Development of formulations for the management and antiviral, immunomodulatory and Anti-inflammatory treatment of the new SARS-cov-2 infection and the associated disease, covid-19, and its variants, formulated from glycyrrhizic acid salt and the derivatives thereof

Abstract

The present invention relates to the development of formulations based on the glycyrrhizic acid compound due to its antiviral, anti-inflammatory and immunomodulatory properties, as a syrup at four different concentrations of 0.1, 0.2, 1 and 2 % of the GA compound, as a solution for nebulising at four different concentrations of 0.1, 0.2, 1 and 2 % of the GA compound, and as a spray of liposomal nanoparticles at four different concentrations of 0.1, 0.2, 1 and 2 % of the GA compound. Cough suppressants, bronchospasm inhibitors and anti-corticoids are added, and lastly, the pH is adjusted in a range of 4 – 7 as this is the most physiological range. The invention is for the therapeutic and prophylactic management of infections and clinical symptoms of the infection due to SARS-CoV2 and COVID-19.

Description

[0001] Development of formulations for the management and treatment of anti-iral, immunomodulatory and anti-inflammatory agents of the new SARS-CoV2 infection and the disease developed by COVID-19 and its variants, formulated from the salt of glycyrrhizinic acid and its derivatives of its chemical structure.

[0002] FIELD OF INVENTION.

[0003] The present invention, as expressed in the following statement, refers to the development of a new formulation of the compound glycyrrhizinic acid (GA) or its derivatives in a syrup formulation with a solution of the compound in gel and propylene glycol as a solvent and absorption enhancer, and subsequently the adjustment of the pH for its physiological conditioning and addition of antitussives for administration to patients with infection and clinical manifestations of COVID-19. In nebulization solution, which is a liquid solution that is converted into fine particles that are inhaled and deposited in the respiratory epithelium, added with previously treated water and adjusting its pH for its physiological conditioning.In a spray of liposomal nanoparticles added with an antibronchospasmodic and antihistamine compound and another with glucocorticoid, improving its bioavailability and absorption by formulating it in nanoliposomes, and adjusting its pH for its physiological conditioning.

[0004] OBJECT OF THE INVENTION.

[0005] The objective of the present invention is to develop pharmaceutical formulations for oral and inhaled administration in the therapeutic management of SARS-CoV2 infections and its associated pathology COVID-19. These formulations reduce the viral load due to the inhibition of the penetration of coronaviruses into the target cells, preventing replication, as well as interfering with the viral cycle; modifying its evolution. It also has an immunomodulatory effect, generating an antiviral immune response. The formulation is added with agents with proven and recognized antitussive effect such as dextromethorphan hydrobromide and guaifenesin, in addition to the use of excipients suitable for the administration routes indicated above and with a proven and recognized agent with an inhibitory effect on bronchospasm.

[0006] Dextromethorphan Hydrobromide 0.133 g, Guaifenesin 1.33 g, Vehicle q.s. 100 mL. It has antitussive properties and is an aid in the expectoration of phlegm. They belong to the group of expectorants and are responsible for softening and expelling secretions from the respiratory system. Their joint action is also useful in acute and chronic conditions of the upper and lower airways when their origin is irritative, inflammatory or infectious. And it is used as a mucus thinner.

[0007] Dextromethorphan is chemically related to the opiate agonists and may suppress cough as effectively as codeine, it appears to work through different mechanisms to suppress cough. Sites in the brain have been identified where dextromethorphan binds with high affinity, it is thought that more than one mechanism exists for cough suppression. it may act directly on the cough center in the medulla to suppress cough. Therapeutic doses do not affect ciliary activity, it acts as a low affinity antagonist for the N-methyl-D-aspartate (NMDA) receptor subtype of glutamate.

[0008] With respect to its pharmacokinetics and pharmacodynamics . Dextromethorphan administered orally . It is rapidly absorbed in the gastrointestinal tract , appearing antitussive activity within 15-30 minutes, undergoes rapid and extensive hepatic metabolism producing demethylated metabolites including the active metabolite, dextrorphan. Dextromethorphan is metabolized mainly through cytochrome P450 isoenzymes CYP2D6 . The rate of metabolism varies among individuals according to phenotype (extensive metabolizers or poor metabolizers). The plasma half-life is normally about 11 hours, and the antitussive activity may last between 5-6 hours. Dextromethorphan (D-3 methoxy-N-methylnorphinane) is the disomer of the codeine analogue of levorphanol, but unlike the L- isomer it has no analgesic or addictive properties.In controlled studies in patients it has demonstrated its effectiveness on pathological cough similar to codeine. Although its antitussive effect at therapeutic doses does not inhibit ciliary activity and its antitussive effect persists for 5 to 6 hours; its toxicity is low, but at high doses it produces CNS depression. In standard release oral administration formulations the dosage is as follows: Adults and adolescents: The recommended dose is 10-20 mg PO every 4 hours, or 30 mg PO every 6-8 hours. The maximum daily dose is 120 mg, Children 6-11 years: The recommended dose is 5 to 10 mg orally every 4 hours, or 15 mg PO every 6-8 hours. The maximum daily dose is 60 mg, Children 2-5 years: The recommended dose is 2.5-5 mg orally every 4 hours, or 7.5 mg PO every 6-8 hours.The maximum daily dose is 30 mg, in oral administration as a prolonged-release formulation: Adults and adolescents: The recommended dose is 10 ml (2 teaspoons) PO every 12 hours, not to exceed 20 ml / day, Children 6-11 years: The recommended dose is 5 ml (1 teaspoon) PO every 12 hours, not to exceed 10 ml / day.

[0009] Children 2-5 years: The recommended dose is 2.5 ml (teaspoonful) PO every 12 hours, not to exceed 5 ml / day. Children <2 years: The dose should be individualized by the physician.

[0010] Guayaf enesin (guaiacol) or glyceryl guaiacolate is considered a semi-synthetic substance derived from guaiacolfen. which develops an expectorant action because it increases the production of respiratory tract fluid by reducing the adhesiveness and surface tension of endobronchial mucus. The increased flow of less viscous secretions stimulates ciliary action and facilitates the elimination of mucus through coughing. It has an action superior to that of ammonium chloride, being able to increase respiratory tract secretions by 121%. It is an expectorant that is thought to act by irritating the gastric mucosa and subsequently stimulating respiratory tract secretions, as the fluid increases, the volume increases and the viscosity of bronchial secretions decreases, facilitating expectoration and elimination, achieving a productive and beneficial cough.It is easily absorbed by the digestive tract, and like other expectorants, its metabolites are eliminated renally; Guaifenesin is excreted in the urine unchanged, along with the inactive metabolites p - (2- methoxyphenyl) lactic acid and p - (4-hydroxy-2- methoxyphenyl) lactic acid. The plasma half-life of guaifenesin after oral administration is 1 hour. After administering a dose of 600 mg of guaifenesin to 3 healthy male volunteers, the tl / 2 was approximately 1 hour, and was not detectable in blood after 8 hours. It is used in pathological cough such as dry, unproductive cough, smoker's cough, tracheobronchitis and lung disease.For oral administration: Adults and children over 12 years: the recommended doses are 200 mg to 400 mg every four hours, not to exceed 2400 mg in 24 hours, Children 2 to 6 years: oral, 50 to 0 Omg every four hours (no more than 600mg a day), Children 6 to 12 years: oral, 100 to 200mg every four hours (no more than 1,200mg a day), Guaifenesin is very well tolerated and has a wide safety margin. After administration of 600mg of guaifenesin to healthy adult volunteers, the Cmax was approximately 1.4pg / ml with a tmax of approximately 15 minutes. Distribution: approximately 60% of the absorbed dose undergoes rapid hepatic metabolism, giving rise to metabolites such as beta-(2-methoxy-phenoxy)-lactic acid.

[0011] The sodium salt of cromolyn or sodium cromoglycate, is a compound that has the ability to inhibit bronchospasms induced by antigens, this does not do so through bronchodilator activity, but, it acts on the surface of mast cells inhibiting their degranulation, which prevents the release of histamines and the reactions of late anaphylaxis, these two are mediators of type 1 allergic reactions, in addition it also reduces the release of inflammatory leukocytes, since it inhibits the influx of calcium into these cells. Therefore, sodium cromoglycate reduces bronchial hyperactivity, the asthmatic response to antagonistic stimulation, or exercise.On the other hand, sodium cromoglycate prevents the inhibition of beta 2 adrenergic receptors present in lymphocytes, which inhibits bronchospasm induced by tachykinins. Regarding its pharmacokinetics and pharmacodynamics, we have that its systemic bioavailability after being administered orally is 1%, in the case of intranasal or inhaled administration routes, 5 - 10% reaches the lungs, added to the present bronchoconstriction, in addition it does not cross cell membranes due to its high lipid insolubility, approximately 98% of the dose is eliminated in the feces.

[0012] For inhalation administration for adults and children over 5 years, 20 mg every eight hours (no more than 60 mg per day).

[0013] Beclomethasone is a synthetic halogenated glucocorticoid active by inhalation, used for the treatment of asthma that responds to glucocorticoids and to relieve symptoms associated with allergic and non-allergic rhinitis . Intranasal beclomethasone is about 5000 times more potent than hydrocortisone as an anti-inflammatory and vasoconstrictor . The mechanism of action of beclomethasone, being a glucocorticoid, is a hormone that prevents or suppresses immune and inflammatory responses when administered in pharmacological doses . Free glucocorticoids easily cross cell membranes and bind to specific cytoplasmic receptors, inducing a series of responses that modify transcription and, therefore, protein synthesis.These responses are the inhibition of leukocyte infiltration at the site of inflammation, interference with inflammatory mediators, and suppression of immune responses . The consequence of these effects is the reduction of edema or scar tissue and the suppression of the humoral immune response . The anti-inflammatory action of glucocorticoids involves proteins that inhibit phospholipase A2, called lipocortins . In turn, lipocortins control the biosynthesis of a series of potent mediators of inflammation such as prostaglandins and leukotrienes . Some of the responses of glucocorticoids are the reduction of edema and a general suppression of the immune response.

[0014] Inhaled glucocorticoids decrease IgE synthesis, increase the number of beta-adrenergic receptors on leukocytes, and decrease arachidonic acid synthesis. They are therefore effective in the treatment of chronic bronchial asthma and allergic reactions. During an allergic reaction, allergens bind to IgE antibodies on the surface of mast cells, triggering the release of chemotactic substances by these cells. Activation of mast cells and the substances they secrete are known to be partly responsible for the hyperirritability and inflammation of the pulmonary mucosa in asthmatic subjects. This inflammation can be delayed by the administration of glucocorticoids.

[0015] With regard to pharmacokinetics and pharmacodynamics, beclomethasone is administered by oral or nasal inhalation. After nasal inhalation, beclomethasone is absorbed through the nasal mucosa, with minimal systemic absorption. After oral inhalation, the drug is rapidly absorbed by the lungs and digestive tract, with part of the dose passing into the systemic circulation. However, the absorbed fraction is insufficient to cause systemic effects. The onset of drug action occurs within a few days but may occasionally take up to 3 weeks. Approximately 10-25% of the dose applied by oral inhalation enters the systemic circulation, while a small part, which is deposited in the mouth, is swallowed.

[0016] Beclomethasone entering the systemic circulation is rapidly metabolized in the liver to inactive or slightly active metabolites. The portion absorbed by the lungs is largely metabolized in situ before entering the systemic circulation. Beclomethasone entering the systemic circulation is eliminated primarily in the feces, although a small portion is eliminated in the urine. The elimination half-life is 15 hours.

[0017] Regarding the dosage for inhalation administration: Adults and children over 12 years: The recommended dose is two sprays (42 µg / spray) inhaled orally 3 or 4 times a day. Alternatively, a dose of 4 sprays (42 µg / spray) inhaled orally twice a day may be effective. Doses higher than 20 sprays / day are not recommended (total dose = 840 µg / day).

[0018] Children 6-12 years: The usual recommended dose is 1-2 sprays (42 mcg / spray) inhaled orally 3 or 4 times a day. It is not advisable to exceed 10 sprays (total dose = 420 mcg / day).

[0019] Children < 6 years: The efficacy and safety of beclomethasone have not been established.

[0020] BACKGROUND .

[0021] The COVID-19 pandemic represents a major public health crisis worldwide, where despite accelerated research studies, there is still no specific antiviral drug for the prevention or treatment of COVID-19. Since the first case was reported, more than two hundred countries have also reported cases of COVID-19 and the number of infections reported worldwide is 690,334,600, which has caused 6,891,094 deaths. In Mexico, with a total of 7,627,964 cases and 334,250 deaths, it is in third place, only below countries like the United States and Brazil.

[0022] Coronaviruses are a family of viruses that have caused various epidemic outbreaks, including SARS in 2003, MERS in 2012, and currently the COVID19 pandemic. SARS-CoV2 is a new coronavirus that is characterized by being an enveloped virus and containing RNA as genetic material, which comes from bats and is transmitted from human to human mainly through respiratory droplets, although it can also occur through aerosols; causing a highly infectious and pathogenic disease of the airways of varying severity. The incubation period in most cases is three to seven days, and can reach up to fourteen days, and 95% of patients develop symptoms within thirteen days after exposure.The immune response represents the fundamental mechanism for the effective control of the infection; however , a poorly regulated response can trigger greater lung damage and consequently higher patient mortality . The factors to generate this immune response are rapid viral replication , its ability to recruit cells of the immune system, mainly macrophages and neutrophils , the release of cytokines that mediate inflammation, as well as the decrease in the number and response of T lymphocytes. During infection, an exacerbated immune response against the virus is initiated, which is responsible for the different clinical manifestations and damage to the respiratory epithelium, which would be the central point of the pathophysiology of COVID19, and the cause of patients presenting acute respiratory failure syndrome, septic shock, multiple organ failure and eventually death.Additionally, it is important to mention that one of the effects caused by SARS-CoV2 infection is the manifestation of different symptoms and signs of coagulopathy, this condition is associated with a higher risk of death and has been a determining factor in the outcome of critically ill patients. Among the different coagulopathies associated with COVID-19, thrombotic microangiopathy stands out, with the lungs being the main affected organs and disseminated intravascular coagulation, which is a sepsis-induced coagulopathy and has a substantial impact on organ dysfunction in severely affected patients. Considering the described background and the lack of a specific antiviral treatment, it is necessary to continue researching to explore the potential of new compounds derived from natural products for the prevention and treatment of COVID-19.

[0023] In addition to the above, it is worth describing the characteristics of what has been called long COVID , which is a multisystemic condition that includes symptoms that follow a SARS-CoV2 infection , so it is known that around 10% - 30% of infected people have long COVID , that is, more than 150 million people have some complication caused by long COVID . The different hypotheses that are taken as causes for this pathogenesis are: persistent reservoirs of SARS-CoV2 in different tissues; immune dysregulation with reactivation of pathogens such as herpesvirus; the effect of SARS-CoV2 infection on the microbiota and virome; and the generation of autoimmunity.Long-term COVID affects different organs and causes different diseases and symptoms such as: in the heart, it causes heart failure and inflammation of the cardiac tissue, this is reflected in chest pain and tachycardia; in the lungs, it causes abnormal exchange of oxygen and carbon dioxide, which is reflected in dyspnea and cough; in the gastrointestinal tract, it causes an alteration in the microbiota as the intestinal mucosa is where the reservoir and viral persistence occur; in the nervous system: it causes dysautonomia, which is the dysfunction of the nerves of the autonomic nervous system, neuroinflammation, reduction of cerebral blood flow, which manifests itself in memory loss, ringing in the ears, sleep disorders, and fatigue; while in the pancreas it causes damage that can cause type 2 diabetes; in addition to other pathologies and symptoms.

[0024] Continuing with the writing, we have that glycyrrhizic compounds are extracted from the root of a legume called Glycyrrhiza glabra, whose common name is licorice and has been used since ancient times in the botanical medicine of Japan, Russia, Spain, India, the Middle East and China. There are written references to its use since the year 2, 100 BC. Glycyrrhizinic acid is a triterpenoid glycosan derived from beta-amyrin, whose chemical name is (3beta-20p)-20-carboxyl- l l-oxo-30-norolean-12-en-3-yl-2-0-p- D-glucopyranuronosyl-aD-glucopyranosiduronic acid; its formula is C42-H62-O16 and its molecular weight is 822. 94.

[0025] Glycyrrhizinic Acid is made up of two structures, the structure of 1813-glycyrrhetinic acid and the structure of glucuronic acid. These sugars allow the absorption of the active ingredient to be metabolized and have a greater effect of its pharmaceutical properties in the human body, glucuronic acid which has greater malleability due to its dissolution for different presentations or pharmaceutical products.

[0026] Based on the above, we can say that glucuronic acid has an important function in phase II of hepatic metabolism, since it helps with hepatic detoxification through expulsion through urine or bile, and through conjugation with compounds mediated by UDP-glucuronosyltransferase, since this enzyme is also present in other organs such as the intestine, kidneys, brain, among others. On the other hand, the enzyme that carries out the separation of glucuronic acid and the compounds to which it is bound by a hydrolysis process is b-glucoranidase, which is present in the intestine where hydrolysis is carried out, so that glucuronic acid is absorbed into the bloodstream.In this context, glucuronic acid is considered to be a highly water-soluble molecule and, when conjugated with other compounds or drugs, it gives them greater solubility in the human physiological environment, so that its distribution throughout the human body is favored, as well as its pharmacokinetic and pharmacodynamic properties. Likewise, the different properties described above (such as its participation in important biological processes) make glucuronic acid a highly useful compound as a pharmaceutical intermediate.

[0027] That said, glucuronic acid provides the ideal property to the complete glycyrrhizinic acid molecule to be properly absorbed and distributed throughout the body, which helps to reach the different lodging sites of SARS-CoV2, generating infectious and inflammatory processes in Prolonged COVID.

[0028] Finally, as previously mentioned and according to the authors Kowalska and Kalinowska-Lis (2019), glycyrrhizinic acid (figure la) has two glucuronic acid molecules coupled to its structure (figure Ib), therefore, it can be affirmed that its pharmacological properties antiviral, anti-inflammatory, immunomodulatory, hepatoprotective, neuroprotective, and on metabolic syndrome and diabetes mellitus II, which are direct effects on Prolonged COVID, which will be described later, as well as its pharmacokinetics and pharmacodynamics are objectively improved and enhanced compared to the derived molecule 1813-glycyrrhetinic acid (AGZ) (figure 1c), the latter and according to PubChem (2023b), has a molecular formula of C30H46O4 and its molecular weight is 470 g / mol, this molecule does not present the two molecules of glucuronic acid as shown in image 1c.Furthermore, since this is a triterpenoid, it does not have adequate water solubility for the human physiological environment, resulting in limited bioavailability. On the other hand, the conjugation of diaglucuronic acid to glycyrrhizinic acid gives it greater bioavailability at the location where the different proteins and molecules that are the pharmacological targets it has to reach and where it exerts its therapeutic action are located. For these different reasons, the administration of glycyrrhizinic acid exerts a distinguishable therapeutic action, compared to its derivative, 1813-glycyrrhetinic acid, which has to be modified by conjugating it with accessory molecules such as liposomes to provide it with the solubility and bioavailability of the predecessor molecule.

[0029] Glycyrrhizinic acid has been used as an anti-inflammatory, antiulcer, antithrombotic, antiallergenic, anticarcinogenic in hepatocarcinomas secondary to viral hepatitis and as an antiviral. Its effect is due to the inhibition of enzymes that metabolize prostaglandins (PGE2 and PGE2a) to their inactive form; in the gastroduodenal mucosa it acts as an antiulcer, and a possible therapeutic agent against strains of Helycobacter pylori; it is antithrombotic, by inhibiting thrombin; as an anticarcinogenic in hepatocarcinomas secondary to Hepatitis C and its antiviral activity has been tested particularly against Coronaviruses associated with severe acute respiratory syndrome, respiratory syncytial virus, arboviruses, flaviviruses causing yellow fever, dengue and Japanese encephalitis, herpes simplex virus, HIV-1, vesicular stomatitis virus, CHIKY and SFV viruses and chickenpox virus.

[0030] The antiviral activity of glycyrrhizinic acid is attributed to its interaction with the protein structure of the capsid and interference with the viral cycle, inhibiting the replication of viral DNA and RNA . In the case of Herpes simplex, it irreversibly inactivates the virus and promotes the activation of interferon . The characteristic of these viruses is that they have the property of infecting the epithelium and mucous membranes . Regarding its effect on Coronaviruses, various tests carried out in vitro have been reported where its effect has been evaluated compared to antivirals such as ribavirin, 6-azauridine, pyrazofurin and mycophenolic acid; and of all the compounds, glycyrrhizinic acid showed greater inhibitory potency of the replication activity of SARS-related viruses, as well as inhibition of the adsorption and penetration of the virus into its target cells, during the early stages of the viral replication cycle.An effect similar to that of interferon-beta, but without the toxicity effects that this can present, due to the higher doses at which the antiviral effect is achieved. Another important mechanism of glycyrrhizinic acid is its immunomodulatory effect, and the best known is the antagonistic effect of the mechanisms dependent on the Tolk-4 type receptors (TLR4), as a consequence of its antagonistic effect is the reduction of inflammation in various tissues, including the lung. It also leads to a reduction in the expression of these TLR4 receptors in the heart and lungs, this is accompanied by a significant reduction in the release of cytokines (TNFa, IL6 and ILl p), consequently, it has a protective effect on the respiratory syndrome induced by TLR4, activated by lipopolysaccharides (LPS). Another important mechanism of action is on the "Spike" protein.

[0031] ( S ) of coronaviruses, these proteins play an important role in the entry of viruses into host cells mediated by receptors, so an inhibitor of these S proteins would be of clinical relevance to inhibit the entry of coronaviruses into cells. Glycyrrhizinic acid has demonstrated a high affinity of interaction with the SI subunit of the Spike protein of SARS-CoV-2 and MERS-CoV, at the binding interface with its ACE2 receptor. Also demonstrating low toxicity towards normal lung cells. In addition to the above, it is necessary to highlight the importance and characteristics of the anticoagulant effect of the AG compound as a therapeutic agent, because this lies in the pathologies that involve the generation of thrombi in people.

[0032] Glycyrrhizinic acid has an anticoagulant effect, since it can interact with thrombin, which is an enzyme present in the blood and active in blood coagulation. Likewise, glycyrrhizin binds to the anion-binding exosite 1, which is far from the catalytic site of thrombin. Consequently, glycyrrhizin selectively inhibits thrombin-induced platelet aggregation and fibrinogen coagulation, since these are two events dependent on the anion-binding exosite 1. For their part, Jiang et al. (2014) found that the compound AG has anticoagulant activity, since it directly inhibits factor Xa, which is a relevant factor in the coagulation cascade, since it can be activated by the extrinsic and intrinsic pathways.Likewise, its mechanism consists of binding in a site different from the active site, so, this is a non-competitive inhibitor, in addition to this, it was found that, unlike other drugs used as anticoagulants, the AG compound did not present itself as a hemorrhagic agent in mice, which is a clear advantage compared to other drugs.

[0033] Finally, it can be summarized that the AG compound has clear anticoagulant properties and can interfere with fundamental factors that trigger the formation of blood clots, which is the main condition in various pathologies, such as thrombosis and various embolisms. That said, it is considered important to conduct clinical trials in humans to verify the efficacy of the AG compound as an anticoagulant agent, since, to date, only in vitro and mouse trials have been conducted. This is aimed at obtaining a drug based on the AG compound for application in humans and that can restore health. The therapeutic doses of AG used vary and were generally determined based on its concentrations in plasma and its elimination time from the body through different clinical trials.Acceptable doses are considered to be: Intravenously 20 to 50 mg / kg of weight every 24 hours of Neo-Minophage C (SNMC), and ingested 1 to 10 mg daily. Another recommended dose is 200-800 mg in infusion equivalent to 5-15 g of dry extract in 150 ml of water three times a day after meals; for up to 4-6 weeks, and the root is used as a flavoring in a daily dose equivalent to 100 mg of glycyrrhizinic acid . It is proposed that the maximum safe dose is 1,500 mg / kg of weight with an accumulation time in the body of 2 to 4 months. The maximum reported time of exposure to the compound is 16 years. Another recommended safe dose is 100 mg / day, used chronically and does not induce pathophysiological changes. In the context of SARS a dose greater than 300 mg / day has been recommended for oral administration and 240 mg / day for intravenous administration.For a primary prevention indication, a dose of 150 mg / day orally has been recommended, although further studies are recommended to evaluate the effect of this dose.

[0034] Based on what has been described above, in addition to having carried out clinical trials in volunteer patients based on protocol Official Letter No. DEI / 1566 / 13, Registration No. 101 / 100 / 003 / 13 authorized by the Public Health Ethics Committee of the Federal District (now Mexico City) at the "Dr. Manuel Pesqueira" Health Center in Mexico City in the dysplasia area of ​​​​said health center, in order to evaluate the antiviral activity of the compound glycyrrhizinic acid (AG) and its derivatives and following the provisions of the standards and actions used in health emergencies indicated by the Mexican health secretary, the compound AG was used in two different formulations, syrup and nebulization solution, obtaining the following results:

[0035] Patients diagnosed with a molecular biology test positive for SARS-CoV2 infection and subsequently treated with AG compound-based syrup for 10 days, so that at the end of their treatment their result of the diagnosis by molecular biology test for SARS-CoV2 infection was negative.

[0036] Pac to . sex f. Result, f. Result pretx . posttx .

[0037] It is important to mention that the term Pac . refers to patient , a . refers to age, f . pretx is pre-treatment result , f . post-treatment is post-treatment result, FEM. is female, MASC. is male, (+) is positive and (-) is negative.

[0038] Patients diagnosed with a molecular biology test positive for SARS-CoV2 infection and subsequently treated with a nebulizer solution based on AG compound for 10 days, so that at the end of their treatment their molecular biology test result for SARS-CoV2 infection was negative.

[0039] Pac to . sex f. Result, f. Result pretx . posttx .

[0040] SOM 38 FEM. 06 / 25 / 20 (+) 07 / 29 / 20 (-)

[0041] RSV 25 MASC. 07 / 10 / 20 (+) 08 / 05 / 20 (-)

[0042] TMJ 27 FEM. 07 / 22 / 20 (+) 08 / 17 / 20 (-)

[0043] It is important to mention that the term Pac. refers to patient, a. refers to age, f. pretx is pre-treatment result, f. post-treatment is post-treatment result, FEM. is female, MASC. is male, (+) is positive and (-) is negative.

[0044] Therefore, the AG compound can be considered a therapeutic agent for restoring the health of patients infected with SARS-CoV2, since it helped eliminate the virus from said patients.

[0045] Below we will describe the properties that make Polyoxyethylene-polyoxypropylene-polyoxyethylene the vehicle of choice for formulating Glycyrrhizinic Acid and its justification in terms of its pharmaceutical use.

[0046] Polyoxyethylene-polyoxypropylene-polyoxyethylene is a gel that can be used as a carrier of active molecules by several routes of administration such as oral, respiratory tract and intranasal (via nebulization), ocular, vaginal, rectal, topical, intramuscular and even as artificial skin has also been reported. Surface-active block copolymers such as polyoxyethylene-polyoxypropylene-polyoxyethylene (POE-POP-POE) are widely used as solubilizing and wetting agents. Some of these possess special properties that make them particularly useful for use in topical formulations; these include their low toxicity and their ability to form clear gels in aqueous media. Polyoxyethylene-polyoxypropylene-polyoxyethylene is of particular interest because concentrated solutions of >20% w / w of the copolymer transform from clear, low-viscosity solutions to solid gels at body temperature.This suggests that when these gels are placed on the skin or injected into a body cavity, the preparation will form a solid artificial barrier and therefore a sustained release reservoir of the drug. These characteristics were taken into consideration when choosing Polyoxyethylene-polyoxypropylene-polyoxyethylene as the vehicle for the new formulation of glycyrrhizinic acid. However, for a technician with average knowledge in the field, obtaining the formulation of the present invention is not obvious, since it is not a simple union of two already known pharmacological molecules, but it had to be tested in these same ones to achieve the stability of the AG compound with the other molecules and with the previously treated water, which generated new formulations for us.

[0047] DETAILED DESCRIPTION OF THE INVENTION.

[0048] Solubility tests. Before preparing the gels, it was necessary to determine the solubility of the AG in aqueous solution - since the gels are prepared in water - and a low solubility value was found: 1.1 mg / ml.

[0049] Which means that the amount that can be dissolved in water is very small. The AG turned out to be very soluble at pH greater than 9.0, hence it was necessary to test the solubility of the AG in different polar and non-polar organic solvents: Methyl alcohol, ethyl alcohol, isopropyl alcohol, ether, acetone, dichloromethane, chloroform, hexane, etc. Referred to in the patent with registration number PA / a / 2006 / 003643.

[0050] It was found to be insoluble in all of them, this fact is important because it also laid the groundwork for implementing the analytical method by HTPLC (High Performance Thin Layer Chromatography) for the quantification of glycyrrhizinic acid. Finally, it was necessary to test its solubility in other substances that are commonly used in the pharmaceutical industry as vehicles.

[0051] The substances that were tested as co-solvents to solubilize glycyrrhizinic acid were: Glycerin, Transcutol and

[0052] Propylene glycol.

[0053] In Glycerin and Transcutol, glycyrrhizinic acid was insoluble, however, in Propylene glycol the acid dissolved adequately: 89.6 mg / ml

[0054] This is one of the main reasons why it was chosen as part of the vehicle to formulate AG in a Polyoxyethylene-polyoxypropylene-polyoxyethylene gel. Furthermore, PG has been shown to be a penetration promoter - a chemical substance that increases the partitioning and diffusion - of active ingredients for pharmaceutical or cosmetic use towards and through the skin permeability barrier. This is a property that can be used to promote the passage of AG through the gastric mucosa at a given time.

[0055] Analytical method. It is also important to mention that the analytical method for the quantification of AG is practically already in place and this will be HTPLC on reversed phase plates, showing the following analytical response by AG. The concentration range in which the analytical response is linear is already available and this will serve to quantify AG in in vitro tests consisting of permeation tests through the mucosa of a pig's vagina. This is why the formulation of the present invention proves to be viable and inventive since there is no precedent that has any formulation of glycyrrhizinic acid as an active ingredient in syrup, nebulization solution, and liposomal nanoparticle spray for epithelial tissue of the respiratory tract such as the one described below and for the therapeutic uses that we have given it.

[0056] Dextromethorphan hydrobromide is a drug widely used for its properties as an antitussive, because it has a pronounced and specific inhibitory action of the antitussive center, without narcotic or analgesic effects. It does not interfere with expectoration and cough to keep the airways clear of secretion. Its structure C18H25NOHBr H20, with a molecular mass of 271.41 g / mol is a white, crystalline, odorless powder, practically insoluble in water and freely soluble in chloroform.

[0057] The proportions and methodologies with respect to each of the new formulations proposed in this writing will be described below, so we will take as a reference for this utility model the application with identification code PA / a / 2006 / 003643, where different formulations of thermoreversible gels at different concentrations of active ingredient compound AG are described, which were used for the lower genital tract (vagina, cervix, anus, vulva and penis), so that said concentrations are 10, 20, 100 and 200 mg / mL and we will refer to them as El, El i, FU I, FIV respectively. And of which their preparation and formulation will be described below.

[0058] For the first in a container we place previously treated water equivalent to 60 - 65% v / v, with constant gentle stirring and at a temperature of 2 to 6 ° C, and add 20 - 23 % of Polyoxyethylene-polyoxypropylene-polyoxyethylene. This solution will be left for 12 hours or until the polymer is completely dissolved. In another container place 13 - 15 % v / v of propylene glycol and add 1 % w / v of compound AG and 0. 1 % of Methyl-Paraben, the latter as a preservative agent, mix with constant stirring and at 65-75 ° C until a homogeneous solution is obtained and finally this is added to the first solution and mixed until both solutions are completely combined. Continuing with FI I first in a container we place previously treated water equivalent to 60 - 65% v / v, with constant gentle stirring and at a temperature of 2 to 6 ° C, and add 20 - 23% of Polyoxyethylene-polyoxypropylene-polyoxyethylene.This solution is left for 12 hours or until the polymer is completely dissolved. In another container, 12-16% v / v of propylene glycol is placed and 2% w / v of the AG compound and 0.1% of Methyl-Paraben are added, the latter as a preservative agent, mix with constant stirring and at 65-75 ° C until a homogeneous solution is obtained and finally this is added to the first solution and mixed until both solutions are completely combined.

[0059] Continuing with the FU I first in a container we place previously treated water equivalent to 25 - 30% v / v, with constant gentle stirring and at a temperature of 2 to 6 ° C, and add 7 - 10% of Polyoxyethylene-polyoxypropylene-polyoxyethylene. This solution will be left for 12 hours or until the polymer is completely dissolved. In another container, place 53 - 57% v / v of propylene glycol and add 10% w / v of the AG compound and 0. 1% of Methyl-Paraben, the latter as a preservative agent, mix with constant stirring and at 65-75 ° C until a homogeneous solution is obtained and finally this is added to the first solution and mixed until both solutions are completely combined.

[0060] Finally, for IVF first in a container we place previously treated water equivalent to 25-30% v / v, with constant gentle stirring and at a temperature of 2-6°C and add 7-10% of Polyoxyethylene-polyoxypropylene-polyoxyethylene. This solution will be left for 12 hours or until the polymer is completely dissolved. In another container place 58-52% v / v of propylene glycol and add 20% w / v of compound AG and 0. 1% of Methyl-Paraben, the latter as a preservative agent, mix with constant stirring and at 65-75°C until a homogeneous solution is obtained and finally this is added to the first solution and mixed until both solutions are completely combined.

[0061] It is worth mentioning that the 4 thermoreversible gels obtained were prepared under sterile conditions, and were also packaged in previously sterilized containers and stored at a temperature of 2 to 6 ° C. That said, and continuing with the description, the following methodologies corresponding to the different syrup formulations as a pharmaceutical form will be detailed, which will be presented in 4 different concentrations of active ingredient compound AG, said concentrations are 1 mg / mL, 2 mg / mL, 10 mg / mL and 20 mg / mL, so we will refer to each syrup as jarabel, jarabell, jarabelll and jarabelV respectively. And of which their elaboration and formulation will be described below.

[0062] For the production of syrup, which has a concentration of 0.1% of AG compound, therefore, we start with a container add the equivalent of 18 - 22% v / v of previously treated water, which will be heated between 70 - 80 ° C and then add 38 - 42% w / v of sucrose, this solution will be subjected to gentle stirring and constant temperature until the sucrose is completely incorporated, when this happens, the constant gentle stirring will be left and the temperature will be lowered to 40 ° C, then add 7 - 9% v / v of glycerin. In another container add 1.8 - 2.2% v / v of ethanol and dissolve 0.15 - 0.18% w / v of Methyl-Paraben, this solution is added to the one obtained previously. Similarly, in another container, add 3 - 5% v / v of previously treated water and dissolve 0.06 - 0.09% w / v of Propyl-paraben, the resulting solution will be added to the solution obtained previously.Subsequently in another container place 2 - 4 % ethanol and add 0.06 - 0.1 % w / v dextromethorphan hydrobromide an, and mix until obtaining a homogeneous solution, this will be added to the solution obtained previously. In another container add 8 - 10 % v / v of previously treated water and add 0.7 - 0.9 % w / v of 3— (2 - methoxyphenoxy) -1 , 2-propanediol (guaifenesin) and mix until completely homogenized, the resulting solution will be added to the solution obtained previously.

[0063] To the resulting solution add 10% v / v of the AG El thermoreversible gel, and 3-5% of 90% glucose. Mix with gentle stirring and constant temperature until all components are fully integrated, finally the resulting solution is made up to 100% of the volume created, allowed to cool to room temperature and filtered, before finally storing and refrigerating. The entire process must be carried out under sterile conditions. For the production of jarabell, which has a concentration of 0.2 of compound AG, so we start with a container add the equivalent of 18 - 22% v / v of previously treated water, which will be heated between 70 - 80 ° C and then add 38 - 42% w / v of sucrose, this solution will be subjected to gentle stirring and constant temperature until the sucrose is completely incorporated, when this happens, the constant gentle stirring will be left and the temperature will be lowered to 40 ° C, then add 7 - 9% v / v of glycerin. In another container add 1.8 - 2.2% v / v of ethanol and dissolve 0.15 - 0.18% w / v of Methyl-Paraben, this solution is added to the one obtained previously. Similarly, in another container, add 3-5% v / v of previously treated water and dissolve 0.06-0.09% w / v of propylparaben. The resulting solution will be added to the previously obtained solution. Subsequently, in another container, place 2-4% ethanol and add 0.06-0.1 % w / v dextromethorphan hydrobromide an, and mix until obtaining a homogeneous solution, this will be added to the solution obtained previously. In another container add 8 - 10 % v / v of previously treated water and add 0.7 - 0.9 % w / v of 3— (2 — methoxyphenoxy) -1 , 2-propanediol (guaifenesin) and mix until completely homogenized, the resulting solution will be added to the solution obtained previously.

[0064] Add 10% v / v of AG Eli's thermoreversible gel and 3-5% 90% glucose to the resulting solution. Mix with gentle stirring and constant temperature until all components are fully integrated. Finally, the resulting solution is diluted to 100% of the volume obtained, allowed to cool to room temperature, filtered, and then stored and refrigerated. The entire process must be carried out under sterile conditions.

[0065] For the preparation of jarabellll, which has a concentration of 2% of compound AG, so we start with a container add the equivalent of 18 - 22% v / v of previously treated water, which will be heated between 70 - 80 ° C and then add 38 - 42% w / v of sucrose, this solution will be subjected to gentle stirring and constant temperature until the sucrose is completely incorporated, when this happens, the constant gentle stirring will be left and the temperature will be lowered to 40 ° C, then add 7 - 9% v / v of glycerin. In another container add 1.8 - 2.2% v / v of ethanol and dissolve 0.15 - 0.18% w / v of Methyl-Paraben, this solution is added to the one obtained previously. Similarly, in another container, add 3-5% v / v of previously treated water and dissolve 0.06-0.09% w / v of propylparaben. The resulting solution will be added to the previously obtained solution. Then, in another container, place 2-4% ethanol and add 0.06 - 0.1 % w / v dextromethorphan hydrobromide an, and mix until obtaining a homogeneous solution, this will be added to the solution obtained previously. In another container add 8 - 10 % v / v of previously treated water and add 0.7 - 0.9 % w / v of 3— (2 — methoxyphenoxy) -1 , 2-propanediol (guaifenesin) and mix until completely homogenized, the resulting solution will be added to the solution obtained previously.

[0066] To the resulting solution, add 10% v / v of the AG FUI thermoreversible gel and 3-5% 90% glucose. Mix with gentle stirring and constant temperature until all components are fully integrated. Finally, the resulting solution is diluted to 100% of the volume obtained, allowed to cool to room temperature, filtered, and finally stored and refrigerated. The entire process must be carried out under sterile conditions.

[0067] For the preparation of syrupV, so we start with a container add the equivalent of 18 - 22% v / v of previously treated water, which will be heated between 70 - 80 ° C and then add 38 - 42% w / v of sucrose, this solution will be subjected to gentle stirring and constant temperature until the sucrose is completely incorporated, when this happens, the constant gentle stirring will be left and the temperature will be lowered to 40 ° C, then add 7 - 9% v / v of glycerin. In another container add 1.8 - 2.2% v / v of ethanol and dissolve 0.15 - 0.18% w / v of Methyl-Paraben, this solution is added to the one obtained previously. Similarly, in another container, add 3-5% v / v of previously treated water and dissolve 0.06-0.09% w / v of propylparaben. The resulting solution will be added to the previously obtained solution. Subsequently, in another container, place 2-4% ethanol and add 0.06-0.1% w / v dextromethorphan hydrobromide and mix until a homogeneous solution is obtained, this will be added to the solution obtained previously. In another container, add 8 - 10% v / v of previously treated water and add 0.7 - 0.9% w / v of 3- (2-methoxyphenoxy) -1, 2-propanediol (guaifenesin) and mix until completely homogenized, the resulting solution will be added to the solution obtained previously.

[0068] To the resulting solution add 10% v / v of the thermoreversible AG FIV gel, and 3 - 5% of 90% glucose. Mix with gentle stirring and constant temperature until all components are fully integrated, finally the obtained solution is made up to 100% of the previously treated water. It is allowed to cool to room temperature and filtered, and finally stored and refrigerated.

[0069] Additionally, it is important to mention that all solutions had their pH adjusted to 5 - 6 and that the entire process was carried out under sterile conditions.

[0070] Continuing with the description of the formulations, we will explain the processes for making four nebulizer solutions, which present different concentrations of the active ingredient compound AG, said concentrations being 1 mg / mL, 2 mg / mL, 10 mg / mL and 20 mg / mL, so we will refer to each nebulizer solution as nebulization!, nebulization!!, nebulization!!! and nebulizationlV. And their preparation and formulation will be described below.

[0071] To prepare the nebulizer solution, which has a concentration of 0.1% AG compound, 85-95% v / v of previously treated water is initially placed in a container, with gentle stirring and a constant temperature of 60 °C, then 5-15% of the FI thermoreversible gel is added and mixed until fully incorporated. Finally, it is packaged and stored in refrigeration. It is worth mentioning that the entire manufacturing process was carried out under sterile conditions.

[0072] For the preparation of the nebulization solution!!, which has a concentration of 0.2% of AG compound, initially 85 - 95% v / v of previously treated water is placed in a container, with gentle stirring and a constant temperature of 60 ° C, then 5 - 15% of the FII thermoreversible gel will be added, and it will be mixed until completely incorporated. Finally, it will be packaged and stored in refrigeration. It is worth mentioning that the entire manufacturing process was carried out under sterile conditions.

[0073] For the preparation of the nebulization solution II, which has a concentration of 1% of AG compounds, initially 85 - 95% v / v of previously treated water is placed in a container, with gentle stirring and a constant temperature of 60 ° C, subsequently 5 - 15% of the thermoreversible gel FU I will be added, and it will be mixed until it is completely incorporated. Finally, it will be packaged and stored in refrigeration.

[0074] For the preparation of the nebulization solutionlV, which has a concentration of 2% of AG compound, initially 85 - 95% v / v of previously treated water is placed in a container, with gentle stirring and a constant temperature of 60 ° C, subsequently 5 - 15% of the FIV thermoreversible gel will be added, and it will be mixed until it is completely incorporated. Finally, it will be packaged and stored in refrigeration.

[0075] It is worth mentioning that the pH of the solutions was adjusted to 6-7 and that the entire manufacturing process was carried out under sterile conditions. It is also important to mention that a crucial process for administering the nebulization solutions is the phoneticization of the vowels for proper distribution and absorption of the nebulization solution.

[0076] Continuing with the description of the formulations, the methodology corresponding to four formulations for liposomal nanoparticle spray for administration through the respiratory tract will be detailed. These formulations have as active ingredient the sodium salt of cromolyn and the compound AG, of the latter the following 4 different concentrations will be used at 1 mg / mL, 2 mg / mL, 10 mg / mL and 20 mg / mL, so that consequently we will refer to these as sprayl, sprayl l, sprayl lly spraylV. And their preparation and formulation will be described below.

[0077] For the preparation of the spray, which has a concentration of 0. 1% of compound AG, so it starts by placing in a container 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol and 4 - 6% v / v of propylene glycol, this solution will be placed under constant stirring with medium intensity, until the components are fully integrated, then 0.15 - 0.18% w / v of Methyl-Paraben will be added, this will act as a preservative agent, in addition 7 - 9% w / v of the sodium salt of cromolyn and 5 - 15% v / v of the thermoreversible gel of compound AG FI will be added, maintaining constant stirring, then 18 - 22% of Guinoxome will be added, which is a liposomal solution composed of phosphatidylcholine, ethanol and polysorbate 20. Once the solution is completely homogeneous, the pH will be adjusted between 6.5 and 7.5 with lactic acid or sodium hydroxide.The solution will then be filtered using a 220-nanometer filter to ensure the nanoliposomes are of a uniform size. Finally, it will be packaged in a glass container at room temperature, in a cool, dry place protected from light.

[0078] For the preparation of sprayll, which has a concentration of 0.2% of compound AG, so it begins by placing in a container 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol and 4 - 6% v / v of propylene glycol, this solution will be placed in constant stirring with medium intensity, until the components are fully integrated, then 0.15 - 0.18% w / v of Methyl-Paraben will be added, this will fulfill the function of preservative agent, in addition 7 - 9% w / v of the sodium salt of cromolyn and 5 - 15% v / v of the thermoreversible gel of compound AG FII will be added, maintaining constant stirring, then 18 - 22% of Guinoxome will be added, which is a liposomal solution composed of phosphatidylcholine, ethanol and polysorbate 20. To ensure that the solution is completely homogeneous, the pH will be adjusted between 6.5 and 7.5 with lactic acid or sodium hydroxide.The solution will then be filtered using a 220-nanometer filter to ensure the nanoliposomes are of a uniform size. Finally, it will be packaged in a glass container at room temperature, in a cool, dry place protected from light.

[0079] For the preparation of spraylll, which has a concentration of 2% of compound AG, so it begins by placing in a container 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol and 4 - 6% v / v of propylene glycol, this solution will be placed in constant stirring with medium intensity, until the components are fully integrated, then 0.15 - 0.18% w / v of Methyl-Paraben will be added, this will fulfill the function of preservative agent, in addition 7 - 9% w / v of the sodium salt of cromolyn and 5 - 15% v / v of the thermoreversible gel of compound AG FU I will be added, maintaining constant stirring, then 18 - 22% of Guinoxome will be added, which is a liposomal solution composed of phosphatidylcholine, ethanol and polysorbate 20. Once the solution is completely homogeneous, the pH will be adjusted between 6.5 and 7.5 with lactic acid or sodium hydroxide.Subsequently, the solution will be filtered using a 220 nanometer filter with the objective that the nanoliposomes remain of a homogeneous size, and finally it will be packaged in a glass container at room temperature, in a cool, dry place protected from light.

[0080] For the preparation of spraylV, which has a concentration of 2% of AG compound, it is started by placing in a container 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol and 4 - 6% v / v of propylene glycol, this solution will be placed in constant stirring with medium intensity, until the components are fully integrated, then 0. 15 - 0. 18% w / v of Methyl-Paraben, this will act as a preservative agent, in addition 7-9% w / v of the sodium salt of cromolyn and 5-15% v / v of the thermoreversible gel of AG FIV compound will be added, maintaining constant stirring, then 18-22% of Guinoxome will be added, which is a liposomal solution composed of phosphatidylcholine, ethanol and polysorbate 20. Once the solution is completely homogeneous, the pH will be adjusted between 6.5 and 7.5 with lactic acid or sodium hydroxide.Subsequently, the solution will be filtered using a 220 nanometer filter with the objective that the nanoliposomes remain of a homogeneous size, and finally it will be packaged in a glass container at room temperature, in a cool, dry place protected from light.

[0081] All preparation of the formulations was carried out under sterile conditions involving asepsis and antisepsis, use of a laminar or flammable hood and autoclave.

[0082] Continuing with the description of the formulations, the methodology corresponding to four formulations for liposomal nanoparticle spray for administration through the respiratory tract will be detailed. These formulations have as active ingredient the sodium salt of cromolyn and the compound AG, of the latter the following 4 different concentrations will be used at 1 mg / mL, 2 mg / mL, 10 mg / mL and 20 mg / mL, additionally this formulation integrates beclamethasone, which has the function of adjuvant, for the inhibition of inflammatory processes, so consequently we will refer to these as sprayV, sprayVI, sprayVII and sprayVIII. And of which their elaboration and formulation will be described below.

[0083] For the preparation of sprayV, which has a concentration of 0.1% of compound AG, 0.1% of beclomethasone and 7 - 9% of sodium salt of cromolyn, so it begins by placing in a container 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol and 4 - 6% v / v of propylene glycol, this solution will be placed in constant stirring with medium intensity, until the components are fully integrated, subsequently 0.15 - 0.18% w / v of Methyl-Paraben will be added, this will fulfill the function of preservative agent, in addition 0.1% of beclamethasone, 7 - 9% w / v of the sodium salt of cromolyn and 5 - 15% v / v of the thermoreversible gel of compound AG FI will be added, maintaining constant stirring, then 18-22% of Guinoxome will be added, which is a liposomal solution composed of phosphatidylcholine, ethanol and polysorbate 20. Once the solution is completely homogeneous, the pH will be adjusted between 6.5 and 7.5 with lactic acid or sodium hydroxide.The solution will then be filtered using a 220-nanometer filter to ensure the nanoliposomes are of a uniform size. Finally, it will be packaged in a glass container at room temperature, in a cool, dry place protected from light.

[0084] For the preparation of sprayVI, which has a concentration of 0.2% of compound AG, 0.1% of beclomethasone and 7 - 9% of sodium salt of cromolyn, so it begins by placing in a container 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol and 4 - 6% v / v of propylene glycol, this solution will be placed in constant stirring with medium intensity, until the components are fully integrated, then 0.15 - 0.18% w / v of Methyl-Paraben will be added, this will fulfill the function of preservative agent, in addition 0.1% of beclamethasone, 7 - 9% w / v of the sodium salt of cromolyn and 5 - 15% v / v of the thermoreversible gel of compound AG FII will be added, maintaining constant stirring, then will add 18 - 22% of IT

[0085] Guinoxome, which is a liposomal solution composed of phosphatidylcholine, ethanol, and polysorbate 20. Once the solution is completely homogeneous, the pH is adjusted to between 6.5 and 7.5 with lactic acid or sodium hydroxide. The solution is then filtered using a 220-nanometer filter to ensure the nanoliposomes are of a homogeneous size. Finally, it is packaged in a glass container at room temperature, in a cool, dry, and light-protected place.

[0086] For the preparation of sprayVII, which has a concentration of 1% of compound AG, 0.1% of beclomethasone and 7 - 9% of sodium salt of cromolyn, so it begins by placing in a container 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol and 4 - 6% v / v of propylene glycol, this solution will be placed in constant stirring with medium intensity, until the components are fully integrated, subsequently 0.15 - 0.18% w / v of Methyl-Paraben will be added, this will fulfill the function of preservative agent, in addition 0.1% of beclamethasone, 7 - 9% w / v of the sodium salt of cromolyn and 5 - 15% v / v of the thermoreversible gel of compound AG FUI will be added, maintaining constant stirring, then 18-22% of Guinoxome will be added, which is a liposomal solution composed of phosphatidylcholine, ethanol and polysorbate 20. Once the solution is completely homogeneous, the pH will be adjusted between 6.5 and 7.5 with lactic acid or sodium hydroxide.The solution will then be filtered using a 220-nanometer filter to ensure the nanoliposomes are of a uniform size. Finally, it will be packaged in a glass container at room temperature, in a cool, dry place protected from light.

[0087] For the preparation of sprayVII, which has a concentration of 2% of compound AG, 0.1% of beclomethasone and 7 - 9% of sodium salt of cromolyn, so it begins by placing in a container 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol and 4 - 6% v / v of propylene glycol, this solution will be placed in constant stirring with medium intensity, until the components are fully integrated, subsequently 0.15 - 0.18% w / v of Methyl-Paraben will be added, this will fulfill the function of preservative agent, in addition 0.1% of beclamethasone, 7 - 9% w / v of the sodium salt of cromolyn and 5 - 15% v / v of the thermoreversible gel of compound AG FIV will be added, maintaining constant stirring, then will be added 18 - 22% of Guinoxome, which is a liposomal solution composed of phosphatidylcholine, ethanol and polysorbate 20. Once the solution is completely homogeneous, the pH will be adjusted between 6.5 and

[0088] 7.5 with lactic acid or sodium hydroxide. The solution is then filtered using a 220-nanometer filter to ensure the nanoliposomes are of a uniform size. Finally, it is packaged in a glass container at room temperature, in a cool, dry, and light-protected place.

Claims

CLAIMS Having sufficiently and clearly described my invention, and considering document PA / a / 2006 / 003643 as a reference and background; > I consider the following clauses to be novel and, therefore, claim them as my exclusive property:

1. Syrup formulation, based on 0.1% of AG compound, which is characterized by being composed of 30 - 38% v / v of previously treated water, 38 - 42% w / v of sucrose, 7 - 9% v / v of glycerin, 4 - 6% v / v of ethanol, 0.15 - 0.18% w / v of Methyl-Paraben, 0.06 - 0.09% w / v of Propyl-paraben, 0.06 - 0.1% w / v dextromethorphan hydrobromide, 0.7 - 0.9% w / v 3-(2-methoxyphenoxy)-1,2-propanediol (guaifenesin), 10% v / v AG FI thermoreversible gel, and 3 - 5% v / v 90% glucose.

2. Syrup formulation, based on 0.2% of AG compound, which is characterized by being composed of 30 - 38% v / v of previously treated water, 38 - 42% w / v of sucrose, 7 - 9% v / v of glycerin, 4 - 6% v / v of ethanol, 0.15 - 0.18% w / v of Methyl-Paraben, 0.06 - 0.09% w / v of Propyl-paraben, 0.06 - 0.1% w / v of dextromethorphan hydrobromide, 0.7 - 0.9% w / v of 3- (2-methoxyphenoxy) -1, 2-propanediol (guaifenesin), 10% v / v of AG FI thermoreversible gel, and 3 - 5% v / v of 90% glucose.

3. Syrup formulation, based on 1% of AG compound, which is characterized by being composed of 30 - 38% v / v of previously treated water, 38 - 42% w / v of sucrose, 7 - 9% v / v of glycerin, 4 - 6% v / v of ethanol, 0.15 - 0.18% w / v of Methyl-Paraben, 0.06 - 0.09% w / v of Propyl-paraben, 0.06 - 0.1% w / v dextromethorphan hydrobromide, 0.7 - 0.9% w / v 3-(2-methoxyphenoxy)-1,2-propanediol (guaifenesin), 10% v / v AG FI thermoreversible gel, and 3 - 5% v / v 90% glucose.

4. Syrup formulation, based on 2% of AG compound, which is characterized by being composed of 30 - 38% v / v of previously treated water, 38 - 42% w / v of sucrose, 7 - 9% v / v of glycerin, 4 - 6% v / v of ethanol, 0.15 - 0.18% w / v of Methyl-Paraben, 0.06 - 0.09% w / v of Propyl-paraben, 0.06 - 0.1% w / v dextromethorf an hydrobromide, 0.7 - 0.9% w / v of 3-(2-methoxyphenoxy)-1, 2-propanediol (guaifenesin), 10% v / v of AG FI thermoreversible gel, and 3-5% v / v of 90% glucose.

5. Nebulization solution formulation! based on 0.1% AG compound, which is characterized by being composed of 5 - 10% v / v of the thermoreversible AG FI gel and 85 - 95% v / v of previously treated water.

6. Nebulization solution formulation!! Based on 0.2% AG compound, it is characterized by being composed of 5-10% v / v of the thermoreversible AG FU gel and 85-95% v / v of previously treated water.

7. Formulation of nebulization solution based on 1% AG compound, characterized by being composed of 5 - 10% v / v of AG FUI thermoreversible gel and 85 - 95% v / v of previously treated water.

8. Formulation of nebulization solutionlV based on 2% AG compound, which is characterized by being composed of 5 - 10% v / v of the thermoreversible AG FIV gel and 85 - 95% v / v of previously treated water.

9. Liposomal nanoparticle spray formulation based on 0.1% of AG compound, which is characterized by being composed of 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol, 4 - 6% v / v of propylene glycol, 0.14 - 0.18% w / v of methyl paraben, 5 - 15% v / v of thermoreversible AG FI gel and 7 - 9% w / v of the sodium salt of cromolyn.

10. Liposomal nanoparticle spray formulation based on 0.2% AG compound, which is characterized by being composed of 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol, 4 - 6% v / v of propylene glycol, 0.14 - 0.18% w / v of methyl paraben, 5 - 15% v / v of AG FII thermoreversible gel and 7 - 9% w / v of the sodium salt of cromolyn.

11. Formulation of liposomal nanoparticle spraylll based on 1% of AG compound, which is characterized by being composed of 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol, 4 - 6% v / v of propylene glycol, 0.14 - 0.18% w / v methyl paraben, 5-15% v / v AG FUI thermoreversible gel and 7-9% w / v cromolyn sodium salt.

12. Formulation of sprayIV of liposomal nanoparticles based on 2% of AG compound, which is characterized by being composed of 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol, 4 - 6% v / v of propylene glycol, 0.14 - 0.18% w / v of methyl paraben, 5 - 15% v / v of thermoreversible AG FIV gel and 7 - 9% w / v of the sodium salt of cromolyn.

13. SprayV formulation of liposomal nanoparticles based on 0.1% of AG compound, which is characterized by being composed of 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol, 4 - 6% v / v of propylene glycol, 0.14 - 0.18% w / v of methyl paraben, 5 - 15% v / v of thermoreversible AG FI gel, 7 - 9% w / v of the sodium salt of cromolyn and 0.1% of beclomethasone.

14. SprayVI formulation of liposomal nanoparticles based on 0.2% of AG compound, which is characterized by being composed of 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol, 4 - 6% v / v of propylene glycol, 0.14 - 0.18% w / v of methyl paraben, 5 - 15% v / v of AG FII thermoreversible gel, 7 - 9% w / v of the sodium salt of cromolyn and 0.1% of beclomethasone.

15. SprayVII formulation of liposomal nanoparticles based on 1% of AG compound, which is characterized by being composed of 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol, 4 - 6% v / v of propylene glycol, 0.14 - 0.18% w / v of methyl paraben, 5 - 15% v / v of AG FUI thermoreversible gel, 7 - 9% w / v of the sodium salt of cromolyn and 0.1% of beclomethasone.

16. Spray formulationVIII of liposomal nanoparticles based on 2% of AG compound, which is characterized by being composed of 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol, 4 - 6% v / v of propylene glycol, 0.14 - 0.18% w / v of methyl paraben, 5 - 15% v / v of AG FUI thermoreversible gel, 7 - 9% w / v of the sodium salt of cromolyn and 0.1% of beclomethasone.

17. Process according to claims 1 to 4, wherein to achieve the preparation of the syrup formulations at concentrations 0.1, 0.2, 1 and 2% of the glycyrrhizinic acid (GA) compound, the following is required: In a container, add the equivalent of 18 - 22% v / v of previously treated water, which will be heated between 70 - 80 ° C and then add 38 - 42% w / v of sucrose, this solution will be subjected to gentle stirring and constant temperature until the sucrose is completely incorporated, when this occurs, the constant gentle stirring will be left and the temperature will be lowered to 40 ° C, then add 7 - 9% v / v of glycerin. In another container, add 1.8 - 2.2% v / v of ethanol and dissolve 0.15 - 0.18% w / v of Methyl-Paraben, this solution is added to the one obtained previously. Similarly, in another container, add 3 - 5% v / v of previously treated water and dissolve 0.06 - 0.09% w / v of Propyl-paraben, the resulting solution will be added to the solution obtained previously. Later, in another container, place 2 - 4% ethanol and add 0.06 - 0.1% w / v dextromethorphan hydrobromide and mix until a homogeneous solution is obtained, this will be added to the solution obtained previously. In another container add 8 - 10% v / v of previously treated water and add 0.7 - 0.9% w / v of 3— (2— methoxyphenoxy) -1 , 2-propanediol (guaifenesin) and mix until completely homogenized, the resulting solution will be added to the solution obtained previously. To the resulting solution add 10% v / v of the thermoreversible gel (El, Eli, Eli and FIV) of AG El, and 3 - 5% of 90% glucose. Mix with gentle stirring at a constant temperature until all components are fully integrated. Finally, the resulting solution is diluted to 100% of the volume obtained. It is then allowed to cool to room temperature, filtered, and the pH adjusted to 5-6. The entire process must be carried out under sterile conditions.

18. Process according to claims 5 to 8, where to achieve the preparation of the nebulization solution formulations at concentrations 0.1, 0.2, 1 and 2% of the glycyrrhizinic acid (GA) compound, the following is required: 85 - 95% v / v of previously treated water is placed in a container, with gentle stirring and a constant temperature of 60 °C, then it is 5-15% of the thermoreversible gel (FI, FII, FUI, and FIV) of compound AG will be added and mixed until fully incorporated, adjusting the pH to 6-7. Finally, it will be packaged and stored in refrigeration. It is worth mentioning that the entire manufacturing process was carried out under sterile conditions.

19. Process according to claims 9 to 12, where to achieve the preparation of the liposomal nanoparticle spray formulations at concentrations of 0.1, 0.2, 1 and 2% of the glycyrrhizinic acid (GA) compound, the following is required: in a container, 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol and 4 - 6% v / v of propylene glycol, this solution will be placed under constant stirring with medium intensity, until the components are fully integrated, then 0.15 - 0.18% w / v of Methyl-Paraben will be added, this will fulfill the function of preservative agent, in addition 7 - 9% w / v of the sodium salt of cromolyn and 5 - 15% v / v of the thermoreversible gel of compound AG (FI, FII, FUI and FIV) will be added, maintaining constant stirring, then 18 - 22% of Guinoxome will be added, which is a liposomal solution composed of phosphatidylcholine, ethanol and polysorbate 20. Once the solution is completely homogeneous, the pH will be adjusted between 6.5 and 7.5 with lactic acid or sodium hydroxide. The solution will then be filtered using a 220-nanometer filter to ensure the nanoliposomes are of a uniform size. Finally, it will be packaged in a glass container at room temperature, in a cool, dry place protected from light.All preparation of the formulations was carried out under sterile conditions.

20. Process according to claims 13 to 16, where to achieve the preparation of the liposomal nanoparticle spray formulations at concentrations of 0.1, 0.2, 1 and 2% of the glycyrrhizinic acid (GA) compound, the following is required: in a container, 45 - 55% v / v of previously treated water, 8 - 12% v / v of ethanol and 4 - 6% v / v of propylene glycol, this solution will be placed under constant stirring with medium intensity, until the components are fully integrated, then 0.15 - 0.18% w / v of Methyl-Paraben will be added, this will act as a preservative agent, in addition 7 - will be added 9% w / v of the sodium salt of cromolyn, 0.1% of beclomethasone and 5-15% v / v of the thermoreversible gel of compound AG (FI, FU, FU and FIV), maintaining constant stirring, then 18-22% of Guinoxome, a liposomal solution composed of phosphatidylcholine, ethanol, and polysorbate 20, was added. Once the solution was completely homogeneous, the pH was adjusted to between 6.5 and 7.5 with lactic acid or sodium hydroxide. The solution was then filtered using a 220-nanometer filter to ensure the nanoliposomes were of a homogeneous size. Finally, it was packaged in a glass container at room temperature, in a cool, dry, and light-protected place. All formulation preparation was carried out under sterile conditions.

21. Administration process of claims 5 to 8, where in order to have the expected therapeutic effect, it is necessary to phoneticize the vowels during the administration of the nebulization solution, since this ensures adequate distribution and absorption of the AG compound.

22. Use of the formulations in syrup, nebulization solution and spray of liposomal nanoparticles, according to claims 1 to 20, for the management of the SARS-CoV-2 and COVID19 infections described above, where the formulation is used for a period of 7 to 15 days on average and even up to 20-30 days depending on the degree of symptoms or persistence of the viral infection.

23. Use of the formulations in syrup, nebulization solution and spray of liposomal nanoparticles, according to claims 1 to 20, for the prophylaxis of COVID-19 and other severe clinical manifestations caused by SARS-CoV2, and prolonged COVID.

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