WO2022078563A1 - A new mixed compound for treatment and protection from covid-19 (corona) virus - Google Patents

Abstract

A multimodal antiviral compound is described,it is effective against a wide range of respiratory viruses that invade the upper airway. The compound is supplied as a nasal spray, nasopharyngeal oral spray and a modified structure of the compound as oral medicine. Application of both nasal and nasopharyngeal spray will inhibit the virus and limit its spread; in the meantime, the oral food supplement works as a systemic antivirus and increases the immunity. The compound for spray is composed of Povidone Iodine, Glycyrrhizic acid, Deglycyrrhizinated licorice extract, black seed extract and diluted clover honey. The food supplement is comprised ofammonium glycyrrhizate, black seed extract in a diluted cloverhoney. Combining multiple effective antiviral compounds working both topically and systemically provide a multimodal new insight for protection and early treatment of Corona, influenza and other respiratory tract viruses.

Description

A new mixed compound for treatment and protection from COVID-19 (Corona) virus.

Field of the invention

The present invention relates generally to a compound mixture comprising a chemical and natural compound to protect and treat the viruses of the upper respiratory tracts, and more specifically to prevent spread and treat the novel corona virus (SARS-COV2).

Background of the invention

Covid- 19 pandemic is considered a huge health and economic problem affecting all the world population. Since its emergence many people were hospitalized and admitted to ICU, some lost their lives and others lost their jobs. In addition, strict restrictions have been applied limiting the travel freedom and outdoor activities.

The striking feature of this group of viruses is its incredible ability to spread, high infectivity, rapid mutations and widespread affection of all human systems. SARS CO V2 is a compound virus that is composed of SARS virus which infects the respiratory passages and corona virus is attached with its spike like surface. The main differences between SARS-COV2 and other versus are its relative heat resistance, high infectivity rate, its transmission via air hence the difficulty in its contentment or treatment. The virus enters the human body via upper respiratory passages where it resides in the nasopharynx for its incubation period. This incubation period varies from 7-14 days. During this period, the viruses multiply and increase its number then upper respiratory irritation symptoms starts such as dry cough, loss of taste and smell sore throat. In an attempt to fry the virus, the body responds by fever, then activation of the immune system to fight the intruding guest. I called the previous stage Phase I of the disease. When the virus beats the immune system, it starts to invade the lower respiratory passages where it binds the ACE receptors and the lung infiltrates is formed at this stage difficulty in breathing starts. In addition, the virus spread to other body systems like the liver and brain in this phase the patient may need ICU admission and artificial ventilation. Currently, respiratory droplets and contact transmission are the main transmission routes. Recent reports indicate that SARS-CoV-2 can be detected in the urine and stool of laboratory confirmed patients, implying a risk of fecal-oral transmission. However, it is not yet certain that the consumption of virus-contaminated foods will cause infection and transmission. There is still no evidence that SARS-CoV-2 can be transmitted through aerosols or from mother to baby during pregnancy or childbirth.

SARS-CoV-2 is transmitted predominantly via respiratory droplet, contact, and potential in fecal-oral. Primary viral replication is presumed to occur in mucosal epithelium of upper respiratory tract (nasal cavity and pharynx), with further multiplication in lower respiratory tract.

SARS-CoV-2 infection can cause five different outcomes: asymptomatically infected persons (1.2%); mild to medium cases (80.9%); severe cases (13.8%); critical case (4.7%); and death (2.3% in all reported cases). CO VID-19 patients are the main source of infection, and severely ill patients are more contagious than mild ones. Asymptomatically infected persons or patients in incubation who show no signs or symptoms of respiratory infection proven to shed infectious virus, may also be potential sources of infection. Asymptomatically infected persons and patients in incubation or recovered from COVID-19 may pose serious challenges for disease prevention and control.

Description of the previous and related art

Any discussion of the prior art throughout the specification should in no way be considered an admission that such prior art is widely known or forms a part of common general knowledge in the field.

Most of the newly erupted medications are directed into three main directions; either vaccines to protect against the virus by giving acquired immunity, systemic antiviral medications like Remidesivir or immune-system helpers like immunoglobulins. All these treatment modalities have to be applied either before phase one (vaccines) or as a systemic injection to inhibit the virus.

The difficulty to find a suitable and effective vaccines came from the complex composition of the virus and its continuous mutation. Therefore, too many vaccines were introduced for clinical studies but still none of them have been approved for SARS-COV2.

The efficacy of hydroxychloroquine; an antimalarial drug is controversial with conflicting results where some studies found its use is harmful, others found no role in COV2 treatment.

Remidesvir is a broad-spectrum antiviral drug is currently under investigational trials and is not approved by any country. A study on Remidesvir on EBOLA virus was aborted due to increased mortality in the treatment group. There is limited information as regarding safety and effectiveness of Remidesvir in Corona virus treatment. Boosting the immune system is the last method tried to fight the corona virus, in this context the plasma of recovered cases From CO VID 19 and immunoglobulins have been tried with conflicting and non-satisfactory results.

In the present time, there are no specific antiviral drugs or vaccines for the control of SARS- CoV-2. Symptomatic treatment strategies are the only available options for clinical practice. The following three main lines of research represent the previous art, followed by specifying the merits of the present invention, and the differences between the present invention and the previous art.

First, the group of systemic antiviral drug-trials such as type I interferons which represent a group of antiviral cytokines that induce a large range of proteins that can impair viral replication in the targeted cells.

Potential antiviral Compounds such as, Ribavirin. Ribavirin and IFN-0 could synergistically inhibit SARS-associated CoV replication in vitro but due to adverse reactions, the proper dose of ribavirin in clinical application should be given carefully. Others used the combination of lopinavir/ritonavir that is used in the treatment of HIV infection. It has been reported that the use of lopinavir/ritonavir with ribavirin has a good therapeutic effect in SARS. Remdesivir a systemic antivirus, was previously reported to restrain SARS-CoV in vivo, and the antiviral protection of Remdesivir and interferon-0 (IFN-p) was found to be superior to that of lopinavir/ritonavir-IFN-P against MERS-CoV in vitro and in vivo. Remdesivir was used in the treatment of the first CO VID-19 patient in the United States and was shown to have antiviral activity against SARS-CoV-2 in vitro. However, its effectiveness and safety have not been verified in clinical trials yet.

Another antiviral, Nelfinavir is a selective inhibitor of HIV protease, which has been shown to have a strong inhibition of SARS-CoV, denoting a possible therapeutic for COVID-19; Arbidol, a broad-spectrum antiviral compound, is able to block viral fusion against influenza viruses. In addition, arbidol and its derivative, arbidolmesylate, have been reported to have antiviral activity against SARS-CoV in vitro. The antiviral activity of arbidol against SARS-CoV-2 has been confirmed in vitro and recommended for clinical trials. Chloroquine has many interesting biochemical properties including antiviral effect. It has been found to be a potent inhibitor of SARS-CoV through interfering with ACE2. Chloroquine can effectively inhibit SARS-CoV-2 in vitro and is recommended for the clinical control of viral replication. The efficacy of hydroxychloroquine; an antimalarial drug is controversial with conflicting results where some studies found its use is harmful, others found no role in COV2 treatment.

Second is the immune therapy like

Convalescent Plasma has been tried for CO VID-19, but the effect of convalescent plasma cannot be discerned from the effects of patient comorbidities, stage of illness, or effect of other treatments.

Protective Monoclonal Antibody has been shown to neutralize SARS-CoV and inhibit syncytia formation between cells expressing the S protein and those expressing the SARS-CoV receptor ACE2. However, monoclonal antibodies can only recognize a single epitope, and the anti- infective effect is limited. In addition, the development of monoclonal antibodies requires a certain period of time, which is difficult to achieve in clinical application in a short time.

Immunoglobulins, and systemic anti-inflammatory drugs have been tried to reduce cytokine storm are also under trial for severe CO VID-19.

Third is the development of a safe and effective vaccine

Vaccination is a protective option for COVID-19 control. Epitopes, mRNA, and S protein-RBD structure-based vaccines have been proposed. Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platform has been reported, and this technical advance is helpful for vaccine development. Human ACE2 transgenic mouse and rhesus monkey models of COVID-19 have been well established for vaccine development, and some SARS-CoV-2 vaccines are already under clinical trial. Examples of reported patents comprise the following;

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The above mentioned methods utilize either a systemic vaccine that is proposed to trigger acquired immune response to the corona virus or a systemic antiviral drug that would inhibit the virus growth or boosting the human immune system to increase its power in fighting the corona virus. Most of the vaccines target either the spike protein, S protein or the M, N and S protein by forming antibodies against these proteins for virus recognition. The main problem of the vaccine is that the virus has actually mutated and is a compound virus so statements about its effectiveness is still controversial. Regarding the systemic antivirals, none of them has been clinically proven to be effective and the failure of hydroxychloroquine in clinical trials is a good example. Furthermore, systemic antivirals have a widespread side effects that could worsen the condition especially in elderly people who are more vulnerable to complications. Finally, the use of plasma of the cured persons or immunoglobulins did not yield satisfactory results particularly in advanced cases. Mundipharma company has employed the use of betadine only as a spray for the influenza virus. However, they did not use other synergistic antivirals and their used concentration of povidone iodine is not enough to kill the corona virus alone, using higher concentrations my result in systemic absorption and result in systemic toxicity. Furthermore, For the spray to reach the targeted spot (Nasopharynx) effectively a special atomizer is required. Using the ordinary atomizer that is used by Mundipharma would only hit the base of the tongue and hardly the oropharynx but would never reach the nasopharynx. In the present invention, I have designed a special atomizer with a long and curved stick that can reach the nasopharynx, oropharynx and hypopharynx if rotated. While povidone iodine used alone is unlikely to be effective against the Corona virus, the present invention provides a novel combination with its unique constituents that is acting on the virus through more than one mechanism. Effective reach to the desired site for the spray is as important as the efficacy of the compound, what is the benefit of a bullet that do not hit the target?

In the present invention we introduce a safe, simple, effective and an unusual way for corona virus treatment. The present invention utilizes the power of a multimodal mechanism-antiviral compound. The constituents of the compound have a viricidal activity in vitro against SARS- COV2. Being active in vitro, it is logical that sprays applied on the targeted residence site of the virus would inhibit the virus invasion to the cells and inhibit its multiplication. For these reasons the compound ideally should be applied as a nasal spray, nasopharyngeal and oropharyngeal spray, as a protective measure and as a cure for the virus carriers. In addition, it can treat early cases before the invasion progress to the lower respiratory tract. Furthermore, the use of a food supplement comprising three antiviral herbal compounds to initiate a safe systemic antiviral response and raise the immunity. The details of preparation and uses of such compound are described below. Disclosure of the invention

Brief summary of the invention

In the view of the foregoing disadvantages, lack of the effectiveness now present in the prior art, the present invention provides a new compound mixture that possess a multimodal antiviral effects wherein it can be applied topically in a non-traditional way to protect and treat early cases of the new CO VID-19 virus and other respiratory system invading viruses. The compound is designed to act on the virus in an early stage based on the understanding of the pathophysiology of the disease therefore, tis compounds offers protection, limiting the spread and treat early cases of the virus infection.

The general purpose of the present invention, which will be described subsequently in more detail, is to provide a novel compound that is working by topical application to the naso-pharynx and the nose by different antiviral mechanisms to provide a simple, effective and novel way to control the spread, prevent transmission and treat early cases of COVID- SARS2.

To attain this, the present invention generally describes a compound that is comprised of a chemical Povidone iodine 0.35 : 0.5% that is well known by its antiviral, antibacterial and antifungal properties combined with Glycyrrhizin (GL) and glycyrrhetinic acid (GA) in licorice extract 5%, which exhibit strong antiviral in-vitro effects, Black seed extract which is known to have antiviral effects and diluted clover honey 1% with its active phenolic antiviral effects. In addition, a food supplement that is comprised of Licorice extract containing 100 mg of glycyrrhetinic acid (GA) and 38.5 mg of Glycyrrhizin (GL), black cumin extract containing thymoquinone that possess antiviral, antioxidant, anti-inflammatory, anticoagulant, immunomodulatory, bronchodilator, antihistaminic, antitussive, antipyretic and analgesic activities and diluted clover honey 7% that have antiviral and antimicrobial action. The compound acts by multimode to combat the viruses if applied topically as a nasal and nasopharyngeal spray.

There has been outlined rather broadly, the more important features of the invention in order that the detailed description thereof may be better understood and the present contribution to the art may be better appreciated. There are additional features of the invention that will be described hereinafter and will form the subject of matter of the claims hereto. In this respect, it is to be understood that the invention is not limited in its application to the detailed composition and components. Other percentages and combinations may be practiced and carried out in other ways. It is to be noted that the current phraseology and terminology are for the purpose of description and should not be regarded as limiting.

Detailed description of the invention

As mentioned in the background Corona virus invades human body via nasal and oral opening through breathing air or touching by the infected hand. The virus then resides in the nasopharynx for its incubation period where it multiplies and prepare itself to move forward down to the lower respiratory tract. 1 have termed this a phase 1 of the disease.

The idea of the present invention is to attack and weaken the virus through application of a complex mixture which acts synergistically as a topical antivirus in order to kill the virus before its progress and before inducing more harm. The Idea of application of topical antivirus composed of some natural herb extract and a known chemical compound in a concentration that would be harmless to the patients, yet it is effective. Stoppage of the virus at this stage will enable easy control and contentment of the infection. In addition, this method will enable to get rid of the asymptomatic carriers by killing the living virus where it is hiding in the nasopharynx and oropharynx. Herbal medicine can contribute as an alternative measure to manage the patients with COVID-19 as there are many traditional herbs shown antiviral and other medicinal properties.

Methods to achieve the goals

Preparation of a spray mixture containing antiviral natural compounds and antiviral chemical in one mixture to be sprayed in the nose, nasopharynx and oropharynx. The objective of this compound is to act as a topical antivirus, for this reason the active constituents of the compound should have an effect on the virus in vitro, where it inhibits and kill the isolated virus in the culture plates.

All the constituents of this mixtures have a scientific proof of antiviral activities but the novel use in the present invention is to employ these compounds to act topically and synergistically to kill the virus and stop its propagation. Another object of the present invention is to boost the immune system to help in the fight against the virus, to accomplish this goal a food supplement has been introduced and is comprised of 100% herbal extracts that are rich in known compounds comprising antioxidants, anti-inflammatory, antiviral and immunostimulants. For this purpose, the food supplement should be taken by oral route.

The compound mixture is comprised of.

A- Nasopharynx and oropharynx spray; the spray is formed of mixtures comprising the following:

1- Povidone Iodine (0.4% for protective bottles and 0.5% for therapeutic bottles) which is a known antivirus, antibacterial and antifungal where it acts topically to kill the virus in its place and before its multiplication and deep invasion.

2- Licorice extract 5% the antiviral active compounds are Glycyrrhizin (GL) and glaberdine acid (GA). In addition, Licorice is anti-inflammatory and throat cooling demulcent.

3- black seed oil /extract 1%, its active antiviral principle is N. sativa. In addition, black seed oil extract is anti-inflammatory and immunostimulant.

4- Diluted organic clover honey 1%, diluted in distilled water at 45 degrees, its active antiviral is glucose oxidase which converts glucose into hydrogen peroxide in diluted solution, other phenolic acids. In addition, it contains flavonoids, antioxidant and antimicrobial agents.

5- Clover oil 1% as anti-inflammatory and soothing.

6- Menthol oil 1% as refresher and odor yielding agent.

7- Glycerin 2% as soothing agent.

The reset is completed by normal saline as a vehicle.

B- Nasal spray

The spray is formed of mixtures comprising the following

1- Povidone Iodine (0.35% for protective bottles and 0.4% for therapeutic bottles)

2- Licorice 5%

3- Clover honey 1% diluted in normal saline. 4-Black seed oil 0.5%.

6- glycerin 0.5%.

7- in the therapeutic bottle pseudoephedrine is added as a nasal decongestant.

The rest is completed by normal saline 0.9% as a vehicle.

For oral food supplement preparation

Component Percent in the mixture Action

Licorice extract 48.8 ml 41.8% Licorice extract Antiviral, antibacterial, anti-inflammatory

Diluted honey 28% 25 ml 7% diluted honey Antiviral, antioxidant, antimicrobial

Black seed extract 3 ml 3% black seed extract Antiviral, antioxidant, anti-inflammatory

Distilled water 22 ml 22% water Vehicle

A-Scientific background of the Active constituents.

1- Povidone Iodine (Betadine)

Povidone iodine is a well-known antiseptic that is capable of killing a wide range of microorganisms when applied topically. It has a therapeutic effect on viruses, bacteria, fungi and others. The most famous two indications of povidone iodine are wound disinfection and sterilization of patient skin before surgical incision. It is also used as oral mouth wash in a concentration of 1%. Recently it has been used as a throat spray 0.45%and as a nasal buff by Mundipharma for influenza and common cold. Side effects of betadine are; local swelling, itching, irritation and rashes in sensitive people to Iodine compounds. Large ingestions to povidone iodine are expected only to cause minimal symptoms such as diarrhea. Caution and seeking medical advice are recommended for patients suffering from kidney dysfunction and thyroid disorders. The lowest effective in vitro viricidal dose has been shown to be 0.2%. The adverse effects of povidone Iodine could be manifest with large concentration. In the present formula we intended to use double the least effective concentration against SARS-COV2. The reason for selecting this dosage is to obtain a reasonable concentration that would be effective in vivo, and in the meantime, this small dose would not produce systemic side effects.

2-Licorice. is a very well-known herb in traditional Chinese medicine.

The roots and rhizomes are the main medicinal parts of licorice. Numerous studies have revealed many pharmacological activities of licorice, such as antiviral, anti-inflammatory, antitumor, antimicrobial and many other activities. Among the pharmacological activities of licorice mentioned above, the antiviral and antimicrobial activities have been most commonly reported. Viral and other microbial infections play a critical role in many highly prevalent diseases, especially in developing countries. The development of safe and effective antiviral or antimicrobial agents is very important, and licorice deserves more attention for its outstanding activities. Licorice has been demonstrated to possess antiviral activities in -vitro.

Licorice contains more than 20 triterpenoids and nearly 300 flavonoids. Among them, glycyrrhizin (GL), 18/Lglycyrrhetinic acid (GA), liquiritigenin (LTG), licochalcone A (LCA), licochalcone E (LCE) and glabridin (GLD) are the main active components which possess antiviral and antimicrobial activities. Glycrrhizine, acts by targeting the release step and gene expression of the virus thus have a marked inhibitory effect on a large scale of viruses. In Addition, GL has a marked immunostimulant effect. For more specific description and to reveal the purpose of choice of licorice extract as a component of the compound of the present invention, as known from literature, Licorice extract components; Glycyrrizin (GL) and glycyrrhetinic acid (GA) act by affecting the virus release step during cell infection, inhibit full length viral particles and core gene expression, reduce adhesion force and stress, activate T lymphocyte proliferation, reduce levels of virus proteins and prevent viral attachment and internalization. Each one gram of licorice gives 2.39 mg/g of GA and 0.92 mg/g of GL. Where each 1-gram extract represents 1% so, 5% would represent the content of 5 gram of Licorice.

Using the below described method of extraction, the licorice extract is mixed as 5% in the mixture which contain 5x 2.39 mg=l 1.95 m l8/Lglycyrrhetinic acid (GA) and 4.6 mg of Glycyrrhizine per 100 ml of the mixture. 3- Diluted honey

All honey worldwide contains similar types of phenolic acids, including caffeic, ellagic, ferulic and p-coumaric acids; flavonoids, such as apigenin, chrysin, galangin, hesperetin, kaempferol, pinocembrin and quercetin; and antioxidants, such as tocopherols, ascorbic acid, superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH). Each constituent has unique nutritional and medicinal properties, and the components act synergistically, lending honey utility in a variety of applications. The ideal environment for activity of phenolic compounds and enzymes is dilution from 1% to 7%. With higher concentrations of honey, the activity of glucose oxidase takes priority; this enzyme acts on the sugar and the water liberating hydrogen peroxide which keep the honey solution safe. One of the secrets of organic honey is its tendency to keep its sterility in different forms; the raw undiluted honey is kept sterile by its high content of sugar and low PH. The high content of sugars creates a high osmotic environment that is unsuitable for the microbial growth. When honey is diluted to 25 to 50%, glucose oxidase which is naturally present in honey acts on sugars and liberates hydrogen peroxide which disinfect the solution. If honey is diluted with high dilution from 1 to 7 % the phenolic acids and compounds are activated that combat viruses, bacteria and fungi.

Several research studies of honey have confirmed its biological properties, such as antioxidant, anti-inflammatory, anti-bacterial, antiviral, anti-ulcer activities; and antihyperlipidemic, antidiabetic and anticancer properties. Honey has strong antiviral properties, studies revealed antiviral effects of honey against the Varicella zoster and influenza viruses.

Hydrogen peroxide (H2O2) is an important oxidizing and sanitizing agent. It is produced enzymatically in honey and can be an important feature in its antibacterial activity. Although the enzyme, glucose oxidase, is naturally present in honey, it is inactive in undiluted honey because of the low pH conditions. Glucose oxidase is activated when honey is diluted, however, which allows it to act on the endogenous glucose to produce hydrogen peroxide. Indeed, the maximum level of hydrogen peroxide produced can be obtained from a 25-50% honey dilution, potentially ranging between 5 and 100 //g^CE/g honey. The production of hydrogen peroxide in some honey samples can increase continuously over time to a point depending on the dilution used. H2O levels in honey can reach 2.5 mmol in 30-minute, and this can double on prolonged incubation. the maximum level of hydrogen peroxide produced can be obtained from a 25%-50% honey dilution. phenolic acids and flavonoids were recognized as important components of the antimicrobial substances in honey. Honey contains protocatechuic acid, p-hydroxybenzoic acid, caffeic acid, chlorogenic acid, vanillic acid, p-coumaric acid, and benzoic acid. Flavonoids found in honey were naringenin, kaempferol, apigenin, pinocembrin, and chrysin. The effects of flavonoids such as pinocembrin and rutin were shown to correlate with antibacterial activity of honey. Other unknown phenolic compounds were present in similar quantities, but these were not specifically identified due to a lack of analytical standards.

4- Black seed extract/oil

There is a potential of Nigella sativa (black cumin seeds) to treat the patients with CO VID-19, as it has been shown to possess antiviral, antioxidant, anti-inflammatory, anticoagulant, immunomodulatory, bronchodilator, antihistaminic, antitussive, antipyretic and analgesic activities.

The Phytochemical screening of N. Sativa revealed that it contains various compounds including terpenes, flavonoids, phytosterols, tannins, coumarins, phenolic compounds, alkaloids, cardiac glycosides, saponins, fatty acids, and volatile oils. The bioactive constituents of N. sativa include terpenes such as thymoquinone (TQ), di-thymoquinone (DTQ), carvone, limonine, trans-anethol, and p-cymene, indazole alkaloids like nigellidine and nigellicine, and isoquinoline alkaloids including nigellicimine, nigellicimine-N-oxide and a-hederin. As N. sativa possesses antiviral, antioxidant, anti-inflammatory, anticoagulant, immunomodulatory, bronchodilator, antihistaminic, antitussive, antipyretic and analgesic activities, it would be a potential herbal candidate to treat the patients with COVID-19. Thymoquinone represents about 30: 48% of the active principles in the extract depending on the extraction method. Dithymoquinone — P-cymene 7%-15%, others are present in lesser amounts. Most of pharmacological actions ofN-sativa are attributed to quinine compounds. The seeds also contain various amounts of vitamins and minerals like cupper, phosphorus and zinc. The present invention introduces a simple and effective way of aqueous ethanolic extract of black seeds. B- The effect of combination of the antiviral chemical and herbs.

The concept multimodal antiviral topical treatment: Because COVID 19 is a compound, virulent and relatively resistant virus a single treatment is unlikely to be effective and the war against the virus should employ multiple weapons. Similar to severe pain a single analgesic can reduce pain, but a satisfactory analgesia is only achieved with a multimodal approach. In the present invention and for the first time I have combined the power of a chemical (Povidone Iodine) and a mixture of herbs and natural antivirals which act synergistically to attack the virus before it makes more multiplication or spread. I intended to use the extracts with a known amounts of the active principle and not to separate only the active ingredients because, other constituents have beneficial action and buffers the side effects of the chemicals such as antioxidants in Licorice, honey and black seed extract and other anti-inflammatory, antimicrobial and immune system boosters which are present in the milieu of the extract that would help to overcome the symptoms and help in increasing the immunity. The application of topical spray especially in the nose can be absorbed systematically. For this reason, the concentration of Povidone Iodine the only synthetic chemical in the present compound is markedly reduced to the minimal effective dose to avoid the side effects. The presence of Licorice adds a soothing and a refreshing effect on the nasal and nasopharyngeal mucosa and together with diluted honey and black seed extract would reduce the inflammation. The combination, constituents and percentages of the mentioned compounds are not limited by those mentioned in the description and other percentages or uses are possible in the present invention.

This novel combination in such percentages for each constituent would utilize the power of all antiviral weapons to beat the virus and abort its multiplication. Therefore, both nasal and nasopharyngeal spray can be used not only for protection against Corona virus, influenza virus and other respiratory viruses but also for treatment of early Virus attack (phase one) and virus carrier state. The previous effects would be of great clinical significance as treating the carrier state the issue that would limit the spread of the novel SARS-COV2 and other viruses that are transmitted via the respiratory route. Importantly, all these antiviral compounds (Povidone Iodine, GL and GA in Licorice, phenolic compounds in diluted honey and N. Sativa of black seed affect the virus invitro where the antiviral is applied to a culture plate and inhibit the growth and multiplication of the virus. This issue supports their use as a topical spray to kill and inhibit the virus. The interaction between Povidone Iodine and these herbs is unlikely. All these herbs and medicinal plants are already used in combination with other materials as food supplements or in cosmetic products and has already been consumed by the humans. The differences between what was used, and the present invention are; It was mixed with other compounds as trace elements with small and ineffective doses. Second, the extracts were used without calculating the dosage or paying attention to the active principles e.g. GA and GL as antiviral active principles in licorice. The present invention pay attention to an effective dosage of the extract and the method of extraction and provides a unique combination of these compounds. Third, this is the first time combining these specific compounds in such percentages and concentrations.

The present invention for the first time combines the power of a chemical (Povidone Iodine) and the active herb extracts (Licorice, Black seed extract and the diluted honey). The cumulative antiviral power in the compound when applied in the right method and effective doses would fight CO VID-19 and the influenza virus in an unpreceded manner. The safety of the compound is warranted as most of the constituents are already consumed by the humans and the povidone of very low concentration has been used before for common cold.

C- The preparation and supply of the compound

1- Preparation of povidone iodine

Povidone Iodine 10% is purchased and mixed in the mixture with its intended percent to reach 0.4% in the protection bottles and 0.5% in the therapeutic bottles for the nasopharyngeal spray.

For the Nasal spray it is mixed in a percent of 0.35 or protection and 0.5% in the therapeutic bottles. See the details in the structure formula.

2-Preparation of Licorice extract

A maceration extraction method is used to extract glycyrrhizic acid from licorice, by mixing ethanol to water in a volume of 30:70 respectively for 10 gram of licorice root (30 ml ethanol+ 70 ml distilled water+ 10 gram Licorice root) incubated at 50 degree centigrade for 1 hour.

For augmentation of the yield of phenolic compounds and other antioxidants a microwave can be used for one to two minutes to separate more active ingredients. Licorice extract containing the antivirus, each 1-gram Licorice yields 2.39 mg glycyrrhizic acid and Glaberdine 0.92 mg.

3-Preparation of black seed extract

Black seeds were purchased and then washed with filtered water. Then put in distilled water in a volume of 1 black seeds: 2 water so, one third of the volume occupies one third of the container. A 100 ml total volume 33 ml occupied by the seeds and 67 occupied by distilled water is put in a microwave for three successive cessions 30 second each. Between each cession 5 minutes of continuous stirring of the whole seeds with water. A 67 ml 70% ethyl alcohol is added to the mixture, so the final concentration of ethanol is 35%. The seeds in ethanol/water was incubated for 6 hours in room temperature. After, 6 hours ethanol is removed by evaporation or vacuum distillation.

Another method of aqueous extraction using only water; the seeds are soaked in water overnight where the volume of water is double of that of the seeds. Then, the container is put in the microwave for 5 consecutive cessions 30 seconds each. A 5-minute interval is allowed between the cessions where continuous stirring of the solution occur. After getting through the 5 sets of microwaving, the solution is left for one hour, then incubated for 6 hour at 55 degrees. Finally, the seeds are filtered to obtain the extract.

Oil/ extraction method

The seeds are grinded and crushed several times in a grinder until obtaining a smooth cream-like matter, then put n the blender and mixed with olive oil. Blinding for 5 minutes, then a 30-minute stop then blinding for 5 minutes and repeating blinding/stopping for three times. Then, filtering the mixture to separate the pure oil from the crushed seeds. The previous method is referred as cold press. The advantages of oil extract over aqueous extract are that the oil contain more antioxidants, and more percentages of active ingredients. The disadvantage of oil is that it is insoluble in mixtures and you need to shake the bottle of mixture every time you use. So if we are going to use the oil in the antiviral mixture it would be mixed in a 2% concentration, if aqueous ethanolic extract is used it will be mixed as 3% and if water extract is used it will be mixed as 5%. 4- Preparation of diluted honey 1% and 7%.

Normal saline is heated to 45 degrees, then a 28% whole clover honey solution was prepared by adding 28 ml of raw honey to 72 ml of the heated normal saline with continuous stirring until making a honey solution of 28% concentration. Then 25 ml of the 28% diluted honey solution would make a 100 ml of the compound. So, 28/4=7% this d ilution is used for food supplement syrup. For the diluted honey preparation in the sprays, 1% dilution is simply obtained by dissolving 1 ml raw honey in 99 ml of the compound mixture, (heated normal saline(45) degrees is used as a vehicle) .

So, provided below are examples of drug formulation of nasopharyngeal, nasal sprays and oral syrup medicine that may be used as combined antiviral therapy for COVID-19 and other respiratory viruses.

1- An example for the protective nasopharyngeal spray bottle

Each 100 ml contains

Component Percent of total Action

Povidone Iodine 0.4% Povidone Iodine Antiviral, antibacterial, antifungal

Glycyrrizic acid (powder) 2.5 mg/ml 2.5% Glycyrrhizic acid Antiviral, antiinflammatory

Deglycyrrhizinated licorice extract 5% licorice extract Antifungal, antibacterial, anti-inflammatory

Black seed oil extract 2% black seed oil Antioxidant, antiinflammatory

Menthol oil 2% menthol Refresher

Clover oil 0.5% clover oil Anti-inflammatory

Glycerin 2% Glycerin Humidifying, soothing Diluted honey I % diluted honey Antiviral, antibacterial, antiinflammatory

Normal saline 0.9% 85% Normal saline Vehicle

B- Example for the therapeutic nasopharyngeal spray bottle

Each 100 ml contains

Component Percent of total Action

Povidone Iodine 0.5% Povidone Iodine Antiviral, antibacterial, antifungal

Glycyrrhizic acid 5mg/ml 5% Glycyrrhizic acid Antiviral and antiinflammatory

Deglycyrrhizinated licorice 7% licorice extract Antiviral, antibacterial, anti-inflammatory

Black seed oil extract 2% black seed oil Anti-oxidant, antiinflammatory

Menthol oil 1% menthol oil Refresher

Clover oil 0.5% clover oil Anti-inflammatory

Diluted clover honey 1% diluted honey Antiviral, antibacterial, anti-inflammatory

Glycerin 2% Glycerin Humidifying, soothing

NB .Honey diluted with normal saline 0.9% at 45 degrees

C- Example for the protective nasal spray

Each 100 ml contains

Component Percent of total Action

Povidone Iodine 0.35% Povidone iodine Antiviral, antifungal Glycyrrhizic acid 2.5 mg/ml (powder) 2.5% Antiviral, antiinflammatory

Deglycyrrhizinated Licorice 3 ml 3% licorice extract Antifungal, antimicrobial

Diluted honey 1% diluted honey Antiviral, antiinflammatory

Normal saline 93.15% Normal saline vehicle

NB .Honey diluted with normal saline 0.9% at 45 degrees

C- Example For the therapeutic nasal spray

Each 100 ml contains

Component Percent of total Action

Povidone Iodine 0.5 % Povidone iodine Antiviral, antifungal

Glycyrrhizic acid powder 5mg/ml 5% Glycyrrhizic acid Antiviral, antiinflammatory

DG licorice extract 5% licorice extract Antiviral, antimicrobial

Diluted honey 1% diluted honey Antiviral, antiinflammatory

Normal saline 89.5% vehicle

NB. Honey diluted with normal saline 0.9% at 45 degrees.

Example

For oral food supplement preparation

Component Percent in the mixture Action

Ammonium glycyrrhizate 3mg/ml Ani-viral Deglycyrrhizinated Licorice 7% Licorice extract Antioxidant, demulcent, anti-inflammatory

Diluted honey 7% diluted honey Antiviral, antioxidant, antimicrobial

Black seed extract 3 ml 3% black seed extract Antiviral, antioxidant, anti-inflammatory

Distilled water 22 ml 80% water Vehicle

Sodium benzoate 0.1% 0.1% preservative

So, in this example each 100 ml of the food supplement contains 90 mg of Glycyrrizic acid acid (GA) as active ingredient.

D- The atomizer bottle and method of administration

In order to have an effective application of the drug that would cover the targeted area we have to use an unusual atomizer for nasopharyngeal application. As mentioned earlier, the nasopharynx is the preferred residence spot of the Corona virus. The nasopharyngeal swabs are the most sensitive and predictive method to diagnose the virus this points to the nasopharynx as a preferred spot of residence of the virus. For the spray to reach this spot effectively a special atomizer is required. Using the ordinary atomizer that is used by Mundipharma would only hit the base of the tongue and hardly the oropharynx but would never reach the nasopharynx. For this reason, I have designed an atomizer with a long stick and a 35 degree upward curved end that is capable of directing the spray to the nasopharynx where the maximal viral load exists. To apply to the nasopharynx the curved end should look upward. For application into the oropharynx the stick and nozzle is rotated a 90 degree so as the curved end look to one side. For the other side of the oropharynx, it should be rotated 180 degrees.

For the hypopharynx the curved end is rotated to look downwards.

Claims

23

Claims

It is to be noted that the present invention is not limited to the compositions and percentages of each compound, other percentages and components may be added to the main idea for multimodal topical antiviral effects, the components and percentages are only given as a way of example and not limitation but only in the scope of the appended claims.

Claim 1:- An antiviral mixture which acts by different antiviral mechanisms resulting in multimodal synergistic effects, the mixture is comprised of povidone iodine from 0.35% to 0.5% and Glycyrrhizic acid from 2.5 to 5 mg per ml, an extract of deglycyhrrizinated licorice (DGL) from 3 to7%, a black seed extract 1% to 5% and a diluted clover honey 1% for sprays and 7% for the syrup, the compound mixture can be used for topical application as oro-nasopharyngeal spray and nasal spray to protect against and treat early cases of Corona virus (SARS-COV2), influenza virus and other respiratory viruses, and Another mixture of Ammonium glycyrrhizate 3 mg/ml, DGL extract 7%, black seed extract 3% to 5% and diluted honey 7%for oral intake for systemic antiviral benefit and increasing the immunity.

Claim 2: - The said Povidone Iodine mentioned in claim 1 can be mixed in the nasal spray solution mentioned in claiml in a percent of 0.37 for the purpose of protection and in a percent of 0.5% for the purpose of treatment of upper respiratory invasion while it can be mixed as a nasopharyngeal spray in a percent of 0.5% for protection and 1% for early treatment of COVID 19 cases and influenza with its subtypes.

Claim3: - The said Glycyrrhizic acid said in claim 1 is obtained in powder form and is preferably used in the form of one of Glycyrrhizic acid salts preferably dipotassium glycyrrhizate or sodium glycyrrhizate or ammonium glycyrrhizate or as glycyrrhizic acid nanoparticles for their easy solubility in water and mix with other ingredients to be used topically on the mucous membrane of the nose, nasopharynx and oro-pharynx to act as topical broad-spectrum antiviral.

Claim 4: - The DGL extract said in claim one by its contents of Glaberdine and other flavonoids, can be applied topically through spray to share some anti-fungal, antioxidant and antiinflammatory effects to the upper airway to relieve the symptoms of sore throat by its demulcent and anti-inflammatory properties. Claim 5: - The said clover honey mentioned in claim 1 when diluted to 1-7% percent, activation of phenolic compounds takes precedence in the antiviral mechanism over the generation of hydrogen peroxide, and it will exert antiviral and anti-inflammatory action when used as a nasopharyngeal or nasal spray.

Claim 6:- The combination of the said Povidone Iodine, Glycyhrrizic acid, DGL, black seed extract and the diluted honey said in claim 1 exerts a synergistic antiviral effects by working through different mechanisms to inhibit Corona virus replication and gene expression in addition to inhibiting other upper airway viruses and this represents a novel compound and method of protection and treatment of early COVI-19 , influenza with its subtypes such as HIM 1, Spanish flu, swine flu and other respiratory viruses.

Claim?: - The said food supplement said in claim 1 contains 3mg I ml of ammonium glycyrrhizinate; a newly emerging anti-viral plus 7% of DGL extract thus this mixture would contain 90 mg of Glycyrrhizic acid salt to be taken on three daily doses as a 10 ml (30 mg) per dose therefore, 90mg/day to avoid side effects. [ Side effects start to appear at 4mg/kg which is about 240 mg for a 60 KG person]; the food supplement should be used concomitantly with the topical nasal and oropharyngeal antiviral sprays mentioned in claim 6.

Claim 8: - The application of the spray said in claim 1 to the nasopharynx will be done through a specially designed atomizer that have a long arm which can be rotated for 360 degrees, with a curved distal end to pass the uvula and apply the spray in an upward direction to hit the targeted area of the nasopharynx.