WO2021262749A1 - Compositions and methods for preventing and/or treating viral infection - Google Patents

Abstract

Compositions and methods for preventing and/or treating viral infections, particularly coronavirus infections, utilize H₂O₂ and quercetin, and optionally EGCG are disclosed. The compositions and methods can utilize nanoformulations based on nanoparticles with H₂O₂ and quercetin for preventing and/or treating for preventing and/or treating viral infections, particularly coronavirus infections.

Description

COMPOSITIONS AND METHODS FOR PREVENTING AND/OR TREATING

VIRAL INFECTIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application

63/044871, filed June 26, 2020, and U.S. Provisional Application 63/062267, filed August 6,

2020, which are hereby incorporated by reference in their entireties.

BACKGROUND

Field

[0002] The present disclosure is generally related to compositions and methods for preventing and/or treating a viral infections (e.g., viral infection caused by coronavirus).

SUMMARY

[0003] In some embodiments, a pharmaceutical composition for prophylaxis, treatment or both of a viral infection is provided.

[0004] In some embodiments, the pharmaceutical composition comprises an amount of Quercetin, and an amount of H₂O₂.

[0005] In some embodiments of the pharmaceutical composition, the amount of quercetin is 0.1 g to 2.5 g.

[0006] In some embodiments of the pharmaceutical composition, the quercetin is in solution at a concentration of 10 mg/ml to 500 mg/ml.

[0007] In some embodiments of the pharmaceutical composition, the amount of H₂O₂ is 1-3 niL.

[0008] In some embodiments of the pharmaceutical composition, the quercetin and H₂O₂ are in a single dosage form for co-administration.

[0009] In some embodiments of the pharmaceutical composition, the quercetin and H₂O₂ are in a single dosage form suitable for IV, oral, mist, aerosol (nebulizer), and/or sublingual administration. [0010] In some embodiments of the pharmaceutical composition, the quercetin and H₂O₂ are in a separate dosage forms.

[0011] In some embodiments of the pharmaceutical composition, the quercetin and H2.O2 are each in dosage forms suitable for IV, oral, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose, and/or sublingual administration.

[0012] In some embodiments of the pharmaceutical composition, either quercetin or H₂O₂ is in a dosage form suitable for IV, oral, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose, and/or sublingual administration and the other is in a dosage form for IV, oral, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose, and/or sublingual administration.

[0013] In some embodiments of the pharmaceutical composition, the viral infection is caused by coronavirus selected from the group consisting of human coronavirus, human SARS coronavirus, MERS coronavirus, SARS coronavirus 2, and Covid 19.

[0014] In some embodiments of the pharmaceutical composition, the composition is a nanoparticle formulation.

[0015] In some embodiments, use of a pharmaceutical composition according to any of the embodiments herein for treatment, prevention or both of a viral infection a subject in need thereof are provided.

[0016] In some embodiments, a method of prevention, treatment or both of a viral infection is provided.

[0017] In some embodiments, the method comprises administering the composition of any one of the preceding claims to a patient in need thereof.

[0018] In some embodiments of the method, the pharmaceutical composition is administered to the subject IV, orally or both.

[0019] In some embodiments of the method, the amount of quercetin is 0.1 g to

2.5 g.

[0020] In some embodiments of the method, the quercetin is in solution at a concentration of 10 mg/ml to 500 mg/ml.

[0021] In some embodiments of the method, the amount of H₂O₂ is 1-3 mL.

[0022] In some embodiments of the composition, use, or method herein, quercetin is in a nanoparticle formulation. [0023] In some embodiments of the composition, use, or method herein, H₂O₂ is in a nanoparticle formulation.

[0024] In some embodiments of the composition, use, or method herein, both quercetin and H₂O₂ are in a nanoparticle formulation.

[0025] In some embodiments of the composition, use, or method herein, the nanoparticle formulation comprises a first population of nanoparticles with quercetin, and a second population of nanoparticles with H2.O2.

[0026] In some embodiments of the composition, use, or method herein, a dimension of the nanoparticle in the nanoparticle formulation ranges from about 100 nm to about 250 nm.

[0027] In some embodiments of the composition, use, or method herein, the nanoparticle is selected from the group consisting of PLGA-PEG-NPs, FA-PLGA-PEG-NPs,

DSPE-PEG-NPs and FA-DSPE-PEG-NPs.

[0028] In some embodiments of the composition, use, or method herein, quercetin is provided alone as a prophylactic treatment for a subject at risk of a coronaviorus infection.

[0029] In some embodiments of the composition, use, or method herein, quercetin and H₂O₂ are provided in combination as a treatment for a subject in an acute phase of a coronaviorus infection.

[0030] In some embodiments of the composition, use, or method herein, quercetin and H₂O₂ are provided in combination as a treatment for a subject in a chronic phase of a coronaviorus infection.

[0031] In some embodiments of the composition, use, or method herein, quercetin is provided orally, intravenously, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose, and/or sublingually.

[0032] In some embodiments of the composition, use, or method herein, quercetin is provided orally, intravenously, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose, and/or sublingually, and H₂O₂ is provided intravenously.

[0033] In some embodiments of the composition, use, or method herein, quercetin is provided orally, intravenously, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose, and/or sublingually, and H₂O₂ is provided intravenously and/or via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose.

[0034] In some embodiments, the composition, use, or method herein further comprise EGCG.

[0035] In some embodiments of the composition, use, or method herein, the amount of EGCG is 0.1 g to 1.5 g.

[0036] In some embodiments of the composition, use, or method herein, the EGCG is in solution at a concentration of 1 mg/ml to 50 mg/ml.

[0037] In some embodiments of the composition, use, or method herein, the EGCG is administered at a dose is 0.1 g to 1.5 g.

DETAILED DESCRIPTION

[0038] Provided herein are compositions and methods comprising quercetin alone or in combination with H₂O₂ for preventing and/or treating viral infections, In some embodiments, the present disclosure is related to quercetin alone or in combination with H₂O₂ for prevention and/or treatment of infection with coronavirus.

[0039] Also provided herein are embodiments of case studies based on a novel combinatorial therapy comprising H₂O₂ and quercetin that provide superior clinical results in coronavirus infection. Embodiments of the novel combinatorial therapy comprising H₂O₂ and quercetin is also contemplated to provide superior clinical results in other viral infections.

[0040] Without being limited by any particular theory, several DNA replication genes are induced in neoplasms, Several genes are also induced in infection with corona virus. Applicant unexpectedly found that the gene encoding PI3K is induced in both neoplasms and coronavirus infection. It was also unexpectedly found that quercetin inhibits the PI3K gene that is commonly upregulated in patients with neoplasms and in patients with coronavirus infection. Without being limited by any particular theory, it is believed that quercetin inhibits the expression/suppressed the expression of mutated alleles of DNA replication genes that are commonly upregulated in patients with in neoplasms and in patients with coronavirus infection. It was unexpectedly found that coronavirus infection was suppressed in a cancer patient receiving quercetin for the treatment of the cancer. Thus, in some embodiments, the present disclosure is related to treatment of coronavirus with quercetin.

[0041] In some embodiments, the present disclosure relates to at least three protocols for the prevention and/or treatment of coronavirus infection in patients with a neoplasm.

[0042] In some embodiments, the patient, optionally a patient with a neoplasm, has not been exposed to coronavirus. These patients test negative for coronavirus, for example, as determined by a nasal swab for viral detection through PCR and/or serum antibody testing for anti-viral antibodies (IgM and/or IgG). Other methods of viral detection such as using RT-PCT and assays based viral antigen detection (e.g., ELISA, etc.) are also contemplated. However, these patients are at risk of exposure. In such, patients, quercetin can be administered for the prevention of coronavirus infection. In some embodiments, quercetin can be administered orally. In some embodiments, quercetin can be administered nasally/in the nasal cavity. In some embodiments, quercetin can be administered orally and nasally/in the nasal cavity, In some embodiments, quercetin is administered as a nanoformulation . In some embodiments, quercetin is administered as a liposomal formulation. In some embodiments, the liposomal formulation of quercetin for oral administration is absorbed in the circulation directly in oral cavity, e.g., in a sublingual formulation. In some embodiments, quercetin is administered as a nanoformulation and a liposomal formulation.

[0043] In some embodiments, the patient, optionally a patient with a neoplasm, has been exposed to coronavirus. These patients test positive for coronavirus, for example, as determined by a nasal swab for viral detection through PCR and/or serum antibody testing for anti-viral antibodies. As these patients have been recently exposed, these patients have IgM antibodies associated with the acute phase of the infection. Thus, these patients are in the acute phase of the infection. These patients are either asymptomatic or symptomatic. However, these patients are not under intensive care for their infection. These patients are currently infected and have not recovered. In some embodiments, these patients are treated with intravenous (IV) quercetin and intravenous (IV) H₂O₂. In some embodiments, the quercetin is administered as a nanoformulation. Without being limited by any particular theory, it is believe that IV H₂O₂ treatment increases NK cell activity. Normal NK cell activity is around 50. However, in patients, the NK cell activity decreases significantly to about 5-10. Patients are administered IV quercetin and H₂O₂. In some embodiments, 5 injections are administered over 2 weeks (i.e., one injection every other day). In some embodiments, at least 1 injection is administered over 2 weeks. In some embodiments, at most 10 injections are administered over 2 weeks. In some embodiments, about 1-3 mL of H₂O₂ is administered. In some embodiments, at least 0.5 mL of H₂O₂ is administered. In some embodiments, at most 5 mL of H₂O₂ is administered. Without being limited by any particular theory, it is believed that administering more H₂O₂ can cause hemolysis. In some embodiments, the H₂O₂ is administered over 0.5-5 hours.

[0044] In some embodiments, the patient, optionally a patient with a neoplasm, has acute respiratory distress syndrome (ARDS) due to coronavirus. These patients are in the chronic phase of the infection. In such patients, treatment with maximum effectiveness is required. Without being limited by any particular theory, H₂O₂ has been used as a nebulizer to treat metastasis. H₂O₂ is also used as a nebulizer to achieve immediate results with pulmonary infections. In some embodiments, the use of H₂O₂ as a nebulizer in the treatment of infection with coronavirus is contemplated.

[0045] In some embodiments, the present disclosure is related to analysis of survival measures for patients diagnosed with Covid 19 by using nebulized hydrogen peroxide and Quercetin.

[0046] In some embodiments, the primary end point is survival assessment.

[0047] In some embodiments, secondary endpoints include without limitations Duration of respiratory support requirement/ICU duration of stay/ Analysis of Human to Human Transmission of Respiratory Syndrome Coronavirus.

[0048] The end-stage patients with Covid 19 do not have options for curative therapies; and their prognosis poor, however there is substantial data suggesting the antiviral efficacy of the therapies studied here, including 300 patients treated by a pilot therapy of the Quercetin with good safety records.

[0049] In some embodiments, prevention of infection with Covid 19 is achieved by prophylactically treating with intravenous hydrogen peroxide and pegylated Quercetin. In some embodiments, the dose of pegylated Quercetin is 500 mg/m². In some embodiments, the dose of pegylated Quercetin ranges from about 250 mg/m² to about 1000 mg/m². [0050] In some embodiments, the combination of H₂O₂ and quercetin is administered on daily basis for ten consecutive treatments. In some embodiments, the combination of H₂O₂ and quercetin is administered on daily basis for ten consecutive treatments and tapered down in six weeks. In some embodiments, H₂O₂ is administered at a rate of 5 ml/minute

[0051] In some embodiments, the administration of H₂O₂ does not cause any side effects. In some embodiments, the administration of quercetin does not cause any side effects. In some embodiments, no side effects occur by administration of both the H₂O₂ and quercetin.

[0052] In some embodiments, the testing for Covid 19 infection is performed by one or more of nasal swab for viral detection through PCR and serum antibody testing.

[0053] In some embodiments, presence of IgG and/or IgM is indicative of presence of anti-viral immunity. IgM is indicative of early stages of infection. IgG is indicative of later stages of infection. In some embodiments, the patient has no symptoms.

[0054] In some embodiments, the patient has cancer diagnosed and treated with watchful waiting (active surveillance), elevated PSA and positive circulating tumor cells, referred for enhancing his immunity against all infections, as he was concerned about exposure to corona virus during his visit to NY, in January 2020.

[0055] In some embodiments, the patient is prophylactically treated with intravenous hydrogen peroxide and pegylated Quercetin. In some embodiments, the dose is about 500 mg/m². In some embodiments, the dose of II2O2 is about 0.5=5 m L. In some embodiments, the dose of quercetin is about 250 mg/m² to about 1000 mg/m². In some embodiments, the treatment is administered daily. In some embodiments, the treatment is administered daily for ten consecutive days. In some embodiments, the treatment is administered daily for ten consecutive days, and then tapered down over six weeks. In some embodiments, H₂O₂ is administered at the rate of 5 ml/minute at a concentration of 3% v/v. In some embodiments, H₂O₂. is administered at the rate of 5 ml/minute at a concentration of about 3% v/v. In some embodiments, H2.O2 is administered at the rate of 5 ml/minute at a concentration of about 1.5% to about 6% v/v. In some embodiment’s, no negative side effects occur. [0056] In some embodiments, intravenous H₂O₂ and quercetin are administered prophylactically to prevent infection with corona virus. In some embodiments, intravenous H₂O₂ and quercetin are administered to treat infection with coronavirus. In some embodiments, the administration of the intravenous H₂O₂. and quercetin prevents transmission of coronavirus.

[0057] In some embodiments, the patient is a male or a female. A patient is typically human but animals other than human are also contemplated. Non-limiting examples of the animals other than human include without limitation domestic animals, pets, experimental animals, and/or commercially important animals.

[0058] Non-limiting examples of neoplasms, which could be a tumor, a cancer, any new and/or abnormal growth resembling a tumor and/or cancer, or any combination thereof, include breast adenocarcinoma, pancreatic adenocarcinoma, lung carcinoma, prostate cancer, glioblastoma multiform, hormone refractory prostate cancer, solid tumor malignancies such as colon carcinoma, non-small cell lung cancer (NSCLC), anaplastic astrocytoma, bladder carcinoma, sarcoma, ovarian carcinoma, rectal hemangiopericytoma, pancreatic carcinoma, advanced cancer, cancer of large bowel, stomach, pancreas, ovaries, melanoma pancreatic cancer, colon cancer, bladder cancer, hematological malignancies, squamous cell carcinomas, breast cancer, glioblastoma, or any neoplasm associated with brain including, but not limited to, astrocytomas (e.g., pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, and brain stem gliomas), glioblastomas (e.g., glioblastomas multiforme), meningioma, other gliomas (e.g., ependymomas, oligodendrogliomas, and mixed gliomas), and other brain tumors (e.g., pituitary tumors, crani opharyngiomas, germ cell tumors, pineal region tumors, medul loblastomas, and primary CNS lymphomas) (See, cancercenter.com/brain-cancer/types/tab/overview/, which is hereby incorporated by reference in its entirety). In some embodiments, the neoplasm is related to one or more types of neoplasm provided herein.

[0059] In some embodiments, a pharmaceutical composition for prophylaxis, treatment or both of a viral infection is provided. In some embodiments, the pharmaceutical composition comprises an amount of Quercetin, and an amount of H₂O₂.

[0060] In some embodiments of the pharmaceutical composition, the amount of quercetin is 0.1 g to 2.5 g. [0061] In some embodiments of the pharmaceutical composition, the quercetin is in solution at a concentration of 10 mg/ml to 500 mg/ml.

[0062] In some embodiments of the pharmaceutical composition, the amount of H₂O₂ is 1-3 mL.

[0063] In some embodiments of the pharmaceutical composition, the quercetin and H₂O₂ are in a single dosage form for co-administration.

[0064] In some embodiments of the pharmaceutical composition, the quercetin and H₂O₂ are in a single dosage form suitable for IV administration.

[0065] In some embodiments of the pharmaceutical composition, the quercetin and H₂O₂ are in a single dosage form suitable for oral administration.

[0066] In some embodiments of the pharmaceutical composition, the quercetin and H₂O₂ are in a separate dosage forms.

[0067] In some embodiments of the pharmaceutical composition, the quercetin and H₂O₂ are each in dosage forms suitable for IV administration.

[0068] In some embodiments of the pharmaceutical composition, the quercetin and H₂O₂ are each in dosage forms suitable for oral administration.

[0069] In some embodiments of the pharmaceutical composition, either quercetin or H₂O₂ is in a dosage form suitable for oral administration and the other is in a dosage form for IV administration. In some embodiments of the pharmaceutical composition, either quercetin or II2O2 is in a dosage form suitable for oral administration and the other is in a dosage form for administration via a nebulizer. In some embodiments of the pharmaceutical composition, either quercetin or H₂O₂ is in a dosage form suitable for IV administration and the other is in a dosage form for via a nebulizer.

[0070] In some embodiments of the pharmaceutical composition, the viral infection is caused by one or more virus listed in Table 0.1.

Table 0.1 --- List of virus

[0071J In some embodiments of pharmaceutical composition, the viral infection is caused by one or more coronavirus. In some embodiments of the pharmaceutical composition, the viral infection is caused by a coronavirus selected from the group consisting of human coronavirus, human SARS coronavirus, MERS coronavirus, SARS coronavirus 2, and Covid 19.

[0072] In some embodiments of the pharmaceutical composition, the composition is a nanoparticle formulation.

[0073] Some embodiments relate to use of any of the pharmaceutical compositions provided herein for treatment, prevention or both of a viral infection a subject in need thereof.

[0074] In some embodiments, a method of prevention, treatment or both of a viral infection is provided.

[0075] In some embodiments, the method comprises administering any of the pharmaceutical compositions provided herein to a patient in need thereof.

[0076] In some embodiments of the method, the pharmaceutical composition is administered to the subject IV, orally or both.

[0077] In some embodiments of the method, the amount of quercetin is 0.1 g to

2.5 g-

[0078] In some embodiments of the method, the quercetin is in solution at a concentration of 10 mg/ml to 500 mg/ml. [0079] In some embodiments of the method, the amount of H₂O₂ is 1-3 mL.

[0080] In some embodiments of the composition, use, or method herein, the quercetin is in a nanoparticle formulation.

[0081] In some embodiments of the composition, use, or method herein, the H2.Q2 is in a nanoparticle formulation.

[0082] In some embodiments of the composition, use, or method herein, both quercetin and H₂O₂ are in a nanoparticle formulation.

[0083] In some embodiments of the composition, use, or method herein, the nanoparticle formulation comprises a first population of nanoparticles with quercetin, and a second population of nanoparticles with H₂O₂.

[0084] In some embodiments of the composition, use, or method herein, a dimension of the nanoparticle in the nanoparticle formulation ranges from about 100 nm to about 250 nm.

[0085] In some embodiments of the composition, use, or method herein, the nanoparticle is selected from the group consisting of PLGA-PEG-NPs, FA-PLGA-PEG-NPs,

DSPE-PEG-NPs and FA-DSPE-PEG-NPs.

[0086] In some embodiments of the composition, use, or method herein, quercetin is provided alone as a prophylactic treatment for a subject at risk of a coronaviorus infection.

[0087] In some embodiments of the composition, use, or method herein, quercetin and H₂O₂ are provided in combination as a treatment for a subject in an acute phase of a coronaviorus infection.

[0088] In some embodiments of the composition, use, or method herein, quercetin and H₂O₂ are provided in combination as a treatment for a subject in a chronic phase of a corona viorus infection.

[0089] In some embodiments of the composition, use, or method herein, quercetin is provided orally, intravenously, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose), and/or sublingually for prophylactic treatment.

[0090] In some embodiments of the composition, use, or method herein, quercetin is provided orally, intravenously, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose), and/or sublingually, and H₂O₂. is provided intravenously when a subject is in an acute phase of a coronaviorus infection. [0091] In some embodiments of the composition, use, or method herein, quercetin is provided orally, intravenously, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose), and/or sublingually, and H₂O₂ is provided intravenously and/or via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose) when a subject is in a chronic phase of a coronaviorus infection.

[0092] In some embodiments, quercetin is administered intravenously, The concentration of quercetin in a solution for intravenous administration is about 5 mg/ml to about 500 mg/ml. In some embodiments, the concentration of quercetin in a solution for intravenous administration is about 50 mg/ml. In some embodiments, quercetin is administered intravenously at a dose of about 0.05 g to about 10 g. In some embodiments, quercetin is administered intravenously at a dose of about 0.5 g to about 1 g. In some embodiments, quercetin is administered intravenously at a dose of about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 g, or within a range defined by any two of the aforementioned values.

[0093] In some embodiments, quercetin is administered orally. The amount of quercetin in a composition for oral administration is about 100 mg to about 10 g. In some embodiments, quercetin is administered orally at a dose of about 0.5 g to about 4 g. In some embodiments, quercetin is administered orally at a dose of about 1 g. In some embodiments, quercetin is administered orally at a dose of about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 g, or within a range defined by any two of the aforementioned values.

[0094] In some embodiments, quercetin is administered sublingually, The amount of quercetin in a composition for sublingual administration is about 100 mg to about 10 g. In some embodiments, quercetin is administered sublingually at a dose of about 0.5 g to about 4 g. In some embodiments, quercetin is administered sublingually at a dose of about 1 g. In some embodiments, quercetin is administered sublingually at a dose of about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 g, or within a range defined by any two of the aforementioned values. [0095] In some embodiments, the composition for oral and/or sublingual administration can be prepared into a solution for intravenous administration, wherein the concentration of quercetin is about 10 mg/ml to about 100 mg/ml.

[0096] In some embodiments, quercetin is administered in a liposomal formulation. In some embodiments, quercetin is administered in a liposomal formulation at 50 mg a day. In some embodiments, quercetin is administered in a liposomal formulation at about 25 mg a day to about 75 mg a day. In some embodiments, quercetin is administered in a liposomal formulation at about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 mg a day, or within a range defined by any two of the aforementioned values.

[0097] In some embodiments, Quercetin by itself is not water soluble and therefore is administered in the oral dosage form. In some embodiments, Quercetin in the form of PG/PEG Propylene Glycol Quercetin (Quercetin PG) is water soluble and is used in the clinic as the IV dosage form.

[0098] In some embodiments, the composition of quercetin for oral administration comprises Phosphati dylcholine (PC). In some embodiments, Quercetin can be in the form of a nanoformulation. In some embodiments, Quercetin is in the form of liposomes. In some embodiments, Quercetin in the form of a nanoformulation and/or in the form of liposomes is encapsulated with PC. In some embodiments, Quercetin in the form of a nanoformulation and/or in the form of liposomes is encapsulated with PEG. In some embodiments, Quercetin in the form of a nanoformulation and/or in the form of liposomes is encapsulated with PC and PEG.

[0099] A surprising and unexpected anti-viral effect was observed when H₂O₂ was used in combination with quercetin. The surprising and unexpected result was anti-viral effect of H₂O₂ when used in combination with quercetin. The surprising and unexpected result was achieved by co-administering H₂O₂ with quercetin.

[0100] Therefore, provided herein are combinations of H₂O₂ and quercetin. In some embodiments, each of H2.O2 and quercetin can potentiate the effects of the other in several ways. Non-limiting examples include enhancing the effectiveness, increasing the length of time of effectiveness, decreasing the effective dose of administration, decreasing the duration of time of administration, decreasing the frequency of administration, and/or enabling the administration via a more amenable route. [0101] In some embodiments, the quercetin can be provided can be provided at any dose, via any of the routes of administration, in any order of administration, at any frequency of administration, and/or any dosage form provided herein. Similarly, H₂O₂ can be provided at any dose, via any of the routes of administration, in any order of administration, at any frequency of administration, and/or any dosage form provided herein. Also, the combination of quercetin and H₂O₂ can be provided at any dose, via any of the routes of administration, in any order of administration, at any frequency of administration, and/or any dosage form provided herein. In some embodiments, quercetin and H₂O₂ can be administered via any combination of routes as shown in the non-limiting examples of Table

0.2.

Table 0.2 - Routes of administration

[0102] The potentiation can be additive or synergistic. A synergistic effect is greater than an additive effect. An additive effect is observed when the potentiation is equal to the sum of the individual effects of quercetin and H₂O₂. A synergistic effect is observed when the potentiation is greater than the sum of the individual effects of quercetin and H₂O₂. Synergistic effect, additive effect or both can occur human patients, non-human patients, non-patient human volunteers, in vivo models, ex vivo models, in vitro models, etc.

[0103] Potentiation can range from about <1 to about 100 fold. In some embodiments, the synergistic effect is about 3 to about 30 fold. In some embodiments, the potentiation ranges from <1, 1, >1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 fold, or within a range defined by any two of the aforementioned values. In some embodiments, a synergistic effect allows for a reduction in the requirement of quercetin and/or H₂O₂ to about 25% to about 75% of the recommended dose. In some embodiments, a synergistic effect allows for a reduction in the requirement of quercetin and/or H₂O₂ to about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95% of the recommended dose, or a value within a range defined by any two of the aforementioned values.

[0104] In some embodiments, “combination therapy” is intended to encompass administration of these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of therapeutic agents concurrently, or in a substantially simultaneous manner. Simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form, for example a solution, pill or capsule, having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.

[0105] In some embodiments, mixtures of compositions of the present invention can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. In some embodiments, combination therapy can be achieved by administering two or more agents, e.g., two or more other therapeutic agents, each of which is formulated and administered separately, or by administering two or more agents in a single formulation. Other combinations are also encompassed by combination therapy. For example, two agents can be formulated together and administered in conjunction with a separate formulation containing a third agent. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.

[0106] Applicant unexpectedly found that the gene encoding PI3K is induced in both neoplasms and coronavirus infection. Applicant also unexpectedly found that quercetin inhibits the PI3K gene that is commonly upregulated in patients with neoplasms and in patients with coronavirus infection. Applicant unexpectedly observed that significant reductions in the mutated allele frequencies of PI3K in patients with all types of solid tumors can occur by IV PEG Quercetin administration. [0107] In some embodiments, patients with cancer and/or Covid can be treated by suppression of one or more mutated alleles of the PI3K gene by IV PEG Quercetin administration.

[0108] In some embodiments, patients with cancer and/or Covid can also be treated by suppression of one or more mutated alleles of the PI3K gene by a treatment comprising providing com fungus. In some embodiments, the corn fungus is maize fungus or com smut. In some embodiments, the com fungus is provided in a composition for oral administration. In some embodiments, the dose of corn fungus in the composition for oral administration is about 1-10 gm. In some embodiments, the dose of corn fungus in the composition for oral administration is about 0.5-5 gm. In some embodiments, the dose of corn fungus in the composition for oral administration is about 5-10 gm. In some embodiments, the dose of com fungus in the composition for oral administration is about 10- 15 gm. In some embodiments, the dose of com fungus in the composition for oral administration is about 15-20 gm. In some embodiments, the com fungus is administered in a liposomal formulation.

[0109] In some embodiments, patients with cancer and/or Covid can be treated by suppression of one or more mutated alleles of the PI3K gene by IV PEG Quercetin administration combined with a treatment comprising providing corn fungus.

[0110] Epigall ocatechin-3 -gallate is a polyphenol and the most abundant catechin m tea. In preclinical research, Epigallocatechin gallate (EGCG) shows broad antiviral mechanisms for an array of vimses that affect human health. EGCG also has the advantage of being active across a range of cells, from viral host cells to immune cells. The virus that causes COVID- 19 is a positive-sense single-stranded RNA virus, similar to hepatitis C, Zika, and West Nile viruses. EGCG is known to inhibit viral entry of hepatitis C and Zika, but the effect is not known for SARS-CoV-2. SARS-CoV-2 enters cells through the angiotensinconverting enzyme-2 (ACE2) receptor on the surface of lung cells, and one study suggests EGCG may have some ACE-inhibitory activity, especially at higher concentrations and has also been identified as a target for SARS-CoV-2. Another compound in tea, TF3, does show inhibition of this target [0111] Epigallocatechin gallate and quercetin inhibit the SARS-CoV main protease (3CLpro) with an ICso (50% inhibitory concentration) in vitro of 73 μΜ. In addition, Park et al. reported that quercetin inhibits in vitro both of the SARS-CoV proteases (3CLpro and PLpro) as well as the Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV) 3CLpro protease with ICso values of 52.7, 8.6 and 34.8 μΜ respectively and therefore combination with Quercetin is preferred to inhibit this target.

[0112] In some embodiments, quercetin, and optionally H₂O₂, is provided in combination with EGCG. In some embodiments of the composition, the amount of EGCG is 0.1 g to 1.5 g. In some embodiments of the composition, the EGCG is in solution at a concentration of 1 mg/ml to 50 mg/ml. In some embodiments of the method, the EGCG is administered at a dose is 0.1 g to 1.5 g.

[0113] In some embodiments, EGCG is administered intravenously, The concentration of EGCG in a solution for intravenous administration is about 1 mg/ml to about 100 mg/ml, 1 mg/ml to 50 mg/ml, or 1 mg/ml to 10 mg/ml. In some embodiments, the concentration of EGCG in a solution for intravenous administration is about 5 mg/ml. In some embodiments, EGCG is administered intravenously at a total dose of about 0.01 g to about 15 g. In some embodiments, EGCG is administered intravenously at a total dose of about 0.1 g to about 1.5 g. In some embodiments, EGCG is administered intravenously at a total dose of about 0.01, 0.05, 0.1 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 or 15 g, or within a range defined by any two of the aforementioned values.

[0114] In some embodiments, EGCG is administered orally. The amount of EGCG in a composition for oral administration is about 0.1 g to about 3 g. In some embodiments, EGCG is administered orally at a dose of about 0.2 g to about 1 g. In some embodiments, EGCG is administered orally at a dose of 0.5 g to about 2.5 g. In some embodiments, EGCG is administered orally at a dose of about 0.1 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5 or 3 g, or within a range defined by any two of the aforementioned values. In some embodiments, the composition for oral administration can be prepared into a solution for intravenous administration, wherein the concentration of EGCG is about 5 mg/ml to about 100 mg/ml. In some embodiments, a preventive dose of EGCG is about 0.27 g administered 2 times a day. In some embodiments, a preventive dose of EGCG is about 0.27 g administered 3 times a day. Route of administration

[0115] The route of administration of the quercetin and H₂O₂ can be determined by one of ordinary skill in the art based on the circumstances. Several non-limiting routes of administrations are possible including parenteral, subcutaneous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intraperi cardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, vaginal, rectal, buccal, sublingual, intranasal, transdermal, or via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose).

[0116] Any route of administration provided herein can be used for the combination of quercetin and H₂O₂ or for the individual components of the combination. For example, the combination of quercetin and H₂O₂ can be administered intravenously, orally or both. In some embodiments, one or more components in the combination can be administered via one route (e.g., intravenously) and the other components can be administered via a different route (e.g., orally). In some embodiments, all components in the combination are administered via the same route (e.g., either intravenously or orally).

[0117] In some embodiments, one or more components in the combination can be administered via one route (e.g., intravenously) and the other components can be administered via a different route (e.g., via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose), In some embodiments, all components in the combination are administered via the same route (e.g., either intravenously or via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose).

[0118] In some embodiments, one or more components in the combination can be administered via one route (e.g., intravenously) and the other components can be administered via a different route (e.g., sublingually). In some embodiments, all components in the combination are administered via the same route (e.g., either intravenously or sublingually).

Order of administration [0119] Any order of administration can be used for the quercetin and H₂O₂ in a combination. For example, the quercetin and H2.O2 in the combination can be administered simultaneously or sequentially. For example, all components of the combination are administered simultaneously, or only some of the components of the combination are administered simultaneously and the rest are administered sequentially, In some embodiments, none of the components are administered simultaneously, i.e., all the components are administered sequentially. When administering sequentially, any order of administration can be used. For example, when administering a combination of quercetin and H₂O₂, the quercetin can be administered first followed by H₂O₂.

Frequency of administration

[0120] Frequency of administration of quercetin and H₂O₂ can be varied depending various parameters such as level of potentiation, prognosis following administration of a combination provided herein, patient compliance, side effects, etc., for example, daily, weekly, biweekly, monthly, bimonthly, or as is known in the art. Quercetin and H₂O₂ can be administered daily, weekly, biweekly, monthly, or bimonthly. Quercetin can be administered less frequently compared to and H₂O₂, or more frequently compared to and H₂O₂.

[0121] Administration can be daily, or 1, 2, 3, 4, 5, 6 or more times weekly, or more or less frequently as required. Administration can be provided as a single dose or as divided doses, such that a daily dose may be given in 2, 3, 4, or more portions in a single day.

[0122] Co-administration of the components of a combination may comprise, consist of, or consist essentially of administering the components simultaneously, or within about 1, 5, 15, 30, 45 or 60 minute of one another, or within any range defined by the aforementioned values. Co-administration of the components of a combination may comprise, consist of, or consist essentially of administering the components within about 1 hour to within about 6 hours of one another, or within any range defined by the aforementioned values.

Pharmaceutical formulations

[0123] In some embodiments, pharmaceutical formulations for prophylaxis, treatment or both of a viral infection are provided. The formulation can be a single composition for co-administration comprising, consisting of, or consisting essentially of quercetin and H₂O₂. In some embodiments, the formulation comprises, consists of, or consists essentially of more than one composition, e.g., quercetin in one dosage form, and H₂O₂ in a second dosage form. Several compositions are contemplated. The type of composition to be administered can be determined by one of ordinary skill in the art based on the circumstances under which administration is desired.

[0124] The compositions provided herein comprise, consist of, or consist essentially of active ingredients, inactive ingredients, excipients, additives, and/or pharmaceutically acceptable carriers. Examples of additives include natural polymer compounds, inorganic salts, binders, lubricants, disintegrants, surfactants, thickeners, coating agents, pH adjusters, antioxidants, flavoring agents, preservatives, and colorants among others. Examples of other pharmaceutically acceptable carriers include liquid carriers such as water, alcohol, emulsion, and solid carriers such as gel, powder, etc. Standard pharmaceutical formulation techniques and ingredients can be used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), which is hereby incorporated by reference in its entirety.

[0125] Compositions for intravenous administration comprise, consist of, or consist essentially of excipient and pharmaceutically acceptable carries including one or more of sodium chloride, dextrose, and sterile water. Compositions can comprise, consist of, or consist essentially of aqueous isotonic sterile injection solutions, which can comprise, consist of, or consist essentially of one or more of antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.

[0126] Compositions for oral administration can be any dosage form that is suitable for oral ingestion, for example, liquid compositions such as elixir, suspension, syrup, emulsion, ampoule, etc., solid compositions such as gel, gum, drop, powder, granule, pill, sugar-coated tablet, film-coated tablet, capsule, package agent, etc. Also contemplated are sustained-release compositions such as gel-coated compositions, multi-coated compositions, localized release compositions. [0127] In some embodiments, the compositions are administered by intravenous infusion. The compositions can be presented in unit-dose or multi-dose sealed containers, such as ampules and/or vials. Injection solutions and suspensions can be prepared from sterile powders, granules, and/or tablets. In some embodiments, the compositions to be administered can be formulated as pharmaceutical formulations for delivery via one or more of the routes provided herein.

[0128] A composition can comprise, consist of, or consist essentially of a combination of quercetin and H₂O₂, wherein the quercetin and H₂O₂ can be present in any dosage form. For example, in a composition comprising, consisting of, or consisting essentially of a combination of quercetin and H₂O₂, both quercetin and H₂O₂ can be in the same dosage form (e.g., for intravenous administration or for oral administration), or one of the components in the combination can be of one dosage form (e.g., for intravenous administration or for oral administration) and other two component in the combination can be of a different dosage form (e.g., for intravenous administration or for oral administration). In some embodiments, all components in the combination may be of a different dosage form (e.g., for intravenous administration, for oral administration, and a third dosage form). The various dosage forms can be administered in an order as disclosed herein.

Nanoparticle formulations

[0129] In some embodiments, the pharmaceutical formulation is formulated as one or more of a nanoparticle formulation, a liposomal formulation, or folic acid receptor conjugates. Nanoparticle formulations have many advantages over traditional dosage forms, such as enhanced dissolution properties and potential for efficient intracellular delivery of drugs. Nanoparticles have unique physical and chemical properties that offer several advantages as drug delivery carriers, or ‘nano-carriers.’ Nanoparticles-based composition for detection and/or treatment of viral infections can comprise, consist of, or consist essentially of nanoparticles in the form of, without limitations, quantum dots, magnetic nanoparticles, gold nanoshells (which are useful in detecting tumors and metastasis in many solid tumors), poly (lactide-co-glycolide) (PLGA)-based nanoparticles (e.g., PLGA/montmorillonite (PLGA/MMT) nanoparticles, Vitamin E-TPGS-emulsified PLGA nanoparticles, PLGA- mPEG nanoparticles), dendrimers, and SPIO and USPIO nanoparticles. See, Mousa S.A. and Bharali D.J., Nanotechnology-Based Detection and Targeted Therapy in Cancer: Nano-Bio Paradigms and Applications, Cancers (Basel), Vol. 3, No. 3, pp. 2888-2903, September 2011, which is hereby incorporated by reference in its entirety. Other nanoparticle-based examples are provided in Bharali D.J. and Mousa S.A., Emerging nanomedicines for early cancer detection and improved treatment: current perspective and future promise, Pharmacology & Therapeutics, Vol. 128, No. 2, pp. 324-335, Nov 2010, and Bharali D.J., et al., Nanoparticles and cancer therapy: a concise review with emphasis on dendrimers, International Journal of Nanomedicine, Vol. 4, pp. 1-7, April 1, 2009, which are hereby incorporated by reference in their entirety. Pharmaceutical compositions can also be formulated as nano-micelles-based compositions, for example, as provided in US 9,308,270 B2, which is hereby incorporated by reference in its entirety. Folic acid receptor conjugates based on a conjugating a molecule/drug with folic acid to form a “folate conjugate.”

[0130] Liposomal formulations comprise, consist of, or consist essentially of liposomes that are used as vehicles for administration of drugs. Liposomes are most often composed of phospholipids, especially phosphatidylcholine, but may also include any lipids that are compatible with a lipid bilayer structure (e.g., as egg phosphatidy lethanolamine) . A liposomal formulation can comprise, consist of, or consist essentially of liposomes that may employ surface ligands for attaching to unhealthy tissue. The major types of liposomes are multilamellar vesicle with several lamellar phase lipid bilayers, small unilamellar liposome vesicle with one lipid bilayer, large unilamellar vesicle, and cochleate vesicle.

[0131] In some embodiments, nanoparticle formulations are provided, The nanoparticle formulations comprise, consist of, or consist essentially of quercetin and H₂O₂, wherein the quercetin and H₂O₂ can be present in any dosage form, for example liquids for injection or oral administration, or pills or capsules. In some embodiments, the nanoparticles contain a single compound, i.e., quercetin or H₂O₂. In some embodiments, the nanoparticles contain both quercetin and U2O2.

[0132] In some embodiments, nanoparticles comprise, consist of, or consist essentially of quercetin and H₂O₂. In some embodiments, nanoparticle formulations comprise, consist of, or consist essentially of a combination of nanoparticles wherein a first population of nanoparticles contains quercetin, and a second population of nanoparticles contains H₂O₂. In some embodiments, the formulation comprises, consists of, or consists essentially of a first population of nanoparticles containing H₂O₂, and a second population of nanoparticles containing quercetin.

[0133] In some embodiments, the nanoparticles can be one or more nanospheres, nanocylinders, nanoplates, nanoshells, nanorods, nanorices, nanofibers, nanowires, nanopyramids, nanoprisms, nanostars, nanocrescents, nanorings, and nanoantennas. In some embodiments, the dimensions of the nanoparticles can range from about 1 nm to about 100 nm. In some embodiments, the dimensions of the nanoparticles can range from about 100 nm to about 250 nm. In some embodiments, the dimensions of the nanoparticles can range from about 20 nm to about 1000 nm. In some embodiments, the dimensions of the nanoparticles can range from about 4 nm to about 6250 nm. In some embodiments, the dimensions of the nanoparticles is about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 750, 1000, 1250, 2500, 3750, 5000, 7500, 10000 nm, or a value within a range defined by any two of the aforementioned values. In some embodiments, the amount quercetin that can be incorporated within a nanoparticle depends on the size of the nanoparticle. Thus, the greater the size of a nanoparticle, the greater the amount of quercetin and/or H₂O₂ that can be incorporated within the nanoparticle.

[0134] In some embodiments, the nanoparticles comprise, consist of, or consist essentially of one or more stabilizers, which comprise, consist of, or consist essentially of the structural components of the nanoparticle. Non-limiting examples of stabilizers include deoxycholic acid, polyvinyl alcohol (PVA), Polyvinylpyrrolidone (PVP), and polyethylene glycol (PEG). Stabilizers and their use in the production of nanoparticles are well known to one of ordinary skill in the art. In some embodiments, physico-chemical characterization of nanoparticles is well known to one of ordinary skill in the art. For example, in some embodiments, the heterogeneity of sizes (molecular weight) of the nanoparticles can be measured by determining the dispersity of the nanoparticles, which can be expressed in terms of the polydispersity index (PDI).

Examples

[0135] The following Examples are non-limiting and other variants within the scope of this disclosure are also contemplated. Example 1 - Analysis of survival measures for patients diagnosed with Covid 19 by using nebulized hydrogen peroxide and Quercetin, a nutraceutical agent Table 0.3 - Protocol Synopsis

Example 2 - Case Report [0136] A 69 years old male patient with history of prostate cancer diagnosed and treated with watchful waiting( active surveillance), elevated PSA and positive circulating tumor cells, referred for enhancing his immunity against all infections, as he was concerned about exposure to corona virus during his visit to NY, in January 2020.

[0137] As the protocol was developed to prevent infection with Covid 19, he was prophylactically treated with intravenous hydrogen peroxide and pegylated Quercetin which was applied at dose of 500 mg/m², to him, per protocol, on daily basis for ten consecutive treatments, and tapered down in six weeks. He received the therapies at rate of 5 ml/minute, and experienced no negative side effects. Further he was tested for Covid 19 infection both through nasal swab for viral detection through PCR and serum antibody testing. The results showed positive presence of IgM and IgG, and no presence of active virus (by negative PCR). He had no symptoms of viral infection what so ever.

[0138] His wife and intimate partner, 63 years old female, was also treated for prevention of the disease, for ten treatment sessions, and further tested and had no presence of virus (by negative PCR), or the antibodies.

[0139] One with the common knowledge and expectation would expect that since he had the antibodies, he was exposed and as it is expected from cancer patients, they have more tendency to be symptomatic according to at least one report, yet he had no symptoms. It is also expected that since his wife was also exposed to him, she would have the viral infection, but she did not, meaning that although she was expected to be exposed, but the virus was not able to be passed to her, due to reduced transmissibility of the viral infection after he was treated.

[0140] Although there are studies on using natural therapies such as Plant Terpenoids in treatment of Corona virus infections, specific formulations and dosing to be effective is unclear. The therapy we have developed is specific and targeted in its mode of delivery and action. References here below reflect a collective knowledge of prior art.

[0141] This person as an example received specific formulation and doses which he received and was able to prevent the inoculation to the next person, and it played a role in reducing the risk of transfer. Also, it reduced the viral ability to replicate and cause symptoms, consistent with its mechanism of action.

Example 3 - Case Report

[0142] A cohort of 205 samples patients with advanced solid tumors, who were treated with IV PEG Quercetin at a dose of 500-1000 mg/m², were collected and analyzed. Pre-treatment blood samples were collected from the patients prior to initiation of IV PEG Quercetin administration. After an average of 14 days/2 weeks of TV PEG Quercetin administration, post-treatment blood sample were collected. The frequencies of the mutated alleles of PI3K were evaluated in every patient by pre- and post-treatment blood samples. A statistically significant reduction of the mutated allele fraction of PI3K was observed in more than 80-85% of the sampl es after .

[0143] The case reports that we have is on series of patients treated with IV PEG Quercetin for whom the PI3k gene mutated allele frequencies have been tracked. These are 205 samples with statistically significant reduction of the mutated allele fraction for more than 80-85 percent of these samples as a result of IV PEG Quercetin administration.

[0144] These data indicated that IV PEG Quercetin administration can cause significant reductions in the mutated allele frequencies of PI3K.

Example 4 - Quercetin Dihvdrate

[0145] Quercetin for oral use has been designated as Generally Recognized as Safe (GRN No. 341). Quercetin, which is structurally related to luteolin, is an ingredient of antioxidant and antiallergy medicines that had been approved by the U.S. Food and Drug Administration (FDA; the national drug code numbers of the medicines are 65448-3085, 65448-3005), As an FDA-approved drug ingredient, quercetin offers great promise as a potential drug in the clinical treatment of SARS.

[0146] Many clinics have been using IV formulated quercetin dihydrate in the course of oncology treatments. Without being limited by any particular theory, pure quercetin exhibits broad antiviral properties, including against SARS-CoV (Yi 2004). In addition, there are references in the popular press to potential Canadian/Chinese clinical trials using quercetin for the current COVID-19 pandemic (“A made-in-Canada solution to the coronavirus outbreak?”), but as of the date of this submission no studies were identified on ClinicalTrials.gov, the Chinese Clinical Trial Registry, or Health Canada’s Clinical Trials Database using quercetin as a treatment.

[0147] Without being limited by any particular theory, formulation and the IV administration of quercetin for treatment of solid tumors (in approximately 350 patients) and has found doses of 500 to 1000 mg/m² to be generally safe, with no observed AEs of grade 2 or higher.

[0148] Without being limiting, a summary of the potential activity and safety of quercetin is provided herein.

BACKGROUND

Product Description

Quercetin Dihydrate Formula: Per 100 mL

Quercetin Dihydrate Powder 0.5 to 5 g Polyethylene Glycol NF 300 MW 20-40 mL Benzyl Alcohol NF 0.5 to 4 mL Sterile Water for Injection quantity sufficient 100 mL Diluted in saline prior to administration.

Status

[0149] Quercetin for oral use has been designated as Generally Recognized as Safe (GRN No. 341). Quercetin, which is structurally related to luteolin, is an ingredient of antioxidant and antiallergy medicines that had been approved by the US. Food and Drug Administration (FDA; the national drug code numbers of the medicines are 65448-3085, 65448-3005). As an FDA-approved drug ingredient, quercetin offers great promise as a potential drug in the clinical treatment of SARS. Yi L, Li Z, Yuan K, Qu X, Chen J, Wang G, et al. Small Molecules Blocking the Entry of Severe Acute Respiratory Syndrome Coronavirus into Host Cells. Journal of Virology. 2004;78(20): 11334-9.

Effectiveness

Table 0.4 - IC50 estimate (from in vitro studies)

[0150] Other studies (in silico; Bhowmik 2020) indicate that quercetin binds to the ACE receptor. This result is supported by a study in pigs demonstrating inhibition of angiotensin converting enzyme (Nicolau 2003).

[0151] The therapeutic index (the ratio of viral toxicity to cellular toxicity) for quercetin can be calculated from values reported by Yi et al. (2004) as 3.32 mM/83.4 uM or 39.8.

Clinical

[0152] For treatment of patients that are hospitalized due to complications from

SARS-CoV-2.

[0153] Suggested dose: 500 mg/m² from a formulation of 12.5 mg/mL potency / 30% PEG (NF) v/v in water, diluted into 500 mL infusion grade saline, infused at a rate of 3 mL/min (total infusion period of ~3h). Treatment would be daily for ten (10) consecutive days or until discharge from an ICU, whichever is longer.

Risk / Benefit

[0154] No effective treatment has been established for SARS-CoV-2.

[0155] Intravenous quercetin treatment is intended to slow or stop replication of the SARS-CoV virus. Drug safety has been demonstrated through animal model studies and the practical use of intravenous doses of 500 to 1000 mg/m² in hundreds of patients undergoing cancer treatment and has been found to be generally safe (no adverse events ▻grade 2).

[0156J Hospitalization with infection by SARS-CoV-2 is associated with serious morbidity and mortality. Anti-viral action resulting in reduction of the sequalae of infection would reduce hospitalization and save lives.

Example 5 - Case Study

[0157] This is a case study of a 69 years old male with a diagnosis of mantle cell lymphoma diagnosed based on an orbital mass and confirmed by pathology status post four cycles of Maxi-ChopX. The patient was referred to Dr. Nezami for metabolic and epigenetic evaluation and treatments. The patient refused further chemotherapy due to severe side effects. The patient’s laboratory tests revealed increased LDH. His original pathology was positive for both bcl and Ki 67 and his macroglobulin was elevated, all suggestive of poor prognosis and aggressiveness of his cancer.

[0158] His initial labs showed LDH (tumor marker) of 252, ferritin of 850, and presence of metamyelocytes and myelocytes. He was immediately started on the epigenetic and antioxidant IV protocol. The patient was administered a daily dose of 600 mg (30 ml X 1.25mg/ ml X 1.6% potency). After three sessions, his fatigue improved and his function increased. After 5 treatments, his labs tests were repeated. His LDH dropped to 231, his ferritin to 509 and his beta 2microglobulin showed normal results. In contrast, increased levels were seen in his electrophoresis before starting the treatments.

[0159] His meta myelocytes and myelocytes both disappeared in his labs after the 5 sessions of therapy. His LDH normalized at 132. His CRP dropped from 56 to 0.5 over two months. His natural killer cell activity increased from 14 to 19 over three months and to 51.1 another three months later. His IGF-1 dropped from 218 to 133 over one month.

[0160] After about two months of treatment, his bone marrow biopsy was negative for malignancy and his PET scan was negative, giving him diagnosis of complete clinical remission.

[0161] He had a local recurrence on his left orbit about two years after the initial diagnosis, which was reported with a focal FDG avid lesion in PET scan. He immediately started the IV epigenetic therapy on twice weekly program and continued the program for 4 weeks, along with daily intake of Ibrutinib at 140 mg per day. The restaging PET scan about two month later revealed complete resolution of the lesion with normal activity.

[0162J Further, about a year later, he was diagnosed with Parkinson’s disease and treated accordingly. Between about two and five years after being diagnosed with Parkinson’s disease, he also had increased PSA, which was treated with active surveillance and IV epigenetic therapies.

[0163] Around this time, i.e., after about five years of being diagnosed with Parkisnon’s disease, the patient was referred to the clinic for maintenance therapies for his lymphoma when he was suspected to have a recurrent disease in his PET scan at same site (left orbit). He responded well to the therapy with improved vision within three days. However, within about two months he developed cough and fever, severe fatigue and shortness of breath which required oxygen supplementation, as he developed hypoxia with pulse oximetry of 85 percent on room air. His physical examination was suggestive of pneumonia, with right lung field ronchi and crackes.

[0164] He tested positive for Covid 19 through PCR (nasal swab).

[0165] He was immediately started on IV H₂O₂ 3 percent, 3 ml, Pegylated Quercetin at 600 mg total per session IV, which he received per protocol to treat Covid 19 on daily basis, receiving 20 treatments in 21 days (a single day was missed). EGCG 5 mg/ ml, 75 ml (375 mg) IV was administered daily along with the H₂O₂ and PEG-Quercetin during the final six days of treatment After 21 days of treatment he tested negative for the virus by PCR In addition, his oxygenation improved within three days of beginning treatment and his saturation increased from 85 percent on room air to 95 percent. His requirement for supplemental oxygen was lowered each and every time he received the IV therapy. For example, on days 3-5 he was on 4 liters of oxygen, and on day 5-7 reduced to 2 liters only at night time. His cough stopped in 5 days and his physical examination showed resolution of right pulmonary crackles. He did not receive any other therapies during this time.

[0166] This case shows unexpected results from treatment of a patient with cancer and Covid 19 with severe symptoms, using this protocol, without toxicity.

Example 6 - Case study [0167] This is a case study of 52 subjects who carried the genetic alterations in the PI3K gene. The patients were treated with IV H₂O₂ 3 percent, 3 ml() and PEGylated quercetin at 500-1000 mg/m² IV daily to once a month. Following treatment, it was found that 86 percent of the subjects had responded to treatment as determined by biomarker reduction of mutated allele frequencies for PI3K.

References

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[0170] Ferry DR, Smith A, Malkhandi J, Fyfe DW, deTakats PG, Anderson D, et al. Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res. 1996;2(4):659-68.

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[0185] Park J.Y., Yuk H.J., Ryu H.W., Lim S.H., Kim K.S., Park K.H. Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors. J Enzyme Inhib Med Chem. 2017;32:504-515. doi: 10.1080/14756366.2016.1265519. [PMC flee article] [PubMed] [CrossRef] [Google Scholar] [0186] The terminology used in the description presented herein is not intended to be interpreted in any limited or restrictive manner and unless otherwise indicated refers to the ordinary meaning as would be understood by one of ordinary skill in the art in view of the specification. Furthermore, embodiments may comprise, consist of, or consist essentially of several novel features, no single one of which is solely responsible for its desirable attributes or is believed to be essential to practicing the embodiments herein described. As used herein, the section headings are for organizational purposes only and are not to be construed as limiting the described subject matter in any way. All literature and similar materials cited in this application, including but not limited to, patents, patent applications, articles, books, treatises, and internet web pages are expressly incorporated by reference in their entirety for any purpose. When definitions of terms in incorporated references appear to differ from the definitions provided in the present teachings, the definition provided in the present teachings shall control. It will be appreciated that there is an implied “about” prior to the temperatures, concentrations, times, etc. discussed in the present teachings, such that slight and insubstantial deviations are within the scope of the present teachings herein.

[0187] Although this disclosure is in the context of certain embodiments and examples, those of ordinary skill in the art will understand that the present disclosure extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses of the embodiments and obvious modifications and equivalents thereof. In addition, while several variations of the embodiments have been shown and described in detail, other modifications, which are within the scope of this disclosure, will be readily apparent to those of ordinary skill in the art based upon this disclosure. It is also contemplated that various combinations or sub-combinations of the specific features and aspects of the embodiments may be made and still fall within the scope of the disclosure. It should be understood that various features and aspects of the disclosed embodiments can be combined with, or substituted for, one another in order to form varying modes or embodiments of the disclosure. Thus, it is intended that the scope of the present disclosure herein disclosed should not be limited by the particular disclosed embodiments described above.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition for prophylaxis, treatment or both of a viral infection, the pharmaceutical composition comprising: an amount of Quercetin, and an amount of H₂O₂.

2. The pharmaceutical composition of any of the preceding claims, wherein the amount of quercetin is 0.1 g to 2.5 g.

3. The pharmaceutical composition of any of the preceding claims, wherein the quercetin is in solution at a concentration of 10 mg/ml to 500 mg/ml.

4. The pharmaceutical composition of any of the preceding claims, wherein the amount of H₂O₂ is 1-3 mL.

5. The pharmaceutical composition of any of the preceding claims, wherein the quercetin and H₂O₂ are in a single dosage form for co-administration.

6. The pharmaceutical composition of any of the preceding claims, wherein the quercetin and H₂O₂ are in a single dosage form suitable for IV, oral, mist, aerosol (nebulizer), and/or sublingual administration.

7. The pharmaceutical composition of any of the preceding claims, wherein the quercetin and H₂O₂ are in a separate dosage forms.

8. The pharmaceutical composition of any of the preceding claims, wherein the quercetin and H₂O₂ are each in dosage forms suitable for IV, oral, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose, and/or sublingual administration.

9. The pharmaceutical composition of any of the preceding claims, wherein either quercetin or H₂O₂ is in a dosage form suitable for IV, oral, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose, and/or sublingual administration and the other is in a dosage form for IV, oral, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose, and/or sublingual administration.

10. The pharmaceutical composition of any of the preceding claims, wherein the viral infection is caused by coronavirus selected from the group consisting of human corona virus, human SARS coronavirus, MERS coronavirus, SARS coronavirus 2, and Covid

19.

11. The pharmaceutical composition of any of the preceding claims, wherein the composition is a nanoparticle formulation.

12. Use of a pharmaceutical composition according to any of the preceding claims for treatment, prevention or both of a viral infection a subject in need thereof.

13. A method of prevention, treatment or both of a viral infection comprising: administering the pharmaceutical composition of any one of the preceding claims to a patient in need thereof.

14. The method of Claim 13, wherein the pharmaceutical composition is administered to the subject IV, orally or both.

15. The method of any of the preceding claims, wherein the amount of quercetin is 0.1 g to 2.5 g.

16. The method of any of the preceding claims, wherein the quercetin is in solution at a concentration of 10 mg/ml to 500 mg/ml.

17. The method of any of the preceding claims, wherein the amount of H₂O₂ is 1-

3 m_L.

18. The composition, use, or method of any of the preceding claims, wherein quercetin is in a nanoparticle formulation.

19. The composition, use, or method of any of the preceding claims, wherein H₂O₂ is in a nanoparticle formulation.

20. The composition, use, or method of any of the preceding claims, wherein both quercetin and H₂O₂ are in a nanoparticle formulation.

21. The composition, use, or method of any of the preceding claims, wherein the nanoparticle formulation comprises a first population of nanoparticles with quercetin, and a second population of nanoparticles with H₂O₂.

22. The composition, use, or method of any of the preceding claims, wherein a dimension of the nanoparticle in the nanoparticle formulation ranges from about 100 nm to about 250 nm.

23. The composition, use, or method of any of the preceding claims, wherein the nanoparticle is selected from the group consisting of PLGA-PEG-NPs, FA-PLGA-PEG-NPs, DSPE-PEG-NPs and FA-DSPE-PEG-NPs.

24. The composition, use, or method of any of the preceding claims, wherein quercetin is provided alone as a prophylactic treatment for a subject at risk of a coronaviorus infection.

25. The composition, use, or method of any of the preceding claims, wherein quercetin and H₂O₂ are provided in combination as a treatment for a subject in an acute phase of a coronaviorus infection.

26. The composition, use, or method of any of the preceding claims, wherein quercetin and H₂O₂ are provided in combination as a treatment for a subject in a chronic phase of a coronaviorus infection.

27. The composition, use, or method of Claim 24, wherein quercetin is provided orally, intravenously, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose, and/or sublingually.

28. The composition, use, or method of Claim 25, wherein quercetin is provided orally, intravenously, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose, and/or sublingually, and H₂O₂ is provided intravenously.

29. The composition, use, or method of Claim 26, wherein quercetin is provided orally, intravenously, via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose, and/or sublingually, and H₂O₂ is provided intravenously and/or via mist and/or aerosol, e.g., via nebulizer, administered by mouth and/or nose.

30. The composition, use, or method of any of the preceding claims, further comprising EGCG.

31. The composition, use, or method of claim 30, wherein the amount of EGCG is

0.1 g to 1.5 g.

32. The composition, use, or method of claim 30, wherein the EGCG is in solution at a concentration of 1 mg/ml to 50 mg/ml.

33. The composition, use, or method of claim 30, wherein the EGCG is administered at a dose is 0.1 g to 1.5 g.

34. The composition, use or method of any of the preceding claims wherein EGCG is in a composition for, or administered by, IV.