Compositions and methods for treating lungs

Abstract

The present invention provides methods of use and liquid pharmaceutical compositions that are orally administered to the lungs via vaporization and aerosol generating devices, thereby providing multifunctional treatments for lung and respiratory diseases.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This international application claims the benefit of the filing date of U.S. Provisional Application No. 62 / 749,446, filed on October 23, 2018, the entire contents of which are incorporated herein by reference. Background Art

[0003] Smoking

[0004] According to the CDC, more than 16 million Americans have a disease caused by smoking. Smoking causes cancer, heart disease, stroke, lung disease, diabetes, and chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis. Smoking and secondhand smoke are associated with some types of asthma and can worsen its symptoms. Smoking also increases the risk of tuberculosis, certain eye diseases, and immune system problems, including rheumatoid arthritis. The World Health Organization (2018) reports that globally, an estimated 1.1 billion people smoke, tobacco use kills nearly 7 million people each year, and current trends show that tobacco use will kill more than 8 million people each year by 2030.

[0005] The Centers for Disease Control (2018) states that approximately 37.8 million people smoke in the United States, accounting for 15.5% of all adults. Smoking causes more than 480,000 deaths each year in the United States, of which more than 41,000 are due to secondhand smoke exposure; this is approximately one-fifth of the annual death toll, or 1,300 deaths per day. On average, smokers die 10 years earlier than non-smokers.

[0006] Tobacco smoke is a complex mixture of gaseous compounds and particulates. Current literature shows that there are 4800 identified gaseous and particulate bound compounds in cigarette smoke (Sahu et al., 2013).

[0007] Particulate matter (PM), especially fine particles, in the air have been associated with various adverse health effects. Environmental tobacco smoke (ETS) has also been identified as an important source of anthropogenic pollution in the indoor environment, for example through secondhand smoke. Cigarette smoke consists of gaseous pollutants; such as carbon monoxide (CO), sulfur dioxide (SO2), nitric oxide (NO), nitrogen dioxide (NO2), methane (CH4), non-methane hydrocarbons (NMHC), carbonyl compounds, and volatile organic compounds (VOCs); as well as particulate matter (PM). The concentration of particles in tobacco smoke is usually high, with 1012 particles per cigarette, and the particle size is small, ranging from 0.01nm to 1.00μm, with a median count size ranging from 186nm to 198nm (Sahu et al., 2013). Despite the small diameter of smoke particles, the deposition efficiency of smoke in the lungs has been reported to be 60% to 80%. The concentration of nicotine in cigarettes varies from brand to brand. A comprehensive study was conducted in 1998 reporting nicotine content in 92 brands of cigarettes in the United States, Canada, and the United Kingdom (Kozlowski et al., 1998). The total nicotine content and percentage of nicotine (by weight of tobacco) in the tobacco averaged 10.2 mg (standard error of the mean (SEM) 0.25, range 7.2 mg to 13.4 mg) and 1.5% (SEM 0.03, range 1.2% to 2%) in the United States, 13.5 mg (SEM 0.49, range 8.0 mg to 18.3 mg) and 1.8% (SEM 0.06, range 1.0% to 2.4%) in Canada, and 12.5 mg (SEM 0.33, range 9 mg to 17.5 mg) and 1.7% (SEM 0.04, range 1.3% to 2.4%) in the United Kingdom. However, nicotine intake per cigarette averaged 1.04 mg (+ / - 0.36), indicating that nicotine absorption and actual dose from smoking is much lower than the amount of nicotine in cigarette tobacco (Benowitz et al., 1984).

[0008] Air pollution

[0009] More than 80% of people living in urban areas where air pollution is monitored are exposed to air quality levels that exceed World Health Organization (WHO) limits. As urban air quality declines, people living in cities are at increased risk of stroke, heart disease, lung cancer, and chronic and acute respiratory diseases (including COPD and asthma). Globally, 4.2 million people die each year as a direct result of air pollution, and 91% of the world's population lives in areas that exceed WHO air pollution standards. In 2016, WHO reported annual median concentrations of PM2.5 (μg / m 3 ). PM2.5 concentrations in most parts of Asia, Africa, and India exceed 26 μg / m 3The WHO Air Quality Guidelines (AQG) stipulates that the PM2.5 air pollutant concentration is 10 μg / m 3 PM2.5 refers to atmospheric particulate matter (PM) with a diameter of less than 2.5 μg (micrometers), which is about 3% of the diameter of a human hair. Due to their tiny size, particles smaller than 2.5 μg are able to bypass the nose and throat and penetrate deep into the lungs, and some may even enter the circulatory system. Studies have reported a strong link between exposure to fine particles and premature death from heart and lung disease. Fine particles are also known to cause or aggravate chronic diseases such as asthma, COPD, heart attacks, bronchitis and other respiratory problems.

[0010] Chronic obstructive pulmonary disease (COPD)

[0011] COPD is currently the fourth leading cause of death in the world and is projected to become the third leading cause of death by 2030. Most typically, the prevalence of COPD is directly linked to smoking, although in many countries outdoor, occupational and indoor air pollution (e.g., pollution caused by burning wood and other biomass fuels) are also major risk factors for COPD. More than a quarter of COPD patients are non-smokers, and air pollution is thought to be a major cause of these cases.

[0012] COPD patients experience dyspnea on exertion caused by bronchoconstriction, mucus secretion, airway wall edema and loss of airway terminal attachments. The World Health Organization (WHO) predicts that by 2030, COPD will become the third leading cause of disease-related death worldwide.

[0013] COPD is a common, preventable and treatable disease characterized by airflow limitation and chronic respiratory symptoms as a result of alveolar and airway abnormalities, often caused by exposure to noxious gases or particulate matter. The chronic airflow limitation caused by COPD is caused by a combination of small airway disease (e.g., chronic bronchiolitis) and parenchymal destruction (emphysema). Chronic inflammation leads to changes in lung structure, including narrowing of the small airways and destruction of the lung parenchyma, resulting in reduced alveolar attachment to the small airways and weakened lung elastic recoil. These changes reduce the ability of the airways to remain open during exhalation. Small airway narrowing can also lead to airflow limitation and mucociliary dysfunction. Airflow limitation is often measured by spirometry because it is the most widely available and reproducible lung function test (Global Initiative for Chronic Obstructive Lung Disease, 2019).

[0014] Mitochondrial dysfunction and increased oxidative stress can trigger a fundamental cellular degradation process called autophagy. Depending on the stimulus, the role of autophagy in lung pathologies can be either deleterious or protective. In cigarette smoke-induced COPD, autophagy plays a key role in mediating airway epithelial cell apoptosis and ciliary shortening. Autophagy, in turn, accelerates lung aging and emphysema and contributes to the pathogenesis of COPD by promoting epithelial cell death. In experimental COPD, pneumocyte autophagy is increased, leading to inflammation and emphysematous destruction. Autophagy is key in mediating epithelial cell inflammation and mucus overproduction through NF-κB and activator protein 1 (AP-1) transcription factors.

[0015] Spirometry is the most commonly performed lung function test and plays an important role in diagnosing the presence and type of lung abnormalities and classifying their severity. Spirometry is used to evaluate and monitor individuals with COPD, asthma, and other diseases associated with respiratory impairment. In addition, it is used to evaluate occupational lung disease to determine whether preventive or therapeutic measures should be taken and to grant benefits to individuals with lung function impairment. Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) spirometry data are compared with reference data and can be expressed as a percentage of predicted values ​​based on age, sex, height, and race (American Thoracic Society, 1995). Spirometry is also used as a measure to assess an individual's response to treatment. The FEV1 / FVC ratio, the percentage of FEV1 reversibility, and the percentage of normal FEV1 are commonly used assessment parameters for assessing the severity, diagnosis, and effectiveness of treatment of airway obstructive diseases.

[0016] There are several mechanisms that explain how cigarette smoke can lead to airway inflammation and subsequent disease. Barnes (2004) identified one mechanism in the role of cigarette smoke in the imbalance of pro-inflammatory cytokines such as interferon-1β (IL-1β), IL-6, IL-8, interferon-γ, tumor necrosis factor-α (TNF-α) and anti-inflammatory cytokines such as IL-1 receptor antagonist, IL-4, IL-10, IL-11 and IL-13. The second mechanism is the oxidative stress generated due to the imbalance between oxidant and antioxidant defense mechanisms in the airways and lungs. The alveolar macrophages and neutrophils of COPD patients release oxidants. The activated inflammatory cells are attracted to the alveolar space by chemokines and cytokines, and release myeloperoxidase and large amounts of hypochlorous acid (HOCl) in the airway and near the alveolar epithelial cells, in the range of 0.1-1.0 mM.

[0017] Cigarette smoke itself is also a rich source of oxidants, as each cigarette smoke contains approximately 1015 oxidant free radical molecules and each gram of tar contains 1017 electron spin resonance (ESR) detectable free radicals (Cantin, 2010). Antioxidants are natural molecules in biological systems that scavenge oxidants, including free radicals, and protect against free radicals and other reactive oxygen species. Antioxidants can be synthesized endogenously in the body or exogenously through food intake or supplementation. In one embodiment of the present invention, antioxidants form part of a multifunctional composition inhaled by a patient to minimize reactive oxygen species present in the respiratory tract associated with COPD, asthma, and other respiratory diseases.

[0018] Leonard et al. (2000) studied exposure to wood smoke and reported that wood smoke can induce carbon-centered free radicals as well as reactive hydroxyl (·OH) radicals, which can lead to cellular damage. They also reported that wood smoke can cause lipid peroxidation, DNA damage, activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and induction of TNF-α. These authors proposed that the ·OH radical plays an important role in these immune system responses and that the iron present in wood smoke and the H2O2 produced in the respiratory tract during ingestion of wood smoke particles can generate ·OH radicals and other reactive oxygen species (ROS) in the lung. These authors suggest that wood smoke can cause acute lung injury and may have the potential to act as a fibrogenic agent.

[0019] asthma

[0020] Asthma is a chronic inflammatory lung disease that causes airflow limitation, hyperresponsiveness, and airway remodeling. Approximately 235 million people worldwide suffer from asthma, and in 2015, there were approximately 383,000 asthma-related deaths worldwide. (World Health Organization, 2018). Asthma symptoms vary, including wheezing, shortness of breath, and coughing that occur more often at night and in the early morning. Asthma symptoms are often sporadic and can be triggered by a variety of triggers, such as respiratory irritants; including cigarette smoke, secondhand smoke, air pollution, specific allergens, and exercise. Asthma usually begins in early childhood and is characterized by intermittent wheezing and shortness of breath. Although asthma and COPD share some similar clinical features, there are significant differences in the pattern of airway inflammation, with different inflammatory cells, mediators, consequences, and responses to treatment.

[0021] Based on airway or peripheral blood cell characteristics, asthma can be broadly divided into eosinophilic or non-eosinophilic, with each category accounting for approximately half of the cases (Carr et al., 2018). Cytokines play a key role in the coordination, persistence, and amplification of the inflammatory response in asthma. It has been reported that patients with severe asthma have airway inflammation similar to that of patients with COPD (Barnes, 2001, 2008). Eosinophilic asthma is considered to be a T helper 2 (Th2) cell-driven inflammatory disease characterized by eosinophilic inflammation, Th2 cell-related cytokine production, and airway hyperresponsiveness (Lloyd et al., 2010). In patients with eosinophilic asthma, Th2-related cytokine secretion of IL-4, IL-5, IL-9, IL-13, IL-25, IL-33, thymic stromal lymphopoietin (TSLP), and granulocyte-macrophage colony-stimulating factor (GM-CSF) is thought to drive the pathology of the disease. Patients with neutrophilic (non-eosinophilic) asthma have low levels or non-Th2-related cytokine production of IL-8, IL-17, IL-22, IL-23, interferon-γ (IFNγ), tumor necrosis factor-α (TNFα), chemokine receptor 2 (CXCR2), IL-10, and IL-6, which drive disease pathology (Carr et al., 2018).

[0022] Heavy Metals and Smokers

[0023] According to the U.S. Department of Health and Human Services (2006), cigarette smoke inhaled by smokers contains more than 4,000 chemicals, and secondhand smoke (SHS) is similar in nature. Heavy metals in tobacco smoke are of public health concern due to their potential toxicity and carcinogenicity. Richter et al. (2009), reporting on the results of the National Health and Nutrition Examination Survey (NHANES) from 1999-2004, concluded that individuals who smoked had higher levels of cadmium, lead, antimony, and barium than nonsmokers. The highest lead levels were in the youngest subjects. Adults with high SHS exposure had lead levels comparable to those of smokers. Cadmium levels in older smokers indicate the potential for cadmium-related toxicity. Cadmium is a known group 1 carcinogen. The results of Richter et al. (2009) showed that children exposed to SHS (a population particularly susceptible to lead toxicity at low exposure levels) had higher urinary lead levels than children not exposed to SHS. Urinary lead levels respond rapidly to changes in body lead burden and increase with increasing lead exposure.

[0024] Cadmium is considered a causative factor for emphysema in smokers. Hassan et al. (2014) reported that cadmium concentrations in lung tissue of smokers with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV COPD (58 ± 10.8 pack-years) were proportional to the patients’ total tobacco consumption (“tobacco load”). Sunblad et al. (2016) published evidence for a link between local cadmium concentrations and alterations in lung innate immunity. They reported that cadmium concentrations in acellular bronchial lavage fluid (BLF) were significantly elevated in smokers compared with nonsmokers, regardless of COPD. In these smokers, measured cadmium concentrations were positively correlated with macrophage TNF-α mRNA in BAL, neutrophil and cytotoxic T cell (CD8+) cell concentrations in blood, and finally with inflammatory cytokines IL-6, IL-8, and matrix metalloproteinase 9 (MMP-9) proteins in sputum. They also concluded that extracellular cadmium is enhanced in the bronchoalveolar space of long-term smokers and exhibits a pro-inflammatory signature. Local accumulation of cadmium in the lung appears to be a key factor in the susceptibility of chronic smokers to lung disease. This is particularly important given that the biological half-life of cadmium in humans is >25 years (a considerable period of time), suggesting that chronic smokers may retain significant amounts of cadmium in their lungs. Summary of the invention

[0025] In one embodiment of the present invention, the pharmaceutical composition comprises at least one plant extract transient receptor potential cation channel subfamily A member 1 (TRPA1) antagonist, at least one compound containing a thiol amino acid, at least one vitamin, at least one chelating agent and at least one antioxidant. The plant extract TRPA1 antagonist can be 1,8-cineole, borneol, camphor, 2-methylisoborneol, fench alcohol, cardamom, or a combination. The compound containing a thiol amino acid can be a naturally occurring compound. The compound containing a thiol amino acid can be glutathione, N-acetylcysteine, carboxymethylcysteine, taurine, methionine, or a combination. The vitamin can be cobalamin, methylcobalamin, hydroxocobalamin, adenosylcobalamin, cyanocobalamin, cholecalciferol, thiamine, dexpanthenol, biotin, nicotinic acid, nicotinamide, nicotinamide riboside, ascorbic acid, provitamin, or a combination. The chelating agent can be glutathione, N-acetylcysteine, citric acid, ascorbic acid, ethylenediaminetetraacetic acid (EDTA), or a combination. The antioxidant may be a naturally occurring compound. The antioxidant may be berberine, catechin, curcumin, epicatechin, epigallocatechin, epigallocatechin-3-gallate, beta-carotene, quercetin, kaempferol, luteolin, ellagic acid, resveratrol, silymarin, nicotinamide adenine dinucleotide, thymoquinone, 1,8-cineole, glutathione, N-acetylcysteine, cobalamin, methylcobalamin, hydroxocobalamin, adenosylcobalamin, cyanocobalamin, beta-caryophyllene, or a combination.

[0026] The pharmaceutical composition may include about 0.05% to about 10% epigallocatechin-3-gallate and about 0.1% to about 10% resveratrol.

[0027] The pharmaceutical composition may further comprise a carrier. The carrier may be a liquid carrier. The carrier may include a liquid, such as water, saline, degassed water, degassed saline, water purged with a pharmaceutically inert gas, saline purged with a pharmaceutically inert gas, or a combination. The carrier may comprise water or saline and a polysorbate, such as polysorbate 20.

[0028] The pharmaceutical composition may include a lubricating, emulsifying and / or viscosity-increasing compound. The lubricating, emulsifying and / or viscosity-increasing compound may be carbomer, polymer, gum arabic, alginic acid, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, poloxamer, polyvinyl alcohol, lecithin, sodium alginate, tragacanth gum, guar gum, sodium hyaluronate, hyaluronic acid, xanthan gum, glycerin, vegetable glycerin, polyethylene glycol, polyethylene glycol (400), polysorbate, polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polysorbate 20, polysorbate 60, polysorbate 100, polysorbate 20, polysorbate 30, polysorbate 400, polysorbate 50, polysorbate 60, polysorbate 70, polysorbate 80, polysorbate 90, polysorbate 100, polysorbate 100, polysorbate 100, polysorbate 200, polysorbate 300, polysorbate 500, polysorbate 800, polysorbate 90 ... Oxyethylene (20) sorbitan monooleate (polysorbate 80), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), sorbitan tristearate, polyglyceryl-3 stearate, polyglyceryl-3 palmitate, polyglyceryl-2 laurate, polyglyceryl-5 laurate, polyglyceryl-5 oleate, polyglyceryl-5 dioleate, polyglyceryl-10 diisostearate or a combination.

[0029] The pharmaceutical composition may include a pH adjusting compound. The pH adjusting compound may be sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate, benzoic acid, ascorbic acid, or a combination.

[0030] The pharmaceutical composition may contain a preservative. The preservative may be ethylenediaminetetraacetic acid (EDTA), benzalkonium chloride, benzoic acid, sorbic acid, or a combination.

[0031] The carrier may include about 0% to about 95% vegetable glycerin and about 5% to about 98% water. The carrier may also include about 0.001% to about 1.00% sodium bicarbonate. The carrier may also include about 0.001% to about 0.06% ethylenediaminetetraacetic acid (EDTA).

[0032] The pharmaceutical composition may further comprise an amino acid. The amino acid may be a proteinogenic amino acid. The amino acid may be an essential amino acid. The amino acid may be alanine, leucine, isoleucine, lysine, valine, methionine, L-theanine, phenylalanine, or a combination thereof.

[0033] The pharmaceutical composition may include about 0.05% to about 10% dexpanthenol, about 0.05% to about 10% L-theanine, and about 0.05% to about 10% taurine.

[0034] The pharmaceutical composition may further comprise a cannabinoid receptor type 2 (CB2) agonist. The CB2 agonist may be a naturally occurring CB2 agonist. For example, the CB2 agonist may be β-caryophyllene, cannabidiol, or cannabinol. The pharmaceutical composition may comprise about 0.1% to about 1% β-caryophyllene.

[0035] The pharmaceutical composition may further comprise a cannabinoid compound, such as cannabidiol. The pharmaceutical composition may comprise about 0.005% to about 5% of a cannabinoid compound.

[0036] The pharmaceutical composition may further comprise nicotine.The pharmaceutical composition may comprise about 0.01% to about 2.5% nicotine.

[0037] The pH of the pharmaceutical composition may be about 6 to about 8, such as about 7.2.

[0038] The ionic strength of the pharmaceutical composition may be equal to the ionic strength of normal lung epithelial cell lining fluid.

[0039] The pharmaceutical composition may further comprise liposomes. The liposomes may comprise the plant extract TRPA1 antagonist, a compound containing a thiol amino acid, vitamins and / or antioxidants. The liposomes may comprise the plant extract TRPA1 antagonist, a compound containing a thiol amino acid, vitamins, antioxidants, amino acids and / or CB2 agonists.

[0040] The pharmaceutical composition may further comprise a microemulsion or a nanoemulsion. The microemulsion or the nanoemulsion may comprise the plant extract TRPA1 antagonist, a compound containing a thiol amino acid, a vitamin and / or an antioxidant. The microemulsion or the nanoemulsion may comprise the plant extract TRPA1 antagonist, a compound containing a thiol amino acid, a vitamin, an antioxidant, an amino acid and / or a CB2 agonist.

[0041] In one embodiment, the pharmaceutical composition comprises about 0.1% to about 10% 1,8-cineole, about 0.1% to about 10% N-acetylcysteine, about 0.1% to about 20% glutathione, about 0.01% to about 1% ascorbic acid, about 0.001% to about 1.0% methylcobalamin, and a carrier.

[0042] In one embodiment, the pharmaceutical composition comprises about 0.8% 1,8-cineole, about 0.8% beta-caryophyllene, about 1.35% N-acetylcysteine, about 1.35% glutathione, about 0.01% ascorbic acid, about 0.003% methylcobalamin, about 0.8% polysorbate 20, and sterile saline containing 0.9% sodium chloride (NaCl), and sodium bicarbonate is added to adjust the pH to about 7.2. In one embodiment, the pharmaceutical composition further comprises at least one of: about 0.05% EDTA, about 1% dexpanthenol, about 0.7% L-theanine, about 0.5% taurine, about 0.05% epigallocatechin-3-gallate, about 0.5% resveratrol, and about 3% cannabidiol.

[0043] In one embodiment, the pharmaceutical composition comprises about 1.7% 1,8-cineole, about 1.7% beta-caryophyllene, about 1.2% N-acetylcysteine, about 1.5% glutathione, about 0.01% ascorbic acid, about 0.003% methylcobalamin, about 1.7% polysorbate 20, about 91% vegetable glycerin and sterile deionized water, and sodium bicarbonate is added to adjust the pH to about 7.2. In one embodiment, the pharmaceutical composition further comprises at least one of the following: about 0.05% EDTA, about 1% dexpanthenol, about 0.7% L-theanine, about 0.5% taurine, about 0.05% epigallocatechin-3-gallate, about 0.5% resveratrol and about 3% cannabidiol. In one embodiment, the pharmaceutical composition further comprises about 1.8% nicotine.

[0044] In one embodiment, the pharmaceutical composition of claim 1 comprises about 10 g / L to about 30 g / L glutathione, about 7 g / L to about 25 g / L N-acetylcysteine, about 10 g / L to about 30 g / L 1,8-cineole, and about 0.02 g / L to about 0.06 g / L cobalamin or methylcobalamin, and the pharmaceutical composition is a liquid. In one embodiment, the pharmaceutical composition further comprises about 6 g / L to about 20 g / L polysorbate 20 and about 0 g / L to about 1150 g / L glycerol, and the balance is water or saline. In one embodiment, the pharmaceutical composition further comprises about 6 g / L to about 20 g / L polysorbate 20 and about 500 g / L to about 1150 g / L glycerol, and the balance is water or saline.

[0045] In one embodiment, the pharmaceutical composition comprises about 20 g / L glutathione, about 15 g / L N-acetylcysteine, about 20 g / L 1,8-cineole, about 0.04 g / L cobalamin or methylcobalamin and about 1100 g / L vegetable glycerin, and the pharmaceutical composition is liquid. In one embodiment, the pharmaceutical composition further comprises about 12 g / L polysorbate 20, and the balance is deionized water.

[0046] In one embodiment, the pharmaceutical composition comprises glutathione, N-acetylcysteine, and cobalamin or methylcobalamin. In one embodiment, the pharmaceutical composition further comprises 1,8-cineole and / or β-caryophyllene.

[0047] In one embodiment, the pharmaceutical composition comprises about 0.5% to about 2% glutathione, about 0.5% to about 2% N-acetylcysteine, about 0.4% to about 1.2% 1,8-cineole, about 0.0002% to about 0.01% cobalamin or methylcobalamin, and about 0.1% to about 1.2% beta-caryophyllene. In one embodiment, the pharmaceutical composition further comprises about 0.1% to about 1.5% polysorbate 20 and about 0% to about 90% glycerol, and the balance is water or saline.

[0048] In one embodiment, the pharmaceutical composition comprises about 1.1% glutathione, about 1.1% N-acetylcysteine, about 0.8% 1,8-cineole, about 0.003% cobalamin or methylcobalamin, and about 0.8% beta-caryophyllene. In one embodiment, the pharmaceutical composition further comprises about 0.3% polysorbate 20, and the balance is sterile saline solution. In one embodiment, the sterile saline solution is about 0.9% saline solution.

[0049] In one embodiment, the pharmaceutical composition comprises about 0.3% to about 1% glutathione, about 0.3% to about 1% N-acetylcysteine, and about 0.001% to about 0.01% cobalamin or methylcobalamin. In one embodiment, the pharmaceutical composition further comprises about 0% to about 0.5% polysorbate 20 and about 0% to about 90% glycerol, and the balance is water or saline.

[0050] In one embodiment, the pharmaceutical composition comprises about 0.7% glutathione, about 0.7% N-acetylcysteine, and about 0.003% cobalamin or methylcobalamin. In one embodiment, the balance is sterile saline solution, such as about 0.9% saline solution.

[0051] The pharmaceutical composition may be in atomized or sprayed form.

[0052] A method for treating a respiratory disease comprises administering a pharmaceutical composition according to the present invention in atomized or sprayed form to the patient's lungs. The respiratory disease may be airway inflammation, chronic cough, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, and cystic fibrosis. The patient may be an active smoker or a former smoker; the patient may be currently or have been exposed to secondhand smoke; the patient may be currently or have been exposed to wood or forest fire smoke; and / or the patient may be currently or have been exposed to gaseous or particulate natural or artificial air pollutants. The pharmaceutical composition may be in liquid form and may be atomized using a nebulizer, an ultrasonic vaporization device, a thermal vaping device, or a device that generates an aerosol or gas phase from a liquid. The pharmaceutical composition in the liquid phase and a pharmaceutically inert gas may be sealed in an airtight container.

[0053] The smoking cessation and respiratory treatment method according to the present invention comprises: in a first step, applying a first mixture of the pharmaceutical composition and nicotine in atomized or sprayed form to the patient's lungs within a first period of time, nicotine being at a first concentration in the first mixture, and in a final step, applying a pharmaceutical composition of the present invention (without nicotine) in atomized or sprayed form to the patient's lungs within a final period of time. The atomized or sprayed pharmaceutical composition and / or nicotine can be administered to the patient's lungs by the patient using a nebulizer, an ultrasonic vaporization device, a thermal electronic cigarette vaporization device, or a device that generates an aerosol, spray, or gas phase from the pharmaceutical composition and / or nicotine to inhale the pharmaceutical composition and / or nicotine in a series of jets. In the first step, the patient can inhale the first mixture with multiple jets per day, and ingest nicotine close to the amount of nicotine in the patient's most recent active smoking behavior every day. In the first step, the patient can inhale the first mixture with about 50 to about 400 jets, such as about 150 jets per day. In the first step, the patient can inhale about 5 mg to about 40 mg, such as about 20 mg nicotine per day. In the first step, the patient may inhale about 0.5 mL to about 2 mL, for example, about 1 mL, of the first mixture per day. In the first step, the first concentration of nicotine may be about 0.5% to about 4%, for example, about 1.4%, of the first mixture. In the first step, the first time period may be about 2 weeks to about 4 months, for example, about 40 days to about 60 days. In the final step, the patient may inhale about 0.5 mL to about 2 mL, for example, about 1 mL, of the pharmaceutical composition per day.

[0054] The method may further include at least one intermediate step, i.e., administering to the patient's lungs another mixture according to the invention of the pharmaceutical composition in the form of atomization or spray and nicotine in another concentration in the other mixture, the other concentration being lower than the first concentration. For example, the method may include a second step, i.e., administering to the patient's lungs a second mixture according to the invention of the pharmaceutical composition of the invention in the form of atomization or spray and nicotine in the second mixture in a second concentration, the second concentration being lower than the first concentration. In the second step, the patient can inhale the second mixture with about 40 to about 320 sprays, such as about 125 sprays per day. In the second step, the patient can inhale about 4 mg to about 30 mg nicotine, such as about 14 mg nicotine per day. In the second step, the patient can inhale about 0.5 mL to about 2 mL, such as about 1 mL of the second mixture per day. In the second step, the second concentration of nicotine can be about 0.3% to about 3%, such as about 1%, of the second mixture in the second step. In the second step, the second period of time may be about 2 weeks to about 2 months, such as about 14 days to about 30 days.

[0055] The method may further include a third step, i.e., applying to the patient's lungs in a third time period a third mixture of the pharmaceutical composition and nicotine in a nebulized or sprayed form, wherein nicotine is at a third concentration in the third mixture, and the third concentration is lower than the second concentration. In the third step, the patient can inhale the third mixture with about 25 to about 200 sprays, such as about 75 sprays per day. In the third step, the patient can inhale about 2mg to about 15mg nicotine, such as about 5mg nicotine, per day. In the third step, the patient can inhale about 0.5mL to about 2mL, such as about 1mL of the third mixture per day. In the third step, the third concentration of nicotine can be about 0.1% to about 1% of the third mixture, such as about 0.4%. In the third step, the third time period is about 2 weeks to about 2 months, such as about 14 days to about 30 days.

[0056] In one embodiment of the smoking cessation and respiratory treatment method according to the present invention, the pharmaceutical composition comprises about 0.5% to about 5% (e.g., about 1.4%) of glutathione, about 0.3% to about 3% (e.g., about 1%) of N-acetylcysteine, about 0.3% to about 3% (e.g., about 0.8%) of 1,8-cineole, about 0.0002% to about 0.002% (e.g., about 0.0007%) of methylcobalamin and about 0.1% to about 1.2% (e.g., about 0.4%) of β-caryophyllene. The pharmaceutical composition may further comprise about 0% to about 2% (e.g., about 0.7%) of polysorbate 20 and about 0% to about 90% (e.g., about 80%) of glycerol, and the balance may be water or saline.

[0057] In one embodiment of the method for smoking cessation and respiratory system treatment according to the present invention, the pharmaceutical composition comprises about 1.4% glutathione, about 1% N-acetylcysteine, about 0.8% 1,8-cineole, about 0.0007% methylcobalamin and about 0.4% β-caryophyllene. The pharmaceutical composition may further comprise about 0.7% polysorbate 20 and about 80% glycerol, and the balance may be water or saline.

[0058] For example, a nebulizer may generate an aerosol, spray, or gas phase from the pharmaceutical composition and / or nicotine. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] The foregoing summary, as well as the following detailed description of the preferred embodiments of the present application, may be better understood when read in conjunction with the accompanying drawings. It should be understood, however, that the present application is not limited to the precise embodiments shown in the drawings.

[0060] Figure 1 The graph provided shows the FEV1 spirometry test results over time for five patients in the preclinical trial. As can be seen, FEV1 improved linearly over time, with substantial improvements in spirometry results.

[0061] Figure 2 The graph provided shows a comparison between patient treatment outcomes (ie, percentage of normal FEV1) before (light grey bars) and after (black bars) treatment.

[0062] Figure 3 The graphs provided show comparisons between patient treatment outcomes before (light grey solid bars) and after (black solid bars) treatment FEV1, and normal FEV1 calculated for age, sex, height, and race (striped bars).

[0063] Figure 4 A graph is provided showing the results for percent FEV1 reversibility for each of the five patients.

[0064] Figure 5 The graph provided shows the mean results of FEV1 before (light grey bars) and after treatment (black bars). The t-test analysis showed that the results were significant at the P=0.0001 level. DETAILED DESCRIPTION

[0065] Embodiments of the present invention are discussed in detail below. When describing the embodiments, for the sake of clarity, specific terms are used. However, the present invention is not intended to be limited to the specific terms so selected. Those skilled in the relevant art will recognize that other equivalent parts and other methods can be adopted without departing from the spirit and scope of the present invention. All references cited herein are incorporated herein by reference in their entirety, just as each reference is incorporated individually.

[0066] The present invention relates to a method for using a liquid and a liquid composition that is transferred to a gas phase and an aerosol phase for inhaled drug treatment of lung and respiratory diseases. More specifically, the present invention relates to a method for using a liquid and a liquid composition that is orally administered to the lungs by vaporization and aerosol generating devices, thereby providing a multifunctional treatment for lung and respiratory diseases, the liquid composition comprising a plant-based TRPA1 antagonist, a natural compound containing thiol amino acids, a CB2 agonist, an amino acid, a naturally occurring antioxidant, a vitamin and a bioflavonoid compound, and a heavy metal complexing compound. The present invention also relates to a multifunctional liquid composition comprising a cannabinoid compound, a plant-based TRPA1 antagonist, a natural compound containing thiol amino acids, a CB2 agonist, an amino acid, a naturally occurring antioxidant, a vitamin and a bioflavonoid compound, and a heavy metal complexing compound. The present invention relates to a liquid composition and a method for using a liquid to reduce lung damage in patients who are exposed to cigarette smoke from active smoking or secondhand cigarette smoke, forest fire smoke, and other types of smoke inhalation, including those patients who may have been active smokers in the past or may have been exposed to cigarette smoke.

[0067] The present invention relates to methods and compositions for use of liquid pharmaceutical compositions, which are transferred to gas phases and aerosol phases for inhaled drug treatment of lung and respiratory diseases. More specifically, the present invention relates to methods for use of liquids and liquid compositions, which are orally administered to the lungs by vaporization and aerosol generating devices, thereby providing multifunctional treatment for lung and respiratory diseases, and the liquid compositions contain plant-based transient receptor potential cation channel subfamily A member 1 (TRPA1) antagonists, natural compounds containing sulfhydryl amino acids, one or more vitamins, naturally occurring antioxidants, heavy metal complex compounds and carriers. The present invention also includes pharmaceutical liquid compositions and methods for use, which contain amino acids, natural cannabinoid receptor type 2 (CB2) receptor agonists, cannabinoid compounds and nicotine. More specifically, the present invention relates to methods for use of liquids and liquid compositions for reducing lung damage in patients, who are exposed to air pollution, cigarette smoke from active smoking, second-hand cigarette smoke and wood smoke. In addition, the present invention also relates to methods for use of liquids and liquid compositions for smoking cessation (helping smokers quit smoking) and respiratory system treatment.

[0068] COPD includes chronic bronchitis and emphysema. Environmental exposures, primarily caused by cigarette smoking, result in high oxidative stress and are a major factor in the development of COPD. Cigarette smoke also promotes an oxidant / antioxidant imbalance due to exogenous reactive oxygen species associated with cigarette smoke. Endogenously released reactive oxygen species and mitochondrial dysfunction during inflammatory processes contribute to the progression of COPD. Reactive oxygen species and reactive nitrogen species (RNS) can oxidize different biomolecules, such as DNA, proteins, and lipids, leading to epithelial cell damage and death.

[0069] Oxidative stress causes structural changes in the basic components of the lungs, resulting in irreversible damage to the parenchyma and airway walls. In addition, oxidative stress may also lead to changes in local immune responses. However, cells can be protected from oxidative stress by enzyme and non-enzymatic antioxidant systems. The reduction of oxidative stress reduces lung damage and local infections, thereby helping to slow the progression of COPD. Reducing oxidative stress in the lungs by inhaling naturally occurring antioxidants is an embodiment of the present invention.

[0070] Pharmacological treatment of COPD is used to relieve symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance and health status. To date, there is no definitive clinical trial evidence that any of the existing COPD medications improve long-term declines in lung function. Pharmacological treatment of patients with COPD typically focuses on bronchodilation via inhaled anticholinergics and beta2-agonists. Anti-inflammatory therapy is another treatment option for patients with COPD and includes inhaled corticosteroids, oral glucocorticoids, PDE4 inhibitors, antibiotics, mucomodulators, and antioxidants. Bronchodilators are medications that increase FEV1 and / or alter other spirometry measurements. They work by changing airway smooth muscle tone and improving expiratory flow and reflect widening of the airways rather than changes in lung elastic recoil. It is not uncommon for treatment of patients with COPD to include combination therapy, such as inhaled corticosteroids combined with long-acting bronchodilator therapy. In order to improve lung function, patient-reported outcomes and prevent exacerbations, triple inhalation therapy has also been developed, using a long-acting antimuscarinic antagonist (LAMA), a long-acting β2-agonist (LABA) and an inhaled corticosteroid in a single inhaler. There are significant reported side effects with the use of anticholinergics, short-acting β2-agonists, inhaled corticosteroids, LAMAs and LABAs. Increasing a patient's FEV1 response by bronchodilating is an embodiment of the present invention.

[0071] Neither inhaled corticosteroids nor high-dose oral corticosteroids affect the number of inflammatory cells or the concentrations of cytokines and proteases in induced sputum from patients with COPD. The inhaled corticosteroid dexamethasone does not suppress basal or stimulated release of IL-8 by alveolar macrophages in patients with COPD compared with healthy smokers. Corticosteroids inhibit apoptosis and thus stimulate neutrophil survival. Corticosteroids are known to reduce serum IL-8 levels, which may result in a decrease in neutrophil influx. Inhaled corticosteroid treatment reduces the concentrations of exhaled NO and H2O2 in expired breath.

[0072] One embodiment of the present invention is an alternative treatment for COPD patients using corticosteroids and bronchodilators with a multifunctional inhalation aerosolized pharmaceutical liquid composition comprising natural antioxidants, natural anti-inflammatory compounds and vitamins. Another embodiment of the present invention is a combination of an inhalation aerosolized pharmaceutical liquid composition comprising natural antioxidants, natural anti-inflammatory compounds and vitamins with existing prescription corticosteroids and bronchodilators.

[0073] Similar to COPD, there is strong evidence that endogenous and exogenous reactive oxygen and nitrogen species play a major role in airway inflammation and influence the severity of asthma. Asthma symptoms are triggered by cigarette smoke, inhalation of airborne pollutants (ozone, nitrogen dioxide, sulfur dioxide), and particulate matter in the air. A clear relationship between traffic density and asthma exacerbations has also been demonstrated. Cigarette smoke is associated with asthma exacerbations, especially in young children, and there is a dose-dependent relationship between exposure to cigarette smoke and asthma incidence.

[0074] The goals of asthma treatment are to reduce symptoms and limit exacerbations. Currently, rescue treatment with a short-acting beta-2 agonist (SABA) inhaler (e.g., albuterol, levalbuterol, terbutaline, metaproterenol, and pirbuterol) is recommended for all patients with asthma. For patients with moderate to severe persistent asthma, a long-acting beta-2 agonist (LABA) such as salmeterol and formoterol or a leukotriene inhibitor is often added to inhaled corticosteroid therapy. Commonly used corticosteroids include: beclomethasone, triamcinolone, flunisolide, ciclesonide, budesonide, fluticasone, and mometasone. Antimuscarinic drugs are also used to relieve bronchoconstriction and dyspnea in patients with asthma. There are short-acting and long-acting antimuscarinic drugs available. For patients with more severe, difficult-to-control forms of asthma, biologics may be considered. Omalizumab is the first biologic approved for eosinophilic asthma and works by binding to immunoglobulin E (IgE) and downregulating the activation of airway inflammation. Omalizumab is FDA-approved for the treatment of moderate to severe allergic asthma in patients over the age of 6 years and improves asthma symptoms, reduces exacerbations and eosinophil counts. New biologics that target the IL-5 pathway are also available, including: mepolizumab, reslizumab, and benralizumab. IL-5 is the main cytokine responsible for the growth, differentiation, and survival of eosinophils, which play an important role in airway inflammation in patients with asthma. Clearly, the main strategy for managing eosinophilic asthma is to antagonize the production of interleukin cytokines, especially IL-5. Unfortunately, the synthetic biologics currently available on the market have very severe side effects and are very costly, with treatment costs typically in the tens of thousands of dollars per year.

[0075] One embodiment of the present invention is a replacement treatment for asthmatic individuals currently using corticosteroids, short-acting and long-acting beta-2 agonists and antimuscarinic drugs with a multifunctional inhaled aerosolized pharmaceutical liquid composition comprising natural antioxidants, natural anti-inflammatory compounds and vitamins.

[0076] One embodiment of the invention is an inhaled aerosolized pharmaceutical liquid composition and method of treatment to reduce heavy metal concentrations in the lungs of current and former smokers, individuals exposed to secondhand smoke, and individuals exposed to air pollutants using metal chelates in the liquid composition.

[0077] Inhalation therapy

[0078] Inhalation refers to the process by which a gas or substance enters the lungs. Inhalation can occur by the following: a gas or substance, e.g., a substance in aerosol form, e.g., a pharmaceutical composition of the present invention in aerosol form, enters the lungs through the mouth or nose (or in the case of an individual who has undergone a tracheotomy, into the opening (hole) of the trachea), the respiratory tract. Therefore, unless otherwise indicated, the terms "inhalation", "administration" and other similar terms include administration of a substance to the lungs by inhalation through the mouth (i.e., through the mouth) and by inhalation through the nose (i.e., through the nose) (and in the case of an individual who has undergone a tracheotomy, by inhalation through the opening (hole) into the trachea).

[0079] The particle size of inhaled cigarette smoke is typically between 0.1 micrometers (μm) and 1.0 μm. In an experimental device developed by Sahu et al. (2013), the particle size of inhaled cigarette smoke varied between 186 nm and 198 nm at a puff volume of 35 mL / puff. When the puff volume was increased to 85 mL / puff, the particle size increased to about 300 nm. Smokers typically retain approximately 30-66% of the particulate phase contained in cigarette smoke, and the amount of particulate absorption by the smoker's respiratory tract is related to the size and solubility of the substance. Sahu et al. (2013) calculated that 61.3% of inhaled cigarette smoke particles are deposited in the human respiratory tract. In contrast, e-cigarette aerosol is best described as a mist, which is an aerosol formed by condensation or atomization consisting of spherical droplets in the submicron to 200 μm size range. Alderman et al. (2014) reported that the particle size measurements of e-cigarettes ranged from 260-320 nm count median diameter.

[0080] Various types of medical conditions can be treated by inhaling various natural and synthetic liquid substances. These chemicals can be applied to patients using different types of inhaled drug delivery system applicators, including: nebulizers, in which liquid drugs are converted into mist and then inhaled into the lungs; metered dose inhalers (MDIs), which include pressurized inhalers that deliver drugs using propellant sprays (e.g., a mixture of drugs and propellants); soft mist inhalers (SMIs), which are multi-dose, propellant-free, handheld aerosol-generating liquid inhalers that use compression springs instead of compressed gas to generate aerosols; ultrasonic electronic cigarette vaporization devices and thermal atomization devices, including electronic cigarette vaporization (vaping) devices, which are triggered to atomize the liquid stored in the reservoir by heating with a heating element or coil to produce an atomized mixture (i.e., steam) and inhaled by the user. Commercially available nebulizers can vaporize a solution or stable suspension of a liquid into an aerosol mist by means of compressed gas, through a venturi orifice, or by means of ultrasound.

[0081] The liquid compositions presented in this application of the present invention can be vaporized or atomized by any of the above or any other liquid-based inhalation drug delivery systems for oral or nasal administration. Those of ordinary skill in the art will recognize that the liquids set forth in the present invention can be used to treat respiratory diseases and lung diseases, and can also be administered by any type of device that produces a vapor or atomized liquid that can be orally administered to a patient.

[0082] Particle size, as well as particle velocity and settling time, play an important role in lung deposition. As the particle size increases to more than 3 μm, aerosol deposition shifts from the periphery of the lung to the conducting airways. When the particle size increases to more than 6 μm, oropharyngeal deposition increases. At very small particles of 1 μm or less, exhalation losses are high. Therefore, particles with a particle size of 1-5 μm effectively reach the periphery of the lung, while particles of 5-10 μm are mainly deposited in the conducting airways, and particles of 10-100 μm are mainly deposited in the nose and mouth (American Respiratory Care Association, 2017). The preferred particle size of the aerosolized liquid in the present invention is about 1 μm to about 5 μm.

[0083] In one embodiment of the invention, the liquid composition and methods of use of the nebulizable liquid composition include nicotine salts as part of a nicotine replacement therapy smoking cessation system, providing simultaneous treatment of lung and respiratory diseases and the effects from a person's smoking history. In one embodiment of the invention, the nebulizable liquid composition comprises nicotine salts, plant-based TRPA1 antagonists, natural thiol-containing amino acid compounds, CB2 agonists, amino acids, naturally occurring antioxidants, vitamins and flavonoid compounds, and heavy metal complexing compounds.

[0084] In another embodiment of the invention are liquid compositions and methods of use wherein the liquid is vaporized, aerosolized, or both, and inhaled by a patient to reduce airway inflammation in an individual associated with COPD, asthma, cystic fibrosis, and other respiratory diseases associated with reduced lung capacity. In yet another embodiment of the invention are multifunctional compositions that reduce the concentration and effects of reactive oxygen species in the lungs caused by one or more diseases including exposure to cigarette smoke, other types of smoke, and air pollutants.

[0085] Another embodiment of the present invention is a nebulizable liquid composition and method of use for reducing reactive oxygen species in the lung, including lung epithelial cell lining fluid, epithelial cells, neutrophils, eosinophils, macrophages, lymphocytes, monocytes and tissues in the lungs of patients with diseases that cause an imbalance in oxidant / antioxidant concentrations due to endogenous causes of reactive oxygen species. Another embodiment of the present invention is a nebulizable liquid composition and method of use for reducing inflammatory cytokines in the lung, including lung epithelial cell lining fluid, epithelial cells, neutrophils, eosinophils, macrophages, lymphocytes, monocytes and tissues in the lungs of patients, as a result of smoking, asthma, COPD and other respiratory diseases, present in the epithelial cell lining fluid covering the alveoli, small airways and large airway mucosa. In one embodiment of the present invention, the inflammatory cytokines inhibited are interferon-1β (IL-1β), IL-6, IL-8, IL-12, interferon-γ, tumor necrosis factor-α (TNF-α). In another embodiment of the present invention is a liquid composition that activates anti-inflammatory cytokines, including IL-1 receptor antagonist (IL-1r), IL-4, IL-10, IL-11 and IL-13.

[0086] The pharmaceutical composition of the present invention can be administered together with another therapeutic agent. The other therapeutic agent can be a prescription drug or an over-the-counter drug (i.e., an over-the-counter drug). For example, the other therapeutic agent can also be used to treat lung or respiratory tract disorders, such as asthma, COPD, emphysema, and chronic bronchitis. For example, the additional therapeutic agent may include a short-acting β2-adrenergic receptor agonist (SABA) (e.g., salbutamol, salbutamol, terbutaline, metaproterenol, pirbuterol), an anticholinergic (e.g., ipratropium, tiotropium, aclidinium, umeclidinium), an adrenergic agonist (e.g., epinephrine), a corticosteroid (e.g., beclomethasone, triamcinolone, flunisolide, ciclesonide, budesonide, fluticasone propionate, mometasone), a long-acting β2-adrenergic receptor agonist (LABA) (e.g., salmeterol, formoterol, indacaterol), a leukotriene receptor antagonist (e.g., montelukast, zafirlukast), a 5-LOX inhibitor (e.g., zileuton), an antimuscarinic agent, a bronchodilator, and / or a combination of two or more of these.

[0087] The present invention also relates to the use of one or more water-soluble natural sulfhydryl-containing amino acid compounds, including glutathione, N-acetylcysteine ​​and carboxymethylcysteine ​​in a liquid that is atomized, vaporized or both, for inhalation to reduce, neutralize and / or inhibit the formation of reactive oxygen species, reactive nitrogen species and other types of free radical species that may otherwise cause damage to the upper and / or lower respiratory tract of a person. The present invention further relates to the use of a water-soluble natural sulfonic acid amino acid, namely taurine, which can react with hypochlorous acid produced endogenously in the lungs to form taurine chloramine (Tau-Cl), which is much less toxic. Taurine acts to neutralize reactive oxidant species and neutralize inflammatory cytokines in the composition by forming Tau-Cl. Optional additives to the liquid composition of the present invention include preservatives (if the composition is not prepared aseptically), additional antioxidants, flavoring agents, volatile oils, buffers and surfactants.

[0088] In the present invention, "inflammatory disease" or "inflammation" refers to any disease that specifies respiratory inflammation as the main cause or inflammation caused by the disease. Specifically, inflammatory diseases may include systemic or localized inflammatory diseases (e.g., allergies; immune complex diseases; hay fever; and respiratory diseases (e.g., asthma; epiglottitis; bronchitis; emphysema; rhinitis; cystic fibrosis; interstitial pneumonia; chronic obstructive pulmonary disease, acute respiratory distress syndrome; dust disease; alveolitis; bronchiolitis; pharyngitis; pleurisy or sinusitis); but are not limited to these diseases. In the present invention, inflammatory respiratory diseases may also be caused by exogenous environmental and occupational exposure to particulate and non-particulate air pollutants, which are collectively referred to as indoor or outdoor air pollutants, including in closed or semi-enclosed spaces, such as cars, buses, trains, ships, or any other transportation or space-related vehicles.

[0089] For the purposes of the present invention, "vapor" is defined as diffused matter suspended in the air and impairing its transparency (e.g., smoke or fog), and gaseous matter as distinct from a liquid or solid state. Thus, vapors can be compounds in the gas phase, e.g., volatile liquids vaporizing and transitioning from the liquid phase to the gas phase, as well as suspended liquid particles. For the purposes of the present invention, "aerosol" is defined as a suspension of fine solid particles or liquid droplets in the air or other gas.

[0090] One embodiment of the invention is a composition and method of use for antagonizing, inactivating or blocking TRPA1 activation in the lungs resulting from exogenous chemicals that would otherwise cause TRPA1 activation, such as from cigarette smoke, by inhaling aerosolized natural plant compound TRPA1 antagonists using an electronic cigarette vaporization device, ultrasonic vaporization device or other thermal atomization or vaporization device, nebulizer or other type of device for transferring a liquid to an aerosol phase and / or gas phase that is then inhaled by a person. Another embodiment of the present invention is to limit damage to lung tissue due to reactive oxygen species, such as from cigarettes and other exogenous smoke sources and exogenous air pollutants, by inhaling natural sulfhydryl amino acid containing compounds, CB2 agonists, amino acids, naturally occurring antioxidants, phytochemicals and flavonoid compounds, vitamins and heavy metal complex compounds using an electronic cigarette vaporization device, an ultrasonic vaporization device or other thermal atomization or vaporization device, a nebulizer or other type of device for transferring a liquid to an aerosol phase and / or a gas phase, which is then inhaled by a person. Another complementary feature of the present invention includes plant-based TRPA1 antagonists, natural sulfhydryl amino acid containing compounds, CB2 agonists, amino acids, naturally occurring antioxidants, vitamins and bioflavonoid compounds, and heavy metal complex compounds to a liquid, which uses an electronic cigarette vaporization device, an ultrasonic vaporization device or other thermal atomization or vaporization device, a nebulizer or other type of device for transferring a liquid to an aerosol phase and / or a gas phase, which is then inhaled by a person, having one or more antioxidant, anti-inflammatory, anti-allergic, anti-viral or anti-cancer properties.

[0091] The present invention relates in part to a method of reducing the damage to the lungs from current and past smoking and other exogenous or endogenous chemicals or particulate matter.

[0092] Another feature of the present invention is a method for inhibiting or neutralizing the release of calcitonin gene-related peptide (CGRP) in lung tissue by inactivation of TRPA1. CGRP is a member of the calcitonin peptide family and exists in two forms: α-CGRP and β-CGRP. When TRPA1 is activated in the lung by cigarette smoke activating TRPA1, CGRP is released. Cigarette smoke initially causes elevated levels of extracellular reactive oxygen species, which in turn activate lung epithelial TRPA1. The activation of TRPA1 then converts this cigarette smoke-induced stimulus into transcriptional regulation of lung inflammation through Ca2+ influx. In another embodiment of the present invention, the liquid composition is inhaled into the respiratory tract while being vaporized, atomized, or both, resulting in an increase in the concentration of a compound in the lung, which is a natural TRPA1 antagonist, a natural TRPM8 agonist, a natural thiol-containing amino acid compound, a CB2 agonist, an amino acid, an antioxidant, a bioflavonoid compound, a vitamin, and a metal chelate. In another embodiment of the present invention, a liquid composition comprising primarily naturally occurring compounds is inhaled into the respiratory tract while being vaporized, atomized, or both, resulting in an increased concentration of the compound in the lungs, the compound being a TRPA1 antagonist, a TRPM8 agonist, a natural thiol-containing amino acid compound, a CB2 agonist, an amino acid, an antioxidant, a bioflavonoid compound, a vitamin, and a natural metal chelate. The effect of inhaling the naturally occurring chemical substances contained in the liquid of the present invention, which is vaporized, atomized, or both, is to reduce one or more tissue damage, inflammation, excess mucus accumulation, cough, and cancer caused by reactive oxygen species, but not limited to these, which are the result of an oxidant / antioxidant chemical imbalance in the lungs. Reducing inflammation in the lungs by inhaling the gas phase and aerosol phase of the liquid described in the present invention includes modulating the immune system response, increasing antibacterial and antifungal conditions in the lungs, and inhibiting the production of tumor necrosis factor-a (TNF-α), interleukin-1β (IL-1β), interleukin-4 (IL-4), interleukin-5 (IL-5), leukotriene B4 (LTB4), thromboxane B2 (TXB2) and prostaglandin E2 (PGE2).

[0093] The present invention further relates in part to cannabinoid compounds (both phytocannabinoids and synthetic cannabinoids), including but not limited to: 9-tetrahydrocannabinol (δ-9-THC), 9-THC propyl analog (THC-V), cannabidiol (CBD), cannabidiol propyl analog (CBD-V), cannabinol (CBN), cannabichromene (CBC), cannabichromene propyl analog (CBC-V), cannabigerol (CBG), cannabinoid terpenes and cannabinoid flavonoids; cannabichromene (CBN) in combination with TRPA1 antagonists, TRPM8 agonists, natural sulfhydryl amino acid compounds, CB2 agonists, amino acids, antioxidants, vitamins, bioflavonoid compounds and natural metal chelates. Cannabidiol is a preferred phytocannabinoid in the present invention due to the lack of psychoactive properties.

[0094] Surprisingly, it has been found in the present invention that natural compounds can be combined to control gating to inhibit TRPA1 activation, thereby reducing lung inflammation and inflammatory effects caused by TRPA1 activation caused by exogenous and endogenous chemicals (including cigarette smoke). In other compositions of the present invention, 1,8-cineole and / or borneol are TRPA1 antagonists. Other compositions of the present invention include 1,8-cineole and / or borneol and natural compounds containing thiol amino acids. Other compositions of the present invention include CB2 agonists. The preferred CB2 agonist in the present invention is β-caryophyllene. The preferred composition in the present invention includes: 1,8-cineole as a TRPA1 antagonist and TRPM8 agonist; N-acetylcysteine ​​and glutathione, which are naturally occurring compounds containing thiol amino acids and are also antioxidants; and emulsifying compounds and water. In another preferred composition, vitamin C (ascorbic acid) and vitamin B12 (methylcobalamin) are added to 1,8-cineole, N-acetylcysteine ​​and glutathione to increase the multifunctional properties of the atomized or vaporized liquid described in the present invention. Other compositions of the present invention include 1,8-cineole and / or borneol and a water-soluble antioxidant, a bioflavonoid compound, a heavy metal chelator, an emulsifying compound and water.

[0095] The present invention relates to the use of the bioflavonoid compound thymoquinone in a liquid for inhalation via vaporization to impart antioxidant, anti-inflammatory, anti-allergic, antiviral and anti-cancer properties to the lungs of individuals exposed to cigarette smoke. In addition, the present invention relates to the use of the bioflavonoid compound thymoquinone in a liquid for inhalation via atomization or vaporization to reduce inflammatory mediators in the upper and lower respiratory tracts, including IL-8, neutrophil elastase, TNF-α and malondialdehyde.

[0096] The present invention relates to the use of the bioflavonoid compound berberine in a liquid for inhalation via atomization or vaporization to impart antioxidant, anti-inflammatory, anti-allergic, antiviral and anti-cancer properties to the lungs of individuals exposed to cigarette smoke. In addition, the present invention relates to the use of the bioflavonoid compound berberine in a liquid for inhalation via atomization or vaporization to reduce inflammatory mediators in the upper and lower respiratory tracts, including IL-8, neutrophil elastase, TNF-α and malondialdehyde.

[0097] Another feature of the invention relates to the use of the bioflavonoid compound curcumin in a liquid for inhalation via vaporization to neutralize and / or inhibit the formation of reactive oxygen species and other types of free radical species that would otherwise cause damage to the upper and / or lower respiratory tract. Curcumin is known to have antioxidant and anti-inflammatory properties. The anti-inflammatory effects of curcumin are likely mediated by its ability to inhibit cyclooxygenase-2 (COX-2), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS). Since inflammation is closely related to tumor promotion, curcumin, by virtue of its potent anti-inflammatory properties, will play a chemopreventive role in the development of cancer.

[0098] Another feature of the invention relates to the use of other natural compounds that exhibit anti-inflammatory properties in respiratory therapy, including andrographolide, astragaloside, cardamom, kaempferol, luteolin, naringin, oroxylin A, quercetin, gardenia glycoside, genistein, ellagic acid, escin, glycyrrhizin, hydroxysafflor yellow A, baicalin, baicalin, cephalothin, columbia lactone, escin, imperatorin, imperatorin, isoorientin, isovitexin, sansin M, orientin, forsythin, platycodon saponin D, resveratrol, schisandrin A, silymarin, tectorius, triptolide, dan Piperidinol, zingerone, paeonol, protocatechuic acid, limonene, linalool, forsythiaside, phytosylcimifugin, prime-O-glucosylcimifugin, cannabidiol, flavonoids, quercetin, luteolin, apigenin-7-glucoside, baicalein, baicalin, afudanoside, hyperoside, quercetin, morin, quercetin, fisetin, tectorius, eriodictyol, naringin, hesperidin, sakurain, taraxasterol, vitexin, mogroside V, triptolide, minnelide, phytolaccarin, columbia lactone, esculin and imperatorin. In addition, the present invention relates to compositions and methods for reducing respiratory inflammation, including extracts and essential oils from the following plants: Acanthopanax senticosus, Aconitum tanguticum, Alisma orientale Juzepzuk, Angelica decursiva, Antrodia camphorate, Alstonia scholaris, Artemisia annua, Azadirachta indica, Callicarpa japonica Thunb., Canarium lyi CDDai & Yakovlev, Chrysanthemum indicum, Coscinium fenestratum, Cnidium monnieri, Eleusine indica, Eucalyptus cinerea, Eucalyptus globulus, Euterpe palm oleracea Mart.), Galla chinensis, Ginkgo biloba, Gleditsia sinensis, Glycyrrhiza uralensis, Houttuynia cordata, Juglans regia L.kernel, Lonicera japonicaflos, Lysimachia clethroides Duby, Melaleuca linariifolia, Mikania glomerata Spreng, Mikania laevigata Schultz, Mikania chamomile, Nigella sativa, Paeonia suffruticosa, Phellodendri cortex, Punica granatum, Rabdosia japonica var.glaucocalyx, Rosmarinus officinalis, Schisandra chinensis Baillon), Stemona tuberosa, Taraxacum officinale, Taraxacum mongolicum hand.-Mazz, Thymus satureioides, Uncariatomentosa and Viola yedoensis.

[0099] The aerosolizable liquid pharmaceutical composition of the present invention may also include a carrier that enables the liquid and the resulting aerosolized compound to be most effectively delivered to the lungs, typically but not limited to a nebulizer, an ultrasonic vaporization device, and a thermal electronic vaporization system, such as an electronic cigarette and other types of electronic cigarette vaporization devices. The carrier composition may include such compounds, but not limited to, sterile water, pH buffers, acids, bases, surfactants, emulsifiers, glycols, vegetable glycerin, and inorganic salts to make the composition isotonic with the lung epithelial cell lining fluid.

[0100] Another feature of the present invention is a lubricating viscosity modifier added to the liquid for atomization or vaporization for inhalation. The lubricating viscosity modifier can be selected from one or more of the group consisting of carbomer, polymer, gum arabic, alginic acid, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, poloxamer, polyvinyl alcohol, sodium alginate, tragacanth gum, guar gum, sodium hyaluronate, hyaluronic acid, xanthan gum, glycerin, vegetable glycerin, polyethylene glycol and polyethylene glycol (400).

[0101] Another feature of the present invention is a stable suspension generating component, which can be added to one or more components alone, or added to a bulk liquid, which is added to a liquid for atomization or vaporization for inhalation. The stable suspension generating component can be selected from one or more of an emulsifier or a liposome group. Liposomes can encapsulate both hydrophobic and hydrophilic compounds, and can be used in the present invention to target, locate or specifically absorb or adsorb chemicals into or on specific tissues, fluids or cell types in the lungs. Liposomes have an aqueous solution core surrounded by a hydrophobic membrane in the form of a lipid bilayer. Solutes dissolved in the liposome core cannot easily pass through the bilayer. Hydrophobic chemicals are associated with the bilayer. Therefore, liposomes can be loaded with hydrophobic and / or hydrophilic molecules. Although most of the compounds constituting the present invention are hydrophilic, some compounds are more hydrophobic, such as 1,8-cineole, β-caryophyllene, resveratrol, thymoquinone, epigallocatechin gallate and other catechin compounds, curcumin and borneol. Compositions containing any of these compounds or other hydrophobic compounds at concentrations greater than their solubility in aqueous bulk solutions may require emulsification of them in bulk solutions in oil-in-water (O / W) microemulsions and nanoemulsions, or incorporation of separate hydrophobic compounds in liposomal structures. Those of ordinary skill in the art will readily appreciate that a variety of methods can be used to produce stable, uniform suspensions using mixtures of hydrophilic and hydrophobic compounds described herein.

[0102] Another feature of the invention is the use of a pH buffer to adjust the pH of the liquid to the pH of healthy lung epithelial fluid, which is about 7.2. Another feature of the invention is the addition of salt to render the liquid composition isotonic with lung epithelial fluid.

[0103] One feature of the invention provides liquid formulations and methods of use to treat various respiratory diseases associated with exposure to cigarette smoke and other types of smoke, which produces reactive oxygen species that subsequently lead to inflammation, DNA damage, and a cascade of cytokine, neuropeptide, and nociceptor activation. Cigarette smoke can produce 10 15The present invention discloses a composition and a method for using a nicotine-containing liquid, which can be atomized in an ultrasonic vaporization device, a thermal vaporization system (e.g., an electronic cigarette vaporization device and an electronic cigarette), and also provides a multifunctional treatment for lung and respiratory diseases, wherein the treatment comprises a plant-based TRPA1 antagonist, a CB2 agonist, a natural compound containing thiol amino acids, a naturally occurring antioxidant, an amino acid and a flavonoid compound, and a heavy metal complex compound. The method for using this combined nicotine-respiratory drug therapy includes quitting smoking completely or replacing both with a nicotine-containing respiratory drug therapy composition disclosed in the present invention. If a smoker cannot quit smoking completely, a portion of his daily nicotine consumption can be replaced by using the nicotine-containing composition disclosed in this patent. Completely quitting smoking, as well as replacing a portion of the nicotine consumed by an individual from cigarettes daily by inhaling the nicotine-containing atomizable pharmaceutical liquid composition disclosed in the present invention, will reduce respiratory damage and other health effects from active smoking.

[0104] Transient receptor potential (TRP) ion channels and smoking

[0105] Transient receptor potential (TRP) ion channels are a heterogeneous system for environmental perception and are involved in the perception of visual, taste, olfactory, auditory, mechanical, thermal, osmotic, chemical, and itch-causing stimuli. The transient receptor potential channel family currently contains more than 50 different channels, 27 of which are found in humans. Transient receptor potential channel gating is achieved by the direct effects of a large number of exogenous and endogenous physicochemical stimuli on the channels. A large body of evidence suggests that the TRPA1 ion channel plays a key role in detecting pungent or irritating compounds; including compounds contained in different spicy foods, such as allyl isothiocyanate (in mustard oil), horseradish, allicin and diallyl disulfide in garlic, cinnamaldehyde in cinnamon, gingerol (in ginger), eugenol (in cloves), methyl salicylate (in wintergreen), menthol (in peppermint), carvacrol (in oregano), thymol (in thyme and oregano), and the cannabinoid compounds, namely cannabidiol (CBD), cannabichromene (CBC), and cannabinol (CBN) (in marijuana and industrial hemp). In addition, environmental irritants and industrial pollutants such as acetaldehyde, formalin, formaldehyde, hydrogen peroxide, hypochlorite, isocyanates, ozone, carbon dioxide, ultraviolet light, and acrolein (a highly reactive α,β-unsaturated aldehyde found in tear gas, cigarette smoke, smoke from burning vegetation, vaping liquids, and vehicle exhaust) have been implicated as TRPA1 activators. Many TRP channels (TRPA1, TRPV1, and TRPV4) have been linked to sensory perception associated with cough responses.

[0106] Bessac et al. (2008) reported that both hypochlorite (an oxidizing mediator of chlorine) and hydrogen peroxide (a reactive oxygen species) activated Ca2+ in mouse cells. 2+In the respiratory tests of TRPA1-deficient mice, they showed a profound lack of hypochlorite- and hydrogen peroxide-induced respiratory depression, as well as reduced oxidant-induced pain behaviors. The authors concluded that TRPA1 is an oxidant sensor in sensory neurons, initiating neuronal excitation and subsequent physiological responses in vitro and in vivo. Based on their data, they also concluded that TRPA1 activation may also contribute to the effects of chlorine and other TRPA1 agonists on chemosensory nerve endings in the lower airways. Because reactive irritants are efficiently cleared in the upper airways, sensory activation in the lower airways requires higher exposure levels. Prolonged or high-level exposure to oxidants, such as those experienced by victims of chlorine exposure, can cause severe pain, coughing, mucus secretion, and bronchospasm. The authors also concluded that TRPA1 antagonists or blockers could be used to inhibit the hyperexcitability of sensory neurons in airway diseases and that TRPA1 is a promising new target for the development of drug candidates with potential antitussive, analgesic, and anti-inflammatory properties. In one embodiment of the invention is an inhaled aerosolized pharmaceutical liquid composition and a method for treating an individual or soldier exposed to a chemical warfare agent that is a respiratory irritant, a cough agent, and / or an asphyxiant. Such chemical warfare agents may include tear agents (tear gas), emetic agents, vesicants (e.g., nitrogen mustard and sulfur mustard, and arsenic agents (e.g., Lewisite)), and asphyxiants (e.g., chlorine, chloropicrin, diphosgene, phosgene, decafluoride, perfluoroisobutylene, acrolein, and diphenylcyanarsine).

[0107] Kichko et al. (2015) reported that cigarette smoke contains volatile reactive carbonyl compounds such as formaldehyde and acrolein, both of which activated TRPA1 in vitro and in isolated mouse trachea and larynx, as measured by the production of calcitonin gene-related peptide (CGRP), which regulates the production of proinflammatory cytokines. In the trachea, the vapor phase (vapor phase only) and whole cigarette smoke were equally effective in releasing CGRP, whereas the larynx showed a much greater response to whole cigarette smoke than to vapor phase. They concluded that nicotinic receptors contribute to the sensory effects of cigarette smoke on the trachea, primarily TRPA1, and not TRPV1.

[0108] Mukhopadhyay et al. (2016) reported that TRPA1 ion channels are abundantly expressed on C fibers that innervate almost the entire respiratory tract starting from the oral cavity and oropharynx, trachea, bronchi, terminal bronchioles, respiratory bronchioles, and up to the alveolar ducts and alveoli. They reported that TRPA1 functions as a "chemical sensor"; detecting the presence of exogenous irritants and endogenous proinflammatory mediators involved in airway inflammation and sensory symptoms such as chronic cough, asthma, COPD, allergic rhinitis, and cystic fibrosis. TRPA1 can remain activated for a long time due to the elevated levels and persistent presence of such endogenous ligands and proinflammatory mediators. They also reported that various harmful chemicals and environmental / industrial irritants that activate TRPA1 are also causative agents of asthma or reactive airway dysfunction syndrome (RADS) and are known to exacerbate asthma attacks. They concluded that there is promising evidence that targeting TRPA1 may represent a new therapeutic approach for the treatment of respiratory diseases in the near future.

[0109] Li et al. (2015) demonstrated an important role for lung epithelial TRPA1 in the induction of IL-8 by cigarette smoke extract in primary human bronchial epithelial cells. These in vitro findings using primary human bronchial epithelial cells suggest that exposure to cigarette smoke extract initially results in increased extracellular levels of reactive oxygen species, which in turn activate lung epithelial TRPA1. TRPA1 activation subsequently activates IL-8 via Ca 2+ They report that the Ca influx is prevented by reducing extracellular reactive oxygen species using the antioxidant free radical scavenger N-acetylcysteine. 2+ Ca influx. 2+ The reduction in inflows was similar.

[0110] Yang et al. (2006) demonstrated that exposure of human MonoMac6 cells to 1% and 2.5% cigarette smoke extract increased the production of IL-8 and TNF-α, which, in addition to NF-κB activation, led to a significant depletion of glutathione levels due to increased release of reactive oxygen species. They reported that inhibition of inhibitor of κB (IκB) kinase abrogated the cigarette smoke extract-mediated IL-8 release, allowing the authors to propose that this inflammatory process is dependent on the NF-κB pathway. These authors also observed that cigarette smoke extract reduced histone deacetylase (HDAC) activity and HDAC1, HDAC2, and HDAC3 protein levels. When these researchers pretreated the cells with glutathione, they reversed the cigarette smoke-induced decrease in HDAC levels and significantly inhibited IL-8 release.

[0111] Facchinetti et al. (2007) reported that many substances contained in cigarette smoke, including reactive oxygen species, are thought to contribute to the inflammatory process in COPD. These authors reported that micromolar concentrations of acrolein and crotonaldehyde, both α,β-unsaturated aldehydes, contained in aqueous cigarette smoke extract (CSE) induced the release of the neutrophil chemoattractant IL-8 and the pleiotropic inflammatory cytokine TNF-α from the human macrophage cell line U937. They concluded that α,β-unsaturated aldehydes are major mediators of cigarette smoke-induced macrophage activation, suggesting that they contribute to cigarette smoke-related lung inflammation.

[0112] Blocking TRPA1 is emerging as a therapeutic strategy for a variety of respiratory diseases, and the role of TRPA1 in airway pathology has been demonstrated by studies using TRPA1 knockout (KO) mice and TRPA1 antagonists. In wild-type mice, airway exposure to hypochlorite or hydrogen peroxide causes respiratory depression, as evidenced by decreased respiratory rate and increased endexpiratory pause, both of which are attenuated in TRPA1 KO mice. Allyl isothiocyanate (AITC), acrolein, crotonaldehyde, and cinnamaldehyde are potent TRPA1 agonists that have been shown to induce a dose-dependent and robust cough response in guinea pigs, which was attenuated by the TRPA1 antagonist HC-030031 synthesized by Hydra Biosciences. Similarly, citric acid-induced cough responses in guinea pigs were also inhibited by the potent and selective TRPA1 antagonist GRC 17536. The anti-cough effects of other TRPA1 antagonists have also been demonstrated in animal cough models.

[0113] Takaishi et al. (2012) reported that 1,8-cineole (eucalyptol) activates human TRPM8 (hTRPM8) and is an hTRPA1 antagonist. They also confirmed that 1,8-cineole does not activate hTRPV1 or hTRPV2. 1,8-cineole is present in eucalyptus oils from several species at highly variable concentrations (less than 5% to greater than 80%), in several chemotypes of rosemary (Rosmarinus officinalis) (up to about 50%) and in Spanish sage (Salvia lavandulifolia) (up to about 25%). Activation of TRPM8 has been shown to reduce inflammation and pain. Although these researchers reported activation of TRPM8 by menthol, this did not reduce inflammatory responses in humans because it also activates TRPA1, which causes inflammation. Furthermore, application of octanol, a known TRPA1 agonist and skin irritant, to the neck of human subjects followed by 1,8-cineole significantly reduced the irritation of octanol via the inhibitory effect of 1,8-cineole on TRPA1.

[0114] As a follow-up to this study, the same research group published another study (Takaishi et al., 2014) on the effects of several monoterpene analogs of camphor and their ability to inhibit hTRPA1. They reported that 1,8-cineole, camphor, borneol, 2-methylisoborneol, norcamphor, and fenchol did not activate hTRPA1, and that borneol, 2-methylisoborneol, and fenchol at 1 mM completely inhibited the activation of hTRPA1 by menthol and allyl isothiocyanate (AITC from mustard oil) at 1 mM and 10 μM, respectively. TRPA1 activated by 20 μM AITC was found to be inactivated by 2-methylisoborneol (0.12 mM), borneol (0.20 mM), fenchol (0.32 mM), camphor (1.26 mM), and 1,8-cineole (3.43 mM) in the order from lowest to highest concentration (IC-50 concentration).

[0115] Wang et al. (2016) reported that cardamomine is a TRAPA1 antagonist (IC50 = 454 nM) but does not affect TRPV1 and TRPV4. They also reported that cardamomine did not significantly reduce HEK293 cell viability or impair cardiomyocyte contraction.

[0116] In cell studies, Juergens et al. (1998) reported that 1,8-cineole, traditionally used to treat symptoms of airway diseases exacerbated by infection, showed a dose-dependent, highly significant inhibitory effect on the production of TNF-α, interleukin-1β (IL-1β), leukotriene B4 (LTB4), and thromboxane B2 (TXB2). In a follow-up clinical study, Juergens et al. (2003) evaluated the anti-inflammatory efficacy of 1,8-cineole by determining its prednisolone-equivalent potency in patients with severe asthma. Thirty-two patients with steroid-dependent bronchial asthma were enrolled in a double-blind, placebo-controlled trial. After a 2-month run-in phase to determine the effective oral steroid dose, subjects were randomized to receive either 200 mg of 1,8-cineole orally (three times daily) or placebo in an enterosoluble capsule for 12 weeks. Oral glucocorticoids were reduced in 2.5 mg increments every 3 weeks. The primary endpoint of the study was to determine the oral glucocorticoid-sparing ability of 1,8-cineole in patients with severe asthma. They reported that a 36% reduction in the daily dose of prednisolone was tolerated with active treatment (range, 2.5 to 10 mg, mean: 3.75 mg), compared with only a 7% reduction in the placebo group (2.5 to 5 mg, mean: 0.91 mg) (P = .006). Oral steroid reduction occurred in 12 of 16 patients in the 1,8-cineole group and in 4 of 16 patients in the placebo group (P = .012). They concluded that long-term systemic treatment with 1,8-cineole has a significant steroid-sparing effect in steroid-dependent asthma. They also reported that their results provide evidence for the anti-inflammatory activity of 1,8-cineole in asthma and provide new rationale for its use as a mucolytic agent in both upper and lower airway disease. Their studies show that 1,8-cineole is a potent cytokine inhibitor and can be used as a long-term treatment for airway inflammation in bronchial asthma and other steroid-sensitive conditions. They report a novel mechanism of action for 1,8-cineole to inhibit the production of inflammatory mediators in monocytes. They also conclude that their findings explain the effective bronchial dilation reported in their clinical studies using 1,8-cineole. Their data show that the concentration-response curve of 1,8-cineole is similar to a steroid-like mode of action, possibly mediated by nuclear transcription inhibition. Their work suggests that 1,8-cineole has strong anti-inflammatory activity and can be used as a well-tolerated treatment for airway inflammation in obstructive airway conditions, especially in mild bronchial asthma and more severe forms of asthma, and can be used as a supplemental treatment with the goal of being able to reduce or replace glucocorticoids in the long term. In one embodiment of the present invention is an inhaled aerosolized pharmaceutical liquid composition and treatment method for individuals with asthma, COPD and other respiratory diseases to eliminate or reduce the use of oral or inhaled corticosteroid compounds for their medical treatment.

[0117] Worth et al. (2009) conducted a randomized, placebo-controlled, multicenter clinical trial in patients with stable COPD with a concomitant prescription of 1,8-cineole at a dose of 200 mg three times daily in an oral capsule. The primary hypothesis was that 1,8-cineole would reduce the number, severity, and duration of exacerbations. Secondary outcome measures were lung function, dyspnea severity, and quality of life, as well as related adverse effects. They reported significant improvements in airway resistance after one week (-23%) and eight weeks (-21%) of treatment in a placebo-controlled, double-blind study in patients with reversible obstructive ventilatory disorders. They also reported statistically significant reductions in the frequency, duration, and severity of exacerbations during the study period. Their combined findings emphasize that 1,8-cineole not only reduces the rate of exacerbations, but also provides clinical benefits in the form of improved airflow obstruction, reduced dyspnea severity, and improved health status. They also cite that in a placebo-controlled, double-blind study of asthma requiring steroid therapy, long-term treatment with 1,8-cineole (3 × 200 mg / day) resulted in a significant reduction in the need for systemic glucocorticoids. Because glucocorticoids do not interfere with histamine release from mast cells, more studies are needed to determine the effects of 1,8-cineole on histamine release.

[0118] In an in vitro study, Juergens et al. (1998b) investigated the effect of 1,8-cineole capsules (200 mg / day-3 times / day) on arachidonic acid (AA) metabolism in blood monocytes from patients with bronchial asthma. The production of arachidonic acid metabolites LTB4 and PGE2 by isolated monocytes stimulated with the calcium ionophore A23187 was measured in vitro: before treatment with 1,8-cineole, after 3 days of treatment (day 4), and 4 days after cessation of 1,8-cineole (day 8). The in vitro production of LTB4 and PGE2 from monocytes was significantly inhibited on day 4 in patients with bronchial asthma (-40.3%, n=10 and -31.3%, respectively, p=0.1, n=3) and in healthy volunteers (-57.9%, n=12 and -42.7%, n=8, respectively). These authors concluded that 1,8-cineole was shown to inhibit LTB4 and PGE2, both arachidonic acid metabolic pathways.

[0119] In another in vitro study by Juergens et al. (2004), therapeutic concentrations of 1,8-cineole (1.5 μg / mL) significantly inhibited (n=13-19, p=0.0001) cytokine production in lymphocytes, with TNFα, IL-1β, IL-4, and IL-5 inhibited by 92%, 84%, 70%, and 65%, respectively. The production of cytokines TNFα, IL-1β, IL-6, and IL-8 in monocytes was also significantly inhibited (n=7-16, p<0.001) by 99%, 84%, 76%, and 65%, respectively. In the presence of 1,8-cineole (0.15 μg / ml), the production of TNFα and IL-1β by monocytes and IL-1β and TNF-α by lymphocytes were significantly inhibited by 77%, 61%, 36%, and 16%, respectively. These results indicate that 1,8-cineole is a strong inhibitor of TNFα and IL-1β and shows less effect on chemotactic cytokines. Increasing evidence suggests that 1,8-cineole has a role in controlling airway mucus hypersecretion by inhibiting cytokines, suggesting long-term treatment to reduce exacerbations of asthma, sinusitis, and COPD.

[0120] TRPA1 is activated by cigarette smoke and many other environmental pollutants and industrial chemicals. In the respiratory system, TRPA1 is activated, at least in part, by reactive oxygen species, which lead to the production of NF-κB and a range of neuropeptides; including CGRP and substance P, leading to the production of proinflammatory cytokines; including TNFα, IL-1β, IL-4 and IL-5, IL-6 and IL-8. The antioxidants glutathione and N-acetylcysteine ​​have also been shown to reduce the reactive oxygen species produced by cigarette smoke in the lung. Further activation of TRPA1 by reactive oxidant species in the respiratory system has been clearly shown to be blocked by TRPA1 antagonists.

[0121] In one embodiment of the present invention, by combining a natural compound antioxidant and a natural compound TRPA1 antagonist, the TRPA1 antagonist is combined with the antioxidant in a nebulizable pharmaceutical liquid composition to reduce respiratory damage caused by cigarette smoke, environmental and industrial air pollutants, lung irritants and / or damaging chemical warfare agents, and respiratory diseases in a multifunctional manner.

[0122] Transient receptor potential nociceptors and cancer

[0123] Prevarskaya et al. (2007, 2011) and Wu et al. (2010) demonstrated that TRP channels are involved in the regulation of proliferation, differentiation, apoptosis, angiogenesis, migration and invasion during cancer progression, and that the expression and / or activity of these channels are altered in cancer.

[0124] Takahashi et al. (2018) reported that TRPA1 is upregulated by nuclear factor erythroid 2-related factor 2 (NRF2) and promotes oxidative stress tolerance in cancer cells. Cancer cell survival depends on oxidative stress defense against reactive oxygen species that accumulate during tumorigenesis. Together with the known importance of NRF2 in inducing the expression of reactive oxygen species neutralizing genes, they showed that cancer cells mobilize a suite of adaptive mechanisms, including TRPA1-mediated atypical oxidative stress defense as well as typical reactive oxygen species neutralization mechanisms, to cope with severe oxidative challenges. In TRPA1-enriched breast and lung cancer spheroids, TRPA1 was essential for the survival of inner cells that exhibited reactive oxygen species accumulation. Furthermore, TRPA1 promoted resistance to chemotherapy that produces reactive oxygen species, while TRPA1 inhibition blocked xenograft tumor growth and enhanced chemosensitivity. These findings reveal an oxidative stress defense program in which TRPA1 participates, and TRPA1 could be exploited for targeted cancer therapy.

[0125] Wu et al. (2016) reported that TRPA1 mRNA levels were significantly upregulated in tumor specimens compared with normal lung tissue and NSCLC samples in human small cell lung cancer (SCLC). Treatment of respiratory-derived SCLC cell lines with the TRPA1 agonist allyl isothiocyanate, a volatile toxic compound, in vitro caused an increase in intracellular calcium concentration. In an expression profiling and TRPA1 expression assessment of a cohort of 124 NSCLC patients, TRPA1 protein levels were detectable by immunohistochemistry in all cases. In addition to higher primary tumors, TRPA1 upregulation was independently and negatively predictive of disease-specific, distant metastasis-free, and local recurrence-free survival. In addition, Schaefer et al. (2013) reported that TRPA1 was expressed in a panel of human SCLC cell lines. They also reported that TRPA1 mRNA expression was also higher in tumor samples from SCLC patients compared with NSCLC cell tumor samples or non-malignant lung tissue. Stimulation of SCLC cells with allyl isothiocyanate resulted in an increase in intracellular calcium concentration. Furthermore, the authors reported that calcium responses were inhibited by a TRPA1 antagonist. Activation of TRPA1 in small cell lung cancer cells prevented serum starvation-induced apoptosis and thereby promoted cell survival, an effect that could be blocked by inhibition of TRPA1. Conversely, TRPA1 downregulation severely impaired the anchorage-independent growth of small cell lung cancer cells. As TRPA1 appears to play a key role in cell survival of small cell lung cancer cells, the authors suggest that TRPA1 may represent a promising target for therapeutic intervention. Finally, the authors also concluded that exogenous, inhalable TRPA1 activators are able to exert tumor-promoting effects in small cell lung cancer cells.

[0126] Cannabinoid type 2 receptor signaling

[0127] CB2 receptors are peripheral receptors for cannabinoids. They are mainly expressed in immune tissues, indicating that the endocannabinoid system has an immunomodulatory effect. In this regard, CB2 receptors have been shown to regulate immune cell function in vitro and in animal models of inflammatory diseases. A large number of studies have reported that mice lacking CB2 receptors have an aggravated inflammatory phenotype. This suggests that therapeutic strategies aimed at regulating CB2 signaling are expected to be used to treat various inflammatory diseases. CB2 is mainly expressed in immune cells (including neutrophils, eosinophils, monocytes and natural killer cells). In experimental models of various ischemia-reperfusion injury, atherosclerosis / cardiovascular inflammation and other conditions, activation of CB2 receptors by endocannabinoids or selective synthetic agonists has been shown to protect tissues from damage by limiting inflammatory cell chemotaxis / infiltration, activation and related oxidative / nitrosative stress.

[0128] It was also shown that CB2 was upregulated in non-small cell lung cancer tissues, and this upregulation was correlated with tumor size and pathological grade of advanced non-small cell lung cancer (Xu et al., 2019).

[0129] In addition to binding to various phytocannabinoids, including CBD (Ki = 2.680 μM), delta-9-THC (Ki = 0.035 μM), and CBN (Ki = 0.096 μM), CB2 also binds to the endocannabinoids anandamide (AEA) (Ki = 0.371 μM) and 2-arachidonoylglycerol (2-AG) (Ki = 0.650 μM). Importantly, the CB2 receptor also binds to β-caryophyllene (BCP) (Ki = 0.155 μM) (Turcotte et al., 2016), which clearly shows that it is more effective than CBD at lower concentrations. β-Caryophyllene is found in the essential oils of cloves (Syzygium aromaticum), cinnamon (Cinnamomum spp.), black pepper (Piper nigrum L.) and rosemary (Rosmarinus officinalis L), and can be obtained in pure form from natural sources by distillation. Due to the low toxicity of β-caryophyllene, its use in food has been approved by the U.S. Food and Drug Administration. Although β-caryophyllene is a potent CB2 agonist, it is not a cannabinoid compound, nor a CB1 receptor agonist, and has no psychoactive properties. The present invention relates to the use of the natural sesquiterpene compound β-caryophyllene (BCP), and its use as a CB2 agonist in atomizable pharmaceutical liquid preparations.

[0130] Glutathione

[0131] Glutathione is an important water-soluble antioxidant in plants, animals, fungi and some bacteria. Therefore, it can prevent reactive oxygen species such as free radicals, peroxides, lipid peroxides and heavy metals from causing damage to important cell components. In the lung, glutathione plays an important role in regulating immune function and participates in the lung epithelial host defense system (Buhl et al., 1990). The depletion of intracellular glutathione can inhibit the activation of lymphocytes by mitogens, which is very important in lymphocyte-mediated cytotoxicity. Many lung diseases are related to increased oxidant load on the surface of the lung epithelium and damage to lung epithelial cells, including idiopathic pulmonary fibrosis, asbestosis, smoking, adult respiratory distress syndrome, cystic fibrosis and acute and chronic bronchitis. Supplementing glutathione helps other organ diseases related to increased oxidant load, including enhancing the antioxidant protection in the lung epithelial fluid.

[0132] The intracellular redox (oxidation-reduction, redox) state is maintained in homeostasis in the lung and is tightly regulated by the intracellular antioxidant system. Glutathione (γ-L-glutamyl-L-cysteinyl-glycine, GSH) is the most abundant non-protein thiol amino acid and redox buffer in mammalian cells. Very importantly, glutathione provides the first line of defense against reactive oxidant species. Glutathione compounds have a variety of biological effects, including protection of cells against oxidative stress and several toxic molecules, and participation in the synthesis and modification of leukotrienes and prostaglandins. For example, glutathione S-transferase protects cellular DNA from oxidative damage, which can lead to increased DNA mutations or induce DNA damage, thereby promoting cancer.

[0133] Glutathione S-transferases are able to react and bind to a wide range of hydrophobic and electrophilic molecules, including many carcinogens, therapeutic drugs, and many oxidative metabolites, rendering them less toxic and amenable to further modification for excretion from the cell. Glutathione not only interacts directly with reactive oxygen species, serving as a substrate for different enzymes to eliminate endogenous and exogenous compounds, but can also directly bind to xenobiotics such as chemotherapeutic agents. Since many anticancer chemotherapeutic drugs are in fact toxic xenobiotics, this may lead to elevated glutathione levels and, in turn, anticancer drug resistance. However, glutathione is also involved in protecting cells against free radicals, as well as in many cellular functions that are particularly relevant to the regulation of carcinogenesis, including sensitivity to xenobiotics, ionizing radiation, and some cytokines, DNA synthesis, and cell proliferation.

[0134] In cell studies, van der Toorn et al. (2007) demonstrated that the vapor phase of cigarette smoke reduces the free sulfhydryl (-SH) groups of glutathione in solution and in airway epithelial cells. They reported that glutathione is irreversibly modified by unsaturated aldehydes generated during tobacco combustion. In their in vitro experiments, exposure to cigarette smoke demonstrated that almost the entire glutathione pool is converted to the glutathione E-aldehyde component. Enzymatic redox cycling is usually activated after oxidative stress and the formation of the oxidized form of glutathione, glutathione disulfide, but due to the depletion of glutathione to the non-reducible glutathione component, the glutathione pool is lost and therefore the enzymatic redox cycling cannot be activated. Depletion of this reduced glutathione pool may lead to a long-term lack of antioxidant protection. Persistent smokers inhale more reactive oxygen species than can be removed by residual antioxidants, resulting in increased susceptibility to oxidative stress. This makes the synthesis of glutathione essential for cell survival and lung protection. The development of COPD is associated with increased oxidative stress and reduced antioxidant resources. Smoking is the most important factor leading to COPD.

[0135] Smoking-induced cellular stress is critically dependent on intracellular reduced glutathione concentrations. The lung responds to this challenge with an adaptive response that includes upregulation of glutathione antioxidant defenses. Gould et al. (2011) demonstrated that the glutathione adaptive response consists of a coordinated reaction between glutathione synthesis, utilization, recycling, and transport into the lung epithelial cell lining fluid. Elevated levels of glutathione in the lung epithelial cell lining fluid are thought to serve as a defense mechanism to limit the damaging effects of chronic smoking. Gould et al. (2010) also showed that age adversely affects the lung glutathione adaptive response to acute cigarette smoke exposure in mice, and that this response results in increased airway inflammation and increased lung DNA oxidation. In humans, glutathione levels drop dramatically around the age of 45, which is quickly approaching the age at which chronic smokers develop COPD.

[0136] In human studies, Gould et al. (2015) showed that steady-state epithelial lining fluid glutathione levels decrease with age and that elderly smokers have an impaired adaptive epithelial lining fluid glutathione response to smoking and a corresponding increase in inflammation, as evidenced by elevated exhaled nitric oxide (eNO) levels. These authors concluded that glutathione levels and the endogenous ability to increase glutathione levels in response to stimulation are important factors in protecting the lung from the deleterious effects of smoking.

[0137] Rusnack et al. (2000) used human bronchial epithelial cells (HBEC) from biopsy materials of three groups of people: people who smoke and have normal lung function, smokers with normal lung function, and smokers with COPD. They exposed these HBEC cells to cigarette smoke or clean air for 20 minutes. They also measured the intercellular glutathione concentration in HBEC before and after exposure to cigarette smoke. The results showed that when exposed to air only, the HBEC primary culture derived from smokers with normal lung function and COPD patients contained significantly more glutathione than the culture from healthy people who never smoked. These results are consistent with subsequent studies, indicating that smokers endogenously produce more glutathione in the lungs than non-smokers. When HBEC cells were exposed to cigarette smoke, the concentration of intracellular glutathione in all cultures was significantly lower than that of cells exposed to air only. However, the magnitude of the decrease in glutathione concentrations (mean percent change) in HBEC cells exposed to cigarette smoke varied between the study groups: 72.9% in cells from COPD patients, 61.4% in cells from healthy never-smokers, and 43.9% in cells from smokers with normal lung function. The decrease in glutathione in cells from COPD patients was significantly greater than the decrease in glutathione in cells from healthy never-smokers or smokers with normal lung function. They also reported that increased levels of antioxidant capacity (i.e., higher glutathione concentrations) may protect against oxidant-mediated damage.

[0138] Rusnack et al. (2000) also reported that HBECs from COPD patients exhibited greater increases in cell permeability and release of the inflammatory cytokines soluble intercellular adhesion molecule-1 (sICAM-1) and IL-1β than controls from smokers without COPD. They also observed that endogenous increases in glutathione concentrations were associated with decreased epithelial cell permeability and release of the inflammatory cytokines IL-1β and sICAM-1 in HBECs from smokers with normal lung function.

[0139] Buhl et al. (1990) demonstrated that aerosol nebulizer administration of 4 mL of a 150 mg / mL glutathione solution increased glutathione lung epithelial fluid concentration to a concentration of about 337 μM within 25 minutes, which is 7 times the baseline concentration before treatment (45.7 μM), and remained elevated for 2 hours. In contrast, when these authors administered 600 mg of glutathione solution intravenously, they reported no measurable increase in glutathione concentration in lung epithelial fluid. Buhl et al. (1990) proposed that aerosol administration of glutathione is a practical method to significantly increase glutathione levels on the surface of human lower respiratory epithelium. They also reported that aerosol administration of glutathione not only increased lung epithelial fluid glutathione levels, but also had no adverse effects. Their results are consistent with Witschi et al. (1992) who reported that oral administration of glutathione was ineffective in increasing plasma glutathione levels when given to healthy subjects, therefore it is questionable whether oral supplementation of glutathione would help increase lung concentrations.

[0140] Prousky (2008) conducted a literature review to examine the clinical effectiveness of inhaled glutathione as a treatment for various lung diseases and respiratory-related disorders. The author concluded that inhaled glutathione is an effective treatment for a variety of lung diseases and respiratory-related disorders. Even very severe and difficult-to-treat diseases, including cystic fibrosis and idiopathic pulmonary fibrosis, may benefit from inhaled glutathione treatment. The author concluded that glutathione inhalation is very safe and rarely causes serious or life-threatening side effects. He noted that potential applications for glutathione treatment include farmer's lung, pre- and post-exercise, multichemical allergy disorder, and smoking. Prousky (2008) also concluded that glutathione inhalation should not be used to treat primary lung cancer.

[0141] Mah et al. (2012) conducted a structural analysis of the lead-glutathione complex and concluded that the complexation of Pb2+ with glutathione is of great significance for the rational design of chelators for the therapeutic treatment of lead poisoning. One problem associated with commonly used chelators, including EDTA, is that they are not selective and also bind the essential Fe 2+ , Ca 2+ and Zn 2+ metal ions, resulting in relevant toxic effects. These authors concluded that in aqueous solution, Pb 2+ The preference for binding to up to three glutathione ligands via the cysteine-thiolate group suggests that tailor-made chelators with three sulfur donor atoms available for binding may be useful in chelating Pb 2+ Ionic aspects can be very effective.

[0142] N-Acetylcysteine

[0143] N-acetylcysteine ​​(NAC) is a water-soluble antioxidant that is widely used in the treatment of patients with COPD. Its use is reviewed by Dekhuijzen (2004). Preclinical studies and clinical trials have shown that antioxidant molecules such as small thiol molecules (N-acetyl-L-cysteine ​​and carboxymethylcysteine), antioxidant enzymes (glutathione peroxidase), Nrf2-regulated antioxidant defense system activators (sulforaphane), and vitamins such as vitamins C, E, and D can enhance the endogenous antioxidant system and reduce oxidative stress. In addition, they can also slow the progression of COPD. N-acetylcysteine ​​exhibits both direct and indirect antioxidant properties. The free sulfhydryl groups in N-acetylcysteine ​​can interact with the electrophilic groups of reactive oxygen species. The indirect antioxidant effect exerted by N-acetylcysteine ​​is related to its role as a glutathione precursor. Glutathione is an important factor for protecting against internal toxic agents (e.g., cellular aerobic respiration and phagocyte metabolism) and external agents (e.g., NO, sulfur oxides and other components in cigarette smoke, and pollution). The sulfhydryl groups of cysteine ​​neutralize these agents. Maintaining sufficient intracellular glutathione levels is essential for overcoming the harmful effects of toxic agents. The synthesis of glutathione occurs mainly in the liver (as a reservoir) and the lungs. In the case of depletion of glutathione levels or increased demand, additional cysteine ​​can be delivered by N-acetyl-L-cysteine ​​to increase glutathione levels. However, in vivo studies have shown that when N-acetyl-L-cysteine ​​is administered orally, due to its rapid metabolism into glutathione and other metabolites, bioavailability is very low. Therefore, although N-acetyl-L-cysteine ​​is very effective in protecting cells from different sources from the toxicity of active components and reactive oxygen species in tobacco smoke, N-acetylcysteine ​​is unlikely to produce a direct scavenging effect in vivo, particularly when administered orally. Therefore, the bioavailability of N-acetylcysteine ​​itself is very low when administered by the oral route. A more relevant in vivo mechanism for any protective effect that N-acetylcysteine ​​may exert against toxic substances may be due to the fact that N-acetyl-L-cysteine ​​acts as a precursor for glutathione and promotes its biosynthesis. Glutathione will then act as a protective agent and detoxify the active substances by enzymatic and non-enzymatic means.

[0144] Antioxidant supplementation has been studied as a method to combat disease-related oxidative stress. Several antioxidants have been used with varying degrees of success. However, although commonly used antioxidants, including vitamin C, vitamin K, and lipoic acid, can directly neutralize free radicals, they cannot supplement glutathione synthesis and replenish the required cysteine. The cysteine ​​prodrug N-acetylcysteine ​​provides the necessary cysteine ​​for glutathione synthesis and has been shown to be more effective in treating disease-related oxidative stress. N-acetylcysteine ​​has been used clinically to treat a variety of conditions, including drug toxicity (acetaminophen toxicity), human immunodeficiency virus / AIDS, cystic fibrosis, COPD, and diabetes.

[0145] Schmid et al. (2002) reported that treatment of COPD patients with N-acetylcysteine ​​at concentrations of 1.2 mg / day or 1.8 mg / day for 2 months improved erythrocyte morphology, reduced H2O2 concentrations by 38% to 54%, and increased thiol levels by 50% to 68%. Oral administration of N-acetyl-L-cysteine ​​(600 mg / day) increased lung lavage fluid glutathione levels (Bridgeman et al., 1991), reduced superoxide production by alveolar macrophages (Linden et al., 1998), and reduced sputum eosinophil cationic protein concentrations and polymorphonuclear leukocyte adhesion in COPD patients (DeBacker et al., 1997).

[0146] Odewumi et al. (2016) reported that 2.5 mM N-acetylcysteine ​​treatment restored the morphology and viability of human lung cells treated with CdCl2. They concluded that the protection against CdCl2 toxicity was due to the immunomodulatory effects of N-acetylcysteine ​​on the expression of various cytokines in human lung cells co-treated with 2.5 mM N-acetylcysteine ​​and 75 μM CdCl2. These authors concluded after further testing that N-acetylcysteine ​​could be used to treat CdCl2 toxicity in humans. N-acetylcysteine ​​is known to be an effective metal chelator for cadmium with a stability constant of 10 -7.83 M -1 (Romani et al., 2013). In addition, Berthon (1995) reported that cysteine ​​and Pb 2+ (10 -12.2 ) and Hg 2+ (10 -20.5 ) is even greater than the stability constant of the complex with cysteine ​​and Cd 2+ (10 -9.89 These results clearly demonstrate the potential of N-acetylcysteine ​​as an effective chelator of cadmium, mercury, and lead in lung epithelial fluid and blood.

[0147] In a study on idiopathic pulmonary fibrosis and N-acetylcysteine ​​treatment, Hargiwara et al. (2000) demonstrated in mice that inhaled N-acetylcysteine ​​inhibited bleomycin-induced lung fibrosis, a chemical that reduces molecular oxygen to superoxide and hydroxyl radicals, which can then attack DNA and cause strand breaks. In the lung, inflammatory and immune processes are the main pathogenic mechanisms that damage tissue and stimulate fibrosis. These authors concluded that inhaled N-acetylcysteine ​​has the potential to be a potential treatment for interstitial pneumonia, as reactive oxygen species are involved in the development of almost all interstitial pneumonias. They also concluded that since N-acetylcysteine ​​inhibits NF-kB activation, N-acetylcysteine ​​can inhibit the production of chemokines (i.e., IL-8) and the expression of intercellular adhesion molecule-1 (ICAM-1) through the inactivation of NF-κB, thereby reducing the accumulation of inflammatory cells in the lung.

[0148] Rhoden et al. (2004) applied an in vivo model of inhalation exposure to “real-world” particles to confirm the important role of reactive oxygen species in particles with a size of 0.1 μ to 2.5 μ and thus determine the biological effects of particulate air pollution. These authors demonstrated that N-acetylcysteine ​​was effective in preventing particulate air pollution-induced inflammation at doses sufficient to prevent increases in reactive oxygen species and accumulation of thiobarbiturate reactive species and partially reduce protein oxidation. They concluded that the preventive effect of N-acetylcysteine ​​suggests that treatment with low doses of N-acetylcysteine ​​could be used to ameliorate the toxic effects of particulate air pollution.

[0149] Carboxymethylcysteine

[0150] Carboxymethylcysteine ​​(S-carboxymethylcysteine) is a sulfhydryl-containing amino acid compound and has significant mucolytic, antioxidant and anti-inflammatory properties. Carboxymethylcysteine ​​is also effective in maintaining the activity of alpha-1-antitrypsin inactivated by oxidative stress. Alpha-1-antitrypsin inactivation is associated with extensive tissue damage in patients with chronic emphysema. It is reported that the antioxidant and anti-inflammatory properties of carboxymethylcysteine ​​play an important role in the long-term treatment of COPD and reduce the rate of exacerbation. It is reported that carboxymethylcysteine ​​can effectively reduce the concentration of exhaled interleukin-6 and interleukin-8, thereby improving the ability of clinical variables to predict mortality in COPD patients.

[0151] Lambert et al. (2008) reported that the uptake of epigallocatechin-3-gallate (100 μM) by cells was increased 2.5-fold in the presence of 2 mM N-acetylcysteine. They also reported that the increase in cytoplasmic levels of epigallocatechin-3-gallate appeared to be due to the increased stability of epigallocatechin-3-gallate in the presence of N-acetylcysteine. They suggested that the increased growth inhibitory activity observed with the combination of epigallocatechin-3-gallate and N-acetylcysteine ​​may be a result of the activity of the epigallocatechin-3-gallate-2 / -N-acetylcysteine ​​adduct. These authors also reported that the epigallocatechin-3-gallate-2 / -N-acetylcysteine ​​adduct was biologically active and may be more redox active than epigallocatechin-3-gallate alone.

[0152] Bucca et al. (1992) reported that long-term treatment with high-dose vitamin C may improve airway stress symptoms, provide protection against severe air pollution-induced airway and lung damage in industrialized areas, and improve the prognosis of chronic obstructive pulmonary disease.

[0153] Polyphenols and Phytochemicals

[0154] Liang et al. (2017) investigated the effects of daily oral administration of epigallocatechin-3-gallate (50 mg / kg) in rats randomized to sham air (SA) or cigarette smoke exposure (1 h / day for 56 days). They measured oxidative stress and inflammatory markers by analysis of serum and / or bronchoalveolar lavage fluid. (-)-Epigallocatechin-3-gallate treatment ameliorated cigarette smoke-induced oxidative stress and neutrophilic inflammation, as well as airway mucus production and collagen deposition in rats. They concluded that (-)-Epigallocatechin-3-gallate has a therapeutic effect on chronic airway inflammation and airway mucus abnormalities by inhibiting the estimated glomerular filtration rate (EGFR) signaling pathway. They also concluded that supplementation with (-)-epigallocatechin-3-gallate may be a promising therapeutic strategy to limit neutrophil recruitment and treat mucus hypersecretion in the airways of smokers without or with COPD.

[0155] Chan et al. (2009) reported that Chinese green tea (Lung Chen) has protective effects against cigarette smoke-induced air cavity enlargement, goblet cell hyperplasia, and suppresses systemic and local oxidative stress in rats. Approximately 80% of the active ingredient in this green tea is (-)-epigallocatechin-3-gallate.

[0156] Li et al. (2007) reported that pulmonary inflammation is a feature of many lung diseases. Elevated levels of proinflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) have been associated with pulmonary inflammation. These authors demonstrated that various inflammatory agents, including lipopolysaccharide, 12-O-tetradecanoylphorbol-13-acetate, hydrogen peroxide, okadaic acid, and ceramide, were able to induce the production of IL-β and TNF-α by human lung epithelial cells (A-549), fibroblasts (HFL1), and lymphoma cells (U-937). They reported that berberine, a phytochemical and protoberberine alkaloid, was able to inhibit inflammatory agent-induced cytokine production in lung cells and that berberine inhibited cytokine production in a dose-dependent and cell type-independent manner. It was also reported that the inhibitory effect of berberine on cytokine production was due to the inhibition of inhibitory NF-κα phosphorylation and degradation. They concluded that berberine has a potential role in treating lung inflammation.

[0157] Xu et al. (2015) investigated the effects of berberine on cigarette smoke-induced airway inflammation and mucus hypersecretion in mice. Berberine (5 mg / kg-d and 10 mg / kg-d) was administered intraperitoneally to mice exposed to cigarette smoke. Levels of inflammatory cytokines TNF-α, IL-1β, and monocyte chemoattractant protein 1 (MCP-1) in bronchoalveolar lavage fluid were analyzed, and lung tissues were examined for histopathological lesions and goblet cell hyperplasia. They reported that cigarette smoke exposure significantly increased the release of inflammatory cytokines TNF-α, IL-1β, MCP-1 in bronchoalveolar lavage fluid and increased inflammatory cells, and also induced goblet cell hyperplasia and mucin-5ac expression in the mouse airways. When mice were pretreated with berberine, both cigarette smoke-induced airway inflammation and mucus production were inhibited. Cigarette smoke exposure also increased the expression of extracellular signal-regulated kinase (ERK) and P38, while berberine intervention inhibited these changes.

[0158] Several additional polyphenols, phytochemicals, and natural antioxidant compounds can be incorporated into the liquids disclosed herein that are transferred to the gas and aerosol phases for inhaled medication treatment of lung and respiratory diseases, including, but not limited to: berberine, catechins, curcumin, epicatechin, epigallocatechin, epigallocatechin-3-gallate, β-carotene, quercetin, kaempferol, luteolin, ellagic acid, resveratrol, silymarin, nicotinamide adenine dinucleotide, thymoquinone, β-caryophyllene, and dimethyl sulfoxide.

[0159] One embodiment of the present invention is to deliver N-acetyl-L-cysteine, glutathione and a plant-based TRPA1 antagonist along with polyphenols, phytochemicals and water-soluble antioxidants in an aerosolized form for direct inhalation into the respiratory tract.

[0160] Taurine

[0161] Taurine (2-aminoethanesulfonic acid) is an amino acid compound widely distributed in animal tissues, accounting for up to 0.1% of the total body weight of humans. (EFSA Response Letter, EFSA-Q-2007-113, 2009). Taurine is a sulfonic amino acid, relatively non-toxic, and a normal part of the human diet. Dietary sources provide most of taurine, either directly, or synthesized in the liver and brain from methionine or cysteic acid or hypotaurine, or in the heart and kidneys through cysteamine. Taurine stabilizes cell membranes, regulates calcium transport, and can eliminate the toxic effects of hypochlorous acid (HOCl) by forming relatively stable taurine chloride molecules (generated by myeloperoxidase from oxygen free radicals). The ability of taurine to bind to xenobiotics, retinoic acid, and bile salts and its role as the main free amino acid regulating cell osmotic pressure are also examples of its protective functions. Taurine can protect cell membranes by detoxifying destructive compounds and / or directly preventing changes in cell membrane permeability. The protective effects of taurine have been extensively studied, including its effects against arteriosclerosis, lung damage caused by oxidative gases, the deleterious effects of various drugs (e.g., the antitumor agent tauromustine), and the hepatotoxicity of sulfolithocholate, and its effects in promoting the recovery of leukocytes in irradiated rats. In addition, the therapeutic effects of taurine have been used clinically for elderly Alzheimer's disease, macular degeneration, epilepsy, ischemia, obesity, diabetes, hypertension, congestive heart failure, the deleterious effects of smoking, methotrexate toxicity, cystic fibrosis, myocardial infarction, alcohol craving, and neurodegeneration. It is reported that taurine can also prevent carbon tetrachloride-induced toxicity. Carbon tetrachloride is widely used as an industrial degreasing compound and dry cleaning compound (Birdsdall, 1998).

[0162] Patients with cystic fibrosis are deficient in taurine, a condition reflected by a high bile acid glycine / taurine ratio. The cause of this deficiency is thought to be excessive loss of taurine from the digestive tract. Taurine concentrations are particularly high in human neutrophils and lung epithelial cells, at 19 mM and 14 mM, respectively. Although taurine concentrations in extracellular fluids are normally low, cystic fibrosis airway secretions are rich in activated neutrophils, neutrophil-derived products, and cell debris, a condition that could conceivably favor high concentrations of taurine on the lung epithelial surface. Myeloperoxidase concentrations are also very high in the sputum of patients with cystic fibrosis (Cantin, 1994). Several studies have shown a substantial increase in hydrogen peroxide in exhaled breath condensate of COPD subjects compared with healthy controls.

[0163] Taurine has been reported to be an important regulator of oxidative stress, and reduced taurine levels have been shown to trigger a reduction in respiratory chain complexes (Li et al., 2017). Taurine, along with niacin, has been shown to protect against lung damage caused by a variety of oxidants such as ozone, nitrogen dioxide, amiodarone, and paraquat.

[0164] Phagocyte lysosomes contain myeloperoxidase, which catalyzes the oxidant hydrogen peroxide (H2O2) found in the lungs of patients with COPD, asthma, cystic fibrosis, and other respiratory diseases to produce the highly oxidizing hypochlorous acid (HOCl). Reactive oxygen species from environmental sources are common in the lung epithelium. Reactive oxygen species can be found in cigarette smoke, organic combustion products, and oxidant-active air pollutant gases such as ozone and nitrogen dioxide. These reactive oxygen species deplete oxidant defenses and increase the oxidant load in the lung.

[0165] Recent evidence suggests that taurine chloramine (Tau-Cl) is produced by the myeloperoxidase-catalyzed reaction of taurine with endogenously produced highly toxic hypochlorous acid. March (1995) concluded that taurine is critical in the regulation of inflammation. In leukocytes, taurine acts to capture chlorinated oxidants (HOCl). In another study, Tau-Cl has also been shown to reduce lymphocyte proliferation. Tau-Cl has also been shown to inhibit a large number of cytokines, including: IL-1β, IL-6, IL-8, TNF-α (Marcinkiewicz et al., 2014). Several researchers have also attributed the antioxidant effects of taurine to the increase in antioxidant enzyme activity and the reduction in the amount of damaging reactive oxygen species produced by neutrophils. Taurine indirectly increases the activity of endogenous antioxidant defenses. Second, taurine acts as an important anti-inflammatory agent through the production of taurine chloramine.

[0166] One embodiment of the present invention is to deliver N-acetyl-L-cysteine, glutathione and a plant-based TRPA1 antagonist, a water-soluble antioxidant and taurine in an aerosolized form for direct inhalation into the respiratory tract.

[0167] Thiamine

[0168] Thiamine (vitamin B1) is a member of the water-soluble vitamin family and is essential for normal cellular function. Thiamine deficiency can lead to oxidative stress and mitochondrial dysfunction. Thiamine also plays a key role in reducing cellular oxidative stress and maintaining mitochondrial health and function. Thiamine deficiency is detrimental to normal cellular physiology and can lead to impaired oxidative energy metabolism (acute energy failure), making cells susceptible to oxidative stress. Nicotine is known to accumulate in the pancreas and is associated with the production of free radicals, which can cause oxidative stress and thus pancreatic damage. In a clinical study of 163 elderly patients with COPD, more than 75% of the patients were found to be thiamine deficient (less than 75% of the recommended daily allowance (RDA)).

[0169] Dexpanthenol

[0170] Dexpanthenol is an alcohol derivative of pantothenic acid, a component of the B-complex vitamins and an essential component of normal functioning epithelium. Dexpanthenol is a prodrug of vitamin B5, a precursor of coenzyme A, required for acetylation reactions, and involved in the synthesis of acetylcholine. Dexpanthenol plays a major role in cellular defense and repair systems against oxidative stress and inflammation. The use of dexpanthenol as an antioxidant strategy has been reported to be effective in the prevention and treatment of pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic progressive lung disease of unknown cause that is associated with inflammation, oxidative stress, and accumulation of fibroblasts / myofibroblasts, leading to abnormal deposition of extracellular collagen, especially in the early stages of the disease (Ermis et al., 2013).

[0171] As used herein, the term "vitamin" encompasses provitamins and related compounds.

[0172] L-Theanine

[0173] L-theanine is a water-soluble amino acid isolated from green tea (Camellia sinensis) that has anti-inflammatory activity, antioxidant properties, and hepatoprotective effects. Hwang et al. (2017) reported that L-theanine treatment significantly reduced inflammatory cells in bronchoalveolar lavage fluid (BALF). They also reported that histological studies showed that L-theanine significantly inhibited mucus production and inflammatory cell infiltration in the respiratory tract and blood vessels. L-theanine administration also significantly reduced the production of IgE, monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-4, IL-5, IL-13, tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ) in BALF. L-theanine also significantly reduced reactive oxygen species and the activation of nuclear factor κB (NF-κB) and matrix metalloproteinase-9 in BALF. These authors suggest that L-theanine reduces asthmatic airway inflammation, possibly via the oxidative stress-responsive NF-κB pathway, highlighting the potential of L-theanine as a useful therapeutic agent for asthma management.

[0174] Several studies have reported that theanine inhibits the growth of hepatoma, prostate cancer, and colon cancer cells (Friedman et al., 2007). Theanine has been shown to have anticancer activity against the growth of human lung cancer and leukemia cells as well as the migration and invasion of human lung cancer cells (Liu et al., 2009). They also reported that theanine significantly inhibited the growth of human lung cancer A549 and leukemia K562 cells in vitro and ex vivo. In addition, they also demonstrated that theanine also significantly inhibited the migration and invasion of A549 cells.

[0175] Resveratrol

[0176] Resveratrol has been shown to have anti-inflammatory and anti-asthmatic properties in a mouse model of allergic asthma. Although less potent than glucocorticoids, resveratrol appears to be more effective in inhibiting inflammatory activity. Clinical use of glucocorticoids carries a high risk of side effects, and the role of glucocorticoids is controversial, especially in non-eosinophilic asthma. Resveratrol has been shown to inhibit the development of non-eosinophilic asthma. Resveratrol has the potential to be an alternative to corticosteroids for the treatment of non-allergic forms of asthma. Resveratrol holds great promise as a natural agent, as it has been shown to have beneficial effects in a variety of diseases, including cancer, cardiovascular disease, neurological disorders, and obesity.

[0177] The anti-inflammatory and antioxidant properties of resveratrol in the lung have been confirmed in preclinical models. Resveratrol reduces neutrophils and proinflammatory cytokines in lung tissue (Birrell et al., 2005). Resveratrol treatment in vitro inhibits the release of inflammatory cytokines from bronchoalveolar lavage macrophages and human bronchial smooth muscle cells isolated from COPD patients. These anti-inflammatory effects of resveratrol are attributed to the inhibition of NF-kB activation. Resveratrol also showed an inhibitory effect on autophagy in human bronchial epithelial cells in vitro and in a COPD mouse model induced by cigarette smoke in vivo (Liu et al., 2014). These researchers reported that cigarette smoke exposure increased the number of inflammatory cells in the lungs, while the production of TNF-α and IL-6 in bronchoalveolar lavage fluid also increased. Resveratrol treatment alleviated cigarette smoke-induced lung inflammation. Resveratrol restored the activity of superoxide dismutase, GSH peroxidase, and catalase in mice treated with cigarette smoke. It was also demonstrated that cigarette smoke significantly enhanced NF-κB production and NF-κB DNA binding activity, while resveratrol pretreatment attenuated both. These authors concluded that resveratrol attenuated cigarette smoke-induced lung oxidative damage, including decreased NF-κB activity and increased heme oxygenase 1 (HO-1) expression and activity.

[0178] Nicotinamide adenine dinucleotide

[0179] Nicotinamide adenine dinucleotide (NAD + ) is a major metabolic cofactor and coenzyme in eukaryotic cells, which plays an important role in regulating cellular metabolism and energy homeostasis. + (i.e., NADH) serves as the major electron donor in the mitochondrial respiratory chain, which involves the production of adenosine triphosphate by oxidative phosphorylation. Mammalian NAD + The biosynthesis of NAD occurs through de novo and salvage pathways and involves four major precursors, including the essential amino acids L-tryptophan (Trp), nicotinic acid (NA), nicotinamide (NAM), and nicotinamide riboside (NR). Nicotinamide riboside (NR) is a precursor of NAD. + NA, NAM and NR are all variants of vitamin B3.

[0180] Sirtuins are a unique class of NAD +Sirt1 is a sirtuin-dependent deacetylase that regulates a variety of biological functions such as aging, metabolism, and stress resistance. In recent years, it has been shown that sirtuins may have anti-inflammatory activity by inhibiting pro-inflammatory transcription factors such as NF-kB. Serotonin transporter 1 (Sert1) is one of the seven members of the sirtuin family. It has been shown that Sirt1 may also limit inflammatory processes by inhibiting NF-kB and activator protein 1 (AP-1), two transcription factors that are closely associated with the expression of pro-inflammatory cytokines such as TNF-α. It is known that lung cells from patients with chronic obstructive pulmonary disease (COPD) and rats exposed to cigarette smoke show reduced Sirt1 expression associated with increased NF-kB activity and matrix metalloproteinase-9 expression compared with lung cells from healthy controls.

[0181] In one embodiment of the present invention is a liquid composition comprising NAD + , one or more of NA, NAM and NR, plant-based TRPA1 antagonists, natural thiol-containing amino acid compounds, CB2 agonists, amino acids, naturally occurring antioxidants, additional vitamins and bioflavonoid compounds, and heavy metal complexing compounds.

[0182] Antioxidants

[0183] Oxidants as well as imbalances between the cellular redox state and the lung defense system play a role in the onset and progression of lung malignancies. Lung cancer is the most common malignancy worldwide, highly associated with smoking, and its incidence is increasing. There is clear evidence linking free radicals to both carcinogenesis and tumor behavior. A leading hypothesis explaining the importance of oxidants and imbalances in the cellular redox state in lung cancer development is that an altered pro-oxidant intracellular environment favors mutation and / or inactivation of tumor suppressor genes and activation of oncogenes, thereby altering cell growth, survival, and apoptosis (Kinnula et al., 2004).

[0184] Wang et al. (2018) reported that glutathione concentrations are relatively high in a variety of cancer cells, such as lung cancer, breast cancer, pancreatic cancer, and leukemia. In addition, it has been confirmed that the anti-apoptotic characteristics of cancer cells are associated with increased intracellular glutathione levels. Several reports have shown that reducing intracellular glutathione content activates a variety of apoptosis-related enzymes. Therefore, reducing glutathione concentrations has become a new strategy for anti-tumor treatment.

[0185] Dysregulation of glutathione biochemistry in tumors has been observed in many different murine and human cancers. A review by Ortega et al. (2011) reported that glutathione has been shown to play an important role in combating tumor microenvironment-associated invasion, apoptosis evasion, colonization ability, and multidrug and radiation resistance. Elevated levels of glutathione and resistance to chemotherapeutic drugs (e.g., platinum-containing compounds and alkylating agents, such as cisplatin and melphalan, anthracyclines, doxorubicin, and arsenic) have been observed. Zu et al. (2017) noted that glutathione depletion is considered a promising strategy to reduce chemoresistance and induce apoptosis through both extrinsic and intrinsic apoptotic pathways.

[0186] Thymoquinone is a bioflavonoid volatile oil extracted from the seeds of the plant Nigella sativa, which has antioxidant, anti-inflammatory, neuroprotective, antiallergic, antiviral, antidiabetic and anticancer properties. In addition, it has been determined to have an inhibitory effect on histamine receptors. Thymoquinone has been shown to inhibit the production of leukotriene B4, thromboxane B2 and inflammatory mediators through the 5-lipoxygenase and cyclooxygenase pathways of arachidonic acid metabolism. The antioxidant and immunomodulatory properties of thymoquinone have also been confirmed. Thymoquinone has been shown to be effective in treating cancer as well as allergic diseases, including allergic rhinitis, atopic eczema and asthma. Kalemci et al. (2013) demonstrated that injection of thymoquinone reduced chronic inflammatory changes in an experimental asthma model established in mice. Azemi et al. (2016) reported that mice receiving black seed oil showed a significant reduction in the number of eosinophils and a potential inhibitory effect on the mRNA expression levels of Th2-driven immune response cytokines and mucins, resulting in a reduction in the production of interleukins and mucins in allergic asthma. They concluded that black seed oil has anti-inflammatory and immunomodulatory effects during lung allergic reactions and can be a promising treatment for human allergic asthma.

[0187] El-Sakkar et al. (2007) induced significant lung inflammation in guinea pigs, as evidenced by elevated levels of IL-8, LTB4, NE and TNF-α (in bronchoalveolar lavage fluid) and myeloperoxidase (in lung tissue homogenate). Cigarette smoke also resulted in a significant increase in glutathione peroxidase activity in lung tissue. Lipid peroxidation was significantly increased in guinea pigs exposed to cigarette smoke, as evidenced by an increase in lung tissue malondialdehyde. Pretreatment of guinea pigs exposed to cigarette smoke with thymoquinone significantly reduced IL-8 in bronchoalveolar lavage fluid, but did not significantly alter bronchoalveolar lavage fluid leukotriene B4 (LTB4) levels. Levels of inflammatory mediators, namely neutrophil elastase, TNF-α and malondialdehyde, were also significantly reduced after thymoquinone pretreatment.

[0188] El-Sakkar et al. (2007) also reported that pretreatment of guinea pigs exposed to cigarette smoke with epigallocatechin-3-gallate (the main polyphenol in green tea) mitigated the inflammatory consequences of exposure to cigarette smoke. This was confirmed by a significant decrease in the levels of IL-8, LTB4, NE, TNF-α (in bronchoalveolar lavage fluid) and myeloperoxidase (in lung homogenate). Epigallocatechin-3-gallate also mitigated cigarette smoke-induced oxidative stress, as evidenced by increased glutathione peroxidase activity and a significant decrease in myeloperoxidase levels in lung homogenate, although superoxide dismutase activity was not significantly affected.

[0189] El-Sakkar et al. (2007) concluded that thymoquinone and epigallocatechin-3-gallate had protective effects against cigarette smoke-induced lung inflammation and oxidative damage in guinea pigs. They reported that the protective effects on the lungs may be the result of effects on inflammatory cells, cytokine production, and oxidative stress. They also reported that if their results are extrapolated to humans, it would indicate that thymoquinone and epigallocatechin-3-gallate have the potential to be novel therapeutic agents for patients with chronic obstructive pulmonary disease and could be used to design and develop new therapeutic strategies aimed at limiting cellular inflammation and oxidative damage.

[0190] Electronic atomization device

[0191] Electronic cigarettes, also known as vape pens, electronic cigars or electronic cigarette vaporization devices, are generally used as electronic nicotine delivery systems, which heat generates an atomized mixture containing flavored liquids and nicotine for the user to inhale. Electronic thermal atomization devices are also used for the inhalation of CBD, THC and selected vitamins. The wide diversity of electronic cigarettes stems from the various nicotine concentrations present in the e-cigarette liquid, the various e-cigarette liquid volumes for each product, different carrier compounds, additives, flavors, coil impedances and battery voltages. Regardless of the exact design, each electronic cigarette device has a common functional system consisting of a rechargeable lithium battery, a vaporization chamber and a cartridge. The lithium-ion battery is connected to the vaporization chamber containing the atomizer. In order to deliver nicotine to the lungs, the user inhales through the mouthpiece, the airflow triggers the sensor, and then turns on the atomizer. The atomizer thermally vaporizes the liquid nicotine in the small cartridge and delivers it to the lungs.

[0192] Ultrasonic e-cigarette vaporization devices that do not heat the liquid in the e-vaporization device like typical commercially available e-cigarettes or thermal atomization devices are available and can also be used to atomize the liquids disclosed in the present invention.

[0193] Recently, nicotine content was studied on 27 e-cigarette liquid preparations obtained in the United States. Nicotine content reportedly varies between 6mg / L and 22mg / L (Peace, 2016). In another study, 16 e-cigarettes were selected based on their popularity in the Polish, British and American markets, and nicotine vapor production was evaluated in an automatic smoking machine. The experimental conditions were designed to simulate the puffing conditions of human e-cigarette users. The total nicotine level in the vapor produced by 20 series of 15 puffs varied between about 0.5mg and 15.4mg. Most of the e-cigarettes analyzed effectively delivered nicotine in the first 150-180 puffs. On average, 50%-60% of the nicotine in the cartridge was vaporized.

[0194] Recently, it was reported that the average nicotine concentration in Juul e-cigarettes was 60.9 mg / mL, 63.5 mg / mL, and 41.2 mg / mL in un-vaped, vaped, and aerosol samples, respectively. The effective transfer of nicotine to aerosol was between 56% and 75% (Omaiye et al., 2019). Juul reported that each of their flavorpods contained 0.7 mL of liquid.

[0195] In November 2018, the FDA’s Center for Tobacco Products (CTP) banned all flavored nicotine e-cigarettes except tobacco, mint, and menthol flavors due to the formation of toxic compounds inhaled from thermally generated aerosolized liquids containing nicotine. In recent studies, specific flavor aldehyde compounds, including benzaldehyde, cinnamaldehyde, citral, ethyl vanillin, and vanillin, were reported to react with other common compounds present in liquids used in e-cigarette vaporization, such as propylene glycol (PG), at room temperature and elevated temperatures to form toxic flavor aldehyde PG acetals. These flavor aldehyde PG acetals were also reported to be detected in commercial e-cigarette liquid compounds at ambient temperatures. When these flavor aldehyde PG acetals in e-cigarette liquids are subsequently thermally aerosolized and inhaled in e-cigarette vaporization devices, they can cause serious health effects in individuals using these products. Flavor aldehyde PG acetals have also been shown to activate TRPA1 and aldehyde-insensitive TRPV1 stimulators and inflammation-related receptors (Erythropel et al., 2018). It is clear that activation of the inflammatory nociceptors TRPA1 and TRPV1 by the flavor aldehyde PG acetal in the lungs of individuals who use e-cigarette vaporization products is extremely unhealthy for these individuals.

[0196] In another recent study, toxic ambient temperature reaction products vanillin PG acetal and vanillin VG acetal were detected in JUUL e-liquid and transferred to the e-cigarette aerosol at 68.4% and 59%, respectively. Nicotine and benzoic acid were also transferred from JUUL e-liquid to the e-cigarette aerosol at 98.6% and 82.5%, respectively (Erythropel et al., 2019).

[0197] In one embodiment of the present invention, a nicotine-containing atomizer liquid is provided that does not contain aldehyde flavoring agents and does not form toxic flavoring acetal compounds at ambient or elevated temperatures, and is safer to use in electronic cigarettes and other hot liquid atomizing devices than existing electronic cigarette liquids available on the market to date. In other embodiments of the present invention, a nicotine-containing atomizer liquid is provided that provides health benefits to the respiratory system of individuals who are nicotine users. In another embodiment of the present invention, a method of using a liquid composition containing nicotine and a plant-based TRPA1 antagonist, a natural compound containing thiol amino acids, a CB2 agonist, an amino acid, a naturally occurring antioxidant, an additional vitamin, a bioflavonoid compound, and a heavy metal complexing compound, which, when hot atomized, provides a source of nicotine and respiratory health benefits from the non-nicotine components of the composition.

[0198] Recently, companies have begun marketing thermal atomization systems where vitamins are inhaled for vitamin supplementation. VitaminVape, Q Sciences, Biovape, and Nutrovape Vita are examples of companies that produce and market e-cigarette vaporization systems for vitamin supplementation. Inhalation can be an inefficient way to take vitamins because the concentration of vitamins required throughout the body may be higher than what can be delivered via e-cigarette vaporization. Inhalation is generally reserved as a delivery mechanism for drugs that require very small doses or are targeted to the lungs.

[0199] Quitting smoking

[0200] The most important way to reduce ongoing damage to an active smoker’s general health, and in particular, their respiratory system, is to quit smoking completely and to break exposure to and addiction to nicotine. While quitting smoking eliminates ongoing damage to the respiratory system caused by cigarette smoke, it cannot reverse past damage to the respiratory system caused by past smoking, disease that is already active in an individual due to exposure to cigarette smoke, and future disease that may result from past smoking activity. Historically, it has been well documented that cumulative exposure to smoking, usually expressed as pack-years (i.e., packs per day multiplied by years of smoking), is a major factor in the risk of lung cancer and COPD. Recently, it has been shown that duration of smoking is more strongly associated with COPD than pack-years alone (Bhatt et al., 2018). These researchers analyzed cross-sectional data from a large multicenter cohort (10,187 individuals) of current and former smokers. The primary outcome measure was airflow obstruction, measured by the FEV1 / FVC ratio and other parameters including FEV1 alone. They reported a linear relationship between the FEV1 / FVC ratio and years of active smoking, revealing that duration of smoking is more influential than individual pack-years of smoking. Likewise, there was a strong relationship between smoking duration and reduced FEV1 values.

[0201] Nicotine replacement therapy (NRT) is a recognized smoking cessation method that provides individuals with nicotine in the form of gum, patches, sprays, inhalers, or lozenges without the other harmful chemicals found in tobacco and its byproducts. NRT gum and lozenges are available without a prescription and provide 2mg to 4mg per patch. NRT patches provide a passive time-integrated dose of nicotine per day. Nicoderm CQ is an over-the-counter patch that provides 21mg per day (step 1), 14mg per day (step 2), and 7mg per day (step 3). Nicotrol patches are also available in a 3-step system of 15mg per day (step 1), 10mg per day (step 2), and 5mg per day (step 3). NRT helps relieve some of the physical nicotine withdrawal symptoms, allowing a person to focus more on the psychological aspects of quitting. Many studies have shown that using NRT can nearly double the chances of successfully quitting smoking.

[0202] In one embodiment of the invention, atomizable liquid compositions and methods of using these liquid compositions include nicotine salts as part of a nicotine replacement therapy smoking cessation system, providing simultaneous treatment of lung and respiratory diseases and the effects from a person's smoking history. In one embodiment of the invention are compositions comprising nicotine salts, plant-based TRPA1 antagonists, natural sulfhydryl amino acid-containing compounds, CB2 agonists, amino acids, naturally occurring antioxidants, vitamins and flavonoid compounds, and heavy metal complexing compounds.

[0203] Glutathione

[0204] The use of glutathione in the present invention and the results reported in Examples 15 and 16 are unexpected, as asthma is a condition for which known side effects of inhaled glutathione (including dyspnea, bronchoconstriction, and cough) have led researchers and practitioners to discourage the use of glutathione for asthma (Prousky et al., 2008). The effectiveness of using glutathione in the present invention is further unexpected based on a study published by Marrades et al. (1997), which reported that inhaled glutathione caused major airway narrowing (change from baseline: FEV1 of -19%, total lung resistance of +61%) and induced cough (four patients) or dyspnea (three patients). In contrast, control patients treated with inhaled saline solution alone had a negligible change in FEV1 of -1% and a small change in total lung resistance of +17%.

[0205] Inhaled glutathione is also known to reduce zinc levels in the blood. Reduced serum zinc levels can reduce immune function and can potentially increase infections, such as bronchitis or pneumonia.

[0206] A person of ordinary skill in the art would not recommend inhaled glutathione because it is contraindicated for asthma on several medical websites, including WebMd (https: / / www.webmd.com / vitamins / ai / ingredientmono-717 / glutathione, “Side Effects & Safety”), where the side effects of asthma include: “If you have asthma, do not inhale glutathione. It can increase some asthma symptoms.”

[0207] Those of ordinary skill in the art will be taught not to use glutathione in combination with other compounds in this formulation for treating individuals with asthma. Surprisingly and unexpectedly, the studies leading to the present invention have shown that the use of glutathione is very effective in raising the FEV1 levels of patients who do suffer from asthma. One of the asthmatic patients, who had smoked 2 packs a day for 28 years (56 pack years), had the unexpected result of 45.1% FEV1 reversibility after 53 days of treatment, and his normal FEV1 percentage increased from 67.2% to 97.4%. This is contrary to what Marrades et al. (1997) taught those of ordinary skill in the art.

[0208] N-Acetylcysteine

[0209] N-acetylcysteine ​​(NAC) was used as an "antioxidant" in studies investigating gene expression, signaling pathways, and outcomes in acute and chronic lung injury models. It is also known that N-acetylcysteine ​​can also undergo autooxidation and also act as an oxidant. Chan et al. (2001) demonstrated that N-acetylcysteine ​​can act as an oxidant leading to activation of the key pro-inflammatory signaling pathway nuclear factor κB (NF-κB).

[0210] According to the online medical website WebMd (https: / / www.webmd.com / vitamins / ai / ingredientmono-1018 / n-acetyl-cysteine), when N-acetylcysteine ​​is administered by inhalation, it can cause oral inflammation, runny nose, drowsiness, clammy coldness, and chest tightness. In addition, according to WebMd, there is concern that inhaled N-acetylcysteine ​​may cause bronchospasm in asthma patients. The National Institutes of Health reports that N-acetylcysteine ​​can cause inflammation of the airways, leading to runny nose, bronchospasm, oral inflammation, and bleeding. Due to the known side effects of N-acetylcysteine, those of ordinary skill in the art are taught not to use N-acetylcysteine ​​for inhaled treatment of individuals with COPD, asthma, and other respiratory diseases.

[0211] Considering that N-acetylcysteine ​​can act as an oxidant, leading to the formation of NF-κB and causing bronchospasm in asthmatic patients, it is surprising that the use of N-acetylcysteine ​​in the formulations of the present invention in Examples 15 and 16 showed a reduction in respiratory inflammation, as evidenced by a reduction in the FEV1 and FVC lung function parameters.

[0212] Vitamin B12

[0213] According to the health website Healthline (https: / / www.healthline.com / health / food-nutrition / vitamin-b12-side-effects), side effects of taking vitamin B12 orally or by inhalation include increased anxiety, pulmonary edema, and congestive heart failure. It is also reported to increase the risk of swelling of the trachea and bronchial tubes. Due to the known side effects of methylcobalamin, a person of ordinary skill in the art would be taught not to use methylcobalamin (vitamin B12) in liquids used for inhalation treatment of respiratory diseases. Although methylcobalamin is known to cause increased anxiety in some patients, individuals evaluated in preclinical trials as disclosed in Examples 15 and 16 surprisingly and unexpectedly reported significantly lower anxiety levels after treatment.

[0214] Interaction of one component with other components

[0215] Surprising and unexpected results were achieved by administering liquid formulations to patients by heat-induced atomization disclosed in Example 15 and ultrasonic membrane atomization disclosed in Example 16, because the individual compounds in these formulations have complementary and synergistic effects. For example, although the primary use of 1,8-cineole in the formulations disclosed in the present invention is as a TRPA1 antagonist, it also acts as a TRPM8 agonist to a lesser extent, modulates immune function, acts as an antioxidant, is bacteriostatic and fungistatic, and inhibits the production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-4 (IL-4), interleukin-5 (IL-5), leukotriene B4 (LTB4), thromboxane B2 (TXB2), and prostaglandin E2 (PGE2). 1,8-cineole has also been shown to reduce anxiety in a human clinical trial on preoperative patients. Unexpectedly, this anxiolytic property of 1,8-cineole is very helpful for patients with dyspnea, which can lead to anxiety and, in severe cases, panic. Verbal qualitative reports were made by patients who were administered the formulations in Examples 15 and 16, reporting feeling more relaxed, significantly increased energy levels, greater endurance under normal activities and under exercise conditions, lower anxiety levels, and less anxiety compared to taking other medications to treat their illnesses. Typical inhaled steroid administration has side effects, including tremors, nervousness, and a burning sensation in the chest. Unexpectedly, in the present invention, no patient reported any adverse side effects associated with inhalation treatment with the formulations disclosed in Examples 15 and 16.

[0216] The primary and secondary effects of 1,8-cineole unexpectedly achieve synergy with β-caryophyllene, the primary effect of which in the formulation disclosed in the present invention is to reduce inflammation as a CB2 agonist. In the present invention, β-caryophyllene also has a secondary effect as an antioxidant, and in addition to inhibiting the production of proinflammatory cytokines such as TNF-α, IL-1β, IL-6, it also acts as an analgesic, anti-inflammatory, neuroprotective, antidepressant, antianxiety and antioxidant compound. 1,8-cineole and β-caryophyllene are used together to provide different and complementary primary anti-inflammatory functions as TRPA1 antagonists and CB2 agonists, respectively, and 1,8-cineole and β-caryophyllene unexpectedly complement each other through the synergistic effects of the primary and secondary properties of each compound. These antioxidant properties of 1,8-cineole and β-caryophyllene also unexpectedly act synergistically with glutathione and N-acetylcysteine, which serve as the primary antioxidants and sulfhydryl-containing amino acids in the disclosed formulations.

[0217] One of ordinary skill in the art would generally have been taught not to use the β-caryophyllene preparations disclosed in the present invention because it has been shown to be a TRPA1 agonist (activator) that causes inflammation (Moon et al., 2015). Therefore, one of ordinary skill in the art would have thought that it would not be desirable to include β-caryophyllene in a preparation because it would excite the TRPA1 receptor, causing inflammation and coughing.

[0218] For the compositions described herein, the components may, for example, be within the following ranges:

[0219] 1,8-cineole, borneol, camphor, 2-methylisoborneol, fenchyl alcohol, or cardamomine - from about 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3%, or 10% to about 0.03%, 0.1%, 0.3%, 1%, 3%, 10%, or 30%;

[0220] glutathione, N-acetylcysteine, carboxymethylcysteine, taurine, or methionine - from about 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3%, or 10% to about 0.03%, 0.1%, 0.3%, 1%, 3%, 10%, 20%, 30%, or 50%;

[0221] cobalamin, methylcobalamin, hydroxocobalamin, adenosylcobalamin, cyanocobalamin, cholecalciferol, thiamine, dexpanthenol, biotin, niacin, niacinamide, nicotinamide riboside, or ascorbic acid - from about 0.0001%, 0.0003%, 0.001%, 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1% or 3% to about 0.0003%, 0.001%, 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3% or 10%;

[0222] Citric acid or ethylenediaminetetraacetic acid (EDTA) - about 0.0001%, 0.0003%, 0.001%, 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1% or 3% to about 0.0003%, 0.001%, 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3% or 10%;

[0223] berberine, catechin, curcumin, epicatechin, epigallocatechin, epigallocatechin-3-gallate, beta-carotene, quercetin, kaempferol, luteolin, ellagic acid, resveratrol, silymarin, nicotinamide adenine dinucleotide, or thymoquinone - from about 0.001%, 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1% or 3% to about 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3% or 10%;

[0224] Alanine, leucine, isoleucine, lysine, valine, methionine, L-theanine, or phenylalanine - from about 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3%, or 10% to about 0.03%, 0.1%, 0.3%, 1%, 3%, 10%, 30%, or 50%;

[0225] beta-caryophyllene, cannabinoids, cannabidiol, or cannabinol - about 0.001%, 0.003%, 0.005%, 0.01%, 0.03%, 0.1%, 0.3%, 1% or 3% to about 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3%, 5% or 10%;

[0226] Nicotine - about 0.001%, 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1%, 2.5%, or 3% to about 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1%, 2.5%, 3%, or 10%;

[0227] Lubricating, emulsifying or viscosity-increasing compounds - from about 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3% or 10% to about 0.03%, 0.1%, 0.3%, 1%, 3%, 10%, 30%; and

[0228] Glycerin - about 1%, 3%, 10%, 30% or 50% to about 10%, 30%, 50%, 70%, 80%, 90%, 95% or 98%.

[0229] For example, the pH can be about 5, 5.5, 6, 6.5, 7, 7.2, 7.5, or 8 to about 5.5, 6, 6.5, 7, 7.2, 7.5, 8, or 8.5.

[0230] The present invention is further described in the accompanying drawings, the following examples and experiments, which are only for the purpose of illustrating specific embodiments of the present invention and should not be construed as limiting the scope of the present invention in any way. The composition of the present invention may comprise, consist essentially of or consist of the necessary and optional ingredients and components described herein. As used herein, "consisting essentially of" means that a composition or component may include additional ingredients, but the condition is that the additional ingredients do not substantially change the basic and novel features of the claimed composition or method. The entire contents of all publications cited herein are incorporated herein by reference.

[0231] Example

[0232] The following examples are provided to illustrate, but not to limit, the claimed invention.

[0233] Example 1

[0234] In Example 1, a composition and a manufacturing method of a drug liquid are disclosed, the drug liquid is atomized, vaporized or both, and it contains 1,8-cineole, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, emulsifier, vegetable glycerin, water, sodium bicarbonate (as needed) and preservative (as needed). The manufacturing method consists of: a certain amount of nitrogen-purged purified sterile water or isotonic saline solution is mixed and dissolved with ascorbic acid powder or crystals, sodium bicarbonate and preservative (if needed), and then a certain amount of N-acetylcysteine, glutathione and methylcobalamin are added, and then a certain amount of vegetable glycerin (if needed) is added and mixed until the liquid composition is uniform. Nitrogen purging can be used throughout the mixing period to minimize the oxygenation of water in the mixture and the oxidation of the compound. Then 1,8-cineole is mixed separately with an emulsifier, and after the mixture is uniform, it is then slowly added to the mixture and slowly mixed until it is dissolved in the liquid to minimize the volatilization of 1,8-cineole. Mixing can be performed in a zero or low headspace reactor to further minimize the volatilization of 1,8-cineole and oxidation of compounds in the mixture. If a certain amount of 1,8-cineole is added to the mixture at a concentration greater than the solubility of 1,8-cineole in the mixture, 1,8-cineole can be emulsified in the liquid composition with the addition of a suitable emulsifier, such as Tween 20 (also known as polysorbate 20) and polyoxyethylene (20) sorbitan monooleate. Mixing is limited to mixing required to produce a stable single-phase homogeneous solution or emulsion and to minimize the volatilization of 1,8-cineole. The method of using the liquid composition in Example 1 includes, but is not intended to be limited to, placing a certain amount of the composition in an electronic cigarette vaporization device, an electronic thermal vaporization device, a nebulizer, an ultrasonic nebulizer, an ultrasonic electronic cigarette vaporization device, or an inhaler, and inhaling the atomized vapor obtained by producing the atomized mixture. The liquid composition as a TRPA1 antagonist that can be nebulized or vaporized in Example 1 can be optionally made of borneol or a mixture of 1,8-cineole and borneol, and the mixture of 1,8-cineole and borneol is in the same or different total concentration range compared to the range when 1,8-cineole is used alone. Such nebulizable liquid compositions are disclosed in Table 1 (in this article, when discussing compositions or mixtures, unless otherwise specified, the term "percent" (%) generally refers to weight percentage). The nebulizable liquid composition can be transferred to a container that can store one or more doses, the headspace of the container may contain or not contain nitrogen, and the container may be refrigerated or not refrigerated.

[0235] Table 1. Basic inhalation fluids

[0236]

[0237]

[0238]

[0239] Example 2

[0240] In Example 2, a preferred composition and manufacturing method of a pharmaceutical liquid is disclosed, which is atomized, vaporized, or both using a nebulizer, and contains 1,8-cineole, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifier, a sterile saline solution, sodium bicarbonate (as needed), and a preservative (as needed). The manufacturing method consists of mixing 96.09g of a nitrogen-purged 0.9% sterile saline solution with 0.01g of ascorbic acid powder and dissolving the ascorbic acid, then adding 1.35g of N-acetylcysteine, 1.35g of glutathione, 0.003g of methylcobalamin, and mixing until the liquid composition is uniform. Then add a mixture of 0.80g of 1,8-cineole and 0.40g of polysorbate 20 and slowly mix until they are dissolved together. Once the 1,8-cineole and polysorbate 20 are uniformly mixed, the mixture is added to the liquid mixture and dissolved into the liquid to minimize the volatilization of the 1,8-cineole. Mixing is limited to the mixing required to produce a stable single-phase uniform solution and minimize the volatilization of 1,8-cineole. The pH of the solution is then measured and an amount of sodium bicarbonate is added to raise the pH to about 7.20. A certain amount of preservative may be added, or the mixture may be refrigerated before use. The method of using the composition of the liquid composition in Example 2 includes but is not intended to be limited to placing the composition in an ultrasonic, vibrating mesh or jet nebulizer and inhaling the vapor obtained by producing the atomized mixture. The method of using the liquid composition in Example 2 includes adding about 1 mL to about 5 ml of the mixture to a liquid nebulizer for inhalation by the patient. This liquid composition is disclosed in Table 2.

[0241] Table 2. Preferred base nebulizer fluids

[0242]

[0243]

[0244] Example 3

[0245] In Example 3, a preferred pharmaceutical composition and a manufacturing method of a drug liquid are disclosed, wherein the drug liquid is atomized, vaporized, or both in an ultrasonic or thermal vaporization device, and comprises 1,8-cineole, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifier, vegetable glycerin, sterile deionized water, sodium bicarbonate (as needed), and a preservative (as needed). The manufacturing method consists of mixing 16.94g of nitrogen-purged sterile deionized water with 0.01g of ascorbic acid powder and dissolving the ascorbic acid, then adding 1.20g of N-acetylcysteine, 1.53g of glutathione, 0.003g of methylcobalamin, and then mixing until the liquid composition is uniform. Then add 93.55g of vegetable glycerin and mix. Then add a mixture of 1.69g of 1,8-cineole and 1.01g of polysorbate 20, and slowly mix until they are dissolved together. Once 1,8-cineole and polysorbate 20 are uniformly mixed, the mixture is added to a glycerol-water-based mixture and dissolved into the liquid to minimize the volatilization of 1,8-cineole. Mixing is limited to the mixing required to produce a stable single-phase homogeneous solution and minimize the volatilization of 1,8-cineole. The pH of the solution is then measured, and an amount of sodium bicarbonate is added to raise the pH to 7.20. A certain amount of preservative may be added, or the mixture may be refrigerated before use. The liquid composition in Example 3 may be prepared with vegetable glycerin in an amount less than 93.55 g, and the amount may be reduced by increasing the amount of nitrogen purge water added in a corresponding amount. The method of use of the composition of the liquid composition in Example 3 includes, but is not intended to be limited to, placing the composition in an electronic cigarette vaporization device, an electronic thermal vaporization device, an electronic cigarette vaporization pen, an electronic thermal vaporization device, an ultrasonic electronic cigarette vaporization device, an electronic cigarette vaporization module (electronic vaping mod), and inhaling the vapor obtained by producing an atomized mixture. The preferred electronic cigarette vaporization device is a device with temperature control and a temperature limit of 200°C. The aerosolizable drug liquid composition can be transferred to a container that can store one or more doses, the container may or may not contain nitrogen in the headspace, and the container may or may not be refrigerated. Such a liquid composition is disclosed in Table 3.

[0246] Table 3. Preferred base e-cigarette liquids

[0247]

[0248] Example 4

[0249] In Example 4, a liquid pharmaceutical composition and manufacturing method are disclosed, wherein the liquid is atomized, vaporized, or both, and comprises 1,8-cineole, β-caryophyllene, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifier, vegetable glycerin (as needed), water, sodium bicarbonate (as needed), and a preservative (as needed). The manufacturing method consists of mixing and dissolving a certain amount of nitrogen-purged purified sterile water or isotonic saline solution with ascorbic acid powder or crystals, sodium bicarbonate (as needed), and a preservative (as needed), then adding a certain amount of N-acetylcysteine, glutathione, and methylcobalamin, then adding a certain amount of vegetable glycerin (as needed) and mixing until the liquid composition is uniform. Nitrogen purging can be used throughout the mixing period to minimize the oxygenation of water and oxidation of compounds in the mixture. The β-caryophyllene and 1,8-cineole are then mixed separately with an emulsifier, which is slowly added to the mixture after the mixture is homogeneous and the mixture is slowly mixed until it dissolves in the liquid, minimizing the volatilization of the 1,8-cineole and β-caryophyllene. The mixing can be performed in a zero or low headspace reactor to further minimize the volatilization of the β-caryophyllene and 1,8-cineole and oxidation of the compounds in the mixture. If a certain amount of β-caryophyllene and 1,8-cineole is added to the mixture at a concentration greater than the solubility of 1,8-cineole and β-caryophyllene in the mixture, the β-caryophyllene and 1,8-cineole can be emulsified in the liquid composition with the addition of a suitable emulsifier, such as Tween 20 (also known as polysorbate 20) and polyoxyethylene (20) sorbitan monooleate. Mixing is limited to that required to produce a stable single-phase homogeneous solution or emulsion and to minimize the volatilization of the β-caryophyllene and 1,8-cineole.

[0250] The method of using the liquid composition in Example 4 includes, but is not intended to be limited to, placing a certain amount of the composition in an electronic cigarette vaporization device, an electronic thermal vaporization device, an ultrasonic electronic cigarette vaporization device, a nebulizer or an inhaler, and inhaling the atomized vapor obtained by producing an atomized mixture. The liquid composition component that can be atomized or vaporized as a TRPA1 antagonist in Example 4 can be optionally made of borneol or a mixture of 1,8-cineole and borneol, and the mixture is in the same or different total concentration range compared to the concentration range when 1,8-cineole is used alone. Such atomizable liquid compositions are disclosed in Table 4. The atomizable liquid composition can be transferred to a container that can store one or more doses, the headspace of the container may contain or not contain nitrogen, and the container can be refrigerated or not refrigerated.

[0251] Table 4. Basic inhalation liquids containing β-caryophyllene

[0252]

[0253]

[0254]

[0255] Example 5

[0256] A preferred composition and manufacturing method of a pharmaceutical liquid is disclosed in Example 5, which is atomized, vaporized, or both using a nebulizer, and contains 1,8-cineole, β-caryophyllene, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifier, a sterile saline solution, sodium bicarbonate (as needed), and a preservative (as needed). The manufacturing method consists of mixing 94.89 g of a nitrogen-purged 0.9% sterile saline solution with 0.01 g of ascorbic acid powder and dissolving the ascorbic acid, then adding 1.35 g of N-acetylcysteine, 1.35 g of glutathione, 0.003 g of methylcobalamin, and mixing until the liquid composition is uniform. A mixture of 0.80 g of 1,8-cineole, 0.80 g of β-caryophyllene and 0.80 g of polysorbate 20 is then added to the mixture and slowly mixed until it is dissolved in the liquid to minimize the volatilization of 1,8-cineole and β-caryophyllene. Mixing is limited to the mixing required to produce a stable single-phase homogeneous solution and minimize the volatilization of 1,8-cineole and β-caryophyllene. The pH of the solution is then measured and an amount of sodium bicarbonate is added to raise the pH to 7.20. A certain amount of preservative may be added, or the mixture may be refrigerated before use. The method of using the composition of the liquid composition in Example 5 includes, but is not intended to be limited to, placing the composition in an ultrasonic, vibrating mesh or jet nebulizer and inhaling the vapor obtained by producing an atomized mixture. The method of using the liquid composition in Example 5 includes adding about 1 mL to 5 ml of the mixture to a liquid nebulizer for inhalation by the patient. The liquid composition that can be atomized or vaporized in Example 5 can optionally be made of borneol or a mixture of 1,8-cineole, β-caryophyllene and borneol in the same total concentration range as 1,8-cineole and β-caryophyllene. Such a liquid composition is disclosed in Table 5.

[0257] Table 5. Preferred base sprayer liquids containing β-caryophyllene

[0258]

[0259] Example 6

[0260] In Example 6, a composition and a manufacturing method of a drug liquid are disclosed, wherein the drug liquid is atomized, vaporized, or both in an ultrasonic or thermal vaporization device, and comprises 1,8-cineole, β-caryophyllene, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifier, vegetable glycerin, sterile deionized water, sodium bicarbonate (as needed), and a preservative (as needed). The manufacturing method consists of: 16.93g of nitrogen-purged sterile deionized water is mixed with 0.01g of ascorbic acid powder and the ascorbic acid is dissolved, and then 1.20g of N-acetylcysteine, 1.50g of glutathione, 0.003g of methylcobalamin are added, and mixed until the liquid composition is uniform. Then 90.72g of vegetable glycerin is added and mixed. Then a mixture of 1.69g1,8-cineole and 1.69gβ-caryophyllene is added and slowly mixed until they are dissolved together. Once 1,8-cineole, β-caryophyllene and polysorbate 20 are uniformly mixed, the mixture is added to a glycerol-water-based mixture and dissolved in the liquid to minimize the volatilization of 1,8-cineole and β-caryophyllene. The pH value of the solution is then measured, and a certain amount of sodium bicarbonate is added to raise the pH value to 7.20. A certain amount of preservative may be added, or the mixture may be refrigerated before use. The liquid composition in Example 6 may be prepared with vegetable glycerin in an amount less than 90.72 g, and the amount may be reduced by increasing the nitrogen purge water added in a corresponding amount.

[0261] The method of using the liquid composition of Example 6 includes, but is not intended to be limited to, placing the composition in an electronic cigarette vaporization device, a thermal vaporization device, an electronic cigarette vaporization pen, an electronic cigarette vaporization module, or an ultrasonic electronic cigarette vaporization device, and inhaling the vapor obtained by generating an atomized mixture. The preferred electronic cigarette vaporization device is a device with temperature control and a temperature limit of 200°C. The atomizable drug liquid composition can be transferred to a container that can store one or more doses, the headspace of the container may or may not contain nitrogen, and the container may be refrigerated or not refrigerated. Such a liquid composition is disclosed in Table 6.

[0262] Table 6. Preferred base e-cigarette liquids containing β-caryophyllene

[0263]

[0264]

[0265] Example 7

[0266] In Example 7, a composition and manufacturing method of a pharmaceutical liquid are disclosed, wherein the liquid is atomized, vaporized, or both, and comprises 1,8-cineole, β-caryophyllene, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, dexpanthenol, L-theanine, taurine, emulsifier, vegetable glycerin (as needed), water, sodium bicarbonate (as needed), and preservative (as needed). The manufacturing method consists of mixing and dissolving a certain amount of nitrogen-purged purified sterile water or isotonic saline solution with ascorbic acid powder or crystals, sodium bicarbonate (as needed), and preservative (as needed), then adding a certain amount of N-acetylcysteine, glutathione, dexpanthenol, L-theanine, taurine, and methylcobalamin, then adding a certain amount of vegetable glycerin (as needed) and mixing until the liquid composition is uniform. Nitrogen purging can be used throughout the mixing period to minimize the oxygenation of water and oxidation of compounds in the mixture. The β-caryophyllene and 1,8-cineole are then mixed separately with an emulsifier and, after the mixture is homogeneous, are then slowly added to the mixture and slowly mixed until it dissolves in the liquid, minimizing the volatilization of the 1,8-cineole and β-caryophyllene. The mixing may be performed in a zero or low headspace reactor to further minimize the volatilization of the β-caryophyllene and 1,8-cineole and oxidation of the compounds in the mixture. If an amount of β-caryophyllene and 1,8-cineole is added to the mixture at a concentration greater than the solubility of 1,8-cineole and β-caryophyllene in the mixture, the β-caryophyllene and 1,8-cineole may be emulsified in the liquid composition with the addition of a suitable emulsifier, such as Tween 20 (also known as polysorbate 20) and polyoxyethylene (20) sorbitan monooleate. Mixing is limited to that required to produce a stable single-phase homogeneous solution or emulsion and to minimize the volatilization of the β-caryophyllene and 1,8-cineole.

[0267] The method of using the liquid composition in Example 7 includes, but is not intended to be limited to, placing a certain amount of the composition in an electronic cigarette vaporization device, an electronic thermal vaporization device, an ultrasonic electronic cigarette vaporization device, a nebulizer or an inhaler, and inhaling the atomized vapor obtained by producing an atomized mixture. The liquid composition component that can be atomized or vaporized as a TRPA1 antagonist in Example 7 can be optionally made of borneol or a mixture of 1,8-cineole and borneol, and the mixture is in the same or different total concentration range compared to when 1,8-cineole is used alone. Such atomizable liquid compositions are disclosed in Table 7. The atomizable liquid composition can be transferred to a container that can store one or more doses, the headspace of the container may contain or not contain nitrogen, and the container can be refrigerated or not refrigerated.

[0268] Table 7. Base liquids containing amino acids

[0269]

[0270]

[0271]

[0272]

[0273] Example 8

[0274] In Example 8, a preferred composition and manufacturing method of a pharmaceutical liquid is disclosed, the liquid being atomized, vaporized, or both, which contains 1,8-cineole, β-caryophyllene, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, dexpanthenol, L-theanine, taurine, an emulsifier, a sterile saline solution, sodium bicarbonate (as needed), and a preservative (as needed). The manufacturing method consists of mixing 92.69 g of a nitrogen-purged 0.9% sterile saline solution with 0.01 g of ascorbic acid powder and dissolving the ascorbic acid, then adding 1.35 g of N-acetylcysteine, 1.35 g of glutathione, 0.003 g of methylcobalamin, 1.00 g of dexpanthenol, 0.70 g of L-theanine, and 0.50 g of taurine, and mixing until the liquid composition is uniform. Then add 0.80g 1,8-cineole, 0.80g β-caryophyllene and 0.80g polysorbate 20 mixture, and slowly mix until they dissolve together.This mixture is added to the mixture based on glycerol-water and dissolved in the liquid, and the volatilization of 1,8-cineole and β-caryophyllene is minimized.Mixing is limited to the mixing required for producing a stable single-phase uniform solution and minimizing the volatilization of 1,8-cineole and β-caryophyllene.Then measure the pH value of the solution, and add a certain amount of sodium bicarbonate to raise the pH value to 7.20.A certain amount of preservative can be added, or the mixture can be refrigerated before use.The method of use of the composition of the liquid composition in Example 8 includes but is not intended to be limited to placing the composition in an ultrasound, a vibrating screen or a jet nebulizer, and inhaling the steam obtained by producing an atomized mixture.

[0275] The method of using the liquid composition in Example 8 includes adding about 1 mL to 5 ml of the mixture to a liquid nebulizer for inhalation by the patient. The liquid composition that can be atomized or vaporized in Example 8 can optionally be made of borneol or a mixture of 1,8-cineole, β-caryophyllene and borneol in the same total concentration range as 1,8-cineole and β-caryophyllene. Such a liquid composition is shown in Table 8.

[0276] Table 8. Preferred base nebulizer fluids containing amino acids

[0277]

[0278]

[0279] Example 9

[0280] In Example 9, a composition and a method for manufacturing a drug liquid are disclosed, wherein the drug liquid is atomized, vaporized, or both in an ultrasonic or thermal vaporization device, and comprises 1,8-cineole, β-caryophyllene, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, dexpanthenol, L-theanine, taurine, an emulsifier, vegetable glycerin, sterile deionized water, sodium bicarbonate (as needed), and a preservative (as needed). The manufacturing method consists of mixing 16.94 g of nitrogen-purged sterile deionized water with 0.01 g of ascorbic acid powder and dissolving the ascorbic acid, then adding 1.20 g of N-acetylcysteine, 1.50 g of glutathione, 0.003 g of methylcobalamin, 1.00 g of dexpanthenol, 0.70 g of L-theanine, and 0.50 g of taurine, and mixing until the liquid composition is uniform. Then 89.99 g of vegetable glycerin is added and mixed. Then add 1.70g 1,8-cineole, 1.70g β-caryophyllene and 1.70g polysorbate 20 mixture, and slowly mix until they dissolve together.Once 1,8-cineole, β-caryophyllene and polysorbate 20 are evenly mixed, the mixture is added to a mixture based on glycerol-water and dissolved in the liquid to minimize the volatilization of 1,8-cineole and β-caryophyllene.Then measure the pH value of the solution, and add a certain amount of sodium bicarbonate to raise the pH value to 7.20. A certain amount of preservative can be added, or the mixture can be refrigerated before use.The liquid composition in Example 9 can be prepared with the vegetable glycerin of the amount less than 89.99g, and the amount can be reduced by increasing the nitrogen purge water added by the corresponding amount.

[0281] The method of using the liquid composition of Example 9 includes, but is not intended to be limited to, placing the composition in an electronic cigarette vaporization device, a thermal vaporization device, an electronic cigarette vaporization pen, an electronic cigarette vaporization module, or an ultrasonic electronic cigarette vaporization device, and inhaling the vapor obtained by generating an atomized mixture. The preferred electronic cigarette vaporization device is a device with temperature control and a temperature limit of 200°C. The atomizable drug liquid composition can be transferred to a container that can store one or more doses, the headspace of the container may or may not contain nitrogen, and the container may be refrigerated or not refrigerated. Such a liquid composition is disclosed in Table 9.

[0282] Table 9. Preferred base e-cigarette liquids containing amino acids

[0283]

[0284]

[0285] Example 10

[0286] In Example 10, a composition and manufacturing method of a pharmaceutical liquid are disclosed, wherein the liquid is atomized, vaporized, or both, and comprises 1,8-cineole, β-caryophyllene, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, epigallocatechin, resveratrol, emulsifier, vegetable glycerin (as needed), water, sodium bicarbonate (as needed), and preservative (as needed). The manufacturing method consists of mixing and dissolving a certain amount of nitrogen-purged purified sterile water or isotonic saline solution with ascorbic acid powder or crystals, sodium bicarbonate (as needed), and preservative (as needed), then adding a certain amount of N-acetylcysteine, glutathione, pre-dissolved epigallocatechin, pre-dissolved resveratrol, and methylcobalamin, then adding a certain amount of vegetable glycerin (as needed) and mixing until the liquid composition is uniform. Nitrogen purging can be used throughout the mixing period to minimize the oxygenation of water and oxidation of compounds in the mixture. The β-caryophyllene and 1,8-cineole are then mixed separately with an emulsifier and, after the mixture is homogeneous, are then slowly added to the mixture and slowly mixed until it dissolves in the liquid, minimizing the volatilization of the 1,8-cineole and β-caryophyllene. The mixing may be performed in a zero or low headspace reactor to further minimize the volatilization of the β-caryophyllene and 1,8-cineole and oxidation of the compounds in the mixture. If an amount of β-caryophyllene and 1,8-cineole is added to the mixture at a concentration greater than the solubility of 1,8-cineole and β-caryophyllene in the mixture, the β-caryophyllene and 1,8-cineole may be emulsified in the liquid composition with the addition of a suitable emulsifier, such as Tween 20 (also known as polysorbate 20) and polyoxyethylene (20) sorbitan monooleate. Mixing is limited to that required to produce a stable single-phase homogeneous solution or emulsion and to minimize the volatilization of the β-caryophyllene and 1,8-cineole.

[0287] The method of using the liquid composition in Example 10 includes, but is not intended to be limited to, placing a certain amount of the composition in an electronic cigarette vaporization device, an electronic thermal vaporization device, an ultrasonic electronic cigarette vaporization device, a nebulizer or an inhaler, and inhaling the atomized vapor obtained by producing an atomized mixture. The liquid composition component that can be atomized or vaporized as a TRPA1 antagonist in Example 10 can optionally be made of borneol or a mixture of 1,8-cineole and borneol with the same or different total concentration range compared to when 1,8-cineole is used alone. Such atomizable liquid compositions are disclosed in Table 10. The atomizable liquid composition can be transferred to a container that can store one or more doses, the headspace of the container may contain or not contain nitrogen, and the container can be refrigerated or not refrigerated.

[0288] Table 10. Base liquids containing polyphenols

[0289]

[0290]

[0291]

[0292] Embodiment 11

[0293] In embodiment 11, a composition and manufacturing method of a drug liquid are disclosed, the drug liquid is atomized, vaporized or both, and it contains 1,8-cineole, β-caryophyllene, cannabidiol, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, emulsifier, vegetable glycerin, water, sodium bicarbonate (as needed) and preservative (as needed). The manufacturing method consists of: a certain amount of nitrogen-purged purified sterile water or isotonic saline solution is mixed and dissolved with ascorbic acid powder or crystal, sodium bicarbonate and preservative (if needed), then a certain amount of N-acetylcysteine, glutathione and methylcobalamin are added, and then a certain amount of vegetable glycerin (as needed) is added and mixed until the liquid composition is uniform. Nitrogen purging can be used throughout the mixing period to minimize the oxygenation of water in the mixture and the oxidation of the compound. Cannabidiol is dissolved in a mixture of β-caryophyllene and 1,8-cineole, and limited mixing is used to minimize the volatilization loss of β-caryophyllene and 1,8-cineole. After this step, the cannabidiol, β-caryophyllene, 1,8-cineole mixture is mixed separately with an emulsifier, which is then slowly added to the mixture and slowly mixed until it is dissolved in the liquid, minimizing the volatilization of 1,8-cineole and β-caryophyllene. Mixing can be performed in a zero or low headspace reactor to further minimize the volatilization of β-caryophyllene and 1,8-cineole and oxidation of the compounds in the mixture. Mixing is limited to that required to produce a stable single-phase homogeneous solution or emulsion and minimize the volatilization of β-caryophyllene and 1,8-cineole.

[0294] The method of using the liquid composition in Example 11 includes but is not intended to be limited to placing a certain amount of the composition in an electronic cigarette vaporization device, an electronic thermal vaporization device, an ultrasonic vaporization device, a nebulizer or an inhaler, and inhaling the atomized steam obtained by generating an atomized mixture. The liquid composition component that can be atomized or vaporized as a TRPA1 antagonist in Example 11 can optionally be made of a mixture of borneol or 1,8-cineole, β-caryophyllene and / or borneol with the same or different total concentration range compared to the concentration range when 1,8-cineole is used alone. In another embodiment of the liquid composition, cannabidiol can be replaced by one or more cannabinoid compounds, including but not limited to 9-tetrahydrocannabinol (δ-9-THC), 9-THC propyl analog (THC-V), cannabidiol (CBD), cannabidiol propyl analog (CBD-V), cannabinol (CBN), cannabichromene (CBC), cannabichromene propyl analog (CBC-V), cannabichromene (CBG). This atomizable liquid composition is shown in Table 11. The nebulizable liquid composition may be transferred to a container that may store one or more doses, may or may not contain nitrogen in the headspace, and may or may not be refrigerated.

[0295] Table 11. Base liquids containing CBD

[0296]

[0297]

[0298]

[0299] Example 12

[0300] In Example 12, a composition and a method for manufacturing a drug liquid are disclosed, wherein the drug liquid is atomized, vaporized, or both, and comprises 1,8-cineole, β-caryophyllene, nicotine, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifier, vegetable glycerin, water, sodium bicarbonate (as needed), and a preservative (as needed). The manufacturing method consists of mixing and dissolving a certain amount of nitrogen-purged purified sterile water or isotonic saline solution with ascorbic acid powder or crystals, sodium bicarbonate, and a preservative (if needed), and then adding a certain amount of N-acetylcysteine, glutathione, and methylcobalamin. After mixing the mixture, a certain amount of nicotine salt is added to a certain amount of vegetable glycerin (if used) to dissolve the nicotine salt. The nicotine salt-vegetable glycerin mixture is then added to a mixture of water, ascorbic acid, N-acetylcysteine, and glutathione, and mixed until the liquid composition is uniform. A nitrogen purge may be used throughout the mixing period to minimize oxygenation of water and oxidation of compounds in the mixture. Alternatively, if free base (unprotonated nicotine) is used in the formulation, the unprotonated nicotine is dissolved in a mixture of β-caryophyllene and 1,8-cineole, with limited mixing to minimize the volatilization losses of β-caryophyllene and 1,8-cineole. After this step, the nicotine, β-caryophyllene, 1,8-cineole mixture is mixed separately with an emulsifier, and after the mixture is uniform, it is then slowly added to the vegetable glycerin-water mixture and slowly mixed until it is dissolved in the liquid, minimizing the volatilization of 1,8-cineole and β-caryophyllene. Mixing can be performed in a zero or low headspace reactor to further minimize the volatilization of β-caryophyllene and 1,8-cineole in the mixture and the oxidation of compounds. Mixing is limited to the mixing required to produce a stable single-phase homogeneous solution or emulsion and minimize the volatilization of β-caryophyllene and 1,8-cineole.

[0301] The method of using the liquid composition of Example 12 includes, but is not intended to be limited to, placing the composition in an electronic cigarette vaporization device, a thermal vaporization device, an electronic cigarette vaporization pen, an ultrasonic electronic cigarette vaporization device, or an electronic electronic cigarette vaporization module, and inhaling the vapor obtained by generating an atomized mixture. The preferred electronic cigarette vaporization device is a device with temperature control and a temperature limit of 200° C. The atomizable drug liquid composition can be transferred to a container that can store one or more doses, the headspace of the container may or may not contain nitrogen, and the container may be refrigerated or not refrigerated. Such a liquid composition is disclosed in Table 12.

[0302] Table 12. Nicotine-containing base liquids

[0303]

[0304]

[0305]

[0306] Embodiment 13

[0307] In Example 13, a composition and a method for manufacturing a drug liquid are disclosed, wherein the drug liquid is atomized, vaporized, or both in an ultrasonic electronic cigarette vaporization device or a thermal vaporization device, and comprises 1,8-cineole, β-caryophyllene, nicotine salt, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifier, vegetable glycerin, sterile deionized water, sodium bicarbonate (as needed), and a preservative (as needed). The manufacturing method consists of mixing 16.93 g of nitrogen-purged sterile deionized water with 0.01 g of ascorbic acid powder and dissolving the ascorbic acid, then adding 1.20 g of N-acetylcysteine, 1.53 g of glutathione, 0.003 g of methylcobalamin, and mixing until the liquid composition is uniform. 1.75 g of nicotine salt (54% nicotine) is added to 87.93 g of vegetable glycerin and mixed until the nicotine salt is dissolved. A mixture of 1.08 g 1,8-cineole, 1.08 g β-caryophyllene, and 1.18 g polysorbate 20 is then added and slowly mixed until they are dissolved together, with limited mixing to minimize the volatilization loss of β-caryophyllene and 1,8-cineole. The vegetable glycerin-nicotine mixture is then added to the mixture of β-caryophyllene, 1,8-cineole, and polysorbate 20, and slowly mixed to produce a stable single-phase homogeneous solution and minimize the volatilization of 1,8-cineole and β-caryophyllene. Water, glutathione, N-acetylcysteine, and methylcobalamin are then added and slowly mixed until uniform. The pH of the solution is then measured, and an amount of sodium bicarbonate is added to raise the pH to 7.20. A certain amount of preservative may be added, or the mixture may be refrigerated before use. The liquid composition of Example 13 can be prepared with an amount of vegetable glycerin less than 87.93 g, and this amount can be reduced by increasing the amount of nitrogen sparged water added in response.

[0308] The method of using the liquid composition of Example 13 includes, but is not intended to be limited to, placing the composition in an electronic cigarette vaporization device, a thermal vaporization device, an electronic cigarette vaporization pen, an ultrasonic electronic cigarette vaporization device, or an electronic electronic cigarette vaporization module, and inhaling the vapor obtained by generating an atomized mixture. The preferred electronic cigarette vaporization device is a device with temperature control and a temperature limit of 200°C. The atomizable drug liquid composition can be transferred to a container that can store one or more doses, the headspace of the container may or may not contain nitrogen, and the container may be refrigerated or not refrigerated. Such a liquid composition is disclosed in Table 13.

[0309] Table 13. Preferred base e-cigarette liquids containing nicotine

[0310]

[0311] Embodiment 14

[0312] A preferred composition and method of manufacture of a drug liquid that is atomized, vaporized, or both in an ultrasonic electronic cigarette vaporization device or a thermal vaporization device that is part of a combination product for smoking cessation and respiratory health improvement is disclosed in Example 14. The smoking cessation method consists of four separate liquid compositions that are atomized and inhaled, each containing similar concentrations of N-acetylcysteine, glutathione, 1,8-cineole, beta-caryophyllene, methylcobalamin, emulsifier, vegetable glycerin, and water.

[0313] In this embodiment, smoking cessation is first achieved by eliminating the use of combusted cigarettes with nicotine replacement therapy using an ultrasonic electronic cigarette vaporization device or an electronic hot liquid atomization device. The smoking cessation method of the present invention utilizes a nicotine step-by-step reduction process by which the daily consumption of nicotine is reduced over time using higher to lower nicotine concentrations to achieve complete elimination of nicotine in the preparation. In this smoking cessation method, there are four nicotine reduction steps as part of a smoking and nicotine addiction cessation system. The first step in quitting smoking includes switching from smoking to using an electronic hot liquid atomization device to consume nicotine. The unique and distinctive feature of the present invention is that in addition to providing a nicotine replacement therapy that causes an individual to completely quit nicotine, the preparation additionally provides health benefits of repairing respiratory damage and diseases caused by an individual's smoking history. The health benefits achieved by inhalation of aerosolized N-acetylcysteine, glutathione, 1,8-cineole, β-caryophyllene, and methylcobalamin are the result of a multifunctional mechanism of action using TRPA1 antagonists, CB2 agonists, glutathione replacement in the lung, epithelial lining fluid, and epithelial tissues, antioxidant therapy with the glutathione precursor N-acetylcysteine, and vitamin B12 replacement therapy.

[0314] The method of reducing an individual's daily nicotine intake using the first of the four steps is to inhale approximately 20 mg of nicotine per day by vaporizing the formulation disclosed in Table 14. Table 14 provides the formulation for Step 1. Based on the consumption of approximately 1 mL of liquid vaporized from an ultrasonic vaporization device, a hot liquid atomization device, or an electronic cigarette using 150 puffs per day, the daily consumption of nicotine is approximately 20 mg. The daily doses of the other non-carrier components of the composition disclosed in Table 14 are as follows: glutathione (19.65 mg); N-acetylcysteine ​​(13.76 mg); 1,8-cineole (10.87 mg); β-caryophyllene (5.34 mg); and vitamin B12 (9.38 μg). An emulsifier, such as polysorbate 20, can be provided at 9.73 mg; sterile deionized water can be provided at 212 mg; and vegetable glycerin can be provided at 1,096 mg. Depending on the individual's smoking history, the nature of their nicotine addiction, their susceptibility to nicotine addiction, their willingness to quit smoking, and their psychological support system, the time for which an individual consumes the composition through aerosolization of the step 1 formulation disclosed in Table 14 can be variable. The time for an individual to use the step 1 nicotine replacement composition may be as short as two weeks and as long as several months. For example, the duration of step 1 can be 40 to 60 days. One of ordinary skill in the art will recognize that the exact concentration of each component determined in Table 14 can be varied within a range to achieve the same results as using the actual concentrations determined in Table 14. The use of deionized water and vegetable glycerin can also vary depending on the type of liquid atomization device used. For example, if a spray device or ultrasonic vaporization device is used to provide the aerosol phase of the liquid composition, the concentration of vegetable glycerin can be greatly reduced or even completely eliminated and supplemented with the water phase. Similarly, if a spray device or ultrasonic vaporization device is used, the deionized water can be replaced with a simple saline solution that is isotonic with the lining fluid of the lung epithelial cells, for example, about 0.9% sodium chloride. One of ordinary skill in the art will recognize that if an electronic thermal vaporization device, an electronic cigarette vaporization device, an electronic cigarette pen, an ultrasonic vaporization device, or an electronic cigarette is used to deliver the composition in Table 14, the aqueous phase can be replaced primarily by vegetable glycerin or another non-aqueous phase carrier. One of ordinary skill in the art will also recognize that the concentration of each component disclosed in Table 14 can be increased or decreased by increasing or decreasing the total liquid volume of the composition to accommodate the specific liquid atomization device used and the number of puffs or duration required for the device to deliver the approximately 1 mL dose of the liquid composition determined in Table 14.

[0315] In step 1 of the smoking cessation system, one embodiment of the present invention is to provide approximately similar number of puffs as the individual would normally take when smoking before using the system. This helps to satisfy the oral retention associated with smoking. The programmable electronic vaporizer can substantially vary the number of puffs used per milliliter of the liquid composition disclosed in Table 14. One of ordinary skill in the art will recognize that if a person who wants to quit smoking is unable to proceed to the next step of the smoking cessation system, then the health benefits of remaining in step 1 will be better than if the person resumes smoking for a longer period of time than contemplated in step 1, including many years.

[0316] Table 14. E-cigarette liquids for quitting smoking - Step 1

[0317]

[0318] Based on dosage of 150 puffs per ml

[0319] As part of the smoking cessation method, step 2 is based on the consumption of approximately 1 mL of liquid vaporized from an ultrasonic electronic cigarette vaporization device or an electronic hot liquid atomization device using 125 puffs per day. As disclosed in the composition of Table 15, the daily consumption of nicotine is about 14 mg. The time for an individual to use the step 2 nicotine replacement preparation may be as short as two weeks and as long as two months, for example, 14 to 30 days. One embodiment of the present invention is to enable an individual to reduce the oral retention associated with his smoking habits and behaviors. Therefore, the number of puffs is reduced from 150 puffs per day in step 1 to 125 puffs per day in step 2. Those of ordinary skill in the art will recognize that if a person who wants to quit smoking cannot enter the next step of the smoking cessation system, then the health benefits of staying in step 2 will be better than if the person resumes smoking for a longer period of time than envisioned in step 2, including many years.

[0320] Table 15. E-cigarette liquids for quitting smoking - Step 2

[0321]

[0322] Based on dosage of 125 puffs per ml

[0323] As part of the smoking cessation method, step 3 is based on the consumption of approximately 1 mL of liquid vaporized from an ultrasonic electronic cigarette vaporization device or an electronic hot liquid atomization device using 75 puffs per day. As disclosed in the composition of Table 16, the daily consumption of nicotine is about 5 mg. The time for an individual to use the step 3 nicotine replacement preparation may be as short as two weeks and as long as two months, for example, 14 to 30 days. The number of puffs is reduced from 125 puffs per day in step 2 to 75 puffs per day in step 3. Those of ordinary skill in the art will recognize that if a person who wants to quit smoking cannot enter the next step of the smoking cessation system, then the health benefits of staying in step 3 will be better than if the person resumes smoking for a longer period of time than envisioned in step 3, including many years.

[0324] Table 16. E-cigarette liquids for quitting smoking - Step 3

[0325]

[0326]

[0327] Based on dosage of 75 puffs per ml

[0328] As part of a smoking cessation method, step 4 is based on the consumption of approximately 1 mL of liquid vaporized from an ultrasonic electronic cigarette vaporization device or an electronic hot liquid atomization device using 75 puffs per day, as disclosed in the composition of Table 17, with the daily consumption of nicotine completely eliminated. The time for an individual to use the step 4 nicotine replacement formulation will depend on the person's respiratory health status and the type of respiratory damage and lung disease that the person suffers from as a result of his or her smoking history. The time for an individual to use the step 4 composition can be months, years, or decades.

[0329] Table 17. E-cigarette liquids for quitting smoking - Step 4 - Nicotine-free

[0330] Compound Liquid concentration unit 75 spray doses unit Glutathione 19.79 mg / mL 19.79 mg N-Acetylcysteine 13.86 mg / mL 13.86 mg 1,8-Cineole 10.95 mg / mL 10.95 mg β-Caryophyllene 5.37 mg / mL 5.37 mg Vitamin B12 9.90 μg / mL 9.90 μg Polysorbate 20 9.80 mg / mL 9.80 mg Deionized water 213.77 mg / mL 213.77 mg Vegetable Glycerin 1151.05 mg / mL 1151.05 mg

[0331] Based on dosage of 75 puffs per ml

[0332] Alternatively, step 4 may consist of providing continuous treatment of respiratory lung diseases associated with the individual's past smoking history using a nebulizer or ultrasonic electronic cigarette vaporization device. Alternatively, the nebulizer formulation disclosed in step 4 may be a formulation disclosed in Table 2, Table 5 or Table 8, which may be preferably used for nebulization after step 3 in the smoking cessation system because they contain β-caryophyllene, which is a CB2 agonist and helps addiction withdrawal.

[0333] The manufacturing method of the four liquid preparations provided in Example 14 includes mixing a certain amount of nitrogen-purged purified water with a certain amount of N-acetylcysteine, a certain amount of glutathione, a certain amount of methylcobalamin, and then adding a certain amount of vegetable glycerin and mixing until the liquid composition is uniform. Then, a mixture of a certain amount of 1,8-cineole, β-caryophyllene and a certain amount of polysorbate 20 previously mixed is added to the mixture and slowly mixed until it is dissolved in the liquid, minimizing the volatilization of 1,8-cineole and β-caryophyllene. Mixing is limited to the mixing required to produce a stable single-phase uniform suspension and minimize the volatilization of 1,8-cineole and β-caryophyllene. The liquid composition that can be atomized or vaporized in Example 14 can be optionally made of borneol, β-caryophyllene or the following mixtures in a total concentration range that is the same as 1,8-cineole alone in Example 14: a mixture of 1,8-cineole with one or more of borneol and β-caryophyllene. The pH of each liquid composition should be measured and adjusted to 7.20 with sodium bicarbonate. If the liquid composition is not manufactured under sterile conditions, a preservative may be added to improve the physical, chemical, and biological stability of the formulation. The liquid composition in Example 14 may be made with an amount of vegetable glycerin less than the amount disclosed in Tables 14, 15, 16, and 17, and this amount may be reduced by increasing the corresponding amount of nitrogen purged water added.

[0334] Embodiment 15

[0335] A preclinical trial was conducted on five patients who were current or former smokers with a previous diagnosis of asthma or COPD. The preferred liquid pharmaceutical composition was vaporized using a commercially available electronic thermal e-cigarette vaporizer pen having a 3.0 mL refillable tank, a 1300 mAH rechargeable lithium-ion battery, and a 0.5 Ohm coil operating at 3.7 volts (Kanger SUBVOD-Kit TM ). Patients inhaled at least 40 puffs per day for up to 73 days. Spirometry testing, including forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) measurements, was performed before, during, and at the end of treatment. Spirometry is the most commonly performed lung function test and plays an important role in diagnosing the presence and type of lung abnormalities, classifying their severity, and evaluating treatment outcomes. Patients were also interviewed about their breathing ability, energy levels, and overall well-being and health.

[0336] The procedure followed by each patient consisted of placing the preferred liquid composition disclosed in Table 18 in an e-cigarette pen tank with a dropper and then pressing the start button on the side of the e-cigarette pen to initiate heating of the coil while the patient inhaled the aerosolized liquid through the attached mouthpiece.

[0337] Table 18. Preclinical test liquid composition

[0338]

[0339] Dosage is based on patient use of 75 puffs per mL and 40 puffs per day

[0340] Patients inhaled at least 75 puffs from the e-cigarette pen every day. Before starting treatment, as part of the test, each patient's past and current smoking history, age, height, weight, sex and race were recorded to allow calculation of normal FEV1 and FVC values. As shown in Table 19, all individuals had a history of smoking, and only 1 patient was currently smoking. As shown in Table 19, the patient was diagnosed with COPD or asthma. Before undergoing liquid atomization treatment, each patient underwent a spirometry test to measure FEV1 and FVC to provide baseline conditions. These results were compared with normal values ​​calculated using the method of Hankinson et al. (1999) from the National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention. Patient medical history and spirometry test results are summarized in Table 19. The percentage of normal FEV1 value was calculated for each patient using the normal FEV1 value calculated for each individual based on age, height, sex, and race and the baseline FEV1 measurement before treatment to provide baseline conditions to compare treatment outcomes.

[0341] Table 19. CuraBreath preclinical trial data

[0342]

[0343]

[0344]

[0345] Women generally have smaller vital capacity than men, and as can be seen in Table 19, the baseline FEV1 capacity of the three female patients (baseline FEV1 values ​​before treatment were 1.33L to 1.70L) was lower than that of the two male patients (baseline FEV1 values ​​before treatment were 2.82L to 2.84L). The normal FEV1 value for female patients was calculated to be 1.98L to 2.80L. The normal FEV1 values ​​for male patients were 4.18L and 4.44L. The baseline FEV1 value of each patient was significantly lower than the normal value for healthy individuals. For the five patients, the percentage of normal FEV1 values ​​before treatment ranged from 63.96% to 68.83%. For example, individuals with COPD with a percentage of normal FEV1 values ​​less than 80% were classified as GOLD2 moderate COPD. Based on these values, it is clear that each patient exhibited significant airway limitation. The baseline FVC capacity of all patients was also significantly lower than the normal value for healthy individuals, ranging from 62.61% to 68.01%.

[0346] Spirometry testing after inhaled breathing therapy was repeated for each individual after 21 days of treatment and at the end of treatment (ranging from 42 to 73 days). The FEV1 spirometry test results for each patient were plotted and the results are shown in Figure 1 It is clear that the rate of improvement in FEV1 values ​​over time was linear and significant. The female patients had FEV1 reversibility values ​​of 32.35%, 34.21%, and 45.11% after the entire treatment period. The female patients also had an increase in forced vital capacity (FVC) of 20.37%, 32.29%, and 36.81% after the entire treatment period. Patient 102, a 61-year-old female with a diagnosis of COPD who had smoked for at least 28 years and was still an active smoker at the time of these tests, had an increase in FEV1 and FVC of 32.45% and 20.37%, respectively. Patient 104, a 67-year-old female with a diagnosis of asthma, was the oldest person in the preclinical study and had been a two-pack smoker for 28 years. Patient 104 had the highest FEV1 reversibility of 45.11%.

[0347] Men generally have larger lung capacity, as shown in Table 19 and Figure 1 It can be clearly seen from the results provided in Figure 1 As can be seen, FEV1 also improved linearly over time, while spirometry results improved substantially. The FEV1 reversibility values ​​after the entire treatment period were 46.48% and 39.01% for the male patient and 103 and 106, respectively. The forced vital capacity (FVC) after the entire treatment period also increased by 40.28% and 32.39%, respectively, for the male patient. Patient 103 was a male, 45 years old, had been smoking for 15 years, and was not an active smoker at the time these tests were performed.

[0348] Various organizations are relevant to assessing improvement in COPD patients. FEV1 results reported in preclinical trials have shown significant improvement in FEV1 compared to the following FEV1 improvement assessment criteria established by these organizations: America College of Chest Physicians – FEV1 > 15%; American Thoracic Society – FEV1 or FVC > 12%; and > 0.200 L; GOLD -> 12% and > 0.200 L. The preclinical trial results shown in Table 19 showed that FEV1 reversibility varied from 32.35% to 46.48%; FVC reversibility varied from 20.37% to 40.28%; and FEV1 value improvements varied from 0.55 L to 1.32 L.

[0349] Example 16

[0350] Preclinical trials were conducted on a single patient using a preferred atomizable liquid that was sprayed using a commercially available portable ultrasonic mesh nebulizer with a 5.0 mL refillable reservoir and a rechargeable lithium-ion battery (Flyp nebulizer, Convexity Scientific, Inc.). The patient was a 49-year-old male, 174.86 cm tall, with a history of diagnosed mild to moderate asthma. The patient had about 10 to 15 asthma attacks requiring medication each year, which were caused by seasonal allergies, induced by cold air, and induced by exercise. In these events, the patient usually used bronchodilator salbutamol as a rescue inhaler and regularly used fluticasone furoate (an inhalable corticosteroid powder). The patient also required the use of prednisone (an oral corticosteroid) for the most severe asthma attacks, about 1 to 2 times a year.

[0351] Prior to the first spray of the preferred liquid composition, the patient reported moderate asthma symptoms, including a feeling of chest tightness and difficulty breathing and breathing completely. The patient continued to inhale albuterol and fluticasone furoate daily for one week before using the spray liquid, with no substantial relief of symptoms. Based on previous asthma experience and symptoms, he reported that if the symptoms persisted, he thought he would need to use prednisone. Using a portable ultrasonic mesh sprayer, the patient sprayed 1 mL of a liquid containing the following substances: 1.10% (w / w) glutathione, 1.10% (w / w) N-acetylcysteine, 0.80% (w / w) 1,8-cineole, 0.80% (w / w) β-caryophyllene, 0.003% (w / w) methylcobalamin, 0.3% (w / w) polysorbate 20, and 95.3% (w / w) sterile saline solution (0.9% saline). Within 30 minutes after the spray, the patient reported that his chest felt significantly more relaxed, chest tightness was reduced, he was able to breathe more completely, and felt more energetic. After the spray treatment, he was able to stop taking albuterol and fluticasone furoate completely. After this single spray event, the patient reported that his symptoms remained improved over the next week, although the degree of improvement decreased after about 4 to 5 days. Three days after the spray of the drug liquid, the patient underwent a spirometry test. The patient's normal spirometry values ​​were calculated to be FEV1=3.81L, FVC=4.89 (Hankinson, 1999). The spirometry values ​​measured three days after a single spray treatment were FEV1=2.99L, FVC=3.65L, and the percentage of normal values ​​was FEV1=78.4%, FVC=74.6%.

[0352] One week after the single spray treatment, the patient started a 7-day daily spray treatment. Before starting the 8-day treatment period, the patient received a baseline spirometry test, and the results were as follows: FEV1=3.09L, FVC=3.57L, and the percentage of normal values ​​was for FEV1=81.0%, FVC=73.0%. The patient continued to spray increasing amounts of nebulizer liquid for 8 days, which contained the following substances: 0.70% (w / w) glutathione, 0.70% (w / w) N-acetylcysteine, 0.003% (w / w) methylcobalamin, and 98.4% (w / w) sterile saline solution (0.9% saline). On days 1 to 3, 1.5mL was sprayed, and on days 4 to 8, 3.0mL was sprayed. After spraying the liquid composition on day 7, the patient was tested for spirometry. The spirometry results after nebulizing 3.0 mL of liquid were FEV1 = 3.39 L, FVC = 3.84 L, and the percentage of normal values ​​were for FEV1 = 86.8%, FVC = 78.5.0%. Compared to the first baseline spirometry values, the percentage reversibility of FEV1 was calculated to be 12%, and the percentage reversibility of FVC was 5.2%. Compared to the first patient spirometry result, the improvement in the FEV1 / FVC% ratio increased from 81.9% to 88.3%. It is clear that this patient used a greater percentage of his lung capacity in the second spirometry test.

[0353] The patient reported that even with only one nebulization during the first week of treatment, followed by 11 days of only moderate nebulization, he did not experience any asthma attacks and did not have to take prescription bronchodilators or any corticosteroids at any time during the trial. The patient reported that he had more energy and was breathing easier and more completely.

[0354] The embodiments described and discussed in this specification are intended only to teach those skilled in the art to prepare and use the present invention in the best manner known to the inventor. Any content in this specification should not be considered as limiting the scope of the present invention. All given examples are representative and non-restrictive. As those skilled in the art understand according to the above teachings, the above-mentioned embodiments of the present invention can be modified or changed without departing from the present invention. Therefore, it should be understood that within the scope of the claims and their equivalents, the present invention can be implemented in a manner different from that specifically described.

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Claims

1. A pharmaceutical composition comprising: at least one plant extract transient receptor potential cation channel subfamily A member 1 (TRPA1) antagonist; at least one thiol amino acid-containing compound; at least one vitamin; at least one chelating agent; and At least one antioxidant. 2 . The pharmaceutical composition according to claim 1 , wherein the plant extract TRPA1 antagonist is selected from the group consisting of 1,8-cineole, borneol, camphor, 2-methylborneol, fenchyl alcohol, cardamomine, and combinations thereof.

3. The pharmaceutical composition of claim 1, wherein the thiol amino acid-containing compound is selected from the group consisting of glutathione, N-acetylcysteine, carboxymethylcysteine, taurine, methionine, and combinations thereof.

4. The pharmaceutical composition according to claim 1, wherein the vitamin is selected from the group consisting of cobalamin, methylcobalamin, hydroxocobalamin, adenosylcobalamin, cyanocobalamin, cholecalciferol, thiamine, dexpanthenol, biotin, niacin, nicotinamide and nicotinamide riboside, ascorbic acid, and combinations thereof.

5. The pharmaceutical composition of claim 1, wherein the chelating agent is selected from the group consisting of glutathione, N-acetylcysteine, citric acid, ascorbic acid, ethylenediaminetetraacetic acid (EDTA), and combinations thereof.

6. The pharmaceutical composition according to claim 1, wherein the antioxidant is selected from the group consisting of berberine, catechin, curcumin, epicatechin, epigallocatechin, epigallocatechin-3-gallate, β-carotene, quercetin, kaempferol, luteolin, ellagic acid, resveratrol, silymarin, nicotinamide adenine dinucleotide, thymoquinone, 1,8-cineole, glutathione, N-acetylcysteine, cobalamin, methylcobalamin, hydroxocobalamin, adenosylcobalamin, cyanochlorocobalamin, β-caryophyllene, and combinations thereof.

7. The pharmaceutical composition according to claim 1, further comprising a liquid carrier, the liquid carrier comprising a liquid carrier selected from the group consisting of: water, saline, degassed water, degassed saline, water purged with a pharmaceutically inert gas, saline purged with a pharmaceutically inert gas.

8. The pharmaceutical composition of claim 1, further comprising a pH adjusting compound selected from the group consisting of sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate, benzoic acid, ascorbic acid, and combinations thereof.

9. The pharmaceutical composition according to claim 1, further comprising a preservative selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), benzalkonium chloride, benzoic acid, sorbic acid, and combinations thereof.

10. The pharmaceutical composition of claim 1, further comprising a naturally occurring cannabinoid receptor type 2 (CB2) agonist selected from the group consisting of β-caryophyllene, cannabidiol, and cannabinol. The pharmaceutical composition according to claim 1 , wherein the pH value of the composition is 6 to 8.

12. The pharmaceutical composition of claim 1, wherein the ionic strength of the composition is equivalent to the ionic strength of normal lung epithelial cell lining fluid.

13. The pharmaceutical composition according to claim 1, further comprising a microemulsion or a nanoemulsion.

14. The pharmaceutical composition according to claim 1, comprising: 0.1% to 10% by weight of 1,8-citralone; 0.1% to 10% by weight of beta-caryophyllene; 0.1% to 10% by weight of N-acetylcysteine; 0.1% to 20% by weight glutathione; 0.001% to 1.0% by weight of methylcobalamin; and carrier.

15. The pharmaceutical composition according to claim 14, comprising: About 0.8% by weight of 1,8-dimethoate; about 0.8% by weight of beta-caryophyllene; about 1.11% by weight N-acetylcysteine; about 1.11% by weight glutathione; about 0.003% by weight methylcobalamin; About 0.8% by weight polysorbate 20; and Sterile saline containing about 0.9% by weight sodium chloride (NaCl), The pH was adjusted to about 7.2 with the addition of sodium bicarbonate.

16. The pharmaceutical composition of claim 1, further comprising a therapeutic agent for treating the lungs and / or respiratory tract.

17. The pharmaceutical composition of claim 16, wherein the therapeutic agent for treating the lungs and / or respiratory tract is selected from the group consisting of short-acting beta2-adrenergic receptor agonists (SABA), salbutamol, terbutaline, metaproterenol, pirbuterol, anticholinergics, ipratropium, tiotropium, aclidinium, umeclidinium, adrenergic agonists, epinephrine, corticosteroids, beclomethasone, triamcinolone, flunisolide, ciclesonide, budesonide, fluticasone propionate, mometasone, long-acting beta2-adrenergic receptor agonists (LABA), salmeterol, formoterol, indacaterol, leukotriene receptor antagonists, montelukast, zafirlukast, 5-LOX inhibitors, zileuton, antimuscarinics, bronchodilators, and combinations thereof.

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