Pharmaceutical Compositions

Abstract

Pharmaceutical compositions are provided for administration to the pulmonary epithelium for the treatment of respiratory disorders. The pharmaceutical composition of the present invention comprises The composition comprises ibuprofen and arginine dissolved in a hypertonic aqueous solution having a pH of 7.5-9.5, the molar ratio of said arginine / ibuprofen being greater than or equal to 1 and less than 6.5, the concentration of said ibuprofen being between 10 mM and 50 mM, and the concentration of said arginine being between 10 mM and 250 mM.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition for use in the treatment of respiratory diseases and epithelial tissues, such as COVID-19 infection, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), respiratory viral, fungal or bacterial infections, and cystic fibrosis (CF). [Background technology]

[0002] Nonsteroidal anti-inflammatory drugs (NSAIDs) are a diverse group of drugs that share the same therapeutic effect (analgesic, anti-inflammatory, antipyretic) but differ in their relative toxicity and efficacy. The ibuprofen molecule, with a molecular weight of 206.3 g / mol, and other derivatives of 2-arylpropionates (including ketoprofen, flurbiprofen, naproxen, etc.) contain a chiral carbon at the alpha position of the propionate.

[0003] Ibuprofen is used as an antipyretic, for symptomatic relief of cluster headaches, dental pain, muscle pain, myalgia, menstrual discomfort, mild nerve pain, and post-operative pain. It is also used to treat inflammation such as arthritis, rheumatoid arthritis, and gouty arthritis. L-arginine is a semi-essential endogenous amino acid that plays a vital role in cell division, wound healing, removal of ammonia from the body, immune function, and hormone release, and is also the only biological precursor to nitric oxide (NO).

[0004] [Patent Document 1] US10973787B2 [Non-Patent Document 1] Ricciardolo, F. L. M. et al.. (2004). Nitric Oxide in Health and Disease of the Respiratory System. Physiological Reviews, 84(3), 731-765. https: / / doi.org / 10.1152 / physrev.00034.2003

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[0005] Nitric oxide (NO), produced from L-arginine by a group of isoenzymes called nitric oxide synthase (NOS), plays an important role in a variety of biological processes in the lung, including host defense against pathogens, smooth muscle relaxation, bronchiectasis, and inflammation (Non-Patent Document 1).

[0006] In the vascular endothelium, NO exerts antithrombotic and antibacterial effects. In this regard, NO, released from the endothelium and platelets, plays an important role in maintaining fluidity and preventing coagulation. NO-induced vasodilation helps to remove "microaggregates", inhibits platelet adhesion and aggregation, and helps to prevent vascular occlusion (Non-Patent Document 2). On the other hand, virucidal and bactericidal effects are also described in the same document. The antibacterial effect of NO has been shown against infection-causing pathogens. Examples of infection-causing pathogens are Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Listeria monocytogenes, Enterococcus faecalis. The antibacterial mechanisms of NO include nitration of amines and thiols in the extracellular matrix, lipid peroxidation and tyrosine nitration in the cell wall, and DNA cleavage in the cellular matrix (Non-Patent Document 3). In addition, the ability of NO to inhibit the replication of respiratory coronaviruses, which is unique to NO among other vasodilators, has been reported (Non-Patent Document 4).

[0007] In the lungs, NO exerts a variety of effects (serves a purpose), including, for example, functioning as a selective pulmonary vasodilator, improving oxygenation and reducing pulmonary vascular resistance (5-8). As a bronchial / airway dilator, NO increases oxygen intake and blood flow in the capillaries (which exchange gases with cells), promoting oxygen circulation in the body (Non-Patent Document 9). As a regulator of the immune system, NO has been shown to perform multiple functions in systems that produce and respond to NO, particularly where there are large numbers of cells present (Non-Patent Document 10). As a vascular anticoagulant, NO inhibits blood clotting and excessive platelet activation. As an antiflammatory molecule, NO prevents excessive inflammation through early nonspecific immunity and regulates vascular inflammation and immune cell proliferation (Non-Patent Document 11).

[0008] In cystic fibrosis patients (hereinafter referred to as "CF patients"), high-concentration NO inhalation is closely related to the improvement of lung function (Non-Patent Documents 12-14). According to Non-Patent Document 15, it was found that inhalation administration of L-arginine leads to temporary improvement of lung function in CF patients. Subsequent studies, such as those in Non-Patent Document 16, found that inhalation of L-arginine was well tolerated and led to a significant increase in exhaled NO. FEV1 increased by an average of 56 ml compared to 8 ml of saline, but this difference did not reach statistical significance. Furthermore, there were no changes in inflammatory markers in sputum. The conclusion from this is that repeated inhalation of L-arginine alone in CF patients is safe and well tolerated. Although inhaled L-arginine increased NO production, no evidence of changes in airway inflammation was found. Interestingly, twice daily inhalation of 5 ml of a 100 mg / ml solution resulted in a cumulative daily dose of 1 g of L-arginine. This indicates that after 14 days of inhalation treatment with high concentrations of L-arginine, there is a measurable increase in the concentration of the NOS inhibitor ADMA and in the L-arginine / ADMA ratio (NOS substrate divided by inhibitor). This ratio is decreased in CF patients and correlates with lower airway NO. However, studies have found that the potential benefits of increasing L-arginine concentrations are offset by increases in both L-ornithine and ADMA. L-ornithine competes with L-arginine for transport into cells, and ADMA acts as a competitive NOS inhibitor.

[0009] Non-Patent Document 17 presents a study on supplementing CF patients with gaseous NO to treat antibiotic-resistant pulmonary infections. Non-Patent Document 17 claims a significant reduction in bacteria resulting in reduced pulmonary inflammation and a significant increase in the pulmonary function parameter FEV1 (increasing from baseline to a level rarely observed in CF patients after antibiotic therapy). However, it is clear that long-term treatment with gaseous NO leads to the formation of toxic NO2 levels, MetHb, and hypoxemia, which are major drawbacks of alternative treatments.

[0010] On the other hand, NO is known to have adverse effects on the organs of patients with lung disease. For example, asthmatics exhale higher concentrations of NO than healthy people, and reactive nitrogen species are known to be involved in the pathogenesis of asthma and the development of "nitrosative stress" (Non-Patent Document 18). In patients with pneumonia caused by COVID-19, high production of reactive oxygen species (ROS) and reactive nitrogen species (RNS e.g., nitric oxide NO) can lead to septic shock (Non-Patent Document 19). Furthermore, cells damaged due to NO production express nitrotyrosine, which in turn reacts with many types of molecules and is therefore damaged.

[0011] In summary, NO is useful in treating pulmonary diseases and has many beneficial effects, but excess NO exerts cytotoxic effects, causing oxidative damage and cell death. Whether NO has toxic or protective effects depends on many factors.

[0012] Oxidative stress is caused by the excessive systemic expression of reactive oxygen species (ROS) compared to the reduced functional capacity of biological systems to rapidly neutralize reactive intermediates or repair the resulting damage. Increased ROS concentrations reduce the amount of bioactive NO, which is due to chemical inactivation forming toxic peroxynitrite. Peroxynitrite can "uncouple" endothelial NO synthase, resulting in a dysfunctional superoxide-generating enzyme, which further increases vascular oxidative stress (Non-Patent Document 21). In this context, correlations between the presence of systemic or local oxidative stress (including all the examples of the present invention) and various lung diseases have been described in Non-Patent Documents 22-30. Therefore, disease treatments targeting ROS inhibition and restoration of oxidant / antioxidant imbalance have also been proposed.

[0013] Considering the current state of the art, it is clear that there is a need for therapeutic treatments that use low doses of active pharmaceutical ingredients to control oxidative stress in respiratory diseases. The present invention provides a solution to this problem, achieving therapeutic benefits for respiratory diseases by reducing oxidative stress. The present invention provides a method for reducing oxidative stress by using a hypertonic alkaline solution for nebulization therapy. JPEG2024541669000001.jpg143101By using the synergistic combination of ibuprofen and arginine, the therapeutic effects of the present invention in patients with various lung diseases could not be achieved by the prior art.

[0014] Concerning the combination of ibuprofen and arginine, several preparations of ibuprofen and arginine, including ibuprofen arginate salt (1:1 molar ratio), are commercially available. The reason is that this combination provides rapid absorption and high peak plasma concentrations of ibuprofen as well as a low tmax value compared to the free acid form and other preparations (Non-Patent Document 31). On the other hand, Non-Patent Document 32 discloses a method for the determination of ibuprofen in human plasma samples. This method is used to measure the concentration of ibuprofen in serum samples of rats aspirating ibuprofen and arginine in saline. However, Non-Patent Document 32 does not disclose or suggest the existence of a range of concentrations in which the combination of ibuprofen and arginine improves pathological lung function. In addition, all of these preparations are based on ibuprofen arginate salt, with an arginine / ibuprofen molar ratio of 1.

[0015] In contrast, the composition of the present invention contains ibuprofen and arginine, and the molar ratio of arginine / ibuprofen is 1 to 6.5, which has a synergistic effect on blocking reactive oxygen species. The pharmaceutical composition is administered in the form of aerosol to treat various lung diseases. Examples of pulmonary diseases are asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) pulmonary hypertension, bronchopulmonary dysplasia acute respiratory distress syndrome (ARDS), SARS-CoV-2, respiratory viral, fungal or bacterial infections, bilateral pneumonia, and bronchiectasis.

[0016] The pharmaceutical composition of the present invention shows important physiological benefits for improving oxygen saturation, respiratory rate, heart rate, blood pressure, and treating pulmonary diseases. The composition contains very simple molecules such as an anti-inflammatory agent (ibuprofen) and a basic amino acid (arginine). When combined at a given concentration, ionic strength and pH value, they show a synergistic effect in the synthesis and release of nitric oxide (NO), while improving vasodilation. Furthermore, the presence of arginine combined with nebulized ibuprofen not only affects NO levels, but also exerts a significant synergistic effect on the reduction of oxidative stress. This results in improved O2 saturation levels and improved lung function (FEV1) in patients. This protective strategy is associated with a reduction in acute lung injury (ALI). This synergistic effect is achieved with much lower concentrations of arginine than those used in other treatments, the effect is long-lasting, and no inhibitory effects were observed in sustained treatment over time. Summary of the Invention [Problem to be solved by the invention]

[0017] Moreover, this pharmaceutical composition contains an anti-inflammatory molecule (ibuprofen) and exhibits antibacterial properties against Gram+ and Gram- bacteria, in particular by inhibiting bacteria (e.g. P. awrugiNOSa, S. aureus, B. cepacia), while at the same time having a virucidal effect against lipid-envelope viruses (Patent Document 1, Non-Patent Documents 33, 34). Furthermore, the pharmaceutical composition of the present invention contains a salt dissolved therein, which exhibits the synergistic bactericidal and antiviral effects disclosed in US Patent No. 5,399,663, enhancing the bactericidal and antiviral effects of the pharmaceutical composition, making it suitable for treating pulmonary diseases caused by pathogens. It is therefore an object of the present invention to provide a pharmaceutical composition for administration to the pulmonary epithelium for the treatment of respiratory diseases. [Means for solving the problem]

[0018] The pharmaceutical composition of the present invention comprises ibuprofen and arginine dissolved in a hypertonic aqueous solution having a pH between 7.5-9.5. The molar ratio of arginine / ibuprofen is between 1 and 6.5. A preferred molar ratio is between 1.5 and 5. A more preferred molar ratio is between 2 and 5. The most preferred molar ratio is 2. The concentration of ibuprofen is between 10 mM and 50 mM. The ibuprofen is racemic. The ibuprofen is the S enantiomeric or R enantiomeric form. The ibuprofen comprises, as a counterion, a monovalent cation selected from the following group: sodium, potassium, lithium, alginate, lysinate, histidate, and combinations thereof. The concentration of arginine is between 10 mM and 250 mM. In an embodiment of the present invention, the pH of the hypertonic aqueous solution is between 8.0-9.0, with a preferred pH of 8.5.

[0019] The pharmaceutical composition of the present invention is formulated for spray (mist) or inhalation, and may be in a liquid, powder, or lyophilized form.

[0020] In one embodiment, the pharmaceutical composition of the present invention is hypertonic and comprises a salt, the concentration of which is between 0.3M and 2.0M. A preferred concentration is between 0.4M and 1.1M. A more preferred concentration is between 0.5M and 1.0M. The salt is suitable for human digestion. The salt is selected from the group consisting of sodium chloride, potassium chloride, sodium carbonate, and combinations thereof. Most preferably, the salt is sodium chloride (NaCl).

[0021] The pharmaceutical composition of the present invention is suitable for treating pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pulmonary hypertension, bronchopulmonary dysplasia acute respiratory distress syndrome (ARDS), SARS-CoV-2, respiratory viral, fungal or bacterial infection, bilateral pneumonia, and bronchiectasis.

[0022] According to another embodiment, the pharmaceutical composition of the present invention is administered to the pulmonary epithelium to improve pulmonary function. The pharmaceutical composition of the present invention comprises ibuprofen and arginine dissolved in a hypertonic aqueous solution having a pH of 7.5-9.5, the molar ratio of arginine / ibuprofen being ≧1 and ≦6.5.

[0023] According to another embodiment, the pharmaceutical composition of the present invention is administered to the pulmonary epithelium to improve lung function. The pharmaceutical composition of the present invention comprises ibuprofen and arginine dissolved in a hypertonic aqueous solution of pH 7.5-9.5, the molar ratio of arginine / ibuprofen being greater than or equal to 1 and less than 6.5. The concentration of ibuprofen is between 10 mM and 50 mM. The concentration of arginine is between 10 mM and 250 mM.

[0024] Another object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which exhibits bactericidal, virucidal and anti-inflammatory properties and is administered to the pulmonary epithelium for the treatment of respiratory diseases. The method for preparing the pharmaceutical composition of the present invention comprises the following steps (A)-(E): (A) Mixing ibuprofen in its acid state with an aqueous solution of Na2CO3 at 40°C or higher and stirring to maintain the suspension. (B) adding arginine to said step (A). (C) Add NaOH or Na2CO3 to adjust the pH to 7.5-9.5, and stir to completely dissolve the ibuprofen and arginine, to obtain ibuprofen at a concentration of 1-100 mg / mL and basic amino acid at a concentration of 5-100 mg / mL. (D) adding salt suitable for human consumption to the preparation of step (C) at a concentration of 0.3-1.0 M. (E) filtering the preparation of step (D) through a filter having a pore size of 0.22 microns (μm).

[0025] Optionally, the method for producing the pharmaceutical composition of the present invention further comprises the steps (F) and (G) of: (F) freeze-drying the solution filtered in step (E). (G) When applicable, resuspending the composition lyophilized in step (F) in water or a 2.5% glucose solution.

[0026] Another object of the present invention is to provide a method for treating pulmonary disease by administering an effective amount of a pharmaceutical composition to the pulmonary epithelium of a patient. The pharmaceutical composition of the present invention is administered to the patient in a nebulized form. In one embodiment, the pharmaceutical composition of the present invention is administered to the patient in a volume between 1 mL-25 mL. A preferred dosage is between 1 mL-10 mL. A more preferred dosage is between 1 mL-5 mL. A more preferred dosage is 3 mL.

[0027] An example of a pulmonary disease is selected from the group including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pulmonary hypertension, bronchopulmonary dysplasia acute respiratory distress syndrome (ARDS), SARS-CoV-2, respiratory viral, fungal or bacterial infection, bilateral pneumonia, and bronchiectasis.

[0028] The patient is a patient with hypoxic syndrome or a patient with a pulse-measured blood oxygen saturation level of 92% or less. The patient's respiratory rate is 25-30 breaths / min or 30-40 breaths / min. The patient's respiratory rate is 41 breaths / min or greater. The patient's heart rate is 91-110 beats / min, 111-130 beats / min or greater than 131 beats / min. The patient's NEWS2 score is between 0-4, or between 5-6, or greater than 7. The patient is intubated or pre-intubated. The patient may not be hypoxic. [Brief description of the drawings]

[0029] [Figure 1] Graph showing lung capacity test results for Patient 9 before nebulization treatment. [Diagram 2] Graph showing lung capacity test results for Patient 9 60 minutes after nebulization with ibuprofen-arginine solution. [Diagram 3] Graph showing the inhibitory effect of alkaline hypertonic ibuprofen (Ibu) and arginine (Arg) solutions on the production of superoxide anion in macrophages stimulated with LPS. *p<0.05, **p<0.01, ***p<0.001 vs. control group. [Figure 4] Graph showing the inhibitory effect of alkaline hypertonic ibuprofen solution (10 μM) alone or various amounts of arginine solution (5, 10, 20, 50, 65, 85, 100 μM) on the production of superoxide anion in macrophages stimulated with LPS. ****p<0.0001 vs. control, $p<0.05, $$$p<0.001 vs. LPS DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] The pharmaceutical composition of the present invention for application to the pulmonary epithelium comprises a non-steroidal anti-inflammatory drug (NSAID), a basic amino acid, dissolved in an alkaline aqueous solution having a pH between 7.5-9.5.

[0031] The nonsteroidal anti-inflammatory drug is selected from ibuprofen, nabroxen, flurbiprofen, cutoprofen, diclofenac, etodonac, fenoprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, oxaprozin, proxicam, sulindac, celecoxib, acetylated salicylates, and combinations thereof. The concentration of the NSAID is between 5 mM and 500 mM, preferably between 5 mM and 180 mM, more preferably between 5 mM and 50 mM. The NSAID is in a deprotonated form, which refers to a state in which a proton has been replaced with another cation. The NSAID contains a monovalent cation as a counterion selected from the group including sodium, potassium, lithium, alginate, lysinate, histidate, and combinations thereof. In one embodiment, the preferred formulation contains ibuprofen.

[0032] Considering that ibuprofen has one chiral center, it has an R enantiomer (also called optical isomer, hereinafter referred to as "enantiomer") and an S enantiomer. In the present invention, the use of the R enantiomer and the S enantiomer (racemic mixture) is contemplated. The mixture of R and S enantiomers in this racemic mixture is in a 1:1 ratio. The designation of the R enantiomer or the S enantiomer means that it contains at least 90%, 95%, 98%, 99% by weight of it. "Optical purity" refers to the proportion of the designated enantiomer by weight of both R and S enantiomers combined.

[0033] In the present invention, ibuprofen, which is soluble in an aqueous solution, can be added in acid form or as a salt, which contains as a counterion a monovalent cation selected from the following group: sodium, potassium, lithium, alginate, lysinate, histidinate, and combinations thereof.

[0034] "Basic amino acid" refers to an amino acid with a pH-neutral basic side chain. Examples are arginine, lysine, and histidine. This side chain contains nitrogen and resembles ammonia, which is basic. In one embodiment, the concentration of the basic amino acid is between 5 mM-500 mM, preferably between 25 mM-300 mM, more preferably between 50 mM-250 mM, and most preferably between 80 mM-150 mM. The basic amino acid is preferably arginine.

[0035] An "aqueous solution" uses a polar liquid as a solvent, preferably water, and has an NSAID and a basic amino acid dissolved therein. In one embodiment, the aqueous solution further comprises a salt suitable for human consumption. Examples of salts are Na2CO3, KCl, NaCl, more preferably NaCl. The aqueous solution is hypertonic, with the salt concentration being between 0.3M-2M, preferably between 0.4M-1.1M, more preferably between 0.5M-1.0M. The molar ratio of ibuprofen / salt (ibuprofen / amino acid) is between 1:0.6 and 1:400.

[0036] Furthermore, the pH of the aqueous solution of the pharmaceutical composition of the present invention is between 7.5-9.5, preferably between 8-9, and most preferably pH 8.5.

[0037] The pharmaceutical compositions of the present invention are administered by inhalation or nebulization. Administering a formulation by "inhalation" refers to administering the formulation directly to the lungs through the oral or nasal passages. This is generally accomplished by inhaling the formulation.

[0038] The pharmaceutical composition of the present invention is administered by nebulization. Specifically, a nebulizer converts a liquid medicine into fine droplets (aerosol, mist) that are inhaled through a mouthpiece or mask. Nebulization is achieved by a jet (1) or ultrasound (2). Jet (1) uses compressed gas, while ultrasound (2) uses high frequency vibrations to generate an aerosol (tiny particles of drug suspended in the air). In one embodiment, nebulization uses a piston nebulizer. In one embodiment, the nebulized droplets are large enough to reach the alveoli.

[0039] Alternatively, the pharmaceutical composition may be administered using an inhaler. In one embodiment, the pharmaceutical formulation is administered via an MDI metered dose inhaler, which uses a hydrofluoric alkane aerosol nebulizer to deliver a predetermined amount of the pharmaceutical composition. Another embodiment uses an SMI soft mist inhaler to deliver a predetermined amount of the pharmaceutical formulation in the form of a slow moving mist.

[0040] Furthermore, the pharmaceutical composition of the present invention can be prepared by lyophilization, either in liquid form or as a powder, which is formed by drying or freeze-drying from a final aqueous solution of the pharmaceutical composition. The process of drying and freeze-drying pharmaceutical compositions is well known in the art, and therefore will not be described in detail.

[0041] The pharmaceutical compositions of the present invention are useful for treating pulmonary diseases, viral or non-viral pulmonary infections, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) pulmonary hypertension, bronchopulmonary dysplasia acute respiratory distress syndrome (ARDS), SARS-CoV-2, respiratory viral, fungal or bacterial infections, bilateral pneumonia, and bronchiectasis.

[0042] Cystic fibrosis (CF), a serious disease that mainly affects children, is a genetic condition that causes sticky mucus to build up in the lungs and digestive system. This leads to lung infections and problems digesting food. Asthma is a respiratory disease characterized by chronic inflammation of the airways that affects both children and adults. Chronic obstructive pulmonary disease (COPD) is the name for a group of lung conditions that cause breathing difficulties and is a common condition that affects middle-aged and elderly people who smoke. Respiratory problems tend to get worse over time. Pulmonary hypertension is high blood pressure in the blood vessels that supply blood to the lungs (pulmonary arteries), a serious condition that can damage the right side of the heart. The walls of the pulmonary arteries become thicker and stiffer, and do not expand to allow blood to pass through.

[0043] Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that affects newborns. Newborns are often born prematurely and require oxygen therapy. In BPD, the lungs and airways (bronchi) are damaged, causing tissue destruction (dysplasia) in the tiny air sacs of the lungs (alveoli). Acute Respiratory Distress Syndrome (ARDS) occurs when fluid fills the elastic air sacs of the lungs (alveoli). As a result, this fluid prevents the lungs from getting enough air. This means less oxygen reaches the bloodstream. This means that organs do not receive the oxygen they need to function.

[0044] SARS-CoV-2 is a recent viral disease in which patients present with pneumonia. In this case, fever is the most common symptom, followed by coughing. Many patients have low oxygen saturation levels and difficulty breathing. Bilateral lungs with ground-glass opacities are the most common finding from CT imaging of the chest.

[0045] The agent of the present invention exerts the therapeutic effect described in the examples. This is achieved by acting on oxidative stress. Oxidative stress (also called "oxidative stress") is caused by an excessive global expression of reactive oxygen species (ROS) reactive oxygen stress. This excess means that it is greater than the reduced capacity of the biological system to rapidly neutralize reactive intermediates or to rapidly repair the damage that has been done. In this context, the relationship between the presence of global or local oxidative stress and various lung diseases (including all those treated in the examples) is described in the literature. Therefore, a treatment aimed at inhibiting ROS and restoring the oxidant / non-oxidant imbalance is also proposed.

[0046] For example, non-patent literature 34 discusses the interplay between ROS and autophagy in lung diseases (examples of which are chronic obstructive pulmonary disease, acute lung injury, cystic fibrosis, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, and asthma) and concludes that this interplay plays an important and complex role in the pathogenesis of these lung diseases. In particular, Non-Patent Document 35 reviewed the literature related to oxidative stress biomarkers in COPD patients with exacerbations compared to the stable phase of the disease and identified reliable oxidative stress biomarkers that are useful for monitoring disease progression in COPD patients, especially those susceptible to exacerbations. Non-patent literature 36 found that oxidative stress markers and antioxidant vitamin levels were significantly higher in patients with bullous lung disease compared with controls, and that oxidative stress plays an important role in the pathogenesis of the disease.

[0047] Oxidative stress plays an important role in pulmonary fibrosis, pulmonary inflammation, collagen deposition, and respiratory and pulmonary fibrosis. Free radical activity, lipid products, and oxidized proteins have been identified in exhaled breath, bronchoalveolar lavage fluid, serum, and lungs of patients with pulmonary fibrosis (Non-Patent Document 37). Similarly, it is known that the pathogenesis of bronchiectasis is related to oxidative stress, and oxidative stress biomarkers have been found in the exhaled breath of patients with bronchiectasis (Non-Patent Document 38).

[0048] It is generally accepted that oxidative stress plays an important role in the pathogenesis of bronchial asthma (Non-Patent Document 39). It has also been confirmed that the development and maintenance of inflammatory processes in the respiratory tract are associated with oxidative and nitrosative stress found in asthmatic patients (Non-Patent Document 40).

[0049] Furthermore, respiratory viruses, including human respiratory syncytial virus (RSV), influenza virus (IV), human rhinovirus (HRV), human metapneumovirus (HMPV), valine fluenza, adenovirus, and coronaviruses (CoVs), induce ROS-generating enzymes, nicotinamide adenine dinucleotide phosphate oxidase (NADpH, oxidase, NOx), generating imbalanced antioxidant levels (antioxidant viruses) (Non-Patent Document 41).

[0050] Finally, patients with moderate and severe pneumonia due to COVID-19 may develop sepsis. Sepsis was the leading cause of death in intensive care units worldwide during the last pandemic. Septic shock is the consequence of sepsis. In sepsis, there is high production of ROS and RNS (nitric oxide (NO)). ROS and RNS can cause multiple organ (lung, heart, nerve, liver) failure (Non-Patent Document 42).

[0051] The advantages of the present invention have not been reported in the literature. The advantages of the present invention are that it combines a very low dose of NSAID with a basic amino acid at a defined concentration, pH and salt concentration, which reduces the synthesis and release of nitric oxide (NO) and oxidative stress, while improving vasodilation, resulting in improved oxygen saturation and ultimately inducing an improvement in the patient's pulmonary function FEV1.

[0052] Technically, the use of very low concentrations of NSAIDs and arginine (a basic amino acid) synergizes oxygen saturation and FEV1, aiding in lowering blood pressure and reducing the common side effects of anti-inflammatory drugs. On the other hand, the low dose of arginine in this formulation prevents the increase in asymmetric dimethylarginine (ADMA), an inhibitor of endothelial NOS, which appears when high doses of arginine are used.

[0053] Furthermore, due to the properties of the composition, the present invention achieves the synergistic bactericidal and antiviral effects described in Patent Document 1, enhancing the bactericidal and virucidal effects of this pharmaceutical composition, making it more suitable for the treatment of pulmonary diseases caused by pathogens.

[0054] Another object of the present invention is to provide a method for preparing a pharmaceutical composition for administration to the pulmonary epithelium for the treatment of a respiratory disease, the method comprising the steps of: (A) Mixing the NSAID with water and stirring to maintain the suspension. (B) adding a basic amino acid to said step (A). (C) Adding NaOH or Na2CO3 to pH 7.5-9.5 and stirring to completely dissolve the ibuprofen and basic amino acid to obtain an NSAID concentration between 1-100 mg / mL and a basic amino acid concentration between 1-250 mg / mL. (D) adding said salt suitable for human consumption to the preparation of step (C) at a concentration of between 0.3-1.0 M. (E) filtering the preparation of step (D) through a 0.22 micron pore filter.

[0055] In one embodiment of the present invention, the manufacturing method further includes the following steps (F) and (G). (F) freeze-drying the solution filtered in step (E). (G) When applicable, resuspending the composition lyophilized in step (F) in water or a 2.5% glucose solution.

[0056] Another object of the present invention is to provide a method for preparing a pharmaceutical composition for administration to the pulmonary epithelium for the treatment of a respiratory disease, the method comprising the steps of: (A) Dissolving NaOH or Na2CO3 in a volume of 70% of the final volume of pure water heated to 45°C. (B) Adding the NSAID (as a fine powder) to the solution of step (A) and stirring until dissolved. (C) adding a basic amino acid to the solution of step (B); (D) adding salt suitable for human consumption to the composition of step (C) and stirring until dissolved. (E) Adding NaOH or Na2CO3 solution to the solution of step (D) to achieve a pH between 7.5-9.5. (F) cooling the solution obtained in step (E) to room temperature and adding purified water to reach the final volume to obtain an NSAID at a concentration between 1-100 mg / mL, a basic amino acid at a concentration between 1-250 mg / mL, and a salt suitable for human consumption at a concentration between 0.3-1.0 M. (G) filtering the preparation of step (F) through a 0.22 micron pore filter.

[0057] In a more preferred embodiment of the present invention, the manufacturing method includes the following steps (H)(I). (H) freeze-drying the solution filtered in step (E). (I) When applicable, resuspending the composition lyophilized in step (H) in water or a 2.5% glucose solution.

[0058] Another object of the present invention is the use of the pharmaceutical composition for the treatment of a pulmonary disease in a subject (also called a "patient").

[0059] The term "subject" refers to any animal in need of veterinary treatment, including mammals, preferably humans. Examples include pets (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Subjects are collectively referred to as "patients."

[0060] The terms "treat", "treating" and "treatment", when applied to a patient with pulmonary disease, include ameliorating the effects or symptoms of pulmonary disease and shortening the duration of the disease. In cases where the patient is hypoxic, this means returning blood oxygen levels to normal more quickly than would occur without treatment. In cases where the patient is experiencing severe disease, this means reducing the likelihood of needing intubation, shortening the time required for intubation, shortening the recovery period and decreasing mortality.

[0061] The term "effective amount" refers to an amount that, when administered to a patient with a pulmonary disease, provides a beneficial or desired effect, including, but not limited to, ameliorating the effects or symptoms of the pulmonary disease, normalizing blood oxygen levels, shortening recovery time, reducing the likelihood that a critically ill patient will require intubation, and reducing mortality rates.

[0062] The exact amount of an effective amount of pharmaceutical solution to be administered to a patient will depend on the type and severity of the pulmonary disease and the characteristics of the patient (general health, age, sex, weight, tolerance to drugs). Those skilled in the art can determine the appropriate dosage depending on these factors. Appropriate dosages are known to licensed practitioners and can be adjusted by those skilled in the art depending on the condition of the patient and the type of pulmonary disease being treated. The amount of pharmaceutical composition to be administered is reported in the literature and is recommended in the Physician's Desk Reference (57th Edition, 2003). In one example of an "effective amount," the pharmaceutical composition used in the disclosed methods of treatment is between 1 mL and 50 mL. Alternatively, between 1 mL and 25 mL. In another embodiment, between 1 mL and 10 mL. In another embodiment, the "effective amount" is between 3 mL and 7 mL. In another embodiment, the "effective amount" is 3 mL. The "frequency of administration" is between 1 and 5 times per day. Alternatively, between 1 and 3 times per day. The duration of administration varies between 5 minutes and 1 hour, alternatively between 5 minutes and 30 minutes, and in another embodiment, between 10 minutes and 20 minutes.

[0063] A small but significant percentage of patients with respiratory viral infections may progress to severe and even fatal disease (e.g., pneumonia or acute respiratory distress syndrome (ARDS)) (referred to herein as "severe disease"). Pneumonia is an infection that causes inflammation of the air sacs (alveoli) in one or both lungs. The air sacs fill with fluid or pus (purulent material), causing a cough accompanied by mucus or phlegm, fever, chills, and difficulty breathing. ARDS is characterized by fluid building up in the air sacs in the lungs, but may also be accompanied by hyperinflammation. Hyperinflammation can trigger a condition called a "cytokine storm" or systemic inflammation. This can lead to difficulty breathing or death. Symptoms of ARDS include extreme shortness of breath and labored, abnormally rapid breathing, low blood pressure, confusion, and extreme fatigue.

[0064] Low blood oxygen saturation levels also occur in pneumonia and ARDS and are at least partially responsible for the severe symptoms associated with these conditions. Blood oxygen saturation levels provide an integrated assessment of pulmonary and cardiac function. Noninvasive measurement of blood oxygen saturation levels by transcutaneous pulse oximetry has become routine in the assessment of disease severity. A patient is said to have low blood oxygen levels when their blood oxygen saturation by pulse oximetry is less than 95%. This value is the lower limit of normal for normal subjects (patients with chronic hypoxemic hypercapnic respiratory disease). An oxygen saturation of less than 92% is considered an emergency and requires urgent treatment, especially if it changes rapidly from baseline normal values ​​(as is often observed in patients with viral pneumonia). Patients with low blood oxygen levels are also referred to herein as "hypoxic." Patients with respiratory viral infections that have progressed to pneumonia or ARDS, when treated according to the disclosed methods of treatment, experience a return to normal blood oxygenation levels (including alleviation of the severe symptoms associated with ARDS and improved blood oxygen saturation levels).

[0065] The second measure of cardiopulmonary status is the respiratory rate. In healthy adults, this is below 20 breaths / min. Patients with respiratory viral infections that have progressed to pneumonia or ARDS have respiratory rates much higher than this normal value (maximum 21-25 breaths / min). In severe cases, 25-30 breaths / min. In severe cases, 30-40 breaths / min. Such patients, when treated according to the disclosed method of treatment, will see an improvement in their respiratory rate to the normal range, which is one of the factors that alleviate the severe symptoms associated with ARDS mentioned above.

[0066] The third measure of cardiopulmonary status is heart rate. In healthy adults, this is typically 90 beats per minute at rest. In patients with respiratory viral infections that have progressed to pneumonia or ARDS, this number is significantly higher. Patients with respiratory viral infections that have progressed to pneumonia or ARDS have heart rates that are much higher than normal, ranging from 91-110 beats per minute; in severe cases, 111-130 beats per minute; and in extreme cases, 131 beats per minute or higher. Such patients, when treated according to the disclosed methods of treatment, will see an improvement in their heart rate back into the normal range.

[0067] The National Early Warning Score (NEWS2) is a commonly accepted assessment tool to identify patients who will or may develop acute disease. It is disclosed in Non-Patent Document 43. Specifically, a NEWS2 score of 0-4 indicates a low level of clinical risk for the patient, a score of 5-6 indicates a medium level of clinical risk for the patient, and a score of 7 or higher indicates a high level of clinical risk for the patient. Treating patients with a score of 0-4 or 5-6 or 7 or higher using the disclosed treatment methods reduces the likelihood of increasing the score, reduces the score, or reduces the patient to a low score, resulting in an improved condition.

[0068] In particularly severe cases, patients with ARDS require respiratory assistance and are placed on a ventilator. When on a ventilator, the patient is said to be "intubated." The disclosed treatment methods are useful for increasing blood oxygen levels and reducing the likelihood that a patient with severe low blood oxygen levels who is not intubated but will subsequently be intubated will be "intubated." The disclosed treatment methods are also effective in increasing blood oxygen levels in intubated patients, thereby increasing the chances of recovery and reducing the time the patient is on a ventilator.

[0069] In some cases, patients with mild lung disease may be hypoxic, i.e., have low blood oxygen levels. Low blood oxygen levels are an indicator that patients with mild disease are at risk of progressing to severe disease, such as pneumonia or ARDS. The disclosed treatment methods are effective in reducing the likelihood that patients with mild hypoxia will progress to severe disease, such as pneumonia or ARDS. The disclosed treatment methods are effective in treating patients with hypoxia who have already developed severe disease, such as pneumonia or ARDS.

[0070] The disclosed method of treatment treats non-hypoxic patients suffering from mild lung disease, reducing the likelihood that the patient will become hypoxic and progress to severe disease.

[0071] With reference to the above information and the results shown in the examples below, it has been demonstrated that the composition of the present invention shows a significant improvement for the treatment of various pulmonary diseases affecting the lungs. Examples of pulmonary diseases are selected from the group including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pulmonary hypertension, bronchopulmonary dysplasia acute respiratory distress syndrome (ARDS), SARS-CoV-2, respiratory virus, fungal or bacterial infection, bilateral pneumonia, and bronchiectasis. In these pathobiologies, the composition of the present invention, which comprises a mixture of ibuprofen and arginine salts and has a pH of 8.5, administered in a nebulized form, promotes anti-inflammatory effects and improvements in blood oxygen saturation, respiratory rate, heart rate, and blood pressure.

[0072] Working Example Example 1: An alkaline hypertonic ibuprofen (AHI) solution is prepared for the tests conducted in the following examples. In a clear container, add water for injection, equivalent to 70% of the final volume of the dose solution. Then add and dissolve the amount of sodium carbonate required to prepare the dose solution. This process is carried out by mechanical stirring, avoiding contamination and loss of the solution.

[0073] Once the sodium carbonate has dissolved, add the ibuprofen and stir vigorously until completely dissolved.

[0074] Add sodium citrate and once dissolved, add sodium chloride and maintain moderate stirring until the solution is homogenous. Measure the pH of the solution. Adjust the pH of the solution to 8.6 ± 0.1 at 25 degrees C. Add 10% sodium carbonate solution if necessary. After adjusting the pH, add purified water to obtain the final solution.

[0075] Table 1: Composition of alkaline hypertonic ibuprofen (AHI) solution 5ml each 5ml each Concentration Concentration (mg) (mmol) (mg / mL) (mM) Ibuprofen 50.00 0.242 10.00 48.48 Sodium chloride 146.10 2.500 29.22 500.00 Sodium carbonate 30.00 0.283 6.00 56.61 Sodium citrate 10.00 0.039 2.00 7.55 Sodium hydroxide 9.75 0.244 1.95 48.75 Purified water remaining. 5.00 0.277 - -

[0076] Example 2: Preparation of a formulation of the present invention (ibuprofen and arginine solution). The best method known to the inventors for preparing the formulations used in the examples of the present invention is described below, and includes the following steps, although this is not intended to be the only one: (A) Dissolving Na2CO3 in 70% of the final volume of pure water at 45 °C. (B) adding ibuprofen (in fine powder form) to the solution of step (A) and stirring until dissolved; (C) adding arginine hydrochloride to the solution of step (B); (D) adding sodium chloride to the solution of step (C) and stirring until dissolved; (E) Adding Na2CO3 to the solution of step (D) to achieve a pH of 8.5. (F) Cooling the solution obtained in step (E) to room temperature and adding purified water to reach the final volume of the solution. (G) filtering the preparation obtained in step (F) through a filter having a pore size of 0.22 microns (μm);

[0077] Table 2: Composition of preferred compositions of the present invention 5ml each 5ml each Concentration Concentration (mg) (mmol) (mg / mL) (mM) Ibuprofen 50.00 0.242 10.00 48.48 Arginine Hydrogen Chloride 102.2 0.485 20.4 97.3 Sodium chloride 146.10 2.500 29.2 500.00 Sodium carbonate 30.00 0.283 6.00 56.61 Purified water qs 5.00 0.277

[0078] Example 3: The effect of nebulized treatment with AHI solutions containing increasing concentrations of arginine on oxygen saturation, heart rate, and respiratory rate in COVID-19 positive patients. The following abbreviations are used in this and the following examples: "RF" refers to respiratory rate, expressed in breaths / minute. "CF" refers to heart rate, expressed in beats per minute. "PO" refers to oxygen saturation, measured with a pulse oximeter and expressed as a percentage. "BP" refers to systolic / diastolic blood pressure, expressed in mmHg. "HBP" stands for high blood pressure.

[0079] patient 1 Gender: Female Age: 62 Date of hospitalization: August 21, 2021 Discharge date: September 3, 2021 Diagnosis: Mild bilateral pneumonia due to SARS-CoV-2 Pathological personal history: Type 2 diabetes and obesity

[0080] Progression of Patient 1’s Disease Date of admission: August 20, 2021 (had COVID-19 for 8 days prior). PO is 92-93%. Measured at room temperature without supplemental oxygen. RF is 22. CF is 89. The patient receives supplemental oxygen (O2, 2 L / h) and is treated with dexmethasone and heparin. The patient will receive nebulized treatment with AHI solution every 8 hours from August 20, 2021 to August 28, 2021. *August 28, 2021, 11:00 AM: The patient receives 3 mL of nebulized AHI solution containing 6 mM L-arginine hydrochloride. No substantial changes. After 6 hours, the PO value remained at 93%. *August 28, 2021, 5:00 PM: The patient receives 3 mL of nebulized AHI solution containing 12 mM L-arginine hydrochloride. After nebulization, RF is 22. CF is 86. PO is still 93%. *August 28, 2021, 11:00 PM: The patient receives 3 mL of nebulized AHI solution containing 25 mM L-arginine hydrochloride. The PO value remains at 93-94%. *August 29, 2021 at 6:00 AM: Patient receives 3 mL nebulized AHI solution containing L-arginine hydrochloride 50 mM. After nebulized treatment, RF is 22. CF is 86. PO is increased to 96% and maintained at 96% for at least 6 hours. *August 29, 2021, 12:00 AM: The patient receives 3 mL of nebulized AHI solution containing 100 mM L-arginine hydrochloride. After nebulization, RF is 18-19. CF is 75-76. PO is back up, reaching 98-99% and maintained for 8-10 hours. *The patient continued this treatment and was discharged on September 3, 2021. No adventitioius or "added" sounds were observed. The patient reported a much better sensation. No side effects were observed during treatment.

[0081] Example 4: The effect of nebulized treatment with a formulation of the present invention (ibuprofen-arginine solution) on oxygen saturation, heart rate, and respiratory rate in COVID-19 positive patients. patient 2 Gender: Female Age: 52 Date of hospitalization: August 31, 2021 Discharge date: September 6, 2021 Diagnosis: Mild bilateral pneumonia due to SARS-CoV-2 Pathological personal medical history: Obesity (+); Type 2 diabetes (+)

[0082] Progression of Patient 2’s Condition Date of admission: August 31, 2021 (had COVID-19 for 8 days prior). At room temperature, PO is 91-93%. RF is 20. CF is 69. The patient was placed on supplemental oxygen (O2, 2 L / h) and supported with dexamethasone and heparin. Atypical sounds were observed. Bibasilar crackles, predominantly on the right side. Patients will receive nebulized treatment with AHI solution every six hours from August 24, 2021 to August 31, 2021. *August 31, 2021: Patient receives nebulized ibuprofen-arginine solution 3mL every 8 hours. After nebulized treatment, PO was 97% without supplemental oxygen. 8 hours after nebulized treatment, PO was 95% without supplemental oxygen. *The patient continued this treatment and was discharged on September 6, 2021. At this time, PO was 97%. RF was 18. CF was 88. No indeterminate or "added" sounds were observed at this time.

[0083] patient 3 Gender: Male Age: 61 Date of hospitalization: August 21, 2021 Discharge date: September 26, 2021 Diagnosis: Bilateral pneumonia with moderate / severe pattern (TAC) due to SARS-CoV-2 Pathological personal medical history: HBP(+)

[0084] Progression of Patient 3’s condition Date of admission: August 21, 2021. PO is 93%. RF is 21. CF is 70. The patient received supplemental oxygen (intermittent O2 as needed) and was treated with dexamethasone and heparin. Observations: Decreased vesicular murmur, significant dyspnea. The patient will receive nebulized treatment with AHI solution every 8 hours from 08 / 14 / 2021 through 08 / 21 / 2021. *August 21, 2021: The patient received nebulized treatment with 3 mL of ibuprofen-arginine solution every 8 hours. PO reached 98%. 8 hours after nebulized treatment, PO was 95%. *The patient continued this treatment and was discharged on September 26, 2021. At this time, PO was 97%. RF was 20. CF was 68. No adventitious or "added" sounds were observed at this time.

[0085] patient 4 Gender: Male Age: 52 Date of hospitalization: August 31, 2021 Discharge date: September 6, 2021 Diagnosis: Severe bilateral pneumonia due to SARS-CoV-2 Pathological Personal History: Type 1 Diabetes

[0086] Progression of Patient 4’s Condition Date of admission: August 31, 2021 (had COVID-19 for 8 days prior). At room temperature, PO is 88-90%. RF is 22. CF is 88. The patient is given supplemental oxygen (O2, at a rate of 2 L / h) and treated with dexamethasone and heparin. The patient presents with fever, headache, and global hypoventilation. Chronic sounds are observed. The patient is given nebulized treatment with AHI solution every 6 hours on August 26, 2021. *August 31, 2021: The patient received nebulized treatment with 3 mL of ibuprofen-arginine solution every 6 hours. PO reached 94%. 8 hours after nebulized treatment, PO was 91%. *The patient continued this treatment and was discharged on September 6, 2021. At this time, PO was 97%. RF was 17. CF was 74. No indeterminate or "added" sounds were observed.

[0087] Example 5: The effect of nebulized treatment with a formulation of the present invention (ibuprofen-arginine solution) on oxygen saturation, heart rate, and respiratory rate in patients with scar pulmonary fibrosis. patient 5 Gender: Female COVID-19 test: Negative (-) Inspection date: September 10, 2021 Age: 77, Weight: 54kg, Height: 146cm Diagnosis: scar pulmonary fibrosis, traction brochiectasis Progress: At age 48 she inhaled acids (peridine, hydrochloric acid, sulfuric acid) in a laboratory accident. Pathological personal medical history; surgery (appendectomy, amylase resection, bile duct resection), type 2 diabetes (+) HBP (+). Adverse background: Tobacco (+) (smoked 20 cigarettes a day for 16 years, quit 30 years ago. Alcohol (+) Drugs (+) (in the laboratory) Treatment: Atrovent (Ipratropium Bromide) SOS: Physiotherapy. Supplemental Oxygen: 4 litres at night, less during the day. Baseline: PO=91-90-86%. RF=24. CF=115. BP=110 / 80This is with an oxygen backpack. Without the oxygen backpack, PO was reduced to 82%.

[0088] Progression of Patient 5’s Condition Patient 5 began nebulized AHI solution therapy 7 months ago. PO improved from 84% to 90%. Oxygen requirements decreased. Patient 5 was unable to speak or make telephone calls. *September 10, 2021: Patient 5 begins nebulized treatment with ibuprofen-arginine solution, 3 mL every 12 hours. PO improved to 96%. CF decreased to 110. *One hour after nebulization, Patient 5's RF was 24. CF was 102. PO was 92% (without oxygen backpack). Patient 5 was not coughing. He was able to speak. Subjective and objective improvement was observed.

[0089] Example 6: The effect of nebulized treatment with a formulation of the present invention (ibuprofen-arginine solution) on oxygen saturation, heart rate, and respiratory rate in patients with chronic obstructive pulmonary disease (COPD). patient 6 Gender: Male COVID-19 (urgent) test: Negative (-) Date of hospitalization: September 10, 2021 Discharge date: September 25, 2021 Age: 79, Weight: 60kg, Height: 169cm Diagnosis: Chronic obstructive pulmonary disease (COPD), emphysema, pulmonary fibrosis, Progress: Since 2007 the patient has been a passive smoker (kitchen, oven smoke). Pathological personal medical history: Prior to the start of treatment for AHI, patient 6 had recurrent bactrial pneumonias (twice in one year) (requiring hospitalization). He had undergone cholecystectomy. Type 2 diabetes, HBT. Harmful background: tobacco (+), alcohol (+) drugs (-) Treatment: Indacaterol capsules every 12 hours; Hexaler (Desloratadine) every 12 hours

[0090] Progression of Patient 6’s condition Two years ago, Patient 6 started nebulized treatment with 5 mL of AHI solution every 8 hours. (Baseline status: PO 94%, RF 20, CF 72, BP=140 / 80) Patient 6 did not require rehospitalization after that. Patient 6 had pneumonia once, but was cured with antibiotic treatment. He stated that he had continuous white secretion. *September 10, 2021: Patient 6 begins nebulized ibuprofen-arginine solution 5 mL every 8 hours. During nebulized treatment, PO reached 95-97%. CF was 71. Nebulized treatment was temporarily suspended and patient spat out. *One hour after nebulization, CF was 71. PO was 96%. Clinical symptoms improved. The patient continued this treatment and was discharged on September 25, 2021.

[0091] Example 7: The effect of nebulized treatment with a formulation of the present invention (ibuprofen-arginine solution) on oxygen saturation, heart rate, and respiratory rate in patients with bronchiectasis. patient 7 Gender: Female COVID-19 (urgent) test: Negative (-) Date of visit: September 10, 2021 Age: 72, Weight: 58kg, Height: 157cm Diagnosis: Central cylindrical bronchiectasis (partially separated by traction). History of pulmonary disease without medication. Disease evolution: Since 2013. Pathological personal history: Surgery (-) Diabetes (-) HBP (+) 2 normal deliveries (eutocic deliveries) Harmful background: tobacco (-), alcohol (-), drugs (-), stress (+) Treatment: Seretide 250 and fluticasone / salmeterol every 12 hours

[0092] Progression of Patient 7’s Disease Eight months ago, patient 7 was started on nebulized AHI solution at 3 mL every 12 hours (basal line: PO 94%, RF 18, CF 77, BP=125 / 70). This treatment allowed a reduction in the dose of seretide. *September 10, 2021: Patient 6 received nebulized treatment with 3 mL of ibuprofen-arginine solution. During nebulized treatment, PO reached 99%. CF was 75. Patient 7 did not take cough tablets. *One hour after nebulization, CF was 68. PO was 98%. Significant improvement in clinical symptoms was observed.

[0093] Example 8: The effect of nebulized treatment with a preferred formulation of the present invention (ibuprofen-arginine solution) on oxygen saturation, heart rate and blood pressure in patients with bullous emphysema. patient 8 Gender: Male COVID-19 test: Negative (-) Inspection date: September 11, 2021 Age: 72, Weight: 65kg, Height: 176cm Diagnosis: Severe bullous emphysema Disease progression: The patient had been diagnosed with COPD 12 years earlier. He had been suffering from dyspnea since 1977. Pathological personal medical history: Surgery (bile duct resection, prostatic adenocarcinoma, hernia) Diabetes (+) HBP (+) Cerebrovascular accident in 2010. Background: COVID-19(+), COVID-19 was treated with aerosolized AHI solution. Harmful background: Tobacco (+) (60 cigarettes per day, quit 10 years ago), Alcohol (+), Drugs (-) Treatment: inducaterol, frevia (budesonide / formoterol), SOS oxygen therapy, carvedilol, valsartan 160mg.

[0094] Progression of Patient 8’s condition One year ago, the patient began nebulizing with 3 mL of AHI solution every 8 hours (basal line: PO 90-92%, RF 24, CF 76, BP 150 / 90). Patient 8 felt dizzy with this treatment, but his oxygen saturation improved. *September 11, 2021: The patient received nebulized treatment with 3mL of ibuprofen-arginine solution. During nebulized treatment, PO increased to 96-97%. RF was 23. CF was 72. BP=150 / 90. Patient was well enough for treatment. *One hour after nebulization, PO was 98%. RF was 21. CF was 70. BP=130 / 80. No adverse side effects were observed and the patient appeared well.

[0095] Example 9: The effect of nebulized treatment with the formulation of the present invention (ibuprofen-arginine solution) on oxygen saturation, heart rate and blood pressure in patients with bronchial asthma. patient 9 Gender: Female COVID-19 test: Negative Date: September 11, 2021. Nebulized treatment with ibuprofen-arginine solution was started. Age: 64, Weight: 80kg, Height: 162cm Diagnosis: Severe or moderate bronchial asthma, with bronchial hyperresponsiveness (HRB). Evolution of the disease: She had suffered from bronchial asthma since early childhood. During her last pregnancy 35 years ago, she began to suffer from respiratory failure. Pathological personal medical history: Caesarean section to improve respiratory failure, diabetes (+), HBP (+), obesity (+), stress (+++), 3 pregnancies, 2 deliveries Background: COVID-19(+) asymptomatic. Harmful background: Tobacco (-) Alcohol (-) Drugs (-) Treatment: neumoterol, micronized budesonide / micronized formoterol fumarate dihydrate once a day

[0096] Progression of Patient 9’s Condition Nine months ago, the patient was started on nebulized AHI solution. (Baseline: PO 94%, RF 21, CF 74, BP=120 / 80). With this treatment, the patient experienced less croaking. He was able to speak, and dyspnea and coughing with exercise decreased. Sleep quality improved (he was unable to sleep on his back). With this treatment, the pneumoterol dosage was reduced. The patient continues to experience symptoms of bronchospasm, choking, and coughing. *September 11, 2021: The patient received nebulized treatment with 3 mL of ibuprofen-arginine solution. During nebulized treatment, PO reached 99%. RF was 12. CF was 71. Treatment improved breath and reduced itching. *One hour after nebulization, PO was 99%. RF was 13. CF was 71. BP=100 / 60. Subjective and objective symptom improvement was observed. *Walking test: PO at rest 96%. 2 min. Asthma with basal wheezing, PO 94%. At rest and after recovery PO 96%. *After nebulization treatment, patient climbed stairs for the first time in a long time, PO 97%. *In addition, patient 9 underwent spirometry tests before and 60 minutes after nebulized ibuprofen-arginine solution treatment. The results of these tests are shown in Figures 1 and 2, respectively.

[0097] Example 10: The effect of nebulized treatment with a formulation of the present invention (ibuprofen-arginine solution) on oxygen saturation, heart rate, and blood pressure in patients with pulmonary fibrosis after COVID-19. patient 10 Gender: Female COVID-19 test: Negative Age: 53, Weight: 83kg (gained 20kg after COVID-19); Height: 157cm Inspection date: September 11, 2021 The diagnosis: pulmonary fibrosis after COVID-19. Disease progression: COVID-19 infection on September 11, 2021. Asymptomatic. Patient receives nebulized treatment with AHI solution every 8 hours. Next week starts with post-COVID dyspnea, nebulization treatment. Patient is a sportswoman (biking, trekking, crossfit). Pathological personal medical history: bile duct resection surgery, hysterectomy surgery, insulin-dependent obesity after COVID, type 2 diabetes mellitus (+) HBP (+) Treatment: Sertraline and topiramate were administered (to treat depression). Harmful background: Tobacco (-) Alcohol (-) Drugs (-)

[0098] Progression of Patient 10’s Condition Three months ago, Patient 10 began nebulizing with 5 mL of AHI solution every 8 hours. (Basin lines: PO 92-93%. RF 24. CF 85. BP=120 / 90). Patient 10 was experiencing dyspnea. *September 11, 2021: Patient 9 received nebulized ibuprofen-arginine solution, 3 mL. During nebulized treatment, PO was 98-99%. RF was 18. CF was 80. Patient had minimal shivering. *Four hours after nebulization, PO was 98-99%. RF was 17. CF was 82. BP=110 / 70. Patient reported no longer shaking and could breathe through nose. Medical improvement was noticeable. Patient was able to ascend and descend stairs.

[0099] Example 11: The effect of nebulization treatment with the formulation of the present invention and an arginine solution with a pH of 7.0-8.5 on oxygen saturation, heart rate and blood pressure in patients with bronchial asthma. patient 11 Gender: Female Date of admission: September 28, 2021 Age: 71, Weight: 78kg, Height: 162cm COVID-19 test: Negative (-) Diagnosis: Bronchial asthma for 53 years Disease progression: Asthma, requiring several hospitalizations with oxygen therapy. Allergy to ambient dust HRB (+) Pathological personal medical history: Gallbladder surgery, diabetes (-), HRB (+), COVID-19 (+), hospitalization and treatment with AHI solution. Post-COVID fatigue, 4 pregnancies, 3 deliveries, 1 spontaneous abortion. Harmful background: Tobacco (+) Alcohol (+) Drugs (-) Treatment: Seretide Diskus 500 (fluticasone / salmeterol) Normal PO is 95%

[0100] Progression of Patient 11’s Condition Patient's baseline: PO 95%. RF 17. CF 71. BP=165 / 100. Patient is in respiratory distress. *The patient was treated with 3mL of 100mM arginine solution at pH 8.5 by nebulization. During nebulization, PO was maintained at 95%. RF was 19. CF was 63. BP=165 / 100. No changes were observed after 2 hours. *The patient then received nebulized treatment with 3 mL of 100 mM arginine solution, pH 8.5. Thereafter, PO was maintained at 95%. No change was observed after 2 hours. *Finally, the patient was treated with 3mL of ibuprofen-arginine solution, pH 8.5, by nebulization. Immediately after nebulization, PO was 100%. RF was 18. CF was 67. 6 hours after nebulization, PO was 100%. RF was 18. CF was 68. BP=150 / 100. 8 hours after nebulization, PO was still 100%.

[0101] Example 12: The effect of nebulization treatment with a formulation of the present invention at pH 8-8.5 and an arginine solution at pH 7.0-8.5 on oxygen saturation, heart rate and blood pressure in COPD patients. patient 12 Gender: Female Date of admission: September 28, 2021 Age: 81, Weight: 75kg, Height: 164cm COVID-19 test: Negative (-) Diagnosis: COPD, dyspnea on exertion Pathological personal medical history: carpal tunnel surgery, diabetes (negative), HBP (positive), COVID (positive), two pregnancies, two deliveries Harmful background: Tobacco (+) (20 cigarettes a day for 30 years) Alcohol (-) Drugs (-) Treatment: neumoterol (micronized budesonide / micronized fermoterol fumarate dihydrate) administration

[0102] Progression of Patient 12’s Condition Patient's baseline: PO 93%. RF 20. CF 78. BP=135 / 74. Patient is experiencing exertional dyspnea. Some isolated rhonchi are detected. *The patient was treated with 3mL of nebulized arginine solution, 100mM, pH 7. PO was maintained at 93-94%. RF was 20. CF was 70. BP=133 / 75. No clinical changes were observed after 2 hours. *The patient was then treated with 3 mL of 100 mM arginine solution, pH 8.5, by nebulization. PO increased from 94% to 98% in 30 seconds, then dropped rapidly to 93% at the end of nebulization. RF was 21. CF was 66. *The patient then received nebulized treatment with 3 mL of ibuprofen-arginine solution, pH 8. Immediately after the end of nebulized treatment, PO was 97%. RF was 19. CF was 65. BP=134 / 75. 6 hours after the end of nebulized treatment, PO was 96%. RF was 20. CF was 69. BP=132 / 73. Note: In this case, less Na2CO3 was added to the ibuprofen-arginine solution of Example 2, resulting in a final pH of the solution of 8. *Finally, the patient was treated with 3mL of ibuprofen-arginine solution, pH 8.5, by nebulization. Immediately after treatment, PO was 96%. CF was 64. 6 hours after nebulization, PO was 96%. RF was 24. CF was 78. BP=135 / 75. 8 hours after nebulization, PO was 95-98%. RF was 17. CF was 75. BP=130 / 70.

[0103] Example 13: The effect of nebulized treatment with a formulation of the present invention at pH 8.5-9 and an arginine solution at pH 7.0-8.5 on oxygen saturation, heart rate and blood pressure in COPD patients. patient 13 Gender: Male Date of admission: September 28, 2021 Age: 72, Weight: 120kg, Height: 178cm COVID-19 test: Negative (-) Diagnosis: COPD for 15 years, dyspnea due to exercise, grade 2 / 3, Pathological personal medical history: hernia surgery, diabetes (-), HBP (-), COVID-19 (-), obesity (+) Harmful background: Tobacco (+) (20 cigarettes a day for 50 years) Alcohol (-) Drugs (-) Treatment: Nighttime administration of neumoterol (micronized budesonide / micronized formoterol fumarate dihydrate)

[0104] Progression of Patient 13’s Disease Patient's baseline: PO 88-93%. RF 25. CF 84. BP=157 / 95. Bibasilar crackles were observed. *Patient was treated with 3mL nebulized arginine solution, 100mM, pH 7. PO was maintained at 92-93%. No changes were observed. *The patient was then treated with 3 mL of 100 mM arginine solution, pH 8.5, by nebulization. After 5 minutes, PO increased from 94% to 98%, but decreased to 93% by the end of nebulization. *Furthermore, patient 13 received nebulized treatment with 3 mL of ibuprofen-arginine solution, pH 8.5. Immediately after nebulization, PO increased from 93% to 98-100%, and RF was 24. CF was 85. BP=130 / 87. Six hours after nebulization, PO was 97%. RF was 21. CF was 89. BP=134 / 88. Eight hours after nebulization, PO was 94%. RF was 22. CF was 82. BP=134 / 90. *Finally, the patient was treated with 3mL of ibuprofen-arginine solution, pH 9. Immediately after nebulization, PO was 99%. RF was 23. CF was 83. BP=132 / 89. 6 hours after nebulization, PO was 96%. RF was 22. CF was 80. BP=133 / 89. Note: In this case, increasing amounts of Na2CO3 were added to the ibuprofen-arginine solution of Example 2, resulting in a final pH of the solution of 9.

[0105] Example 14: The effect of nebulization treatment with hypertonic alkaline ibuprofen (AHI) solution and the formulation of the present invention (ibu-arginine solution) on oxygen saturation in patients with bilateral pneumonia caused by SARS-CoV-2. Three patients were treated with bilateral pneumonia due to SARS-CoV-2, but PCR(+). First, the patients were treated with AHI solution by nebulization every 8 hours for 48 hours. The treatment response was measured by pulse oximeter readings. The patients were then treated with Eve-Arg solutions containing different concentrations of arginine by nebulization. These solutions were prepared by varying the amount of arginine hydrochloride added to the formulation described in Example 2. Again, at the end of the nebulization treatment, the treatment response was measured by pulse oximeter readings.

[0106] Table 3: Clinical evolution of patients 14, 15 and 16 "Ibu-Argi Solution" is an abbreviation for "Ibuprofen-Arginine Solution." Patient number Treatment 1 PO value before and after treatment 1 Treatment 2 PO value before and after treatment 2 14 AHI solution 88-90 Eve-Argi solution 1 90-93 15 AHI solution 90-91 Eve-Argi solution 2 90-95 16 AHI solution 88-91 Eve-Argi solution 3 92-99 Note: AHI solution: AHI solution is sprayed every 8 hours for 48 hours. Eve-Arginine Solution 1: One spray treatment with Eve-Arginine Solution (arginine 25 mM) Eve-Arginine Solution 2: One spray treatment with Eve-Arginine Solution (50 mM arginine) Eve-Arginine Solution 3: One spray treatment with Eve-Arginine Solution (100 mM arginine)

[0107] Example 15: In vivo determination of superoxide anion production in mouse macrophages. The reaction mechanism of oxidative stress, widely recognized as an important factor in the occurrence and progression of various lung diseases, was inhibited by the formulation of the present invention. To measure the synergistic effect of the ibuprofen-arginine combination on oxidative stress and to determine the extent of the synergistic effect, the inhibitory effect of reactive oxygen species in living cells stimulated by LPS (i.e., exposed to the formulation of the present invention) was studied, and the reduction of ROS was correlated with the therapeutic effect of the formulation of the present invention.

[0108] The method selected determines the inhibitory effect of various preparations on the generation of (O2-) in mouse macrophages stimulated with LPS by measuring the fluorescence of DHE generated from the interaction with superoxide anion (O2-). This method was selected because it is useful for determining (O2-) concentrations and can predict damage to cell systems (Non-Patent Document 44).

[0109] Methods and Materials The commercially available cell line RAW264.7 (mouse macrophage) with passage numbers 20-30 was used. 60,000 cells were seeded per well in a 96-well plate and incubated overnight with DMEM / F12 growth medium (Gibco). The growth medium was supplemented with 0.1% fetal bovine serum (Internegocios) and an antibiotic / antimycotic mixture. The following morning, the growth medium was removed and the cells were washed with phosphate buffered saline (PBS) and incubated for 30 min at 37°C. This incubation was performed with dihydroethidium fluorescent dye (DHE, Invitrogen) at a final concentration of 5 μM in PBS. After this incubation, the cells were washed and incubated for 1 h with the solutions to be tested. The solutions to be tested were ibuprofen (10, 50, 100 μM), arginine (5-100 μM SIGMA) and their combinations, all prepared in PBS solution. Ibuprofen in PBS solution was obtained by dilution of the formulation of Example 1, and arginine in PBS solution was prepared with arginine hydrochloride. Apocinin (50 μM; SIGMA), an uncoupling agent of NAD(P)H oxidase, an inhibitor of superoxide anion production, was included as a control.

[0110] After this incubation, basal fluorescence was measured on a Fluorodkan Ascent plate reader Labsystems using λex=458nm, λem=538nm. LPS (25μg / mL: SIGMA) was added directly to each well, leaving unstimulated controls, and incubated for 60 minutes at 37°C. The fluorescence of the plates was then re-recorded, using the same filters as for basal conditions. For analysis of the results, the value corresponding to the basal fluorescence for each well was subtracted from each final time value. Statistical analysis was performed using GraphPad Prism 6.0 software. One-way ANOVA was performed followed by Tukey's multiple comparison post-test. Data represent the mean ± standard error of the mean (SEM) of two independent experiments.

[0111] Example 16: Inhibitory effect of AHI solution and arginine solution on the production of superoxide anion in macrophages stimulated with lipopolysaccharide (LPS). Mouse macrophages were stimulated with LPS (25 μM / mL) and treated with arginine 50 μM alone or alkaline hypertonic ibuprofen at different concentrations (10, 50, and 100 μM) in PBS saline solution. Cells were loaded with dihydroethidium (DHE) for 30 min at 37°C and normalized fluorescence was determined at basal readings after 60 min of stimulation. As can be seen in Figure 3, LPS (26 μM / mL) stimulated the production of superoxide anion in mouse macrophages, but this effect could not be inhibited by ibuprofen (10, 50, and 100 μM) alone or by arginine (50 μM) alone. Apocynin (50 μM) was used as an inhibitor of NADPH oxidase, an enzyme that generates O2.

[0112] Example 17: Inhibitory effect of AHI solution and arginine on the production of superoxide anion in LPS-stimulated macrophages. Mouse macrophages were stimulated with LPS (25 μM / mL) and treated with hypertonic alkaline ibuprofen 10 μM alone or with different concentrations of arginine (5, 10, 20, 50, 65, 85, 100 μM) in PBS saline solution. Cells were stimulated with dihydroethidium (DHE) for 30 min at 37°C and normalized fluorescence was determined at basal readings after 60 min of stimulation. As can be seen from Figure 4, the molar ratio of arginine / ibuprofen between 1 and 6.5 has a good synergistic effect, i.e., inhibits the increase in the concentration of superoxide anion stimulated by LPS. Examples 16 and 17 clearly show that the formulation of the present invention has a new synergistic effect of reducing the concentration of ROS in living cells. However, this only occurs when arginine is present in solution together with ibuprofen molecules in a certain concentration range.

[0113] In the above description, due to conversion to html, subscript numbers in chemical formulas may be displayed in standard sizes. For example, NA2CO3 stands for Na2CO3. Other examples include MM for mM, ML for mL, and O2 for O2. Unless otherwise stated, the number of devices or means may be singular or plural.

Claims

1. 1. A pharmaceutical composition for administration to the pulmonary epithelium for the treatment of respiratory disorders, comprising: Ibuprofen and arginine are dissolved in a hypertonic aqueous solution with a pH of 7.5-9.

5. The arginine / ibuprofen molar ratio is 6.5 or less.

1. A pharmaceutical composition for administration to the pulmonary epithelium for the treatment of respiratory diseases, comprising:

2. The arginine / ibuprofen molar ratio is greater than or equal to 1. The pharmaceutical composition according to claim 1.

3. The concentration of ibuprofen is between 10 mM and 50 mM The pharmaceutical composition according to claim 1.

4. The ibuprofen is racemic The pharmaceutical composition according to any one of claims 1 to 3.

5. The ibuprofen is the S enantiomer The pharmaceutical composition according to any one of claims 1 to 3.

6. The ibuprofen is the R enantiomer The pharmaceutical composition according to any one of claims 1 to 3.

7. The ibuprofen comprises as a counterion a monovalent cation selected from the group consisting of sodium, potassium, lithium, alginate, lysinate, histidate, and combinations thereof. The pharmaceutical composition according to any one of claims 1 to 6.

8. The concentration of arginine is between 10 mM and 250 mM The pharmaceutical composition according to any one of claims 1 to 7.

9. The pH of the hypertonic aqueous solution is between 8.0 and 9.

0. The pharmaceutical composition according to any one of claims 1 to 8.

10. The pH of the hypertonic aqueous solution is 8.

5. A pharmaceutical composition according to any one of claims 1 to 8.

11. The pharmaceutical composition is administered by spray or inhalation. The pharmaceutical composition according to any one of claims 1 to 10.

12. The form in which the pharmaceutical composition is administered is selected from the group consisting of a liquid form, a powder form, and a freeze-dried form. The pharmaceutical composition according to any one of claims 1 to 10.

13. The salt concentration of the hypertonic aqueous solution is between 0.3M and 2.0M. A pharmaceutical composition according to any one of claims 1 to 12.

14. The salt concentration of the hypertonic aqueous solution is between 0.4M and 1.1M. A pharmaceutical composition according to any one of claims 1 to 12.

15. The salt concentration of the hypertonic aqueous solution is between 0.5M and 1.0M salt. A pharmaceutical composition according to any one of claims 1 to 12.

16. The salt is suitable for human digestion. The pharmaceutical composition according to any one of claims 13 to 15.

17. The salt is selected from the group consisting of sodium chloride, potassium chloride, sodium carbonate, and combinations thereof. The pharmaceutical composition according to any one of claims 13 to 15.

18. The salt is sodium chloride A pharmaceutical composition according to any one of claims 13 to 17.

19. The pulmonary disease is selected from the group comprising asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pulmonary hypertension, bronchopulmonary dysplasia acute respiratory distress syndrome (ARDS), SARS-CoV-2, respiratory viral, fungal or bacterial infection, bilateral pneumonia, bronchiectasis. It is a disease A pharmaceutical composition according to any one of claims 1 to 18.

20. 1. A pharmaceutical composition for administration to the pulmonary epithelium for the treatment of respiratory disorders, comprising: Ibuprofen and arginine are dissolved in a hypertonic aqueous solution with a pH of 7.5-9.

5. The molar ratio of arginine to ibuprofen is equal to or greater than 1 and less than 6.

5.

1. A pharmaceutical composition for administration to the pulmonary epithelium for the treatment of respiratory diseases, comprising:

21. 1. A pharmaceutical composition for administration to the pulmonary epithelium for the treatment of respiratory disorders, comprising: Ibuprofen and arginine are dissolved in a hypertonic aqueous solution with a pH of 7.5-9.

5. the arginine / ibuprofen molar ratio is equal to or greater than 1 and less than 6.5; the concentration of ibuprofen is between 10 mM and 50 mM; The concentration of arginine is between 10 mM and 250 mM 1. A pharmaceutical composition for administration to the pulmonary epithelium for the treatment of respiratory diseases, comprising:

22. A method for producing a pharmaceutical composition according to any one of claims 1 to 21, comprising: (A) mixing the oxidized ibuprofen with an aqueous solution of Na2CO3 at 40°C or above and stirring to maintain a suspension; (B) adding the arginine to step (A); (C) adding NaOH or Na2CO3 to a pH between 7.5-9.5 and stirring to completely dissolve the ibuprofen and arginine, to obtain a concentration of ibuprofen between 1-100 mg / mL and a concentration of basic amino acid between 5-100 mg / mL; (D) adding said salt suitable for human consumption to said preparation of step (C) at a concentration of between 0.3-1.0 M; (E) filtering the preparation of step (D) through a 0.22 micron pore filter; have A method for producing a pharmaceutical composition according to any one of claims 1 to 21.

23. (F) freeze-drying the solution filtered in step (E). Further having 23. The method of claim 22.

24. (G) When applicable, resuspending the lyophilized composition of step (F) in water or a 2.5% glucose solution. Further having 24. The method of claim 23.

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