Oral pharmaceutical formulations of cannabidiol and tetrahydrocannabinol

Abstract

The present invention relates to a modified-release solid oral pharmaceutical composition, which is in the form of an enteric-coated capsule, wherein said capsule comprises cannabidiol (CBD), tetrahydrocannabinol (THC) and an emulsifier, and wherein the capsule optionally further comprises one or more cannabis terpenes. The solid oral pharmaceutical composition provided herein has a particularly advantageous modified release profile as well as an improved oral bioavailability as compared to conventional formulations of CBD and THC.

Description

[0001] New PCT patent application

[0002] LUKAS Heil-Betriebsstatte GmbH

[0003] Vossius Ref.: AJ3886 PCT BS 1

[0004] Oral pharmaceutical formulations of cannabidiol and tetrahydrocannabinol

[0005] The present application claims the benefit of priority of European patent application EP24214632.2 filed on November 21 , 2024, which is incorporated herein by reference in its entirety.

[0006] The present invention relates to a modified-release solid oral pharmaceutical composition, which is in the form of an enteric-coated capsule, wherein said capsule comprises cannabidiol (CBD), tetrahydrocannabinol (THC) and an emulsifier, and wherein the capsule optionally further comprises one or more cannabis terpenes. The solid oral pharmaceutical composition provided herein has a particularly advantageous modified release profile as well as an improved oral bioavailability as compared to conventional formulations of CBD and THC.

[0007] Cannabidiol and tetrahydrocannabinol are the predominantly occurring cannabinoids in cannabis plant materials. These naturally occurring compounds have attracted growing interest in the pharmacological field and have been suggested for the treatment of a range of medical conditions, including epilepsy, pain, inflammation, anxiety, sleep disorders, multiple sclerosis (MS), neuropathic pain, spasticity, and overactive bladder, as well as for antiemesis and appetite stimulation.

[0008] More specifically, CBD and THC have been reported to be effective in the treatment and / or prevention of pain (e.g., chronic pain), neurological disorders, psychiatric disorders (e.g., anxiety), spasms (e.g., muscle spasms caused by multiple sclerosis or convulsions), gastrointestinal disorders (e.g., convulsions in the digestive system), anorexia, weight loss (e.g., AIDS-related weight loss), sleep disturbance, sleep loss, diabetes, bacterial infections, hypertension, inflammation, glaucoma, cancer, and side effects resulting from chemotherapy (e.g., nausea) (Bilbao A et al., BMC Med, 2022, 20, 259; Klumpers LE et al., J AOAC Int, 2019, 102(2), 412-420; Corroon J et al., BMC Fam Pract, 2019, 20, 174). CBD, in particular, has been described to be effective in the treatment and / or prevention of pain, sleep disturbance, convulsions (including, e.g., convulsions in the digestive system), anxiety, diabetes, and bacterial infections.

[0009] So far, CBD and THC have been used in therapy primarily by inhalation. The inhalation of CBD and THC leads to increased bioavailability and a shorter time until the maximum (or peak) serum concentration (Cmax) is reached when compared to oral administration. However, the sudden peak, followed by a rapid fall-off in Cmax, makes this mode of administration undesirable for most therapeutic uses of CBD and THC. Orally administered medicaments are easier to dose and offer an extended treatment effect. On the other hand, oral dosing of CBD and THC leads to a delayed treatment effect and reduced bioavailability because of significant first-pass metabolism in the liver. The metabolism of THC predominantly proceeds via cytochrome P450 (CYP 450) isozymes CYP2C9, CYP2C19 and CYP3A4 in the liver, forming mainly 11-hydroxy-THC (11- OH-THC) and 11-carboxy-THC (11-COOH-THC), which then undergo glucuronidation and are subsequently excreted in the faeces and urine (Lucas CJ et al., Br J Clin Pharmacol, 2018, 84(11), 2477-2482). Moreover, the oral bioavailability of THC is very limited and variable and has been reported to range from 4% to 12% (Chayasirisobhon S, Perm J, 2020, 25, 1-3). The oral bioavailability of CBD is likewise low and variable and has been reported to be approximately 9% to 13% (Hossain KR et al., Int J Mol Sci, 2023, 24(19), 14514). Moreover, both CBD and THC are poorly water soluble.

[0010] There is hence an unmet need for improved pharmaceutical formulations of CBD and THC having advantageous pharmacokinetic properties that render them better suitable for use in therapy.

[0011] The present invention addresses the above-discussed shortcomings in the art and provides solid oral pharmaceutical compositions of CBD and THC, which are particularly well suited for oral administration due to their advantageous modified release profile and their improved oral bioavailability.

[0012] Accordingly, the present invention provides a solid oral pharmaceutical composition (particularly a modified-release solid oral pharmaceutical composition), which is in the form of an enteric- coated capsule, wherein said capsule comprises cannabidiol (CBD), tetrahydrocannabinol (THC) and an emulsifier.

[0013] In the context of the present invention, it was surprisingly found that the use of a capsule with enteric coating in combination with the use of an emulsifier (within the capsule) for formulating CBD and THC results in a particularly advantageous modified release profile as well as improved oral bioavailability as compared to conventional formulations of CBD and THC. Moreover, the fractions / ratios of CBD and THC (as well as any optionally comprised terpenes) can be conveniently adjusted to provide an optimal therapeutic effect for the respective therapeutic indication. Remarkably, the use of the emulsifier results in an in situ gel formation in the small intestine, which enhances the bio-resorption of CBD and THC through the walls of the digestive system into the circulatory system of the body and thus increases bioavailability. In addition, the use of enteric-coated capsules comprising CBD and THC (and optionally one or more terpenes) together with the emulsifier allows to modify the release of the active ingredients by retardation, which equalizes the plasma concentration of these active ingredients over time. The resulting modified-release (or retarded-release) profile of the solid oral pharmaceutical composition according to the present invention is highly advantageous as it ensures a steady and prolonged therapeutic effect and facilitates patient compliance, especially where patients are under multiple or chronic treatments, or for elderly patients who often have difficulties regarding compliance with multiple daily dosages. In addition, the modified-release solid oral pharmaceutical composition according to the invention allows to minimize side effects, as it avoids sudden high concentrations of CBD and THC (and any optional terpenes) in the circulation and prevents or reduces any corresponding adverse effects or toxicity. The solid oral pharmaceutical composition according to the present invention is also referred to herein as a modified-release solid oral pharmaceutical composition or, in particular, as a retarded-release solid oral pharmaceutical composition.

[0014] CBD and THC, which are comprised in the solid oral pharmaceutical composition according to the invention, can be provided in multiple ways. For example, they can be obtained by extraction from cannabis plants, or they can employed in the form of commercially available cannabis extracts (including approved commercial cannabis extracts), or they can be chemically synthesized (see, e.g., Bloemendal VRLJ et al., Org Biomol Chem, 2020, 18, 3203-3215; Lange K et al., JBiotechnol, 2015, 211 , 68-76; Cheng LJ et al., Org Lett, 2013, 15(4), 764-767; Pauvert Y et al., Org Lett, 2024, 26(29), 6081-6085; Capucciati A et al., J Nat Prod, 2024, 87(4), 869- 875; Gong X et al., J Org Chem, 2020, 85(4), 2704-2715; Chiurchiu E et al., European Journal of Organic Chemistry, 2021 , 2021(8), 1286-1289; Aguillon AR et al., Chemistry, 2021 , 27(18), 5577-5600; each of the aforementioned documents is incorporated herein by reference in its entirety). Corresponding extracts may contain a higher CBD content or a higher THC content.

[0015] Regarding the extraction of CBD and THC from cannabis plants, the plant strains to be used may be, e.g., Cannabis sativa, Cannabis indica, or a hybrid thereof. Cannabis sativa extracts generally have a higher THC content (typically about 20% to 30%) and a lower CBD content. Such extracts are particularly useful for the treatment or prevention of chronic pain, migraine, depression, anorexia, or nausea. Cannabis indica extracts, on the other hand, generally have a higher CBD content and a lower THC content; they are particularly useful for the treatment or prevention of chronic pain, sleep disorders, infectious diseases (e.g., bacterial infections), or symptomatic relief for Parkinson’s disease or multiple sclerosis.

[0016] Examples of cannabis plants from which CBD and THC can be extracted include the following, whereby the contents of CBD and THC are indicated in parentheses (Uberall MA, Schmerzmedizin, 2018, 34(1), 24-35):

[0017] - Bedrocan (THC 22%, CBD 1 %)

[0018] - Bedrobinol (THC 13.5%, CBD 1%)

[0019] - Bediol (THC 6.3%, CBD 8%)

[0020] - Bedica (THC 14%, CBD 1 %)

[0021] - Bedrolite (THC 1%, CBD 9%)

[0022] Extraction of CBD and THC from such plants, as described above, can be performed using, for example, oily extraction, extraction with supercritical carbon dioxide (CO2), extraction with organic solvents, or ethanolic extraction. The products from such extractions may further contain one or more terpenes at varying concentrations. The type of terpenes and their relative content depend on the type of plant and plant breed used, as well as the extraction method. The desired mixture and ratio of terpenes may be obtained by selecting and / or mixing oily extracts comprising the relevant terpene fractions.

[0023] Examples of cannabis extracts with varying terpene contents are shown in Table 1 :

[0024] Table 1

[0025] Thus, the solid oral pharmaceutical composition according to the invention (which is in the form of an enteric-coated capsule) optionally comprises one or more terpenes, particularly one or more cannabis terpenes (i.e. , terpenes that can be found in cannabis plants).

[0026] In some embodiments, the solid oral pharmaceutical composition according to the present invention further comprises one or more cannabis terpenes. Preferably, the one or more terpenes (or cannabis terpenes) is / are selected from monoterpenes, monoterpenoids, sesquiterpenes, and sesquiterpenoids. More preferably, the one or more terpenes (or cannabis terpenes) is / are selected from linalool, p-myrcene, d-limonene, p-caryophyllene, caryophyllene oxide, a-humulene, terpineol, phellandrene, ocimene, p-cymene, terpinolene, guaiol, y- terpinene, p-elemene, nerolidol, a-pinene, p-pinene, and citral.

[0027] Terpenes can interact with cannabinoids and modulate their therapeutic effects in what is known as the “entourage effect” (Ferber SG et al., Curr Neuropharmacol, 2020, 18(2), 87-96). Moreover, the presence and concentration of specific terpenes can also provide an indication for the quality of the extract. Certain terpenes furthermore exert a therapeutic effect themselves. For example, p-caryophyllene and p-myrcene have been reported to exhibit anti-inflammatory and analgetic properties, respectively (see, e.g., Popescu-Spinei et al., Rev Roum Chim, 2021 , 66(7), 583-592; Mazzantini et al., Pharmaceuticals, 2024, 17(4), 467). Examples of therapeutic effects that have been reported with various cannabis terpenes are summarized in Table 2: Table 2

[0028] The ratio in which CBD and THC are comprised in the solid oral pharmaceutical composition is not particularly limited. For example, CBD and THC may be present in a ratio of from 1:100 to 100:1. Preferably, the solid oral pharmaceutical composition comprises CBD and THC in a ratio of from 1:50 to 50:1, more preferably in a ratio of from 1:20 to 20:1 (including, e.g., a ratio of about 1:20, about 1 :15, about 1 :10, about 1 :5, about 1 :3, about 1 :2, about 1:1, about 2:1, about 3:1 , about 5:1 , about 10:1, about 15:1, or about 20:1).

[0029] Examples of commercially available extracts comprising CBD and THC in varying ratios are shown in Table 3:

[0030] Table 3 It is preferred that the solid oral pharmaceutical composition is in the form of an enteric-coated capsule comprising an oily mixture of CBD and THC (and optionally one or more cannabis terpenes).

[0031] The emulsifier comprised in the solid oral pharmaceutical composition according to the invention (which is in the form of an enteric-coated capsule) supports the in situ gel-formation in the digestive system, supporting an improved bio-resorption. Accordingly, the emulsifier is an in situ gel-forming emulsifier. In particular, the emulsifier may be e.g., a lecithin (e.g., soybean lecithin), a bile acid or a pharmaceutically acceptable salt thereof (e.g., cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, or a pharmaceutically acceptable salt (e.g., a sodium salt or a potassium salt) of any of the aforementioned acids; exemplary salts include, in particular, sodium cholate, sodium deoxycholate, sodium glycocholate, or sodium taurocholate), a phospholipid (e.g., a soybean phospholipid, an egg phospholipid, or a phosphatidylcholine), a non-ionic surfactant (e.g., a poloxamer or teloxamer), or an alcohol (e.g., a C1-5 alkanol, such as butanol). It may also be a combination of two or more different emulsifiers, e.g., a combination of any two or more of the aforementioned exemplary emulsifiers. Preferably, the emulsifier is a lecithin, a bile acid or a pharmaceutically acceptable salt thereof (including any of the corresponding examples mentioned above), or a phosphatidylcholine. More preferably, the emulsifier is a lecithin and / or a bile acid or a pharmaceutically acceptable salt thereof (including any of the corresponding examples mentioned above). Even more preferably, the emulsifier is a lecithin (e.g., soybean lecithin), cholic acid or a pharmaceutically acceptable salt thereof (e.g., sodium cholate), deoxycholic acid or a pharmaceutically acceptable salt thereof (e.g., sodium deoxycholate), glycocholic acid or a pharmaceutically acceptable salt thereof (e.g., sodium glycocholate), taurocholic acid or a pharmaceutically acceptable salt thereof (e.g., sodium taurocholate), or any combination thereof.

[0032] Without being bound by theory, the use of an emulsifier is particularly advantageous as it allows micelle formation by in situ gel-formation in the small intestine and, consequently, allows for a delayed / extended release of CBD and THC (and any optionally comprised terpenes / cannabis terpenes) in the small intestine of the patient / subject.

[0033] The solid oral pharmaceutical composition may thus comprise micelles. Such micelles may have a size of, e.g., about 1 nm to about 1000 nm (such as, e.g., about 1 nm to about 500 nm, or about 10 nm to about 200 nm, particularly about 10 nm to about 100 nm). The size of micelles can be determined using methods known in the art. For example, the micelle size can be determined by dynamic light scattering (DLS; e.g., using an apparatus such as a Zetasizer), small-angle X-ray scattering (SAXS), Taylor dispersion analysis (TDA), or laser diffraction (e.g., using a Beckman Coulter LS 13 320 or an LA-960 Horiba). Preferably, the micelle size is to be determined by dynamic light scattering. The solid oral pharmaceutical composition of the present invention may optionally further comprise one or more gel-forming agents, which may be selected, for example, from cellulose derivatives (e.g., carboxymethyl cellulose, cellulose acetate, methyl cellulose, hydroxyethyl cellulose, or hydroxypropyl cellulose), natural gums (e.g., gum arable, xanthan gum, tragacanth gum, or guar gum), poly-L-arginine (PLA), gelatin, silicon dioxide, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., Soluplus®), hydroxypropyl methylcellulose (HPMC), and synthetic polymers (e.g., carbomers). These agents can form three-dimensional networks which contribute to the retarded-release profile of the formulation. Without being bound by theory, the encapsulation of CBD, THC, and optionally one or more additional terpenes in such a three-dimensional matrix allows the further retardation of the release of these hydrophobic compounds in the small intestine by delaying their diffusion.

[0034] As explained above, the solid oral pharmaceutical composition is in the form of an enteric-coated capsule. The capsule may be, e.g., a hard capsule or a soft capsule, particularly a soft gelatine capsule.

[0035] Enteric-coated capsules (also referred to as enteric capsules) have shells that are resistant to acid and, therefore, do not disintegrate in the stomach, but rather in the intestines to release the contents of the capsule. In accordance with the present invention, the use of enteric-coated capsules allows CBD and THC (and any optionally comprised terpenes / cannabis terpenes) to be released slowly and gradually in the small intestine to sustain the desired therapeutic effect for an extended period of time.

[0036] The enteric coating (of the enteric-coated capsule) may be an enteric polymer coating. In particular, the enteric coating may be a coating with, e.g., hydroxypropyl methylcellulose (HPMC), hydroxymethyl cellulose, hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate succinate, ethylcellulose, sodium alginate, xanthan gum, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), pectin, dextran, gelatine, a polyvinyl alcohol-polyethylene glycol (PVA-PEG) copolymer, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate trimellitate, zein, shellac, polyethylacrylate, polymethyl-methacrylate, poly(ethylacrylate, methyl-methacrylate, and chloro trimethyl-ammonioethyl methacrylate), or a methacrylic acid copolymer. Such enteric coatings are commercially available, e.g., cellulose acetate phthalate (Aquateric®), hydroxypropyl methyl cellulose acetate succinate (AQOAT®), hydroxypropyl methylcellulose phthalate (HPMCP®), polyvinyl acetate phthalate (Opadry®), polymethacrylate-polymethylmethacrylate copolymer (PMA-PMMA) (Eudragit® or Kollicoat® MAE; e.g., Eudragit® L100-55). The enteric-coated capsule may thus be, e.g., an acid-resistant HPMC capsule. The capsule may also have multiple coatings. In particular, the capsule may have an inner coating (e.g., with HPMC, or with polyvinyl alcohol, or with a combination of ethylcellulose and sodium alginate) and an outer enteric coating (e.g., with Eudragit® L100-55, Eudragit® L30 D-55, or Eudragit S100).

[0037] The composition of the solid oral pharmaceutical composition can be adjusted to increase the time during which CBD and THC (and any optionally comprised terpenes / cannabis terpenes) are present at steady state levels. Preferably, the composition is adjusted to prevent initial spiking of CBD and THC. It is particularly preferred that the composition is adjusted so that CBD and THC are present in the plasma at a concentration of about 5 to about 10 ng / mL over a time of least about 180 min. Such adjustments can be achieved by using an enteric coating that facilitates a corresponding retardation of the release of CBD and THC. For this purpose, the above-described enteric coatings can be used, particularly hydroxymethyl cellulose (e.g., Methocel™), hydroxypropyl cellulose, xanthan gum, alginic acid, polyvinylpyrrolidone (e.g., PVP K90), polyvinyl alcohol (PVA), pectin, dextran, gelatine, a cellulose derivative (e.g., cellulose acetate succinate), or a methacrylate ester copolymerisation derivative.

[0038] The solid oral pharmaceutical composition according to the present invention is particularly well- suited for use in therapy. Accordingly, the present invention relates to the solid oral pharmaceutical composition (as described herein) for use in therapy (or for use as a medicament, or for use in the treatment or prevention of a disease / disorder), particularly for use in the treatment or prevention of pain, a neurological disorder, a psychiatric disorder, spasms, a gastrointestinal disorder, anorexia, weight loss, sleep disturbance, sleep loss, diabetes, a bacterial infection (or a bacterial infectious disease), hypertension (or high blood pressure), an inflammatory disorder, glaucoma, or cancer. The solid oral pharmaceutical composition can also be used as an anti-emetic or for the treatment or prevention of chemotherapy side effects.

[0039] The present invention further relates to the use of the solid oral pharmaceutical composition for the manufacture of a medicament for the treatment of prevention of pain, a neurological disorder, a psychiatric disorder, spasms, a gastrointestinal disorder, anorexia, weight loss, sleep disturbance, sleep loss, diabetes, a bacterial infection (or a bacterial infectious disease), hypertension (or high blood pressure), an inflammatory disorder, glaucoma, or cancer, or for the manufacture of a medicament for the treatment or prevention of chemotherapy side effects, or for the manufacture of an anti-emetic medicament.

[0040] The invention likewise relates to a method of treating or preventing a disease / disorder in a subject (e.g., a human) in need thereof, the method comprising orally administering a therapeutically effective amount of the solid oral pharmaceutical composition to the subject, wherein the disease / disorder is selected from pain, a neurological disorder, a psychiatric disorder, spasms, a gastrointestinal disorder, anorexia, weight loss, sleep disturbance, sleep loss, diabetes, a bacterial infection (or a bacterial infectious disease), hypertension (or high blood pressure), an inflammatory disorder, glaucoma, cancer, and chemotherapy side effects.

[0041] The pain to be treated or prevented is preferably selected from chronic pain, pain associated with multiple sclerosis, pain associated with spinal cord injury, headache pain, cluster headache pain, migraine pain, neuropathic pain, post-injury pain, back pain, acute pain, severe pain, intractable pain, inflammatory pain, post-operative pain, cancer pain, post-traumatic pain, and visceral pain. The treatment or prevention of chronic pain is particularly preferred.

[0042] The neurological disorder to be treated or prevented is preferably selected from Tourette syndrome, epilepsy, seizures, multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, dementia, and Alzheimer's disease. More preferably, it is selected from epilepsy, seizures, and multiple sclerosis.

[0043] The psychiatric disorder to be treated or prevented is preferably selected from anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), social phobia, cyclothymic disorder, depression, dysthymic disorder, major depressive disorder, substance-induced mood disorder, mood disorder due to a general medical condition, mania, manic depression, seasonal affective disorder, schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, drug and / or alcohol addiction, depression, and schizophrenia. The treatment or prevention of PTSD is particularly preferred.

[0044] The spasms to be treated or prevented are preferably selected from muscle spasms, tremors, epilepsy spasms, convulsions, migraine spasms, spasticity related to Parkinson disease, multiple sclerosis (MS)-related spasticity, and spasms related to spinal cord injury. The treatment or prevention of MS-related spasticity is particularly preferred.

[0045] The gastrointestinal disorder to be treated or prevented is preferably selected from Crohn’s disease, irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), convulsions in the digestive system, inflammatory bowel disease (IBD), and gastroparesis. The treatment or prevention of IBD or IBS is particularly preferred.

[0046] The weight loss to be treated or prevented is preferably AIDS-related weight loss.

[0047] The chemotherapy side effects to be treated or prevented are preferably selected from nausea and vomiting, more preferably nausea.

[0048] Therapeutic applications of CBD and / or THC have been described in the literature (see, e.g., Uberall MA, “21 Fragen und Antworten zum Urngang mit Cannabis in der Praxis”, Schmerzmedizin, 2018, 34(1), 24-37, doi:10.1007 / s00940-018-0699-4; Bilbao A et al., BMC Med, 2022, 20, 259; Klumpers LE et al., J AOAC Int, 2019, 102(2), 412-420; Corroon J et al., BMC Fam Pract, 2019, 20, 174; White CM, J Clin Pharmacol, 2019, 59(7), 923-934, doi: 10.1002 / jcph.1387; Peng J et al., Basic Clin Pharmacol Toxicol, 2022, 130(4), 439-456, doi: 10.1111 / bcpt.13710; Reddy DS et al., J Pharmacol Exp Ther, 2016, 357(1), 45-55, doi: 10.1124 / jpet.115.230151 ; Ahmed S et al., Front Psychiatry, 2021 , 12, 694394, doi: 10.3389 / fpsyt.2021.694394; Russo EB, Front Integr Neurosci, 2018, 12, 51 , doi: 10.3389 / fnint.2018.00051 ; Ahmed W et al., Gastroenterol Hepatol (NY) , 2016, 12(11), 668-679; each of the aforementioned documents is incorporated herein by reference in its entirety). The present invention also relates to the treatment or prevention of any of the diseases / disorders described in any of the aforementioned documents using the solid oral pharmaceutical composition provided herein.

[0049] In accordance with the present invention, it is intended that the solid oral pharmaceutical composition is administered orally, i.e. , that it is for oral administration.

[0050] Accordingly, the solid oral pharmaceutical composition is preferably to be administered orally, particularly perorally (or is formulated for oral administration, particularly peroral administration). More preferably, the solid oral pharmaceutical composition is to be administered by oral ingestion, particularly by swallowing. The solid oral pharmaceutical composition can thus be administered to pass through the mouth into the gastrointestinal tract, which can also be referred to as “oral-gastrointestinal” administration.

[0051] The solid oral pharmaceutical composition may be administered orally (particularly by oral- gastrointestinal administration) to a subject / patient in fed state. Accordingly, the solid oral pharmaceutical composition can be administered orally after a meal, i.e. after the intake of food (e.g., within about 1 to 2 hours after a meal). The solid oral pharmaceutical composition may also be administered orally (particularly by oral-gastrointestinal administration) to a subject / patient together with a meal, preferably with a meal having a high lipid content, which is advantageous as it may enhance the bioavailability of CBD (Hossain KR et al., Int J Mol Sci, 2023, 24(19), 14514).

[0052] The solid oral pharmaceutical composition may be administered in monotherapy, or it may be administered in combination with one or more further medications, particularly with one or more further medications for the treatment or prevention of the same disorder. Such further medications may be, e.g., selected from pain medications (e.g., opioids or NSAIDs), medications for neurological disorders, medications for psychiatric disorders (e.g., antidepressants), and antispasmodic medications (e.g., muscle relaxants). The subject or patient to be treated in accordance with the present invention may be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., a male human or a female human) or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, cattle, or a pig). Most preferably, the subject / patient to be treated in accordance with the invention is a human. Accordingly, it is most preferred that the solid oral pharmaceutical composition is to be administered to a human subject.

[0053] The term “treatment” of a disorder or disease as used herein is well known in the art. “T reatment” of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient / subject. A patient / subject suspected of suffering from a disorder or disease typically shows specific clinical and / or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease). The “treatment” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only). The “treatment” of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject / patient suffering from the disorder or disease. Accordingly, the “treatment” of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject / patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above). The treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).

[0054] The term “prevention” of a disorder or disease as used herein is also well known in the art. For example, a patient / subject suspected of being prone to suffer from a disorder or disease may particularly benefit from a prevention of the disorder or disease. The subject / patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition. Such a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators. It is to be understood that a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient / subject (for example, the patient / subject does not show any clinical or pathological symptoms). Thus, the term “prevention” comprises the use of the solid oral pharmaceutical composition according to the invention before any clinical and / or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician. The term “pharmaceutically acceptable salt” is well known in the art. Pharmaceutically acceptable salts may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Further pharmaceutically acceptable salts are described in the literature, e.g., in Stahl PH & Wermuth CG (eds.), “Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Wiley-VCH, 2002 and in the references cited therein.

[0055] As used herein, the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of “containing, inter alia”, i.e., “containing, among further optional elements, ...”. In addition, this term also includes the narrower meanings of “consisting essentially of” and “consisting of”. For example, the term “A comprising B and C” has the meaning of “A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., “A containing B, C and D” would also be encompassed), but this term also includes the meaning of “A consisting essentially of B and C” and the meaning of “A consisting of B and C” (i.e., no other components than B and C are comprised in A). As used herein, unless explicitly indicated otherwise or contradicted by context, the terms “a”, “an” and “the” are used interchangeably with “one or more” and “at least one”. Thus, for example, a composition comprising “an” emulsifier can be interpreted as referring to a composition comprising “one or more” emulsifiers.

[0056] As used herein, the term "about" preferably refers to ±10% of the indicated numerical value, more preferably to ±5% of the indicated numerical value, and even more preferably to the exact numerical value indicated.

[0057] It is to be understood that wherever numerical ranges are provided / disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, including the upper and lower endpoints of each numerical range, as well as each subrange encompassed by a numerical range disclosed herein.

[0058] Unless specifically indicated otherwise, all properties and parameters referred to herein (including, e.g., any amounts / concentrations indicated in “mg / ml” and any pH values) are preferably to be determined at standard ambient temperature and pressure conditions, particularly at a temperature of 25°C (298.15 K) and at an absolute pressure of 101.325 kPa (1 atm). Moreover, unless indicated otherwise, all amounts / contents indicated as a percentage (%) refer to weight-% (wt-%).

[0059] In this specification, a number of documents including scientific literature are cited. The disclosure of these documents, while not considered relevant for the patentability of the present invention, is herewith incorporated by reference in its entirety.

[0060] Furthermore, it is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and / or preferred features / embodiments. In particular, the invention specifically relates to all combinations of preferred features described herein.

[0061] The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. EXAMPLES

[0062] Example 1 : Preparation of CBD / THC compositions comprising phosphatidylcholine

[0063] Mixtures of oil extracts with the following compositions are prepared: a. 1 :1 CBD / THC with a content of 20 mg / ml CBD and 20 mg / ml THC b. 20:1 CBD / THC with a content of 20 mg / ml CBD and 1 mg / ml THC c. 1 :20 CBD / THC with a content of 1 mg / ml CBD and 20 mg / ml THC

[0064] The final concentration of the mixture is adjusted with Miglyol 812N (CAS no. 73398-61-5) to contain 20 mg of CBD (a and b) or 20 mg THC (c) in a total volume of 1000 pl. 2%, 5%, 10% or 15 wt-% phosphatidylcholine (PC) is then added to the oily solution and mixed until equally distributed or dissolved. 500 pL of the oily fractions with different PC concentrations is mixed with 5 mL phosphate-buffered saline (PBS; pH 7) under continuous stirring at 37 °C for 15 min. Finally, the zeta potential and average micelle size are determined in a Zetasizer.

[0065] Example 2: Preparation of CBD / THC compositions comprising deoxycholic acid

[0066] Mixtures of oil extracts with the following compositions are prepared: a. 1 :1 CBD / THC with a content of 20 mg / ml CBD and 20 mg / ml THC b. 20:1 CBD / THC with a content of 20 mg / ml CBD and 1 mg / ml THC c. 1 :20 CBD / THC with a content of 1 mg / ml CBD and 20 mg / ml THC

[0067] The final concentration of the mixture is adjusted with Miglyol 812N to contain 20 mg of CBD (a and b) or 20 mg THC (c) in a total volume of 1000 pl. 0.01 mM, 0.1 mM or 0.5 mM deoxycholic acid (DC) is then added to the oily solution and mixed until equally distributed or dissolved. 500 pL of the oily fractions with different DC concentration is mixed with 5 mL PBS (pH 7) under continuous stirring at 37 °C for 15 min. Finally, the zeta potential and average micelle size are determined in a Zetasizer.

[0068] Example 3: Preparation of CBD / THC compositions comprising phosphatidylcholine and deoxycholic acid

[0069] The three CBD / THC formulations from Example 1 are each adjusted to comprise 20 mg CBD or THC in a total volume of 1000 pL with Miglyol 812N. Phosphatidylcholine is added in the concentration determined in Example 1 to result in the droplet size with the smallest diameter, and deoxycholic acid is added in each of the concentrations mentioned in Example 2. They are mixed until homogenous, followed by mixing of 500 pL of the oily mixture with 5 mL PBS (pH 7) under continuous stirring at 37 °C for 15 min. Finally, the zeta potential and average micelle size are determined in a Zetasizer. Example 4: Preparation of formulations using hydrophobic basis gel DAC

[0070] Each of the formulations prepared in Examples 1 to 3 is used to make four different dissolutions of each formulation by adding hydrophobic basis gel DAC (Bouchemal K et al., Int J Pharm, 2004, 280(1-2), 241-251) in the concentration of 1 wt-%, 5 wt-%, 10 wt-% and 20 wt-%, respectively. Then, the concentration with the best handling properties with respect to viscosity and dosing ability is determined using an EP dissolution apparatus.

[0071] Example 5: Preparation of formulations using highly disperse silicon dioxide

[0072] Each of the formulations prepared in Examples 1 to 3 is used to make four different dissolutions of each formulation by adding highly disperse silicon dioxide in the concentration of 1 wt-%, 5 wt-%, 10 wt-% and 20 wt-%, respectively. Then, the concentration with the best handling properties with respect to viscosity and dosing ability is determined.

[0073] Example 6: Preparation and dissolution of enteric HPMC capsules

[0074] Enteric coated HPMC capsules are filled with the mixtures from Examples 4 and 5. The capsules are closed and then dissolved in 10 mL PBS solution (pH 7) at 37 °C and the dissolution and drug release profiles are analysed.

[0075] Example 7: Preparation and dissolution of enteric HPMC capsules filled with CBD / THC and soybean lecithin as an emulsifier and Xanthan gum

[0076] Mixtures of oil extracts with the following compositions are prepared: a. 1 :1 CBD / THC with a content of 50 mg / ml CBD and 50 mg / ml THC b. 50:1 CBD / THC with a content of 50 mg / ml CBD and 1 mg / ml THC c. 1 :50 CBD / THC with a content of 1 mg / ml CBD and 50 mg / ml THC

[0077] The final concentration of the mixture is then adjusted with Miglyol 812N to contain 50 mg of CBD (a and b) or 50 mg THC (c) in a total volume of 1000 pl. 5 mL of this solution is prepared. 10 g of soybean lecithin is blended with 6 % PBS (pH 7) in a beaker and stirred for 30 min until the lecithin is fully hydrated. 1 mL or 1 g of the lecithin mixture is transferred to a new beaker with a stirrer. 1 mL of the oily THC / CBD phase is added slowly and gradually under continuous stirring. The mixture is stirred until it is homogenous. Then, the remaining 4 mL of the oily solution is gradually added and stirred until it is fully dissolved. 1% xanthan gum is added to the solution and is stirred until it is equally distributed. One portion is taken out and dissolved in 5 mL PBS (pH 7.4) at 37 °C and is used for determining the zeta potential and measuring the droplet size by dynamic light scattering (DLS). The remaining solution is used to fill enteric coated HPMC capsules. The capsules are closed and then dissolved in 10 mL PBS solution (pH 7) at 37 °C and the dissolution and drug release profiles are analysed.

Claims

CLAIMS1. A modified-release solid oral pharmaceutical composition, which is in the form of an enteric-coated capsule, wherein said capsule comprises cannabidiol (CBD), tetrahydrocannabinol (THC) and an emulsifier.

2. The solid oral pharmaceutical composition according to claim 1 , wherein the emulsifier is an in situ gel former selected from a lecithin, a bile acid or a pharmaceutically acceptable salt thereof, a phospholipid, a non-ionic surfactant, and an alcohol.

3. The solid oral pharmaceutical composition according to claim 1 or 2, wherein the emulsifier is selected from a lecithin, a bile acid or a pharmaceutically acceptable salt thereof, and a phosphatidylcholine.

4. The solid oral pharmaceutical composition according to any one of claims 1 to 3, wherein the emulsifier is selected from a lecithin, cholic acid or a pharmaceutically acceptable salt thereof, deoxycholic acid or a pharmaceutically acceptable salt thereof, glycocholic acid or a pharmaceutically acceptable salt thereof, taurocholic acid or a pharmaceutically acceptable salt thereof.

5. The solid oral pharmaceutical composition according to any one of claims 1 to 4, wherein said capsule further comprises one or more cannabis terpenes.

6. The solid oral pharmaceutical composition according to claim 5, wherein the one or more cannabis terpenes is / are selected from linalool, p-myrcene, d-limonene, p-caryophyllene, caryophyllene oxide, a-humulene, terpineol, phellandrene, ocimene, p-cymene, terpinolene, guaiol, y-terpinene, p-elemene, nerolidol, a-pinene, p-pinene, and citral.

7. The solid oral pharmaceutical composition according to any one of claims 1 to 6, wherein the enteric-coated capsule is an enteric-coated hard capsule or an enteric-coated soft gelatine capsule.

8. The solid oral pharmaceutical composition according to any one of claims 1 to 7, wherein the capsule is coated with a polymer selected from hydroxypropyl methylcellulose (HPMC), hydroxymethyl cellulose, hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate succinate, ethylcellulose, sodium alginate, xanthan gum, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), pectin, dextran, gelatine, a polyvinyl alcohol-polyethylene glycol (PVA-PEG) copolymer, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methyl cellulose acetatesuccinate, cellulose acetate trimellitate, zein, shellac, polyethylacrylate, polymethylmethacrylate, poly(ethylacrylate, methyl-methacrylate, and chloro trimethyl- ammonioethyl methacrylate), and a methacrylic acid copolymer.

9. The solid oral pharmaceutical composition according to any one of claims 1 to 8, wherein the enteric-coated capsule is an acid-resistant HPMC capsule.

10. The solid oral pharmaceutical composition according to any one of claims 1 to 9, wherein the ratio of CBD to THC is in the range from 1 :50 to 50: 1.

11. The solid oral pharmaceutical composition according to any one of claims 1 to 10, wherein the ratio of CBD to THC is about 1 :1.

12. The solid oral pharmaceutical composition according to any one of claims 1 to 11 , wherein the capsule comprises an oily mixture of CBD, THC, and optionally one or more cannabis terpenes.

13. The solid oral pharmaceutical composition according to any one of claims 1 to 12, wherein said composition is a retarded-release solid oral pharmaceutical composition.

14. The solid oral pharmaceutical composition according to any one of claims 1 to 13 for use in the treatment or prevention of pain, a neurological disorder, a psychiatric disorder, spasms, a gastrointestinal disorder, anorexia, weight loss, sleep disturbance, sleep loss, diabetes, a bacterial infection, hypertension, an inflammatory disorder, glaucoma, or cancer.

15. The solid oral pharmaceutical composition for use according to claim 14, wherein said composition is for use in the treatment or prevention of pain, wherein said pain is selected from chronic pain, pain associated with multiple sclerosis, pain associated with spinal cord injury, headache pain, cluster headache pain, migraine pain, neuropathic pain, postinjury pain, back pain, acute pain, severe pain, intractable pain, inflammatory pain, postoperative pain, cancer pain, post-traumatic pain, and visceral pain.

16. The solid oral pharmaceutical composition for use according to claim 14, wherein said composition is for use in the treatment or prevention of a neurological disorder selected from Tourette syndrome, epilepsy, seizures, multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, dementia, and Alzheimer's disease.

17. The solid oral pharmaceutical composition for use according to claim 14, wherein said composition is for use in the treatment or prevention of a psychiatric disorder selected from anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), obsessive- compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), social phobia, cyclothymic disorder, depression, dysthymic disorder, major depressive disorder, substance-induced mood disorder, mood disorder due to a general medical condition, mania, manic depression, seasonal affective disorder, schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, drug and / or alcohol addiction, depression, and schizophrenia.

18. The solid oral pharmaceutical composition for use according to claim 14, wherein said composition is for use in the treatment or prevention of spasms selected from muscle spasms, tremors, epilepsy spasms, convulsions, migraine spasms, spasticity related to Parkinson disease, multiple sclerosis (MS)-related spasticity, and spasms related to spinal cord injury.

19. The solid oral pharmaceutical composition for use according to claim 14, wherein said composition is for use in the treatment or prevention of a gastrointestinal disorder selected from Crohn’s disease, irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), convulsions in the digestive system, inflammatory bowel disease (IBD), and gastroparesis.

20. The solid oral pharmaceutical composition for use according to claim 14, wherein said composition is for use in the treatment or prevention of weight loss, wherein the weight loss is AIDS-related weight loss.

21. The solid oral pharmaceutical composition according to any one of claims 1 to 13 for use as an anti-emetic.

22. The solid oral pharmaceutical composition for use according to any one of claims 14 to21 , wherein the solid oral pharmaceutical composition is to be administered orally.

23. The solid oral pharmaceutical composition for use according to any one of claims 14 to22, wherein said solid oral pharmaceutical composition is to be administered to a human subject.

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