Topical treatment of inflammatory conditions in airway tissue with cannabinoid microemulsion compositions

Abstract

A method of treating an inflammatory condition in mucosal tissue of the airways of a subject, the method comprising locally contacting mucosal airway tissue of the subject with a microemulsion comprising a cannabinoid compound, and wherein the microemulsion when in a diluted form has a viscosity of 15cP or less, a surface tension of 45 mN / m or less and a hydrodynamic radius of 100 nm or less. Also a kit for treating an inflammatory condition in mucosal tissue of the airways in a subject, comprising (a) the microemulsion comprising the cannabinoid; and (b) a device for delivering the microemulsion to the mucosal tissue of the airways of the subject, wherein the device delivers the microemulsion in a liquid, spray, or aerosolized form.

Description

TOPICAL TREATMENT OF INFLAMMATORY CONDITIONS IN AIRWAY TISSUEWITH CANNABINOID MICROEMULSION COMPOSITIONSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to United States Provisional Patent Application No. 63 / 661,540, filed June 18, 2024, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] The present disclosure relates to topical treatment of inflammatory conditions in mucosal tissue of the upper airways and / or lower airways with cannabinoid microemulsion compositions.BACKGROUND OF THE INVENTION

[0003] The common function to all epithelial tissue is to serve as a gatekeeper, allowing passage to nutrients and other components that are required for various biological functions and rejecting passage to undesired chemicals and microbes from entering the body. In the case of mucosal tissue, such as those present in the airways (sinonasal, oropharynx, lower airways), the rejected chemical and biological species are carried off the epithelial surface by mucosal fluid.

[0004] A compromised epithelial barrier is associated with allergic and autoimmune diseases, including asthma, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, inflammatory bowel disease, and othersl. The pharmacological standard of care to mitigate hyper- or chronic- inflammatory conditions, such as chronic rhinosinusitis (CRS), is the administration of corticosteroids to suppress the expression of genes that are activated in chronic inflammatory diseases. Short-term use of corticosteroids often produces temporary side effects including hypertension, hyperglycemia, pancreatitis, hematologic, immunologic, and neuropsychologic effects. Long-term use of corticosteroids, especially in the treatment of chronic inflammatory diseases, can produce long-lasting consequences such as osteoporosis, aseptic joint necrosis, adrenal insufficiency, gastrointestinal, hepatic, and ophthalmologic effects, hyperlipidemia, growth suppression, psychosis, and possible congenital malformations2. Therefore, alternativetreatment methods for inflammatory conditions, such as antimicrobials (antibiotics, silver), monoclonal antibodies, and cannabinoids, are necessary for patients undergoing treatment for chronic conditions or for patients that are highly susceptible to the acute side effects of corticosteroid use.

[0005] Cannabinoids, and in particular the non-psychoactive cannabidiol (CBD), have been proposed as an adjuvant to reduce the use of corticosteroids3.

[0006] The evidence of cellular and tissue-level studies on the anti-inflammatory effects of cannabinoids, including CBD, has prompted several attempts at using cannabinoids as anti-inflammatory therapies in animal and clinical studies. Vuolo and collaborators4 reported that i.p. injections of CBD to a murine asthma model of inflammation, at a concentration of 5mg / mL, prepared in a 2% solution of polyoxyethylenesorbitan monooleate (Tween® 80) resulted in statistically significant reductions in Thl and Th2 cytokines.

[0007] U.S. Pat. Appl. Publ. No. 2023 / 0131989 discloses the use of aerosols of liposomal suspensions containing CBD for the treatment of Thl inflammatory conditions, but no effect or even detrimental effects with respect to Th2 inflammatory conditions were noted. This patent application suggests that the small size of the aerosol drops allows the liposomes to penetrate and deposit on the airways, including the lower airways. The lack of Th2 response in U.S. 2023 / 0131989 illustrates that the outcome of the treatment method is highly influenced by the method of delivery of the cannabinoid. According to US Pat. Appl. Publ. No. 2023 / 0131989, CBD has no effect in eosinophilic asthma, and it appears to exacerbate the disease.

[0008] U.S. Pat. Appl. Publ. No. 2023 / 0338397A1 only describes the use of cannabinoids to prevent or inhibit the growth of nasal polyps, however, this document is not concerned with the treatment of nasal mucosal inflammation. It is noteworthy to point out that U.S. 2023 / 0338397A1 does not describe administering cannabinoids with the use of microemulsions. For topical administration, U.S. 2023 / 0338397A1 teaches the use of gels, ointments, creams, lotions, drops and the like; and for topical administration, this publication teaches that the cannabinoids are combined with an additional therapeutic agent. That is, for topical administration, the cannabinoid is not used alone, but in combination with another therapeutic agent. Furthermore, U.S. 2023 / 0338397 describesthat cells from human nasal polyps start to detach after a long 3 hours incubation with CBD, which represents an unrealistic amount of time for a treatment with CBD.

[0009] There is a need for topical formulations that can be used in the treatment of inflammatory conditions localized to mucosal airway tissue while minimizing the chances of systemic delivery that could produce undesirable side effects.SUMMARY

[0010] In one embodiment, the present disclosure relates to a method of treating an inflammatory condition in mucosal tissue of the airways of a subject, the method comprising locally contacting mucosal airway tissue of the subject with a microemulsion comprising a cannabinoid compound, and wherein the microemulsion when in a diluted form has a viscosity of 15cP or less, a surface tension of 45 mN / m or less and a hydrodynamic radius of 100 nm or less.

[0011] In one embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the microemulsion comprises: (a) the cannabinoid compound, (b) a lecithin having a net zero charge with 12 or more carbons in the tail group, and (c) an uncharged hydrophilic linker with 6 to 10 carbons in its tail group.

[0012] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the cannabinoid compound concentration is higher than 5 wt.%, or higher than 10 wt.%, or higher than 20 wt. %

[0013] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the mucosal tissue includes upper airways, or lower airways, wherein the upper airways include sinonasal cavity and trachea, and the lower airways include bronchi.

[0014] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the inflammatory condition is chronic rhinosinusitis (CRS) without polyps.

[0015] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the inflammatory condition is chronic rhinosinusitis (CRS) or allergic rhinitis.

[0016] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the inflammatory condition is asthma.

[0017] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the cannabinoid is one or more of cannabidiol (CBD), cannabichromene (CBC), cannabigerolic acid (CBGa), tetrahydrocannabinol (THC), cannabigerol (CBG), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), Cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarinic acid (THCVA), in their purified isolate form or in mixtures with other phytochemicals.

[0018] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, compound wherein the microemulsion has a minimum hydrophilic linker to lecithin molar ratio of 9: 1.

[0019] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the uncharged hydrophilic linker comprises one or more of C6-C10 esters of polyhydric alcohols, polyvinyl alcohol, polyglycerols and their co-polymers with a degree of polymerization (n) higher than 2, sucrose, maltose, oligosaccharides, polyglucosides with n higher than 2, sorbitol, sorbitan, C6-C10 alkyl aminopropionic acids, betaines, sulfobetaines, phosphatidylcholines or mixtures thereof.

[0020] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the microemulsion further comprises of up to 80 wt% water or an electrolyte solution.

[0021] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the microemulsion is a dilutable microemulsion.

[0022] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the microemulsion furthercomprises of up to 60 wt% of a carrier or solvent oil, wherein the carrier oil comprises of alkyl esters of fatty acids, monoglycerides, diglycerides, alkanes, terpenes, or mixtures thereof, having a molecular weight of 400 g / mol or lower.

[0023] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the microemulsion is free of a carrier or solvent oil.

[0024] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the microemulsion further comprises a therapeutic active ingredient, wherein the therapeutic active ingredient includes antibiotics, glucocorticoids, vitamin A, vitamin E, vitamin C, hyaluronic acid, Coenzyme Q10, or mixtures thereof.

[0025] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the microemulsion is free of corticosteroids.

[0026] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the microemulsion is formulated such that contact time of the microemulsion with the mucosal tissue is less than 10 minutes.

[0027] In another embodiment of the method of treating an inflammatory condition in mucosal tissue of the airways of the present disclosure, the microemulsion is delivered to the subject's mucosal tissue of the airways by an inhalation device, by flushing, or by spraying.

[0028] In another embodiment, the present disclosure relates to a use of the microemulsion described in the embodiments of the present disclosure in the treatment of inflammation of airway mucosal tissue in a subject.

[0029] In one embodiment of the use of the microemulsion in the treatment of inflammation of airway mucosal tissue in a subject of the present disclosure, the microemulsion comprises a cannabinoid compound, and wherein the microemulsion when in a diluted form has a viscosity of 15cP or less, a surface tension of 45 mN / m or less and a hydrodynamic radius of 100 nm or less.

[0030] In another embodiment of the use of the microemulsion in the treatment of inflammation of airway mucosal tissue in a subject of the present disclosure, themicroemulsion comprises: (a) the cannabinoid compound, (b) a lecithin having a net zero charge with 12 or more carbons in the tail group, and (c) an uncharged hydrophilic linker with 6 to 10 carbons in its tail group.

[0031] In another embodiment of the use of the microemulsion in the treatment of inflammation of airway mucosal tissue in a subject of the present disclosure, the cannabinoid compound concentration is higher than 5 wt.%, or higher than 10 wt.%, or higher than 20 wt. %.

[0032] In another embodiment, the present disclosure relates to the microemulsion described in the embodiments of the present disclosure for use in the treatment of inflammation of airway mucosal tissue in a subject.

[0033] In one embodiment of the microemulsion for use in the treatment of inflammation of airway mucosal tissue in a subject of the present disclosure, the microemulsion comprises a cannabinoid compound, and wherein the microemulsion when in a diluted form has a viscosity of 15cP or less, a surface tension of 45 mN / m or less and a hydrodynamic radius of 100 nm or less.

[0034] In another embodiment of the microemulsion for use in the treatment of inflammation of airway mucosal tissue in a subject of the present disclosure, the microemulsion comprises: (a) the cannabinoid compound, (b) a lecithin having a net zero charge with 12 or more carbons in the tail group, and (c) an uncharged hydrophilic linker with 6 to 10 carbons in its tail group.

[0035] In another embodiment of the microemulsion for use in the treatment of inflammation of airway mucosal tissue in a subject of the present disclosure, the cannabinoid compound concentration is higher than 5 wt.%, or higher than 10 wt.%, or higher than 20 wt. %.

[0036] In another embodiment, the present disclosure relates to a use of the microemulsion described in an embodiment of the present disclosure in the manufacture of a medicament for use in the treatment of inflammation of airway mucosal tissue in a subject.

[0037] In one embodiment of the use of a microemulsion for the manufacture of a medicament of the present disclosure, the microemulsion comprises a cannabinoid compound, and wherein the microemulsion when in a diluted form has a viscosity of 15cP or less, a surface tension of 45 mN / m or less and a hydrodynamic radius of 100 nm or less.

[0038] In another embodiment of the use of a microemulsion for the manufacture of a medicament of the present disclosure, the microemulsion comprises: (a) the cannabinoid compound, (b) a lecithin having a net zero charge with 12 or more carbons in the tail group, and (c) an uncharged hydrophilic linker with 6 to 10 carbons in its tail group.

[0039] In another embodiment of the use of a microemulsion for the manufacture of a medicament of the present disclosure, the cannabinoid compound concentration is higher than 5 wt.%, or higher than 10 wt.%, or higher than 20 wt. %.

[0040] In another embodiment, the present disclosure provides a kit for treating an inflammatory condition in mucosal tissue of the airways in a subject, the kit comprising (a) the microemulsion described in an embodiment of the present disclosure; and (b) a device for delivering the microemulsion to the mucosal tissue of the airways of the subject, wherein the device delivers the microemulsion in a liquid, spray, or aerosolized form. In one aspect the device is a nebulizer or a nasal sprayer.

[0041] In one embodiment of the kit of the present disclosure, the microemulsion comprises a cannabinoid compound, and wherein the microemulsion when in a diluted form has a viscosity of 15cP or less, a surface tension of 45 mN / m or less and a hydrodynamic radius of 100 nm or less; and (b) a device for delivering the microemulsion to the mucosal tissue of the airways of the subject, wherein the device delivers the microemulsion in a liquid, spray, or aerosolized form.

[0042] In another embodiment of the kit of the present disclosure, the microemulsion comprises: (a) the cannabinoid compound, (b) a lecithin having a net zero charge with 12 or more carbons in the tail group, and (c) an uncharged hydrophilic linker with 6 to 10 carbons in its tail group.

[0043] In another embodiment of the kit of the present disclosure, the cannabinoid compound concentration is higher than 5 wt.%, or higher than 10 wt.%, or higher than 20 wt. %

[0044] In another embodiment of the kit of the present disclosure, the device is a nebulizer or a nasal sprayer.

[0045] In another embodiment of the present disclosure, the subject is a subject in need of treatment of the inflammatory condition in mucosal tissue of the airways of the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0046] A detailed description of the preferred embodiments is provided herein below by way of example only and with reference to the following drawings, in which:

[0047] Fig. 1. Ternary phase diagram for formulations loaded with 10% CBD, using a mixture of polyglycerol- 10-caprylate (PG-10-C8, HL) and lecithin (Sur) at HL / Sur=9 / 1 at the top vertex; an equal volume mixture of ethyl oleate and limonene as solvent oil (SO) at the right vertex; and a saline solution (SS, 0.9%w / v NaCl) in the left vertex. The circles represent the experimental points. The black circles represent single-phase microemulsions. The grey circles represent emulsions that separated within 24 hours. The grey region represents a region that produced liquid crystal systems and viscous systems that are unsuitable as fast topical systems.

[0048] Figs. 2A-2D. Respiratory epithelium of (2A) healthy mice, (2B) OVA- induced CRS mice, (2C) Mometasone treated CRS mice, and (2D) mice treated with CBD at 10 mg / mL in the fast-penetrating topical microemulsion (Formulation A). White arrows indicate the presence of hyaline and Charcot-Leyden crystals. Black arrow represents an example of epithelial hyperplasia.

[0049] Figs. 3A-3E. Comparison of histopathological characteristics representing chronic sinonasal inflammation (eosinophils count (3A), epithelium hyperplasia / folding (3B), hyaline droplets (3C), Charcot-Leyden crystals (3D), and epithelial thickness (3E) between experimental and control groups. Analysis was performed at the end of week 7. All cohorts were compared to the untreated group for statistical testing.

[0050] In the drawings, one embodiment of the invention is illustrated by way of example. It is to be expressly understood that the description and drawings are only for the purpose of illustration and as an aid to understanding and are not intended as a definition of the limits of the invention.DETAILED DESCRIPTION OF THE DISCLOSUREDefinitions

[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of the present disclosure, the preferred methods, devices and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein is to be construed as an admission that the disclosure is not entitled to antedate such disclosure by virtue of prior disclosure.

[0052] All numerical designations, e.g., Characteristic curvature (Cc), pH, temperature, time, concentration and molecular weight, including ranges, are approximations which are varied ( + ) or ( - ) by increments of 1.0 or 0.1, as appropriate, or alternatively by a variation of + / - 20%, + / - 15 %, or alternatively + / - 10%, or alternatively + / - 5% or alternatively + / - 2%. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about”. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0053] As used in the specification and claims, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a compound” includes a plurality of compounds, including mixtures thereof.

[0054] As used herein, the terms “comprising,” “including,” “having” are intended to mean that the compositions and methods include the recited elements, but do not exclude others. “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the intended use. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives and the like. “Consisting of’ shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure. Embodiments defined by each of these transition terms are within the scope of this disclosure.

[0055] “Cannabinoid" is defined as a class of compounds, derived naturally from Cannabis plant or prepared synthetically (synthetic or artificial cannabinoid), that bind to a cannabinoid receptor, including one or more of cannabidiol (CBD), cannabichromene (CBC), cannabigerolic acid (CBGa), tetrahydrocannabinol (THC), cannabigerol (CBG),cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), Cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarinic acid (THCVA), in their purified isolate form or in mixtures with other phytochemicals. “Cannabinoid” includes cannabimimetic compounds and cannabinoid agonistic compounds.

[0056] A “fast penetrating” microemulsion refers to a microemulsion that passes through an airway mucous membrane / mucosal tissue in a delay that is less than 5 minutes after the microemulsion comes into contact with the airway tissue.

[0057] In this document, the term “dilutable microemulsion” is defined as a microemulsion or a microemulsion preconcentrate (SMEDS) that, upon dilution with an aqueous solution or phase, produces a single-phase microemulsion (pE), without excess phases (no liquid phase separation), no formation of precipitate and avoiding viscous (more than 1000 cP) liquid crystals, regardless of the aqueous solution content (from 0 / 100 of aqueous solution / dilutable microemulsion to 99.99 / 0.001 of aqueous solution / dilutable microemulsion). In this document, unless stated otherwise, the term microemulsion refers to a single-phase microemulsion.Overview

[0058] The present disclosure relates to compositions and methods of treatment of inflammatory conditions. In embodiments, the compositions of the present invention for the treatment of inflammatory conditions in the airways are lecithin-based microemulsions containing solubilized cannabinoids. In embodiments, the present disclosure relates to a fast-penetrating lecithin-based microemulsion (in dilutable form (self-microemulsifying delivery system (SMEDS)) or in diluted form (mE)) for the treatment of inflammatory conditions.Method of Treating Airway Mucosal Inflammation

[0059] In one embodiment, the present disclosure relates to a method of treating an inflammatory condition in a subject, the method comprising, or consisting essentially of,or consisting of, locally applying to mucosal airway tissue of the subject a lecithin-based microemulsion of the present disclosure having solubilized cannabinoids.

[0060] Target mucosal airway tissue of the present disclosure includes sinonasal tissue, mucosa of the upper airways and lower airways.

[0061] Inflammatory conditions of the airways that can be treated with the methods and compositions of the present disclosure include chronic rhinosinusitis with nasal polyposis (CRSwNP), CRS without nasal polyposis (CRSsNP), allergic rhinitis, asthma, among others.Microemulsion

[0062] In one embodiment, the lecithin-based microemulsion of the present disclosure (SMEDS or mE) comprises, or alternatively consists essentially of, or alternatively consists of, a low-viscosity (<15 cP), low surface tension (< 45 mN / m) uncharged lecitihin-based microemulsions (<100 nm) containing or including, or alternatively consisting essentially of, or alternatively consisting of, solubilized cannabinoids (natural cannabinoids or artificial cannabinoids or cannabimimetic or cannabinoids agonists). In aspects, the solubilized cannabinoids are capable of binding to cannabinoid receptors capable of downregulating the immune response. In one embodiment, the microemulsions of the present disclosure are water-continuous, oil-swollen micelles or bicontinuous microemulsion systems.

[0063] In one embodiment, the present disclosure, is a mE or a SMEDS comprising, or alternatively consisting essentially of, or alternatively consisting of:(a) a cannabinoid compound,(b) a lecithin having net zero charge, and(c) a hydrophilic linker having 6 to 10 carbon molecules in its tail group.

[0064] In embodiments, the SMEDS (the dilutable preconcentrate) and the mE microemulsions (the diluted form) of the present disclosure are free of polyethylene and free of propylene glycol.

[0065] The hydrophilic linker (HL), in embodiments, has a negative Cc, 10 or less carbons in the tail group, and a headgroup that is free of PEG and PPG. In embodiments, theSMEDS and mE microemulsions can be further comprised of a pharmaceutically acceptable solvent oil with a molecular weight lower than 400 g / mol that is suitable to dissolve the cannabinoid of interest.

[0066] In embodiments, the microemulsion is further comprised of an aqueous phase that can contain a mixture of electrolytes required to maintain the osmolality of the formulation.

[0067] In embodiments, the microemulsion of the present disclosure is provided as a dilutable microemulsion (SMEDS). In other embodiments, the microemulsion of the present disclosure is provided as a diluted single-phase microemulsion.

[0068] In embodiments, a diluted microemulsion of the present disclosure contains at least 80% aqueous solution at the time of contact with the tissue to prevent phase changes upon contact with the mucous layer of the tissue. The aqueous solution may include, for example, water or a saline diluent or mucosal fluid.

[0069] The microemulsion (SMEDS and mE) of the present disclosure can be produced by mixing the required components at a temperature that allows the dissolution of the cannabinoid, and then cooled down to room temperature, if needed. In embodiments, the microemulsion of the present disclosure can be first produced in the form of a microemulsion preconcentrate (i.e., dilutable microemulsion). In embodiments, the preconcentrate contains less than 80 wt.% water. In another embodiment, the preconcentrate microemulsion is diluted with a suitable aqueous solution to form a diluted microemulsion and to adjust the required dose. In one embodiment, the preconcentrate microemulsion (SMEDS) is diluted to a final water content of 80 wt.% or more. This final dilution content may involve mixing with an impeller-mixer, a vortex-mixer, a wrist-action shaker or simple manual shake for 30 seconds or more at room temperature. The diluted microemulsion should have a viscosity of 15 cP or less, a surface tension of 45 mN / m or less, and a hydrodynamic radius of 100 nm or less.

[0070] The microemulsions of the present disclosure are formulated for local application on mucosal tissue of the airways. In embodiments, the microemulsions of the present disclosure are formulated for topical application on the mucosal airways, for example in the form of an irrigating or rinse solution, or an aerosol. In one embodiment, a daily dose regime includes a once-a-day delivery, but it can also involve multiple daily doses. Irrigating and rinsing solutions can be applied by gravity using droppers or a neti pot. Themicroemulsions of the present disclosure can also be applied as pressurized jets using squeeze bottles, syringe-pressurized jets, or squeeze bulbs. The microemulsions of the present disclosure can also be applied by a nebulizer in the form of a mist, spray or aerosol. In one embodiment, the microemulsion of the present disclosure is applied by a nasal sprayer such as that commercialized under the trademark XHANCE®.

[0071] In another embodiment, the present disclosure provides for a kit for treating an inflammatory condition in mucosal tissue of the airways in a subject, the kit comprising (a) the microemulsion according to an embodiment of the present disclosure; and (b) a device for delivering the microemulsion to the mucosal tissue of the airways of the subject, wherein the device delivers the microemulsion in a liquid, spray, or aerosolized form. In one aspect the device is a nebulizer. In an embodiment, the nebulizer is a metered-dose nebulizer. In another aspect the device is a nasal sprayer. In an embodiment, the nasal sprayer is a metered-dose nasal sprayer. An example of a device is XHANCE®.

[0072] The cannabinoids that can be used in the microemulsion compositions of the present disclosure include cannabidiol (CBD), cannabichromene (CBC), cannabigerolic acid (CBGa), tetrahydrocannabinol (THC), cannabigerol (CBG), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), Cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarinic acid (THCVA), in their purified form or in mixtures with terpenes, in tinctures or in resin form. Combination of cannabinoids can also be used with the microemulsion compositions of the present disclosure.

[0073] Unlike the microemulsions of the prior art, the microemulsions of the present disclosure incorporate high CBD loading. In one embodiment, the microemulsion of the present disclosure comprises 5 wt.% or more of the cannabinoid. In another embodiment, the microemulsion of the present disclosure comprises 10 wt.% or more of the cannabinoid. In another embodiment, the microemulsion of the present disclosure comprises 20 wt.% or more of the cannabinoid.

[0074] In one embodiment, the disclosed microemulsion compositions are PEG-free and polypropylene glycol (PPG)-free as there is mounting evidence of PEG-induced Accelerated Blood Clearance (ABC) and an autoimmune response called the complement (C) activation-related pseudoallergy (CARPA)19. The potential risk for PEG-induced allergic reactions has been publicly exposed by the PEG-triggered allergic reactions to the Pfizer-BioNTech COVID-19 vaccines.

[0075] In one embodiment, a feature of the microemulsion compositions used in the fastpenetrating method of treatment of inflammation of mucosal airways, is being dilutable in a fluid solution. In one embodiment, the fluid solution includes solutions that mimic the osmolality and pH of the fluid in contact with the mucosal airway tissue. In another embodiment, the fluid solution includes solutions that does not mimic the osmolarity and pH of the fluid in contact with the mucosal airway tissue. The dilutable condition means that no second phase, precipitate or gels are formed when a concentrated microemulsion (with less than 80 wt.% water) is diluted with an aqueous phase that is relevant to the target mucosal tissue. A dilutable microemulsion preconcentrate that is free of water is also referred to as a self-microemulsifying delivery system (SMEDS) or as a selfmicroemulsifying drug delivery system (SMEDDS). SMEDDS need to be carefully formulated, using the hydrophilic-lipophilic-difference (HLD) and net-average curvature (NAC) equation of state to predict the range surfactant dilution line (SDL) compositions in ternary phase diagrams (TPDs) of surfactant-oil-water (SOW) systemsl4. The HLD is a set of empirical equations that assess the proximity to the surfactant phase inversion point, where HLD=0 20. For nonionic surfactants, HLD = b-S -k-EACN + Cc + cT-(T-25°C), where b, k and cT are surfactant-dependent constants; S is the salinity of the aqueous phase, (grams of NaCl / 100 mL solution). T is the temperature in Celsius. The Cc is the characteristic curvature of the surfactant. EACN represent the oil hydrophobicity expressed as the Equivalent Alkane Carbon Number, that for simply n-alkanes is the number of carbons in their chain. In the case of polar hydrophobic molecules, such as cannabinoids, these molecules have a surfactant-like behavior with its Cc and an oil-like behavior with an EACN 21.

[0076] In one embodiment, the target HLD range to produce oil-swollen micelle microemulsions is between -6 to 0, with a preferred range of -4 to 0. According to the net-average curvature (NAC), within this negative HLD range, the radius of solubilization of oil can be estimated as Ro = -L / HLD, where L is the length parameter of the surfactant, often around 1.4 times the tail length of the surfactant. The value of Ro is related to the surfactant dilution line (SDL, volume fraction of the surfactant + linker in mixture with the oil and the drug) via the equation SDL=100 / (l+Ro / (3*(vs / as))).Surfactants

[0077] The microemulsion of the present disclosure includes a lecithin.

[0078] In one embodiment, the lecithin contains at least 50% w / w of a mixture of C12+ phosphatidylcholine, C12+ phosphatidylethanolamine, and C12+ lysotecithins or any other uncharged phospholipid or any phospholipid with net zero charge.

[0079] The fast-penetrating topical microemulsion composition of the present disclosure can also incorporate additional antibiotics for inflammatory conditions caused by microbial infiltrations. The fast-penetrating topical formulations can also incorporate additives that contribute to tissue repair such as hyaluronic acid, Coenzyme Q10, Vitamin E, Vitamin A, Vitamin C. The fast-penetrating topical formulation of the present disclosure can also include pain management additives such as lidocaine.Hydrophilic Linker

[0080] The microemulsion compositions of the present disclosure require the incorporation of a hydrophilic linker (HL) or the combination of two or more HLs with 6 to lOlcarbons in the tail group and a head group (i.e., 6, 7, 8, 9, 10, 11 or 12 carbons), that are neutral or have an isoelectric point between pH 5 and pH8, and that have a negative characteristic curvature (Cc<0). Suitable hydrophilic linkers include C6-C10 esters of polyhydric alcohols, polyvinyl alcohol, polyglycerols and their co-polymers with a degree of polymerization (n) higher than 1 (n>l), sucrose, maltose, oligosaccharides, polyglucosides (n>l), polyglucosamines, sorbitol, sorbitan, poly alpha hydroxy acids and their esters or amides or amine oxides, C6-C10 alkyl aminopropionic acids, betaines, sulfobetaines or mixtures thereof.

[0081] In one embodiment, the HL is an uncharged HL. In another embodiment, the HL includes a negative charge.

[0082] In another embodiment, the microemulsions of the present disclosure (mE and SMEDS) have an HL to lecithin ratio of at least 9: 1.Carrier Oil

[0083] In some embodiments, a solvent oil is used to facilitate the dissolution of the cannabinoid and the formation of the microemulsion. The solvent or carrier oil can be a single solvent or a mixture of more than one solvent. Since larger molecular weights (MW) may not be fully solubilized in the microemulsion, in one embodiment, the solvent oil has a MW lower than 400 g / mol. In another embodiment, the mixture of more than one solvent has an average molecular weight lower than 400 g / mol. Examples of solvent oils include alkyl esters of fatty acids such as isopropyl myristate, ethyl caprate, methyl oleate, ethyl oleate; terpenes such as limonene, pinene; and mixtures of with mono- di - and triglycerides used as cosolvents. In embodiments, the microemulsion of the present disclosure is free of a carrier oil. Excluding allows increase the CBD loading in the microemulsion.Other Additives

[0084] In one embodiment, the microemulsion (mE or SMEDS) of the present disclosure further comprises a therapeutic active ingredient. Therapeutic active ingredient includes antibiotics, glucocorticoids, corticosteroids, vitamin A, vitamin E, vitamin C, hyaluronic acid, Coenzyme Q10, or mixtures thereof.

[0085] In another embodiment, the microemulsion of the present disclosure is free of corticosteroids.

[0086] In another embodiment, the microemulsion of the present disclosure further includes processing-aid compounds such as antioxidants, flavouring agent, preservatives and so forth.EXAMPLESIntroduction

[0087] U.S. Pat. Appl. Publ. No. 2023 / 0131989 and the work of Silvestri et al. the method of use of CBD involved the delivery of CBD to the luminal side of the mucosal tissue. It isknown to those skilled in the art that delivering active ingredients, such as cannabinoids, to mucosal tissue is challenging because the mucin glycoproteins, non-mucin compounds of the mucus and the fluids present in the mucus in the mucosal tissue pose a barrier to penetration of large molecules or delivery vehicle micro / nanoparticless such as Lipid nanoparticle, and because the constant flow of the mucosal fluid is designed to expel particles and other undesirable material from the luminal surface of the mucosal tissue6. The literature on delivery to mucosal epithelial tissue supports three methods of delivery. The first is gel tablets produced with polymers and surfactants containing the solubilized drug. The tablets are placed next to the mucosal tissue and gradually release micelles (containing the solubilized drug), next to the targeted tissue, increasing the chances of absorption because it increases the release time. The second method is the use of muco- adhesive particles (MAPs) that could attach to the mucous layer and increase the residence time of drug-loaded micelles to the surface of the mucosal tissue. The third method of delivery involves the use of muco-penetrating particles (MPPs), which, rather than adhering to the mucous layer, escape entrapment by this layer to directly target the luminal surface of the mucosal tissue, where they can subsequently attach.

[0088] The method of delivery, for example, nasal spray (aerosol) vs. nasal irrigation can also affect the outcome of the treatment method. Nasal irrigation is commonly employed in the delivery of topical antibiotics (e.g. mupirocin) and corticosteroids (e.g. budesonide) in the form of suspensions in saline solution for the treatment of various conditions in the sinonasal cavity, including CRS. Compared to other methods of treatments, the nasal irrigation is less invasive. For the treatment of sinonasal conditions, nasal irrigation is preferred to aerosol treatments because it ensures diffuse mucosal contact with the medication throughout the entire sinonasal cavity. In contrast, a spray or aerosol may only reach a portion of the upper airways, including the sinonasal area, and is best suited to deliver to lower airways The drawback of nasal irrigation as the method of delivery is the relatively short contact time and that only partial surface coverage is obtained with the treatment?. In vitro models demonstrate that the primary bolus of a nasal rinse makes contact with the sinonasal surface for only 5-10 seconds. Moreover, within the initial 30 seconds of contact, only 2.7% of maximal mometasone absorption is achieved. This underscores a significant limitation in the efficiency of drug delivery through nasalirrigation.25 While there are portions of the sinuses where small pockets of the saline solution can remain occluded, another challenge in many patients experiencing allergic rhinitis is an increased production of mucosal fluid leading to mucous clearance time as short as 4.2 minutes8. It is known to those skilled in the art, that the delivery time scale to mucosal tissue must be shorter than the mucous clearance time 10. Considering the time- constrained nature of delivering to the luminal side of mucosal tissue, particularly in the sinonasal cavity via nasal irrigation, compositions requiring hours of exposure are made irrelevant, such as disclosed CBD-terpene compositions that require from 3 to 72 hours (U.S. Pat. Appl. Publ. No. 2023 / 0338397A1) to show a decrease in Th2 inflammatory response using ex-vivo tissue and cells relevant to CRS conditions with nasal polyps (CRSwNP).

[0089] One possible way of accelerating the permeation through nasal mucosal tissue is the use of microemulsion-based systems. Microemulsions are thermodynamically stable surfactant-oil -water (SOW) systems, that can consist of oil-swollen micelles present in an aqueous continuous phase (often referred to as Type I microemulsions); or they can consist of water-swollen reverse micelles present in an oil -continuous phase (often referred to as Type II microemulsions); or they can consist of systems containing interpenetrating (bicontinuous) channels of oil and aqueous environments (often referred to Type III or IV microemulsions). Microemulsions have sphere-equivalent volume / area ratios that are typically less than 30 nm, and a hydrodynamic diameter that is typically less than 100 nm. The relatively small size of microemulsion domains facilitates their penetration through small junctions. The mechanism of transport of material from and into microemulsion environments is partially controlled by the ability of the microemulsion environment to coalesce or spread on the surface where the material is being deliveredll. The ease of coalescence or spreading of the microemulsion environments is controlled by the interfacial rigidity of the system (Er), where systems with low interfacial rigidity achieve fast rates of coalescence and solubilizationl2. The interfacial rigidity of SOW systems can be reduced by introducing short-chain surfactants with 10 or less carbons in their tail group, known as hydrophilic linkers (HL)12. Microemulsion formulations prepared with lecithin (Le, having a Cc ~ + 4 to +9) as a surfactant, and a combination of lipophilic linkers (LL, surfactant-like molecules with 12 or more carbon in their tail group and a weak polar groupsuch as a single alcohol, a monoglyceride, a single fatty acid or amine or amide group) and a hydrophilic linker have been found to penetrate skin with a lag time (period without significant permeation) of 15 to 30 minutes and requiring between 30 minutes and 1 hour to reach a steady state flux through the skinl3. A fully-dilutable, self-microemulsifying drug delivery system (SMEDDS) comprising Le and extreme hydrophilic linkers HL (HL- with characteristic curvature of Cc more negative than -5) has been used for oral delivery of a polar hydrophobic active (ibuprofen) 14. This Le + HL- formula was found to produce the shortest time to achieve the maximum or peak plasma concentration of the drug (Tmax = 22 minutes) among all the formulations compared in that work. PCT application publ. No. WO2022 / 140843A1, of the present inventors, discloses Le + HL-SMEDDS compositions for the oral delivery of cannabinoids and reports an example for CBD delivery that produces a Tmax of 30 minutes.

[0090] The penetration through the mucosal tissue is limited by the continuous mucosal fluid flow, and the mucous clearance process, even for systems with nanoscale sizes. For a delivery system to pass the mucous layer barrier, the size of the delivery system should be up to 500 nm, but in order to pass the periciliary layer (PCL) barrier, the size of the delivery system should be 40 nm or smaller than 40 nml5. However, size of the delivery system alone does not govern its penetration through the mucous layer barrier, as other factors may be at work.

[0091] Other than the Tmax (22 to 30 minutes) indicators for oral delivery in Le-HL microemulsions, there is no available information on the time scale of the delivery of Le- HL microemulsions through epithelial tissue. There is, however, information on transport through nasal porcine tissue using a water-in-oil microemulsion, for the delivery of insulin, comprising of glycerol monooleate (Cc around + 6) as surfactant, and a polyethylene glycol (PEG)-8-C8 / C10 cosurfactant (Labrasol®, Cc= -2.9) that acted as a hydrophilic linker because of its C8 / C10 tail range. This formulation produced a lag time (no permeation) for insulin (introduced in the form of aerosol) of more than 10 minutes through porcine nasal tissue and a Tmax for insulin plasma in rabbits in the ranged between 15 and 25 minutes 16. A disadvantageous property of the reported Labrasol® formulas, and other PEG-based hydrophilic linkers, is that they tend to produce viscous (15 cP or greater viscosity) formulations that are undesirable for nasal irrigation purposes. The viscosity of the nasalirrigation formula must be less than 15 cP for the formulation to reach most of the small spaces of the sinonasal cavity and be easily drained out of those spaces. Another desirable property for formulations used in nasal irrigation is to obtain surface tensions (air vs. liquid) of 45 mN / m or less 17, and best if the formulations have surface tensions of 35 mN / m , as this secures that Marangoni-type flows that promote the spreading of the formulation to areas of the sinonasal cavity that are not covered by the rinsing liquid.

[0092] While microemulsion-based delivery systems are likely the fastest route for transport of CBD and related cannabinoids to epithelial airway tissue, all the current evidence points to transport times of more than 10 minutes, which may not result in an effective delivery to mucosal tissue due to mucus turnover. This illustrates the need for a fast-penetrating topical formulation that can be used in the treatment of inflammatory conditions localized to mucosal tissue lining the upper airways and the lower airways while minimizing the chances of systemic delivery that could produce undesirable side effects.Example 1. Formulation of a fast-penetrating topical CBD formulation for mucosal tissue.

[0093] To guide the formulation of dilutable systems, the HLD-NAC framework was used. The CBD microemulsions disclosed in example 4 of WO2022 / 140843A1 (WO ‘843) were formulated using the HLD framework with CBD (CCCBD= +2.6, Molecular Weight or MW = 314 g / mol, area per molecule at the interface as = 0 A2), soybean lecithin (Le, Cc=+5.5, Mw = 750 g / mol, as = 90 A2) as the principal surfactant, polyglycerol- 10-caprylate or PG10-C8 (HL, Cc=-7.4, Mw = 885 g / mol, as = 95 A2) as the extreme hydrophilic linker, and an oil phase containing ethyl caprate with EACN = 5.1. Three important inputs to develop a suitable formulation: (i) selecting the mass ratio of hydrophilic linker to lecithin (HL / Le), (iii) selecting the cannabinoid loading in the SMEDDS (CB_wt%), and (iv) having an initial guess for the surfactant dilution line (SDL).

[0094] Considering 100 grams of SMEDDS, the grams of cannabinoids are CB_wt%. The mass of solvent oil in grams is (100-CBwt%)*(100-SDL) / 100, the mass of lecithin in grams is (100-CBwt%)*(l / (l+HL / Le))*(SDL) / 100, and the mass of hydrophilic linker in grams is (100-CBwt%)*((HL / Le) / (l+HL / Le))*(SDL) / 100. The moles of HL, Le and cannabinoid (CBD in this example) are obtained by dividing their grams by their respective molecular weights. The molar fraction of HL, Le and cannabinoid in relation to each other(as the surface-active species, assuming the cannabinoid segregates to the interface) is calculated by dividing the moles of the species by the total moles of the three components. The Cc of the Le + HL + cannabinoid mixture is then calculated as the sum of the Cc of each individual component times its Cc. Using EACN = 5.1, and the salinity of an isotonic solution (S= 0.9g NaCl / 100 mL aqueous solution), the HLD of the system can be calculated using HLD = 0.13*0.9+Cc_mixture -0.16*5.1. The temperature term for this HLD equation was not added because the lecithin + HL system is temperature insensitive within 15°C and 55°C. Using this HLD equation, the SDL can now be confirmed using the net- average curvature (NAC) more, SDL=100 / (l -(L / HLD) / (3*(vs / as))). From Nouraei and Acosta, for Lecithin - linker system L ~ 90A. To calculate the surfactant volume-to-area ratio (vs / as), the total volume of surface-active species (volume of Le, HL and cannabinoid) and interfacial area (using the as for Le and HL, the polar oils such as cannabinoids are not expected to increase the interfacial area). For most systems, vs / as ~ 25A.

[0095] Setting HL / Le = 9 / 1 and CB_wt%=10, the iterative process described above generates a HLD-NAC-predicted SDL= 78.3. To confirm this prediction, a partial ternary phase diagram was produced using a PG10-C8 (HL, obtained from Lonza) to lecithin (surfactant, soybean lecithin) mass ratio of 9 to 1 (CHL / Csurf =9), a CBD loading of 10 wt% (CcB%wt=10%), using as solvent oil a mixture of equal volume parts of limonene and ethyl oleate, and a 0.9% NaCl solution as the saline (aqueous) solution. Two SDL lines were produced, one at SDL=70 and one at SDL =80. Selected systems at SDL>80 were attempted but resulted in the production of highly viscous gel phases that are characteristic of liquid crystalline phases, unsuitable for fast-penetrating topical formulations. The most concentrated microemulsions contained only 20 wt% of the saline solution. A saline dilution path was followed for each of the SDL lines by adding enough saline solution to produce 30, 40, 50, 60, 70, 80, 90 and 99 wt% saline solution in the microemulsion system. After the addition of the saline solution, the microemulsions were shaken for 5 minutes before the systems were inspected for any signs of phase separation. The systems were then left to rest at room temperature for 24 hours to notice any signs of phase separation or the presence of turbidity that could be evidence of the formation of emulsions, instead of microemulsions. During the first 8 hours, the drop size of the microemulsions was evaluated using a BL90 dynamic light scattering (DLS) instrument. The viscosity of thesystems was assessed using a Gilmont falling ball viscometer. The surface tension of the system was determined using a KSV sigma 700 tensiometer. Table 1 shows the composition and properties of the SDL=80 composition found that produced microemulsions at all dilutions. Fig. 1 presents the partial ternary phase diagram obtained for these formulations, including the predicted minimum dilution lines. The NAC model correctly predicted that the minimum SDL to produce fully dilutable microemulsions was between 70 and 80.

[0096] Table 1. Composition and properties of microemulsions prepared from a preconcentrate formulation containing 10% CBD, prepared with hydrophilic linker (PG10C8) to lecithin ratio of 9, and at SDL=80, using 1 : 1 volume mixture of limonene and ethyl oleate as solvent oil (SO). The first column indicates the wt% of aqueous saline solution (0.9% NaCl) used to dilute the microemulsion. The system containing 90 wt% saline solution was used as the “Formulation A” used in the murine model.Example 2, Effect of hydrophilic linker to lecithin (HL / Le) ratio on the dilution performance of topical CBD formulations for mucosal tissue.

[0097] The use of high ratios of the hydrophilic linker to lecithin (HL / Le) has the advantage of reducing the interfacial rigidity of the formulation and hindering the formation of highly viscous liquid crystalline phases that can interfere with the manufacture and delivery of the topical composition. The disadvantage of a high HL / Le ratio is that it tends to increase the required SDL. Following the HLD-NAC protocol of Example 1, using an HL / Le ratio of 8.8 / 1.2 reduces the NAC-predicted SDL from 78.3 to76.9. Table 2 presents a summary of the dilution behavior of formulations produced with the same components and procedure as Example 1, except that the HL / Le ratio used 8.9 / 1.1 for case A and 8.8 / 1.2 for case B. For both cases, the dilution line explored was SDL=80.

[0098] Table 2. Composition and properties of microemulsions prepared from a preconcentrate formulation containing 10% CBD, prepared with hydrophilic linker (PG10C8) to lecithin ratio of 8.9 / 1.1 and 8.8 / 1.2, and at SDL=80, using 1 : 1 volume mixture of limonene and ethyl oleate as solvent oil (SO).

[0099] As shown in Table 2, the diluted microemulsions with 80% water content or more are single phase systems, as predicted by the NAC. However, the phase separation is observed in the more concentrated microemulsion, which is consistent with the more prevalent liquid crystal phases seen at higher total surfactant (Le + HL) concentrations when the HL / Le is not high enough. The formation of liquid crystal phases cannot be predicted with the HLD-NAC model at this time.

[0100] While the diluted compositions of Table 2 could be used as topical formulations, the preferred compositions are also single-phase systems and maintain low viscosity (<15 cP) and surface tension (< 45 mN / m) even in the concentrated (< 80% aqueous phase) state. Table 2 indicate that the preferred compositions should have a HL / Le ratio of 9 or higher.Example 3, Topical CBD microemulsion in a murine model of sinonasal inflammation.Murine model of sinonasal inflammation.

[0101] The model of allergic rhinosinusitis murine model was adapted from a previously validated model24. Sinonasal inflammation was induced in 20 Balb / c mice using ovalbumin (OVA) and A. oryzae protease. The induction started with intraperitoneal injection of 25 pg of OVA and 2mg of Alum (Aluminum hydroxide adjuvant) on day 0 and 4 (Week 1). In week 2, mice received intranasal rinse with 75pg of OVA in 30 pL of PBSfor 5 consecutive days. In weeks 3 - 7, mice received, three times a week, intranasal rinse containing 75pg of OVA and 0.54U of A. oryzae protease. Control mice (n=10) were administered PBS. At the end of week 7, six mice (3 males and 3 females) were euthanized, and blood and tissue were collected for analysis. Fifteen challenged mice (n=15) were additionally treated with intranasal saline (n=5) as negative control or mometasone (n=10) as positive control. The treatments were performed three times a week for three weeks (week 5-7). The concentration of mometasone was 0.5mg / ml with 0.02mg delivered each dose. Mice were euthanized for sample collection and analysis at week 7. Control groups of untreated challenged mice (n=5) and healthy mice (n=5) were compared after week 7.

[0102] Administration of intranasal induction and treatment was done via nasal rinse done under light anesthesia (isoflurane, 5% induction, 2% maintenance). Mice were held in a left lateral position with the head pointed very slightly down and the liquid sample (30 pL) was applied slowly (application completed in about 1 minute) to the right nostril. The sample traveled through the nasal cavity and exited the nose through the left nostril. Usually, once a drop exited the left nostril it was gently wiped away to draw the excess of liquid from the nose. The procedure was completed within 5 minutes and was done in a manner to avoid any liquid being drawn into the lungs.Histological Analysis.

[0103] Mice were euthanized, with head specimens initially fixed in 10% formalin. Tissue samples were further processed, sectioned, and stained. Nasal cavity sections with a thickness of 4 pm were stained with Hematoxylin and Eosin (H&E) to study the tissue morphology and to evaluate the symptoms of inflammation. Stained sections were scanned at 20x magnification.

[0104] Respiratory epithelium was evaluated in various areas around the nasal septum, vomeronasal organ (VNO), and the turbinates (maxilloturbinates). The infiltration of eosinophils was evaluated by counting the eosinophils in H&E-stained sections and recorded as cells per mm2. Respiratory epithelial thickness was measured as the distance between the apex of the epithelial cells and the upper border of the subepithelial glands zone. Fifteen measurements were taken for each specimen (three cross sections, 5 measurements each). The following additional markers of inflammation were evaluated(via scoring performed blinded to study groups): degranulation of eosinophils, the presence and amount of hyaline droplet material, and the occurrence of eosinophilic crystals (Charcot-Leyden crystals). Scores from 0 to 4 were used to describe the severity of the markers: (0) none, (1) minimal, (2) mild, (3) moderate, and (4) severe. Minimal was defined as barely detectable, mild as slightly detectable, moderate as easily detectable, and severe as very evident. Whole blood was also collected vial cardiac puncture and used for CBC analysis (lymphocytes, monocytes, neutrophils) and to prepare blood smear samples (eosinophils).Treatment protocol and topical compositions.

[0105] All treatments were given intranasally (using the same application protocol described in the murine model section) and initiated at week 5 and continued until week 7. Intra-nasal treatment was administered five times a week (Mon-Fri) for a total of 3 weeks.

[0106] Both the induction (OVA and protease) and treatments (CBD, vehicle, mometasone, saline) were administered to mice daily (once a day) with the dosing separated by 3 hours, with the OVA / protease given first followed by the treatment dosing 3 hours later.

[0107] Two topical CBD compositions were compared, one noted as “Formulation A” containing 10 mg / mL of CBD and with a composition noted as “FA” in Table 1 of Example 3. The second composition, noted as “Formulation B”, contained 5 mg / mL CBD prepared in an aqueous solution of 5 vol% Tween® 80. To homogenize Formulation B, this mixture was agitated for 24 hours at room temperature (20±l°C), and then filtered prior to analysis. The sample was subjected to accelerated stability study at 40°C, finding that after 2 weeks the sample lost 25% of its initial activity (in terms of CBD concentration measured in solution). In addition to the two formulations, the two corresponding “vehicles” were tested, which contained all the components of the formulation, except for CBD. A saline (0.9 % NaCl solution) treatment, and a 0.5 mg / mL Mometasone (corticosteroid) in saline solution treatment were also included among the topical compositions.

[0108] It should be noted that 5 mg CBD per ml in Formulation B was found to be the highest possible amount of CBD given the instability of Formulation B.Histological observations.

[0109] Figs. 2Ato 2D present examples of the histological observations obtained with (2A) healthy (unchallenged) tissue, (2B) challenged tissue (CRS model) that did not received any form of treatment, (2C) challenged tissue that received the standard corticosteroid (mometasone) treatment, (2D) challenged tissue that received the CBD microemulsion (Formulation A) treatment. The white arrows shown in the untreated (2B) and (2C) mometasone images indicate the presence of hyaline and Charcot-Leyden crystals. The black arrow shown in the untreated (2B) model represents an example of epithelial hyperplasia. The images in Fig2. 2A-2D present a surprising result, the treatment with CBD in formulation A, a corticosteroid free formulation, not only prevented the extensive tissue damage observed in the untreated tissue, but it matched or outperformed the standard corticosteroid treatment. The appearance of the tissue treated with formulation A resembles that of the unchallenged healthy tissue, indicating not only the prevention of a hyperinflammatory response, but the promotion of tissue repair.

[0110] Figs. 3A-3E compare the histopathological characteristics representing chronic sinonasal inflammation (epithelial thickness (Fig. 3E), eosinophils count (Fig. 3 A), hyaline droplets (Fig. 3C), Charcot-Leyden crystals (Fig. 3D), and epithelial hyperplasia / folding (Fig. 3B)) between experimental and control groups. Analysis was performed at the end of week 7. All cohorts were compared to the untreated group for statistical testing. Histological markers of CRS were compared between the multiple treatment groups and untreated CRS mice. The Levels of eosinophil (Fig. 3A, p = 0.041), epithelial hyperplasia / folding (Fig. 3B, p = 0.0067), hyaline droplets (Fig. 3C, p = 0.0058) and Charcot-Leyden crystals (Fig. 3D, p= 0.0046) were significantly reduced in CRS mice treated with the CBD microemulsion (Formulation A) compared to untreated CRS mice. CRS mice treated with mometasone demonstrated a significant decrease in epithelial hyperplasia / folding (Fig. 3B, p = 0.0004), hyaline droplets (Fig. 3C, p = 0.0024), Charcot- Leyden crystals (Fig. 3D, p = 0.011), and epithelial thickening (Fig. 3E, p = 0.042), but no significant differences were observed in eosinophil count (Fig. 3A). Overall, respiratory (mucosal) epithelium of CRS mice treated with intranasal CBD (Formulation A) demonstrated a general reversal of inflammatory markers compared to untreated CRS mice and a similar post-treatment appearance with mometasone-treated CRS mice.

[0111] It is important to note that formulation B (5 mg / mL CBD in 5% Tween®80 solution), nor the vehicles of formulation A or B produced any significant decrease, compared to the untreated CRS group, in any the inflammatory markers shown in Figs. 3A-3E. Given that Formulation B does include CBD, one would expect a significant reduction in at least one of the inflammatory markers when compared to the untreated group. The lack of reduction of any of the inflammatory markers with formulation B shows the importance of the ability of the delivery vehicle to provide a fast penetration of the mucosal tissue. The Tween®80 formulation is the type of formulation that a person of ordinary skill in the art would develop for fast topical delivery of CBD to mucosal tissue considering the principles of muco-penetrating particles (MPP), where relatively short oligomers of PEG-based surfactants are used to produce delivery system that can avoid being trapped by the mucous layer6. Furthermore, Vuolo et al. used 5 mg / mL CBD in a 2% Tween®80 solution, that was injected intraperitonially (systemic delivery) in rats to treat an OVA-induced murine model of asthma. The systemic delivery of 5 mg / mL CBD in Tween®80 used by Vuolo et al. resulted in a reduction of Thl and Th2 inflammatory markers4. This observation illustrates that given enough exposure time, such as systemic delivery, CBD is to be expected that CBD can produce a reduction in Thl and Th2 inflammatory markers of mucosal tissue. However, guaranteeing the same level of effective delivery with a topical formulation requires the unexpected performance obtained with the microemulsion of Formulation A.REFERENCES(1) Akdis, C. A. Does the Epithelial Barrier Hypothesis Explain the Increase in Allergy, Autoimmunity and Other Chronic Conditions? Nat. Rev. Immunol. 2021, 21 (11), 739- 751. https: / / doi.org / 10.1038 / s41577-021-00538-7.(2) Buchman, A. L. Side Effects of Corticosteroid Therapy. J. Clin. 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[0112] Although various embodiments of the disclosure have been described and illustrated, it will be apparent to those skilled in the art in light of the present description that numerous modifications and variations can be made. The scope of the invention is defined more particularly in the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A method of treating an inflammatory condition in mucosal tissue of the airways in a subject, the method comprising: locally contacting mucosal airway tissue of the subject with a microemulsion comprising a cannabinoid compound, and wherein the microemulsion when in a diluted form has a viscosity of 15cP or less, a surface tension of 45 mN / m or less and a hydrodynamic radius of 100 nm or less.

2. The method of claim 1, wherein the microemulsion comprises:(a) the cannabinoid compound,(b) a lecithin having a net zero charge with 12 or more carbons in the tail group, and(c) an uncharged hydrophilic linker with 6 to 10 carbons in its tail group.

3. The method according to any one of claims 1 to 2, wherein the cannabinoid compound concentration is higher than 5 wt.%, or higher than 10 wt.%, or higher than 20 wt. %4. The method according to any one of claims 1 to 3, wherein the mucosal tissue includes upper airways, or lower airways, wherein the upper airways include sinonasal cavity and trachea, and the lower airways include bronchi.

5. The method according to any one of claims 1 to 4, wherein the inflammatory condition is chronic rhinosinusitis (CRS) without polyps.

6. The method according to any one of claims 1 to 4, wherein the inflammatory condition is chronic rhinosinusitis (CRS) or allergic rhinitis.

7. The method according to any one of claims 1 to 4, wherein the inflammatory condition is asthma.

8. The method according to any one of claims 1 to 7, wherein the cannabinoid is one or more of cannabidiol (CBD), cannabichromene (CBC), cannabigerolic acid (CBGa), tetrahydrocannabinol (THC), cannabigerol (CBG), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethylether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), Cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarinic acid (THCVA), in their purified isolate form or in mixtures with other phytochemicals.

9. The method of claim 2, compound wherein the microemulsion has a minimum hydrophilic linker to lecithin molar ratio of 9: 1.

10. The method according to any one of claims 2 to 9, wherein the uncharged hydrophilic linker comprises one or more of C6-C10 esters of polyhydric alcohols, polyvinyl alcohol, polyglycerols and their co-polymers with a degree of polymerization (n) higher than 2, sucrose, maltose, oligosaccharides, polyglucosides with n higher than 2, sorbitol, sorbitan, C6-C10 alkyl aminopropionic acids, betaines, sulfobetaines, phosphatidylcholines or mixtures thereof.

11. The method according to any one of claims 2 to 10, wherein the microemulsion further comprises of up to 80 wt% water or an electrolyte solution.

12. The method according to any one of claims 1 to 10, wherein the microemulsion is a dilutable microemulsion.

13. The method according to any one of claims 2 to 12, wherein the microemulsion further comprises of up to 60 wt% of a carrier or solvent oil, wherein the carrier oil comprises of alkyl esters of fatty acids, monoglycerides, diglycerides, alkanes, terpenes, or mixtures thereof, having a molecular weight of 400 g / mol or lower.

14. The method according to any one of claims 2 to 12, wherein the microemulsion is free of a carrier or solvent oil.

15. The method according to any one of claims 2 to 14, wherein the microemulsion further comprises a therapeutic active ingredient, wherein the therapeutic active ingredient includes antibiotics, glucocorticoids, vitamin A, vitamin E, vitamin C, hyaluronic acid, Coenzyme Q10, or mixtures thereof.

16. The method according to any one of claims 1 to 14, wherein the microemulsion is free of corticosteroids.

17. The method according to any one of claims 1 to 16, wherein the microemulsion is formulated such that contact time of the microemulsion with the mucosal tissue is less than 10 minutes.

18. The method according to any one of claims 1 to 17, wherein the microemulsion is delivered to the subject's mucosal tissue of the airways by an inhalation device, by flushing, or by spraying.

19. A use of a microemulsion in the treatment of inflammation of airway mucosal tissue in a subject, the microemulsion comprising a cannabinoid compound, and wherein the microemulsion when in a diluted form has a viscosity of 15cP or less, a surface tension of 45 mN / m or less and a hydrodynamic radius of 100 nm or less.

20. The use of claim 19, wherein the microemulsion comprises: (a) the cannabinoid compound, (b) a lecithin having a net zero charge with 12 or more carbons in the tail group, and (c) an uncharged hydrophilic linker with 6 to 10 carbons in its tail group.

21. The use according to any one of claims 19 to 20, wherein the cannabinoid compound concentration is higher than 5 wt.%, or higher than 10 wt.%, or higher than 20 wt. %.

22. A microemulsion for use in the treatment of inflammation of airway mucosal tissue in a subject, the microemulsion comprising a cannabinoid compound, and wherein the microemulsion when in a diluted form has a viscosity of 15cP or less, a surface tension of 45 mN / m or less and a hydrodynamic radius of 100 nm or less.

23. The microemulsion for use of claim 22, wherein the microemulsion comprises: (a) the cannabinoid compound, (b) a lecithin having a net zero charge with 12 or more carbons in the tail group, and (c) an uncharged hydrophilic linker with 6 to 10 carbons in its tail group.

24. The microemulsion for use according to any one of claims 22 to 23, wherein the cannabinoid compound concentration is higher than 5 wt.%, or higher than 10 wt.%, or higher than 20 wt. %.

25. A use of a microemulsion for the manufacture of a medicament for use in the treatment of inflammation of airway mucosal tissue in a subject, the microemulsion comprising a cannabinoid compound, and wherein the microemulsion when in a diluted form has a viscosity of 15cP or less, a surface tension of 45 mN / m or less and a hydrodynamic radius of 100 nm or less.

26. The use of claim 25, wherein the microemulsion comprises: (a) the cannabinoid compound, (b) a lecithin having a net zero charge with 12 or more carbons in the tail group, and (c) an uncharged hydrophilic linker with 6 to 10 carbons in its tail group.

27. The use according to any one of claims 25 to 26, wherein the cannabinoid compound concentration is higher than 5 wt.%, or higher than 10 wt.%, or higher than 20 wt. %.

28. A kit for treating an inflammatory condition in mucosal tissue of the airways in a subject, the kit comprising (a) a microemulsion comprising a cannabinoid compound, and wherein the microemulsion when in a diluted form has a viscosity of 15cP or less, a surface tension of 45 mN / m or less and a hydrodynamic radius of 100 nm or less; and (b) a device for delivering the microemulsion to the mucosal tissue of the airways of the subj ect, wherein the device delivers the microemulsion in a liquid, spray, or aerosolized form.

29. The kit of claim 28, wherein the microemulsion comprises: (a) the cannabinoid compound, (b) a lecithin having a net zero charge with 12 or more carbons in the tail group, and (c) an uncharged hydrophilic linker with 6 to 10 carbons in its tail group.

30. The kit according to any one of claims 28 to 29, wherein the cannabinoid compound concentration is higher than 5 wt.%, or higher than 10 wt.%, or higher than 20 wt. %.

31. The kit according to any one of claims 28 to 30, wherein the device is a nebulizer or a nasal sprayer.

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