Immunomodulatory formulations and related methods

Abstract

A composition for immunomodulation and a corresponding method. The composition comprises an emulsion formed by mixing a pharmaceutically acceptable carrier and an active component. The pharmaceutically acceptable carrier accounts for 15 wt% to 85 wt% of the composition. The active ingredients include an effective amount of a cannabis extract to provide a source of exogenous cannabinoids, an effective amount of a cannabinoid enhancer to inhibit cannabinoid hydrolase, an effective amount of a fatty acid amide to enhance cannabinoid activity through an accompanying effect, an effective amount of a piper nigrum extract to alleviate anxiety and an effective amount of an alkaloid to enhance the bioavailability of one or more of the active ingredients.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 065,301, filed August 13, 2020, the entire contents of which are incorporated herein by reference for all purposes. TECHNICAL FIELD

[0003] The present disclosure relates to methods and compositions for treating and / or preventing a disease or disorder caused by a coronavirus infection. BACKGROUND

[0004] SARS-CoV-2 (COVID-19) is a positive-sense RNA virus with an envelope-like and spike-like protrusion on its surface. Coronaviruses can infect a variety of vertebrates, including humans. Coronaviruses can manifest a variety of symptoms, from mild to severe (e.g., flu, fever, cough, fatigue, shortness of breath, lower respiratory tract infection, pneumonia, pulmonary microvascular fibrosis with thrombosis, etc.), and even death. Coronaviruses can also cause complications associated with uncontrolled immune response, such as disseminated intravascular coagulation (DIC). The severity of the disease can depend on the efficiency of the immune system of the infected individual and the presence of comorbidities. A common feature is a strong inflammatory response, manifested by elevated C-reactive protein (CRP), production of pro-inflammatory cytokines (IL-6, IL-10, IL-1), higher TNF-a, neutrophil count, D-dimer, and blood urea. SARS-CoV-2 has a transmission rate of 0.8-3% in the human population, higher than the common flu, and binds to angiotensin-converting enzyme 2 (ACE2) with high affinity to infect humans. SUMMARY

[0005] The disclosed principles provide a composition for immunomodulation against a coronavirus, a method of manufacturing the composition, and an immunomodulation method for combating and treating a coronavirus and symptoms caused by a coronavirus infection found in humans.

[0006] In one embodiment, the composition includes an emulsion formed by mixing a pharmaceutically acceptable carrier with active ingredients. The pharmaceutically acceptable carrier comprises 15 wt% to 85 wt% of the composition. The active ingredients include an effective amount of a cannabis extract to provide an exogenous cannabinoid source, an effective amount of a cannabinoid enhancer to inhibit cannabinoid hydrolytic enzymes, an effective amount of a fatty acid amide to enhance cannabinoid activity through the entourage effect, an effective amount of a kava extract to reduce anxiety, and an effective amount of an alkaloid to enhance bioavailability of one or more of the active ingredients. As used herein, the term "effective amount" refers to a sufficient amount of a compound that can significantly induce a positive change in the condition being treated, but low enough to avoid unwanted side effects, within the sound judgment of those skilled in the art. The effective amount of a compound can vary with the particular condition being treated, the age and condition of the biological subject being treated, the severity of the condition, the duration of the treatment, and other factors within the knowledge and expertise of those skilled in the art.

[0007] In another embodiment, a method of making a composition can include the step of combining a pharmaceutically acceptable carrier with active ingredients to form a solution. The active ingredients include an effective amount of a cannabis extract to provide an exogenous cannabinoid source, an effective amount of a cannabinoid enhancer to inhibit cannabinoid hydrolytic enzymes, an effective amount of a fatty acid amide to enhance cannabinoid activity through the entourage effect, and an effective amount of an alkaloid to enhance bioavailability of one or more of the active ingredients. The method further includes the steps of cooling the solution to a temperature below about 60 °C, adding a kava extract to the cooled solution, and further cooling the cooled solution to a temperature below about 0 °C to form the composition. BRIEF DESCRIPTION OF DRAWINGS

[0008] For a more complete understanding of the present disclosure and its advantages, reference is now made to the following description taken in conjunction with the accompanying drawings in which:

[0009] Figure 1 A flowchart illustrating a method of forming an immunomodulatory composition according to illustrative embodiments is described;

[0010] Figure 2 A flowchart illustrating a method of combining a pharmaceutically acceptable carrier with active ingredients to form a solution according to illustrative embodiments is described; and

[0011] Figure 3 A flowchart illustrating a method of treating a disease using an immunomodulatory composition according to illustrative embodiments is described. DETAILED DESCRIPTION

[0012] The following detailed description includes exemplary embodiments of the present disclosure and refers to the accompanying drawings that form a part of this disclosure. The drawings presented herein illustrate embodiments in which the disclosed principles can be practiced. Other embodiments that can include structural changes and modifications will be used without departing from the scope of the present disclosure.

[0013] Currently, supportive treatments for COVID-19 focus on the side effects caused by the virus, such as inflammation and lung fibrosis (the recognized leading cause of death), as well as symptomatic and respiratory support (oxygen therapy and extracorporeal membrane oxygenation). In some cases, convalescent plasma and immunoglobulin G are administered to patients. Antiviral drugs and systemic corticosteroid treatments, which are typically used against influenza viruses, are ineffective in treating COVID-19. Vaccines developed to protect individuals from the virus are not entirely effective in preventing infection. Moreover, some vaccines have been shown to have reduced effect on mutants of the COVID-19 virus.

[0014] One of the reasons the SARS-CoV-2 virus is so “successful” and thus dangerous is that it can suppress this non-specific immune response. In addition, it also causes human cells to produce the viral protein PLpro (papain-like protease). PLpro has two functions: it plays a role in the maturation and release of new viral particles, and it suppresses the development of type 1 interferons. Interferons (IFNs) are a group of signaling proteins produced by host cells and released in response to the presence of a variety of viruses. IFNs belong to a large class of proteins called cytokines, which are molecules used for cell-to-cell communication that trigger protective defenses of the immune system, thus helping to eradicate the pathogen. Interferons are named for their ability to “interfere” with viral replication by protecting cells from viral infection. IFNs also have a variety of other functions: they activate immune cells, such as natural killer cells and macrophages; they upregulate antigen presentation by increasing the expression of major histocompatibility complex (MHC) antigens, thus enhancing host defenses. Certain symptoms of infection, such as fever, muscle aches, and “flu-like symptoms,” are also caused by the production of IFNs and other cytokines.

[0015] Cannabinoids can downregulate the production of cytokines and chemokines, and in some models, upregulate T regulatory cells to suppress the inflammatory response. The endocannabinoid system is also involved in immune regulation. For example, administration of endocannabinoids or use of inhibitors of enzymes that break down endocannabinoids results in immune suppression and recovery from immune-mediated organ damage, such as the liver. Manipulation of endocannabinoids in vivo and / or use of exogenous cannabinoids can constitute an effective treatment modality for inflammatory diseases.

[0016] The compounds disclosed herein can be used as an immunomodulatory multi-receptor approach (immunity enhancer) to combat and treat the likelihood of coronavirus (e.g., COVID-19) and other autoimmune related diseases including multiple sclerosis (MS), Lyme disease, and lymphoma. The disclosed formulation of components can synergistically “immunomodulate” or modulate / enhance immune function and also reduce hypertension. The disclosed compounds can include components (i.e., ingredients) that have been shown to modulate ACE2 expression in tissues into which the SARS CoV-2 virus enters and downregulate TMPRSS2 that is used by the virus for S protein priming at the ACE2 site (Hoffmann et al., 2020). The disclosed components stimulate the release of type 1 interferon and counteract the substance PlPro produced by the virus that produces and releases new viruses and suppresses the development of type 1 interferon (Hoffmann et al., 2020). The disclosed compounds can target the classic type 2 cannabinoid receptor or CB2 receptor with CB2 agonists to release interferon.

[0017] ACE2 stands for angiotensin-converting enzyme 2, which is a protein located on the surface of many cells in the human body. The ACE2 receptor mediates entry of three strains of coronavirus into cells: SARS-CoV, NL63, and SARS-CoV-2. The ACE2 receptor is ubiquitous and is widely expressed in the heart, blood vessels, intestines, lungs (particularly in type 2 lung cells and macrophages), kidneys, testes, and brain. ACE2 is primarily bound to cell membranes and is rarely present in soluble form in the circulation. One important beneficial function of membrane-bound and soluble ACE2 is to degrade angiotensin II to angiotensin 1-7. Thus, the ACE2 receptor limits several adverse effects of angiotensin II binding to the AT1 receptor, including vasoconstriction, increased inflammation, and thrombosis. The increase in angiotensin 1-7 production also triggers a counter-regulatory protective effect by binding to the G protein-coupled Mas receptor.

[0018] Unfortunately, SARS-CoV2 entry into cells via membrane fusion significantly downregulates ACE2 receptors, thus losing the catalytic action of these receptors outside the membrane. Increased lung inflammation and coagulation are reported to be the adverse effects of enhanced and unopposed angiotensin II action through the ACE->angiotensin II->AT1 receptor axis. Patients infected with SARS-CoV-2 show varying degrees of ACE2 deficiency in several characteristics associated with infection and disease severity (e.g., advanced age, hypertension, diabetes, cardiovascular disease). With respect to the disclosed compounds, ACE2 downregulation caused by viral invasion can be detrimental to people with baseline ACE2 deficiency associated with the aforementioned conditions. Additional ACE2 deficiency after viral invasion can amplify the imbalance between the “adverse” ACE->angiotensin II->AT1 receptor axis and the “protective” ACE2->angiotensin 1-7->Mas receptor axis. In the lungs, this imbalance would favor the progression of inflammatory and thrombotic processes triggered by local angiotensin II hyperactivity unopposed by angiotensin 1-7 (Hoffmann et al., 2020). ACE2 is important because it binds to SARS-CoV-2. ACE2 amino acids form a groove-like pocket into which the spike of SARS-CoV-2 fits or “binds.” This is where SARS-CoV-2 hijacks the cell and begins to replicate, creating a COVID-19 infection. Therefore, the more ACE2 is expressed, the more binding sites there are for the subject coronavirus to invade and spread. By modulating ACE2 expression in the pathway tissues, we reduce the coronavirus’s ability to invade cells, both lowering disease susceptibility and reducing entry points for currently infected individuals.

[0019] While ACE2 is the receptor for viral entry, TMPRSS2 primes the viral spike protein, thus being essential for SARS-CoV2 entry into host cells. Recent studies have shown that TMPRSS inhibitors prevent viral entry. Some cannabis (C. sativa) extracts have been shown to downregulate TMPRSS2 gene expression in EpiOral and EpiIntestinal tissues (Wang et al., 2020).

[0020] The disclosed components have also been shown to stimulate endogenous interleukin-1 receptors to release the pro-anti-inflammatory cytokine Il-1Ra, thus enhancing the release of the anti-inflammatory cytokines IL-4, IL-10, and IL-6 myokines. This would prevent the “cytokine storm” produced by COVID-19.

[0021] The disclosed compounds can be used to alleviate the symptoms of COVID-19 by modulating the immune system in a number of ways. At least one of the disclosed compounds includes a compound that is considered natural, GRAS (generally regarded as safe) by the FDA, sold as a nutritional supplement, or is an endogenous neurochemical. The disclosed compounds can focus on the endocannabinoid system. Cannabinoids have demonstrated their ability to downregulate cytokine and chemokine production and upregulate T regulatory cells (Tregs) to suppress inflammatory responses. The endocannabinoid system is also involved in immunomodulation. For example, administration of endocannabinoids or use of inhibitors of endocannabinoid breakdown enzymes results in immune suppression and recovery from immune-mediated organ (e.g., liver) damage. Manipulation of endocannabinoids in vivo and / or use of exogenous cannabinoids can constitute an effective treatment modality for inflammatory diseases.

[0022] The compounds disclosed herein can be formulated to target the human cannabinoid system. For example, the compounds can target the classic type 1 cannabinoid receptor (CB1) and type 2 cannabinoid receptor (CB2), GPR55, and GPR119. In addition, the disclosed compounds can target IL-1B as well as TRPV ion channels. An example of a different type of eCBE includes fatty acid amide hydrolase (FAAH) inhibitors. It enhances the effects and duration of cannabinoids in the human body. The selected cannabinoids as well as the eCBEs in the formulation can be naturally occurring. The disclosed compounds can utilize cannabinoids that have shown high affinity for the CB2 receptor. Stimulation of CB2 has been shown to reduce the inflammatory response in patients with SARS-CoV-2, improving the overall condition of the patient. Given the ability of CB2 to reduce the production of a large number of cytokines, stimulation of CB2 controls the inflammatory cascade at several checkpoints. In addition, by utilizing a variety of cannabinoids from multiple sources and enhancing their effects through eCBEs, we create what is commonly referred to as the “Entourage effect.” The Entourage effect is a proposed mechanism by which, in addition to tetrahydrocannabinol (THC), cannabinoids work in concert with each other to modulate the overall effect of the plant (cannabinoids). In addition to the cannabinoid system, we also target gamma-aminobutyric acid type A receptors (GABAARs) to reduce hypertension and give a sense of comfort.

[0023] Some components of the disclosed compounds can be endocannabinoid enhancers (eCBEs) that can be used to enhance the activity of the endocannabinoid system by increasing the extracellular concentration of endocannabinoids. The disclosed compounds can comprise eCBEs and cannabinoids with high affinity for CB2 receptors, as stimulating CB2 receptors can reduce the inflammatory response in SARS-CoV-2 patients and release interferon (IFN). Targeting cannabinoid receptors with agonists produces IL-1ra receptors, an important anti-inflammatory cytokine. By targeting the cannabinoid system, the disclosed compounds can enhance the release of IL-1ra, thereby stimulating the immune system to produce anti-inflammatory cytokines. The production of anti-inflammatory cytokines prevents the release and production of new viruses. The disclosed compounds can also stimulate the release of “messenger” interferons, which tell the body which cells are infected and inform neighboring cells to enhance their defensive capabilities. The disclosed compounds can be formulated to target gamma-aminobutyric acid type A receptors (GABA A R), which lower high blood pressure and provide a sense of comfort.

[0024] Proinflammatory cytokines play a central role in inflammatory diseases of infectious or non-infectious origin. PAMPs and DAMPs trigger a cytokine cascade that initially consists of proinflammatory cytokines (IL-1, IL-6, IL-8, IL-12, IFN-gamma, IL-18, and TNF itself) (Srinivasan et al., 2017). These cytokines control and resolve the inflammatory focus by activating local and systemic inflammatory responses. TNF also triggers a cytokine cascade of anti-inflammatory cytokines that block the synthesis of proinflammatory cytokines and cytokine inhibitors that block the action of proinflammatory cytokines. In most cases, the inflammatory response is successfully resolved. However, excessive production of cytokines or failure to stop the production of proinflammatory cytokines leads to an increase in the concentration of cytokines in the systemic circulation (“cytokine storm”). This sustained cytokine production has deleterious effects on the host, leading to hypotension, intravascular thrombosis, pulmonary edema, and hemorrhage; if this process progresses, it leads to multiple organ failure and death. This condition is commonly referred to as systemic inflammatory response syndrome (SIRS). The term describes the clinical manifestations of widespread endothelial inflammation that leads to increased vascular permeability. This disorder is the initiating pathophysiological process for a group of different conditions such as bacterial sepsis, ischemia, burns, trauma, and tissue injury, and hemorrhagic shock.

[0025] It is clear that the interaction between pro- and anti-inflammatory mediators modulates the inflammatory response. Anti-inflammatory cytokines, particularly IL-10, suppress pro-inflammatory cytokine synthesis and adhesion molecule expression, while increasing levels of specific cytokine inhibitors. However, an excess production of anti-inflammatory cytokines can impair the host’s ability to clear microorganisms by suppressing immune cell function. If not kept in balance, the result is either an excessive pro-inflammatory response or immune suppression and increased susceptibility to secondary infections. Thus, the cytokine cascade can be beneficial to the host by initiating an inflammatory response; however, an excess production or insufficient production of pro- or anti-inflammatory endogenous mediators can actually be detrimental to the host (Srinivasan et al., 2017).

[0026] To date, therapeutic strategies targeting pro-inflammatory cytokines such as TNF and IL-1 β have proven ineffective for the treatment of SIRS - multiple clinical trials of antagonists of pro-inflammatory mediators have shown no improvement and in some cases, worsened survival. Pro-inflammatory cytokines are essential for the initiation of the inflammatory response; however, their levels can peak before the clinical signs and symptoms of SIRS become apparent. Moreover, while excessive inflammatory responses can be the cause of some cases of sepsis-related death, in many other cases, a predominant anti-inflammatory response or overall cytokine suppression can be the cause, particularly in populations with a weaker immune system, such as neonates or the elderly. Therefore, more recent therapeutic approaches have focused more on immune modulating or immune stimulating mediators, such as granulocyte-monocyte colony-stimulating factor or IL-7, which has an important role in lymphocyte repletion. Furthermore, mediators that emerge later in the course of disease can also be promising for therapeutic intervention of uncontrolled inflammation in the case of severe sepsis and autoimmune diseases. DAMPs such as HMGB1, mitochondrial DNA and heat shock proteins, and mitochondrial formyl peptides are important late pro-inflammatory mediators. HMGB1 was originally identified as a DNA-binding protein and is now recognized as a late mediator of sepsis and SIRS. HMGB1 is actively released by macrophages and endothelial cells during the inflammatory response and also passively released by necrotic cells. HMGB1 mediates many pro-inflammatory effects locally and systemically. Antibodies or antagonists against HMGB1 have a protective effect in animal models of sepsis and SIRS.

[0027] Another late pro-inflammatory mediator, macrophage inhibitory factor, was originally identified as a regulator of macrophage migration; it is now recognized as a key regulator of the inflammatory response. Anti-macrophage inhibitory factor therapy significantly improved survival in animal models of infection and sepsis. Thus, these "late" pro-inflammatory mediators can provide new therapeutic targets for the treatment of SIRS. Strategies that selectively target DAMP-associated inflammatory responses while allowing for proper immune responses to PAMPs are of particular interest in the context of SIRS and sepsis. Both exogenous and endogenous cannabinoids inhibit the production of pro-inflammatory cytokines by macrophages stimulated through Toll-like receptors (TLRs). TLRs play a crucial role in the perception of danger by macrophages to trigger the inflammatory response. Further, the antibacterial properties of Manuka honey (which distinguishes it from traditional honey) can also be incorporated into the exemplary disclosed formulations. Methylglyoxal is its active ingredient and is likely responsible for these antibacterial effects. In addition, Manuka honey has antiviral, anti-inflammatory, and antioxidant benefits.

[0028] Formulation of the composition

[0029] In general embodiments, the composition is an emulsion formed from an active ingredient mixed with a pharmaceutically acceptable carrier. The active ingredient can include a cannabis extract, a cannabinoid enhancer, a fatty acid amide, a kava extract, and an alkaloid. In more specific embodiments, the pharmaceutically acceptable carrier is medium-chain triglyceride (MCT), the cannabinoid enhancer is oleamide, the fatty acid amide is palmitoylethanolamide (PEA), and the alkaloid is piperine. In some embodiments, the composition can include lecithin.

[0030] The MCT can be caproic acid, caprylic acid, capric acid, lauric acid, or any combination thereof. The MCT of the compounds disclosed herein can be obtained from natural sources such as coconut oil and / or palm kernel oil by various isolation techniques known in the art. The MCT can be used as a solvent for the preparation of the compounds disclosed herein. For example, the compounds disclosed herein can be made in the form of a tincture in MCT. The use of a tincture medium can facilitate sublingual mucosal absorption, which can be advantageous in situations where patient intubation is indicated.

[0031] The kava kava extract can include one or more kavalactones. The kavalactones in the kava kava extract can be methysticin, yangonin, methoxymethysticin, dihydromethysticin, dihydromethysticin, kavalactone, 10-methoxymethysticin, 11-methoxymethysticin, 11-hydroxymethysticin, 11-methoxy-12-hydroxydehydro-methysticin, 7,8-dihydromethysticin, 5-hydroxymethysticin, 5,6-dihydromethysticin, 7,8-dihydromethysticin, 5,6,7,8-tetrahydro-methysticin, 5,6-didehydromethysticin, 7,8-didehydromethysticin, or any combination thereof.

[0032] Kavalactones have been shown to be effective in alleviating anxiety. For example, kavalactones have been shown to positively modulate all receptors regardless of subunit composition. Kavalactones have been shown to have a greater degree of potentiation of the a4b2d GABAAR. Kavalactones have also been shown to be able to induce attenuation of a and g spinal motor systems directed from supraspinal sites, and it has been reported to be an inhibitor of CYP450 enzymes (CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9 / 11), which contributes to muscle relaxation. In addition, kavalactones can inhibit calcium channels, and various kavalactones can produce additive effects, reducing calcium influx by almost 70%. Thus, kavalactones can facilitate widespread inhibition of neuronal firing.

[0033] Some kavalactones have also been found to inhibit sodium channels, which further facilitates the inhibitory effects. Kavalactones can have other beneficial psychoactive properties. Kavalactones have also been shown to be able to reversibly block the platelet MAO B enzyme. Kavalactones have been shown to have the ability to be potent in vitro inhibitors of human MAO-B. Kavalactones interact reversibly and competitively with MAO-A and MAO-B. Methoxymethysticin has been shown to be able to be a potent MAO inhibitor against MAO-A and MAO-B. Thus, some of the central effects of kavalactones (e.g., anxiolysis) can be mediated by MAO inhibition. Kava kava-kava extract can be a reversible inhibitor of MAO-B in both intact platelets and in broken platelet homogenates. Structural differences in kava kava pyrones result in different MAO-B inhibitory potencies. In at least one example, the potency order of selected kava kava pyrones was methysticin > yangonin > methoxymethysticin > dihydromethysticin > dihydromethysticin > kavalactone. In this example, the two most potent kava kava pyrones (methysticin and yangonin) facilitated a particularly high inhibitory profile. Thus, to inhibit MAO-B for psychoactive activity, an extract comprising kava kava pyrones can be advantageous.

[0034] The functional profile of a major anxiolytic kavalactone-voacamine in human recombinants can include a1 b2, b2y2L, a1 b2y2L, axb2y2L (x = 1, 2, 3 and 5), a1 bxy2L (x = 1, 2 and 3) and a4b2d GABAAR expressed in Xenopus oocytes using the two-electrode voltage-clamp technique. Voacamine has been shown to positively modulate the ability of all receptors regardless of subunit composition, but showed a higher degree of potentiation at a4b2d than a1 b2y2L GABAAR (Ligresti et al., 2012). In contrast to CB2 receptors (K i > 10 mM), methoxymyristicin has affinity (K i = 0.72 mM) and selectivity for human recombinant CB1 receptors. The CB1 receptor affinity of methoxymyristicin suggests that the endocannabinoid system can contribute to the complex human psychopharmacology of traditional kava and anxiolytic preparations obtained from kava pepper plants.

[0035] Lecithin is known in the art to comprise glycolipids, triglycerides and phospholipids. Examples of suitable phospholipids can be phosphate-dylcholine, phosphatidyl ethanolamine and phosphatidyl inositol. Soy lecithin has been shown to enable encapsulation, controlled release and successful delivery of therapeutic factors to intracellular regions where they gain these properties from their flexible physicochemical and biophysical properties such as large aqueous core and biocompatible lipids, self-assembly, tunable properties and high loading capacity. SARS-CoV2 uses the lungs as its power plant for replication. Soy lecithin can be used to increase half-life and target lung delivery (for aerosol or possibly vaporizable products).

[0036] Soy lecithin liposomes as drug carriers have proven to have the ability to treat tuberculosis (TB). Soy lecithin liposomes can provide an additional biological mechanism to achieve targeted administration of anti-TB drugs with lower dosage and minimal side effects, while circumventing the drug resistance mechanisms of Mycobacterium tuberculosis strains. Nanodevices, such as liposomes, provide a much-needed additional biological mechanism to achieve targeted administration of anti-TB drugs with lower dosage and minimal side effects, while circumventing the drug resistance mechanisms of Mycobacterium tuberculosis strains. In some cases, inhaled drugs can be more suitable as a therapeutic strategy because they are able to reach the cavitary lesions of the bronchial tree, where bacteria are abundantly present and Mycobacterium tuberculosis strains rapidly multiply. With the help of liposomes, the half-life and targeting efficiency of anti-TB therapies can be improved compared to inhalable dry powder formulations without liposomes. However, previous studies have documented certain difficulties in embedding anti-TB drugs in liposomes. In one example, when ethionamide was used to incorporate into the lipid membrane, the capture efficiency increased to 42%, but the equivalent molar ratio of drug to lipid was too low (0.04) to achieve the desired therapeutic effect. Liposomes are small spherical artificial vesicles that can be made from natural phospholipids and non-toxic cholesterol (Cruz et al., 2009) and are designed to improve the biodistribution of compounds to specific locations in the body. Therefore, they are considered carriers of biologically active compounds with the ability to enhance and / or modify the activity of the compounds associated with them. This influence depends on the chemical composition and phospholipid structure (Machado et al., 2014). One method for preparing DRV-type liposomes based on a dehydration and rehydration process involves mixing a small suspension of empty liposomes (prepared in water), which is freeze-dried after mixing. The preparation of this rehydration under specific conditions of temperature (> Tt) and lipid concentration results in obtaining liposomes with high encapsulation efficiency, called DRV (“dehydration-rehydration vesicles”) and allows high encapsulation efficiency (Frezard et al., 2005). Due to its simplicity and low cost, the classic method for the hydration of the lipid membrane used to produce nanoscale liposomes is still used (Mertins, 2004). In the present disclosure, the application of atomization, lyophilization, stirring, sonication and freeze-thaw extrusion as complementary techniques allows the standardization of the structure.

[0037] Cannabinoids act on glia and neurons to suppress the release of proinflammatory molecules including interleukin 1 (IL-1), tumor necrosis factor (TNF) alpha and nitric oxide (NO) (Molina-Holgado et al., 1997, 2002; Shohami et al., 1997; Puffenbarger et al., 2000; Cabral et al., 2001), and enhance the release of the anti-inflammatory cytokines IL-4, IL-10 (Klein et al., 2000) and IL-6 (Molina-Holgado et al., 1998). Specifically, targeting the cannabinoid receptors with agonists results in the production of IL-1ra, an important anti-inflammatory cytokine. Notably, however, both CB1 and CB2 receptors modulate the release of endogenous IL-1ra. The mechanism of neuroprotection by CBs can be used to respond to inflammatory or excitotoxic injury mediated by CB1 and CB2 receptor-dependent pathways. Furthermore, the anti-inflammatory cytokine IL-1ra is an important mediator of the effects of CBs on neurons and glia, and both CB1 and CB2 receptors modulate the release of IL-1ra from primary cultured glial cells. Thus, by targeting the cannabinoid system, we can mediate IL-1 by enhancing the release of Il1-ra, thereby stimulating the immune system to produce anti-inflammatory cytokines that mediate the effects of PLpro, which in turn prevents the effects of new virus release and production. The disclosed compounds and / or formulations can stimulate the release of the body’s “messenger” interferon, which tells the body which cells are infected and tells neighboring cells to strengthen their defenses.

[0038] The cannabinoids in the cannabis extract can be any of the following: N-acyl ethanolamines, kaempferol, any N-alkyl amides, rutin, 3,3'-diindolylmethane, virodhamine, guineesine, cannabidiol (CBD), any tetrahydrocannabinol (THC) isomer, any of the terpenes, cannabigerol, or any combination thereof. Some examples of functional groups that bond with N-acyl ethanolamines can include linoleoyl, oleoyl, and palmitoyl. N-acyl ethanolamines can act as FAAH inhibitors. N-acyl ethanolamines can also target the GPR55 receptor. Kaempferol can act as a MAGL and FAAH inhibitor at different concentrations. For example, kaempferol as a MAGL inhibitor can be therapeutically effective at a concentration of IC 50 <100 nM. Furthermore, kaempferol as a FAAH inhibitor can be therapeutically effective at a concentration of IC 50 <1 mM. N-alkyl amides exhibit selective affinity for CB2 receptors at different concentrations. For example, N-alkyl amides as CB2 receptor agonists can be therapeutically effective at a concentration of IC iconcentrations < 100 nM can be therapeutically effective in selecting CB2 receptors. N-alkylamides also exhibit the ability to target (ECS) PPARs, ion channels, inhibit AEA transport, partial FAAH inhibitors. Rutin exhibits selective affinity for CB2 receptors at different concentrations. For example, at K i concentrations < 10 μΜ can be therapeutically effective in selecting CB2 receptors. 3,3'- indolinylmethane exhibits selective affinity for CB2 receptors at different concentrations. For example, 3,3'-indolinylmethane is a partial agonist of CB2 receptors at concentrations < 10 μΜ. concentrations < 10 μΜ can be therapeutically effective in selecting CB2 receptors. 3,3'- indolinylmethane exhibits selective affinity for CB2 receptors at different concentrations. For example, 3,3'-indolinylmethane is a partial agonist of CB2 receptors at concentrations < 10 μΜ.

[0039] O-arachidonoylethanolamine is an arachidonic acid and ethanolamine linked by an ester bond, as opposed to the amide bond in anandamide. Virodhamine acts as an antagonist of CB1 receptors and an agonist of CB2 receptors. Virodhamine concentrations in the human hippocampus are similar to those of anandamide, but virodhamine concentrations can be 2 to 9 times higher than anandamide concentrations in peripheral tissues that express CB2. O-AEA is an inhibitor of CYP2J2 epoxygenase. In summary, O-AEA as an eCB inhibitor of CYP2J2 can control vascular CYP2J2 activity in vivo and can cross-talk the interaction between the vascular endocannabinoid and cytochrome P450 systems. Guineensine can act as a cannabinoid transport modulator. Guineensine can inhibit cellular re-uptake of anandamide and 2-arachidonoylglycerol. This results in increased activity of the two neurotransmitters that are classified as cannabinoids. Guineensine can produce dose-dependent cannabimimetic effects that manifest as potent anxiogenic, analgesic, locomotor-depressant, and hypothermic effects. Guineensine is also a monoamine oxidase inhibitor (MAOI) in vitro at different concentrations. For example, guineensine is an MAOI at IC 50= 139.2 μΜ can be therapeutically effective. Guinea pepper amide has demonstrated the ability to inhibit the production of pro-inflammatory cytokines in endotoxemia. Thus, it is advantageous to include Guinea pepper amide in the disclosed compounds.

[0040] CBD has demonstrated the ability to modulate inflammatory processes through CB2-dependent mechanisms. CBD can indirectly induce CB2 activation by increasing AEA levels. CBD exerts its anti-inflammatory properties by reducing pro-inflammatory cytokines. CBD has been demonstrated to be able to act as an immunosuppressant, the mechanisms of which can involve direct inhibition of activation of various immune cell types, induction of apoptosis, and promotion of regulatory cells, which in turn control other immune cell targets. Targets for inhibition can include cytokines such as TNF-a, IFN-g, IL-6, IL-1 b, IL-2, IL-17A, and chemokines such as CCL-2. Generally, CBD can inhibit target cells such as effector T cells and microglia by inhibiting kinase cascades and various transcription factors. For example, CBD-induced inhibition of phosphorylated p38 can result in impaired AP-1 or NF-KB activity. Direct inhibition of target cells can also include induction of IKB, which can contribute to reduced NF-KB activity. CBD involvement in the induction of regulatory cells is also a major part of the mechanisms by which CBD controls the immune response, CBD has been demonstrated to induce Tregs and MDSCs. Finally, CBD-induced apoptosis can be an important mechanism for many target cells. Furthermore, A 9 - Tetrahydrocannabinol (A 9 - THC) can effectively act on TRPV2, moderately modulate TRPV3, TRPV4, TRPA1, TRPM8, and Cb1. THC values: CB1 affinity (Ki) = 10 nM partial agonist; CB2 affinity (Ki) = 24 nM partial agonist. Table 1 illustrates the receptors involved in mediating cannabidiol action.

[0041]

[0042] Some examples of terpenes that can be included in the composition can be b-Caryophyllene ((E)-BCP) and / or a-Humulene. (E)-BCP can selectively bind to CB2 receptors (K i= 155 ± 4 nM), which can make (E)-BCP a functional CB2 agonist. Upon binding to CB2 receptors, (E)-BCP can inhibit adenylyl cyclase, which can result in intracellular calcium transients and weakly activate mitogen-activated kinases Erk1 / 2 and p38 in primary human monocytes. (E)-BCP can also inhibit lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuate LPS-stimulated Erk1 / 2 and JNK1 / 2 phosphorylation in monocytes. (E)-BCP is a functional non-psychoactive CB2 receptor ligand in food and a macrocyclic anti-inflammatory cannabinoid. (E)-BCP has been shown to be orally bioavailable. It would therefore be advantageous to include (E)-BCP for oral consumption. Humulene, also known as a-caryophyllene or a-humulene, is a ring-opened isomer of β-caryophyllene. Humulene has been shown to have potent anti-inflammatory activity. Humulene has both local and systemic anti-inflammatory properties (Chaves et al., 2008) and is an effective analgesic when taken locally, orally, or via aerosol (Rogerio et al., 2009). Humulene can produce anti-tumor effects by inducing apoptosis. β-caryophyllene can be used synergistically ((Legault and Pichette, 2007). Humulene, also known as a-caryophyllene, is a ring-opened isomer of β-caryophyllene. Humulene has potent anti-inflammatory activity in animal models comparable to dexamethasone (Fernandes et al., 2007). Humulene has been shown to increase secretion of IL-8, a chemotactic factor with multiple functions including promoting angiogenesis, which can aid in wound healing, but is generally not associated with anti-cancer compounds (Satsu et al., 2004).

[0043] Piperine has been shown to have chemopreventive and antioxidant activities. In addition, immunomodulatory, anticancer, stimulant, hepatoprotective, anti-inflammatory (Darshan and Doreswamy 2004), antibacterial (Yang et al 2002) and antiulcer activities (Bai and Xu 2000) of piperine have also been shown. Piperine also has a bioconversion effect that can increase the bioavailability of different drugs (such as rifampicin, sulfadiazine, tetracycline and phenytoin) by increasing the absorption of the drug, slowing down the metabolism of the drug or a combination of both (Atal and others 1985; Wu 2007). Piperine can stimulate pancreatic digestive enzymes, prevent oxidative damage, reduce lipid peroxidation, and increase the bioavailability of many therapeutic drugs. In addition, the anti-inflammatory activity of piperine has been demonstrated in rat models of carrageenan-induced paw edema, cotton pellet-induced granuloma, and rat models of granuloma pouch induced by croton oil. The constituents of the Piper species showed in vitro inhibitory activity against the enzymes responsible for leukotriene and prostaglandin biosynthesis, 5-lipoxygenase and COX-1, respectively. Therefore, it is advantageous to incorporate piperine to treat inflammatory diseases accompanied by severe pain. The stimulant component of piperine is due to the activation of the heat and acid sensing TRPV ion channels TRPV1 and TRPA1 on pain receptors (nociceptive nerve cells). Piperine has been shown to be able to inhibit the expression of IL6 and MMP13 and reduce the production of PGE2 in a dose-dependent manner at different concentrations. For example, piperine can be therapeutically effective at a concentration between about 10 pg / ml and about 100 pg / ml. In another example, piperine is therapeutically effective in inhibiting PGE2 at a concentration of about 10 pg / ml of piperine. Therefore, piperine has been shown to be able to produce anti-inflammatory, analgesic and anti-arthritic effects through Il-lb, a member of the IL family of cytokines. In addition, piperine can increase the bioavailability of various drugs by 30% to 200%. Therefore, it is advantageous to incorporate piperine into therapeutic compounds to help modulate immune function to prevent the negative effects of diseases such as SARS CoV-2.

[0044] Peperidine can also activate TPRV ion channels. These channels regulate ion entry, mediating various neural signaling processes associated with temperature, pressure, and pH sensation, as well as olfaction, taste, vision, and pain sensation. Many diseases involve TRP channel dysfunction, including neuropathic pain, inflammation, and respiratory diseases. Cannabinoids have been shown to have the ability to modulate a specific subset of TRP channels. The TRP vanilloid (TRPV), TRP ankyrin (TRPA), and TRP melastatin (TRPM) subfamilies were found to all contain channels that can be modulated by a variety of endogenous, plant-derived, and synthetic cannabinoids. At least six TRP channels from the above three subfamilies were reported to mediate cannabinoid activity: TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8. Peperidine is sparingly soluble in water (40 mg / L at 18 °C; Vasavirama and Upender 2014). The low solubility of peperidine in water and its poor dissolution are rate-controlling in the absorption process of peperidine. Because of the low water solubility of peperidine and the potential toxicity of peperidine to the central nervous system and reproductive system at high concentrations, the pharmaceutical activity of peperidine can be limited (Veerareddy and others 2004; Pachauri and others 2015). In some embodiments of the compounds disclosed herein, lipid encapsulation of peperidine can be incorporated to increase the bioavailability of peperidine and other components of the compounds.

[0045] Cis-9,10-octadecanoic acid amide (oleamide, ODA) can be used as a sleep-inducing substance (Cravatt et al., 1995). A “chaperoning” effect has been proposed (Lambert & Di Marzo, 1999). ODA can enhance or prolong the effects of endocannabinoids (e.g., AEA) by competitively inhibiting the enzyme FAAH (Mechoulam et al., 1997). In addition, ODA can act as a full cannabinoid CB1 receptor agonist. Thus, in addition to allosteric modulation of other receptors and chaperoning effects that can result from fatty acid amide hydrolase inhibition, the effects of ODA can be mediated directly through the CB1 receptor. Some studies on ODA have shown decreased protein levels and metabolic activity of CYP1A2, CYP2B, and CYP2C11, while metabolic activity of CYP2D2 was decreased. Oleamide did not show a tendency to interact with human pregnane X, constitutive androstane, or aryl hydrocarbon receptors in reporter gene assays, and did not modulate their target P450 genes in primary human hepatocytes. In vitro, oleamide was neither an agonist nor an antagonist of the major human nuclear receptors involved in the regulation of xenobiotic metabolism.

[0046] Palmitoylethanolamide (PEA) is a fatty acid amide belonging to the class of nuclear receptor agonists. PEA has demonstrated the ability to bind to nuclear receptors, through which it exerts a variety of biological effects, some of which are associated with chronic inflammation and pain. In some cases, PEA exhibits a tendency to target the peroxisome proliferator-activated receptor alpha (PPAR-a). PEA also exhibits affinity for the cannabinoid-like G-coupled receptors GPR55 and GPR119. Generally, PEA can not exhibit affinity for the cannabinoid receptors CB1 and CB2. However, the presence of PEA (or other structurally related N-acyl ethanolamines) tends to enhance anandamide activity through a “chaperoning effect”. Moreover, PEA can stimulate CB2 receptors, directly or indirectly (Re, Barbero, Miolo, & Di Marzo, 2007). PEA also demonstrates the ability to bind to CB1 receptors (Lin, Lu, Wu, Huang, & Wang, 2015). PEA and OEA tend to exert their effects through the proliferator-activated receptor alpha (PPARa) or GPR119 (Hansen & Artmann, 2008). PEA has also been demonstrated to be able to improve all macroscopic signs of colitis and reduce pro-inflammatory cytokines. In the presence of acute or chronic inflammation, PEA levels change and the endocannabinoid system (ECS) tends to be imbalanced. In at least one case, dysregulation of cannabinoid receptors and their endogenous ligands accompanies the development and progression of beta-amyloid-induced neuroinflammation. PEA has also been demonstrated to have the ability to be anti-inflammatory, antinociceptive, neuroprotective, and anticonvulsant.

[0047] Anandamide (AEA), PEA, and oleoylethanolamide (OEA) are synthesized from membrane phospholipids by N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD). PEA and OEA do not bind to CB1R, but they can enhance AEA activity in the transient receptor potential vanilloid type 1 channel (TRPV1). AEA, PEA, and OEA are all degraded by fatty acid amide hydrolase (FAAH). OEA and PEA can increase AEA levels by competing with AEA for FAAH (mainly OEA) or by downregulating FAAH expression (mainly PEA). Cannabidiol (CBD), a non-psychoactive component of the cannabis plant, activates the peroxisome proliferator-activated receptors (PPARs) and TRPV1 and inhibits FAAH, and thus can compensate for lower levels of AEA, OEA, and PEA in children with ASD.

[0048] The disclosed compounds can include epigallocatechin gallate (EGCG), which is also known as epigallocatechin-3-gallate. EGCG has been shown to have affinity for CB1 receptors. EGCG is a CB2 agonist and a modulator of GABAA receptor 44. The disclosed compounds can also include scutellarein A. Scutellarein A is commonly known as a flavonoid. Scutellarein A is a FAAH inhibitor. Scutellarein A does not show any tendency to interact with CB1 or CB2 receptors or with FAAH-2 to any major extent. Scutellarein A has been shown to be able to inhibit hydrolysis of 0.5 mM AEA FAAH, IC 50 ranging from about 1.8 mM to about 2.4 mM. Scutellarein A has been shown to be able to inhibit spinal cord phosphorylation of extracellular signal-regulated kinase produced by plantar injection of formalin. CB1 receptor antagonist / inverse agonist AM251 (30 mg i.pl.) significantly reduced the effect of both compounds. Scutellarein A (15 mg·kg -1 i.v.) was not shown to be able to increase brain AEA concentrations, but 10 mg·kg - 1 i.v. AEA produced a modest enhancement of effect.

[0049] The disclosed compounds include at least one of the following flavonoids: taxifolin, morin, quercetin, fisetin, apigenin, and galangin. The disclosed flavonoids have been shown to have the ability to inhibit enzymes associated with viral infection and autoimmune diseases. For example, the disclosed flavonoids exhibit the ability to inhibit the MAOB enzyme, which exhibits elevated levels during illness (e.g., coronavirus infection, autoimmune disease, and cancer). Apigenin is a common dietary flavonoid that is abundantly present in many fruits, vegetables, and Chinese herbs, with multiple physiological functions, such as strong anti-inflammatory, antioxidant, antibacterial, and antiviral activities, and a blood pressure-lowering effect. Apigenin has been shown to be able to inhibit a variety of human cancers in vitro and in vivo through a variety of biological effects, such as triggering apoptosis and autophagy, inducing cell cycle arrest, inhibiting cell migration and invasion, and stimulating immune responses. Apigenin has been shown to be able to be developed as a dietary supplement or an adjuvant chemotherapeutic agent for cancer therapy. As mentioned above, the antibacterial properties of manuka honey, as well as the antiviral, anti-inflammatory, and antioxidant benefits, can be added to a formulation for cancer.

[0050] The disclosed compounds can include curcumin. Curcumin (and resveratrol) has been shown to be able to inhibit the constitutive activation of STAT3 by upregulating PIAS3. Curcumin can act as a MAO inhibitor (MAO-A and MAO-B).

[0051] A composition for treating SARS-CoV-2 infection by targeting cannabinoid receptors can include an emulsion formed by mixing a pharmaceutically acceptable carrier with active ingredients. The pharmaceutically acceptable carrier can be 15wt% to 85wt% of the composition. In an embodiment where the composition is in liquid form, the pharmaceutically acceptable carrier can be 50wt% to 85wt%. In another embodiment where the composition is in gel form, the pharmaceutically acceptable carrier can be 15wt% to 35wt%. The active ingredients can include: an effective amount of a cannabis extract to provide a source of endogenous cannabinoids, an effective amount of an endogenous cannabinoid enhancer to inhibit endogenous cannabinoid hydrolyzing enzymes, an effective amount of a fatty acid amide to enhance endogenous cannabinoid activity through a trophic effect, an effective amount of a kava extract to reduce anxiety, and an effective amount of an alkaloid to enhance bioavailability of one or more of the active ingredients.

[0052] The pharmaceutically acceptable solvent can be a medium-chain triglyceride. The medium-chain triglyceride can be derived from an oil, such as palm kernel oil and coconut oil. For example, the extract from the oil can be hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, or any combination thereof. In one example, the cannabinoid enhancer can be oleamide. The fatty acid can be at least one of PEA and virodhamine. The alkaloid can be piperine.

[0053] The effective amount of the cannabis extract can be 5wt% to 40wt% of the composition. In an embodiment where the composition is in liquid form, the cannabis extract can be 5wt% to 13wt%. In another embodiment where the composition is in gel form, the cannabis extract can be 15wt% to 40wt%. The effective amount of the fatty acid primary amide can be 1.5wt% to 6wt% of the composition. In an embodiment where the composition is in liquid form, the fatty acid primary amide can be 1.5wt% to 4wt%. In another embodiment where the composition is in gel form, the fatty acid primary amide can be 2wt% to 6wt%. The effective amount of the fatty acid amide can be 1.5wt% to 11wt% of the composition. In an embodiment where the composition is in liquid form, the fatty acid amide can be 1.5wt% to 4wt%. In another embodiment where the composition is in gel form, the fatty acid amide can be 5wt% to 11wt%. The effective amount of the alkaloid can be 0.2wt% to 3wt% of the composition. In an embodiment where the composition is in liquid form, the alkaloid can be 0.2wt% to 3wt%. In another embodiment where the composition is in gel form, the alkaloid can be 0.5wt% to 3wt%.

[0054] Kava extract can include at least one of methoxylated pyrones, methysticin, methysticin, dihydro methysticin, dihydro kavalactone, kavalactone, 10-methoxylated pyrone, 11-methoxylated pyrone, 11-hydroxylated methoxylated pyrone, 11-methoxyl-12-hydroxylated dehydrokavalactone, 7,8-dihydro methoxylated pyrone, 5-hydroxylated kavalactone, 5,6-dihydro methoxylated pyrone, 7,8-dihydro kavalactone, 5,6,7,8-tetrahydro methoxylated pyrone, 5,6-dehydro methysticin, and 7,8-dihydro methysticin. An effective amount of kava extract can be 6.0 wt% to 35 wt%. In embodiments where the composition is in a liquid form, the kava extract can be 6.0 wt% to 12.0 wt%. In another embodiment where the composition is in a gel form, the kava extract can be 15 wt% to 35.0 wt%.

[0055] At least some of the active ingredients are at least partially encapsulated by lecithin, and the lecithin can be present in an amount of about 2 wt% of the composition. In embodiments where the composition is in a liquid form, the lecithin can be 0.2 wt% to 3 wt%. In another embodiment where the composition is in a gel form, the lecithin can be 0.5 wt% to 3 wt%. The active ingredients at least partially encapsulated by lecithin can include alkaloids.

[0056] Cannabis extract can include at least one of cannabidiol (CBD), tetrahydrocannabinol (THC), cannabigerol, cannabinol, and terpenes. In embodiments where CBD is present, the CBD can comprise 99.5% of the cannabinoids in the cannabis extract. The cannabis extract can comprise full-spectrum CBD or CBD isolate. An effective amount of the cannabis extract can be xx-8 wt%. The cannabis extract can include beta-caryophyllene in an amount of 0.005 wt% to 0.03 wt% of the composition.

[0057] The disclosed compounds can include at least one of taxifolin, morin, quercetin, fisetin, apigenin, and galangin. In one embodiment, the disclosed composition can include 0.1 wt% to 3 wt% of taxifolin, 0.6 wt% to 4 wt% of morin, 1.0 wt% to 6 wt% of quercetin, 2 wt% to 8 wt% of fisetin, 0.3 wt% to 2 wt% of apigenin, and 8 wt% to 20 wt% of galangin. In another embodiment, the disclosed composition can include 1 wt% to 15 wt% of curcumin.

[0058] Effective amounts of ingredients in the disclosed composition can vary depending on the form of the composition. Table 2 illustrates one embodiment of effective amounts of ingredients in a composition in a liquid form. Table 3 illustrates one embodiment of effective amounts of ingredients in a composition in a gel form.

[0059]

[0060] Manufacture of the composition

[0061] Reference Figure 1 A method for manufacturing a composition according to exemplary embodiments is provided. The flowchart 100 begins at step 102, where a pharmaceutically acceptable carrier is combined with active ingredients to form a solution. The active ingredients can include an effective amount of a cannabis extract to provide an endocannabinoid source, an effective amount of an endocannabinoid enhancer to inhibit endocannabinoid hydrolytic enzymes, an effective amount of a fatty acid amide to enhance endocannabinoid activity through a trophic effect, an effective amount of a kava extract to reduce anxiety, and an effective amount of an alkaloid to enhance bioavailability of one or more of the active ingredients. As used herein, the term "effective amount" refers to a sufficient amount of a compound that can significantly induce a positive change in the condition being treated, but low enough to avoid unwanted side effects, within the sound judgment of one skilled in the art. The effective amount of a compound can vary with the particular condition being treated, the age and condition of the biological subject being treated, the severity of the condition, the duration of the treatment, and other factors within the knowledge and expertise of one skilled in the art.

[0062] In step 104, the solution is cooled to a temperature below about 60 °C.

[0063] In step 106, the kava extract is added to the cooled solution. In embodiments where the cannabis extract comprises a cannabidiol isolate, beta-caryophyllene can be added to the cooled solution with the kava extract. In some embodiments, the cooled solution is emulsified to sufficiently disperse the one or more active ingredients throughout the carrier. In one particular embodiment, the emulsification occurs for about 1 minute.

[0064] In step 108, the cooled solution is further cooled to a temperature below about 0 °C, thereby forming the composition. In one or more non-limiting embodiments, the solution is further steadily cooled to a temperature below about 0 °C over a period of between 5 to 10 hours. In other embodiments, the solution is further cooled to a temperature below about 0 °C and then held for a period of 5 to 10 hours.

[0065] Figure 2 is a flowchart of the step of combining a pharmaceutically acceptable carrier with active ingredients to form a solution according to illustrative embodiments. The flowchart 200 begins at step 202, where a solvent is heated to a temperature of about 80 °C before any active ingredients are combined with the pharmaceutically acceptable carrier.

[0066] In step 204, lecithin is dissolved into the pharmaceutically acceptable carrier to form a first intermediate solution when the temperature of the pharmaceutically acceptable carrier is between about 80 °C and about 90 °C.

[0067] In step 206, the endocannabinoid enhancer is dissolved into the first intermediate solution to form a second intermediate solution when the temperature of the first intermediate solution is between about 70 °C and about 80 °C.

[0068] In step 208, the fatty acid amide is dissolved into the second intermediate solution to form a third intermediate solution when the temperature of the second intermediate solution is between about 70 °C and about 80 °C.

[0069] In step 210, the alkaloid is dissolved into the third intermediate solution to form a fourth intermediate solution when the temperature of the third intermediate solution is between about 70 °C and about 85 °C.

[0070] In step 212, the cannabis extract is added to the fourth intermediate solution to form a solution when the temperature of the fourth intermediate solution is between about 70 °C and about 85 °C. In some embodiments, the solution is emulsified to adequately disperse the active ingredients throughout the carrier. In one particular embodiment, the emulsification occurs for about 1 minute.

[0071] In embodiments using tinctures, the disclosed principles can use different methods, including agitation (homogenization) and freezing, to achieve a degree of encapsulation. In other preparations, the method can utilize in-line sonication.

[0072] As disclosed herein, these compounds and treatments have been used for coronavirus (e.g., COVID-19), autoimmune diseases, pulmonary fibrosis, cancer, and multiple sclerosis, with favorable results. The disclosed principles can also have favorable results for many other diseases. Positive results have been observed for shingles virus outbreaks (shingles): a reduction in personal symptoms experienced (perceived pain) in about 10 minutes. The disclosed principles are a particularly effective treatment for “shingles” pain. Thus, the disclosed principles can also be used to treat shingles and COVID-19. The disclosed principles can also be used for systemic inflammatory response syndrome (SIRS). This term describes the clinical manifestations of widespread endothelial inflammation that leads to increased vascular permeability. Since this condition (SIRS) is a starting pathologic process in a group of different conditions (e.g., bacterial sepsis, ischemia, burns, trauma, and tissue injury), the disclosed principles should also be considered a treatment for these conditions. In addition, some people with genetic “autoimmune diseases” that make people “constantly injured” or “constantly in pain” or “body and bone pain” have used the disclosed principles. These people claim to “feel better,” “have a better quality of life,” “feel normal for the first time” after ingesting the disclosed invention. Individuals exhibit a feeling of feeling better or “normal” within 10-30 minutes.

[0073] One start of this disclosed formula has proven to be able to fight COVID-19, working in as little as 15 minutes and reducing some symptoms, and feeling completely well in a few hours. The SARS-CoV-2 virus has to overcome various defense mechanisms of the human body, including its non-specific or innate immune defenses. In the process, infected body cells release messenger substances called type 1 interferons. These messenger substances attract natural killer cells, which kill the infected cells.

[0074] Method of use

[0075] The disclosed compounds can be used to target multiple receptor sites to achieve immune modulation. The disclosed compounds can target type 1 (CB1) and type 2 (CB2) cannabinoid receptors, GPR55, GPR119, PPAR-a, IL-1B, and TPRV ion channels, GABBA, TLR, and the Ras / Raf / MAPK signaling pathway. The disclosed compounds reduce inflammatory responses and stimulate the production of type I interferons, which are key antiviral mediators. By doing so, the disclosed compounds address the “deception” of our immune system by Sars-Cov2. Since Sars-Cov2 has been shown to be highly pro-inflammatory, the disclosed compounds can include cannabinoids that have been shown to have anti-inflammatory effects. Stimulation of CB2 reduces inflammatory responses, which improves the overall condition of patients with SARS-CoV-2. Given the ability of CB2 to reduce the production of a large number of cytokines 33, stimulation of CB2 controls the inflammatory cascade at several checkpoints. The use of the disclosed compounds can also take advantage of TRPV1 or capsaicin receptor agonists, as the TRPV1 channel is involved in the regulation of calcium signaling, which is essential for many cellular processes, including proliferation, apoptosis, cytokine secretion, or T cell activation. In addition, TRPV1 behaves as a multi-modal receptor involved in cell- environment cross-talk. Therefore, it can not only influence cellular behavior, but also cell fate.68The disclosed compounds can include other components that activate PPAR-a receptors to inhibit fatty acid amide hydrolase (FAAH), thereby increasing the levels and effects of endogenous cannabinoids anandamide as well as all the exogenous cannabinoids we present; in addition to reducing inflammation and stimulating the production of type I interferons. The disclosed compounds can produce what is commonly referred to as “entourage effect”. The entourage effect is a proposed mechanism by which cannabinoids work together (with each other) to modulate the overall effects of cannabinoids. Inflammation, anxiety, and hypertension are common symptoms of COVID-19. Therefore, in addition to the cannabinoid system, the disclosed compounds can also include natural components that target gamma-aminobutyric acid type A receptors (GABAAR). GABBA-A receptors are closely related to inflammation and hypertension. GABAergic components have properties that include anti-hypertensive, anti-anxiety, and anti-inflammatory. GABA is the main inhibitory neurotransmitter in the adult brain and has a parallel inhibitory role in the immune system. Immune cells synthesize GABA and have mechanisms for GABA catabolism. Antigen-presenting cells (APCs) express functional GABA receptors and produce electrophysiological responses to GABA. Therefore, the immune system contains all the components required for GABA signaling, while GABA itself can act as a paracrine or autocrine factor. GABAergic agents act directly on APCs, reducing MAPK signaling and likewise reducing subsequent adaptive inflammatory responses in certain models of multiple sclerosis.GABA receptor transcripts are present in immune cells, and GABA treatment reduces the production of inflammatory cytokines in peripheral macrophages. GABA and GABA type A receptor (GABA-A-R) agonists reduce cytotoxic immune responses and cutaneous delayed-type hypersensitivity reactions. Treatment with GABA reduces the development of T cell autoimmunity and inflammation in a non-obese diabetic mouse model of type 1 diabetes. However, the site of action of GABA in adaptive immune responses remains unclear.

[0076] The SARS-CoV-2 virus must overcome various defense mechanisms of the human body, including its non-specific or innate immune defenses. In the process, infected somatic cells release messenger substances called type 1 interferons. These messenger substances attract natural killer cells, which kill the infected cells. One of the reasons why the SARS-CoV-2 virus is so “successful” and thus dangerous is that it can suppress this non-specific immune response. In addition, it also causes the invaded human cells to produce the viral protein PLpro (papain-like protease). PLpro has two functions: it plays a role in the maturation and release of new virus particles, and it suppresses the development of type 1 interferons.

[0077] The disclosed compositions can be used to treat SARS-CoV-2 infection. The release of type 1 interferons triggers the immune system to react to the viral infection. For example, stimulating endogenous interleukin-1 receptors to release the pro-anti-inflammatory cytokine Il-1Ra, while enhancing the release of the anti-inflammatory cytokines IL-4, IL-10, and IL-6. Inhibition of papain-like protease production reduces the ability of coronavirus enzymes to process viral polyproteins to produce functional replicase complexes and enable viral transmission. Modulation of ACE2 expression reduces the ability of coronaviruses to invade cells. In addition, modulation of ACE2 expression reduces disease susceptibility and reduces entry points for infected individuals. Dysregulation of TMPRSS2 gene expression reduces the ability of coronaviruses to replicate in the lungs. In addition, dysregulation of TMPRSS2 gene expression triggers pathology in the body.

[0078] Reference is now made to Figure 3 a method of treating a disease using an immunomodulatory composition, in accordance with illustrative embodiments. Flowchart 300 begins with step 302: stimulating the release of type 1 interferons. In step 304, the production of papain-like protease is inhibited. In step 306, the release of pro-inflammatory molecules is inhibited. In step 308, ACE2 expression is modulated in gateway tissues to reduce the number of viral binding sites. In illustrative embodiments in which the disease is an infection caused by SARS-CoV-2, ACE2 expression is modulated to reduce the number of SARS-CoV-2 binding sites. In step 310, TMPRSS2 gene expression is downregulated.

[0079] While various embodiments according to the principles disclosed herein have been described above, it should be understood that they have been presented by way of example only, and not limitation. Thus, the breadth and scope of the present disclosure should not be limited by any of the above described exemplary embodiments, but should be defined in accordance with any claims and their equivalents issued by the patent office. Furthermore, the above advantages and features are provided in described embodiments, but shall not limit the application of claims to processes and structures necessary to achieve any or all of the above advantages.

[0080] Furthermore, the section headings provided herein are for consistency with the suggestions of 37 C.F.R. 1.77, and are not to be interpreted in any way as limiting the scope of the application. Additionally, the description provided herein is presented in the order of occurrence in the patent application itself, and is not necessarily the order in which the description is presented in the patent application. Furthermore, the section headings provided herein are for consistency with the suggestions of 37 C.F.R. 1.77, and are not to be interpreted in any way as limiting the scope of the application. Specifically, although the heading "Technical Field" is provided above, it should not be construed as limiting the scope of the claims to the subject matter described in the section under that heading. Additionally, the description provided herein should not be construed as admitting that the technology described as background art is prior art to any of the embodiments of the present disclosure. The "SUMMARY" should not be viewed as a limitation on the scope of the claims. Specifically, the claims should not be limited to the embodiments described in the "SUMMARY." Furthermore, any reference to "invention" in the present disclosure should not be interpreted as an admission that only a single novel, inventive concept is presented by the present disclosure. Multiple embodiments can be presented according to the limitations of the claims as issued by the patent office, and the claims accordingly define the embodiments for which protection is sought. In all cases, the scope of such claims should be construed according to the principles of the patent statutes, and should not be limited by the description set forth herein.

[0081] Furthermore, the abstract is provided to comply with 37 C.F.R. § 1.72(b), requiring an abstract that will allow the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. Also, in the above Detailed Description, various features are grouped together in single embodiments for the purpose of streamlining the disclosure. This disclosure is not to be interpreted as reflecting an intention that the claimed embodiments require more features than are expressly recited in each claim. Rather, as the claims reflect, inventive subject matter lies in less than all features of a single disclosed embodiment. Thus, the following claims are hereby expressly incorporated into this Detailed Description, with each claim standing on its own as a separate embodiment.

Claims

1. A composition for treating SARS-CoV-2 infection by targeting cannabinoid receptors, the composition comprising: an emulsion formed by mixing a pharmaceutically acceptable carrier with active ingredients, wherein the pharmaceutically acceptable carrier comprises from 15 wt% to 85 wt% of the composition, and wherein the active ingredients comprise: an effective amount of a cannabis extract to provide an exogenous source of cannabinoids; an effective amount of a cannabinoid enhancer to inhibit cannabinoid hydrolytic enzymes; an effective amount of a fatty acid amide to potentiate cannabinoid activity through a Trojan effect; an effective amount of a kava extract to reduce anxiety; and an effective amount of an alkaloid to enhance bioavailability of one or more of the active ingredients.

2. The composition of claim 1, wherein: the pharmaceutically acceptable solvent is a medium-chain triglyceride; the cannabinoid enhancer is oleamide; the fatty acid amide is palmitoylethanolamide (PEA); and the alkaloid is piperine.

3. The composition of claim 1, wherein: the effective amount of the cannabis extract is from 5 wt% to 40 wt% of the composition; the effective amount of the cannabinoid enhancer is from 1.5 wt% to 6 wt% of the composition; the effective amount of the fatty acid amide is from 1.5 wt% to 11 wt% of the composition; and the effective amount of the alkaloid is from 0.2 wt% to 3 wt% of the composition. at least some of the active ingredients are at least partially encapsulated by lecithin, and wherein the lecithin is present in an amount of from about 0.2 wt% to 3 wt% of the composition.

4. The composition of claim 1, wherein, the at least some of the active ingredients comprise an alkaloid.

5. The composition of claim 4, wherein, the cannabis extract comprises at least one of cannabidiol (CBD), tetrahydrocannabinol (THC), cannabigerol, cannabichromene, a terpene.

6. The composition of claim 1, wherein, the CBD is 99.5% of the cannabinoids in the cannabis extract.

7. The composition of claim 6, wherein, the cannabis extract comprises CBD, and wherein the CBD is one of a full-spectrum CBD or a CBD isolate.

8. The composition of claim 6, wherein, the CBD is the CBD isolate, and wherein the effective amount of the cannabis extract is 8 wt%.

9. The composition of claim 8, wherein, the cannabis extract comprises beta-caryophyllene in an amount of from 0.005 wt% to 0.03 wt% of the composition.

10. The composition of claim 8, wherein, 11. A method of making a composition for treating SARS-CoV-2 infection, the method comprising the steps of: combining a pharmaceutically acceptable carrier with active ingredients to form a solution, wherein the active ingredients comprise: an effective amount of a cannabis extract to provide an exogenous source of cannabinoids, an effective amount of a cannabinoid enhancer to inhibit cannabinoid hydrolytic enzymes, an effective amount of a fatty acid amide to potentiate cannabinoid activity through a Trojan effect, and an effective amount of an alkaloid to enhance bioavailability of one or more of the active ingredients; cooling the solution to a temperature of less than about 60 °C; adding a kava extract to the cooled solution; and further cooling the cooled solution to a temperature of less than about 0 °C to form the composition. ​ 12. The method of claim 11, wherein, The step of combining a pharmaceutically acceptable carrier with an active ingredient further comprises heating the pharmaceutically acceptable carrier to a temperature of at least about 80 °C prior to combining the active ingredient with the pharmaceutically acceptable carrier.

13. The method of claim 11, wherein, The step of combining a pharmaceutically acceptable carrier with an active ingredient further comprises dissolving the lecithin into the pharmaceutically acceptable carrier to form a first intermediate solution when the temperature of the pharmaceutically acceptable carrier is between about 80 °C to about 90 °C.

14. The method of claim 12, wherein, The step of combining a pharmaceutically acceptable carrier with an active ingredient further comprises dissolving the cannabinoid enhancer into the first intermediate solution to form a second intermediate solution when the temperature of the first intermediate solution is between about 70 °C to about 80 °C.

15. The method of claim 13, wherein, The step of combining a pharmaceutically acceptable carrier with an active ingredient further comprises dissolving the fatty acid amide into the second intermediate solution to form a third intermediate solution when the temperature of the second intermediate solution is between about 70 °C to about 80 °C.

16. The method of claim 14, wherein, The step of combining a pharmaceutically acceptable carrier with an active ingredient further comprises dissolving the alkaloid into the third intermediate solution to form a fourth intermediate solution when the temperature of the third intermediate solution is between about 70 °C to about 85 °C.

17. The method of claim 15, wherein, The step of combining a pharmaceutically acceptable carrier with an active ingredient further comprises adding the cannabis extract to the fourth intermediate solution to form the solution when the temperature of the fourth intermediate solution is between about 70 °C and about 85 °C.

18. The method of claim 16, further comprising emulsifying the solution.

19. The method of claim 17, wherein, The further cooling step is performed for about 5 hours to about 10 hours, and wherein adding the kava extract to the cooled solution further comprises emulsifying the cooled solution.

20. The method of claim 10, wherein, The cannabis extract is a cannabidiol isolate, and wherein the method further comprises adding beta-caryophyllene to the cooled solution. The step of combining a pharmaceutically acceptable carrier with an active ingredient further comprises heating the pharmaceutically acceptable carrier to a temperature of at least about 80 °C prior to combining the active ingredient with the pharmaceutically acceptable carrier. The step of combining a pharmaceutically acceptable carrier with an active ingredient further comprises dissolving the lecithin into the pharmaceutically acceptable carrier to form a first intermediate solution when the temperature of the pharmaceutically acceptable carrier is between about 80 °C to about 90 °C. The step of combining a pharmaceutically acceptable carrier with an active ingredient further comprises dissolving the cannabinoid enhancer into the first intermediate solution to form a second intermediate solution when the temperature of the first intermediate solution is between about 70 °C to about 80 °C. The step of combining a pharmaceutically acceptable carrier with an active ingredient further comprises dissolving the fatty acid amide into the second intermediate solution to form a third intermediate solution when the temperature of the second intermediate solution is between about 70 °C to about 80 °C. The step of combining a pharmaceutically acceptable carrier with an active ingredient further comprises dissolving the alkaloid into the third intermediate solution to form a fourth intermediate solution when the temperature of the third intermediate solution is between about 70 °C to about 85 °C. The step of combining a pharmaceutically acceptable carrier with an active ingredient further comprises adding the cannabis extract to the fourth intermediate solution to form the solution when the temperature of the fourth intermediate solution is between about 70 °C and about 85 °C.

18. The method of claim 16, further comprising emulsifying the solution. The further cooling step is performed for about 5 hours to about 10 hours, and wherein adding the kava extract to the cooled solution further comprises emulsifying the cooled solution. The cannabis extract is a cannabidiol isolate, and wherein the method further comprises adding beta-caryophyllene to the cooled solution.

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