WO2022258125A1 - Pharmaceutical compositions of vanillin and wheat germ oil for treatment of covid-19 viral infection and methods of preparation - Google Patents
Pharmaceutical compositions of vanillin and wheat germ oil for treatment of covid-19 viral infection and methods of preparation Download PDFInfo
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- WO2022258125A1 WO2022258125A1 PCT/EG2021/000017 EG2021000017W WO2022258125A1 WO 2022258125 A1 WO2022258125 A1 WO 2022258125A1 EG 2021000017 W EG2021000017 W EG 2021000017W WO 2022258125 A1 WO2022258125 A1 WO 2022258125A1
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- WIPO (PCT)
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- covid
- vanillin
- pharmaceutical preparation
- wheat germ
- germ oil
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Abstract
Coronavirus disease 2019 (COVID-19) has affected the world in a devastating way since December 2019. The virus that causes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has acquired new characteristics through differences in original profile. The current pandemic and outburst represented a real challenge and a huge threat to global public health The present invention provides novel compositions and methods of preparation of an effective pharmaceutical Antiviral formula for treatment of COVID-19 viral infection. The invention relates to an antiviral formula composed of a combination of vanillin and wheat germ oil that proved highly effective in prevention and treatment of corona virus Covid-19 infection. The patent invention Not only prevents the pathogenicity of viruses, but potentially also alleviates the associated inflammatory and immune reaction named as cytokine storm. The outcome is rapid with no side effects and the patients completely recovered within few days. The rational of the combination and mechanisms underlying the antiviral activity is disclosed. This invention represents a 100% curative antiviral remedy for this pandemic with the advantage of high safety and very low cost. Current situation demonstrates the still lack of a 100% effective anti-COVID-19. The devastating symptoms comprise, the cytokine storm, thrombosis, fever, arthralgia, GIT upsets, respiratory infections and inflammatory process in the lungs, all are currently treated with a plethora of drug combination with a mediocre result. These complications obviously resulted from the absence of an early effective anti-COVID-19 drug.
Description
PHARMACEUTICAL COMPOSITIONS OF VANILLIN AND WHEAT GERM OIL FOR TREATMENT OF COVID-19 VIRAL INFECTION AND METHODS OF PREPARATION
1- Technical Field
This invention includes a pharmaceutical preparation of an antiviral agent in the form of oral soft gelatin capsule , tablets, liquid, as well as liquid for inhaler and nebulizer.
The invention is a combination of vanillin and wheat germ oil formulated for oral absorption. Where, the formula maximizes the bioavailability of vanillin.
The patent invention prevents the pathogenicity of viruses, specially COVID-19 - induced virus. Treatment resulted in aborting the virus spread and is effective to ensure rapid recovery. The invention showed high efficacy with no side effects and at very low cost.
2- Background Art
The current situation after more than 18 months of the COVID-19 pandemic, there is no drug approved as an effective anti-COVID-19 disease, that is capable to limit the spread of the pandemic. The success of introduction of several vaccines is a one step to give hope to circumvent the disaster, but with considerable handicap capabilities such as, only use for prophylaxis, give protection for a limited period, global need cannot be fulfilled in suitable time schedule and some cases can be infected even had taken the vaccine recent studies, are looking for new cellular barriers targeting specific cytokines, such as interleukin (IL)-l and IL-6, or the potential to reintroduce some known therapies for treating COVID-19. Conventional anti-inflammatory drugs, including corticosteroids and colchicine, are also being explored for COVID-19 and repurposing of registered medications is the solution currently available and the ongoing search for effective medications to combat COVID-19 continues.
In addition, there is a potential need for an effective CDK-6 inhibitor to abort the virus-host immune reactions and its devastating consequences on victim health. l
Drug repurposing is currently the available solution to the still ongoing research for effective anti-COVID-19 agents. These include, Remdesivir, hydroxychloroquine, ivermectin, lopinavir, ritonavir and azithromycin.This Drug repurposing However, is often theoretical due to the lack of clinical evidence or mechanisms underlying its rational use. Other drug regimes include glucocorticoids , anticoagulants, analgesic antibiotics and general tonics.
Therefore, the present invention addresses such problem and designed pharmaceutical formula highly effective as anti-COVID-19 remedy. The patent also addresses methods of preparation of the patent to enhance vanillin oral bioavailability.
3- Disclosure of the Invention
The hyperinflammatory condition associated with COVID-19 is related to a viral-induced host cytokine cascade. The presence of raised circulating levels of IL-6 appears to be a key and is closely connected to disease severity (1).
Two IL-6 inhibitors are being attempted in treatment of COVID-19. In a few case series, sarilumab and tocilizumab have shown beneficial effects in reducing severity and mortality in severe COVID-19. However, with tocilizumab, the risk of superinfection significantly increased (2).
In addition, several plant-derived constituents seem to effectively inhibit RNA virus activities (3). From these, some patents have been submitted and granted such as the European patent (EP0346451A1).
The pathogenicity of the infection is characterized by two phases. The first phase is the virus entry to host mucosal tissues such as the respiratory tissues or the GIT. This phase involves interplay of E protein of the virus and ACE2 receptors on the mucosal cells of the host. In addition to other mechanism with the ultimate of viral attachment and invasion of the host cells. This is the stage of an early infection. The second phase begins with the host defense mechanisms against the virus and viral replication inside the host cells. The virus versus host reactions is responsible for the burst of the inflammatory and immune reactions. A process that is responsible for all the signs and symptoms of the disease and the complications which could lead to death.
Klinger et al, (2021)(4). reported that the first phase where the virus enters the cell and starts viral replication can be blocked by vaccines and monoclonal antibodies.
Nonetheless, after entry into the cell via the ACE2 receptor, currently, no therapeutic option for intervention exists. The authors outline that There is good reason to think that IL-6 and CDK4/6 might both be good drug targets for the treatment of COVID-19.
From this article, In the beginning of the second phase, so-called host response phase, an overreaction of the host immune system occurs inflammations observed by high C-reactive protein levels and high neutrophil cell count trigger the immune system’s overreaction resulting in thrombotic inflammation in the lungs and, from there, respiratory failure. The authors concluded that a central role in host response displays the cytokine IL-6. Therefore, it is reasonable to inhibit IL-6 in a therapeutic intervention. This approach however is not fully met by current drugs. The authors motioned that, immunomodulators can only be administered to tackle the overreaction of the immune system. However, Immunomodulators given in the early infection phase are harmful for patients. In contrast to IL-6 inhibitors, CDK4/6 inhibitors selectively block the NET (Neutrophil Extracellular Traps) formation and have no impact on other important host immune reactions such as phagocytosis so that they can be given earlier in the infection than IL-6 inhibitors, filling the therapeutic gap between vaccines and monoclonal antibodies in early infection and immunomodulators in the late stage. Therefore, prediction of a role for CDK6 in the response to SARS2 infection, led the authors to hypothesize that CDK4/6 inhibitors are superior to IL-6 inhibitors in the treatment of critically ill COVID-19 patients. The role of CDK6 and CDK6 inhibitors is well acknowledged by the review reported by Ochsner et al (2020) (5).
On the other hand, the current oral bioavailability of vanillin, which is the core in this invention, is low. It is estimated as 7.6% in a rat model (6).
In one embodiment, the present invention relates to preparation and composition of an effective pharmaceutical combination of evidence-based antiviral capability and anti-inflammatory activity. The pharmaceutical formula composed of vanillin or related analogues such as vanillic acid, ethyl vanillin and vanillyl acetate as the major component. The second component is wheat germ oil or one or more of its ingredients, namely octacosanol, oleic acid and linoleic acid. This combination is intended to treat patients infected with COVID-19 virus. Treatment encompasses prophylaxis, prevention and curethe established disease at various severity. Treatment also involves eradication of the virus, preventing
fusion to host cells, replication and aborting and alleviating associated host inflammatory response and immune reaction known as cytokine storm.
Both vanillin and wheat germ oil are considered as safe food supplements the acceptable daily intake (ADI) value for vanillin of 10 mg/kg body weight (bw) per day established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 2002.
The following underly the rational of selection of both vanillin and wheat germ oil as an effective combination to eradicate and treat COVID-19 virus and to save lives of thousands of patients.
According to Conti et al, (2020)(7) When COVI-19 infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)- 1 b and IL-6. The binding of COVI-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-Ib leading to a downstream lung inflammation, fever, and fibrosis. Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections. This is evident as IL-6 is a marker of severity of COVID-19 infection and morbidity.
Several studies have indicated a “cytokine storm” with release of IL-6, IL-1, IL-12, and IL-18, along with tumor necrosis factor alpha (TNFa) and other inflammatory mediators. The increased pulmonary inflammatory response may result in making oxygenation difficult in patients with severe illness (8). It was found that early blockade of the IL-1 receptor is therapeutic in acute hyperinflammatory respiratory failure in COVID-19 patients. Because interleukin- 1 (IL-1) induces the production of IL-6 and other proinflammatory cytokines (9).
As an evidence-based medicine, the wheat germ oil (WGO) is known to be rich in oleic, linoleic, linolenic andoctacosanol (10). In addition, wheat germ oil is the richest herbal product containing vitamin E.
Vitamin E is well known for its Immune-Boosting Effects That Can Help Combat COVID-19.
In one reportAsmahan et al, (2019), showed anti-inflammatory activity for WGO via reduction of in IL-1 and TNF-a values (11). Pretreatment with wheat germ oil in a model of endotoxemia in rats, decreased Lipopolysaccharide (LPS) -triggered pathogenic responses and prevented the increase of TNF-a, IL-6 (12).
In a model of invitro cell line, wheat germ oil had inhibitory effects on the production of LPS induced NO and pro-inflammatory cytokines (IL-6, TNF-alpha, and IL-lbeta). (13)
For octacosanol, an ingredient of wheat germ oil, Anti-COVID-19 activity using molecular docking showed comparable RNA-dependent RNA polymerase inhibition as compared to remdesivir (Remdesivir (RNA-dependent RNA polymerase inhibitor and represents one of the pharmacotherapy guidelines for COVID-19 treatment). The binding score (kcal/mol)for RNA-dependent RNA polymerase accounted (- 6.96 and -6.77) for octacosanol and remdesivir, respectively .In addition, Octacosanol showed good binding to Spike protein SI and main protease (-6.26 and -6.77) respectively (14).
In a recent article, Das et al, concluded that Octacosanol can be utilized both as a tissue cholesterol lowering agent to reduce risk of viral entry beside its repurposed role to inhibit E-protein oligomerization (15).
It is interesting that oleic acid a component of wheat germ oil also could bear antiviral activity and interfering with the entry of the viral genome into the host cell. (16). An European patent (EP0346451A1) titled Antiviral activity of fatty acids and monoglycerides, addressed antiviral and antibacterial activity of fatty acids and monoglycerides. Namely long chain unsaturated oleic, linoleic and linolenic acids, having potential anti-viral activity. As stated, wheat germ oil is rich in these fatty acids.
Based on the composition of what germ oil, and the scientific reports, it is verified that wheat germ oil could bear potential antiviral activity against COVID-19 and its anti-inflammatory activity could help in reducing cytokine storm and the devastating complication of COVID-19 infection.
The wheat germ oil is added as such or one or more of its components such as octacosanol, alpha tocopherol or oleic, linoleic and linolenic
Vanillin or vanillic acid is the main ingredient in the invention. vanillin partially could be converted to vanillic acid in the GIT
Vanillin targeting COVID-19 as an effective antiviral and as an inhibitor to EL-6 and other cytokines that have crucial role in cytokine storm and other devastating sequala of the viral load on the host.
Vanillin and Vanillic acid are well-known, generally regarded as a safe flavoring agent with beneficial biological activities such as anti-oxidant and anti inflammatory.
Vanillic acid involves antioxidant effects and NFicB-related inhibition of pro- inflammatory cytokine production such as IL6, COX2, IL-Ib and TNF-a (17)
As mentioned, IL-6 and CDK4/6 might both be good drug targets for the treatment of COVID- 19, Vanillin inhibits both CDK6 and IL-6.
In addition, CDKIs can be considered as a new treatment option in COVID- 19 based on their proven experimental antiviral effect, broad spectrum antiviral activity, less risk of development of viral resistance and relative safety profile according to the results from cancer clinical trials (18).
In another study, regression modeling and propensity score stratification identified cyclin-dependent kinase 6 (CDK6) as a more promising drug target to selectively treat critically ill COVID- 19 patients than the previously reported interleukin 6. Four existing CDK6, inhibitorsabemaciclib, ribociclib, trilaciclib, and palbociclib have been approved for breast cancer. Clinical evidence for CDK6 inhibitors in treating critically ill COVID- 19 has been reported (4)
Vanillin showed potential activity as CDK6 inhibitorusing combined experimental and computational methods (19)
In addition, in a model of LPS induced acute liver injury, vanillin resulted in the reduction of inflammatory cytokines IL-6 and TNF-a and IL-1 b expression (20).
In another model of LPS-induced Neuroinflammatory Effects in microglia, vanillin significantly reduced pro-inflammatory cytokines, including interleukin (IT)-Ib, tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6) (21). In vitro gingival fibroblasts cells, Vanillin also inhibited IL-Ib, as inductor of proinflammatory cytokines resulting in reduced IL-6, IL-8, COX-2, and iNOS expression and NO release (22).
In a review article by Arya et al, (2021), about a novel vanillin derivative MY21 with anti-neuraminidase (NA) activity comparable to those of oseltamivir and zanamivir. As recently reports on SARS-CoV-2 suggests that vanillin has moderate affinity towards spike protein and main protease. The authors suggest further studies should be undertaken to enhance the inhibitory potential of vanillin and its derivative on SARS-CoV-2 (23).
From the quoted activity as antiviral and anti-inflammatory addressing key cytokine in COVID-19 induced inflammatory and immune reactions in the host, namely IL-6, CDK6, IL1 beta and others, vanillin does possess potential AntiCOVID-19 activity
In one embodiment, the pharmaceutical preparation is formulated in a suitable dosage form for oral administration such as soft or hard gelatin capsules, tablets, syrup, and similar. Another pharmaceutical form as inhaler and nebulizer liquid formula.
In one embodiment, the pharmaceutical form is formulated in a matrix that enable improvement of vanillin bioavailability.
The concentration of the unit dose of the combination for vanillin is ranged from lO-lOOOmg, preferably from 50-500 mg and most preferably from 150-300mg.
The concentration of the unit dose of the combination for wheat germ oil is ranged from 50-1000mg, preferably from 50-500 mg and most preferably from 100- 300mg per unit dose
Inactive ingredients are selected to improve bioavailability and stability of vanillin and to establish rapid absorption.
The said pharmaceutical core compositions of the invention can also contain one or more additional active pharmaceutical ingredients, with the purpose of adding synergistic or targeting other issues associated with COVID-19 infection. These active ingredients include, but are not limited to other antiviral, anti-inflammatory, analgesics and antipyretic sor mixtures thereof.
The said pharmaceutical composition may also include soluble bile acids or their salts such as ursodeoxycholic acid, ursolic acid and alike
Molecular features of vanillin, including hydrophobicity, efficacy for forming hydrogen bonds and reactive carbonyl group, which could influence the fate of vanillin during various handling stages, in addition the tendency of vanillin to form aggregates. Orally vanillin shows poor bio availability (7.6 % in rats). Solvent selection and co-soivents and surfactants are all selected, so as the solubilized vanillin keep its stability and forming partitioning to the aqueous phase in the milieu of the GIT to enhance bioavailability.
The oral administration of said active ingredients are formulated in capsule, tablets, solutions or inhaler or nebulizer solution agents in a suitable pharmaceutically accepted excipient are added in quantities sufficient to be effective in enhancing the rate of oral absorption of vanillin.
The said dosage form is preferably in the form of liquid filled capsules. It is an object of the present invention to provide soft gelatin capsules with which vanillin powder is solubilized in the matrix and the capsule filling remains pumpable.
Particularly preferred solvents include ethyl alcohol, polyethylene glycols (400- 4000), polyvinylpyrrolidone and propylene glycol, preferred are the polyethylene glycols having a molecular weight range from about 300 to about 1000. Solvents and filling agents may include oils, fats, waxes, and lecithin. vegetable oils, animal oils, mineral oils, liquid hydrocarbons, ethereal oils Fats and waxes are also used or added to the filling to increase the required volume. Such solvents, oils and fats must be on the one hand, acceptable for use in the human body and on the other hand are compatible with the shell composition of the capsule.
This resulting solution is suitable for encapsulation in a soft gelatin capsule using standard encapsulation techniques
Oils, surfactants and co-surfactants
The main excipients in a self-emulsifying system include the lipids (oils), surfactant, and co-surfactant.
Oils
Olive oil, almond oil, Com oil, mono-, di-, triglycerides, DL-alpha-Tocopherol, Mixture of mono- and diglycerides of caprylic/capric acid, Triglyceride of the fractionated plant fatty acids, propylene glycol monocaprylate, glyceryl mono- dicaprylatel,2,3- propanetriol decanoic acid monoester, Oleic acid/ethyl oleate
Surfactants/co-surfactants
Soybean lecithin, soluble bile acids (ursolic acid, ursodeoxycholic acid), Polysorbate 20 (Tween 20), Polysorbate 80 (Tween 80), Sorbitanmonooleate(Span
80), Polyoxy-35-castor oil (Cremophor EL), Polyoxy-40-hydrogenated castor oil (Cremophor RH40), (PEG 40 hydrogenated castor oil), Polyoxyethylated glycerides, Polyoxyethylated oleic glycerides, cetyl alcohol, cetostearyl alcohol.
Surfactants improve the bioavailability of vanillin, via several mechanisms based on the selected agents, which include enhancing the solubility and permeability of drugs by momentarily opening tight intracellular junctions.
For tablet formulation, in one embodiment, the said pharmaceutical formulation is in tablet dosage form with the design for enhancing oral absorption.
Nano-technologies, micronization, self-emulsifying and micro-emulsifying systems, solid dispersions, surfactant-based formulations, complexation with b- cyclodextrins, and adsorption onto hydrophilic inert carriers or ion-exchange resins can be adopted. Absorption and permeability enhancers, lipid-based formulations, is another preferred option for different dosage formulation including tablets.
Lipid-Based Formulations
In one embodiment, the Lipid-based formulations is a good choice for the said pharmaceutical preparation to enhance absorption of the patent mixture formulated in hard gelatin capsule, solid or liquid filled, tablet or soft gelatin capsule, oral liquids in the form of solutions or suspensions thereof. In the same embodiment, lipid-based systems can be further classified into lipid solutions, lipid suspensions, emulsions, multiple emulsions, micro- and nanoemulsions, self-emulsifying and self-micro-emulsifying systems, solid lipid nanoparticles, solid lipid dispersions and liposomes.
The inclusion of vegetable oils and fatty acids in the formula stimulates the secretions of bile salt from the gall bladder, Bile salts with lipid ingredients are assembled into a colloidal structure, including vesicles, mixed micelles, and micellar carrier. These carriers increase the solubilization of vanillin in the intestine with consequent increase in its bioavailability. This is Further augmented by the presence of surfactants, co-solvents in the said formula.
In one embodiment the addition of bile acid such as ursolic or ursodeoxycholic acid or alike and phospholipids such as soybean lecithin augments absorption.
In one embodiment the tablet formulation based on Lipid-Based Formulations applying Solidification Techniques for Transforming Liquid SEDDS to Solid- SEDDS (S-SEDDS)
Solid SEDDSs are being developed from liquid/semisolid SEDDS mainly by adsorption on solid carriers, spray drying, lyophilization, melt extrusion, and nanoparticle technology.
EXAMPLES
The following examples describe and demonstrate embodiments within the scope of the present invention. Illustrative examples are given but are not to be interpreted as limitations of the present invention.
Procedure
Polyethylene glycol4000 and cetostearyl alcohol are melted at 60-70C0, olive oil, tween 80, and lecithin are added to the melted mixture and mixed. At a temperature of 50C°, monopropyline glycol andethyl alcoholare added. At a temperature of 45C° wheat germ oil is added and mixed, followed by addition of vanillin and mixed. The prepared formula is kept at 40C°during soft gelatin capsule filling.
Example 2. Formula for soft gelatin capsule
Procedure
Cetyl alcohol and PEG 1500 are heated to 60-70C0. Ursodeoxycholicacid, olive oil, monopropyline glycol, Tween 80 are added and mixed. At a temperature of 50C°, Ethanol is added. Vanillin is added and mixed followed by wheat germ oil. The prepared formula is kept at 40C°during soft gelatin capsule filling.
The said pharmaceutical combination of vanillin and wheat germ oil formulated in a soft gelatin capsule was tested for its antiviral activity against COVID-19 infection in several patients.
The response of the patients was as the following:
9 patients were afflicted by COVID-19 virus and manifested the following cardinal symptoms: fever, tiredness, loss of smell and headache. One patient in addition, suffered from diarrhea. After two to three days from the start of symptoms, each patient started the regimen by taking one capsule three times daily. By the third day all patients were completely recovered from theirillness, but they continue taking the pills for another three days.
In another case, one patient infected with CVID-19, male aged 53 years, had COVID-19, and received the standard protocols. After 9 days his symptoms were severe with decrease in oxygen saturation to 88%and IL-6 was 57. At this stage, the patient administered 2 capsule of the patent formula 3 times daily and continue his standard therapy. After only 24 hours there was a great improvement in his condition, Oxygen saturation raised to 93% and IL-6 decreased to 31 and the
patient could eatwith substantial improvement in breathing. Treatment continued by 2 capsules TID for 3 days, then 1 capsule TID for 7 days. By the end of 7 days almost all symptoms disappeared.
In another case, one patient infected with CVID-19, male aged 39 years, had COVID-19, and received the standard protocols. After 7 days his symptoms were severe with decrease in oxygen saturation to 90% and IL-6 was 42. At this stage, the patient administered 2 capsule of the patent formula 3 times daily and continue his standard therapy. After only 24 hours he stated that he is feeling great improvement, with recovery of his voice, smell, no ache and he regained his appetite and can breathe easily. By the end of the three days of using 2 capsules TID, Oxygen saturation raised to 96% and IL-6 decreased to 9. The patient continued taking the patent capsules as one TID for another 7 days.
Methods of application of the Invention:
Manufacture of soft gel capsules, tablets or a solution of a mixture of vanillin and wheat germ oil to treat viral diseases and infections.
The Invention is directed for treatment of the current most important viral infections mentioned is SARS-CoV-2 (COVID-19), in addition of other viruses. Vanillin concentration ranges from 150-300 mg per dose unit, and the concentration of wheat germ oil ranges from 100-300 mg per dose unit Where the invention aims to prevent, treat and relieve symptoms of COVID -19 or other viral infections and the invention is used in early, mild, moderate or severe infection. Dosing regimen ranges from 1 or 2 capsules per day for prophylaxis to 8 capsules for severe infections, to be taken 4 times daily.
References
1. Kim JS, Lee JY, Yang JW, Lee KH, et al. Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics. 2021; 11(1): 316-329.
2. Pagliano P, Scarpati G, Sellitto C, Conti V, et al. Experimental Pharmacotherapy for COVID-19: The Latest Advances. J ExpPharmacol. 2021 Jan 7; 13 : 1-13. doi: 10.2147/JEP.S255209
3. Shree P, Mishra P, Selvaraj C, Singh SK, et al. Targeting COVID-19 (SARS- CoV-2) main protease through active phytochemicals of ayurvedic medicinal
plants - Withaniasomnifera (Ashwagandha), Tinosporacordifolia (Giloy) and Ocimum sanctum (Tulsi) - a molecular docking study.J BiomolStructDyn. 2020 Aug 27; 1-14. doi: 10.1080/07391102.2020.1810778.
4. Klinger JE, Ravarani CN, Bannard C, Lamparter MR, Schwinges AR, Cope
JL, et al. Critically ill COVED- 19 status associated trait genetics reveals CDK6 inhibitors as potential treatment. https://www.medrxiv.org. doi: https://doi.Org/l 0.1101 /2021.05.18.21256584.
5. Ochsner SA, Pillich RT, McKenna NJ. Consensus transcriptional regulatory networks of corona virus infected human cells. Nature Scientific Data | (2020) 7:314 I https://doi.org/10.1038/s41597-020-00628-6
6. Beaudry F, Ross A, Lema PP, Vachon P. Pharmacokinetics of vanillin and its effects on mechanical hypersensitivity in a rat model of neuropathic pain.
Phytother Res. 2010 Apr;24(4):525-30. doi: 10.1002/ptr.2975.
7. Conti P, Ronconi G, Caraffa A, Gallenga C, et al. Induction of pro- inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J BiolRegulHomeost Agents, . 2020 March-April,;34(2):327-331.
8. David J Cennimo, Michael Stuart Bronze. What is the role of interleukin (IL) inhibitors in the treatment of corona virus disease 2019 (COVID-19)?
Medscape, Coronavirus Disease 2019 (COVID-19), Updated: May 14, 2021
9. Cauchois R, ,Koubi M, Delarbre D, et al. Early IL-1 receptor blockade in severe inflammatory respiratory failure complicating COVID-19.ProcNatlAcadSci U S A. 2020 Aug 11;117(32): 18951-18953.
10. Kashif G, Mehmet MO, Fahad AL-J, Zaidul IS, Isam AM,, Mohammed AH. Nutritional composition, extraction, and utilization of wheat germ oil. European Journal of Lipid Science and Technology, Volumell9, Issue7, July 2017
11. AsmahanT., Arafat RA. Ameliorative Effect of Wheat Germ Oil in Potassium bromate Induced Biochemical and Histopathological Changes in Male Rat's. International Journal of Pharmaceutical and Phytopharmacological Research (elJPPR) I October 2019| Volume 9| Issue 5| Page 126-131.
12. Hussein sa, Abdel-aal, sa, Elghwab aim. Biochemical role of wheat germ oil on biomarkers of oxidative stress and inflammatory response in a rat model of endotoxemia.Benha Veterinary Medical Journal, vol. 27, no. 2:157-167, December 2014.
13. Kang, B.K., Kim, M.J.; Jeong, D.H.; Kim, K.B.W.R., et al. Anti-Inflammatory Effect of Wheat Germ Oil on Lipopolysaccharide-stimulated RAW 264.7 Cells and Mouse Ear Edema. Microbiology and Biotechnology Letters, Volume 44 Issue 3 / Pages.236-245 / 2016 / 1598-642X(pISSN)
14. Elwakil BH, MM,Bekhit AA, El-Naggar MY, Olama ZA. Potential anti- COVID-19 activity of Egyptian propolis using computational modeling
Future Virol. 2021 Feb : 10.2217/fvl-2020-0329.
15. Das G, Das T, Chowdhury N, Chatterjee D, et al. Repurposed drugs and nutraceuticals targeting envelope protein: A possible therapeutic strategy against COVID-19. Genomics
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17. Ikram RUM, TJ, Ahmad R, SaeedK, Alam SI, et al. Vanillic Acid, a Bioactive Phenolic Compound, Counteracts LPS-Induced Neurotoxicity by Regulating c-Jun N-Terminal Kinase in Mouse Brain. Int J Mol Sci. 2021 Jan; 22(1): 361.
18. Gargouri M,Alzwi A, Abobaker A. Cyclin dependent kinase inhibitors as a new potential therapeutic option in management of COVJD-19.Med Hypotheses. 2021 Jan;146:l 10380.
19. Yousuf M, Shamsi A, Queen A, Shahbaaz M, Khan P, et al. Targeting cyclin-dependent kinase 6 by vanillin inhibits proliferation of breast and lung cancer cells: Combined computational and biochemical studies. J Cell Biochem; 2021 Apr 8. doi: 10.1002/jcb.29921. Online ahead of print.
20. Peng Y, Liu L, Wang Y, Yao J, et al. Treatment with toll-like receptor 2 inhibitor ortho-vanillin alleviates lipopolysaccharide-induced acute kidney injury in mice. ExpTher Med. 2019 Dec; 18(6): 4829-4837.
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Claims
1. A pharmaceutical formulation of a combination of vanillin and wheat germ oil.
2. The formula in claim 1, where vanillin or its related vanillic acid, vanillyl alcohol or vanilla extract is the main constituent
3. The preparation in claim 1, where wheat germ oil is added as crude oil or one or more of its ingredients octacosanol, oleic acid, linoleic acid
4. The method of preparation of the pharmaceutical preparation in claims 1-3, is designed to increase oral bioavailability of vanillin
5. The viral infection in claim 1-3 is SARS-CoV-2 infections (COVID-19)
6. The viral infection in claims 1-5, where the virus is one of retroviruses
7. The pharmaceutical formula in claims 1-6, where the dosage form is oral soft gelatin capsule, hard gelatin capsule, tablet, or solution.
8. The pharmaceutical preparation in claims 1-6, where the dosage form as inhaler or nebulizer liquid.
9. The pharmaceutical preparation in claims 1-8, where vanillin concentration in the range of lO-lOOOmg per unit dosage, preferably from 50-500 mg and most preferably from 150-300mg per unit dosage from
10. The pharmaceutical preparation in claims 1-9, where wheat germ oil concentration in the range of 50-1000mg per unit dosage, preferably from 50- 500 mg and most preferably from 100-300mg per unit dosage form
11. The pharmaceutical formula in claims 1-10, where other active ingredients could be added such as other antiviral agents, anti-inflammatory, antibiotics, analgesic and antipyretic drugs and antioxidants and herbal active products with antiviral activity.
12. The pharmaceutical preparation in claims 1-11, where inactive ingredients include agents to enhance the oral bioavailability of vanillin, such as solvents, oils, surfactants, co-surfactants, and solid fillers for adsorption.
13. The method and pharmaceutical preparation in claims 1-12, where the invention may comprise a soluble bile salt such as ursolic acid and urosodeoxycholic acid as surfactants.
14. The method and pharmaceutical preparation in claims 1-13, where the invention is intended to prevent, treat, and alleviate the symptoms of COVID - 19 or other viral infections.
15. The method and pharmaceutical preparation in claims 1-14, where the invention is used in early, mild, moderate, or severe infection.
16. The method and pharmaceutical preparation in claims 1-15, where the dosage regimen, ranged from one or two capsule for prophylaxis per day to a total of 8 capsules per day for severe infection divided over 4 times per day
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Citations (5)
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BG103774U (en) * | 1999-10-04 | 2001-04-30 | "Рамкофарм" ООД | Prophylactic form |
US20130131121A1 (en) * | 2007-03-19 | 2013-05-23 | Yuuzou Tsuchida | Anti-viral agent |
US20200237689A1 (en) * | 2018-11-15 | 2020-07-30 | Bluewillow Biologics, Inc. | Prevention and treatment of coronavirus and other respiratory infections using nanoemulsion compositions |
IN202041026972A (en) * | 2020-06-25 | 2021-01-01 | Zacharia Jacob Dr | |
US10980756B1 (en) * | 2020-03-16 | 2021-04-20 | First Wave Bio, Inc. | Methods of treatment |
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2021
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BG103774U (en) * | 1999-10-04 | 2001-04-30 | "Рамкофарм" ООД | Prophylactic form |
US20130131121A1 (en) * | 2007-03-19 | 2013-05-23 | Yuuzou Tsuchida | Anti-viral agent |
US20200237689A1 (en) * | 2018-11-15 | 2020-07-30 | Bluewillow Biologics, Inc. | Prevention and treatment of coronavirus and other respiratory infections using nanoemulsion compositions |
US10980756B1 (en) * | 2020-03-16 | 2021-04-20 | First Wave Bio, Inc. | Methods of treatment |
IN202041026972A (en) * | 2020-06-25 | 2021-01-01 | Zacharia Jacob Dr |
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