Compositions containing terpene mixtures and methods of use thereof

Abstract

The disclosure relates generally to pharmaceutical compositions, kits, and methods of treating a disease or disorder associated with inhibition of NF-KB by administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising two or more terpenes selected from limonene, a-pinene, linalool, P-caryophyllene, borneol, and 1,8-cineole and a pharmaceutically acceptable carrier.

Description

Attorney Docket No.137030-5001-WO COMPOSITIONS CONTAINING TERPENE MIXTURES AND METHODS OF USE THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional ApplicationSerial No.63 / 550,385 filed on February 6, 2024, the entire disclosure of which is incorporated herein by reference for all purposes. TECHNICAL FIELD

[0002] The disclosure relates generally to pharmaceutical compositions comprising terpenes,kits, and methods of use thereof for inhibiting NF-κB to treat a disease or disorder. BACKGROUND

[0003] Attenuation of NF-κB pathways play roles in the pathology of lung diseases. NF-κBsignaling can occur through two pathways: classical and non-classical. The classical pathway typically involves tumor necrosis factor ^ (TNF-^) leading to phosphorylation of I^B kinases (IKK) which activates N-terminal serine residues on I^B proteins. NF-^B activity leads to dissociation of I^B units, causing NF^B proteins, P65 / P50 heterodimer to transport into the nucleus of effected cells and induce gene expression. An alternative pathway involves cytokines like B-cell activating factor, CD40 ligand binding to its receptor and lymphotoxins. It relies heavily on TNF receptor associated factor (TRAF) proteins and NF-^B inducing kinase (NIK). NF-^B can also be activated through cigarette smoke through ROS production, and through lipopolysaccharides (LPS) through a TLR4 mediated path. NF-^B plays a critical role as a transcription factor regulating immune responses. Upregulation of proinflammatory chemokines, cell adhesion molecules, proteases, and cytokines recruit leukocytes such as neutrophils, macrophages, and eosinophils to inflammation sites. Components of cigarette smoke, such as bioactive LPS, contribute to increased inflammation and progression of chronic obstructive pulmonary disease (COPD). Inflammation as a result of cigarette smoke results in NF-^B-dependent immune cascades that result in acute lung injury and emphysema.

[0004] Despite intense research and development efforts, none of the prior attempts to provide atherapy with the ability to specifically target the NF-κB pathway in cancers and in inflammatory DB1 / 142640384.5 1Attorney Docket No.137030-5001-WO or autoimmune diseases has led to the development of any medicine approved by regulatory authorities. Therefore, there is still an urgent and unmet need for novel and improved therapies targeting the NF-κB pathway for use in therapy, particularly for the therapeutic intervention in respiratory diseases and disorders. SUMMARY

[0005] In aspects, the disclosure provides a method of treating a disease or disorder associatedwith inhibition of NF-κB, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising two or more terpenes selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8-cineole and a pharmaceutically acceptable carrier.

[0006] In aspects, the disclosure provides a pharmaceutical composition for inhibiting NF-κBcomprising two or more terpenes selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8-cineole and a pharmaceutically acceptable carrier.

[0007] In aspects, the disclosure provides a kit comprising: (a) a pharmaceutical composition forinhibiting NF-κB comprising two or more terpenes selected from limonene, α-pinene, linalool, β- caryophyllene, borneol, and 1,8-cineole and a pharmaceutically acceptable carrier; (b) an inhalation or nasal spray device containing the pharmaceutical composition; and (c) instructions for administering a dosage of the pharmaceutical formulation. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Fig. 1 shows the role of CFTR in NF-κB immune response.

[0009] Fig. 2 shows compromised CFTR inducing hyper-inflammation through NF-κB.

[0010] Fig. 3 shows CFTR functional inhibition increases NF-κB activity.

[0011] Fig. 4 shows a classical and non-classical pathway of NF-κB activation.

[0012] Fig. 5 shows NF-κB (top panel), IκB (middle panel) and IKK (bottom panel) genes.ANK: Ankyrin Repeats; CC: coiled-coil; DD: Death Domain; GRR: Glycine-rich region; HLH: Helix-Loop-Helix; LZ: Leucine-zipper; NBD: Nemo Binding Domain; TAD: Transactivation Domain; and ZF: Zinc Finger. DB1 / 142640384.5 2Attorney Docket No.137030-5001-WO

[0013] Fig. 6 shows domain mapping of kinase subunits IKK^ (top) and IKK^ (bottom).

[0014] Fig. 7 shows domain mapping of a NEMO (NF-κB Essential Modulator) molecule.

[0015] Fig. 8 shows structural regions of NEMO with IKK peptide binding locations. ^H:^helix; CC: coiled-coil; LZ: leucine zipper; ZF: zinc finger.

[0016] Fig. 9 shows the domain structure of NEMO.

[0017] Fig. 10 shows sequence motifs of NIK kinase domain constructs.

[0018] Fig. 11 shows sequence motifs of the NIK domain.

[0019] Fig. 12 shows NIK structure and mutations.

[0020] Fig. 13 shows NIK activation.

[0021] Fig. 14 shows NF-κB / REL family structure domains.

[0022] Fig. 15A–Fig. 15E show 2D structures of terpenes. Fig. 15A shows the 2D structure oflimonene [SMILES: CC1=CCC(CC1)C(=C)C]. Fig.15B shows the 2D structure of linalool [SMILES: CC(=CCCC(C)(C=C)O)C]. Fig.15C shows the 2D structure of ^-pinene [SMILES: CC1=CCC2CC1C2(C)C]. Fig.15D shows the 2D structure of beta-caryophyllene [SMILES: CC1=CCCC(=C)C2CC(C2CC1)(C)C]. Fig.15E shows the 2D structure of borneol [SMILES: OC1CC2C(C1(C)CC2)(C)C].

[0023] Fig. 16 shows limonene binding to NEMO / IKK complex (13 residues).

[0024] Fig. 17 shows limonene binding to NF-κB p50 Homodimer (6 residues).

[0025] Fig. 18 shows limonene binding to p65+IκB^ complex (17 residues).

[0026] Fig. 19 shows limonene binding to NEMO CCZ-LZ domain (4 residues).

[0027] Fig. 20 shows limonene binding to NF-κB Inducing Kinase (NIKs) (9 residues).

[0028] Fig. 21 shows linalool binding to NEMO-CCZ-LZ domain (5 residues).

[0029] Fig. 22 shows linalool binding to NEMO / IKK complex (18 residues).

[0030] Fig. 23 shows linalool binding to p65+ IκB^ complex (18 residues).DB1 / 142640384.5 3Attorney Docket No.137030-5001-WO

[0031] Fig. 24 shows linalool binding to NF-κB Inducing Kinase (NIKs) (11 residues).

[0032] Fig. 25 shows ^-pinene binding to NEMO / IKK complex binding (14 residues).

[0033] Fig. 26 shows ^-pinene binding to p65+ IκB^ complex (16 residues).

[0034] Fig. 27 shows ^-pinene binding to p50 homodimer (7 residues).

[0035] Fig. 28 shows ^-pinene binding to NF-κB Inducing Kinase (NIKs) (9 residues).

[0036] Fig. 29 shows β-caryophyllene binding to NEMO / IKK (19 residues).

[0037] Fig. 30 shows β-caryophyllene binding NEMO CC2-LZ (4 residues).

[0038] Fig. 31 shows β-caryophyllene binding to NF-κB Inducing Kinase (NIKs) (14 residues).

[0039] Fig. 32 shows β-caryophyllene binding to p65+ IκB^ complex (21 residues).

[0040] Fig. 33 shows β-caryophyllene binding to NF-κB p50 homodimer (5 residues).

[0041] Fig. 34 shows borneol binding to NEMO CC2-LZ domain (3 residues).

[0042] Fig. 35 shows borneol binding NEMO / IKK complex (13 residues).

[0043] Fig. 36 shows borneol binding to NF-κB p50 homodimer (3 residues).

[0044] Fig. 37 shows borneol binding to NF-κB Inducing Kinase (NIKs) (10 residues).

[0045] Fig. 38 shows borneol binding to p65+ IκB^ complex (18 residues).

[0046] Fig. 39 shows 1,8-cineole binding to NEMO / IKK complex (14 residues).

[0047] Fig. 40 shows 1,8-cineole binding to NF-κB p50 homodimer (6 residues).

[0048] Fig. 41 shows 1,8-cineole binding to NF-κB Inducing Kinase (NIKs) (9 residues).

[0049] Fig. 42 shows 1,8-cineole binding to p65+ IκB^ complex (17 residues).DB1 / 142640384.5 4Attorney Docket No.137030-5001-WO DETAILED DESCRIPTION Introduction

[0050] In aspects, the present disclosure provides novel methods and compositions for treatingdiseases or disorders associated with the inhibition of NF-κB comprising two or more terpenes selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and / or 1,8-cineole.

[0051] There are more than 1,000 different mutations in cystic fibrosis (CF) patients’ cysticfibrosis transmembrane conductance regulator (CFTR) gene. These mutations alter production, stability, and functionality of the chloride channel. There are five classes: defective protein processing, defective protein synthesis, disordered regulation, defective chloride conductance, and accelerated channel turnover. Consequence of CFTR mutations result in decreased chloride secretion and resorption of sodium into cellular space, causing increased water retention and thicker mucus secretions on epithelial linings. Organs like the lungs, intestines, and sinuses are some of the most affected systems from resulting mucous plugging. The most frequent mutation in the CFTR gene is ΔF508 – deletion of phenylalanine 508, which causes in degradation of associated endoplasmic reticulum (ERAD). Thick mucus secretions clogging airways combined with compounding bacterial infections lead to lung failure. Analysis of bronchoalveolar fluid (BALF) of patients suffering from cystic fibrosis show elevated levels of neutrophils, proinflammatory cytokines, and chemokines. Cells have been shown to have increased levels of interleukin-8 (IL-8) known to activate nuclear factor kappa light chain enhancer of B-cells (NF- κB). The CFTR gene is an essential component to NF-κB modulation by TNF-^ through its control over TNFR1-associated death domain protein (TRADD), a key adaptor molecule regulating TNF-^.

[0052] Several different cytokines, chemokines and immunoregulatory molecules, such as IL-6,IL-8, CCL11, LKB4, IL-1B, TNF-^ and NF-κB, have all been linked with chronic obstructive lung conditions due to their ability to increase chemotaxis of neutrophils, basophils, eosinophils, and other immune cells that are responsible for inflammation. NF-κB specifically has a significant role in the pathophysiology of cystic fibrosis through exaggerated activation, elevating levels of proinflammatory cytokines initiating IL-8 mediated neutrophilic lung disease. Studies have shown increased NF-κB activation in fetal lungs suffering from CF compared to DB1 / 142640384.5 5Attorney Docket No.137030-5001-WO that of non-CF human fetal lung samples. Suppression of NF-κB has also shown attenuation of lipopolysaccharide (LPS) induced inflammation found in acute lung injuries. Proinflammatory cytokines, such as IL-[x] {x = 1, 1^, 2,4,8,12,15,17,18} mediate NF-^B activation, as does certain viral proteins, T / B-cell mitogens, viruses, exposure to cigarette smoke, and other stresses.

[0053] Suppression of NF-^B has been a target treating for disease pathologies associated withrespiratory diseases such as cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), and pulmonary hypertension (PAH). Inhibition of NF-κB shows protective effects on pulmonary vascular system and prevents development of heart failure in cases of severe pulmonary hypertension with luminal obliteration. In IPF, a progressive fibrotic lung disease, hyperproliferative fibroblasts drives progression of the disease in an undefined mechanism. NF- κB inhibitors decrease fibroblast activity such as proliferation, viability, fibronectin expression, and interleukin (IL)-6 and IL-8 release, indicating NF-κB inhibitors as strong candidates for IPF treatments.

[0054] Terpenes, naturally occurring molecules found in most plant species, have been shown toinhibit NF-^B activation, thereby reducing hyper-inflammatory responses in lung injury models. Different terpenes have varying mechanisms by which they attenuate NF-^B pathways, and other regulators responsible for pulmonary diseases and lung tissue damage. Quantitative Selection and Reasoning (QSAR) analysis, combined with molecular binding software extrapolate how terpene molecules influence assembly factors and complexes responsible for NF-κB signaling cascades such as the NEMO / IKK complex, NF-κB p50 homodimer, P65 / I^B^, NEMO CC2-LZ domain and NIKs.

[0055] In aspects, the present invention provides methods and compositions comprisingcombinations of two or more terpenes (e.g., limonene, α-pinene, linalool, β-caryophyllene, borneol, and / or 1,8-cineole) useful for inhibiting NF-κB, wherein each terpene is capable of binding to a different site on NF-κB to provide inhibition at multiple sites and overall enhanced inhibition compared to the use of one terpene or a combination of terpenes that all bind to the same or similar sites of NF-κB. DB1 / 142640384.5 6Attorney Docket No.137030-5001-WO Definitions

[0056] Unless defined otherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entireties.

[0057] Compounds of the invention also include crystalline and amorphous forms of thosecompounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. “Crystalline form” and “polymorph” are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.

[0058] As used herein, the terms “administer,” “administration,” or “administering” refer to (1)providing, giving, dosing, and / or prescribing by either a health practitioner or his authorized agent or under his or her direction according to the disclosure; and / or (2) putting into, taking or consuming by the mammal, according to the disclosure.

[0059] The term “effective amount” or “therapeutically effective amount” refers to that amountof a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age, and gender of the subject), the severity of the disease condition, the manner of administration, etc., which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that induces a particular response in target cells. The specific dose varies depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0060] A “therapeutic effect” as that term is used herein, encompasses a therapeutic benefitand / or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the DB1 / 142640384.5 7Attorney Docket No.137030-5001-WO appearance of a disease or condition, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0061] As used herein, the terms “treat,” “treatment,” and / or “treating” may refer to themanagement of a disease, disorder, or pathological condition, or symptom thereof with the intent to cure, ameliorate, stabilize, and / or control the disease, disorder, pathological condition, or symptom thereof. Regarding control of the disease, disorder, or pathological condition more specifically, “control” may include the absence of condition progression, as assessed by the response to the methods recited herein, where such response may be complete (e.g., placing the disease in remission) or partial (e.g., lessening or ameliorating any symptoms associated with the condition). As used herein, the terms “prevent,” “preventing,” and / or “prevention” may refer to reducing the risk of developing a disease, disorder, or pathological condition.

[0062] The term “in vivo” refers to an event that takes place in a subject’s body.

[0063] The term “in vitro” refers to an event that takes places outside of a subject’s body. Invitro assays encompass cell-based assays in which cells alive or dead are employed and may also encompass a cell-free assay in which no intact cells are employed.

[0064] The terms “subject” and “patient” are used interchangeably herein to refer to a warm-blooded animal such as a mammal, preferably a human, or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and / or conditions described herein.

[0065] “Pharmaceutically acceptable” refers to those compounds, materials, compositions,and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and non-human animals without excessive toxicity, irritation, allergic response, or other adverse complications commensurate with a reasonable benefit / risk ratio.

[0066] “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or“physiologically compatible” carrier or carrier medium is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or DB1 / 142640384.5 8Attorney Docket No.137030-5001-WO pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient(s), its use in the therapeutic compositions of the disclosure is contemplated.

[0067] For the avoidance of doubt, it is intended herein that particular features (for exampleintegers, characteristics, values, uses, formulae, compounds, or groups) described in conjunction with a particular aspect, embodiment or example of the invention are to be understood as applicable to any other aspect, embodiment or example described herein unless incompatible therewith. Thus, such features may be used where appropriate in conjunction with any of the definition, claims or embodiments defined herein. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of the features and / or steps are mutually exclusive. The invention is not restricted to any details of any disclosed embodiments. The invention extends to any novel one, or novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0068] When ranges are used herein to describe, for example, physical or chemical propertiessuch as, molecular weight, chemical formulae, molar ratios, etc., all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. As used herein, the terms “about” and “around,” and the like, are used herein to modify a numerical value and indicate a defined range around that value. Use of the term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary. Without wishing to be bound to any particular value, the variation can be from 0% to 15%, from 0% to 10%, or from 0% to 5% of the stated number or numerical range. For example, if “X” is the value, “about X” or “around X” generally indicates, without limitation, a value from 0.90X to 1.10X. In some embodiments, a reference to “about X” indicates, without limitation, at least the values X, 0.90X, 0.91X, 0.92X, 0.93X, 0.94X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.0lX, l.02X, 1.03X, l.04X, 1.05X, l.06X, 1.07X, DB1 / 142640384.5 9Attorney Docket No.137030-5001-WO l.08X, l.09X, and 1.10X. Thus, “about X” is intended to disclose, e.g., “0.98X.” In some embodiments, when “about” is applied to the beginning of a numerical range, it applies to both ends of the range. For example, “from about 6 to 8.5” is equivalent to “from about 6 to about 8.5.” In some embodiments, when “about” is applied to the first value of a set of values, it applies to all values in that set. For example, “about 7, 9, or 11%” is equivalent to “about 7%, about 9%, or about 11%.”

[0069] The transitional terms “comprising”, “consisting essentially of” and “consisting of”,when used in the appended claims, in original and amended form, define the claim scope with respect to what unrecited additional claim elements or steps, if any, are excluded from the scope of the claim(s). The term “comprising” is intended to be inclusive or open-ended and does not exclude any additional, unrecited element, method, step, or material. The term “consisting of” excludes any element, step, or material other than those specified in the claim and, in the latter instance, impurities ordinary associated with the specified material(s). The term “consisting essentially of” limits the scope of a claim to the specified elements, steps, or material(s) and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. All embodiments of the invention can, in the alternative, be more specifically defined by any of the transitional terms “comprising,” “consisting essentially of,” and “consisting of.” Compositions

[0070] In aspects, the disclosure provides compositions (e.g., pharmaceutical compositions)useful for inhibiting NF-κB. In some embodiments, the compositions are pharmaceutical compositions, further comprising a pharmaceutically acceptable carrier.

[0071] In embodiments, the compositions (e.g., pharmaceutical compositions) described hereincomprise two or more terpenes, for example, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 terpenes. In embodiments, the composition comprises from about 2 to about 10, from about 3 to about 10, from about 4 to about 10, from about 5 to about 10, from about 2 to about 9, from about 2 to about 8, from about 2 to about 7, from about 2 to about 6, from about 2 to about 5, or from about 2 to about 4 terpenes. In embodiments, the composition comprises about two or more terpenes, about three or more terpenes, about four or more terpenes, about five or more terpenes, or about six or more terpenes. DB1 / 142640384.5 10Attorney Docket No.137030-5001-WO

[0072] In embodiments, the compositions (e.g., pharmaceutical compositions) described hereincomprise any suitable terpene, including terpenoids and derivatives thereof. In embodiments, the terpene is a monoterpene, a sesquiterpene, a diterpene, a sesterterpene, a triterpene, a tetraterpene, a polyterpene, or a meroterpene. In embodiments, the terpene is naturally occurring. In embodiments, the terpene is synthetic. Non-limiting examples of terpenes include, but are not limited to, limonene, α-pinene, linalool, β-caryophyllene, borneol, 1,8-cineole, terpineol-4-ol, p-cymene, 3-carene, humulene, myrcene, α-phellandrene, pulegone, and camphor.

[0073] In embodiments, the two or more terpenes are selected from limonene, α-pinene, linalool,β-caryophyllene, borneol, and 1,8-cineole. In embodiments, the composition comprises limonene. In embodiments, the composition comprises α-pinene. In embodiments, the composition comprises linalool. In embodiments, the composition comprises β-caryophyllene. In embodiments, the composition comprises borneol. In embodiments, the composition comprises 1,8-cineole.

[0074] In embodiments, two or more terpenes are selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8-cineole. In embodiments, three or more terpenes are selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8-cineole. In embodiments, four or more terpenes are selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8-cineole. In embodiments, five or more terpenes are selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8-cineole. In embodiments, composition comprises and / or consists of limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8-cineole.

[0075] In embodiments, the compositions (e.g., pharmaceutical compositions) described hereincomprise from about 0.1 ng to about 10 mg independently of each of the two or more terpenes, for example, from about 0.1 ng to about 1 mg, from about 0.1 ng to about 0.1 mg, from about 0.1 ng to about 10 μg, from about 0.1 ng to about 1 μg, from about 0.1 ng to about 0.1 μg, from about 0.1 μg to about 10 mg, from about 0.1 μg to about 1 mg, from about 0.1 μg to about 0.1 mg, from about 0.1 μg to about 10 μg, from about 1 μg to about 10 mg, from about 1 μg to about 1 mg, from about 1 μg to about 0.1 mg, from about 1 μg to about 10 μg, from about 10 μg to about 10 mg, from about 10 μg to about 1 mg, or from about 10 μg to about 0.1 mg independently of each of the two or more terpenes. In embodiments, the composition comprises from about 0.1 μg to about 1 mg independently of each of the two or more terpenes. DB1 / 142640384.5 11Attorney Docket No.137030-5001-WO

[0076] In embodiments, the compositions (e.g., pharmaceutical compositions) described hereincomprise from about 0.1 ng to about 10 mg of the two or more terpenes, for example, from about 0.1 ng to about 1 mg, from about 0.1 ng to about 0.1 mg, from about 0.1 ng to about 10 μg, from about 0.1 ng to about 1 μg, from about 0.1 ng to about 0.1 μg, from about 0.1 μg to about 10 mg, from about 0.1 μg to about 1 mg, from about 0.1 μg to about 0.1 mg, from about 0.1 μg to about 10 μg, from about 1 μg to about 10 mg, from about 1 μg to about 1 mg, from about 1 μg to about 0.1 mg, from about 1 μg to about 10 μg, from about 10 μg to about 10 mg, from about 10 μg to about 1 mg, or from about 10 μg to about 0.1 mg of the two or more terpenes.

[0077] In embodiments, the compositions (e.g., pharmaceutical compositions) described hereinare manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. In embodiments, the composition is formulated in conventional manner using a pharmaceutically acceptable carriers which facilitates processing of the two or more terpenes into preparations which can be used pharmaceutically. A specific formulation method will be dependent upon the route of administration chosen.

[0078] In embodiments, the compositions (e.g., pharmaceutical compositions) described hereinare formulated for oral, topical, subcutaneous, intravenous, inhalation, or intranasal administration. In embodiments, the composition is formulated for intranasal administration. In embodiments, the composition is formulated for inhalation. In embodiments, the composition is formatted as an aerosol precursor. In embodiments, the composition is within a component of an inhalation or nasal spray device, e.g., a nebulizer device.

[0079] In embodiments, the compositions (e.g., pharmaceutical compositions) described hereincomprise a pharmaceutically acceptable carrier. In embodiments, the pharmaceutically acceptable carrier comprises one or more components selected from a diluent, a binder, an adhesive, a disintegrant, a lubricant, an antiadherent, a glidant, a sweetener, a flavorant, a colorant, a coating, a wetting agent, a dispersant, a flocculation agent, a thickener, a buffer, an emulsifier, an amphiphilic, an osmotic agent, a coloring agent, an anti-oxidant, a flavor, a fragrance, and a preservative.

[0080] In embodiments, the pharmaceutically acceptable carrier comprises an emulsifier. Non-limiting examples of emulsifiers include, but are not limited to, alkyl poly(ethylene oxide), DB1 / 142640384.5 12Attorney Docket No.137030-5001-WO alkylphenol poly(ethylene oxide), copolymers of poly(ethylene oxide) and poly(propylene oxide) (i.e., Poloxamers or Poloxamines), alkyl polyglucosides (e.g., octyl glucoside), decyl maltoside, fatty alcohols (e.g., cetyl alcohol and oleyl alcohol), cocamide MEA, cocamide DEA, polysorbates (e.g., Tween 20 / polysorbate 20, Tween 80 / polysorbate 80), Triton detergents, Tyloxapol, Pluronic acid (e.g., Pluronic F-127), and dodecyl dimethylamine oxide, Cremophor 40, and poly(lactic-co-glycolic acid) (PLGA). In embodiments, the emulsifier is selected from Cremophor 40, polysorbate 80, Pluronic F-127, and poly(lactic-co-glycolic acid) (PLGA). In embodiments, the emulsifier comprises Cremophor 40. In embodiments, the emulsifier comprises polysorbate 80. In embodiments, the emulsifier comprises Pluronic F-127. In embodiments, the emulsifier comprises poly(lactic-co-glycolic acid) (PLGA).

[0081] In embodiments, the pharmaceutically acceptable carrier comprises an aqueous solution.In embodiments, the aqueous solution comprises a salt (e.g., sodium chloride, potassium chloride) and / or a sugar (e.g., dextrose, sucrose). In embodiments, the aqueous solution is saline. In embodiments, the aqueous solution is hypertonic saline (i.e., >0.9% saline). In embodiments, the saline comprises from about 0.1 to about 25% saline, for example, about 0.1%, about 0.2%, about 0.25%, about 0.45%, about 0.5%, about 0.9%, about 1%, about 1.5%, about 1.7%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 7.5%, about 8%, about 9%, about 10%, about 15%, about 20%, about 23.4%, or about 25% saline. In embodiments, the saline is from about 0.1% to about 25%, from about 0.1% to about 20%, from about 0.1% to about 15%, from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 1%, from about 1% to about 25%, from about 1% to about 20%, from about 1% to about 15%, from about 1% to about 10%, or from about 1% to about 5% saline. In a non-limiting embodiment, the saline is 7% hypertonic saline. In embodiments, the saline comprises about 0.1% to about 7% saline.

[0082] In embodiments, the two or more terpenes are encapsulated in a carrier, for example, apolymeric micelle, an exosome, a liposome, a nanosphere, a nanocapsule, or a nanoemulsion. In embodiments, the carrier is a polymeric micelle. In embodiments, the carrier is an exosome. In embodiments, the carrier is a liposome. In embodiments, the carrier is a nanosphere. In embodiments, the carrier is a nanocapsule. In embodiments, the carrier is a nanoemulsion. DB1 / 142640384.5 13Attorney Docket No.137030-5001-WO

[0083] Polymeric micelles are typically formed by block copolymers (e.g., diblock copolymers,triblock copolymers). In embodiments, the polymeric micelles comprise any suitable block copolymers including, but not limited to, poly(ethylene glycol)-poly(γ-benzyl l-glutamate), poly(ethylene glycol)-poly(d,l-lactic acid), poly(ethylene glycol)-poly(l-lactic acid), poly(ethylene glycol)-poly(ε-caprolactone), poly(ethylene glycol)-poly(d,l-lactide-co-glycolide), poly(ethylene glycol)-poly(γ-benzyl l-glutamate), poly(ethylene glycol)-poly(β-benzyl l- aspartate), poly(ethylene glycol)-poly(α-benzyl carboxylate-ε-caprolactone), and poly(ethylene glycol)-poly(δ-valerolactone).

[0084] In embodiments, the compositions (e.g., pharmaceutical compositions) described hereindo not include a steroid. Non-limiting examples of steroids include steroids used in medicaments, such as cortisone, prednisone, and methylprednisolone. Methods of Treatment

[0085] In aspects, the disclosure provides a method of treating a disease or disorder associatedwith inhibition of NF-κB. In embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein comprising two or more terpenes. In embodiments, the two or more terpenes are selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8-cineole and a pharmaceutically acceptable carrier.

[0086] In embodiments, any disease or disorder associated with inhibition of NF-κB is treated bythe methods described herein. In embodiments, the disease or disorder is a respiratory disease or disorder. Non-limiting examples of the respiratory disease or disorder include, but are not limited to, cystic fibrosis (CF), pulmonary fibrosis (including idiopathic pulmonary fibrosis (IPF)), pulmonary hypertension (PAH), chronic obstructive pulmonary disease (COPD) (including emphysema), asthma (including allergic asthma), chronic bronchitis, lung cancer, pneumonia, pleural effusion, bronchiectasis, acute respiratory distress syndrome, silicosis, COVID-19, atherosclerosis, and pulmonary hypertension. In embodiments, the respiratory disease or disorder is cystic fibrosis (CF). In embodiments, the respiratory disease or disorder is idiopathic pulmonary fibrosis (IPF). In embodiments, the respiratory disease or disorder is pulmonary hypertension (PAH). In embodiments, the respiratory disease or disorder is chronic obstructive pulmonary disease (COPD). DB1 / 142640384.5 14Attorney Docket No.137030-5001-WO

[0087] In embodiments, any subject may benefit from the method of treatment described herein.In embodiments, the subject has a disease or disorder associated with inhibition of NF-κB. In embodiments, the subject has a respiratory disease or disorder (e.g., cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PAH), or chronic obstructive pulmonary disease (COPD)). In embodiments, the subject has lung tissue damage.

[0088] In embodiments, any route of administration may be employed in the method describedherein. In embodiments, the administration is oral, topical, subcutaneous, intravenous, inhalation, or intranasal administration. In embodiments, the administration is inhalation. In embodiments, the administration is intranasal. In embodiments, the administration is intranasal administration of an aerosol of the pharmaceutical composition. In embodiments, the administration is topical. In embodiments, the administration is topical administration to mucosa of the respiratory tract.

[0089] The method of administration depends on the route of administration. In embodiments,the pharmaceutical composition is administered using an inhalation or nasal spray device. In embodiments, the inhalation or nasal spray device is a nebulizer device.

[0090] In embodiments, the pharmaceutical composition is administered in a dosage of fromabout 0.1 mg / kg to about 0.1 g / kg independently of each of the two or more terpenes, for example, from about 0.1 mg / kg to about 10 mg / kg, from about 1 mg / kg to about 10 mg / kg, or from about 2.5 mg / kg to about 10 mg / kg independently of each of the two or more terpenes. In embodiments, the pharmaceutical composition is administered in a dosage of from about 2.5 mg / kg to about 10 mg / kg independently of each of the two or more terpenes. Complexes of NF-κB

[0091] In aspects, the combinations of terpenes of the compositions described herein (e.g., twoor more terpenes selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8- cineole) provide interactions with NF-κB at multiple sites, which increases inhibition of NF-κB compared to terpenes and / or combinations of terpenes that bind to NF-κB at a single site. In embodiments, compositions (e.g., pharmaceutical compositions) of the disclosure comprising two or more terpenes selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8-cineole increase inhibition of NF-κB by about 1-fold, about 2-fold, about 5-fold, about 10- DB1 / 142640384.5 15Attorney Docket No.137030-5001-WO fold, about 50-fold, about 100-fold, about 200-fold, about 500-fold, about 1000-fold, or greater than about 1000-fold compared to other terpenes and / or other combinations of terpenes.

[0092] In embodiments, the terpenes disclosed herein interact with one or more molecules (e.g.complexes, domains, kinases) associated with NF-κB inhibition. Non-limiting examples of molecules associated with NF-κB inhibition include the NEMO / IKK Complex, P65 / IκB^, NEMO CC2-LZ, and NF-κB Inducing Kinases (NIKs). NEMO / IKK Complex Role in NF-κB

[0093] The IKK Kinase Complex, composed of IKK^, IKK^ and NEMO, is a crucialcomponent of NF-κB signaling. In both canonical and non-canonical pathways, this complex is responsible for initiating free NF-κB creation to enter cell nuclei, activating genes that control the immune and inflammatory response. Moreover, cell lines that are defective for NEMO do not activate NF-κB signaling, indicating NEMO is the limiting factor in this pivotal initiation step. Analysis of the sequences of these kinases involved in this complex, IKK^ and IKK^, show remarkable similarity between each other. They both contain a kinase domain located at the N-Terminus with an activation loop at amino acid positions 176-180 for IKK^ and 177-181 for IKK^, followed by a ubiquitin domain (in IKKβ at positions 307-384; not found in IKK^), a leucine zipper, a helix loop helix followed by a NEMO Binding Domain (at position 705-743). In order to activate IKK^ and IKK^, serine residues (SER177, SER181 for IKK^ ; SER176, SER180 for IKK^) need to be phosphorylated through an unclear process.

[0094] The NEMO Molecule sequence from N-Terminus contains a CC1 (Coiled Coil 1domain); CC2 (Coiled Coil 2 domain); NOA (Ubiquitin binding domain); and a ZF (Zinc Finger) domain. Interaction regions defined as an IKK^^ binding domain (40-115), TAX, v-FLIP Domain (194-240) Cytokine / LPS domain from 240-393, with NOA region between followed by a ZF Domain from 393-419. P65 / IκB^ Role in NF-κB

[0095] IκB^ as well as IκB^ bind to NF-κB homo / heterodimers (p65; p50) to maintainregulation of NF-κB pathway when varying inducing signals phosphorylate and proteasome- mediated degradation of the IκB proteins, releasing free NF-κB to modulate target gene DB1 / 142640384.5 16Attorney Docket No.137030-5001-WO transcriptions. Where IκB^ results in fast NF-κB activation due to its rapid degradation and resynthesis of NF-κB, IκB^ results in slower NF-κB induction due to a slower degradation rate. Limonene acts on specified residue sites of the p65 / IκB^ complex where both subunits establish ion pairing interactions. IκB^ gene sequence is composed of at least two ANK repeats from N- Terminus end followed by a PEST sequence – a peptide sequence rich in proline (P), glutamic acid (E), serine (S) and threonine (T) - at the C-Terminal. Most interactions between IκB^ and the p65 homodimer occur between the ANK repeats on IκB^ and the NLS-Containing C- terminal portion of p65 subunit A (NLS-Polypeptide; p65 amino acids 291-319) as well as p65 subunit B. ANK repeats occur in a wide array of proteins and typically fold together form ANK repeat domains. They are responsible for maintaining protein stability and accurate folding configuration. Amino acid sequences show residue positions responsible for establishing intra- repeat interactions on like-residues at similar positions occupied by limonene. NEMO CC2-LZ Domain Role in NF-κB

[0096] The NEMO Molecule is a 419-amino-acid structured based on available data from N-Terminus. CC1 (Coiled Coil 1); CC2 (Coiled Coil 2); NOA (Ubiquitin binding domain); ZF (Zinc Finger). Interaction regions defined as an IKK^^ binding domain (40-115), TAX, v-FLIP Domain (194-240) Cytokine / LPS domain from 240-393, with NOA region between followed by a ZF Domain from 393-419. Residue site binding from limonene indicates influence over Cytokine / LPS domain functionality.

[0097] In other studies, sequencing shows IKK^ bind at residue site positions 54-107 in theCC / HLX1 region, IκB^ binding at residue sites 396-417 in the zinc finger region and di- ubiquitin region at residue positions ~250-350. The di-ubiquitin region is responsible for ubiquitination of the NEMO molecule, a critical function in the synthesis of free NF-κB. Limonene interactions within this region indicate potential for causing disruption within this process.

[0098] Zinc fingers are a finger-shaped fold in a protein that permits it to interact with nucleicacid sequences such as DNA and RNA. Such a fold is well known in the art. The fold is created by the binding of specific amino acids in the protein to a zinc atom. Zinc-finger containing DB1 / 142640384.5 17Attorney Docket No.137030-5001-WO proteins (also known as ZF proteins) can regulate the expression of genes as well as nucleic acid recognition, reverse transcription, and virus assembly. NIKs Role in NF-κB

[0099] NF-κB Inducing Kinase is a significant factor in the non-canonical pathway of NF-κBthrough activation of IKK^. Activated IKK^ phosphorylates p100 / NF-κB2 which goes on to activate NF-κB regulated gene activation. NIKs is the upstream kinase for IKK^ and is activated by TNF-Beta related cytokines such as CD40 ligand, lymphotoxin (^ and ^). NIKs hyperactivation appears to be the major cause for NF-κB dysregulation in multiple myeloma. With 947 amino acids in its sequence, its sequence contains a TRAF3-binding domain from the N-terminal end at residue locations 121-318, a negative regulatory domain at residue locations 121-318 – composed of a basic region / leucine zipper (residue location ~121-146), and a proline rich repeat (residue location ~250 – 318), a serine / threonine kinase domain responsible at residue location 390-660, and a non-catalytic region from residue location 660 – 947 responsible for interactions between many factors including: p100 binding, IKKα binding & TRAF[1,2,5,6] binding.

[0100] NIKs are held inactive by a complex comprised of TNF receptor associated factor 3 and 2(TRAF3, TRAF2) and CARD-like apoptotic proteins (cLAPs), which get their name from their N-terminal capase recruitment domains (CARD) and their C-terminal domains (CTD). When TRAF2 binds to a receptor from stimuli, such as lymphotoxin alpha / beta or LPS, cIAPs initiates TRAF3 ubiquitination, thereby releasing free NIK. NIK is held in the complex by binding to TRAF3, which is found N-terminus at residue sites ~121-318. Limonene binding occurs on residue sites further downstream, where NIK binding domains to IKKα, IKK^, TRAF [1, 2, 5 and 6] are found. While not wishing to be bound by theory, it appears that limonene is not acting on NIK activation steps, but rather eliminates NIKs ability to form downstream complexes related to NF-κB activation, mainly, the binding of NIK to IKKα initiating the non-canonical pathway.

[0101] In embodiments, limonene interacts with at least residue sites:(i) ASN714, LEU715, THR717, LEU718, LEU719, ALA722, ASN69, LEU72, ARG73, GLU74, CYS76, GLU77, and / or LEU80 of a NEMO / IKK complex; DB1 / 142640384.5 18Attorney Docket No.137030-5001-WO (ii) TYR57, VAL58, CYS59, GLU60, GLY61 and / or LEU140 of a NF-κB p50 homodimer; (iii) SER203, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, LEU133, ARG136, GLU203, ASN204, THR205, ASP206, GLY207, and / or HIS208 of a p65 / IκB^ complex; (iv) ASP306, LYS309, GLN304, and / or TYR308 of a NEMO CC2-LZ domain of NEMO; and / or (v) PRO488, ASP490, LEU655, VAL658, GLY659, GLY660, LEU661, LYS661, LYS662, and / or SER663 of a NF-κB Inducing Kinase (NIK).

[0102] In embodiments, limonene binding activity may indicate molecular interactions at residuesites within / very close range to NEMO Binding domains on IKK^;IKK^ [717-722]; with molecular interactions at residue sites within / very close range to IKK^;IKK^ binding sites on NEMO [69-80], which may point to an interaction within the binding regions between all three subunits of the IKK Kinase Complex.

[0103] In embodiments, limonene interacts with at least residue sites on the NEMO / IKKComplex of the NF-κB Pathway at residue sites ASN714, LEU715, THR717, LEU718, LEU719, ALA722, ASN69, LEU72, ARG73, GLU74, CYS76, GLU77 and LEU80.

[0104] In embodiments, limonene interacts with and / or acts on the NF-κB p50 Homodimer ofNF-κB at residue sites TYR57, VAL58, CYS59, GLU60, GLY61 and LEU140.

[0105] In embodiments, limonene interacts with and / or acts on the p65 / IκB^ Complex of theNF-κB Pathway at residue sites SER203, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, LEU133, ARG136, GLU203, ASN204, THR205, ASP206, GLY207, and HIS208.

[0106] In embodiments, limonene interacts with and / or acts on the NEMO CC2-LZ Domain ofNEMO (NF-κB Essential Modulator) of the NF-κB Pathway at residue sites ASP306, LYS309, GLN304, and TYR308. DB1 / 142640384.5 19Attorney Docket No.137030-5001-WO

[0107] In embodiments, limonene interacts with and / or acts on NIKs (NF-κB Inducing Kinase)of the NF-κB Pathway at residue sites PRO488, ASP490, LEU655, VAL658, GLY659, GLY660, LEU661, LYS661, LYS662, and SER663.

[0108] In embodiments, linalool interacts with at least residue sites:(i) LYS302, ASP306, LYS309, GLN304, and / or TYR308 of a NEMO CCZ-LZ domain of NEMO; (ii) GLU711, ALA712, HIS713, ASN714, LEU715, CYS716, THR717, LEU718, LEU719, GLU720, ALA722, ASN69, LEU72, ARG73, GLU74, CYS76, GLU77, and / or LEU80 of a NEMO / IKK complex; (iii) ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, ARG136, ALA202, GLU203, ASN204, TYR205, ASP206, GLY207, HIS208, THR209, and / or VAL213 of a p65 / IkB^ complex; and / or (iv) PRO488, GLU489, ASP490, ARG491, LEU655, VAL658, GLY659, GLY660, LEU661, LYS662, and / or SER663 of a NF-κB Inducing Kinase (NIK).

[0109] In embodiments, linalool interacts with and / or acts on the NEMO CCZ-LZ Domain ofNEMO (NF-κB Essential Modulator) of the NF-κB Pathway at residue sites LYS302, ASP306, LYS309, GLN304, and TYR308.

[0110] In embodiments, linalool interacts with and / or acts on the NEMO / IKK Complex of theNF-κB Pathway at residue sites GLU711, ALA712, HIS713, ASN714, LEU715, CYS716, THR717, LEU718, LEU719, GLU720, ALA722, ASN69, LEU72, ARG73, GLU74, CYS76, GLU77, and LEU80.

[0111] In embodiments, linalool interacts with and / or acts on the p65 / IκB^ Complex of the NF-κB Pathway at residue sites ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, ARG136, ALA202, GLU203, ASN204, TYR205, ASP206, GLY207, HIS208, THR209, and VAL213.

[0112] In embodiments, linalool interacts with and / or acts on NIKs (NF-κB Inducing Kinase) ofthe NF-κB Pathway at residue sites PRO488, GLU489, ASP490, ARG491, LEU655, VAL658, GLY659, GLY660, LEU661, LYS662, and SER663. DB1 / 142640384.5 20Attorney Docket No.137030-5001-WO

[0113] In embodiments, ^-pinene interacts with at least residue sites:(i) ASN714, LEU715, LEU718, LEU719, ALA722, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, GLU78, LEU79, and / or LEU80 of a NEMO / IKK complex; (ii) SER203, LEU289, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, ARG136, GLU203, ASN204, TYR205, ASP206, GLY207, and / or HIS208 of a p65+ IκB^ complex; (iii) TYR57, VAL58, CYS59, GLU60, GLY61, PRO62, and / or LEU140 of a NF-κB p50 homodimer; and / or (iv) PRO488, ASP490, VAL658, GLY659, GLY660, LEU661, LYS662, SER663, and / or PRO664 of a NF-κB Inducing Kinase (NIK).

[0114] In embodiments, ^-pinene interacts with and / or acts on the NEMO / IKK Complex of theNF-κB Pathway at residue sites ASN714, LEU715, LEU718, LEU719, ALA722, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, GLU78, LEU79, and LEU80.

[0115] In embodiments, ^-pinene interacts with and / or acts on the p65+ IκB^ Complex of theNF-κB Pathway at residue sites SER203, LEU289, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, ARG136, GLU203, ASN204, TYR205, ASP206, GLY207, and HIS208.

[0116] In embodiments, ^-pinene interacts with and / or acts on the p50 Homodimer of the NF-κB Pathway at residue sites TYR57, VAL58, CYS59, GLU60, GLY61, PRO62, and LEU140.

[0117] In embodiments, ^-pinene interacts with and / or acts on the NF-κB Inducing Kinase(NIKs) of the NF-κB Pathway at residue sites PRO488, ASP490, VAL658, GLY659, GLY660, LEU661, LYS662, SER663, and PRO664.

[0118] In embodiments, β-caryophyllene interacts with at least residue sites:(i) ALA710, GLU711, ALA712, HIS713, ASN714, LEU715, CYS716, THR717, LEU718, LEU719, ALA722, ASN69, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, and / or LEU80 of a NEMO / IKK complex; DB1 / 142640384.5 21Attorney Docket No.137030-5001-WO (ii) SER203, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, ARG136, ALA202, GLU203, ASN204, TYR205, ASP206, GLY207, HIS208, THR209, PRO210, HIS212, and / or VAL213 of a p65+ IκB^ complex; (iii) PRO488, GLU489, ASP490, LEU493, ALA654, GLN657, VAL658, GLY659, GLY660, LEU661, LYS662, SER663, and PRO664 of a NF-κB Inducing Kinase (NIK); (iv) ASP306, LYS309, GLN304, and / or TYR308 of a NEMO CC2-LZ domain; and / or (v) TYR57, VAL58, CYS59, GLY61, and / or LEU140 of a NF-κB p50 homodimer.

[0119] In embodiments, β-caryophyllene interacts with and / or acts on the NEMO / IKK Complexof the NF-κB Pathway at residue sites ALA710, GLU711, ALA712, HIS713, ASN714, LEU715, CYS716, THR717, LEU718, LEU719, ALA722, ASN69, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, and LEU80.

[0120] In embodiments, β-caryophyllene interacts with and / or acts on the p65+ IκB^ Complexof the NF-κB Pathway at residue sites SER203, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, ARG136, ALA202, GLU203, ASN204, TYR205, ASP206, GLY207, HIS208, THR209, PRO210, HIS212, and VAL213.

[0121] In embodiments, β-caryophyllene interacts with and / or acts on the NIKs (NF-κBInducing Kinase) of the NF-κB Pathway at residues sites PRO488, GLU489, ASP490, LEU493, ALA654, GLN657, VAL658, GLY659, GLY660, LEU661, LYS662, SER663, and PRO664.

[0122] In embodiments, β-caryophyllene interacts with and / or acts on the NEMO CC2-LZDomain of the NF-κB Pathway at residue sites ASP306, LYS309, GLN304, and TYR308.

[0123] In embodiments, β-caryophyllene interacts with and / or acts on the NF-κB p50homodimer of the NF-κB Pathway at residue sites TYR57, VAL58, CYS59, GLY61, and LEU140.

[0124] In embodiments, borneol interacts with at least residue sites:(i) LYS309, GLN304, and / or TYR308 of a NEMO CC2-LZ domain; (ii) VAL58, CYS59, and / or GLY61 of a NF-κB p50 homodimer; DB1 / 142640384.5 22Attorney Docket No.137030-5001-WO (iii) ASN714, LEU715, CYS716, LEU718, LEU719, ASN69, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, and / or LEU80 of a NF-κB Inducing Kinase (NIK); (iv) SER203, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, LEU133, ARG136, GLU203, ASN204, TYR205, ASP206, GLY207, HIS208, and / or VAL213 of a p65+ IκB^ complex; and / or (v) ASN714, LEU715, CYS716, LEU718, LEU719, ASN69, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, and / or LEU80 of a NEMO / IKK complex.

[0125] In embodiments, borneol interacts with and / or acts on the NEMO CC2-LZ Domain of theNF-κB Pathway at residue sites LYS309, GLN304, and TYR308.

[0126] In embodiments, borneol interacts with and / or acts on the NF-κB p50 homodimer of theNF-κB Pathway at residue sites VAL58, CYS59, and GLY61.

[0127] In embodiments, borneol interacts with and / or acts on the NIKs (NF-κB Inducing Kinase)of the NF-κB Pathway at residues sites ASN714, LEU715, CYS716, LEU718, LEU719, ASN69, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, and LEU80.

[0128] In embodiments, borneol interacts with and / or acts on the p65+ IκB^ Complex of the NF-κB Pathway at residue sites SER203, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, LEU133, ARG136, GLU203, ASN204, TYR205, ASP206, GLY207, HIS208, and VAL213.

[0129] In embodiments, borneol interacts with and / or acts on the NEMO / IKK Complex of theNF-κB Pathway at residue sites ASN714, LEU715, CYS716, LEU718, LEU719, ASN69, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, and LEU80.

[0130] In embodiments, 1,8-cineole interacts with at least residue sites:(i) VAL58, CYS59, and / or GLY61 of a NF-κB p50 homodimer; (ii) PRO488, ASP490, VAL658, GLY659, GLY660, LEU661, LYS662, SER663, and / or PRO664 of a NF-κB Inducing Kinase (NIK); DB1 / 142640384.5 23Attorney Docket No.137030-5001-WO (iii) LEU93, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, LEU133, ARG136, GLU203, ASN204, TYR205, ASP206, GLY207, and / or HIS208 of a p65+ IκB^ complex; and / or (iv) ASN714, LEU715, THR717, LEU718, LEU719, ALA722, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, GLU78, and / or LEU80 of a NEMO / IKK complex.

[0131] In embodiments, 1,8-cineole interacts with and / or acts on the NF-κB p50 homodimer ofthe NF-κB Pathway at residue sites VAL58, CYS59, and GLY61.

[0132] In embodiments, 1,8-cineole interacts with and / or acts on the NIKs (NF-κB InducingKinase) of the NF-κB Pathway at residues sites PRO488, ASP490, VAL658, GLY659, GLY660, LEU661, LYS662, SER663, and PRO664.

[0133] In embodiments, 1,8-cineole interacts with and / or acts on the p65+ IκB^ Complex of theNF-κB Pathway at residue sites LEU93, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, LEU133, ARG136, GLU203, ASN204, TYR205, ASP206, GLY207, and HIS208.

[0134] In embodiments, 1,8-cineole interacts with and / or acts on the NEMO / IKK Complex ofthe NF-κB Pathway at residue sites ASN714, LEU715, THR717, LEU718, LEU719, ALA722, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, GLU78, and LEU80. Kits

[0135] In aspects, the disclosure provides a kit comprising a pharmaceutical composition asdescribed herein for inhibiting NF-κB; a container and / or device containing the pharmaceutical composition; and instructions for administering a dosage of the pharmaceutical composition. In a non-limiting embodiment, the disclosure provides a kit comprising a pharmaceutical composition as described herein for inhibiting NF-κB comprising two or more terpenes selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8-cineole and a pharmaceutically acceptable carrier; an inhalation or nasal spray device containing the pharmaceutical composition; and instructions for administering a dosage of the pharmaceutical composition. DB1 / 142640384.5 24Attorney Docket No.137030-5001-WO

[0136] In embodiments, the administration is oral, topical, subcutaneous, intravenous, inhalation,or intranasal administration. In embodiments, the administration is inhalation. In embodiments, the administration is intranasal. In embodiments, the administration is intranasal administration of an aerosol of the pharmaceutical composition. In embodiments, the administration is topical. In embodiments, the administration is topical administration to mucosa of the respiratory tract.

[0137] In embodiments, the pharmaceutical composition is administered by the container and / ordevice. In embodiments, the pharmaceutical composition is administered using an inhalation or nasal spray device. In embodiments, the inhalation or nasal spray device is a nebulizer device.

[0138] In embodiments, the kits described herein provide instructions for administering a dosageof the pharmaceutical composition. In embodiments, the dosage comprises from about 0.1 ng to about 10 mg independently of each of the two or more terpenes, for example, from about 0.1 ng to about 1 mg, from about 0.1 ng to about 0.1 mg, from about 0.1 ng to about 10 μg, from about 0.1 ng to about 1 μg, from about 0.1 ng to about 0.1 μg, from about 0.1 μg to about 10 mg, from about 0.1 μg to about 1 mg, from about 0.1 μg to about 0.1 mg, from about 0.1 μg to about 10 μg, from about 1 μg to about 10 mg, from about 1 μg to about 1 mg, from about 1 μg to about 0.1 mg, from about 1 μg to about 10 μg, from about 10 μg to about 10 mg, from about 10 μg to about 1 mg, or from about 10 μg to about 0.1 mg independently of each of the two or more terpenes. In embodiments, the dosage comprises from about 0.1 μg to about 1 mg independently of each of the two or more terpenes.

[0139] In embodiments, the dosage comprises from about 0.1 ng to about 10 mg of the two ormore terpenes, for example, from about 0.1 ng to about 1 mg, from about 0.1 ng to about 0.1 mg, from about 0.1 ng to about 10 μg, from about 0.1 ng to about 1 μg, from about 0.1 ng to about 0.1 μg, from about 0.1 μg to about 10 mg, from about 0.1 μg to about 1 mg, from about 0.1 μg to about 0.1 mg, from about 0.1 μg to about 10 μg, from about 1 μg to about 10 mg, from about 1 μg to about 1 mg, from about 1 μg to about 0.1 mg, from about 1 μg to about 10 μg, from about 10 μg to about 10 mg, from about 0 μg to about 1 mg, or from about 10 μg to about 0.1 mg of the two or more terpenes.

[0140] In embodiments, the instructions are a component of a Dosage and Administrationsection of Complete Prescribing Information. In a non-limiting embodiment, the instructions provide guidance for intranasal administration of a dosage of the pharmaceutical composition. DB1 / 142640384.5 25Attorney Docket No.137030-5001-WO

[0141] Suitable packaging and additional articles for use (e.g., measuring cup for liquidpreparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. Kits described herein can be provided, marketed and / or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in selected embodiments, be marketed directly to the consumer.

[0142] While preferred embodiments of the invention are shown and described herein, suchembodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in practicing the invention. EXAMPLES

[0143] The embodiments encompassed herein are now described with reference to the followingexamples. These examples are provided for the purpose of illustration only and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations which become evident as a result of the teachings provided herein. Example 1

[0144] A solution is prepared comprising a combination of 2 or more of limonene, ^-pinene,linalool, beta-caryophyllene, borneol, and 1,8-cineole, suspended as polymeric micelles, in a salt based solution, using emulsifying agents (e.g., Cremophor 40, polysorbate 80, Pluronic F-127, and / or PLGA) for nebulization to inhibit the Nuclear Facto Kappa of B Cells (NF-κB) pathway in target cells by blocking, e.g., activity, construction, fold configuration, etc., of the following mechanisms / components / gene transduction of the NF-κB pathway: NEMO / IKK complex, NEMO CC2-LZ domain, NF-κB p50 homodimer, P65 / IκB^ complex, and / or NF-κB Inducting Kinase (NIKs). Example 2

[0145] A combination of any of limonene, linalool, ^-pinene, beta-caryophyllene, borneol,and / or 1,8-cineole as a NF-κB inhibitor is prepared. NF-κB Inhibitor solution is suspended in a saline or hypertonic saline solution (~7%) with emulsifying agents (e.g., Cremophor 40, DB1 / 142640384.5 26Attorney Docket No.137030-5001-WO polysorbate 80, Pluronic F-127, and / or PLGA), prepared by homogenization (e.g., high sheer homogenizers, sonicators, and / or microfluidizers) to create polymeric micelles / nanoparticles. Example 3

[0146] The experimental evaluation of the polymeric micelles is outlined hereinbelow.

[0147] The description and composition of the polymeric micelles are evaluated by reviewingmolecular weight and polydispersity index, and their impurity profile.

[0148] The safety and toxicology of the polymeric micelles are evaluated by reviewing thetoxicological profile, exposure response, toxicokinetic in relevant organs, and potential to induce reaction.

[0149] The quality characterization of the polymeric micelles includes evaluating the size (meanand distribution), morphology, and zeta potential; targeting ligands; critical micelle concentration (CMC) or critical aggregation concentration (CAC) and association number; drug loading; fraction of drug that is surface associated; viscosity and osmolarity; in vitro stability and degradation in relevant media; in vivo release rate and place of drug release; and in vivo block copolymer degradation rate and place of degradation.

[0150] The product specification of the polymeric micelles provides a detailed description oftests, procedures, and acceptance criteria for block copolymers and micelles. The detailed description includes appropriate analytical methods for quantification of unimers and micelles; appropriate test conditions and procedure; an assay of incorporated (or conjugated) and unincorporated (or unconjugated) active substances; and an assay of block copolymers or weight fraction to active substance.

[0151] The stability of the polymeric micelles is evaluated by reviewing the chemical stability(i.e., stability of the active substance, unimers, and block copolymer-active substance conjugates, if present) and the physical stability (i.e., mean block copolymer micelle size; release of the incorporated or conjugated active substance; and secondary aggregation).

[0152] The manufacturing process of the polymeric micelles includes a validated manufacturingprocess ensuring consistency, safety, and efficacy; a validated process ensuring sterility; and a validated process for reconstitution. DB1 / 142640384.5 27Attorney Docket No.137030-5001-WO

[0153] An appropriate species and model are selected for the non-clinical pharmacokineticstudies of the polymeric micelles. The non-clinical pharmacokinetic studies of the polymeric micelle are evaluated by reviewing pharmacokinetic parameter determination for free drug and total drug; tissue distribution; protein and cell interaction studies; comparison with drug used by itself; fate (metabolism, excretion) of drug and block copolymer; and sampling schedule, which is dependent on micelle stability after administration.

[0154] The non-clinical pharmacodynamics of the polymeric micelles are evaluated byreviewing the pharmacodynamic response in appropriately justified in vitro and in vivo models. This includes evaluating the appropriateness of the pharmacological model, route of administration, and dose levels and regimen. The physiochemical properties’ (e.g., size, surface charge, and rate of release of active substance) effect on the pharmacodynamic properties are also reviewed, in addition to the block copolymer’s biological activity (i.e., its potency and physicochemical properties).

[0155] First-in-human studies of the polymeric micelles include frequent sampling at early timepoints (which provides information about initial distribution process), with a long enough timeframe to provide reliable estimate of total extent of exposure. The first-in-human studies of the polymeric micelles are evaluated by reviewing pharmacokinetic parameter determination for free drug and total drug; and distribution of micelles and total drug amount in target lesion and major organs at multiple time points over an adequate period of time. References 1. Bodas M, Vij N. The NF-kappaB signaling in cystic fibrosis lung disease:pathophysiology and therapeutic potential. Discov Med.2010 Apr;9(47):346-56. PMID: 20423679; PMCID: PMC3114405. 2. Wang H, Cebotaru L, Lee HW, Yang Q, Pollard BS, Pollard HB, Guggino WB. CFTRControls the Activity of NF-κB by Enhancing the Degradation of TRADD. Cell Physiol Biochem.2016;40(5):1063-1078. doi: 10.1159 / 000453162. Epub 2016 Dec 14. PMID: 27960153; PMCID: PMC7067292. 3. Verhaeghe C, Tabruyn SP, Oury C, Bours V, Griffioen AW. Intrinsic pro-angiogenicstatus of cystic fibrosis airway epithelial cells. Biochem Biophys Res Commun.2007 DB1 / 142640384.5 28Attorney Docket No.137030-5001-WO May 11;356(3):745-9. doi: 10.1016 / j.bbrc.2007.02.166. Epub 2007 Mar 16. PMID: 17382901. 4. Chi G, Wei M, Xie X, Soromou LW, Liu F, Zhao S. Suppression of MAPK and NF-κBpathways by limonene contributes to attenuation of lipopolysaccharide-induced inflammatory responses in acute lung injury. Inflammation.2013 Apr;36(2):501-11. doi: 10.1007 / s10753-012-9571-1. Erratum in: Inflammation.2013 Aug;36(4):982. PMID: 23180366. 5. Batra S, Balamayooran G, Sahoo MK. Nuclear factor-κB: a key regulator in health anddisease of lungs. Arch Immunol Ther Exp (Warsz).2011 Oct;59(5):335-51. doi: 10.1007 / s00005-011-0136-z. Epub 2011 Jul 26. PMID: 21786215; PMCID: PMC7079756. 6. Farkas D, Alhussaini AA, Kraskauskas D, Kraskauskiene V, Cool CD, Nicolls MR,Natarajan R, Farkas L. Nuclear factor κB inhibition reduces lung vascular lumen obliteration in severe pulmonary hypertension in rats. Am J Respir Cell Mol Biol.2014 Sep;51(3):413-25. doi: 10.1165 / rcmb.2013-0355OC. PMID: 24684441; PMCID: PMC4189489. 7. Jaffar J, Glaspole I, Symons K, Westall G. Inhibition of NF-κB by ACT001 reducesfibroblast activity in idiopathic pulmonary fibrosis. Biomed Pharmacother.2021 Jun;138:111471. doi: 10.1016 / j.biopha.2021.111471. Epub 2021 Mar 15. PMID: 33730605. 8. Kim T, Song B, Cho KS, Lee I-S. Therapeutic Potential of Volatile Terpenes andTerpenoids from Forests for Inflammatory Diseases. International Journal of Molecular Sciences.2020; 21(6):2187. doi: 10.3390 / ijms21062187. 9. Yang F, Chen R, Li WY, Zhu HY, Chen XX, Hou ZF, Cao RS, Zang G, Li YX, ZhangW. D-Limonene Is a Potential Monoterpene to Inhibit PI3K / Akt / IKK-α / NF-κB p65 Signaling Pathway in Coronavirus Disease 2019 Pulmonary Fibrosis. Front Med (Lausanne).2021 Mar 9;8:591830. doi: 10.3389 / fmed.2021.591830. PMID: 33768100; PMCID: PMC7985179. DB1 / 142640384.5 29Attorney Docket No.137030-5001-WO 10. Cho KS, Lim Y, Lee K, Lee J, Lee JH, Lee I. Terpenes from Forests and HumanHealth. ToxicolRes 2017;33:97-106. https: / / doi.org / 10.5487 / TR.2017.33.2.097. 11. Guo, K., Mou, X., Huang, J. et al. Trans-Caryophyllene Suppresses Hypoxia-InducedNeuroinflammatory Responses by Inhibiting NF-κB Activation in Microglia. J Mol Neurosci 54, 41–48 (2014). doi: 10.1007 / s12031-014-0243-5. 12. Zhong W, Cui Y, Yu Q, Xie X, Liu Y, Wei M, Ci X, Peng L. Modulation of LPS-stimulated pulmonary inflammation by Borneol in murine acute lung injury model. Inflammation.2014 Aug;37(4):1148-57. doi: 10.1007 / s10753-014-9839-8. PMID: 24566873. 13. Rogerio, A.P., Andrade, E.L., Leite, D.F., Figueiredo, C.P. and Calixto, J.B. (2009),Preventive and therapeutic anti-inflammatory properties of the sesquiterpene α-humulene in experimental airways allergic inflammation. British Journal of Pharmacology, 158: 1074-1087. doi: 10.1111 / j.1476-5381.2009.00177.x 14. Ana Teresa Rufino, Madalena Ribeiro, Cátia Sousa, Fernando Judas, Lígia Salgueiro,Carlos Cavaleiro, Alexandrina Ferreira Mendes, Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis, European Journal of Pharmacology, Volume 750, 2015, Pages 141-150, ISSN 0014-2999, doi: 10.1016 / j.ejphar.2015.01.018. 15. Kim DS, Lee HJ, Jeon YD, Han YH, Kee JY, Kim HJ, Shin HJ, Kang J, Lee BS, KimSH, Kim SJ, Park SH, Choi BM, Park SJ, Um JY, Hong SH. Alpha-Pinene Exhibits Anti- Inflammatory Activity Through the Suppression of MAPKs and the NF-κB Pathway in Mouse Peritoneal Macrophages. Am J Chin Med.2015;43(4):731-42. doi: 10.1142 / S0192415X15500457. Epub 2015 Jun 28. PMID: 26119957. 16. Emanuel Kennedy-Feitosa, Renata Tiemi Okuro, Vanessa Pinho Ribeiro, ManuellaLanzetti, Marina Valente Barroso, Walter Araújo Zin, Luís Cristóvão Porto, Lycia Brito- Gitirana, Samuel Santos Valenca, Eucalyptol attenuates cigarette smoke-induced acute lung inflammation and oxidative stress in the mouse, Pulmonary Pharmacology & Therapeutics, Volume 41, 2016, Pages 11-18, ISSN 1094-5539, https: / / doi.org / 10.1016 / j.pupt.2016.09.004. DB1 / 142640384.5 30Attorney Docket No.137030-5001-WO 17. Halmisson D'Arley S. Siqueira, Benedito S. Neto, Damião P. Sousa, Bruno S. Gomes,Francilene Vieira da Silva, Francisco V.M. Cunha, Carlos W.S. Wanderley, Gabriel Pinheiro, André G.F. Cândido, Deysi V.T. Wong, Ronaldo A. Ribeiro, Roberto C.P. Lima-Júnior, Francisco A. Oliveira, α-Phellandrene, a cyclic monoterpene, attenuates inflammatory response through neutrophil migration inhibition and mast cell degranulation, Life Sciences, Volume 160, 2016, Pages 27-33, ISSN 0024-3205, doi: 10.1016 / j.lfs.2016.07.008. 18. Israël A. The IKK complex, a central regulator of NF-kappaB activation. Cold SpringHarb Perspect Biol.2010 Mar;2(3):a000158. doi: 10.1101 / cshperspect.a000158. PMID: 20300203; PMCID: PMC2829958. 19. Malek S. X-ray Crystal Structure of an IκBβ·NF-κB p65 Homodimer Complex. Journalof Biological Chemistry, Volume 278, Issue 25, P23094-23100, June 2003. 20. Michaely P, Tomchick DR, Machius M, Anderson RG. Crystal structure of a 12 ANKrepeat stack from human ankyrinR. EMBO J.2002 Dec 2;21(23):6387-96. doi: 10.1093 / emboj / cdf651. PMID: 12456646; PMCID: PMC136955. 21. Mia Rushe, Laura Silvian, Sarah Bixler, Ling Ling Chen, Anne Cheung, Scott Bowes,Hernan Cuervo, Steven Berkowitz, Timothy Zheng, Kevin Guckian, Maria Pellegrini, Alexey Lugovskoy, Structure of a NEMO / IKK-Associating Domain Reveals Architecture of the Interaction Site, Structure, Volume 16, Issue 5, 2008, Pages 798-808, ISSN 0969-2126, doi: 10.1016 / j.str.2008.02.012. 22. Disulfide-Mediated Stabilization of the IκB Kinase Binding Domain of NF-κB EssentialModulator (NEMO) Li Zhou, Alan T. Yeo, Carmine Ballarano, Urs Weber, Karen N. Allen, Thomas D. Gilmore, and Adrian Whitty Biochemistry 201453 (50), 7929-7944 DOI: 10.1021 / bi500920n. 23. Liu J, Sudom A, Min X, Cao Z, Gao X, Ayres M, Lee F, Cao P, Johnstone S, PlotnikovaO, Walker N, Chen G, Wang Z. Structure of the nuclear factor κB-inducing kinase (NIK) kinase domain reveals a constitutively active conformation. J Biol Chem.2012 Aug 10;287(33):27326-34. doi: 10.1074 / jbc.M112.366658. Epub 2012 Jun 20. PMID: 22718757; PMCID: PMC3431628. DB1 / 142640384.5 31Attorney Docket No.137030-5001-WO 24. Thu YM, Richmond A. NF-κB inducing kinase: a key regulator in the immune systemand in cancer. Cytokine Growth Factor Rev.2010 Aug;21(4):213-26. doi: 10.1016 / j.cytogfr.2010.06.002. Epub 2010 Aug 3. PMID: 20685151; PMCID: PMC2939163. 25. Pflug KM, Sitcheran R. Targeting NF-κB-Inducing Kinase (NIK) in Immunity,Inflammation, and Cancer. Int J Mol Sci.2020 Nov 11;21(22):8470. doi: 10.3390 / ijms21228470. PMID: 33187137; PMCID: PMC7696043. 26. Zhang, L., Xiao, X., Arnold, P.R. et al. Transcriptional and epigenetic regulation ofimmune tolerance: roles of the NF-κB family members. Cell Mol Immunol 16, 315–323 (2019). doi: 10.1038 / s41423-019-0202-8. DB1 / 142640384.5 32

Claims

Attorney Docket No.137030-5001-WO CLAIMS 1. A method of treating a disease or disorder associated with inhibition of NF-κB, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising two or more terpenes selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8-cineole and a pharmaceutically acceptable carrier.

2. The method of claim 1, wherein the pharmaceutical composition comprises limonene.

3. The method of claim 1 or 2, wherein the pharmaceutical composition comprises α-pinene.

4. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises linalool.

5. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises β-caryophyllene.

6. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises borneol.

7. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises 1,8-cineole.

8. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises from about 0.1 μg to about 1 mg independently of each of the two or more terpenes.

9. The method of any one of the preceding claims, wherein the two or more terpenes are encapsulated in a carrier.

10. The method of claim 9, wherein the carrier is selected from a polymeric micelle, an exosome, a liposome, a nanosphere, a nanocapsule, and a nanoemulsion.

11. The method of claim 9 or 10, wherein the carrier is a polymeric micelle.

12. The method of any one of the preceding claims, wherein the pharmaceutically acceptable carrier comprises one or more components selected from a diluent, a binder, an adhesive, a disintegrant, a lubricant, an antiadherent, a glidant, a sweetener, a flavorant, a colorant, a coating, a wetting agent, a dispersant, a flocculation agent, a thickener, a buffer, an emulsifier, an DB1 / 142640384.5 33Attorney Docket No.137030-5001-WO amphiphilic, an osmotic agent, a coloring agent, an anti-oxidant, a flavor, a fragrance, and a preservative.

13. The method of any one of the preceding claims, wherein the pharmaceutically acceptable carrier comprises an emulsifier, optionally wherein the emulsifier is selected from Cremophor 40, polysorbate 80, Pluronic F-127, and poly(lactic-co-glycolic acid) (PLGA).

14. The method of any one of the preceding claims, wherein the pharmaceutically acceptable carrier comprises an aqueous solution.

15. The method of claim 14, wherein the aqueous solution comprises a salt.

16. The method of claim 14 or 15, wherein the aqueous solution is saline, e.g., from about 0.1 to about 25% saline.

17. The method of claim 16, wherein the saline is hypertonic saline, e.g., about 7% hypertonic saline.

18. The method of any one of the preceding claims, wherein the pharmaceutical composition does not include a steroid.

19. The method of any one of the preceding claims, wherein the pharmaceutical composition is formatted as an aerosol precursor.

20. The method of any one of the preceding claims, wherein the pharmaceutical composition is formulated for inhalation.

21. The method of any one of the preceding claims, wherein the pharmaceutical composition is within a component of an inhalation or nasal spray device, e.g., a nebulizer device.

22. The method of any one of the preceding claims, wherein the disease or disorder is a respiratory disease or disorder.

23. The method of any one of the preceding claims, wherein the disease or disorder is a respiratory disease or disorder selected from cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PAH), and chronic obstructive pulmonary disease (COPD).

24. The method of any one of the preceding claims, wherein the subject has lung tissue damage. DB1 / 142640384.5 34Attorney Docket No.137030-5001-WO 25. The method of any one of the preceding claims, wherein the administration is topical administration to mucosa of the respiratory tract.

26. The method of any one of the preceding claims, wherein the administration is intranasal.

27. The method of any one of the preceding claims, wherein the administration is intranasal administration of an aerosol of the pharmaceutical composition.

28. The method of any one of the preceding claims, wherein the pharmaceutical composition is administered using an inhalation or nasal spray device, e.g., a nebulizer device.

29. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises limonene, wherein the limonene interacts with at least residue sites: (i) ASN714, LEU715, THR717, LEU718, LEU719, ALA722, ASN69, LEU72, ARG73, GLU74, CYS76, GLU77, and / or LEU80 of a NEMO / IKK complex; (ii) TYR57, VAL58, CYS59, GLU60, GLY61 and / or LEU140 of a NF-κB p50 homodimer; (iii) SER203, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, LEU133, ARG136, GLU203, ASN204, THR205, ASP206, GLY207, and / or HIS208 of a p65 / IkB^ complex; (iv) ASP306, LYS309, GLN304, and / or TYR308 of a NEMO CC2-LZ domain of NEMO; and / or (v) PRO488, ASP490, LEU655, VAL658, GLY659, GLY660, LEU661, LYS661, LYS662, and / or SER663 of a NF-κB Inducing Kinase (NIK).

30. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises linalool, wherein the linalool interacts with at least residue sites: (i) LYS302, ASP306, LYS309, GLN304, and / or TYR308 of a NEMO CCZ-LZ domain of NEMO; DB1 / 142640384.5 35Attorney Docket No.137030-5001-WO (ii) GLU711, ALA712, HIS713, ASN714, LEU715, CYS716, THR717, LEU718, LEU719, GLU720, ALA722, ASN69, LEU72, ARG73, GLU74, CYS76, GLU77, and / or LEU80 of a NEMO / IKK complex; (iii) ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, ARG136, ALA202, GLU203, ASN204, TYR205, ASP206, GLY207, HIS208, THR209, and / or VAL213 of a p65 / IkB^ complex; and / or (iv) PRO488, GLU489, ASP490, ARG491, LEU655, VAL658, GLY659, GLY660, LEU661, LYS662, and / or SER663 of a NF-κB Inducing Kinase (NIK).

31. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises ^-pinene, wherein the ^-pinene interacts with at least residue sites: (i) ASN714, LEU715, LEU718, LEU719, ALA722, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, GLU78, LEU79, and / or LEU80 of a NEMO / IKK complex; (ii) SER203, LEU289, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, ARG136, GLU203, ASN204, TYR205, ASP206, GLY207, and / or HIS208 of a p65+ IkB^ complex; (iii) TYR57, VAL58, CYS59, GLU60, GLY61, PRO62, and / or LEU140 of a NF-κB p50 homodimer; and / or (iv) PRO488, ASP490, VAL658, GLY659, GLY660, LEU661, LYS662, SER663, and / or PRO664 of a NF-κB Inducing Kinase (NIK).

32. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises β-caryophyllene, wherein the β-caryophyllene interacts with at least residue sites: (i) ALA710, GLU711, ALA712, HIS713, ASN714, LEU715, CYS716, THR717, LEU718, LEU719, ALA722, ASN69, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, and / or LEU80 of a NEMO / IKK complex; (ii) SER203, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, ARG136, ALA202, GLU203, ASN204, TYR205, ASP206, GLY207, HIS208, THR209, PRO210, HIS212, and / or VAL213 of a p65+ IkB^ complex; DB1 / 142640384.5 36Attorney Docket No.137030-5001-WO (iii) PRO488, GLU489, ASP490, LEU493, ALA654, GLN657, VAL658, GLY659, GLY660, LEU661, LYS662, SER663, and PRO664 of a NF-κB Inducing Kinase (NIK); (iv) ASP306, LYS309, GLN304, and / or TYR308 of a NEMO CC2-LZ domain; and / or (v) TYR57, VAL58, CYS59, GLY61, and / or LEU140 of a NF-κB p50 homodimer.

33. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises borneol, wherein the borneol interacts with at least residue sites: (i) LYS309, GLN304, and / or TYR308 of a NEMO CC2-LZ domain; (ii) VAL58, CYS59, and / or GLY61 of a NF-κB p50 homodimer; (iii) ASN714, LEU715, CYS716, LEU718, LEU719, ASN69, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, and / or LEU80 of a NF-κB Inducing Kinase (NIK); (iv) SER203, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, LEU133, ARG136, GLU203, ASN204, TYR205, ASP206, GLY207, HIS208, and / or VAL213 of a p65+ IkB^ complex; and / or (v) ASN714, LEU715, CYS716, LEU718, LEU719, ASN69, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, and / or LEU80 of a NEMO / IKK complex.

34. The method of any one of the preceding claims, wherein the pharmaceutical composition comprises 1,8-cineole, wherein the 1,8-cineole interacts with at least residue sites: (i) VAL58, CYS59, and / or GLY61 of a NF-κB p50 homodimer; (ii) PRO488, ASP490, VAL658, GLY659, GLY660, LEU661, LYS662, SER663, and / or PRO664 of a NF-κB Inducing Kinase (NIK); (iii) LEU93, ALA123, GLU124, ARG125, GLY126, GLY127, HIS128, THR129, HIS132, LEU133, ARG136, GLU203, ASN204, TYR205, ASP206, GLY207, and / or HIS208 of a p65+ IkB^ complex; and / or (iv) ASN714, LEU715, THR717, LEU718, LEU719, ALA722, LEU72, ARG73, GLU74, ARG75, CYS76, GLU77, GLU78, and / or LEU80 of a NEMO / IKK complex. DB1 / 142640384.5 37Attorney Docket No.137030-5001-WO 35. A pharmaceutical composition for inhibiting NF-κB comprising two or more terpenes selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8-cineole and a pharmaceutically acceptable carrier.

36. The pharmaceutical composition of claim 35, wherein the pharmaceutical composition comprises limonene.

37. The pharmaceutical composition of claim 35 or 36, wherein the pharmaceutical composition comprises α-pinene.

38. The pharmaceutical composition of any one of claims 35 to 37, wherein the pharmaceutical composition comprises linalool.

39. The pharmaceutical composition of any one of claims 35 to 38, wherein the pharmaceutical composition comprises β-caryophyllene.

40. The pharmaceutical composition of any one of claims 35 to 39, wherein the pharmaceutical composition comprises borneol.

41. The pharmaceutical composition of any one of claims 35 to 40, wherein the pharmaceutical composition comprises 1,8-cineole.

42. The pharmaceutical composition of any one of claims 35 to 41, wherein the pharmaceutical composition comprises from about 0.1 μg to about 1 mg independently of each of the two or more terpenes.

43. The pharmaceutical composition of any one of claims 35 to 42, wherein the two or more terpenes are encapsulated in a carrier.

44. The pharmaceutical composition of claim 43, wherein the carrier is selected from a polymeric micelle, an exosome, a liposome, a nanosphere, a nanocapsule, and a nanoemulsion.

45. The pharmaceutical composition of claim 43 or 44, wherein the carrier is a polymeric micelle.

46. The pharmaceutical composition of any one of claims 35 to 45, wherein the pharmaceutically acceptable carrier comprises one or more components selected from a diluent, a binder, an adhesive, a disintegrant, a lubricant, an antiadherent, a glidant, a sweetener, a DB1 / 142640384.5 38Attorney Docket No.137030-5001-WO flavorant, a colorant, a coating, a wetting agent, a dispersant, a flocculation agent, a thickener, a buffer, an emulsifier, an amphiphilic, an osmotic agent, a coloring agent, an anti-oxidant, a flavor, a fragrance, and a preservative.

47. The pharmaceutical composition of any one of claims 35 to 46, wherein the pharmaceutically acceptable carrier comprises an emulsifier, optionally wherein the emulsifier is selected from Cremophor 40, polysorbate 80, Pluronic F-127, and poly(lactic-co-glycolic acid) (PLGA).

48. The pharmaceutical composition of any one of claims 35 to 47, wherein the pharmaceutically acceptable carrier comprises an aqueous solution.

49. The pharmaceutical composition of claim 48, wherein the aqueous solution comprises a salt.

50. The pharmaceutical composition of claim 48 or 49, wherein the aqueous solution is saline, e.g., from about 0.1 to about 25% saline.

51. The pharmaceutical composition of claim 50, wherein the saline is hypertonic saline, e.g., about 7% hypertonic saline.

52. The pharmaceutical composition of any one of claims 35 to 51, wherein the pharmaceutical composition does not include a steroid.

53. The pharmaceutical composition of any one of claims 35 to 52, wherein the pharmaceutical composition is formatted as an aerosol precursor.

54. The pharmaceutical composition of any one of claims 35 to 53, wherein the pharmaceutical composition is formulated for inhalation.

55. The pharmaceutical composition of any one of claims 35 to 54, wherein the pharmaceutical composition is within a component of an inhalation or nasal spray device, e.g., a nebulizer device.

56. A kit comprising: (a) a pharmaceutical composition for inhibiting NF-κB comprising two or more terpenes selected from limonene, α-pinene, linalool, β-caryophyllene, borneol, and 1,8-cineole and a pharmaceutically acceptable carrier; DB1 / 142640384.5 39Attorney Docket No.137030-5001-WO (b) an inhalation or nasal spray device containing the pharmaceutical composition; and (c) instructions for administering a dosage of the pharmaceutical composition.

57. The kit of claim 56, wherein the pharmaceutical composition comprises limonene.

58. The kit of claim 56 or 57, wherein the pharmaceutical composition comprises α-pinene.

59. The kit of any one of claims 56 to 58, wherein the pharmaceutical composition comprises linalool.

60. The kit of any one of claims 56 to 59, wherein the pharmaceutical composition comprises β- caryophyllene.

61. The kit of any one of claims 56 to 60, wherein the pharmaceutical composition comprises borneol.

62. The kit of any one of claims 56 to 61, wherein the pharmaceutical composition comprises 1,8-cineole.

63. The kit of any one of claims 56 to 62, wherein the two or more terpenes are encapsulated in a carrier.

64. The kit of claim 63, wherein the carrier is selected from a polymeric micelle, an exosome, a liposome, a nanosphere, a nanocapsule, and a nanoemulsion.

65. The kit of claim 63 or 64, wherein the carrier is a polymeric micelle.

66. The kit of any one of claims 56 to 65, wherein the pharmaceutically acceptable carrier comprises one or more components selected from a diluent, a binder, an adhesive, a disintegrant, a lubricant, an antiadherent, a glidant, a sweetener, a flavorant, a colorant, a coating, a wetting agent, a dispersant, a flocculation agent, a thickener, a buffer, an emulsifier, an amphiphilic, an osmotic agent, a coloring agent, an anti-oxidant, a flavor, a fragrance, and a preservative.

67. The kit of any one of claims 56 to 66, wherein the pharmaceutically acceptable carrier comprises an emulsifier, optionally wherein the emulsifier is selected from Cremophor 40, polysorbate 80, Pluronic F-127, and poly(lactic-co-glycolic acid) (PLGA). DB1 / 142640384.5 40Attorney Docket No.137030-5001-WO 68. The kit of any one of claims 56 to 67, wherein the pharmaceutically acceptable carrier comprises an aqueous solution.

69. The kit of claim 68, wherein the aqueous solution comprises a salt.

70. The kit of claim 68 or 69, wherein the aqueous solution is or comprises saline, e.g., from about 0.1% to about 25% saline, or about 0.1% to about 7% saline.

71. The kit of claim 70, wherein the saline is hypertonic saline, e.g., about 7% hypertonic saline.

72. The kit of any one of claims 56 to 71, wherein the pharmaceutical composition does not include a steroid.

73. The kit of any one of claims 56 to 72, wherein the pharmaceutical composition is formatted as an aerosol precursor.

74. The kit of any one of claims 56 to 73, wherein the pharmaceutical composition is formulated for inhalation.

75. The kit of any one of claims 56 to 74, wherein the inhalation or nasal spray device is a nebulizer device.

76. The kit of any one of claims 56 to 75, wherein the pharmaceutical composition is administered using the inhalation or nasal spray device.

77. The kit of any one of claims 56 to 76, wherein the administration is topical administration to mucosa of the respiratory tract.

78. The kit of any one of claims 56 to 77, wherein the administration is intranasal.

79. The kit of any one of claims 56 to 78, wherein the administration is intranasal administration of an aerosol of the pharmaceutical composition.

80. The kit of any one of claims 56 to 79, wherein the dosage is from about 0.1 μg to about 1 mg independently of each of the two or more terpenes. DB1 / 142640384.5 41

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