Cannabinoid use and formulations

Abstract

Uses and formulations of cannabinoids, particularly cannabidiol, are provided. The cannabinoids, particularly cannabidiol, are used to treat patients suffering from COVID-19, the disease caused by the SARS-CoV-2 coronavirus. The formulations are specifically directed to oral administration of cannabinoids, particularly cannabidiol. These formulations are useful for treating patients suffering from COVID-19.

Description

[Technical Field]

[0001] This invention relates to the use and formulation of cannabinoids, particularly cannabidiol. According to this invention, cannabinoids, particularly cannabidiol, are used to treat patients suffering from COVID-19, a disease caused by the coronavirus SARS-CoV-2.

[0002] The present invention also provides formulations for oral administration of cannabinoids, particularly cannabidiol. These formulations are useful for treating patients suffering from COVID-19. [Background technology]

[0003] Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in Wuhan, China in December 2019 and has since spread globally, resulting in a coronavirus pandemic. Due to significant discrepancies in testing rates across different populations, the number of infected individuals is unknown, and the mortality rate of the disease remains uncertain. Furthermore, there are methodological concerns regarding the association between mortality and underlying conditions. However, there are currently reasons to assume that the mortality rate is at least comparable to, or higher than, the <1% mortality rate from influenza. Moreover, COVID-19 is more infectious than influenza: the estimated baseline reproduction number (R0) ranges from 1.4 to 1.6 for influenza, while it ranges from 2 to 3 for COVID-19.

[0004] Based on WHO interim guidelines, the management of patients with COVID-19 consists of symptomatic treatment, monitoring, antimicrobial treatment for co-infections, and management of disease complications such as acute respiratory distress syndrome (ARDS) and sepsis.

[0005] While numerous clinical studies have been initiated to test various drugs and treatment regimens, there is still an urgent need for further treatment options.

[0006] Recent studies have suggested that certain cannabinoids may be useful in the treatment of COVID-19. One in vitro cell culture study suggested that in an artificial model of inflammation, a specific Cannabis sativa extract downregulates ACE2, the receptor for SARS-CoV-2, and also downregulates TMPRSS2, a serine protease, another important protein required for SARS-CoV-2 to enter host cells (Non-Patent Literature 1). It is proposed that the extract could be used to develop prophylactic treatments that are easily usable in the form of mouthwash and throat gargle products.

[0007] Apart from COVID-19, cannabinoids, particularly cannabidiol, are considered drugs. There is evidence that cannabinoids may be beneficial in treating many clinical conditions, including pain, inflammation, epilepsy, sleep disorders, signs of multiple sclerosis, loss of appetite, and schizophrenia (Non-Patent Literature 2).

[0008] While the use of cannabinoids has been proposed for various indications, only a limited number of applications have received market approval so far.

[0009] No data has been disclosed to date demonstrating the usefulness of cannabinoids in the treatment of COVID-19. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] B. Wang et al. (2020). In Search of Preventative Strategies: Novel Anti-Inflammatory High-CBD Cannabis Sativa Extracts Modulate ACE2 Expression in COVID-19 Gateway Tissues. Preprints 2020040315 (doi: 10.20944 / preprints202004.0315.v1) [Non-Patent Document 2] N. Bruni et al., Cannabinoid Delivery Systems for Pain and Inflammation Treatment. Molecules 2018, 23, 2478 [Overview of the project] [Problems that the invention aims to solve]

[0011] The object of the present invention is to provide compositions and therapeutic regimens for the treatment of COVID-19 patients. [Means for solving the problem]

[0012] The present invention provides cannabinoids, particularly cannabidiol, for treating patients infected with SARS-CoV-2. The cannabinoids are administered as antiviral agents and / or to prevent or improve cytokine release syndrome (CRS).

[0013] Cannabinoids reduce viral load.

[0014] Furthermore, this treatment lowers serum IL-6 levels and prevents or improves acute respiratory distress syndrome (ARDS).

[0015] Cannabinoids may be administered prophylactically.

[0016] The treatment of the patient is initiated immediately after the diagnosis of the disease, for example, during the non-severe stage of COVID-19.

[0017] Treatment can be initiated when the patient's IL-6 level has increased.

[0018] The cannabinoid can be combined with one or more antiviral agents such as remdesivir (an inhibitor of viral RNA polymerase) or ritonavir / lopinavir (an HIV treatment drug); combined with a drug for idiopathic pulmonary fibrosis; or combined with a drug for thrombosis or a drug for cardiac arrhythmia and applied.

[0019] The cannabinoid is preferably administered orally. It is administered 1 to 4 times a day at a dose of 150 mg to 5000 mg, for example, 1 to 4 times a day at a dose of 250 mg to 5000 mg.

[0020] The cannabinoid can be formulated as a solid dispersion. The solid dispersion contains the cannabinoid and a solubilizer which is an amphiphilic block copolymer capable of forming a micelle solution when combined with an aqueous medium.

[0021] The block copolymer is preferably a poloxamer.

[0022] The solid dispersion can further contain a water-soluble film-forming agent. <l

[0023] The cannabinoid can also be incorporated into a formulation containing a core and a coating on the core. The coating contains the cannabinoid, one or more water-soluble film-forming agents, and other excipients at 20% by mass or less based on the total weight of all components. [[ID=Z9]]

[0024] Further objects and the means for solving them can be concluded from the following detailed description of the present invention.

[0025] Hereinafter, the present invention will be described in more detail with reference to the drawings. [Brief explanation of the drawing]

[0026] [Figure 1] The preparation of a solid dispersion containing cannabinoids and the interaction between the solid dispersion and an aqueous medium are schematically shown. [Figure 2] This document describes the in vitro release from three pellet products containing 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol as the active substance and low-viscosity hydroxypropyl methylcellulose as a film-forming agent. [Modes for carrying out the invention]

[0027] Patients receiving treatment The course of COVID-19 can generally be divided into three stages: I) Asymptomatic incubation period (the virus may already be detectable) II) Non-severe symptom stage (virus detectable) III) Stages of severe respiratory symptoms An immune response is essential in the early stages of infection to eliminate the virus and prevent progression to severe stage III. Strategies to enhance the immune response at this stage may be important. Immunosuppressive therapy is expected to endanger patients during this early stage of the disease. Treatments that reduce viral load can prevent disease progression. Antiviral agents can be administered at this stage.

[0028] If the initial immune response is impaired or insufficient, or if there is no effective antiviral treatment, the virus will multiply, then cause massive tissue damage, ultimately leading to inflammation induced by pro-inflammatory cytokines. High viral load strongly affects and destroys tissues with high expression of angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2. As a result, damaged cells lead to spontaneous inflammation, primarily mediated by pro-inflammatory macrophages and granulocytes. The lungs, as well as other organs and tissues, can be affected. ACE2 is highly expressed in the lungs and intestinal epithelium, but is also found in other tissues, including the heart, cardiovascular system, and kidneys.

[0029] In severe cases, cytokine release syndrome (CRS) may be observed.

[0030] CRS can occur in many infectious and non-infectious diseases. CRS is a form of systemic inflammatory response syndrome. Immune cells are activated by stressed or infected cells via receptor-ligand interactions. CRS occurs when many leukocytes are activated and release inflammatory cytokines, which further activate leukocytes in a positive feedback loop of pathogenic inflammation, leading to a rapid increase in pro-inflammatory cytokines.

[0031] The term cytokine storm is used in severe cases of CRS.

[0032] In COVID-19, systemic hyperinflammation leads to inflammatory lymphocytic and monocytic infiltration of the lungs and heart, causing ARDS and heart failure. Patients with fulminant COVID-19 and ARDS have classic CRS serum biomarkers, including elevated CRP, LDH, IL-6, and ferritin.

[0033] Patients requiring intensive care typically have higher blood concentrations of pro-inflammatory cytokines than those not requiring intensive care. A retrospective study of COVID-19 cases demonstrated a similar phenomenon: blood concentrations of the pro-inflammatory cytokine IL-6 were significantly higher in patients who died from COVID-19 compared to disease survivors. Furthermore, IL-6 concentrations were already higher in non-survivors than in survivors as early as four days after disease onset. The IL-6 concentration curve in non-survivors was characterized by a sharp increase immediately before death, while IL-6 concentrations remained stable in survivors (F. Zhou et al. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395(10229): 1054-62).

[0034] High levels of IL-6 are a significant and important driving force behind CRS.

[0035] CRS is thought to be the cause of several pathological events.

[0036] For example, a contributing factor to lung pathology is impaired production and regulation of hyaluronan: cytokines are potent inducers of hyaluronan synthase-2. Hyaluronan has the ability to absorb water up to 1000 times its molecular weight, and is therefore presumed to be the underlying reason for the clear liquid jelly observed in the lungs of critically ill patients.

[0037] In patients progressing to severe stage III, pneumonia is the leading cause of acute respiratory distress syndrome (ARDS). The rapid onset of widespread inflammation in the lungs leads to respiratory failure. ARDS is the leading cause of death from COVID-19.

[0038] Another major cause of death in patients with COVID-19 is circulatory failure due to myocardial damage. There have also been reports of patients dying from fulminant myocarditis. Consistent with these findings, elevated D-dimer levels >1 μg / mL and elevated high-sensitivity cardiac troponin I were associated with a higher probability of in-hospital death in retrospective studies. In this study, more than half of the patients who died had elevated cardiac troponin I, and approximately 90% of hospitalized patients with pneumonia had elevated D-dimer concentrations, indicating high coagulation activity (F. Zhou et al., loc. cit.).

[0039] Therefore, the release of pro-inflammatory cytokines that induce a pro-coagulation state and promote plaque rupture makes patients more susceptible to thrombosis and ischemia, contributing to cardiac events in COVID-19 patients.

[0040] Furthermore, pathophysiological processes in COVID-19 patients are also reflected in specific white blood cell counts.

[0041] High white blood cell counts, lymphopenia, and a high neutrophil-to-lymphocyte ratio are common in COVID-19 patients (Y. Liu et al. (2020). Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J Infect).

[0042] Available clinical data indicate that an immune response to the virus is essential in the early stages of the disease course, but that specific components of the immune response actually cause damage in the later stages.

[0043] This invention is based on the finding that pharmacological interventions can reduce viral load and / or prevent or reduce undesirable components of the immune response. The present invention relies on the administration of an active agent having a dual mode of action.

[0044] In particular, this invention makes it possible to prevent or improve the clinical symptoms of cytokine release syndrome (CRS) and undesirable inflammatory processes. This is achieved by pharmacological interventions that inhibit the release of pro-inflammatory cytokines, especially IL-6.

[0045] Preliminary clinical data investigating the use of tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, suggest the beneficial effects of IL-6 deprivation therapy in patients with severe SARS-CoV-2 pneumonia (X. Xu et al., Effective treatment of severe COVID-19 patients with tocilizumab. ChinaXiv:20200300026 (2020)).

[0046] This invention provides a simpler and more convenient treatment, namely a treatment that can be administered orally. Furthermore, according to this invention, the active agent also possesses antiviral activity.

[0047] Furthermore, according to the present invention, treatment is initiated earlier, i.e., before the disease reaches a severe stage. In particular, it is considered to initiate treatment at a point when CRS and its consequences can still be prevented, or at least the progression of CRS to a severe stage can be stopped or significantly slowed.

[0048] This also means that more patients may benefit from treatment compared to an approach that applies treatment only to severely ill cases.

[0049] According to the present invention, the patient being treated is infected with SARS-CoV-2. Infection can be confirmed by PCR.

[0050] Treatment may be initiated upon admission, but is preferably initiated in patients with confirmed SARS-CoV-2 infection if one or more of the criteria discussed below are met.

[0051] Patients in the symptomatic phase of infection exhibit disease symptoms including, but not limited to, fever, dry cough, shortness of breath, evidence of rales / crackles on physical examination, muscle aches, fatigue, dyspnea, loss of appetite, loss of smell and taste, and nephritis.

[0052] Therefore, if a patient tests positive for SARS-CoV-2 and exhibits at least one of the symptoms listed above, treatment can be initiated.

[0053] Pathological features of the lungs in COVID-19 include ground glass opacities, a crazy-craving pattern, and, in later stages, compaction on chest computed tomography (CT) or chest X-ray.

[0054] Treatment may be initiated if a patient tests positive for SARS-CoV-2 and exhibits pathological lung features on either a CT scan or a chest X-ray.

[0055] Treatment may be initiated based on peripheral oxygen saturation (SpO2).

[0056] Treatment may be initiated if a patient tests positive for SARS-CoV-2 and shows a decrease in peripheral oxygen saturation (SpO2). In particular, treatment may be initiated if the patient has a peripheral oxygen saturation (SpO2) of ≤93% in ambient air at rest, or requires 3 L / min to 5 L / min of oxygen to maintain an SpO2 >97%.

[0057] Furthermore, treatment for patients who test positive for SARS-CoV-2 can be initiated when lung lesions worsen, defined as stable FiO2 (inhaled oxygen partial pressure) over the past 24 hours, a >3% deterioration in oxygen saturation, or a >10% decrease in PaO2 (arterial oxygen partial pressure).

[0058] Patients may also be treated at the start of NIV (non-invasive ventilation) or CPAP (continuous positive airway pressure), but earlier initiation of treatment is preferable.

[0059] Appropriate criteria for initiating treatment may also be based on laboratory findings.

[0060] Laboratory findings to initiate treatment for a patient tested positive for SARS-CoV-2 include one or more of the following: serum IL-6 ≥ 5.4 pg / ml; CRP level > 70 mg / L (no other infectious or non-infectious course confirmed); CRP level >= 40 mg / L and doubling within 48 hours (no other infectious or non-infectious course confirmed); lactate dehydrogenase > 250 U / L; D-dimer > 1 μg / mL; serum ferritin > 300 μg / mL.

[0061] Preferably, treatment initiation is based on an increase in IL-6 levels.

[0062] If necessary, initiate treatment if a patient who tests positive for SARS-CoV-2 exhibits at least one of the above symptom criteria and meets at least one of the above clinical laboratory criteria.

[0063] Furthermore, treatment for patients who test positive for SARS-CoV-2 may be initiated if the patient exhibits thrombocytopenia <120,000 × 10⁹ E⁹ / L and / or lymphocyte count <0.6 × 10⁹ E⁹ / L, in addition to one of the above criteria as necessary.

[0064] Patients receiving treatment may belong to a risk group. For example, patients receiving treatment may have stomatitis. In particular, patients receiving treatment may have stomatitis and have serum IL-6 levels ≥ 5.4 pg / ml.

[0065] The progression of treatment can be monitored, for example, by the decrease in IL-6, CRP, transaminase, LDH, D-dimer, ferritin, IL-1β, IL-18, interferon-gamma, neutrophils, lymphocytes, and neutrophil-to-lymphocyte ratio (NLR) (%) between the first dose, day 14, and day 28.

[0066] Treatment continues until relevant clinical improvement is achieved, for example, until the patient is released from supplemental oxygen therapy or until the fever subsides.

[0067] Clinical efficacy can be confirmed by overall clinical improvement; prevention of invasive ventilation in patients with moderate COVID-19; and improvement in laboratory parameters indicating disease severity.

[0068] According to the present invention, cannabinoids may also be used for the treatment (prophylactic administration) of subjects at risk of SARS-CoV-2 infection. Prophylactic administration is based particularly on the antiviral activity of cannabinoids.

[0069] The effectiveness of prevention can be evaluated by the absence or reduction of viral load in subjects after exposure to SARS-CoV-2; by an asymptomatic course of the disease; or by reduced disease severity compared to subjects not treated prophylactically.

[0070] active ingredient Cannabinoids are a heterogeneous group of pharmacologically active substances that have affinity for so-called cannabinoid receptors. Examples of cannabinoids include tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD).

[0071] Cannabinoids may be both phytocannabinoids and synthetic cannabinoids. Phytocannabinoids are a group of approximately 70 terpene phenol compounds (VR Preedy (ed.), Handbook of Cannabis and Related Pathologies (1997)). These compounds typically contain a monoterpene group bonded to a phenol ring and have a C3-C5 alkyl chain at the meta position relative to the phenolic hydroxyl group.

[0072] The preferred group of cannabinoids is tetrahydrocannabinol, represented by the following general formula (1): [ka] In the formula, R is C1~C 20 Alkyl, C2~C 20 Alkenyl, or C2-C 20 Selected from alkynyls, and optionally having one or more substituents.

[0073] In the more preferred group of compounds of the above general formula (1), R is C1 to C 10 Alkyl, or C2-C 10 Selected from alkenyls, and optionally having one or more substituents.

[0074] In particular, in equation (1), R is C5H 11 It is an alkyl group.

[0075] The compound of general formula (1) may exist in the form of stereoisomers. Preferably, centers 6a and 10a each have an R configuration.

[0076] Tetrahydrocannabinol is a Δ9-THC with the chemical name (6aR,10aR)6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol. Its structure is represented by the following formula (2): [ka]

[0077] Another preferred group of cannabinoids is cannabidiol of the following general formula (3):

Chemical formula

[0078] In a further preferred group of the compounds of the above general formula (3), R is selected from C1-C 10 alkyl, or C2-C 10 alkenyl, and optionally has one or more substituents.

[0079] In particular, in formula (3), R is an alkyl group of the formula C5H 11 .

[0080] Cannabidiol is in particular 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol. When the term cannabidiol or its abbreviation CBD is used herein, unless otherwise specified, this specific compound is meant.

[0081] CBD is the main constituent of Cannabis species other than the psychotropic Δ9-THC. The psychotropic effect of THC is mainly mediated by the cannabinoid receptor CB[1] expressed on nerve cells. In contrast to THC, CBD is a peripherally and centrally acting compound that does not have psychotropic activity.

[0082] 。 According to the present invention, a combination of Δ9-THC((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol) and CBD(2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol) can be used.

[0083] A more preferred group of cannabinoids is cannabinol, represented by the following general formula (4): [ka] In the formula, R is C1~C 20 Alkyl, C2~C 20 Alkenyl, or C2-C 20 Selected from alkynyls, and optionally having one or more substituents.

[0084] In the further preferred group of compounds of the general formula (4) described above, R is C1-C 10 Alkyl, or C2-C 10 Selected from alkenyls, and optionally having one or more substituents.

[0085] In particular, in equation (4), R is given by equation C5H 11 It is an alkyl group.

[0086] Cannabinol is, in particular, 6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol.

[0087] According to the present invention, cannabinoids or cannabinoid mixtures derived from cannabis (hemp) extracts can also be used.

[0088] For example, nabiximols is a mixture of plant extracts used as a medicine from the leaves and flowers of the cannabis plant (Cannabis sativa L.), containing standardized amounts of tetrahydrocannabinol (THC) and cannabidiol (CBD).

[0089] Synthetic cannabinoids can also be used.

[0090] These include 3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one. This compound contains two chiral centers. The drug nabilone is a 1:1 mixture (racemate) of the (6aR,10aR) form and the (6aS,10aS) form. Nabilone is a preferred cannabinoid according to the present invention.

[0091] Another example of a synthetic cannabinoid is JWH-018 (1-naphthyl-(1-pentylindole-3-yl)methanone).

[0092] The use of cannabinoids, particularly cannabidiol, is based on their pharmacodynamic properties. Cannabinoid receptors include CB1, which is primarily expressed in the brain, and CB2, which is primarily found on immune system cells. The fact that both CB1 and CB2 receptors are found on immune cells suggests that cannabinoids play a crucial role in regulating the immune system. Apart from this finding, several studies have shown that cannabinoids downregulate cytokine and chemokine production and, in some models, upregulate regulatory T cells (Tregs) as a mechanism to suppress inflammatory responses. The endocannabinoid system is also involved in immunomodulation.

[0093] Cannabinoids, particularly cannabidiol, are especially suitable for preventing CRS in COVID-19 patients, or at least stopping or significantly slowing the progression of CRS to the severe stage in COVID-19 patients.

[0094] This therapeutic utility has been shown to be immunomodulatory or even immunosuppressive, based on the pharmacodynamic properties of cannabinoids, particularly their interactions with the endocannabinoid system, as well as further pharmacological targets including serotonergic receptors, adenosine signaling, vanilloid receptors, PPAR-γ receptors, and GPR55.

[0095] Cannabinoids, particularly cannabidiol, affect the innate immune system (i.e., the part of the immune system that enables rapid responses to pathogens via neutrophils, macrophages, and other myeloid cells). Cell types affected by the innate immune system include, in particular, mononuclear cells, macrophages, neutrophils, dendritic cells, microglia, and myeloid-derived suppressor cells (MDSCs) (JM Nichols and BLF Kaplan (2020). Immune responses regulated by cannabidiol. Cannabis and Cannabinoid Research 5(1): 12-31). • The release of pro-inflammatory cytokines in human mononuclear cells is suppressed by nanomolar or micromolar concentrations of CBD. CBD (20 mg / kg) reduces the number of leukocytes, including macrophages and neutrophils, in bronchoalveolar lavage fluid of mice after LPS-induced pneumonia. This effect is mediated by the adenosine A2A receptor (A. Ribeiro et al. (2012)). Cannabidiol, a non-psychoactive plant-derived cannabinoid, reduces inflammation in a mouse model of acute lung injury (role for the adenosine A(2A) receptor. Eur J Pharmacol 678(1-3): 78-85). Furthermore, CBD also inhibits the migration of human neutrophils (D. McHugh et al. (2008)). Inhibition of human neutrophil chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1 and CB2. Mol Pharmacol 73(2): 441-50). A high neutrophil-to-lymphocyte ratio has been shown to be an independent risk factor for mortality in these patients; therefore, a decrease in neutrophil count is therapeutically relevant in patients with COVID-19 (Y. Liu et al., loc. cit.). CBD suppresses the CD83 dendritic cell activation marker in dendritic cells derived from individuals infected with human immunodeficiency virus (HIV), but not in healthy individuals (AT Prechtel and A. Steinkasserer (2007). CD83: an update on functions and prospects of the maturation marker of dendritic cells. Arch Dermatol Res 299(2): 59-69). CBD (1-16 μmol / l) induces apoptosis in microglia, the major innate immune cells of the central nervous system (HY Wu et al. (2012). Cannabidiol-induced apoptosis in murine microglial cells through lipid raft. Glia 60(7): 1182-90). • The number of natural killer (NK) cells and natural killer T (NKT) cells was not affected by or even increased (2.5 mg / kg / day) CBD in healthy rats, suggesting that CBD may enhance NK / NKT-related nonspecific immune responses (B. Ignatowska-Jankowska et al. (2009). Cannabidiol-induced lymphopenia does not involve NKT and NK cells. J Physiol Pharmacol 60 Suppl 3: 99-103). Furthermore, CBD can induce a regulatory immune cell population of MDSCs. In mice with chemically induced acute hepatitis, CBD (25 mg / kg) induces MDSC expression along with a reduction in pro-inflammatory cytokines such as IL-2, TNF-α, and IL-6; this effect is mediated by the TRPV1 receptor (VL Hegde et al. (2011). Role of myeloid-derived suppressor cells in amelioration of experimental autoimmune hepatitis following activation of TRPV1 receptors by cannabidiol. PLoS One 6(4): e18281).

[0096] Furthermore, cannabinoids, particularly CBD, exert effects on cells of the adaptive immune system. The adaptive immune system consists of T cells and B cells. T cells either directly lyse infected cells, induce apoptosis in infected cells (cytotoxic T cells), or recruit other immune cells (T helper [Th] cells), including B cells that produce antibodies against the pathogen. In a study using healthy rats, daily administration of 5 mg / kg of CBD significantly reduced the number of T cells and B cells, including helper T cells and cytotoxic T cells (B. Ignatowska-Jankowska et al., loc. cit.). The shift in the immune response from Th1 to Th2, which results in a decrease in pro-inflammatory cytokines such as TNF-α and IL-12 and an increase in anti-inflammatory cytokines such as IL-10, has been suggested to be the cause of the anti-inflammatory effect of CBD (L. Weiss et al. (2006). Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity 39(2): 143-51). In activated memory T cell lines, CBD dose-dependently reduced the autoantigen-specific Th17 cell phenotype (1–5 μmol / l), as indicated by a decrease in the Th17 signature cytokine IL-17. This finding was accompanied by decreased IL-6 production and secretion, as well as increased IL-10 production, which were significant changes associated with Th17 cell proliferation (E. Kozela et al. (2013). Cannabinoids decrease the th17 inflammatory autoimmune phenotype. J Neuroimmune Pharmacol 8(5): 1265-76). These results are particularly relevant to COVID-19, as pathological findings in patients who died from COVID-19 included an increased proportion of Th17 cells (Z. Xu et al. (2020). Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 8(4): 420-2). CBD has been shown to induce regulatory T cells (Treg) in several disease models (JM Nichols and BLF Kaplan (2020), loc. cit.). In mice with ischemia-reperfusion-induced kidney injury, levels of regulatory T-17 (Treg17) cells decreased, while Th17 levels increased. The physiological function of Treg17 cells includes suppression of Th17-mediated inflammation. Administration of 10 mg / kg of CBD after induction of kidney injury was renal protective and reversed these effects (B. Baban et al. (2018). Impact of cannabidiol treatment on regulatory T-17 cells and neutrophil polarization in acute kidney injury. Am J Physiol Renal Physiol 315(4): F1149-f58). These results further support the beneficial effects of CBD in COVID-19.

[0097] Numerous studies have demonstrated that cannabinoids, particularly CBD, exert their immunosuppressive and anti-inflammatory effects by suppressing pro-inflammatory cytokines such as TNF-α, IFN-γ, IL-6, IL-1β, IL-2, and IL-17A, as well as chemokines such as CCL-2. The pro-inflammatory cytokine IL-6 plays a central role in cytokine release syndrome (CRS) in patients with severe COVID-19, and IL-6 signaling is one of the major classical pathways affected by cannabinoids, particularly CBD. Since cannabinoids, particularly CBD, suppress circulating IL-6 in various animal models of inflammation, including a model of acute lung injury, the prevention of CRS through IL-6 suppression is considered to be the most relevant mode of action of cannabinoids, particularly CBD, in patients with COVID-19.

[0098] In vitro cell culture studies suggest that certain Cannabis sativa extracts downregulate ACE2, the receptor for SARS-CoV-2, and also downregulate TMPRSS2, a serine protease and another important protein required for SARS-CoV-2 entry into host cells (B. Wang et al., loc. cit.). This suggests that cannabinoids may have further beneficial effects when administered to COVID-19 patients.

[0099] According to the present invention, cannabinoids, particularly cannabidiol, can also be applied as part of a combination therapy.

[0100] Cannabinoids, particularly cannabidiol, can be administered in combination with one or more antiviral agents. Antiviral drugs that may be used for combination therapy were originally developed for HIV, Ebola, hepatitis C, influenza, SARS, or MERS (two of the other coronavirus diseases). They are designed to either inhibit viral replication or prevent the virus from entering human cells.

[0101] In one embodiment, cannabinoids, particularly cannabidiol, are used in combination with remdesivir (an inhibitor of viral RNA polymerase). In another embodiment, cannabinoids, particularly cannabidiol, are used in combination with ritonavir / lopinavir (an HIV drug).

[0102] Cannabinoids, particularly cannabidiol, can also be used in combination with medications developed for lung patients with idiopathic pulmonary fibrosis to prevent the patient's lungs from supplying sufficient oxygen to the blood.

[0103] Furthermore, cannabinoids, particularly cannabidiol, can be used in combination with cardiovascular medications, especially those for treating thrombosis or cardiac arrhythmias.

[0104] Medication and administration According to the present invention, cannabinoids, particularly cannabidiol, are preferably administered orally.

[0105] However, other routes of administration are also considered, particularly for patients who cannot take oral medication. Such other routes include intravenous, intramuscular, or subcutaneous injection.

[0106] The drug is administered 1 to 4 times per day. Typically, it is administered twice daily (BID).

[0107] According to the present invention, the patient is treated with an effective amount of cannabinoid, particularly cannabidiol.

[0108] The single dose may be 150 mg to 5000 mg, for example, 250 mg to 5000 mg, and is administered 1 to 4 times a day, for example, in a BID (Biochemical Intake) dose.

[0109] Exemplary doses are 375 mg, 750 mg, 1500 mg, and 3000 mg, administered 1 to 4 times daily, for example, in a BID (Body Intake Unit).

[0110] A particularly preferred dose is 1500 mg, administered 1 to 4 times a day, preferably in BID (Biochemical Intake).

[0111] As described above, cannabinoids, particularly cannabidiol, possess antiviral activity and exhibit suppressive pharmacodynamic effects on the immune system in various animal models.

[0112] In various animal models, the inflammatory process has been shown to be suppressed in the majority of cases with doses of 2.5–20 mg / kg body weight, primarily administered intraperitoneally or orally. Alternative routes include transdermal, intranasal, and IV (intravenous) administration (JM Nichols and BLF Kaplan BLF (2020), loc. cit.).

[0113] In the majority of cases, the effective concentration in the cell model used to determine the inhibitory effect on IL-6 secretion was 5 μM (J. Chen et al. (2016). Protective effect of cannabidiol on hydrogen peroxide-induced apoptosis, inflammation and oxidative stress in nucleus pulposus cells. Mol Med Rep 14(3): 2321-7).

[0114] Based on the molecular weight of CBD at 314.5 g / mol, the resulting concentration is 1,570 ng / ml.

[0115] Ribeiro et al. investigated the effects of CBD on LPS-induced acute lung injury in mice as a disease model of ARDS, first in a preventive intervention (A. Ribeiro et al. (2012), loc. cit.) and second in a therapeutic intervention during the acute phase (A. Ribeiro et al. (2014). Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury. Immunopharmacol Immunotoxicol 37(1): 35-41). ARDS plays a significant role in the pathological scenario of COVID-19.

[0116] Mice were prophylactically administered 0.3, 1.0, 10, 20, 30, 40, and 80 mg / kg of CBD via the intraperitoneal route. Sixty minutes after administration, acute lung injury was induced by intranasal infusion of E. coli LPS. Mice were killed 1, 2, 4, and 7 days after infusion. Total leukocyte migration, myeloperoxidase activity, production of pro-inflammatory cytokines including TNF-α and IL-6, and vascular permeability were significantly reduced (A. Ribeiro et al. (2012), loc. cit.). The effect was dose-dependent, but nearly maximum at 20 mg / kg in this study with prophylactic application.

[0117] In a subsequent study, the same group investigated the effects of CBD after acute lung injury induced by LPS. The study scenario was similar, except that the intervention time was selected to be 6 hours after LPS administration. Doses of 20 and 80 mg / kg were selected based on the results of the previous study (A. Ribeiro et al. (2014), loc. cit.). This study showed that at 20 mg / kg, there was improvement in mechanical lung function, a decrease in leukocyte migration to the lungs (neutrophils, macrophages, and lymphocytes), a decrease in myeloperoxidase activity in lung tissue, a decrease in vascular permeability, and the production of pro-inflammatory cytokines / chemokines.

[0118] A comparative study of systemic exposure to CBD after intraperitoneal and oral administration in mice and rats showed that a single dose of 120 mg / kg resulted in a maximum plasma concentration of 14,000 ng / ml in mice (S. Deiana et al. (2012). Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Delta(9)-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. Psychopharmacology (Berl) 219(3): 859-73).

[0119] Considering these data and assuming a dose-proportional relationship for the obtained plasma concentrations, a dose of 20 mg / kg, which has been shown to be effective in animal models, results in a target peak exposure of 2,300 ng / ml.

[0120] Regarding systemic exposure data in humans, a maximum dose of 541 ng / ml was observed in the morning under steady-state conditions after fasting administration of Epidyolex®. The maximum dose in the evening was higher. With twice-daily administration of Epidyolex, a 3.8-fold increase in systemic exposure was observed between the morning and evening doses (L. Taylor et al. (2018). A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects. CNS Drugs 32(11): 1053-67).

[0121] Therefore, the standard dose of 1,500 mg of CBD administered twice daily, as already approved for Epidyolex, is considered safe and effective.

[0122] Based on the data above, patients will also benefit from other doses within the range outlined herein.

[0123] Galen preparations The low and variable bioavailability of cannabinoids, particularly when administered orally, hinders the effective clinical use of these compounds.

[0124] Cannabinoids, particularly cannabidiol, are difficult to formulate due to their highly lipophilic properties.

[0125] In fact, cannabinoids are highly lipophilic molecules (logP 6-7) with very low water solubility (2-10 μg / ml). logP is the common logarithm of the n-octanol / water partition coefficient. The partition coefficient can be determined experimentally. The value typically refers to the value at room temperature (25°C). The partition coefficient can also be roughly calculated from the molecular structure.

[0126] In addition to their low solubility, cannabinoids, particularly CBD, are highly susceptible to high first-pass metabolism, which further contributes to their low systemic availability after oral administration.

[0127] Various cannabinoid formulations have been proposed.

[0128] Due to their high lipophilicity, cannabinoids have been explored in conventional formulation strategies for emulsification (including salt formation (i.e., pH adjustment), cosolvation (e.g., ethanol, propylene glycol, PEG400), micelle formation (e.g., polysorbate 80, cremophor-ELP), microemulsion formation, and nanoemulsion formation), complex formation (e.g., cyclodextrin), and encapsulation in lipid-based formulations (e.g., liposomes). Nanoparticle systems have also been proposed (N. Bruni et al., loc. cit.).

[0129] Various oral solid dosage forms have been proposed in patent documents such as International Publication No. 2008 / 024490 and International Publication No. 2018 / 035030. Because these documents do not include data on release behavior, the actual suitability of the proposed forms for cannabinoid administration remains unclear.

[0130] International Publication No. 2015 / 065179 describes compressed tablets containing lactose and sucrose fatty acid monoester in addition to cannabidiol.

[0131] Dronabinol (Δ9-THC) is commercially available in capsule form (Marinol®) and as an oral solution (Syndros®). Marinol® capsules are soft gelatin capsules containing the active ingredient in sesame oil.

[0132] Sativex®, a formulation containing nabiximols, is an oral spray that is applied to the inside of the cheek.

[0133] Self-emulsifying drug delivery systems (SEDDSs), which are mixtures of oils and surfactants and sometimes contain hydrophilic solvents, are also attracting attention as an approach to improve the oral bioavailability of certain cannabinoids (K. Knaub et al. (2019). A Novel Self-Emulsifying Drug Delivery System (SEDDS) Based on VESIsorb Formulation Technology Improving the Oral Bioavailability of Cannabidiol in Healthy Subjects. Molecules, 24(16), 2967). When in contact with an aqueous phase such as gastric or intestinal fluid, SEDDSs emulsify spontaneously under gentle stirring conditions.

[0134] VESIsorb®, a self-emulsifying drug delivery formulation technology developed by Vesifact AG (Baar, Switzerland), has demonstrated increased oral bioavailability of specific lipophilic molecules.

[0135] Epidiolex, a formulation recently approved by the U.S. FDA as an orphan drug for the treatment of certain forms of epilepsy, is provided in the form of an oral solution containing the active ingredient cannabidiol, as well as excipients anhydrous ethanol, sesame oil, strawberry flavor, and sucralose.

[0136] However, despite all these proposals, there is still a need for improved dosage forms of cannabinoids, such as cannabidiol, particularly for oral solid dosage forms.

[0137] The various approaches proposed in the prior art are not entirely satisfactory. Some of these approaches rely on liquid formulations, which are more difficult to handle than solid formulations. The formulations in the prior art are often complex to prepare and sometimes yield only low bioavailability of cannabinoids.

[0138] Formulations known in the art can be used in the therapeutic embodiments of the present invention, but the present invention also provides improved formulations.

[0139] It should be understood that these formulations are not only useful in the context of the therapeutic embodiments of the present invention, but also constitute a contribution of their own. The formulations disclosed herein may be used for any treatment in which the use of the active ingredients contained herein is indicated.

[0140] In one aspect of the present invention, a formulation is provided which is a solid dispersion comprising a cannabinoid, particularly cannabidiol, and a solubilizer. As will be further detailed below, an orally administered solid dosage form exhibiting satisfactory bioavailability can thus be obtained.

[0141] In this embodiment, highly lipophilic cannabinoids such as CBD, which are nearly water-insoluble, are combined with a solubilizer to increase their drug solubility in an aqueous medium. Increased solubility, in turn, increases the absorption rate of the drug compound.

[0142] Preferably, no toxic or other harmful degradation products are formed during the preparation or storage of the formulation.

[0143] Solid dispersions containing cannabinoids, particularly cannabidiol, and solubilizers, upon contact with water or other aqueous media such as gastrointestinal fluid, result in micelle formation. Micelles are essentially formed from the drug substance surrounded by the solubilizer (see Figure 1).

[0144] Accordingly, one aspect of the present invention is a micelle composition comprising an aqueous phase in which micelles are dispersed, the micelles comprising cannabinoids, particularly cannabidiol, and a solubilizer.

[0145] Suitable solubilizers are solid at ambient temperature. They possess surfactant properties and, when used in an aqueous medium, particularly in water, within an appropriate concentration range, can form micelle solutions.

[0146] Suitable solubilizers include, in particular, amphiphilic block copolymers.

[0147] More specifically, a block copolymer comprising at least one polyoxyethylene block and at least one polyoxypropylene block can be used.

[0148] A suitable block copolymer is, in particular, a poloxamer. Poloxamers are block copolymers with molecular weights ranging from 1,100 to over 14,000. Different poloxamers differ only in the relative amounts of propylene and ethylene oxide added during manufacturing.

[0149] Poloxamer has the following general formula: [ka]

[0150] In this general formula, n represents the number of polyoxyethylene units, and m represents the number of polyoxypropylene units.

[0151] In one embodiment, the solubilizer is poloxamer 188 (Kolliphor P188; formerly known as Lutrol F 68) / BASF; CAS number: 9003-11-6).

[0152] Kolliphor P188 is a polyoxyethylene-polyoxypropylene block copolymer of the above general formula, where n is approximately 79 and m is approximately 28.

[0153] Kolliphor P188 is available as a white to slightly yellowish waxy substance in the form of micropearls with a melting point of 52–57°C. This meets the Ph.Eur.,USP / NF requirements for poloxamer 188.

[0154] Cannabinoids and solubilizers are typically present in a cannabinoid:solubilizer weight ratio of 1:0.2 to 10.0, preferably 1:0.5 to 6.0, and particularly 1:1 to 5.

[0155] A solid dispersion according to the above-described embodiment of the formulation of the present invention can be prepared by a hot-melt process. The cannabinoid and solubilizer are heated to a temperature at which a homogeneous melt can be formed in which the cannabidiol and solubilizer exist in molecular form, and then cooled to form a solid dispersion.

[0156] The molten material is processed into pellets. This can be done by batch spray granulation / pelletization (fluidized bed top spray, Wurster bottom spray technology).

[0157] Alternatively, continuous spray granulation / pelletization (fluidized bed MicroPx Technology, ProCell Technology) is preferably used.

[0158] Another preparation method relies on dispersing cannabinoids, particularly cannabidiol, in an aqueous solution of a solubilizer, for example, an aqueous solution of a solubilizer.

[0159] The solution can be processed by batch spray granulation / pelletization (fluidized bed top spray or Wurster-bottom spray technology), or preferably by continuous spray granulation / pelletization (fluidized bed MicroPx Technology, ProCell Technology), to obtain solid granules.

[0160] The formulation may contain one or more excipients in addition to the active ingredient and solubilizer. In particular, it may contain an antioxidant or a combination of antioxidants to protect the cannabinoid, especially cannabidiol, from oxidation.

[0161] Cannabinoids, particularly cannabidiol, are easily oxidized. For example, cannabidiol can be oxidized to monomeric and dimeric hydroxyquinones. Oxidation can lead to discoloration.

[0162] Oxidation can occur not only by molecular oxygen but also by peroxides that may be introduced into the formulation by one or more excipients used.

[0163] Useful antioxidants that may be included in the formulation include ascorbyl palmitate, α-tocopherol, butylhydroxytoluol (BHT, E321), butylhydroxyanisole (BHA, E320), ascorbic acid, and sodium ethylenediaminetetraacetate (EDTA).

[0164] Ascorbyl palmitate is a preferred antioxidant. It can effectively suppress discoloration caused by oxidation.

[0165] Antioxidants or combinations of antioxidants can be added to the solubilizer melt or solution before the addition of cannabinoids, particularly CBD.

[0166] Antioxidants are typically used in amounts of 0.5 to 2.5% by mass, preferably 0.8 to 2% by mass, and particularly 1.0 to 1.8% by mass, relative to the amount of cannabinoids (especially cannabidiol).

[0167] The solid dispersion preferably does not contain any additional excipients exceeding 20% ​​by mass relative to any of the components.

[0168] The solid dispersion is preferably triglyceride-free or essentially triglyceride-free. Essentially triglyceride-free means that the formulation contains less than 5% by mass of triglycerides relative to the total components.

[0169] Furthermore, the solid dispersion preferably does not contain fatty acids or is essentially free of them. Essentially free means that the formulation contains less than 5% by mass of fatty acids relative to the total components.

[0170] Preferably, the total amount of mono-, di-, and triglycerides and fatty acids is less than 5% by mass of the total components.

[0171] Solid dispersion granules or pellets can be filled into rigid gelatin capsules, pouches, or stick packs using commercially available standard techniques and equipment.

[0172] Depending on the active ingredient content per unit, the solid dispersion granules can be filled into swallowable capsules (e.g., capsule size 2-1 for 25 mg / dose). Alternatively, for higher doses, larger capsules can be used as the primary packaging material for the granules. Such capsules are not for swallowing (e.g., capsule size up to 000 / sprinkle cap for 100-200 mg / dose). Rather, the solid dispersion granules can be sprinkled on food or dispersed in a liquid, such as water.

[0173] A composition obtained by dispersing solid dispersion granules in a liquid can be applied to patients who cannot swallow via a syringe through a nasogastric tube.

[0174] Alternatively, the solid dispersion granules can be processed into tablets. The solid dispersion granules are combined with one or more excipients, such as disintegrants, flow enhancers, and / or lubricants. The resulting mixture is then compressed into tablets.

[0175] According to another aspect of the present invention, a product for the release of cannabinoids, particularly cannabidiol, comprises a core and a coating on the core, the coating comprising cannabinoids, particularly cannabidiol, one or more highly lipophilic physiologically active substances, one or more water-soluble film-forming agents, and other excipients in an amount of 20% by mass or less based on the weight of the total components.

[0176] Preferably, no toxic or other harmful degradation products are formed during the preparation or storage of the formulation.

[0177] Surprisingly, it has been found that cannabinoids, particularly cannabidiol, can be provided in solid oral dosage forms, and their release can be controlled by the amount of film-forming agent relative to the amount of cannabinoid.

[0178] The use of one or more film-forming agents not only enables the formation of a coating containing cannabinoids, but also plays a role in controlling their release. In particular, film-forming agents promote the release of cannabinoids that are only slightly soluble in water. With film-forming agents, these are released in sufficient quantities and at a rapid rate.

[0179] For this purpose, the core comprises a coating containing a cannabinoid, particularly cannabidiol, in addition to one or more water-soluble film-forming agents. In addition to the cannabinoid, the coating preferably does not contain any other bioactive substances.

[0180] Suitable examples of water-soluble film-forming agents include methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), and polyvinylpyrrolidone (PVP).

[0181] Hydroxypropyl methylcellulose (HPMC), and especially low-viscosity HPMC such as HPMC in which the viscosity of a 2% (w / w) aqueous solution at 20°C is 6 mPa·s or less, is preferred.

[0182] HPMC, such as the commercially available product Pharmacoat® 603, which has a viscosity of 3 mPa·s in a 2% (w / w) aqueous solution at 20°C, is particularly preferred.

[0183] A coating comprising a cannabinoid and one or more water-soluble film-forming agents may contain other commonly used excipients. According to the present invention, the amount of further excipients is limited to 20% by mass or less based on the weight of the total components. Preferably, the coating contains 10% by mass or less of further excipients based on the weight of the total components.

[0184] In a particularly preferred embodiment, the coating comprises a cannabinoid and a film-forming agent.

[0185] The pellets according to the present invention have a coating containing one or more water-soluble film-forming agents in a total amount of 0.1 to 10% by mass, preferably 0.5 to 8% by mass, and particularly in a total ratio of 1 to 6% by mass, relative to the total amount of cannabinoids.

[0186] If the amount of film-forming agent is too small, the release is likely to be very slow and incomplete. The release of the bioactive substance can be regulated by selecting a ratio within a specified range. For example, the release from an oral formulation can be regulated so that the bioactive substance is released over the normal time of gastrointestinal transit.

[0187] A coating is applied to the core. The core can have any structure and may be composed of any physiologically acceptable material. As the core, for example, tablets, minitablets, pellets, granules, or crystals can be used. The core may contain or consist of, for example, sugar, tartaric acid, or microcrystalline cellulose. An inert starter core, such as pellets made of microcrystalline cellulose, is preferred. Such pellets are commercially available under the name Cellets®.

[0188] The core size is not limited. Suitable sizes are in the range of 10 μm to 2000 μm, for example, 50 μm to 1500 μm, preferably 100 μm to 1000 μm, and the size can be determined by sieve analysis. In particular, pellets consisting of sieve classifiers of 500 to 710 μm may be used.

[0189] Products according to this aspect of the present invention can be manufactured by first preparing a spray solution containing one or more cannabinoids and one or more water-soluble film-forming agents.

[0190] Because cannabinoids have very low water solubility, organic solvents or mixtures of organic solvents and water are typically used.

[0191] Next, the spray solution is applied to the core. The liquid components are evaporated, thereby forming a coating on the core that contains little to no solvent and water. This can be done, for example, in a fluidized bed system, a jet bed system, a spray dryer, or a coater.

[0192] The coated core can then be used as an oral formulation. The coated pellets can be supplied, for example, in a sachet, or may be further processed.

[0193] The core coated according to this embodiment of the present invention may be provided with one or more further coatings. This allows for additional control over emission.

[0194] In preferred embodiments, no further coatings are provided to control emission.

[0195] Coated pellets can be used to obtain multiparticulate dosage forms. For example, they can be filled into capsules or incorporated into tablets. According to one embodiment, they can be processed into orally dispersible tablets.

[0196] Coated pellets having different release profiles can be combined in a single dosage form (capsule / tablet / sachet). Products according to this embodiment of the present invention release the cannabinoids contained therein, or all cannabinoids if two or more are contained therein, in the gastrointestinal tract after ingestion. The products are used particularly for release control. Specifically, they release more than 30% by mass and less than 80% by mass of the contained bioactive substances within 2 hours. Furthermore, they release more than 40% by mass and less than 90% by mass of the contained bioactive substances within 3 hours. Furthermore, they release more than 50% by mass and less than 95% by mass of the contained bioactive substances within 4 hours. If two or more cannabinoids are contained, the information pertains to all the contained substances.

[0197] In each case, the release is determined using a blade stirrer device in 1000 ml of phosphate buffer (pH 6.8) with 0.4% Tween® 80 added at 37°C.

[0198] A further formulation approach of the present invention provides a solid dosage form in which the release rate of cannabinoids, particularly cannabidiol, can be controlled by incorporating a combination of a solubilizer and a water-soluble film-forming agent into the formulation. In such a formulation, the water-soluble film-forming agent acts as a polymer binder and an additional solubilizer. The formulation is in the form of a solid dispersion.

[0199] In this way, a solid dosage form for oral administration exhibiting satisfactory bioavailability can be obtained. The dosage form according to the present invention also exhibits reduced phagocytosis.

[0200] Preferably, no toxic or other harmful degradation products are formed during the preparation or storage of the formulation.

[0201] Solid dispersions containing cannabinoids, particularly cannabidiol, amphiphilic block copolymers, and water-soluble film-forming agents result in micelle formation upon contact with water or other aqueous media such as gastrointestinal fluid. The micelles are essentially formed from the drug substance surrounded by the solubilizing excipient.

[0202] Therefore, one embodiment is a micelle composition comprising an aqueous phase in which micelles are dispersed, wherein the micelles comprise a cannabinoid, particularly cannabidiol, and a solubilizing excipient, particularly an amphiphilic block copolymer and a water-soluble film-forming agent.

[0203] The amphiphilic block copolymers present in the formulation of the present invention act as solubilizing agents. The reference to amphiphilic block copolymers includes the possibility of the presence of multiple such copolymers.

[0204] Cannabinoids and amphiphilic block copolymers are present in formulations containing cannabinoids, particularly cannabidiol, amphiphilic block copolymers, and water-soluble film-forming agents, with the weight ratio of cannabinoid to amphiphilic block copolymer typically being 1:0.11 to 0.41, preferably 1:0.16 to 0.36, and more preferably 1:0.21 to 0.31.

[0205] Amphiphilic block copolymers are solid at ambient temperature.

[0206] These substances possess surfactant properties and, when used in aqueous media, particularly in water, within an appropriate concentration range, can form micelle solutions.

[0207] In particular, a block copolymer comprising at least one polyoxyethylene block and at least one polyoxypropylene block can be used.

[0208] The preferred block copolymer is poloxamer. Poloxamer is a block copolymer with a molecular weight in the range of 1,100 to over 14,000. Different poloxamers differ only in the relative amounts of propylene and ethylene oxide added during manufacturing.

[0209] In one embodiment, the solubilizer is poloxamer 188 (Kolliphor P188; formerly trade name Lutrol F 68) / BASF; CAS number: 9003-11-6).

[0210] Kolliphor P188 is a polyoxyethylene-polyoxypropylene block copolymer of the above general formula, where n is approximately 79 and m is approximately 28.

[0211] Kolliphor P188 is available as a white to slightly yellowish waxy substance in the form of micropearls with a melting point of 52–57°C. This meets the Ph.Eur.,USP / NF requirements for poloxamer 188.

[0212] As a further excipient, the formulation of the present invention contains a water-soluble film-forming agent. The reference to a water-soluble film-forming agent also includes the possibility of using a combination of two or more such film-forming agents.

[0213] The cannabinoid and water-soluble film-forming agent are typically present in a weight ratio of cannabinoid to water-soluble film-forming agent of 1:0.03 to 0.33, preferably 1:0.08 to 0.28, and more preferably 1:0.13 to 0.23.

[0214] The water-soluble film-forming agent acts as a polymer binder and an additional solubilizer in this formulation.

[0215] Suitable examples of water-soluble film-forming agents include methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), and polyvinylpyrrolidone (PVP).

[0216] Preferred film-forming agents are PVP, particularly PVP K30 (e.g., Kollidon® 30).

[0217] Another preferred film-forming agent is hydroxypropyl methylcellulose (HPMC), particularly low-viscosity HPMC, such as HPMC in which the viscosity of a 2% (w / w) aqueous solution is 6 mPa·s or less at 20°C.

[0218] The above components exist in a weight ratio of cannabinoid (especially cannabidiol):amphiphilic block copolymer:water-soluble film-forming agent (polyvinylpyrrolidone) that is typically 1:0.11~0.41:0.03~0.33, preferably 1:0.16~0.36:0.08~0.28, and more preferably 1:0.21~0.31:0.13~0.23.

[0219] In order to protect cannabinoids, particularly cannabidiol, from oxidation, it is especially important to consider including antioxidants or combinations of antioxidants.

[0220] Cannabinoids, particularly cannabidiol, are easily oxidized. For example, cannabidiol can be oxidized to monomeric and dimeric hydroxyquinones. Oxidation can lead to discoloration.

[0221] Oxidation can occur not only by molecular oxygen but also by peroxides that may be introduced into the formulation by one or more excipients used.

[0222] Useful antioxidants that may be included in the formulation include ascorbyl palmitate, α-tocopherol, butylhydroxytoluol (BHT, E321), butylhydroxyanisole (BHA, E320), ascorbic acid, and sodium ethylenediaminetetraacetate (EDTA).

[0223] Ascorbyl palmitate is a preferred antioxidant. It can effectively suppress discoloration caused by oxidation.

[0224] Antioxidants are typically used in amounts of 0.5 to 2.5% by mass, preferably 0.8 to 2% by mass, and particularly 1.0 to 1.8% by mass, relative to the amount of cannabinoids (especially cannabidiol).

[0225] Other excipients may be present.

[0226] In preferred embodiments, the formulation further contains a diluent. Diluents (or fillers) typically used in solid oral dosage forms can be used. A preferred diluent is microcrystalline cellulose (e.g., Avicel® PH101). Another preferred diluent is mannitol (e.g., Pearlitol 160 C).

[0227] Formulations containing a diluent typically have two phases: one phase containing the activator embedded in the polymer excipient as detailed above, and the other phase containing the diluent.

[0228] The active ingredient and diluent are typically present in a weight ratio of cannabinoid (especially cannabidiol) to diluent (especially microcrystalline cellulose) of 1:0.5 to 2.7, preferably 1:0.9 to 2.3, and particularly 1:1.3 to 1.9.

[0229] In further embodiments, silicon dioxide (e.g., Syloid® 244 FP Silica) and / or colloidal silicon dioxide (e.g., Aerosil® 200) are included in the formulation to serve a role particularly as a moisture adsorbent.

[0230] The active ingredients and total silicon dioxide components are typically cannabinoids (especially cannabidiol): the weight ratio of the total amount of all silicon dioxide components is 0.14 to 0.44, preferably 0.19 to 0.39, and particularly 0.24 to 0.34.

[0231] The formulations according to the present invention are not limited to those containing the excipients discussed above, but the formulations preferably do not contain triglycerides or are essentially free of them. Essentially free means that the formulation contains less than 5% by mass of triglycerides relative to the total components.

[0232] The solid dispersion is preferably triglyceride-free or essentially triglyceride-free. Essentially triglyceride-free means that the formulation contains less than 5% by mass of triglycerides relative to the total components.

[0233] Furthermore, the solid dispersion preferably does not contain monoglycerides and diglycerides, or is essentially free of them. Essentially free means that the formulation contains less than 5% by mass of monoglycerides and diglycerides relative to the total components.

[0234] Furthermore, the solid dispersion preferably does not contain fatty acids or is essentially free of them. Essentially free means that the formulation contains less than 5% by mass of fatty acids relative to the total components.

[0235] Preferably, the total amount of mono-, di-, and triglycerides and fatty acids is less than 5% by mass of the total components.

[0236] The pharmaceutical formulation of the present invention in the form of a solid dispersion can be obtained by wet granulation technology. Granulation can be performed in a blender. Preferably, fluidized bed granulation technology can be used.

[0237] According to the present invention, a method for preparing a cannabinoid-containing formulation comprises the following steps: (i) preparing a liquid composition comprising a cannabinoid, an amphiphilic block copolymer, and a solvent capable of at least partially dissolving the cannabinoid and the amphiphilic block copolymer; (ii) introducing the liquid composition into a fluidized bed granulator; (iii) removing the solvent to obtain a solid dispersion in particulate form; and (iv) recovering the solid dispersion in particulate form from the fluidized bed granulator.

[0238] According to the present invention, a liquid composition comprising a cannabinoid, an amphiphilic block copolymer, and a solvent also preferably comprises a water-soluble film-forming agent in at least a partially dissolved form.

[0239] Furthermore, according to the present invention, the liquid composition comprising a cannabinoid, an amphiphilic block copolymer, a solvent, and optionally a water-soluble film-forming agent preferably contains an antioxidant in a form in which at least a portion is dissolved.

[0240] The liquid composition may also contain one or more further excipients, which may be present in any preferred form, for example, in a dissolved or dispersed form.

[0241] For example, silicon dioxide can exist in a dispersed form in a liquid composition.

[0242] Cannabidiol and excipients are preferably present in the liquid composition in the weight ratios shown herein for the pharmaceutical formulation.

[0243] The solvent used to prepare the liquid composition may be any solvent that can at least partially dissolve the cannabinoid, the amphiphilic block copolymer, and preferably the water-soluble film-forming agent and / or antioxidant.

[0244] Preferred solvents are ethanol containing 10% v / v or less water, for example, ethanol containing 4% v / v or less water, for example, 96% v / v ethanol.

[0245] As described above, the liquid composition is introduced into the fluidized bed granulator. In a preferred embodiment, the liquid composition is sprayed into the fluidized bed granulator, which already contains solid particles.

[0246] The solid particles contained in the granulator may contain one or more excipients. In a preferred embodiment, the solid particles contain a diluent such as microcrystalline cellulose.

[0247] One or more additional excipients, such as colloidal silicon dioxide, may also be present.

[0248] The fluidized bed granulator is operated so that the solvent is removed and a solid dispersion in particulate form is obtained. For example, an inlet air temperature of 45±10°C is selected.

[0249] Solvent removal can be continued until a predetermined level of drying (LOD) is reached. For example, the product can be dried to a level of drying of 2.0% or less.

[0250] After drying, the product is drained and sieved.

[0251] The size of the resulting granules is not limited. A suitable size range is 50 μm to 2000 μm, for example, 100 μm to 1000 μm.

[0252] The formulation according to the present invention is preferably stable against discoloration. The color remains stable or changes slightly to off-white when stored for 3 months, preferably 6 months, and especially 12 months under long-term conditions (25°C / 60%rh).

[0253] The granules represent a self-emulsifying solid dispersion. When combined with an aqueous medium, a micelle solution can be obtained.

[0254] When the above formulations are subjected to an in virto dissolution test in 0.1N HCl + 2% CTAB according to the USP paddle method, they release at least 75% by mass, preferably at least 90% by mass, of cannabinoids within 60 minutes. Furthermore, the formulations release at least 75% by mass, preferably at least 85% by mass, of cannabinoids within 45 minutes.

[0255] Solid dispersion granules can be filled into bottles, sachets, or stick packs using commercially available standard techniques and equipment. The solid dispersion granules can be sprinkled onto food or dispersed in liquids, such as water.

[0256] A composition obtained by dispersing solid dispersion granules in a liquid can be applied to patients who cannot swallow via a syringe through a nasogastric tube.

[0257] Depending on the final dose strength per unit, the solid dispersion granules can be filled into swallowable capsules (e.g., capsule size 2-1 for 25 mg / dose). Alternatively, for higher dose units, larger capsules can be used as the primary packaging material for the granules. Such capsules are not for swallowing (e.g., capsule size up to 000 / sprinkle cap for 100-200 mg / dose). Rather, the solid dispersion granules can be sprinkled on food or dispersed in a liquid, such as water.

[0258] Alternatively, the solid dispersion granules can be processed into tablets. The solid dispersion granules are combined with one or more excipients, such as disintegrants, flow enhancers, and / or lubricants. The resulting mixture is then compressed into tablets.

[0259] In one embodiment, they are processed into orally dispersible tablets. [Examples]

[0260] The present invention will be described based on specific examples, but will not be limited thereto.

[0261] Example 1 Cannabidiol-containing granules (solid dispersions) can be obtained using 20 parts by weight of cannabidiol and 80 parts by weight of Kolliphor P188. The following options are available for preparing the granules.

[0262] Option (a) The components are heated to a temperature of approximately 100°C. The molten material is sprayed onto a solid sample of CBD in a fluidized bed at a product temperature of approximately 15-25°C. Top spray, bottom spray, and tangential spray configurations can be used in this batch process.

[0263] Option (b) The components are heated to a temperature of approximately 100°C. The molten material is sprayed into a fluidized bed apparatus, which is initially empty. Granules are formed when the molten material is solidified under fluidized bed conditions at a product temperature of approximately 15-25°C. Top spray, bottom spray, and tangential spray configurations can be used in this batch process.

[0264] Option (c) The preparation of granules from melts can also be performed continuously. This can be done using ProCell or MicroPx Technology (Glatt).

[0265] Option (d) The melt can also be processed in a spray tower. Using a prill nozzle, spherical particles of a defined size can be obtained.

[0266] Example 2 Cannabidiol-containing granules (solid dispersions) can be obtained using 30 parts by weight of cannabidiol and 70 parts by weight of Kolliphor P188. For preparing the granules, the options outlined in Example 1 are available.

[0267] Example 3 Cannabidiol-containing granules (solid dispersions) can be obtained using 40 parts by weight of cannabidiol and 60 parts by weight of Kolliphor P188. For preparing the granules, the options outlined in Example 1 are available.

[0268] Example 4 Cannabidiol-containing granules (solid dispersions) can be obtained using 20.05 parts by weight of cannabidiol, 76 parts by weight of Kolliphor P188, 3.4 parts by weight of Avicel PH 101, 0.5 parts by weight of Aerosil 200, and 0.05 parts by weight of BHT.

[0269] The melt from Kolliphor P188 and BHT having a temperature of about 100 °C is sprayed onto solid CBD, Avicel PH 101 and Aerosil 200 in a fluidized bed. The product temperature is about 15 - 25 °C. In this batch process, top spray, bottom spray and tangential spray configurations can be used.

[0270] Example 5 Compositions based on different weight ratios of CBD / solubilizer were melted and then the melt was cooled. The compositions were analyzed for in vitro dissolution in 0.1 N HCl according to the USP paddle method.

[0271] For comparison, oily cannabidiol solutions and commercially available Bionic Softgels were also tested according to DAC / NRF 22.10.

[0272] CBD release after 60 minutes of in vitro dissolution in 0.1N HCl: CBD / Kolliphor P188 = 33 / 67; 200mg CBD: 69% drug release CBD / Kolliphor P188 = 27 / 73; 200mg CBD: 82% drug release CBD / Kolliphor P188 = 20 / 80; 200mg CBD: 96% drug release CBD in an oily (Miglyol 812) solution; 200 mg CBD: 0% drug release Biotonic softgels; 25mg CBD: 96% drug release.

[0273] Example 6 Tablets are prepared using 93.5% by mass of granules from any of Examples 1 to 4, 5% by mass of Polyplasone XL (disintegrant), 1% of Aerosil 200 (flow enhancer), and 0.5% of magnesium stearate (lubricant).

[0274] Example 7 Preparation of granules Cannabidiol (CBD) granules containing 29.7% w / w of active ingredient are prepared according to the following manufacturing formula: TIFF0007898386000006.tif123165

[0275] In the first processing step, CBD and the pharmaceutical excipients poloxamer 188, ascorbyl palmitate, microcrystalline cellulose, silicon dioxide, colloidal silicon dioxide, and polyvinylpyrrolidone are granulated.

[0276] Fluidized bed granulation technology is used for granulation.

[0277] The pharmaceutical raw material cannabidiol and the pharmaceutical excipients poloxamer 188, ascorbyl palmitate, and polyvinylpyrrolidone are dissolved in 96% v / v ethanol. Silicon dioxide (Syloid® 244 FP) is dispersed in the solution.

[0278] Microcrystalline cellulose and colloidal silicon dioxide (Aerosil® 200) are packed into a fluidized bed granulator and granulated using the described solution. The granules are removed and sieved.

[0279] The 96% v / v volatile component ethanol is removed from the granules during the drying stage in the fluidized bed dryer. The inlet air temperature is 45±10°C, and the product temperature is 30-35°C.

[0280] The granules are dried to a standard level of drying loss (LOD) of 2.0% or less.

[0281] Dosage form Cannabidiol granules containing 29.7% w / w cannabidiol are filled into an HDPE bottle to provide a total dose of 1500 mg of cannabidiol. The granules are applied using a total of 240 ml of tap water (room temperature). The granules are first dispersed in 100 ml of water. The container is then rinsed twice using the remaining amount of water.

[0282] Stability of cannabidiol granules The samples were stored under accelerated conditions (40°C / 75%), intermediate conditions (30°C / 65%rh), and long-term conditions (25°C / 60%rh).

[0283] Under accelerated storage conditions, the appearance changed from white to yellowish after one month, and to yellow after two months. The color changed slightly to off-white under long-term conditions after three months and under intermediate conditions after four months.

[0284] Leaching decreases slightly after 3 months of storage under accelerated conditions, but remains within the specified range. Leaching remains unchanged after 3 months under long-term conditions and after 4 months under intermediate conditions.

[0285] A decrease in assay of approximately 6% is observed under accelerated conditions after 3 months, but the product remains within the specified shelf life. Under intermediate and long-term conditions, a significant decrease in assay is not observed until after 4 months and 3 months, respectively.

[0286] Adducts of cannabidiol and ascorbyl palmitate are observed as impurities.

[0287] It has been found that it is at a level of 0.4% in the long term and at a level of 0.5% under accelerated conditions after 3 months of storage. Under intermediate conditions, the level is 0.5% after 4 months.

[0288] The (Q)SAR evaluation of the four possible structures of this adduct indicates that its presence does not pose an additional risk to patients when the formulation is administered using the dosages and administration schemes disclosed herein.

[0289] Stability of the aqueous dispersion The chemical stability of an aqueous dispersion containing 1500 mg of cannabidiol was examined in a hold-time test. For this purpose, approximately 5 g of a development batch (formulation without Aerosil 200) was dispersed in 240 ml of water and stirred at ambient temperature. The impurity profile was monitored for 2 hours.

[0290] The impurity profile remains unchanged over the 2-hour test period. Thus, the dispersion of the product in water for administration will be stable over the period required for administration.

[0291] CBD release Release is tested according to EP 2.9.3 / USP<711>. A paddle dissolution apparatus is used. The dissolution test is carried out at a standard temperature of 37°C ± 0.5°C and a stirrer speed of 100 rpm.

[0292] After 45 minutes, complete release is observed in 0.1M HCl + 2% (w / v) cetyltrimethylammonium bromide (CTAB).

[0293] Example 8 Additional granules were prepared according to the method outlined in Example 7. Information regarding the composition is included in the table below. TIFF0007898386000007.tif119163

[0294] Pearlitol 160 C is a crystalline D-mannitol powder with an average particle diameter of 160 μm.

[0295] Release was identified using the in virto dissolution method (1000 mL of 0.1 M HCl + 2% (w / v) CTAB).

[0296] Example 9 Pellets were prepared using the quantities of components shown in Table 1 below.

[0297] For this purpose, 2-[1R-3-methyl-6R-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol (Canapure PH) was dissolved in 96% ethanol. This active ingredient has a logP of approximately 6.1.

[0298] HPMC (Pharmacoat® 603) was dissolved in water to prepare another solution.

[0299] Next, the HPMC solution was gradually added to the cannabidiol solution.

[0300] Next, amorphous silicon dioxide (Syloid® 244 FP) was added.

[0301] The mixture was stirred with a propeller stirrer.

[0302] The resulting spray solution was sprayed onto a starter core made of microcrystalline cellulose (Cellets® 500).

[0303] This was performed in a Mini-Glat fluidized bed system with a Wurster insert. The air inlet air temperature was 40°C. The average spray velocity was 0.5 g / min.

[0304] [Table 1]

[0305] [Table 2]

[0306] Example 10 The release from the pellet product obtained in Example 1 was investigated, particularly at 37°C, in 1000 ml of phosphate buffer (pH 6.8) with 0.4% Tween® 80 added, using a blade stirrer. The results are shown in Figure 2.

[0307] Example 11 This example investigates the antiviral activity of cannabidiol (CBD) against SARS-CoV-2 using a cell culture-based infection model. Two different cannabidiol compositions were tested (the formulation from Example 7 and Canapure PH).

[0308] For each substance, a stock solution containing 10 mM cannabidiol in DMSO was prepared. The dissolved and filtered solutions were stored at room temperature for up to one week.

[0309] For the antiviral assay, Vero E6 cells and SARS-CoV-2 virus (isolated BetaCoV / Germany / BavPat1 / 2020 p.1) were incubated at different cannabidiol concentrations for 24 hours. Each experiment was performed in triple replication.

[0310] More specifically, 25,000 Vero E6 cells per well were seeded in a 96-well plate. The following day, the CBD substance was diluted in culture medium (DMEM without FCS + 1% penicillin / streptomycin) to obtain the desired final concentrations (0 μM, 0.25 μM, 0.5 μM, 1 μM, 2.5 μM, or 5 μM).

[0311] Next, the culture medium was removed from the cells, and culture media containing different test concentrations were added to the cells.

[0312] In parallel, approximately 150 FFU (focal unit) per well was mixed with culture media containing different test concentrations.

[0313] After mixing the virus with the compound, the cell culture medium was removed from the 96-well plate containing Vero E6 cells.

[0314] A 200pi sample from a virus-containing plate was transferred to a Vero E6 plate.

[0315] The cells were incubated at 37°C in 5% CO2 for 24 hours.

[0316] Next, residual viral activity was tested in cell cultures by titration, and then infected cells were stained with SARS-CoV-2 specific antibodies. Positive cells were counted, and the "focal unit" (FFU) was calculated.

[0317] The results indicate that both substances (the formulation from Example 7 and Canapure PH) were able to reduce FFU values ​​in a dose-dependent manner, i.e., inhibit the viral activity of SARS-CoV-2 in virto. The difference between the substances was not statistically significant.

[0318] Cell desorption was observed for both substances at the highest concentration (5 μM). Cell desorption was not observed with the respective controls (DMSO), suggesting a toxic effect of the substances at the indicated concentrations. No toxic effects were observed at other concentrations tested.

[0319] To further characterize the inhibition of viral activity, IC was derived from the data determined above. 50 The values ​​were calculated. The highest concentration (5 μM) FFU value was excluded because its cellular toxicity may interfere with the substance's effect on viral activity.

[0320] The substances tested were 1.015 μM (formulation from Example 7) and 0.789 μM (Canapure PH) IC50. 50 The values ​​indicated inhibition of viral activity. The differences in these values ​​were not statistically significant.

[0321] Case Report 12 A 49-year-old male patient contracted Covid-19 on November 26, 2020, and tested positive on November 30, 2020. His initial symptoms included low-grade fever, chills, body aches and pains, lethargy, and loss of appetite. The patient recovered with self-treatment at home, including NSAIDs, vitamin C, bed rest, and drinking large amounts of fluids to control fever and pain.

[0322] On August 4, 2020, the illness took a dramatic turn for the worse. The patient was unable to breathe completely and began experiencing dizziness and hypoxia. The patient was hospitalized and diagnosed with Covid Pneumonia.

[0323] Pulse oximetry showed an oxygen saturation of 86% oxygen. Inspiratory volume was less than 300 ml. The patient was given a 5-day course of remdesivir, heparin, dexamethasone, and 5 L of supplemental oxygen intravenously. The patient remained in the hospital until August 12, 2020, at which point was discharged with supplemental home oxygen. The patient still experienced dyspnea and was unable to maintain blood oxygen above 90% without supplemental oxygen.

[0324] At that point, the patient began taking 3g of the granules from Example 7, mixed with orange juice, daily. The patient noticed an immediate improvement in breathing, the chest tightness disappeared, and within just two days, the patient was able to maintain an oxygen level of 96% without oxygen supplementation. The patient's intravenous intake (IC) increased to 700ml and was able to reach 1500ml in one week. The patient's other residual symptoms, fatigue and loss of appetite, were also reduced.

[0325] A 20-year-old male patient contracted COVID-19. He took the granules from Example 7 for three days. During this time, he experienced only mild COVID symptoms. After stopping CBD intake for one day, his symptoms worsened. When he resumed taking CBD from the fifth day onward, his symptoms improved again.

Claims

1. The use of cannabinoids in the manufacture of therapeutic drugs for patients infected with SARS-CoV-2 or for subjects at risk of infection with SARS-CoV-2, The cannabinoid is cannabidiol (2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol), The cannabinoid is administered orally. A use characterized by the following:

2. The use according to claim 1, characterized in that the treatment is for the purpose of preventing or improving cytokine release syndrome (CRS) and / or reducing the viral load.

3. The use according to claim 2, characterized in that the treatment is for the purpose of preventing or improving cytokine release syndrome (CRS).

4. The use according to any one of claims 1 to 3, characterized in that the treatment lowers serum IL-6 levels.

5. The use according to any one of claims 1 to 4, characterized in that the treatment is for the purpose of preventing or improving acute respiratory distress syndrome (ARDS).

6. The use according to any one of claims 1 to 5, characterized in that the treatment is initiated during the non-severe stage.

7. The use according to any one of claims 1 to 6, characterized in that the treatment is initiated when the patient is diagnosed with having at least one disease symptom selected from fever, dry cough, shortness of breath, evidence of rales / crackles on physical examination, muscle pain, fatigue, dyspnea, loss of appetite, loss of smell and taste, and nephritis.

8. The use according to any one of claims 1 to 6, characterized in that the treatment is initiated when the patient shows pathological lung features by either a CT scan or a chest X-ray.

9. The use according to any one of claims 1 to 6, characterized in that the patient is diagnosed with having at least one disease symptom selected from fever, dry cough, shortness of breath, evidence of rales / crackles on physical examination, muscle pain, fatigue, dyspnea, loss of appetite, loss of smell and taste, and nephritis, and shows pathological pulmonary features by either a CT scan or a chest X-ray.

10. The use according to any one of claims 1 to 6, characterized in that the treatment is initiated based on a decrease in peripheral oxygen saturation (SpO2).

11. The use according to claim 10, characterized in that the treatment is initiated when the patient exhibits a peripheral oxygen saturation (SpO2) of ≤93% in ambient air at rest, or requires 3 L / min to 5 L / min of oxygen to maintain SpO2 > 97%.

12. The use according to any one of claims 1 to 6, characterized in that the treatment is initiated when a lung lesion worsens, defined as having stable FiO2 (inhaled oxygen partial pressure) over the past 24 hours, a deterioration of >3% in oxygen saturation, or a decrease of >10% in PaO2 (arterial blood oxygen partial pressure).

13. The aforementioned treatment is one or more of the following: serum IL-6 ≥ 5.4 pg / ml; CRP level > 70 mg / L (no confirmation of other infectious or non-infectious course); CRP level >= 40 mg / L and doubling within 48 hours (no confirmation of other infectious or non-infectious course); lactate dehydrogenase > 250 U / L; D-dimer > 1 μg / mL; serum ferritin > 300 μg / mL. The use according to any one of claims 1 to 6, characterized in that it is initiated based on

14. The use according to any one of claims 1 to 6, characterized in that the patient is diagnosed with having at least one disease symptom selected from fever, dry cough, shortness of breath, evidence of rales / crackles on physical examination, muscle pain, fatigue, dyspnea, loss of appetite, loss of smell and taste, and nephritis; and exhibits at least one laboratory finding selected from serum IL-6 ≥ 5.4 pg / ml; CRP level > 70 mg / L (without confirmation of other infectious or non-infectious course); CRP level >= 40 mg / L and doubling within 48 hours (without confirmation of other infectious or non-infectious course); lactate dehydrogenase > 250 U / L; D-dimer > 1 μg / mL; serum ferritin > 300 μg / mL.

15. The use according to any one of claims 1 to 6, characterized in that the treatment is initiated when the patient exhibits thrombocytopenia < 120,000 × 10⁹ E⁹ / L and / or lymphocyte count < 0.6 × 10⁹ E⁹ / L.

16. The use according to any one of claims 1 to 6, characterized in that the patient is diagnosed with having at least one disease symptom selected from fever, dry cough, shortness of breath, and evidence of rales / crackles on physical examination, muscle pain, fatigue, dyspnea, loss of appetite, loss of smell and taste, and nephritis; and / or exhibits serum IL-6 ≥ 5.4 pg / ml; CRP level > 70 mg / L (without confirmation of other infectious or non-infectious course); CRP level >= 40 mg / L and doubling within 48 hours (without confirmation of other infectious or non-infectious course); lactate dehydrogenase > 250 U / L; D-dimer > 1 μg / mL; serum ferritin > 300 μg / mL; and exhibits thrombocytopenia < 120,000 × 10⁹ E⁹ / L, and / or lymphocyte count < 0.6 × 10⁹ E⁹ / L.

17. The use according to any one of claims 1 to 16, characterized in that the patient belongs to a risk group.

18. The use according to any one of claims 1 to 17, characterized in that the cannabinoid is applied in combination with one or more antiviral agents selected from remdesivir (an inhibitor of viral RNA polymerase) and ritonavir / lopinavir (an HIV treatment drug); in combination with a drug for idiopathic pulmonary fibrosis; or in combination with a drug for thrombosis or a drug for cardiac arrhythmia.

19. The use according to any one of claims 1 to 18, characterized in that the cannabinoid is administered once to four times a day at a dose of 150 mg to 5000 mg.

20. The use according to claim 19, characterized in that the dose is 375 mg, 750 mg, 1500 mg, or 3000 mg, and this dose is administered once to four times a day.

21. The use according to claim 19, characterized in that the aforementioned dose is administered by BID.

22. The use according to any one of claims 1 to 21, characterized in that the cannabinoid is administered by BID at a dose of 1500 mg.

23. The use according to any one of claims 1 to 22, characterized in that the cannabinoid is formulated as a solid dispersion.

24. The use according to claim 23, characterized in that the solid dispersion contains a cannabinoid and a solubilizer which is an amphiphilic block copolymer capable of forming a micelle solution when combined with an aqueous medium.

25. The use according to claim 24, characterized in that the solubilizer is a block copolymer comprising at least one polyoxyethylene block and at least one polyoxypropylene block.

26. The use according to claim 25, characterized in that the solubilizing agent is poloxamer.

27. The use according to any one of claims 24 to 26, characterized in that the cannabinoid and the solubilizer are present in a weight ratio of cannabinoid:solubilizer of 1:0.2 to 10.

0.

28. The use according to any one of claims 23 to 27, characterized in that the solid dispersion further comprises an antioxidant.

29. The use according to claim 28, characterized in that the antioxidant is used in an amount of 0.5 to 2.5% by mass relative to the amount of the cannabinoid.

30. The use according to claim 28 or 29, characterized in that the antioxidant is ascorbyl palmitate.

31. The use according to claim 23, characterized in that the solid dispersion comprises a mixture of a cannabinoid, an amphiphilic block copolymer as a solubilizer, and a water-soluble film-forming agent.

32. The use according to claim 31, characterized in that the cannabinoid and the amphiphilic block copolymer are present in a weight ratio of cannabinoid:amphiphilic block copolymer of 1:0.11 to 0.

41.

33. The use according to claim 31 or 32, characterized in that the amphiphilic block copolymer comprises at least one polyoxyethylene block and at least one polyoxypropylene block.

34. The use according to claim 33, characterized in that the amphiphilic block copolymer is a poloxamer.

35. The use according to any one of claims 31 to 34, characterized in that the cannabinoid and the water-soluble film-forming agent are present in a weight ratio of 1:0.03 to 0.33 for the cannabinoid and the water-soluble film-forming agent.

36. The use according to any one of claims 31 to 35, characterized in that the water-soluble film-forming agent is polyvinylpyrrolidone.

37. The use according to any one of claims 31 to 35, characterized in that the water-soluble film-forming agent is hydroxypropyl methylcellulose.

38. The use according to any one of claims 31 to 37, characterized in that the component is present in a weight ratio of cannabinoid:amphiphilic block copolymer:water-soluble film-forming agent of 1:0.11 to 0.41:0.03 to 0.

33.

39. The use according to any one of claims 31 to 38, characterized in that the solid dispersion further comprises an antioxidant.

40. The use according to claim 39, characterized in that the antioxidant is used in an amount of 0.5 to 2.5% by mass relative to the amount of the cannabinoid.

41. The use according to claim 39 or 40, characterized in that the antioxidant is ascorbyl palmitate.

42. The use according to any one of claims 31 to 41, characterized in that the solid dispersion contains a diluent.

43. The use according to claim 42, characterized in that the cannabinoid and the diluent are present in a cannabinoid:diluent weight ratio of 1:0.5 to 2.

7.

44. The use according to claim 42 or 43, characterized in that the diluent is microcrystalline cellulose and / or mannitol.

45. The use according to any one of claims 31 to 44, characterized in that the solid dispersion contains a moisture adsorbent.

46. The use according to claim 45, characterized in that the cannabinoid and the water adsorbent are present in a weight ratio of 0.14 to 0.44 for cannabinoid:water adsorbent.

47. The use according to claim 45 or 46, characterized in that the moisture adsorbent contains silicon dioxide.

48. The use according to any one of claims 31 to 47, characterized in that the solid dispersion does not contain triglycerides; and / or mono- and diglycerides; and / or fatty acids.

49. The use according to any one of claims 31 to 48, characterized in that when the formulation is subjected to an in virto dissolution test in 0.1N HCl + 2% CTAB according to the USP paddle method, it releases at least 75% by mass of cannabinoids within 60 minutes.

50. The use according to any one of claims 31 to 49, characterized in that when the formulation is subjected to an in virto dissolution test in 0.1N HCl + 2% CTAB according to the USP paddle method, it releases at least 75% by mass of cannabinoids within 45 minutes.

51. The use according to any one of claims 1 to 22, characterized in that the cannabinoid is incorporated into a formulation comprising a core and a coating on the core, and the coating comprises the cannabinoid, one or more water-soluble film-forming agents, and other excipients in an amount of 20% by mass or less based on the weight of the total components.

52. The use according to claim 51, characterized in that hydroxypropyl methylcellulose (HPMC) is used as the water-soluble film-forming agent.

53. The use according to claim 51 or 52, characterized in that the film-forming agent is included in a total proportion of 0.3 to 10% by mass based on the total amount of cannabinoids.

54. The use according to any one of claims 51 to 53, characterized in that more than 30% by mass and less than 80% by mass of the contained cannabinoids are released within 2 hours; and / or more than 40% by mass and less than 90% by mass of the contained cannabinoids are released within 3 hours; and / or more than 50% by mass and less than 95% by mass of the contained cannabinoids are released within 4 hours.

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