Cannabinoid Uses and Formulations

Abstract

Uses and formulations of cannabinoids, particularly cannabidiol, are provided.Cannabinoids, particularly cannabidiol, are used to treat patients suffering from inflammatory conditions related to autoimmune diseases, chronic inflammatory diseases, and infections, including cytokine release syndrome (CRS).The formulations are particularly directed to oral administration of cannabinoids, particularly cannabidiol.These formulations are useful for treating patients suffering from the above-mentioned conditions.

Description

[Technical Field]

[0001] The present invention relates to the use and formulation of cannabinoids, particularly cannabidiol. According to the present invention, cannabinoids, particularly cannabidiol, are used to treat patients suffering from inflammatory conditions characterized by elevated IL-6 levels. This includes inflammatory conditions associated with autoimmune diseases, chronic inflammatory diseases, and infections, including cytokine release syndrome (CRS).

[0002] The present invention also provides formulations for oral administration of cannabinoids, particularly cannabidiol, which are useful for treating patients suffering from inflammatory conditions. [Background technology]

[0003] Inflammatory conditions associated with autoimmune diseases, chronic inflammatory diseases, and infections, including cytokine release syndrome (CRS), present a significant disease burden to affected patients, and some conditions can even be life-threatening.

[0004] Although various treatments for such conditions have been suggested, there remains a need for further treatment options, particularly simple and convenient pharmacological interventions.

[0005] Apart from the above considerations, cannabinoids, especially cannabidiol, are considered drugs. There is evidence that cannabinoids may be beneficial in treating many clinical conditions, including pain, inflammation, epilepsy, sleep disorders, symptoms of multiple sclerosis, anorexia, and schizophrenia (Non-Patent Document 1).

[0006] Cannabinoids have been proposed for use in a variety of indications, but to date only a limited number of uses have received market approval. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] N. Bruni et al., Cannabinoid Delivery Systems for Pain and Inflammation Treatment. Molecules 2018, 23, 2478 Summary of the Invention [Problem to be solved by the invention]

[0008] It is an object of the present invention to provide compositions and treatment regimens for the treatment of patients suffering from inflammatory conditions characterized by elevated levels of IL-6. [Means for solving the problem]

[0009] The compositions may be administered prophylactically.

[0010] The present invention provides such compositions and treatment regimens.

[0011] Cannabinoids are preferably administered orally, at a dose of 150 mg to 5000 mg, 1 to 4 times daily, for example, at a dose of 250 mg to 5000 mg, 1 to 4 times daily.

[0012] Cannabinoids can be formulated as solid dispersions, which include a cannabinoid and a solubilizer that is an amphiphilic block copolymer that can form a micellar solution when combined with an aqueous medium.

[0013] The block copolymer is preferably a poloxamer.

[0014] The solid dispersion may further comprise a water-soluble film-forming agent.

[0015] The cannabinoid may also be incorporated into a formulation comprising a core and a coating on the core, the coating comprising the cannabinoid, one or more water-soluble film-forming agents, and up to 20% by weight of other excipients based on the weight of all components.

[0016] Further objects and solutions thereof can be concluded from the following detailed description of the invention.

[0017] In the following, the invention will be explained in more detail with reference to the drawings. [Brief explanation of the drawings]

[0018] [Figure 1] 1 shows a schematic representation of the preparation of a cannabinoid-containing solid dispersion and the interaction of the solid dispersion with an aqueous medium. [Figure 2] 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 agent and low viscosity hydroxypropyl methylcellulose as the film-forming agent is shown. DETAILED DESCRIPTION OF THE INVENTION

[0019] Interleukins (ILs) are a group of secreted proteins that act as cytokines, i.e., signaling molecules. The function of the immune system is largely dependent on interleukins.

[0020] One of the interleukins is interleukin-6 (IL-6). By activating different kinase pathways, IL-6 promotes complex biological responses such as cell proliferation, cell differentiation, oxidative stress, and immune regulation.

[0021] IL-6, which acts as a pro-inflammatory cytokine, has important roles in both innate and adaptive immunity.

[0022] IL-6 can be produced by different cell types, among them macrophages, endothelial cells, and T cells. IL-6 production can be initiated in response to infection. IL-6 is also formed in response to certain other cytokines, such as tumor necrosis factor (TNF).

[0023] IL-6 plays a role in the innate immune system and contributes to the acute phase response. IL-6 acts on hepatocytes to induce the expression of C-reactive protein (CRP), fibrinogen, and serum amyloid A.

[0024] IL-6 also plays an important role in adaptive immune responses, mediating the proliferation of antibody-producing B cells, resulting in enhanced antibody responses. IL-6 also acts synergistically with IL-1β and TNF-α to stimulate T cell activation, proliferation, and differentiation.

[0025] In non-infectious inflammation, such as inflammation caused by burns or trauma, damage-associated molecular patterns (DAMPS) derived from damaged or dead cells stimulate Toll-like receptors, which result in the production of IL-6.

[0026] IL-6 plays an important physiological role, and dysregulation of this cytokine is involved in the development and progression of several disease states. Dysregulation of IL-6 production has been demonstrated to play a pathological role in various autoimmune and inflammatory diseases. Targeting IL-6 is a rational approach to the treatment of these diseases.

[0027] Patients being treated Patients treated according to the present invention are suffering from inflammatory conditions associated with autoimmune diseases, chronic inflammatory diseases and infection-related inflammatory conditions, including cytokine release syndrome (CRS).

[0028] IL-6 plays an important role in the inflammatory state associated with autoimmune diseases. More specifically, IL-6, together with TGF-β, promotes the differentiation of IL-17-producing T helper cells (Th17), which play an important role in inducing autoimmune tissue injury. At the same time, IL-6 suppresses TGF-β-induced regulatory T cell (Treg) differentiation. Therefore, IL-6 induces the dominance of Th17 cells over Treg cells.

[0029] The resulting Th17 / Treg imbalance leads to a breakdown of immune tolerance and is pathologically important in the development of various autoimmune and inflammatory diseases.

[0030] IL-6 is elevated in many chronic inflammatory diseases.

[0031] Clinical trials of tocilizumab, a humanized anti-IL-6 receptor antibody, have confirmed its efficacy and tolerability in patients with rheumatoid arthritis and systemic juvenile idiopathic arthritis.

[0032] In activated memory T cell lines, CBD dose-dependently reduces the autoantigen-specific Th17 cell phenotype, as indicated by a decrease in the Th17 signature cytokine IL-17. This decrease is accompanied by a decrease in IL-6 production and secretion and an increase in IL-10 production, important changes associated with decreased Th17 cell proliferation (E. Kozela et al. (2013). Cannabinoids decrease the Th17 inflammatory autoimmune phenotype. J Neuroimmune Pharmacol 8(5): 1265-76).

[0033] Furthermore, cannabinoids, particularly CBD, suppress circulating IL-6 in various animal models of diseases associated with an inflammatory phenotype, including diabetes, asthma, pancreatitis, and hepatitis (see JM Nichols and BLF Kaplan (2020). Immune responses regulated by cannabidiol. Cannabis and Cannabinoid Research 5(1): 12-31).

[0034] Thus, according to the present invention, inflammatory conditions characterized by elevated levels of IL-6 can be treated by administration of cannabinoids, in particular cannabidiol.

[0035] These conditions may also have an autoimmune component.

[0036] Diseases that may be treated according to the present invention, with or without a demonstrated autoimmune component, are rheumatic diseases, including osteoarthritis, rheumatoid arthritis, fibromyalgia, systemic lupus erythematosus, gout, juvenile idiopathic arthritis, infectious arthritis, psoriatic arthritis, polymyositis, bursitis, ankylosing spondylitis, reactive arthritis, scleroderma, and polymyalgia rheumatica.

[0037] A further disease that can be treated is giant cell arteritis (GCA).

[0038] Additionally, inflammatory bowel disease (IBD) can be treated according to the present invention.

[0039] IL-6 is also produced by adipocytes. In patients with metabolic syndrome, serum IL-6 levels increase. This leads to a chronic inflammatory process, which in turn leads to atherosclerosis, insulin resistance, and coagulation disorders. According to the present invention, patients with metabolic syndrome are treated. The treatment prevents, stops, or improves the consequences of the chronic inflammatory process. The treatment particularly prevents, stops, or improves atherosclerosis, insulin resistance, and / or coagulation disorders.

[0040] In infectious diseases, an immune response is essential in the early stages after infection to eliminate infectious agents and prevent progression to the disease stage. Strategies to enhance the immune response at this stage may be important. Immunosuppressive therapy is expected to put patients at risk during this early disease stage.

[0041] If the initial immune response is impaired or insufficient, the infectious agent will grow, causing massive tissue damage and ultimately leading to inflammation caused by proinflammatory cytokines. As a result, damaged cells lead to natural inflammation mediated primarily by proinflammatory macrophages and granulocytes. IL-6 levels are elevated in patients with infection.

[0042] IL-6 levels are particularly elevated in sepsis and sepsis, and correlate with the severity of sepsis as assessed by clinical and laboratory parameters.

[0043] 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 through receptor-ligand interactions. CRS occurs when large numbers of leukocytes are activated and release inflammatory cytokines, which activate further leukocytes in a positive feedback loop of pathogenic inflammation, resulting in a rapid rise in proinflammatory cytokines.

[0044] The term cytokine storm is used in severe cases of CRS.

[0045] Patients have classic serum biomarkers of CRS, including elevated CRP, LDH, IL-6, and ferritin.

[0046] Patients requiring intensive care typically have higher blood levels of proinflammatory cytokines than patients not requiring intensive care. Patients particularly exhibit elevated levels of the proinflammatory cytokine IL-6. Increased levels soon after the onset of disease indicate a severe course of the disease. CRS itself is thought to be the cause of several pathological events.

[0047] High levels of IL-6 are a prominent and important driver of CRS.

[0048] The present invention is based on the discovery that pharmacological intervention can prevent or reduce undesirable components of the immune response.

[0049] This is achieved by pharmacological interventions that prevent the release of pro-inflammatory cytokines, particularly IL-6.

[0050] The present invention makes it possible in particular to prevent or ameliorate cytokine release syndrome (CRS) and its clinical symptoms, including unwanted inflammatory processes.

[0051] The present invention provides a simple and convenient treatment for the above-mentioned diseases, a treatment that can be administered orally.

[0052] Appropriate criteria for initiating treatment are based on laboratory findings.

[0053] Laboratory findings for initiating patient treatment include one or more of the following: serum IL-6 ≥ 5.4 pg / ml; CRP level > 70 mg / L (without other confirmed infectious or non-infectious causes); CRP level >= 40 mg / L and doubling within 48 hours (without other confirmed infectious or non-infectious causes); lactate dehydrogenase > 250 U / L; D-dimer > 1 μg / mL; serum ferritin > 300 μg / mL.

[0054] Preferably, initiation of treatment is based on elevated levels of IL-6.

[0055] Furthermore, treatment of a patient may be initiated if the patient exhibits, in addition to one of the above criteria, a thrombocytopenia <120,000 x 10E9 / L and / or a lymphocyte count <0.6 x 10E9 / L, if necessary.

[0056] The progress of treatment can be monitored, for example, by the decline in IL-6, CRP, transaminases, 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.

[0057] Treatment is continued until relevant clinical improvement is achieved. In conditions involving chronic inflammation, treatment may be long-term.

[0058] According to the present invention, cannabinoids may also be used for the treatment of subjects at risk of suffering from inflammatory conditions characterized by elevated levels of IL-6.

[0059] Efficacy of prophylaxis can be assessed by reduced disease severity compared to subjects not treated prophylactically.

[0060] active ingredient Cannabinoids are a heterogeneous group of pharmacologically active substances that have affinity for so-called cannabinoid receptors, including, for example, tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD).

[0061] Cannabinoids may be both phytocannabinoids and synthetic cannabinoids.

[0062] Phytocannabinoids are a group of approximately 70 terpene-phenolic compounds (V.R. Preedy (ed.), Handbook of Cannabis and Related Pathologies (1997)). These compounds typically contain a monoterpene group attached to a phenolic ring with a C3-C5 alkyl chain meta to the phenolic hydroxyl group.

[0063] A preferred group of cannabinoids are the tetrahydrocannabinols of the following general formula (1): [ka] In the formula, R is C1 to C 20 Alkyl, C2-C 20 Alkenyl, or C2-C 20 alkynyl, optionally bearing one or more substituents.

[0064] In a further preferred group of compounds of the above general formula (1), R is C1 to C 10 Alkyl, or C2-C 10 alkenyl, optionally bearing one or more substituents.

[0065] In particular, in formula (1), R is a group of formula CH 11 is an alkyl group.

[0066] The compounds of general formula (1) may exist in stereoisomeric forms. Preferably, centers 6a and 10a each have the R configuration.

[0067] Tetrahydrocannabinol is specifically Δ9-THC, which has the chemical name (6aR,10aR)6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, and its structure is represented by the following formula (2): [ka]

[0068] Another preferred group of cannabinoids are the cannabidiols of the following general formula (3): [ka] In the formula, R is C1 to C 20 Alkyl, C2-C 20 Alkenyl, or C2-C 20 alkynyl, optionally bearing one or more substituents.

[0069] In a further preferred group of compounds of the above general formula (3), R is C1-C 10 Alkyl, or C2-C 10 alkenyl, optionally bearing one or more substituents.

[0070] In particular, in formula (3), R is a group of formula CH 11 is an alkyl radical.

[0071] Cannabidiol is specifically 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.

[0072] CBD is the major constituent of Cannabis species (Cannabis sp.) other than the psychoactive Δ9-THC. The psychoactive effects of THC are mediated by the cannabinoid receptor CB1, which is primarily expressed on neurons. In contrast to THC, CBD is a peripherally and centrally acting compound that does not have psychoactive activity.

[0073] 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.

[0074] A further preferred group of cannabinoids are the cannabinols of the following general formula (4): [ka] In the formula, R is C1 to C 20 Alkyl, C2-C 20 Alkenyl, or C2-C 20 alkynyl, optionally bearing one or more substituents.

[0075] In a further preferred group of compounds of the above general formula (4), R is C1-C 10 Alkyl, or C2-C 10 alkenyl, optionally bearing one or more substituents.

[0076] In particular, in formula (4), R is a group of formula CH 11 is an alkyl group.

[0077] The cannabinol is specifically 6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol.

[0078] According to the present invention, cannabinoids or cannabinoid mixtures from cannabis (hemp) extracts may also be used.

[0079] For example, nabiximols is a plant extract mixture used as a drug from the leaves and flowers of the cannabis plant (Cannabis sativa L.) containing standardized amounts of tetrahydrocannabinol (THC) and cannabidiol (CBD).

[0080] Synthetic cannabinoids can also be used.

[0081] 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) and (6aS,10aS) forms. Nabilone is the preferred cannabinoid according to the present invention.

[0082] A further example of a synthetic cannabinoid is JWH-018 (1-naphthyl-(1-pentylindol-3-yl)methanone).

[0083] The use of cannabinoids, especially 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 cells of the immune system. The fact that both CB1 and CB2 receptors are found on immune cells suggests that cannabinoids play an important role in regulating the immune system. Apart from this finding, several studies have shown that cannabinoids downregulate cytokine and chemokine production and upregulate regulatory T cells (Tregs) in some models as a mechanism to suppress inflammatory responses. The endocannabinoid system is also involved in immune regulation.

[0084] Cannabinoids, and in particular cannabidiol, are particularly suitable for preventing or at least halting or significantly slowing down the progression of inflammatory conditions associated with autoimmune diseases, chronic inflammatory diseases and inflammatory conditions related to infection, including cytokine release syndrome (CRS).

[0085] This therapeutic utility is based on the pharmacodynamic properties of cannabinoids, particularly their interaction with the endocannabinoid system, as well as additional pharmacological targets including serotonergic receptors, adenosine signaling, vanilloid receptors, PPAR-γ receptors and GPR55, which have been shown to be immunoregulatory or even immunosuppressive.

[0086] Cannabinoids, especially cannabidiol, affect the innate immune system (i.e., the part of the immune system that allows for a rapid response to pathogens via neutrophils, macrophages, and other myeloid cells). Affected cell types of the innate immune system include, among others, monocytes, macrophages, neutrophils, dendritic cells, microglial cells, and myeloid-derived suppressor cells (MDSCs) (JM Nichols and BLF Kaplan (2020), loc.cit.): The release of pro-inflammatory cytokines in human mononuclear cells is inhibited by nanomolar and micromolar concentrations of CBD. CBD (20 mg / kg) reduces the number of leukocytes, including macrophages and neutrophils, in bronchoalveolar lavage fluid in mice after LPS-induced pneumonia. This effect is mediated by the adenosine A2A receptor (A. Ribeiro et al. (2012)). Cannabidiol, a non-psychotropic 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). Reductions in neutrophil counts are of therapeutic relevance. CBD suppresses the CD83 dendritic cell activation marker in dendritic cells from individuals with human immunodeficiency virus (HIV) infection, 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 microglial cells, the main innate immune cells in 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 numbers of natural killer (NK) cells and natural killer T (NKT) cells were either unaffected or even increased (2.5 mg / kg / day) by CBD in healthy rats (5 mg / kg / day), suggesting that CBD may enhance NK / NKT-associated 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 the expression of MDSCs, a regulatory immune cell population. In mice with chemically induced acute hepatitis, CBD (25 mg / kg) induced the expression of MDSCs along with a reduction in pro-inflammatory cytokines such as IL-2, TNF-α, and IL-6; this effect was 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).

[0087] Furthermore, cannabinoids, especially CBD, have effects on cells of the adaptive immune system. The adaptive immune system is composed of T cells and B cells. T cells either directly lyse infected cells or induce apoptosis of infected cells (cytotoxic T cells), or recruit other immune cells, including B cells, that produce antibodies against pathogens (T helper [Th] cells): In a study of healthy rats, daily administration of 5 mg / kg of CBD significantly reduced the number of T and B cells, including helper T cells and cytotoxic T cells (B. Ignatowska-Jankowska et al., loc. cit.). A shift in the immune response from Th1 to Th2, resulting 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 responsible for CBD's anti-inflammatory effects (L. Weiss et al. (2006). Cannabidiol lowers the incidence of diabetes in non-obese diabetic mice. Autoimmunity 39(2): 143-51). In activated memory T cell lines, CBD dose-dependently (1-5 μmol / L) reduced the autoantigen-specific Th17 cell phenotype, as indicated by a decrease in the Th17 signature cytokine IL-17. This finding was accompanied by a decrease in IL-6 production and secretion and an increase in IL-10 production, important changes related to Th17 cell proliferation (E. Kozela et al. (2013), loc.cit.). CBD has been shown to induce regulatory T cells (Tregs) 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 were decreased and Th17 levels were increased. The physiological function of Treg17 cells includes suppressing Th17-mediated inflammatory effects. Administration of 10 mg / kg of CBD after induction of kidney injury was renoprotective 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).

[0088] Many studies have demonstrated that cannabinoids, especially CBD, exert their immunosuppressive and anti-inflammatory effects through the suppression of 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. IL-6 plays a central role in inflammatory conditions related to autoimmune diseases, chronic inflammatory diseases and infections, including cytokine release syndrome (CRS).IL-6 signal transduction is one of the main classical pathways affected by cannabinoids, particularly CBD.Cannabinoids, particularly CBD, suppress circulating IL-6 in various animal models of inflammation, so that the suppression of IL-6 prevents undesired immune and inflammatory responses, which is considered to be the most relevant mode of action of cannabinoids, particularly CBD, in patients considered herein.

[0089] According to the present invention, cannabinoids, particularly cannabidiol, may also be applied as part of a combination treatment.

[0090] Medication and Administration According to the present invention, cannabinoids, in particular cannabidiol, are preferably administered orally.

[0091] However, other routes of administration are also contemplated, particularly for patients who cannot take oral medications, such other routes being, inter alia, intravenous, intramuscular or subcutaneous injection.

[0092] Dosing is 1 to 4 times per day. Typically, dosing is twice daily (BID).

[0093] According to the present invention, the patient is treated with an effective amount of a cannabinoid, particularly cannabidiol.

[0094] A single dose may be from 150 mg to 5000 mg, for example 250 mg to 5000 mg, administered 1 to 4 times daily, for example BID.

[0095] Exemplary doses are 375 mg, 750 mg, 1500 mg, and 3000 mg administered 1 to 4 times daily, e.g., BID.

[0096] A particularly preferred dose is 1500 mg administered 1 to 4 times daily, preferably BID.

[0097] As noted above, cannabinoids, particularly cannabidiol, have suppressive pharmacodynamic effects on the immune system in various animal models.

[0098] In a variety of animal models, inflammatory processes have been shown to be suppressed in the majority of cases at doses of 2.5–20 mg / kg body weight, primarily administered intraperitoneally or orally. Alternative routes include transdermal, intranasal, and intravenous administration (JM Nichols and BLF Kaplan, BLF (2020), loc. cit.).

[0099] In the majority of cases, in cell models determining the inhibitory effect on IL-6 secretion, the effective concentration was in the order of 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).

[0100] Based on the molecular weight of CBD of 314.5 g / mol, the resulting concentration is 1,570 ng / ml.

[0101] Ribeiro et al. investigated the effect of CBD on LPS-induced acute lung injury in mice as a disease model of ARDS, once as a preventive intervention (A. Ribeiro et al. (2012), loc. cit.) and once as a therapeutic intervention in 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).

[0102] Mice were administered prophylactic CBD at doses of 0.3, 1.0, 10, 20, 30, 40, and 80 mg / kg via the intraperitoneal route. Sixty minutes after administration, acute lung injury was induced by intranasal instillation of Escherichia coli LPS. Mice were sacrificed 1, 2, 4, and 7 days after instillation. Total leukocyte migration, myeloperoxidase activity, proinflammatory cytokine production including TNF-α and IL-6, and vascular permeability were significantly reduced (A. Ribeiro et al. (2012), loc. cit.). The effect was dose-dependent, reaching a near-maximum at 20 mg / kg in this study with prophylactic application.

[0103] In a subsequent study, the same group investigated the effects of CBD after acute lung injury induced by LPS. The test scenario was similar, except that the intervention time point was chosen 6 hours after LPS administration. The doses of 20 and 80 mg / kg were selected based on the results of a previous study (A. Ribeiro et al. (2014), loc. cit.). This study showed that at 20 mg / kg, mechanical lung function improved, leukocyte migration (neutrophils, macrophages, and lymphocytes) to the lungs decreased, myeloperoxidase activity in lung tissue decreased, vascular permeability decreased, and proinflammatory cytokine / chemokine production decreased.

[0104] A comparative study of systemic exposure after intraperitoneal and oral administration of CBD 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 behavior. Psychopharmacology (Berl) 219(3): 859-73).

[0105] Considering these data and assuming dose proportionality for the plasma concentrations obtained, the 20 mg / kg dose shown to be effective in animal models results in a target peak exposure of 2,300 ng / ml.

[0106] Regarding systemic exposure data in humans, after fasting administration of Epidyolex®, a morning maximum of 541 ng / ml is observed under steady-state conditions. The evening maximum is higher. With twice-daily Epidyolex administration, a 3.8-fold increase in systemic exposure is observed between morning and evening (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).

[0107] Therefore, a standard dose of 1,500 mg of CBD administered twice daily, as already approved for Epidyolex, appears to be safe and effective.

[0108] Based on the above data, patients may also benefit from other doses within the ranges outlined herein.

[0109] Galenic preparations The low and variable bioavailability of cannabinoids, especially upon oral administration, hinders the effective clinical use of these compounds.

[0110] Cannabinoids, particularly cannabidiol, are difficult to formulate due to their highly lipophilic nature.

[0111] In fact, cannabinoids are highly lipophilic molecules (logP 6-7) with very low water solubility (2-10 μg / ml). LogP is the base 10 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.

[0112] In addition to low solubility, cannabinoids, especially CBD, are subject to extensive first-pass metabolism, which further contributes to low systemic availability after oral administration.

[0113] Various formulations of cannabinoids have been proposed.

[0114] Due to the high lipophilicity of cannabinoids, salt formation (i.e., pH adjustment), cosolvation (e.g., ethanol, propylene glycol, PEG400), micelle formation (e.g., polysorbate 80, Cremophor-ELP), emulsification (emulsification), including microemulsion and nanoemulsion formation, complexation (e.g., cyclodextrins), and encapsulation in lipid-based formulations (e.g., liposomes) have been considered among the formulation strategies in the prior art. Nanoparticle systems have also been proposed (N. Bruni et al., loc. cit.).

[0115] Various oral solid formulations have been proposed in patent literature, such as WO 2008 / 024490 and WO 2018 / 035030. These documents do not contain data on release behavior, so the actual suitability of the proposed forms for the administration of cannabinoids remains unclear.

[0116] WO 2015 / 065179 describes compressed tablets containing, in addition to cannabidiol, lactose and sucrose fatty acid monoesters.

[0117] 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.

[0118] Sativex®, a formulation containing nabiximols, is an oral spray that is sprayed onto the inside of the cheek.

[0119] Self-emulsifying drug delivery systems (SEDDS), which are mixtures of oils, surfactants, and optionally hydrophilic solvents, have also attracted interest as an approach to improving 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). Upon contact with an aqueous phase, such as gastric or intestinal fluids, SEDDS spontaneously emulsify under gentle agitation conditions.

[0120] VESIsorb®, a self-emulsifying drug delivery formulation technology developed by Vesifact AG (Baar, Switzerland), has demonstrated increased oral bioavailability of certain lipophilic molecules.

[0121] The formulation Epidiolex, recently approved by the U.S. FDA as an orphan drug for the treatment of certain forms of epilepsy, comes in the form of an oral solution containing the active ingredient cannabidiol, as well as the excipients absolute ethanol, sesame oil, strawberry flavoring, and sucralose.

[0122] However, despite all of these proposals, there remains a need for improved dosage forms of cannabinoids such as cannabidiol, particularly for oral solid dosage forms.

[0123] The various approaches proposed in the prior art are not entirely satisfactory. Some of these approaches rely on liquid formulations. The handling of such formulations is more difficult than that of solid formulations. Prior art formulations are often complicated to prepare and sometimes result in low bioavailability of cannabinoids.

[0124] While formulations known in the art can be used in the therapeutic aspects of the present invention, the present invention also provides improved formulations.

[0125] It should be understood that these formulations are not only useful in the context of the therapeutic aspects of the present invention, but also constitute contributions in their own right. The formulations disclosed herein can be used for any treatment for which the active ingredient contained therein is indicated.

[0126] In one aspect of the present invention, there is provided a formulation which is a solid dispersion comprising a cannabinoid, in particular cannabidiol, and a solubiliser, and in this way a solid dosage form for oral administration can be obtained which exhibits satisfactory bioavailability, as described in more detail below.

[0127] According to this embodiment, a highly lipophilic cannabinoid, such as CBD, which is nearly water-insoluble, is combined with a solubilizing agent to increase drug solubility by solubilizing it in aqueous media, which in turn increases the absorption rate of the drug compound.

[0128] Preferably, no toxic or other harmful decomposition products are formed during preparation or storage of the formulation.

[0129] Solid dispersions comprising a cannabinoid, particularly cannabidiol, and a solubilizer, upon contact with water or other aqueous media such as gastrointestinal fluids, result in the formation of micelles, which are essentially formed from the drug substance surrounded by the solubilizer (see Figure 1).

[0130] Thus, one aspect of the present invention is a micellar composition comprising an aqueous phase in which micelles are dispersed, the micelles comprising a cannabinoid, particularly cannabidiol, and a solubilizing agent.

[0131] Suitable solubilizers are solid at ambient temperature, have surfactant properties and can form micellar solutions when used in an appropriate concentration range in aqueous media, especially water.

[0132] Suitable solubilizers include, in particular, amphiphilic block copolymers.

[0133] More particularly, block copolymers comprising at least one polyoxyethylene block and at least one polyoxypropylene block can be used.

[0134] Suitable block copolymers are, in particular, poloxamers, which 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 their manufacture.

[0135] Poloxamers have the following general formula: [ka]

[0136] In this general formula, n represents the number of polyoxyethylene units, and m represents the number of polyoxypropylene units.

[0137] In one embodiment, the solubilizer is poloxamer 188 (Kolliphor P188; formerly Lutrol F 68) / BASF; CAS number: 9003-11-6).

[0138] Kolliphor P188 is a polyoxyethylene-polyoxypropylene block copolymer of the above general formula, where n is about 79 and m is about 28.

[0139] 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. It meets the requirements of Ph.Eur., USP / NF for poloxamer 188.

[0140] The cannabinoid and solubiliser are typically present in a weight ratio of cannabinoid:solubiliser of 1:0.2-10.0, preferably 1:0.5-6.0, especially 1:1-5.

[0141] Solid dispersions according to the above formulation aspects of the invention may be prepared by a hot melt process, where the cannabinoid and solubilizer are heated to a temperature capable of forming a homogeneous melt in which the cannabidiol and solubilizer are present in a molecular state, which then forms a solid dispersion upon cooling.

[0142] The melt is processed into pellets, which can be done by batch spray granulation / pelletization (fluidized bed top spray, Wurster = bottom spray technology).

[0143] Alternatively, and preferably, continuous spray granulation / pelletization (fluid bed MicroPx Technology, ProCell Technology) is used.

[0144] Another method of preparation relies on dispersing the cannabinoid, particularly cannabidiol, in an aqueous solution of a solubilizing agent, for example an aqueous solution of a solubilizing agent.

[0145] The solution can be processed to obtain solid granules by batch spray granulation / pelletization (fluid bed top spray or Wurster = bottom spray technology) or preferably by continuous spray granulation / pelletization (fluid bed MicroPx Technology, ProCell Technology).

[0146] In addition to the active ingredient and solubilizer, the formulation may contain one or more excipients. In particular, it is contemplated that an antioxidant or a combination of antioxidants may be included to protect the cannabinoid, particularly cannabidiol, from oxidation.

[0147] Cannabinoids, especially cannabidiol, are susceptible to oxidation. For example, cannabidiol can be oxidized to monomeric and dimeric hydroxyquinones. Oxidation can lead to discoloration.

[0148] Oxidation can occur not only by molecular oxygen but also by peroxides that may be introduced into the formulation by one or more of the excipients used.

[0149] Useful antioxidants that can be included in the formulation include ascorbyl palmitate, alpha-tocopherol, butylated hydroxytoluene (BHT, E321), butylated hydroxyanisole (BHA, E320), ascorbic acid, and sodium ethylenediaminetetraacetic acid (EDTA).

[0150] Ascorbyl palmitate is a preferred antioxidant, which can effectively inhibit discoloration due to oxidation.

[0151] The antioxidant or combination of antioxidants can be added to the melt or solution of the solubilizer prior to the addition of the cannabinoid, particularly CBD.

[0152] The antioxidant is typically used in an amount of 0.5 to 2.5% by weight, preferably 0.8 to 2% by weight, especially 1.0 to 1.8% by weight, relative to the amount of cannabinoid (especially cannabidiol).

[0153] The solid dispersion preferably does not contain more than 20% by weight of additional excipients relative to all components.

[0154] The solid dispersion is preferably free or essentially free of triglycerides, by which we mean that the formulation contains less than 5% triglycerides by weight based on all ingredients.

[0155] Furthermore, the solid dispersion is preferably free or essentially free of fatty acids, where essentially free means that the formulation contains less than 5% fatty acids by weight based on all components.

[0156] Preferably, the total amount of mono-, di- and triglycerides and fatty acids is less than 5% by weight based on all components.

[0157] The solid dispersion granules or pellets can be filled into hard gelatin capsules, sachets or stick packs using standard commercially available techniques and equipment.

[0158] 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 dose units, larger capsules can be used as the primary packaging material for the granules. Such capsules are not intended for swallowing (e.g., capsule size up to 000 / sprinkle cap for 100-200 mg / dose). Rather, the solid dispersion granules are sprinkled on food or dispersed in a liquid, such as water.

[0159] The composition obtained by dispersing the solid dispersion granules in a liquid can be administered to patients who are unable to swallow using a syringe via a gastric tube.

[0160] Alternatively, the solid dispersion granules can be processed into tablets. The solid dispersion granules are combined with one or more excipients, such as disintegrants, glidants, and / or lubricants. The resulting mixture is then compressed into tablets.

[0161] According to another aspect of the present invention, a product for the release of a cannabinoid, particularly cannabidiol, comprises a core and a coating on the core, the coating comprising a cannabinoid, particularly cannabidiol, one or more highly lipophilic bioactive substances, one or more water-soluble film-forming agents, and up to 20% by weight of other excipients based on the weight of all components.

[0162] Preferably, no toxic or other harmful decomposition products are formed during preparation or storage of the formulation.

[0163] It has surprisingly been found that a solid oral dosage form of cannabinoid, particularly cannabidiol, can be provided and release can be controlled by the amount of film-forming agent relative to the amount of cannabinoid.

[0164] The use of one or more film-forming agents not only allows the formation of a coating containing cannabinoids, but also serves to control the release. In particular, film-forming agents promote the release of cannabinoids that are only slightly soluble in water. The film-forming agents ensure that they are released in sufficient amounts and at a sufficient rate.

[0165] For this purpose, the core is provided with a coating that contains one or more water-soluble film-forming agents in addition to a cannabinoid, in particular cannabidiol. In addition to the cannabinoid, the coating preferably does not contain any other physiologically active substances.

[0166] Examples of suitable water-soluble film-forming agents are methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC) and polyvinylpyrrolidone (PVP).

[0167] Hydroxypropylmethylcellulose (HPMC), particularly low viscosity HPMC such as HPMC having a viscosity of 6 mPa·s or less in a 2% (w / w) aqueous solution at 20° C., is preferred.

[0168] Particularly preferred is HPMC, such as that commercially available under the trade name Pharmacoat® 603, which has a viscosity of 3 mPa·s for a 2% (w / w) aqueous solution at 20° C.

[0169] The coating comprising the cannabinoid and one or more water-soluble film-forming agents may contain other conventional excipients. According to the present invention, the amount of additional excipients is limited to 20% by weight or less based on the weight of all ingredients. Preferably, no more than 10% by weight of additional excipients is included based on the weight of all ingredients.

[0170] In a particularly preferred embodiment, the coating consists of a cannabinoid and a film-forming agent.

[0171] The pellets according to the invention have a coating containing one or more water-soluble film-forming agents in a total amount of 0.1 to 10% by weight, preferably in a total amount of 0.5 to 8% by weight, in particular in a total proportion of 1 to 6% by weight, relative to the total amount of cannabinoids.

[0172] If the amount of film-forming agent is too small, the release will be very slow and incomplete. By selecting a ratio within the specified range, the release of the bioactive substance can be adjusted. For example, the release from an oral formulation can be adjusted so that the bioactive substance is released over the normal time of gastrointestinal transit.

[0173] A coating is applied to the core. The core can have any structure and can be made of any physiologically acceptable material. For example, tablets, minitablets, pellets, granules, or crystals can be used as the core. The core can comprise or consist of, for example, sugar, tartaric acid, or microcrystalline cellulose. Inactive starter cores, such as pellets made of microcrystalline cellulose, are preferred. Such pellets are commercially available under the name Cellets®.

[0174] The size of the core is not limited. Suitable sizes are in the range of 10 μm to 2000 μm, for example, in the range of 50 μm to 1500 μm, preferably in the range of 100 μm to 1000 μm, and the size can be determined by sieve analysis. In particular, pellets consisting of a sieve fraction of 500 to 710 μm can be used.

[0175] Products according to this aspect of the invention may be made by first creating a spray liquid that includes one or more cannabinoids and one or more water-soluble film-forming agents.

[0176] Cannabinoids have very low water solubility, so organic solvents or mixtures of organic solvents and water are typically used.

[0177] The spray liquid is then applied to the core. The liquid component is evaporated, thereby forming a coating on the core that is substantially free of solvent and water. This can be done, for example, in a fluidized bed system, a spouted bed system, a spray dryer, or a coater.

[0178] The coated cores can then be used as an oral formulation. The coated pellets (coated pellets) can be provided, for example, in a sachet or may be further processed.

[0179] Cores coated according to this aspect of the invention may be provided with one or more further coatings, which allow for additional control of release.

[0180] In a preferred embodiment, no additional release-controlling coating is provided.

[0181] The 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 are processed into orally dispersible tablets.

[0182] Coated pellets with different release profiles can be combined in one dosage form (capsule / tablet / sachet). Products according to this aspect of the invention release the cannabinoids contained therein, or if two or more cannabinoids are present, all of the cannabinoids contained therein, in the gastrointestinal tract after ingestion. The products are particularly used for controlled release. In particular, they release more than 30% and less than 80% by weight of the bioactive substances contained within 2 hours. Furthermore, they release more than 40% and less than 90% by weight of the bioactive substances contained within 3 hours. Furthermore, they release more than 50% and less than 95% by weight of the bioactive substances contained within 4 hours. If two or more cannabinoids are present, the information relates to all of the substances contained.

[0183] In each case, the release is determined at 37° C. in 1000 ml of phosphate buffer (pH 6.8) supplemented with 0.4% Tween® 80 in a blade stirrer apparatus.

[0184] According to a further formulation approach of the present invention, a solid dosage form is provided in which the release rate of cannabinoids, particularly cannabidiol, can be adjusted by incorporating a combination of a solubilizer and a water-soluble film-forming agent into the formulation. In such formulations, 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.

[0185] A solid dosage form for oral administration exhibiting satisfactory bioavailability can thus be obtained. The dosage form according to the invention also exhibits a reduced food effect.

[0186] Preferably, no toxic or other harmful decomposition products are formed during preparation or storage of the formulation.

[0187] Solid dispersions comprising a cannabinoid, particularly cannabidiol, an amphiphilic block copolymer and a water-soluble film-forming agent, upon contact with water or other aqueous media such as gastrointestinal fluids, result in the formation of micelles, which are essentially formed from the drug substance surrounded by solubilizing excipients.

[0188] Thus, one aspect is a micellar composition comprising an aqueous phase in which micelles are dispersed, the micelles comprising a cannabinoid, particularly cannabidiol, and a solubilizing excipient, particularly an amphiphilic block copolymer and a water-soluble film-forming agent.

[0189] The amphiphilic block copolymer present in the formulation of the present invention acts as a solubilizer. Reference to an amphiphilic block copolymer includes the possibility that multiple such copolymers are present.

[0190] The cannabinoid and amphiphilic block copolymer are present in a formulation comprising a cannabinoid, particularly cannabidiol, an amphiphilic block copolymer and a water-soluble film-forming agent, wherein the weight ratio of cannabinoid:amphiphilic block copolymer is typically 1:0.11-0.41, preferably 1:0.16-0.36, more preferably 1:0.21-0.31.

[0191] The amphiphilic block copolymer is a solid at ambient temperature.

[0192] They have surfactant properties and can form micellar solutions when used in an appropriate concentration range in aqueous media, especially water.

[0193] In particular, block copolymers comprising at least one polyoxyethylene block and at least one polyoxypropylene block can be used.

[0194] A preferred block copolymer is 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 their manufacture.

[0195] In one embodiment, the solubilizer is poloxamer 188 (Kolliphor P188; formerly Lutrol F 68) / BASF; CAS number: 9003-11-6).

[0196] Kolliphor P188 is a polyoxyethylene-polyoxypropylene block copolymer of the above general formula, where n is about 79 and m is about 28.

[0197] 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. It meets the requirements of Ph.Eur., USP / NF for poloxamer 188.

[0198] As a further excipient, the formulation of the present invention contains a water-soluble film-forming agent. Reference to a water-soluble film-forming agent also includes the possibility that a combination of two or more such film-forming agents may be used.

[0199] The cannabinoid and water-soluble film-forming agent are typically present in a weight ratio of cannabinoid:water-soluble film-forming agent of 1:0.03-0.33, preferably 1:0.08-0.28, more preferably 1:0.13-0.23.

[0200] The water-soluble film-forming agent acts as a polymer binder and additional solubilizer in the present formulation.

[0201] Examples of suitable water-soluble film-forming agents are methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC) and polyvinylpyrrolidone (PVP).

[0202] A preferred film former is PVP, in particular PVP K30 (eg Kollidon® 30).

[0203] Another preferred film-forming agent is hydroxypropyl methylcellulose (HPMC), especially low viscosity HPMC, such as HPMC having a viscosity of 6 mPa·s or less in a 2% (w / w) aqueous solution at 20°C.

[0204] The above ingredients are typically present in a weight ratio of cannabinoid (particularly cannabidiol):amphiphilic block copolymer:water-soluble film-forming agent (polyvinylpyrrolidone) of 1:0.11-0.41:0.03-0.33, preferably 1:0.16-0.36:0.08-0.28, more preferably 1:0.21-0.31:0.13-0.23.

[0205] It is specifically contemplated to further include an antioxidant or combination of antioxidants to protect the cannabinoids, particularly cannabidiol, from oxidation.

[0206] Cannabinoids, especially cannabidiol, are susceptible to oxidation. For example, cannabidiol can be oxidized to monomeric and dimeric hydroxyquinones. Oxidation can lead to discoloration.

[0207] Oxidation can occur not only by molecular oxygen but also by peroxides that may be introduced into the formulation by one or more of the excipients used.

[0208] Useful antioxidants that can be included in the formulation include ascorbyl palmitate, alpha-tocopherol, butylated hydroxytoluene (BHT, E321), butylated hydroxyanisole (BHA, E320), ascorbic acid, and sodium ethylenediaminetetraacetic acid (EDTA).

[0209] Ascorbyl palmitate is a preferred antioxidant, which can effectively inhibit discoloration due to oxidation.

[0210] The antioxidant is typically used in an amount of 0.5 to 2.5% by weight, preferably 0.8 to 2% by weight, especially 1.0 to 1.8% by weight, relative to the amount of cannabinoid (especially cannabidiol).

[0211] Other excipients may also be present.

[0212] In a preferred embodiment, 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).

[0213] In formulations containing a diluent, there are typically two phases, one containing the active agent embedded in a polymeric excipient as detailed above, and another containing the diluent.

[0214] The active ingredient and diluent are typically present in a weight ratio of cannabinoid (especially cannabidiol):diluent (especially microcrystalline cellulose) of 1:0.5 to 2.7, preferably 1:0.9 to 2.3, especially 1:1.3 to 1.9.

[0215] In a further embodiment, silicon dioxide (e.g., Syloid® 244 FP Silica) and / or colloidal silicon dioxide (e.g., Aerosil® 200) is included in the formulation, particularly to act as a moisture adsorbent.

[0216] The active ingredient and total silicon dioxide components are typically present in a weight ratio of cannabinoid (particularly cannabidiol):total amount of all silicon dioxide components of from 0.14 to 0.44, preferably from 0.19 to 0.39, especially from 0.24 to 0.34.

[0217] Although formulations according to the present invention are not limited to those containing the excipients discussed above, the formulations are preferably free or essentially free of triglycerides, meaning that the formulation contains less than 5% triglycerides by weight of all ingredients.

[0218] The solid dispersion is preferably free or essentially free of triglycerides, by which we mean that the formulation contains less than 5% triglycerides by weight based on all ingredients.

[0219] Furthermore, the solid dispersion is preferably free or essentially free of mono- and diglycerides, where essentially free means that the formulation contains less than 5% by weight of mono- and diglycerides based on all ingredients.

[0220] Furthermore, the solid dispersion is preferably free or essentially free of fatty acids, where essentially free means that the formulation contains less than 5% fatty acids by weight based on all components.

[0221] Preferably, the total amount of mono-, di- and triglycerides and fatty acids is less than 5% by weight based on all components.

[0222] The pharmaceutical preparation of the present invention in the form of a solid dispersion can be obtained by wet granulation technique. Granulation can be carried out in a blender. Preferably, fluidized bed granulation technique can be used.

[0223] 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 fluid 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 fluid bed granulator.

[0224] According to the present invention, the liquid composition comprising a cannabinoid, an amphiphilic block copolymer and a solvent also preferably comprises a water-soluble film-forming agent in at least partially dissolved form.

[0225] Further according to the present invention, the liquid composition comprising a cannabinoid, an amphiphilic block copolymer and a solvent and optionally a water-soluble film-forming agent preferably comprises an antioxidant in at least partially dissolved form.

[0226] The liquid composition may also contain one or more further excipients, which may be in any suitable form, for example dissolved or dispersed form.

[0227] By way of example, silicon dioxide may be present in dispersed form in the liquid composition.

[0228] The cannabidiol and excipients are preferably present in the liquid composition in the weight ratios indicated herein for pharmaceutical formulations.

[0229] The solvent used to prepare the liquid composition may be any solvent capable of at least partially dissolving the cannabinoid, the amphiphilic block copolymer, and preferably the water-soluble film-forming agent and / or antioxidant.

[0230] A preferred solvent is ethanol containing up to 10% v / v water, for example ethanol containing up to 4% v / v water, for example 96% v / v ethanol.

[0231] The liquid composition is introduced into a fluid bed granulator as described above. In a preferred embodiment, the liquid composition is sprayed into a fluid bed granulator already containing solid particles.

[0232] The solid particles contained in the granulator can include one or more excipients. In a preferred embodiment, the solid particles include a diluent such as microcrystalline cellulose.

[0233] One or more additional excipients, such as colloidal silicon dioxide, may also be present.

[0234] The fluidized bed granulator is operated so as to remove the solvent and obtain a solid dispersion in the form of particles. For example, an inlet air temperature of 45±10° C. is selected.

[0235] Solvent removal can be continued until a predetermined loss on drying (LOD) is reached. For example, the product can be dried to a loss on drying of 2.0% or less.

[0236] After drying, the product is discharged and sieved.

[0237] The size of the resulting granules is not limited, and a suitable size is in the range of 50 μm to 2000 μm, for example, in the range of 100 μm to 1000 μm.

[0238] The formulations according to the invention are preferably stable to discolouration: the colour remains stable or changes slightly to off-white upon storage under long-term conditions (25°C / 60% rh) for 3 months, preferably 6 months, in particular 12 months.

[0239] The granules represent a self-emulsifying solid dispersion that, when combined with an aqueous medium, can give a micellar solution.

[0240] The above formulations, when subjected to in vitro dissolution testing in 0.1 N HCl + 2% CTAB according to the USP paddle method, release at least 75% by weight of the cannabinoid within 60 minutes, preferably at least 90% by weight within 60 minutes. Additionally, the formulations release at least 75% by weight of the cannabinoid within 45 minutes, preferably at least 85% by weight within 45 minutes.

[0241] The solid dispersion granules can be filled into bottles, sachets or stick packs using standard commercially available techniques and equipment, sprinkled onto food products or dispersed in liquids such as water.

[0242] The composition obtained by dispersing the solid dispersion granules in a liquid can be administered to patients who are unable to swallow using a syringe via a gastric tube.

[0243] 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 intended for swallowing (e.g., capsule size up to 000 / sprinkle cap for 100-200 mg / dose). Rather, the solid dispersion granules are sprinkled on food or dispersed in a liquid, such as water.

[0244] Alternatively, the solid dispersion granules can be processed into tablets. The solid dispersion granules are combined with one or more excipients, such as disintegrants, glidants, and / or lubricants. The resulting mixture is then compressed into tablets.

[0245] In one embodiment, they are processed into orally dispersible tablets. [Example]

[0246] The present invention will be described based on specific examples, but is not limited thereto.

[0247] Example 1 Cannabidiol-containing granules (solid dispersion) 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:

[0248] Option (a) The ingredients are heated to a temperature of approximately 100°C. The melt 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.

[0249] Option (b) The ingredients are heated to a temperature of approximately 100°C. The melt is sprayed into an initially empty fluidized bed apparatus. Granules are formed as the melt solidifies 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.

[0250] Option (c) The preparation of granules from the melt can also be carried out continuously, as can be done by using ProCell or MicroPx Technology (Glatt).

[0251] Option (d) The melt can also be processed in a spray tower. Using prill nozzles, spherical particles of a defined size can be obtained.

[0252] Example 2 Cannabidiol-containing granules (solid dispersion) can be obtained using 30 parts by weight of cannabidiol and 70 parts by weight of Kolliphor P188. To prepare the granules, the options outlined in Example 1 are available.

[0253] Example 3 Cannabidiol-containing granules (solid dispersion) can be obtained using 40 parts by weight of cannabidiol and 60 parts by weight of Kolliphor P188. To prepare the granules, the options outlined in Example 1 are available.

[0254] Example 4 Cannabidiol-containing granules (solid dispersion) 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.

[0255] A melt of 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. Top-spray, bottom-spray, and tangential-spray configurations can be used in this batch process.

[0256] Example 5 Compositions based on different weight ratios of CBD / solubilizer were prepared by melting and cooling the melt. The compositions were analyzed for in vitro dissolution in 0.1 N HCl according to the USP paddle method.

[0257] For comparison, an oil-based cannabidiol solution and the commercially available Bionic Softgels were also tested according to DAC / NRF 22.10.

[0258] CBD release after 60 minutes in vitro dissolution testing 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 oil (Miglyol 812) solution; 200mg CBD: 0% drug release Biotonic Softgels; 25mg CBD: 96% drug release.

[0259] Example 6 Tablets are prepared using 93.5% by weight of granules according to any of Examples 1-4, 5% by weight of Polyplasone XL (disintegrant), 1% of Aerosil 200 (glidant) and 0.5% of magnesium stearate (lubricant).

[0260] Example 7 Preparation of granules Cannabidiol (CBD) granules containing 29.7% w / w of the active ingredient are prepared according to the following manufacturing recipe: TIFF0007822324000006.tif123165

[0261] In the first process step, CBD and the pharmaceutical excipients poloxamer 188, ascorbyl palmitate, microcrystalline cellulose, silicon dioxide, colloidal silicon dioxide, and polyvinylpyrrolidone are granulated.

[0262] The granulation is carried out using fluidized bed granulation technology.

[0263] The drug substance cannabidiol and pharmaceutical excipients poloxamer 188, ascorbyl palmitate and polyvinylpyrrolidone are dissolved in ethanol 96% v / v. Silicon dioxide (Syloid® 244 FP) is dispersed in the solution.

[0264] Microcrystalline cellulose and colloidal silicon dioxide (Aerosil® 200) are charged into a fluid bed granulator and granulated with the solution described. The granules are removed and sieved.

[0265] The volatile component ethanol, 96% v / v, is removed from the granules during the drying stage in a fluidized bed dryer. The inlet air temperature is 45±10°C and the product temperature is 30-35°C.

[0266] The granules are dried to a standard loss on drying (LOD) percentage of 2.0% or less.

[0267] Dosage form Cannabidiol granules containing 29.7% w / w cannabidiol are filled into HDPE bottles to provide a total dose of 1500 mg 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 remaining amount of water is used to rinse the container twice.

[0268] Stability of cannabidiol granules Samples are stored under accelerated conditions (40°C / 75%), intermediate conditions (30°C / 65% rh) and long-term conditions (25°C / 60% rh).

[0269] Under storage at accelerated storage conditions, the appearance changed from white to yellowish after 1 month and to yellow after 2 months. The color changed slightly to off-white at long-term conditions after 3 months and at intermediate conditions after 4 months.

[0270] Dissolution decreases slightly after 3 months of storage at accelerated conditions but remains within the specified range. Dissolution remains unchanged after 3 months at long-term conditions and after 4 months at intermediate conditions.

[0271] Approximately 6% assay loss is observed at accelerated conditions after 3 months, but the product is still within the specified shelf life. At intermediate and long-term conditions, no significant assay loss is observed after 4 and 3 months, respectively.

[0272] Adducts of cannabidiol and ascorbyl palmitate are observed as impurities.

[0273] It has been found to have a level of 0.4% in the long term and 0.5% at accelerated conditions after 3 months of storage. At intermediate conditions, the level is 0.5% after 4 months.

[0274] (Q)SAR evaluation of four possible structures of this adduct indicates that its presence poses no additional risk to patients when the formulation is administered using the doses and administration schemes disclosed herein.

[0275] Stability of aqueous dispersions The chemical stability of an aqueous dispersion containing 1500 mg of cannabidiol was examined in a retention time test. For this purpose, approximately 5 g of the developer 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.

[0276] The impurity profile remains unchanged over the 2 hour test period. Therefore, the dispersion of the product in water for administration will be stable for the period required for administration.

[0277] CBD release Release is EP 2.9.3 / USP <711> The dissolution test is carried out according to the following: A paddle dissolution apparatus is used. The dissolution test is carried out at a standard temperature of 37°C ± 0.5°C and an agitator speed of 100 rpm.

[0278] Complete release is observed after 45 minutes in 0.1 M HCl + 2% (w / v) cetyltrimethylammonium bromide (CTAB).

[0279] Example 8 Additional granules were prepared according to the method outlined in Example 7. Composition information is included in the table below. TIFF0007822324000007.tif119163

[0280] Pearlitol 160 C is a crystalline D-mannitol powder with a mean particle diameter of 160 μm.

[0281] Release was determined using an in vitro dissolution method (1000 mL of 0.1 M HCl + 2% (w / v) CTAB).

[0282] Example 9 Pellets were made using the ingredients in the amounts shown in Table 1 below.

[0283] 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 log P of approximately 6.1.

[0284] A separate solution was prepared by dissolving HPMC (Pharmacoat® 603) in water.

[0285] The HPMC solution was then slowly added to the cannabidiol solution.

[0286] Amorphous silicon dioxide (Syloid® 244 FP) was then added.

[0287] The mixture was stirred with a propeller stirrer.

[0288] The resulting spray solution was sprayed onto starter cores made of microcrystalline cellulose (Cellets® 500).

[0289] This was done in a Mini-Glat fluidized bed system with a Wurster insert. The inlet air temperature was 40° C. The average spray rate was 0.5 g / min.

[0290] [Table 1]

[0291] [Table 2]

[0292] Example 10 The release from the pellet product obtained from Example 1 is investigated in particular at 37° C. in 1000 ml of phosphate buffer (pH 6.8) supplemented with 0.4% Tween® 80 using a blade stirrer device. The results obtained are shown in FIG.

Claims

1. 1. Use of a cannabinoid in the manufacture of a medicament for the treatment of a patient suffering from or at risk of suffering from an inflammatory condition characterized by elevated levels of IL-6, comprising: the cannabinoid is formulated as a solid dispersion; the solid dispersion comprises in admixture a cannabinoid, an amphiphilic block copolymer as a solubilizer, and a water-soluble film-forming agent; the water-soluble film-forming agent is selected from methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), and polyvinylpyrrolidone (PVP); The cannabinoid and the water-soluble film former are present in a weight ratio of cannabinoid:water-soluble film former of 1:0.03 to 0.

33. Use characterized by:

2. 2. The use according to claim 1, characterized in that the cannabinoid is cannabidiol (2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol).

3. 3. The use according to claim 1 or 2, characterized in that the patient suffers from an inflammatory condition associated with an autoimmune disease.

4. 3. The use according to claim 1 or 2, characterized in that the patient suffers from an inflammatory condition associated with a chronic inflammatory disease.

5. 3. The use according to claim 1 or 2, characterized in that the patient suffers from an inflammatory condition related to an infection.

6. 6. The use according to claim 5, wherein the treatment is for preventing or ameliorating cytokine release syndrome (CRS).

7. Use according to any one of claims 1 to 4, characterized in that the condition to be treated is a rheumatic disease.

8. 8. The use according to claim 7, characterized in that the disease is selected from osteoarthritis; rheumatoid arthritis; fibromyalgia; systemic lupus erythematosus; gout; juvenile idiopathic arthritis; infectious arthritis; psoriatic arthritis; polymyositis; bursitis; ankylosing spondylitis; reactive arthritis; scleroderma; polymyalgia rheumatica.

9. The use according to any one of claims 1 to 4, characterized in that the condition to be treated is giant cell arteritis (GCA).

10. Use according to any one of claims 1 to 4, characterized in that the condition to be treated is inflammatory bowel disease (IBD).

11. The use according to any one of claims 1 to 4, characterized in that the patient suffers from metabolic syndrome.

12. 12. The use according to claim 11, characterized in that the treatment prevents, arrests or ameliorates atherosclerosis, insulin resistance and / or coagulation disorders.

13. The use according to any one of claims 1 to 12, characterized in that the treatment reduces serum IL-6 levels.

14. The treatment is one or more of the following: serum IL-6 > 5.4 pg / ml; CRP level > 70 mg / L (without other infectious or non-infectious processes identified); CRP level >= 40 mg / L and doubling within 48 hours (without other infectious or non-infectious processes identified); lactate dehydrogenase > 250 U / L; D-dimer > 1 μg / mL; serum ferritin > 300 μg / mL, Use according to any one of claims 1 to 13, characterized in that it is initiated on the basis of

15. Use according to any one of claims 1 to 14, characterized in that the treatment is initiated if the patient shows a thrombocytopenia < 120.000 x 10E9 / L and / or a lymphocyte count < 0.6 x 10E9 / L.

16. 16. Use according to any one of claims 1 to 15, characterized in that the treatment is initiated if the patient presents at least one laboratory finding selected from the group consisting of serum IL-6 ≥ 5.4 pg / ml; CRP level > 70 mg / L (without confirmation of other infectious or non-infectious processes); CRP level >= 40 mg / L and doubling within 48 hours (without confirmation of other infectious or non-infectious processes); lactate dehydrogenase > 250 U / L; D-dimer > 1 μg / mL; serum ferritin > 300 μg / mL; and thrombocytopenia < 120,000 x 10E9 / L and / or lymphocyte count < 0.6 x 10E9 / L.

17. Use according to any one of claims 1 to 16, characterized in that the treatment is initiated when serum IL-6 is ≥ 5.4 pg / ml.

18. Use according to any one of claims 1 to 17, characterized in that the cannabinoid is administered orally.

19. Use according to any one of claims 1 to 18, characterized in that the cannabinoid is administered in a dose of 150 mg to 5000 mg, 1 to 4 times a day.

20. 20. The use according to claim 19, wherein the dose is 375 mg, 750 mg, 1500 mg or 3000 mg, and the dose is administered 1 to 4 times a day.

21. 21. The use according to claim 20, characterized in that the dose is administered BID.

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

23. 23. Use according to any one of claims 1 to 22, characterised 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.

24. Use according to any one of claims 1 to 23, characterized in that the amphiphilic block copolymer comprises at least one polyoxyethylene block and at least one polyoxypropylene block.

25. 24. The use according to claim 23, characterized in that the amphiphilic block copolymer is a poloxamer.

26. 26. Use according to any one of claims 1 to 25, characterised in that the cannabinoid and the water-soluble film former are present in a weight ratio of cannabinoid:water-soluble film former of 1:0.08 to 0.

28.

27. Use according to any one of claims 1 to 26, characterized in that the water-soluble film-forming agent is polyvinylpyrrolidone.

28. Use according to any one of claims 1 to 26, characterized in that the water-soluble film-forming agent is hydroxypropylmethylcellulose.

29. 29. Use according to any one of claims 1 to 28, characterised in that the components are present in a weight ratio of cannabinoid:amphiphilic block copolymer:water-soluble film-forming agent of 1:0.11-0.41:0.03-0.

33.

30. The use according to any one of claims 1 to 29, characterized in that the solid dispersion further comprises an antioxidant.

31. 31. Use according to claim 30, characterized in that the antioxidant is used in an amount of 0.5 to 2.5% by weight relative to the amount of cannabinoid.

32. 32. Use according to claim 30 or 31, characterized in that the antioxidant is ascorbyl palmitate.

33. The use according to any one of claims 1 to 32, characterized in that the solid dispersion comprises a diluent.

34. 34. Use according to claim 33, characterized in that the cannabinoid and the diluent are present in a weight ratio of cannabinoid:diluent of 1:0.5 to 2.

7.

35. 35. Use according to claim 33 or 34, characterized in that the diluent is microcrystalline cellulose and / or mannitol.

36. The use according to any one of claims 1 to 35, characterized in that the solid dispersion comprises a moisture adsorbent.

37. 37. Use according to claim 36, characterised in that the cannabinoid and the moisture sorbent are present in a weight ratio of cannabinoid:moisture sorbent of from 0.14 to 0.

44.

38. 38. Use according to claim 36 or 37, characterized in that the moisture adsorbent comprises silicon dioxide.

39. Use according to any one of claims 1 to 38, characterized in that the solid dispersion is free of triglycerides; and / or mono- and diglycerides; and / or fatty acids.

40. Use according to any one of claims 1 to 39, characterised in that the cannabinoid is cannabidiol.

41. 41. Use according to any one of claims 1 to 40, characterised in that the formulation releases at least 75% by weight of the cannabinoid within 60 minutes when subjected to in vitro dissolution testing in 0.1 N HCl + 2% CTAB according to the USP paddle method.

42. 42. Use according to any one of claims 1 to 41, characterised in that the formulation releases at least 75% by weight of the cannabinoid within 45 minutes when subjected to in vitro dissolution testing in 0.1 N HCl + 2% CTAB according to the USP paddle method.

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