Patent Application
20220000966
Methods of use and pharmaceutical liquid compositions that are orally administered to the lungs through vaporization and aerosol generating devices providing multifunctional treatment for lung and respiratory diseases are presented.
Smoking
According to the CDC, more than 16 million Americans are living with a disease caused by cigarette smoking. Smoking causes cancer, heart disease, stroke, lung diseases, diabetes, and chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis. Smoking and second hand smoke is associated with some types of asthma and exacerbates its symptoms. Smoking also increases the risk for tuberculosis, certain eye diseases, and problems of the immune system, including rheumatoid arthritis. The World Health Organization (2018) reported that worldwide, an estimated 1.1 billion smoke cigarettes, tobacco use causes nearly 7 million deaths per year, and current trends show that tobacco use will cause more than 8 million deaths annually by 2030.
The U.S. Center for Disease Control (2018) stated that 15.5% of all adults, approximately 37.8 million people in the United States smoke cigarettes. Cigarette smoking is responsible for more than 480,000 deaths per year in the United States, including more than 41,000 deaths resulting from second hand smoke exposure; this is about one in five deaths annually, or 1,300 deaths every day. On average, smokers die 10 years earlier than nonsmokers.
Tobacco smoke is a complex mixture of gaseous compounds and particulates. Current literature shows 4800 identified gaseous and particulate bound compounds in cigarette smoke (Sahu, et al. 2013).
Airborne particulate matter (PM), and especially fine particles, has been associated with various adverse health effects. Environmental tobacco smoke (ETS) has also been identified as an important source of anthropogenic pollution in indoor environments, for example though second hand smoke. Cigarette smoke consist of gaseous pollutants; such as carbon monoxide (CO), sulfur dioxide (SO2), nitric oxide (NO), nitrogen dioxide (NO2), methane (CH4), non-methane hydrocarbons (NMHC), carbonyls and volatile organic compounds (VOCs); and particulate matter (PM). The particulate concentration in tobacco smoke is generally very high at 1012 particles per cigarette and has very small particle sizes, varying from 0.01 nm to 1.00 μm, with a count median size in the 186 to 198 nm range (Sahu, et al. 2013). Despite the small diameter of the smoke particles, smoke deposition efficiencies of 60 to 80% in the lung have been reported. The concentration of nicotine in cigarettes is variable depending upon the brand. A comprehensive study was conducted in 1998 in which the nicotine content was reported in 92 brands of cigarettes from the U.S., Canada and the United Kingdom (Kozlowski, et al. 1998). The total nicotine content of tobacco and percent nicotine (by weight of tobacco) averaged 10.2 mg (standard error of the mean (SEM) of 0.25 and range: 7.2 mg to 13.4 mg) and 1.5% (SEM of 0.03 and range 1.2% to 2%) in the United States, 13.5 mg (SEM of 0.49 and range: 8.0 mg to 18.3 mg) and 1.8% (SEM of 0.06 and range: 1.0% to 2.4%) in Canada, 12.5 mg (SEM of 0.33, range: 9 mg to 17.5 mg) and 1.7% (SEM 0.04, range: 1.3% to 2.4%) in the United Kingdom. However, the nicotine intake per cigarette averages 1.04 mg (+/−0.36), indicating the absorption and actual dose of nicotine from smoking a cigarette is much lower than the amount in the tobacco of a cigarette (Benowitz et al. 1984).
Air Pollution
More than 80% of people living in urban areas that monitor air pollution are exposed to air quality levels exceeding World Health Organization (WHO) limits. As urban air quality declines, risks of stroke, heart disease, lung cancer, and chronic and acute respiratory diseases, including COPD and asthma, increase for the people who live in them. There are globally 4.2 million deaths each year directly attributed to air pollution and 91% of the world's population live in areas that exceed WHO air pollution criteria. In 2016, the WHO reported the annual median PM2.5 concentrations (μg/m3) in various regions of the world. Large portions of Asia, Africa and India have PM2.5 concentrations greater than 26 μg/m3. The WHO Air Quality Guideline (AQG) for PM2.5 air pollutant concentrations is 10 μg/m3. PM2.5 refers to atmospheric particulate matter (PM) that have a diameter of less than 2.5 μg (micrometers), which is about 3% the diameter of a human hair. Owing to their minute size, particles smaller than 2.5 μg are able to bypass the nose and throat and penetrate deep into the lungs and some may even enter the circulatory system. Studies report a close link between exposure to fine particles and premature death from heart and lung disease. Fine particles are also known to trigger or worsen chronic disease such as asthma, COPD, heart attack, bronchitis and other respiratory problems.
Chronic Obstructive Pulmonary Disease (COPD)
COPD is currently the fourth leading cause of death in the world and is projected to be the third leading cause of death by 2030. Most typically, the prevalence of COPD is directly related to tobacco smoking, although in many countries outdoor, occupational, and indoor air pollution (e.g., resulting from the burning of wood and other biomass fuels) are also major COPD risk factors. More than one-quarter of all people that have COPD do not smoke cigarettes and it is thought that air pollution is a primary cause in these cases.
Patients with chronic obstructive pulmonary disease experience exertional breathlessness caused by bronchoconstriction, mucous secretion, and edema of the airway wall and loss of attachments to the terminal airways. The World Organization (WHO) predicts that chronic obstructive pulmonary disease will become the third leading cause of disease-related death globally by 2030.
COPD is a common, preventable, and treatable disease that is characterized by airflow limitations and chronic respiratory symptoms the results of alveolar and airway abnormalities, typically caused by exposure to noxious gases or particulate matter. Chronic airflow limitations caused by COPD are caused by a combination of small airways disease (e.g., chronic bronchiolitis) and parenchymal destruction (emphysema). Chronic inflammation results in structural changes in the lungs, including narrowing of the small airways and destruction of the lung parenchyma, leading to a decrease in alveolar attachments to the small airways and lessening of lung elastic recoil. These changes diminish the ability of the airways to remain open during expiration. Narrowing of the small airways also contributes to airflow limitation and mucociliary dysfunction. Airflow limitation is usually measured by spirometry as this is the most widely available and reproducible test of lung function (Global Initiative for Chronic Obstructive Lung Disease, 2019).
Mitochondrial dysfunction and enhanced oxidative stress are capable of triggering an essential cellular degradation process, known as autophagy. The role of autophagy in pulmonary disorders can be either deleterious or protective, depending on the stimuli. In cigarette-smoke-induced COPD, autophagy is critical in mediating apoptosis and cilia shortening in airway epithelia. Autophagy, in turn, accelerates lung aging and emphysema and contributes to COPD pathogenesis by promoting epithelial cell death. Autophagy increases in pulmonary cells, leading to inflammation and emphysematous destruction in experimental COPD. Autophagy is critical in mediating inflammation and mucus hyper-production in epithelia via NF-κB and Activator protein 1 (AP-1) transcription factor.
Spirometry is the most frequently performed pulmonary function test and plays an important role in diagnosing the presence and type of lung abnormality and classifying its severity. Spirometry is used for assessment and surveillance examinations for individuals with COPD, asthma and other diseases associated with breathing impairment. It is additionally used for evaluation of occupational lung diseases in determining whether to institute preventive or therapeutic measures, and in granting benefits to individuals with lung impairment. Forced Expiratory Volume in 1 second (FEV1) and Forced Vital Capacity (FVC) spirometry data are compared to reference data and can be expressed as percent predicted values, based on age, gender, height and race (American Thoracic Society 1995). Spirometry is also used as a measure to assess an individual's response to treatment. FEV1/FVC ratio, percent reversibility of FEV1 and percent normal FEV1 are commonly used assessment parameters to evaluate the severity of airway obstructive diseases, diagnosis and treatment effectiveness.
Several mechanisms may explain how cigarette smoke can cause airway inflammation and subsequent disease. Barnes (2004) identified one mechanism identified in the role that cigarette smoke can play in the imbalance of proinflammatory cytokines, for example, Interferon-1β (IL-1β), IL-6, IL-8, interferon-γ, tumor necrosis factor-α (TNF-α) and anti-inflammatory cytokines (for example the IL-1 receptor antagonist, IL-4, IL-10, IL-11, and IL-13). A second mechanism is oxidative stress due to imbalance between oxidants and anti-oxidant defense mechanisms in airways and lungs. Oxidants are released from alveolar macrophages as well as neutrophils of COPD patients. Activated inflammatory cells, attracted into the alveolar space by chemokines and cytokines, release myeloperoxidase and large amounts of hypochlorous acid (HOCl) in the 0.1-1.0 mM range, in the vicinity of airway and alveolar epithelial cells.
Cigarette smoke itself is also a rich source of oxidants, as each puff of cigarette smoke contains approximately 1015 oxidant radical molecules and 1017 Electron Spin Resonance (ESR)-detectable radicals per gram of tar (Cantin, 2010). Antioxidants are natural molecules in biological system that scavenge oxidants, including free radicals, and protect from effects or free radicals and other reactive oxygen species. Antioxidants can be synthesized endogenously in the body, or exogenously by food intake or by supplementation. In one embodiment of this present invention, antioxidants comprise part of a multifunctional composition that is inhaled by a patient to minimize reactive oxygen species present in the respiratory tract associated with COPD, asthma and other respiratory tract diseases.
Exposure to wood smoke was studied by Leonard et al. (2000) who reported that wood smoke is able to induce carbon centered as well as reactive hydroxyl (.OH) radicals and can in turn cause cellular damage. They also reported that wood smoke can cause lipid peroxidation, DNA damage, Nuclear Factor kappa-Light-Chain-Enhancer of Activated B Cells (NF-κB) activation and TNF-α induction. These authors proposed that the .OH radical plays an important role in these immune system responses and that iron present in wood smoke and H2O2 generated in the respiratory tract during phagocytosis of wood smoke particles creates .OH free radicals and other reactive oxygen species (ROS) in the lungs. These authors suggest that wood smoke is capable of causing acute lung injury and may have the potential to act as a fibrogenic agent.
Asthma
Asthma is a chronic inflammatory lung disease that results in airflow limitations, hyperreactivity and airway remodeling. There are approximately 235 million people worldwide who have asthma and globally, there were approximately 383,000 asthma-related deaths in 2015. (World Health Organization, 2018). Symptoms of asthma can be varied, with wheezing, shortness of breath, and coughing that occurs more frequently during the night and early morning. Asthma symptoms are frequently episodic and can be caused by various triggers, such as respiratory irritants; including cigarette smoke, second hand smoke, air pollution, specific allergens and exercise. Asthma often starts in early childhood and is characterized by intermittent wheezing and shortness of breath. While there are some similar clinical features of asthma and COPD, there are marked differences in the pattern of inflammation in the respiratory tract, with different inflammatory cells, mediators, consequences, and responses to therapy.
Asthma can be broadly classified as eosinophilic or non-eosinophilic on the basis of airway or peripheral blood cellular profiles, with approximately half of individuals falling into each category (Carr et al, (2018). Cytokines play a critical role in orchestrating, perpetuating and amplifying the inflammatory response in asthma. It has been reported that patients with severe asthma have airway inflammation that is similar to those with COPD (Barnes (2001, 2008). Eosinophilic asthma is thought to be a T helper cell 2 (Th2)-cell driven inflammatory disease, characterized by eosinophilic inflammation, Th2-cell associated cytokine production and airway hyper-responsiveness (Lloyd et al. (2010). In patients with eosinophilic asthma, Th2 associated cytokine secretion of IL-4, IL-5, IL-9, IL-13, IL-25, IL-33, thymic stromal lymphopoeitin (TSLP) and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) are thought to drive the disease pathology. Patients with neutrophilic (non-eosinophilic) asthma have low- or non-Th2 associated cytokine production of IL-8, IL-17, IL-22, IL-23, interferon-gamma (IFNγ), tumor necrosis factor-a (TNFα), chemokine receptor 2 (CXCR2), IL-10 and IL-6 that drive the disease pathology (Carr et al. 2018).
Heavy Metals and Smokers
According to the U.S. Department of Health and Human Services (2006), cigarette smoke inhaled by a smoker contains more than 4,000 chemicals and second hand smoke (SHS) is qualitatively similar. Heavy metals in tobacco smoke are of public health concern because of their potential toxicity and carcinogenicity. Richter et al. (2009) reporting on results of The National Health and Nutrition Examination Survey (NHANES) 1999-2004, concluded that individuals who smoked cigarettes had higher cadmium, lead, antimony, and barium levels than nonsmokers. Highest lead levels were in the youngest subjects. Lead levels among adults with high second-hand smoke exposure equaled those of smokers. Older smokers had cadmium levels signaling the potential for cadmium-related toxicity. Cadmium is a known Group 1 carcinogen. The findings of Richter et al. (2009) revealed second hand smoke-exposed children, a population particularly vulnerable to the toxic effects of lead at low levels of exposure, have higher levels of urine lead than children without SHS exposure. Urine lead levels respond rapidly to changes in body lead burdens and increased with increasing lead exposure.
Cadmium has been attributed a causative role in pulmonary emphysema among smokers. Cadmium concentration in lung tissues of smokers with Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage IV COPD (58±10.8 pack-years) was reported by Hassan, et al. (2014) to be directly proportional to the total tobacco consumption (“tobacco load”) among patients. Sunblad et al. (2016) published evidence for a link between local cadmium concentrations and alterations in innate immunity in the lungs. They reported that cadmium concentrations were markedly increased in cell-free Bronchial Lavage Fluid (BLF) of smokers compared to that of nonsmokers, irrespective of chronic obstructive pulmonary disease. In these smokers, the measured cadmium concentrations displayed positive correlations with macrophage TNF-α mRNA in BAL, neutrophil and Cytoxic T-Cell (CD8+) cell concentrations in blood, and finally with the inflammatory cytokines IL-6, IL-8, and matrix metallopeptidase 9 (MMP-9) protein in sputum. They also concluded that extracellular cadmium is enhanced in the bronchoalveolar space of long-term smokers and displays pro-inflammatory features. Local accumulation of cadmium in the lungs appears to be a critical component of predisposition to lung diseases among long-term smokers. This is particularly important considering that the biological half-life of cadmium in the human body is >25 years, a substantial period of time, suggesting the possibility of significant retention of cadmium in the lungs of long-term smokers.
In an embodiment of the invention, a pharmaceutical composition includes at least one plant extract Transient Receptor Potential Cation Channel, Subfamily A, member 1 (TRPA1) antagonist, at least one thiol amino acid containing compound, at least one vitamin, at least one chelating agent, and at least one antioxidant. The plant extract TRPA1 antagonist can be 1,8-cineole, borneol, camphor, 2-methylisoborneol, fenchyl alcohol, cardamonin, or combinations. The thiol amino acid containing compound can be a naturally-occurring compound. The thiol amino acid containing compound can be glutathione, N-acetyl cysteine, carbocysteine, taurine, methionine, or combinations. The vitamin can be a cobalamin, methylcobalamin, hydroxycobalamin, adenosylcobalamin, cyanocobalamin, cholecalciferol, thiamin, dexpanthenol, biotin, nicotinic acid, nicotinamide, nicotinamide riboside, ascorbic acid, a provitamin, or combinations. The chelating agent can be glutathione, N-acetyl cysteine, citric acid, ascorbic acid, ethylenediaminetetraacetic acid (EDTA), or combinations. 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-acetyl cysteine, a cobalamin, methylcobalamin, hydroxycobalamin, adenosylcobalamin, cyanocobalamin, β-caryophyllene, or combinations.
The pharmaceutical composition can include from about 0.05% to about 10% epigallocatechin-3-gallate and from about 0.1% to about 10% resveratrol.
The pharmaceutical composition can further include a carrier. The carrier can be a liquid carrier. The carrier can include a liquid such as water, saline, deaired water, deaired saline, water purged with a pharmaceutically inert gas, saline purged with a pharmaceutically inert gas, or combinations. The carrier can include water or saline and a polysorbate, such as polysorbate 20.
The pharmaceutical composition can include a lubricating, emulsifying, and/or viscosity-increasing compound. The lubricating, emulsifying, and/or viscosity-increasing compound can be a carbomer, a polymer, acacia, alginic acid, carboxymethyl cellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, poloxamers, polyvinyl alcohol, lecithin, sodium alginate, tragacanth, guar gum, sodium hyaluronate, hyaluronic acid, xanthan gum, glycerin, vegetable glycerin, polyethylene glycol, polyethylene glycol(400), a 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 trioctadecanoate, polyglyceryl-3 stearate, polyglyceryl-3 palmitate, polyglyceryl-2 laurate, polyglyceryl-5 laurate, polyglyceryl-5 oleate, polyglyceryl-5 dioleate, polyglyceryl-10 diisostearate, or combinations.
The pharmaceutical composition can include a pH-adjusting compound. The pH-adjusting compound can be sodium hydroxide, sodium bicarbonate, sodium carbonate, sodium citrate, benzoic acid, ascorbic acid, or combinations.
The pharmaceutical composition can include a preservative. The preservative can be ethylenediaminetetraacetic acid (EDTA), benzalkonium chloride, benzoic acid, sorbic acid, or combinations.
The carrier can include from about 0% to about 95% vegetable glycerin and from about 5% to about 98% percent water. The carrier can further include from about 0.001% to about 1.00% sodium bicarbonate. The carrier can further include from about 0.001 to about 0.06% ethylene diamine tetraacetic acid (EDTA).
The pharmaceutical composition can further include an amino acid. The amino acid can be a proteinogenic amino acid. The amino acid can be an essential amino acid. The amino acid can be alanine, leucine, isoleucine, lysine, valine, methionine, L-theanine, phenylalanine, or combinations.
The pharmaceutical composition can include from about 0.05% to about 10% dexpanthenol, from about 0.05% to about 10% L-theanine, and from about 0.05% to about 10% taurine.
The pharmaceutical composition can further include a Cannabinoid Receptor Type 2 (CB2) agonist. The CB2 agonist can be a naturally-occurring CB2 agonist. For example, the CB2 agonist can be β-caryophyllene, cannabidiol, or cannabinol. The pharmaceutical composition can include from about 0.1% to about 1% β-caryophyllene.
The pharmaceutical composition can further include a cannabinoid compound, for example, cannabidiol. The pharmaceutical composition can include from about 0.005% to about 5% of a cannabinoid compound.
The pharmaceutical composition can further include nicotine. The pharmaceutical composition can include from about 0.01% to about 2.5% nicotine.
The pH of the pharmaceutical composition can be from about 6 to about 8, for example, about 7.2.
The ionic strength of the pharmaceutical composition can be equivalent to that of normal lung epithelial lining fluid.
The pharmaceutical composition can further include a liposome. The liposome can include the plant extract TRPA1 antagonist, thiol amino acid containing compound, vitamin, and/or antioxidant. The liposome can include the plant extract TRPA1 antagonist, thiol amino acid containing compound, vitamin, antioxidant, amino acid, and/or CB2 agonist.
The pharmaceutical composition can further include a micro- or nano-emulsion. The micro- or nano-emulsion can include the plant extract TRPA1 antagonist, thiol amino acid containing compound, vitamin, and/or antioxidant. The micro- or nano-emulsion can include the plant extract TRPA1 antagonist, thiol amino acid containing compound, vitamin, antioxidant, amino acid, and/or CB2 agonist.
In an embodiment, the pharmaceutical composition includes from about 0.1% to about 10% 1,8-cineole, from about 0.1% to about 10% N-acetyl cysteine, from about 0.1% to about 20% glutathione, from about 0.01% to about 1% ascorbic acid, from about 0.001% to about 1.0% methylcobalamin, and a carrier.
In an embodiment, the pharmaceutical composition includes about 0.8% 1,8-cineole, about 0.8% β-caryophyllene, about 1.35% N-acetyl cysteine, about 1.35% glutathione, about 0.01% ascorbic acid, about 0.003% methylcobalamin, about 0.8% Polysorbate 20, and sterile saline water including 0.9% sodium chloride (NaCl), and the pH is adjusted to about 7.2 with added sodium bicarbonate. In an embodiment, the pharmaceutical composition further includes at least one of the following: about 0.05% EDTA, about 1% dexpanthenol, about 0.7% L-theanine, about 0.5% taurine, about 0.05% epigallocatechin-3-gallate, about 0.5% resveratrol, and about 3% cannabidiol.
In an embodiment, the pharmaceutical composition includes about 1.7% 1,8-cineole, about 1.7% β-caryophyllene, about 1.2% N-acetyl cysteine, about 1.5% glutathione, about 0.01% ascorbic acid, about 0.003% methylcobalamin, about 1.7% Polysorbate 20, about 91% vegetable glycerin, and sterile deionized water, and the pH is adjusted to about 7.2 with added sodium bicarbonate. In an embodiment, the pharmaceutical composition further includes at least one of the following: about 0.05% EDTA, about 1% dexpanthenol, about 0.7% L-theanine, about 0.5% taurine, about 0.05% epigallocatechin-3-gallate, about 0.5% resveratrol, and about 3% cannabidiol. In an embodiment, the pharmaceutical composition further includes about 1.8% nicotine.
In an embodiment, the pharmaceutical composition of claim 1 includes from about 10 to about 30 g/L glutathione, from about 7 to about 25 g/L N-acetyl cysteine, from about 10 to about 30 g/L 1,8-cineole, and from about 0.02 to about 0.06 g/L of a cobalamin or methylcobalamin, and the pharmaceutical composition is a liquid. In an embodiment, the pharmaceutical composition further includes from about 6 to about 20 g/L Polysorbate 20, and from about 0 to about 1150 g/L glycerine, and the balance is water or saline. In an embodiment, the pharmaceutical composition further comprises from about 6 to about 20 g/L Polysorbate 20, and from about 500 to about 1150 g/L glycerine, and the balance is water or saline.
In an embodiment, the pharmaceutical composition includes about 20 g/L glutathione, about 15 g/L N-acetyl cysteine, about 20 g/L 1,8-cineole, about 0.04 g/L of a cobalamin or methylcobalamin, and about 1100 g/L vegetable glycerine, and the pharmaceutical composition is a liquid. In an embodiment, the pharmaceutical composition further includes about 12 g/L Polysorbate 20, and the balance is deionized water.
In an embodiment, the pharmaceutical composition comprises glutathione, N-acetyl cysteine, and a cobalamin or methylcobalamin. In an embodiment, the pharmaceutical composition further includes 1,8-cineole and/or β-caryophyllene.
In an embodiment, the pharmaceutical composition includes from about 0.5 to about 2% glutathione, from about 0.5 to about 2% N-acetyl cysteine, from about 0.4 to about 1.2% 1,8-cineole, from about 0.0002 to about 0.01% of a cobalamin or methylcobalamin, and from about 0.1 to about 1.2% β-caryophyllene. In an embodiment, the pharmaceutical composition further includes from about 0.1% to about 1.5% Polysorbate 20, and from about 0 to about 90% glycerine, and the balance is water or saline.
In an embodiment, the pharmaceutical composition includes about 1.1% glutathione, about 1.1% N-acetyl cysteine, about 0.8% 1,8-cineole, about 0.003% of a cobalamin or methylcobalamin, and about 0.8% β-caryophyllene. In an embodiment, the pharmaceutical composition further includes about 0.3% Polysorbate 20, and the balance is a sterile saline solution. In an embodiment, the sterile saline solution is an about 0.9% saline solution.
In an embodiment, the pharmaceutical composition includes from about 0.3 to about 1% glutathione, from about 0.3 to about 1% N-acetyl cysteine, and from about 0.001 to about 0.01% of a cobalamin or methylcobalamin. In an embodiment, the pharmaceutical composition further includes from about 0 to about 0.5% Polysorbate 20, and from about 0 to about 90% glycerine, and the balance is water or saline.
In an embodiment, the pharmaceutical composition includes about 0.7% glutathione, about 0.7% N-acetyl cysteine, and about 0.003% of a cobalamin or methylcobalamin. In an embodiment, the balance is a sterile saline solution, such as an about 0.9% saline solution.
The pharmaceutical composition can be in an aerosolized or nebulized form.
A method for treating a respiratory disease includes administering to a patient's lungs the pharmaceutical composition of the invention in an aerosolized or nebulized form. The respiratory disease can be airway inflammation, chronic cough, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, or cystic fibrosis. The patient can be an active or former cigarette smoker; the patient can be currently or have been exposed to second-hand smoke; the patient can be currently or have been exposed to wood or forest fire smoke; and/or the patient can be currently or have been exposed to gaseous or particulate natural or man-made air pollutants. The pharmaceutical composition can be in liquid form, which can be aerosolized using a nebulizer, an ultrasonic vaporization device, a thermal vaping device, or a device that creates an aerosol or gas phase from a liquid. The pharmaceutical composition in a liquid phase and a pharmaceutically inert gas can be sealed in a gas tight container.
A cigarette smoking cessation and respiratory system treatment method according to the invention includes in a first step administering to a patient's lungs a first mixture of the pharmaceutical composition and nicotine, which is at a first concentration in the first mixture, in an aerosolized or nebulized form over a first period of time, and in a final step administering to the patient's lungs the pharmaceutical composition of the invention (without nicotine) in an aerosolized or nebulized form over a final period of time. The aerosolized or nebulized pharmaceutical composition and/or the nicotine can be administered to the patient's lungs by the patient inhaling the pharmaceutical composition and/or the nicotine in a series of puffs using a nebulizer, an ultrasonic vaporization device, a thermal vaping device, or a device that creates an aerosol, nebulized, or gas phase from the pharmaceutical composition and/or the nicotine. In the first step, the patient can inhale the first mixture in a number of puffs per day and ingest an amount of nicotine per day that approximates that in the patient's recent active cigarette smoking behavior. In the first step, the patient can inhale the first mixture in from about 50 to about 400 puffs, such as about 150 puffs, per day. In the first step, the patient can ingest from about 5 to about 40 mg, such as about 20 mg, of nicotine per day. In the first step, the patient can inhale from about 0.5 mL to about 2 mL, such as about 1 mL, of the first mixture per day. In the first step, the first concentration of nicotine can be from about 0.5% to about 4%, such as about 1.4%, of the first mixture. In the first step, the first period of time can be from about 2 weeks to about 4 months, such as from about 40 to about 60 days. In the final step, the patient can inhale from about 0.5 mL to about 2 mL, such as about 1 mL, of the pharmaceutical composition per day.
The method can further include at least one intermediate step of administering to the patient's lungs another mixture according to the invention of the pharmaceutical composition and nicotine, the nicotine being at another concentration in the other mixture that is less than the first concentration, in an aerosolized or nebulized form over another period of time. For example, the method can include a second step of administering to the patient's lungs a second mixture according to the invention of the pharmaceutical composition of the invention and nicotine, the nicotine being at a second concentration in the second mixture that is less than the first concentration, in an aerosolized or nebulized form over a second period of time. In the second step, the patient can inhale the second mixture in from about 40 to about 320 puffs, such as 125 puffs, per day. In the second step, the patient can ingest from about 4 to about 30 mg of nicotine, such as about 14 mg of nicotine, per day. In the second step, the patient can inhale from about 0.5 mL to about 2 mL, such as about 1 mL, of the second mixture per day. In the second step, the second concentration of nicotine can be from about 0.3% to about 3%, such as about 1%, of the second mixture. In the second step, the second period of time can be from about 2 weeks to about 2 months, such as from about 14 to about 30 days.
The method can further include a third step of administering to the patient's lungs a third mixture according to the invention of the pharmaceutical composition and nicotine, the nicotine being at a third concentration in the third mixture that is less than the second concentration, in an aerosolized or nebulized form over a third period of time. In the third step, the patient can inhale the third mixture in from about 25 to about 200 puffs, such as about 75 puffs, per day. In the third step, the patient can ingest from about 2 to about 15 mg of nicotine, such as about 5 mg, of nicotine per day. In the third step, the patient can inhale from about 0.5 mL to about 2 mL, such as about 1 mL, of the third mixture per day. In the third step, the third concentration of nicotine can be from about 0.1% to about 1%, such as about 0.4%, of the third mixture. In the third step, the third period of time is from about 2 weeks to about 2 months, such as from about 14 to about 30 days.
In an embodiment of the cigarette smoking cessation and respiratory system treatment method according to the invention, the pharmaceutical composition includes 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-acetyl cysteine, 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 can further include from about 0% to about 2% (e.g., about 0.7%) Polysorbate 20 and from about 0% to about 90% (e.g., about 80%) glycerine, and the balance can be water or saline.
In an embodiment of the cigarette smoking cessation and respiratory system treatment method according to the invention, the pharmaceutical composition includes about 1.4% glutathione, about 1% N-acetyl cysteine, about 0.8% 1,8-cineole, about 0.0007% methylcobalamin, and about 0.4% β-caryophyllene. The pharmaceutical composition can further include about 0.7% Polysorbate 20 and about 80% glycerine, and the balance can be water or saline.
For example, a nebulizer can creates the aerosol, nebulized, or gas phase from the pharmaceutical composition and/or the nicotine.
The foregoing summary, as well as the following detailed description of preferred embodiments of the present application, may be better understood when read in conjunction with the appended drawings. It should be understood, however, that the application is not limited to the precise embodiments shown in the drawings.
Embodiments of the invention are discussed in detail below. In describing embodiments, specific terminology is employed for the sake of clarity. However, the invention is not intended to be limited to the specific terminology so selected. A person skilled in the relevant art will recognize that other equivalent parts can be employed and other methods developed without parting from the spirit and scope of the invention. All references cited herein are hereby incorporated by reference in their entirety as if each had been individually incorporated.
This present invention relates to methods of use and compositions of liquids that are transferred to gas and aerosol phases for inhalation drug treatment of lung and respiratory tract diseases. More particularly this invention relates to methods of use and composition of liquids that orally administered to the lungs through vaporization and aerosol generating devices providing a multifunctional treatment for lung and respiratory diseases comprising plant-based TRPA1 antagonists, natural thiol amino acid containing compounds, CB2 agonists, amino acids, naturally occurring antioxidants, vitamins and bioflavonoid compounds, and heavy metal complexing compounds. This present invention also relates to multifunctional liquid compositions including cannabinoid compounds, plant-based TRPA1 antagonists, natural thiol amino acid containing compounds, CB2 agonists, amino acids, naturally occurring antioxidants, vitamins, and bioflavonoid compounds and heavy metal complexing compounds. This invention relates to compositions and methods of use of liquids to reduce lung damage in patients who are exposed to cigarette smoke from actively smoking cigarettes or second hand cigarette smoke, forest fire smoke, and other types of smoke inhalation, including those who may have been active cigarette smokers or exposed to cigarette smoke in the past.
This present invention relates to methods of use and compositions of pharmaceutical liquid compositions that are transferred to gas and aerosol phases for inhalation drug treatment of lung and respiratory tract diseases. More particularly this invention relates to methods of use and compositions of liquids that are orally administered to the lungs through vaporization and aerosol generating devices providing multifunctional treatment for lung and respiratory diseases comprising plant-based Transient Receptor Potential Cation Channel, Subfamily A, member 1 (TRPA1) antagonists, natural thiol amino acid containing compounds, one or more vitamins, naturally occurring antioxidants, heavy metal complexing compounds and carriers. This invention also includes pharmaceutical liquid compositions and methods of use including amino acids, natural Cannabinoid Receptor Type 2 (CB2) receptor agonists, cannabinoid compounds and nicotine. Even more specifically, this invention relates to methods of use and compositions of liquids to reduce lung damage in patients who are exposed to air pollution, cigarette smoke from actively smoking cigarettes, second hand cigarette smoke, and wood smoke. In addition, this invention also relates to methods of use and compositions of liquids for smoking cessation (helping smokers to quit smoking) and respiratory system treatment.
COPD includes chronic bronchitis and emphysema. Environmental exposure, primarily from cigarette smoking, causes high oxidative stress and is the main factor of chronic obstructive pulmonary disease development. Cigarette smoke also contributes to the imbalance of oxidant/antioxidant due to exogenous reactive oxygen species associated with cigarette smoke. Reactive oxygen species endogenously released during the inflammatory process and mitochondrial dysfunction 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.
Structural changes to essential components of the lung are caused by oxidative stress, contributing to irreversible damage of both parenchyma and airway walls. In addition, oxidative stress may result in alterations in the local immune response. However, cells can be protected against oxidative stress by enzymatic and non-enzymatic antioxidant systems. Attenuation of oxidative stress results in reduced pulmonary damage and a decrease in local infections, contributing to attenuation of the progression of COPD. Attenuation of oxidative stress in the lungs by inhalation of naturally occurring antioxidants is one embodiment of this present invention.
Pharmacological therapy for COPD is used to reduce symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance and health status. To date, there is no conclusive clinical trial evidence that any existing medications for COPD modify the long-term decline in lung function. Drug treatment in patients with COPD is typically focused on bronchodilation by inhaled anticholinergics and β2-agonists. Anti-inflammatory therapy is another treatment regime in COPD patients and includes inhaled corticosteroids, oral glucocorticoids, PDE4 inhibitors, antibiotics, mucoregulators and antioxidants. Bronchodilators are medications that increase FEV1 and/or change other spirometric measurements. They act by altering airway smooth muscle tone and improvement in expiratory flow and reflect widening of the airways rather than changes in lung elastic recoil. It is not uncommon for COPD patient treatments to include combination treatments, such as inhaled corticosteroids with long acting bronchodilator therapy. To improve lung function, patient reported outcomes and to prevent exacerbations, triple inhaled therapy has also been developed using long-acting antimuscarinic antagonists (LAMAs), long acting β2-agonists (LABAs) and inhaled corticosteroids in a single inhaler. The use of anticholinergics, short-acting β2-agonists, inhaled corticosteroids, LAMAs, and LABAs all have significant reported side effects. Increasing FEV1 responses of patients through bronchodilation is one embodiment of this present invention.
Neither inhaled corticosteroids, nor high dosages of oral corticosteroids affect the number of inflammatory cells or concentrations of cytokines and proteases in induced sputum from COPD patients. The inhaled corticosteroid, dexamethasone does not inhibit basal or stimulated release of IL-8 by alveolar macrophages in COPD patients compared to healthy smokers. Corticosteroids inhibit apoptosis and thus stimulate survival of neutrophils. Corticosteroids are known to reduce serum IL-8 levels, which may result in a reduction in the influx of neutrophils. Treatment with inhaled corticosteroids reduces the concentration of exhaled NO and H2O2 in exhaled air.
One embodiment in this present invention is an alternative treatment of COPD patients using corticosteroids and bronchiodilators with a multifunctional inhaled aerosolized pharmaceutical liquid composition comprising natural antioxidants, natural anti-inflammatory compounds and vitamins. In another embodiment of this present invention are combinations of inhaled aerosolized pharmaceutical liquid composition comprising natural antioxidants, natural anti-inflammatory compounds, and vitamins with existing prescription corticosteroids and bronchodilators.
Similar to COPD, there is strong evidence that both endogenous and exogenous reactive oxygen species and reactive nitrogen species play a major role in the airway inflammation and affect asthma severity. Cigarette smoke, inhalation of airborne pollutants (ozone, nitrogen dioxide, sulfur dioxide) and particulate matter in the air can trigger symptoms of asthma. A clear relationship between traffic density and asthma exacerbations has been also been demonstrated. Cigarette smoke is related to asthma exacerbations, especially in young children, and there is a dose-dependent relationship between exposure to cigarette smoke and rates of asthma.
The goals of asthma treatment are to reduce symptoms and limit exacerbations. Currently, it is recommended that all patients with asthma have short-acting beta-2 agonists (SABA) inhalers (such as albuterol, levalbuterol, terbutaline, metaproterenol and pirbuterol) for rescue therapy. For patients with moderate-to-severe persistent asthma, long-acting beta-2 agonists (LABA) for example, salmeterol and formoterol or leukotriene inhibitors are often added to inhaled corticosteroid treatments. Commonly used corticosteroids include; beclomethasone, triamcinolone, flunisolide, ciclesonide, budesonide, fluticasone and mometasone. Antimuscarinic drugs are also used for alleviating bronchoconstriction and dyspnea in asthma patients. There are both short- and long-acting anti-muscarinic drugs available. Select use of biologic agents can be considered for those patients with more severe, difficult-to-control forms of asthma. Omalizumab was the first approved biologic for eosinophilic asthma and works by binding to immunoglobulin E (IgE) and downregulating activation of airway inflammation. Omalizumab is FDA approved for treatment of moderate to severe allergic asthma, in patients older than 6 years and improves asthma symptoms, reduces exacerbations and eosinophil counts. Newer biologic agents targeting IL-5 pathways are also available, including; mepolizumab, reslizumab and benralizumab. IL-5 is a major cytokine responsible for the growth, differentiation, and survival of eosinophils, which play a significant role in airway inflammation in asthma patients. It is evident that a major strategy in the control of eosinophilic asthma is to antagonize production of interleukin cytokines, particularly IL-5. Unfortunately, existing synthetic biologics on the market come with very severe side effects and at very high costs, frequently in the tens of thousands of dollars per year for treatment.
One embodiment in this present invention is an alternative treatment of individuals with asthma currently using corticosteroids, short- and long-acting beta-2 agonists and antimuscarinic drugs with a multifunctional inhaled aerosolized pharmaceutical liquid composition comprising natural antioxidants, natural anti-inflammatory compounds and vitamins.
One embodiment in this present invention is an inhaled aerosolized pharmaceutical liquid composition and method treatment to reduce the concentration of heavy metals in the lungs of current and former cigarette smokers, individuals exposed to second hand cigarette smoke and individuals exposed to air pollutants using metal chelates in the liquid compositions.
Inhalation Therapy
Inhalation refers to a process by which a gas or substance enters the lungs. Inhalation can occur through a gas or substance, e.g., a substance, such as a pharmaceutical composition according to the invention, in an aerosol form, passing through the mouth or nose (or a stoma (hole) into the trachea in the case of an individual who has had a tracheotomy), the respiratory tract, and into the lungs. Thus, unless otherwise indicated, the terms “inhalation”, “administration”, and other similar terms include administering a substance to the lungs by inhalation through the mouth (i.e., orally) and by inhalation through the nose (i.e., nasally) (as well as by inhalation through a stoma (hole) into the trachea in the case of an individual who has had a tracheotomy).
The particle size of inhaled cigarette smoke is typically between 0.1 and 1.0 microns (μm). The particle sizes of inhaled cigarette smoke varied between 186 nm and 198 nm in an experimental device developed by Sahu et al. (2013) at a puff volume of 35 mL/puff. When the puff volume was increased to 85 mL/puff the particle size increased to about 300 nm. Cigarette smokers typically retain approximately 30-66% of the particulate phase contained in cigarette smoke and the amount of particulate absorption by the smoker's respiratory tract is related to size and solubility of the substance. Sahu et al. (2013) calculated that 61.3% of inhaled cigarette smoke particles are deposited in the human respiratory tract. In contrast, E-cigarette aerosol is best described as a mist, which is an aerosol formed by condensation or atomization composed of spherical liquid droplets in the sub-micrometer to 200 m size range. Alderman et al (2014) reported particle size measurements for e-cigarettes to be in the 260-320 nm count median diameter range.
Many types of medical conditions can be treated by inhalation of various natural and synthetic liquid substances. These chemical substances can be administered to a patient using different type of inhalation drug delivery systems applicators including: nebulizers, in which a liquid medicine is turned into a mist that is subsequently inhaled to the lungs; Metered Dose Inhalers (MDIs) which comprise a pressurized inhaler that delivers medication by using a propellant spray (e.g., a mixture of drug and a propellant); Soft Mist Inhalers (SMI) which is a multi-dose, propellant-free, hand-held, aerosol generating liquid inhaler that uses a compressed spring, instead of a compressed gas, to generated an aerosol; ultrasonic vaping devices and thermal aerosolization devices, including vaping devices, that are trigged to atomize a stored liquid in a reservoir by heating with a heating element or coil to generate an aerosolized mixture (i.e., vapor) that is inhaled by users. Nebulizers are commercially available to vaporize solutions or stable suspensions of a liquid into an aerosol mist either by means of a compressed gas, through a venturi orifice or by means of ultrasonic action.
The liquid compositions presented in this application for the instant invention can be vaporized or aerosolized by any of the above, or any other orally or nasally administered liquid-based inhalation drug delivery systems. A person ordinarily skilled in the art would recognize that the liquids set forth in this present invention can be used to treat respiratory and lung diseases and can also be administered by any type of device that creates a vapor or aerosolized liquid that can be orally administered to a patient.
Particle size plays an important role in lung deposition, along with particle velocity and settling time. As particle size increases above 3 μm, aerosol deposition shifts from the periphery of the lung to the conducting airways. Oropharyngeal deposition increases as particle size increases above 6 μm. Exhaled loss is high with very small particles of 1 μm or less. Consequently, particle sizes of 1-5 μm effectively reach the lung periphery, whereas 5-10 μm particles deposit mostly in the conducting airways, and 10-100 μm particles deposit mostly in the nose and mouth (America Association for Respiratory Care, 2017). The preferred particle size of the aerosolized liquids in this present invention is about 1 μm to about 5 μm.
In an embodiment of this present invention, liquid compositions and methods of use of the aerosolizable liquid compositions include a nicotine salt as part of a nicotine replacement therapy cigarette smoking cessation system, while providing simultaneous treatment of the lung and respiratory tract diseases and impact from a person's history of cigarette smoking. In one embodiment of this present invention, an aerosolizable liquid composition comprises a nicotine salt, a plant-based TRPA1 antagonists, natural thiol amino acid containing compounds, CB2 agonists, amino acids, naturally occurring antioxidants, vitamins, and flavonoid compounds and heavy metal complexing compounds.
In another embodiment of this present invention a liquid composition and methods of use wherein the liquid is either vaporized, aerosolized, or both, and breathed in by a patient to reduce inflammation in the individual's respiratory tract associated with COPD, asthma, cystic fibrosis and other respiratory diseases associated with diminished lung capacity. In yet another embodiment of this present invention is a multifunctional composition that reduces the concentration and effects of reactive oxygen species in the lungs resulting from one or more diseases, including exposure to cigarette smoke, other types of smoke, and air pollutants.
Yet another embodiment of this present invention are aerosolizable liquid compositions and methods of use to reduce reactive oxygen species in the lungs, including lung epithelial lining fluid, epithelial cells, neutrophils, eosinophils, macrophages, lymphocytes, monocytes and tissues in the lungs of patients with diseases that result in an imbalance of oxidant/antioxidant concentrations from endogenous causation of reactive oxygen species. Yet another embodiment of this present invention are aerosolizable liquid compositions and methods of use to reduce inflammatory cytokines in the lungs, including lung epithelial lining fluid, epithelial cells, neutrophils, eosinophils, macrophages, lymphocytes, monocytes and tissues in the lungs of patients the result of cigarette smoking, asthma, COPD and other respiratory diseases present in the epithelial lining fluid that covers the mucosa of the alveoli, the small airways, and the large airways. In an embodiment of this present invention, 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 this present invention are liquid compositions that activate anti-inflammatory cytokines including, IL-1 receptor antagonist (IL-1r), IL-4, IL-10, IL-11, and IL-13).
A pharmaceutical composition according to the invention can be administered together with an additional therapeutic agent. The additional therapeutic agent may be a prescription drug or a non-prescription (i.e., over-the-counter) drug. For example, the additional therapeutic agent also may be used in the treatment of a lung or respiratory tract disorder, such as asthma, COPD, emphysema, and chronic bronchitis. For example, the additional therapeutic agent can include a short acting beta2-adrenoceptor agonist (SABA) (e.g., salbutamol, albuterol, terbutaline, metaproterenol, pirbuterol), an anticholinergic (e.g., ipratropium, tiotropium, aclidinium, umeclidinium bromide), an adrenergic agonist (e.g., epinephrine), a corticosteroid (e.g., beclomethasone, triamcinolone, flunisolide, ciclesonide, budesonide, fluticasone propionate, mometasone), a long acting beta2-adrenoceptor agonist (LABA) (e.g., salmeterol, formoterol, indacaterol), a leukotriene receptor antagonist (e.g., montelukast, zafirlukast), a 5-LOX inhibitor (e.g., zileuton), an antimuscarinic, a bronchodialator, and/or combinations of two or more of these.
This disclosure also relates to the use of one or more water soluble natural thiol amino acid containing compounds including; glutathione, N-acetyl cysteine and carbocysteine in a liquid that is aerosolized, 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 can otherwise cause damage to the upper and/or lower respiratory tracts of a person. This disclosure further relates to the use the of the water soluble natural sulfonic amino acid, taurine that can react with endogenously produced hypochlorous acid in the lungs to form a much less toxic taurine chloramine (Tau-Cl). Taurine acts in our compositions to neutralize reactive oxidant species and to neutralize inflammatory cytokines by the formation of Tau-Cl. Optional additives to the liquid compositions in this present invention include preservatives if the composition is not prepared sterile, additional antioxidants, flavoring agents, volatile oils, buffering agents and surfactants.
In the present invention, an “inflammatory disease” or “inflammation” is a broad indication that refers to any disease that designates inflammation of the respiratory tract as a main cause or inflammation caused by disease. Specifically, an inflammatory disease includes may include general or localized inflammatory diseases (for example: allergies; immune-complex disease; hay fever; and respiratory diseases (for example, asthma; epiglottitis; bronchitis; emphysema; rhinitis; cystic fibrosis; interstitial pneumonitis; chronic obstructive pulmonary disease, acute respiratory distress syndrome; coniosis; alveolitis; bronchiolitis; pharyngitis; pleurisy; or sinusitis); but not limited to those. In this present invention inflammatory respiratory diseases may also be caused by exogenous environmental and occupational exposures to particulate and non-particulate air pollutants, that are collectively either indoor or outdoor air pollutants, including in an enclosed or semi-enclosed space, such as an automobile, bus, train, boat or any other transportation or space-related related vehicle.
In this present invention a “vapor” is defined as diffused matter (such as smoke or fog) suspended floating in the air and impairing its transparency and also a substance in the gaseous state as distinguished from the liquid or solid state. A vapor therefore can be a compound in a gas phase, for example, the volatilization of a volatile liquid being transferred from a liquid phase to a gaseous phase, as well as being suspended liquid particles. In this present invention an “aerosol” is defined as is a suspension of fine solid particles or liquid droplets, in air or another gas.
One embodiment of this present disclosure are compositions and methods of use to antagonize, inactivate or block TRPA1 activation in the lungs from exogenous chemicals that would otherwise cause TRPA1 activation, for example, from cigarette smoke, by inhalation of aerosolized natural plant compound TRPA1 antagonists that are inhaled using electronic vaping devices, ultrasonic vaporization devices or other thermal aerosolization or vaporization devices, nebulizers or other types of devices that are used to transfer a liquid to aerosol and/or gas phases then inhaled by an person. Another embodiment of this disclosure is to limit damage of lung tissues from reactive oxygen species, for example, from cigarette and other exogenous sources of smoke and exogenous air pollutants by natural thiol amino acid containing compounds, CB2 agonists, amino acids, naturally occurring antioxidants, phytochemicals and flavonoid compounds, vitamins and heavy metal complexing compounds that are inhaled using electronic vaping devices, ultrasonic vaporization devices or other thermal aerosolization or vaporization devices, nebulizers or other types of devices that are used to transfer a liquid to aerosol and/or gas phases then inhaled by an person. Yet another complementary feature of this present invention comprises plant-based TRPA1 antagonists, natural thiol amino acid containing compounds, CB2 agonists, amino acids, naturally occurring antioxidants, vitamins and bioflavonoid compounds and heavy metal complexing compounds to a liquid that is inhaled using electronic vaping devices, ultrasonic vaporization devices or other thermal aerosolization or vaporization devices, nebulizers or other types of devices that are used to transfer a liquid to aerosol and/or gas phases then inhaled by an person that have one or more antioxidant, anti-inflammatory, antiallergenic, antiviral, or anti-carcinogenic properties.
This disclosure relates in part to a method of reducing damage to the lungs from current and past cigarette smoking and other exogenous or endogenous chemicals or particulate matter.
Yet another feature of this disclosure is a method to inhibit or neutralize the release of calcitonin gene related peptide (CGRP) in lung tissues through inactivation of TRPA1. CGRP is a member of the calcitonin family of peptides, existing in two forms: α-CGRP and β-CGRP. CGRP is released when TRPA1 is activated in the lungs through the activation of TRPA1 by cigarette smoke. Cigarette smoke initially causes an increase in the extracellular level of reactive oxygen species, which in turn activates lung epithelial TRPA1. Activation of TRPA1 then transduces this stimulation induced by cigarette smoke into the transcriptional regulation of lung inflammation via an influx of Ca2+. In another embodiment of this present invention is a liquid composition, when vaporized, aerosolized or both, and breathed into the respiratory tract results in an increase in concentrations of compounds in the lungs that are natural TRPA1 antagonists, natural TRPM8 agonists, natural thiol amino acid containing compounds, CB2 agonists, amino acids, antioxidants, bioflavinoid compounds, vitamins, and metal chelates. In yet another embodiment of this present invention is a liquid composition containing mostly naturally occurring compounds, when vaporized aerosolized or both, and breathed into the respiratory tract results in an increase in concentrations of compounds in the lungs that are TRPA1 antagonists, TRPM8 agonists, natural thiol amino acid containing compounds, CB2 agonists, amino acids, antioxidants, bioflavinoid compounds, vitamins, and natural metal chelates. The effects of breathing in vaporized, aerosolized or both, naturally occurring chemicals comprised in the liquids set forth in this present invention is to decrease one or more but not limited to tissue damage, inflammation, excess mucous accumulation, cough and cancer caused by reactive oxygen species the result of an imbalance in oxidant/antioxidant chemistry in the lungs. A reduction of inflammation in the lungs by breathing in gaseous and aerosolized phases of liquids set forth in this present invention include modulation of the immune system response, an increase bacteriostatic and fungistatic conditions in the lungs, and inhibition of 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).
This disclosure yet further relates in part to cannabinoid compounds (both phytocannabinoid and synthetic cannabinoids), including but not limited to: 9-Tetrahydrocannabinol (delta-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) that are combined with TRPA1 antagonists, TRPM8 agonists, natural thiol amino acid containing compounds, CB2 agonists, amino acids, antioxidants, vitamins, bioflavinoid compounds and natural metal chelates. Because of its lack of psychoactive properties, cannabidiol is a preferred phytocannabinoid in this disclosure.
Surprisingly, it has been found in this present invention that natural compounds can be combined to control gating to inhibit TRPA1 activation and therefore, can reduce inflammation and the effects of inflammation in the lungs the result of TRPA1 activation caused by exogenous and endogenous chemicals, including cigarette smoke. Yet in further compositions of this present disclosure 1,8-cineole and/or borneol are TRPA1 antagonists. Yet further compositions of this present disclosure include 1,8-cineole and/or borneol with natural thiol amino acid containing compounds. Yet further compositions of this present invention include CB2 agonists. The preferred CB2 agonists in this present invention is β-caryophyllene. Preferred compositions in this present invention include; 1,8-cineole as a TRPA1 antagonist and TRPM8 agonist; n-acetyl cysteine and glutathione that are naturally occurring thiol amino acid containing compounds that are also antioxidants; and an emulsifying compound and water. In yet another preferred composition, vitamin C (ascorbic acid) and vitamin B12 (methylcobalamin) are added to 1,8-cineole, N-acetyl cysteine and glutathione to increase the multifunctional properties of the aerosolized or vaporized liquids set forth in this present invention. Yet further compositions of this present disclosure include 1,8-cineole and/or borneol with water soluble antioxidants, bioflavinoid compounds, heavy metal chelators, emulsifying compounds and water.
This disclosure relates to the use of the bioflavinoid compound thymoquinone in a liquid that is used to become vaporized for inhalation to impart antioxidant, anti-inflammatory, antiallergenic, antiviral and anti-carcinogenic properties to the lungs of individuals exposed to cigarette smoke. Additionally, this disclosure relates to the use of the bioflavinoid compound thymoquinone in a liquid that is used to become aerosolized or vaporized for inhalation to decrease inflammation mediators, including IL-8, neutrophil elastase, TNF-α and malondialdehyde in the upper and lower respiratory tracts.
This disclosure relates to the use of the bioflavinoid compound berberine in a liquid that is used to become aerosolized or vaporized for inhalation to impart antioxidant, anti-inflammatory, antiallergenic, antiviral and anti-carcinogenic properties to the lungs of individuals exposed to cigarette smoke. Additionally, this disclosure relates to the use of the bioflavinoid compound berberine in a liquid that is used to become aerosolized vaporized for inhalation to decrease inflammation mediators, including IL-8, neutrophil elastase, TNF-α and malondialdehyde in the upper and lower respiratory tracts.
Yet another feature of this disclosure relates to the use of the bioflavinoid compound curcumin in a liquid that is used to become vaporized for inhalation to neutralize and/or inhibit the formation of reactive oxygen species and other types of free radical species that can otherwise cause damage to the upper and/or lower respiratory tract. Curcumin is known to have antioxidant and anti-inflammatory properties. The anti-inflammatory effect of curcumin is most likely mediated through its ability to inhibit cyclooxygenase-2 (COX-2), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS). Because inflammation is closely linked to tumor promotion, curcumin with its potent anti-inflammatory property will exert chemopreventive effects on carcinogenesis.
Another feature of this disclosure relates to the use of additional natural compounds that exhibit anti-inflammatory properties in respiratory therapies, including; andrographolide, astragalin, cardamonin, kaempferol, luteolin, naringin, oroxylin A, quercetin, geniposide, genistein, ellagic acid, Escin, Glycyrrhizin, Hydroxysafflor yellow A, baicalein, baicalin, cepharanthine, columbianadin, esculin, imperatorin, imperatorin, isoorientin, isovitexin, moracin M, orientin, phillyrin, platycodin D, resveratrol, schisantherin A, silymarin, tectorigenin, triptolide, paeonol, zingerone, paeonol, protocatechuic acid, limonene, linalool, phillyrin, asperuloside, prime-O-glucosylcimifugin, cannabidiol, flavone, tricetin, luteolin, apigenin-7-glucoside, baicalei, baicalin, afzelin, hyperoside, quercitrin, morin, quercetin, fisetin, tectorigenin, eriodictyol, naringin, hesperidin, sakuranetin, taraxastero, vitexin, mogroside V, triptolide, minnelide, esculentoside, columbianadin, esculin, and imperatorin. Further, this disclosure relates to compositions and methods to reduction inflammation of the respiratory tract 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 Schultz, 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.
Aerosolizable pharmaceutical liquid compositions of this present invention can also be comprised of carriers that enable the liquids and resulting aerosolized compounds to be most effectively delivered into the lungs, generally but not limited to nebulizers, ultrasonic vaporization devices and thermal electronic vaporization systems, such as e-cigarettes and other types of vaping devices. The carrier composition may include such compounds, but not limited to sterile water, pH buffers, acids, bases, surfactants, emulsifiers, glycols, vegetable glycerin and inorganic salts to make the composition isotonic with lung epithelial lining fluid.
Yet another feature of this invention is a lubricating viscosity modifier added to the liquid that is used to become aerosolized or vaporized for inhalation. The lubricating viscosity modifier can be selected from one or more of the group including a carbomer, polymers, acacia, alginic acid, carboxymethyl cellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, poloxamers, polyvinyl alcohol, sodium alginate, tragacanth, guar gum, sodium hyaluronate, hyaluronic acid, xanthan gum, glycerin, vegetable glycerin, polyethylene glycol, and polyethylene glycol (400).
Yet another feature of this invention is a stable suspension creating ingredient that can be added to one or more of the ingredients individually or to the bulk liquid added to the liquid that is used to become aerosolized or vaporized for inhalation. The stable suspension creating ingredient can be selected from one or more of the group of an emulsifiers or liposomes. Liposomes can entrap both hydrophobic and hydrophilic compounds and can be used in this present invention to target, localize or specifically absorb or adsorb the chemicals into or onto specific tissues, fluids or cell types in the lungs. A liposome has an aqueous solution core surrounded by a hydrophobic membrane, in the form of a lipid bilayer. Solutes dissolved in the liposome core cannot readily pass through the bilayer. Hydrophobic chemicals associate with the bilayer. A liposome can be hence loaded with hydrophobic and/or hydrophilic molecules. While the majority of the compounds comprising this present invention are hydrophilic, some are more hydrophobic, such as 1,8-cineole, β-caryophyllene, resveratrol, thymoquinone, epigallocatechin gallate and other catechin compounds, curcumin and borneol. Compositions including any of these compounds or other hydrophobic compounds at concentrations greater than their solubility in the aqueous bulk solutions may require them to be emulsified in the bulk solution in oil-in-water (O/W) micro- and nano-emulsions or to have individual hydrophobic compounds incorporated in liposome structures. A person ordinarily skilled in the art would readily understand that a variety of methods could be used to create stable homogeneous suspensions with the mixtures of hydrophilic and hydrophobic compounds set forth in this present invention.
Yet another feature of this disclosure is the use of a pH buffer to adjust the pH of the liquid to that of healthy epithelial lung fluid of approximately 7.2. Another feature of this present invention is the addition of salts to result in liquid compositions that are isotonic with epithelial lung fluids.
A feature of this instant invention presents liquid formulations and methods of use to treat various respiratory diseases associated with exposure to cigarette smoke and other types of smoke and excessive imbalances of oxidants and antioxidants in the lungs, creating reactive oxygen species that subsequently result in inflammation, DNA damage and a cascade of cytokine, neuropeptide and nociceptor activation. Cigarette smoke can generate 1015 reactive oxygen species radicals per puff and the compositions and methods of use of the presented liquids that are aerosolized in this present invention are intended to decrease damage in the respiratory system of active cigarette smokers, former cigarette smokers and those exposed to second hand smoke. It is understood by individuals ordinarily skilled in the art that both the short- and long-term health of individuals who are active cigarette smokers have the greatest potential to improve by the cessation of smoking. However, the addictive nature of nicotine, in part, makes it difficult for active cigarette smokers to stop smoking. This invention discloses compositions and methods of use of nicotine-containing liquids that can be aerosolized in a ultrasonic vaporization device, a thermal vaporization system, such as vaping devices and e-cigarettes, that also provides a multifunctional treatment for lung and respiratory diseases comprising plant-based TRPA1 antagonists, CB2 agonists, natural thiol amino acid containing compounds, naturally occurring antioxidants, amino acids and flavonoid compounds and heavy metal complexing compounds. Methods of use of this coupled nicotine-respiratory system drug treatment include both the complete cessation of cigarette smoking or substitution with the nicotine-containing respiratory system drug treatment compositions disclosed in this present invention. If a cigarette smoker is not able to complete quit smoking cigarettes, a portion of their daily nicotine consumption can be substitute by using the nicotine-containing compositions disclosed in this patent. Both complete cessation of cigarette smoking, as well substituting a portion of an individual's daily nicotine consumption from cigarettes by inhalation of the nicotine-containing aerosolizable pharmaceutical liquid compositions disclosed in this present invention will reduce respiratory system damage, and other health impacts from active cigarette smoking.
Transient Receptor Potential (TRP) Ion Channels and Smoking
Transient Receptor Potential (TRP) ion channels represent a heterogeneous system oriented towards environment perception and participate in sensing visual, gustatory, olfactive, auditive, mechanical, thermal, osmotic, chemical and pruritogenic stimuli. The Transient Receptor Potential family of channels, currently contains more than 50 different channels and 27 of these are found in humans. Transient Receptor Potential channel gating is operated by both the direct action on the channel by a plethora of exogenous and endogenous physicochemical stimuli. A large and significant amount of evidence indicates that the TRPA1 ion channel plays a key role in the detection of pungent or irritant compounds; including compounds contained in different spicy foods, such as allyl isothiocyanate (in mustard oil), horseradish, allicin and diallyl disulfide in garlic, cinnamaldehyde in cinnamon, gingerol (in ginger), eugenol (in cloves), methyl salicylate (in wintergreen), menthol (in peppermint), carvacrol (in oregano), thymol (in thyme and oregano), and the cannabinoid compounds cannabidiol (CBD), cannabichromene (CBC) and cannabinol (CBN) (in marijuana and industrial hemp). In addition, environmental irritants and industry 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 liquids and vehicle exhaust), have been recognized as TRPA1 activators. A number of TRP channels (TRPA1, TRPV1 and TRPV4) have been linked to sensory perception relevant to a cough response.
Bessac et al. (2008) reported both hypochlorite, the oxidizing mediator of chlorine, and hydrogen peroxide, a reactive oxygen species, activated Ca2+ influx and TRPA1 activation in mice cells and that mice cells genetically lacking TRPA1 had no such response. In respiratory tests with TRPA1-deficient mice, they displayed profound deficiencies in hypochlorite- and hydrogen peroxide-induced respiratory depression as well as decreased oxidant-induced pain behavior. 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 may also contribute to the effects of chlorine and other TRPA1 agonists on chemosensory nerve endings in the lower airways. Because reactive irritants are efficiently cleared in the upper airways, sensory activation in the lower airways requires higher exposure levels. Extended or high-level exposure to oxidants, such as those experienced in victims of chlorine gas exposures, induce severe pain, cough, mucus secretion, and bronchospasm. These authors also concluded that TRPA1 antagonists or blockers, may be used to suppress sensory neuronal hyper-excitability in airway disease and TRPA1 represents a promising new target for the development of drug candidates with potential antitussive, analgesic, and anti-inflammatory properties. In one embodiment of the present invention are inhaled aerosolized pharmaceutical liquid composition and methods for the treatment for individuals or soldiers exposed to chemical warfare agents that are respiratory irritants, coughing agents, and/or choking agents. Such chemical warfare agents can include tear (lachrymator) agents, vomiting agents, blistering agents (such as nitrogen and sulfur mustard agents and arsenicals (e.g., lewisite)), and choking agents (such as chlorine gas, chloropicrin, diphosgene, phosgene, disulfur decafluoride, perfluoroisobutene, acrolein, and diphenylcyanoarsine).
Kichko et al. (2015) reported that cigarette smoke contains volatile reactive carbonyls such as formaldehyde and acrolein that both activate TRPA1 in vitro and ex vivo in mouse trachea and larynx, as measured by means of calcitonin gene related peptide (CGRP) production, which modulates the production of proinflammatory cytokines. In the trachea, the gas phase of cigarette smoke (gas phase only) and whole cigarette smoke were equally effective in releasing calcitonin gene related peptide, whereas the larynx showed much larger whole cigarette smoke than gas phase responses. They concluded that nicotinic receptors contribute to the sensory effects of cigarette smoke on the trachea, which are dominated by TRPA1, but not TRPV1.
Mukhopadhyay et al. (2016) reported that the TRPA1 ion channel is expressed abundantly on the C fibers that innervate almost entire respiratory tract starting from oral cavity and oropharynx, conducting airways in the trachea, bronchi, terminal bronchioles, respiratory bronchioles and up to alveolar ducts and alveoli, They reported that TRPA1 plays the role of a “chemosensor”; detecting presence of exogenous irritants and endogenous pro-inflammatory mediators that are implicated in airway inflammation and sensory symptoms like chronic cough, asthma, COPD, allergic rhinitis and cystic fibrosis. TRPA1 can remain activated chronically due to elevated levels and continued presence of such endogenous ligands and pro-inflammatory mediators. They also reported that various noxious chemicals and environmental/industrial irritants that activate TRPA1 also are triggers for asthma or reactive airways dysfunction syndrome (RADS) and are known to worsen asthma attacks. They conclude that there is promising evidence to indicate targeting TRPA1 may present a new therapy in treatment of respiratory diseases in near future.
Li et al. (2015) confirmed the important role of lung epithelial TRPA1 in the induction of IL-8 by cigarette smoke extract in primary human bronchial epithelial cells. These in vitro findings, using primary human bronchial epithelial cells, suggest that exposure to cigarette smoke extract initially causes an increase in the extracellular level of reactive oxygen species, which in turn activates lung epithelial TRPA1. TRPA1 activation then transduces this stimulation induced by cigarette smoke into the transcriptional regulation of lung inflammation via an influx of Ca2+. They reported that Ca2+ influx was prevented by decreasing extracellular reactive oxygen species with the antioxidant radical scavenger, N-acetyl-cysteine. The decrease in Ca2+ influx was similar using pretreatment of N-acetyl-cysteine and the experimental synthetic TRPA1 antagonist HC030031.
Yang et al. (2006) demonstrated that exposure of human MonoMac6 cells to cigarette smoke extract at 1% and 2.5%, increased IL-8 and TNF-α production, with significant depletion of glutathione levels associated with increased reactive oxygen species release, in addition to activation of NF-κB. They reported that the inhibition of inhibitor of kappa B (IκB) kinase ablated the cigarette smoke extract-mediated IL-8 release, enabling the authors to propose that this inflammatory process was dependent on the NF-κB pathway. These authors also observed that cigarette smoke extract reduced histone deacetylase (HDAC) activity and HDAC1, HDAC2, and HDAC3 protein levels. When these researchers pretreated cells with glutathione, they reversed cigarette smoke-induced reduction in HDAC levels and significantly inhibited IL-8 release.
Facchinetti et al. (2007) reported that many substances contained in cigarette smoke, including reactive oxygen species, have been proposed to be responsible for the inflammatory process of COPD. These authors reported that acrolein and crotonaldehyde at micromolar concentrations, both α,β-unsaturated aldehydes, contained in aqueous cigarette smoke extract (CSE), evoke the release of the neutrophil chemoattractant IL-8 and of the pleiotropic inflammatory cytokine TNF-α from the human macrophagic cell line U937. They concluded that that α,β-unsaturated aldehydes were major mediators of cigarette smoke-induced macrophage activation, suggesting they contribute to pulmonary inflammation associated with cigarette smoke.
Blocking TRPA1 is emerging as a strategic treatment for a number of respiratory diseases and the role of TRPA1 in airway pathologies has been corroborated by studies using the TRPA1 knock-out (KO) mice and TRPA1 antagonists. In wild-type mice, airway exposure to hypochlorite or hydrogen peroxide evoke respiratory depression as manifested by a reduction in breathing frequency and increase in end expiratory pause, both of which were attenuated in TRPA1 KO mice. Allyl isothiocyanate (AITC), acrolein, crotonaldehyde and cinnamaldehyde are potent TRPA1 agonists and have been shown to induce dose dependent and robust tussive response in guinea pigs which was attenuated by the synthetic TRPA1 antagonist from Hydra Biosciences, HC-030031. Similarly, citric acid induced tussive response in guinea pigs was inhibited by a potent and selective TRPA1 antagonist, GRC 17536. Anti-tussive effects of other TRPA1 antagonists have also been demonstrated in animal cough models.
Takaishi et al. (2012) reported that 1,8-cineole (eucalyptol) activates human TRPM8 (hTRPM8) and is a hTRPA1 antagonist. They also demonstrated that 1,8-cineole did not activate hTRPV1 or hTRPV2. 1,8-cineole is present in Eucalyptus oil from several species in highly varying concentrations (less than 5 percent to greater than 80 percent), in several Rosmarinus officinalis chemotypes (up to ˜50 percent) and in Salvia lavandulifolia (up to ˜25 percent). It has been shown that TRPM8 activation decreases inflammation and pain. While TRPM8 activation by menthol was reported by these researchers, it did not decrease human inflammatory response, because it also activated TRPA1, which causes inflammation. Further, application of octanol (a known TRPA1 agonist and skin irritant) on the neck of human subjects followed by 1,8-cineole significantly reduced the irritation of octanol through inhibition of TRPA1 by 1,8-cineole.
As a follow-up to this research, an additional study was published by the same research group (Takaishi, et al., 2014) on the role of several monoterpene analogs of camphor and their ability to inhibit hTRPA1. They reported that 1,8-cineole, camphor, borneol, 2-methylosoborneol, norcamphor and fenchyl alcohol did not activate hTRPA1 and that borneol, 2-methylisoborneol and fenchyl alcohol at 1 mM completely inhibited hTRPA1 activation by menthol and allyl isothiocyanate (AITC from mustard oil) at 1 mM and 10 uM, respectively. It was found that TRPA1 activation by 20 uM AITC was inactivated (IC-50 concentration) in order from lowest to highest concentration by 2-methylosoborneol (0.12 mM), borneol (0.20 mM), fenchyl alcohol 0.32 mM, camphor (1.26 mM) and 1,8-cineole (3.43 mM).
Wang, et al. (2016) reported that cardamonin is a TRAPA1 antagonist (IC50=454 nM), while not affecting TRPV1 and TRPV4. They also reported that cardamonin did not significantly reduce HEK293 cell viability, nor did it impair cardiomyocyte constriction.
In cellular studies, Juergens, et al. (1998) reported that 1,8-cineole, which has been traditionally used to treat symptoms of airway diseases exacerbated by infection, exhibited a 1,8-cineole dose-dependent and highly significant inhibition of production of TNF-α, interleukin-1β (IL-1β), leukotriene B4 (LTB4) and thromboxane B2 (TXB2). In a follow-up clinical study, Juergens et al. (2003) evaluated the anti-inflammatory efficacy of 1,8-cineole by determining its prednisolone equivalent potency in patients with severe asthma. Thirty-two patients with steroid-dependent bronchial asthma were enrolled in a double-blind, placebo-controlled trial. After determining the effective oral steroid dosage during a 2 month run-in phase, subjects were randomly allocated to orally receive either 200 mg of 1,8-cineole 3 times per day or placebo in small gut soluble capsules for 12 weeks. Oral glucocorticosteroids were reduced by 2.5 mg increments every 3 weeks. The primary end point of their investigation was to establish the oral glucocorticosteroid-sparing capacity of 1,8-cineole in patients with severe asthma. They reported reductions in daily prednisolone dosage of 36% with active treatment (range 2.5 to 10 mg, mean: 3.75 mg) were tolerated vs. a decrease of only 7% (2.5 to 5 mg, mean: 0.91 mg) in the placebo group (P=0.006). Twelve of 16 patients in the 1,8-cineole group versus four out of 16 patients in the placebo group achieved a reduction of oral steroids (P=0.012). They concluded that long-term systemic therapy with 1,8-cineole had a significant steroid-saving effect in steroid-depending asthma. They also report that their results provided evidence of the anti-inflammatory activity of 1,8-cineole in asthma and a new rational for its use as mucolytic agent in upper and lower airway diseases. Their research suggested that 1,8-cineole was a strong inhibitor of cytokines and could be a long-term treatment of airway inflammation in bronchial asthma and other steroid-sensitive disorders. The reported a new mechanism of action of 1,8-cineole, which inhibited the production of inflammation mediators in monocytes. They also concluded that their findings explain the effective bronchodilation reported using 1,8-cineole in their clinical studies. Their data revealed similar concentration response curves to a steroid-like mode of action of 1,8-cineole that may be mediated by inhibition of nuclear transcription. Their work suggests the strong anti-inflammatory activity of 1,8-cineole could be a well-tolerated treatment of airway inflammation in obstructive airway disorders, especially in mild bronchial asthma and in more severe forms of asthma, and as a supplementary therapy with the objective of being able to reduce or replace glucocorticosteroids in the long term. In one embodiment of the present invention are inhaled aerosolized pharmaceutical liquid composition and methods treatment for individuals with asthma, COPD and other respiratory diseases to either eliminate or reduce the use of oral or inhaled corticosteriod compounds used in their medical treatment.
Worth et al. (2009) conducted a randomized, placebo-controlled multi-center clinical trial with the concomitant prescription of 1,8-cineole at a dose of 200 mg—3 times per day in capsules orally, on patients with stable chronic obstructive pulmonary disease. The primary hypothesis was that 1,8-cineole would decrease the number, severity and duration of exacerbations. Secondary outcome measures were lung function, severity of dyspnea and quality of life as well as relevant adverse effects. They reported significant improvement of airway resistance after a treatment duration of one week (−23%) and eight weeks (−21%) in placebo-controlled double-blind studies in patients with reversible obstructive ventilatory disorders. They also reported statistically significant reductions the frequency, duration and severity of exacerbations during the study period. Their collective findings underline that 1,8-cineole not only reduced exacerbation rates, but also provides clinical benefits as manifested by improved airflow obstruction, reduced severity of dyspnea and improvement of health status. They also cite a significant decrease of the requirement for systemic glucocorticosteroids in long-term therapy with 1,8-cineole (3×200 mg/day) in a placebo-controlled double-blind study in asthma requiring steroid treatment. Since glucocorticosteroids do not interfere with the release of histamine from mast cells, more research will be needed to determine the effects of 1,8-cineole on histamine release.
In an ex vivo study, Juergens et al. (1998b) investigated the effect of 1,8-cineole capsules (200 mg/day—3 times/day) on arachidonic acid (AA) metabolism in blood monocytes of patients with bronchial asthma. Production of arachidonic acid metabolites, LTB4 and PGE2, from isolated monocytes stimulated with the calcium ionophore A23187 were measured ex vivo; before therapy with 1,8-cineole, after 3 days of treatment (day 4); and 4 days after discontinuation of 1,8-cineole (day 8). The production of LTB4 and PGE2 from monocytes ex vivo was significantly inhibited on day 4 in patients with bronchial asthma (−40.3%, n=10 and −31.3%, p=0.1, n=3 respectively) as well as in healthy volunteers (−57.9%, n=12 and −42.7%, n=8 respectively). These authors concluded that 1,8-cineole was shown to inhibit LTB4 and PGE2, both pathways of arachidonic acid metabolism.
In an additional in vitro study by Juergens et al. (2004) therapeutic concentrations of 1,8-cineole (1.5 μg/mL) significantly inhibited (n=13-19, p=0.0001) cytokine production in lymphocytes of TNFα, IL-1β, IL-4, and IL-5, by 92%, 84%, 70%, and 65%, respectively. Cytokine production in monocytes of TNFα, IL-1β, IL-6, IL-8 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, IL-1β by monocytes and of IL-1β, TNF-α by lymphocytes was significantly inhibited by 77%, 61% and by 36%, 16%, respectively. These results characterize 1,8-cineole as strong inhibitor of TNFα and IL-1β and suggest smaller effects on chemotactic cytokines. This is increasing evidence for the role of 1,8-cineole to control airway mucus hypersecretion by cytokine inhibition, suggesting long-term treatment to reduce exacerbations in asthma, sinusitis and COPD.
TRPA1 is activated by cigarette smoke and many other environmental pollutants and industrial chemicals. In the respiratory system, TRPA1 is at least in part activated by reactive oxygen species resulting in the production NF-κB and a cascade of neuropeptides; including CGRP and Substance P, leading to the production of proinflammatory cytokines; including, TNFα, IL-10, IL-4, and IL-5, IL-6 and IL-8. Reactive oxygen species produced in the lungs from cigarette smoke have also been shown to be reduced by the antioxidants, glutathione and N-acetyl cysteine. Further activation of TRPA1 in the respiratory system by reactive oxidant species has clearly been shown to be blocked by TRPA1 antagonists.
In one embodiment of this invention, TRPA1 antagonists are combined with antioxidants in an aerosolizable pharmaceutical liquid composition to decrease respiratory system damage from cigarette smoke, environmental and industrial air pollutants, lung-irritating and/or damaging chemical warfare agents, and respiratory system diseases in a multifunctional manner by combining natural compound antioxidants and natural compound TRPA1 antagonists.
Transient Receptor Potential Nociceptors and Cancer
Prevarskaya et al., (2007, 2011) and Wu et al., (2010) demonstrated that TRP channels are involved in the regulation of proliferation, differentiation, apoptosis, angiogenesis, migration and invasion during cancer progression, and that the expression and/or activity of these channels is altered in cancers.
Takahashi et al. (2018) reported that TRPA1 is upregulated by nuclear factor erythroid 2-related factor 2 (NRF2) and promotes oxidative-stress tolerance in cancer cells. Cancer cell survival is dependent on oxidative-stress defenses against reactive oxygen species that accumulate during tumorigenesis. Together with the known importance of NRF2 in the induction of reactive oxygen species-neutralizing gene expression, they indicated that cancer cells mobilize a set of adaptive mechanisms, involving TRPA1-mediated non-canonical oxidative-stress defense as well as canonical reactive oxygen species-neutralizing mechanisms, to survive harsh oxidative challenges. In TRPA1-enriched breast and lung cancer spheroids, TRPA1 is critical for survival of inner cells that exhibit reactive oxygen species accumulation. Moreover, TRPA1 promotes resistance to reactive oxygen species-producing chemotherapies, and TRPA1 inhibition suppresses xenograft tumor growth and enhances chemosensitivity. These findings reveal an oxidative-stress defense program involving TRPA1 that could be exploited for targeted cancer therapies.
Wu et al. (2016) reported that in human small cell lung cancer (SCLC), TRPA1 mRNA levels were markedly upregulated in tumor specimens, compared to normal lung tissues and non-small lung cancer samples. In vitro treatment with the TRPA1 agonist, allyl isothiocyanate, a volatile toxic compound, on respiratory system-derived small cell lung cancer cell lines, caused an increment of the concentration of intracellular calcium. In an analysis of expression profile and assessment of TRPA1 expression in a cohort of 124 non-small lung cancer patients, the TRPA1 protein levels could be detected by immunohistochemistry in all cases. In addition to the higher primary tumor, TRPA1 upregulation is independently and negatively predictive disease-specific, distal metastasis-free and local recurrence-free survivals. Additionally, Schaefer et al. (2013) reported that TRPA1 was expressed in a panel of human small cell lung cancer cell lines. They also reported that TRPA1 mRNA was also more highly expressed in tumor samples of small cell lung cancer cell patients as compared to non-small cell lung cancer cell tumor samples or non-malignant lung tissue. Stimulation of small cell lung cancer cells with allyl isothiocyanate resulted in an increase in intracellular calcium concentration. Additionally, these authors reported that the calcium response was inhibited by TRPA1 antagonists. TRPA1 activation in small cell lung cancer cells prevented apoptosis induced by serum starvation and thus promoted cell survival, an effect which could be blocked by inhibition of TRPA1. Conversely, down-regulation of TRPA1 severely impaired anchorage-independent growth of small cell lung cancer cells. Since TRPA1 appears to play a pivotal role for cell survival in small cell lung cancer cells these authors proposed that TRPA1 could represent a promising target for therapeutic interventions. Finally, these authors also concluded that exogenous, inhalable activators of TRPA1 could be able to exert tumor promoting effects in small cell lung cancer cells.
Cannabinoid Type 2 Receptor Signaling
The CB2 receptor is the peripheral receptor for cannabinoids. It is mainly expressed in immune tissues, revealing that the endocannabinoid system has an immunomodulatory role. In this respect, the CB2 receptor has been shown to modulate immune cell functions, both in vitro and in animal models of inflammatory diseases. Numerous studies have reported that mice lacking the CB2 receptor have an exacerbated inflammatory phenotype. This suggests therapeutic strategies aimed at modulating CB2 signaling could be promising for the treatment of various inflammatory conditions. CB2 is mainly expressed in immune cells including neutrophils, eosinophils, monocytes, and natural killer cells Activation of the CB2 receptors by endocannabinoids or selective synthetic agonists has been shown to protect against tissue damage in various experimental models of ischemic-reperfusion injury, atherosclerosis/cardiovascular inflammation and other disorders by limiting inflammatory cell chemotaxis/infiltration, activation, and related oxidative/nitrosative stress.
It has also been shown that CB2 was up-regulated in non-small-cell lung cancer tissues and the up-regulation was correlated with tumor size and advanced non-small-cell lung cancer pathological grading (Xu, et al. 2019).
In addition to the CB2 receptor binding to various phytocannabinoids, including CBD (Ki=2.680 μM), delta-9-THC (Ki=0.035 μM), CBN (Ki=0.096 μM), CB2 also binds to the endocannabinoids arachidonoyl-ethanolamide (AEA) (Ki=0.371 μM) and 2-arachidonoyl-glycerol (2-AG) (Ki=0.650 μM). Importantly, the CB2 receptor also binds to 0-caryophyllene (BCP) (Ki=0.155 μM) (Turcotte, et al. (2016), which clearly demonstrates it is more effective at lower concentrations than is CBD. β-caryophyllene is found in essential oils of cloves (Syzygium aromaticum), cinnamon (Cinnamomum spp.), black pepper (Piper nigrum L.), and rosemary (Rosmarinus officinalis L) and is available in pure form through distillation from natural sources. β-caryophyllene use in foods has been approved by the U.S. Food and Drug Administration due to its low toxicity. While β-caryophyllene is a powerful CB2 agonist it is not a cannabinoid compound and is not a CB1 receptor agonist and has no psychoactive properties. The disclosure relates to the use of the β-caryophyllene (BCP), a natural sesquiterpene compound, and its use in the aerosolizable pharmaceutical liquid formulations as a CB2 agonist.
Glutathione
Glutathione is an important water soluble antioxidant in plants, animals, fungi, and some bacteria. As such, it is capable of preventing damage to important cellular components caused by reactive oxygen species such as free radicals, peroxides, lipid peroxides, and heavy metals. In lungs, glutathione is important in modulating immune function and participates in the pulmonary epithelial host defense system (Buhl, et al. 1990). Depletion of intracellular glutathione suppresses lymphocyte activation by mitogens, and is important in lymphocyte-mediated cytotoxicity. A number of lung disorders are associated with an increased oxidant burden on the pulmonary epithelial surface and pulmonary epithelial cell damage, including idiopathic pulmonary fibrosis, asbestosis, cigarette smoking, adult respiratory distress syndrome, cystic fibrosis, and acute and chronic bronchitis. Glutathione supplementation is helpful in disorders of other organs associated with an increased oxidant burden, including enhancement of antioxidant protection in epithelial lung fluid.
The intracellular oxidation-reduction (redox) state remains homeostatic in the lungs, and is tightly regulated by intracellular antioxidant systems. Glutathione (γ-L-glutamyl-L-cysteinyl-glycine, glutathione) is the most abundant non-protein thiol amino acid and redox buffer in mammalian cells. Very importantly glutathione provides the first-line defense to reactive oxidant species. Glutathione compounds have multiple biological roles, including cell protection against oxidative stress and several toxic molecules, and are involved in the synthesis and modification of leukotrienes and prostaglandins. As an example, glutathione S-transferases protect cellular DNA against oxidative damage that can lead to an increase of DNA mutations or that induce DNA damage promoting carcinogenesis.
Glutathione S-transferases are able with react and conjugate to a wide range of hydrophobic and electrophilic molecules including many carcinogens, therapeutic drugs, and many products of oxidative metabolism, making them less toxic and predisposed to further modification for discharge 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 it can conjugate with xenobiotics such as chemotherapy agents directly. Because many anticancer chemotherapy drugs are effectively toxic xenobiotic compounds, this can result in high glutathione levels and subsequently, anticancer drug resistance. However, glutathione is also involved in cell protection from free radicals, and in many cellular functions being particularly relevant in regulating carcinogenic mechanisms, including; sensitivity against xenobiotics, ionizing radiation and some cytokines, DNA synthesis and cell proliferation.
In cellular studies, van der Toorn et al, (2007) demonstrated that the gaseous phase of cigarette smoke decreases free sulfhydryl (—SH) groups of glutathione in solution and in airway epithelial cells. They reported that glutathione was irreversibly modified by unsaturated aldehydes that are generated during the combustion of tobacco. In their in vitro experiments it was demonstrated that exposure to cigarette smoke changed almost the entire pool of glutathione to glutathione E-aldehyde components. The enzymatic redox cycle, which is normally activated after oxidative stress and the formation of glutathione disulfide, the oxidized form of glutathione, could not be activated because of the depletion of glutathione into non-reducible glutathione components, with loss of the glutathione pool. This exhaustion of the pool of reduced glutathione may induce a chronic lack of antioxidant protection. Persistent smokers inhale more reactive oxygen species than can be scavenged by residual antioxidants, resulting in increased vulnerability to oxidative stress. This makes the synthesis of glutathione essential for cellular survival and protection of the lung. The development of COPD is associated with increased oxidative stress and reduced antioxidant resources. Cigarette smoking is the most important factor for the development of COPD.
Cellular stress induced by cigarette smoking is critically dependent on the intracellular reduced glutathione concentration. The lung responds to this challenge with adaptive responses that include up regulation of glutathione antioxidant defenses. Gould et al. (2011) demonstrated that the glutathione adaptive response consists of a coordinated response between glutathione synthesis, utilization, recycling, and transport into the lung epithelial lining fluid. Elevation in lung epithelial lining fluid glutathione levels is thought to act as a defense mechanism to limit the damaging effects of chronic smoking. Gould et al. (2010) have also shown that age adversely affects the lung glutathione adaptive response to acute cigarette smoking exposure in mice and that this response leads to increases in inflammation in the airways and increased DNA oxidation in the lung. In humans, glutathione levels drop sharply in humans around the age of 45 and this shortly proceeds the age at which COPD develops in chronic smokers.
In human testing, Gould et al. (2015) suggest that steady-state epithelial lining fluid glutathione levels are diminished with age and older smokers have impaired epithelial lining fluid glutathione adaptive responses to cigarette smoking with corresponding increases in inflammation, as evidenced by elevated exhaled nitric oxide (eNO) levels. These authors concluded that it is both glutathione levels and the endogenous ability to increase glutathione levels in response to stimuli that are important factors in the protection of the lung from the damaging effects of cigarette smoking.
Rusnack et al. (2000) used human bronchial epithelial cells (HBEC) from biopsy material obtained from three group of people as follows: those who smoked cigarettes and who had normal pulmonary function, cigarette smokers with normal pulmonary function, and cigarette smokers with COPD. They exposed these HBEC cells for 20 minutes to cigarette smoke or clean air. They also measured intercellular glutathione concentrations in HBECs both before exposure and after exposure to cigarette smoke. Their results indicate when only exposed to air, primary cultures of HBEC derived from smokers with normal pulmonary function and patients with COPD contained significantly more glutathione than did cultures from healthy people who never smoked cigarettes. These results are consistent with subsequent research that indicates cigarette 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 were significantly lower when compared with those exposure only to air. However, the magnitude of glutathione concentration decrease in HBEC cells exposed to cigarette smoke (mean percent change) was different in 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 pulmonary function. The decrease of glutathione in cells from patients with COPD was significantly greater than that in cells from healthy never-smokers or smokers with normal pulmonary function. They also reported that increased levels of antioxidant capacity (i.e., higher glutathione concentrations) may protect against oxidant-mediated damage.
Rusnack et al. (2000) also reported HBEC of patients with COPD demonstrated a larger increase in cellular permeability and release of inflammatory cytokine soluble intercellular adhesion molecule-1 (sICAM-1) and IL-1β, compared with a control group of cigarette smokers without COPD. They also observed that the endogenously increased glutathione concentrations in the HBEC of smokers with normal pulmonary function was related to the decrease of epithelial cell permeability and release of inflammatory cytokine IL-1b and sICAM-1.
Buhl, et al. (1990) demonstrated that an aerosol nebulizer application of 4 mL of a 150 mg/mL glutathione solution over a 25 minute period increased glutathione epithelial lung fluid concentrations to a concentration of about 337 μM, which was a 7-fold increase over baseline concentrations (45.7 μM) prior to treatment and remained elevated for a 2-hour period. In contrast, when these authors intravenously administered a 600 mg glutathione solution, they reported no measurable glutathione concentration increases in epithelial lung fluid. Buhl et al. (1990) suggest that aerosol administration of glutathione is a practical way to significantly augment glutathione levels on the epithelial surface of the human lower respiratory tract. They also reported that the aerosol administration of glutathione not only augmented epithelial lung fluid glutathione levels but it did so with no adverse effects. Their results are consistent with Witschi, et al. (1992) who reported that oral administration of glutathione was ineffective at increasing plasma glutathione levels when given to healthy subjects and therefore, it would be doubtful that oral supplementation of glutathione would be helpful at increasing concentrations in the lungs.
Prousky (2008) conducted a literature review to examine the clinical effectiveness of inhaled glutathione as a treatment for various pulmonary diseases and respiratory-related conditions. This author concluded glutathione inhalation is an effective treatment for a variety of pulmonary diseases and respiratory-related conditions. Even very serious and difficult-to-treat diseases, including cystic fibrosis and idiopathic pulmonary fibrosis yielded benefits from inhaled glutathione treatment. This author concluded that glutathione inhalation is very safe and rarely causes major or life-threatening side effects. He stated potential applications of glutathione treatment include Farmer's lung, pre- and post-exercise, multiple chemical sensitivity disorder and cigarette smoking. Prousky (2008) also concluded that glutathione inhalation should not be used as a treatment for primary lung cancer.
Mah et al. (2012) conducted a structural analysis of lead-glutathione complexes and concluded that Pb2+ complex formation with glutathione have implications for the rational design of chelating agents for therapeutic treatment of lead poisoning. One problem associated with commonly used chelating agents, including EDTA, is that they are not selective and can also bind essential Fe2+, Ca2+ and Zn2+ metal ions resulting in related toxic effects. These authors concluded that Pb2+ prefers to bind a maximum of three glutathione ligands through the cysteine-thiolate group in aqueous solution, suggesting that a specially tailored chelating agent with three sulfur donor atoms available for binding could be very efficient in sequestering Pb2+ ions.
N-Acetyl Cysteine
A water soluble antioxidant widely available for the treatment of patients with chronic obstructive pulmonary disease is N-acetyl cysteine (NAC) and its use is reviewed by Dekhuijzen (2004). Preclinical studies and clinical trials have shown that antioxidant molecules such as small thiol molecules (N-acetyl-L-cysteine and carbocysteine), antioxidant enzymes (glutathione peroxidases), activators of Nrf2-regulted antioxidant defense system (sulforaphane) and vitamins, for example, C, E, and D, can boost the endogenous antioxidant system and reduce oxidative stress. In addition, they may slow the progression of COPD. N-acetyl cysteine exhibits direct and indirect antioxidant properties. The free thiol group in N-acetyl cysteine is capable of interacting with the electrophilic groups of reactive oxygen species. N-acetyl cysteine exerts an indirect antioxidant effect related to its role as a glutathione precursor. Glutathione serves as a central factor in protecting against internal toxic agents (such as cellular aerobic respiration and metabolism of phagocytes) and external agents (such as NO, sulfur oxide and other components of cigarette smoke, and pollution). The sulphydryl group of cysteine neutralizes these agents. Maintaining adequate intracellular levels of glutathione is essential to overcoming the harmful effects of toxic agents. Glutathione synthesis takes place mainly in the liver (which acts as a reservoir) and the lungs. In the case of the depletion of glutathione levels or its increased demand, glutathione levels may be increased by delivering additional cysteine via N-acetyl-L-cysteine. In vivo studies, however, demonstrated when N-acetyl-L-cysteine is administered orally it has very low bioavailability due to rapid metabolism to glutathione among other metabolites. Thus, even though N-acetyl-L-cysteine is very effective in protecting cells of different origins from the toxicity of reactive components in tobacco smoke and reactive oxygen species, a direct scavenging effect by N-acetyl cysteine in vivo, particularly when administered orally, is not likely. As a result, bioavailability of N-acetyl cysteine itself is very low when given through the oral route. A more relevant mechanism in vivo for any protective effect N-acetyl cysteine may exert against toxic species may be due to N-acetyl-L-cysteine acting as a precursor of glutathione and facilitating its biosynthesis. Glutathione will then serve as the protective agent and detoxify reactive species both enzymatically and non-enzymatically.
Antioxidant supplementation has been studied as a method to counter disease-associated oxidative stress. Several antioxidants have been used with varying degrees of success. However, although the 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-acetyl cysteine, which supplies the cysteine necessary for glutathione synthesis, has proven more effective in treating disease-associated oxidative stress. N-acetyl cysteine been clinically used to treat a variety of conditions including drug toxicity (acetaminophen toxicity), human immunodeficiency virus/AIDS, cystic fibrosis, COPD and diabetes.
Schmid et al. (2002) reported the treatment of chronic obstructive pulmonary disease patients with N-acetyl cysteine at a concentration of 1.2 mg/day or 1.8 mg/day for 2 months improved red blood cell shape, reduced H2O2 concentrations by 38 to 54% and increased thiol levels by 50 to 68%. Administering N-acetyl-L-cysteine orally (600 mg/day) increased lung lavage glutathione levels (Bridgeman et al. 1991), reduced superoxide production by alveolar macrophages (Linden et al. 1998) and reduced sputum eosinophil cationic protein concentrations and the adhesion of polymorphonuclear leukocytes in COPD patients (DeBacker et al. 1997).
Odewumi et al. (2016) reported that 2.5 mM of N-acetyl cysteine treatment restored the morphology and viability of CdCl2 treated human lung cells. They concluded that protection against CdCl2 toxicity was due to the immuno-modulatory effect of N-acetyl cysteine on various cytokines expression in co-treated human lung cells with 2.5 mM N-acetyl cysteine and 75 μM CdCl2. These authors concluded that N-acetyl cysteine can be used to treat CdCl2 toxicity in humans after further testing. It is known that N-acetyl cysteine is an effective metal chelator of cadmium with a measured stability constant of 10−7.83 M−1 (Romani et al., 2013). Further, Berthon (1995) report stability constants of complexes with cysteine and Pb2+ (10−12.2) and Hg2+ (10−20.5) are even greater than for Cd2+ (10−9.89). These results clearly identify the potential for N-acetyl cysteine to be an effective chelator of cadmium, mercury and lead in epithelial lung fluid and in blood.
In a study of Idiopathic Pulmonary Fibrosis and N-acetyl cysteine therapy, Hargiwara et al. (2000) demonstrated in mice that inhalation of N-acetyl cysteine inhibited lung fibrosis induced by bleomycin, a chemical that reduces molecular oxygen to superoxide and hydroxyl radicals that can then attack DNA and cause strand cleavage. In the lung, inflammation and immune processes are the major pathogenic mechanisms that injure tissue and stimulate fibrosis. These authors concluded that N-acetyl cysteine inhalation is expected to be a potential therapy for interstitial pneumonia because reactive oxygen species are involved in the development of almost all interstitial pneumonia. They also concluded that because N-acetyl cysteine inhibits NF-kB activation, N-acetyl cysteine may repress chemokine production (i.e. IL-8) and intercellular adhesion molecule-1 (ICAM-1) expression through the inactivation of NF-κB, thereby decreasing inflammatory cell accumulation into the lungs.
Rhoden et al. (2004) applied an in vivo model of inhalation exposure to “real world” particles to demonstrate the central role of reactive oxygen species in 0.1μ to 2.5μ size particles to determine particulate air pollution biological effects. These authors demonstrated that N-acetyl cysteine, at a dose sufficient to prevent an increase in reactive oxygen species and accumulation of thiobarbituric reactive substances and to partially reduce protein oxidation, effectively prevented particulate air pollution-induced inflammation. They concluded the preventive effect of N-acetyl cysteine suggests that treatment with low doses of N-acetyl cysteine could be used to ameliorate the toxic effects of particulate air pollution.
Carbocysteine
Carbocysteine, (S-carboxymethylcysteine) is a thiol containing amino acid compounds and has significant mucolytic, antioxidation and anti-inflammatory properties. Carbocysteine is also effective to preserve alpha-1-antitrypsin activity, which is inactivated by oxidative stress. The inactivation of alpha-1-antitrypsin is associated with extensive tissue damage in patients with chronic emphysema. The antioxidative and anti-inflammatory properties of carbocysteine are reported to play an important role in the long-term treatment of COPD and to reduce exacerbation rates. Carbocysteine has been reported to have efficacy in reducing exhaled interleukin-6 and interleukin-8 concentrations, which improved the ability of clinical variables to predict mortality in patients with COPD.
Lambert et al (2008) reported that in the presence of 2 mM N-acetyl cysteine, the cellular uptake of epigallocatechin-3-gallate (100 μM) increased by 2.5 times. They also reported that this increase in cytosolic levels of epigallocatechin-3-gallate appears to be due to increased stability of epigallocatechin-3-gallate in the presence of N-acetyl cysteine. They suggested that the increase in growth inhibitory activity observed using the combination of epigallocatechin-3-gallate and N-acetyl cysteine may be the result of the activity of an epigallocatechin-3-gallate-2′-N-acetyl cysteine adduct. These authors also reported that the epigallocatechin-3-gallate-2′-N-acetyl cysteine adduct is biologically active and may be more redox active than epigallocatechin-3-gallate alone.
Bucca et al. (1992) reported that chronic treatment with high doses of vitamin C may be expected to improve symptoms of airway irritability, offer protection against airway and lung damage induced by heavy air pollution in industrialized areas, and improve the prognosis of chronic obstructive lung disease.
Polyphenols and Phytochemicals
Liang et al. (2017) investigated effects of epigallocatechin-3-gallate (50 mg/kg) given orally each day in rats that were randomly divided into either a sham air (SA) or cigarette smoke exposed groups (1 hr/day for 56 days). They measured oxidative stress and inflammatory markers thought analysis of serum and/or bronchoalveolar lavage fluid. (−)-Epigallocatechin-3-gallate treatment ameliorated cigarette smoke-induced oxidative stress and neutrophilic inflammation, as well as airway mucus production and collagen deposition in rats. They concluded (−)-Epigallocatechin-3-gallate has a therapeutic effect on chronic airway inflammation and abnormal airway mucus production via inhibition of the estimated glomerular filtration rate (EGFR) signaling pathway. They also concluded that (−)-Epigallocatechin-3-gallate supplementation may be a promising therapeutic strategy to limit neutrophil recruitment and to treat mucus hypersecretion in the airways of smokers without or with COPD.
Chan et al. (2009) reported that Chinese green tea (Lung Chen) has a protective effect on cigarette smoke-induced airspace enlargement, goblet cell hyperplasia as well as a suppressive effect on systemic and local oxidative stresses in rats. Approximately 80% of the active ingredients in in this green tea was (−)-Epigallocatechin-3-gallate.
Li et al. (2007) reported that pulmonary inflammation is a characteristic of many lung diseases. Increased levels of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), have been correlated with lung inflammation. These authors demonstrated that various inflammatory agents, including lipopolysaccharide, 12-o-tetradecanoylphorbol-13-acetate, hydrogen peroxide, okadaic acid and ceramide, were able to induce IL-β and TNF-α productions in human lung epithelial cells (A-549), fibroblasts (HFL1), and lymphoma cells (U-937). They reported that berberine, a phytochemical and a protoberberine alkaloid was capable of suppressing inflammatory agents-induced cytokine production in lung cells and that inhibition of cytokine production by berberine was dose-dependent and cell type-independent. The also reported the suppression of cytokine production by berberine resulted from the inhibition of inhibitory NF-κα phosphorylation and degradation. They concluded that berberine has a potential role of in the treatment of pulmonary inflammation.
Xu et al. (2015) studied the effects of berberine, on cigarette smoke-induced airway inflammation and mucus hypersecretion in mice. Mice with exposure to cigarette smoke were intraperitonealy injected with berberine (5 and 10 mg/kg-d). Inflammatory cytokines TNF-α, IL-1β and Monocyte Chemoattractant Protein 1 (MCP-1) levels in bronchoalveolar lavage fluid were analyzed and lung tissue was 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 and inflammatory cells in bronchoalveolar lavage fluid, and it also induced goblet cell hyperplasia and the expression of mucin-5ac in the airway of mice. When the mice were pretreated with berberine, cigarette smoke-induced airway inflammation and mucus production were inhibited. Cigarette smoke exposure also increased the expression of extracellular signal-regulated kinases (ERK) and P38, while berberine intervention inhibited these changes.
Several additional polyphenolic, phytochemical and natural antioxidant compounds can be incorporated into liquids disclosed in this instant invention that are transferred to gas and aerosol phases for inhalation drug treatment of lung and respiratory tract 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, thymoquinone, β-caryophyllene and dimethyl sulfoxide.
An embodiment in this present invention is to deliver N-acetyl-L-cysteine, glutathione and plant-based TRPA1 antagonists with polyphenolic, phytochemical and water soluble antioxidants in an aerosolized form inhaled directly to the respiratory tract.
Taurine
Taurine (2-aminoethanesulfonic acid) is an amino acid compound that is widely distributed in animal tissue and accounts for up to 0.1% of total human body weight. (EFSA Response Letter, EFSA-Q-2007-113, 2009). Taurine, a sulfonic amino acid, is relatively nontoxic and a normal constituent of the human diet. Dietary sources provide most taurine either directly or by synthesis in the liver and brain from methionine or cysteine via cysteic acid or hypotaurine or by cysteamine in the heart and kidney. Taurine stabilizes membranes, modulates calcium transport, and is able to dissipate the toxic effects of hypochlorous acid (HOCl) by the formation of the relatively stable taurochloramine molecule, generated by myeloperoxidases from oxygen radicals. The ability of taurine to conjugate with xenobiotics, retinoic acid, and bile salts and its role as a major free amino acid in regulating the osmolality of cells are also examples of its protective functions. Taurine may protect membranes by detoxification of destructive compounds and/or by directly preventing alterations in membrane permeability. Protective effects of taurine have been extensively studied including its effects against arteriosclerosis, lung injury by oxidant gases, deleterious effects of various drugs such as tauromustine, an antitumor agent, and hepatotoxicity of sulfolithocholate and its promotion of the recovery of leukocytes in irradiated rats. Further, the therapeutic effects of taurine have been used clinically on Alzheimer's disease, macular degeneration, epilepsy, ischemia, obesity, diabetes, hypertension, congestive, heart failure, noxious effects of smoking, toxicity of methotrexate, cystic fibrosis, myocardial infarction, alcoholic craving, and neurodegeneration in elderly. Taurine has also been reported to protect against carbon tetrachloride-induced toxicity. Carbon tetrachloride was widely used as an industrial degreasing compound and as a dry cleaning compound (Birdsdall, 1998).
Patients with cystic fibrosis are deficient in taurine, a condition reflected by a high bile acid glycine/taurine ratio. The cause of this deficiency is thought to be the excessive loss of taurine from the digestive tract. Human neutrophils and lung epithelial cells have particularly high concentrations of taurine at 19 and 14 mM, respectively. Although the concentration of taurine in extracellular fluids is normally low, cystic fibrosis airway secretions are rich in activated neutrophils, neutrophil-derived products, and cell debris, a situation that could conceivably favor high taurine concentrations at the lung epithelial surface. Patients with cystic fibrosis also have very high myeloperoxidase concentrations in their sputum (Cantin, 1994). Multiple studies have shown that hydrogen peroxide is greatly increased in the exhaled breath condensate of COPD subjects compared to healthy controls.
It has been reported that taurine is an important regulator of oxidative stress and decreased taurine content has been shown to trigger a decline in respiratory chain complexes (Li, et al. 2017). Taurine, in conjunction with niacin, has been shown to protect against lung injury induced by various oxidants such as ozone, nitrogen dioxide, amiodarone and paraquat.
Phagocyte lysosomes contain the enzyme myeloperoxidase which catalyzes the oxidant hydrogen peroxide (H2O2) found in the lungs of COPD, asthma, cystic fibrosis and other respiratory disease patients, producing highly oxidizing hypochlorous acid (HOCl). Environmental derived reactive oxygen species are common in the lung epithelium. Reactive oxygen species are found in cigarette smoke, combustion of organic matter and air pollutant gases capable of oxidant activity such as ozone and nitrogen dioxide. These reactive oxygen species can deplete oxidant defenses and increase the oxidant burden in the lungs.
Recent evidence demonstrates that taurine chloramine (Tau-Cl) is produced from the myeloperoxidase-catalyzed reaction of taurine and endogenously produced and highly toxic hypochlorous acid. March (1995) concluded that taurine is pivotal in regulating inflammation. In leukocytes, taurine acts to trap chlorinated oxidants (HOCl). Tau-Cl has also been demonstrated to reduce lymphocyte proliferation in another study. Tau-Cl has also been demonstrated to inhibit a great number of cytokines, including; IL-1p, IL-6, IL-8, TNF-α (Marcinkiewicz et al. (2014). Several researchers have also attributed taurine's antioxidant actions to elevations in the activity of antioxidant enzymes and by reducing the amount of damaging neutrophil-generated reactive oxygen species. Taurine indirectly elevates the activity of endogenous antioxidant defenses. Second, taurine serves as an important anti-inflammatory agent through the production of taurine chloramine.
An embodiment in this present invention is to deliver N-acetyl-L-cysteine, glutathione and plant-based TRPA1 antagonists, water soluble antioxidants and taurine in an aerosolized form inhaled directly to the respiratory tract.
Thiamin (vitamin B1), is a member of the water-soluble family of vitamins and is essential for normal cellular functions. Thiamin deficiency results in oxidative stress and mitochondrial dysfunction. Thiamin also plays a key role in the reduction of cellular oxidative stress and in maintaining mitochondrial health and function. Deficiency of thiamin is detrimental for normal cell physiology and leads to impairment of oxidative energy metabolism (acute energy failure) predisposing the cells to oxidative stress. Nicotine is known to accumulate in the pancreas and has been implicated in the production of free radicals that lead to oxidative stress and consequently pancreatic injury. Thiamine deficiency (less than 75% of the Recommended Daily Allowance (RDA)) was found in over 75% of patients in a clinical study of 163 elderly COPD patient.
Dexpanthenol is an alcohol derivative of pantothenic acid, a component of the B complex vitamins and an essential component of a normally functioning epithelium. Dexpanthenol is a prodrug to Vitamin B5 and acts as a precursor of coenzyme A, necessary for acetylation reactions and is involved in the synthesis of acetylcholine. Dexpanthenol has a major role in cellular defenses and in repair systems against oxidative stress and inflammation. The use of dexpanthenol as an antioxidant strategy has been reported to be effective for the prevention and treatment of pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic progressive lung disease of unknown cause associated with inflammation, oxidative stress, and accumulation of fibroblasts/myofibroblasts, leading to abnormal deposition of extracellular collagen, particularly in the early stage of the disease (Ermis et al. 2013).
In this text, the term “vitamin” encompasses provitamins and related compounds.
L-theanine, is a water-soluble amino acid isolated from green tea (Camellia sinensis), has anti-inflammatory activity, antioxidative properties, and hepatoprotective effects. Hwang et al. (2017) reported that treatment with L-theanine dramatically attenuated inflammatory cells in bronchoalveolar lavage fluid (BALF). They also reported that histological studies revealed that L-theanine significantly inhibited mucus production and inflammatory cell infiltration in the respiratory tract and blood vessels. L-theanine administration also significantly decreased the production of IgE, monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-4, IL-5, IL-13, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (INF-γ) in BALF. L-theanine also markedly attenuated reactive oxygen species and the activation of nuclear factor kappa B (NF-κB) and matrix metalloprotease-9 in BALF. These authors suggested L-theanine alleviates airway inflammation in asthma, which likely occurs via the oxidative stress-responsive NF-κB pathway, highlighting its potential as a useful therapeutic agent for asthma management.
Several studies report that theanine suppresses the growth in hepatoma, prostate cancer, and colon cancer cells (Friedman et al. 2007). The anticancer activity of theanine has been demonstrated against growth of human lung cancer and leukemia cells as well as migration and invasion of human lung cancer cells (Liu et al. 2009). They also reported that theanine significantly suppressed the growth of human lung cancer A549 and leukemia K562 cells in vitro and ex vivo. In addition, they also demonstrated that theanine also significantly inhibited the migration and invasion of A549 cells.
Resveratrol
Resveratrol has been demonstrated to have anti-inflammatory and anti-asthmatic properties in mouse models of allergic asthma. Although resveratrol is less potent compared to glucocorticoids, it appears to be more effective in suppressing inflammatory activity. The clinical use of glucocorticoids has a high risk of side effects, and the effect of glucocorticoids is controversial, especially in noneosinophilic asthma. Resveratrol has been shown to suppress the development of noneosinophilic asthma. Resveratrol has the potential to be an alternative to corticosteroids for the treatment of non-allergic forms of asthma. Resveratrol hold a great promise as a natural agent, since it has been shown to have beneficial effects in a variety of diseases, including cancer, cardiovascular disease, neurologic disorders as well as obesity.
Anti-inflammatory and antioxidant properties of resveratrol in the lungs have been demonstrated in preclinical models. Resveratrol causes a reduction in lung tissue neutrophilia and proinflammatory cytokines (Birrell et al. 2005). In vitro treatment with resveratrol inhibited the release of inflammatory cytokines from bronchoalveolar lavage fluid macrophages and human bronchial smooth muscle cells isolated from COPD patients. These anti-inflammatory effects of resveratrol were ascribed to the inhibition of NF-kB activation. Resveratrol has also been shown to inhibit autophagy in vitro in human bronchial epithelial cells and in vivo in cigarette smoke-induced COPD mice model (Liu, et al. 2014). These researchers reported cigarette smoke exposure increased the number of pulmonary inflammatory cells, coupled with elevated production of TNF-α and IL-6 in bronchoalveolar lavage fluids. Resveratrol treatment decreased cigarette smoke-induced lung inflammation. Resveratrol restored the activities of superoxide dismutase, GSH peroxidase, and catalase in cigarette smoke-treated mice. The also demonstrated that cigarette smoke significantly enhanced production of NF-κB) and NF-κB DNA binding activity, which was impaired by resveratrol pretreatment. These authors concluded that resveratrol attenuates cigarette smoke—induced lung oxidative injury, which involves decreased NF-κB activity and the elevated Heme Oxygenase 1 (HO-1) expression and activity.
Nicotinamide Adenine Dinucleotide
Nicotinamide adenine dinucleotide (NAD+) is a central metabolic cofactor and coenzyme in eukaryotic cells that plays a key role in regulating cellular metabolism and energy homeostasis. NAD in its reduced form (i.e. NADH) serves as the primary electron donor in mitochondrial respiratory chain, which involves adenosine triphosphate production by oxidative phosphorylation. The mammalian NAD+ biosynthesis occurs via both de novo and salvage pathways, and involves four major precursors, including the essential amino acid 1-tryptophan (Trp), nicotinic acid (NA), nicotinamide (NAM), and nicotinamide riboside (NR). Nicotinamide riboside (NR) is a precursor of NAD+, which is important in regulating oxidative stress. NA, NAM and NR are each a variation of vitamin B3.
Sirtuins are a unique class of NAD+-dependent deacetylases that regulate diverse biological functions such as aging, metabolism, and stress resistance. Recently, it has been shown that sirtuins may have anti-inflammatory activities by inhibiting proinflammatory transcription factors such as NF-kB. Serotonin transporter 1 (Sert1) is one of the seven members of the sirtuin family. It has been demonstrated that Sirt1 may also limit the inflammatory process by inhibiting NF-kB and Activator Protein 1 (AP-1), two transcription factors crucially involved in the expression of proinflammatory cytokines such as TNF-α. It is known that lung cells from patients with chronic obstructive pulmonary disease (COPD) and from rats exposed to cigarette smoke displayed reduced expression of Sirt1 associated with increased NF-kB activity and matrix metalloproteinase-9 expression as compared with lung cells from healthy controls.
In one embodiment of this present invention are liquid compositions comprising one or more of NAD, NA, NAM and NR, plant-based TRPA1 antagonists, natural thiol amino acid containing compounds, CB2 agonists, amino acids, naturally occurring antioxidants, additional vitamins, and bioflavonoid compounds and heavy metal complexing compounds.
Antioxidants
Oxidants and the imbalance between the cellular redox state and pulmonary defense systems play a role both in the pathogenesis and in the progression of malignant lung diseases. Lung cancer, highly associated with cigarette smoking, is the most common malignancy worldwide, and its incidence is increasing. There is clear evidence that free radicals are linked both to carcinogenesis and tumor behavior. One major hypothesis explaining the importance of oxidants and imbalance of the cellular redox state in lung carcinogenesis is an altered pro-oxidant intracellular environment that facilitates mutations and/or inactivation of tumor suppression genes and activates oncogenes with consequent changes in cell growth, survival and apoptosis (Kinnula et al. 2004).
Wang et al. (2018) reported that concentrations of glutathione is relatively high in many cancer cells such as lung cancer, breast cancer, pancreatic cancer and leukemia. In addition, it has been demonstrated that the anti-apoptosis feature of cancer cells is related to the increase of the intracellular glutathione level. Several reports have shown that decreasing intracellular glutathione content activates various apoptosis related enzymes. Therefore, decreasing concentrations of glutathione is becoming a new strategy for anti-tumor therapy.
Glutathione biochemistry deregulation in tumors has been observed in many different murine and human cancers. In a review by Ortega et al. (2011) it is reported that glutathione has been shown to be important in the protection against tumor microenvironment-related aggression, apoptosis evasion, colonizing ability, and multidrug and radiation resistance. Increased levels of glutathione and resistance to chemotherapeutic agents have been observed (e.g., for platinum containing compounds and alkylating agents, such as cisplatin and melphalan, anthracyclines, doxorubicin, and arsenic). Zu, et al. (2017) states that the depletion of glutathione is thought to be a promising strategy of decreasing chemotherapy resistance and inducing apoptosis through both extrinsic and intrinsic apoptotic pathways.
Thymoquinone is bioflavonoid volatile oil extracted from seeds of the plant Nigella sativa with antioxidant, anti-inflammatory, neuroprotective, antiallergenic, antiviral, antidiabetic, and anti-carcinogenic properties. In addition, it has been identified to have inhibitory effects on histamine receptors. Thymoquinone has been shown to suppress the production of leukotriene B4, thromboxane B2, and inflammatory mediators via 5-lipoxygenase and cyclooxygenase pathway of arachidonic acid metabolism. Antioxidant and immunomodulatory properties of thymoquinone have also been demonstrated. Thymoquinone has been shown to effectively treat cancer, as well as allergic diseases, including allergic rhinitis, atopic eczema, and asthma. Kalemci, et al. (2013) demonstrated that thymoquinone injection caused a reduction in chronic inflammatory changes in an experimental asthma model created in mice. 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 mRNA expression levels of Th2-driven immune response cytokines and mucin, resulting in decreased production of interleukin and mucin in allergic asthma. They concluded that black seed oil has an anti-inflammatory and immunomodulatory effect during the allergic response in the lung, and can be a promising treatment for allergic asthma in humans.
El-Sakkar et al. (2007) induced significant lung inflammation in Guinea pigs as evidenced by the increased levels of IL-8, LTB4, NE, and TNF-α (in bronchoalveolar lavage fluid) and myeloperoxidase (in lung tissue homogenates). Cigarette smoke also resulted in a significant increase in lung tissue glutathione peroxidase activity. Lipid peroxidation was significantly increased in cigarette smoke exposed Guinea pigs as evidenced by an increase in lung tissue malondialdehyde. Pretreatment of cigarette smoke-exposed Guinea pigs with thymoquinone significantly decreased the bronchoalveolar lavage fluid IL-8, but did not significantly change bronchoalveolar lavage fluid Leukotriene B4 (LTB4) levels. The levels of the inflammatory mediators; neutrophil elastase, TNF-α and malondialdehyde were also significantly reduced after thymoquinone pretreatment.
El-Sakkar et al. (2007) also reported that the pretreatment of cigarette smoke-exposed Guinea pigs with epigallocatechin-3-gallate (the major polyphenol in green tea) reduced the inflammatory consequences of exposure to cigarette smoke. This was demonstrated by the significantly reduced levels of IL-8, LTB4, NE, TNF-α (in bronchoalveolar lavage fluid) and myeloperoxidase (in lung tissue homogenate). Epigallocatechin-3-gallate also attenuated cigarette smoke-induced oxidative stress as revealed by the increase of glutathione peroxidase activity, and the significant decreased level of myeloperoxidase in lung tissue homogenates, although superoxide dismutase activity was not significantly affected.
El-Sakkar et al. (2007) concluded that thymoquinone and epigallocatechin-3-gallate have protective effects against cigarette smoke-induced inflammatory and oxidative damage in the guinea pig lungs. They reported that the protective effects on the lungs were likely the result of effects on inflammatory cells, cytokine production, and oxidative stress. They also reported that their results, if extrapolated to humans, would indicate that thymoquinone and epigallocatechin-3-gallate have potential as novel therapeutic agents for chronic obstructive pulmonary disease patients and could be promising in the design and development of new treatment strategies aiming at limiting cellular inflammatory and oxidative damage.
Electronic Aerosolization Devices
Electronic-cigarettes, also known as vape pens, e-cigars, or vaping devices, are typically used as electronic nicotine delivering systems, which thermally generate an aerosolized mixture containing flavored liquids and nicotine that is inhaled by the user. Electronic thermal aerosolization devices are also used for inhalation of CBD, THC and select vitamins. The extensive diversity of e-cigarettes arises from the various nicotine concentrations present in e-liquids, miscellaneous volumes of e-liquids per product, different carrier compounds, additives, flavors, coil impedances, and battery voltages. Regardless of the exact design, each e-cigarette device has a common functioning system, which is composed of a rechargeable lithium battery, vaporization chamber, and a cartridge. The lithium ion battery is connected to the vaporization chamber that contains an atomizer. In order to deliver nicotine to the lungs, the user inhales through a mouthpiece, and the airflow triggers a sensor that then switches on the atomizer. The atomizer thermally vaporizes liquid nicotine in a small cartridge and delivers it to the lungs.
Ultrasonic vaping devices that do not heat the liquids in an electronic vaporization device as much as typical commercially available e-cigarettes or thermal aerosolization devices are available and can also be used to aerosolize liquids disclosed in this present invention.
Recently, a study was conducted on the nicotine content on 27 e-cigarette liquid formulations acquired in the U.S. It was reported that the nicotine content varied between 6 and 22 mg/L (Peace, 2016). In another study 16 e-cigarettes were selected based on their popularity in the Polish, U.K. and U.S. markets and nicotine vapor generation was evaluated in an automatic smoking machine. Testing conditions were designed to simulate puffing conditions of human electronic cigarette users. The total level of nicotine in vapor generated by 20 series of 15 puffs varied from about 0.5 mg to 15.4 mg. Most of the analyzed electronic cigarette effectively delivered nicotine during the first 150-180 puffs. On an average, 50%-60% of nicotine from a cartridge was vaporized.
The average concentration of nicotine in Juul electronic cigarettes was recently reported to be 60.9 mg/mL, 63.5 mg/mL, and 41.2 mg/mL in un-vaped, vaped, and aerosol samples, respectively. Transfer efficiently for nicotine to the aerosol was between 56%-75% (Omaiye, et al. 2019). Juul reports that each of their flavor pods contain 0.7 mL of liquid.
Because of the formation of toxic compounds inhaled from thermally generated aerosolized liquids containing nicotine, in November 2018, FDA's Center for Tobacco Products (CTP) banned all flavored nicotine e-cigarettes other than tobacco, mint, and menthol flavors. In recent studies, it has been reported that specific flavorant aldehydes compounds, including benzaldehyde, cinnamaldehyde, citral, ethylvanillin, and vanillin, react with other commonly used compounds present in liquids used in vaping, such as, propylene glycol (PG), to form toxic flavor aldehyde PG acetals at room and elevated temperatures. These flavor aldehyde PG acetals were also reported to be detected in commercial e-liquids compounds at ambient temperatures. When these flavor aldehyde PG acetals in e-liquids are subsequently thermally aerosolized and inhaled in vaping devices, they can cause serious health impacts to individuals using these products. Flavor aldehyde PG acetals have also been demonstrated to activate the TRPA1 and aldehyde-insensitive TRPV1 irritant and inflammation-related receptors (Erythropel, et al. 2018). It is clear that activating inflammatory nociceptors TRPA1 and TRPV1 by flavor aldehyde PG acetals in the lungs of individuals using vaping products is extremely unhealthful for these individuals.
In another recent study, the toxic ambient temperature reaction products vanillin PG acetal and vanillin VG acetals were detected in JUUL e-liquids and carried over to e-cigarette generated aerosols at 68.4% and 59%, respectively. Nicotine and benzoic acid were also carried over from JUUL e-liquids to e-cigarette generated aerosols at 98.6% and 82.5%, respectively (Erythropel, et al. 2019).
In one embodiment of this present invention are aerosolizable liquids that contain nicotine that do not contain aldehyde flavorants and do not form toxic flavorant acetals compounds, either at ambient or elevated temperature and are safer to use in e-cigarettes and other thermal liquid aerosolization devices than existing e-liquids available in the market to date. In yet other embodiments of this present inventions are aerosolizable liquids that contain nicotine that provide health benefits to the respiratory system of individuals that are nicotine users. In another embodiment of this present invention are methods of use liquid compositions containing nicotine and plant-based TRPA1 antagonists, natural thiol amino acid containing compounds, CB2 agonists, amino acids, naturally occurring antioxidants, additional vitamins, bioflavonoid compounds and heavy metal complexing compounds when thermally aerosolized provide a source of nicotine and respiratory health benefits from the non-nicotine components of the composition.
Recently, companies have begun to market thermal aerosolization systems in which vitamins are inhaled to supplement vitamins. Vitamin Vape, Q Sciences, Biovape, and Nutrovape Vita are a sampling of companies that manufacture and sell vaping systems to supplement vitamins. Inhalation is likely an inefficient way to ingest vitamins that may be needed systemically at higher concentrations than can be delivered by vaping. Inhalation is usually reserved as a delivery mechanism for medicines that require very small doses or target the lungs themselves.
Cigarette Smoking Cessation
The most important way to reduce on-going damage to an active cigarette smoker's general health and specifically their respiratory system is the complete cessation of smoking cigarettes and the withdrawal from exposure and addiction to nicotine. While cessation of cigarette smoking eliminates ongoing respiratory system damage from cigarette smoke, it does not reverse past respiratory system damage from past cigarette smoking, diseases already active in an individual the result of exposure to cigarette smoke and future diseases possible from past smoking activities. Historically, it is well documented that the cumulative exposure to cigarette smoking, generally expressed in pack-years (i.e., the number of packs of cigarettes smoked per day multiplied by the number of years smoked) is a primary factor in the risk of lung cancer and COPD. Recently, it has been shown that smoking duration is more strongly associated with COPD than the composite of pack-years alone (Bhatt et al. 2018). These researchers analyzed cross-sectional data from a large multicenter cohort (10,187 people) 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 was more influential than the number of pack-years an individual smoked. Similarly, there was a strong relationship between duration of cigarette smoking and decrease of FEV1 values.
Nicotine replacement therapy (NRT) is an accepted way to quit smoking cigarettes and provides an individual nicotine in the form of gum, patches, sprays, inhalers, or lozenges without the other harmful chemicals in tobacco and their by-products. NRT gums and lozenges are available without a prescription and provide between 2 mg and 4 mg per piece. NRT patches provide a passive time integrated does of nicotine on a daily basis. Nicoderm CQ is a non-prescription patch providing 21 mg per day (Step 1), 14 mg per day (Step 2) and 7 mg per day (Step 3). The Nicotrol patch provides a 3 Step system as well with 15 mg per day (Step 1), 10 mg per day (Step 2) and 5 mg per day (Step 3). NRTs help to relieve some nicotine physical withdrawal symptoms enabling a person to focus more on the psychological aspects of cigarette smoking cessation. Many studies have shown using NRT can nearly double the chances of successful cigarette smoking cessation.
In one embodiment of this present invention, aerosolizable liquid compositions and methods of use of these liquid compositions include a nicotine salt as part of a nicotine replacement therapy cigarette smoking cessation system, while providing simultaneous treatment of the lung and respiratory tract diseases and impact from a person's history of cigarette smoking. In an embodiment of this present invention, is a composition comprising a nicotine salt, a plant-based TRPA1 antagonists, natural thiol amino acid containing compounds, CB2 agonists, amino acids, naturally occurring antioxidants, vitamins, and flavonoid compounds, and heavy metal complexing compounds.
Glutathione
The use of glutathione in this present invention and the results reported in Examples 15 and 16 were unexpected as asthma is a condition where the known side effects of inhaled glutathione, including breathlessness, bronchoconstriction, and cough, led researchers and practitioners to not recommend glutathione for asthma (Prousky et al., 2008). The effectiveness of the use of glutathione in this present invention is further unexpected based on research published by Marrades et al. (1997), who reported that inhaled glutathione caused major airway narrowing (changes from baseline: FEV1 of −19% and total pulmonary resistance of +61%) and induced cough (four patients) or breathlessness (three patients). In contrast, control patients treated only with inhaled saline solution had negligible FEV1 changes of −1% and minor total pulmonary resistance change of +17%.
Inhaled glutathione is also known to reduce zinc levels in the blood. Reduced serum zinc levels will reduce immune functioning and potentially increase infection such as bronchitis or pneumonia.
A person of ordinary skill in the art would not recommend inhaled glutathione as it is contraindicated for use with asthma on several medical websites including WebMd (https://www.webmd.com/vitamins/ai/ingredientmono-717/glutathione, “Side Effects & Safety”) in which the side effects for asthma include: “Do not inhale glutathione if you have asthma. It can increase some asthma symptoms.”
A person of ordinary skill in the art would be taught away from the use of combining glutathione with other compounds in our formulations for the treatment of individuals with asthma. Surprising and unexpectedly, the studies leading to the instant invention indicated that the use of glutathione was highly effective at increasing FEV1 levels in patients with documented asthma. One of the asthma patients (Patient 104 in
N-Acetyl Cysteine
N-acetylcysteine (NAC) is used as an “antioxidant” in studies examining gene expression, signaling pathways, and outcome in acute and chronic models of lung injury. It is also known that N-acetylcysteine can also undergo auto-oxidation and also behave as an oxidant. Chan et al. (2001) demonstrated that N-acetylcysteine can become an oxidant leading to the activation of nuclear factor kappa B (NF-κB), a key proinflammatory signaling pathway.
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 inflammation in the mouth, runny nose, drowsiness, clamminess, and chest tightness. Also according to WebMd, there is concern that N-acetylcysteine might cause bronchospasm in people with asthma if inhaled. The National Institutes of Health report that N-acetylcysteine can result in respiratory inflammation, causes running nose, bronchospasm, inflammation of the mouth, and bleeding. A person ordinarily skilled in the art would be taught away for using N-acetylcysteine for the inhalation treatment of individuals with COPD, asthma and, other respiratory diseases because of N-acetylcysteine's known side effects.
It is an unexpected result that the use of N-acetylcysteine in the formulations in this present invention shown in Examples 15 and 16 led to a decrease in respiratory inflammation as evidenced by decreased FEV1 and FVC lung function parameters, given the ability of N-acetylcysteine to function as an oxidant, result in the formation of NF-κB, and cause bronchospasm in people with asthma.
According the health website Healthline (https://www.healthline.com/health/food-nutrition/vitamin-b12-side-effects), side effects of taking vitamin B12, orally or by inhalation, include increased anxiety, pulmonary edema, and congestive heart failure. It has also been reported to increase the risk for tracheal and bronchial swelling. A person ordinarily skilled in the art would be taught against using methylcobalamin (vitamin B12) in a liquid that would be used for inhalation treatment of respiratory diseases, because of methylcobalamin's known side effects. Although methylcobalamin is known to cause increased anxiety in some patients, the individuals who were evaluated in pre-clinical trials as disclosed in Examples 15 and 16 surprisingly and unexpectedly reported significantly lower anxiety levels following treatment.
Interaction of One Component with the Others
Administering the liquid formulations to patients disclosed in Examples 15, by means of thermally induced aerosolization and by means of ultrasonic membrane aerosolization in Example 16 led to surprising and unexpected results, because individual compounds in these formulations have complementary and synergistic effects. For example while the primary use 1,8-cineole in the formulations disclosed in the present invention is a TRPA1 antagonist, it also acts secondarily as a TRPM8 agonist, modulates immune functions, is an antioxidant, is bacteriostatic and fungistatic, and inhibits production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-11β), interleukin-4 (IL-4), interleukin-5 (IL-5), leukotriene B4 (LTB4), thromboxane B2 (TXB2) and prostaglandin E2 (PGE2). 1,8-cineole has also been demonstrated to reduce anxiety in a human clinical trial for pre-operative patients. Unexpectedly, this anti-anxiety property of 1,8-cineole is very helpful in patients with difficulty breathing, which causes anxiety and in severe cases, panic. Verbal qualitative reports by patients administered formulations in Examples 15 and 16 reported a sense of feeling more relaxed, significantly increased energy levels, greater endurance capabilities under normal activities, as well as under exercising conditions, lower levels of anxiety, and less anxiety compared to taking other medications for their disease treatment. Typical steroid administration by inhalation has side effects including shaking nervousness and burning sensation in the chest area. Unexpectedly, in this present invention, no patients reported any negative side effects associated with the inhalation treatments of the formulations disclosed in Examples 15 and 16.
The primary and secondary roles of 1,8-cineole unexpectedly result in synergy with β-caryophyllene which has a primary role in the formulations disclosed in this present inventions as a CB2 agonist to reduce inflammation. β-caryophyllene also has secondary roles in this present invention as an antioxidant and also acts as an analgesic, anti-inflammatory, neuroprotective, anti-depressive, anxiolytic, and antioxidant compound, in addition to inhibiting production of pro-inflammatory cytokines, such as TNF-α, IL-1β IL-6. This 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 8-cineole and β-caryophyllene unexpectedly complement one another through the synergy of both the primary and secondary properties of each compound. These anti-oxidant properties of 1,8-cineole and β-caryophyllene also unexpectedly act synergistically with glutathione and n-acetyl cysteine that act as the primary antioxidants and thiol containing amino acids in the disclosed formulations.
A person ordinarily skilled in the art would normally have been taught not to use β-caryophyllene formulations disclosed in this present invention as it has been demonstrated to be a TRPA1 agonist (activator) that causes inflammation (Moon et al. 2015). Thus, a person of ordinary skill in the art would have thought that one would not want to include β-caryophyllene in the formulation, because it would agonize the TRPA1 receptor, causing inflammation and coughing.
For compositions set forth herein, components can be, for example, in the following ranges:
1,8-cineole, borneol, camphor, 2-methylisoborneol, fenchyl alcohol, or cardamonin—from about 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3%, or 10% to about 0.03%, 0.1%, 0.3%, 1%, 3%, 10%, or 30%;
glutathione, N-acetyl cysteine, carbocysteine, taurine, or methionine—from about 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3%, or 10% to about 0.03%, 0.1%, 0.3%, 1%, 3%, 10%, 20%, 30%, or 50%;
cobalamin, methylcobalamin, hydroxycobalamin, adenosylcobalamin, cyanocobalamin, cholecalciferol, thiamin, dexpanthenol, biotin, nicotinic acid, nicotinamide, nicotinamide riboside, or ascorbic acid—from about 0.0001%, 0.0003%, 0.001%, 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1%, or 3% to about 0.0003%, 0.001%, 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3%, or 10%;
citric acid or ethylenediaminetetraacetic acid (EDTA)—from about 0.0001%, 0.0003%, 0.001%, 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1%, or 3% to about 0.0003%, 0.001%, 0.003%, 0.01%, 0.03%, 0.10%, 0.30%, 1%, 3%, or 10%;
berberine, catechin, curcumin, epicatechin, epigallocatechin, epigallocatechin-3-gallate, β-carotene, quercetin, kaempferol, luteolin, ellagic acid, resveratrol, silymarin, nicotinamide adenine dinucleotide, or thymoquinone—from about 0.001%, 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1%, or 3% to about 0.003%, 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3%, or 10%;
alanine, leucine, isoleucine, lysine, valine, methionine, L-theanine, or phenylalanine—from about 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3%, or 10% to about 0.03%, 0.1%, 0.3%, 1%, 3%, 10%, 30%, or 50%;
β-caryophyllene, a cannabinoid, cannabidiol, or cannabinol—from 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%;
nicotine—from 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%;
a lubricating, emulsifying, or viscosity-increasing compound—from about 0.01%, 0.03%, 0.1%, 0.3%, 1%, 3%, or 10% to about 0.03%, 0.1%, 0.3%, 1%, 3%, 10%, 30%; and
glycerine—from about 1%, 3%, 10%, 30%, or 50% to about 10%, 30%, 50%, 70%, 80%, 90%, 95%, or 98%.
For example, pH values can be from 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.
This invention is further described by the figures, the following examples and experiments, which are solely for the purpose of illustrating specific embodiments of this invention, and are not to be construed as limiting the scope of the invention in any way. The compositions of the present invention can comprise, consist essentially of, or consist of the essential as well as the optional ingredients and components described herein. As used herein, “consisting essentially of” means that the composition or component may include additional ingredients, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed compositions or methods. All publications cited herein are hereby incorporated by reference in their entirety.
The following examples are offered to illustrate, but not to limit the claimed invention.
A composition and a method of manufacture of a pharmaceutical liquid that is aerosolized, vaporized or both comprising 1,8-cineole, N-acetyl cysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifying agent, vegetable glycerin, water, sodium bicarbonate (as needed) and a preservative (as needed) is disclosed in Example 1. The method of manufacturing consists of mixing an amount of nitrogen purged purified sterile water or isotonic saline solution with ascorbic acid powder or crystals, sodium bicarbonate, and preservative (if needed) and dissolving, then adding amounts of N-acetyl cysteine, glutathione, and methylcobalamin, followed by adding an amount of vegetable glycerin (if needed) and mixing until the liquid composition is homogeneous. Nitrogen gas purging can be used throughout the mixing period to minimize oxygenation of the water and oxidation of the compounds in the mixture. 1,8-cineole is then separately mixed with the emulsifier, and after this mixture is homogeneous, then slowly adding to the mixture and slowly mixing until it is dissolved in the liquid, minimizing the volatilization of the 1,8-cineole. Mixing can be conducted in a zero or low headspace reactor to further minimize volatilization of 1,8-cineole and oxidation of the compounds in the mixture. If an amount of 1,8-cineole is added to the mixture at concentrations greater than the solubility of 1,8-cineole in the mixture, then the 1,8-cineole can be emulsified in the liquid composition with the addition of a suitable emulsifier, for example Tween 20, also known as Polysorbate 20 and polyoxyethylene(20)sorbitan monooleate. Mixing is limited to that required to create a stable single phase homogeneous solution or emulsion and to minimize volatilization 1,8-cineole. Methods of use of the liquid composition in Example 1 include but are not meant to be limited to placing a quantity of the composition in an e-cigarette vaporizing device, an electronic thermal vaporization device, a nebulizer, an ultrasonic nebulizer, an ultrasonic vaping device or an inhaler and inhalation of the aerosolized vapors resulting from creating an aerosolized mixture. The liquid composition that is the TRPA1 antagonist that can be aerosolized or vaporized in Example 1 can optionally be made with borneol or a mixture of 1,8-cineole and borneol in the same or different total concentration range compared to the range when using 1,8-cineole alone. This liquid composition that can be aerosolized is disclosed in Table 1 (in this text, when compositions or mixtures are discussed, the term “percent” (%) usually refers to weight percentage, unless otherwise indicated). The aerosolizable liquid composition can be transferred to containers that can be stored for one or more doses, the containers may or may not have nitrogen gas in the headspace, and the containers may or may not be refrigerated.
polybractea; Eucalyptus
globulus; Eucalyptus radiate;
Eucalyptus camaldulensis;
Eucalyptus smithii;
Eucalyptus globulus;
Rosmarinus offficinalis
A preferred composition and a method of manufacture of a pharmaceutical liquid that is aerosolized, vaporized or both, using a nebulizer comprising 1,8-cineole, N-acetyl cysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifying agent, a sterile saline solution, sodium bicarbonate (as needed) and a preservative (as needed) is disclosed n Example 2. The method of manufacturing 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-acetyl cysteine, 1.35 g of glutathione, 0.003 g of methylcobalamin, and mixing until the liquid composition is homogeneous. This is followed by adding a mixture of 0.80 g of 1,8-cineole and 0.40 g Polysorbate 20 together and slowly mixing until they are dissolved together. Once the 1,8-cineole and Polysorbate 20 are homogeneously mixed, this mixture is added to the liquid mixture and dissolved into the liquid, minimizing the volatilization of the 1,8-cineole. Mixing is limited to that required to create a stable single phase homogeneous solution and to minimize volatilization 1,8-cineole. The pH of the solution is then measured and a quantity of sodium bicarbonate is added to raise the pH to about 7.20. A quantity of a preservative can be added or alternatively the mixture can be refrigerated prior to use. Methods of use of the composition of the liquid composition in Example 2 include, but are not meant to be limited to placing the composition in a an ultrasonic, vibrating mesh or jet nebulizer and inhalation of the vapors resulting from creating an aerosolized mixture. Methods of use of the composition of the liquid in Example 2, include adding about 1 mL to about 5 ml of the mixture to a liquid nebulizer for inhalation by a patient. This liquid composition is disclosed in Table 2.
A preferred pharmaceutical composition and a method of manufacture of a pharmaceutical liquid that is aerosolized, vaporized or both, in an ultrasonic or thermal vaporization device and includes 1,8-cineole, N-acetyl cysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifying agent, vegetable glycerin, sterile deionized water, sodium bicarbonate (as needed) and a preservative (as needed) is disclosed in Example 3. The method of manufacturing 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-acetyl cysteine, 1.53 g of glutathione, 0.003 g of methylcobalamin, and then mixing until the liquid composition is homogeneous. This is followed by adding 93.55 g of vegetable glycerin and mixing. This is then followed by adding a mixture of 1.69 g of 1,8-cineole and 1.01 g of Polysorbate 20 together and slowly mixing until they are dissolved together. Once the 1,8-cineole and Polysorbate 20 are homogeneously mixed, this mixture is added to the glycerin-water based mixture and dissolved into the liquid, minimizing the volatilization of the 1,8-cineole. Mixing is limited to that required to create a stable single phase homogeneous solution and to minimize volatilization 1,8-cineole. 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 a preservative can be added or alternatively the mixture can be refrigerated prior to use. The liquid composition in Example 3 may be made with a quantity of vegetable glycerin that is less than 93.55 g and can be decreased by increasing a corresponding mass of nitrogen purged water added. Methods of use of the composition of the liquid composition in Example 3 include but are not meant to be limited to placing the composition in an e-cigarette vaporizing device, an electronic thermal vaporization device, a vaping pen, electronic thermal vaporization device, an ultrasonic vaping device, an electronic vaping mod and inhalation of the vapors resulting from creating an aerosolized mixture. A preferred vaping device is one that has temperature control and the temperature is limited to an upper limit of 200° C. The aerosolizable pharmaceutical liquid composition can be transferred to containers that can be stored for one or more doses, the containers may or may not have nitrogen gas in the headspace, and the containers may or may not be refrigerated. This liquid composition is disclosed in Table 3.
A pharmaceutical liquid composition and a method of manufacture of the liquid that is aerosolized, vaporized or both comprising 1,8-cineole, β-caryophyllene, N-acetyl cysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifying agent, vegetable glycerin (as needed), water, sodium bicarbonate (as needed) and a preservative (as needed) is disclosed in Example 4. The method of manufacturing consists of mixing an amount of nitrogen purged purified sterile water or isotonic saline solution with ascorbic acid powder or crystals, sodium bicarbonate (as needed) and preservative (as needed) and dissolving, then adding amounts of N-acetyl cysteine, glutathione, and methylcobalamin followed by adding an amount of vegetable glycerin (as needed) and mixing until the liquid composition is homogeneous. Nitrogen gas purging can be used throughout the mixing period to minimize oxygenation of the water and oxidation of the compounds in the mixture. β-caryophyllene and 1,8-cineole are then separately mixed with the emulsifier, and after this mixture is homogeneous it is slowly added to the mixture and the mixture is slowly mixed until there is dissolution in the liquid, minimizing the volatilization of the 1,8-cineole and the β-caryophyllene. Mixing can be conducted in a zero or low headspace reactor to further minimize volatilization of β-caryophyllene and 1,8-cineole and oxidation of the compounds in the mixture. If an amount of β-caryophyllene and 1,8-cineole is added to the mixture at concentrations greater than the solubility of 1,8-cineole and β-caryophyllene in the mixture, then the β-caryophyllene and 1,8-cineole can be emulsified in the liquid composition with the addition of a suitable emulsifier, for example, Tween 20, also known as Polysorbate 20 and polyoxyethylene(20)sorbitan monooleate. Mixing is limited to that required to create a stable single-phase homogeneous solution or emulsion and to minimize volatilization of β-caryophyllene and 1,8-cineole.
Methods of use of the liquid composition in Example 4 include but are not meant to be limited to placing a quantity of the composition in an e-cigarette vaporizing device, an electronic thermal vaporization device, an ultrasonic vaping device, a nebulizer or an inhaler, and inhaling the aerosolized vapors resulting from creating an aerosolized mixture. The liquid composition component that is the TRPA1 antagonist that can be aerosolized or vaporized in Example 4 can optionally be made with borneol or a mixture of 1,8-cineole and borneol in the same or different total concentration range compared to the concentration range when using 1,8-cineole alone. This liquid composition that can be aerosolized is disclosed in Table 4. The aerosolizable liquid composition can be transferred to containers that can stored for one or more doses, the containers may or may not have nitrogen gas in the headspace, and the containers may or may not be refrigerated.
polybractea; Eucalyptus
globulus; Eucalyptus
radiate; Eucalyptus
camaldulensis; Eucalyptus
smithii; Eucalyptus
globulus; Rosmarinus
officinalis
aromaticum, Carum nigrum,
Cinnamomum spp., Humulus
lupulus, Piper nigrum L.,
Cannabis sativa,
Rosmarinus offficinalis,
Ocimum spp., Origanum
vulgare
A preferred composition and a method of manufacture of a pharmaceutical liquid that is aerosolized, vaporized or both using a nebulizer comprising 1,8-cineole, β-caryophyllene, N-acetyl cysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifying agent, sterile saline solution, sodium bicarbonate (as needed) and a preservative (as needed) is disclosed in Example 5. The method of manufacturing consists of mixing 94.89 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-acetyl cysteine, 1.35 g of glutathione, 0.003 g of methylcobalamin and mixing until the liquid composition is homogeneous. This is followed by adding a mixture of 0.80 g of 1,8-cineole, 0.80 g of β-caryophyllene and 0.80 g of Polysorbate 20 to the mixture and slowly mixing until it is dissolved in the liquid, minimizing the volatilization of the 1,8-cineole and β-caryophyllene. Mixing is limited to that required to create a stable single-phase homogeneous solution and to minimize volatilization 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 a preservative can be added or alternatively the mixture can be refrigerated prior to use. Methods of use of the composition of the liquid composition in Example 5 include but are not meant to be limited to placing the composition in a an ultrasonic, vibrating mesh or jet nebulizer and inhalation of the vapors resulting from creating an aerosolized mixture. Methods of use of the composition of the liquid in Example 5, include adding approximately 1 mL to 5 ml of the mixture to a liquid nebulizer for inhalation by a patient. The liquid composition that can be aerosolized or vaporized in Example 5 can optionally be made with borneol or a mixture of 1,8-cineole, β-caryophyllene and borneol in the same total concentration range as 1,8-cineole and -caryophyllene. This liquid composition is disclosed in Table 5.
A composition and a method of manufacture of a pharmaceutical liquid that is aerosolized, vaporized or both in an ultrasonic or thermal vaporization device including 1,8-cineole, β-caryophyllene, N-acetyl cysteine, glutathione, ascorbic acid, methylcobalamin, an emulsifying agent, vegetable glycerin, sterile deionized water, sodium bicarbonate (as needed), and a preservative (as needed) is disclosed in Example 6. The method of manufacturing 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-acetyl cysteine, 1.50 g glutathione, 0.003 g methylcobalamin and mixing until the liquid composition is homogeneous. This is followed by adding 90.72 g of vegetable glycerin and mixing. This is then followed by adding a mixture of 1.69 g of 1,8-cineole, 1.69 g of 0-caryophyllene together and slowly mixing until they are dissolved together. Once the 1,8-cineole, β-caryophyllene and Polysorbate 20 are homogeneously mixed, this mixture is added to the glycerin-water based mixture and dissolved into the liquid, minimizing the volatilization of the 1,8-cineole and -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 a preservative can be added or alternatively the mixture can be refrigerated prior to use. The liquid composition in Example 6 may be made with a quantity of vegetable glycerin that is less than 90.72 g and can be decreased by increasing a corresponding mass of nitrogen purged water added.
Methods of use of the composition of the liquid composition in Example 6 include but are not meant to be limited to placing the composition in an e-cigarette vaporizing device, a thermal vaporization device, a vaping pen, an electronic vaping mod, or an ultrasonic vaping device and inhalation of the vapors resulting from creating an aerosolized mixture. A preferred vaping device is one that has temperature control and the temperature is limited to an upper limit of 200° C. The aerosolizable pharmaceutical liquid composition can be transferred to containers that can be stored for one or more doses, the containers may or may not have nitrogen gas in the headspace and the containers may or may not be refrigerated. This liquid composition is disclosed in Table 6.
A composition and a method of manufacture of a pharmaceutical liquid that is aerosolized, vaporized or both comprising 1,8-cineole, β-caryophyllene, N-acetyl cysteine, glutathione, ascorbic acid, methylcobalamin, dexapanthenol, L-theanine, taurine, an emulsifying agent, vegetable glycerin (as needed), water, sodium bicarbonate (as needed), and a preservative (as needed) is disclosed in Example 7. The method of manufacturing consists of mixing an amount of nitrogen purged purified sterile water or isotonic saline solution with ascorbic acid powder or crystals, sodium bicarbonate (as needed), and preservative (as needed) and dissolving, then adding amounts of N-acetyl cysteine, glutathione, dexpanthenol, L-theanine, taurine, and methylcobalamin, followed by adding an amount of vegetable glycerin (as needed) and mixing until the liquid composition is homogeneous. Nitrogen gas purging can be used throughout the mixing period to minimize oxygenation of the water and oxidation of the compounds in the mixture. β-caryophyllene and 1,8-cineole are then separately mixed with the emulsifier, and after this mixture is homogeneous, then slowly adding to the mixture and slowly mixing until it is dissolved in the liquid, minimizing the volatilization of the 1,8-cineole and the β-caryophyllene. Mixing can be conducted in a zero or low headspace reactor to further minimize volatilization of β-caryophyllene and 1,8-cineole and oxidation of the compounds in the mixture. If an amount of β-caryophyllene and 1,8-cineole is added to the mixture at concentrations greater than the solubility of 1,8-cineole and β-caryophyllene in the mixture, then the β-caryophyllene and 1,8-cineole can be emulsified in the liquid composition with the addition of a suitable emulsifier, for example, Tween 20, also known as Polysorbate 20 and polyoxyethylene(20)sorbitan monooleate. Mixing is limited to that required to create a stable single phase homogeneous solution or emulsion and to minimize volatilization of β-caryophyllene and 1,8-cineole.
Methods of use of the liquid composition in Example 7 include but are not meant to be limited to placing a quantity of the composition in an e-cigarette vaporizing device, an electronic thermal vaporization device, an ultrasonic vaping device, a nebulizer, or an inhaler and inhalation of the aerosolized vapors resulting from creating an aerosolized mixture. The liquid composition component that is the TRPA1 antagonist that can be aerosolized or vaporized in Example 7 can optionally be made with borneol or a mixture of 1,8-cineole and borneol in the same or different total concentration range compared when using 1,8-cineole alone. This liquid composition that can be aerosolized is disclosed in Table 7. The aerosolizable liquid composition can be transferred to containers that can stored for one or more doses, the containers may or may not have nitrogen gas in the headspace and the containers may or may not be refrigerated.
polybractea; Eucalyptus
globulus; Eucalyptus
radiate; Eucalyptus
camaldulensis; Eucalyptus
smithii; Eucalyptus
globulus; Rosmarinus
offficinalis
aromaticum, Carum nigrum,
Cinnamomum spp.,
Humulus lupulus, Piper
nigrum L., Cannabis sativa,
Rosmarinus offficinalis,
Ocimum spp., Origanum
vulgare
A preferred composition and a method of manufacture of a pharmaceutical liquid that is aerosolized, vaporized, or both comprising 1,8-cineole, P3-caryophyllene, N-acetyl cysteine, glutathione, ascorbic acid, methylcobalamin, dexpanthenol, L-theanine, taurine, an emulsifying agent, sterile saline solution, sodium bicarbonate (as needed), and a preservative (as needed) is disclosed in Example 8. The method of manufacturing consists of mixing 92.69 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-acetyl cysteine, 1.35 g glutathione, 0.003 g 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. This is followed by adding a mixture of 0.80 g of 1,8-cineole, 0.80 g of β-caryophyllene and 0.80 g of Polysorbate 20 together and slowly mixing until they are dissolved together. This mixture is added to the glycerin-water based mixture and dissolved into the liquid, minimizing the volatilization of the 1,8-cineole and β-caryophyllene. Mixing is limited to that required to create a stable single-phase homogeneous solution and to minimize volatilization of the 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 a preservative can be added or alternatively the mixture can be refrigerated prior to use. Methods of use of the composition of the liquid composition in Example 8 include, but are not meant to be limited to placing the composition in a an ultrasonic, vibrating mesh, or jet nebulizer and inhaling the vapors resulting from creating an aerosolized mixture.
Methods of use of the composition of the liquid in Example 8 include adding approximately 1 mL to 5 ml of the mixture to a liquid nebulizer for inhalation by a patient. The liquid composition that can be aerosolized or vaporized in Example 8 can optionally be made with borneol or a mixture of 1,8-cineole, β-caryophyllene, and borneol in the same total concentration range as 1,8-cineole and β-caryophyllene. This liquid composition is shown in Table 8.
A composition and a method of manufacture of a pharmaceutical liquid that is aerosolized, vaporized, or both in an ultrasonic or thermal vaporization device comprising 1,8-cineole, β-caryophyllene, N-acetyl cysteine, glutathione, ascorbic acid, methylcobalamin, dexpanthenol, L-theanine, taurine, an emulsifying agent, vegetable glycerin, sterile deionized water, sodium bicarbonate (as needed), and a preservative (as needed) is disclosed in Example 9. The method of manufacturing consists of mixing 16.94 g of nitrogen purged sterile deionized water with 0.01 g of ascorbic acid powder dissolving the ascorbic acid, then adding 1.20 g of N-acetyl cysteine, 1.50 g glutathione, 0.003 g methylcobalamin, 1.00 g of dexapanthenol, 0.70 g of L-theanine, and 0.50 g taurine and mixing until the liquid composition is homogeneous. This is followed by adding 89.99 g of vegetable glycerin and mixing. This is then followed by adding a mixture of 1.70 g of 1,8-cineole, 1.70 g of β-caryophyllene, and 1.70 g Polysorbate 20 and slowly mixing until they are dissolved together. Once the 1,8-cineole, β-caryophyllene, and Polysorbate 20 are homogeneously mixed, this mixture is added to the glycerin-water based mixture and dissolved into the liquid, minimizing the volatilization of the 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 a preservative can be added or alternatively the mixture can be refrigerated prior to use. The liquid composition in Example 9 may be made with a quantity of vegetable glycerin that is less than 89.99 g and can be decreased by increasing a corresponding mass of nitrogen purged water added.
Methods of use of the composition of the liquid composition in Example 9 include but are not meant to be limited to placing the composition in an e-cigarette vaporizing device, a thermal vaporization device, a vaping pen, an electronic vaping mod, or an ultrasonic vaping device and inhalation of the vapors resulting from creating an aerosolized mixture. A preferred vaping device is one that has temperature control and has the temperature limited to an upper limit of 200 TC. The aerosolizable pharmaceutical liquid composition can be transferred to containers that can be stored for one or more doses, the containers may or may not have nitrogen gas in the headspace and the containers may or may not be refrigerated. This liquid composition is disclosed in Table 9.
A composition and a method of manufacture of a pharmaceutical liquid that is aerosolized, vaporized or both comprising 1,8-cineole, β-caryophyllene, N-acetyl cysteine, glutathione, ascorbic acid, methyl cobalamin, epigallocatechin, resveratrol, an emulsifying agent, vegetable glycerin (as needed), water, sodium bicarbonate (as needed) and a preservative (as needed) is disclosed in Example 10. The method of manufacturing consists of mixing an amount of nitrogen purged purified sterile water or isotonic saline solution with ascorbic acid powder or crystals, sodium bicarbonate (as needed), and preservative (if needed) and dissolving, then adding amounts of N-acetyl cysteine, glutathione, pre-solubilized epigallocatechin, pre-solubilized resveratrol, and methyl cobalamin, followed by adding an amount of vegetable glycerin (as needed), and mixing until the liquid composition is homogeneous. Nitrogen gas purging can be used throughout the mixing period to minimize oxygenation of the water and oxidation of the compounds in the mixture. β-caryophyllene and 1,8-cineole are then separately mixed with the emulsifier, and after this mixture is homogeneous, then slowly adding to the mixture and slowly mixing until it is dissolved in the liquid, minimizing the volatilization of the 1,8-cineole and the β-caryophyllene. Mixing can be conducted in a zero or low headspace reactor to further minimize volatilization of β-caryophyllene and 1,8-cineole and oxidation of the compounds in the mixture. If an amount of β-caryophyllene and 1,8-cineole is added to the mixture at concentrations greater than the solubility of 1,8-cineole and β-caryophyllene in the mixture, then the β-caryophyllene and 1,8-cineole can be emulsified in the liquid composition with the addition of a suitable emulsifier, for example, Tween 20, also known as Polysorbate 20 and polyoxyethylene(20)sorbitan monooleate. Mixing is limited to that required to create a stable single-phase homogeneous solution or emulsion and to minimize volatilization β-caryophyllene and 1,8-cineole.
Methods of use of the liquid composition in Example 10 include but are not meant to be limited to placing a quantity of the composition in an e-cigarette vaporizing device, an electronic thermal vaporization device, an ultrasonic vaping device, a nebulizer, or an inhaler and inhalation of the aerosolized vapors resulting from creating an aerosolized mixture. The liquid composition component that is the TRPA1 antagonist that can be aerosolized or vaporized in Example 10 can optionally be made with borneol or a mixture of 1,8-cineole and borneol in the same or different total concentration range compared when using 1,8-cineole alone. This liquid composition that can be aerosolized is disclosed in Table 10. The aerosolizable liquid composition can be transferred to containers that can stored for one or more doses, the containers may or may not have nitrogen gas in the headspace, and the containers may or may not be refrigerated.
polybractea; Eucalyptus
globulus; Eucalyptus radiate;
Eucalyptus camaldulensis;
Eucalyptus smithii;
Eucalyptus globulus;
Rosmarinus offficinalis
Carum nigrum, Cinnamomum
nigrum L., Cannabis sativa,
Rosmarinus offficinalis,
Ocimum spp., Origanum
vulgare
Camellia sinensis
A composition and a method of manufacture of a pharmaceutical liquid that is aerosolized, vaporized, or both comprising 1,8-cineole, β-caryophyllene, cannabidiol, N-acetyl cysteine, glutathione, ascorbic acid, methyl cobalamin, an emulsifying agent, vegetable glycerin, water, sodium bicarbonate (as needed), and a preservative (as needed) is disclosed in Example 11. The method of manufacturing consists of mixing an amount of nitrogen purged purified sterile water or isotonic saline solution with ascorbic acid powder or crystals, sodium bicarbonate, and preservative (if needed) and dissolving, then adding amounts of N-acetyl cysteine, glutathione, and methyl cobalamin, followed by adding an amount of vegetable glycerin (as needed), and mixing until the liquid composition is homogeneous. Nitrogen gas purging can be used throughout the mixing period to minimize oxygenation of the water and oxidation of the compounds in the mixture. Cannabidiol is solubilized in a mixture of β-caryophyllene and 1,8-cineole, with limited mixing to minimize the volatilization loss of β-caryophyllene and 1,8-cineole. Following this step, the cannabidiol, β-caryophyllene, 1,8-cineole mixture is separately mixed with an emulsifier, and after this mixture is homogeneous, then it is slowly added to the mixture and slowly mixed until it is dissolved in the liquid, minimizing the volatilization of the 1,8-cineole and the 0-caryophyllene. Mixing can be conducted in a zero or low headspace reactor to further minimize volatilization of 3-caryophyllene and 1,8-cineole and oxidation of the compounds in the mixture. Mixing is limited to that required to create a stable single-phase homogeneous solution or emulsion and to minimize volatilization β-caryophyllene and 1,8-cineole.
Methods of use of the liquid composition in Example 11 include, but are not meant to be limited to placing a quantity of the composition in an e-cigarette vaporizing device, an electronic thermal vaporization device, an ultrasonic vaporization device, a nebulizer, or an inhaler and inhalation of the aerosolized vapors resulting from creating an aerosolized mixture. The liquid composition component that is the TRPA1 antagonist that can be aerosolized or vaporized in Example 11 can optionally be made with borneol or a mixture of 1,8-cineole, β-caryophyllene, and/or borneol in the same or a different total concentration range compared to the concentration range when using 1,8-cineole alone. In another embodiment of this liquid composition cannabidiol can be substituted with one or more cannabinoid compounds, including but not limited to 9-Tetrahydrocannabinol (delta-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). A liquid composition that can be aerosolized is shown in Table 11. The aerosolizable liquid composition can be transferred to containers that can stored for one or more doses, the containers may or may not have nitrogen gas in the headspace, and the containers may or may not be refrigerated.
Eucalyptus polybractea;
Eucalyptus globulus;
Eucalyptus radiate;
Eucalyptus camaldulensis;
Eucalyptus smithii;
Eucalyptus globulus;
Rosmarinus offficinalis
Syzygium aromaticum,
Carum nigrum,
Cinnamomum spp.,
Humulus lupulus, Piper
nigrum L., Cannabis
sativa, Rosmarinus
offficinalis, Ocimum
A composition and a method of manufacture of a pharmaceutical liquid that is aerosolized, vaporized, or both comprising 1,8-cineole, β-caryophyllene, nicotine, N-acetyl cysteine, glutathione, ascorbic acid, methyl cobalamin, an emulsifying agent, vegetable glycerin, water, sodium bicarbonate (as needed), and a preservative (as needed) is disclosed in Example 12. The method of manufacturing consists of mixing an amount of nitrogen purged purified sterile water or isotonic saline solution with ascorbic acid powder or crystals, sodium bicarbonate, and a preservative (if needed) and dissolving, then adding amounts of N-acetyl cysteine, glutathione, and methyl cobalamin. Following mixing of this mixture, an amount of a nicotine salt is added to an amount of vegetable glycerin (if used) to solubilize the nicotine salt. The nicotine salt-vegetable glycerin mixture is then added to the water, ascorbic acid n-acetyl cysteine, glutathione mixture and mixed until the liquid composition is homogeneous. Nitrogen gas purging can be used throughout the mixing period to minimize oxygenation of the water and oxidation of the compounds in the mixture. Alternatively, if freebase (unprotonated nicotine) is used in the formulation, the unprotonated nicotine is solubilized in a mixture of β-caryophyllene and 1,8-cineole, with limited mixing to minimize the volatilization loss β-caryophyllene and 1,8-cineole. Following this step, the nicotine, β-caryophyllene, 1,8-cineole mixture is separately mixed with an emulsifier, and after this mixture is homogeneous, then it is slowly adding to the vegetable glycerin-water mixture and slowly mixed until it is dissolved in the liquid, minimizing the volatilization of the 1,8-cineole and the β-caryophyllene. Mixing can be conducted in a zero or low headspace reactor to further minimize volatilization of β-caryophyllene and 1,8-cineole and oxidation of the compounds in the mixture. Mixing is limited to that required to create a stable single-phase homogeneous solution or emulsion and to minimize volatilization β-caryophyllene and 1,8-cineole.
Methods of use of the composition of the liquid composition in Example 12 include, but are not meant to be limited to placing the composition in an e-cigarette vaporizing device, a thermal vaporization device, a vaping pen, an ultrasonic vaping device, or an electronic vaping mod and inhalation of (the vapors resulting from creating an aerosolized mixture. A preferred vaping device is one that has temperature control and has the temperature limited to an upper limit of 200° C. The aerosolizable pharmaceutical liquid composition can be transferred to containers that can be stored for one or more doses, the containers may or may not have nitrogen gas in the headspace, and the containers may or may not be refrigerated. This liquid composition is disclosed in Table 12.
Eucalyptus polybractea;
Eucalyptus globulus;
Eucalyptus radiate;
Eucalyptus camaldulensis;
Eucalyptus smithii;
Eucalyptus globulus;
Rosmarinus offficinalis
Syzygium aromaticum,
Carum nigrum,
Cinnamomum spp.,
Humulus lupulus, Piper
nigrum L., Cannabis
sativa, Rosmarinus
offficinalis, Ocimum
Nicotiana rustica,
A composition and a method of manufacture of a pharmaceutical liquid that is aerosolized, vaporized, or both in an ultrasonic vaping device or thermal vaporization device comprising 1,8-cineole, β-caryophyllene, nicotine salt, N-acetyl cysteine, glutathione, ascorbic acid, methyl cobalamin, an emulsifying agent, vegetable glycerin, sterile deionized water, sodium bicarbonate (as needed), and a preservative (as needed) is disclosed in Example 13. The method of manufacturing consists of mixing 16.93 g of nitrogen purged sterile deionized water with 0.01 g of ascorbic acid powder dissolving the ascorbic acid, then adding 1.20 g of N-acetyl cysteine, 1.53 g glutathione, 0.003 g methylcobalamin, and mixing until the liquid composition is homogeneous. 1.75 g of nicotine salt (54% nicotine) is added to 87.93 g vegetable glycerin and mixed until the nicotine salt is dissolved. This is followed by adding a mixture of 1.08 g of 1,8-cineole, 1.08 g 3-caryophyllene and 1.18 g Polysorbate 20 together and slowly mixed until they are dissolved together, with limited mixing to minimize the volatilization loss β-caryophyllene and 1,8-cineole. This is followed by adding the vegetable glycerin-nicotine mixture to the β-caryophyllene, 1,8-cineole and Polysorbate 20 mixture and slowly mixed to create a stable single-phase homogeneous solution and to minimize volatilization of 1,8-cineole and β-caryophyllene. The water, glutathione, N-acetyl cysteine, and methylcobalamin are then added and slowly mixed until homogeneous. 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 a preservative can be added, or alternatively the mixture can be refrigerated prior to use. The liquid composition in Example 13 may be made with a quantity of vegetable glycerin that is less than 87.93 g and can be decreased by increasing a corresponding mass of nitrogen purged water added.
Methods of use of the composition of the liquid composition in Example 13 include but are not meant to be limited to placing the composition in an e-cigarette vaporizing device, a thermal vaporization device, a vaping pen, an ultrasonic vaping device, or an electronic vaping mod and inhalation of the vapors resulting from creating an aerosolized mixture. A preferred vaping device is one that has temperature control and has the temperature is limited to an upper limit of 200° C. The aerosolizable pharmaceutical liquid composition can be transferred to containers that can be stored for one or more doses, the containers may or may not have nitrogen gas in the headspace, and the containers may or may not be refrigerated. This liquid composition is disclosed in Table 13.
A preferred composition and a method of manufacture of a pharmaceutical liquid that is aerosolized, vaporized, or both in an ultrasonic vaping device or a thermal vaporization device that is part of a combined smoking cessation and respiratory system health improvement product is disclosed in Example 14. The method for cessation of smoking consists of four separate liquid compositions that are aerosolized and inhaled, each with similar concentrations of N-acetyl cysteine, glutathione, 1,8-cineole, β-caryophyllene, methylcobalamin, an emulsifier, vegetable glycerin, and water.
In this example, cigarette smoking cessation is achieved first by the elimination of the use of combustion cigarettes by the use of ultrasonic vaping device or an electronic thermal liquid aerosolization devices with nicotine replacement therapy. The method of cigarette smoking cessation in this present invention utilizes a nicotine step-down process by which the daily consumption of nicotine is reduced using higher to lower nicotine concentrations over time, leading to the complete elimination of nicotine in the formulation. There are four nicotine reduction steps in this method of cigarette smoking cessation as part of this cigarette smoking and nicotine addiction withdrawal system. The first step to cigarette smoking cessation comprises switching from smoking cigarettes to the use of an electronic thermal liquid aerosolization device to consume nicotine. A unique and distinctive feature of this present invention is that in addition to providing a nicotine replacement therapy leading to the complete withdrawal of an individual from nicotine, this formulation additionally provides health benefits repairing respiratory system damage and disease caused by an individual's history of smoking cigarettes. The health benefits resulting from the inhalation of aerosolized N-acetyl cysteine, glutathione, 1,8-cineole, β-caryophyllene, and methylcobalamin are the result of the multifunctional mechanisms of using a TRPA1 antagonist, a CB2 agonist, glutathione replacement in the lungs, epithelial lining fluid, and epithelial tissues, antioxidant treatment by the glutathione precursor N-acetyl cysteine, and vitamin B12 replacement therapy.
The method of use of the first of four steps to reduce a person's daily nicotine is the inhalation of approximately 20 mg per day of nicotine by vaporizing the formulation disclosed in Table 14. The formulation of Step 1 is provided in Table 14. Based on an approximated consumption of 1 mL of liquid vaporized using 150 puffs per day from an ultrasonic vaporization device, a thermal liquid aerosolization device; not limited to an electronic vaping device or an e-cigarette, the daily consumption of nicotine is about 20 mg. The daily dose of other non-carrier components of the composition disclosed in Table 14 is as follows: glutathione (19.65 mg); n-acetyl cysteine (13.76 mg); 1,8-cineole (10.87 mg); β-caryophyllene (5.34 mg); and vitamin B12 (9.38 μg). An emulsifier, for example, Polysorbate 20, may be provided at 9.73 mg; sterile deionized water may be provide at 212 mg; and vegetable glycerin may be provided at 1,096 mg. The period of time that a person consumes the composition by aerosolization of the Step 1 formulation disclosed in Table 14 can be variable, depending on a person's smoking history, the nature of their nicotine addiction, their susceptibility to nicotine addiction, their willingness to quit smoking cigarettes, and their psychological support system. The period of time a person would use the Step 1 nicotine replacement composition could vary from as short as two weeks to as long as several months. For example, the period of time at Step 1 may be 40 to 60 days. A person of ordinary skill in the art would recognize that the precise concentrations of each of the components identified in Table 14 could be varied over a range to principally accomplish the same outcomes as using the actual concentrations identified in Table 14. The use of deionized water and vegetable glycerin could also be varied dependent upon the type of liquid aerosolization device used. For example, if a nebulization device or an ultrasonic vaporization device were used to provide an aerosol phase of the liquid composition, the concentration of vegetable glycerin could be greatly reduced or even completely eliminated and made up with a water phase. Similarly, if a nebulization device or an ultrasonic vaporization device were used, deionized water could be replaced with a simple saline solution isotonic with that of epithelial lining fluid of the lungs, approximately 0.9 percent sodium chloride, for example. A person ordinarily skilled in the art would recognize that if an electronic thermal vaporization device, a vaping device, a vape pen, an ultrasonic vaporization device or an e-cigarette were used to deliver the composition in Table 14, then the water phase could predominantly be replaced by vegetable glycerin or another non-aqueous phase carrier. A person ordinarily skilled in the art would also recognize that the concentrations of each component disclosed in Table 14 could be increased or decreased by increasing or decreasing the total liquid volume of the composition to adjust for the specific liquid aerosolization device used and the number of puffs or duration of time required of the device to deliver the approximate dose of 1 mL of the liquid composition identified in Table 14.
An embodiment of the present invention in Step 1 of this smoking cessation system is to provide approximately a similar number of puffs that an individual normally takes when smoking cigarettes prior to using this system. This helps to satisfy the oral fixation associated with smoking cigarettes. A programmable electronic vaporization device can essentially vary the number of puffs used per mL of the liquid composition disclosed in Table 14. A person of ordinary skill in the art would recognize that, if a person wanting to quit smoking cigarettes was unable to progress to the next steps of this system of cigarette smoking cessation, then the health benefits of remaining at Step 1 would be better than if that person returned to smoking cigarettes for a longer term than envisioned in Step 1, including for a period of many years.
As part of the method for cigarette smoking cessation, Step 2 is based on an approximated consumption of 1 mL of liquid vaporized using 125 puffs per day from an ultrasonic vaping device or an electronic thermal liquid aerosolization device. The daily consumption of nicotine is about 14 mg, as disclosed in the composition of Table 15. The period of time a person would use the Step 2 nicotine replacement formulation could vary from as short as 2 weeks to as long as two months, for example, 14 to 30 days. An embodiment of this present invention is for an individual to decrease their oral fixation associated with their cigarette smoking habit and behavior. Therefore, there is a reduction in the number of puffs from 150 puffs per day in Step 1 to 125 puffs per day in Step 2. A person ordinarily skilled in the art would recognize that, if a person wanting to quit smoking cigarettes was unable to progress to the next steps of this system of cigarette smoking cessation, then the health benefits of remaining at Step 2 would be better than if the person returned to smoking cigarettes for a longer term than envisioned in Step 2, including for a period of many years.
As part of the method for cigarette smoking cessation, Step 3 is based on an approximated consumption of 1 mL of liquid vaporized using 75 puffs per day from an ultrasonic vaping device or an electronic thermal liquid aerosolization device. The daily consumption of nicotine is about 5 mg, as disclosed in the composition of Table 16. The period of time a person would use the Step 3 nicotine replacement formulation could vary from as short as 2 weeks to as long as 2 months, for example, 14 to 30 days. There is a reduction in the number of puffs from 125 puffs per day in Step 2 to 75 puffs per day in Step 3. A person of ordinary skill in the art would recognize that, if a person wanting to quit smoking cigarettes was unable to progress to the next steps of this system of cigarette smoking cessation, then the health benefits of remaining at Step 3 would be better than if the person returned to smoking cigarettes for a longer term than envisioned in Step 3, including for a period of many years.
As part of the method for cigarette smoking cessation, Step 4 is based on an approximated consumption of 1 mL of liquid vaporized using 75 puffs per day from an ultrasonic vaping device or an electronic thermal liquid aerosolization device, with the daily consumption of nicotine totally eliminated, as disclosed in the composition of Table 17. The period of time a person would use the Step 4 nicotine replacement formulation would depend on the respiratory health of the person and the type of respiratory system impairment and lung disease(s) the person has based on the impacts of her or his cigarette smoking history. The period of time a person would use the Step 4 composition could be months, years, or decades.
Alternatively, Step 4 can consist of utilizing a nebulizer or an ultrasonic vaping device to provide on-going treatment of respiratory lung diseases associated with an individual's past cigarette consumption history. A nebulizer formulation disclosed in Step 4 could alternatively be a formulation disclosed in Table 2, Table 5, or Table 8, that may be preferred for nebulization following Step 3 in this cigarette smoking cessation system, because they contain 0-caryophyllene, which is a CB2 agonist and helpful with addiction withdrawal.
The method of manufacturing of the four liquid formulations provided in Example 14 includes mixing a quantity of nitrogen purged purified water with a quantity of N-acetyl cysteine, a quantity of glutathione, a quantity of methylcobalamin followed by adding a quantity of vegetable glycerin and mixing until the liquid composition is homogeneous. This is followed by adding a mixture of a quantity of 1,8-cineole, β-caryophyllene and a quantity of Polysorbate 20, previously mixed to the mixture and slowly mixing until it is dissolved in the liquid, minimizing the volatilization of the 1,8-cineole and β-caryophyllene. Mixing is limited to that required to create a stable single-phase homogeneous suspension and to minimize volatilization of 1,8-cineole and β-caryophyllene. The liquid composition that can be aerosolized or vaporized in Example 14 can optionally be made with borneol, β-caryophyllene or a mixture of 1,8-cineole and one or more of borneol and β-caryophyllene in the same total concentration range as 1,8-cineole alone presented in Example 14. The pH of each liquid composition should be measured and the pH should be adjusted to 7.20 with sodium bicarbonate. If the liquid composition is not manufactured under sterile conditions, then a preservative can be added to improve the physical, chemical, and biological stability of the formulations. The liquid composition in Example 14 may be made with a quantity of vegetable glycerin that is less than the amounts disclosed in Tables 14, 15, 16, and 17 and can be decreased by increasing a corresponding mass of nitrogen purged water added.
A pre-clinical trial was conducted on five patients that were either current or ex-cigarette smokers historically diagnosed with either asthma or COPD. A preferred liquid pharmaceutical composition was vaporized using commercially available electronic thermal vaping pens with 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 Tech® SUBVOD-Kit™). Patients inhaled at least 40 puffs per day for up to a 73-day period. Spirometry tests including Forced Expiratory Volume after 1 second (FEV1) and Forced Vital Capacity (FVC) measurements were made before treatment, during treatment, and at the end of treatment. Spirometry is the most frequently performed pulmonary function test and plays an important role in diagnosing the presence and type of lung abnormality, classifying its severity and evaluating treatment outcomes. Patients were also interviewed with respect to their breathing capabilities, energy levels, and general well-being and health.
The procedure followed by each patient consisted of a preferred liquid composition, disclosed in Table 18, being placed into a vape pen tank with a dropper and then the on button being depressed on the side of the vape pen to actuate heating of the coil while the patients inhaled the aerosolized liquids through an attached mouthpiece.
Patients inhaled at least 75 puffs from the vape pen on a daily basis. Prior to commencing treatments, each patient's past and current history of cigarette smoking, age, height, weight, gender, and race was recorded as part of the testing to allow the calculation of normal FEV1 and FVC values. All individuals had a history of cigarette smoking and only 1 patient currently smoked cigarettes as indicated in Table 19. The patients were diagnosed with either COPD or asthma as indicated in Table 19. Prior to the liquid aerosolization treatment, each patient underwent spirometry testing to measure FEV1 and FVC to provide baseline conditions. These results were compared to calculated normal values using the method of Hankinson et al. (1999) from the National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention. Patient histories and spirometry test results are summarized in Table 19. Using the normal FEV1 values calculated for each individual based on age, height, sex, and race and their baseline FEV1 measurements prior to treatment, percent normal FEV1 values for each patient were calculated to provide baseline conditions to compare treatment results.
Females generally have a smaller lung capacities than males, and it can be seen in Table 19 that the 3 female patients had lower baseline FEV1 capacities (baseline values before treatment for FEV1 of 1.33 L to 1.70 L) than the 2 male patients (baseline values before treatment for FEV1 of 2.82 L to 2.84 L). The normal FEV1 values for the female patients were calculated to be 1.98 L to 2.80 L. The normal FEV11 values for the male patients were 4.18 L and 4.44 L. Each patient had substantially lower baseline FEV1 values than what would be normal for a healthy individual. For the 5 patients, the percent normal FEV1 values prior to treatment varied from 63.96% to 68.83%. For example, individuals with COPD that have percent normal FEV1 values less than 80 percent are classified with GOLD 2 moderate COPD. Based on these values, it was evident that each patient exhibited significant airway restriction. FVC baseline capacities for all patients were also significantly lower than what would be normal values for healthy individuals, varying from 62.6100 to 68.01%.
Spirometry tests following the inhalation respiratory treatment were repeated after 21 days of treatment and at the end of treatment, which varied from 42 days to 73 days, for each individual. Results of FEV1 spirometry testing were graphed for each patient with results displayed in
Males generally have larger lung capacities and this is evident from review of results presented in Table 19 and
Various organizations are associated with the assessment of improvement of patients with COPD. FEV1 results reported in our pre-clinical tests indicate a significant improvement when compared to FEV1 improvement assessment criteria established by these organizations as follows: 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 pre-clinical test results presented in
A pre-clinical trial was conducted on a single patient using a preferred aerosolizable liquid that was nebulized using a commercially available portable ultrasonic mesh-type nebulizer with a 5.0 mL refillable liquid reservoir and a rechargeable lithium ion battery (Flyp nebulizer, Convexity Scientific, Inc.). The patient was a 49 year old male, 174.86 cm in height, with a history of diagnosed mild to moderate asthma. The patient was prone to about 10 to 15 asthma attacks per year requiring medication caused by seasonal allergies, induced by cold air and induced by exercise. The patient typically used albuterol, a bronchodilator, as a rescue-type inhaler during these events and periodically also used fluticasone furoate, an inhalable corticosteroid powder. The patient also required the use of prednisone, an oral corticosteroid, about 1 to 2 times per year for the most serious asthma attacks.
Prior to first nebulizing a preferred liquid composition, the patient reported moderate asthma symptoms consisting of a sensation of constriction of the chest and difficulty breathing and taking a full breath. The patient had been inhaling albuterol and fluticasone furoate on a daily basis for one week prior to using the nebulizer fluid, without substantive relief of symptoms. Based on his prior experience with asthma and his symptoms, he reported that he thought he would need to use prednisone, if the symptoms continued. Using the portable ultrasonic mesh nebulizer, the patient nebulized 1 mL of a liquid comprising the following glutathione 1.10% (w/w), N-acetyl cysteine 1.10% (w/w), 1,8-cineole 0.80% (w/w), β-caryophyllene 0.80% (w/w), methylcobalamin 0.003% (w/w), Polysorbate 20 0.3% (w/w), and sterile saline water solution (0.9% saline) 95.3% (w/w). Within 30 minutes following nebulization the patient reported that his chest felt significantly more relaxed and less constricted, he was able to breathe more fully, and he felt more energetic. He was completely able to stop taking albuterol and fluticasone furoate following the nebulization treatment. After this single nebulization event, the patient reported his symptoms remained improved over the next week, although there was a lessening in the extent of improvement after about 4 to 5 days. Three days following nebulization of the pharmaceutical liquid, the patent underwent spirometry testing. The normal spirometry values for the patient were calculated to be FEV1=3.81 L and FVC=4.89 (Hankinson, 1999). Measured spirometry values three days after the single nebulization treatment were FEV1=2.99 L and FVC=3.65 L, with percent normal values for FEV1=78.4% and FVC=74.6%.
The patient then began a 7-day period of daily nebulization treatment one week after the single nebulization treatment. Prior to starting the 8-day treatment period the patient underwent baseline spirometry testing with the following results: FEV1=3.09 L and FVC=3.57 L with percent normal values for FEV1=81.0% and FVC=73.0%. The patient nebulized increasing amounts of a nebulizer liquid for 8 days comprising the following: glutathione—0.70% (w/w); N-acetyl cysteine 0.70% (w/w); methylcobalamin—0.003% (w/w); and sterile saline water solution (0.9% saline)—98.4% (w/w). On days 1 through 3, 1.5 mL was nebulized and on days 4 through 8, 3.0 mL was nebulized. Following nebulizing the liquid composition on day 7, spirometry tests were conducted on the patient. Spirometry results following nebulizing 3.0 mL of the liquid were FEV1=3.39 L and FVC=3.84 L, with percent normal values for FEV1=86.8% and FVC=78.5.0%. Compared to the first baseline spirometry values the percent FEV1 reversibility was calculated to be 12% and the percent FVC reversibility was 5.2%. The improvement of the FEV1/FVC % ratio increased from 81.9% to 88.3% compared to the first patient spirometry results. It is apparent that this patient was using a greater percentage of their lung capacity in the second of the spirometry tests.
The patient reported that even given only one nebulization treatment during the first week of treatment followed by 11 days of only moderate nebulization treatment he did not experience any asthma attacks and did not have to take his prescription bronchodilator or any corticosteroid of any time during the test period. The patient reported that he had more energy and could breathe easier and more fully.
The embodiments illustrated and discussed in this specification are intended only to teach those skilled in the art the best way known to the inventors to make and use the invention. Nothing in this specification should be considered as limiting the scope of the present invention. All examples presented are representative and non-limiting. The above-described embodiments of the invention may be modified or varied, without departing from the invention, as appreciated by those skilled in the art in light of the above teachings. It is therefore to be understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.
The present application is a national phase entry under 35 USC § 371 of international application number PCT/US2019/057722, filed Oct. 23, 2019, which claims priority to and the benefit of the filing date of U.S. Provisional Application No. 62/749,446, filed Oct. 23, 2018, which are each incorporated by reference in their entirety herein.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US19/57722 | 10/23/2019 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62749446 | Oct 2018 | US |
