Compositions and methods for treating lung

Abstract

The present invention provides an application of a pharmaceutical composition in the preparation of a medicament for treating respiratory diseases wherein 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 mercapto amino acid; at least one vitamin; at least one chelating agent; and at least one antioxidant. The invention also provides an application of the pharmaceutical composition in preparation of a medicine for helping a patient to quit smoking and an application of the pharmaceutical composition in preparation of a medicine for treating the lung and / or respiratory tract of a patient exposed to a lung or respiratory tract stimulation or injury agent.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of October 23, 2019, an application number of 201980085379.1, and an invention title of "Compositions and Methods for Treating the Lung".

[0002] This 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 OF THE INVENTION

[0003] Smoking

[0004] According to the CDC, over 16 million Americans suffer from diseases 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 exacerbate 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 causes nearly 7 million deaths per year, and current trends suggest that by 2030, tobacco use will cause over 8 million deaths per year.

[0005] The Centers for Disease Control in the United States (2018) states that approximately 37.8 million people in the United States smoke, representing 15.5% of all adults. In the United States, smoking causes over 480,000 deaths per year, including over 41,000 deaths from secondhand smoke exposure; this is approximately one-fifth of all annual deaths, 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 4,800 identified gaseous and particulate-bound compounds in cigarette smoke (Sahu et al., 2013).

[0007] Particulate matter (PM) in the air, especially fine particles, is associated with various adverse health effects. Environmental tobacco smoke (ETS) has also been identified as an important source of anthropogenic pollution in indoor environments, such as through second-hand smoke. Cigarette smoke consists of gaseous pollutants; for example, carbon monoxide (CO), sulfur dioxide (SO2), nitric oxide (NO), nitrogen dioxide (NO2), methane (CH4), non-methane hydrocarbons (NMHC), carbonyl compounds, and volatile organic compounds (VOC); and particulate matter (PM). The particulate concentration in tobacco smoke is usually high, with 10^12 particles per cigarette, and the particle size is very small, ranging from 0.01 nm to 1.00 μm, with a median count size in the range of 186 nm to 198 nm (Sahu et al., 2013). Despite the small diameter of the smoke particles, the deposition efficiency of the smoke in the lungs has been reported to be 60% to 80%. The concentration of nicotine in cigarettes varies by brand. A comprehensive study was conducted in 1998, reporting the 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 nicotine percentage (by weight of tobacco) in tobacco averaged 10.2 mg (standard error of the mean (SEM) of 0.25, range of 7.2 mg to 13.4 mg) and 1.5% (SEM of 0.03, range of 1.2% to 2%) in the United States, 13.5 mg (SEM of 0.49, range of 8.0 mg to 18.3 mg) and 1.8% (SEM of 0.06, range of 1.0% to 2.4%) in Canada, and 12.5 mg (SEM of 0.33, range of 9 mg to 17.5 mg) and 1.7% (SEM of 0.04, range of 1.3% to 2.4%) in the United Kingdom. However, the average nicotine intake per cigarette is 1.04 mg (+ / -0.36), indicating that nicotine absorption from smoking and the actual dose are much lower than the nicotine amount 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 exceeding the World Health Organization (WHO) limits. As urban air quality deteriorates, the risk of stroke, heart disease, lung cancer, and chronic and acute respiratory diseases (including COPD and asthma) increases among people living in cities. Four million two hundred thousand people die directly from air pollution globally every year, and 91% of the global population lives in areas exceeding the WHO air pollution standards. In 2016, the WHO reported the annual median concentration of PM2.5 (μg / m 3 ) in various regions of the world. The PM2.5 concentration exceeds 26 μg / m 3。The concentration of the PM2.5 air pollutant specified in the WHO Air Quality Guidelines (AQG) is 10 μg / m 3 。PM2.5 refers to atmospheric particulate matter (PM) with a diameter less than 2.5 μg (micrometers), which is about 3% of the diameter of human hair. Due to their tiny size, particles smaller than 2.5 μg can bypass the nose and throat and penetrate deep into the lungs, and some may even enter the circulatory system. Research reports have shown a strong link between exposure to fine particles and premature death from heart and lung diseases. Fine particles are also known to trigger or exacerbate 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 expected to become the third leading cause of death by 2030. Most typically, the prevalence of COPD is directly related to smoking, although in many countries, outdoor, occupational, and indoor air pollution (such as that caused by burning wood and other biomass fuels) are also major risk factors for COPD. More than a quarter of COPD patients do not smoke, and air pollution is considered the main cause in these cases.

[0012] Patients with chronic obstructive pulmonary disease experience exertional dyspnea caused by bronchoconstriction, mucus secretion, airway wall edema, and loss of airway terminal attachments. The World Health Organization (WHO) predicts that by 2030, chronic obstructive pulmonary disease will become the third leading cause of disease-related death globally.

[0013] COPD is a common, preventable, and treatable disease characterized by airflow limitation and chronic respiratory symptoms, which are typically caused by exposure to harmful gases or particulate matter as a result of abnormal alveoli and airways. The chronic airflow limitation caused by COPD is jointly caused by small airway diseases (such as chronic bronchiolitis) and parenchymal destruction (emphysema). Chronic inflammation leads to changes in the structure of the lungs, including narrowing of the small airways and destruction of the lung parenchyma, resulting in reduced attachment of small airways to alveoli and weakened lung elastic recoil. These changes reduce the ability of the airways to remain open during exhalation. Narrowing of the small airways also leads to airflow limitation and mucociliary dysfunction. Airflow limitation is usually 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 enhanced oxidative stress can trigger a fundamental cellular degradation process called autophagy. Depending on the stimulus, the role of autophagy in lung diseases can be either harmful or protective. In cigarette smoke-induced COPD, autophagy plays a key role in mediating airway epithelial cell apoptosis and cilium shortening. Autophagy then accelerates lung aging and emphysema and promotes the development of COPD by facilitating epithelial cell death. In experimental COPD, autophagy increases in lung cells, leading to inflammation and emphysema destruction. Autophagy is a key mediator of epithelial cell inflammation and mucus overproduction through the 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 function impairment. In addition, it is used to evaluate occupational lung diseases to determine whether preventive or therapeutic measures should be taken and to provide benefits to individuals with lung function impairment. Spirometry data on forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) 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 evaluate an individual's response to treatment. The FEV1 / FVC ratio, the percentage of FEV1 reversibility, and the percentage of normal FEV1 are commonly used evaluation parameters for assessing the severity of airway obstructive diseases, diagnosis, and treatment effectiveness.

[0016] There are several mechanisms that can explain how cigarette smoke causes airway inflammation and subsequent diseases. 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). A second mechanism is oxidative stress due to the imbalance between oxidants and antioxidant defense mechanisms in the airways and lungs. Alveolar macrophages and neutrophils in patients with COPD release oxidants. Activated inflammatory cells are attracted into the alveolar lumen by chemokines and cytokines and release myeloperoxidase and large amounts of hypochlorous acid (HOCl) in the range of 0.1 - 1.0 mM near airway and alveolar epithelial cells.

[0017] Cigarette smoke itself is also a rich source of oxidants, as each puff of cigarette smoke contains approximately 10^15 oxidant free radical molecules and each gram of tar contains 10^17 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 the 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 was capable of inducing carbon-centered free radicals as well as reactive hydroxyl (·OH) free radicals, which would then lead to cell damage. They also reported that wood smoke could cause lipid peroxidation, DNA damage, activation of nuclear factor κ-light chain enhancer of activated B cells (NF-κB) activation, and TNF-α induction. These authors proposed that ·OH free radicals play an important role in these immune system responses and that the iron present in wood smoke and the H2O2 generated in the respiratory tract during phagocytosis of wood smoke particles would generate ·OH free radicals and other reactive oxygen species (ROS) in the lung. These authors concluded that wood smoke was capable of causing acute lung injury and potentially had the potential to act as a fibrogenic agent.

[0019] Asthma

[0020] Asthma is a chronic inflammatory lung disease that causes airflow limitation, hyperreactivity, and airway remodeling. Approximately 235 million people worldwide have asthma, and there were approximately 383,000 asthma-related deaths globally in 2015. (World Health Organization, 2018). The symptoms of asthma are diverse and include wheezing, shortness of breath, and coughing, which are more common at night and in the early morning. The symptoms of asthma are usually episodic and can be triggered by various stimuli, 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 have some similar clinical features, there are significant differences in the pattern of airway inflammation, inflammatory cells, mediators, consequences, and response to treatment.

[0021] Asthma can be broadly classified into eosinophilic or non-eosinophilic based on airway or peripheral blood cell characteristics, with each category accounting for approximately half (Carr et al., 2018). Cytokines play a key role in the coordination, persistence, and amplification of the asthmatic inflammatory response. It has been reported that there is similar airway inflammation in patients with severe asthma as in patients with COPD (Barnes, 2001, 2008). Eosinophilic asthma is considered a T helper cell 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, the secretion of Th2-related cytokines such as 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 that drive the pathology of the disease (Carr et al., 2018).

[0022] Heavy metals and smokers

[0023] According to the US 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 have drawn public health concerns due to their potential toxicity and carcinogenicity. Richter et al. (2009), reporting the results of the National Health and Nutrition Examination Survey (NHANES) from 1999 - 2004, concluded that smokers had higher levels of cadmium, lead, antimony, and barium than nonsmokers. The highest lead levels were in the youngest subjects. Lead levels in adults with high secondhand smoke exposure were comparable to those of smokers. Cadmium levels in older smokers predicted the likelihood of cadmium-related toxicity. Cadmium is a known class 1 carcinogen. The findings of Richter et al. (2009) showed that urine lead levels were higher in children exposed to secondhand smoke (a population particularly vulnerable to the toxic effects of lead at low exposure levels) than in children not exposed to SHS. Urine 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 the cadmium concentration in the lung tissue of smokers with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV COPD (58 ± 10.8 pack-years) was proportional to the total tobacco consumption of the patients (“tobacco load”). Sunblad et al. (2016) published evidence of the link between local cadmium concentration and changes in lung innate immunity. They reported that the cadmium concentration in the cell-free bronchoalveolar lavage fluid (BLF) of smokers was significantly elevated compared to non-smokers, regardless of whether they had chronic obstructive pulmonary disease. In these smokers, the measured cadmium concentration was positively correlated with the macrophage TNF-α mRNA in BAL, the neutrophils in the blood, and the concentration of cytotoxic T cells (CD8+), and finally with the inflammatory cytokines IL-6, IL-8, and matrix metalloproteinase 9 (MMP-9) protein in sputum. They also concluded that extracellular cadmium was enhanced in the bronchoalveolar space of long-term smokers and exhibited pro-inflammatory characteristics. The local accumulation of cadmium in the lung seems to be a key factor for the susceptibility of long-term smokers to lung diseases. Considering that the biological half-life of cadmium in the human body > 25 years (a rather long period), it is particularly important to note that a large amount of cadmium may remain in the lungs of long-term smokers. 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 sulfhydryl-containing amino acid compound, 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, fenchyl alcohol, cardamonin, or a combination. The sulfhydryl-containing amino acid compound can be a naturally occurring compound. The sulfhydryl-containing amino acid compound can be glutathione, N-acetylcysteine, carbocysteine, taurine, methionine, or a combination. The vitamin can be cobalamin, methylcobalamin, hydroxocobalamin, adenosylcobalamin, cyanocobalamin, cholecalciferol, thiamine, dexpanthenol, biotin, niacin, 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 can be a naturally occurring compound. The antioxidant can be 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, cyanocobalamin, β-caryophyllene, or a combination.

[0026] The pharmaceutical composition may comprise from about 0.05% to about 10% of epigallocatechin-3-gallate and from about 0.1% to about 10% of 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, brine, degassed water, degassed brine, water purged with a pharmaceutically inert gas, brine purged with a pharmaceutically inert gas, or a combination. The carrier may comprise water or brine and polysorbate, such as polysorbate 20.

[0028] The pharmaceutical composition may comprise lubricating, emulsifying, and / or thickening compounds. The lubricating, emulsifying, and / or thickening compounds may be carbomer, polymers, 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), polyoxyethylene (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 comprise pH adjusting compounds. The pH adjusting compounds may be sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate, benzoic acid, ascorbic acid, or a combination.

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

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

[0032] The pharmaceutical composition may further comprise an amino acid. The amino acid may be a protein 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.

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

[0034] The pharmaceutical composition may further comprise a type 2 cannabinoid receptor (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 from about 0.1% to about 1% of β-caryophyllene.

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

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

[0037] The pH value of the pharmaceutical composition may be from 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 lining fluid.

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

[0040] The pharmaceutical composition may further comprise a microemulsion or nanoemulsion. The microemulsion or nanoemulsion may comprise the plant extract TRPA1 antagonist, a compound containing a mercapto amino acid, vitamins, and / or antioxidants. The microemulsion or nanoemulsion may comprise the plant extract TRPA1 antagonist, a compound containing a mercapto amino acid, vitamins, antioxidants, amino acids, and / or CB2 agonists.

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

[0042] In one embodiment, the pharmaceutical composition comprises about 0.8% of 1,8-cineole, about 0.8% of β-caryophyllene, about 1.35% of N-acetylcysteine, about 1.35% of glutathione, about 0.01% of ascorbic acid, about 0.003% of methylcobalamin, about 0.8% of 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 the following: about 0.05% of EDTA, about 1% of dexpanthenol, about 0.7% of L-theanine, about 0.5% of taurine, about 0.05% of epigallocatechin-3-gallate, about 0.5% of resveratrol, and about 3% of cannabidiol.

[0043] In one embodiment, the pharmaceutical composition comprises about 1.7% of 1,8-cineole, about 1.7% of β-caryophyllene, about 1.2% of N-acetylcysteine, about 1.5% of glutathione, about 0.01% of ascorbic acid, about 0.003% of methylcobalamin, about 1.7% of polysorbate 20, about 91% of 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% of EDTA, about 1% of dexpanthenol, about 0.7% of L-theanine, about 0.5% of taurine, about 0.05% of epigallocatechin-3-gallate, about 0.5% of resveratrol, and about 3% of cannabidiol. In one embodiment, the pharmaceutical composition further comprises about 1.8% of nicotine.

[0044] In one embodiment, the pharmaceutical composition according to claim 1 comprises from about 10 g / L to about 30 g / L glutathione, from about 7 g / L to about 25 g / L N-acetylcysteine, from about 10 g / L to about 30 g / L 1,8-cineole, and from 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 from about 6 g / L to about 20 g / L polysorbate 20 and from 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 from about 6 g / L to about 20 g / L polysorbate 20 and from 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 glycerol, and the pharmaceutical composition is a 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 from about 0.5% to about 2% glutathione, from about 0.5% to about 2% N-acetylcysteine, from about 0.4% to about 1.2% 1,8-cineole, from about 0.0002% to about 0.01% cobalamin or methylcobalamin, and from about 0.1% to about 1.2% β-caryophyllene. In one embodiment, the pharmaceutical composition further comprises from about 0.1% to about 1.5% polysorbate 20 and from 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% β-caryophyllene. In one embodiment, the pharmaceutical composition further comprises about 0.3% polysorbate 20, and the balance is a 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 method for smoking cessation and respiratory system treatment according to the present invention comprises: in a first step, administering to the lungs of a patient, in a first time period, a first mixture of the pharmaceutical composition and nicotine in the form of an aerosol or a spray, the nicotine being at a first concentration in the first mixture, and in a last step, administering to the lungs of the patient, in a last time period, the pharmaceutical composition (without nicotine) of the present invention in the form of an aerosol or a spray. The aerosolized or sprayed pharmaceutical composition and / or nicotine can be administered to the lungs of the patient by a series of jets of the patient using a nebulizer, an ultrasonic vaporization device, a thermal e-cigarette vaporization device or a device that generates an aerosol, a spray or a gas phase from the pharmaceutical composition and / or nicotine. In the first step, the patient can inhale the first mixture by a plurality of jets per day and ingest nicotine in an amount close to the amount in the patient's most recent active smoking behavior per day. In the first step, the patient can inhale the first mixture by about 50 to about 400 jets per day, for example about 150 jets per day. In the first step, the patient can ingest about 5 mg to about 40 mg, for example about 20 mg of nicotine per day. In the first step, the patient can 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 can be about 0.5% to about 4% of the first mixture, for example about 1.4%. In the first step, the first time period can be about 2 weeks to about 4 months, for example about 40 days to about 60 days. In the last step, the patient can 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, namely administering to the patient's lungs, during another period of time, another mixture according to the invention of the pharmaceutical composition and nicotine in atomized or sprayed form, wherein the nicotine is at another concentration in the another mixture, and the another concentration is lower than the first concentration. For example, the method may include a second step of administering to the patient's lungs, during a second period of time, a second mixture according to the invention of the pharmaceutical composition and nicotine in atomized or sprayed form, wherein the nicotine is at a second concentration in the second mixture, and the second concentration is lower than the first concentration. In the second step, the patient may inhale the second mixture about 40 to about 320 sprays per day, for example about 125 sprays. In the second step, the patient may ingest about 4 mg to about 30 mg of nicotine per day, for example about 14 mg of nicotine. In the second step, the patient may inhale about 0.5 mL to about 2 mL, for example about 1 mL of the second mixture per day. In the second step, the second concentration of nicotine may be about 0.3% to about 3% of the second mixture, for example about 1%. In the second step, the second period of time may be about 2 weeks to about 2 months, for example about 14 days to about 30 days.

[0055] The method may further include a third step of administering to the patient's lungs, during a third period of time, a third mixture according to the invention of the pharmaceutical composition and nicotine in atomized or sprayed form, wherein the 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 may inhale the third mixture about 25 to about 200 sprays per day, for example about 75 sprays. In the third step, the patient may ingest about 2 mg to about 15 mg of nicotine per day, for example about 5 mg of nicotine. In the third step, the patient may inhale about 0.5 mL to about 2 mL, for example about 1 mL of the third mixture per day. In the third step, the third concentration of nicotine may be about 0.1% to about 1% of the third mixture, for example about 0.4%. In the third step, the third period of time is about 2 weeks to about 2 months, for example about 14 days to about 30 days.

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

[0057] In one embodiment of the smoking cessation and respiratory system treatment method 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, an atomizer may generate an aerosol, spray, or gas phase from the pharmaceutical composition and / or nicotine. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0060] Figure 1 The provided graph shows the change over time of the FEV1 spirometry test results for five patients in a preclinical trial. It can be seen that the FEV1 improved linearly over time, with a substantial improvement in the spirometry results.

[0061] Figure 2 The provided graph shows a comparison between the treatment results (i.e., percentage of normal FEV1) of FEV1 patients before treatment (light gray bars) and after treatment (black bars).

[0062] Figure 3 The provided graph shows a comparison between the treatment results of FEV1 patients before treatment (light gray solid bars) and after treatment (black solid bars), as well as the normal FEV1 (striped bars) calculated based on age, gender, height, and race.

[0063] Figure 4 The provided graph shows the percentage FEV1 reversibility results for each of the five patients.

[0064] Figure 5 The provided figure shows the average FEV1 results before treatment (light gray bars) and after treatment (black bars). T-test analysis indicated that the results were significant at the P = 0.0001 level. Detailed implementation mode

[0065] The embodiments of the present invention will be discussed in detail below. Specific terms are used for clarity when describing the embodiments. 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 employed without departing from the spirit and scope of the present invention. All references cited herein are incorporated herein by reference in their entirety as if each reference was incorporated separately.

[0066] The present invention relates to methods of using liquids and liquid compositions that are transferred to the gas phase and aerosol phase for inhaled drug treatment of lung and respiratory diseases. More specifically, the present invention relates to methods of using liquids and liquid compositions that are orally administered to the lungs via a vaporization and aerosol generation device to provide a multi-functional treatment for lung and respiratory system diseases, the liquid composition comprising a plant-based TRPA1 antagonist, a natural thiol-containing amino acid compound, a CB2 agonist, amino acids, a naturally occurring antioxidant, vitamins, and bioflavonoid compounds, and a heavy metal complex compound. The present invention also relates to a multi-functional liquid composition comprising a cannabinoid compound, a plant-based TRPA1 antagonist, a natural thiol-containing amino acid compound, a CB2 agonist, amino acids, a naturally occurring antioxidant, vitamins, and bioflavonoid compounds, and a heavy metal complex compound. The present invention relates to a liquid composition and a method of using a liquid for reducing lung injury in patients exposed to cigarette smoke from active smoking or second-hand 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 of use and compositions of liquid pharmaceutical compositions that are transferred into the gas phase and aerosol phase for inhaled drug therapy of lung and respiratory diseases. More specifically, the present invention relates to methods of use of a liquid and a liquid composition that are orally administered to the lungs by a vaporization and aerosol generating device to provide a multi-functional treatment for lung and respiratory system diseases, the liquid composition comprising a plant-based transient receptor potential cation channel subfamily A member 1 (TRPA1) antagonist, a natural thiol-containing amino acid compound, one or more vitamins, a naturally occurring antioxidant, a heavy metal complexing compound, and a carrier. The present invention also includes a pharmaceutical liquid composition and a method of use that comprises an amino acid, a natural cannabinoid receptor type 2 (CB2) receptor agonist, a cannabinoid compound, and nicotine. More specifically, the present invention relates to methods of use of a liquid and a liquid composition for reducing lung injury in a patient exposed to air pollution, cigarette smoke from active smoking, second-hand cigarette smoke, and wood smoke. Additionally, the present invention also relates to methods of use of a liquid and a liquid composition for smoking cessation (assisting smokers to quit smoking) and respiratory system treatment.

[0068] COPD includes chronic bronchitis and emphysema. Environmental exposures, mainly caused by smoking, result in high oxidative stress, which is the main factor leading to the development of chronic obstructive pulmonary disease. Cigarette smoke also contributes to an oxidant / antioxidant imbalance due to exogenous reactive oxygen species associated with cigarette smoke. Endogenously released reactive oxygen species and mitochondrial dysfunction during the inflammatory process 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 injury and death.

[0069] Oxidative stress causes structural changes in the basic components of the lung, contributing to irreversible damage to the parenchyma and airway walls. In addition, oxidative stress may also lead to changes in the local immune response. However, cells can be protected from oxidative stress through enzymatic and non-enzymatic antioxidant systems. The attenuation of oxidative stress results in reduced lung injury and reduced local infection, thus helping to slow the progression of COPD. Attenuating oxidative stress in the lung by inhaling a naturally occurring antioxidant is one embodiment of the present invention.

[0070] Medications for the treatment of COPD are used to relieve symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance and health status. So far, there is no conclusive clinical trial evidence that any existing COPD medications improve the long-term decline in lung function. Pharmacological treatment of COPD patients typically focuses on bronchodilation through inhaled anticholinergics and β2-agonists. Anti-inflammatory treatment is another treatment option for COPD patients, including inhaled corticosteroids, oral glucocorticoids, PDE4 inhibitors, antibiotics, mucolytics, and antioxidants. Bronchodilators are medications that increase FEV1 and / or alter other spirometry measurements. They act by altering airway smooth muscle tone and improving expiratory flow, and reflect airway widening rather than changes in lung elastic recoil. It is not uncommon for the treatment of COPD patients to include combination therapy, such as inhaled corticosteroid combined with long-acting bronchodilator therapy. A triple inhaler therapy has also been developed to improve lung function, patient-reported outcomes, and prevent exacerbations, using a long-acting muscarinic antagonist (LAMA), a long-acting β2-agonist (LABA), and an inhaled corticosteroid in a single inhaler. The use of anticholinergics, short-acting β2-agonists, inhaled corticosteroids, LAMA, and LABA all have significantly reported side effects. Increasing the patient's FEV1 response through bronchodilation is an embodiment of the present invention.

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

[0072] One embodiment of the present invention is the use of corticosteroids and bronchodilators for alternative treatment of COPD patients with a multifunctional inhaled nebulized pharmaceutical liquid composition containing natural antioxidants, natural anti-inflammatory compounds, and vitamins. Another embodiment of the present invention is the combination of an inhaled nebulized pharmaceutical liquid composition containing 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. Cigarette smoke, inhaled airborne pollutants (ozone, nitrogen dioxide, sulfur dioxide), and particulate matter in the air can trigger asthma symptoms. A clear relationship between traffic density and asthma exacerbation has also been demonstrated. Cigarette smoke is associated with asthma exacerbation, especially in young children, and there is a dose-dependent relationship between exposure to cigarette smoke and the incidence of asthma.

[0074] The goals of asthma treatment are to relieve symptoms and limit exacerbations. Currently, all asthma patients are recommended to take short-acting β-2 agonist (SABA) inhalers (such as albuterol, levalbuterol, terbutaline, metaproterenol, and pirbuterol) for rescue treatment. For patients with moderate to severe persistent asthma, long-acting β-2 agonists (LABAs), such as salmeterol and formoterol, or leukotriene inhibitors are often added to inhaled corticosteroid therapy. Commonly used corticosteroids include: beclomethasone, triamcinolone, flunisolide, ciclesonide, budesonide, fluticasone, and mometasone. Anticholinergic drugs are also used to relieve bronchoconstriction and dyspnea in asthma patients. There are short-acting and long-acting anticholinergic drugs available. For patients with more severe and difficult-to-control forms of asthma, the use of biologics may be considered. Omalizumab is the first biologic approved for eosinophilic asthma and acts by binding 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 6 years of age and older and improves asthma symptoms, reduces exacerbations, and eosinophil counts. New biologics targeting the IL-5 pathway are also available, including: mepolizumab, reslizumab, and benralizumab. IL-5 is the main cytokine responsible for eosinophil growth, differentiation, and survival and plays an important role in airway inflammation in asthma patients. Clearly, the main strategy for controlling eosinophilic asthma is to antagonize the production of interleukin cytokines, especially IL-5. Unfortunately, the existing synthetic biologics on the market have very serious side effects and are very costly, with treatment costs usually in the tens of thousands of dollars per year.

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

[0076] One embodiment of the present invention is an inhaled nebulized pharmaceutical liquid composition and a treatment method to reduce the heavy metal concentration in the lungs of current smokers 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 in the following ways: a gas or substance, for example, a substance in aerosol form, such as the 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 had a tracheostomy, through the opening (hole) into the trachea), via the respiratory tract. Thus, unless otherwise stated, the terms "inhalation", "administration", and other similar terms include the administration of a substance to the lungs by oral inhalation (i.e., via the mouth) and by nasal inhalation (i.e., via the nose) (and, in the case of an individual who has had a tracheostomy, 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 micrometer. In the experimental device developed by Sahu et al. (2013), at a puff volume of 35 mL / puff, the particle size of inhaled cigarette smoke varied between 186 nm and 198 nm. When the puff volume was increased to 85 mL / puff, the particle size increased to approximately 300 nm. Smokers typically retain approximately 30 - 66% of the particulate phase contained in cigarette smoke, and the amount of particulate matter absorbed 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 the inhaled cigarette smoke particles are deposited in the human respiratory tract. In contrast, e-cigarette aerosols are best described as a mist, which is an aerosol formed by condensation or atomization and consisting of spherical droplets in the size range from submicron to 200 micrometers. Alderman et al. (2014) reported that the particle size measurements of e-cigarettes are in the range of 260 - 320 nm count median diameter.

[0080] A variety of types of medical disorders can be treated by inhaling various natural and synthetic liquid substances. These chemical substances can be administered to patients using different types of inhaled drug delivery system applicators, including: nebulizers, in which the liquid drug is transformed into a mist and then inhaled into the lungs; metered-dose inhalers (MDIs), which are pressurized inhalers that use a propellant spray (e.g., a mixture of drug and propellant) to deliver the drug; soft mist inhalers (SMIs), which are multi-dose, propellant-free, hand-held aerosol-generating liquid inhalers that use a compressed spring rather than compressed gas to generate the aerosol; ultrasonic e-cigarette vaporization devices and thermal atomization devices, including e-cigarette vaping devices that are triggered to atomize the liquid stored in a reservoir by heating with a heating element or coil to produce an atomized mixture (i.e., vapor) that is 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 ultrasonic action.

[0081] The liquid compositions presented in the present application of the present invention can be vaporized or atomized by any of the above or any other liquid-based inhaled drug delivery system for oral or nasal administration. Those of ordinary skill in the art will recognize that the liquids described 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 the patient.

[0082] Particle size, as well as particle velocity and sedimentation time, play important roles in lung deposition. As the particle size increases above 3 μm, aerosol deposition shifts from the lung periphery to the conducting airways. When the particle size increases above 6 μm, oropharyngeal deposition increases. At extremely small particles of 1 μm or less, exhalation losses are higher. Thus, particles with a size of 1-5 μm effectively reach the lung periphery, 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 Association for Respiratory Care, 2017). The preferred particle size of the atomized liquid in the present invention is from about 1 μm to about 5 μm.

[0083] In one embodiment of the present invention, the liquid composition and method of use of the atomizable liquid composition include nicotine salts as part of a nicotine replacement therapy smoking cessation system while providing concurrent treatment of lung and respiratory diseases and the effects from a person's smoking history. In one embodiment of the present invention, the atomizable liquid composition contains 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 complex compounds.

[0084] In another embodiment of the present invention is a liquid composition and method of use, wherein the liquid is vaporized, atomized, or both, and inhaled by a patient to reduce individual airway inflammation associated with COPD, asthma, cystic fibrosis, and other respiratory diseases associated with reduced lung volume. In yet another embodiment of the present invention is a multifunctional composition that reduces the concentration and action of reactive oxygen species in the lung 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 an atomizable liquid composition and method of use for reducing reactive oxygen species in the lung, including the lung epithelial lining fluid, epithelial cells, neutrophils, eosinophils, macrophages, lymphocytes, monocytes, and tissues in the lungs of patients with diseases that cause an imbalance in the oxidant / antioxidant concentration due to endogenous causes of reactive oxygen species. Another embodiment of the present invention is an atomizable liquid composition and method of use for reducing inflammatory cytokines in the lung, including the lung epithelial lining fluid, epithelial cells, neutrophils, eosinophils, macrophages, lymphocytes, monocytes, and tissues in the lungs of a patient, which are present in the epithelial lining fluid covering the alveoli, small airways, and mucosa of the large airways as a result of smoking, asthma, COPD, and other respiratory diseases. In one embodiment of the present invention, the inflammatory cytokines that are 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 additional therapeutic agents. The additional therapeutic agents can be prescription drugs or over-the-counter drugs (i.e., non-prescription drugs). For example, the additional therapeutic agents can also be used to treat lung or respiratory tract disorders such as asthma, COPD, emphysema, and chronic bronchitis. For example, the additional therapeutic agents can include short-acting β2-adrenergic receptor agonists (SABA) (such as albuterol, salbutamol, terbutaline, orciprenaline, pirbuterol), anticholinergics (such as ipratropium, tiotropium, aclidinium, umeclidinium), adrenergic agonists (such as adrenaline), corticosteroids (such as beclomethasone, triamcinolone, flunisolide, ciclesonide, budesonide, fluticasone propionate, mometasone), long-acting β2-adrenergic receptor agonists (LABA) (such as salmeterol, formoterol, indacaterol), leukotriene receptor antagonists (such as montelukast, zafirlukast), 5-LOX inhibitors (such as zileuton), antimuscarinic agents, bronchodilators, and / or combinations of two or more of these.

[0087] The present invention also relates to the use of one or more water-soluble natural sulfur-containing amino acid compounds, which compounds include glutathione, N-acetylcysteine, and carboxymethylcysteine in a liquid that is nebulized, 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 human. The present invention further relates to the use of the water-soluble natural sulfonic acid amino acid, namely taurine, which can react with endogenously produced hypochlorous acid in the lung to form the much less toxic taurine chloramine (Tau-Cl). Taurine acts to neutralize reactive oxidant species and neutralize inflammatory cytokines in the composition by forming Tau-Cl. Optional additives for 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" generally refers to any disease that designates respiratory tract inflammation as the main cause or inflammation caused by a disease. Specifically, inflammatory diseases may include systemic or localized inflammatory diseases (such as: allergy; immune complex disease; hay fever; and respiratory diseases (such as asthma; epiglottitis; bronchitis; emphysema; rhinitis; cystic fibrosis; interstitial pneumonia; chronic obstructive pulmonary disease, acute respiratory distress syndrome; pneumoconiosis; alveolitis; bronchiolitis; pharyngitis; pleurisy or sinusitis)); but are not limited to these diseases. In the present invention, inflammatory respiratory diseases can 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 enclosed or semi-enclosed spaces, such as cars, buses, trains, ships or any other transportation or space-related vehicle.

[0089] In the present invention, "vapor" is defined as a diffused substance (such as smoke or fog) that is suspended in the air and impairs its transparency, as well as a gaseous substance that is different from the liquid or solid state. Thus, vapor can be a compound in the gas phase, for example, a volatile liquid vaporizes and changes from the liquid phase to the gas phase, as well as suspended liquid particles. In the present invention, "aerosol" is defined as a suspension of fine solid particles or droplets in air or other gases.

[0090] One embodiment of the present invention is a composition and method of use for antagonizing, inactivating or blocking TRPA1 activation in the lung, said TRPA1 activation being caused by exogenous chemicals which would otherwise cause TRPA1 activation, such as due to cigarette smoke, the method being by inhalation of an aerosolized natural plant compound TRPA1 antagonist 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 converting a liquid to the aerosol phase and / or gas phase and then inhaled by a human. Another embodiment of the present invention is to limit lung tissue damage due to, for example, reactive oxygen species from cigarettes and other exogenous smoke sources and exogenous air pollutants, by inhaling a natural thiol-containing amino acid compound, a CB2 agonist, an amino acid, a naturally occurring antioxidant, a phytochemical and a flavonoid compound, a vitamin and a heavy metal complex compound 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 converting a liquid to the aerosol phase and / or gas phase and then inhaled by a human. Another complementary feature of the present invention includes a plant-based TRPA1 antagonist, a natural thiol-containing amino acid compound, a CB2 agonist, an amino acid, a naturally occurring antioxidant, a vitamin and a bioflavonoid compound, and a heavy metal complex compound into a liquid which is inhaled 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 converting a liquid to the aerosol phase and / or gas phase and then inhaled by a human, having one or more antioxidant, anti-inflammatory, anti-allergic, antiviral or anti-cancer properties.

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

[0092] Another feature of the present invention is a method of 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 an increase in the level of extracellular reactive oxygen species, which in turn activates lung epithelial TRPA1. Activation of TRPA1 then converts this cigarette smoke-induced stimulus into transcriptional regulation of lung inflammation via Ca2+ influx. In another embodiment of the present invention, a liquid composition is inhaled into the respiratory tract while being vaporized, atomized, or both, resulting in an increased concentration of a compound in the lung, the compound being 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 mainly comprising naturally occurring compounds is inhaled into the respiratory tract while being vaporized, atomized, or both, resulting in an increased concentration of a compound in the lung, 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 chemicals contained in the liquid of the present invention that are vaporized, atomized, or both is to reduce one or more of tissue damage, inflammation, excessive mucus accumulation, coughing, and cancer caused by reactive oxygen species, but not limited to these, which are the result of an oxidant / antioxidant chemical imbalance in the lung. Reducing inflammation in the lung by inhaling the gas phase and the atomized phase of the liquid of the present invention includes modulating the immune system response, increasing the antibacterial and antifungal conditions in the lung, 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] A further aspect of the present invention relates to cannabinoid compounds (both phytocannabinoids and synthetic cannabinoids), including but not limited to: 9-tetrahydrocannabinol (δ-9-THC), 9-THC propyl analogue (THC-V), cannabidiol (CBD), cannabidiol propyl analogue (CBD-V), cannabinol (CBN), cannabichromene (CBC), cannabichromene propyl analogue (CBC-V), cannabigerol (CBG), cannabinoid terpenoids and cannabinoid flavonoids; cannabinol (CBN) in combination with a TRPA1 antagonist, a TRPM8 agonist, a natural thiol-containing amino acid compound, a CB2 agonist, an amino acid, an antioxidant, a vitamin, a bioflavonoid compound and a natural metal chelate. Due to its lack of psychoactive properties, cannabidiol is the preferred phytocannabinoid in the present invention.

[0094] Surprisingly, it has been found in the present invention that natural compounds can be combined to control gating to inhibit TRPA1 activation, and thus, the lung inflammation and inflammatory effects caused by TRPA1 activation induced by exogenous and endogenous chemicals, including cigarette smoke, can be reduced. In other compositions of the present invention, 1,8-cineole and / or borneol are TRPA1 antagonists. Other compositions of the present invention contain 1,8-cineole and / or borneol and a natural thiol-containing amino acid compound. Other compositions of the present invention contain a CB2 agonist. The preferred CB2 agonist in the present invention is β-caryophyllene. Preferred compositions in the present invention contain: 1,8-cineole as a TRPA1 antagonist and a TRPM8 agonist; N-acetylcysteine and glutathione, which are natural thiol-containing amino acid compounds and also antioxidants; and an emulsifying compound 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 contain 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 by vaporization to confer antioxidant, anti-inflammatory, anti-allergic, antiviral and anti-cancer properties to the lungs of an individual exposed to cigarette smoke. In addition, the present invention relates to the use of the bioflavonoid compound thymoquinone in a liquid for inhalation by 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 by atomization or vaporization to confer antioxidant, anti-inflammatory, anti-allergic, antiviral and anti-cancer properties to the lungs of an individual exposed to cigarette smoke. In addition, the present invention relates to the use of the bioflavonoid compound berberine in a liquid for inhalation by 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 present invention relates to the use of the bioflavonoid compound curcumin in a liquid for inhalation by 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 tracts. Curcumin is known to have antioxidant and anti-inflammatory properties. The anti-inflammatory effect of curcumin is likely mediated by its ability to inhibit cyclooxygenase-2 (COX-2), lipoxygenase (LOX) and inducible nitric oxide synthase (iNOS). Since inflammation is closely associated with tumor promotion, curcumin, by virtue of its potent anti-inflammatory properties, will exert a chemopreventive effect on cancer development.

[0098] Another feature of the present invention relates to the use of other natural compounds exhibiting anti-inflammatory properties in respiratory therapy, said other natural compounds including: andrographolide, astragaloside, cardamonin, kaempferol, luteolin, naringin, oroxylin A, quercetin, geniposide, genistein, ellagic acid, aesculetin, glycyrrhizin, hydroxysafflor yellow A, baicalein, baicalin, stepholidine, colombianadin, aesculin, imperatorin, isoimperatorin, isoorientin, isovitexin, sanggenon M, orientin, phillyrin, platycodin D, resveratrol, schisandrin A, silymarin, irigenin, triptolide, paeonol, gingerone, paeonol, protocatechuic acid, limonene, linalool, phillyrin, asperuloside, prime-O-glucosylcimifugin, cannabidiol, flavone, pentahydroxyflavone, luteolin, apigenin-7-glucoside, baicalein, baicalin, afzelin, hyperoside, quercitrin, morin, quercetin, fisetin, irigenin, eriodictyol, naringin, hesperidin, prunin, taraxasterol, vitexin, mogroside V, triptolide, minnelide, phytolaccasaponin, colombianadin, aesculin 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 C.D.Dai&Yakovlev, Chrysanthemum indicum, Coscinium fenestratum, Cnidium monnieri, Eleusine indica, Eucalyptus cinerea, Eucalyptus globulus, Euterpe 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 laevigata, 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, Uncaria tomentosa, and Viola yedoensis.

[0099] The atomizable liquid pharmaceutical composition of the present invention may further comprise a carrier that enables the most effective delivery of the liquid and the resulting atomized compound to the lungs, typically but not limited to nebulizers, ultrasonic vaporization devices, and thermal electron vaporization systems, such as electronic cigarettes and other types of electronic cigarette vaporization devices. The carrier composition may contain such compounds, but is not limited to sterile water, pH buffers, acids, bases, surfactants, emulsifiers, diols, vegetable glycerin, and inorganic salts to make the composition isotonic with the pulmonary epithelial lining fluid.

[0100] Another feature of the present invention is a lubricating viscosity modifier added to a liquid for atomization or vaporization for inhalation. The lubricating viscosity modifier can be selected from one or more of the group consisting of carbomer, polymers, 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, glycerol, vegetable glycerol, polyethylene glycol, and polyethylene glycol (400).

[0101] Another feature of the present invention is a stable suspension generating component, which can be added alone to one or more components or to the 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 the group of emulsifiers or liposomes. Liposomes can encapsulate both hydrophobic and hydrophilic compounds and can be used in the present invention to target, localize, or specifically absorb or adsorb a chemical to or onto a specific tissue, fluid, or cell type in the lung. Liposomes have an aqueous 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 associate with the bilayer. Thus, liposomes can be loaded with hydrophobic and / or hydrophilic molecules. Although most of the compounds that make up the present invention are hydrophilic, some compounds are more hydrophobic, such as 1,8-cineole, β-caryophyllene, resveratrol, thymolquinone, epigallocatechin gallate, and other catechin compounds, curcumin, and borneol. Compositions containing any of these compounds or other hydrophobic compounds at a concentration greater than their solubility in the aqueous bulk solution may require emulsifying them in an oil-in-water (O / W) microemulsion and nanoemulsion of the bulk solution or incorporating the individual hydrophobic compounds in a liposome structure. Those of ordinary skill in the art will readily understand that a variety of methods can be used to produce a stable homogeneous suspension with a mixture of hydrophilic and hydrophobic compounds described in the present invention.

[0102] Another feature of the present invention is to use a pH buffer to adjust the pH value of the liquid to the pH value of healthy lung epithelial fluid, i.e., about 7.2. Another feature of the present invention is to add salts to produce a liquid composition that is isotonic with lung epithelial fluid.

[0103] One feature of the present invention provides a liquid formulation and method of use for treating various respiratory diseases associated with exposure to cigarette smoke and other types of smoke, as well as an over-imbalance of oxidants and antioxidants in the lung, which produce reactive oxygen species, subsequently leading to inflammation, DNA damage, and a cascade of cytokine, neuropeptide, and nociceptor activation. Each puff of cigarette smoke can produce 10 15active oxygen species free radicals, and the compositions and methods of use of the liquid of the present invention atomized in the present invention are intended to reduce damage to the respiratory systems of active smokers, former smokers, and those exposed to secondhand smoke. Those of ordinary skill in the art understand that both the short-term and long-term health of an individual who is an active smoker has the greatest potential for improvement by quitting smoking. However, the addictive nature of nicotine makes it somewhat difficult for active smokers to quit. The present invention discloses compositions and methods of use of nicotine-containing liquids that can be atomized in ultrasonic vaporization devices, thermal vaporization systems (such as e-cigarette vaporization devices and e-cigarettes), which also provide a multi-functional treatment for lung and respiratory diseases, the treatment comprising plant-based TRPA1 antagonists, CB2 agonists, naturally occurring mercapto amino acid-containing compounds, naturally occurring antioxidants, amino acids, and flavonoid compounds, and heavy metal complexing compounds. The method of use of this combined nicotine-respiratory drug treatment includes complete smoking cessation or replacement of both with the nicotine-containing respiratory drug treatment composition disclosed in the present invention. If a smoker cannot completely quit smoking, a portion of their daily nicotine consumption can be replaced by using the nicotine-containing composition disclosed in this patent. Both complete smoking cessation and replacement of a portion of the nicotine consumed daily by an individual from cigarettes by inhalation of the nicotine-containing atomizable pharmaceutical liquid composition disclosed in the present invention will reduce respiratory system 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 heterogeneous systems oriented towards environmental sensing and are involved in sensing visual, gustatory, olfactory, auditory, mechanical, thermal, osmotic, chemical, and pruritogenic stimuli. The transient receptor potential channel family currently contains more than 50 different channels, 27 of which have been found in humans. Transient receptor potential channel gating is achieved through the direct action 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 mint), carvacrol (in oregano), thymol (in thyme and oregano), and cannabinoid compounds, namely cannabidiol (CBD), cannabinol (CBC), and cannabinol (CBN) (in cannabis 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 present in tear gas, cigarette smoke, smoke from burning vegetation, vaping liquid, and vehicle exhaust) have been identified as TRPA1 activators. Many TRP channels (TRPA1, TRPV1, and TRPV4) have been linked to the sensory perception associated with cough responses.

[0106] Bessac et al. (2008) reported that both hypochlorite (an oxidizing medium of chlorine) and hydrogen peroxide (a reactive oxygen species) activate Ca in mouse cells 2+Influx and TRPA1 activation, while mouse cells genetically lacking TRPA1 did not show such responses. In respiratory tests of TRPA1-deficient mice, they showed a severe lack of hypochlorite- and hydrogen peroxide-induced respiratory inhibition, as well as a reduced pain behavior induced by oxidants. These 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 might also contribute to the effects of chlorine and other TRPA1 agonists on the chemosensory nerve endings in the lower airways. Since reactive irritants are efficiently cleared in the upper airways, higher exposure levels are required for sensory activation in the lower airways. Prolonged or high-level exposure to oxidants, such as those experienced by chlorine gas exposure victims, causes severe pain, coughing, mucus secretion, and bronchospasm. These 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 candidate drugs with potential antitussive, analgesic, and anti-inflammatory properties. In one embodiment of the present invention is an inhaled nebulized pharmaceutical liquid composition and a method for treating an individual or soldier exposed to a chemical warfare agent that is a respiratory irritant, a coughing agent, and / or a choking agent. Such chemical warfare agents can include lacrimators (tear gases), vomiting agents, vesicants (e.g., nitrogen mustard and sulfur mustard agents) and arsenicals (e.g., lewisite) and choking agents (e.g., chlorine gas, chloropicrin, diphosgene, phosgene, sulfur decafluoride, perfluoroisobutene, 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 activate 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 pro-inflammatory cytokines. In the trachea, the gas phase (only the gas phase) of cigarette smoke and whole cigarette smoke were equally effective in releasing calcitonin gene-related peptide, while the larynx showed a much greater response to whole cigarette smoke than to the gas phase. They concluded that nicotinic receptors contribute to the sensory effects of cigarette smoke on the trachea, mainly TRPA1, rather than TRPV1.

[0108] Mukhopadhyay et al. (2016) reported that the TRPA1 ion channel is highly expressed on C fibers, and C fiber innervation begins in the conducting airways of the oral cavity and oropharynx, trachea, bronchi, terminal bronchioles, respiratory bronchioles, and extends to almost the entire respiratory tract from the alveolar ducts to the alveoli. They reported that TRPA1 acts as a "chemical sensor"; detecting the presence of exogenous irritants and endogenous pro-inflammatory mediators involved in airway inflammation and sensory symptoms such as chronic cough, asthma, COPD, allergic rhinitis, and cystic fibrosis. Due to the elevated and persistent levels of such endogenous ligands and pro-inflammatory mediators, TRPA1 can remain activated for a long time. They also reported that various harmful chemicals and environmental / industrial irritants that activate TRPA1 are also triggers for 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 therapy for respiratory diseases in the near future.

[0109] Li et al. (2015) confirmed the important role of lung epithelial TRPA1 in the induction of IL-8 in primary human bronchial epithelial cells by cigarette smoke extract. These in vitro findings using primary human bronchial epithelial cells showed that exposure to cigarette smoke extract initially led to an increase in the extracellular level of reactive oxygen species, which in turn activated lung epithelial TRPA1. TRPA1 activation then converted this cigarette smoke-induced stimulus into transcriptional regulation of lung inflammation through Ca 2+ influx. They reported that preventing Ca 2+ influx by reducing extracellular reactive oxygen species using the antioxidant free radical scavenger N-acetylcysteine. Similar reduction in Ca 2+ influx was observed when pretreated with N-acetylcysteine and the experimentally synthesized TRPA1 antagonist HC030031.

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

[0111] Facchinetti et al. (2007) reported that many substances contained in cigarette smoke, including reactive oxygen species, are thought to be the cause of the inflammatory processes in COPD. These authors reported that micromolar concentrations of acrolein and crotonaldehyde (both α,β-unsaturated aldehydes) contained in aqueous cigarette smoke extract (CSE) cause 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 the main mediators of cigarette smoke-induced macrophage activation, suggesting that they contribute to cigarette smoke-related lung inflammation.

[0112] Blocking TRPA1 is emerging as a strategy for treating multiple respiratory diseases, and the role of TRPA1 in airway pathology has been confirmed by studies using TRPA1 knockout (KO) mice and TRPA1 antagonists. In wild-type mice, airway exposure to hypochlorite or hydrogen peroxide causes respiratory depression, manifested as a decrease in respiratory rate and an increase in end-expiratory 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 robust dose-dependent cough response in guinea pigs, which is attenuated by the TRPA1 antagonist HC-030031 synthesized by Hydra Biosciences. Similarly, the cough response induced by citric acid in guinea pigs is also inhibited by the potent and selective TRPA1 antagonist GRC 17536. The antitussive effects of other TRPA1 antagonists have also been confirmed 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 Rosmarinus officinalis (up to about 50%), and in Salvia lavandulifolia (up to about 25%). Activation of TRPM8 has been shown to reduce inflammation and pain. Although these researchers reported the activation of TRPM8 by menthol, this did not reduce the inflammatory response in humans because it also activates TRPA1, which causes inflammation. In addition, when octanol, a known TRPA1 agonist and skin irritant, was applied to the necks of human subjects and then 1,8-cineole was applied, the irritancy of octanol was significantly reduced by the inhibitory effect of 1,8-cineole on TRPA1.

[0114] As a follow-up study to this research, 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 fenchyl alcohol did not activate hTRPA1, and that borneol, 2-methylisoborneol, and fenchyl alcohol completely inhibited the activation of hTRPA1 by menthol and allyl isothiocyanate (AITC from mustard oil) at 1 mM and 10 μM, respectively. It was found that TRPA1 activated by 20 μM AITC was inactivated (IC-50 concentration) by 2-methylisoborneol (0.12 mM), borneol (0.20 mM), fenchyl alcohol (0.32 mM), camphor (1.26 mM), and 1,8-cineole (3.43 mM) in ascending order of concentration from the lowest to the highest.

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

[0116] In cell studies, Juergens et al. (1998) reported that 1,8-cineole, which is traditionally used to treat symptoms of airway diseases exacerbated by infection, showed a dose-dependent and highly significant inhibitory effect on the production of TNF-α, interleukin-1β (IL-1β), leukotriene B4 (LTB4), and thromboxane B2 (TXB2). In a subsequent 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 steroid-dependent bronchial asthma patients were enrolled in a double-blind, placebo-controlled trial. After determining the effective oral steroid dose during a 2-month run-in phase, the subjects were randomly assigned to receive either 200 mg of 1,8-cineole orally (three times daily) or a placebo in small intestine-soluble capsules for 12 weeks. Oral glucocorticoids were reduced by 2.5 mg increments every 3 weeks. The primary endpoint of the study was to determine the ability of 1,8-cineole to reduce oral glucocorticoids in patients with severe asthma. They reported that a 36% reduction in the daily dose of prednisolone was tolerated in the active treatment group (range: 2.5 to 10 mg, mean: 3.75 mg), compared with only a 7% decrease in the placebo group (2.5 to 5 mg, mean: 0.91 mg) (P = 0.006). Twelve out of 16 patients in the 1,8-cineole group had a reduction in oral steroids, while 4 out of 16 patients in the placebo group had a reduction in oral steroids (P = 0.012). They concluded that long-term systemic treatment with 1,8-cineole had a significant steroid-sparing effect in steroid-dependent asthma. They also reported that their results provided evidence of the anti-inflammatory activity of 1,8-cineole in asthma and provided new rationale for its use as a mucolytic in upper and lower airway diseases. Their study showed that 1,8-cineole is a potent cytokine inhibitor and can be used for the long-term treatment of airway inflammation in bronchial asthma and other steroid-sensitive conditions. They reported a new mechanism of action by which 1,8-cineole inhibits the production of monocyte inflammatory mediators. They also concluded that their findings explained the effective bronchodilation reported in their clinical study with 1,8-cineole. Their data showed that the concentration-response curve of 1,8-cineole was similar to the steroid-like mode of action and was likely mediated by nuclear transcriptional inhibition. Their work showed that 1,8-cineole has strong anti-inflammatory activity and can be used as a well-tolerated treatment for airway inflammation in obstructive airway diseases, especially in mild bronchial asthma and more severe forms of asthma, and can be used as an adjunctive treatment with the aim of being able to reduce or replace glucocorticoids in the long term. In one embodiment of the present invention, it is an inhaled nebulized pharmaceutical liquid composition and a treatment method for individuals suffering from 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, multi-center clinical trial in patients with stable chronic obstructive pulmonary disease with 1,8-cineole at a dose of 200 mg as an adjunct prescription - three times daily, in oral capsules. The primary hypothesis was that 1,8-cineole would reduce the number, severity, and duration of exacerbations. Secondary outcome measures were lung function, severity of dyspnea, and quality of life, as well as associated adverse effects. They reported that in a placebo-controlled, double-blind study in patients with reversible obstructive ventilatory disorders, airway resistance was significantly improved after one week (-23%) and eight weeks (-21%) of treatment. They also reported a statistically significant reduction in the frequency, duration, and severity of exacerbations during the study. Their combined findings emphasized that 1,8-cineole not only reduces the exacerbation rate but also provides clinical benefits, manifested as improved airflow obstruction, reduced severity of dyspnea, and improved health status. They also cited that in a placebo-controlled, double-blind study of asthma requiring steroid treatment, long-term treatment with 1,8-cineole (3 × 200 mg / day) significantly reduced the need for systemic glucocorticoids. Since glucocorticoids do not interfere with the release of histamine by mast cells, more studies are needed to determine the effect 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 - three times a day) on arachidonic acid (AA) metabolism in blood monocytes of 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 1,8-cineole treatment, 3 days after treatment (day 4), and 4 days after discontinuation of 1,8-cineole (day 8). In patients with bronchial asthma ( -40.3%, n = 10 and -31.3%, p = 0.1, n = 3) and healthy volunteers ( -57.9%, n = 12 and -42.7%, n = 8), the in vitro production of LTB4 and PGE2 from monocytes was significantly inhibited on day 4. These authors concluded that 1,8-cineole shows inhibition of LTB4 and PGE2, both of which are arachidonic acid metabolic pathways.

[0119] In another in vitro study by Juergens et al. (2004), treatment 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. Production of the cytokines TNFα, IL-1β, IL-6, and IL-8 in monocytes was also significantly (n = 7 - 16, p < 0.001) inhibited by 99%, 84%, 76%, and 65% respectively. In the presence of 1,8-cineole (0.15 μg / ml), production of TNFα and IL-1β in monocytes and IL-1β and TNF-α in 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 suggest a lesser effect on chemokines. There is increasing evidence that 1,8-cineole has a role in controlling airway mucus hypersecretion by inhibiting cytokines, which suggests long-term treatment to reduce exacerbations in 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, generating NF-κB and a range of neuropeptides; including CGRP and substance P, leading to the production of pro-inflammatory cytokines; including TNFα, IL-1β, IL-4, and IL-5, IL-6, and IL-8. It has also been shown that the antioxidants glutathione and N-acetylcysteine reduce the reactive oxygen species generated 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 system damage caused by cigarette smoke, environmental and industrial air pollutants, lung irritants and / or injurious chemical warfare agents, and respiratory system diseases in a multifunctional manner.

[0122] Transient Receptor Potential Nociceptors and Cancer

[0123] Prevarskaya et al. (2007, 2011) and Wu et al. (2010) have confirmed that during cancer progression, TRP channels are involved in the regulation of proliferation, differentiation, apoptosis, angiogenesis, migration, and invasion, and 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. The survival of cancer cells depends on the oxidative stress defense against the reactive oxygen species (ROS) accumulated during tumorigenesis. Along with the known importance of NRF2 in the neutralization of ROS and gene expression, they showed that cancer cells mobilize a set of adaptive mechanisms, including TRPA1-mediated atypical oxidative stress defense and the canonical ROS neutralization mechanism, to cope with the severe oxidative challenge. In breast and lung cancer spheroids rich in TRPA1, TRPA1 is crucial for the survival of inner cells showing ROS accumulation. Moreover, TRPA1 promotes resistance to chemotherapy that generates ROS, while TRPA1 inhibition blocks xenograft tumor growth and enhances chemosensitivity. These findings reveal an oxidative stress defense program in which TRPA1 is involved, and TRPA1 can be developed for targeted cancer therapy.

[0125] Wu et al. (2016) reported that, compared with normal lung tissue and non-small cell lung cancer samples, the level of TRPA1 mRNA was significantly upregulated in tumor specimens of human small cell lung cancer (SCLC). Treatment of small cell lung cancer cell lines of respiratory origin with the TRPA1 agonist allyl isothiocyanate, a volatile toxic compound, in vitro caused an increase in intracellular calcium concentration. In the expression profiling and evaluation of TRPA1 expression in a cohort of 124 non-small cell lung cancer patients, the level of TRPA1 protein could be detected by immunohistochemistry in all cases. In addition to higher primary tumors, TRPA1 upregulation had an independent and negative predictive effect on disease-specific, distant metastasis-free, and local recurrence-free survival rates. Moreover, Schaefer et al. (2013) reported that TRPA1 was expressed in a panel of human small cell lung cancer cell lines. They also reported that the expression of TRPA1 mRNA was higher in tumor samples from patients with small cell lung cancer cells compared with non-small cell lung cancer cell tumor samples or non-malignant lung tissue. Stimulation of small cell lung cancer cells with allyl isothiocyanate led to an increase in intracellular calcium concentration. In addition, these authors reported that the calcium response was inhibited by a TRPA1 antagonist. Activation of TRPA1 in small cell lung cancer cells blocked serum starvation-induced apoptosis, thus promoting cell survival, and this effect could be blocked by inhibiting TRPA1. Conversely, TRPA1 downregulation severely impaired the anchorage-independent growth of small cell lung cancer cells. Since TRPA1 seems to play a key role in the cell survival of small cell lung cancer cells, these authors considered that TRPA1 could represent a promising therapeutic intervention target. Finally, these authors also concluded that exogenous, inhalable TRPA1 activators were able to exert a tumor-promoting effect in small cell lung cancer cells.

[0126] Cannabinoid type 2 receptor signaling

[0127] The CB2 receptor is a peripheral receptor for cannabinoids. It is mainly expressed in immune tissues, indicating that the endocannabinoid system has immunomodulatory effects. In this regard, in vitro and in animal models of inflammatory diseases, the CB2 receptor has been shown to regulate immune cell function. Numerous studies have reported that mice lacking the CB2 receptor have an exacerbated inflammatory phenotype. This suggests that therapeutic strategies aimed at modulating CB2 signaling hold promise for treating various inflammatory disorders. CB2 is mainly expressed in immune cells, including neutrophils, eosinophils, monocytes, and natural killer cells. In experimental models of various ischemia-reperfusion injuries, atherosclerosis / cardiovascular inflammation, and other conditions, activation of the CB2 receptor by endocannabinoids or selective synthetic agonists has been shown to protect tissues from damage by limiting inflammatory cell chemotaxis / infiltration, activation, and associated oxidative / nitrosative stress.

[0128] It has also been shown that CB2 is upregulated in non-small cell lung cancer tissues, and this upregulation is associated 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), δ-9-THC (Ki = 0.035 μM), CBN (Ki = 0.096 μM), the CB2 receptor also binds to the endocannabinoids arachidonoyl ethanolamide (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 potent 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 by distillation from natural sources. Due to the low toxicity of β-caryophyllene, its use in food has been approved by the US Food and Drug Administration. Although β-caryophyllene is a potent CB2 agonist, it is not a cannabinoid compound, nor is it a CB1 receptor agonist, and it 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 a nebulizable pharmaceutical liquid formulation.

[0130] Glutathione

[0131] Glutathione is an important water-soluble antioxidant in plants, animals, fungi, and some bacteria. Thus, it can prevent damage to important cellular components caused by reactive oxygen species such as free radicals, peroxides, lipid peroxides, and heavy metals. In the lung, glutathione plays an important role in regulating immune function and is involved in the pulmonary epithelial host defense system (Buhl et al., 1990). Depletion of intracellular glutathione inhibits the activation of lymphocytes by mitogens, which is important in lymphocyte-mediated cytotoxicity. Many pulmonary disorders are associated with increased oxidant burden on the pulmonary epithelial surface and pulmonary epithelial cell damage, including idiopathic pulmonary fibrosis, asbestosis, smoking, adult respiratory distress syndrome, cystic fibrosis, and acute and chronic bronchitis. Supplementation of glutathione helps with other organ disorders associated with increased oxidant burden, including enhancing antioxidant protection in the pulmonary epithelial lining fluid.

[0132] The intracellular oxidation-reduction (redox) state is maintained in a steady state 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. Importantly, glutathione provides the first line of defense against reactive oxidant species. Glutathione compounds have multiple biological functions, including protecting cells against oxidative stress and several toxic molecules, and are involved in the synthesis and modification of leukotrienes and prostaglandins. For example, glutathione S-transferase protects cellular DNA from oxidative damage that can lead to increased DNA mutations or induce DNA damage, thus promoting carcinogenesis.

[0133] Glutathione S-transferase can react with and conjugate various hydrophobic and electrophilic molecules, including many carcinogens, therapeutic drugs, and many oxidative metabolites, making them less toxic and facilitating further modification for excretion from the cell. Glutathione not only directly interacts with reactive oxygen species and acts as a substrate for different enzymes to eliminate endogenous and exogenous compounds, but also can directly conjugate with foreign substances such as chemotherapeutic agents. Since many anticancer chemotherapeutic drugs are actually toxic exogenous compounds, this may lead to increased glutathione levels and, in turn, the development of anticancer drug resistance. However, glutathione is also involved in protecting cells against free radicals and is involved in many cellular functions particularly relevant to the regulation of carcinogenic mechanisms, 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 gas phase of cigarette smoke reduces the free sulfhydryl (-SH) groups of glutathione in solution and 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 was shown to convert nearly the entire glutathione pool to the glutathione-E-aldehyde component. Enzymatic redox cycling is normally activated after oxidative stress and the formation of the oxidized form of glutathione, glutathione disulfide, but the glutathione pool is lost due to depletion of glutathione to non-reducible glutathione components, and thus 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 scavenged by residual antioxidants, rendering them more vulnerable to oxidative stress. This makes the synthesis of glutathione crucial 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 contributing to the development of COPD.

[0135] Smoking-induced cellular stress is highly dependent on the intracellular concentration of reduced glutathione. The lung's response to this challenge is an adaptive response that includes upregulation of glutathione antioxidant defenses. Gould et al. (2011) demonstrated that the glutathione adaptive response consists of a coordinated response among glutathione synthesis, utilization, recycling, and transport into the lung epithelial lining fluid. An increase in lung epithelial lining fluid glutathione levels is thought to serve as a defense mechanism to limit the damaging effects of long-term smoking. Gould et al. (2010) also showed that age has an adverse effect on the lung glutathione adaptive response to acute smoking exposure in mice, and that this response leads to increased airway inflammation and increased lung DNA oxidation. In humans, glutathione levels decline sharply around the age of 45, which soon enters the age range at which long-term smokers develop COPD.

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

[0137] Rusnack et al. (2000) used human bronchial epithelial cells (HBEC) from biopsy materials of three groups of people: those who smoked and had 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 intracellular glutathione concentration in HBEC before and after exposure to cigarette smoke. The results showed that when exposed only to air, the primary cultures of HBEC from smokers with normal lung function and patients with COPD contained significantly more glutathione than cultures from healthy never-smokers. These results are consistent with subsequent studies showing 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 compared to cells exposed only to air. However, the magnitude of the decrease in glutathione concentration (percentage change on average) in HBEC cells exposed to cigarette smoke differed among the study groups: 72.9% in cells from patients with COPD; 61.4% in cells from healthy never-smokers; and 43.9% in cells from smokers with normal lung function. The decrease in glutathione was significantly greater in cells from patients with COPD than in cells from healthy never-smokers or smokers with normal lung function. They also reported that an increase in the level of antioxidant capacity (i.e., higher glutathione concentration) could prevent oxidant-mediated damage.

[0138] Rusnack et al. (2000) also reported that compared to the control group of smokers without COPD, the HBEC of patients with COPD showed a greater increase in cell permeability and the release of the inflammatory cytokines soluble intercellular adhesion molecule-1 (sICAM-1) and IL-1β. They also observed that in the HBEC of smokers with normal lung function, the endogenous increase in glutathione concentration was associated with a decrease in epithelial cell permeability and the release of the inflammatory cytokines IL-1b and sICAM-1.

[0139] Buhl et al. (1990) demonstrated that aerosol nebulizer administration of 4 mL of a 150 mg / mL glutathione solution increased the glutathione pulmonary epithelial lining fluid concentration to a concentration of approximately 337 μM within 25 minutes, which is 7 times the pre-treatment baseline concentration (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 the pulmonary epithelial lining fluid. Buhl et al. (1990) proposed that aerosol administration of glutathione is a practical method to significantly increase glutathione levels on the epithelial surface of the human lower respiratory tract. They also reported that aerosol administration of glutathione not only increased the glutathione levels in the pulmonary epithelial lining fluid but also had no adverse effects. Their results are consistent with those of Witschi et al. (1992), who reported that oral administration of glutathione is ineffective in increasing plasma glutathione levels when given to healthy subjects. Therefore, it would be doubtful whether oral supplementation of glutathione would help increase the concentration in the lungs.

[0140] Prousky (2008) conducted a literature review to examine the clinical efficacy of inhaled glutathione as a treatment for various lung diseases and respiratory-related disorders. The author concluded that inhaled glutathione is an effective method for treating various lung diseases and respiratory-related disorders. Even very severe and difficult-to-treat diseases, including cystic fibrosis and idiopathic pulmonary fibrosis, can 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 of glutathione treatment include farmer's lung, before and after exercise, multiple chemical sensitivity disorder, and smoking. Prousky (2008) also concluded that glutathione inhalation should not be used to treat primary lung cancer.

[0141] Mah et al. (2012) performed a structural analysis of the lead-glutathione complex and concluded that the formation of a complex between Pb2+ and glutathione is important for the rational design of chelating agents for the therapeutic treatment of lead poisoning. One problem associated with commonly used chelating agents, including EDTA, is that they lack selectivity and also bind essential Fe 2+ , Ca 2+ and Zn 2+ metal ions, thereby producing associated toxic effects. These authors concluded that in aqueous solution, Pb 2+ tends to bind to up to three glutathione ligands through cysteine-thiolate groups, indicating that a specially designed chelating agent with three sulfur donor atoms available for binding may be very effective in chelating Pb 2+ ions.

[0142] N-acetylcysteine

[0143] N-acetylcysteine (NAC) is a water-soluble antioxidant that can be widely used to treat patients with chronic obstructive pulmonary disease, and its uses were reviewed by Dekhuijzen (2004). Preclinical studies and clinical trials have shown that antioxidant molecules such as small thiol molecules (N-acetyl-L-cysteine and carbocisteine), antioxidant enzymes (glutathione peroxidase), activators of the Nrf2-regulated antioxidant defense system (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 delay the progression of COPD. N-acetylcysteine exhibits both direct and indirect antioxidant properties. The free thiol group 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 in protecting against internal toxicants (such as the metabolism of cellular aerobic respiration and phagocytes) and external agents (such as NO, sulfur oxides, and other components in cigarette smoke, as well as pollution). The thiol group of cysteine neutralizes these agents. Maintaining sufficient intracellular glutathione levels is crucial for overcoming the harmful effects of toxicants. The synthesis of glutathione mainly occurs in the liver (as a reservoir) and the lungs. In cases of glutathione level depletion or increased demand, additional cysteine can be delivered through N-acetyl-L-cysteine to increase glutathione levels. However, in vivo studies have shown that when N-acetyl-L-cysteine is administered orally, its bioavailability is very low due to its rapid metabolism to glutathione and other metabolites. Therefore, although N-acetyl-L-cysteine is very effective in protecting cells from different sources against the toxicity of the active components in tobacco smoke and reactive oxygen species, N-acetylcysteine is unlikely to have a direct scavenging effect in vivo, especially when administered orally. Therefore, when administered via the oral route, the bioavailability of N-acetylcysteine itself is very low. For any protective effect that N-acetylcysteine may exert against toxic substances, a more relevant in vivo mechanism may be that N-acetyl-L-cysteine acts as a glutathione precursor and promotes its biosynthesis. Glutathione will then act as a protector and detoxify the active substances in both enzymatic and non-enzymatic ways.

[0144] Antioxidant supplementation has been investigated as a means to counter 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 replenish the cysteine required for glutathione synthesis and replenishment. The cysteine prodrug N-acetylcysteine provides the essential cysteine for glutathione synthesis and has been shown to be more effective in treating disease-related oxidative stress. N-acetylcysteine has been clinically used to treat a variety of disorders, including drug toxicity (acetaminophen toxicity), human immunodeficiency virus / AIDS, cystic fibrosis, COPD, and diabetes.

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

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

[0147] In a study on idiopathic pulmonary fibrosis and treatment with N-acetylcysteine, Hargiwara et al. (2000) demonstrated in mice that inhaled N-acetylcysteine inhibits bleomycin-induced pulmonary fibrosis. Bleomycin is 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 holds promise as a potential therapy for interstitial pneumonia because reactive oxygen species are involved in the development of almost all forms of interstitial pneumonia. They also concluded that since N-acetylcysteine inhibits NF-kB activation, it can reduce 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 sized from 0.1 μ to 2.5 μ, and thus to determine the biological effects of particulate air pollution. These authors demonstrated that N-acetylcysteine, at a dose sufficient to prevent an increase in reactive oxygen species and the accumulation of thiobarbituric acid-reactive substances and partially reduce protein oxidation, effectively prevents inflammation induced by particulate air pollution. They concluded that the preventive effect of N-acetylcysteine suggests that treatment with low doses of N-acetylcysteine can be used to ameliorate the toxic effects of particulate air pollution.

[0149] Carbocysteine

[0150] Carbocysteine (S-carboxymethylcysteine) is a sulfur-containing amino acid compound and has significant mucolytic, antioxidant, and anti-inflammatory properties. Carbocysteine can also effectively maintain the activity of α-1-antitrypsin inactivated by oxidative stress. Inactivation of α-1-antitrypsin is associated with extensive tissue damage in patients with chronic emphysema. It has been reported that the antioxidant and anti-inflammatory properties of carbocysteine play an important role in the long-term treatment of COPD and reduce the rate of exacerbation. It has been reported that carbocysteine can effectively reduce the concentrations 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 in the presence of 2 mM N-acetylcysteine, the cellular uptake of epigallocatechin-3-gallate (100 μM) increased 2.5-fold. They also reported that the increase in the cytoplasmic level 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 when using the combination of epigallocatechin-3-gallate and N-acetylcysteine might be the 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 had biological activity and might be more redox-active than epigallocatechin-3-gallate alone.

[0152] Bucca et al. (1992) reported that long-term treatment with high-dose vitamin C was expected to improve airway responsiveness symptoms, provide protection against airway and lung damage induced by heavy air pollution 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 epigallocatechin-3-gallate (50 mg / kg) in rats, which were randomly divided into sham air (SA) or cigarette smoke-exposed groups (1 hour / day for 56 days). They measured oxidative stress and inflammation markers by analysis of serum and / or bronchoalveolar lavage fluid. (-)-Epigallocatechin-3-gallate treatment improved 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 had a therapeutic effect on chronic airway inflammation and abnormal airway mucus production by inhibiting the epidermal growth factor receptor (EGFR) signaling pathway. They also concluded that supplementation with (-)-epigallocatechin-3-gallate might be a promising therapeutic strategy to limit neutrophil recruitment and treat mucus hypersecretion in the airways of smokers with or without COPD.

[0155] Chan et al. (2009) reported that Chinese green tea (Lung Chen) had a protective effect against cigarette smoke-induced airspace enlargement and goblet cell hyperplasia and an inhibitory effect on systemic and local oxidative stress in rats. Approximately 80% of the active components in this green tea were (-)-epigallocatechin-3-gallate.

[0156] Li et al. (2007) reported that pulmonary inflammation is a feature of many lung diseases. Elevated levels of pro-inflammatory 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, can induce the production of IL-β and TNF-α in human lung epithelial cells (A-549), fibroblasts (HFL1), and lymphoma cells (U-937). They reported that berberine (a phytochemical and protoberberine alkaloid) can inhibit the production of cytokines in inflammatory agent-induced lung cells, and the inhibition of cytokine production by berberine is dose-dependent and independent of cell type. It has also been reported that the inhibitory effect of berberine on cytokine production is due to the inhibition of inhibitory NF-κα phosphorylation and degradation. They concluded that berberine has a potential role in the treatment of pulmonary inflammation.

[0157] Xu et al. (2015) investigated the effects of berberine on cigarette smoke-induced airway inflammation and mucus hypersecretion in mice. Mice exposed to cigarette smoke were intraperitoneally injected with berberine (5 mg / kg-d and 10 mg / kg-d). The 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 airway goblet cell hyperplasia and mucin-5ac expression in mice. 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 liquid disclosed in the present invention, which is transferred to the gas phase and aerosol phase for inhaled drug treatment of lung and respiratory diseases, including but not limited to: berberine, catechin, curcumin, epicatechin, epigallocatechin, epigallocatechin-3-gallate, β-carotene, quercetin, kaempferol, luteolin, ellagic acid, resveratrol, silymarin, nicotinamide adenine dinucleotide, thymolquinone, β-caryophyllene, and dimethyl sulfoxide.

[0159] One embodiment of the present invention is to deliver N-acetyl-L-cysteine, glutathione, and plant-based TRPA1 antagonists together with polyphenols, phytochemicals, and water-soluble antioxidants in the form of an aerosol directly inhaled 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 human body weight. (EFSA Response Letter, EFSA-Q-2007-113, 2009). Taurine is a sulfonic acid amino acid, relatively non-toxic, and is a normal component of the human diet. Dietary sources provide most of the taurine, either directly, or synthesized from methionine or cysteine via hypotaurine or sulfinoalanine in the liver and brain, or provided by cysteamine in the heart and kidneys. Taurine stabilizes cell membranes, regulates calcium transport, and can eliminate the toxic effects of hypochlorous acid (HOCl) by forming relatively stable taurine chloramine molecules (generated from oxygen free radicals by myeloperoxidase). 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 widely studied, including its effects against atherosclerosis, lung injury caused by oxidative gases, the harmful effects of various drugs (such as the antitumor agent tauromustine), and the hepatotoxicity of lithocholate, and its effect on promoting the recovery of white blood cells in irradiated rats. In addition, the therapeutic effects of taurine have been clinically used for senile Alzheimer's disease, macular degeneration, epilepsy, ischemia, obesity, diabetes, hypertension, congestive heart failure, the harmful effects of smoking, methotrexate toxicity, cystic fibrosis, myocardial infarction, alcohol craving, and neurodegeneration. Taurine has also been reported to 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 lack taurine, which can be reflected by a high bile acid glycine / taurine ratio. The cause of this deficiency is thought to be the excessive loss of taurine from the digestive tract. The concentration of taurine in human neutrophils and lung epithelial cells is particularly high, 19 mM and 14 mM respectively. Although the concentration of taurine in extracellular fluid is usually low, the airway secretions in cystic fibrosis are rich in activated neutrophils, neutrophil-derived products, and cell debris, which presumably may contribute to the high concentration of taurine on the lung epithelial surface. The concentration of myeloperoxidase in the sputum of cystic fibrosis patients is also very high (Cantin, 1994). Multiple studies have shown that the hydrogen peroxide in the exhaled breath condensate of COPD subjects increases significantly compared with healthy controls.

[0163] It has been reported that taurine is an important regulator of oxidative stress and it has been shown that a decrease in taurine content leads to a reduction in respiratory chain complexes (Li et al., 2017). It has been shown that taurine together with nicotinic acid can counteract lung injury caused by various 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 of environmental origin are common in lung epithelium. Reactive oxygen species are found in cigarette smoke, combustion products of organic matter and air pollutant gases with oxidant activity such as ozone and nitrogen dioxide. These reactive oxygen species deplete oxidant defenses and increase the oxidant load in the lungs.

[0165] Latest evidence indicates that taurine chloramine (Tau-Cl) is produced by the reaction of taurine with endogenously produced highly toxic hypochlorous acid catalyzed by myeloperoxidase. March (1995) concluded that taurine is crucial in the regulation of inflammation. In white blood cells, taurine acts to capture the chlorinated oxidant (HOCl). In another study, Tau-Cl was also 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 action of taurine to an increase in the activity of antioxidant enzymes and a decrease in the amount of damaging reactive oxygen species produced by neutrophils. Taurine indirectly enhances the activity of endogenous antioxidant defenses. Secondly, 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, water-soluble antioxidants and taurine in the form of an aerosol directly inhaled into the respiratory tract.

[0167] Thiamine

[0168] Thiamine (vitamin B1) is a member of the water-soluble vitamin family and is essential for normal cell function. Thiamine deficiency leads 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 harmful to normal cell physiology and causes impaired oxidative energy metabolism (acute energy failure), making cells vulnerable to oxidative stress. Nicotine is known to accumulate in the pancreas and is associated with the production of free radicals that cause oxidative stress and lead to pancreatic damage. In a clinical study of 163 elderly COPD patients, more than 75% of the patients were found to have thiamine deficiency (less than 75% of the recommended daily allowance (RDA)).

[0169] D-panthenol

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

[0171] In this article, 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) and 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 the production of reactive oxygen species and the activation of nuclear factor κB (NF-κB) and matrix metalloproteinase-9 in BALF. These authors suggested that L-theanine alleviates asthma 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 hepatocellular carcinoma, prostate cancer, and colon cancer cells (Friedman et al., 2007). Theanine has been demonstrated to have anticancer activity against the growth, migration, and invasion of human lung cancer and leukemia 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 confirmed that theanine significantly inhibited the migration and invasion of A549 cells.

[0175] Resveratrol

[0176] Resveratrol has been demonstrated to have anti-inflammatory and anti-asthmatic properties in a murine model of allergic asthma. Although resveratrol is less potent compared to glucocorticoids, it appears to be more effective in inhibiting inflammatory activity. The risk of side effects is high with the clinical use of glucocorticoids, and the effects of glucocorticoids are 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 has broad prospects as a natural agent since it has been shown to have beneficial effects in multiple diseases, including cancer, cardiovascular diseases, neurological disorders, and obesity.

[0177] The anti-inflammatory and antioxidant properties of resveratrol in the lung have been demonstrated in preclinical models. Resveratrol reduces neutrophils and pro-inflammatory 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. In human bronchial epithelial cells in vitro and in a cigarette smoke-induced COPD mouse model in vivo, resveratrol also shows an inhibitory effect on autophagy (Liu et al., 2014). These researchers reported that cigarette smoke exposure increased the number of inflammatory cells in the lung, and at the same time, 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 activities of superoxide dismutase, GSH peroxidase, and catalase in cigarette smoke-treated mice. It was also confirmed that cigarette smoke significantly enhanced the production of NF-κB and NF-κB DNA binding activity, while resveratrol pretreatment weakened both. These authors concluded that resveratrol could alleviate cigarette smoke-induced oxidative lung injury, including a decrease in NF-κB activity and an increase in the expression and activity of heme oxygenase 1 (HO-1).

[0178] Nicotinamide adenine dinucleotide

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

[0180] Anti-aging enzymes (sirtuins) are a unique class of NAD +A deacetylase that regulates various biological functions such as aging, metabolism, and stress resistance. In recent years, it has been shown that anti-aging enzymes 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 anti-aging enzyme family. It has been demonstrated that Sirt1 may also limit the inflammatory process by inhibiting NF-kB and activating protein 1 (AP-1), two transcription factors closely related to the expression of pro-inflammatory cytokines such as TNF-α. It is known that compared with lung cells from healthy controls, lung cells from patients with chronic obstructive pulmonary disease (COPD) and rats exposed to cigarette smoke exhibit reduced Sirt1 expression associated with increased NF-kB activity and matrix metalloproteinase-9 expression.

[0181] In one embodiment of the present invention is a liquid composition that comprises NAD + , one or more of NA, NAM, and NR, a plant-based TRPA1 antagonist, a natural thiol-containing amino acid compound, a CB2 agonist, an amino acid, a naturally occurring antioxidant, additional vitamins and bioflavonoid compounds, and a heavy metal chelating compound.

[0182] Antioxidant

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

[0184] Wang et al. (2018) reported that the concentration of glutathione is relatively high in various cancer cells such as lung cancer, breast cancer, pancreatic cancer, and leukemia. In addition, it has been demonstrated that the anti-apoptotic characteristics of cancer cells are related to the elevated intracellular glutathione level. Several reports have shown that reducing the intracellular glutathione content activates various apoptosis-related enzymes. Therefore, reducing the glutathione concentration has become a new strategy for anti-tumor therapy.

[0185] Tumor glutathione biochemical dysregulation 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 important roles in counteracting tumor microenvironment-related invasion, apoptosis evasion, colonization ability, and multi-drug and radiation resistance. Elevated levels of glutathione and resistance to chemotherapeutic drugs (such as platinum-containing compounds and alkylating agents, such as cisplatin and melphalan, anthracyclines, doxorubicin, and arsenic) have been observed. Zu et al. (2017) pointed out that glutathione depletion is considered a promising strategy for reducing chemoresistance and inducing apoptosis through 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, anti-allergic, antiviral, anti-diabetic, and anti-cancer properties. In addition, its inhibitory effect on histamine receptors has been determined. 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 and allergic diseases, including allergic rhinitis, atopic eczema, and asthma. Kalemci et al. (2013) confirmed that in an experimental asthma model established in mice, injection of thymoquinone reduced chronic inflammatory changes. Azemi et al. (2016) reported that mice receiving black seed oil showed a significant decrease 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 decrease in the production of interleukin and mucin in allergic asthma. They concluded that black seed oil has anti-inflammatory and immunomodulatory effects during pulmonary allergic reactions and could be a promising treatment for human allergic asthma.

[0187] El-Sakkar et al. (2007) induced significant pulmonary inflammation in guinea pigs, as demonstrated by elevated levels of IL-8, LTB4, NE, and TNF-α (in bronchoalveolar lavage fluid) and myeloperoxidase (in lung tissue homogenate). Cigarette smoke also led to a significant increase in glutathione peroxidase activity in lung tissue. Lipid peroxidation in guinea pigs exposed to cigarette smoke increased significantly, as demonstrated by an increase in malondialdehyde in lung tissue. Pretreatment of guinea pigs exposed to cigarette smoke with thymoquinone significantly reduced IL-8 in bronchoalveolar lavage fluid but did not significantly change the level of leukotriene B4 (LTB4) in bronchoalveolar lavage fluid. The levels of inflammatory mediators, namely neutrophil elastase, TNF-α, and malondialdehyde, also decreased significantly 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 major polyphenol in green tea) alleviated the inflammatory consequences of exposure to cigarette smoke. This was confirmed by significantly decreased levels of IL-8, LTB4, NE, TNF-α (in bronchoalveolar lavage fluid) and myeloperoxidase (in lung tissue homogenate). Epigallocatechin-3-gallate also alleviated cigarette smoke-induced oxidative stress, as confirmed by increased glutathione peroxidase activity and significantly decreased levels of myeloperoxidase in lung tissue homogenate, although superoxide dismutase activity was not significantly affected.

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

[0190] Electronic atomization device

[0191] An electronic cigarette, also known as a vape pen, e-cigar or electronic cigarette vaporization device, is commonly used as an electronic nicotine delivery system that thermally generates an aerosolized mixture containing a flavored liquid 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 e-cigarettes stems from the various nicotine concentrations present in e-cigarette liquids, the various e-cigarette liquid volumes of each product, different carrier compounds, additives, flavors, coil impedances and battery voltages. Regardless of the exact design, each e-cigarette device has a common functional system that consists of a rechargeable lithium battery, a vaporization chamber and a cartridge. The lithium-ion battery is connected to the vaporization chamber containing an atomizer. To deliver nicotine to the lungs, the user inhales through the mouthpiece, the airflow triggers a 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] An ultrasonic e-cigarette vaporization device that does not heat the liquid in the e-cigarette vaporization device like a typical commercially available e-cigarette or thermal atomization device is available and can also be used to atomize the liquids disclosed in the present invention.

[0193] Recently, a study on the nicotine content of 27 e-liquid formulations obtained in the United States was conducted. The nicotine content was reported to vary between 6 mg / L and 22 mg / L (Peace, 2016). In another study, 16 e-cigarettes were selected based on their popularity in the Polish, UK, and US markets, and the nicotine vapor production was evaluated in an automatic smoking machine. The test conditions were designed to simulate the puffing conditions of human e-cigarette users. The total nicotine level in the vapor generated by 15 puffs in 20 series varied between approximately 0.5 mg and 15.4 mg. 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 reported, the average concentrations of nicotine in Juul e-cigarettes in un-vaped, vaped, and aerosol samples were 60.9 mg / mL, 63.5 mg / mL, and 41.2 mg / mL, respectively. The effective transfer rate of nicotine to the aerosol was between 56% - 75% (Omaiye et al., 2019). Juul reported that each of their flavorpods contains 0.7 mL of liquid.

[0195] Due to the formation of toxic compounds inhaled from heat-generated aerosolized liquids containing nicotine, in November 2018, the FDA's Center for Tobacco Products (CTP) banned all flavored nicotine e-cigarettes except for tobacco, menthol, and menthol flavors. In a recent study, it was reported that specific flavor aldehyde compounds, including benzaldehyde, cinnamaldehyde, citral, ethyl vanillin, and vanillin, react with other commonly used compounds such as propylene glycol (PG) present in the liquids used in e-cigarette vaping 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 commercially available e-liquid compounds at ambient temperature. When these flavor aldehyde PG acetals in e-liquid are subsequently thermally aerosolized and inhaled in an e-cigarette vaping device, they can cause serious health effects to individuals using these products. Flavor aldehyde PG acetals have also been shown to activate TRPA1 and aldehyde-insensitive TRPV1 stimulants as well as inflammation-related receptors (Erythropel et al., 2018). It is clear that the activation of inflammatory nociceptors TRPA1 and TRPV1 by flavor aldehyde PG acetals in the lungs of individuals using e-cigarette vaping products is extremely unhealthy for these individuals.

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

[0197] In one embodiment of the present invention is a nicotine-containing aerosolizable liquid that does not contain aldehyde flavorants and does not form toxic flavorant acetal compounds at ambient temperature or elevated temperature, and is safer to use in e-cigarettes and other thermal liquid atomization devices than the existing e-cigarette liquids available on the market to date. In other embodiments of the present invention is a nicotine-containing aerosolizable liquid that provides health benefits to the respiratory system of an individual who is a nicotine user. In another embodiment of the present invention is a method of using a liquid composition containing nicotine and a plant-based TRPA1 antagonist, a natural thiol-containing amino acid compound, a CB2 agonist, an amino acid, a naturally occurring antioxidant, additional vitamins, a bioflavonoid compound, and a heavy metal complexing compound, which, when thermally atomized, provides a source of nicotine and respiratory health benefits from the non-nicotine components of the composition.

[0198] Recently, companies have started selling thermal atomization systems in which vitamins are inhaled to supplement vitamins. VitaminVape, Q Sciences, Biovape, and Nutrovape Vita are examples of companies that produce and sell e-cigarette vaporization systems for vitamin supplementation. Inhalation may be an inefficient way to ingest vitamins because the vitamin concentration required systemically may be higher than the vitamin concentration that can be delivered by e-cigarette vaporization. Inhalation generally remains a delivery mechanism for drugs that require very small doses or are targeted at the lungs.

[0199] Quitting smoking

[0200] The most important way to reduce the continued damage to the general health of active smokers, especially to their respiratory systems, is to completely quit smoking and abstain from exposure to and addiction to nicotine. While quitting smoking eliminates the continued respiratory damage caused by cigarette smoke, it cannot reverse past respiratory damage caused by past smoking, diseases that have become active in an individual due to exposure to cigarette smoke, and future diseases that may result from past smoking activities. Historically, there is ample literature demonstrating that cumulative exposure to smoking, typically expressed as pack-years (i.e., the number of packs smoked per day multiplied by the number of years smoked), is a major factor in the risk of lung cancer and COPD. More recently, it has been shown that the 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 multi-center 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 the number of years of active smoking, revealing that the duration of smoking has a greater impact than the individual's pack-years. Similarly, there is a strong relationship between the duration of smoking and a decrease in the FEV1 value.

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

[0202] In one embodiment of the present invention, the nebulizable liquid compositions and methods of using these liquid compositions include nicotine salts as part of a nicotine replacement therapy smoking cessation system, while providing simultaneous treatment for lung and respiratory diseases and the effects from a person's smoking history. In one embodiment of the present invention is a composition comprising a nicotine salt, a plant-based TRPA1 antagonist, a natural thiol-containing amino acid compound, a CB2 agonist, an amino acid, a naturally occurring antioxidant, a vitamin, and a flavonoid compound, as well as a heavy metal chelating compound.

[0203] Glutathione

[0204] The use of glutathione in the present invention and the results reported in Examples 15 and 16 were unexpected because asthma is a condition in which the side effects of inhaled glutathione, including dyspnea, bronchoconstriction, and coughing, have led researchers and practitioners to not recommend the use of glutathione for asthmatic conditions (Prousky et al., 2008). Based on the study published by Marrades et al. (1997), the effectiveness of using glutathione in the present invention was further unexpected, as that study reported that inhaled glutathione caused major airway narrowing (change from baseline: -19% in FEV1 and +61% in total pulmonary resistance) and induced coughing (in four patients) or dyspnea (in three patients). In contrast, the change in FEV1 in control patients treated with only inhaled saline solution was negligible, at -1%, and the change in total pulmonary resistance was less, at +17%.

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

[0206] Ordinary skilled artisans in the art would not recommend inhaled glutathione because several medical websites, including WebMd (https: / / www.webmd.com / vitamins / ai / ingredientmono-717 / glutathione, “Side Effects & Safety”), list inhaled glutathione as contraindicated for asthma, where the side effects for asthma include: “Do not inhale glutathione if you have asthma. It can increase some asthma symptoms.”

[0207] Ordinary skilled artisans in the art would be taught not to use a combination of glutathione with other compounds in a formulation for treating an individual with asthma. Surprisingly and unexpectedly, the studies leading to the present invention showed that the use of glutathione was highly effective in raising the FEV1 levels in patients who definitely had asthma. One of the asthmatic patients who had smoked 2 packs of cigarettes per day for 28 years (56 pack-years) had an unexpected result of 45.1% FEV1 reversibility after 53 days of treatment and an increase in their normal FEV1 percentage from 67.2% to 97.4%. This is contrary to what Marrades et al. (1997) taught ordinary skilled artisans in the art.

[0208] N-acetylcysteine

[0209] N-acetylcysteine (NAC) is 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 undergo auto-oxidation and also act as an oxidant. Chan et al. (2001) demonstrated that N-acetylcysteine can become an oxidant and cause 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, cold sweats, and chest tightness. Additionally, according to WebMd, there is concern that inhalation of N-acetylcysteine may cause bronchospasm in asthma patients. The National Institutes of Health reported that N-acetylcysteine can cause respiratory inflammation, resulting in runny nose, bronchospasm, oral inflammation, and bleeding. Due to the known side effects of N-acetylcysteine, a person of ordinary skill in the art is taught not to use N-acetylcysteine for inhalation therapy in individuals with COPD, asthma, and other respiratory diseases.

[0211] Considering that N-acetylcysteine can act as an oxidant, lead to the formation of NF-κB, and cause bronchospasm in asthma patients, the unexpected result is that the use of N-acetylcysteine in the formulations of the present invention shows a reduction in respiratory inflammation, as demonstrated by the reduction of lung function parameters such as FEV1 and FVC in Examples 15 and 16.

[0212] Vitamin B12

[0213] According to the health website Healthline (https: / / www.healthline.com / health / food-nutrition / vitamin-b12-side-effects), the 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 tracheal and bronchial swelling. 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 for inhalation therapy for respiratory diseases. Although it is known that methylcobalamin can cause increased anxiety in some patients, the individuals evaluated in preclinical trials as disclosed in Examples 15 and 16 surprisingly and unexpectedly reported significantly lower anxiety levels after treatment.

[0214] The interaction of one component with other components

[0215] Surprisingly and unexpectedly, the administration of liquid formulations to patients by the thermal-induced atomization disclosed in Example 15 and the ultrasonic membrane atomization disclosed in Example 16 achieved results 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 secondarily acts as a TRPM8 agonist, modulates immune function, acts as an antioxidant, is antibacterial and antifungal, 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). In a human clinical trial of preoperative patients, 1,8-cineole has also been confirmed to reduce anxiety. Unexpectedly, this anxiolytic property of 1,8-cineole is very helpful to patients with dyspnea, which can lead to anxiety and, in severe cases, panic. Oral qualitative reports were made by the patients who received the formulations in Examples 15 and 16, reporting that they felt more relaxed, had a significantly increased energy level, greater endurance under normal activities and under exercise conditions, lower anxiety levels, and less anxiety compared to taking other medications to treat their diseases. Typical inhaled steroid administrations have side effects including tremors, nervousness, and a burning sensation in the chest. Unexpectedly, in the present invention, no patients reported any adverse side effects associated with the inhalation treatment of the formulations disclosed in Examples 15 and 16.

[0216] The primary and secondary effects of 1,8-cineole unexpectedly achieve a synergistic effect with β-caryophyllene, the primary role of which in the formulations disclosed in the present invention is to reduce inflammation as a CB2 agonist. In the present invention, β-caryophyllene also has a secondary role as an antioxidant and, in addition to inhibiting the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, acts as an analgesic, anti-inflammatory, neuroprotective, antidepressant, anxiolytic, and antioxidant compound. The use of 1,8-cineole and β-caryophyllene together provides different and complementary primary anti-inflammatory functions as a TRPA1 antagonist and a CB2 agonist, respectively, and 1,8-cineole and β-caryophyllene unexpectedly complement each other through the synergistic effect of the primary and secondary properties of each compound. These antioxidant properties of 1,8-cineole and β-caryophyllene also unexpectedly synergize with glutathione and N-acetylcysteine, which act as primary antioxidants and sulfur-containing amino acids in the disclosed formulations.

[0217] One of ordinary skill in the art would typically have been taught not to use the β-caryophyllene formulation disclosed in the present invention because it has been shown to be a TRPA1 agonist (activator) that causes inflammation (Moon et al., 2015). Thus, one of ordinary skill in the art would consider it undesirable to include β-caryophyllene in a formulation because it would activate the TRPA1 receptor, causing inflammation and coughing.

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

[0219] 1,8-cineole, borneol, camphor, 2-methylisoborneol, fenchyl alcohol or cardamonin - 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, carbocysteine, taurine or methionine - 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, nicotinamide, nicotinamide riboside or ascorbic acid - 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, β-carotene, quercetin, kaempferol, luteolin, ellagic acid, resveratrol, silymarin, nicotinamide adenine dinucleotide or thymol quinone - 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 - 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] β-caryophyllene, cannabinoid, 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 thickening compounds - 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] Glycerol - about 1%, 3%, 10%, 30% or 50% to about 10%, 30%, 50%, 70%, 80%, 90%, 95% or 98%.

[0229] For example, the pH value 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 accompanying drawings, the following examples and experiments further describe the present invention. These drawings, examples and experiments are only for illustrating the specific embodiments of the present invention and should not be construed as limiting the scope of the present invention in any way. The compositions of the present invention can contain the essential and optionally present ingredients and components described herein, consist essentially of them or consist of them. As used herein, "consisting essentially of" means that the composition or component can include additional ingredients, provided 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] Examples

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

[0233] Example 1

[0234] In Example 1, a composition and manufacturing method of a pharmaceutical liquid are disclosed, wherein the pharmaceutical liquid is atomized, vaporized or both, and it contains 1,8-cineole, 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), then adding a certain amount of N-acetylcysteine, glutathione and methylcobalamin, and then adding a certain amount of vegetable glycerin (if needed) and mixing until the liquid composition is homogeneous. Nitrogen purging can be used throughout the mixing to minimize the oxygenation of water and the oxidation of compounds in the mixture. Then 1,8-cineole is mixed separately with the emulsifier, and after this mixture is homogeneous, it is then slowly added to the mixture and slowly mixed until it is dissolved in the liquid, minimizing the volatilization of 1,8-cineole. The mixing can be carried out in a zero or low headspace reactor to further minimize the volatilization of 1,8-cineole and the 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, then 1,8-cineole can be emulsified in the liquid composition in the presence of a suitable emulsifier, such as Tween 20 (also known as polysorbate 20) and polyoxyethylene (20) sorbitan monooleate. The mixing is limited to the mixing required to produce a stable single-phase homogeneous solution or emulsion and to minimize the volatilization of 1,8-cineole. The usage method of the liquid composition in Example 1 includes but is not limited to placing a certain amount of the composition in an e-cigarette vaporization device, an electronic heat vaporization device, a nebulizer, an ultrasonic nebulizer, an ultrasonic e-cigarette vaporization device or an inhaler, and inhaling the atomized vapor obtained by generating an atomized mixture. The liquid composition that can be atomized or vaporized as a TRPA1 antagonist in Example 1 can optionally be 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 an atomizable liquid composition is disclosed in Table 1 (herein, when discussing a composition or mixture, unless otherwise specified, the term "percentage" (%) generally refers to weight percentage). The atomizable 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 can be refrigerated or not refrigerated.

[0235] Table 1. Basic Inhalation Liquid

[0236]

[0237]

[0238] Example 2

[0239] Example 2 discloses a preferred composition and method of manufacture of a medicated liquid, which is atomized, vaporized, or both, using a nebulizer, and which comprises 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 method of manufacture consists of mixing 96.09 g of 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 homogeneous. Then a mixture of 0.80 g of 1,8-cineole and 0.40 g of polysorbate 20 is added and slowly mixed until they are dissolved together. Once the 1,8-cineole and polysorbate 20 are homogeneously mixed, the mixture is added to the liquid mixture and dissolved into the liquid to minimize the evaporation of the 1,8-cineole. Mixing is limited to that required to produce a stable single-phase homogeneous solution and to minimize the evaporation of the 1,8-cineole. The pH of the solution is then measured and a quantity of sodium bicarbonate is added to raise the pH to approximately 7.20. A quantity of preservative may be added, or the mixture may be refrigerated prior to use. The method of use 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 resulting from the production of an atomized mixture. The method of use of the liquid composition in Example 2 includes adding from about 1 mL to about 5 mL of the mixture to a liquid nebulizer for patient inhalation. This liquid composition is disclosed in Table 2.

[0240] Table 2. Preferred Base Nebulizer Liquid

[0241]

[0242] Example 3

[0243] In Example 3, a preferred pharmaceutical composition and manufacturing method of a pharmaceutical liquid are disclosed, which is atomized, vaporized or both in an ultrasonic or thermal vaporization device, and it contains 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 16.94 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, 1.53 g of glutathione, 0.003 g of methylcobalamin, and then mixing until the liquid composition is homogeneous. Then 93.55 g of vegetable glycerin is added and mixed. Then a mixture of 1.69 g of 1,8-cineole and 1.01 g of polysorbate 20 is added and slowly mixed until they are dissolved together. Once the 1,8-cineole and polysorbate 20 are homogeneously mixed, the mixture is added to the glycerol-water based mixture and dissolved into the liquid to minimize the volatilization of 1,8-cineole. Mixing is limited to that required to produce a stable single-phase homogeneous solution and to minimize the volatilization of 1,8-cineole. Then the pH value of the solution is measured, and a certain amount of sodium bicarbonate is added 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 3 can be prepared with an amount of vegetable glycerin less than 93.55 g, and this amount can be reduced by increasing the corresponding amount of added nitrogen-purged water. The method of using the composition of the liquid composition in Example 3 includes but is not 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 vaping mod, 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 upper limit. The atomizable pharmaceutical 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 can be refrigerated or not refrigerated. This liquid composition is disclosed in Table 3.

[0244] Table 3. Preferred Base Electronic Cigarette Liquids

[0245]

[0246] Example 4

[0247] In Example 4, a liquid pharmaceutical composition and method of manufacture are disclosed, wherein the liquid is atomized, vaporized, or both, and which 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 method of manufacture consists of mixing and dissolving a quantity 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 quantity of N-acetylcysteine, glutathione, and methylcobalamin, then adding a quantity of vegetable glycerin (as needed) and mixing until the liquid composition is homogeneous. Nitrogen purging may be used throughout the mixing to minimize oxygenation of the water and oxidation of the compounds in the mixture. Then β-caryophyllene and 1,8-cineole are separately mixed with the emulsifier, and after the mixture is homogeneous, it is slowly added to the mixture and the mixture is slowly mixed until it is dissolved in the liquid, minimizing the volatilization of 1,8-cineole and β-caryophyllene. Mixing may be carried out in a zero or low headspace reactor to further minimize the volatilization of β-caryophyllene and 1,8-cineole and the oxidation of the compounds in the mixture. If a quantity 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, then β-caryophyllene and 1,8-cineole may be emulsified in the liquid composition in the presence 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 β-caryophyllene and 1,8-cineole.

[0248] The method of using the liquid composition in Example 4 includes, but is not intended to be limited to, placing a quantity 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 aerosolized vapor resulting from producing an aerosolized mixture. The liquid composition components that can be atomized or vaporized as TRPA1 antagonists in Example 4 can optionally be made of borneol or a mixture of 1,8-cineole and borneol, the mixture being in the same or a 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 capable of storing one or more doses, the headspace of the container may or may not contain nitrogen, and the container may or may not be refrigerated.

[0249] Table 4. Basic Inhalation Liquids Containing β-Caryophyllene

[0250]

[0251]

[0252]

[0253] Example 5

[0254] In Example 5, a preferred composition and method of manufacture of a medicated liquid are disclosed, the medicated liquid being atomized, vaporized, or both, using a nebulizer, and comprising 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 method of manufacture 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 homogeneous. Then, a mixture of 0.80 g of 1,8-cineole, 0.80 g of β-caryophyllene, and 0.80 g of polysorbate 20 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 that required to produce a stable single-phase homogeneous solution and to minimize the volatilization of 1,8-cineole and β-caryophyllene. The pH of the solution is then measured and a quantity of sodium bicarbonate is added to raise the pH to 7.20. A quantity of preservative may be added, or the mixture may be refrigerated prior to use. The method of use of the liquid composition in Example 5 includes, but is not limited to, placing the composition in an ultrasonic, vibrating mesh, or jet nebulizer and inhaling the vapor resulting from the production of an atomized mixture. The method of use of the liquid composition in Example 5 includes adding about 1 mL to 5 mL of the mixture to a liquid nebulizer for patient inhalation. The liquid composition that can be atomized or vaporized in Example 5 may optionally be made of borneol or a mixture of 1,8-cineole, β-caryophyllene, and borneol having the same total concentration range as 1,8-cineole and β-caryophyllene. This liquid composition is disclosed in Table 5.

[0255] Table 5. Preferred Base Nebulizer Liquid Containing β-Caryophyllene

[0256]

[0257]

[0258] Example 6

[0259] In Example 6, a composition and manufacturing method of a pharmaceutical liquid are disclosed, the pharmaceutical liquid being atomized, vaporized, or both in an ultrasonic or thermal vaporization device, and comprising 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: 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, 1.50 g of glutathione, 0.003 g of methylcobalamin, and mixing until the liquid composition is homogeneous. Then 90.72 g of vegetable glycerin is added and mixed. Then a mixture of 1.69 g of 1,8-cineole and 1.69 g of β-caryophyllene is added and slowly mixed until they are dissolved together. Once the 1,8-cineole, β-caryophyllene, and polysorbate 20 are uniformly mixed, the mixture is added to the glycerol-water-based mixture and dissolved into the liquid to minimize the volatilization of 1,8-cineole and β-caryophyllene. Then the pH value of the solution is measured, and a certain amount of sodium bicarbonate is added 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 6 can be prepared with an amount of vegetable glycerin less than 90.72 g, and this amount can be reduced by increasing the corresponding amount of added nitrogen-purged water.

[0260] The method of using the composition of the liquid composition in Example 6 includes but is not intended to be limited to placing the composition in an e-cigarette vaporization device, a thermal vaporization device, an e-cigarette vaporization pen, an e-cigarette vaporization module, or an ultrasonic e-cigarette vaporization device, and inhaling the vapor obtained by generating an atomized mixture. The preferred e-cigarette vaporization device is a device with temperature control and a temperature limit of 200 °C upper limit. The atomizable pharmaceutical 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 can be refrigerated or not refrigerated. This liquid composition is disclosed in Table 6.

[0261] Table 6. Preferred basic e-cigarette liquid containing β-caryophyllene

[0262]

[0263] Example 7

[0264] In Example 7, a composition and method of manufacture of a pharmaceutical liquid are disclosed, wherein the liquid is atomized, vaporized, or both, and which comprises 1,8-cineole, β-caryophyllene, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, dexpanthenol, L-theanine, taurine, an emulsifier, vegetable glycerin (as needed), water, sodium bicarbonate (as needed), and a preservative (as needed). The method of manufacture consists of mixing and dissolving a quantity 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 quantity of N-acetylcysteine, glutathione, dexpanthenol, L-theanine, taurine, and methylcobalamin, then adding a quantity of vegetable glycerin (as needed) and mixing until the liquid composition is homogeneous. Nitrogen purging can be used throughout the mixing to minimize oxygenation of the water and oxidation of the compounds in the mixture. Then β-caryophyllene and 1,8-cineole are separately mixed with the emulsifier, and after the mixture is homogeneous, it 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 carried out in a zero or low headspace reactor to further minimize the volatilization of β-caryophyllene and 1,8-cineole and the oxidation of the compounds in the mixture. If a quantity 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, then β-caryophyllene and 1,8-cineole can be emulsified in the liquid composition in the presence 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 β-caryophyllene and 1,8-cineole.

[0265] The method of use of the liquid composition in Example 7 includes, but is not intended to be limited to, placing a quantity 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 resulting from the production of an atomized mixture. The liquid composition components that can be atomized or vaporized in Example 7 and that act as TRPA1 antagonists can optionally be made of borneol or a mixture of 1,8-cineole and borneol, the mixture being in the same or a different total concentration range compared to when using 1,8-cineole alone. Such atomizable liquid compositions are disclosed in Table 7. The atomizable liquid composition can be transferred to a container capable of storing one or more doses, the headspace of the container can contain or not contain nitrogen, and the container can be refrigerated or not refrigerated.

[0266] Table 7. Base Liquid Containing Amino Acids

[0267]

[0268]

[0269]

[0270] Example 8

[0271] In Example 8, a preferred composition and method of manufacture of a pharmaceutical liquid are disclosed, which liquid is atomized, vaporized, or both, and which comprises 1,8-cineole, β-caryophyllene, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, D-panthenol, L-theanine, taurine, an emulsifier, a sterile saline solution, sodium bicarbonate (as needed), and a preservative (as needed). The method of manufacture 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 D-panthenol, 0.70 g of L-theanine, and 0.50 g of taurine, and mixing until the liquid composition is homogeneous. Then a mixture of 0.80 g of 1,8-cineole, 0.80 g of β-caryophyllene, and 0.80 g of polysorbate 20 is added and slowly mixed until they are dissolved together. This mixture is added to a glycerol-water-based mixture and dissolved into the liquid to minimize the volatilization of 1,8-cineole and β-caryophyllene. Mixing is limited to that required to produce a stable single-phase homogeneous solution and to minimize the volatilization of 1,8-cineole and β-caryophyllene. The pH of the solution is then measured, and a quantity of sodium bicarbonate is added to raise the pH to 7.20. A quantity of preservative may be added, or the mixture may be refrigerated prior to use. The method of use of the liquid composition in Example 8 includes, but is not intended to be limited to, placing the composition in an ultrasonic, vibrating mesh, or jet nebulizer and inhaling the vapor resulting from the production of an atomized mixture.

[0272] The method of use of the liquid composition in Example 8 includes adding about 1 mL to 5 mL of the mixture to a liquid nebulizer for patient inhalation. The liquid composition that can be atomized or vaporized in Example 8 may optionally be made of borneol or a mixture of 1,8-cineole, β-caryophyllene, and borneol having the same total concentration range as 1,8-cineole and β-caryophyllene. Such a liquid composition is shown in Table 8.

[0273] Table 8. Preferred Base Nebulizer Liquids Containing Amino Acids

[0274]

[0275]

[0276] Example 9

[0277] In Example 9, a composition and method of making a pharmaceutical liquid are disclosed, the pharmaceutical liquid being atomized, vaporized, or both in an ultrasonic or thermal vaporization device, and comprising 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 method of making 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 homogeneous. Then 89.99 g of vegetable glycerin is added and mixed. Then a mixture of 1.70 g of 1,8-cineole, 1.70 g of β-caryophyllene, and 1.70 g of polysorbate 20 is added and slowly mixed until they are dissolved together. Once the 1,8-cineole, β-caryophyllene, and polysorbate 20 are homogeneously mixed, the mixture is added to the glycerol-water-based mixture and dissolved into the liquid to minimize the volatilization of the 1,8-cineole and β-caryophyllene. Then the pH of the solution is measured, and a quantity of sodium bicarbonate is added to raise the pH to 7.20. A quantity of preservative may be added, or the mixture may be refrigerated prior to use. The liquid composition in Example 9 can be prepared with an amount of vegetable glycerin less than 89.99 g, and this amount can be reduced by increasing the correspondingly added nitrogen-purged water.

[0278] The method of using the composition of the liquid composition in Example 9 includes, but is not intended to be limited to, placing the composition in an e-cigarette vaporization device, a thermal vaporization device, an e-cigarette vaporization pen, an e-cigarette vaporization module, or an ultrasonic e-cigarette vaporization device, and inhaling the vapor resulting from the production of an atomized mixture. A preferred e-cigarette vaporization device is one having temperature control with a temperature limit of 200 °C as an upper limit. The atomizable pharmaceutical liquid composition can be transferred to a container capable of storing one or more doses, the headspace of the container may or may not contain nitrogen, and the container may or may not be refrigerated. This liquid composition is disclosed in Table 9.

[0279] Table 9. Preferred Base E-Cigarette Liquids Containing Amino Acids

[0280]

[0281]

[0282] Example 10

[0283] A pharmaceutical liquid composition and method of manufacture are disclosed in Example 10, the liquid being atomized, vaporized, or both, and comprising 1,8-cineole, β-caryophyllene, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, epigallocatechin, resveratrol, an emulsifier, vegetable glycerin (as needed), water, sodium bicarbonate (as needed), and a preservative (as needed). The method of manufacture consists of mixing and dissolving a quantity 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 quantity of N-acetylcysteine, glutathione, pre-dissolved epigallocatechin, pre-dissolved resveratrol, and methylcobalamin, then adding a quantity of vegetable glycerin (as needed) and mixing until the liquid composition is homogeneous. Nitrogen purging may be used throughout the mixing to minimize oxygenation of the water and oxidation of the compounds in the mixture. Then β-caryophyllene and 1,8-cineole are separately mixed with the emulsifier, and after the mixture is homogeneous, it 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 may be carried out in a zero or low headspace reactor to further minimize the volatilization of β-caryophyllene and 1,8-cineole and the oxidation of the compounds in the mixture. If a quantity 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, then β-caryophyllene and 1,8-cineole may be emulsified in the liquid composition in the presence 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 β-caryophyllene and 1,8-cineole.

[0284] The method of use of the liquid composition in Example 10 includes, but is not intended to be limited to, placing a quantity 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 resulting from producing an atomized mixture. The liquid composition components that are atomizable or vaporizable in Example 10 and that are TRPA1 antagonists may optionally be made of borneol or a mixture of 1,8-cineole and borneol having the same or a different total concentration range compared to when using 1,8-cineole alone. Such atomizable liquid compositions are disclosed in Table 10. The atomizable liquid composition may be transferred to a container capable of storing one or more doses, the headspace of the container may or may not contain nitrogen, and the container may or may not be refrigerated.

[0285] Table 10. Base Liquids Containing Polyphenols

[0286]

[0287]

[0288]

[0289] Example 11

[0290] In Example 11, a composition and method of manufacture of a pharmaceutical liquid are disclosed, the pharmaceutical liquid being atomized, vaporized or both, which comprises 1,8-cineole, β-caryophyllene, cannabidiol, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifier, vegetable glycerin, water, sodium bicarbonate (as required) and a preservative (as required). The method of manufacture consists of: mixing and dissolving a quantity of nitrogen purged purified sterile water or isotonic saline solution with ascorbic acid powder or crystals, sodium bicarbonate and a preservative (if required), then adding a quantity of N-acetylcysteine, glutathione and methylcobalamin, then adding a quantity of vegetable glycerin (as required) and mixing until the liquid composition is homogeneous. Nitrogen purging can be used throughout the mixing to minimize oxygenation of water and oxidation of compounds in the mixture. Dissolve cannabidiol in a mixture of β-caryophyllene and 1,8-cineole, with limited mixing to minimize the loss of volatile β-caryophyllene and 1,8-cineole. After this step, the cannabidiol, β-caryophyllene, 1,8-cineole mixture is mixed separately with the emulsifier, and after this mixture is homogeneous, it is then slowly added to and slowly mixed with the mixture until it is dissolved in the liquid, minimizing the volatilization of 1,8-cineole and β-caryophyllene. Mixing can be carried out in a zero or low headspace reactor to further minimize the volatilization of β-caryophyllene and 1,8-cineole and the oxidation of compounds in the mixture. Mixing is limited to that required to produce a stable single-phase homogeneous solution or emulsion and to minimize the volatilization of β-caryophyllene and 1,8-cineole.

[0291] The method of using the liquid composition in Example 11 includes, but is not intended to be limited to, placing an amount of the composition in an e-cigarette vaporization device, an electronic thermal vaporization device, an ultrasonic vaporization device, a nebulizer, or an inhaler, and inhaling the aerosolized vapor resulting from the production of an aerosolized mixture. The components of the liquid composition that can be aerosolized 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 having the same or different total concentration ranges compared to the concentration range when using 1,8-cineole 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 analogue (THC-V), cannabidiol (CBD), cannabidiol propyl analogue (CBD-V), cannabinol (CBN), cannabichromene (CBC), cannabichromene propyl analogue (CBC-V), cannabigerol (CBG). Such an aerosolizable liquid composition is shown in Table 11. The aerosolizable 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 can be refrigerated or not refrigerated.

[0292] Table 11. Base Liquid Containing CBD

[0293]

[0294]

[0295] Example 12

[0296] A composition and method of manufacture of a medicated liquid are disclosed in Example 12, the medicated liquid being atomized, vaporized or both, which comprises 1,8-cineole, β-caryophyllene, nicotine, N-acetylcysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifier, vegetable glycerin, water, sodium bicarbonate (as required) and a preservative (as required). The method of manufacture consists of: mixing and dissolving a quantity of nitrogen purged purified sterile water or isotonic saline solution with ascorbic acid powder or crystals, sodium bicarbonate and a preservative (if required), then adding a quantity of N-acetylcysteine, glutathione and methylcobalamin. After mixing this mixture, a quantity of nicotine salt is added to a quantity of vegetable glycerin (if used) to dissolve the nicotine salt. Then the nicotine salt-vegetable glycerin mixture is added to the water, ascorbic acid, N-acetylcysteine, glutathione mixture and mixed until the liquid composition is homogeneous. Nitrogen purging may be used throughout the mixing to minimize the oxygenation of water and the oxidation of the 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 loss of volatilization of β-caryophyllene and 1,8-cineole. After this step, the nicotine, β-caryophyllene, 1,8-cineole mixture is mixed separately with the emulsifier and after this mixture is homogeneous, 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 may be carried out in a zero or low headspace reactor to further minimize the volatilization of β-caryophyllene and 1,8-cineole and the oxidation of the compounds in the mixture. Mixing is limited to that required to produce a stable single-phase homogeneous solution or emulsion and to minimize the volatilization of β-caryophyllene and 1,8-cineole.

[0297] The method of use of the composition of the liquid composition in Example 12 includes but is not intended to be limited to placing the composition in an electronic cigarette vaporizing device, a thermal vaporizing device, an electronic cigarette vaporizing pen, an ultrasonic electronic cigarette vaporizing device or an electronic electronic cigarette vaporizing module and inhaling the vapor resulting from producing an atomized mixture. The preferred electronic cigarette vaporizing device is a device having temperature control with a temperature limited to an upper limit of 200 °C. The atomizable medicated liquid composition may be transferred to a container capable of storing one or more doses, the headspace of the container may or may not contain nitrogen, and the container may or may not be refrigerated. Such a liquid composition is disclosed in Table 12.

[0298] Table 12. Base Liquids Containing Nicotine

[0299]

[0300]

[0301]

[0302] Example 13

[0303] In Example 13, a pharmaceutical liquid composition and a manufacturing method are disclosed, wherein the pharmaceutical liquid is atomized, vaporized or both in an ultrasonic e-cigarette vaporization device or a thermal vaporization device, and it contains 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 homogeneous. Add 1.75 g of nicotine salt (54% nicotine) to 87.93 g of vegetable glycerin and mix until the nicotine salt is dissolved. Then add a mixture of 1.08 g of 1,8-cineole, 1.08 g of β-caryophyllene and 1.18 g of polysorbate 20 together and mix slowly until they are dissolved together, with limited mixing to minimize the volatilization loss of β-caryophyllene and 1,8-cineole. Then add the vegetable glycerin-nicotine mixture to the mixture of β-caryophyllene, 1,8-cineole and polysorbate 20 and mix slowly to produce a stable single-phase homogeneous solution and minimize the volatilization of 1,8-cineole and β-caryophyllene. Then add water, glutathione, N-acetylcysteine and methylcobalamin and mix slowly until homogeneous. 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 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-purged water added in response.

[0304] The method of using the composition of the liquid composition in Example 13 includes but is not limited to placing the composition in an e-cigarette vaporization device, a thermal vaporization device, an e-cigarette vaporization pen, an ultrasonic e-cigarette vaporization device or an electronic e-cigarette vaporization module, and inhaling the vapor obtained by generating an atomized mixture. The preferred e-cigarette vaporization device is a device with temperature control and a temperature limit of 200 °C upper limit. The atomizable pharmaceutical 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 can be refrigerated or not refrigerated. Such a liquid composition is disclosed in Table 13.

[0305] Table 13. Preferred basic e-cigarette liquids containing nicotine

[0306]

[0307]

[0308] Example 14

[0309] In Example 14, a preferred composition and method of manufacture of a medicated liquid are disclosed, which is atomized, vaporized or both in an ultrasonic electronic cigarette vaporization device or a thermal vaporization device, which is part of a smoking cessation and respiratory health improvement combination product. The smoking cessation method consists of four separate liquid compositions which are atomized and inhaled, each composition containing similar concentrations of N-acetylcysteine, glutathione, 1,8-cineole, β-caryophyllene, methylcobalamin, an emulsifier, vegetable glycerin and water.

[0310] In this example, smoking cessation is first achieved by eliminating the use of combustible cigarettes by nicotine replacement therapy using an ultrasonic electronic cigarette vaporization device or an electronic thermal liquid atomization device. The smoking cessation method in the present invention utilizes a nicotine tapering process by which, over time, higher to lower nicotine concentrations are used to reduce the daily nicotine consumption, thereby achieving complete elimination of nicotine in the formulation. In this smoking cessation method, there are four nicotine reduction steps as part of a smoking and nicotine addiction withdrawal system. The first step in smoking cessation involves switching from smoking to using an electronic thermal liquid atomization device to consume nicotine. The unique and distinctive feature of the present invention is that, in addition to providing nicotine replacement therapy that leads to complete nicotine withdrawal in an individual, the formulation also additionally provides the health benefit of repairing respiratory system damage and diseases caused by the individual's smoking history. The health benefits achieved by inhaling the atomized N-acetylcysteine, glutathione, 1,8-cineole, β-caryophyllene and methylcobalamin are the result of a multi-functional mechanism of using a TRPA1 antagonist, a CB2 agonist, glutathione replacement in the lung, epithelial lining fluid and epithelial tissue, antioxidant therapy with the glutathione precursor N-acetylcysteine and vitamin B12 replacement therapy.

[0311] The method of using the first of four steps to reduce an individual's daily nicotine amount is to inhale approximately 20 mg of nicotine per day by vaporizing the formulations disclosed in Table 14. Table 14 provides the formulations for Step 1. Based on a consumption of approximately 1 mL of liquid from an ultrasonic vaporization device, a thermal liquid atomization device; not limited to an e-cigarette vaporization device or the vaporization of an e-cigarette, with 150 puffs per day, the daily consumption of nicotine is approximately 20 mg. The daily doses of the other non-carrier components of the compositions 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 glycerol can be provided at 1,096 mg. Depending on an 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 an individual to consume the composition by atomizing the Step 1 formulation disclosed in Table 14 can be variable. The time for an individual to use the Step 1 nicotine replacement composition can be as short as two weeks or as long as several months. For example, the duration of Step 1 can be 40 to 60 days. Those of ordinary skill in the art will recognize that the exact concentration of each component determined in Table 14 can vary within a range to primarily achieve the same results as using the actual concentrations determined in Table 14. The use of deionized water and vegetable glycerol can also vary depending on the type of liquid atomization device used. For example, if a spray device or an ultrasonic vaporization device is used to provide the aerosol phase of the liquid composition, the concentration of vegetable glycerol can be greatly reduced or even completely eliminated and supplemented with an aqueous phase. Similarly, if a spray device or an ultrasonic vaporization device is used, deionized water can be replaced with a simple saline solution isotonic with the lung epithelial lining fluid, for example, approximately 0.9% sodium chloride. Those of ordinary skill in the art will recognize that if an electronic thermal vaporization device, an e-cigarette vaporization device, an e-cigarette pen, an ultrasonic vaporization device, or an e-cigarette is used to deliver the composition in Table 14, the aqueous phase can be primarily replaced by vegetable glycerol or another non-aqueous phase carrier. Those 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.

[0312] In step 1 of the smoking cessation system, one embodiment of the present invention is to provide approximately a similar number of puffs as the individual typically takes when smoking prior to using the system. This helps to satisfy the oral craving associated with smoking. The programmable electronic vaporization device can substantially vary the number of puffs used per milliliter of the liquid composition disclosed in Table 14. Those of ordinary skill in the art will recognize that if a person attempting to quit smoking cannot progress to the next step of the smoking cessation system, the health benefits of remaining in step 1 will be superior to those if the person resumes smoking for a longer period than envisioned in step 1, including many years.

[0313] Table 14. Smoking Cessation E-cigarette Liquid - Step 1

[0314]

[0315] Dosage based on 150 puffs per milliliter

[0316] As part of the smoking cessation method, step 2 is based on the consumption of approximately 1 mL of liquid vaporized from an ultrasonic e-cigarette vaporization device or an electronic thermal liquid atomization device at 125 puffs per day. As disclosed in the composition of Table 15, the daily nicotine consumption is approximately 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 reduce the oral craving associated with the individual's smoking habits and behaviors. Thus, 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 attempting to quit smoking cannot progress to the next step of the smoking cessation system, the health benefits of remaining in step 2 will be superior to those if the person resumes smoking for a longer period than envisioned in step 2, including many years.

[0317] Table 15. Smoking Cessation E-cigarette Liquid - Step 2

[0318]

[0319] Dosage based on 125 puffs per milliliter

[0320] As part of a smoking cessation method, Step 3 is based on a consumption of approximately 1 mL of liquid vaporized from an ultrasonic e-cigarette vaporization device or an e-liquid atomization device using 75 sprays per day. As disclosed by the composition of Table 16, the daily consumption of nicotine is approximately 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 sprays is reduced from 125 sprays per day in Step 2 to 75 sprays per day in Step 3. One of ordinary skill in the art will recognize that if a person who wants to quit smoking cannot progress to the next step of the smoking cessation system, the health benefits of remaining in Step 3 will be superior to the person resuming smoking for a longer period than contemplated in Step 3, including many years.

[0321] Table 16. Smoking Cessation E-Cigarette Liquid - Step 3

[0322] Compound Liquid Concentration Unit Dose for 75 Sprays Unit Glutathione 19.76 mg / mL 19.76 mg N-Acetylcysteine 13.83 mg / mL 13.83 mg 1,8-Cineole 10.93 mg / mL 10.93 mg β-Caryophyllene 5.36 mg / mL 5.36 mg Nicotine Salt (54% Nicotine) 5.00 mg / mL 5.00 mg Vitamin B12 9.88 μg / mL 9.88 μg Polysorbate 20 9.78 mg / mL 9.78 mg Deionized Water 212.39 mg / mL 212.39 mg Vegetable Glycerin 1137.42 mg / mL 1137.42 mg

[0323] Dosage based on 75 sprays per milliliter

[0324] As part of a smoking cessation method, Step 4 is based on a consumption of approximately 1 mL of liquid vaporized from an ultrasonic e-cigarette vaporization device or an e-liquid atomization device using 75 sprays per day, and as disclosed by the composition of Table 17, the daily consumption of nicotine is completely eliminated. The time for an individual to use the Step 4 nicotine replacement preparation will depend on the person's respiratory health condition, the type of respiratory system damage, and the lung diseases the person has due to the effects of their smoking history. The time for an individual to use the Step 4 composition can be several months, several years, or several decades.

[0325] Table 17. Smoking Cessation E-Cigarette Liquid - Step 4 - No Nicotine

[0326] Compound Liquid Concentration Unit Dose for 75 Sprays 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

[0327] Dosage based on 75 sprays per milliliter

[0328] Alternatively, Step 4 may consist of using a nebulizer or an ultrasonic e-cigarette vaporization device to provide continuous treatment of a respiratory lung disease associated with an individual's past smoking history. Alternatively, the nebulizer preparation disclosed in Step 4 may be the preparation disclosed in Table 2, Table 5, or Table 8, which may preferably be used for nebulization after Step 3 in the smoking cessation system because they contain β-caryophyllene, which is a CB2 agonist and helps with addiction withdrawal.

[0329] 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, and a certain amount of methylcobalamin, and then adding a certain amount of vegetable glycerol and mixing until the liquid composition is homogeneous. Then, a previously mixed mixture of a certain amount of 1,8-cineole, β-caryophyllene, and a certain amount of polysorbate 20 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. The mixing is limited to that required to produce a stable single-phase homogeneous suspension and to minimize the volatilization of 1,8-cineole and β-caryophyllene. The liquid composition that can be atomized or vaporized in Example 14 can optionally be made of borneol, β-caryophyllene, or the following mixture with the same total concentration range as 1,8-cineole present alone in Example 14: a mixture of 1,8-cineole with one or more of borneol and β-caryophyllene. The pH value of each liquid composition should be measured and adjusted to 7.20 with sodium bicarbonate. If the liquid composition is not manufactured under aseptic conditions, then preservatives can be added to improve the physical, chemical, and biological stability of the preparation. The liquid composition in Example 14 can be made with a certain amount of vegetable glycerol less than the amounts disclosed in Tables 14, 15, 16, and 17, and this amount can be reduced by increasing the corresponding amount of nitrogen-purged water added.

[0330] Example 15

[0331] A preclinical trial was conducted on five patients who were current or former smokers and had been previously diagnosed with asthma or COPD. The preferred liquid pharmaceutical composition was vaporized using a commercially available electronic thermal e-cigarette vaporizer pen that had 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 ). Over a period of up to 73 days, the patients inhaled at least 40 puffs per day. Spirometry tests, including forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) measurements, were performed before treatment, during treatment, 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. The patients were also interviewed regarding their breathing ability, energy level, and overall well-being and health status.

[0332] The procedure followed by each patient consisted of placing the preferred liquid composition disclosed in Table 18 into the e-cigarette pen tank with a dropper, and then pressing the start button on the side of the e-cigarette pen to activate the heating of the coil while the patient inhaled the atomized liquid through the attached mouthpiece.

[0333] Table 18. Preclinical Trial Liquid Compositions

[0334]

[0335] The dose is based on 75 puffs per milliliter and 40 puffs per day used by the patient.

[0336] Patients inhaled at least 75 puffs per day from the e-cigarette pen. Before starting treatment, as part of the test, the past and current smoking history, age, height, weight, gender, and race of each patient were recorded to allow calculation of normal FEV1 and FVC values. As shown in Table 19, all individuals had a smoking history and only 1 patient was currently smoking. As shown in Table 19, the patients were diagnosed with COPD or asthma. Before the liquid atomization treatment, each patient underwent a spirometry test to measure FEV1 and FVC, providing baseline conditions. These results were compared with the 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. The patient history and spirometry test results are summarized in Table 19. Using the normal FEV1 value calculated for each individual based on age, height, gender, and race and the baseline FEV1 measurement before treatment, the percentage of the normal FEV1 value for each patient was calculated to provide baseline conditions for comparing treatment outcomes.

[0337] Table 19. CuraBreath Preclinical Trial Data

[0338]

[0339]

[0340] The vital capacity of females is generally smaller than that of males. As can be seen from Table 19, the baseline FEV1 volumes of 3 female patients (the FEV1 baseline values before treatment were from 1.33 L to 1.70 L) were lower than those of 2 male patients (the FEV1 baseline values before treatment were from 2.82 L to 2.84 L). The normal FEV1 values for female patients were calculated to be from 1.98 L to 2.80 L. The normal FEV1 values for male patients were 4.18 L and 4.44 L. The baseline FEV1 value of each patient was significantly lower than the normal value of healthy individuals. For the 5 patients, the percentages of normal FEV1 values before treatment ranged from 63.96% to 68.83%. For example, individuals with COPD with a percentage of normal FEV1 value less than 80% were classified as GOLD2 moderate COPD. Based on these values, it is obvious that each patient showed significant airway limitation. The FVC baseline volumes of all patients were also significantly lower than the normal values of healthy individuals, ranging from 62.61% to 68.01%.

[0341] At 21 days after treatment and at the end of treatment (ranging from 42 days to 73 days), the spirometry tests after repeated inhalation therapy were performed on each individual. The results of the FEV1 spirometry tests of each patient were plotted, and the results are shown in Figure 1 . It is obvious that over time, the growth rate of the improvement of the FEV1 value was linear and significant. The FEV1 reversibility values of female patients after the entire treatment period were 32.35%, 34.21%, and 45.11%. The forced vital capacity (FVC) of female patients also increased by 20.37%, 32.29%, and 36.81% after the entire treatment period. Patient 102 is a 61-year-old female diagnosed with COPD, who had smoked for at least 28 years and was still an active smoker when these tests were conducted. Her FEV1 and FVC increased by 32.45% and 20.37% respectively. Patient 104 is a 67-year-old female diagnosed with asthma and was the oldest in the preclinical study. She had smoked two packs of cigarettes for 28 years. Patient 104 had the highest FEV1 reversibility, which was 45.11%.

[0342] Males generally have a larger vital capacity, which is obvious from the results provided in Table 19 and Figure 1 . As can be seen from Figure 1 , the FEV1 also improved linearly over time, while the spirometry results showed substantial improvement. The FEV1 reversibility values of male patients after the entire treatment period were 46.48% and 39.01% for patients 103 and 106 respectively. The forced vital capacity (FVC) of male patients also increased by 40.28% and 32.39% respectively after the entire treatment period. Patient 103 is male, 45 years old, who had smoked for 15 years and was not an active smoker when these tests were conducted.

[0343] Various tissues are associated with the improvement of COPD patients. The FEV1 results reported in preclinical trials indicate a significant improvement in FEV1 compared to the following FEV1 improvement assessment criteria established by these tissues: 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 indicate that the FEV1 reversibility ranges from 32.35% to 46.48%; the FVC reversibility ranges from 20.37% to 40.28%; and the improvement in FEV1 values ranges from 0.55 L to 1.32 L.

[0344] Example 16

[0345] A preclinical trial was conducted on a single patient using a preferred nebulizable liquid that was nebulized using a commercially available portable ultrasonic mesh nebulizer that had 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 diagnosed history of mild to moderate asthma. The patient had approximately 10 to 15 asthma attacks per year that required medical treatment, which were caused by seasonal allergies, induced by cold air, and induced by exercise. During these events, the patient typically used the bronchodilator albuterol as a rescue inhaler and regularly used fluticasone furoate (an inhaled corticosteroid powder). The patient also required prednisone (an oral corticosteroid) for the most severe asthma attacks, approximately 1 to 2 times per year.

[0346] Before the first spray of the preferred liquid composition, the patient reported moderate asthma symptoms, including a feeling of chest tightness, as well as difficulty breathing and full respiration. The patient had been inhaling salbutamol and fluticasone furoate daily for one week before using the spray liquid, and the symptoms had not been substantially relieved. Based on his previous asthma experiences and symptoms, he reported that he thought he would need to use prednisone if the symptoms persisted. Using a portable ultrasonic mesh nebulizer, the patient nebulized 1 mL of a liquid that contained the following: 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 nebulization, the patient reported that his chest felt significantly more relaxed, the chest tightness had decreased, he was able to breathe more fully, and he felt more energetic. After the nebulization treatment, he was able to completely stop taking salbutamol and fluticasone furoate. After this single nebulization event, the patient reported that his symptoms remained improved during the following week, although the degree of improvement decreased somewhat after about 4 to 5 days. Three days after the nebulization of the medicinal liquid, the patient underwent a spirometry test. The patient's normal spirometry values were calculated as FEV1 = 3.81 L and FVC = 4.89 (Hankinson, 1999). The spirometry values measured three days after the single nebulization treatment were FEV1 = 2.99 L and FVC = 3.65 L, and the percentage of normal values was 78.4% for FEV1 and 74.6% for FVC.

[0347] One week after a single spray treatment, the patient began a 7-day daily spray treatment. Before starting the 8-day treatment period, the patient underwent a baseline spirometry test with the following results: FEV1 = 3.09 L, FVC = 3.57 L, percentage of normal values for FEV1 = 81.0%, FVC = 73.0%. The patient continued the nebulizer liquid with an increased dose 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, 1.5 mL was nebulized, and on days 4 to 8, 3.0 mL was nebulized. After nebulizing the liquid composition on day 7, the patient underwent a spirometry test. The spirometry results after nebulizing 3.0 mL of the liquid were FEV1 = 3.39 L, FVC = 3.84 L, percentage of normal values for FEV1 = 86.8%, FVC = 78.5%. Compared with the first baseline spirometry values, the percentage reversibility of FEV1 was calculated to be 12%, and that of FVC was 5.2%. Compared with the first patient spirometry results, the improvement in the FEV1 / FVC% ratio increased from 81.9% to 88.3%. It is clear that the patient used a greater percentage of vital capacity in the second spirometry test.

[0348] The patient reported that even though only one spray treatment was performed during the first week of treatment, followed by 11 days of only moderate spray treatment, he did not experience any asthma attacks and did not have to take a prescribed bronchodilator or any corticosteroids at any time during the trial. The patient reported that he had more energy and easier and more complete breathing.

[0349] The embodiments described and discussed in this specification are only intended to teach those skilled in the art how to make and use the present invention in the best manner known to the inventor. Nothing in this specification should be construed as limiting the scope of the present invention. All the examples given are representative and not restrictive. As those skilled in the art will understand from the above teachings, the above 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 practiced in a manner different from that specifically described.

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Claims

1. Use of a pharmaceutical composition in the preparation of a medicament for treating respiratory diseases, wherein, 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 mercapto amino acid; at least one vitamin; at least one chelating agent; and at least one antioxidant.

2. The application according to claim 1, wherein The respiratory disease is selected from the group consisting of: airway inflammation, chronic cough, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, and cystic fibrosis.

3. The application according to claim 1, wherein The treatment includes reducing inflammation in the lungs by modulating the immune system response and increasing the antibacterial and antifungal conditions in the lungs.

4. The application according to any one of claims 1 to 3, wherein The pharmaceutical composition is in a dosage form administered orally or nasally.

5. The application according to any one of claims 1 to 4, wherein The pharmaceutical composition is in the form of an aerosol or spray, and is preferably administered to the lungs of the patient by means of a nebulizer, atomizer, ultrasonic vaporization device, or thermionic vaporization device.

6. Use of a pharmaceutical composition in the preparation of a medicament for assisting a patient to quit smoking, wherein, 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 mercapto amino acid; at least one vitamin; at least one chelating agent; and at least one antioxidant.

7. The application according to claim 6, wherein The pharmaceutical composition further comprises nicotine.

8. The application according to claim 6 or 7, wherein The patient is an active smoker or a former smoker, currently or previously exposed to second-hand smoke, currently or previously exposed to wood or forest fire smoke, and / or currently or previously exposed to gaseous or particulate natural or artificial air pollutants.

9. The application according to any one of claims 6 to 8, wherein, During the process of assisting the patient to quit smoking, the concentration of nicotine contained in the pharmaceutical composition is gradually reduced until it reaches zero.

10. Use of a pharmaceutical composition for the preparation of a medicament for treating the lung and / or respiratory tract of a patient after exposure to a lung or respiratory tract irritant or damaging agent, wherein, 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 mercapto amino acid; at least one vitamin; at least one chelating agent; and at least one antioxidant.

11. The use according to claim 10, wherein the lung or respiratory tract irritant or damaging agent is a coughing agent, asphyxiant, lung-acting agent, lacrimator (tear gas), emetic, and / or vesicant.

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