provides a prophylactic treatment in a mammal, such as a human, for treating chronic obstructive pulmonary disease and asthma, for the treatment of respiratory disease and/ or disorders such as, respiratory obstruction, inflammatory or obstructive airway disease, respiratory obstruction due to Covid-19, which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention. The prophylactic treatment may be characterized in that the pharmaceutical compositions according to the present invention are administered once or twice daily in therapeutically effective amounts.

The present invention also provides a method for the treatment in a mammal, such as a human, for treating chronic obstructive pulmonary disease and asthma, for the treatment of respiratory disease and/ or disorders such as, respiratory obstruction, inflammatory or obstructive airway disease, respiratory obstruction due to corona virus or Covid-19 infection, which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention. The method of treatment may be characterized in that the pharmaceutical compositions according to the present invention are administered once or twice daily in therapeutically effective amounts.

In another embodiment, the inventors have studied the below compositions:

I. Ivermectin Inhalation Solution:

II. Ivermectin Inhalation Suspension:

III. Combination of Ivermectin and Formoterol inhalation Solution:

IV. Combination of Ivermectin and Formoterol inhalation Suspension

V. Combination of Ivermectin and Tobramycin inhalation Solution:

VI. Combination of Ivermectin and Tobramycin inhalation Suspension

VII. Ivermectin Nasal Spray Solution:

VIII. Ivermectin Nasal Spray Suspension;

To further illustrate the invention, the following examples are provided. It is to be understood that these examples are provided for illustrative purposes and are not to be construed as limiting the scope of the present invention in any manner whatsoever.

Examples:

Example 1 : Ivermectin Inhalation Solution

Stability details of example 1 composition

Example 2: Ivermectin Inhalation Solution

Stability details of example 2 composition:

From the above examples and the stability details, the compositions were found to be stable at both accelerated and real time conditions.

Claims

We Claim,

1. A nasal and inhalation composition comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients.

2. A nasal and inhalation composition comprising ivermectin and/ or its acceptable salt thereof with other suitable excipients for the prophylactic treatment and/or for treatment of respiratory disease and/ or disorders such as, respiratory obstruction, inflammatory or obstructive airway disease, respiratory obstruction due to coronaviruses, comprising administering a therapeutically effective amount of nasal and inhalation composition.

3. The composition according to claim 1 and claim 2, wherein suitable excipients are selected from surfactants and/or co-surfactants, solvents and/or co solvents, buffering agents, complexing agents or chelating agents, preservatives, antioxidants, viscosity modifying agents and the like or mixtures thereof.

4. The composition according to claim 1 and claim 2, further comprises of one or more active agents.

5. The composition according to claim 4, wherein active agents are antibiotics, antiemetics, anticholinergics, bronchodilators, corticosteroids, antihistamines, antiviral agents and the like or combinations thereof.

6. The composition according to claim 1 , wherein composition can be administered as a metered dose inhalers (MDI), dry powder inhalers (DPI), nebuliser, nasal spray, nasal drops, inhalation spray, nasal aerosol, nasal inhalation, soft mist inhalation, propellant-containing metered-dose aerosols, inhalable solution or inhalable suspensions, propellant- free inhalable solutions and the like.

7. The composition according to claim 1, wherein ivermectin is administered alone or in combination with other active agents to the upper respiratory tract and lower respiratory tracts.

8. The composition according to claim 1, wherein ivermectin is administered alone or in combination with other active agents for prophylaxis of Coronavirus infections.

9. The composition according to claim 1, wherein ivermectin is administered alone or in combination with other active agents for treatment of Coronavirus infections.

10. The composition according to claim 4, wherein is the nasal and inhalation compositions additionally provide kits for use in prophylaxis and treatment of the respiratory diseases.