WO2022226613A1

WO2022226613A1 - Mouthwash formulation with activity in inhibiting the sars-cov-2 virus and reducing related pathologies

Info

Publication number: WO2022226613A1
Application number: PCT/BR2022/050137
Authority: WO
Inventors: Ygurey Tiaraju Elmano DE OLIVEIRA
Original assignee: Sternberg, Eric; MUNHOZ, Rubia Fernanda De Oliveira
Priority date: 2021-04-26
Filing date: 2022-04-25
Publication date: 2022-11-03
Also published as: BR102021007901A2

Abstract

The present invention relates to a formulation for producing a product to be used to prevent infections by coronavirus, especially SARS-CoV-2, with the aim of reducing the viral load in persons who have tested positive, have symptoms or are asymptomatic. The formulation contains a mixture of components with, in a volume q.s. for 100 of a purified water base, the addition of: 0.2% chlorhexidine digluconate (chlorhexidine); 0.2% liquid mint aroma (AROMAX MENTA LÍQUIDO); 0.1% Nipazol; 0.1% Nipagin; and 0.1% crystal BHT (butylhydroxytoluene). The product is mixed in a conventional mixing device. The resulting product is a liquid, in the form of a mouthwash, for use in particular by persons who are healthy or infected with coronavirus, especially the SARS-CoV-2 strain. The product is used by rinsing the mouth and gargling with 10 ml of the product, a full rinse lasting 30 seconds and being carried out twice daily, resulting in a decrease in the viral load in the saliva of persons diagnosed with Covid-19 and forming a long-lasting protective layer in the region of the oral cavity, oropharynx and epiglottis, inactivating the virus. In the case of persons who are not infected, this layer protects the region the virus first attaches to, thereby preventing potential infection.

Description

DESCRIPTIVE REPORT

"FORMULATION FOR MOUTH RINSE WITH INHIBITING ACTION OF THE SARS-COV-2 VIRUS AND REDUCER OF RELATED PATHOLOGIES"

Introduction

[001] This descriptive report refers to a patent application for a formulation developed with the purpose of inhibiting or reducing the action of contagion by viruses, in particular SARS-CoV-2 and other similar strains, as well as how to minimize the action of the disease caused by the virus in the body of an infected person.

[002] More specifically, the product resulting from the formulation, after its use by oral rinse, results in the reduction of the salivary viral load of the person diagnosed with covid-19, forming a long-lasting protective layer in the region of the oral cavity, oropharynx. and epiglottis, inactivating the virus. In the case of uninfected people, this layer protects the first binding site of the virus, controlling possible infection.

Technique comments

[003] As is well known, since the end of 2019 the world has been highly affected by a new strain of coronavirus, SARS-CoV-2.

[004] Coronaviruses are a large family of viruses common in many different species of animals, including camels, cattle, cats, and bats. Rarely, coronaviruses that infect animals can infect people, for example MERS-CoV and SARS-CoV. However, in December 2019, there was the transmission of a new coronavirus. (SARS-CoV-2), which was identified in Wuhan, China and caused COVID-19, then spread and transmitted person to person.

[005] COVID-19 is a disease caused by the coronavirus, called SARS-CoV-2, which has a clinical spectrum ranging from asymptomatic infections to severe conditions. According to the World Health Organization, the majority (about 80%) of patients with COVID-19 may be asymptomatic or oligosymptomatic (few symptoms), and approximately 20% of detected cases require hospital care due to respiratory difficulties, of which approximately 5% may require ventilatory support. The symptoms of COVID-19 can range from a cold, to an Influenza-GS Syndrome (presence of an acute respiratory condition, characterized by at least two of the following symptoms: feverish sensation or fever associated with sore throat, headache, cough, runny nose) to severe pneumonia.

[006] The most common symptoms of the disease are:

• Cough

• Fever

• Coryza

• Sore throat

• Difficulty breathing

• Loss of smell (anosmia)

• Change in taste (ageusia)

• Gastrointestinal disorders (nausea/vomiting/diarrhea)

• Tiredness (asthenia) • Decreased appetite (hyporexia)

• Dyspnea (shortness of breath)

[007] Transmission happens from one sick person to another or by close contact through contaminated handshake touch, droplets of saliva, sneezing, coughing, phlegm, contaminated objects or surfaces.

[008] Prevention measures that greatly help to reduce the transmission of the virus between people are also known globally, such as: using easy protective masks; frequently wash your hands with soap and water or sanitize them with 70% alcohol-based hand rub; cover nose and mouth with tissue or the inside of the elbow when coughing or sneezing; do not touch eyes, nose, mouth or the easy protection mask with unsanitized hands; maintain a minimum distance of 1 (one) meter between people in public and social places; avoid physical contact; sanitize frequently and not share personal objects; keep environments clean and well ventilated; among others.

[009] In summary, since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, there have been more than 113 million confirmed cases of coronavirus disease in 2019 (COVID-19) worldwide. , resulting in more than 2.5 million deaths. In the absence of effective systemic antimicrobial agents, prophylaxis is crucial for disease control. The gold standard of epidemic disease prophylaxis is a combination of vaccine immunization, use of prophylactic antimicrobial agents, and isolation of the causative microorganism. As public distribution of a SARS-CoV-2 vaccine is underway, prophylactic recommendations currently focus on in isolating the virus through social distancing, wearing a mask, washing hands and disease tracking.

[010] Currently, in addition to vaccines that are being administered to people at a considerably slow pace, laboratories have been studying other actions and products that inhibit the transmission and contamination of the virus and/or the symptoms of the disease.

[011] As an example of solutions presented, the following patent documents can be cited, which represent the state of the applied technique:

- CN111904971A, entitled “Application of saikosaponin A to preparation of anti-COVID-19 virus drug”, and which claims an application of saikosaponin A for the preparation of a COVID-19 anti-virus drug. Through the binding effect of drugs and an ACE2 protein and infectivity of seudovirus, the drug-restriction effect on COVID-19 virus can be evaluated, and saicosaponin A can be determined to be used for COVID antivirus drug preparation -19. Saicosaponin A and ACE2 protein have a certain binding ability, so the infectivity of anti-COVID-19 pseudovirus can be effectively reduced, and saicosaponin A has a certain antiviral effect;

- W02 005037296A1, entitled “ANTI-CORONA VIRUS AGENT” and which claims an effective antiviral agent in the treatment of coronavirus that can be applied in several products, whose durability of effectiveness is promising. In particular, an antiviral agent being effective in the treatment of coronaviruses, comprising a silver ion carrier; a product capable of inactivating coronavirus, comprising the same; and a method of inactivating coronavirus. The silver ion transporter is a member selected from potassium titanate, potassium uranate, potassium vanadate, potassium niobate, sodium tungstate, magnesium molybdate, potassium pentaborate, aluminosilicate, aluminum phosphate, nickel hexacyanoferrate, sepiolite , montmorolite, silica gel, montmorolite, beta-alumina, titanium oxide hydrate, hydroxyapatite and glass carriers, represented by the formula (1): AgaAbM2c (P04) d.nH20 (1).

[012] Even so, the main action to be taken nowadays is precisely to minimize the spread of the virus, since, despite the excellent application of the products available until then, as is the case of the above exposed, the transmission of the virus is high and uncontrolled.

[013] In addition, products with high efficacy in combating the symptoms of the disease caused by the virus in the human body, which are the main causes of mortality among people of all ages, are not yet known.

Objectives of the invention

[014] Aiming precisely to solve and/or minimize the problems exposed above, the inventor comes to teach a formulation for a mouthwash type product, easy to access and use, with an inhibitory action on the transmission of SARS-CoV-2 and other similar strains , as well as the reduction of symptoms caused by the disease and its duration.

[015] In studies performed, the authors of the present application investigated the use of chlorhexidine gluconate as an oropharyngeal antimicrobial agent against SARS-CoV-2 infection, where concluded that chlorhexidine is a simple and safe addition to current COVID-19 prevention guidelines and can play a significant role in reducing the spread of the disease.

Detailed description of the invention

[016] The "FORMULATION FOR MOUTHWRINSE WITH INHIBITING ACTION OF THE SARS-COV-2 VIRUS AND REDUCER OF RELATED PATHOLOGIES", object of this patent application, consists of a formulation to obtain a product that inhibits the transmission power of the coronavirus, in particular SARS-CoV-2, and reducing the symptoms that affect the body of infected people and their duration.

[017] The formulation contains a mixture of components where, in volume q.s.p 100 of a base of purified water, are added by weight:

- The amount of 0.2% of Chlorhexidine Digluconate (Chlorhexidine), this component being responsible for providing the product with antiseptic action, presenting antifungal, bactericidal and antiviral action. Its antimicrobial action inhibits bacterial and viral proliferation. This component was selected because of its toxicity of 1,800mg/kg/day (body weight), which makes it practically non-toxic, in addition to being non-polluting and not exhaling gases;

- The amount of 0.2% of liquid mint aroma (AROMAX MENTA LÍQUIDO), this component being responsible for the mentholated aroma of the product;

- The amount of 0.1% of Nipazol, for its preservative and antimicrobial properties; - The amount of 0.1% of Nipagin, for its preservative properties and effective action against bacteria, fungi and yeasts;

- The amount of 0.1% of BHT Cristal (ButylHydroxyToluene), as it is an organic compound with antioxidant and preservative properties and antimicrobial activity.

[018] The mixture of the product is carried out to obtain 40 liters of mouthwash product preferentially, and the components in weight measurement are listed below for a better understanding of the balance.

[019] For 40L of product, therefore, in 39,404.9g of purified water are added:

- The amount of 400g of Chlorhexidine Digluconate (Chlorhexidine);

- The amount of 80 ml of liquid mint aroma (AROMAX LIQUID MINT), ·

- The amount of 40g of Nipazol;

- The amount of 40g of Nipagin; and

- The amount of 40g of BHT Cristal.

[020] The mixing of components is performed in common mixing equipment.

[021] Thus composed and after mixed, the formulation results in a liquid product of the mouthwash type to be used especially by people infected by the coronavirus, especially the SARS-CoV-2 strain, symptomatic or asymptomatic, and by healthy people (not infected by this strain). Use with a mouthwash and gargle with 10 ml of the product resulting from the formulation. above, being a complete oral rinse for 30 seconds twice a day, resulting in the reduction of the salivary viral load of the person diagnosed with covid-19, forming a long-lasting protective layer in the region of the oral cavity, oropharynx and epiglottis, inactivating the virus. In the case of uninfected people, this layer protects the first binding site of the virus, controlling possible infection.

Studies and methods carried out to define the formulation for the mouthwash product

[022] Materials and methods:

[023] The authors performed a prospective cohort study conducted at four community hospitals in Los Angeles, California (East Los Angeles Doctors Hospital, Community Hospital Huntington Park, Alhambra Hospital Medical Center, and Garfield Medical Center). The study was conducted in accordance with the guidelines of the Declaration of Helsinki and approved by the Ethics Committees of Pipeline Health (EI Segundo, CA) and AHMC Sistemas Hospitalares de Saúde (Alhambra, CA). Informed consent was obtained from all subjects involved in the study. Patients with COVID-19 infection between May 20, 2020 and December 15, 2020 who were admitted to COVID-19 wards were identified. All COVID-19 diagnoses were confirmed through detection of SARS-CoV-2 in Nasopharyngeal swab samples by real-time reverse transcriptase polymerase chain reaction (rRT-PCR) by WestPac Labs (Los Angeles, CA) using the cobas 6800 SARS-CoV-2 Test (Roche Molecular Systems, Branchburg, NJ ). The study population included patients who were able to follow instructions for using chlorhexidine as a rinse. oral. Patients with nasogastric or endotracheal tubes in place were excluded from the study. Patients who were symptomatic for more than one week before admission were also excluded.

[024] From this population, patients were randomly assigned to the study and control groups. Both groups received the standard of care in their treatment plans. The study group received chlorhexidine to use as an oropharyngeal rinse, while the control group did not. For each chlorhexidine administration, a unit-dose cup containing 0.5 ounces (15 milliliters) of commercially available chlorhexidine gluconate (0.12%) was provided to each patient. Patients were then observed to self-administer the solution as a full oral rinse for 30 seconds, twice daily. After 4 days, the oropharynx was swabbed and tested for the presence of SARS -CoV-2 by rRT-PCR.

[025] Since an oral rinse alone would not reach the posterior oropharynx effectively, a chlorhexidine spray was added to the oral rinse regimen in the second study group. After the patient used chlorhexidine as an oral rinse as stated above, a healthcare professional used a spray applicator to apply 3 sprays (a total of approximately 1.5 milliliters) of the chlorhexidine solution to the posterior oropharynx. To open the posterior pharynx, the patient was instructed to vocalize “ah” for 5 seconds while the solution was sprayed. This process was performed twice a day for 4 days. After four days of chlorhexidine administration, the oropharynx was swabbed and tested for the presence of SARS-CoV-2 by rRT-PCR. A paired T test was used to compare the findings, with a significance level of 0.05. [026] 14 nurses and a physician at the hospitals where this study was conducted followed the regimen of chlorhexidine oral rinse with oropharyngeal spray twice daily, in addition to social distancing, mask use, and hand washing to avoid contracting COVID-19. Healthcare providers were followed throughout the study, and adherence to the chlorhexidine regimen and COVID-19 status was self-reported. The SARS-CoV-2 infection rate among this group was compared to the infection rate among all healthcare workers in their respective hospitals.

[027] Results:

[028] We identified 684 patients with positive SARS-CoV-2 infection (Figure 1). The mean onset of symptoms was 5.6 days before admission (standard deviation, 2.3) (range, 1-16). 390 patients were excluded for symptom onset more than six days before admission, placement of nasogastric or endotracheal tubes, or failure to follow instructions for use of chlorhexidine. 58% of the study population was male, 42% female, and the mean age was 62 years (range, 23-89). 294 patients were included in the analysis, with 159 patients in the study group receiving chlorhexidine and 135 patients in the control group. All patients received standard treatment for COVID-19, which included remdesivir, anticoagulation, steroids, and oxygen therapy. There was no significant difference in treatment response between the two groups.

[029] Oropharyngeal samples after oral rinse only:

[030] A total of 121 patients were included in the analysis of the use of chlorhexidine as an oral rinse in patients with COVID-19 (Table 1). Of the 66 patients in the chlorhexidine-treated group, 41 (62.1%) were considered negative and 25 (37.9%) were considered negative. positive for SARS-CoV-2 in the oropharynx. In the same test in the control group of 55 patients, 3 (5.5%) were negative and 52 (94.6%) were positive. Differences in results were statistically significant between the two groups (P < 0.01).

[031] Oropharyngeal samples after oral rinse with oropharyngeal spray:

[032] Oropharyngeal samples from 173 patients were included in the evaluation of the use of chlorhexidine oral rinse with additional posterior oropharyngeal chlorhexidine spray in patients with COVID-19 (Table 2). 80 of 93 (86.0%) of the chlorhexidine-treated patients were negative for the presence of SARS-CoV-2, while 5 of 80 (6.2%) of the control patients were negative for the virus. Differences in results were statistically significant between the two groups (P < 0.01).

[033] Use of chlorhexidine in healthcare professionals:

[034] A group of 15 healthcare professionals (14 nurses and 1 physician) who used chlorhexidine as an oral rinse and oropharyngeal spray twice daily as described above during the study. None of them developed SARS-CoV-2 infection during the course of this study. In contrast, the rate of COVID-19 among all healthcare workers in hospitals during the same period was around 50%.

[035] Adverse effects:

[036] No adverse effects of using chlorhexidine as described were observed.

[037] Discussion: [038] Chlorhexidine is an antimicrobial agent commonly used in preoperative skin preparation to prevent postoperative infections, prevent dental plaque, and prevent ventilator-associated pneumonia [6-8] Due to its cationic nature, chlorhexidine shown to be effective in killing enveloped viruses [9] As SARS-CoV-2 is an enveloped virus, chlorhexidine has been shown to be effective against SARS-CoV-2 [10]

[039] The data from this study show a significant elimination of SARS-CoV-2 with application of chlorhexidine in the oral cavity and pharynx. In an effort to deliver chlorhexidine to the posterior oropharynx more effectively, a spray applicator was used to apply chlorhexidine to the posterior oropharynx directly. In this study population, the addition of chlorhexidine posterior oropharyngeal spray was associated with clearing SARS-CoV-2 from the oropharynx in 86.0% of patients, compared with 62.1% in patients who used chlorhexidine only as an oral rinse. This result suggests that application of chlorhexidine to the posterior oropharynx greatly improved the clearance of SARS-CoV-2 from the oropharynx.

[040] In this study, chlorhexidine was found to be very effective in preventing SARS-CoV-2 infection in a small group of healthcare workers when compared to the general hospital healthcare worker population. Observation is encouraging, but formal analysis was not performed in this group. More studies with a larger cohort are needed to investigate the use of chlorhexidine in the prevention of COVID-19 in healthcare professionals.

[041] The authors propose that the use of chlorhexidine as an oropharyngeal rinse may serve two purposes: 1) to prevent the spread virus from COVID-19 patients to others and 2) to prevent SARS-CoV-2 infection in the event of exposure to the virus. For the prevention of viral spread from individuals infected with SARS-CoV-2 to others, the authors recommend using 0.12% chlorhexidine gluconate mouthwash twice daily as follows: 1) spray 1 milliliter into the nostrils, 2 ) rinse the throat with 15 milliliters for at least 30 seconds, and 3) use a spray applicator to spray the back throat 3 times (1.5 milliliters). This process can be continued until the virus is naturally cleared from the body, which takes approximately 2 to 3 weeks [11]. For post-exposure prophylaxis, the authors recommend the above chlorhexidine regimen for 2 to 4 days. The authors must emphasize that chlorhexidine cannot be used to treat COVID-19 and strongly caution against ingesting chlorhexidine in any attempt to eradicate the disease.

[042] Tables and Flowchart:

Table 1. Detection of SARS-CoV-2 by rRT-PCR in the oropharynx of patients with COVID-19 after a four-day course of chlorhexidine oropharyngeal rinse:

[043] Study group patients used chlorhexidine oral rinse twice daily for 4 days. Patients in the control group did not receive chlorhexidine. Oropharyngeal samples tested for the presence of SARS-CoV-2 by rRT-PCR on the fourth day. The P value of the chlorhexidine vs. control was <0.01.

Table 2. Detection of SARS-CoV-2 by rRT-PCR in the oropharynx of patients with COVID-19 after a four-day course of oropharyngeal rinse with chlorhexidine and posterior oropharyngeal spray:

[044] Study group patients used chlorhexidine oral rinse and posterior oropharyngeal spray twice daily for 4 days. Patients in the control group did not receive chlorhexidine. Oropharyngeal samples tested for the presence of SARS-CoV-2 by rRT-PCR on the fourth day. The P value of the chlorhexidine vs. control was <0.01.

[045] Below is a flowchart of participants in a randomized clinical trial of chlorhexidine in hospitalized patients with COVID-19:

Claims

1 - “FORMULATION FOR MOUTHWRINSE WITH INHIBITING ACTION ON THE SARS-COV-2 VIRUS AND REDUCER OF RELATED PATHOLOGIES”, a formulation for obtaining a mouthwash-type product that inhibits the action of coronavirus, in particular SARS-CoV-2 , which inactivates the virus in the region of the oral cavity, oropharynx and epiglottis of the infected person and protects this region against infection in healthy people, said formulation comprising a volume q.s.p 100 of purified water base, characterized by receiving Chlorhexidine Digluconate (Chlorhexidine) as antimicrobial action component; liquid mint aroma (AROMAX MENTA LÍQUIDO) as a component responsible for the minty aroma of the product; Nipazol for its preservative and antimicrobial properties; Nipagin, for its preservative properties and effective action against bacteria, fungi and yeasts; and BHT Cristal (ButylHydroxiT oluene), as it is an organic compound with antioxidant, preservative and antimicrobial properties.

2 "FORMULATION FOR MOUTH RINSE WITH THE INHIBITING ACTION OF THE SARS-COV-2 VIRUS AND REDUCER OF RELATED PATHOLOGIES", according to claim 1, characterized in that in the volume q.s.p 100 of the purified water base, the amount of 0.2% Chlorhexidine Digluconate (Chlorhexidine); the amount of 0.2% of liquid mint flavor (AROMAX LIQUID MINT), the amount of 0.1% of Nipazol; the amount of 0.1% Nipagin; and the amount of 0.1% BHT Cristal (ButylHydroxyT oluene).